EP1448173A2

EP1448173A2 - A process for manufacture of a sustained release pharmaceutical composition containing microbeads of trimetazidine dihydrochloride

Info

Publication number: EP1448173A2
Application number: EP02803493A
Authority: EP
Inventors: Amit Krishna Antarkar; Rajendra Ghanshamlal Lala; Gaurang Hasmukhlal Thanawala; Maya Janak Shah; Janak Ramanlal Shah
Original assignee: Themis Laboratories Pvt Ltd
Current assignee: Inventia Healthcare Pvt Ltd
Priority date: 2001-11-21
Filing date: 2002-11-20
Publication date: 2004-08-25
Also published as: AU2002356425A1; HUP0500382A3; WO2003043610A2; WO2003043610A3; HUP0500382A2; AU2002356425A8

Abstract

The present invention relates to novel compositions and process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of trimetazidine dihydrochloride and further coating of the beads with polymeric membrane to tailor the drug release characteristics enabling 'once a day' dosing for 60 mg dose of trimetazidine dihydrochloride per unit dose.

Description

A PROCESS FOR MANUFACTURE OF A SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION CONTAINING MICROBEADS OF

TRIMETAZIDINE HCI

Background of the Invention :

Trimetazidine Dihydrochloride (TMZ HCI) is an anti ischemic agent that has been used in the management and prophylaxis of angina pectoris and in ischemia of neuro-sensorial tissues as in menieres disease. TMZ HCI regulates ionic and extracellular exchanges correcting the abnormal flow of ions across the cell membrane caused by ischemia & preventing cellular edema caused by anoxia.

TMZ HCI has been in market for above 20 years, as 20-mg tablets. The plasma half-life of trimetazidine Dihydrochloride is 6 ± 1.4 hours, and T_max is around 1.8 ± 0.7 hours and is therefore recommended for dosing regimen of 2-3 times a day.

Though general methods for controlled release of drugs are known in literature, processes need to be tailored for a specific system, based on the desired pharmacokinetic and pharmacodynamic properties, physicochemical characteristics, stability, etc. TMZ HCI is highly water-soluble and has a potential problem of burst release. In the case of TMZ HCI it is desirable to develop dosage form that ensure consistent d elivery a nd p rolonged p lasma levels with insignificant contribution to the initial release in case of a failure of the system avoiding a situation of dose dumping, exhibiting less variation in gastro- intestinal transit time thereby providing dosage forms with minimized inter subject and intra subject variation. Prior art:

US Patent 4814176 describes sustained release preparation comprising chitin, chitosan, or a mixture thereof, anionic polymer having carboxyl group, sulfonic acid group or a group capable of providing the same and a pharmaceutical active agent including TMZ HCI. The process involves pulverization of each of these components to a particle size of about 5-500 mu.m followed by mixing of all the polymers with pharmaceutical active agent in a single step and then preparing dosage forms in the form of tablets, granules, grains, dental cones, films, or tablets in hard gelatin capsules. This patent does not disclose any relevant information on the release characteristic for TMZ HCI.

EP 0673649 describes pharmaceutical compositions for the prolonged release of trimetazidine or its salts, a polymer insoluble in water and a plasticizer to control its liberation. The manufacturing process involves preparation of tablets or minigranules with 80mg dose for once a day dosing followed by coating with ethyl cellulose or acrylic derivatives and specific plasticizers such as acetyl tributyl citrate or dibutyl sebacate for prolonged release. This patent specifically discourages the use of plasticizers like triacetin, triethylcitrate and acetyltriethylcitrate and demonstrate that their use cause an undesirable latency period of upto 4 hours, at the end of which the release is very fast. In such a case the loading dose of trimetazidine dihydrochloride is not available for immediate absorption and pharmacological action. The formulation described releases only upto 75% of the drug in-vitro in a period of 16 hours. This incomplete drug release can lead to non- utilization of the total amount of drug administered to the patient. Bioavailability studies conducted on 12 volunteers shows steady state plasma concentration at around 110ng/ml with 80mg oral dose. The total daily recommended dose in case of trimetazidine dihydrochloride is 40 - 60 mg in single or divided doses. The dose of TMZ HCI in this patent is 80mg, which far exceeds the recommended dose. The publication EP 1195160 A1 relates to sustained release matrix pharmaceutical tablet compositions containing 60 mg of TMZ HCI and hydrocolloid forming materials and or hydrophobic polymers and or other hydrophobic materials as a retardant, which release TMZ HCI in a sustained and reproducible manner over a prolonged period of time to achieve the sustained effect of trimetazidine over a 24 hour period after oral administration. This invention makes use of multi-step process involving multiple equipments that is laborious, time consuming with potential of cross - contamination.

EP1108424 describes matrix tablets for sustained release of TMZ HCI for oral administration characterized in that the prolonged release is controlled by the use of a polymer derived from cellulose. The invention describes sustained release tablet composition containing 35 mg of TMZ HCI for twice a day dosing. This invention also makes use of multi-step process involving multiple equipments that is laborious, time consuming with potential of cross - contamination.

The prior art described above disclose methodologies for producing sustained release tablet formulation for a dose 35mg, 60mg and 80mg or minigranules for the dose of 80mg. Manufacturing the controlled formulation in tablet form involves multiple steps, multiple equipment's and thus becomes laborious and time-consuming process with risk of cross contamination. Minigranules preparations by extrusion spheronizer or coating pan are also multistep, multi-equipment, laborious and time-consuming process.

