阅读说明：本技术 肝病瘙痒症状的治疗 (Treatment of pruritus symptoms of liver disease ) 是由 T·希萨西亚 A·霍伊 于 2019-07-10 设计创作，主要内容包括：本公开涉及用于使用止痒组合物治疗患有与肝病相关的瘙痒的患者的方法；用于治疗患有与继发于由非肝组织疾病引起的胆管阻塞的阻塞性胆汁淤积相关的瘙痒的患者的方法；以及用于此类方法中的止痒组合物。(The present disclosure relates to methods for treating patients with pruritus associated with liver disease using anti-pruritus compositions; a method for treating a patient suffering from itch associated with obstructive cholestasis secondary to bile duct obstruction caused by a non-liver tissue disease; and anti-itch compositions for use in such methods.)

1. A method of treating pruritus associated with liver disease comprising orally administering to a patient in need of such treatment an effective amount of nalbuphine or a pharmaceutically acceptable salt or ester thereof,

wherein the liver disease is selected from the group consisting of: cholestatic liver disease, infectious hepatitis, cirrhotic liver disease, drug-induced liver disease, idiopathic portal hypertension, congenital malformations or genetic diseases affecting liver function, sarcoidosis, primary or metastatic liver tumor involvement, and autoimmune hepatitis-cholangitis (overlap syndrome).

2. The method of claim 1, wherein the pruritus is selected from the group consisting of: chronic pruritus, pruritus refractory to treatment with other antipruritic agents; pruritus refractory to treatment with bile chelators; and pruritus refractory to treatment with rifampicin.

3. The method of claim 1, wherein the pruritus is chronic pruritus.

4. The method of claim 1, wherein the pruritus is a refractory pruritus to treatment with other antipruritics.

5. The method of claim 1, wherein the pruritus is a treatment-refractory pruritus using a bile chelating agent selected from the group consisting of cholestyramine, colestipol, and colesevelam.

6. The method of claim 1, wherein the pruritus is a treatment-refractory pruritus with rifampicin, a mu-opioid antagonist, a kappa-opioid agonist, an antidepressant, a serotonin antagonist, or an antihistamine.

7. The method of claim 6, wherein the kappa-opioid agonist is naftifine.

8. The method of claim 6, wherein the mu-opioid antagonist is naltrexone.

9. The method of claim 1, wherein the patient does not have a bile duct obstruction.

10. The method of claim 1, wherein the liver disease is cholestatic liver disease.

11. The method of claim 10, wherein the cholestatic liver disease is selected from primary sclerosing cholangitis and primary biliary cholangitis.

12. The method of claim 1, wherein the liver disease is infectious hepatitis.

13. The method of claim 12, wherein said infectious hepatitis is selected from Hepatitis C (HCV) and Hepatitis B (HBV).

14. The method of claim 13, wherein the HCV is selected from chronic HCV and HCV after a persistent virological response.

15. The method of claim 13, wherein the hepatitis b is selected from inactive HBV and active HBV infection in a carrier.

16. The method of claim 1, wherein the liver disease is a cirrhotic liver disease.

17. The method of claim 14, wherein the cirrhotic liver disease is selected from the group consisting of alcoholic liver disease, autoimmune hepatitis, and non-alcoholic fatty liver disease.

18. The method of claim 1, wherein the liver disease is selected from drug-induced liver disease, idiopathic portal hypertension, congenital malformations or genetic diseases affecting liver function, sarcoidosis, primary or metastatic liver tumor involvement, and autoimmune hepatitis-cholangitis (overlap syndrome).

19. The method of claim 1, wherein the patient's serum level of endogenous opioids is elevated as compared to normal serum levels.

20. The method of claim 1, wherein about 15mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

21. The method of claim 1, wherein about 15mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered twice daily.

22. The method of claim 1, wherein about 30mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

23. The method of claim 1, wherein about 30mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered twice daily.

24. The method of claim 1, wherein about 60mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

25. The method of claim 1, wherein about 60mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered twice daily.

26. The method of claim 1, wherein about 90mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

27. The method of claim 1, wherein about 90mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered twice daily.

28. The method of claim 1, wherein about 120mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

29. The method of claim 1, wherein about 120mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered twice daily.

30. The method of claim 1, wherein about 180mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

31. The method of claim 1, wherein about 180mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered twice daily.

32. The method of claim 1, wherein about 360mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

33. The method of claim 1, wherein the administration is for about 8 weeks, about 10 weeks, about 12 weeks, about 24 weeks, or about 50 weeks.

34. The method of claim 1, further comprising titrating the dose of the anti-pruritic agent for at least one week until a steady state is reached in the patient.

35. The method of claim 1, further comprising titrating the dose of the anti-pruritic agent for about 2 weeks until a steady state is reached in the patient.

36. The method of claim 1, further comprising titrating the dose of the anti-pruritic agent for about 7 to 30 days until a steady state is reached in the patient.

37. The method of claim 1, further comprising titrating the dose of anti-pruritic agent for about 14 to 20 days until a steady state is reached in the patient.

38. The method of claim 34, wherein the titration comprises administering an ascending dose of the anti-pruritus agent until a steady state is reached in the patient.

39. The method of claim 34, wherein the titration comprises administering an ascending dose of the anti-pruritic agent until an effective amount of 15mg, 30mg, 60mg, 90mg, 120mg, 180mg, 240mg, or 360mg is achieved in the patient.

40. The method of claim 34, wherein the titration further comprises administering an initial dose of about 30mg once or twice daily.

41. The method of claim 34, wherein the titration comprises administering the anti-pruritus agent in increments ranging from about 15mg to about 60 mg.

42. The method of claim 1, wherein said patient experiences a significant reduction in itch following said treatment as compared to prior to said treatment.

43. The method of claim 1, wherein said patient experiences a reduction in itch following said treatment, which is characterized by a reduction in the most intense itch intensity Numerical Rating Scale (NRS) value by at least two points.

44. The method of claim 43, wherein said itch reduction is a decrease in the strongest itch intensity NRS value of at least three points.

45. The method of claim 43, wherein said itch reduction is a decrease in the strongest itch intensity NRS value of at least four points.

46. The method of claim 1, wherein said patient experiences a reduction in itch characterized by a decrease in the average itch intensity NRS value of at least two points following said treatment.

47. The method of claim 46, wherein said itch reduction is a decrease in the average itch intensity NRS value of at least three points.

48. The method of claim 46, wherein said itch reduction is a decrease in the average itch intensity NRS value of at least four points.

49. The method of claim 1, wherein after the treatment, the patient experiences a reduction in itch characterized by a visual analog scale with a most intense itch or average itch (VAS) value (VAS scale used in the range "no itch when VAS-0 to" most intense itch possible "when VAS-100 mm) that varies by at least about 10 mm.

50. The method of claim 49, wherein after said treatment, said patient experiences a reduction in itch characterized by a most scratchy or average itch VAS value (using the VAS scale ranging from no itch when VAS-0 to "most scratchy possible" when VAS-100 mm) that varies by at least about 20 mm.

51. The method of claim 49, wherein after said treatment, said patient experiences a reduction in itch characterized by a most scratchy or average itch VAS value (using the VAS scale ranging from no itch when VAS-0 to "most scratchy possible" when VAS-100 mm) that varies by at least about 30 mm.

52. The method of claim 1, wherein the nalbuphine or pharmaceutically acceptable salt or ester thereof is administered in combination with one or more antipruritic agents.

53. The method of claim 52, wherein the one or more antipruritic agents are selected from the group consisting of: antihistamines, antidepressants, serotonin antagonists, anti-inflammatory corticosteroids, topical anti-infective and antifungal agents, antibacterial agents, antiviral agents, cytotoxic agents and anti-irritant/analgesic agents.

54. The method of claim 1, wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is nalbuphine hydrochloride.

55. The method of claim 1, wherein the nalbuphine or pharmaceutically acceptable salt or ester thereof is in an extended release oral dosage form.

56. The method of claim 1, wherein the nalbuphine or pharmaceutically acceptable salt or ester thereof is administered in a formulation comprising nalbuphine hydrochloride, mannitol, hydroxypropyl cellulose, locust bean gum, xanthan gum, calcium sulfate dihydrate, fumaric acid, and magnesium stearate.

Technical Field

In some embodiments, the present disclosure relates to methods for treating patients with itch associated with liver disease using anti-itch compositions, such as nalbuphine (nalbuphine) compositions; methods for treating patients with pruritus associated with liver disease with obstructive cholestasis secondary to bile duct obstruction caused by non-liver tissue disease, and anti-itch compositions for use in such methods.

Background

Itching or itch is a sensation that stimulates the desire to scratch. Itching can be related to multiple discrete anatomical areas on the surface of the body's skin or limited to one specific anatomical area. The causes of pruritus are not fully understood. Suggested factors that contribute to the pathogenesis of pruritus may include anemia or other manifestations of erythropoietin deficiency, histamine release from skin mast cells, dry skin, secondary hyperparathyroidism, hyperphosphatemia with increased calcium phosphate deposition in the skin, and alterations in the endogenous opioid energy (opioidergic) system with opioid μ receptor overexpression.

Pruritus is a common symptom of chronic liver disease. As with other pruritic conditions (above), the etiology of pruritus (or liver itch) associated with liver disease is not fully understood. However, liver itch is often refractory to treatment with common antipruritic agents, and effective treatment of the condition is needed.

Disclosure of Invention

The present disclosure provides, among other things, methods of treating pruritus comprising administering to a patient in need of such treatment an effective amount of an anti-pruritus agent. In some embodiments, the anti-pruritic agent is nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof.

In some embodiments, the patient in need of treatment for pruritus is a patient with pruritus associated with liver disease. In some embodiments, the patient has chronic pruritus associated with liver disease. In some embodiments, the patient in need of treatment for pruritus is a patient with pruritus associated with obstructive cholestasis secondary to biliary obstruction caused by non-liver tissue disease.

In some embodiments, the patient in need of treatment for pruritus is a patient with pruritus associated with liver disease that is refractory to other therapies. In some embodiments, the patient's itch associated with liver disease is refractory to treatment with other antipruritic agents. In some embodiments, the patient's pruritus associated with liver disease ("liver itch") is refractory to treatment with a bile chelator. In some embodiments, the patient's pruritus associated with liver disease is refractory to treatment with rifampin (rifampicin). In some embodiments, the patient's pruritus associated with liver disease is refractory to treatment with a mu-opioid antagonist. In some embodiments, the patient's pruritus associated with liver disease is refractory to treatment with a kappa-opioid agonist.

In some embodiments, the patient in need of treatment for pruritus is a patient with pruritus associated with a liver disease selected from the group consisting of: cholestatic liver diseases (e.g., primary biliary and primary sclerosing cholangitis), infectious hepatitis; cirrhotic liver disease, drug-induced liver disease, idiopathic portal hypertension, congenital malformations or genetic diseases affecting liver function, sarcoidosis, primary or metastatic liver tumor involvement, and autoimmune hepatitis-cholangitis (overlap syndrome).

According to some embodiments of the disclosure, a method of treating pruritus associated with liver disease comprises administering to a patient in need thereof a daily dose of at least about 15mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof for at least one week. In some embodiments, the method of treating pruritus associated with liver disease comprises administering to a patient in need thereof for at least one week at least about 30mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof. In some embodiments, the method of treating pruritus associated with liver disease comprises administering to a patient in need thereof for at least one week at least about 60mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof. In some embodiments, a method of treating pruritus associated with liver disease comprises administering to a patient in need thereof a daily dose of at least about 120mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof for at least one week. In some embodiments, a method of treating pruritus associated with liver disease comprises administering to a patient in need thereof a daily dose of at least about 180mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof for at least one week. In some embodiments, a method of treating pruritus associated with liver disease comprises administering to a patient in need thereof a daily dose of at least about 360mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof for at least one week. In some embodiments, about 15mg of the anti-pruritus agent is administered twice daily. In some embodiments, about 30mg of the anti-pruritus agent is administered twice daily. In some embodiments, about 60mg of the anti-pruritus agent is administered twice daily. In some embodiments, about 90mg of the anti-pruritus agent is administered twice daily. In some embodiments, about 180mg of the anti-pruritus agent is administered once per day. In some embodiments, about 180mg of the anti-pruritus agent is administered twice daily. In some embodiments, about 360mg of the anti-pruritus agent is administered once per day.

In some embodiments, the anti-pruritus agent is administered for about 8 weeks. In some embodiments, the anti-pruritus agent is administered for about 10 weeks. In some embodiments, the anti-pruritus agent is administered for about 12 weeks. In some embodiments, the anti-pruritus agent is administered for about 18 weeks. In some embodiments, the anti-pruritus agent is administered for about 50 weeks.

In some embodiments, the patient experiences a significant reduction in itch after treatment as compared to before treatment.

In some embodiments, the method of treating pruritus further comprises the step of titrating the dose of the anti-pruritus agent for at least about one week until a steady state is reached in the patient. In one embodiment, the titration is performed for about 2 weeks until a steady state is reached in the patient. In another embodiment, the titration is performed for about 7 days to about 30 days until a steady state is reached in the patient. In another embodiment, the titration is performed for about 12 days to about 20 days until a steady state is reached in the patient.

In some embodiments, incremental doses of the anti-pruritus agent are administered during the titration period until a steady state is reached in the patient. In some embodiments, increasing doses of the anti-pruritus agent are administered during the titration period until an effective amount of 15mg, 30mg, 60mg, 90mg, 120mg, 180mg, 240mg, or 360mg is achieved in the patient.

In one embodiment, the titration is initiated at a dose of about 15mg once or twice daily. In another embodiment, the titration is initiated at a dose of about 30mg once or twice daily. In some embodiments, the titration comprises administering the anti-pruritus agent in increments ranging from about 15mg to about 30 mg. In some embodiments, the titration comprises administering the anti-pruritus agent in increments ranging from about 15mg to about 60 mg. In some embodiments, the titration is performed twice daily with an AM dose and a PM dose, wherein the PM dose is greater than or equal to the AM dose.

According to some embodiments of the disclosure, the incidence of adverse events following treatment with an anti-pruritus agent is substantially the same as the incidence of adverse events following administration of a placebo for the same period of time. In some embodiments, the incidence of liver-related adverse events after treatment with the anti-pruritus agent is substantially the same as the incidence of adverse events after administration of a placebo over the same time period.

According to some embodiments of the present disclosure, clinical studies indicate that patients treated with antipruritic experience a statistically significant reduction in itch as compared to patients treated with placebo. In some embodiments, a statistically significant reduction in itch is indicated by a p-value of less than or equal to about 0.05. In some embodiments, a patient with moderate or severe baseline itch prior to treatment experiences mild itch after treatment.

According to some embodiments of the present disclosure, after treatment, the patient experiences a reduction in itch characterized by a reduction in the most scratchy intensity Numerical Rating Scale (NRS) value of at least about 30%, 40%, or 50%. In some embodiments, after treatment, the patient experiences a reduction in itch characterized by a decrease in the average itch intensity Numerical Rating Scale (NRS) value of at least about 30%, 40%, or 50%. In some embodiments, following treatment, the patient experiences a reduction in itch characterized by at least a 3 point reduction in the most scratchy intensity NRS or at least a 4 point reduction. In some embodiments, after treatment, the patient experiences a reduction in itch characterized by a decrease in the average itch intensity NRS of at least 3 points or at least 4 points.

According to some embodiments of the present disclosure, after treatment, the patient experiences a reduction in itch characterized by a reduction in itch intensity speech rating scale (VRS) value by at least about one category (or one unit).

According to some embodiments of the disclosure, after treatment, the patient experiences a reduction in itch characterized by an ItchyQoL^TMAt least about a 10%, 20%, or 30% improvement in any of the corresponding sub-scales of the total scale score or symptom sub-scale score, function sub-scale score, or mood sub-scale score.

According to some embodiments of the disclosure, after treatment, the patient experiences a reduction in itch characterized by an improvement in the patient benefit index-itch version (PBI-P) scale of at least about 10%, 20%, or 30%.

According to some embodiments of the disclosure, the method of treating pruritus does not produce a substantial drainage promoting effect.

In some embodiments, the method of treating pruritus further comprises administering at least one additional anti-pruritus agent. In some embodiments, the at least one additional antipruritic is selected from the group consisting of: antihistamines (e.g. loratadine), corticosteroids (e.g. prednisone), capsaicin, calcineurin inhibitors (e.g. tacrolimus), antibiotics (e.g. tetracycline), anticonvulsants (e.g. gabapentin), immunosuppressants (e.g. methotrexate), antidepressants (e.g. amitriptyline), tranquilizers (e.g. clozapine), benzodiazepines (e.g. diazepam), serotonin antagonists or immunomodulators (e.g. thalidomide). In some embodiments, the method of treating pruritus further comprises administering cholestyramine (cholestyramine). In some embodiments, the method of treating pruritus further comprises administering rifampicin.

In some embodiments, the anti-pruritus agent is in the form of an extended release oral dosage form.

In some embodiments, the anti-pruritus agent is administered in a formulation comprising nalbuphine hydrochloride, mannitol, hydroxypropyl cellulose, locust bean gum, xanthan gum, calcium sulfate dihydrate, and magnesium stearate.

The process of the present invention and its advantages are further illustrated by the following non-limiting detailed description, including the examples.

Definition of

The term "about" when immediately preceding a numerical value means a range (e.g., the value ± 10%). Unless the context of the present disclosure indicates otherwise or is inconsistent with such interpretation, for example, "about 50" may mean 45 to 55, "about 25,000" may mean 22,500 to 27,500, and so forth. For example, in a numerical list such as "about 49, about 50, about 55, …," about 50 "means that the range is expanded to less than half the interval between the previous value and the subsequent value, e.g., greater than 49.5 to less than 52.5. Further, the phrases "less than about" one value or "greater than about" one value should be understood in light of the definition of the term "about" provided herein. Similarly, the term "about" when preceded by a range of values or a series of values (e.g., "about 10, 20, 30" or "about 10-30") is intended to refer to the endpoints of all values or ranges in the range, respectively.

Throughout this disclosure, reference is made to various patents, patent applications, and publications. The disclosures of these patents, patent applications, and publications in their entireties are hereby incorporated by reference into this disclosure for all purposes to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between cited patents, patent applications and publications and the present disclosure, the present disclosure shall control.

For convenience, certain terms used in the specification, examples, and claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

As used herein, the term "administering" refers to the direct administration of a compound or a pharmaceutically acceptable salt or ester of the compound or a composition comprising the compound or a pharmaceutically acceptable salt or ester of the compound to a patient.

As used herein, the term "adverse event" (AE) is defined as any untoward medical event in a clinical study patient reported at or after the date of the first screening. AEs are not necessarily causal to treatment. Thus, an AE can be any adverse and unexpected sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of a pharmaceutical (research) product, whether or not associated with the pharmaceutical (research) product. Typical adverse events include nausea, vomiting, lethargy and dizziness. According to the present disclosure, the incidence of adverse events after treatment is substantially the same as the incidence of adverse events after administration of placebo over the same time period.

