PROCESS FOR PREPARATION OF PURE NALTREXONE DECANOATE, ITS SALTS, COMPOSITION AND METHOD OF USE THEREOF

Abstract

Disclosed herein is an improved process for preparation of naltrexone decanoate under a monophasic medium using a single solvent by esterifying naltrexone with a decanoyl chloride in the presence of an organic base, wherein the solvent is preferably cyclo-pentyl-methyl-ether (CPME) which is non-toxic in nature. The invention further discloses the elimination of an impurity bis-decanoyl naltrexone obtained during the preparation of naltrexone decanoate by preparing acid addition salts of naltrexone decanoate and reconverting into naltrexone decanoate from its acid addition salts by neutralizing using a base in the presence of suitable solvent to obtain naltrexone decanoate with a purity of more than 99% The invention also discloses pharmaceutical composition of naltrexone decanoate with at least one pharmaceutically acceptable excipient and method of use of naltrexone decanoate for the treatment of opioid dependence, alcohol dependence for a period of 7 days to 90 days in a patient in need thereof.

Claims

1-20. (canceled)

21. A process for the preparation of an ester of naltrexone, comprising the steps of: a) reacting naltrexone or a salt thereof with an acylating agent in the presence of an organic base and an organic solvent to obtain an ester of naltrexone, wherein the acylating agent is a halide of a saturated or unsaturated carboxylic acid having 2-18 carbon atoms, wherein the ester of naltrexone comprises a saturated or unsaturated acyl moiety having 2-18 carbon atoms; b) converting the ester of naltrexone into an acid addition salt by treating the ester of naltrexone with an acid in an organic solvent; and c) neutralizing the acid addition salt by treating the acid addition salt with a base to isolate a purified ester of naltrexone.

22. The process as claimed in claim 21, wherein the step of reacting naltrexone or the salt thereof with an acylating agent is carried out in the presence of an organic base selected from the group consisting of triethylamine, diisopropylethylamine, tripropyl amine, trimethyl amine, N-methyl pyrrolidine, pyridine, N-methyl morpholine, N,N-dimethyl aminopyridine, and mixtures thereof.

23. The process as claimed in claim 21, wherein the step of reacting naltrexone or the salt thereof with an acylating agent is carried out in the presence of an organic solvent selected from the group consisting of a non-polar organic solvent selected from the group consisting of dichloromethane, diethyl ether, methyl tertiary-butyl ether, cyclopentyl methyl ether, 1,4-dioxane, toluene, pentane, cyclopentane, hexane, cyclohexane, heptane, and mixtures thereof; a polar organic solvent selected from the group consisting of methanol, ethanol, n-butanol, isopropanol, n-propanol, ethyl acetate, tetrahydrofuran, dichloromethane, acetonitrile, acetone, dimethyl formamide, and mixtures thereof; and mixtures thereof.

24. The process as claimed in claim 21, wherein the step of reacting naltrexone or the salt thereof with an acylating agent is carried out in the presence of the non-polar organic solvent, wherein the non-polar organic solvent is cyclopentyl methyl ether.

25. The process as claimed in claim 21, wherein: the step of reacting naltrexone or the salt thereof with an acylating agent is carried out at a temperature between 0° C. and 1100° C.; and the step of reacting naltrexone or the salt thereof with an acylating agent is carried out for a period between 20 minutes and 48 hours.

26. The process as claimed in claim 21, wherein the acylating agent is selected from the group consisting of decanoyl chloride, palmitoyl chloride, stearoyl chloride, myristoyl chloride sebacoyl chloride, acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, undecanoyl chloride, dodecanoyl chloride, tridecanoyl chloride, pentadecenoyl chloride, heptadecanoyl chloride, isobutyroyl chloride, and mixtures thereof.

27. The process as claimed in claim 21, wherein converting the ester of naltrexone into the acid addition salt comprises treating the ester of naltrexone with an acid selected from the group consisting of acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, decanoic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid, salicylic acid, and mixtures thereof.

28. The process as claimed in claim 21, wherein the step of neutralizing the acid addition salt comprises treating the acid addition salt with an inorganic base in a non-polar organic solvent at a temperature in the range of 10° C. to 35° C.; wherein the inorganic base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, lithium bicarbonate, lithium carbonate, lithium hydroxide, calcium hydroxide, barium hydroxide, and mixtures thereof.

