Modified release pharmaceutical compositions of trimetazidine

Abstract

Modified release pharmaceutical compositions of Trimetazidine comprising a core containing trimetazidine or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients, on which a first layer of coating is applied comprising one or more polymer / s showing a pH dependent release and one or more plasticizer / s and another layer of comprising one or more polymer / s showing time dependent release and one or more plasticizer / s.

Description

MODIFIED RELEASE PHARMACEUTICAL COMPOSITIONS OF TRIMETAZIDINECROSS-REFERENCE TO PRIORITY APPLICATION

[0001] The present application claims priority from Indian patent application number 202421045976 filed on 14 June 2024.PREAMBLE TO THE DESCRIPTION

[0002] The following specification particularly describes this invention and the manner in which it is to be performed:FIELD OF THE INVENTION

[0003] The present invention relates to a dual layer coated modified release pharmaceutical composition comprising of Trimetazidine or pharmaceutically acceptable salts.BACKGROUND OF THE INVENTION

[0004] Trimetazidine is a piperazine compound. Chemically, it is 1-2, 3, 4- trimethoxybenzyl piperazine dihydrochloride. It is a member of 3-ketoacyl coenzyme A thiolase (3-KAT) inhibitor or fatty acid oxidation inhibitor. It is a metabolic modulator and improves myocardial energetics.

[0005] Trimetazidine is a BCS class I drug having good solubility and permeability. Trimetazidine is rapidly absorbed from GIT after oral administration. Food does not significantly affect its bioavailability. It is available in the market as 20 mg immediate release tablets administered three times a day, 35 mg modified release tablets administered twice a day, and 80 mg modified release tablet administered once a day. It has been reported that the steady state peak plasma concentration of the IR formulation was found to be 53.6 pg / L and it was reached within 1.8 +_ 0.7 hours hours ( tmax ), and plasma half-life of 6 +_ 1.4 hrs. The area under the plasma concentration time curve was found to be 508.09 pgL^h'1after single and 813.4 pgL^h'1after multiple doses.

[0006] Trimetazidine is absorbed quickly and because of its short 11 / 2, it is given in the dose of 20 mg thrice daily. However, it is believed that the patient compliance decreases as the number of doses per day increases.

[0007] It is believed to act by inhibiting partial fatty acid oxidation and enhancing utilization of glucose dependent oxidation, which generates ATP more efficiently in low oxygen environment. It has shown to reduce symptomatic episodes of angina, and prolong the interval before ST depression.

[0008] European patent EPl 108424 by Servier laboratories describes a twice a daily matrix tablet of Trimetazidine comprising Hydroxypropyl methyl cellulose as matrix forming polymer, a binder, a diluent, a lubricant and a flow modifying agent.

[0009] European patent EP2623096 by Servier laboratories describes a prolonged release once a daily pharmaceutical composition for prolonged release of Trimetazidine mini granules comprising: an inner phase comprising a neutral core coated with trimetazidine and an outer layer comprising a release retardant and agglomerant.

[0010] European patent EP1195160by USV Ltd describes a modified release pharmaceutical composition of Trimetazidine comprising of 60 mg Trimetazidine at least one of (a) one or more hydrocolloid forming materials (b) one or more hydrophobic polymers and (c) one or more other categories of hydrophobic materials.

[0011] European patent EP2200591 by Ranbaxy Lab Ltd describes a monolithic matrix dosage form comprising (a) therapeutically effective amount of trimetazidine or its pharmaceutically acceptable salts, (b) one or more rate controlling polymers selected from the group consisting of a water- insoluble polymer , water- swellable polymer, and mixture thereof, and (c) one or more pharmaceutically acceptable excipients, wherein the dosage form exhibits in vitro release of trimetazidine or its pharmaceutically acceptable salt in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours.

[0012] European patent EP2391353 by Lupin Ltd describes a once daily retard modified release pharmaceutical composition comprising a matrix core comprising trimetazidine and one or more modified release polymers and this core coated with an extended-release coating. However, this composition is shown to sustain the drug release upto 12 hours only.

[0013] There can be more ways by which once a daily dosage form of Trimetazidine dihydrochloride can be formulated, wherein its drug release is sustained over a period of 24 hours and is comparable with the once daily dosage forms of Trimetazidine.

