阅读说明：本技术 用于治疗口腔粘膜炎的方法和组合物 (Methods and compositions for treating oral mucositis ) 是由 S·A·凯茨 S·帕金森 P·C·奥康纳 于 2019-10-17 设计创作，主要内容包括：公开了用于治疗患者的口腔粘膜炎的方法和包含双磷脂素的药物组合物。(Methods and pharmaceutical compositions comprising a bisphosphineol for treating oral mucositis in a patient are disclosed.)

1. A method of treating oral mucositis in a patient in need thereof comprising administering to said patient an effective amount of a bisphosphlipin, or a pharmaceutically acceptable salt thereof, wherein the bisphosphlipin is selected from Nu-2, Nu-3, Nu-4, Nu-5 and Nu-8.

2. The method of claim 1, wherein the administration is topical administration.

3. The method of claim 2, wherein the topical administration is applied to the oral cavity of the patient.

4. The method of claim 1, wherein said administering is performed using a bisphosphclaimed in a gel, ointment, oil, solution, suspension, emulsion, or other viscous composition.

5. The method of claim 1, wherein the administering is performed using a bisphosphithin in a mouthwash.

6. The method of claim 1, wherein at least one additional active ingredient is administered to the patient.

7. The method of claim 1, wherein the bisphosphatilin is administered with a pharmaceutically acceptable carrier.

8. The method of claim 1, wherein the administering is performed in a multiple dose regimen.

9. The method of claim 8, wherein said administering is performed one or more times per day.

10. The method of claim 1, wherein the patient is a human.

11. A method of treating oral mucositis in a patient in need thereof, comprising topically administering to the oral cavity of said patient an effective amount of a pharmaceutical composition comprising a bisphosphclaimed in or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein said bisphosphclaimed in is selected from Nu-2, Nu-3, Nu-4, Nu-5 and Nu-8.

12. The method of claim 11, wherein said administering is performed using a bisphosphclaimed in a gel, ointment, oil, solution, suspension, emulsion, or other viscous composition.

13. The method of claim 11, wherein the administering is performed using a bisphosphithin in a mouthwash.

14. The method of claim 11, wherein the bisphosphatilin is present in the pharmaceutical composition in an amount of about 1% to about 20% (weight/weight).

15. The method of claim 14, wherein the bisphosphatilin is present in the pharmaceutical composition in an amount of about 5% to about 15% (weight/weight).

16. The method of claim 11, wherein the bisphosphatilin is present in the pharmaceutical composition in an amount of about 30% to about 50% (weight/weight).

17. The method of claim 11, wherein the administering is performed in a multiple dose regimen.

18. The method of claim 11, wherein said administering is performed one or more times per day.

19. The method of claim 11, wherein the patient is a human.

20. A pharmaceutical composition for use in the treatment of oral mucositis comprising a bisphosphipidin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the bisphosphipidin is selected from Nu-2, Nu-3, Nu-4, Nu-5 and Nu-8.

21. The pharmaceutical composition of claim 20, wherein the bisphosphatilin is present in the pharmaceutical composition in an amount of about 1% to about 20% (weight/weight).

22. The pharmaceutical composition of claim 21, wherein the bisphosphatilin is present in the pharmaceutical composition in an amount from about 5% to about 15% (weight/weight).

23. The pharmaceutical composition of claim 20, wherein the bisphosphatilin is present in the pharmaceutical composition in an amount of about 30% to about 50% (weight/weight).

24. The pharmaceutical composition of claim 20, wherein the pharmaceutically acceptable carrier is a diluent.

25. The pharmaceutical composition of claim 24, wherein the diluent is selected from the group consisting of water, glycerol, mannitol, and saline.

26. The pharmaceutical composition of claim 25, wherein the saline is phosphate buffered saline.

27. The pharmaceutical composition of claim 24, wherein the diluent is present in the pharmaceutical composition in an amount of about 1% to about 10% (weight/weight).

28. The pharmaceutical composition of claim 24, wherein the diluent is present in the pharmaceutical composition in an amount of about 1% to about 15% (weight/weight).

29. The pharmaceutical composition of claim 24, wherein the diluent is present in the pharmaceutical composition in an amount of about 1% to about 20% (weight/weight).

30. A method of treating oral mucositis in a patient in need thereof, comprising topically administering to the oral cavity of the patient an effective amount of the pharmaceutical composition of claim 20.

31. The method of claim 30, wherein the pharmaceutical composition has a pH of about pH 1.5 to about pH 4.

32. The method of claim 30, wherein the pharmaceutical composition has a pH of about pH 3 to about pH 4.

33. A bisphosphineol selected from Nu-2, Nu-3, Nu-4, Nu-5 and Nu-8, or a pharmaceutically acceptable salt thereof, for use in the treatment of oral mucositis.

34. Use of a bisphosphineol or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of oral mucositis.

35. A pharmaceutical composition for use in the treatment of oral mucositis, said pharmaceutical composition comprising a bisphosphineine, or a pharmaceutically acceptable salt thereof, selected from Nu-2, Nu-3, Nu-4, Nu-5 and Nu-8 and a pharmaceutically acceptable carrier.

36. Use of a pharmaceutical composition comprising a bisphosphineol, or a pharmaceutically acceptable salt thereof, selected from Nu-2, Nu-3, Nu-4, Nu-5 and Nu-8, and a pharmaceutically acceptable carrier in the manufacture of a medicament for the treatment of oral mucositis.

Technical Field

The present disclosure relates generally to the use of bisphosphinite (bisphoscin) for the prevention and treatment of oral mucositis in a patient.

Background

Oral mucositis is a condition characterized by inflammation and ulceration in the oral cavity. Oral mucositis is a common complication in patients receiving cancer chemotherapy or radiation therapy. Oral mucositis can lead to a variety of problems including pain, nutritional problems due to inability to eat, and an increased risk of infection due to open ulceration of the mucosa. Oral mucositis can also have a significant impact on the quality of life of cancer patients and can limit the effectiveness of certain treatment options (i.e., the need to reduce subsequent chemotherapeutic doses). Oral mucositis is also an important side effect of bone marrow transplantation.

Clinically, mucositis progresses through three stages, including: (1) early painful mucosal erythema, which can be alleviated by local anesthetics or non-narcotic analgesics; (2) painful ulcerations and pseudomembranous formation, and the intensity of pain often requires parenteral narcotic analgesia; (3) spontaneous healing, which occurs about 2 to 4 weeks after cessation of anti-tumor therapy.

Oral mucositis is often difficult to treat and current methods are not adequately controlled. Current estimates indicate that over 500,000 patients suffer from oral mucositis annually in the united states alone. Considering that patients typically receive multiple cycles of chemotherapy and/or radiation therapy, it is estimated that more than 1,000,000 cases of oral mucositis occur annually in the united states. The incidence of oral mucositis depends on the tumor type, the age of the patient and the oral health. The therapies used in these different tumor types are important factors, with aggressive chemotherapy regimens associated with higher oral mucositis incidence. Younger patients also have a higher incidence of oral mucositis, probably due to their faster epithelial cell renewal and therefore higher sensitivity to cytotoxic drugs.

Current methods for treating and preventing oral mucositis are not optimal. The most common approaches include oral hygiene regimens, anti-inflammatory agents, and cryoprotectants. Different results have also been achieved using biological response modifiers and physical therapy (e.g., cryotherapy and laser therapy). Each of these approaches has met with limited success. For example, a reduction in oral mucositis using allopurinol mouthwashes, oral sucralfate and pentoxifylline was reported in preliminary studies. However, subsequent randomized and controlled studies failed to demonstrate any therapeutic benefit using these drugs. In addition, chlorhexidine, an antibacterial mouthwash, has been widely used to treat and prevent oral mucositis. However, it is noteworthy that the efficacy of chlorhexidine is significantly reduced in saliva, and that this compound is relatively ineffective against gram-negative bacteria that tend to colonize the oral cavity of patients receiving radiotherapy. Furthermore, at least one study has demonstrated that the use of chlorhexidine can be harmful and lead to a higher incidence of mucositis. Further, several studies have demonstrated that the use of vancomycin paste and antibiotic lozenges comprising polymyxin B, tobramycin and amphotericin B in patients receiving myelosuppressive chemotherapy or radiotherapy can reduce oral mucositis, as well as reduce the incidence of sepsis due to alpha hemolytic streptococci.

Current therapies for mucositis are mainly palliative and focus on pain control and nutritional maintenance. However, recent data indicate that even opioids are often insufficient to control mucositis pain. Currently, the only approved treatment for oral mucositis is paliferminIts use is limited to mucositis in patients receiving conditioning therapy prior to hematopoietic stem cell transplantation.

The complexity of mucositis as a biological process is constantly becoming established. It has been proposed that this condition represents a continuous interaction of oral mucosal cells and tissues, reactive oxygen species, pro-inflammatory cytokines, mediators of apoptosis, and local factors (such as saliva and oral microbiota). Although degeneration and destruction of the epithelium ultimately leads to mucosal ulceration, it appears that early changes associated with radiation-induced mucosal toxicity occur within the endothelium and submucosal connective tissue. Electron microscopic evaluation of the mucosa within 1 week of irradiation showed damage to both endothelium and connective tissue, but no damage to epithelium. This damage is most likely mediated by the formation of free radicals. It appears that the overall mechanism of development of mucositis is similar in both radiation therapy and chemotherapy. No data supports the direct bacterial etiology of mucositis. The data indicate that bacterial load of ulcerative lesions follows the development of the lesion, suggesting secondary colonization.

Topical application of drugs for the treatment of oral diseases such as oral mucositis presents unique problems. For example, it is often difficult to obtain sufficient mucoadhesion and intraoral residence time for the drug to be effective due to salivation and/or ingestion of food or liquid. Topical application of peptides is even more problematic because the peptides must be stable to proteolytic enzymes present in saliva. Other difficulties associated with topical oral application of medications include dental discoloration and patient compliance. Oral pharmaceutical compositions providing good mucoadhesion and intraoral residence time while providing a high level of patient compliance are not readily available. All treatment or prevention options currently used for oral mucositis are not considered ultimately effective.

Although there are strategies to address the above-mentioned problems associated with oral mucositis, these strategies are inconvenient and have significant drawbacks. Thus, there remains a need for better options for preventing and treating oral mucositis.

Disclosure of Invention

The present disclosure provides a method of treating oral mucositis in a patient in need thereof, which addresses the problems and needs described above. In some embodiments, the method comprises administering to the patient an effective amount of a bisphosphipidin or a pharmaceutically acceptable salt thereof. In some embodiments, the bisphosphithins are selected from Nu-2, Nu-3, Nu-4, Nu-5, and Nu-8.

In some embodiments, the administration is topical administration. In some embodiments, the topical application is applied to the oral cavity of the patient.

In some embodiments, the administration is performed using a bisphosphineol in a gel, ointment, oil, solution, suspension, emulsion, or other viscous composition. In some embodiments, administration is performed using a bisphosphithicin in a mouthwash. In some embodiments, at least one additional active ingredient is administered to the patient. In some embodiments, the bisphosphatilin is administered with a pharmaceutically acceptable carrier.

In some embodiments, the administering is performed in a multiple dose regimen. In some embodiments, the administering is performed one or more times per day. In some embodiments, the patient is a human.

Another aspect of the disclosure provides a method of treating oral mucositis in a patient in need thereof. In some embodiments, the method comprises topically administering to the oral cavity of the patient an effective amount of a pharmaceutical composition comprising a bisphosphipin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the bisphosphithins are selected from Nu-2, Nu-3, Nu-4, Nu-5, and Nu-8.