29. The process as claimed in claim 21, wherein the ester of naltrexone is selected from the group consisting of naltrexone acetate, naltrexone butyrate, naltrexone velarate, naltrexone hexanoate, naltrexone heptanoate, naltrexone octanoate, naltrexone nonaoate, naltrexone undecanoate, naltrexone dodecanoate, naltrexone tridecanoate, naltrexone myristate, naltrexone pentadecanoate, naltrexone palmitate, naltrexone heptadecanoate, naltrexone isobutyrate, naltrexone pivaloate, naltrexone propionate, naltrexone stearate, naltrexone decanoate, and naltrexone sebacate, and mixtures thereof.

30. The process as claimed in claim 21, wherein: the ester of naltrexone is naltrexone decanoate; and the acid addition salt is selected from the group consisting of naltrexone decanoate hydrochloride, naltrexone decanoate oxalate, naltrexone decanoate succinate, naltrexone decanoate tartrate, naltrexone decanoate maleate and naltrexone decanoate decanoate, and mixtures thereof.

31. A process for the preparation of naltrexone decanoate, comprising the steps of: a) reacting naltrexone or a salt thereof with a halide of decanoic acid to obtain naltrexone decanoate; b) converting the naltrexone decanoate into an acid addition salt by treating the ester of naltrexone with an acid in an organic solvent; and c) neutralizing the acid addition salt by treating the acid addition salt with a base to isolate purified naltrexone decanoate in a yield of >90%; wherein the naltrexone decanoate has a purity of >98% and is devoid of bis-decanoyl naltrexone.

32. The process as claimed in claim 31, wherein the naltrexone decanoate has a purity of >98% after storage for a period of up to 60 months at a storage temperature of less than 25° C.

33. A sustained release pharmaceutical composition, comprising an ester of naltrexone, wherein the ester of naltrexone is produced by the method of claim 1, wherein a single dose of the sustained release pharmaceutical composition delivers naltrexone to a patient in need thereof for over a period ranging from 7 days to 90 days.

34. The sustained release pharmaceutical composition as claimed in claim 33, wherein the ester of naltrexone is selected from the group consisting of naltrexone acetate, naltrexone butyrate, naltrexone velarate, naltrexone hexanoate, naltrexone heptanoate, naltrexone octanoate, naltrexone nonaoate, naltrexone undecanoate, naltrexone dodecanoate, naltrexone tridecanoate, naltrexone myristate, naltrexone pentadecanoate, naltrexone palmitate, naltrexone heptadecanoate, naltrexone isobutyrate, naltrexone pivaloate, naltrexone propionate, naltrexone stearate, naltrexone decanoate and naltrexone sebacate, and mixtures thereof, having a concentration in the range of 50 to 1500 mg/ml.

35. The sustained release pharmaceutical composition as claimed in claim 33, further comprising at least one pharmaceutical excipient selected from the group consisting of: a) a vehicle in a concentration of about 30.0% w/w to 90.0% w/w of the total composition; b) a stabilizer in a concentration of about 0.01% w/w to 30.0% w/w of the total composition; and c) a rate limiting polymer in a concentration of about 0.2% w/w to 50% w/w of the total composition.

36. The sustained release pharmaceutical composition as claimed in claim 35, further comprising the vehicle, wherein the vehicle is selected from the group consisting of vegetable oils, water miscible organic solvents, water immiscible organic solvents, and mixtures thereof.

37. The sustained release pharmaceutical composition as claimed in claim 35, further comprising the stabilizer, wherein the stabilizer is selected from the group consisting of benzyl alcohol, butylated hydroxyl anisole (BHA), butylated hydroxyl toluene (BHT), alpha-tocopherol, and mixtures thereof.

38. The sustained release pharmaceutical composition as claimed in claim 35, further comprising the rate limiting polymer, wherein the rate limiting polymer is selected from the group consisting of: poly(lactic acid-co-glycolic acid), wherein the Lactide:Glycolide ratio is between 50:50 and 85:15; poly(lactic acid); polycaprolactone; a fatty acid; and mixtures thereof.

39. A method for treating a patient addicted to an opioid and/or alcohol, comprising administering an effective amount of the sustained release pharmaceutical composition as claimed in claim 33 to the patient.

40. The method of claim 39, wherein the sustained release pharmaceutical composition is administered by subcutaneous or intramuscular injection in a volume ranging from 0.5 to 5 ml.

Description

DESCRIPTION OF DRAWING

[0065] FIG. 1: Blood plasma concentration of Naltrexone in rats after administration of different formulations of Naltrexone decanoate compositions (Formulation A, Formulation B and Formulation F).

