Novel compositions of cyclophosphamide with odd-chain fatty acids or their derivatives

Abstract

The present invention describes novel formulations of cyclophosphamide, comprising cyclophosphamide and one or more odd chain fatty acids or derivatives of odd chain fatty acids. Wherein the odd chain fatty acid is further selected from pentadecanoic acid and heptadecanoic acid. These formulations have utility to alleviate cyclophosphamide-induced inflammation and its associated toxicities.

Description

[0001] NOVEL COMPOSITIONS OF CYCLOPHOSPHAMIDE WITH ODDCHAIN FATTY ACIDS OR THEIR DERIVATIVES

[0002] FIELD OF INVENTION

[0003] This invention pertains to novel formulations of cyclophosphamide with odd-chain fatty acids or their derivatives to reduce systemic inflammation and its associated toxicities of cyclophosphamide.

[0004] BACKGROUND

[0005] Cyclophosphamide is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-l,3,2- oxazaphosphorine 2-oxide monohydrate and occurs as a white crystalline powder with the molecular formula C7H15Q2N2O2P.H2O and a molecular weight of 279.1. It is soluble in water, saline, or ethanol. It has the following chemical structure:

[0006] Cyclophosphamide, a commonly used clinical immunosuppressant and anti- neoplastic drug for treating various cancers, is known to cause damage to healthy cells and induce oxidative damage in the kidneys, liver, and other tissues (Abarikwu et al., 2012; Devi and Mazumder, 2016; Cao et al., 2017; Kocahan et al., 2017; Zhai et al., 2018). The oxidative damage to organs caused by liver cytochrome P450- dependent conversion of cyclophosphamide is supported by disturbance in redox balance, leading to increased formation of reactive oxygen species (Devi and Mazumder, 2016). Exposure to cyclophosphamide, commonly leads to compromised liver and kidney function, evidenced by heightened levels of serum creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, tissue malondialdehyde, and reduction in antioxidant markers (Zhai et al., 2018). Drug-induced hepatotoxicity and nephrotoxicity are characterised by cellular necrosis and injury resulting from inflammation (Hoshi et al., 2020; Volarevic et al., 2019). The involvement of free radical species and inflammation caused by immune cells significantly contributes to the pathways leading to tissue damage (Zeng et al., 2020).

[0007] U.S Patent No. 4952575 (A) to Sauerbier Dieter et al., covers a solution of cyclophosphamide with 80-100% v / v of ethanol. The patent also describes solvents such like glycofurol, polyethylene glycol 300, polyethylene glycol 400, 1,2 propylene glycol, 1,3 butylene glycol.

[0008] US Publication No. 20140005148 (Al) to Neelakantan Sundar et al., covers compositions of cyclophosphamide with polyethylene glycol or propylene glycol or glycerin or dimethyl acetamide, polysorbate, polyethoxylated castor oil or combinations thereof.

[0009] U.S Patent No. 11931370 (B2) to Mandge Shailendra et al., relates to a stable, ready-to-administer, liquid composition for oral administration comprising cyclophosphamide, a non-aqueous lipid solvent and a co-solvent wherein the level of total impurities in said liquid composition is less than 5%.

[0010] The prior art formulations are directed to methods of making stable formulations or methods of reducing impurities in cyclophosphamide formulations. There are no formulations that are designed to reduce the associated side effects and toxicities.

[0011] Chemotherapy administered to cancer patients frequently initiates inflammation, leading to cascading undesirable toxicities. A significant unmet necessity exists for mitigating the systemic inflammation burden associated with chemotherapy. Accordingly, there is a necessity to develop cyclophosphamide compositions that exhibit reduced incidences of inflammation and associated toxicities.

[0012] SUMMARY OF INVENTION

[0013] The present invention relates to novel formulations of cyclophosphamide to reduce the toxicities and systemic inflammation associated with the administration of cyclophosphamide.