[0014] Thus, this invention provides a once daily modified release formulation of Trimetazidine or its pharmaceutically acceptable derivatives with two release retarding layers, showing a release sustained over a period of 24 hours. The two retardant layerscomprising a blend of hydrophilic and hydrophobic polymers prevents the burst release of a BCS class I drug like Trimetazidine which has very high solubility in the GIT.OBJECTS OF THE INVENTION

[0015] The object of the present invention is to provide a modified release pharmaceutical composition of trimetazidine or its pharmaceutically acceptable salts comprising a core comprising trimetazidine or its pharmaceutically acceptable salts, a first layer of sustained release polymer followed by a second layer of sustained release polymer.

[0016] Another object of the present invention is to provide a modified release pharmaceutical composition of trimetazidine or its pharmaceutically acceptable salts, such that at least 8-28% trimetazidine is released in first four hours, at least 37 to 57% is released in first 8 hours and not less than 75% is released in 24 hours when tested in vitro in 6.8 pH phosphate buffer. Another object of the present invention is to provide the modified release pharmaceutical composition of trimetazidine or its pharmaceutically acceptable salts wherein the said composition is a tablet or capsule.SUMMARY OF THE INVENTION

[0017] The embodiments of the present invention provide a dual layer coated modified release pharmaceutical composition comprising: a. a core containing trimetazidine or a pharmaceutically acceptable salt(s) thereof and other pharmaceutically acceptable excipients; b. a first layer comprising one or more pH dependent polymer(s)and / or time dependent polymer(s) and one or more plasticizer(s) coated on the core a; c. a second layer comprising one or more pH dependent polymer(s) and / or time dependent polymer(s) and one or more plasticizer(s) applied on top of layer b; wherein if b is comprising one or more pH dependent polymer(s)then c is comprising one or more time dependent polymer(s) or alternatively if b is comprising of one or more time dependent polymer(s) then c is comprising of one or more pH dependent polymer(s).

[0018] Another embodiment of the present invention discloses a dual layer coated modified release pharmaceutical composition comprising: a. a core containing trimetazidine or a pharmaceutically acceptable salt(s) thereof and other pharmaceutically acceptable excipients;b. a first layer comprising one or more pH dependent polymer(s)and / or time dependent polymer(s) and one or more plasticizer(s) coated on the core a; c. a second layer comprising one or more pH dependent polymer(s) and / or time dependent polymer(s) and one or more plasticizer(s) applied on top of layer b; wherein if b is comprising one or more pH dependent polymer(s)then c is comprising of one or more time dependent polymer(s) or alternatively if b is comprising of one or more time dependent polymer(s) then c is comprising of one or more pH dependent polymer(s), wherein about 8 to 28% of drug is released in first 4 hours, about 37 to 57% of drug is released in at the end of 8 hours and not less than 75% drug is released at the end of 24 hours.

[0019] Another embodiment of present invention is to provide a dual layer coated modified release pharmaceutical composition comprising: a. a core containing trimetazidine or a pharmaceutically acceptable salt(s) thereof and other pharmaceutically acceptable excipients; b. a first layer comprising one or more pH dependent polymer(s)and / or time dependent polymer(s) and one or more plasticizer(s) coated on the core a; c. a second layer comprising one or more pH dependent polymer(s) and / or time dependent polymer(s) and one or more plasticizer(s) applied on top of layer b; wherein if b is comprising one or more pH dependent polymer(s)then c is comprising of one or more time dependent polymer(s) or alternatively if b is comprising of one or more time dependent polymer(s) then c is comprising of one or more pH dependent polymer(s), wherein the said composition is in the form of pellets or granules.

[0020] Another embodiments of the present invention provide a dual layer coated modified release pharmaceutical composition comprising: a. a core containing trimetazidine or a pharmaceutically acceptable salt(s) thereof and other pharmaceutically acceptable excipients; b. a first layer comprising one or more pH dependent polymer(s)and / or time dependent polymer(s) and one or more plasticizer(s) coated on the core a; c. a second layer comprising one or more pH dependent polymer(s) and / or time dependent polymer(s) and one or more plasticizer(s) applied on top of layer b; wherein if b is comprising one or more pH dependent polymer(s)then c is comprising of one or more time dependent polymer(s) or alternatively if b is comprising of one or moretime dependent polymer(s) then c is comprising of one or more pH dependent polymer(s), wherein the said pellets or granules are filled in capsules or compressed into tablets.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Detailed description of the invention will be more readily understood in conjunction with the accompanying drawing, in which:

[0022] Figure 1 : Cumulative % drug release of example 2 and Preductal OD 80 mg in 0.1N HC1

[0023] Figure 2: Cumulative % drug release of example 2 and Preductal OD 80 mg in 4.5 pH phosphate buffer

[0024] Figure 3: Cumulative % drug release of example 2 and Preductal OD 80 mg in 6.8 pH phosphate buffer

[0025] Figure 4: Cumulative % drug release of example 2 and Preductal OD 80 mg in 7.2 pH phosphate bufferDETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention relates to a dual layer coated modified release pharmaceutical composition comprising a core containing trimetazidine or a pharmaceutically acceptable salt(s), coated with a first layer of one or more polymers having pH dependent release and plasticizers and a second layer of one or more polymers having time dependent release and plasticizers.

