Methods and compositions for treating congenital diarrhea disorders
阅读说明：本技术 用于治疗先天性腹泻障碍的方法和组合物 (Methods and compositions for treating congenital diarrhea disorders ) 是由 L·A·康特 P·R·查特维迪 于 2018-05-31 设计创作，主要内容包括：本发明提供了用于治疗先天性腹泻障碍(CDD)的方法和组合物。所述方法包含对有此需要的患者施用有效量的原花青素聚合物组合物,其来自龙血巴豆,优选crofelemer。施用原花青素聚合物组合物解决了与CDD导致的相关的分泌性腹泻和症状,并且可以改善患者的营养状况、电解质平衡、水合、生长和发育。(The present invention provides methods and compositions for treating Congenital Diarrhea Disorder (CDD). The method comprises administering to a patient in need thereof an effective amount of a procyanidin polymer composition from croton biflorus, preferably crofelemer. Administration of the procyanidin polymer composition addresses the secretory diarrhea and symptoms associated with CDD induction and can improve the nutritional status, electrolyte balance, hydration, growth and development of the patient.)
1. A method of treating secretory diarrhea associated with Congenital Diarrhea Disorder (CDD) in a subject, the method comprising administering to a subject in need thereof an amount of a composition comprising an isolated procyanidin polymer from Croton tomatidis (Croton lechleri) effective to treat secretory diarrhea associated with CDD.
2. The method of claim 1, wherein the CDD is microvilli inclusion body disease, congenital clusteric bowel disease, hair-liver-small intestine syndrome, immune dysfunction polyendocrine adenopathy, X-linked IPEX-like syndrome, congenital sodium diarrhea, congenital chloride diarrhea, or primary bile acid malabsorption.
3. The method of claim 1 or 2, wherein the subject is a human infant.
4. The method of any one of claims 1-3, wherein the subject is in need of parenteral nutrition.
5. The method of any one of claims 1-4, wherein the subject has an intestinal resection or intestinal graft.
6. The method of any one of claims 1-5, wherein the composition is administered after the subject begins to exhibit symptoms of CDD.
7. The method of any one of claims 1-6, wherein the composition is administered within 1 week of birth.
8. The method of any one of claims 1-6, wherein the composition is administered within 1 month of birth.
9. The method of any one of claims 1-6, wherein the composition is administered within 1 year of birth.
10. The method of any one of claims 1-9, wherein the administering comprises administering to a subject in need thereof about 250mg to about 1000mg crofelemer/day; administering about 250mg crofelemer/day; administering about 500mg crofelemer/day; administering about 1000mg crofelemer/day; about 125mg crofelemer was administered 2 times per day; administering about 250mg of the composition 2 times per day; or about 500mg crofelemer was administered 2 times per day.
11. The method of any one of claims 1-10, wherein the composition is administered in an enterically coated oral dosage form.
12. The method of any one of claims 1-10, wherein the composition is administered in a non-enteric coated oral dosage form.
13. The method of any one of claims 1-9, wherein the administering comprises administering the composition in an aqueous vehicle at a dose of 2mg/kg-10mg/kg 2 times/day.
14. The method of claim 13, wherein the procyanidin polymer is formulated with an aqueous vehicle without any enteric coating.
15. The method of claim 13, wherein the procyanidin polymer is formulated into an enterically coated granule or powder with an aqueous vehicle.
16. The method of any one of claims 1-9 or 12, wherein the administering comprises administering a procyanidin polymer composition from croton agalactiae with a dosage of about 250mg to about 1000 mg/day; about 250 mg/day; about 500 mg/day; about 1000 mg/day; about 125mg 2 times per day; about 250mg 2 times per day; or a dose of crofelemer for gut protection of about 500mg 2 times/day is bioequivalent.
17. The method of any one of claims 1-9, wherein the administering comprises administering a procyanidin polymer composition from croton agalactiae bioequivalent to a dose of 2mg/kg to 10mg/kg enteric coating crofelemer 2 times/day.
18. The method of any one of claims 1-17, wherein the subject is considered treated if the subject exhibits an improvement in hydration, nutritional status, or electrolyte balance.
19. The method of any one of claims 1-18, wherein the subject is considered treated if the subject exhibits a reduced number of bowel movements per day, a reduced number of watery bowel movements per day, an improvement in daily scores for abdominal pain or discomfort, an improvement in scores for daily stool consistency, a reduction in the number of days the subject encounters urgency per week, a reduction in the number of days the subject experiences fecal incontinence per week, or a reduction in the number of unplanned visits due to severe exacerbations of diarrhea.
20. A composition for treating secretory diarrhea associated with Congenital Diarrhea Disorder (CDD) in a subject, the composition comprising an amount of isolated proanthocyanidin polymer from croton agalactiae effective to treat secretory diarrhea associated with CDD.
21. The composition of claim 20, wherein the CDD is microvilli inclusion body disease, congenital clusteric bowel disease, hair-liver-small intestine syndrome, immune dysfunction polyendocrine adenopathy, X-linked IPEX-like syndrome, congenital sodium diarrhea, congenital chloride diarrhea, or primary bile acid malabsorption.
22. The composition of claim 20 or 21, wherein the subject is a human infant.
23. The composition of any one of claims 20-22, wherein the subject is in need of parenteral nutrition.
24. The composition of any one of claims 20-23, wherein the subject has an intestinal resection or intestinal graft.
25. The composition of any one of claims 20-24, wherein the composition is administered after the subject begins to exhibit symptoms of CDD.
26. The composition of any one of claims 20-25, wherein the composition is administered within 1 week of birth.
27. The composition of any one of claims 20-25, wherein the composition is administered within 1 month of birth.
28. The composition of any one of claims 20-25, wherein the composition is administered within 1 year of birth.
29. The composition of any one of claims 20-28, wherein the administering comprises administering to a subject in need thereof about 250mg to about 1000mg crofelemer/day; administering about 250mg crofelemer/day; about 500mg crofelemer/day; administering about 1000mg crofelemer/day; about 125mg crofelemer was administered 2 times per day; administering about 250mg of the composition 2 times per day; or about 500mg crofelemer was administered 2 times per day.
30. The composition of any one of claims 20-29, wherein the composition is an enterically coated oral dosage form.
31. The composition of any one of claims 20-29, wherein the composition is in a non-enterically coated oral dosage form.
32. The composition of any one of claims 20-28, wherein the composition is in a dosage form to be administered in an aqueous vehicle at a dose of 2mg/kg-10mg/kg 2 times/day.