As used herein, the term "carrier" encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting an agent from one organ or portion of the body to another organ or portion of the body.

The term "chronic pruritus" is used in this disclosure to mean pruritus that lasts at least 6 weeks.

Unless otherwise indicated, the term "disorder" is used in this disclosure to mean the term disease, condition, or disorder, and is used interchangeably with the term.

The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound, or a salt, solvate, or ester thereof, that is capable of performing the intended result when administered to a patient. For example, an effective amount of an anti-pruritic agent is an amount required to reduce at least one symptom of itch in a patient, such as an amount required to reduce the patient's perception of itch. The actual amount comprising an "effective amount" or a "therapeutically effective amount" will vary depending on a number of conditions including, but not limited to, the severity of the condition, the size and health of the patient, and the route of administration. Appropriate amounts can be readily determined by the skilled medical practitioner using methods known in the medical arts.

As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the term "salt" includes pharmaceutically acceptable salts commonly used to form alkali metal salts of the free acids and to form addition salts of the free bases. The nature of the salt is not critical as long as it is pharmaceutically acceptable. The term "salt" also includes solvates of addition salts (such as hydrates) as well as polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from carboxylic and sulfonic acids containing aliphatic, cycloaliphatic, aromatic, araliphatic and heterocyclic groups, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, methanesulfonic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylsulfamic acid, alginic acid, 3-hydroxybutyric acid, galactaric acid and galacturonic acid.

As used herein, the term "treating" with respect to a patient refers to ameliorating at least one symptom of a condition in the patient. The treatment may be a cure, amelioration, or at least partial alleviation of the condition.

As used herein, the term "therapeutic effect" refers to a desired or beneficial effect provided by the methods and/or compositions. For example, a method for treating pruritus provides a therapeutic effect when the method alleviates at least one symptom of pruritus (e.g., itch) in a patient.

Detailed Description

According to the present disclosure, pruritus includes any itching or pruritus condition, such as causing a feeling of scratching.

Pruritus is a common and debilitating symptom of chronic liver disease. Chronic liver disease can be characterized as cholestatic or non-cholestatic. Cholestatic liver disease (or cholestasis) is the formation of bile or impaired bile flow. Non-cholestatic liver disease is a liver disease that does not cause cholestasis (i.e., liver cell damage that is not severe enough to disrupt the normal liver cell secretion of bile into the biliary tract's malleable system and thus is not associated with elevated circulating levels of bilirubin in the blood). According to one study, about 40% of all patients with chronic liver disease (cholestatic and non-cholestatic) report itching, and about 60% of patients reporting itching do not respond to treatment with oral and/or topical antipruritic agents (S.Oeda et al, Prevalence of pruritus in patients with chronic viral disease: A multicenter study, Hepatology Research,2018,48: E252-E262).

Although the occurrence of pruritus associated with liver disease is common, little is known about its etiology. Some data (including Lindor et al, Primary Biliary Cirrhosis, Hepatology,2009, month 7, 291-. However, other data (such as Kremer et al, Pathologenesis and Treatment of Pruritus in Cholestastis Drugs, 2008; 68 (15); 2163-.

The European Association of Liver Itch research (EASL) guidelines recommend cholestyramine as a first-line therapy, rifampin (pregnane X receptor agonist) as a second-line therapy, and oral opioid antagonists as a third-line therapy to alleviate the Itch associated with cholestatic Liver disease and primary cholecholangitis, also known as Primary Biliary Cirrhosis (PBC), a type of cholestatic Liver disease. (EASL Clinical practices: Management of volatile liquid diseases, J.hepatology,2009,51, 237-. The use of oral opioid antagonists provides "disappointing" treatment outcomes and is associated with opioid withdrawal-like symptoms as well as decreased pain thresholds and confusion (2009EASL guideline 258). The kappa-opioid receptor agonist naftifine (nalfurafine) is approved in japan for the treatment of pruritus associated with cholestatic liver disease. However, there is no FDA approved therapy for treating pruritus associated with liver disease.

In one aspect, the present disclosure provides a method of treating pruritus comprising administering to a patient in need of such treatment an effective amount of an antipruritic agent for at least about one week, wherein the antipruritic agent is nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof. According to some embodiments of the disclosure, at least about 15mg, 30mg, 60mg, 90mg, 120mg, or 180mg of the anti-pruritus agent is administered.

In another embodiment, the methods of the present disclosure are used to treat pruritus associated with liver disease. In some embodiments, nalbuphine HCl is used or indicated for use in treating itch in patients with chronic itch associated with liver disease. In some embodiments, nalbuphine HCl is for use in or is indicated for treating itch in a patient having itch associated with liver disease, wherein the patient does not have bile duct obstruction.

In another embodiment, the methods of the present disclosure are used to treat pruritus associated with obstructive cholestasis secondary to biliary obstruction caused by non-liver tissue disease. In some embodiments, nalbuphine HCl is used or indicated for treating itch in a patient suffering from chronic itch associated with obstructive cholestasis secondary to bile duct obstruction caused by non-liver tissue disease. In some embodiments, nalbuphine HCl is for use in or is indicated for treating itch in a patient having itch associated with obstructive cholestasis secondary to biliary obstruction caused by a non-liver tissue disease, wherein the obstruction is caused by a condition selected from the group consisting of: pancreatic cancer, pancreatitis, congenital or acquired biliary stricture, lymph node obstruction (such as from lymphoma), or bile duct stones.

In another embodiment, the methods of the present disclosure are used to treat pruritus associated with cholestatic liver disease. In some embodiments, the cholestatic liver disease is primary sclerosing cholangitis. In some embodiments, the cholestatic liver disease is primary biliary cholangitis.

In another embodiment, the methods of the present disclosure are used to treat pruritus associated with non-cholestatic liver disease.

In some embodiments, the methods of the present disclosure are used to treat pruritus associated with a liver disease selected from the group consisting of: infectious hepatitis; cirrhotic liver disease, drug-induced liver disease, idiopathic portal hypertension, congenital malformations or genetic diseases affecting liver function, sarcoidosis, primary or metastatic liver tumor involvement, and autoimmune hepatitis-cholangitis (overlap syndrome).

In some embodiments, the methods of the present disclosure are used to treat pruritus associated with infectious hepatitis. In some embodiments, the infectious hepatitis is selected from Hepatitis C (HCV) and Hepatitis B (HBV). In some embodiments, the HCV is selected from chronic HCV and HCV after a persistent virological response. In some embodiments, the hepatitis b is selected from inactive HBV and active HBV infection in a carrier.

In some embodiments, the methods of the present disclosure are used to treat pruritus associated with cirrhotic liver disease. In some embodiments, the cirrhotic liver disease is selected from the group consisting of alcoholic liver disease, autoimmune hepatitis, and non-alcoholic fatty liver disease.

In some embodiments, the methods of the present disclosure are used to treat pruritus associated with a liver disease selected from the group consisting of: drug-induced liver disease, idiopathic portal hypertension, congenital malformations or genetic diseases affecting liver function, sarcoidosis, primary or metastatic liver tumor involvement, and autoimmune hepatitis-cholangitis (overlap syndrome).

In some embodiments, the methods of the present disclosure are used to treat pruritus associated with liver disease, wherein the patient's serum levels of endogenous opioids are elevated as compared to normal serum levels. In some embodiments, the endogenous opioid is one or more endogenous mu opioid receptor agonists. In some embodiments, the endogenous mu-opioid receptor agonist is selected from the group consisting of enkephalins and beta-endorphins.

In accordance with the present disclosure, an antipruritic is administered once or twice daily to effectively alleviate the symptoms of itching associated with liver disease (or obstructive cholestasis secondary to bile duct obstruction caused by non-liver tissue disease) that cannot be effectively alleviated by other therapies (i.e., the itching is otherwise refractory to treatment).

In some embodiments, the methods of the present disclosure are used to treat pruritus associated with liver disease (or obstructive cholestasis secondary to biliary obstruction caused by non-liver tissue disease), wherein the pruritus is refractory to treatment with other antipruritic agents. In some embodiments, the pruritus is refractory to treatment with an anti-pruritic agent selected from an antidepressant, a serotonin antagonist, a serotonin reuptake inhibitor, or an antihistamine. In some embodiments, the pruritus is refractory to treatment with sertraline (sertraline).

In some embodiments, the methods of the present disclosure are used to treat pruritus associated with liver disease (or obstructive cholestasis secondary to bile duct obstruction caused by non-liver tissue disease), wherein the pruritus is refractory to treatment with a bile chelator. In some embodiments, the pruritus is refractory to treatment with a bile-chelating agent selected from the group consisting of cholestyramine, colestipol (colesevelam), and colesevelam (colesevelam). In some embodiments, the pruritus is refractory to treatment with cholestyramine.

In some embodiments, the methods of the present disclosure are used to treat pruritus associated with liver disease (or obstructive cholestasis secondary to biliary obstruction caused by non-liver tissue disease), wherein the pruritus is refractory to treatment with one or more pregnane X receptor agonists. In some embodiments, the pruritus is refractory to treatment with rifampicin.

In some embodiments, the methods of the present disclosure are used to treat pruritus associated with liver disease (or obstructive cholestasis secondary to biliary obstruction caused by non-liver tissue disease), wherein the pruritus is refractory to treatment with a mu-opioid antagonist. In some embodiments, the pruritus is refractory to treatment with a mu-opioid antagonist selected from the group consisting of naltrexone (naltrexone) and naloxone (naloxone).

In some embodiments, the methods of the present disclosure are used to treat pruritus associated with liver disease (or obstructive cholestasis secondary to biliary obstruction caused by non-liver tissue disease), wherein the pruritus is refractory to treatment with kappa-opioid agonists. In some embodiments, the pruritus is refractory to treatment with naftifine.

According to some embodiments of the disclosure, the method provides a therapeutic effect without generating substantial adverse events. In some embodiments, the incidence of adverse events following treatment with an anti-pruritus agent is substantially the same as the incidence of adverse events following administration of a placebo over the same time period. In some embodiments, the incidence of liver-related adverse events, such as liver function enzymes (i.e., elevated serum alkaline phosphatase ("AP"), gamma-glutamyl transpeptidase ("GGT"), serum transaminase ("ALT"), and/or aspartate transaminase ("AST")) following treatment with an antipruritic is substantially the same as the incidence of adverse events following administration of a placebo over the same period of time.

According to some embodiments of the disclosure, the method of treating pruritus does not produce a substantial drainage promoting effect.

In some embodiments of the present disclosure, the patient treated for pruritus is a pediatric patient. In some embodiments of the disclosure, the patient treated for pruritus is an elderly patient.

Nalbuphine

The nalbuphine used in the methods of the present invention may form part of a pharmaceutical composition by combining nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof with a pharmaceutically acceptable carrier. Further, the composition may comprise an additive selected from the group consisting of adjuvants, excipients, diluents, release modifiers and stabilizers. The composition may be an immediate release formulation, a delayed release formulation, a sustained release formulation or an extended release formulation.

Nalbuphine HCl (17- (cyclobutylmethyl) -4,5 α -epoxymorphine-3, 6 α, 14-triol hydrochloride) is a synthetic opioid. Structurally, nalbuphine is a derivative of 14-hydroxymorphine.

Nalbuphine HCl is currently only available as a general drug in injectable form. Since 1978, nalbuphine in injectable form has been available as an approved pharmaceutical formulation.Is an innovative brand injectable form of nalbuphine, based on which the currently marketed universal bioequivalent injectable formulation is based. The injectable formulations are currently approved for the relief of moderate to severe pain, as a supplement to balanced anaesthesia, for preoperative and postoperative analgesia during labor and delivery, and obstetrical analgesia.

The present disclosure also includes pharmaceutically acceptable esters of antipruritic agents. The term "ester" refers to a derivative of an agent containing an ester functional group (as described herein) that is capable of releasing the agent when the ester form is administered to a patient. The release of the active ingredient takes place in vivo. Pharmaceutically acceptable esters can be prepared by techniques known to those skilled in the art. These techniques typically modify the appropriate functional groups in a given compound. However, these modified functional groups regenerate the original functional groups by metabolism of the compound in vivo. Esters include compounds in which a hydroxyl, carboxyl, or similar group is modified.

Suitable pharmaceutically acceptable esters for the hydroxy group include inorganic esters such as phosphate esters and α -acyloxyalkyl ethers and related compounds which provide the parent hydroxy group as a result of hydrolysis of the ester in vivo. The in vivo hydrolysable ester-forming group of a hydroxy group includes alkanoyl (e.g. C)_1-10Straight, branched or cyclic alkyl), benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate), dialkylcarbamoyl and N- (N, N-dialkylaminoethyl) -N-alkylcarbamoyl (to give carbamate), N-dialkylaminoacetyl and carboxyacetyl.

In some embodiments, the nalbuphine used in the formulations and methods of the present disclosure is a pharmaceutically acceptable co-crystal of nalbuphine.

Preparation

The methods of the present disclosure can be administered to patients (e.g., humans and animals) using a variety of formulations, in unit dosage forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, as well as oil and water emulsions containing appropriate amounts of antipruritic agents (e.g., nalbuphine or a pharmaceutically acceptable salt or ester thereof).

Oral pharmaceutical dosage forms may be solid or liquid. The solid dosage forms can be tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed chewable lozenges and tablets, which may be enteric-coated, sugar-coated or film-coated. The capsules may be hard or soft gelatin capsules, while the granules and powders may be provided in non-effervescent or effervescent form in combination with other ingredients known to those skilled in the art. In other embodiments, the oral dosage form may be an osmotic pump controlled release oral delivery system (OROS). In other embodiments, the oral dosage form may include a matrix-embedded dosage form or an associated device. In some embodiments, the oral dosage form of the present invention may comprise orally disintegrating tablets.

Pharmaceutically acceptable carriers for use in tablets include binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents.

Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent formulations reconstituted from effervescent granules.

Aqueous solutions include, for example, elixirs and syrups. Elixirs are clear, sweetened, hydroalcoholic formulations. Pharmaceutically acceptable carriers used in elixirs include solvents. The syrup may be a concentrated aqueous solution of a sugar, such as sucrose, and may contain a preservative. Emulsions are two-phase systems in which one liquid is dispersed in the form of globules in another liquid. Emulsions may be oil-in-water or water-in-oil. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifiers and preservatives. The suspension may employ pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable materials for use in non-effervescent granules to be reconstituted into liquid oral dosage forms include diluents, sweeteners and wetting agents. Pharmaceutically acceptable materials used in effervescent granules to be reconstituted into liquid oral dosage forms may include organic acids and a source of carbon dioxide. Coloring and flavoring agents may be used in all of the above dosage forms.

Parenteral administration of the formulations of the present disclosure includes intravenous, subcutaneous, and intramuscular administration of immediate, sustained (e.g., long acting), extended, and/or modified release formulations (e.g., as described herein). Formulations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products (including subcutaneous injection tablets) ready for combination with a solvent prior to use, sterile suspensions ready for injection, sterile dry insoluble products ready for combination with a vehicle prior to use, and sterile emulsions. The solution may be aqueous or non-aqueous. Pharmaceutically acceptable carriers for use in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, chelating/chelating agents, and other pharmaceutically acceptable materials.

The concentration of the pharmaceutically active compound can be adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. The exact dosage will depend upon the age, weight and condition of the patient or animal, as is known in the art. The unit dose of parenteral formulation is packaged in ampoules or syringes with needles. As known and practiced in the art, all formulations for parenteral administration must be sterile. Illustratively, intravenous or intra-arterial infusion of sterile aqueous solutions containing an anti-itch agent is an effective mode of administration.

Pharmaceutical dosage forms for rectal administration may be rectal suppositories, capsules and tablets for systemic action. As used herein, rectal suppositories mean solids for insertion into the rectum that melt or soften at body temperature to release the pharmacologically and/or therapeutically active ingredient contained in the compositions of the present disclosure. Pharmaceutically acceptable substances used in rectal suppositories are bases or vehicles for increasing the melting point and agents for the neutralization. Examples of bases include cocoa butter (cocoa butter), glycerol-gelatin, carbowaxes, mixtures of mono-, di-and triglycerides of polyoxyethylene glycols and fatty acids. Combinations of various bases may be used. Agents that increase the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared by compression methods or by molding. A typical weight for rectal suppositories is about 2 to 3 g. Tablets and capsules for rectal administration may be made using the same pharmaceutically acceptable materials and by the same methods as formulations for oral administration.

The composition may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product. The form of the resulting composition depends on a number of factors, including the intended mode of administration and the solubility of the anti-pruritic agent in the selected carrier or vehicle. The effective concentration is sufficient to treat or alleviate itch and can be determined empirically. The concentration is typically greater than the concentration used for systemic administration of the compound.

The resulting mixture may be a solution, suspension, emulsion, etc., and may be formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, irrigation fluid, spray, suppository, bandage, or any other formulation suitable for topical administration. Modes of administration may include topical application to the skin, scalp, eye and/or nasal mucosa, buccal mucosa or sublingual mucosa.

Pharmaceutical and cosmetic carriers or vehicles suitable for administration of the compositions include any such carrier known to those skilled in the art to be suitable for a particular mode of administration. The anti-pruritic agent may be included in the carrier in an amount sufficient to exert a therapeutically useful effect without severe toxic effects on the subject being treated.

To formulate these compositions, a weight fraction of an anti-pruritic agent is dissolved, suspended, dispersed, or otherwise mixed in a selected vehicle at an effective concentration to alleviate or reduce the pruritic condition. Generally, emollients or lubricating vehicles that aid in moisturizing the skin are preferred over volatile vehicles that dry the skin, such as ethanol. Examples of suitable bases or vehicles for preparing compositions for use on human skin are petrolatum, petrolatum plus volatile silicones, lanolin, cold cream (USP) and hydrophilic ointment (USP).

The compositions used in the methods of the present invention provide relief from itching when applied to the skin. The relief can be temporary or permanent, and can be apparent even after a single dose of the composition. When the composition is administered in a form other than a topical formulation, it should be administered in an amount sufficient to provide relief from itching, within safety guidelines established by the FDA. In conjunction with the teachings provided by the present disclosure, it is within the skill of one of ordinary skill in the art to determine the appropriate amount to administer to a patient.

Solutions of the compositions of the present disclosure intended for topical application comprise an amount of the composition effective to deliver an antipruritic amount, typically at a concentration of between about 0.01% w/w and about 5% w/w. The remainder of the solution is water, a suitable organic solvent, or other suitable solvent or buffer. These compositions, formulated as solutions or suspensions, can be applied to the skin, or can be formulated as aerosols or foams and applied to the skin in spray form. The aerosol composition typically comprises from 25% to 80% w/w, preferably from 30% to 50% w/w of a suitable propellant. Gel compositions can be formulated by simply mixing the appropriate thickening agent into a solution or suspension.