[0014] One aspect of the invention relates to a composition comprising cyclophosphamide and one or more odd chain fatty acids.

[0015] Another aspect of the invention relates to a composition comprising cyclophosphamide and one or more odd chain fatty acids selected from odd chain saturated fatty acids and odd chain unsaturated fatty acids.

[0016] Another aspect of the invention relates to a composition comprising cyclophosphamide and one or more derivatives of odd chain fatty acids.

[0017] Another aspect of the invention relates to a composition comprising cyclophosphamide and one or more odd chain fatty acids and one or more derivatives of odd chain fatty acids.

[0018] Another aspect of the invention relates to a composition comprising cyclophosphamide and an odd chain fatty acid selected from pentadecanoic acid and heptadecanoic acid.

[0019] Yet another aspect of the invention relates to a composition comprising cyclophosphamide and a carnitine, choline, derivative of odd chain fatty acid. Yet another aspect of the invention relates to a composition comprising cyclophosphamide and a carnitine, choline, derivative of odd chain fatty acid selected from pentadecanoic acid and heptadecanoic acid.

[0020] Another aspect of invention relates to a composition comprising cyclophosphamide and a carnitine, choline, derivative of odd chain fatty acid selected from pentadecanoic acid and heptadecanoic acid. The composition may comprise the combination of the said odd chain fatty acids or their derivatives with choline or their derivatives, with carnitine.

[0021] Another aspect of the invention relates to a method of reducing toxicities in a patient requiring treatment with cyclophosphamide by administering a composition of cyclophosphamide and one or more odd chain fatty acids.

[0022] DETAILED DESCRIPTION OF THE INVENTION

[0023] Cyclophosphamide is an alkylating agent used to treat various types of tumours. Different dosage forms of cyclophosphamide like tablets and parenteral formulations are currently in use. The parenteral formulations are available as dry powder vials and concentrate for infusion. Cyclophosphamide is a cytotoxic agent that triggers inflammatory responses that cascade into adverse events.

[0024] Most of the formulations reported in the prior art are directed to methods of making stable formulations of cyclophosphamide. There are no formulations that are designed to reduce the associated side effects and toxicities.

[0025] The inventors of this invention discovered novel compositions of cyclophosphamide with odd-chain fatty acids or their derivatives. These compositions showed a reduced inflammatory response when compared to cyclophosphamide alone. Inflammation is a biological or cellular response to stimuli that releases inflammatory markers. The term “cyclophosphamide” is intended to include any of the alternative forms in which cyclophosphamide can be administered such as salts, esters, anhydrous, hydrates such as monohydrate or dihydrate, solvates, amides, cocrystals, adducts, crystalline or amorphous polymorphs, racemic mixtures, enantiomeric isomers.

[0026] The term “pharmaceutically acceptable” refers to generally safe, non-toxic ingredients that are useful for preparing pharmaceutical compositions.

[0027] The compositions of cyclophosphamide may comprise 5mg / unit dose to 5000mg / unit dose of cyclophosphamide and odd chain fatty acids or their derivatives in a dose range of 5mg to 2500 mg / unit dose.

[0028] The odd chain fatty acids in this invention are selected from odd chain saturated fatty acids (OCSFA) or odd chain unsaturated fatty acids (OCUFA). OCSFA refers to fatty acids characterized by an odd number of carbon atoms and a fully saturated structure with no double bond between the carbon atoms. OCUFA refers to odd chain unsaturated fatty acids that have one or more double bonds between the carbon atoms.

[0029] OCSFA, including tridecanoic acid (Cl 3:0 or n-13:0), pentadecanoic acid (Cl 5:0 or n-15:0), and heptadecanoic acid (Cl 7:0 or n-17:0), are naturally present in dairy products and seafood. In dairy foods, the ratio of n-15:0 to n-17:0 is observed to be 2: 1, while in seafood and human tissues, this ratio changes to 1 :2. OCUFA include 17: ln-8, 19: ln-8, 17: ln-ll and 19:ln-ll.