In some embodiments, the administration is performed using a bisphosphineol in a gel, ointment, oil, solution, suspension, emulsion, or other viscous composition. In some embodiments, the administration is performed using a bisphosphithicin in a mouthwash.

In some embodiments, the bisphosphatilin is present in the pharmaceutical composition in an amount from about 1% to about 20% (weight/weight). In some embodiments, the bisphosphatilin is present in the pharmaceutical composition in an amount from about 5% to about 15% (weight/weight). In some embodiments, the bisphosphatilin is present in the pharmaceutical composition in an amount from about 30% to about 50% (weight/weight).

In some embodiments, the administering is performed in a multiple dose regimen. In some embodiments, the administering is performed one or more times per day. In some embodiments, the patient is a human.

Another aspect of the present disclosure provides a pharmaceutical composition for treating oral mucositis comprising a bisphosphinite or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the bisphosphithins are selected from Nu-2, Nu-3, Nu-4, Nu-5, and Nu-8.

In some embodiments, the bisphosphatilin is present in the pharmaceutical composition in an amount from about 1% to about 20% (weight/weight). In some embodiments, the bisphosphatilin is present in the pharmaceutical composition in an amount from about 5% to about 15% (weight/weight). In some embodiments, the bisphosphatilin is present in the pharmaceutical composition in an amount from about 30% to about 50% (weight/weight).

In some embodiments, the pharmaceutically acceptable carrier is a diluent. In some embodiments, the diluent is selected from the group consisting of water, glycerol, mannitol, and saline. In some embodiments, the saline is phosphate buffered saline.

In some embodiments, the diluent is present in the pharmaceutical composition in an amount from about 1% to about 10% (weight/weight). In some embodiments, the diluent is present in the pharmaceutical composition in an amount from about 1% to about 15% (weight/weight). In some embodiments, the diluent is present in the pharmaceutical composition in an amount from about 1% to about 20% (weight/weight).

Another aspect of the disclosure provides a method of treating oral mucositis in a patient in need thereof. In some embodiments, the method comprises topically administering to the oral cavity of the patient an effective amount of a pharmaceutical composition of the present disclosure.

In some embodiments, the pharmaceutical composition has a pH of about pH 1.5 to about pH 4. In some embodiments, the pharmaceutical composition has a pH of about pH 3 to about pH 4.

Another aspect of the disclosure provides a bisphosphinite, or a pharmaceutically acceptable salt thereof, selected from Nu-2, Nu-3, Nu-4, Nu-5 and Nu-8, for use in the treatment of oral mucositis.

Another aspect of the disclosure provides the use of a bisphosphinite, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of oral mucositis.

Another aspect of the disclosure provides a pharmaceutical composition for use in the treatment of oral mucositis, said pharmaceutical composition comprising a bisphosphineerine, or a pharmaceutically acceptable salt thereof, selected from Nu-2, Nu-3, Nu-4, Nu-5 and Nu-8 and a pharmaceutically acceptable carrier.

Another aspect of the disclosure provides the use of a pharmaceutical composition comprising a bisphosphineol, or a pharmaceutically acceptable salt thereof, selected from Nu-2, Nu-3, Nu-4, Nu-5 and Nu-8, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for the treatment of oral mucositis.

An advantage of the methods and/or pharmaceutical compositions according to one embodiment of the present disclosure is that the mechanism of action of the activity of the compounds of the present disclosure is effective against a number of different clinically relevant pathogenic bacteria, including gram positive and gram negative bacteria. Another advantage of the methods and/or pharmaceutical compositions according to one embodiment of the present disclosure is that the compounds of the present disclosure according to one embodiment are non-toxic to patients treated with an effective amount of the compounds of the present disclosure.

Another advantage of the methods and/or pharmaceutical compositions comprising the compounds of the present disclosure is that such compounds act relatively quickly, and thus the duration of contact of such compounds with mucosal ulcers need not exceed the typical duration of efficacy for clinical or daily oral hygiene (typically 10 seconds to 5 minutes), although longer treatment times may also be used.

Another advantage of the method and/or pharmaceutical composition according to an embodiment of the present disclosure is that such method and/or pharmaceutical composition may be used to treat infections caused by biofilms. This biofilm-induced infection is described in oral mucositis caused by Candida glabrata (Candida glabrate) biofilm. Another advantage of the pharmaceutical composition according to one embodiment of the present disclosure is that such pharmaceutical composition may be used during or after chemotherapy.

These and other objects, advantages and features of the present disclosure will become apparent to those skilled in the art upon a reading of the details of the compounds and pharmaceutical compositions and their use in accordance with the present disclosure as more fully described below.

Drawings

The teachings of some embodiments of the present invention will be better understood by reference to the following description taken in conjunction with the accompanying drawings, in which:

figure 1A shows that animals had a mucositis score of zero (0);

FIG. 1B shows that the animals had a mucositis score of one (1);

figure 1C shows that animals had a mucositis score of two (2);

figure 1D shows animals scored three (3) for mucositis;

figure 1E shows that the animals had a mucositis score of four (4);

figure 1F shows that the animals had a mucositis score of five (5);

figure 2 shows the average percent daily weight change data for animals;

figure 3 shows the average daily mucositis score for animals; and

FIG. 4 shows the percentage of animal days (animal day) with a mucositis score of 3 or more throughout the study.

Detailed Description

The embodiments described below are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art may appreciate and understand the principles and practices of the present disclosure.

The present disclosure provides a method of controlling oral mucositis in a patient in need thereof. In some embodiments, an effective amount of a bisphosphatilin or a pharmaceutically acceptable salt thereof is administered to a patient.

As used herein, the term "bisphosphinite" refers to a class of compounds having antimicrobial activity, including Nu-2, Nu-3, Nu-4, Nu-5, and Nu-8, or pharmaceutically acceptable salts thereof. U.S. patent nos. 6,627,215, 6,211,162, 7,868,162, 7,176,191, 8,435,960 and 6,211,349, and U.S. patent application publication nos. 2017-0191062, 2018-0258128 and 2018-0353529, which are all incorporated herein by reference in their entirety, disclose bisphosphatitides and how to make and use bisphosphatitides. The terms "bisphosphatilin" and "a compound of the present disclosure" are used interchangeably herein.

Nu-2 has the chemical name ((2R,3R,4R,5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -3- ((hydroxy (4-hydroxybutoxy) phosphoryl) oxy) -4-methoxytetrahydrofuran-2-yl) methyl (4-hydroxybutyl) hydrogenphosphate. Nu-2 has a molecular formula of C₁₈H₃₂N₂O₁₄P₂. Nu-2 has the following formula:

nu-3 has the chemical name (2R,3S) -2- ((butoxy (hydroxy) phosphoryl) oxy) methyl) -5- (5-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) tetrahydrofuran-2-yl) butylphosphonate. Nu-3 has a molecular formula of C₁₈H₃₂N₂O₁₁P₂. Nu-3 has the following formula:

nu-4 has the chemical name ((2R,3S) -3- ((butoxy (hydroxy) phosphoryl) oxy) tetrahydrofuran-2-yl) methylbutyl hydrogen phosphate. Nu-4 has a molecular formula of C₁₃H₂₈O₉P₂. Nu-4 has the following formula:

nu-5 has the chemical name dibutyl (oxybis (ethane-2, 1-diyl)) bis (hydrogen phosphate). Nu-5 has a molecular formula of C₁₂H₂₈O₉P₂. Nu-5 has the following formula:

conversion of Nu-8The scientific name is ((2R,3S,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- ((butoxyoxophosphoryl-yl) oxy) tetrahydrofuran-2-yl) methylbutyl phosphate. Nu-8 has a molecular formula of C₁₇H₂₉N₃Na₂O₁₀P₂. Nu-8 has a molecular weight of 543.11 Da. Nu-8 has the following formula:

the compounds of the present disclosure are described with reference to specific compounds set forth herein. Furthermore, the compounds of the present disclosure may exist in any number of different forms or derivatives, all within the scope of the present disclosure. Alternative forms or derivatives include, for example, pharmaceutically acceptable salts, prodrugs and active metabolites, tautomers, and solid forms, including but not limited to different crystalline forms, polymorphs, or amorphous solids, including hydrates and solvates thereof, among others.

Unless stated to the contrary herein, the description of a compound of the present disclosure includes pharmaceutically acceptable salts of the compound. Thus, the compounds of the present disclosure may be in the form of, or may be formulated as, pharmaceutically acceptable salts. Contemplated pharmaceutically acceptable salt forms of the present disclosure include, but are not limited to, monosalts, disalts, trisalts, tetrasalts, and the like. The pharmaceutically acceptable salts of the present disclosure are non-toxic when administered in such pharmaceutically acceptable salt amounts and concentrations. The formulation of such pharmaceutically acceptable salts of the present disclosure may facilitate the pharmacological use of the compounds of the present disclosure by altering their physical properties without preventing them from exerting their physiological effects.

As used herein, the term "pharmaceutically acceptable" with respect to salts and formulation components such as carriers, excipients, and diluents, refers to those salts and components that are not deleterious to the patient and are compatible with other ingredients, active ingredients, salts, or components. Pharmaceutically acceptable includes "veterinarily acceptable" and thus independently includes human and non-human mammalian applications.

As used herein, the term "pharmaceutically acceptable salt" refers to salts commonly used to form alkali metal salts and to form addition salts of a free acid or a free base. Such Salts include, for example, the pharmaceutically acceptable Salts listed in the Handbook of Pharmaceutical Salts, which are known to those skilled in the art. Salt formation may occur at one or more sites having labile protons. Pharmaceutically acceptable salts of the compounds of the present disclosure include acid addition salts and base addition salts.

In some embodiments, suitable pharmaceutically acceptable acid addition salts of the compounds of the present disclosure may be prepared from inorganic or organic acids. Examples of such inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic, and sulfonic organic acids, exemplified by formic, acetic, propionic, succinic, glycolic, gluconic, maleic, pamoic (pamoic), methanesulfonic (methanesulfonic) acid, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, methanesulfonic (mesylic) acid, cyclohexylsulfamic, stearic, alginic, β -hydroxybutyric, malonic, hemi-lactic (galactic) acid, and galacturonic acid, to name a few. Pharmaceutically acceptable acid/anion salts also include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium ethylenediaminetetraacetate, camphorsulfonate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, mucate, napthoate, nitrate, pamoate, pantothenate, phosphate/diphosphate, salts of citric acid, salts of maleic acid, malonate, mandelate, methanesulfonate, methylsulfate, mucate, naphthoate, nitrate, pamoate, nitrate, and salts of phosphoric acid/diphosphate, Polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, bisulfate, tannate, tartrate, theachlorate (teoclate), tosylate, triiodonium (triethiodoxide) salts, and the like.

In some embodiments, suitable pharmaceutically acceptable base addition salts of the compounds of the present disclosure include, but are not limited to, metal salts formed from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts formed from N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, lysine, arginine, and procaine. All of these salts can be prepared from the compounds of the present disclosure by conventional means by treating the compounds of the present disclosure with a suitable acid or base. Pharmaceutically acceptable basic/cationic salts also include diethanolamine, ammonium, ethanolamine, piperazine and triethanolamine salts, to name a few. In some embodiments, the pharmaceutically acceptable salts of the present disclosure comprise a monovalent cation or a divalent cation.