33. The composition of claim 32, wherein the procyanidin polymer is formulated with an aqueous vehicle without any enteric coating.
34. The composition of claim 32, wherein the procyanidin polymer is formulated as an enterically coated granule or powder with an aqueous vehicle.
35. The composition of any one of claims 20-28 or 31, wherein the composition comprises a procyanidin polymer composition from croton agalactiae in an amount from about 250mg to about 1000mg per day; about 250 mg/day; about 500 mg/day; about 1000 mg/day; about 125mg times/day; about 250mg 2 times per day; or a dose of approximately 500mg of enteroprotective crofelemer 2 times/day is bioequivalent.
36. The composition of any one of claims 20-28, wherein the composition comprises a procyanidin polymer composition from croton agalactiae bioequivalent to a dose of 2mg/kg to 10mg/kg enteric coating crofelemer 2 times/day.
37. The composition of any one of claims 20-36, wherein the subject is considered treated if the subject exhibits an improvement in hydration, nutritional status, or electrolyte balance.
38. The composition of any one of claims 20-37, wherein a subject is considered treated if the subject exhibits a reduced number of bowel movements per day, a reduced number of watery bowel movements per day, an improvement in the daily score of abdominal pain or discomfort, an improvement in the score of daily stool consistency, a reduction in the number of days the subject encounters urgency per week, a reduction in the number of days the subject experiences fecal incontinence per week, or a reduction in the number of unplanned visits due to severe exacerbations of diarrhea.
Technical Field
The present invention relates to methods of preventing, ameliorating and/or treating diarrhea associated with Congenital Diarrhea Disorder (CDD) in a subject in need thereof using a procyanidin polymer composition, such as Crofelemer.
Background
Congenital Diarrhea Disorders (CDD) are a group of inherited chronic bowel diseases characterized by a mixed etiology. (Guarino A et al, Best practice Res Clin gastroenterol.2012; 26(5):649- & 661). Because the disorder is extremely rare and severe, epidemiological studies on CDD are limited. Experts determined that the incidence of disease is only 200 cases in the united states. (Terrin, G. et al Int J Mol Sci.2012; 13(4): 4168-. Early infancy is a typical age of onset, in which the disease manifests as severe watery diarrhea, a chemical imbalance in serum, and developmental arrest. (Berni Canani R et al, JPeditr Gastroenterol Nutr.2010; 50(4): 360-. Massive dehydration, metabolic acidosis or alkalosis and malnutrition, as well as other secondary symptoms, occur rapidly and are life threatening. (Overeem AW et al, Dis model Mech.2016; 9(1): 1-12; Posovszky C., Best practice Res Clin gastroenterol.2016; 30(2): 187-. Genetically, autosomal recessive genetic mutations are inserted into a variety of genes that can quantify each disorder. However, these disorders have major common symptoms; chronic diarrhea, and thus secondary symptoms associated with diarrhea. (Guindalini S, Diarrhea Diagnostic and Therapeutic Advances). Most CDD mortality is reported to be high, while the severity of chronic diarrhea is dependent on the disease and the classification of the defects associated with each. (Field, M., Journal of Clinical investigation. 2003; 111(7): 931-943). Apart from being genetic, no identifiable risk factor is associated with CDD.
Early and appropriate diagnosis, classification and treatment are beneficial to reduce the manifestation of harmful disease. Since clinical manifestations and pathology can mimic a variety of conditions, delays in diagnosis are common, leading to high mortality in CDD-challenged infants. Molecular analysis is a modern diagnostic technique that provides excellent accuracy, timely diagnosis, and correct classification. Unfortunately, despite early discovery and treatment, existing therapies rarely alleviate the burden of CDD outcomes. (Field, M., Journal of clinical investigation. 2003; 111(7): 931-943). Patients receiving standard therapy, Parenteral Nutrition (PN) and bowel resection are prone to serious complications, increasing the risk of premature death. (Overeem AW et al, DisModel Mech.2016; 9(1): 1-12; Posovszky C., Best practice Res Clingagastroenterol.2016; 30(2): 187-. Therefore, new and improved therapies are urgently needed for CDD patients to reduce mortality and reduce life-long disability. (Guarino A et al, Best practice Res Clin gastroenterol.2012; 26(5):649- & 661). No specific antidiarrheal agent has been studied and approved for CDD chronic diarrhea.
The classification of CDD is used in differential diagnosis and depends on the pathophysiological mechanisms of the underlying disease. In the small intestine, nutrients are absorbed from the lumen into the villus by intestinal cells (absorptive cells lining the intestinal mucosa), and also play a role in secretion. Intestinal cell defects underlie the major diarrheal complication in all CDDs. These defects are layered by four different mechanisms: 1) deficiencies in digestion, absorption and transport of nutrients and electrolytes; 2) defects in intestinal cell differentiation and polarization; 3) defects in intestinal secretory cell differentiation; and 4) defects in the regulation of intestinal immune responses; and thus, digestion, absorption, and gastrointestinal activity are imbalanced. In addition, defects in the innate and adaptive immune response may involve several types of epithelial cells as well as immune cells of the lamina propria of the mucosa, leading to inflammation and tissue damage.
The absorption and secretion of nutrients and water in the intestine are two separate but interrelated processes. Generally, with respect to the intestinal mechanism, the diarrheal condition is further subdivided. Those of chronic diarrhea and CDD are classified into osmotic and secretory forms based on the etiology of the disease, pathophysiology, and response to fasting. Furthermore, determining the fecal electrolyte concentration and the fecal ion gap is important to distinguish between the two mechanisms responsible for this. Thus, the classification of the type of diarrhea determines the treatment options for CDD patients.
Osmotic diarrhea is manifested as unabsorbed luminal material, which results in fluid accumulation in the intestinal lumen, and diarrhea improves significantly during fasting. The ion gap was noted as > 50. When osmotic mechanisms are suspected, the next step in the laboratory study involves measuring blood gas, blood glucose, ammonium, albumin, triglycerides and cholesterol, amino acid urine and searching for reducing substances in stool, steptocrit and sweating tests.
Secretory diarrhea is an active process of secreting fluid into the intestinal lumen. It is the most severe form of diarrhea, manifested within the first three weeks of life and rapidly requires Total Parenteral Nutrition (TPN). It is characterized by fluid accumulation in the intestinal lumen independent of fasting and an ionic gap of <50 was noted.
Thus, CDD represents an important and unmet clinical need, which requires more effective treatment. Currently prescribed therapies are only partially effective or are plagued by unacceptable side effects such as constipation and the possibility of addiction. The development of CDD therapeutic drugs with low drug-drug interaction potential, impact on drug metabolism, or abuse potential would provide significant benefits to patients with CDD.