[0030] These odd-chain fatty acids or their derivatives have anti-inflammatory activity. Among the odd chain fatty acids, pentadecanoic acid (Cl 5:0) and heptadecanoic acid (C17:0) are accepted biomarkers for dairy fat intake in humans. Published studies show inverse relationship of Cl 5:0, Cl 7:0, or both combined in plasma phospholipids or RBCs and the risk of cardiovascular disease (CVD), and type-2 diabetes. OCFAs (C15:0 and C17:0) regulate the production of proinflammatory cytokine and lipid mediators in macrophages.

[0031] The preferred derivates of odd-chain fatty acids are pentadecanoic acid and heptadecanoic acid.

[0032] The antioxidants in the present invention are selected from DL-Alpha tocopherol (Vitamin E), monothioglycerol (MTG), ascorbic acid, citric acid, tartaric acid, ascorbyl palmitate, butylated hydroxy anisole (BHA) and butylated hydroxytoluene (BHT).

[0033] The solvents and co-solvents in the present invention are selected from dehydrated alcohol, water, N-methyl pyrrolidine, (NMP), and dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA) and glycerol.

[0034] In some embodiments the compositions may comprise (i) 5mg / unit dose to 5000mg / unit dose of cyclophosphamide (ii) odd chain fatty acids or their derivatives in a dose range of 5mg to 2500 mg / unit dose and (iii) pharmaceutically acceptable excipients.

[0035] Pharmaceutically acceptable excipients may be selected from cyclodextrins, modified derivatives of cyclodextrins (ex: Sugamadex, SBECD, HPBCD, betacyclodextrin, gamma cyclodextrin, alpha-cyclodextrin, substituted cyclodextrins), bulking agents or cake-forming agents, sugars, carbohydrates, amino alcohols, amino sugars, amino acids, complex carbohydrates, dextrans, dextrins, salts, buffers, pH adjusting agents, chelating agents, surfactants, co-surfactants, aqueous vehicles including water, polymers, rate release modifying agents, lipids, phospholipids, fatty acid derivatives, proteins, peptides, modified phospholipids, fatty acids & their derivatives, vitamins, metal salts, osmotic modifying agents, suspending agents, stabilizers, phenolic compounds, flavonoids, flavanols, flavonols, flavanones, flavones, isoflavones, chaicones, anthocyanin or their derivatives, and preservatives.

[0036] The compositions can be made into various dosage forms such as dry powder, lyophilized preparations, liquid preparations, solutions, suspensions, premix powder, premix solutions, tablets, capsules, sachets, suppositories or semisolid preparations.

[0037] The novel parenteral composition of cyclophosphamide with odd-chain fatty acids or their derivatives is described as below:

[0038] Example 1

[0039] The above composition can be made as tablets, capsules, powder, lyophilized products, parenteral dosage forms, solutions, semi-solid preparations.

[0040] Example 2 Example 3

[0041] The solution is prepared by mixing all the ingredients together to form a solution. The solution can be administered to a patient needing cyclophosphamide infusion, or orally or by inhalation or parenterally at a prescribed dosing regimen to reduce toxicity.

Claims

We claim1. A composition comprising (i) cyclophosphamide and (ii) one or more odd chain fatty acids or its derivatives.

2. The composition as claimed in claim 1, wherein the odd chain fatty acid is an odd chain saturated fatty acid.

3. The composition as claimed in claim 1, wherein the odd chain fatty acid is an odd chain unsaturated fatty acid.

4. The composition as claimed in claim 1, comprising 5mg / unit dose to 5000mg / unit dose of cyclophosphamide.

5. The composition as claimed in claim 1, comprising odd chain fatty acids or their derivatives in a dose range of 5mg to 2500 mg / unit dose.

6. The composition as claimed in claim 1, additionally comprising of pharmaceutically acceptable excipients.

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