[0027] It has been scientifically proven that patient compliance in taking medicines is a function of frequency of dosing. In a study conducted at Department of Pharmacoepidemiology and Pharmacotherapy, at University of Utrecht, Netherlands( A.H. Paes et al, Impact of dosage frequency on patient compliance, Diabetes care, 1997 Oct 20(10)- 1512-7) , it was found that the average compliance of a group of patients taking medicines was 79% in case of a once daily dose compared to 38% in case of a dose three times daily. However, Trimetazidine is a drug having short half-life and its dosing frequency is three times a day. In order to decrease the dosing frequency, twice daily and once daily compositions of Trimetazidine are available in the market. However, the present invention presents a newer way of preparing a modified release once a daycomposition of Trimetazidine wherein the dissolution study has been performed for a period of 24 hours in order to ensure that the peaks and troughs in the serum concentration are avoided.

[0028] As used herein, “pharmaceutically acceptable salts” refer to derivatives of trimetazidine formed by reacting the ionizable groups of the molecule with counter ions to form a neutral complex. Formation of pharmaceutical salts by simply reacting with an acid or base via a simple neutralization reaction can change the physicochemical properties of a drug like solubility and dissolution rate. Non-toxic salts are formed by reacting the drug with nontoxic organic or inorganic acids. The salts made from inorganic acids may include hydrochloride, hydrobromide, sulphate, nitrate, sulfamate, phosphorate salts etc. The organic acids used to form salts may include maleic, hydromaleic, lactic, palmitic, acetic, propionic, succinic, stearic, glycolic, tartaric, ascorbic, phenyl acetic, salicylic acids, amino acids etc. The various salts forms that me be made of a pharmaceutical compound may be found mentioned in a research paper entitled “Salts of therapeutic agents: Chemical, physicochemical and biological considerations” D. Gupta et al, Molecules, 2018, July, 23(7): 1719. The most preferred salt of Trimetazidine is Trimetazidine dihydrochloride.

[0029] “Modified release pharmaceutical composition” used herein refers to a pharmaceutical composition which is not immediate release. And immediate release pharmaceutical composition, as mentioned in are designed to make the active ingredient available to the body without relevant impact of the dosage form. The term “immediately” according to European pharmacopeia means an IR formulation should normally achieve in vitro dissolution of at least 80% of the drug substance within not more than 45 minutes. According to United States Pharmacopoeia more than 85% of the drug substance should be released within 30-45 minutes. According to Biopharmaceutical Classification System based biowaiver very rapid dissolution is defined as 85% of the labeled content is dissolved in 15 minutes and rapid dissolution would reach the same amount within a maximum time of 30 minutes. But also, formulations containing a drug substance with e.g., a long half-life, limited solubility, or slow absorption of the drug substance are still considered as immediate release formulations, if they do not contain any excipients that are added in order to intentionally alter drug release. The term modified release formulation comprises different type of formulations like delayed release, prolongedrelease, timed release, sustained release, extended release or controlled release formulations. (EMEA versus US-FD A regulatory requirements regarding bioequivalence of orally administered generics, W. Prufungsarbeit,

[0030] A pharmaceutically acceptable excipient means everything other than the active pharmaceutically ingredient which is not biologically or otherwise undesirable.

[0031] Polymers showing pH dependent release refer to anionic polymers responsive to and soluble in intestinal basic pH which are used to prevent the release of drugs in acidic pH of stomach. Examples of some polymers showing pH dependent release are methacrylic acid methacrylate copolymers, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methyl acetate phthalate, hydroxypropyl methyl cellulose acetate succinate. The most preferred polymer showing pH dependent release either in the first or in the second layer of the coating is methacrylic acid: methyl methacrylate copolymer 1 :2.