Disclosure of Invention
Disclosed herein are methods of preventing, ameliorating and/or treating secretory diarrhea in a subject having a Congenital Diarrhea Disorder (CDD). Secretory diarrhea is characterized by independent fluid accumulation in the fasted intestinal lumen, and ionic gaps of less than 50 are noted.
In one aspect, provided herein is a method of treating CDD in a subject comprising administering to a subject in need thereof a composition comprising an effective amount of a procyanidin polymer composition from croton lechleri, preferably Crofelemer, to treat, ameliorate symptoms, particularly diarrhea symptoms of CDD, or prevent CDD. In certain embodiments, Crofelemer is an enteric-protected formulation.
In particular embodiments, CDD is initiated prenatally or during infancy (i.e., within the first year of life). In further embodiments, the subject with CDD is a child, adolescent, or adult. In particular embodiments, the subject is at risk of dehydration, metabolic acidosis or alkalosis, and/or malnutrition and/or electrolyte imbalance. In a preferred embodiment, the subject is a human.
In one embodiment, a method is provided for treating, preventing or ameliorating microvilli inclusion body disease (MVID), particularly secretory diarrhea associated with MVID, in a subject, particularly an infant, having the above-described disease, by administering to a subject in need thereof a procyanidin polymer composition from croton agalactiae, preferably crofelemer.
In one embodiment, a method is provided for treating, preventing or ameliorating congenital cluster bowel disease (CTE), particularly CTE-related secretory diarrhea, in a subject, particularly an infant, having the above-mentioned disease by administering to a subject in need thereof a procyanidin polymer composition from croton biflorus, preferably crofelemer.
In one embodiment, there is provided a method of treating, preventing or ameliorating hair-liver-gut syndrome (THES), particularly secretory diarrhea associated with THES, in a subject, particularly an infant, by administering to a subject in need thereof a procyanidin polymer composition from croton agalactiae, preferably crofelemer, the subject having the disease described above.
In one embodiment, there is provided a method of treating, preventing or ameliorating immune dysfunction X-linked multiple endocrinopathy (IPEX), in particular secretory diarrhea associated with IPEX, in a subject, in particular an infant, by administering to a subject in need thereof a procyanidin polymer composition from croton agalactiae, preferably crofelemer, the subject having the disease described above.
In one embodiment, there is provided a method of treating, preventing or ameliorating IPEX-like syndrome, in particular secretory diarrhea associated with IPEX-like syndrome, in particular in infants, in a subject, in particular an infant, having the above-mentioned disease, by administering to a subject in need thereof a procyanidin polymer composition from croton biflorus, preferably crofelemer.
In one embodiment, there is provided a method of treating, preventing or ameliorating Congenital Sodium Diarrhea (CSD), in particular secretory diarrhea associated with CSD, in a subject, in particular an infant, having the above-mentioned disease, by administering to a subject in need thereof a procyanidin polymer composition from croton biflorus, preferably crofelemer.
In one embodiment, there is provided a method of treating, preventing or ameliorating Congenital Chloride Diarrhea (CCD), particularly CCD-associated secretory diarrhea, in a subject, particularly an infant, by administering to a subject in need thereof a procyanidin polymer composition from croton agalactiae, preferably crofelemer, having a disease described above.
In one embodiment, a method is provided for treating, preventing or ameliorating Primary Bile Acid Malabsorption (PBAM), particularly secretory diarrhea associated with PBAM, in a subject, particularly an infant, having the above-mentioned disease, by administering to a subject in need thereof a procyanidin polymer composition from croton agalactiae, preferably crofelemer.
In particular embodiments, the subject is administered parenteral complete nutrition, and in certain embodiments, lifetime parenteral complete nutrition is required. In other specific embodiments, the subject has undergone or is in need of a surgical bowel resection. In other specific embodiments, the subject has or is in need of an intestinal transplant, particularly a small intestine transplant or has or is in need of a Hematopoietic Stem Cell Transplant (HSCT). In certain embodiments, administration of Crofelemer to an infant or child with CDD may reduce growth retardation and delay. In further embodiments, administration of the proanthocyanidin polymer composition reduces electrolyte imbalance, dehydration, metabolic acidosis, or metabolic alkalosis.
In certain embodiments, the subject exhibits grade 1, grade 2, grade 3, or grade 4 diarrhea according to the Common Toxicity Criteria (Common susceptibility criterion) from the National cancer institute (National cancer institute) or various diarrhea grades as defined based on the National Institutes of Health.
In various embodiments, administering comprises: from about 250mg to about 1000mg per day; about 250 mg/day; about 500 mg/day; about 1000 mg/day; about 125mg 2 times per day; about 250mg 2 times per day; or about 500mg of 2 crofelemer per day, particularly enteric protective crofelemer formulated as an orally administered tablet to a subject in need thereof. In further embodiments, Crofelemer is formulated for oral administration but without enteric protection, e.g., without an enteric coating. In further embodiments, the dosage of the procyanidin polymer composition is combined with about 250mg to about 1000mg per day; about 250 mg/day; about 500 mg/day; about 1000 mg/day; about 125mg 2 times per day; about 250mg 2 times per day; or about 500mg of an enteric protective crofelemer oral dosage form 2 times per day.
In certain embodiments, particularly for pediatric use, Crofelemer is administered at a dose of 1-10mg/kg, particularly about 1mg/kg, 2mg/kg, 5mg/kg, 7mg/kg, or 10mg/kg, 1 time per day, or more preferably, 2 times per day, or even 3 times per day. Crofelemer may be formulated as a solid oral dosage form, but is more preferably formulated in a liquid form for administration to an infant or adolescent. For example, Crofelemer may be dissolved at a concentration of 20 μ g/ml to 2mg/ml Crofelemer and administered in an appropriate volume at the desired dose of about 1 to 10 mg/kg. Crofelemer can be enteric-coated powder or granule, and can also be dissolved in aqueous preparation without enteric coating. In certain embodiments, the Crofelemer formulation is administered by a feeding tube. Alternatively, the formulation is delivered orally. In a specific embodiment, Crofelemer is dissolved at a concentration of 20 μ g/ml to 2mg/ml and is not enteric coated and is administered orally twice daily or twice daily via a feeding tube at a dose of 2mg/kg to 10mg/kg per day.
The dose may be an amount of the composition comprising the proanthocyanidin polymer composition from croton biflorus that is bioequivalent to a dose of the enteric-protective formulation of Crofelemer.