Compositions in solid form intended for topical application may be formulated as stick-type compositions intended for application to the lips or other parts of the body. Such compositions comprise an effective amount of an antipruritic agent, for example, nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof. The antipruritic agent is typically present in an amount of about 0.01% w/w to about 5% w/w. The solids also comprise from about 40% to 98% w/w, preferably from about 50% to 90% w/w of emollient. The composition may also comprise from 1% to 20% w/w, preferably from 5% to 15% w/w of a suitable thickening agent, and may also comprise emulsifiers and water or buffers, as desired or required.

Sustained release

Nalbuphine formulations that may be used in the methods of the present invention include those disclosed in U.S. patent publication nos. 2019/0117576, 2019/0099416, 2015/03597892009/0030026 and 2007/0048376; and oral sustained release nalbuphine formulations as described in PCT publication nos. 2015/192071 and 2007/025005; each of which is incorporated herein by reference in its entirety.

By "sustained release" or "extended release" is meant that the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is released from the formulation at a controlled rate so as to maintain a therapeutically beneficial blood level (but below toxic levels) of the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof for an extended period of time. Alternatively, "sustained release" or "extended release" means that the desired pharmacological effect is maintained over an extended period of time.

The half-life of injectable formulations of nalbuphine (i.e. IV or IM or SC) is reported to be relatively short, only about 2-3 hours. In some embodiments, the present methods may employ an oral sustained release formulation of nalbuphine comprising an antipruritic effective amount of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof. The oral sustained release formulation can provide controlled release and lower antipruritic C over a longer period of time (e.g., at least about 8-12 hours) than observed for a bolus injection or immediate release oral formulation_max. Reducing the frequency of administration provides the possibility of enhancing patient convenience and compliance with the methods of the invention. Lower dosing frequency also has the potential to provide reduced side effects, as patients may be exposed to lower peak concentrations of agent over time.

Without wishing to be bound by a particular theory, the longer duration of the antipruritic effect is due to enterohepatic recirculation of nalbuphine than expected. Nalbuphine forms glucuronic acid or other types of conjugated metabolites in vivo by enzymatic reaction with an enzyme system such as UDP-glucuronosyltransferase. Enterohepatic recirculation may also occur when the parent drug in the bile is released from the gallbladder into the intestine and reabsorbed. Once formed, the conjugated nalbuphine product is believed to be transported into the gastrointestinal tract by bile secretion, thereby cleaving the drug conjugate and releasing the nalbuphine which can be reabsorbed from the intestine. The sustained release formulations can improve the duration of antipruritic effect by releasing nalbuphine more slowly into the in vivo system and allowing more drug conjugation and thus available for recirculation and subsequent reabsorption from the intestine.

The methods of the present invention may employ compositions comprising nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof and a sustained release delivery system. A sustained release delivery system comprising: (i) at least one hydrophilic compound, at least one cross-linking agent, and at least one pharmaceutical diluent; (ii) at least one hydrophilic compound, at least one cross-linking agent, at least one pharmaceutical diluent, and at least one cationic cross-linking agent different from the first cross-linking agent; or (iii) at least one hydrophilic compound, at least one cationic cross-linking compound and at least one pharmaceutical diluent. Alternatively, in other embodiments, the methods of the present invention may employ compositions comprising nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof and a sustained release delivery system, which methods may employ a hydrophobic compound in the sustained release system.

The nalbuphine may be homogeneously dispersed in the sustained release delivery system. In some embodiments, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is present in the composition in an amount of: about 1mg to about 240 mg; about 1mg to about 150 mg; from about 1mg to about 125 mg; or from about 1mg to about 100 mg. In some embodiments, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is present in the composition in an amount of: about 5mg to about 80 mg; about 10mg to about 70 mg; about 15mg to about 60 mg; about 40mg to about 80 mg; about 50mg to about 70 mg; or from about 45mg to about 60 mg. In one embodiment, nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is present in said composition in an amount of: about 15mg, about 20mg, about 25mg, about 30mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, or about 240 mg. In another embodiment, nalbuphine or a pharmaceutically acceptable salt thereof is present in said composition in the following amounts: about 15mg, about 30mg, about 45mg, about 60mg, about 90mg, about 120mg, or about 180 mg.

In yet another embodiment, a pharmaceutically acceptable salt of nalbuphine (e.g. nalbuphine HCl) is present in the composition in an amount of about 15mg, about 30mg, about 60mg, about 90mg, about 120mg or about 180 mg. For compositions comprising a pharmaceutically acceptable salt of nalbuphine, the amount of nalbuphine in said composition may be expressed as an equivalent amount of nalbuphine free base in the composition calculated on the basis of the actual amount of the pharmaceutically acceptable salt of nalbuphine in said composition. The amount of equivalents of nalbuphine free base in the composition will vary during the manufacturing process, and the compositions of the present disclosure encompass pharmaceutically acceptable deviations from the nalbuphine content recited in the present disclosure (i.e., FDA acceptable).

The table below shows the equivalent amounts of nalbuphine free base for compositions containing 15mg, 30mg, 60mg, 90mg, 120mg, 180mg and 240mg nalbuphine HCl:

amount of nalbuphine HCl	Equivalents of nalbuphine free base
		15mg	13.61
30mg	27.2
		60mg	54.4
90mg	81.6
		120mg	108.8
180mg	163.2
		240mg	217.6

Throughout this disclosure, the amount of nalbuphine in the composition is typically expressed in terms of the amount of nalbuphine hydrochloride present in the composition. However, the present disclosure contemplates embodiments in which nalbuphine is present in another form of nalbuphine (such as a different pharmaceutically acceptable salt and/or ester) and provides about the same equivalent of the nalbuphine free base as the embodiments explicitly described herein. For example, about 251mg of nalbuphine citrate (FW ═ 549.57g/mol) provided about the same equivalent of nalbuphine free base as about 180mg of nalbuphine hydrochloride. The equivalent of nalbuphine free base in the composition may be calculated by the formula:

the equivalent amount of nalbuphine free base content of the dosage form calculated using the above formula may be adjusted by a pharmaceutically acceptable amount (e.g. within the amount allowed by FDA safety standards, which in some embodiments is 1% or less of the calculated nalbuphine free base equivalent amount) to allow product labeling using integers at the reference dose strength. For example, the equivalent calculated for nalbuphine free base of 240mg nalbuphine hydrochloride is 217.6 mg. In accordance with the present disclosure, the nalbuphine content in the composition may be adjusted to give a product label of 216mg equivalents of nalbuphine free base.

In some embodiments, the sustained release delivery system is present in the composition in the following amounts: about 10mg to about 420 mg; about 25mg to about 225 mg; about 21mg to about 198 mg; about 80mg to about 200 mg; about 80mg to about 220 mg; about 90mg to about 210 mg; about 100mg to about 200 mg; about 110mg to about 190 mg; about 120mg to about 180 mg; about 130mg to about 170 mg; about 140mg to about 160 mg; about 30mg to about 60 mg; about 60mg to about 180 mg; about 30mg to about 180 mg; about 75mg to about 150 mg; about 80mg to about 160 mg; about 90mg to about 150 mg; about 100mg to about 140 mg; about 110mg to about 130 mg; about 100mg to about 300 mg; from about 200mg to about 300mg or from about 200mg to about 250 mg. In one embodiment, the sustained release delivery system is present in the composition in an amount from about 75mg to about 150 mg.

In some embodiments, the sustained release delivery system is present in the composition in the following amounts: about 15mg, about 30mg, about 60mg, about 75mg, about 80mg, about 90mg, about 100mg, about 110mg, about 112mg, about 115mg, about 117mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 225mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 300mg, about 320mg, about 340mg, about 360mg, about 380mg, about 400mg, or about 420 mg. In another embodiment, the sustained release delivery system is present in the composition in an amount of about 112 mg.

The ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to sustained release delivery system in said composition is typically from about 4:1 to about 1: 25. In some embodiments, the ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to sustained release delivery system is typically from about 2.5:1 to about 1:4. In some embodiments, the ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system is typically from about 5:1 to about 1:5, from about 4:1 to about 1:4, from about 3:1 to about 1:3, from about 2:1 to about 1:2, from about 1:1 to about 1:5, from about 1:1 to about 1:4, from about 1:1 to about 1:3, from about 1:1 to about 1.2 and from about 1:2 to about 1:3. In some embodiments, the ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to sustained release delivery system is about 1:1, about 1:2, about 1:2.5, about 1:3, about 1:4 or about 1: 5.

In one embodiment, the at least one hydrophilic compound is present in the sustained release delivery system in an amount from about 5% to about 80% by weight; the at least one cross-linking agent is present in the sustained release delivery system in an amount from about 0.5 wt% to about 80 wt%; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount from about 20% to about 80% by weight. In another embodiment, the at least one hydrophilic compound is present in the sustained release delivery system in an amount from about 8% to about 31% by weight; the at least one cross-linking agent is present in the sustained release delivery system in an amount from about 12% to about 47% by weight; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount from about 20% to about 78% by weight. In another embodiment, the at least one hydrophilic compound is present in the sustained release delivery system in an amount from about 10% to about 20% by weight; the at least one cross-linking agent is present in the sustained release delivery system in an amount from about 15 wt% to about 25 wt%; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount from about 50% to about 85% by weight. In some embodiments, the at least one hydrophilic compound is present in the sustained release delivery system in an amount of about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, about 22 wt.%, about 24 wt.%, about 26 wt.%, about 28 wt.%, about 30 wt.%, about 32 wt.%, about 34 wt.%, or about 36 wt.%; the at least one crosslinking agent is present in the sustained release delivery system in an amount of about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, about 22 wt.%, about 24 wt.%, about 26 wt.%, about 28 wt.%, about 30 wt.%, about 32 wt.%, about 33 wt.%, about 34 wt.%, or about 35 wt.%; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount of about 40 wt.%, about 45 wt.%, about 50 wt.%, about 55 wt.%, about 60 wt.%, about 65 wt.%, about 70 wt.%, about 80 wt.%, or about 85 wt.%.

In some embodiments, the at least one hydrophilic compound is present in the sustained release delivery system in an amount of about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, or about 20 wt.%; the at least one crosslinking agent is present in the sustained release delivery system in an amount of about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, or about 22 wt.%; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount of about 55 wt.%, about 60 wt.%, about 65 wt.%, about 70 wt.%, about 80 wt.%, or about 85 wt.%. In one embodiment, the at least one hydrophilic compound is present in the sustained release delivery system in an amount of about 8 wt.%, about 12 wt.%, or about 20 wt.%; the at least one cross-linking agent is present in the sustained release delivery system in an amount of about 12 wt.%, about 18 wt.%, or about 30 wt.%; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount of about 40 wt.%, about 60 wt.%, or about 70 wt.%.

In one embodiment, the nalbuphine is in the form of any pharmaceutically acceptable salt known in the art. Exemplary pharmaceutically acceptable salts include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, maleic acid, malic acid, ascorbic acid, citric acid, tartaric acid, pamoic acid, lauric acid, stearic acid, palmitic acid, oleic acid, myristic acid, lauryl sulfuric acid, naphthalenesulfonic acid, linoleic acid, linolenic acid, and the like. One embodiment includes the hydrochloride salt of nalbuphine.

The sustained release delivery system comprises at least one hydrophilic compound. The hydrophilic compound preferably forms a gel matrix that releases nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof at a sustained rate upon exposure to a liquid. The rate of release of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof from the gel matrix depends on the partition coefficient of the drug between the components of the gel matrix and the aqueous phase in the gastrointestinal tract. The weight ratio of nalbuphine to hydrophilic compound is typically in the range of from about 10:1 to about 1:10, from about 9:1 to about 1:9, from about 8:1 to about 1:8, from about 7:1 to about 1:7, from about 6:1 to about 1:6, from about 5:1 to about 1:5, from about 4:1 to about 1:4, from about 3:1 to about 1:3 and from about 2:1 to about 1:2. In some embodiments, the weight ratio of nalbuphine to hydrophilic compound is in the range of from about 10:1 to about 1:1, from about 10:1 to about 2:1, from about 9:1 to about 1:1, from about 8:1 to about 1:1, from about 7:1 to about 1:1, from about 6:1 to about 1:1, from about 5:1 to about 1:1, from about 4:1 to about 1:1, from about 3:1 to about 1:1, and from about 2:1 to about 1:1. In some embodiments, the weight ratio of nalbuphine to hydrophilic compound is in the range of from about 6:1 to about 1:1, from about 5:1 to about 2:1, from about 4:1 to about 3:1, from about 4:1 to about 2:1 and from about 5:1 to about 2: 1. In some embodiments, the weight ratio of nalbuphine to hydrophilic compound is about 1:5, about 1:4.5, about 1:4.4, about 1:4, about 1:3.5, about 1:3.3, about 1:3, about 1:2.5, about 1:2, about 1:1 and about 1: 1.5.

Sustained release delivery systems typically comprise hydrophilic compounds in an amount of about 5% to about 80% by weight. In some embodiments, the sustained release delivery system typically comprises the hydrophilic compound in an amount from about 5% to about 30%, from about 8% to about 31%, from about 10% to about 20%, from about 20% to about 60%, or from about 40% to about 60% by weight. In one embodiment, the sustained release delivery system comprises the hydrophilic compound in an amount from about 8% to about 31% by weight. In one embodiment, the sustained release delivery system comprises the hydrophilic compound in an amount from about 10% to about 20% by weight. In some embodiments, the sustained release delivery system comprises the hydrophilic compound in an amount of about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, or about 20 wt.%. In one embodiment, the sustained release delivery system comprises the hydrophilic compound in an amount of about 12% by weight. In one embodiment, the sustained release delivery system comprises the hydrophilic compound in an amount of about 8% by weight. In one embodiment, the sustained release delivery system comprises the hydrophilic compound in an amount of about 20% by weight. In one embodiment, the sustained release delivery system comprises the hydrophilic compound in an amount of about 28% by weight.

The hydrophilic compound is any pharmaceutically acceptable compound known in the art to be hydrophilic. Exemplary hydrophilic compounds include, but are not limited to, pharmaceutically acceptable gums, cellulose ethers, polyvinylpyrrolidone, protein-derived compounds, and mixtures thereof. Exemplary gums include, but are not limited to, heteropolysaccharide gums and homopolysaccharide gums, such as xanthan gum, tragacanth gum, pectin, acacia gum, karaya gum, alginate, agar, guar gum, hydroxypropyl guar gum, carrageenan, locust bean gum, and gellan gum. Exemplary cellulose ethers include, but are not limited to, hydroxyalkyl cellulose and carboxyalkyl cellulose. In some embodiments, the cellulose ethers include hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, and mixtures thereof. In some embodiments, the hydrophilic compound is a gum. In other embodiments, the hydrophilic compound is a heteropolysaccharide gum. In other embodiments, the hydrophilic compound is xanthan gum or a derivative thereof. Derivatives of xanthan gum include, but are not limited to, for example, deacylated xanthan gum, carboxymethyl esters of xanthan gum, and propylene glycol esters of xanthan gum.

In another aspect, the sustained release delivery system further comprises at least one cross-linking agent. In one embodiment, the crosslinking agent is a compound capable of crosslinking a hydrophilic compound in the presence of a liquid to form a gel matrix. As used herein, "liquid" includes, for example, gastrointestinal fluids and aqueous solutions, such as those used for in vitro dissolution testing. Sustained release delivery systems typically comprise a cross-linking agent in an amount of about 0.5% to about 80% by weight. In one embodiment, the sustained release delivery system typically comprises a cross-linking agent in an amount from about 12% to about 47% by weight. In another embodiment, the sustained release delivery system generally comprises the crosslinking agent in an amount of about 20% to about 30% by weight. In one embodiment, the sustained release delivery system typically comprises a cross-linking agent in an amount from about 15% to about 25% by weight. In some embodiments, the at least one cross-linking agent is present in the sustained release delivery system in an amount of: about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, or about 25 wt%. In one embodiment, the sustained release delivery system comprises the crosslinking agent in an amount of about 18% by weight. In one embodiment, the sustained release delivery system comprises the crosslinking agent in an amount of about 12% by weight. In one embodiment, the sustained release delivery system comprises the crosslinking agent in an amount of about 30% by weight. In one embodiment, the sustained release delivery system comprises the crosslinking agent in an amount of about 42% by weight.

Exemplary cross-linking agents include homopolysaccharides. Exemplary homopolysaccharides include, but are not limited to, galactomannan gums (such as guar gum), hydroxypropyl guar, and locust bean gum. In some embodiments, the cross-linking agent is locust bean gum or guar gum. In other embodiments, the cross-linking agent is an alginic acid derivative or a hydrocolloid.

In some embodiments, when the sustained release delivery system comprises at least one hydrophilic compound and at least one crosslinking agent, the weight ratio of hydrophilic compound to crosslinking agent is from about 1:9 to about 9:1, from about 1:8 to about 8:1, from about 1:7 to about 7:1, from about 1:6 to about 6:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, or from about 1:2 to about 2: 1. In some embodiments, the weight ratio of hydrophilic compound to crosslinker is about 1:5, about 1:4.5, about 1:4, about 1:3.5, about 1:3, about 1:2.5, about 1:2, about 1:1.5, and about 1:1.

When the sustained release delivery system comprises at least one hydrophilic compound and at least one cross-linking agent, the weight ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sum of the at least one hydrophilic compound and the at least one cross-linking agent is from about 10:1 to about 1:10, from about 9:1 to about 1:9, from about 8:1 to about 1:8, from about 7:1 to about 1:7, from about 6:1 to about 1:6, from about 5:1 to about 1:5, from about 4:1 to about 1:4, from about 3:1 to about 1:3 or from about 2:1 to about 1:2. In some embodiments, the weight ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sum of the at least one hydrophilic compound and the at least one cross-linking agent is from about 4:1 to about 1:1, from about 4:1 to about 1:1.5, from about 3:1 to about 1:1 or from about 2:1 to about 1:1. In one embodiment, the ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sum of the at least one hydrophilic compound and the at least one cross-linking agent is about 5:1, about 4:1 (i.e. 1:0.25), about 3.5:1, about 3:1, about 2.5:1, about 2:1 (i.e. 1:0.5), about 1.9:1, about 1.8:1, about 1.7:1, about 1.6:1, about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1.1:1, about 1:1.5, about 1:2, about 1:3, about 1:4 and about 1: 5.

The sustained release delivery system further comprises one or more pharmaceutical diluents known in the art. Exemplary pharmaceutical diluents include, but are not limited to, monosaccharides, disaccharides, polyols, and mixtures thereof. In some embodiments, the pharmaceutical diluent comprises, for example, starch, mannitol, lactose, dextrose, sucrose, microcrystalline cellulose, sorbitol, xylitol, fructose, and mixtures thereof. In some embodiments, the pharmaceutical diluent is water soluble. Non-limiting examples of water-soluble pharmaceutical diluents include lactose, dextrose, sucrose, or mixtures thereof. The weight ratio of the pharmaceutical diluent to the hydrophilic compound is typically from about 1:9 to about 9:1, from about 1:8 to about 8:1, from about 1:7 to about 7:1, from about 1:6 to about 6:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, or from about 1:2 to about 2: 1. In some embodiments, the weight ratio of the pharmaceutical diluent to the hydrophilic compound is generally from about 9:1 to about 1: 1.5. In some embodiments, the weight ratio of the pharmaceutical diluent to the hydrophilic compound is about 9:1, about 8.75:1, about 8.5:1, about 8.25:1, about 8:1, about 7.5:1, about 7:1, about 6.5:1, about 6:1, about 5.5:1, about 5:1, about 4.5:1, about 4:1, about 3.5:1, about 3:1, about 2.5:1, about 2:1, about 1.5:1, or about 1:1.