[0032] Polymers showing time dependent release refer to polymers exhibiting low water solubility and hence delayed release. Examples of some polymers showing time dependent release are ammonio methacrylate copolymers type A and B, ethyl cellulose, poly(methyl methacrylate), poly(butyl methacrylate), methacrylic acid copolymer type A, B and C, polyvenyl acetate, cellulose acetate, cellulose triacetate, poly(ethyl ethacrylate), poly(butyl methacrylate), poly (isobutyl methacrylate), poly(hexyl methacrylate), poly(octadecyl acrylate) and waxes such as carnauba wax, bees wax, microcrystalline wax, fatty alcohols, ozokerites, ceresin etc. The most preferred polymer showing time dependent release either in the first or in the second layer of the coating is methacrylic acid: ammonio methacrylate copolymer type B.

[0033] Plasticizers refer to the substances added to the film forming agents to make the polymer films flexible and soft and enhance the flexibility and plasticity of the film. Examples of some plasticizers are acetyl tributyl citrate, glycerol triacetate, acetyl triethyl citrate, acetyl ethyl citrate, diethyl sebacate, dibutyl sebacate, ethyl and dibutyl phthalate, polyethylene glycol, glycerol and / or propylene glycol. The most preferred plasticizer in layer one and two is triethyl citrate.

[0034] Pellets refer to small free flowing spherical multiparticulate dosage forms which are formed by the agglomeration of fine powdered excipients and / or active ingredients.

[0035] The modified release pharmaceutical composition according to the present invention are prepared preferably by following procedure: i) blend trimetazidine and pharmaceutically acceptable excipients by adding an aqueous binder solution ii) convert the wet mass into pellets by extrusion spheronization and dry. iii) Prepare the polymer coats by dissolving the respective polymers and plasticizers in selected solvents. iv) Coat the pellets by first layer of polymers by fluid bed granulation and dry. v) Coat the second layer of polymers on the first layer by fluid bed granulation and dry. vi) Fill the formed pellets in capsules.EXAMPLESExample 1PROCEDURECoreE Sift Trimetazidine dihydrochloride and microcrystalline cellulose and talc through sieve and mix.2. Add water to this mixture and make a wet mass3. Convert this mixture to pellets by extrusion spheronization.4. Dry the pellets in tray dryer and size by passing through sievesFirst layer1. Disperse polymer, plasticizer, and talc in the mixture of alcohol and water and filter2. Coat on the core pellets using fluid bed coater and drySecond layer1. Disperse the second coating polymer, plasticizer and colloidal silicon dioxide in water and filter2. Coat this solution on the first coat using fluid bed coater and dry.3. Fill the pellets so formed in capsules.Example 2PROCEDURECore1. Sift Trimetazidine dihydrochloride and microcrystalline cellulose and talc through sieve and mix.2. Add water to this mixture and make a wet mass3. Convert this mixture to pellets by extrusion spheronization.4. Dry the pellets in tray dryer and size by passing through sievesFirst layer1. Disperse polymer, plasticizer, and talc in the mixture of alcohol and water and filter2. Coat on the core pellets using fluid bed coater and drySecond layer1. Disperse the second coating polymer, plasticizer and colloidal silicon dioxide in water and filter2. Coat this solution on the first coat using fluid bed coater and dry.3. Fill the pellets so formed in capsules.Example 3PROCEDURECore1. Sift Trimetazidine dihydrochloride and microcrystalline cellulose and talc through sieve and mix.2. Disperse PVP 30-K in water to form a binder solution.3. Add aqueous binder solution to this mixture and make a wet mass4. Convert this mixture to pellets by extrusion spheronization.5. Dry the pellets in tray dryer and size by passing through sievesFirst layer1. Disperse polymer, plasticizer, and talc in the mixture of alcohol and water and filter2. Coat on the core pellets using fluid bed coater and drySecond layer1. Disperse the second coating polymer, plasticizer and colloidal silicon dioxide in water and filter2. Coat this solution on the first coat using fluid bed coater and dry.3. Fill the pellets so formed in capsules.Example 4PROCEDURECoreE Sift Trimetazidine dihydrochloride and microcrystalline cellulose and talc through sieve and mix.2. Add water to this mixture and make a wet mass3. Convert this mixture to pellets by extrusion spheronization.4. Dry the pellets in tray dryer and size by passing through sievesFirst layer1. Disperse polymer, plasticizer, and talc in the mixture of acetone and isopropyl alcohol and filter2. Coat on the core pellets using fluid bed coater and drySecond layer1. Disperse the second coating polymer, plasticizer and colloidal silicon dioxide in water and filter2. Coat this solution on the first coat using fluid bed coater and dry.3. Fill the pellets so formed in capsules.Example 5PROCEDURECoreE Sift Trimetazidine dihydrochloride and microcrystalline cellulose and talc through sieve and mix.2. Add water to this mixture and make a wet mass3. Convert this mixture to pellets by extrusion spheronization.4. Dry the pellets in tray dryer and size by passing through sievesFirst layer3. Disperse polymer, plasticizer, and talc in the mixture of alcohol and water and filter4. Coat on the core pellets using fluid bed coater and dry Second layer1. Disperse the second coating polymer, plasticizer and colloidal silicon dioxide in water and filter2. Coat this solution on the first coat using fluid bed coater and dry.3. Fill the pellets so formed in capsules.Example 6In vitro dissolution studyThe compositions described in this invention have a 24 hour in vitro release profile compared to the marketed formulation having 12 hr release. The in vitro drug release study for the marketed formulation and the compositions of this invention were carried out:ProcedureThe dissolution study was conducted in four different media, 0.1N HC1, 6.8 pH phosphate buffer, 7.2 pH phosphate buffer and 4.5 pH phosphate buffer using paddle type apparatus at 50 rpm. 900 ml of the medium was placed in the bowl of the apparatus. Composition of the examples given before equivalent to 80 mg Trimetazidine dihydrochloride filled in capsules and the reference standard Preductal OD 80 mg (Servier laboratories) were kept in the bowls of the apparatus and drug release was determined for the period of 24 hrs. Fig. 1,2,3, and 4 indicate comparison of cumulative percent drug release of example 2 and Preductal OD 80 mg. The difference factor(Fl) and similarity factor(F2) were also calculated.Table 1 : Cumulative % drug release in 0. IN HCLTable 2: Cumulative % drug release in 4.5 pH phosphate bufferTable 3: Cumulative % drug release in 6.8 pH phosphate bufferTable 4: Cumulative % drug release in 7.2 pH phosphate bufferTable 5: Fl and F2 values for dissolution study of example no 2 in comparison with PreductalOD-80 mg