In one embodiment, a subject is considered to be treated if the subject exhibits one or more of the following: reduced number of bowel movements per day, reduced number of watery bowel movements per day, improved daily or weekly scores for abdominal pain or discomfort, improved daily stool consistency scores, reduced stool consistency scores (from watery to formed), reduced number of days a subject is experiencing urgency per week, reduced number of days a subject is experiencing fecal incontinence per week.
In additional embodiments, a subject is considered treated or symptom ameliorated if the subject exhibits one or more of the following: a reduction in the need for parenteral nutrition, a reduction in electrolyte imbalance, an improvement in nutritional status, an improvement in hydration, a reduction in growth delay.
Additional embodiments are disclosed below.
Detailed Description
Congenital diarrheal disorders are a group of miscellaneous diarrheal diseases, mainly inherited, which appear early in life, typically in infancy, with severe watery diarrhea, serum chemical imbalance and developmental arrest. With the rapid progression of the disease, immediate and long-term TPN becomes important and may be the only treatment option in most cases of CDD. Infants are usually hospitalized to receive supportive care, nutritional rehabilitation, and medications. Eventually, intestinal transplantation becomes necessary for survival. Hematopoietic Stem Cell Transplantation (HSCT) is used for diseases with potential immunodeficiency, similar to intestinal transplantation. Invasive treatment carries serious complications and risk of death. In all respects, CDD is a life-threatening disease with a high mortality rate for life.
In contrast to osmotic diarrhea, certain CDDs are characterized by secretory diarrhea and apparently result from small intestinal cell defects that regulate nutrient absorption and secretion. Secretory diarrhoea is caused by fluid secreted into the intestinal lumen and is the most severe form of diarrhoea, usually requiring total parenteral nutrition. There are no antidiarrheal drugs approved for the treatment of CDD-related secretory diarrhea. Crofelemer and other procyanidin polymer compositions of croton longum are antagonists of the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channels (CaCC), which mediate intestinal fluid secretion by intestinal epithelial cells. By inhibiting these pathways, Crofelemer and other proanthocyanidin polymer compositions of croton bifidus can treat, prevent, or ameliorate symptoms of secretory diarrhea associated with CDD. In addition, Crofelemer and other procyanidin polymer compositions of croton biflorus have significant therapeutic potential for CDD, particularly for infants, due to minimal drug absorption and thus high safety.
The methods disclosed herein involve administering an effective amount of a procyanidin polymer, e.g., crofelemer, to a subject having, e.g., CDD.
I. Definition of
Where a term is provided in the singular, the inventors also contemplate aspects of the invention described by the plural of that term. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise, e.g., "a compound" includes a plurality of compounds. Thus, for example, reference to "a method" includes one or more methods and/or types of steps described herein and/or which will become apparent to those skilled in the art upon reading the present disclosure.
"improve," "improvement," "improving," and the like refer to, for example, a detectable improvement or a detectable change consistent with an improvement that occurs in the subject or at least a minority of the subjects, e.g., in at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%, or between any two of these values. Such an improvement or alteration can be observed in a treated subject compared to a subject not treated with Crofelemer, wherein the untreated subject has or is developing the same or similar disease, disorder, symptom, or the like. The improvement in the disease, disorder, symptom, or assay parameter can be determined in a subjective or objective manner, e.g., self-assessment of the subject (or assessment by a caregiver), assessment by a clinician, or making an appropriate assay or measurement. The improvement may be transient, prolonged or permanent, or may vary over time during or after administration of Crofelemer to the subject, or used in assays or other methods described in the references described or cited herein, e.g., within the time ranges described below, or about 1 hour after administration or use of Crofelemer to about 7 days, 2 weeks, 28 days, or 1,3, 6, 9 months or more after the subject receives such treatment. In certain embodiments, the procyanidin polymer composition, particularly Crofelemer, is administered chronically.
For example, "modulation" of a symptom, level, or biological activity, etc., of a molecule refers to, for example, a detectable increase or decrease in the symptom, level, or biological activity, etc. Such an increase or decrease is observed in treated subjects compared to subjects not treated with Crofelemer, where the untreated subjects have or are experiencing the same or similar disease, disorder, symptom, or the like. Such increase or decrease can be at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 1000% or more or between any two of these values. The adjustment may be determined in a subjective or objective manner. Modulation may be transient, prolonged, or permanent, or may be variable at relevant times during or after administration of Crofelemer to a subject, or used in assays or other methods described in the references described or cited herein, e.g., within the time ranges described below, or about 1 hour after administration or use of Crofelemer to about 7 days, 2 weeks, 28 days, or 1,3, 6, 9 months or more after a subject receives such treatment.
As used herein, a "subject" includes an animal, including an adult or pediatric patient, e.g., a human, that has or is at risk of CDD or otherwise may benefit from administration of Crofelemer as described herein.
The phrase "therapeutically effective amount" of a compound refers to an amount of Crofelemer or its equivalent that is effective to treat, or ameliorate the symptoms of CDD when administered to a subject in a single or multiple doses.
The phrase "prophylactically effective amount" of a compound refers to an amount of Crofelemer or its equivalent that is effective to prevent or delay the onset of CDD symptoms upon single or multiple dose administration to a subject.
The term "administering" includes the route by which crofelemer is introduced into a subject to perform its intended function. Examples of routes of administration that may be used include injection, oral, inhalation, vaginal, rectal and transdermal. The pharmaceutical preparation may be administered in a form suitable for each route of administration. For example, these formulations are administered by injection, inhalation, ointment or suppository in the form of tablets or capsules. Administration can also be by oral, injection, infusion or inhalation; typically by lotion or ointment external application; and rectal administration by suppository. Oral administration is preferred. Depending on the route of administration, Crofelemer may be coated with, or placed in, selected materials to protect it from natural conditions that may adversely affect its ability to perform its intended function. crofelemer may be administered alone, or with another or more active agents as described above, or with a pharmaceutically acceptable carrier, or both. Exemplary enteric coating forms of Crofelemer are described, for example, in U.S. patent 7,556,831.
Administration "in combination with" one or more other therapeutic agents includes simultaneous (concomitant) and sequential administration, in any order.
The phrase "pharmaceutically acceptable" refers to Crofelemer, compositions and/or dosage forms containing Crofelemer, as described herein, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication and commensurate with a reasonable benefit/risk ratio.
The phrase "pharmaceutically acceptable carrier" includes pharmaceutically acceptable materials, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, which are involved in carrying or transporting the subject chemical from one organ or portion of the body to another organ or portion of the body.