In some embodiments, the pharmaceutically acceptable salt of the present disclosure is selected from the group consisting of ammonium, calcium, sodium, potassium, magnesium, and cobalt salts. In some embodiments, the ammonium salt is ((2R,3S,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- ((butoxyphosphato-yl) oxy) tetrahydrofuran-2-yl) methylbutylamine ammonium phosphate. In some embodiments, the calcium salt is ((2R,3S,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- ((butoxyphosphatyl) oxy) tetrahydrofuran-2-yl) methylbutyl calcium phosphate. In some embodiments, the sodium salt is ((2R,3S,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- ((butoxyphosphoxy) oxy) tetrahydrofuran-2-yl) methyl butyl sodium phosphate. In some embodiments, the potassium salt is ((2R,3S,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- ((butoxyphosphoxy) oxy) tetrahydrofuran-2-yl) methylbutyl potassium phosphate. In some embodiments, the magnesium salt is magnesium ((2R,3S,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- ((butoxyphosphato-yl) oxy) tetrahydrofuran-2-yl) methylbutyl phosphate. In some embodiments, the cobalt salt is ((2R,3S,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -3- ((butoxyphosphato-yl) oxy) tetrahydrofuran-2-yl) methylbutyl cobalt phosphate.

Pharmaceutically acceptable salts of the present disclosure can be prepared by standard techniques known in the art to which the disclosure pertains. For example, the free base form of a compound of the present disclosure can be dissolved in a suitable solvent, such as an aqueous or hydro-alcoholic solution containing a suitable acid, and then isolated by evaporating the solution. In another example, a salt can be prepared by reacting a free base and an acid in an organic solvent. If the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method including, for example, treating the free acid with a suitable inorganic or organic base.

In addition to the compounds of the present disclosure, the present disclosure also includes prodrugs (e.g., pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and pharmaceutically acceptable salts thereof.

A prodrug is a compound or a pharmaceutically acceptable salt thereof that, when metabolized under physiological conditions or converted by solvolysis (solvolysis), will yield the desired active compound. In general, prodrugs are inactive or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties. Some prodrugs are activated enzymatically to yield the active compound, or the compound may undergo further chemical reactions to yield the active compound. A prodrug may be converted from a prodrug form to an active form in one step, or may have one or more intermediate forms that are active or may be inactive.

Conceptually, prodrugs can be divided into two non-exclusive categories, including bioprecursor prodrugs and carrier prodrugs. In general, a bioprecursor prodrug is a compound that is inactive or has low activity compared to the corresponding active pharmaceutical compound, contains one or more protecting groups, and is converted to the active form by metabolic or solvolytic action. The active drug form and any released metabolites should have acceptably low toxicity. Generally, the formation of an active pharmaceutical compound involves a metabolic process or reaction of one of the following types:

oxidation reaction: examples of oxidation reactions include, but are not limited to, reactions such as oxidation of alcohol, carbonyl, and acid functional groups, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O-and S-dealkylation, oxidative deamination, and other oxidation reactions.

Reduction reaction: examples of reduction reactions include, but are not limited to, reactions such as reduction of a carbonyl functional group, reduction of an alcohol functional group and a carbon-carbon double bond, reduction of a nitrogen-containing functional group, and other reduction reactions.

Reaction with unchanged oxidation state: examples of reactions in which the oxidation state is unchanged include, but are not limited to, reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration of multiple bonds, new atom attachment by dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecules, and other such reactions.

A carrier prodrug is a pharmaceutical compound that contains a transport moiety that, for example, improves uptake and/or targeted delivery to the site of action. Ideally, for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and the prodrug and any released transport moiety are acceptably non-toxic. For prodrugs in which the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it may be desirable to use moieties that produce slow release, for example certain polymers or other moieties, such as cyclodextrins. Such carrier prodrugs are often advantageous for drugs that are administered orally. In some cases, the transport moiety provides for targeted delivery of the drug. For example, the drug may be conjugated to an antibody or antibody fragment. Carrier prodrugs can be used, for example, to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effect, increased site specificity, reduced toxicity and adverse effects, and/or improved pharmaceutical formulation (e.g., stability, water solubility, inhibition of poor organoleptic or physicochemical properties). For example, lipophilicity may be increased by esterification of a hydroxyl group with a lipophilic carboxylic acid or esterification of a carboxylic acid group with an alcohol (e.g., an aliphatic alcohol).

The metabolite (e.g., active metabolite) overlaps with the prodrug (e.g., bioprecursor prodrug) as described above. Thus, these metabolites are pharmacologically active compounds, or compounds that are further metabolized to pharmacologically active compounds, which are derivatives produced by metabolic processes in the body of a subject. Wherein the active metabolite is such a pharmacologically active derivative compound. For prodrugs, the prodrug compound is generally inactive, or less active than the metabolite. For active metabolites, the parent compound may be either an active compound or a non-active prodrug. For example, in some compounds, one or more alkoxy groups may be metabolized to a hydroxyl group while retaining pharmacological activity, and/or a carboxyl group may be esterified, such as glucuronidation (glucuronidation). In some cases, more than one metabolite may be present, with one or more intermediate metabolites being further metabolized to provide an active metabolite. For example, in some cases, derivative compounds produced by metabolic glucuronidation may be inactive or less active, and may be further metabolized to provide active metabolites.

Metabolites of the compounds of the present disclosure can be identified using conventional techniques known in the art and their activity determined using assays such as those described in Bertolini et al, Wermuth, supra.

It is understood by those skilled in the art that some compounds may exhibit tautomerism. In this case, the chemical formula provided herein explicitly describes only one possible tautomeric form. Thus, it is to be understood that the compounds of the present disclosure are intended to represent any tautomeric form of the compound being described and are not to be limited solely to the specific tautomeric form being described by the structural formula of the compound.

In the case of reagents that are solids, those skilled in the art understand that the compounds and salts may exist in different crystalline or polymorphic forms, or may be formulated as co-crystals, or may be in amorphous form, or may be any combination thereof (e.g., mixtures of partially crystalline, partially amorphous, or polymorphic forms), all of which are intended to fall within the scope of the present disclosure and specific chemical formulas. Salts are formed by acid/base addition (i.e., the free base or free acid of the target compound forms an acid/base reaction with the corresponding addition base or addition acid, respectively, resulting in ionic charge interactions), while co-crystals are new chemical species formed between neutral compounds resulting in the compounds and other molecular species being in the same crystal structure.

In some cases, the compounds of the present disclosure are complexed with an acid or base, including but not limited to base addition salts, such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, tert-butylamine, piperazine, meglumine; acid addition salts such as acetate, acetylsalicylate, benzenesulfonate, camphorate, citrate, formate, fumarate, glutarate, hydrochloride, maleate, methanesulfonate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate and tosylate; and amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

Furthermore, the compounds of the present disclosure are intended to encompass hydrated or solvated forms, as well as non-hydrated or non-solvated forms. Other examples of solvates include, but are not limited to, compounds of the present disclosure in combination with a suitable solvent (e.g., isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine, etc.).

In some embodiments, the compounds of the present disclosure are protonated compounds. As used herein, the term "protonated compound" refers to a compound of the present disclosure that is protonated by the addition of a proton (or positively charged hydrogen ion) to the proton accepting site of the compound of the present disclosure. In some embodiments, the proton accepting site includes the phosphate group of a compound of the present disclosure, as well as any other proton accepting site on the ribose or butyl group of a compound of the present disclosure.

As the number of proton accepting sites protonated in the disclosed compounds increases, the pH obtained when a compound of the disclosure is dissolved in water at pH 7 will decrease, and thus the amount of protonation of a compound of the disclosure can be determined by measuring the pH of the aqueous solution after addition of a compound of the disclosure. The pH represents the concentration of hydrogen ions in the solution. Solutions with a high concentration of hydrogen ions have a low pH and are therefore acidic, whereas solutions with a low concentration of hydrogen ions have a high pH and are therefore basic. In some embodiments, the compounds of the present disclosure are protonated such that, when dissolved in water (pH 7), such compounds form aqueous solutions having a pH of less than about pH 7 to about pH 1. As used herein, the term "about" when used with a numerical value should be understood to include the specified amount as well as variations of 20%, 10%, 5%, 1%, 0.5%, and 0.1% of the specified amount. In some embodiments, the compounds of the present disclosure are protonated compounds, having a pH of less than about pH 6 to about pH 1 when dissolved in water. In some embodiments, the compounds of the present disclosure are protonated compounds, having a pH of about pH 5 to about pH 1 when dissolved in water. In some embodiments, the compounds of the present disclosure are protonated compounds, having a pH of about pH 4.5 to about pH 1 when dissolved in water. In some embodiments, the compounds of the present disclosure are protonated compounds, having a pH of about pH 4 to about pH 1 when dissolved in water. In some embodiments, the compounds of the present disclosure are protonated compounds, having a pH of about pH 3 to about pH 1 when dissolved in water. In some embodiments, the compounds of the present disclosure are protonated compounds, having a pH of about pH 2 to about pH 1 when dissolved in water. In some embodiments, the compounds of the present disclosure are protonated compounds, having a pH of about pH 3 to about pH 5 when dissolved in water. In some embodiments, the compounds of the present disclosure are protonated compounds, having a pH of about pH 3 to about pH 4 when dissolved in water.

In some embodiments, protonation may be achieved by incubating a compound of the present disclosure in the presence of a strong acid. Although the compounds of the present disclosure may be protonated by adding a proton to the reactive site of the compound, other modifications of the compounds of the present disclosure are possible and are intended to be encompassed by the term protonated compound as used herein. In some embodiments, protonated forms of the disclosed compounds can be produced by subjecting a purified, partially purified, or crude compound to a low pH (e.g., acidic) environment. In some embodiments, the purified or crude compound may be protonated with acids, including phosphoric acid, nitric acid, hydrochloric acid, and acetic acid.

Other procedures known to those skilled in the art for preparing the protonated compounds of the present disclosure are likewise understood to fall within the scope of the present disclosure. In some embodiments, when the compounds of the present disclosure are protonated, these compounds can be separated from any undesired components (e.g., excess acid). One skilled in the art is aware of many methods for separating compounds from undesired components, including but not limited to the use of H + cation exchangers (e.g., H + -SCX). In some embodiments, the compounds of the present disclosure may be subjected to chromatography after protonation. In some embodiments, after protonation, the compounds of the present disclosure are eluted on poly (styrene-divinylbenzene) -based resins (e.g., PRP-1 or 3 of Hamilton, and PLRP of Polymer Lab).

In some embodiments, the protonated compounds of the present disclosure may be used directly. In some embodiments, the protonated compounds of the present disclosure may be further processed to remove any excess acid or salt, for example, via precipitation, reverse phase chromatography, diafiltration, or gel filtration. In some embodiments, the protonated compounds of the present disclosure may be concentrated by lyophilization, solvent evaporation, and the like. In some embodiments, when suspended in water or saline, the compounds of the present disclosure typically exhibit a pH of about pH 3 to about pH 5, depending on the level of protonation/acidification, which is determined by how much acid is used in the acidification process. In some embodiments, the compounds of the present disclosure may be protonated by passing them through a cation exchange column bearing hydrogen ions.

In some embodiments, two butyl groups are utilized in the compounds of the present disclosure to prevent or limit substantial nuclease degradation of the compounds of the present disclosure, including but not limited to exonuclease degradation. In some embodiments, the butyl group is placed to protect the ribose of the disclosed compounds. Loss of functional molecules can be assessed using analytical HPLC, or the percentage of acid degradation can be determined by other suitable methods. Acid degradation typically changes over time. In some embodiments, the compounds of the present disclosure are also nuclease resistant, which enables the compounds to maintain activity (e.g., pH stability) in an in vivo environment. The percent degradation of the compounds of the disclosure in a nuclease-containing environment can be determined by methods known to those skilled in the art (e.g., mass spectrometry). Nuclease degradation typically changes over time. In some embodiments, a reference compound is used in determining the degree or rate of acid or nuclease degradation. In some embodiments, the stability of a compound of the disclosure is 10%, 20%, 30%, 40%, 50%, 70%, 90%, 100%, 150%, 200%, 300%, 500%, or 750% greater than the stability of a reference compound.