Sustained release delivery systems typically comprise one or more pharmaceutical diluents in an amount of about 20% to about 80%, about 30% to about 70%, about 40% to about 70%, or about 40% to about 60%. In one embodiment, the sustained release delivery system comprises one or more pharmaceutical diluents in an amount from about 20% to about 70% by weight. In one embodiment, the sustained release delivery system comprises one or more pharmaceutical diluents in an amount from about 50% to about 85% by weight. In some embodiments, the sustained release delivery system comprises one or more pharmaceutical diluents in an amount of about 55%, about 60%, about 65%, about 70%, about 80%, or about 85% by weight. In one embodiment, the sustained release delivery system comprises one or more drug diluents in an amount of about 20% by weight. In one embodiment, the sustained release delivery system comprises one or more drug diluents in an amount of about 30% by weight. In one embodiment, the sustained release delivery system comprises one or more drug diluents in an amount of about 40% by weight. In one embodiment, the sustained release delivery system comprises one or more drug diluents in an amount of about 50% by weight. In one embodiment, the sustained release delivery system comprises one or more drug diluents in an amount of about 60% by weight. In one embodiment, the sustained release delivery system comprises one or more drug diluents in an amount of about 70% by weight.

In another aspect, the sustained release delivery system comprises one or more cationic crosslinking compounds. In some embodiments, the one or more cationic crosslinking compounds are used in place of the crosslinking agent. In some embodiments, one or more cationic crosslinking compounds are used in addition to the crosslinking agent. In one embodiment, the one or more cationic cross-linking compounds are used in an amount sufficient to cross-link the hydrophilic compound in the presence of a liquid to form a gel matrix. In some embodiments, the one or more cationic cross-linking compounds are present in the sustained release delivery system in the following amounts: from about 0.5 wt% to about 30 wt%, from about 0.5 wt% to about 25 wt%, from about 0.5 wt% to about 20 wt%, from about 0.5 wt% to about 15 wt%, from about 0.5 wt% to about 10 wt%, or from about 0.5 wt% to about 5 wt%. In some embodiments, the one or more cationic cross-linking compounds are present in the sustained release delivery system in the following amounts: about 5 wt% to about 20 wt%, about 5 wt% to about 15 wt%, about 6 wt% to about 14 wt%, about 7 wt% to about 13 wt%, about 8 wt% to about 12 wt%, or about 9 wt% to about 11 wt%. In some embodiments, the one or more cationic cross-linking compounds are present in the sustained release delivery system in the following amounts: about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, or about 15 wt%. In one embodiment, the cationic crosslinking compound is present in the sustained release delivery system in an amount of about 10% by weight.

Exemplary cationic crosslinking compounds include, but are not limited to, monovalent metal cations, polyvalent metal cations, and inorganic salts including alkali and/or alkaline earth metal sulfates, chlorides, borates, bromides, citrates, acetates, lactates, and mixtures thereof. For example, the cationic crosslinking compound includes, but is not limited to, one or more of calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate, sodium fluoride, or mixtures thereof.

When the sustained release delivery system comprises at least one hydrophilic compound and at least one cationic crosslinking compound, the weight ratio of hydrophilic compound to cationic crosslinking compound ranges from about 1:9 to about 9:1, from about 1:8 to about 8:1, from about 1:7 to about 7:1, from about 1:6 to about 6:1, from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, or from about 1:2 to about 2: 1. In one embodiment, the weight ratio of hydrophilic compound to cationic crosslinking compound ranges from about 1:3 to about 3: 1. In some embodiments, the weight ratio of hydrophilic compound to cationic crosslinking compound is about 3:1, about 2.75:1, about 2.5:1, about 2.25:1, about 2:1, about 1.8:1, about 1.6:1, about 1.4:1, about 1.2:1, about 1:1.25, about 1:1.5, or about 1:2. In one embodiment, the weight ratio of hydrophilic compound to cationic crosslinking compound is about 1: 1.25. In one embodiment, the weight ratio of hydrophilic compound to cationic crosslinking compound is about 1.2: 1. In one embodiment, the weight ratio of hydrophilic compound to cationic crosslinking compound is about 2: 1. In one embodiment, the weight ratio of hydrophilic compound to cationic crosslinking compound is about 2.8: 1.

In one embodiment, the at least one hydrophilic compound is present in the sustained release delivery system in an amount from about 5% to about 80% by weight; the at least one cationic crosslinking agent is present in the sustained release delivery system in an amount from about 0.5 wt.% to about 30 wt.%; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount from about 20% to about 80% by weight. In another embodiment, the at least one hydrophilic compound is present in the sustained release delivery system in an amount from about 8% to about 30% by weight; the at least one cationic crosslinking agent is present in the sustained release delivery system in an amount of about 10% by weight; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount from about 20% to about 70% by weight. In another embodiment, the at least one hydrophilic compound is present in the sustained release delivery system in an amount from about 5% to about 30% by weight; the at least one cationic crosslinking agent is present in the sustained release delivery system in an amount from about 5% to about 20% by weight; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount from about 20% to about 85% by weight. In another embodiment, the at least one hydrophilic compound is present in the sustained release delivery system in an amount from about 10% to about 20% by weight; the at least one cationic crosslinking agent is present in the sustained release delivery system in an amount from about 5% to about 15% by weight; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount from about 50% to about 85% by weight.

In some embodiments, the at least one hydrophilic compound is present in the sustained release delivery system in an amount of: about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 22 wt%, about 24 wt%, about 26 wt%, about 28 wt%, or about 30 wt% is present in the sustained release delivery system; the at least one cationic crosslinking agent is present in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, or about 20 wt%; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount of: about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 80 wt%, or about 85 wt%. In one embodiment, the at least one hydrophilic compound is present in the sustained release delivery system in an amount of: present in the sustained release delivery system in an amount of about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, or about 20 wt.%; the at least one cationic crosslinking agent is present in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount of: about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 80 wt%, or about 85 wt%. In one embodiment, the at least one hydrophilic compound is present in the sustained release delivery system in an amount of about 8 wt.%, about 12 wt.%, or about 20 wt.%; the at least one cationic crosslinking agent is present in the sustained release delivery system in an amount of about 10 wt.%, about 12 wt.%, or about 14 wt.%; and the at least one pharmaceutical diluent is present in the sustained release delivery system in an amount of about 40 wt.%, about 60 wt.%, or about 70 wt.%.

In one embodiment, the sustained release delivery system comprises from about 0.5% to about 80% locust bean gum, from about 5% to about 80% xanthan gum, from about 20% to about 80% mannitol, and from about 0.5% to 80% calcium sulfate dihydrate. In one embodiment, the sustained release delivery system comprises from about 12% to about 47% locust bean gum, from about 8% to about 31% xanthan gum, from about 20% to about 78% mannitol, and from about 0.5% to 25% calcium sulfate dihydrate. In one embodiment, the sustained release delivery system comprises from about 15% to about 25% locust bean gum, from about 10% to about 20% xanthan gum, from about 50% to about 85% mannitol, and from about 5% to 15% calcium sulfate dihydrate. In one embodiment, the sustained release delivery system comprises about 18% locust bean gum, about 12% xanthan gum, about 60% mannitol, and about 10% calcium sulfate dihydrate. In one embodiment, the sustained release delivery system comprises about 12% locust bean gum, about 8% xanthan gum, about 70% mannitol, and about 10% calcium sulfate dihydrate. In one embodiment, the sustained release delivery system comprises about 20% locust bean gum, about 30% xanthan gum, about 40% mannitol, and about 10% calcium sulfate dihydrate. In one embodiment, the sustained release delivery system comprises about 30% locust bean gum, about 20% xanthan gum, about 40% mannitol, and about 10% calcium sulfate dihydrate. In one embodiment, the sustained release delivery system comprises about 42% locust bean gum, about 28% xanthan gum, about 20% mannitol, and about 10% calcium sulfate dihydrate.

Two characteristics of the components of this sustained release system (e.g., the at least one hydrophilic compound and the at least one cross-linking agent; or the at least one hydrophilic compound and the at least one cationic cross-linking compound) are their ability to form a gel matrix upon exposure to liquid, i.e., rapid hydration of the compounds/agents and formation of a gel matrix with high gel strength. Both of these properties are desirable to achieve a slow release gel matrix that is maximized by the particular compound combination (e.g., the at least one hydrophilic compound and the at least one crosslinking agent; or the at least one hydrophilic compound and the at least one cationic crosslinking compound). For example, hydrophilic compounds (e.g., xanthan gum) have excellent water absorption characteristics, which provide rapid hydration. The combination of the hydrophilic compound and a material capable of crosslinking the rigid helical ordered structure of the hydrophilic compound (e.g., a crosslinker and/or a cationic crosslinking compound) thus acts synergistically to provide a higher than expected gel matrix viscosity (i.e., high gel strength).

In some embodiments, the sustained release composition is further mixed with one or more wetting agents (e.g., polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, polyethoxylated fatty acids from hydrogenated castor oil), one or more lubricants (e.g., magnesium stearate, sodium stearyl fumarate, etc.), one or more buffering agents, one or more coloring agents, and/or other conventional ingredients.

In some embodiments, the compositions used in the methods of the invention may comprise additional pharmaceutical excipients. For example, in some embodiments, fumaric acid may be added to the formulations described herein.

In other embodiments, non-functional coatings may be applied, for exampleTo the compositions described herein.

In some embodiments, the compositions described herein further comprise a second hydrophilic compound. In some embodiments, the second hydrophilic compound is a cellulose ether. In some embodiments, the second hydrophilic compound is a hydroxyalkyl cellulose or a carboxyalkyl cellulose. In some embodiments, the second hydrophilic compound is hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, or a mixture thereof. In some embodiments, the second hydrophilic species is ethyl cellulose or a wax (e.g., including but not limited to cetyl alcohol, stearyl alcohol, white wax, or carnauba wax). The second hydrophilic compound is present in the formulation in an amount ranging from about 5% to about 45%, from about 5% to about 25%, from about 10% to about 20%, or from 12% to about 18% by weight. In some embodiments, the second hydrophilic compound is present in the formulation in an amount of: about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 30%, about 35%, about 40%, or about 45%.

In some embodiments, the weight ratio of the second hydrophilic compound to nalbuphine or a pharmaceutically acceptable salt, solvate or ester ranges from about 5:1 to about 1:5, from about 4:1 to about 1:4, from about 3:1 to about 1:3, from about 2:1 to about 1:2, from about 1:1 to about 1:3 or from about 1:1 to about 1:2. In some embodiments, the weight ratio of the second hydrophilic compound to nalbuphine or a pharmaceutically acceptable salt, solvate or ester is about 5:1, about 4:1, about 3:1, about 2:1, about 1:2, about 1:3, about 1:4 or about 1: 5.

In some embodiments, the weight ratio of the second hydrophilic compound to the sustained release delivery system ranges from about 10:1 to about 1:10, from about 8:1 to about 1:8, from about 6:1 to about 1:6, from about 4:1 to about 1:4, from about 2:1 to about 1:3, from about 1:1 to about 1:10, from about 1:1 to about 1:6, or from about 1:2 to about 1: 6. In some embodiments, the weight ratio of the second hydrophilic compound to the sustained release delivery system is about 10:1, about 8:1, about 6:1, about 4:1, about 2:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1: 10.

In some embodiments, the oral sustained release solid dosage formulation comprises about 1mg to 200mg of nalbuphine hydrochloride and about 10mg to about 420mg of a sustained release delivery system. In these embodiments, the sustained release delivery system comprises from about 12% to about 42% locust bean gum; about 8.0% to about 28% xanthan gum; about 20% to about 70% mannitol; and from about 5% to about 20% calcium sulfate dihydrate. In some embodiments, the methods of the present invention may employ oral sustained release solid dosage formulations comprising from about 5mg to about 80mg of nalbuphine hydrochloride and from about 80mg to about 360mg of a sustained release delivery system. In some embodiments, the methods of the present invention may employ oral sustained release solid dosage formulations comprising from about 50mg to about 150mg of nalbuphine hydrochloride and from about 100mg to about 300mg of a sustained release delivery system.

In some embodiments, the methods of the present invention use oral sustained release solid dosage formulations comprising about 15mg of nalbuphine hydrochloride and from about 25mg to about 225mg (e.g., about 195mg) of a sustained release delivery system. In these embodiments, the sustained release delivery system comprises about 14% locust bean gum; about 9% xanthan gum; about 47% mannitol; and about 8% calcium sulfate dihydrate.

In some embodiments, the methods of the present invention use oral sustained release solid dosage formulations comprising about 30mg of nalbuphine hydrochloride and from about 25mg to about 225mg (e.g., about 180mg) of a sustained release delivery system. In these embodiments, the sustained release delivery system comprises about 18% locust bean gum; about 12% xanthan gum; about 60% mannitol; and about 10% calcium sulfate dihydrate.

In some embodiments, the methods of the present invention use oral sustained release solid dosage formulations comprising about 60mg of nalbuphine hydrochloride and from about 25mg to about 225mg (e.g., about 120mg) of a sustained release delivery system. In these embodiments, the sustained release delivery system comprises about 10% locust bean gum; about 12% xanthan gum; about 60% mannitol; and about 10% calcium sulfate dihydrate. In some embodiments, the methods of the present invention use oral sustained release solid dosage formulations comprising from about 5mg to about 80mg of nalbuphine hydrochloride and from about 80mg to about 360mg of a sustained release delivery system.

In some embodiments, the methods of the present invention use oral sustained release solid dosage formulations comprising about 120mg of nalbuphine hydrochloride and from about 25mg to about 250mg (e.g., about 240mg) of a sustained release delivery system. In these embodiments, the sustained release delivery system comprises about 18% locust bean gum; about 12% xanthan gum; about 60% mannitol; and about 10% calcium sulfate dihydrate.

In some embodiments, the methods of the invention use oral sustained release solid dosage formulations comprising about 30mg of nalbuphine hydrochloride and from about 25mg to about 350mg (e.g., about 270mg) or about 360mg of a sustained release delivery system. In these embodiments, the sustained release delivery system comprises about 18% locust bean gum; about 12% xanthan gum; about 60% mannitol; and about 10% calcium sulfate dihydrate.

In some embodiments, the methods of the present invention use oral sustained release solid dosage formulations comprising from about 45mg to about 60mg of nalbuphine hydrochloride and from about 100mg to about 200mg of a sustained release delivery system. In these embodiments, the sustained release delivery system comprises from about 15% to about 25% locust bean gum; about 10% to about 20% xanthan gum; about 50% to about 85% mannitol; and from about 5% to about 15% calcium sulfate dihydrate.

In some embodiments, the methods of the present invention use an oral sustained release solid dosage formulation comprising about 30mg of nalbuphine hydrochloride, about 32.4mg of locust bean gum; about 21.6mg xanthan gum; about 108mg mannitol; about 18mg calcium sulfate dihydrate, about 35mg hydroxypropyl cellulose, and about 1.9mg magnesium stearate.

In some embodiments, the methods of the present invention use an oral sustained release solid dosage formulation comprising about 29.8mg nalbuphine hydrochloride, about 32.2mg locust bean gum; about 21.4mg xanthan gum; about 107mg mannitol; about 18mg calcium sulfate dihydrate, about 35mg hydroxypropyl cellulose, and about 1.9mg magnesium stearate.

In some embodiments, the methods of the present invention use an oral sustained release solid dosage formulation comprising about 60mg of nalbuphine hydrochloride, about 21.6mg of locust bean gum; about 14.4mg xanthan gum; about 72mg mannitol; about 12mg calcium sulfate dihydrate, about 30mg hydroxypropyl cellulose, and about 1.6mg magnesium stearate.

In some embodiments, the methods of the present invention use an oral sustained release solid dosage formulation comprising about 59.5mg nalbuphine hydrochloride, about 21.4mg locust bean gum; about 14.3mg xanthan gum; about 71mg mannitol; about 12mg calcium sulfate dihydrate, about 30mg hydroxypropyl cellulose, and about 1.6mg magnesium stearate.

In some embodiments, the methods of the present invention use an oral sustained release solid dosage formulation comprising about 120mg of nalbuphine hydrochloride, about 43.2mg of locust bean gum; about 28.8mg xanthan gum; about 144mg mannitol; about 24mg calcium sulfate dihydrate, about 60mg hydroxypropyl cellulose, and about 3.2mg magnesium stearate.

In some embodiments, the methods of the present invention use an oral sustained release solid dosage formulation comprising about 119.0mg nalbuphine hydrochloride, about 42.9mg locust bean gum; about 25.6mg xanthan gum; about 143mg of mannitol; about 24mg calcium sulfate dihydrate, about 60mg hydroxypropyl cellulose, and about 3mg magnesium stearate.

In some embodiments, the methods of the present invention use an oral sustained release solid dosage formulation comprising about 180mg of nalbuphine hydrochloride, about 64.8mg of locust bean gum; about 43.2mg xanthan gum; about 216mg mannitol; about 36mg calcium sulfate dihydrate, about 90mg hydroxypropyl cellulose, about 5mg magnesium stearate, and about 25mg fumaric acid.

In some embodiments, the methods of the present invention use an oral sustained release solid dosage formulation comprising about 180mg of nalbuphine hydrochloride, about 48.6mg of locust bean gum; about 32.4mg xanthan gum; about 162mg mannitol; about 27mg calcium sulfate dihydrate, about 60mg hydroxypropyl cellulose, about 4mg magnesium stearate, and about 25mg fumaric acid.

In some embodiments, the methods of the present invention use an oral sustained release solid dosage formulation comprising about 30mg of nalbuphine hydrochloride, about 32.4mg of locust bean gum; about 21.6mg xanthan gum; about 108mg mannitol; about 18mg calcium sulfate dihydrate, about 35mg hydroxypropyl cellulose, about 1.9mg magnesium stearate, and about 7.4mg Opadry II White.

In some embodiments, the methods of the present invention use an oral sustained release solid dosage formulation comprising about 178.5mg nalbuphine hydrochloride, about 48.2mg locust bean gum; about 32.2mg xanthan gum; about 161mg mannitol; about 27mg calcium sulfate dihydrate, about 60mg hydroxypropyl cellulose, about 4mg magnesium stearate, and about 25mg fumaric acid.

The sustained release formulation of nalbuphine is a solid dosage formulation that can be administered orally. Non-limiting examples of oral solid dose formulations include tablets, capsules comprising a plurality of particles, sublingual tablets, powders, granules, syrups, and buccal dosage forms or devices (e.g., buccal patches, tablets, etc.). In some embodiments, the tablets have an enteric coating or a hydrophilic coating.