As used herein, the term "treating" is intended to include reducing or ameliorating the progression, severity and/or duration of a disorder or one or more symptoms or CDD.
For example, treating CDD can include ameliorating the symptoms of CDD, e.g., reduced number of bowel movements per day (frequency), reduced number of watery bowel movements per day, reduced frequency of symptoms (urgency, fecal incontinence), reduced severity of symptoms (abdominal pain or discomfort), reduced daily stool consistency score (watery to formed), resulting in reduced stool consistency from watery to formed stools, improved electrolyte balance, improved nutritional status, reduced parenteral nutritional requirements, improved growth or reduced growth delay, etc.
The term "obtaining" as in "obtaining Crofelemer" is intended to include purchasing, synthesizing, isolating, extracting, or otherwise obtaining Crofelemer.
Active compounds
A. Procyanidins
Procyanidins are a group of condensed tannins. In animal experiments, crude extracts from medicinal plants such as Pythus angolensis and Baphica beans (Baphica nitida) have been shown to have antidiarrheal properties (Onwukaeme and Anuforo,1993, Discovery and Innovation,5: 317; Onwukaeme and Lot,1991, Phytotherapy Res.,5: 254). Crude tannin-containing extracts, particularly extracts from carob pods and sweet chestnut wood, have been proposed as therapeutic or prophylactic agents (U.S. Pat. No. 5,043,160; European patent 481,396).
Procyanidins are composed of at least two or more monomeric units that may have the same or different monomeric structures. The monomeric units (commonly referred to as "anthocyanins") are typically monomeric flavonoids, which include catechin, epicatechin, gallocatechin, epigallocatechin, flavanols, flavonols and flavan-3, 4-diols, white cyanidin and anthocyanins. Thus, the polymer chains are based on different building blocks, which produce a wide variety of polymeric procyanidins and a large number of possible isomers (Hemingway et al, 1982, J.C.S.Perkin,1: 1217). In most plants, larger polymers of flavonoid 3-alcohol units predominate, and they are found to have average molecular weights in excess of 2,000 daltons, containing 6 or more units (Newman et al, 1987, Mag. Res. chem.,25: 118).
Procyanidin polymers are found in a variety of plants, particularly plants with a woody growth habit (e.g., Croton spp.) and calabash spp. (Calophyllum spp.). many different Croton species found in south america, including Croton sakurtaris, Croton gossypiifolius, Croton palainostim, Croton dragon, Croton erythorhilus, and Croton deacoides all produce a red, viscous latex tree fluid known as dragon tree or "dragon's blood". us 5,211,944 first describes the isolation of water-soluble procyanidin polymer compositions from Croton species, and the use of such compositions as antiviral agents (see also urbillas et al, 1994, phytodicine, 1: 77.) the procyanidin polymer compositions have been shown to have antiviral activity against a variety of plants, including respiratory viruses, influenza viruses, parainfluenza viruses, and calophylla virus 5,211,944. the isolation of water-soluble procyanidin compositions from Croton sakura (also discloses the isolation of Calophyllum echinacea) Use as an antiviral agent.
Exemplary proanthocyanidin polymer compositions useful in the methods set forth herein are preferably isolated from a croton species or a calabash species or by any method known in the art. For example, proanthocyanidin polymer compositions may be isolated from Croton species or Calophyllum species by methods disclosed in U.S. Pat. No. 5,211,944 or Ubillas et al, 1994, phytomedine 1: 77-106.
In a particular embodiment, the procyanidin polymer composition useful in the methods set forth herein is crofelemer.
Crofelemer is an oligomeric procyanidin extracted and purified from the red viscous latex of croton pilosus (Euphorbiaceae) plant. The plant is widely distributed throughout central america and tropical regions of south america, and its properties, including the treatment of diarrhea, are widely recognized by ethnic botists and local therapists (McRae 1988). Crofelemer is believed to block and/or modulate CFTR (cystic fibrosis transmembrane conductance regulator) chloride (Cl) by the lumen-) The channel exerts its antidiarrheal effect. Crofelemer has demonstrated in vitro activity on cholera toxin, forskolin, escherichia coli LT and STa toxin-mediated Cl-secretion and normalized electrolyte and humoral accumulation in CT-treated mice through its effect on CFTR chloride channels (Gabriel1999, Fischer 2004, Adam 2005). Crofelemer also significantly ameliorates secretory diarrhea in humans due to enterotoxigenic e.coli (DiCesare 2002), and is also thought to cause secretory diarrhea through activation of CFTR (Kunzelmann 2002). Blocking or inhibitory modulation of the CFTR channel is expected to have a negative effect on humans, even mimicking cystic behaviorAnd (4) fibrosis is carried out. Crofelemer, however, has little systemic bioavailability in humans. When studied, the results showed little or no absorption by the gastrointestinal tract and that the normal male subjects were well tolerated by Crofelemer. Thus, the site of action of Crofelemer is localized in the gastrointestinal tract.
Crofelemer (CAS 148465-45-6) is an oligomeric procyanidin with varying chain length derived from croton dragon's blood of the family euphorbiaceae. Crofelemer has an average molecular weight between about 1500 daltons to about 2900 daltons. The Crofelemer-containing monomers include catechin, epicatechin, gallocatechin, and epigallocatechin. Crofelemer has a chain length in the range of about 3 to about 30 units and an average chain length of about 7 to 8 units. The structure of Crofelemer is shown below.
Wherein the average value n is 6.
Another method of isolating crofelemer may be found in U.S. patent publication No. 2005/0019389, the contents of which are expressly incorporated herein.
Alternatively, the procyanidin polymer composition may be SB300, as described, for example, by Fischer, H. et al (2004, J.Ethnopharmacol.,93(2-3): 351-. SB300 is a natural product extract that is particularly suitable for use in non-enteric coated or protected formulations and compositions. In one embodiment, a pharmaceutically acceptable composition comprising a procyanidin polymer from croton agalactiae useful in the treatment methods of the invention can be obtained from croton agalactiae, for example, as described in WO 00/47062 by Shaman Pharmaceuticals, inc.
In further embodiments, raw latex from or extracts from the genus croton or calabash species may be used in the methods set forth herein. Exemplary extracts are described in Persinos et al, 1979, J.Pharma.Sci.68:124 and Sethi,1977, Canadian J.Pharm.Sci.12: 7.
It is to be understood that while various embodiments of the present invention are described herein, if Crofelemer is referred to herein, bioequivalent amounts of other proanthocyanidin polymer compositions from croton japonicas, such as SB300, can also be used.