[0066] FIG. 2: The chromatogram of naltrexone decanoate for the analysis of impurity using HPLC method.

DESCRIPTION OF THE INVENTION

[0067] Accordingly, the present invention describes an improved process for the synthesis of naltrexone decanoate with high purity and its sustained release pharmaceutical composition with the release of naltrexone ranging from 7 days to 90 days. The present invention further describes synthesis of Naltrexone decanoate and its pharmaceutically acceptable acid addition salts which includes organic and inorganic salts, more preferably organic salts. The present invention also describes the process for reconverting organic acid addition salt of naltrexone decanoate to naltrexone decanoate with substantial purity and yield by treating with a suitable base in a non-polar solvent.

[0068] The acids commonly employed to form acid addition salts may include but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, decanoic acid, p-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such salts include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, phenylacetate, phenylpropionate, phenyibutyrate, citrate, lactate, gamma-propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, hydroxybutyrate, glycolate, tartrate, methanesulfonate and the like.

[0069] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives wherein the parent compound, naltrexone decanoate is modified by making acid or base salts thereof. Suitable acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluene sulfonic, methane-sulfonic, ethane disulfonic, oxalic, isethionic, and the like. Specifically, the acceptable salts can include, for example, those salts that naturally occur in vivo in a mammal.

[0070] Preparation of Naltrexone Decanoate:

[0071] The process for preparation of naltrexone decanoate wherein the reaction is carried out in a monophasic medium using a single non-aqueous solvent, wherein the reaction involves esterifying the hydroxyl group of Naltrexone with decanoyl chloride which serves as an acylating agent in the presence of a base, wherein the base is an organic amine, preferably triethylamine or Hunig's base in the presence of a non-aqueous solvent which include, but are not limited to, ethyl acetate, cyclo-pentyl-methyl-ether, tetrahydrofuran, acetonitrile, acetone, dimethyl formamide and dichloromethane. Preferably the reaction is carried out by using the solvent, cyclopentyl methyl ether (CPME), cyclopentyl ethyl ether, cyclopentyl propyl ether.

[0072] The preparation of Naltrexone to Naltrexone decanoate, is shown in scheme 1.

##STR00004##

[0073] After completion of reaction, water was added to reaction mixture, then aqueous layer and organic layer were separated wherein the aqueous layer was separated with dichloromethane and the organic layer was washed with water and brine solution, dried over anhydrous magnesium sulphate or anhydrous sodium sulphate, and concentrated typically under reduced pressure, to provide naltrexone decanoate in the form of a viscous oil.

[0074] The naltrexone decanoate can be further purified by using any conventional methods well known to those skilled in the art including, but not limited to, column chromatography, high pressure liquid chromatography (HPLC), gas chromatography (GC), recrystallization, and/or distillation.

[0075] After the purification step, naltrexone decanoate is obtained with the levels of an impurity (0.5-1.5%), bis-decanoyl naltrexone. This impurity can be eliminated by preparing acid addition salts of naltrexone decanoate obtained by the above process and further reconverting into naltrexone decanoate from its organic acid addition salts by neutralizing the acid addition salts using a base in the presence of suitable solvent for obtaining substantially pure naltrexone decanoate with an HPLC purity of more than 99.6 to 99.9% with impurity levels between (0.05-0.3%).

[0076] Preparation of Organic Acid Addition Salts of Naltrexone Decanoate:

[0077] The organic acid addition salt of naltrexone decanoate is prepared by reacting naltrexone decanoate with an organic acid, in polar protic solvent, preferably n-propanol and non-polar solvent, preferably methyl-tertiary-butyl ether at a temperature in the range of 5° C. to 70° C., preferably in the range of 30° C. to 35° C. for a period of 20 minutes to 24 hours.

[0078] The synthesis of various organic acid addition salts of naltrexone decanoate, is shown in below scheme 2.

##STR00005##

[0079] Decanoate Salt of Naltrexone Decanoate

##STR00006##

Further, the organic acid addition salt of naltrexone decanoate may be isolated by the steps of filtration, centrifugation, washing and drying.

[0080] Preparation of Highly Pure Naltrexone Decanoate from the Organic Acid Addition Salts of Naltrexone Decanoate:

[0081] The organic acid addition salt of naltrexone decanoate is converted into pure naltrexone decanoate by treating the organic acid addition salt of naltrexone decanoate with an inorganic base, in a solvent, at a temperature in the range of 10° C. to 35° C., preferably in the range of 30° C. to 35° C. for a period of 15 minutes to 1 hour.