According to some embodiments, the compounds of the present disclosure may be used as antimicrobial agents, which have activity against any microorganism. As used herein, the terms "microorganism", "microbial" and similar terms refer to bacteria, fungi, protozoa, viruses, yeasts and the like. As used herein, the term "antimicrobial agent" refers to a compound of the present disclosure that has the ability to kill or inhibit the growth of microorganisms, or reduce the severity of a microbial infection. A non-limiting list of bacteria against which the disclosed compounds are effective includes, but is not limited to, gram-positive bacteria, gram-negative bacteria, slow-growing bacteria, and acid-resistant bacteria, as well as any species included in the genera: aerococcus (Aerococcus), Listeria (Listeria), Streptomyces (Streptomyces), Chlamydia (Chlamydia), Lactobacillus (Lactobacillus), Eubacterium (Eubacterium), Burkholderia (Burkholderia), stenotrophomonas (Stentrophoromonas), Achromobacter (Achromobacter), Arachnical (Mycobacterium), Streptococcus (Peptostreptococcus), Staphylococcus (Staphylococcus), Corynebacterium (Corynebacterium), Rhodococcus (Erysipelothrix), Thermophilus (Dermatophilus), Rhodococcus (Rhodococcus), Pseudomonas (Pseudomonas), Streptococcus (Streptococcus), Bacillus (Bacillus), Peptococcus (Streptococcus), Streptococcus (Bacillus), Neisseria (Streptococcus), Streptococcus (Lactobacillus), Streptococcus (Streptococcus), Streptococcus (Streptococcus), Streptococcus (Streptococcus), Streptococcus, Propionibacterium (Propionibacterium), Actinomyces (Actinomyces), Helicobacter (Helicobacter), Enterococcus (Enterococcus), Shigella (Shigella), Vibrio (Vibrio), Clostridium (Clostridium), Salmonella (Salmonella), Yersinia (Yersinia) and Haemophilus (Haemophilus).

A non-limiting list of fungi that the disclosed compounds are effective against includes, but is not limited to Trichophyton (Trichophyton), Epidermophyton (Epidermophyton), Microsporum (Microsporium), Candida albicans (Candida albicans) and other Candida species, Pityrosporum orbiculare (Pityrosporum orbiculare), Trichophyton mentagrophytes (Trichophyton aggregations), Trichophyton rubrum (Trichophyton rubrum), Epidermophyton (Epidermophyton flocouver), and Trichophyton trichotomum (Trichophyton tonsurans). A non-limiting list of viruses against which the disclosed compounds are effective includes, but is not limited to, Human Immunodeficiency Virus (HIV), Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and influenza virus.

The terms "treat," "treating," and the like, as used herein generally refer to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic for complete or partial prevention of a disease or symptom thereof, and/or therapeutic for partial or complete cure of a disease (or infection) and/or adverse effects due to a disease (or infection). The terms "treatment", "treating" and the like as used herein also include, but are not limited to:

(a) preventing oral mucositis in a patient who may be susceptible to, but has not been diagnosed with oral mucositis;

(b) reducing the risk of developing oral mucositis in a patient (e.g., after radiation or chemotherapy treatment);

(c) inhibiting the progression or spread of oral mucositis; or

(d) Alleviating one or more symptoms of oral mucositis.

The terms "treating", "treating" and the like also include preventing, inhibiting or alleviating the symptoms of oral mucositis in a patient. The disclosure also relates to treating a patient suffering from, or susceptible to, oral mucositis, or alleviating one or more symptoms of oral mucositis in a patient suffering from such a disease. As used herein, "symptoms" associated with oral mucositis include any clinical or laboratory manifestations associated with the disease, and are not limited to those manifestations that a subject can feel or observe. It is also understood that "treating" may include reducing the symptoms of oral mucositis in a patient after determining or diagnosing oral mucositis in the patient.

As used herein, the term "patient" refers to a living organism treated with a compound of the present disclosure, including, but not limited to, any mammal, such as humans, other primates (e.g., monkeys, chimpanzees, etc.), companion animals (e.g., dogs, cats, horses, etc.), farm animals (e.g., goats, sheep, pigs, cattle, etc.), laboratory animals (e.g., mice, rats, etc.), and wild and zoo animals (e.g., wolves, bears, deer, etc.).

In practicing the methods of the present disclosure, an effective amount of a compound of the present disclosure is administered to a patient in need thereof. As used herein, the term "effective amount," when administered, refers to an amount of a compound or pharmaceutical composition of the present disclosure that, when administered to a patient, is sufficient to prevent, alleviate or ameliorate one or more symptoms of a disease or disorder (i.e., indication) and/or prolong the survival of the patient being treated. Such an amount should cause no adverse events or only few adverse events in the treated patient. Similarly, such an amount should cause no or little toxic effects in the patient being treated. One skilled in the art will appreciate that the amount of a compound or pharmaceutical composition of the present disclosure will vary depending on a number of factors including, but not limited to, the activity of the compound of the present disclosure (in vitro activity, e.g., the compound of the present disclosure relative to a target, or in vivo activity in an animal efficacy model), the pharmacokinetic results in an animal model (e.g., biological half-life or bioavailability), the type of patient being treated, the age, size, weight, and general physical condition of the patient, the disease associated with the patient, and the dosing regimen employed in the treatment.

In some embodiments of the present disclosure, an effective amount of a compound of the present disclosure may be quantified for delivery to a patient in need thereof by determining the microgram value of the compound of the present disclosure per kilogram body weight of the patient. In some embodiments, the amount of a compound of the present disclosure administered to a patient is from about 0.1 to about 1000 milligrams (mg) of a compound of the present disclosure per kilogram (kg) of the patient's body weight. In some embodiments, the amount of a compound of the present disclosure administered to a patient is from about 0.1 to about 500mg of a compound of the present disclosure per kg of body weight of the patient. In some embodiments, the amount of a compound of the present disclosure administered to a patient is from about 0.1 to about 300mg of a compound of the present disclosure per kg of body weight of the patient. In some embodiments, the amount of a compound of the present disclosure administered to a patient is from about 0.1 to about 200mg of a compound of the present disclosure per kg of body weight of the patient. In some embodiments, the amount of a compound of the present disclosure administered to a patient is from about 0.1 to about 100mg of a compound of the present disclosure per kg of body weight of the patient. As will be appreciated by one of ordinary skill in the art, multiple doses may be used.

The present disclosure also provides a pharmaceutical composition for treating oral mucositis. In some embodiments, the pharmaceutical composition comprises a bisphosphithin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the bisphosphithins are selected from Nu-2, Nu-3, Nu-4, Nu-5, and Nu-8. As used herein, the term "pharmaceutical composition" refers to a pharmaceutical formulation containing a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and which is suitable for administration to a patient for therapeutic purposes. The terms "pharmaceutical composition" and "formulation" are used interchangeably herein.

In some embodiments, the pharmaceutical composition may comprise at least one pharmaceutically acceptable component to provide improved formulation of the compounds of the present disclosure, including but not limited to one or more pharmaceutically acceptable carriers, excipients, or diluents. The carrier, excipient or diluent may take a wide variety of forms depending on the form of preparation desired for administration.

As used herein, the term "carrier" includes, but is not limited to, calcium carbonate, calcium phosphate, various sugars such as lactose, glucose or sucrose, starches, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, pharmaceutically acceptable liquids as solvents or for suspensions including, for example, sterile solutions of water for injection (WFI), saline solutions, glucose solutions, Hank's solution, ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like.

As used herein, the term "excipient" generally includes, but is not limited to, fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers, stabilizers, preservatives, and surfactants, which may be selected to facilitate administration of a compound by a particular route. Suitable excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethylcellulose, croscarmellose sodium, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate, glycerol monostearate, glycerol dibehenate, glycerol palmitostearate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor seed oil, mineral oil, polyethylene glycol (e.g., PEG4000-8000), polyoxyethylene glycol, poloxamer, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, divinylbenzene methacrylate copolymer, sodium docusate (sodium docusate), Cyclodextrins (e.g., 2-hydroxypropyl-delta-cyclodextrin), polysorbates (e.g., polysorbate 80), cetrimide (cetrimide),TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether, a di-fatty acid ester of polyethylene glycol, or a polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester)) Polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters (e.g., sorbitan fatty acid esters from fatty acids such as oleic, stearic or palmitic acid), mannitol, xylitol, sorbitol, maltose, lactose monohydrate or spray dried lactose, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrates, dextran, dextrose, cellulose acetate, maltodextrin, dimethicone, polyglucan, chitosan, gelatin, HPMC (hydroxypropylmethylcellulose), HPC (hydroxypropylcellulose), hydroxyethylcellulose, and the like.

As understood by the skilled artisan, any diluent known in the art may be used in accordance with the present disclosure. In some embodiments of the present disclosure, the diluent is water soluble. In some embodiments of the present disclosure, the diluent is water insoluble. As used herein, the term "diluent" includes, but is not limited to, water, saline, Phosphate Buffered Saline (PBS), dextrose, glycerol, ethanol, sodium or ammonium acetate buffered solutions, and the like, and combinations thereof.

In some embodiments, the pharmaceutical composition is a human pharmaceutical composition. As used herein, the term "human pharmaceutical composition" refers to a pharmaceutical composition intended for administration to a human.

In some embodiments, the pharmaceutical compositions of the present disclosure are in the form of a mouthwash or are mixed with a gel-like carrier. In some embodiments, a mouthwash typically comprises an aqueous mixture of a diluent, soap, flavoring, and/or coloring agent. In some embodiments, the mouthwash is combined with other antibacterial agents. In some embodiments, the gel-like carrier generally comprises a mixture of a water-soluble gelling agent and a humectant, and may optionally comprise other ingredients, such as sweeteners and preservatives. In some embodiments, mouthwashes and gelatinous pharmaceutical compositions provide excellent mucoadhesive properties and residence time in the oral cavity, with favorable moisturization and flavor properties associated with high patient compliance.

In some embodiments, the pharmaceutical compositions of the present disclosure comprise a diluent selected from the group consisting of water, glycerol, mannitol, saline, and phosphate buffered saline. In some embodiments, the diluent is water. In some embodiments, water is present in the pharmaceutical composition in an amount of about 65% to about 97.5% (weight/weight).

In some embodiments, the pharmaceutical composition further comprises a saline diluent, wherein the compound of the present disclosure is dissolved at a concentration of about 1 to about 20%, such as about 1 to about 10%, and wherein the pH is typically a value of about 1.25 to about 5, such as 1.5, 2, 3 and 4. In some embodiments, the pH may be adjusted by any pharmaceutically acceptable means, such as by the addition of an effective amount of 10% HCl.

In some embodiments, the mouthwash pharmaceutical composition is a non-sterile aqueous solution for deodorant, refreshing and/or antibacterial effects. In some embodiments, the mouthwash pharmaceutical composition comprises an alcohol as a preservative and a semi-active ingredient. In some embodiments, the amount of alcohol is 18 to 26%, and in some embodiments, the remainder of the pharmaceutical composition consists essentially of water. In some embodiments, the mouthwash comprises one or more bisphosphatides present in an amount effective to treat or prevent oral mucositis.

In some embodiments, the gel and mouthwash pharmaceutical compositions disclosed herein are useful for treating infections caused by biofilms. Biofilms are formed when individual microorganisms attach to hydrated surfaces and grow as adherent cellular matrices for other microorganisms. In some embodiments, the biofilm forms a tightly packed microbial cell community surrounded by secreted polymer. In some embodiments, biofilms are notoriously difficult to treat and are associated with oral mucositis. Accordingly, some embodiments of the present disclosure include the treatment of infections caused by biofilms.