The sustained release delivery system is prepared by dry granulation or wet granulation, followed by addition of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof, although the components may be held together by agglomeration techniques to produce an acceptable product. In wet granulation techniques, the components (e.g., hydrophilic compound, cross-linking agent, pharmaceutical diluent, cationic cross-linking compound, hydrophobic polymer, etc.) are mixed together and then wetted with one or more liquids (e.g., water, propylene glycol, glycerol, alcohol) to produce a wetted material, followed by drying. The dried material is then ground into particles of a sustained release delivery system using conventional equipment. Thereafter, the sustained release delivery system is mixed in the required amount with nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof, and optionally one or more wetting agents, one or more lubricants, one or more buffers, one or more colorants, one or more second hydrophilic compounds or other conventional ingredients to produce a particulate composition. The sustained release delivery system and the nalbuphine may be blended together using, for example, a high shear mixer. The nalbuphine is preferably finely and homogeneously dispersed in the sustained release delivery system. The particulate composition is compressed in a conventional production scale tablet press at typical compression pressures (i.e., about 2,000-16,000psi) in an amount sufficient to make a uniform batch of tablets. In some embodiments, the mixture should not be compressed to a degree that is subsequently difficult to hydrate upon exposure to liquid.

In some embodiments, the nalbuphine formulation is prepared by dry granulation or wet granulation. Adding a component of a sustained release delivery system and nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof. Alternatively, all components may be held together by agglomeration techniques to produce an acceptable product. In wet granulation techniques, nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof and the components (e.g. hydrophilic compound, cross-linking agent, pharmaceutical diluent, cationic cross-linking compound, hydrophobic polymer, etc.) are mixed together and then wetted with one or more liquids (e.g. water, propylene glycol, glycerol, alcohol) to produce a wetted material, followed by drying. The dried material is then ground into granules using conventional equipment. Optionally, one or more wetting agents, one or more lubricants, one or more buffering agents, one or more colorants, one or more second hydrophilic compounds, or other conventional ingredients are also added to the granulation. The particulate composition is compressed in a conventional production scale tablet press at typical compression pressures (i.e., about 2,000-16,000psi) in an amount sufficient to make a uniform batch of tablets. In some embodiments, the mixture should not be compressed to a degree that is subsequently difficult to hydrate upon exposure to liquid.

The particulate composition has an average particle size of about 50 μm to about 400 μm by weight. In some embodiments, the average particle size by weight is from about 185 μm to about 265 μm. The particulate composition has an average density of about 0.3g/mL to about 0.8 g/mL. In some embodiments, the average density is about 0.5g/mL to about 0.7 g/mL. Tablets formed from the granulation generally have a hardness of about 4Kp to about 22 Kp. The mean flow rate of the granulation is from about 25 to about 40 g/s.

In some embodiments, the present methods may employ a multilayer solid dosage form wherein the layers are formulated to release nalbuphine hydrochloride at different rates. For example, in one embodiment, the second layer is an extended release layer comprising nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof and a sustained release delivery system designed to release the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof at a controlled rate so as to maintain therapeutically effective blood levels for an extended period of time (e.g., from about 8 hours to about 12 hours). The first layer is an immediate release layer comprising a formulation of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof, designed to release the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof at a faster rate than the rate of the second layer to reach therapeutically effective blood levels over an immediate period of time (e.g. from about 1 hour to about 2 hours). In some embodiments, the first layer comprises a sustained release delivery system. In some embodiments, the first layer does not comprise a sustained release delivery system.

In some embodiments, the weight ratio of the second layer to the first layer is from about 10:1 to about 1:10, from about 9:1 to about 1:9, from about 8:1 to about 1:8, from about 7:1 to about 1:7, from about 6:1 to about 1:6, from about 5:1 to about 1:5, from about 4:1 to about 1:4, from about 3:1 to about 1:3, from about 2:1 to about 1:2. In one embodiment, the weight ratio of the second layer to the first layer is from about 5:1 to about 1: 5. In another embodiment, the weight ratio of the second layer to the first layer is from about 1:1 to about 1:2. In some embodiments, the weight ratio of the second layer to the first layer is about 1:1, about 1:1.2, about 1:1.4, about 1:1.6, about 1:1.8, or about 1:2. In one embodiment, the weight ratio of the second layer to the first layer is about 1:2. In one embodiment, the weight ratio of the second layer to the first layer is about 1: 1.4. In some embodiments, the weight ratio of the second layer to the first layer is about 3:1, about 2.5:1, about 2:1, about 1.5: 1. In one embodiment, the weight ratio of the second layer to the first layer is about 2.5: 1.

A sustained release delivery system for a multi-layered dosage form comprising: (i) at least one hydrophilic compound, at least one cross-linking agent, and at least one pharmaceutical diluent; (ii) at least one hydrophilic compound, at least one cross-linking agent, at least one pharmaceutical diluent, and at least one cationic cross-linking agent different from the first cross-linking agent; or (iii) at least one hydrophilic compound, at least one cationic cross-linking compound and at least one pharmaceutical diluent. In some embodiments, when the first layer comprises a sustained release delivery system, the sustained release delivery system of the first layer comprises the same components as the sustained release delivery system of the second layer (e.g., both the first and second layers are one of embodiments (i) - (iii) listed above). In other embodiments, the sustained release delivery system of the first layer comprises different components than the sustained release delivery system of the second layer (e.g., the first layer is embodiment (i) listed above and the second layer is embodiment (iii) listed above). It is recognized that the sustained release delivery system of any layer may be one of the embodiments (i) - (iii) listed above. Further, it is recognized that in some embodiments, the first layer does not comprise a sustained release delivery system.

The sustained release delivery system is typically present in the second layer (e.g., extended release layer) in an amount ranging from about 10mg to about 420 mg. In some embodiments, the sustained release delivery system is present in the second layer in an amount ranging from about 110mg to about 200 mg. In some embodiments, the sustained release delivery system is present in the second layer in an amount ranging from about 110mg to about 150 mg. In some embodiments, the sustained release delivery system is present in the second layer in an amount ranging from about 90mg to about 150 mg. In some embodiments, the sustained release delivery system is present in the second layer in the following amounts: about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, or about 200 mg. In one embodiment, the sustained release delivery system is present in the second layer in an amount of about 123 mg. In one embodiment, the sustained release delivery system is present in the second layer in an amount of about 101 mg. In one embodiment, the sustained release delivery system is present in the second layer in an amount of about 92 mg. In another embodiment, the sustained release delivery system is present in the second layer in an amount of about 112.5 mg. In one embodiment, the sustained release delivery system is present in the second layer in an amount of about 135 mg. In one embodiment, the sustained release delivery system is present in the second layer in an amount of about 150 mg.

Nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is typically present in the second layer in an amount in the range of from about 15mg to about 60 mg. In some embodiments, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is present in the second layer in an amount in the range of from about 30mg to about 60 mg. In some embodiments, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is present in the second layer in an amount in the range of from about 45mg to about 60 mg. In one embodiment, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is present in the second layer in an amount of about 15 mg. In one embodiment, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is present in the second layer in an amount of about 30 mg. In one embodiment, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is present in the second layer in an amount of about 45 mg. In one embodiment, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is present in the second layer in an amount of about 15mg, about 30mg, about 60mg, about 90mg, about 120mg or about 180 mg.

In some embodiments, the weight ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system in the second layer is from about 10:1 to about 1:10, from about 9:1 to about 1:9, from about 8:1 to about 1:8, from about 7:1 to about 1:7, from about 6:1 to about 1:6, from about 5:1 to about 1:5, from about 4:1 to about 1:4, from about 3:1 to about 1:3 or from about 2:1 to about 1:2. In one embodiment, the weight ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system in the second layer is from about 1:2 to about 1:4. In one embodiment, the weight ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system in the second layer is from about 1:1 to about 1: 5. In some embodiments, the weight ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system in the second layer is about 1:1, about 1:1.2, about 1:1.4, about 1:1.6, about 1:1.8, about 1:2, about 1:2.5, about 1:3 or about 1: 3.5. In one embodiment, the weight ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system in the second layer is about 1: 2.5. In another embodiment, the weight ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system in the second layer is about 1: 3.3. In another embodiment, the weight ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system in the second layer is about 1:3. In yet another embodiment, the ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to sustained release delivery system in the second layer is about 1:2.

When present in the first layer (e.g., immediate release layer), the sustained release delivery system is typically present in an amount ranging from about 0mg to about 50 mg. In some embodiments, the sustained release delivery system is present in the first layer in an amount ranging from about 5mg to about 25mg or from about 5mg to about 15 mg. In one embodiment, the sustained release delivery system is present in the first layer in an amount from about 3mg to about 9 mg. In one embodiment, the sustained release delivery system is present in the first layer in an amount from about 4mg to about 6 mg. In some embodiments, the sustained release delivery system is present in the first layer in the following amounts: about 2mg, about 4mg, about 6mg, about 8mg, about 10mg, about 12mg, about 14mg, about 15mg, about 16mg, about 18mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, or about 50 mg. In one embodiment, the sustained release delivery system is present in the first layer in an amount of about 6 mg.

In some embodiments, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is typically present in the first layer (e.g. immediate release layer) in an amount ranging from about 5mg to about 180 mg. In some embodiments, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is present in the first layer in an amount from about 5mg to about 25mg or from about 10mg to about 20 mg. In some embodiments, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is present in the first layer in an amount of: about 5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, or about 50 mg. In one embodiment, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is present in the first layer in an amount of: about 15mg, about 30mg, about 60mg, about 90mg, about 120mg, or about 180 mg.

In some embodiments, when the first layer comprises a sustained release delivery system, the ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system in the first layer is from about 10:1 to about 1:10, from about 9:1 to about 1:9, from about 8:1 to about 1:8, from about 7:1 to about 1:7, from about 6:1 to about 1:6, from about 5:1 to about 1:5, from about 4:1 to about 1:4, from about 3:1 to about 1:3, from about 2:1 to about 1:2. In one embodiment, the ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to sustained release delivery system in the first layer is from about 2:1 to about 4: 1. In some embodiments, the ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to the sustained release delivery system in the first layer is about 5:1, about 4.5:1, about 4:1, about 3.5:1, about 3:1, about 2.5:1, about 2:1, about 1.5:1 or about 1:1. In one embodiment, the ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to sustained release delivery system in the first layer is about 2.5: 1. In another embodiment, the ratio of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof to sustained release delivery system in the first layer is about 3: 1.

In some embodiments, the multilayer dosage form further comprises a pharmaceutical disintegrant. The disintegrant facilitates dissolution and absorption of the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof from the immediate release layer. Non-limiting examples of pharmaceutical disintegrants include croscarmellose sodium, starch glycolate, crospovidone, and unmodified starch. In one embodiment, the disintegrant is in the first layer (i.e., the immediate release layer) of the dosage form. The disintegrant is typically present in the layer in an amount of about 1.5mg to about 4.5 mg. In one embodiment, the disintegrant is present in an amount of about 3 mg. In one embodiment, the disintegrant is present in the layer in an amount of about 2-10% by weight. In one embodiment, the disintegrant is present in the layer in an amount of about 5% by weight. When the layer comprises a sustained release delivery system, the weight ratio of sustained release delivery system to disintegrant is in the range of about 5:1 to about 1: 5. In some embodiments, the ratio of sustained release delivery system to disintegrant is in the range of about 1:1 to about 3: 1. In other embodiments, the ratio of sustained release delivery system to disintegrant is in the range of about 2: 1.

In some embodiments, the multilayer tablet is prepared by first separately preparing an immediate release layer and an extended release layer blend. The extended release layer was prepared as described above. The wet granulation of the extended release layer is then dried and milled to the appropriate size. Magnesium stearate is added and mixed with the milled granulation. The immediate release layer is prepared by first mixing nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof with one or more diluents (e.g. microcrystalline cellulose). This mixture is then optionally mixed with one or more disintegrants. The blend was mixed with magnesium stearate. Finally, the immediate release layer blend and extended release layer blend are compressed into a multilayer (e.g., bilayer) tablet.

In some embodiments, the chemical nature of certain components of the formulation, such as hydrophilic compounds (e.g., xanthan gum), is such that said components are considered self-buffering agents that are substantially insensitive to the solubility of nalbuphine and pH changes along the length of the gastrointestinal tract. Furthermore, the chemistry of the components is believed to be similar to certain known mucoadhesive substances, such as polycarbophil (polycarbophil). Mucoadhesive properties are desirable for buccal delivery systems. Thus, the sustained release formulation may interact loosely with mucin in the gastrointestinal tract, providing another way in which a constant delivery rate of nalbuphine may be achieved.

The phenomenon discussed above (mucoadhesive properties) is a mechanism by which sustained release formulations can interact with mucins and fluids of the gastrointestinal tract and provide a constant rate of delivery of nalbuphine.

Sustained release formulations used in the methods of the invention typically exhibit an in vitro dissolution of about 15 to about 50% by weight of nalbuphine after 1 hour, an in vitro dissolution of about 45 to about 80% by weight of nalbuphine after 4 hours or an in vitro dissolution of at least about 80% by weight of nalbuphine after 10 hours, as measured by USP procedure total chapter of drug release <711> dissolution, which is incorporated herein by reference in its entirety. In some embodiments, the in vitro and in vivo release characteristics of the sustained release formulation are modified using a mixture of one or more different water insoluble and/or water soluble compounds, using different plasticizers, varying the thickness of the sustained release film (including providing a release modifying compound in the coating), and/or by providing channels through the coating. In some embodiments, the dissolution rate is determined using apparatus USP type III/250 mL at pH 6.8, 37 ℃ and 15 dpm. In some embodiments, the dissolution rate is determined using a device USP type III/250 mL operating at 37 ℃ and 15dpm in a pH change (0-1 hour pH 1.2, pH 4.5 after 1 hour, pH 6.8 after 2 hours).

In some embodiments, the sustained release formulation has an in vitro dissolution of about 50% to about 100% by weight nalbuphine after about 6 hours. In some embodiments, the sustained release formulation has an in vitro dissolution rate of about 75% to about 100% by weight nalbuphine after about 6 hours. In other embodiments, the sustained release formulation has an in vitro dissolution of about 75% to about 100% by weight nalbuphine over about 6 hours to about 8 hours. In other embodiments, the sustained release formulation has an in vitro dissolution of about 80% to about 100% by weight nalbuphine after about 12 hours. In other embodiments, the sustained release formulation has an in vitro dissolution of about 80% to about 100% by weight of nalbuphine over about 12 hours to about 24 hours. In some embodiments, the sustained release formulation has an in vitro dissolution rate of about 80% to about 100% after about 8 hours to about 12 hours. In yet other embodiments, the sustained release formulation has an in vitro dissolution of about 15% to about 75% by weight of nalbuphine after about 1 hour. In further embodiments, the sustained release formulation has an in vitro dissolution of about 50% by weight nalbuphine after about 1 hour. In some embodiments, the sustained release formulation has an in vitro dissolution of about 50% by weight nalbuphine after about 1 hour and an in vitro dissolution of about 75% to about 100% by weight nalbuphine after about 6 hours to about 8 hours. In some embodiments, the sustained release formulation has an in vitro dissolution of about 50% by weight nalbuphine after about 1 hour and an in vitro dissolution of about 75% to about 100% by weight nalbuphine after about 8 hours to about 12 hours. In some embodiments, the sustained release formulation has an in vitro dissolution of about 50% by weight nalbuphine after about 1 hour and an in vitro dissolution of about 75% to about 100% by weight nalbuphine after about 12 hours to about 24 hours. In some embodiments, the sustained release formulation has an in vitro dissolution of about 50% by weight nalbuphine after about 1 hour and an in vitro dissolution of about 80% to about 100% by weight nalbuphine after about 12 hours.

When the tablet is a multi-layered dosage form having a first extended release layer and a second immediate release layer, the sustained release formulation has an in vitro dissolution of about 25% to about 75% by weight of nalbuphine after about 1 hour. In some embodiments, the multi-layered dosage form has an in vitro dissolution of about 25% nalbuphine by weight after about 1 hour. In some embodiments, the multi-layered dosage form has an in vitro dissolution of about 50% by weight nalbuphine after about 1 hour. In some embodiments, the multi-layered dosage form has an in vitro dissolution of about 75% to about 100% nalbuphine after about 6-8 hours. In some embodiments, the multi-layered dosage form has an in vitro dissolution of about 75% to about 100% nalbuphine after about 8-12 hours. In some embodiments, the multi-layered dosage form has an in vitro dissolution of about 75% to about 100% nalbuphine after about 12-24 hours. In some embodiments, the multi-layered dosage form has an in vitro dissolution of about 75% to about 100% nalbuphine after about 12 hours.

In some embodiments, the sustained release formulations described herein exhibit the following in vivo properties when administered orally to a patient having normal or impaired (e.g., reduced) renal function: (a) peak plasma levels of nalbuphine occur within about 4 to about 6 hours after administration, e.g. for patients with uremic pruritus or renal impairment, or within about 3 to about 5 hours, e.g. for patients without renal impairment; (b) the onset of the antipruritic effect of nalbuphine is within about 30 minutes to about 6 hours of administration; (c) the duration of the antipruritic effect of nalbuphine is from about 2 hours to about 24 hours; and (d) the relative bioavailability of nalbuphine compared to an aqueous solution of nalbuphine for oral administration is about 0.5, about 1, about 1.5 or between about 0.5 and about 1.5. The time to onset of the antipruritic effect may depend at least on the administration and the severity of the pruritus symptoms. In some embodiments, the duration of the antipruritic effect of nalbuphine is at least about 8 hours. In some embodiments, the duration of the antipruritic effect of nalbuphine is at least about 9 hours. In some embodiments, the duration of the antipruritic effect of nalbuphine is at least about 10 hours. In some embodiments, the duration of the antipruritic effect of nalbuphine is at least about 11 hours. In some embodiments, the duration of the antipruritic effect of nalbuphine is at least about 12 hours. In some embodiments, the duration of the anti-pruritic effect of nalbuphine is about 6 hours, 8 hours, 10 hours, 12 hours, 15 hours or 18 hours. In some embodiments, the relative bioavailability of nalbuphine compared to an aqueous solution of nalbuphine administered orally is about 0.94. In some embodiments, the relative bioavailability of nalbuphine compared to an aqueous solution of nalbuphine administered orally is about 1.35.

In some embodiments, the sustained release nalbuphine formulation provides an oral unit dosage form comprising nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof. The oral dosage form provides antipruritic effect over a period of at least about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the oral dosage form provides antipruritic effect over a period of about 6-18 hours, about 8-16 hours, about 8-12 hours, about 8 hours to about 24 hours, about 12 hours to about 24 hours, about 18 hours to about 24 hours, or about 8-10 hours. The oral dosage form provides antipruritic effect over a period of about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours.

In one embodiment, the oral dosage form provides antipruritic effects as well as cycle-breaking effects, e.g., after a certain period of treatment, the feeling of itch is no longer restored.