Methods of treatment
Provided herein are methods of treating, preventing, or ameliorating secretory diarrhea or other gastrointestinal symptoms caused by CDD, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a proanthocyanidin polymer composition isolated from croton agalactiae. In particular embodiments, a therapeutically effective amount of Crofelemer is administered to the subject. In a particular embodiment, the Crofelemer is enteric coated. In another embodiment, the Crofelemer is enteric-coated. The subject is preferably a human.
CDD, which has been identified as being associated with secretory diarrhea and which may be treated with a procyanidin polymer composition from Croton tiglium, particularly crofelemer, includes microvilli inclusion body disease (MVID) which may be caused by a mutation in the MYO5B gene, congenital clusteriform bowel disease (CTE) which may be caused by a mutation in the EPCAM gene, hair-liver-bowel syndrome (THES) which may be caused by a mutation in the TTC37 gene, immune dysfunction X-linked multiple endocrine disease (IPEX) which may be caused by a mutation in the FOXP3 gene, IPEX-like syndrome which may be caused by a mutation in the IL2R α gene and the STAT5b gene, Congenital Sodium Diarrhea (CSD) which may be caused by a mutation in the GUCY2C gene and/or the SLC9A3 gene, Congenital Chloride Diarrhea (CCD) which may be caused by a mutation in the SLC26A3 gene, and primary bile acid malabsorption (PBA 2) which may be caused by a mutation in the SLC10A2 gene.
CDD is characterized by a very early onset, including within the first month of life, and results in severe and often persistent secretory diarrhea, low birth weight, developmental arrest, growth and development delays, dehydration, malnutrition, electrolyte imbalance, with high morbidity and mortality risks. Accordingly, the treatment methods provided herein include administering to a patient with CDD an enteric-protective formulation of a proanthocyanidin polymer composition of croton biflorus, preferably crofelemer, more preferably crofelemer, which reduces the incidence and/or severity of secretory diarrhea, thereby improving hydration, nutritional status, electrolyte balance, growth and development, and reducing the risk of mortality and morbidity. In certain embodiments, methods of reducing the severity or incidence of metabolic acidosis, metabolic alkalosis, and/or malnutrition in a subject with CDD are provided. Methods of treatment are provided to administer Crofelemer or another procyanidin polymer composition of croton biflorum to reduce the need for parenteral nutrition, bowel resection, or bowel transplantation. In certain embodiments, the subject has undergone a small bowel resection and/or bowel transplantation. In additional embodiments, the subject receives parenteral nutrition, and in certain embodiments, parenteral complete nutrition.
In certain embodiments, the subject is a neonate, an infant, a child, an adolescent, or an adult. In particular embodiments, treatment with Crofelemer (or other proanthocyanidin polymer composition from croton japonicas) is initiated at birth, within the first week after birth, within the first two weeks after birth, within the first month after birth, within the first two months after birth, within the first six months after birth, or within the first year after birth.
In particular embodiments, the subject has secretory diarrhea associated with CDD for the following reasons: 1) deficiencies in digestion, absorption and transport of nutrients and electrolytes; 2) defects in intestinal cell differentiation and polarization; 3) defective differentiation of enteroendocrine cells; or 4) a deficiency in the regulation of the intestinal immune response; and, as a result, disturbances in digestion, absorption and gastrointestinal activity.
In one embodiment, treating CDD comprises amelioration of symptoms of CDD including, for example, a reduction in the number of bowel movements per day (number of stools), a reduction in the number of watery stools per day (frequency of abnormal stools), a reduction in the frequency of symptoms occurring (urgency, fecal incontinence), a reduction in symptom severity (abdominal pain or discomfort), a reduction in the daily stool consistency score (watery to formed) or a reduction in stool consistency, resulting in watery stool formation. The drop can be measured from baseline. The baseline may be determined several days prior to treatment with crofelemer.
In one aspect, provided herein is a method of treating CDD in a subject, the method comprising administering to a subject in need thereof a composition comprising an effective amount of crofelemer to treat, prevent or ameliorate secretory diarrhea associated with CDD. In a particular embodiment, Crofelemer is an enterically coated oral dosage form. In another embodiment, Crofelemer is an oral dosage form without enteric protection.
In certain embodiments, Crofelemer is administered until symptoms of CDD improve, and then is terminated. Since CDD is a chronic disease and causes severe and persistent secretory diarrhea, crofelemer may be administered chronically as needed to reduce the severity of secretory diarrhea and reduce dehydration, malnutrition, and electrolyte imbalance caused by severe secretory diarrhea.
As will be apparent to those skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration may vary depending upon the age, weight and type of mammal being treated, the particular compound being used and/or the particular use for which the compound is being used. Determination of an effective dosage level, which is the dosage level necessary to achieve the desired result, can be accomplished by one of skill in the art using routine pharmacological methods and with reference to the data provided herein.
Crofelemer (or other proanthocyanidin polymer composition from croton agalactiae) may be administered, for example, once daily, twice daily, three times daily, or four times daily or, if necessary, multiple times daily. For example, Crofelemer, preferably enterically coated Crofelemer, may be administered in doses such as 25mg BID to about 3000mg TID, preferably about 125mg to about 1000mg per day; about 250mg to about 1000mg per day; about 250 mg/day; or about 1000 mg/day Crofelemer. In another embodiment, depending on the symptoms, 125mg BID to about 500mg BID Crofelemer is administered. In another embodiment, crofelemer is administered once daily at 125mg, at 125mg BID, at 250mg BID, or at 500mg BID. In another embodiment, Crofelemer is administered in the form of 125mg BID. In another embodiment, Crofelemer is administered in the form of 500mg BID. In additional embodiments, methods are provided for treating or ameliorating CDD-related secretory diarrhea in a subject in need thereof, a dose of a procyanidin polymer composition (including a crofelemer oral dosage form without enteric protection) to about 125mg to about 1000mg per day; 250mg to about 1000mg per day; about 250 mg/day; about 1000 mg/day; about 125mg BID to 500mg BID; about 125mg 1 or 2 times per day; about 250mg BID; or about 500mg 2 times/day of an enteric-protected crofelemer oral dosage form is bioequivalent. Crofelemer may be administered orally, for example in the form of tablets, powders, liquids or capsules. In a preferred embodiment, Crofelemer is formulated as an enterically coated oral dosage form. In another embodiment, the Crofelemer is an enteric-coated oral dosage form.