Some embodiments of the present disclosure include a method for treating or preventing oral mucositis caused by biofilm, comprising administering to the oral cavity of a patient in need thereof an effective amount of a mouth rinse pharmaceutical composition comprising a bisphosphithin or a pharmaceutically acceptable salt thereof, or any combination thereof, dissolved in a diluent selected from saline and phosphate buffered saline at a concentration of about 1 to about 10%, typically at a pH of about 1.25 to about 5, other embodiments at a pH of 1.5 to about pH 4, or about pH 3 to about pH 4.

In some embodiments, the bisphosphatilin and/or pharmaceutical composition is suitable for administration to a patient by any suitable means, including but not limited to those means used for administration of conventional antimicrobial agents. The bisphosphatides and/or pharmaceutical compositions of the present disclosure may be administered using any suitable route contemplated by one of ordinary skill, including, but not limited to, oral, intravenous ("IV") injection or infusion, subcutaneous ("SC"), intramuscular ("IM"), intradermal, transdermal, subcutaneous, topical, and mucosal. Such a formulation should allow the bisphosphclaimed element to reach the target cell. Other factors are well known in the art and include considerations such as toxicity and dosage forms that prevent the bisphosphclaimed element from exerting its effect. Techniques and formulations are commonly found in Remington, The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005.

In some embodiments, the compounds and/or pharmaceutical compositions of the present disclosure are suitable for topical administration. As used herein, the term "topical administration" refers to the application of a compound of the present disclosure to the skin surface or mucosa of a patient such that the compound of the present disclosure passes through the skin layer or mucosa. The term topical administration also encompasses transdermal administration and transmucosal administration. As used herein, the term "transdermal" refers to the passage of a compound of the present disclosure through at least one skin layer or mucosal membrane of a patient. As used herein, "transmucosal" refers to the passage of a compound of the disclosure across the mucosa of a patient. Unless otherwise stated or implied, the terms "topical administration", "transdermal administration" and "transmucosal administration" are used interchangeably herein.

A variety of topical delivery systems for delivering biologically active compounds to microorganisms in a patient are well known in the art. By selecting a suitable carrier in the art, such systems include, but are not limited to, lotions, creams, gels, oils, ointments, solutions, suspensions, emulsions, and the like. In some embodiments, the compounds of the present disclosure are applied in the form of a gel comprising a polyol. In some embodiments, the compounds of the present disclosure are administered in the form of a mouthwash.

In some embodiments, suitable carriers include, but are not limited to, vegetable or mineral oils, white petrolatum (e.g., white soft paraffin), branched fats or oils, animal fats, and high molecular weight alcohols (e.g., greater than C12). In some embodiments, the carrier is selected such that the compounds of the present disclosure are soluble. In some embodiments, emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents that impart color or fragrance, if desired. In some embodiments, an organic solvent or co-solvent (such as ethanol or propanol) may be used in the bisphosphithins and/or pharmaceutical compositions of the present disclosure. In some embodiments, evaporation of the solvent leaves a residue on the treated surface to inhibit re-infection. In some embodiments, a penetrant appropriate to the barrier to be permeated is used. Such penetrants are generally known in the art, and include, but are not limited to, bile salts and fusidic acid derivatives. In some embodiments, a cleaning agent may be used to facilitate penetration. In some embodiments, a cream for topical application is formulated from a mixture of mineral oil, self-emulsifying beeswax and water, wherein a compound of the present disclosure dissolved in a small amount of solvent (e.g., oil) is mixed in the mixture. In some embodiments, the particular local delivery system used depends on the location of the microorganism.

In some embodiments, other materials may also be added to the topical pharmaceutical compositions of the present disclosure, which materials have additional moisturizing effects and improve the consistency of the pharmaceutical composition. Examples of such compounds include, but are not limited to, cetyl esters wax, stearyl alcohol, cetyl alcohol, glycerin, methyl paraben, propyl paraben, quaternary ammonium salt-15 (quaternium-15), humectants, volatile methyl silicone fluids, and polydiorganosiloxane polyoxyalkylenes. See, for example, U.S. patent nos. 5,153,230 and 4,421,769. In some embodiments, if additional cleaning action of the pharmaceutical composition is desired, chemicals such as sodium lauryl sulfate or metal salts of carboxylic acids may be added.

In some embodiments, a number of non-volatile emollients may be used in the pharmaceutical compositions of the present disclosure. Non-limiting examples of such non-volatile emollients are listed in McCutcheon's. In some embodiments, the non-volatile emollient includes silicones, hydrocarbons, esters, and mixtures thereof. In some embodiments, the esters include esters of mono-and di-functional fatty acids esterified with alcohols and polyols (i.e., alcohols having two or more hydroxyl groups). In some embodiments, long chain esters of long chain fatty acids (i.e., C10-40 fatty acids esterified with C10-40 fatty alcohols) are used in the pharmaceutical compositions of the present disclosure. Non-limiting examples of esters that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, those selected from the group consisting of diisopropyl adipate, isopropyl myristate, isopropyl palmitate, myristyl propionate, ethylene glycol distearate, 2-ethylhexyl palmitate, isodecyl neopentanoate, C12-15 alcohol benzoate, di-2-ethylhexyl maleate, ceryl palmitate (myristyl myristate), stearyl stearate, cetyl stearate, behenyl behenate (behenyl behenate), and mixtures thereof.

Examples of silicone emollients useful in the pharmaceutical compositions of the present disclosure include, but are not limited to, polyalkylsiloxanes, cyclic polyalkylsiloxanes, and polyalkylarylsiloxanes. Suitable commercially available polyalkylsiloxanes include polydimethylsiloxanes, also known as dimethicones (dimethicones), non-limiting examples of which include Vicasil sold by General Electric Company^TMSeries and Dow Corning sold by Dow Corning Corporation^TM200 series. Commercially available polyalkylsiloxanes include cyclomethicone (Dow Corning)^TM244 liquid, Dow Corning^TM344 liquid, Dow Corning^TM245 liquid and Dow Corning^TM345) And the like. Suitable commercially available trimethylsiloxysilicate as a mixture with dimethicone, as described in Dow Corning^TM593 liquid is sold. Dimethiconol (dimethiconol), which is a hydroxy-terminated dimethyl siloxane, may also be used in the pharmaceutical compositions of the present disclosure. Suitable commercially available dimethiconols are typically used as mixtures with dimethicone or cyclomethicone (e.g., Dow Corning)^TM1401. 1402 and 1403 liquid). Suitable commercially available polyalkylaryl siloxanes include SF1075 methylphenyl fluid (sold by General Electric Company) and 556 cosmetic grade phenyl trimethicone fluid (sold by Dow Coring Corporation).

Hydrocarbons suitable for use in the pharmaceutical compositions of the present disclosure include, but are not limited to, straight and branched chain hydrocarbons having from about 10 to about 30 carbon atoms. In some embodiments, the straight and branched chain hydrocarbons have from about 12 to about 24 carbon atoms. In some embodiments, the straight and branched chain hydrocarbons have from about 16 to about 22 carbon atoms. Non-limiting examples of such hydrocarbon materials include dodecane, squalane, cholesterol, 5 hydrogenated polyisobutylene, docosane (i.e., a C22 hydrocarbon), hexadecane, and isohexadecane (supplied by Presperse, South plainfield, n.j. as Permethyl @)^TM101A commercially available hydrocarbon) and the like.

In some embodiments, the topical pharmaceutical compositions of the present disclosure comprise propylene glycol. In some embodiments, propylene glycol acts as a surfactant and aids in the penetration, contact, and absorption of the compounds of the present disclosure. In some embodiments, propylene glycol is used as a preservative. In some embodiments, the pharmaceutical compositions of the present disclosure comprise a nonionic surfactant, such as a polysorbate. By further reducing the surface tension, such surfactants provide better surface contact of the pharmaceutical compositions of the present disclosure with the mucosa.

Topical pharmaceutical compositions of the present disclosure may also optionally be formulated with lipophilic phases, such as emulsions and liposomal dispersions. In some embodiments, liposome formulations can prolong the circulation time of the compounds of the present disclosure, increase the permeability of the compounds of the present disclosure, and improve the overall efficacy of the compounds of the present disclosure as antimicrobial agents. In some embodiments, the compounds of the present disclosure may be combined with a lipid, a cationic lipid, or an anionic lipid. In some embodiments, the resulting emulsion or liposomal suspension together with the pH-stabilizing property of the compounds of the present disclosure may be effective to increase the in vivo active half-life of the pharmaceutical compositions of the present disclosure. Examples of anionic lipids suitable for use with the pharmaceutical compositions of the present disclosure include, but are not limited to, cardiolipin, dimyristoyl, dipalmitoyl, dioleoylphosphatidylcholine, phosphatidylglycerol, palmitoyloleoylphosphatidylcholine, phosphatidylglycerol, phosphatidic acid, lysophosphatidic acid, phosphatidylserine, phosphatidylinositol, and cholesterol in anionic form.

In some embodiments, the compounds of the present disclosure are incorporated into liposomes. In some embodiments, neutral lipids, cholesterol, and/or polyethylene glycol (PEG) are used in these liposomes. In some embodiments, the liposome composition consists of partially hydrogenated soy Phosphatidylcholine (PHSC), cholesterol, methoxy-terminated peg (mpeg), and/or distearoyl phosphatidylethanolamine (DSPE). Liposomes can be prepared according to any suitable method known in the art.

In some embodiments, the bisphosphatilin and/or pharmaceutical composition of the present disclosure is suitable for oral administration. As used herein, the term "oral administration" refers to administration of a compound of the present disclosure to the oral cavity of a patient for ingestion into the gastrointestinal tract. In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated into conventional oral dosage forms, including, but not limited to, capsules, tablets, powders, and liquid preparations such as suspensions, solutions, elixirs, syrups, concentrated drops, and the like. In some embodiments, the compounds of the present disclosure may be combined with a solid excipient, optionally grinding the resulting mixture, and optionally processing the mixture of granules, if desired after adding suitable adjuvants, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g., aqueous, alcoholic, or oily solutions), and the like. In some embodiments, excipients suitable for use in the oral pharmaceutical compositions of the present disclosure include, but are not limited to, fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, for example corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC) and/or polyvinylpyrrolidone (PVP or povidone); and oily vehicles including vegetable oils and animal oils, such as sunflower oil, olive oil or cod liver oil. In some embodiments, the oral pharmaceutical compositions of the present disclosure may also contain a disintegrant, for example, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate; lubricants, such as talc or magnesium stearate; plasticizers, such as glycerol or sorbitol; sweeteners, such as sucrose, fructose, lactose or aspartame; natural or artificial flavoring agents, such as peppermint, oil of wintergreen, or cherry flavoring; or dyes or pigments, which can be used to determine or characterize different dosages or combinations. In some embodiments, oral pharmaceutical compositions of the present disclosure may also contain dragee cores with suitable coatings. In some embodiments, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol, titanium dioxide, lacquer (lacquer) solutions, and suitable organic solvents or solvent mixtures.

In some embodiments, the bisphosphatitides and/or pharmaceutical compositions of the present disclosure that may be used orally include, but are not limited to, push-fit (push-fit) capsules ("gelcaps") made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). In some embodiments, push-fit capsules can contain a compound of the present disclosure in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In some embodiments, including soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, liquid polyethylene glycols and the like.