In some embodiments, the oral dosage form provides plasma levels of nalbuphine characterized by one or more peaks followed by plateau regions. The plateau region is characterized by its relatively consistent nalbuphine plasma levels (e.g., the plasma levels of nalbuphine do not rise or fall consistently between different time points). In some embodiments, the plateau regions are characterized by having a consistent average plasma level of nalbuphine. The plateau region is in contrast to the region behind the plateau region, where the plasma levels of nalbuphine typically decrease from one time point to the next. In some embodiments, the plateau region has a duration of at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours. In some embodiments, the duration of the plateau region is from about 1 hour to about 12 hours, from about 2 hours to about 10 hours, from about 2 hours to about 8 hours, from about 2 hours to about 7 hours, or from about 4 hours to about 10 hours, from about 4 hours to about 8 hours, or from about 4 hours to about 6 hours. In some embodiments, the nalbuphine plasma level at each time point in the plateau region ranges from about 75% to about 125% of the mean plasma level in the plateau region. In some embodiments, the nalbuphine plasma level at each time point in the plateau region ranges from about 80% to about 120% of the mean plasma level in the plateau region. In some embodiments, the nalbuphine plasma level at each time point in the plateau region ranges from about 85% to about 115% of the mean plasma level in the plateau region. In some embodiments, the nalbuphine plasma level at each time point in the plateau region ranges from about 90% to about 110% of the mean plasma level in the plateau region.

In some embodiments, the lowest plasma level of nalbuphine observed during the plateau region is no more than about 25% below the mean plasma level at all time points in the plateau region. In some embodiments, the lowest plasma level of nalbuphine observed during the plateau region is no more than about 20% lower than the mean plasma level in the plateau region. In some embodiments, the lowest plasma level of nalbuphine observed during the plateau region is no more than about 15% lower than the mean plasma level in the plateau region. In some embodiments, the minimum plasma level of nalbuphine observed during the plateau region ranges from about 75% to about 100% of the mean plasma level in the plateau region. In some embodiments, the minimum plasma level of nalbuphine observed during the plateau region ranges from about 80% to about 100% of the mean plasma level in the plateau region. In some embodiments, the minimum plasma level of nalbuphine observed during the plateau region ranges from about 85% to about 100% of the mean plasma level in the plateau region. In some embodiments, the minimum plasma level of nalbuphine observed during the plateau region ranges from about 80% to about 95% of the mean plasma level in the plateau region.

Synergistic therapy

While the compositions may be administered as the sole active pharmaceutical ingredient or the sole active anti-itch ingredient in the methods described herein, in other embodiments, they may also be used in combination with one or more ingredients known to be therapeutically effective against itch and/or to supplement the effects of anti-itch ingredients.

For example, in some embodiments, the methods of the invention may be used with nalbuphine or a pharmaceutically acceptable salt thereofThe solvate or ester is used in combination with one or more antipruritic agents. In some embodiments, additional compounds in combination with an anti-itch agent, such as nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof, include antihistamines, anti-inflammatory corticosteroids, topical anti-infective and antifungal agents, serotonin antagonists, antibacterial and antiviral agents, cytotoxic agents and anti-irritant/analgesic agents. Other antipruritic agents include antidepressants, vitamin D, kappa agonists, stimulants (such as coal tar derivatives and psoralens), 5-HT3 antagonists (such as ondansetron), H2 receptor antagonists (such as cimetidine), H1 receptor antagonists (such as cetirizine), immunomodulators (such as tacrolimus), immunosuppressants (such as cyclosporin a), mu-antagonists, capsaicin, cannabinoids, latex extracts of the various croton species found in amazonian jungles (e.g., latex extracts of the species croton species found in the amazonian jungle) Fumarate diesters (e.g., monoethylfumarate and dimethylfumarate), or Nk1 antagonists, and the like.

In some embodiments, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is not administered in combination (e.g., co-formulated or administered alone) with the second anti-pruritic agent.

In some embodiments, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is administered in combination with one or more bile chelating agents. In some embodiments, the one or more bile chelating agents are selected from the group consisting of cholestyramine, colestipol, and colesevelam. In some embodiments, the bile chelator is cholestyramine.

In some embodiments, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is administered in combination with one or more pregnane X receptor agonists. In some embodiments, the pregnane X receptor agonist is rifampin.

In some embodiments, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is administered in combination with one or more serotonin reuptake inhibitors. In some embodiments, the serotonin reuptake inhibitor is sertraline.

Administration of drugs

The present invention provides a method for treating pruritus by administering an effective amount of an antipruritic, namely nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof, to a patient in need thereof. An effective amount is an amount sufficient to eliminate or significantly reduce the symptoms of pruritus or alleviate those symptoms (e.g., reduce symptoms such as pruritus as compared to those present prior to treatment). The formulations used in the methods of the invention may incorporate an anti-itch agent into the sustained release formulations such that the formulations provide therapeutically effective plasma levels of nalbuphine to treat itch.

According to some embodiments of the present disclosure, the administration of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof provides a statistically significant therapeutic effect. In one embodiment, the statistically significant therapeutic effect is determined based on one or more standards or guidelines provided by one or more regulatory agencies in the united states (e.g., FDA) or other countries. In another embodiment, the statistically significant therapeutic effect is determined based on results obtained from regulatory approval of clinical trial settings and/or procedures.

In some embodiments, a statistically significant therapeutic effect is determined based on a patient population of at least 20, 50, 60, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 2000. In some embodiments, the statistically significant therapeutic effect is determined based on data obtained from randomized and double-blind clinical trial settings. In some embodiments, a statistically significant therapeutic effect is determined based on data having a p-value less than or equal to about 0.05, 0.04, 0.03, 0.02, or 0.01. In some embodiments, a statistically significant therapeutic effect is determined based on data having a confidence interval greater than or equal to 95%, 96%, 97%, 98%, or 99%. In some embodiments, a statistically significant therapeutic effect is determined after approval (e.g., the us FDA) of a phase III clinical trial of the methods provided by the present disclosure.

In some embodiments, the statistically significant therapeutic effect is determined by a randomized, double-blind clinical trial on patients treated with nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof, optionally in combination with standard of care. In some embodiments, a statistically significant therapeutic effect is determined by randomized clinical trials and using the Numerical Rating Scale (NRS) as the primary efficacy parameter, optionally in combination with any other generally accepted pruritus assessment criteria.

In general, the statistical analysis may include any suitable method permitted by regulatory agencies (e.g., FDA or europe in the united states or any other country). In some embodiments, the statistical analysis comprises non-hierarchical analysis, log rank analysis (e.g., from Kaplan-Meier, Jacobson-Truax, Gulliken-Lord-Novick, Edwards-Nunnally, Hageman-Arring, and Hierarchical Linear Model (HLM)), and Cox regression analysis.

According to the present disclosure, an antipruritic agent is administered once or twice a day to effectively relieve symptoms of pruritus associated with liver diseases (e.g., pruritus associated with primary sclerosing cholangitis, primary biliary cholangitis, etc.). In some embodiments, the total daily dose is about 15mg, about 30mg, about 60mg, about 90mg, about 120mg, about 180mg, about 240mg, about 360mg, or about 480 mg.

In accordance with the present disclosure, an anti-pruritus agent is administered once or twice daily to effectively alleviate symptoms of pruritus associated with obstructive cholestasis secondary to biliary obstruction caused by non-liver tissue disease (e.g., pruritus associated with pancreatic cancer, pancreatitis, congenital or acquired biliary stenosis, lymph node obstruction (such as from lymphoma), or bile duct stones). In some embodiments, a total daily dose of about 15mg, about 30mg, about 60mg, about 90mg, about 120mg, about 180mg, about 240mg, about 360mg, or about 480mg is administered.

The dosage embodiments described herein refer to the dosage required to treat pruritus associated with liver disease. However, the present disclosure contemplates dosages described herein for treating pruritus associated with obstructive cholestasis secondary to biliary obstruction caused by non-liver tissue disease.

In some embodiments, the total daily dose of the anti-pruritic agent may be at least about 15mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be at least about 30mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be at least about 60mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be at least about 90mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be at least about 120mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be at least about 180mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be at least about 240mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be at least about 360mg per day to treat pruritus associated with liver disease.

In some embodiments, the total daily dose of the anti-pruritic agent may be about 15mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be about 30mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be about 60mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be about 90mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be about 120mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be about 180mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be about 240mg per day to treat pruritus associated with liver disease. In some embodiments, the total daily dose of the anti-pruritic agent may be about 360mg per day to treat pruritus associated with liver disease.

In some embodiments, about 15mg of the anti-pruritic agent once per day is selected to significantly reduce the itch perception in patients with itch associated with liver disease. In some embodiments, about 15mg of the anti-pruritic agent is selected twice daily to significantly reduce the itchy sensation in patients with pruritus associated with liver disease. In some embodiments, about 30mg of the anti-pruritic agent once per day is selected to significantly reduce the itch perception in patients with itch associated with liver disease. In some embodiments, about 30mg of the anti-pruritic agent is selected twice daily to significantly reduce the itchy sensation in patients with pruritus associated with liver disease. In some embodiments, about 60mg of the anti-pruritic agent is selected once daily to significantly reduce the itching sensation in patients with pruritus associated with liver disease. In some embodiments, about 60mg of the anti-pruritic agent is selected twice daily to significantly reduce the itch perception in patients with itch associated with liver disease. In some embodiments, about 90mg of the anti-pruritic agent is selected once daily to significantly reduce the itch perception in patients with itch associated with liver disease. In some embodiments, about 90mg of the anti-pruritic agent is selected twice daily to significantly reduce the itch perception in patients with itch associated with liver disease. In some embodiments, about 120mg of the anti-pruritic agent once per day is selected to significantly reduce the itching sensation in patients with pruritus associated with liver disease. In some embodiments, about 120mg of the anti-pruritic agent twice daily is selected to significantly reduce the itch perception in patients with itch associated with liver disease. In some embodiments, about 180mg of the anti-pruritic agent once per day is selected to significantly reduce the itch perception in patients with itch associated with liver disease. In some embodiments, about 180mg of the anti-pruritic agent twice daily is selected to significantly reduce the itchy sensation in patients with pruritus associated with liver disease. In some embodiments, about 360mg of the anti-pruritic agent once daily is selected to significantly reduce the itch perception in patients with itch associated with liver disease. In some embodiments, about 480mg of the anti-pruritic agent once per day is selected to significantly reduce the itch perception in patients with itch associated with liver disease.

In some embodiments, about 15mg of the anti-pruritic agent is selected once daily to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 15mg of the anti-pruritic agent is selected twice daily to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 30mg of the anti-pruritic agent is selected once daily to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 30mg of the anti-pruritic agent is selected twice daily to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 60mg of the anti-pruritic agent is selected once daily to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 60mg of the anti-pruritic agent is selected twice daily to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 90mg of the anti-pruritic agent is selected once daily to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 90mg of the anti-pruritic agent is selected twice daily to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 120mg of the anti-pruritic agent is selected once daily to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 120mg of the anti-pruritic agent is selected twice daily to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 180mg of the anti-pruritic agent once per day is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 180mg of the anti-pruritic agent twice daily is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 360mg of the anti-pruritic agent once daily is selected to significantly reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 480mg of the anti-pruritic agent once per day is selected to significantly reduce chronic itch in patients with itch associated with liver disease.

In some embodiments, the amount of the anti-pruritic agent administered to a patient in need thereof is in the form of a pharmaceutically acceptable salt and is expressed in terms of equivalents of the nalbuphine free base provided to the patient.

In some embodiments, the equivalent total daily dose of nalbuphine free base may be at least about 14mg per day to treat pruritus associated with liver disease. In some embodiments, the equivalent total daily dose of nalbuphine free base may be at least about 27mg per day to treat pruritus associated with liver disease. In some embodiments, the equivalent total daily dose of nalbuphine free base may be at least about 54mg per day to treat pruritus associated with liver disease. In some embodiments, the equivalent total daily dose of nalbuphine free base may be at least about 81mg per day to treat pruritus associated with liver disease. In some embodiments, the equivalent total daily dose of nalbuphine free base may be at least about 108mg per day to treat pruritus associated with liver disease. In some embodiments, the equivalent total daily dose of nalbuphine free base may be at least about 162mg per day to treat pruritus associated with liver disease. In some embodiments, the equivalent total daily dose of nalbuphine free base may be at least about 216mg per day to treat pruritus associated with liver disease.

In some embodiments, the equivalent total daily dose of nalbuphine free base may be about 14mg per day to treat pruritus associated with liver disease. In some embodiments, the equivalent total daily dose of nalbuphine free base may be about 27mg per day to treat pruritus associated with liver disease. In some embodiments, the equivalent total daily dose of nalbuphine free base may be about 54mg per day to treat pruritus associated with liver disease. In some embodiments, the equivalent total daily dose of nalbuphine free base may be about 81mg per day to treat pruritus associated with liver disease. In some embodiments, the equivalent total daily dose of nalbuphine free base may be about 108mg per day to treat pruritus associated with liver disease. In some embodiments, the equivalent total daily dose of nalbuphine free base may be about 162mg per day to treat pruritus associated with liver disease. In some embodiments, the equivalent total daily dose of nalbuphine free base may be about 216mg per day to treat pruritus associated with liver disease.

In some embodiments, about 14mg equivalents of nalbuphine free base once daily is selected to significantly reduce itch in patients with itch associated with liver disease. In some embodiments, about 14mg equivalents of nalbuphine free base twice daily is selected to significantly reduce itch in patients with itch associated with liver disease. In some embodiments, about 27mg equivalents of nalbuphine free base once daily is selected to significantly reduce itch in patients with itch associated with liver disease. In some embodiments, about 27mg equivalents of nalbuphine free base twice daily is selected to significantly reduce itch in patients with itch associated with liver disease. In some embodiments, about 54mg equivalents of nalbuphine free base once daily is selected to significantly reduce itch in patients with itch associated with liver disease. In some embodiments, about 54mg equivalents of nalbuphine free base twice daily is selected to significantly reduce itch in patients with itch associated with liver disease. In some embodiments, about 81mg equivalents of nalbuphine free base once daily is selected to significantly reduce itch in patients with itch associated with liver disease. In some embodiments, about 81mg equivalents of nalbuphine free base twice daily is selected to significantly reduce itch in patients with itch associated with liver disease. In some embodiments, about 108mg equivalents of nalbuphine free base once daily is selected to significantly reduce itch in patients with itch associated with liver disease. In some embodiments, about 108mg equivalents of nalbuphine free base twice daily is selected to significantly reduce itch in patients with itch associated with liver disease. In some embodiments, about 162mg equivalents of nalbuphine free base once daily is selected to significantly reduce itch in patients with itch associated with liver disease. In some embodiments, about 162mg equivalent of nalbuphine free base twice daily is selected to significantly reduce itch in patients with itch associated with liver disease. In some embodiments, about 216mg equivalents of nalbuphine free base once daily is selected to significantly reduce itch in patients with itch associated with liver disease.

In some embodiments, about 14mg equivalents of nalbuphine free base once daily is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 14mg equivalents of nalbuphine free base twice daily is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 27mg equivalents of nalbuphine free base once daily is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 27mg equivalents of nalbuphine free base twice daily is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 54mg equivalents of nalbuphine free base once daily is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 54mg equivalents of nalbuphine free base twice daily is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, an equivalent amount of nalbuphine free base of about 81mg once daily is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 81mg equivalents of nalbuphine free base twice daily is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 108mg equivalents of nalbuphine free base once daily is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 108mg equivalents of nalbuphine free base twice daily is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 162mg equivalents of nalbuphine free base once daily is selected to reduce chronic itch in patients with itch associated with liver disease. In some embodiments, about 162mg equivalent of nalbuphine free base twice daily is selected to reduce chronic itch in patients with itch associated with liver disease.

Reduction of itch in patients with itch conditions can be determined by various methods. In some embodiments, the effectiveness of a dosage regimen can be determined by evaluating via a visual analog scale of itch (VAS) test, such as the most pruritic VAS. In some embodiments, the effectiveness of a dosage regimen may be determined by assessing via the strongest or average itch intensity Numerical Rating Scale (NRS). In some other embodiments, the clinical outcome may be determined by the clinical outcome of the patient via the strongest or average itch intensity Numerical Rating Scale (NRS), patient global index scale, global physician index scale, patient benefit index-itch version (PBI-P), itch speech rating scale (VRS) score, ItchyQoL^TM(Emory University); http:// emoryott. technologypublisher. com/technictle ═ ItchyQol% 3a _ A _ Pruritus-Specific _ Quality _ of _ Life _ Instrument) or any combination thereof to determine the effectiveness of a dosage regimen. In yet another embodiment, the patient's rated treatment global assessment scale, physician's rated treatment global assessment scale, patient benefit index-itch version (PBI-P), itch speech rating scale (VRS) score, ItchyQoL may be evaluated by using the strongest or average itch intensity NRS as a primary efficacy endpoint and a secondary efficacy endpoint such as the PROMIS sleep disorder profile 8a questionnaire, the PROMIS project library v1.0 fatigue profile 7a scale, the PROMIS project library v1.0 PROMIS sleep disorder-profile 8a questionnaire, the patient's rated treatment global assessment scale, the physician's rated treatment global assessment scale, the patient's benefit index-itch version (PBI-P), the itch^TMThe scale or any combination thereof is evaluated to determine the effectiveness of the dosage regimen.

According to some embodiments of the disclosure, the frequency of administration and the amount of dose of the antipruritic agent per administration are selected to provide a therapeutic effect for treating pruritus associated with obstructive cholestasis secondary to biliary obstruction caused by non-liver tissue disease (e.g., pruritus associated with pancreatic cancer, pancreatitis, congenital or acquired biliary stenosis, lymph node obstruction (such as from lymphoma), or bile duct stones).

According to some embodiments of the present disclosure, the frequency of administration and the amount of dose of the antipruritic agent per administration are selected to provide a therapeutic effect for treating pruritus associated with liver disease (e.g., pruritus associated with primary sclerosing cholangitis, primary biliary cholangitis, etc.).

According to some embodiments of the present disclosure, the dosing frequency and the dose amount of the antipruritic agent per administration are selected to provide a therapeutic effect for treating pruritus associated with a liver disease selected from the group consisting of: cholestatic liver disease, infectious hepatitis; cirrhotic liver disease, drug-induced liver disease, idiopathic portal hypertension, congenital malformations or genetic diseases affecting liver function, sarcoidosis, primary or metastatic liver tumor involvement, and autoimmune hepatitis-cholangitis (overlap syndrome).

According to some embodiments of the disclosure, the frequency of administration and the amount of dose of the anti-pruritic agent per administration are selected to provide a therapeutic effect for treating otherwise therapeutically refractory pruritus associated with liver disease. In some embodiments, the frequency of administration and the amount of dose of each administration of the antipruritic are selected to provide a therapeutic effect for treating pruritus associated with liver disease that is refractory to treatment with other antipruritics, refractory to treatment with bile chelators, or refractory to treatment with rifampicin.

In some embodiments, the nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is administered once daily or twice daily for at least one week, e.g., about one week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks, about 18 weeks, about 24 weeks and about 50 weeks.