In certain embodiments, particularly for pediatric use, Crofelemer is administered at a dose of 1-10mg/kg, specifically about 1mg/kg, 2mg/kg, 5mg/kg, 7mg/kg, or 10mg/kg, once per day, or more preferably, 2 times per day, or even 3 times per day. Crofelemer may be formulated as a solid oral dosage form, but is more preferably formulated in a liquid form for administration to an infant or adolescent. For example, Crofelemer may be dissolved at a concentration of 20 μ g/ml to 2mg/ml Crofelemer and administered in an appropriate volume at the desired dose of about 1 to 10 mg/kg. Crofelemer can be enteric-coated powder or granule, and can also be dissolved in aqueous preparation without enteric coating. In certain embodiments, the Crofelemer formulation is administered by a feeding tube. Alternatively, the formulation is delivered orally. In a specific embodiment, Crofelemer is dissolved at a concentration of 20 μ g/ml to 2mg/ml and is not enteric coated, and is administered twice daily orally or through a feeding tube at a dose of 2mg/kg to 10 mg/kg.
In additional embodiments, the subject is treated with crofelemer for 2, 4, 6,8, 10, 12, 14, 16, 18, 20, 22, 24 or more weeks or 26 or more weeks. In a preferred embodiment, crofelemer is administered chronically. The duration of treatment may vary depending on the severity of the secretory diarrhoea.
In one aspect, provided herein is a method of ameliorating CDD-associated, severe, secretory diarrhea in a subject, wherein a subject is considered to have been treated if the subject experiences a reduced number of watery bowel movements per day and/or over a few days, one or more weeks of Crofelemer administration, comprising administering to a subject in need thereof a composition comprising an effective amount of Crofelemer to ameliorate the secretory diarrhea.
In certain embodiments, crofelemer (or other proanthocyanidin polymer composition from croton agalactiae) is administered to a subject for the treatment of CDD in combination with one or more anti-diarrhea drugs (such as, but not limited to, loperamide, octreotide, probiotics) and any other drugs that may be used in the treatment of CDD.
Pharmaceutical preparations
Also provided herein are pharmaceutical compositions comprising an effective amount of a procyanidin polymer composition of croton biflorus, e.g., crofelemer described herein, and a pharmaceutically acceptable carrier. In another embodiment, the effective amount is effective to treat, prevent or ameliorate secretory diarrhea associated with CDD.
Examples of the preparation and use of Crofelemer have been described in U.S. patent 7,556,831, U.S. patent publication No. 20070254050, and U.S. patent publication No. 20080031984, which are all incorporated herein by reference in their entirety.
One embodiment includes a pharmaceutical composition comprising a procyanidin polymer composition of croton biflorus, e.g., crofelemer, and a pharmaceutically acceptable carrier. In a preferred embodiment, the pharmaceutical composition is an enterically protected oral dosage form, such as a tablet or capsule. Alternatively, the pharmaceutical composition is an enteric-protected oral dosage form.
The pharmaceutical compositions described herein may further comprise excipients, for example, one or more of diluents, binders, lubricants, disintegrants, colorants, flavorants or sweeteners. The compositions may be formulated for use in selected coated and uncoated tablets, hard and soft gelatin capsules, dragees, lozenges, wafers, pills and powders in sealed packages. For example, compositions for topical use, such as ointments, pomades, creams, gels, and lotions, may be formulated.
In certain embodiments, these pharmaceutical compositions are suitable for topical or oral administration to a subject. In further embodiments, as described in detail below, the pharmaceutical compositions may be specifically formulated for administration in solid or liquid form, including those suitable for: (1) oral administration, e.g., as a liquid medicine (aqueous or non-aqueous solution or suspension), tablet, bolus, powder, granule, paste; (2) parenteral administration, for example by subcutaneous, intramuscular or intravenous injection, as a sterile solution or suspension; (3) topical application, e.g. to the skin in the form of a cream, ointment or spray; (4) intravaginal or intrarectal, such as a vaginal ring, cream or foam; (5) aerosols, for example as aqueous aerosols, liposome formulations or solid particles containing the compound.
The pharmaceutical carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc powder; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) a phosphate buffer solution; and (21) other non-toxic compatible materials used in pharmaceutical formulations.
Wetting, emulsifying and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring, mold release, coating, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.
Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like, (2) oil-soluble antioxidants such as ascorbyl palmitate, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, α -tocopherol, and the like, and (3) metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
Compositions comprising procyanidin polymer compositions, such as Crofelemer, include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Typically, the amount can range from about 0.01% to about 99% of the active ingredient, for example, from about 5% to about 70% or from about 10% to about 30% in one hundred percent.
Liquid dosage forms for oral or rectal administration of Crofelemer or its equivalent may include, for example, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
In addition to Crofelemer or its equivalent, suspensions may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Dosage forms for topical or transdermal administration of Crofelemer may include, for example, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. Ointments, pastes, creams and gels may contain, in addition to crofelemer, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof. In addition to Crofelemer, powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can also contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions can include, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. For example, proper fluidity can be maintained, for example, by the use of a coating material, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
In one embodiment, Crofelemer is enterically coated to protect it from degradation by the acidic conditions of the stomach and/or from interaction with proteins present in the stomach, such as pepsin, e.g., an enteric protective formulation. In a particular embodiment, the Crofelemer is in the form of a tablet. In another embodiment, the tablets are enteric coated, e.g. by
In certain embodiments, the composition is formulated with one or more compounds that neutralize gastric acid. Alternatively, the pharmaceutical composition containing the composition may be administered simultaneously or sequentially or subsequently with the administration of the pharmaceutical composition that neutralizes gastric acid. Compounds useful for neutralizing gastric acid, such as antacids include, but are not limited to, aluminum carbonate, aluminum hydroxide, bismuth subnitrate, bismuth subsalicylate, calcium carbonate, dihydroxyaluminum sodium carbonate, magaldrate, magnesium carbonate, magnesium hydroxide, magnesium oxide, and mixtures thereof. Compounds capable of reducing gastric acid secretion and/or reducing gastric acidity are well known in the art and include, but are not limited to, antacids (aluminum hydroxide, aluminum carbonate, aluminum glycinate, magnesium oxide, magnesium hydroxide, magnesium carbonate, calcium carbonate, sodium bicarbonate), gastric acid blockers and combinations of any of the foregoing. Generally, any drug approved for sale by the relevant governmental agency and capable of reducing gastric acid production and/or reducing gastric acidity can be administered in combination with an inhibitor molecule (e.g., crofelemer) according to the methods set forth herein.