In some embodiments, the bisphosphatilin and/or pharmaceutical composition of the present disclosure is suitable for parenteral administration. As used herein, the term "parenteral administration" refers to injection or infusion of a compound of the present disclosure into a patient, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular (subericular), intraarticular, subcapsular, subarachnoid, intraspinal, intracerobrospinal, and intrasternal injection and infusion. In some embodiments, pharmaceutical compositions of the present disclosure suitable for parenteral administration may be formulated in sterile liquid solutions, including but not limited to physiologically compatible buffers or solutions, such as saline solution, hank's solution, or ringer's solution. In some embodiments, pharmaceutical compositions of the present disclosure suitable for parenteral administration can be prepared as dispersions in non-aqueous solutions (e.g., glycerol, propylene glycol, ethanol, liquid polyethylene glycols, triacetin, vegetable oils, and the like). In some embodiments, the solution may also contain preservatives, such as methyl paraben, propyl paraben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In addition, pharmaceutical compositions of the present disclosure suitable for parenteral administration can be formulated in solid form, including, for example, lyophilized form, and reconstituted or suspended prior to use. In some embodiments, the pharmaceutical composition is administered via a needle.

In some embodiments of the present disclosure, the compounds and/or pharmaceutical compositions of the present disclosure are administered in a multi-dose regimen. As used herein, the term "multiple dose regimen" refers to a treatment period of more than one day. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about 2 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about 3 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about 4 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about 5 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about 6 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about 7 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about 14 days. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about one month. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about two months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about three months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about four months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about five months. In some embodiments of the present disclosure, the multiple dose regimen is for a period of time up to about six months. Other time periods may be used herein.

In some embodiments of the present disclosure, the compounds and/or pharmaceutical compositions of the present disclosure are administered as part of a long-term treatment regimen. As used herein, the term "long-term treatment regimen" refers to treatment with a compound of the present disclosure over an extended period of time during a patient's lifetime. In some embodiments, the long-term treatment is lifetime treatment.

In some embodiments of the present disclosure, the compounds and/or pharmaceutical compositions of the present disclosure are administered in a single dose. In some embodiments of the disclosure, a compound of the disclosure is administered in a single unit dose. As used herein, the term "unit dose" is a predetermined amount of a compound of the present disclosure. The amount of a compound of the present disclosure is generally equal to the dose of a compound of the present disclosure administered to a patient, or a convenient fraction of such dose, e.g., one-half or one-third of such dose. The terms "single dose" and "single unit dose" include embodiments in which a compound of the present disclosure may be administered as a single application and as multiple applications in accordance with the methods of the present disclosure.

In some embodiments, the compounds of the present disclosure may also be combined with one or more additional active ingredients for the treatment of the same disease or disorder. As used herein, the term "active ingredient" refers to therapeutically active compounds and any prodrugs thereof, as well as pharmaceutically acceptable salts, hydrates, and solvates of the compounds and prodrugs. In some embodiments, such a combined use comprises administering a compound of the disclosure and one or more additional active ingredients at different times, or co-administering a compound of the disclosure and one or more additional active ingredients. In some embodiments, the dosages of the compounds of the present disclosure or one or more additional active ingredients used in combination can be varied by methods well known to those of ordinary skill in the art, e.g., by decreasing the amount administered relative to the amount of the compound of the present disclosure or one or more additional active ingredients used alone. In some embodiments, co-administration comprises administering a compound of the disclosure and an additional active ingredient simultaneously in the same dosage form, administering a compound of the disclosure and an additional active ingredient simultaneously in separate dosage forms, and administering a compound of the disclosure and an additional active ingredient separately. The amount of additional active ingredient to be administered can be determined by one skilled in the art based on the treatment with the compounds of the present disclosure. In some embodiments, the compounds of the present disclosure may be co-formulated, or co-administered, with other active ingredients in the gel or mouthwash pharmaceutical compositions described herein.

It is to be understood that the combined use includes the use of one or more additional active ingredients or other pharmaceutical programs, wherein the one or more additional active ingredients or other pharmaceutical programs can be administered at different times (e.g., within a short time, such as within hours (e.g., 1, 2, 3,4 to 24 hours, etc.), or within a longer time (e.g., 1-2 days, 2-4 days, 4-7 days, 1-4 weeks, etc.) than, or concurrently with, the compounds or pharmaceutical compositions of the present disclosure. Combination use also includes the use of one or more additional active ingredients or other pharmaceutical procedures (which are administered only once or infrequently, such as surgery) and the compounds or pharmaceutical compositions of the present disclosure administered for a short or longer period of time before or after the administration of the one or more additional active ingredients or the completion of other pharmaceutical procedures.

In some embodiments, the present disclosure provides for the delivery of a compound or pharmaceutical composition of the present disclosure and one or more additional active ingredients delivered by different routes of administration or by the same route of administration. In some embodiments, the combined use for any route of administration includes delivering a compound of the present disclosure or a pharmaceutical composition in any pharmaceutical composition, including pharmaceutical compositions, wherein the two compounds are chemically linked such that the compounds retain their therapeutic activity upon administration, and one or more additional active ingredients delivered together by the same route of administration. In some embodiments, one or more additional active ingredients may be co-administered with a compound or pharmaceutical composition of the present disclosure. In some embodiments, the combined use by co-administration comprises administration of a co-formulation (co-formulation) or formulation of chemically linked compounds, or administration of two or more compounds within a short time of each other (e.g., within 1 hour, 2 hours, 3 hours, up to 24 hours, etc.) in separate formulations, administered by the same or different routes. In some embodiments, co-administration of separate formulations includes co-administration by delivery via one device (e.g., the same inhalation device, the same syringe, etc.), or administration by separate devices within a short time of each other. In some embodiments, co-formulation of a compound or pharmaceutical composition of the present disclosure and one or more additional active ingredients delivered by the same route includes preparing the materials together so that they can be administered by one device, including separate compounds combined in one formulation, or compounds modified so that the compounds are chemically linked but retain their biological activity. In some embodiments, such chemically linked compounds may have a linkage that remains substantially in vivo, or the linkage may be cleaved in vivo, thereby separating the two active components.

The present disclosure also provides a kit. In some embodiments, the kit comprises a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present disclosure. As used herein, the term "kit" refers to any article of manufacture, e.g., a package, container, etc., containing a compound according to the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the present disclosure. In some embodiments, a compound according to the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the present disclosure is packaged in a vial, bottle, tube, flask, or patch, which may be further packaged in a box, envelope, bag, or the like. In some embodiments, a compound according to the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the present disclosure is approved for administration to a patient by the U.S. food and drug administration or similar regulatory agency in the united states or other jurisdictions or regions outside the united states. In some embodiments, the kit comprises written instructions for use and/or other instructions that indicate that a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present disclosure is suitable or approved for administration to a patient. In some embodiments, the compounds or compositions of the present disclosure are packaged in unit dose or single unit dose forms, such as single unit dose pills, capsules, and the like. In some embodiments, the kit comprises a dispenser.

The present disclosure also provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament. As used herein, the term "drug" refers to a pharmaceutical composition according to the present disclosure. In some embodiments, the medicament is for treating oral mucositis. In some embodiments, the pharmaceutical composition is contained in any article of manufacture, such as a package, container, or the like.

Examples

Embodiments related to the present disclosure are described below. In most cases, alternative techniques may be used. The examples are intended to illustrate, but not to limit or restrict the scope of the invention as set forth in the claims.

Example 1

The disclosed compounds are synthesized according to methods known to those of ordinary skill in the art. The methods described in U.S. patent nos. 6,627,215, 6,211,162, 7,868,162, 7,176,191, 8,435,960 and 6,211,349 and U.S. patent application publication nos. 2017-0191062, 2018-0258128 and 2018-0353529, which are incorporated herein by reference in their entirety, are well suited for the synthesis of the compounds of the present disclosure.

Example 2

Nu-8 was synthesized according to the following method:

synthesis of Nu-8

Step-1, protection of the amine (Building Block Key intermediate)

Hexamethyldisilazane (HMDS), 4- (dimethylamino) pyridine (DMAP), trimethylsilyltrifluoromethanesulfonate and di-tert-butyl dicarbonate ((BOC) with cytidine 2a added to methanol₂O) to protect the nitrogen atom of 2a by generating a BOC protected compound Int-2.

Step-2, preparation of Phosphorylylation reagent (building Block Key intermediate)

N-butanol was reacted with phosphoramidite 1 in THF in the presence of N, N-Diisopropylethylamine (DIEA) with tetrazole as a catalyst. The crude product was chromatographed on neutral alumina, eluting with hexane and then 2% ethyl acetate in hexane. Pure fractions were combined (by TLC) and evaporated to a residue under vacuum.

Step-3, coupling of key intermediates

The BOC protected species Int-2 is diphosphinated with reagent 2 in Dichloromethane (DCM)/Dimethylformamide (DMF) solvent with tetrazole as catalyst to yield 3. The reaction mixture was concentrated to a residue and the crude product was immediately oxidized in the next step.

Steps-4 and 5, Oxidation and deprotection of the amino group

The crude product 3 is oxidized with tert-butyl hydroperoxide (TBTH) in the presence of decane to give the bisphosphate species 4. The BOC group was removed in DCM in the presence of trifluoroacetic acid (TFA) to give 5. The crude product is chromatographed on silica gel, eluting with ethyl acetate. Pure fractions were combined (by TLC) and evaporated to a residue under vacuum.

Step-6 deprotection of the phosphodiester

With methanolic ammonium hydroxide (NH)₄OH, MeOH) hydrolysis of 5 to obtain the crude (I) ammonium salt (6).

Steps-7 and 8, purification

6 was purified by preparative HPLC and converted to the free acid using Dowex 50WX8-200 resin. Evaporation of the aqueous eluent gave (I), which was diluted with purified water to provide a 20% solution at its ambient pH.

Synthesis of Nu-8 sodium salt

Synthesis of Compound-2

To a solution of compound-1 (1.0kg, 3.3222mol) in THF (6L) was added DIEA (1.370mL, 8.3055mol) and tetrazole (230g, 3.3222mol), followed by dropwise addition of n-butanol (275mL, 2.99mol) in THF (6L) at 0 deg.C for 12 h. The reaction mixture was stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC and the solid was filtered off after completion of the reaction. The filtrate was evaporated at 40 ℃ under reduced pressure to give crude compound. The crude compound was dissolved in ethyl acetate (5L). The organic layer was washed with water (3L) and brine (2L). The organic layer was passed over anhydrous Na₂SO₄Dried, filtered, and the solvent evaporated under reduced pressure to obtain crude compound. In basic alumina (Al) by column chromatography₂O₃) The crude compound was purified above, eluting the compound with 0-2% EtOAc in petroleum ether to give compound-2 (700g, 76.92%) as a pale yellow liquid. H-NMR (400MHz, chloroform-d) δ 4.18-4.07 (m,1H),4.02(q, J ═ 6.6Hz,1H),3.93-3.74(m,4H),2.65(td, J ═ 6.5,3.6Hz,2H), 1.31-1.23 (m,4H),1.18(dd, J ═ 6.8,3.8Hz,12H),0.93(td, J ═ 7.4,3.1Hz, 3H). LC-MS:275(M + H).