In some embodiments, at least about 15mg or about 15mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is administered once daily or twice daily for at least one week. In some embodiments, at least about 30mg or about 30mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is administered once daily or twice daily for at least one week. In some embodiments, at least about 60mg or about 60mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is administered once daily or twice daily for at least one week. In some embodiments, at least about 90mg or about 90mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is administered once daily or twice daily for at least one week. In some embodiments, at least about 120mg or about 120mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is administered once daily or twice daily for at least one week. In some embodiments, at least about 180mg or about 180mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is administered once daily or twice daily for at least one week. In some embodiments, at least about 240mg or about 240mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is administered once daily or twice daily for at least one week. In some embodiments, at least about 360mg or about 360mg of nalbuphine or a pharmaceutically acceptable salt, solvate or ester thereof is administered once daily or twice daily for at least one week.

According to some embodiments, the significant reduction in itch provided by the methods of the present disclosure requires a specific time period before the patient experiences a significant reduction in itchTreatment is administered at intervals (e.g., at least one week) (i.e., there is an induction period before the patient experiences a significant reduction in itch). In some embodiments, the patient experiences a significant reduction in itch after at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, or at least eight weeks of treatment as compared to before treatment. In some embodiments, the patient experiences a significant reduction in itch after at least one week of treatment as compared to before treatment. According to this embodiment, a significant reduction in itch can be achieved using any of the methods described herein (e.g., a reduction in the strongest or average itch intensity value rating scale value as compared to pre-treatment, an ItchyQoL as compared to pre-treatment)^TMImproved scale, etc.).

In some embodiments, after treatment, the patient experiences a significant reduction in itch characterized by at least about a 30% reduction in the strongest or average itch intensity Numerical Rating Scale (NRS) value as compared to prior to treatment. In some embodiments, itch reduction is characterized by a decrease in NRS value compared to pre-treatment ranging from about 30% to about 100%, e.g., about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%.

In some embodiments, after treatment, the patient experiences a significant reduction in itch characterized by at least one point decrease in the strongest or average itch intensity Numerical Rating Scale (NRS) value as compared to before treatment. In some embodiments, itch reduction is characterized by a decrease in the NRS value for the strongest or mean itch intensity as compared to before treatment ranging from about one point to about five points, e.g., about one point, about two points, about three points, about four points, and about five points. In some embodiments, itch reduction is characterized by a decrease in the most intense or average itch intensity NRS value by about two points. In some embodiments, itch reduction is characterized by a decrease in the most intense or average itch intensity NRS value by about three points. In some embodiments, itch reduction is characterized by a decrease in the most intense or average itch intensity NRS value by about four points. In some embodiments, itch reduction is characterized by a decrease in the most intense or average itch intensity NRS value by about five points.

In some embodiments, the treatment is followed byPatients experienced significant reduction in itch characterized by ItchyQoL compared to pre-treatment^TMThe improvement in gauge is at least about 10%. In some embodiments, the itch reduction is characterized by ItchyQoL compared to pre-treatment^TMThe scale improvement ranges from about 10% to about 100%, e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%.

In some embodiments, following treatment, the patient experiences a significant reduction in itch characterized by an improvement in sleep characterized by at least one category change in at least one of the 8 questions of the PROMIS project library v1.0 PROMIS sleep disorder-profile 8a questionnaire. In some embodiments, itch reduction is characterized by a range (one unit) of improvement in the total raw score, or any corresponding subtyping, of the PROMIS sleep disorder profile 8a questionnaire compared to pre-treatment.

In some embodiments, after treatment, the patient experiences a significant reduction in itch characterized by reduced fatigue as compared to before treatment, the reduced fatigue characterized by at least one category change in at least one of the 7 questions of the fatigue profile 7a questionnaire of the PROMIS project library v 1.0. In some embodiments, itch reduction is characterized by a range (one unit) of improvement in the total raw score of the PROMIS fatigue profile 7a questionnaire or any corresponding subtyping compared to pre-treatment.

In some embodiments, the patient experiences a significant reduction in scratchy speech rating scale (VRS) score after treatment as compared to before treatment. In some embodiments, itch reduction is characterized by an improvement in itch VRS score compared to pre-treatment ranging from at least one category (or units of change) to about three categories, e.g., about one category, about two categories, and about three categories. In some embodiments, itch reduction is characterized by an improvement in itch VRS score by at least one category (or unit of change). In some embodiments, itch reduction is characterized by an improvement in itch VRS score by at least two categories (or units of change). In some embodiments, itch reduction is characterized by an improvement in itch VRS score by at least three categories (or units of change).

In some embodiments, after treatment, the patient experiences a significant reduction in itch characterized by at least about a 10% improvement in the patient benefit index-itch version (PBI-P) scale compared to prior to treatment. In some embodiments, itch reduction is characterized by an improvement in the patient benefit index-itch version (PBI-P) scale compared to pre-treatment ranging from about 10% to about 100%, e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%.

In some embodiments, the daily dose of the anti-pruritic agent is a once or twice daily dose, and then titrated upward until the patient is satisfied with relief from the pruritic condition. The daily dose may be titrated in increments ranging from about 15mg to about 60mg (e.g., about 15mg, about 30mg, or about 60 mg). The daily dose may be titrated in one or more steps. The daily dose may be titrated by increasing each dose of a single daily dose or a twice daily dosing regimen. The dose amount is stepwise and in case of multiple titration steps may be the same or may be different.

In some embodiments, titration may be initiated with about 15mg, about 30mg, or about 60mg of the anti-pruritus agent once or twice daily. In some embodiments, the dosage may be adjusted in increments of 30mg every 1 to 4 days. The patient can self-titrate to achieve a dose that provides adequate relief from itch and minimizes adverse reactions in about 7 days to about 30 days (e.g., about 12 days to about 20 days). In some embodiments, the titration is performed for at least about one week, about 2 weeks, about 3 weeks, about 4 weeks, or about 5 weeks until a steady state is reached in the patient.

In some embodiments, the patient may be initially provided with 15mg, 30mg, or 60mg tablets for self-titration to achieve up to about 60mg, about 90mg, about 120mg, about 180mg, about 240mg, about 360mg, or about 480mg once or twice daily. In some embodiments, the titration dose is started from about 15mg or about 30mg and then gradually increased to about 60mg or 120mg twice daily, for example for patients with pruritus associated with liver disease. In some embodiments, the titration dose is started from about 15mg or about 30mg and then gradually increased to about 60mg or 120mg once a day, for example for patients with pruritus associated with liver disease. In another embodiment, the titration dose is started from about 15mg or about 30mg and then gradually increased to about 120mg or 240mg twice daily, for example for patients with pruritus associated with liver disease. In another embodiment, the titration dose is started from about 15mg or about 30mg and then gradually increased to about 120mg or 240mg once a day, for example for patients with pruritus associated with liver disease.

In some embodiments, the anti-pruritic agent is nalbuphine and the two week titration is performed according to the dose schedule provided in the following table:

in some embodiments, the anti-pruritic agent is nalbuphine and the two week titration is performed according to the dose schedule provided in the following table:

number of days	AM dose (mg)	PM dose (mg)
			Day 1	0	30
Day 2	0	30
			Day 3	30	30
Day 4	30	30
			Day 5	30	60
Day 6	60	60
			Day 7	60	60
Day 8	60	90
			Day 9	90	90
Day 10	90	90
			Day 11	90	120
Day 12	120	120
			Day 13	120	120
Day 14	120	120

In some embodiments, the anti-pruritic agent is nalbuphine and the titration is performed for seventeen days according to the dose schedule provided in the following table:

according to some embodiments of the present disclosure, the methods of the present disclosure provide therapeutically effective plasma levels of nalbuphine for treating patients suffering from pruritus associated with liver disease. The plasma levels of nalbuphine may be expressed using pharmacokinetic parameters known to the skilled person, such as steady state plasma levels, AUC, Cmax and Cmin. Nalbuphine plasma levels are described in U.S. publication nos. 2014/0171459, 2014/0350042, 2015/0359789 and 2017/0216277, which are incorporated by reference herein in their entirety.

In some embodiments, the methods of the invention provide steady state nalbuphine plasma levels associated with one or more statistically significant therapeutic effects. In some embodiments, therapeutically effective steady-state nalbuphine plasma levels provided by the methods of the present disclosure range from about 10ng/mL to about 80ng/mL, including about 20ng/mL, about 25ng/mL, about 30ng/mL, about 35ng/mL, about 40ng/mL, about 45ng/mL, about 50ng/mL, about 55ng/mL, about 60ng/mL, about 65ng/mL, about 70ng/mL, about 75ng/mL and about 80ng/mL, including all ranges therebetween. In some embodiments, a therapeutically effective steady state nalbuphine plasma level is provided by administering a daily dose of about 360mg of nalbuphine or a pharmaceutically acceptable salt or ester. In other embodiments, the therapeutically effective steady state nalbuphine plasma level is provided by administering about 180mg of nalbuphine or a pharmaceutically acceptable salt or ester twice daily.

In some embodiments, the methods of the invention provide a mean steady state AUC of nalbuphine associated with one or more statistically significant therapeutic effects_0-24h(expressed as ng x h/mL) level. In some embodiments, the therapeutically effective nalbuphine mean steady state AUC provided by the methods of the present disclosure_0-24hLevels range from about 200ng x h/mL to about 1600ng x h/mL, including about 300ng x h/mL, about 400ng x h/mL, about 500ng x h/mL, about 600ng x h/mL, about 700ng x h/mL, about 800ng x h/mL, about 900ng x h/mL, about 1000ng x h/mL, about 1100ng x h/mL, about 1200ng x h/mL, about 1300ng x h/mL, about 1400ng x h/mL, and about 1500ng x h/mL, including all ranges therebetween. In some embodiments, the therapeutically effective nalbuphine mean steady state AUC_0-24hThe levels are provided by administering a daily dose of about 360mg of nalbuphine or a pharmaceutically acceptable salt or ester. In other embodiments, the therapeutically effective nalbuphine mean steady state AUC_0-24hThe levels are provided by administering about 180mg of nalbuphine or a pharmaceutically acceptable salt or ester twice daily.

In some embodiments, the anti-itch agent is nalbuphine, and the metabolites include glucuronic acid (most likely on the phenol and cyclohexane rings), two hydroxylated nalbuphine metabolites (on the cyclobutane ring), and three ketones (hydroxylation of the cyclobutane ring followed by oxidation to a carbonyl group or followed by cyclobutane ring opening). In some embodiments, the nalbuphine metabolite comprises nalbuphine 3-glucuronic acid or 6-glucuronic acid. In some other embodiments, the nalbuphine metabolite comprises trihydroxylated nalbuphine, monohydroxylated nalbuphine or monoglucuronidated nalbuphine or a combination thereof. In some embodiments, one or more metabolites of the anti-pruritic agent has no detectable anti-pruritic activity. In other embodiments, one or more metabolites of the anti-pruritic agent exhibits anti-pruritic activity.

In embodiments where one or more metabolites of the anti-pruritus agent exhibit anti-pruritus activity, the dosing regimen of the anti-pruritus agent may be adjusted and/or titrated as described above with respect to the clearance rate of the one or more metabolites exhibiting anti-pruritus activity. Such dose adjustments and/or titrations of the antipruritic agent may be made to prevent accumulation of the antipruritic agent and/or one or more metabolites that may also exhibit antipruritic activity to avoid toxic effects in patients treated with the antipruritic agents of the present invention.

In some embodiments, the anti-pruritus agent is fully metabolized (e.g., about 100% metabolized). In other embodiments, the anti-pruritus agent is not completely metabolized (e.g., less than about 100% metabolized). For example, in some embodiments, the anti-itch agent is about 100% metabolized, about 95% metabolized, about 90% metabolized, about 85% metabolized, about 80% metabolized, about 75% metabolized, about 70% metabolized, about 65% metabolized, about 60% metabolized, about 55% metabolized, about 50% metabolized, about 45% metabolized, about 40% metabolized, about 35% metabolized, about 25% metabolized, about 20% metabolized, about 15% metabolized, about 10% metabolized, about 5% metabolized, about 1% metabolized, or about 0% metabolized. In some embodiments, the amount of the elutable agent can be measured or monitored by the accumulated level (e.g., plasma level) of the anti-pruritus agent or one or more metabolites thereof.

The embodiments described herein should be understood as illustrative of the present disclosure and should not be construed as limiting. On the contrary, the present disclosure includes the alternatives, as embodied by the appended claims, and equivalents thereof. Each of the references disclosed herein is incorporated by reference in its entirety.

The following non-limiting examples illustrate various aspects of the present disclosure.

Examples

Example 1

Tablets of 30mg, 60mg, 120mg or 180mg Extended Release (ER) nalbuphine are prepared as follows: nalbuphine HCl, mannitol, xanthan gum, locust bean gum, and calcium sulfate dihydrate were added to a high shear mixer and dry mixed at low speed. The granulation solution (water for injection or purified water) is introduced into the mixer at low speed. The wet granulation is granulated at high speed and dried in a fluid bed processor. The dried granulation was milled using a conventional mill and screened for size. The milled granulation was transferred to a diffusion (roller) mixer. Hydroxypropyl cellulose and, where applicable, fumaric acid (only 180mg of formulation) were added to the diffusion mixer and blended. Thereafter, magnesium stearate was added to the diffusion mixer and blended. The final blend was tabletted using a rotary tablet press. The tablets may be coated with a non-functional Opadry white coating.

TABLE 1

Extended release nalbuphine tablets of 30mg, 60mg, 120mg and 180mg

Composition (I)	mg/tablet
		Nalbuphine HCI	29.8
Mannitol	107.3
		Hydroxypropyl cellulose	34.7
Locust bean gum	32.2
		Xanthan gum	21.4
Calcium sulfate dehydrate	17.9
		Magnesium stearate	1.9
Water for injection or purified water	QS
		In total:	245.1

composition (I)	mg/tablet
		Nalbuphine HCI	59.5
Mannitol	71.5
		Hydroxypropyl cellulose	29.8
Locust bean gum	21.4
		Xanthan gum	14.3
Calcium sulfate dehydrate	11.9
		Magnesium stearate	1.6
Water for injection or purified water	QS
		In total:	210.0

composition (I)	mg/tablet
		Nalbuphine HCI	119.0
Mannitol	143.0
		Hydroxypropyl cellulose	59.6
Locust bean gum	42.9
		Xanthan gum	28.6
Calcium sulfate dehydrate	23.8
		Magnesium stearate	3.2
Water for injection or purified water	QS
		In total:	432.6

composition (I)	mg/tablet
		Nalbuphine HCI	178.5
Mannitol	160.8
		Hydroxypropyl cellulose	59.6
Locust bean gum	48.2
		Xanthan gum	32.2
Calcium sulfate dehydrate	26.8
		Magnesium stearate	4.0
Fumaric acid	24.8
		Water for injection or purified water	QS
In total:	246.9

the tablets were coated with a non-functional coating (Opadry II White).

TABLE 2

Nalbuphine HCl ER tablets, 30mg, 60mg or 180mg compositions

Components	Tablet (mg/tablet)
		Nalbuphine HCl	30.0
Mannitol	108.0
		Hydroxypropyl cellulose	35.0
Locust bean gum	32.4
		Xanthan gum	21.6
Calcium sulfate dihydrate	18.0
		Magnesium stearate	1.9
Opadry II White	7.4
		Sterilizing water for washing	QS
Total of	254.3

Components	Tablet (mg/tablet)
		Nalbuphine HCl	60.0
Mannitol	72.0
		Hydroxypropyl cellulose	30.0
Locust bean gum	21.6
		Xanthan gum	14.4
Calcium sulfate dihydrate	12.0
		Magnesium stearate	1.6
Opadry II White	6.355
		Sterilizing water for washing	QS
Total of	218

Example 2:

healthy and liver-impaired patients will be treated with Extended Release (ER) tablets of nalbuphine prepared according to the formulations described herein to study the effect of liver impairment on pharmacokinetics at steady state as a function of dose. The dose and dose frequency will be evaluated to select a regimen appropriate for a subject with impaired liver function. According to the results of the study, the potential of oral nalbuphine to reduce liver itching in a dose-dependent manner will be evaluated.

Design of research

The study will be an open-label multiple ascending dose study consisting of 2 cohorts, each cohort receiving a nalbuphine ER tablet of the present disclosure. Cohort 1 will consist of three groups of subjects with impaired liver function, with some subjects in each of the mild Child-Pugh category (cohort 1), the moderate Child-Pugh category, and the severe Child-Pugh category. Cohort 2 will consist of healthy subjects.

Administration: on the morning of day 1, subjects will receive a 27mg single dose of an ER tablet of nalbuphine. Subsequently, the dose per subject will be escalated to 27mg, 54mg, 108mg and 162mg (equivalents of nalbuphine free base), twice daily (BID), for 13 days. On the last treatment day (day 14), subjects will receive a 162mg bolus dose in the morning. The subject will maintain each dose level for 2-3 days, with at least 4-6 consecutive doses provided (see table 3). Dose escalation will depend on tolerability of previous doses and may be stopped upon adverse events. The subjects in the cohort group 1 may be dosed staggered to allow for interim PK analyses.

Blood and urine will be obtained at the indicated times during each treatment period for PK and other analyses (see below). Standard safety assessments will be measured during each treatment session.

Pharmacokinetic (PK) assessment

Comparison of PK parameters (e.g., C) between healthy and patients with liver damage_max、T_max、T_1/2AUC, relative bioavailability, etc.) to assess the suitability of the nalbuphine ER tablet for treating liver itch. Data will be obtained from plasma samples collected from each cohort according to the provided schedule. Once the analysis is complete, a graphical representation of data such as nalbuphine plasma concentration versus time may be prepared.

Plasma samples will be analyzed using validated assay methods to determine the nalbuphine concentration. Pharmacokinetic variables (including but not limited to C) will be calculated using non-compartmental analysis_max、T_maxAnd AUC_(0-Final)). Storage clothPK parameters for buprenorphine will be derived from plasma concentration data by non-compartmental analysis using WinNonlin professional software (version 5.2 or higher).

The scheme is as follows:

blood: blood from each cohort will be collected at K₂EDTA tubes. The plasma fraction will be separated by centrifugation and stored frozen until analysis. To calculate the terminal T_1/2For purposes of (a), blood samples will be collected on days 1 and 13 at the following time points: 0h (before morning dosing), 1h, 2h, 3h, 4h, 5h, 6h, 7h, 9h, 12h, 18h, 24h and 30h, 36h, 48h and 72h (day 13 only) after morning dosing.

On days 2, 4, 7, 10 and 12, trough level blood samples were collected before morning and evening dose administration. The trough blood samples prior to day 2 morning dosing were used as the 24h post-dose samples of the day 1 PK profile. Additional samples may be collected by the investigator as appropriate.

Urine: urine can be collected at 0-12h, 12-24h and 24-48h intervals before dosing on day 1 (-2h to 0h), after morning dosing, after the last dose of nalbuphine. The volume of urine and time of collection will be recorded and repeated aliquots transferred to cryovials and stored frozen until analysis. Urine samples will be analyzed using validated assay methods to determine the nalbuphine concentration. If the volume is insufficient for an individual assay, the urine of the patient may be allowed to pool.