In particular embodiments where the Crofelemer has no enteric coating, the Crofelemer is formulated with one or more compounds capable of reducing gastric acid secretion and/or capable of reducing gastric acidity. In an exemplary embodiment, Crofelemer is formulated as a controlled release (delayed release) composition, such as Merck GEM, Alza OROS, wax matrix, (release is significantly delayed until the formulation begins after passing from the stomach and into the intestine).
Also provided herein is a pharmaceutical formulation of Crofelemer comprising the composition and a pharmaceutically acceptable carrier in an amount effective to treat secretory diarrhea associated with CDD. In one embodiment, a directly compressible crofelemer (e.g., a tablet that can be directly compressed to a pharmaceutically acceptable hardness and friability without excipients), optionally compressed into a tablet using a lubricant such as, but not limited to, magnesium stearate, is enteric coated. These formulations can be prepared by methods known in the art, see, e.g., Remington's pharmaceutical sciences, 18 th edition, ed.
In a particular embodiment, the procyanidin polymer composition comprises crofelemer (CAS 148465-45-6).
In another embodiment, the composition is enteric coated. Enteric coating layers are those that remain intact in the stomach, but dissolve and release the contents of the dosage form once they reach the small intestine. A number of enteric coatings are prepared with ingredients having acidic groups such that at the very low pH found in the stomach, i.e., pH 1.5-2.5, the acidic groups are not ionized and the coating layer remains in undissociated, insoluble form. At higher pH levels, such as in the intestinal environment, the enteric coating will convert to an ionized form, which can dissolve to release the inhibitor molecule. Other enteric coatings remain intact until they are degraded by enzymes in the small intestine; other enteric coatings rupture upon definitive exposure to a wet environment, leaving the coating layer intact until after entry into the small intestine.
Polymers that can be used to prepare the enteric coating include, but are not limited to, shellac, starch and amylose acetate phthalate, styrene-maleic acid copolymers, cellulose acetate succinate, Cellulose Acetate Phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate (grades HP-50 and HP-55), ethyl cellulose, fats, butyl stearate and methacrylic acid-methacrylate copolymers with acid ionizable groups. In one embodiment, the pharmaceutical composition comprises a polymeric procyanidin composition and an enteric coating polymerL30D, an anionic copolymer of methacrylic acid and methyl acrylate having an average molecular weight of 250,000 daltons. In another embodiment, the enteric coating polymer isL30D-55. The enteric coating may be applied to the Crofelemer composition by any method known in the art for applying enteric coatings. For example, but not limited to, enteric polymers may be applied using an organic solvent based solution containing 5-10% w/w polymer for spray application and up to 30% w/w polymer for pan applicationAnd (4) coating. Commonly used solvents include, but are not limited to, acetone/ethyl acetate mixtures, dichloromethane/methanol mixtures and ternary mixtures containing these solvents. Some enteric polymers, such as methacrylic acid-methacrylate copolymers, can be coated using water as a dispersant. The volatility of the solvent system must be adjusted to prevent sticking due to stickiness and to prevent high porosity of the coating due to premature spray drying or precipitation of the polymer upon evaporation of the solvent.
In another embodiment, the pharmaceutical composition comprising Crofelemer is formulated as an enterically coated granule or powder (with microspheres having a diameter of 300-. Enteric coated powders or granules may also be mixed with food, particularly for pediatric administration. Granules and powders may be prepared using any method known in the art, such as, but not limited to, crystallization, spray drying or any comminuting method, such as using a high speed mixer/granulator. Exemplary formulations can be found, for example, in the following U.S. patents and U.S. patent application nos.: 7,341,744, respectively; USSN 11/510,152; and USSN 12/175,131.
In a further embodiment, the pharmaceutical composition comprising Crofelemer is formulated as an aqueous solution, wherein no enteric coating or protection in any suitable aqueous vehicle is used.
Crofelemer can be formulated into pharmaceutically acceptable dosage forms by methods known to those skilled in the art, regardless of the route of administration chosen.
In combination therapy treatment, the compound and other pharmaceutically active agents are administered to a mammal (e.g., a human, male or female) by methods known in the art. The active agents may be administered in a single dosage form or in separate dosage forms. Effective amounts of other therapeutic agents are well known to those skilled in the art. However, it is well within the ability of the skilled person to determine the optimal effective amount range of the other therapeutic agent. In one embodiment, the effective amount of the compound is less than the effective amount in the absence of administration of the other therapeutic agent to the animal. In another embodiment, the effective amount of the active agent is less than the effective amount in the absence of administration of another of the compounds. In this manner, the adverse side effects associated with high doses of any one of the active agents can be minimized. Other potential advantages, including but not limited to improved dosing regimens and/or reduced drug costs, will be apparent to those skilled in the art.
In various embodiments, the therapy (e.g., prophylactic or therapeutic agent) is administered at the following intervals: less than 5 minute intervals, less than 30 minute intervals, 1 hour intervals, at about 1 to about 2 hour intervals, at about 2 hour to about 3 hour intervals, at about 3 hour to about 4 hour intervals, at about 4 hour to about 5 hour intervals, at about 5 hour to about 6 hour intervals, at about 6 hour to about 7 hour intervals, at about 7 hour to about 8 hour intervals, at about 8 hour to about 9 hour intervals, at about 9 hour to about 10 hour intervals, at about 10 hour to about 11 hour intervals, at about 11 hour to about 12 hour intervals, at about 12 hour to 18 hour intervals, 18 hour to 24 hour intervals, 24 hour to 36 hour intervals, 36 hour to 48 hour intervals, 48 hour to 52 hour intervals, 52 hour to 60 hour intervals, at intervals of 60 hours to 72 hours, at intervals of 72 hours to 84 hours, at intervals of 84 hours to 96 hours or at intervals of 96 hours to 120 hours. In one or more embodiments, two or more therapies are administered during the visit of the same patient.
V. medicine box
Also provided herein are kits, e.g., kits for treating diarrhea, e.g., secretory diarrhea associated with CDD in a subject. The kit may comprise, for example, Crofelemer or a pharmaceutical composition comprising Crofelemer and instructions for use. The instructions for use may include prescription information, dosage information, stored information, and the like.
The label instructions include, for example, instructions for taking crofelemer for at least 3 days to treat CDD. The instructions may also show, for example, that 125mg BID to 500mg BID of crofelemer is taken until the symptoms disappear. The instructions may also show, for example, that 500mg BID of Crofelemer is taken until the CDD symptoms disappear.
All publications, patents, and patent applications cited herein are incorporated by reference in their entirety.