Synthesis of Compound-4

DMAP (16.11g, 0.132 mol) was added to a solution of Compound-3 (300g, 1.321mol) in hexamethyldisilazane (638g, 3.964mol)) TMSOTf (7.22g, 0.039mol) was then added at 0 deg.C and the resulting reaction mixture was stirred at room temperature for 1 h. After completion of the starting material, Boc-anhydride (1.4L, 6.605mol) was added at 0 ℃ for 1h and the reaction mixture was stirred at room temperature for 16 h. Methanol (3L) was added to the reaction followed by triethylamine (1.5L) at 0 ℃ for 1h and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated under reduced pressure to give crude compound. The crude compound was diluted with ethyl acetate (3L) and washed with water (1.0L) and brine (1.0L); the organic layer was passed over anhydrous Na₂SO₄Drying, filtration and evaporation of the solvent under reduced pressure gave the crude compound. The crude compound was purified by column chromatography on silica gel (100-200 mesh) eluting with 0-3% MeOH in DCM to afford compound-4 as an off-white solid (180g, 31.89%). H-NMR (300MHz, DMSO-d6) δ 8.41(d, J ═ 7.5Hz,1H),6.84(d, J ═ 7.5Hz,1H),6.06(t, J ═ 6.2Hz,1H),5.28(d, J ═ 4.3Hz,1H),5.07(q, J ═ 4.6,4.0Hz,1H),4.21(q, J ═ 4.1Hz,1H),3.87(q, J ═ 3.7Hz,1H), 3.71-3.49 (m,2H),2.32(m,1H),2.03(dt, J ═ 13.0,6.2Hz,1H),1.49(s, 18H). LC-MS:275(M + H).

Synthesis of Compound-6

To a stirred solution of compound-4 (180g, 0.421mol) in THF (1.0L) at 0 deg.C was added DIEA (348mL, 2.105mol) and tetrazole (176g, 2.526 mol). To the resulting reaction mixture was added dropwise a solution of Compound-2 (519g, 1.896mol) in THF (800mL) at 0 ℃ for 1 h. The reaction mixture was stirred at rt for 16 h. After completion of the reaction, tert-butyl peroxide in decane (505mL, 5M) was added dropwise at 0 ℃ and the reaction mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated at 40 ℃, diluted with ethyl acetate (3L), and washed with water (1L) and brine (1L) solution. The organic layer was passed over anhydrous Na₂SO₄Drying, filtration and evaporation of the solvent under reduced pressure gave the crude compound (350g crude product). The crude compound was purified by column chromatography on a silica gel (100200 mesh) column eluting with 0-5% MeOH in DCM. All collected pure fractions were concentrated to give pure compound-6 (220g, 64.83%) as a wine-red liquid. H-NMR (300MHz, DMSO-d)₆)δ8.19(dd,J＝7.6,1.3Hz,1H),6.88(d,J＝7.5Hz,1H),6.13(t,J＝10.5Hz,1H),4.99(s,1H),4.44(s,1H),4.26–3.96(m,10H),3.00–2.84(m,4H),2.57–2.79(m,2H),1.70–1.54(m,4H),1.50(s,18H),1.35(m,4H),0.88(qd,J＝7.5,2.5Hz,6H)；LC-MS:806(M+H)。

Synthesis of Compound-7

To a solution of compound-6 (220g, 0.273mol) in DCM (4.4L) was added TFA (210mL, 2.732mol) dropwise at 0 ℃. The reaction mixture was stirred at room temperature for 24 h. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure to give crude compound. The crude compound was purified by column chromatography on silica gel (230-400 mesh). The compound was eluted with 0-10% MeOH in DCM. All collected pure fractions were concentrated to give pure compound-7 (170g, 84.67%) as a pale yellow liquid. H-NMR (300MHz, DMSO-d)₆)δ7.61(d,J＝7.5Hz,1H),7.27(d,J＝13.9Hz,2H),6.19(t,J＝6.9Hz,1H),5.74(d,J＝7.4Hz,1H),4.96(s,1H),4.10–3.93(m,11H),2.93(q,J＝6.2Hz,4H),2.29(d,J＝13.1Hz,2H),1.61(h,J＝7.1Hz,4H),1.35(p,J＝7.3Hz,4H),0.89(dq,J＝7.9,4.2Hz,6H)；LC-MS:606(M+H)。

Synthesis of Nu-8

To a stirred solution of Compound-7 (720g, 1.1900mol) in MeOH (5.0L) at 0 deg.C was added aqueous ammonia (600 mL). The reaction mixture was stirred at rt for 4 h. The reaction was monitored by TLC. After completion of the reaction, MeOH was evaporated under reduced pressure and the aqueous layer was washed with DCM (1.5L). Passing the aqueous layer through Dowex-H⁺And (3) resin. Water was removed under reduced pressure to give Nu-8(260g, 43.84%) as an off-white solid. H-NMR (300MHz, DMSO-d)₆)δ8.94(s,1H),8.49(s,1H),7.97(d,J＝7.8Hz,1H),6.08(t,J＝6.1Hz,1H),5.95(d,J＝7.7Hz,1H),4.76(q,J＝5.8Hz,1H),4.15(q,J＝4.1Hz,1H),4.08(s,1H),3.83(m,6H),2.43(t,J＝5.6Hz,2H),1.67–1.44(m,4H),1.44–1.26(m,4H),0.95–0.82(m,6H),LC-MS:500.15(M+H)。

Synthesis of Nu-8 sodium salt

To a stirred solution of compound-Nu-8 (260g, 0.478mol) in water (2.6L) was added dropwise 1N NaOH (950mL) at 0 ℃. The reaction mixture was stirred at rt for 2 h. The reaction was monitored by TLC. After completion of the reaction, the aqueous layer was washed with DCM (1.5L). The aqueous layer was evaporated under reduced pressure to give Nu-8 sodium salt (265g, 93%). H-NMR (300MHz, DMSO-d)₆)δ7.81(d,J＝7.2Hz,1H),7.2(bs,1H),7.0(bs,1H),6.16(t,J＝4Hz,1H),5.71(d,J＝7.6Hz,1H),4.69(bs,1H),3.75(m,1H),3.71(m,1H),3.8(m,4H),2.2(q,1H),1.89-1.96–1.44(m,1H),1.49–1.39(m,4H),1.34–1.23(m,4H),0.88–0.84(m,6H)。

Example 3

Nu-8 study for treating oral mucositis in hamsters caused by acute radiation

The purpose of this study was to test the efficacy of Nu-8 for the treatment of acute radiation-induced oral mucositis in hamsters.

Where the study was conducted

The study was conducted at the Biomodels' AAALAC facility of Watertin (Watertown), Mass. The in vivo phase (in-life delivery) of the study was performed between 13 days 8 and 11 days 9 and 2019. The approval book for this study (approval No. 19-0611-1) was obtained from Biomodels IACUC. The Office of Welfare for Laboratory animals (OLAW) has a guarantee number A4591-01.

Animal(s) production

Normal male syrian golden hamsters (Charles River Laboratories) were used, 5 to 6 weeks old, with a mean body weight (+ -SD) of 92.83 + -3.36 g at the start of the study. Animals were individually numbered using ear clamp and kept in groups. Animals were acclimated prior to study initiation. During this period, animals were observed daily to eliminate ill-conditioned animals.

Raising

The study was conducted in an animal house providing filtered air at 70 + -5 deg.F and 50 + -20% relative humidity. The animal house was set to remain ventilated at least 12 to 15 times per hour. Automatic timers were set in the room with light/dark cycles of 12 hours and 12 hours, respectively, without dusk. Use ofAnd (7) padding. Dunnage is changed a minimum of once a week. The cages, tops, bottles, etc. were washed with a commercially available detergent and air dried. For introducing smoke hoods (hood) using commercially available disinfectantsSurfaces and materials are sterilized. The floor was cleaned daily and wiped with a commercial cleaner at least twice a week. The walls and cages are wiped at least once a month with a dilute disinfectant solution. All cages were labeled with cage cards or tags containing the appropriate information necessary to identify the study, dose, animal number and treatment group. Temperature and relative humidity were recorded during the study and the record was kept.

Diet

By Purina5053 the animals are fed with sterile rodent feed. Food and sterile water were provided ad libitum.

Animal randomization and distribution

Prior to irradiation, animals were randomly and prospectively divided into three (3) groups of eight (8) animals each. Each animal was identified by an ear clamp corresponding to a single number. Cage cards are used to identify each cage or tag, which is labeled with study number (LKW-01), treatment group number, and animal number.

Preparation and administration of test article/vehicle (vehicle)

Test article and carrier test article

Identity and lot number: nu-8(lot # LWA-03-14)

Physical description: dry powder

The source is as follows: lakewood Amedex, Inc.

Carrier: 0.9% physiological saline

The administration route is as follows: local (direct connection to left cheek pocket)

Details of administration: 0.2 mL/dose-dose concentration (low) ═ 1% dose concentration (high) ═ 10%

Preparation:

1. fresh configuration every day. The necessary amount of the compound was weighed and dissolved in physiological saline. Titration with citric acid reduced the pH of the solution to about 3.5(pH range 3 to 4).

2. The vehicle administered to the animals of group 1 was also titrated with citric acid to a pH of-3.5 (pH range 3 to 4).

Application of test article

The routes and methods of application: local part

Reasons for the route of administration: this route of administration has been used to demonstrate the efficacy of various test compounds.

Frequency and duration of dosing: TID-days 1 to 28

The dose administered is: low as 1%

High (10%)

Induction of mucositis

On day 0, a single dose of radiation (40Gy) was used to induce mucositis. The radiation was generated with a 160 kilovolt potential (18.75-ma) light source at a focal length of 10cm and hardened by a 3.0mm Al filter system. Radiation was targeted to the left buccal pouch mucosa at a power of 2 to 2.5 Gy/min. Prior to irradiation, animals were anesthetized by intraperitoneal injection of ketamine (160mg/kg) and xylazine (8 mg/kg). The left buccal pouch was everted, fixed and isolated using a lead screen.

Mucositis score

From day 6 onwards, every two days (days 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28) were continued, each animal was photographed and assessed for a mucositis score. To evaluate mucositis, animals were anesthetized with inhalation anesthetic and the left buccal pouch was everted. Mucositis was scored visually by comparison to a validated photographic scale (fig. 1A-1F) ranging from 0 for normal to 5 for severe ulcers (clinical score). In descriptive terms, the scale is defined as follows:

TABLE 1 mucositis score

Scores 1 to 2 are considered to represent a mild stage of the disease, while scores 3 to 5 are considered to represent moderate to severe ulcerative mucositis. After visual clinical scoring, the mucosa of each animal was photographed using standardized techniques. At the end of the experiment, the photographs were randomly numbered and scored by two independent trained observers who scored the images blindly (blinded assessment) using the scale described above. For each photograph, the actual blind score is based on the average of the scores of the two observers. Only scores from blind photographic evaluations were recorded and used for statistical analysis. Hamsters with mucositis severity score of 4 or higher received buprenorphine (0.5mg/kg) subcutaneous administration (SC) twice daily for 48 hours or until the score dropped below 4.

Statistical analysis

Statistical differences between treatment groups were determined using Mann-Whitney Rank Sum test and chi-square analysis (cut-off 0.05) using blind photographs. It is expected that up to 10% of animal deaths may occur, primarily due to the administration of anesthetics. However, the number of animals expected to remain viable on day 28 (6 per treatment group) was acceptable for statistical evaluation.

The hamsters in each group were analyzed for differences in days with severe mucositis (score ≧ 3). On each day, animals were scored (evaluation day), and the number of animals in each treatment group with a blind mucositis score of > 3 was compared to the vehicle control group. Differences were analyzed on a daily basis (day basis) and a cumulative basis (cumulative basis). The number of hamsters with this score in the drug treatment group was statistically significantly lower compared to vehicle controls as determined by chi-square analysis, confirming the success of the treatment.

The rank and difference (rank sum difference) of the daily mucositis scores of the treatment groups compared to the vehicle control group was determined. For each evaluation day, the scores of the vehicle control group were compared to the scores of the treatment groups using a nonparametric rank sum analysis. The treatment group scores were statistically significantly reduced on days 2 or more from day 6 to day 28, confirming the success of the treatment.