[0082] Then organic layer was separated and washed with water. The resulting organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain pure naltrexone decanoate in the form of a viscous oil. The naltrexone decanoate is obtained in the yield of more than 93% and with an HPLC purity of about 99.9%.

[0083] The pure naltrexone decanoate obtained in the form of viscous oil with a purity of 99.9% is collected by filtration or centrifugation. The pure naltrexone decanoate compound is then optionally subjected to washing, re-crystallizing and drying using conventional drying techniques like vacuum oven drying.

[0084] Composition of Naltrexone Decanoate Sustained Release Injection:

[0085] Naltrexone decanoate obtained in the form of a viscous oil by the process can be formulated into a sustained release pharmaceutical composition by adding a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient selected from vegetable oil such as cottonseed oil or sesame oil, an organic solvent selected from the group consisting of ethyl alcohol, benzyl alcohol, benzyl benzoate, N-methyl pyrrolidone and a mixture thereof and a release retarding agent selected from the group consisting of poly ortho esters such as poly(lactic-co-glycolic acid) of L:G ratio of 50:50, 75:25, 85:15, etc., poly(lactic acid) or polycaprolactone or fatty acid such as stearic acid and palmitic acid and a mixture thereof. This composition can be used for the treatment of opioid dependence, alcohol dependence, for a period of 7 days to 90 days in a patient in need thereof, wherein the composition provides sustained release of Naltrexone and can be administered by subcutaneous injection or intramuscular injection.

EXAMPLES

Example 1

[0086] Synthesis of Naltrexone Decanoate in Dichloromethane:-

[0087] To a stirred solution of Naltrexone HCl 2.5 g (7.3 mmol) in dichloromethane at 0-5° C. triethyl amine 0.91 g (9.15 mmol) was added. To above reaction mixture decanoyl chloride1.83 mL (8.7 mmol) was added at 0-5° C. The reaction mixture was stirred at 0-5° C. for 30 min. After completion of reaction, water was added to reaction mixture. After the reaction, the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, brine and dried on sodium sulphate. Further, evaporation of the solvent provided with an oil of naltrexone decanoate.

[0088] Yield: 3-3.21 gm (92-98%)

[0089] Purity: 98-99.9%

[0090] bis-decanoyl naltrexone impurity: 0.15-0.3

Example 2

[0091] Synthesis of Naltrexone Decanoate in Cyclo-Pentyl-Methyl-Ether Solvent:-

[0092] To a stirred solution of Naltrexone HCl 25 g (66 mmol) in cyclo-pentyl-methyl-ether at 0° C. to 5° C. triethyl amine 16.7 g (165 mmol) was added. To above reaction mixture decanoyl chloride13.5 mL (65.3 mmol) was added at 0-5° C. The reaction mixture was at 0-5° C. for 30 min. After completion of reaction, water was added to reaction mixture. The aqueous and organic layers were separated; aqueous layer was extracted with cyclo-pentyl-methyl-ether. The combined organic layer was washed with water, brine and dried on sodium sulphate. Further, evaporation of the solvent provided with an oil of naltrexone decanoate.

[0093] Yield: (92-98%)

[0094] Purity: 98-99.8%

[0095] bis-decanoyl naltrexone Impurity: 0.15-0.3%

Example 3

[0096] Synthesis of Naltrexone Decanoate Oxalate Salt:-

[0097] To a stirred solution of Naltrexone decanoate 10.0 g (20.2 mmol) in methyl-tert-butyl-ether (80 mL), n-propanol 20 mL was added at room temperature. Prepared a solution of oxalic acid 1.81 g in methyl-tert-butyl ether (60 mL) and n-propanol(10 mL). The above solution was added to a mixture of naltrexone decanoate at room temperature. Stirred the reaction mixture at room temperature for 16 hr. Filtered the precipitates obtained and gave washings with methyl-tert-butyl ether (50 mL). Dried the solid under vacuum at 65° C. till constant weight is obtained. The yield obtained is 6.4 g (54%).