Claims

CLAIMS1. A dual layer coated modified release pharmaceutical composition comprising: a. a core containing trimetazidine or a pharmaceutically acceptable salt(s) thereof and other pharmaceutically acceptable excipients; b. a first layer applied on core a comprising one or more polymer(s) having pH dependent release or one or more polymer(s) having time dependent release and one or more plasticizer(s); c. a second layer applied on layer b comprising one or more polymer(s) having pH dependent release or one or more polymer(s) having time dependent release and one or more plasticizer(s); wherein if b is comprising of one or more pH dependent polymer(s) c is comprising of one or more time dependent polymer(s) or alternatively if b is comprising of one or more time dependent polymer(s) c is comprising of one or more pH dependent polymer(s).

2. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein b is comprising of one or more pH dependent polymer(s) and one or more plasticizer(s) and c is comprising of one or more-time dependent polymer(s) and one or more plasticizers.

3. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein one or more pH dependent polymer(s) in coat b are selected form a group comprising of methacrylic acid methacrylate copolymers, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methyl acetate phthalate, hydroxypropyl methyl cellulose acetate succinate.

4. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein the time dependent polymer(s) in coat c are selected from a group comprising of ammonio methacrylate copolymers type A and B, ethyl cellulose, poly(methyl methacrylate), poly(butyl methacrylate), methacrylic acid copolymer type A, B and C, polyvenyl acetate, cellulose acetate, cellulose triacetate, poly(ethyl ethacrylate), poly(butyl methacrylate), poly (isobutyl methacrylate), poly(hexylmethacrylate), poly(octadecyl acrylate) and waxes such as carnauba wax, bees wax, microcrystalline wax, fatty alcohols, ozokerites, ceresin.

5. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein the pH dependent polymer in coat b is methacrylic acid-methyl methacrylate copolymer 1:2.

6. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein the time dependent polymer in coat c is ammonio methacrylate copolymer.

7. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein the plasticizers in coat b and c are selected from the group of acetyl tributyl citrate, glycerol triacetate, acetyl triethyl citrate, acetyl ethyl citrate, diethyl sebacate, dibutyl sebacate, ethyl and dibutyl phthalate, polyethylene glycol, glycerol and / or propylene glycol.

8. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein the plasticizers in coat a and b are same.

9. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein the plasticizers in coat a and b are different.

10. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein the plasticizers in coat a and b is tri ethyl citrate.

11. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein the core a is comprising of trimetazidine dihydrochloride.

12. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein anti agglomerant is talc.

13. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein the core a are particles, granules, pellets, tablets or capsules.

14. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein the core a are pellets.

15. The dual layer coated modified release pharmaceutical composition according to claim 1, wherein the said pellets are compressed into tablets.

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