To determine the effect of the test article on the resolution of mucositis, the healing time of the treated and control groups were compared. Regression was defined as the absence of ulcerative lesions (mucositis score < 3).

Design of research

Twenty-four (24) male syrian golden hamsters were used in the study. Mucositis is caused by a 40Gy acute radiation dose targeted to its left buccal pouch on day 0 at a power of 2 to 2.5 Gy/min. This is achieved by anaesthetizing the animal, turning the left buccal pouch outwards, while protecting the rest of the animal's body with a lead shield. Mucositis was evaluated clinically starting on day 6 and continuing every other day until day 28. Hamsters with mucositis severity score of 4 or higher received buprenorphine (0.5mg/kg) subcutaneous administration (SC) twice daily for 48 hours or until the score dropped below 4.

As detailed in table 2, the test article or carrier was administered by topical application to the left buccal pouch (TID from day 1 to 28). On day 0, dosing was performed 1 to 2 hours prior to radiation.

On day 28, via inhalation of CO₂All animals were euthanized and death was confirmed by monitoring heartbeats according to USDA guidelines. No endpoint collection (tertiary collection) was performed. Table 2 shows the details of the study design.

TABLE 2 study design

Results and discussion

Survival

During the study, one (1) animal was unexpectedly dead; animal #22 in group 3 was sacrificed due to incomplete irradiation on day 0.

Weight change

Figure 2 shows the average percent daily weight change data for animals in all groups. The weight of the animals steadily increased throughout the study period. Animals in group 3 exhibited a statistically significantly lower percent mean weight change (p <0.05) compared to the vehicle group as determined by area under the curve (AUC) analysis followed by one-way ANOVA evaluation with Holm-Sidak multiple comparison post hoc tests.

Mucositis

The average daily mucositis score is shown in figure 3. The maximum mean mucositis score observed in the vehicle group was 3.00 ± 0.00, which was first observed on day 18. Animals given TID to 1% Nu-8 (group 2) experienced a peak mean mucositis score of 2.88. + -. 0.13 on day 18. Animals given TID 10% Nu-8 (group 3) experienced a peak mean mucositis score of 2.29. + -. 0.18 on days 16 and 18. In both groups treated with Nu-8, the animals showed a modest reduction in the onset of disease, especially in animals dosed at 10% concentration (group 3). In fact, animals given 10% Nu-8 showed a strong remission of disease severity compared to animals given the vehicle.

Duration of ulcerative mucositis

The significance of the observed differences between the control and treated groups was assessed using the chi-square assay by comparing days with mucositis scores ≧ 3 and <3 between groups. The results of this analysis throughout the duration of the study (up to day 28) are shown in table 3 and figure 4. The percentage of animal days in the vehicle group that scored > 3 during the study (Table 3, FIG. 4) was 52.08%. The percentage of days scoring ≧ 3 in animals given 10% Nu-8 was statistically different compared to the vehicle control group.

TABLE 3-chi square analysis of percentage of animal days with a mucositis score > 3

To examine the level of clinically significant mucositis, defined as the appearance of open ulcers (score ≧ 3), the total number of days for which the animals exhibited an increase in score was summed up and expressed as a percentage of the total number of days scored per group. Statistical significance of the observed differences was calculated using chi-square analysis.

Severity of mucositis

A mucositis severity analysis was performed using Mann-Whitney rank sum analysis to compare the visual mucositis score of the treated group to the vehicle control group on each day of evaluation. The analysis results are shown in Table 4. In this analysis, a significant reduction in mucositis score of 2 days is generally required to be considered meaningful. Animals given 1% Nu-8 (group 2) showed a significant improvement in the one-day mucositis score compared to the vehicle control group. Using this evaluation method, animals given 10% Nu-8 (group 3) showed significant improvement over multiple days.

TABLE 4 comparison of daily mucositis scores

The significance of the group differences observed in the daily mucositis score was determined using the Mann-Whitney rank sum test. This non-parametric statistics is applicable to the visual mucositis scoring scale. The p-value for each calculation is shown. Solid grey shading indicates decreased mucositis score (disease improvement) compared to vehicle group, diagonal shading indicates increased mucositis score (disease progression).

Percentage of animals with ulcerative mucositis by day

Table 5 shows the percentage of animals with ulcerative mucositis in each group on each evaluation day. This evaluation was intended to elucidate which days of treatment had the greatest effect on the course of ulcerative mucositis. The percentage of Nu-8 treated ulcers over several days was lower (lower percentage of ulcers compared to vehicle could be interpreted as an improvement in disease severity) at both dose concentrations used in this study compared to vehicle administered animals.

TABLE 5 percent of ulcerative animals with a daily mucositis score of 3 or more

To examine the level of clinically significant mucositis, defined as the appearance of open ulcers (score ≧ 3), the percentage of animals exhibiting open ulcers in each treatment group on each day of the study was determined. Solid grey shading indicates decreased mucositis score (disease improvement) compared to vehicle group, and diagonal shading indicates increased mucositis score (disease progression).

Conclusion

1. During the study, one (1) animal was unexpectedly dead.

2. The weight of the animals steadily increased throughout the study period. Animals in group 3 exhibited a statistically significantly lower percent mean weight change (p <0.05) compared to the vehicle group as determined by area under the curve (AUC) analysis followed by one-way ANOVA evaluation with Holm-Sidak multiple comparison post hoc tests.

3. In both groups treated with Nu-8, the animals showed a modest reduction in the onset of disease, especially in animals dosed at 10% concentration (group 3). In fact, animals given 10% Nu-8 showed a strong remission of disease severity compared to animals given the vehicle.

4. The percentage of animal days in the vehicle group scored > 3 was 52.08%. The percentage of days scoring ≧ 3 in animals given 10% Nu-8 was significantly lower compared to the vehicle control group.

5. Animals given 1% Nu-8 (group 2) showed a significant improvement in the one-day mucositis score compared to the vehicle control group. Using this evaluation method, animals given 10% Nu-8 (group 3) showed significant improvement over multiple days.

6. The percentage of ulcers in days for animals treated with Nu-8 administered was lower for both dose concentrations used in this study compared to animals given vehicle (lower percentage of ulcers compared to vehicle may be interpreted as an improvement in disease severity).

Example 4

Cellulose gel mixture (compounding)

A 100g scale of cellulose gel was prepared using the following procedure using a solution of Nu-3 as the free acid.

1. Nu-3 was added to a portion of the water and mixed until homogeneous.

2. Add sodium chloride and mix until homogeneous.

3. The pH was adjusted to 1.5 using 4% NaOH (1.4-1.6 is an acceptable range).

4. Add the remaining water and mix until homogeneous.

5. Hydroxyethyl cellulose powder (Natrosol 250HHX PH, Ashland) was slowly added to the mixing propeller vortex.

6. Mixing was continued until the polymer gel was clear (-45 to 60 minutes).

Example 5

Fatty Alcohol (FA) gel mixtures

Using a solution of Nu-3 as disodium salt, a 100g scale FA gel was prepared using the following procedure.

1. Nu-3 was added to a portion of the water and mixed until homogeneous.

2. The pH was adjusted to 1.5 using 10% HCl (1.4-1.6 is an acceptable range).

3. Add the remaining water and mix until homogeneous.

4. In a separate container, cetearyl alcohol (crodecol CS 50NF, Croda) and ceteareth-20 (Cetomacrogol 1000NF, Croda) were mixed and heated on a hot plate to-60 ℃ while mixing to melt the fatty alcohol and surfactant. Maintained at-60 ℃.

5. The API solution was heated to-60 ℃ on a hot plate while mixing with a propeller mixer.

6. The fatty alcohol/surfactant mixture was added to the API solution while mixing with a propeller mixer. The propeller mixer was removed, the vessel was removed from the heat source, and high shear mixing was initiated.

7. High shear mixing (45 to 50 ℃) was continued as the gel cooled and thickened.

8. When the gel became too thick to mix with the homogenizer, high shear mixing was stopped and mixing with the propeller mixer was continued until the gel reached 35 to 40 ℃.

Example 6

Set up HPLC analysis and autoclaving study

The Nu-3 preparation of this example was analyzed using the chromatographic conditions in table 6.

TABLE 6 chromatographic conditions

Linearity was assessed using a Nu-3 solution of 0.05 to 0.4 mg/mL. The peak area has a correlation coefficient value of 0.9994 compared to mg/mL. The Relative Standard Deviation (RSD)% of 0.2mg/mL standard injected repeatedly was < 1.0%.

Example 7

Carrier gel for evaluation

Three carrier gels were prepared for evaluation. Sodium phosphate was used to mimic the presence of Nu-3 and benzyl alcohol was used as an antimicrobial preservative. Their compositions are summarized in table 7.

TABLE 7 Carrier gel composition

Gels 2 and 3 were selected for formulation with Nu-3 at 5% w/w due to their superior physical properties. The pH of the formulation is lowered to the target value of 1.5 to ensure optimal activity of Nu-3.

Example 8

5% Nu-3 cellulose gel: formulation and stability

The composition of the gel is shown in table 8.

TABLE 8-5% cellulose gel composition

The initial results and stability results for the 5% Nu-3 cellulose gel are summarized in Table 9.

TABLE 9-5% initial and stability results for Nu-3 cellulose gel

During storage, the viscosity of the cellulose Nu-3 gel decreases significantly with temperature. This may be due to hydrolysis of the cellulose in the polymer. However, there was no significant change in the assay and pH after 1 month of storage at 40 ℃.

Example 9

5% NU-3FA gel: formulation and stability

The compositions of these gels are shown in table 10.

TABLE 10-5% FA gel composition

Composition (I)	Nu-3FA gel 1	Nu-3FA gel 2
			Nu-3 disodium salt	5.36	5.36
10% HCl (moderate to pH 1.5)	2.8	2.8
			Crodacol CS 50NF	4.0	7.25
Cetomacrogol 1000NF	1.0	1.0
			Purified water, USP	The proper amount is 100 percent	The proper amount is 100 percent

FA gel 1 did not thicken during mixing.

For FA gel 2, cetearyl alcohol levels increased from 4.0 to 7.25% w/w. This increases the gel viscosity of the vehicle and the 5% Nu-3 formulation. The stability data for Nu-3FA gel 2 are summarized in Table 11.

TABLE 11-5% initial and stability results for Nu-3FA gel 2

FA gel 2 showed no significant changes in analysis, appearance and pH after 1 month at 25 or 40 ℃. There was a slight increase in viscosity during storage, which is not uncommon in fatty alcohol gels. After 1 to 3 months of storage, their viscosity tends to be stable.

Higher strength Nu-3FA gel: formulation and stability

The compositions of these gels are shown in table 12, and the stability results are shown in table 13.

TABLE 12-FA gel composition

TABLE 13 stability results for Nu-3FA gels

After being placed at 25 or 40 ℃ for 1 month, no significant changes were observed in the analysis, appearance and pH of the 10-20% Nu-3FA gel. There was a slight increase in viscosity during storage, which is not uncommon in fatty alcohol gels. After 1 to 3 months of storage, their viscosity tends to be stable.

Example 10

Nu-8 treatment of human patients with oral mucositis

The human patient is identified as having oral mucositis. A pharmaceutical composition in the form of a liquid solution containing an effective amount of Nu-8 is topically applied directly to the oral cavity of the patient. The patient is monitored until the symptoms are alleviated or reduced, and if it is determined that such administration is necessary or helpful for treatment, the pharmaceutical composition may be administered one or more times again.

Although embodiments have been disclosed above, the present invention is not limited to the disclosed embodiments. On the contrary, this application is intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and which fall within the limits of the appended claims.