Example 4

[0098] Synthesis of Naltrexone Decanoate Maleate Salt:-

[0099] To a stirred solution of Naltrexone decanoate 2.0 g (4.0 mmol) in methyl-tert-butyl ether(16 mL) was added n-propanol (2 mL) at room temperature. Prepared a solution of maleic acid 0.46 g (4.0 mmol) in methyl-tert-butyl ether(12 mL) and n-propanol(1 mL). The above solution was added to a mixture of naltrexone decanoate at room temperature. Heated the above reaction mixture at 50-55° C. for 30 min. Cooled the reaction mixture to 0-5° C. gradually, white precipitate obtained. Filtered the precipitates obtained and gave washings with methyl-tert-butyl ether(10 mL). Dried the solid under vacuum at 55° C. till constant weight is obtained. The yield obtained is 1.28 gm to 1.54 g (54-65%)

Example 5

[0100] Preparation of Pure Naltrexone Decanoate from Acid Addition Salt of Naltrexone Decanoate:-

[0101] A solution of acid addition salt (Oxalate salt) of Naltrexone decanoate (25 gm) in dichloromethane (250 ml) was added (7-8%) aqueous solution of sodium bicarbonate (170 ml) up to pH 8.0 at 10-15° C. and then resulting reaction mixture was stirred for 30 minutes at 25-30° C. Then organic layer was separated and washed with water. The resulting organic layer was dried over sodium sulphate and concentrated under reduced pressure to get pure Naltrexone decanoate as yellow viscous oil. The yield obtained is 3.4 g (93%) and with the purity of about 99.9%.

[0102] MS:- m/z 496.7(M+)

[0103] Bis-Decanoyl Naltrexone Impurity: NIL.

[0104] In similar manner, the pure Naltrexone decanoate was prepared from other maleate salt of Naltrexone decanoate, with bis-decanoyl naltrexone Impurity in undetectable limits.

Example 6

[0105] Composition of Naltrexone Decanoate Sustained Release Injection:-

[0106] 100 ml sesame oil was taken and 41.84 g Naltrexone decanoate (276 mg/ml) slowly

[0107] added with continuous stirring at 800 rpm for 35 min using magnetic stirrer. The drug was miscible with sesame oil and then 1.81 g benzyl alcohol (12 mg/ml) was added to drug solution with continuously stirring at 800 rpm for 1 hr. using magnetic stirring, then the volume was made up to 150 ml using sesame oil to obtain a clear solution. This solution was filtered using 0.45 um PTFE filter by vacuum

[0108] filtration, then the formulation was stored at 2-8° C. This formulation (FormulationA) was administered by SC injection in Wistar rats with the dose equivalent to 100 mg/kg Naltrexone. The blood plasma concentration of active metabolite,Naltrexone observed was above 2 ng/mL till 14 days.

Example 7

[0109] Composition of Naltrexone Decanoate Sustained Release Injection:-

[0110] A formulation containing 276 mg/mL Naltrexone decanoate, 100 mg/mL PLGA in N-Methylpyrrolidone (0.44 ml) & Benzyl benzoate (0.46 mL) (Formulation B) wastested in-vivo in Wistar rats after subcutaneous injection with the dose equivalent

[0111] to Naltrexone 100 mg/kg. The formulation of naltrexone decanoate resulted into naltrexone with the blood plasma concentration of above 1 ng/mL till 28 days. A quantifiable amount of Naltrexone was also observed till 49 days in these rats.

Example 8

[0112] Composition of Naltrexone Decanoate Sustained Release Injection:-

[0113] A composition containing 736 mg/mL Naltrexone decanoate in N-Methylpyrrolidone (quantity sufficient to 1 ml) (Formulation F) resulted into about 6.5 ng/mL on 15th day post-administration, in rat blood plasma after administration of dose equivalent to Naltrexone 100 mg/kg by intramuscular route.

[0114] FIG. 1 shows the naltrexone plasma concentrations in rats after a single subcutaneous or Intramuscular injection of naltrexone decanoate composition equivalent to Naltrexone 100 mg/kg dose. It is apparent from the figure that the in vivo drug release of active moiety, Naltrexone after the injection of Naltrexone decanoate occurred in a controlled manner. After the injection of naltrexone decanoate prepared with sesame oil and benzyl alcohol (Formulation A), the bloodplasma concentration of naltrexone observed was above 2 ng/mL till 14 days and after the injection of Formulation B of naltrexone decanoate, prepared with PLGA in N-Methylpyrrolidone, the blood plasma concentration of active moiety, Naltrexone observed was above 1 ng/mL till 28 days and a quantifiable amount of Naltrexone was also observed till 49 days in these rats. After the injection of Formulation F of naltrexone decanoate, prepared in N-Methylpyrrolidone, the blood plasma concentration of active moiety, Naltrexone was observed about 6.5 ng/mL on 15th day post-administration.