Table 3. representative dose escalation and time schedules for patients treated with nalbuphine ER tablets.

^aSubjects will maintain each dose level for at least two days for at least four consecutive doses^bBID constitutes morning and evening administration^cMorning drug administration constitutes a day 2 trough blood sample^dMorning drug administration constitutes a day 3 trough blood sample^eMorning drug administration constitutes a day 4 trough blood sample

Pharmacodynamic evaluation

A Numerical Rating Scale (NRS) will be used to determine the severity of itch experienced by subjects at set time points (perhaps twice a day-once within an hour to complete breakfast and supper) per day.

Security assessment/monitoring

Adverse Events (AEs) will be monitored throughout the duration of the study.

To monitor possible adverse events, sitting blood pressure, heart rate, body temperature, clinical laboratory tests (hematology, chemistry and urinalysis) and respiratory rate were monitored during the study and physical examination and 12 lead ECG were performed.

Statistical analysis

For all subjects (safe population) receiving at least one dose of nalbuphine, treatment emergency ae (teae) will be summarized by systemic organ class and preferred terminology, by maximum severity and by relationship to treatment according to each nalbuphine dose level (each time period).

All AEs will be presented in a list sorted by subject and number of episodes. Severe Adverse Events (SAE), AEs leading to study discontinuation, and AEs with mortality outcomes will be presented in separate lists as needed.

Vital signs, clinical safety laboratory tests and ECG interval data were dose-wise descriptively summarized (sample size (N), mean, median, standard deviation, minimum and maximum). Vital signs, safety laboratory parameters, ECG and physical examination results will be listed by cohort, subject, treatment and study days during the treatment period. The list will include planned, unplanned, and repeated evaluations. The list of vital signs will include changes prior to dosing for the current treatment period. All clinically significant changes in vital signs, safety laboratory parameters, and physical examination results will be listed by cohort, subject, treatment, and study days during the treatment period.

Pharmacokinetic parameters will be generated for all subjects with nalbuphine plasma concentration data above the lowest quantitative level (LLOQ) for any treatment and PK evaluable population information will be provided in the data list. Pharmacokinetic parameters from urine will also be generated and presented in a data list.

The PK evaluable population will be defined to include all subjects receiving nalbuphine and having evaluable PK data.

All nalbuphine PK results for the PK evaluable population will be summarized using appropriate descriptive statistics, including number of subjects (N), mean, standard deviation, minimum and maximum and CV%. Nalbuphine Cmax and AUC will also be obtained_(0-Final)Geometric mean and geometric CV% values of the parameters. Descriptive statistics of Tmax were summarized using only mean, median, minimum and maximum values and number of subjects (N).

Within each group, dose proportionality will be assessed by visual assessment of individual and average nalbuphine PK parameters. For all subjects (safe population) receiving at least 1 dose of study drug, AEs will be analyzed and summarized descriptively in terms of total number of AEs per treatment and in terms of number and frequency of subjects reporting any AEs both physically and therapeutically. AEs will be classified as all treatment-emergent AEs, all severe AEs, treatment-related AEs, and treatment-related severe AEs. Vital signs, clinical safety laboratory tests and ECG interval data were analyzed and summarized by treatment descriptively (sample size (n), mean, median, standard deviation, minimum and maximum). All clinically significant changes in vital signs, safety laboratory parameters, physical examination results and ECG abnormalities will be listed by treatment group, subject, time period and study day during the treatment period.

Example 3:

in a two-part study design, liver-impaired patients will be treated with extended-release (ER) tablets of nalbuphine prepared according to the formulations described herein. The first part will be a single escalating dose study followed by multiple escalating dose studies to determine the effect of liver damage on pharmacokinetics at steady state as a function of dose. Healthy subjects will receive a single dose of the drug at the highest dose studied in liver-impaired subjects for relative comparison with the PK aspect of Extended Release (ER) of nalbuphine.

Design of research

The study will be a two-part open-label single and multiple escalated dose study consisting of six cohorts, each cohort receiving a nalbuphine ER tablet of the present disclosure. Section 1 will be a single incremental dose (SAD) group and will consist of five cohorts. Cohorts 1-4 will consist of subjects with impaired liver function divided into three groups, with some subjects in each of the mild Child-Pugh category (group 1), the moderate Child-Pugh category (group 2), and the severe Child-Pugh category (group 3). Cohort 5 will consist of healthy control subjects appropriately matched in age, Body Mass Index (BMI) and gender to subjects with mild and moderate liver damage in cohorts 1 to 4. Cohort 6 will consist of subjects with impaired liver function divided into two groups, with some subjects in each of the mild Child-Pugh category (group 1) and the moderate Child-Pugh category (group 2).

Part 2 will be a multiple increment dose cohort and will consist of one cohort. Cohort 6 will consist of subjects with impaired liver function divided into two groups, with some subjects in each of the mild Child-Pugh category (group 1) and the moderate Child-Pugh category (group 2).

Part 1:

administration: subjects will receive a single ascending dose under fasting conditions at the following dose levels:

queue	Dosage form
		1	27mg
2	54mg
		3	108mg
4	162mg
		5	Up to 162mg

Each cohort will be dosed in order starting with the lowest dose. Subjects enrolled in cohort 1 may also be enrolled in cohorts 2, 3 and 4. Subjects with mild or moderate liver damage can be enrolled simultaneously for each dose cohort. The safety and tolerability of the combined mild and moderate liver damage subject data will be evaluated at each dose level before proceeding to the next dose level.

After completion of the highest dose test in patients with mild or moderate lesions, patients with severe lesions will be enrolled starting from the lowest dose cohort. After reviewing the safety and tolerability of the first 2 subjects with severe lesions, it will be determined whether the dose cohort is complete. Safety and tolerability assessments will be made at each dose level for this group.

Pharmacokinetics in the liver compromised subject population will be compared against a healthy subject population (cohort 5).

Each cohort will obtain blood at the designated time for PK and other analyses (see below). Standard safety assessments will be measured during each treatment session.

The scheme is as follows:

blood: blood from each cohort will be collected at K₂EDTA tubes. The plasma fraction will be separated by centrifugation and stored frozen until analysis. Blood samples will be collected at the following time points: 0h (pre-dose), 1.5h, 3h, 5h, 7h, 9h, 12h, 24h, 36h, 48h and 72h post-dose.

Security assessment/monitoring

Adverse Events (AEs) will be monitored throughout the duration of the study.

To monitor possible adverse events, sitting blood pressure, heart rate, body temperature, clinical laboratory tests (hematology, chemistry and urinalysis) and respiratory rate were monitored during the study and physical examination and 12 lead ECG were performed.

Statistical analysis

Statistical analysis will be performed using statistical methods approved for FDA clinical trials. Will use what has been validated by inVentiv for bioequivalence/bioavailability studiesPharmacokinetic analysis was performed. Will be used according to FDA guidelinesInferential statistical analysis was performed.

The following pharmacokinetic parameters for nalbuphine and metabolites (if desired) will be calculated by standard non-compartmental methods.

1)AUC_0-t: the area under the concentration-time curve from time zero to the last non-zero concentration;

2)AUC_0-inf: the area under the concentration-time curve from time zero to infinity (extrapolated);

3)C_max: the maximum concentration observed;

4)T_max: observe C_maxThe time of (d);

5)T_1/2el: elimination of half-life;

6) residual area: calculated as 100 x (1-AUC)_0-t/AUC_0-inf)；

7)K_el: a cancellation rate constant;

8) Cl/F: apparent overall clearance of drug from plasma; and

9) Vd/F: apparent volume of distribution, calculated as dose/(K)_el×AUC_0-inf)。

Section 2:

in part 2 (MAD) of the study, subjects will receive multiple doses according to the protocol described in the MAD study described in example 2. Section 2 of the study can begin after completion of study section 1 (SAD) in groups 1 and 2 (mild and moderate liver damage) and after satisfactory review of safety and tolerability data by the safety committee. Subjects included in part 1 can also be included in part 2.

The implementation scheme is as follows:

1. a method of treating pruritus associated with liver disease comprising orally administering to a patient in need of such treatment an effective amount of an antipruritic, wherein the antipruritic is nalbuphine or a pharmaceutically acceptable salt or ester thereof.

2. The method of embodiment 1, wherein the liver disease is selected from the group consisting of: cholestatic liver disease, infectious hepatitis, cirrhotic liver disease, drug-induced liver disease, idiopathic portal hypertension, congenital malformations or genetic diseases affecting liver function, sarcoidosis, primary or metastatic liver tumor involvement, and autoimmune hepatitis-cholangitis (overlap syndrome).

3. A method of treating pruritus associated with obstructive cholestasis secondary to biliary obstruction caused by non-liver tissue disease, comprising orally administering to a patient in need of such treatment an effective amount of an antipruritic, wherein the antipruritic is nalbuphine or a pharmaceutically acceptable salt or ester thereof.

4. The method of embodiment 3, wherein the obstruction is caused by a condition selected from the group consisting of: pancreatic cancer, pancreatitis, congenital or acquired biliary stricture, lymph node obstruction (such as from lymphoma), or bile duct stones.

5. The method of any one of embodiments 1-4, wherein the pruritus is selected from the group consisting of: chronic pruritus, pruritus refractory to treatment with other antipruritic agents; pruritus refractory to treatment with bile chelators; and pruritus refractory to treatment with rifampicin.

6. The method of any one of embodiments 1-5, wherein the pruritus is chronic pruritus.

7. The method of any one of embodiments 1-6, wherein the pruritus is a refractory pruritus to treatment with other antipruritics.

8. The method of any one of embodiments 1-7, wherein the pruritus is a treatment-refractory pruritus using a bile chelating agent selected from the group consisting of cholestyramine, colestipol, and colesevelam.

9. The method of any one of embodiments 1-8, wherein the pruritus is a treatment-refractory pruritus that is refractory to treatment with rifampicin, a mu-opioid antagonist, a kappa-opioid agonist, an antidepressant, a serotonin antagonist, or an antihistamine.

10. The method of embodiment 9, wherein the kappa-opioid agonist is naftifine.

11. The method of embodiment 9, wherein the mu opioid antagonist is naltrexone.

12. The method of any of embodiments 1-2 and 5-11, wherein the patient does not have a biliary obstruction.

13. The method of any one of embodiments 1-2 and 5-12, wherein the liver disease is cholestatic liver disease.

14. The method of embodiment 13, wherein the cholestatic liver disease is selected from primary sclerosing cholangitis and primary biliary cholangitis.

15. The method of any one of embodiments 1-2 and 5-12, wherein the liver disease is infectious hepatitis.

16. The method of embodiment 15, wherein said infectious hepatitis is selected from Hepatitis C (HCV) and Hepatitis B (HBV).

17. The method of embodiment 16, wherein said HCV is selected from chronic HCV and HCV after a persistent virological response.

18. The method of embodiment 16, wherein said hepatitis b is selected from the group consisting of inactive HBV and active HBV infection in a carrier.

19. The method of any one of embodiments 1-2 and 5-12, wherein the liver disease is a cirrhotic liver disease.

20. The method of embodiment 19, wherein said cirrhotic liver disease is selected from the group consisting of alcoholic liver disease, autoimmune hepatitis, and non-alcoholic fatty liver disease.

21. The method of any of embodiments 1-2 and 5-12, wherein the liver disease is selected from drug-induced liver disease, idiopathic portal hypertension, a congenital malformation or genetic disease affecting liver function, sarcoidosis, primary or metastatic liver tumor involvement, and autoimmune hepatitis-cholangitis (overlap syndrome).

22. The method of any one of embodiments 1-21, wherein the patient has an elevated serum level of an endogenous opioid as compared to a normal serum level.

23. The method of any of embodiments 1-22, wherein about 14mg equivalents of nalbuphine free base is administered once daily.

24. The method of any of embodiments 1-22, wherein about 14mg equivalents of nalbuphine free base is administered twice daily.

25. The method of any of embodiments 1-22, wherein about 27mg equivalents of nalbuphine free base is administered once daily.

26. The method of any of embodiments 1-22, wherein about 27mg equivalents of nalbuphine free base is administered twice daily.

27. The method of any of embodiments 1-22, wherein about 54mg equivalents of nalbuphine free base is administered once daily.

28. The method of any of embodiments 1-22, wherein about 54mg equivalents of nalbuphine free base is administered twice daily.

29. The method of any of embodiments 1-22, wherein about 81mg equivalents of nalbuphine free base is administered once daily.

30. The method of any of embodiments 1-22, wherein about 81mg equivalents of nalbuphine free base is administered twice daily.

31. The method of any of embodiments 1-22, wherein about 108mg equivalents of nalbuphine free base are administered once daily.

32. The method of any of embodiments 1-22, wherein about 108mg equivalents of nalbuphine free base are administered twice daily.

33. The method of any of embodiments 1-22, wherein about 162mg equivalents of nalbuphine free base is administered once daily.

34. The method of any of embodiments 1-22, wherein about 162mg equivalents of nalbuphine free base is administered twice daily.

35. The method of any of embodiments 1-22, wherein about 324mg equivalents of nalbuphine free base is administered once daily.

36. The method of any of embodiments 1-22, wherein about 15mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

37. The method of any of embodiments 1-22, wherein about 15mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered twice daily.

38. The method of any of embodiments 1-22, wherein about 30mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

39. The method of any of embodiments 1-22, wherein about 30mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered twice daily.

40. The method of any of embodiments 1-22, wherein about 60mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

41. The method of any of embodiments 1-22, wherein about 60mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered twice daily.

42. The method of any of embodiments 1-22, wherein about 90mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

43. The method of any of embodiments 1-22, wherein about 90mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered twice daily.

44. The method of any of embodiments 1-22, wherein about 120mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

45. The method of any of embodiments 1-22, wherein about 120mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered twice daily.

46. The method of any of embodiments 1-22, wherein about 180mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

47. The method of any of embodiments 1-22, wherein about 180mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered twice daily.

48. The method of any of embodiments 1-22, wherein about 360mg of nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered once daily.

49. The method of any one of embodiments 1-48, wherein said administering is for about 8 weeks, about 10 weeks, about 12 weeks, about 24 weeks, or about 50 weeks.

50. The method of any one of embodiments 1-49, further comprising titrating the dose of the anti-pruritic agent for at least one week until a steady state is reached in the patient.

51. The method of any one of embodiments 1-49, further comprising titrating the dose of the anti-pruritic agent for about 2 weeks until a steady state is reached in the patient.

52. The method of any one of embodiments 1-49, further comprising titrating the dose of the anti-pruritic agent for about 7 to 30 days until a steady state is reached in the patient.

53. The method of any one of embodiments 1-49, further comprising titrating the dose of the anti-pruritus agent for about 14 to 20 days until a steady state is reached in the patient.

54. The method of embodiment 51, wherein said titrating comprises administering an ascending dose of said anti-pruritic agent until a steady state is reached in said patient.

55. The method of embodiment 51, wherein said titrating comprises administering an ascending dose of said anti-pruritic agent until an effective amount of 15mg, 30mg, 60mg, 90mg, 120mg, 180mg, 240mg, or 360mg is achieved in said patient.

56. The method of embodiment 51, wherein said titration comprises administering an ascending dose of equivalent amounts of nalbuphine free base until an effective amount of 14mg, 27mg, 54mg, 81mg, 108mg, 162mg, 216mg or 324mg is achieved in said patient.

57. The method of embodiment 51, wherein said titration further comprises administering an initial dose of about 30mg once or twice daily.

58. The method of embodiment 50, wherein said titrating comprises administering said anti-pruritus agent in increments ranging from about 15mg to about 60 mg.

59. The method of embodiment 50, wherein said titration further comprises administering once or twice daily an equivalent of about 27mg of nalbuphine free base.

60. The method of embodiment 50, wherein said titrating comprises administering said anti-pruritic agent in increments ranging from about 14mg to about 54mg nalbuphine free base equivalent.

61. The method of any one of embodiments 50, wherein said administering comprises administering twice daily with an AM dose and a PM dose, wherein said PM dose is greater than or equal to said AM dose.

62. The method of any one of embodiments 1-61, wherein said patient experiences a significant reduction in itch following said treatment as compared to prior to said treatment.

63. The method of any one of embodiments 1-62, wherein after said treatment, said patient experiences a reduction in itch characterized by a decrease in the most intense itch intensity Numerical Rating Scale (NRS) value of at least two points.

64. The method of embodiment 63, wherein said itch reduction is a decrease in the most intense itch intensity NRS value by at least three points.

65. The method of embodiment 63, wherein said itch reduction is a decrease in the most intense itch intensity NRS value by at least four points.

66. The method of any one of embodiments 1-65, wherein after said treatment, said patient experiences a reduction in itch characterized by a decrease in the average itch intensity Numerical Rating Scale (NRS) value of at least two points.

67. The method of embodiment 66, wherein said itch reduction is a decrease in the average itch intensity NRS value by at least three points.

68. The method of embodiment 66, wherein said itch reduction is a decrease in the average itch intensity NRS value by at least four points.

69. The method of any one of embodiments 1-68, wherein after the treatment, the patient experiences a reduction in itch characterized by a change in visual analog scale of at least about 10mm in the most intense itch or average itch (VAS) value (using a VAS scale ranging from "no itch when VAS is 0" to "most intense itch possible" when VAS is 100 mm).

70. The method of embodiment 69, wherein after said treatment, said patient experiences a reduction in itch characterized by a change in the most itchy or average itch VAS value (using the VAS scale ranging from "no itch when VAS is 0" to "most itchy possible" when VAS is 100 mm) of at least about 20 mm.

71. The method of embodiment 69, wherein after said treatment, said patient experiences a reduction in itch characterized by a change in the most itchy or average itch VAS value (using the VAS scale ranging from "no itch when VAS is 0" to "most itchy possible" when VAS is 100 mm) of at least about 30 mm.

72. The method of any of embodiments 1-71, wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered in combination with one or more anti-pruritic agents.

73. The method of embodiment 72, wherein the one or more antipruritic agents are selected from the group consisting of: antihistamines, antidepressants, serotonin antagonists, anti-inflammatory corticosteroids, topical anti-infective and antifungal agents, antibacterial agents, antiviral agents, cytotoxic agents and anti-irritant/analgesic agents.

74. The method of any one of embodiments 1-73, wherein the anti-pruritus agent is nalbuphine hydrochloride.

75. The method of any one of embodiments 1-74, wherein the anti-pruritus agent is in the form of an extended release oral dosage form.

76. The method of any one of embodiments 1-75, wherein the anti-pruritus agent is administered in a formulation comprising nalbuphine hydrochloride, mannitol, hydroxypropyl cellulose, locust bean gum, xanthan gum, calcium sulfate dihydrate, fumaric acid, and magnesium stearate.

77. The method of any one of embodiments 1-76, wherein the patient is a pediatric patient.

78. The method of any one of embodiments 1-76, wherein the patient is an elderly patient.