It is further clear from the prior art that they do not describe any simple process using single equipment for manufacturing of pharmaceutical compositions of TMZ HCI in dosage forms with release characteristics enabling "once a day" dosing for 60mg dose of trimetazidine dihydrochloride per unit dose. Further there are no dosage forms of TMZ HCI in microbeads with the desired release characteristics. Moreover the prior art specifically discourages the use of plasticizers like triacetin, triethylcitrate and acetyltriethylcitrate and demonstrate that their use cause an undesirable latency period of upto 4 hours, at the end of which the release is very fast. In such a case the loading dose of TMZ HCI is not available for immediate absorption and pharmacological action. It is therefore necessary to d evelop novel formulations that are capable of using such plasticizers for processing them into a variety of dosage forms including microbeads. Further, microbeads are desirable forms of drug delivery systems as they can be packed into capsules for patient convenience. It may also be noted that though prior art describes several process of manufacturing of sustained release microbeads and tablets, there is no teaching related to processes involving TMZ HCI formulations in microbeads.

Summary of invention:

The main object of the present invention is to provide novel compositions and process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of TMZ HCI and further coating of the beads with polymeric membrane to tailor the drug release characteristics enabling "once a day" dosing for 60 mg dose of TMZ HCI per unit dose.

Another object of the invention is to provide continuous process for efficient manufacturing of novel pharmaceutical compositions in the form of agglomeration free, uniform shaped and sized microbeads comprising of TMZ HCI in a single equipment viz. fluid bed processor.

Another object of the invention is to provide a continuous process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of TMZ HCI which can be encapsulated in size '3' capsules for d ose 60 m g thus p roviding a patient easy to consume dosage form.

Another object of the invention is to provide a continuous process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of TMZ HCI, which will provide therapeutic blood levels of the drug for once a day dosing for a dose of 60mg. Another object of the invention is to provide a continuous process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of TMZ HCI without the problem of dose dumping and burst effect from the formulation.

Another object of the invention is to provide a continuous process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of T MZ H CI which when tested in vitro provides pH independent release of TMZ HCI atleast for a period of 8 - 10 hours without any latent period.

Another object of the invention is to provide a continuous process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of TMZ HCI in a single equipment fluid bed processor which essentially consists of spraying aqueous TMZ HCI solution with binder, antitack agent, glidants on inert seeds such as sugar spheres to produce drug core. The drug cores are further coated with water insoluble polymer/s with or without plasticizers in fluid bed processor to produce sustained release microbeads comprising of TMZ HCI.

Further the objective of the invention is to provide novel compositions and process for optional but "novel use" of plasticizers such as triacetin and triethylcitrate.

It is clear that the products obtained by the process of extrusion spheronization, coating pan are totally outside the scope of present invention.

Description:

This invention relates to novel compositions and continuous process using a single equipment for manufacturing novel pharmaceutical compositions in the form of microbeads comprising of TMZ HCI wherein TMZ HCI solution with inert excipients in aqueous or hydroalcoholic media is sprayed on inert seeds such as sugar sphere which are further sequentially coated with a polymer/s with or without plasticizers for controlling the release of TMZ HCI to obtain a stable, patient convenient dosage form. Thus in accordance with the present invention the manufacturing process is carried out essentially in two stages with a n o ptional third stage continuously in single equipment to give a product capable of being filled in hard gelatin capsules as follows: Stage I: Production of drug core

Stage II: Production of sustained release microbeads (SR I) Stage III: Optionally a second polymer coat on SR I (SR II)

Stage I : Production of drug core :

The first stage in manufacturing TMZ HCI sustained release microbeads is to manufacture drug core. This is carried out by dissolving TMZ HCI in water. Water-soluble binder, antitack agent and glidants are added to above solution. The resulting suspension is then filtered through 100 mesh and is sprayed on sugar spheres in a bottom spray fluid bed coater with inlet air temperature between 50 - 80°C, outlet air temperature 40 - 55°C, atomization air pressure 1.5 - 3.5 bars, fluidization flap open between 15 - 90%. After spraying this drug suspension, the drug cores are dried in the same equipment maintaining the inlet temperature between 50-80°C and outlet temperature between 40 - 60°C to have moisture content of less than 5% and preferably less than 3%.

The content of TMZ HCI in drug core is about 20 to about 70% by weight and preferably from about 20 to about 50% by weight.

The particle size of sugar spheres may vary from about 1405 to about 420 m icrons a nd a re p referably b etween a bout 1 000 to a bout 500 microns. The sugar spheres have hardness, which can withstand the rigors of the fluid bed processor.

The binder is selected but not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrollidone, sodium carboxymethylcellulose, methylcellulose and their mixtures thereof. Hydroxypropyl methylcellulose is preferred as a binder, which has a nominal viscosity of 5 - 15 cps, measured on 2% w/w solution at 20°C. The concentration of binder in drug core is optimized and is 5 - 30% w/w of TMZ HCI and preferably between 7.5 - 20% w/w. Antitack agent and glidants wherever used such as talc, colloidal silicon dioxide, glycerin monostearate, glycerin behenate are optimized and used in the concentration level of 10 - 30% w/w of TMZ HCI and is preferably around 15 - 25 % w/w. The total solid content in the spray solution is in the range of 20 - 60% w/w. This is illustrated with an example below.

Quantity

No. Ingredients (mg/capsule)

1 Trimetazidine HCI 60

2 Sugar sphere 67

3 Hydroxypropylmethylcellulose 8

4 Talc 9

5 Aerosil 1

6 Water QS

Stage II : Production of sustained release microbeads :

The drug cores after drying are coated with water insoluble polymer/s with or without plasticizer and antitack agent. The water insoluble polymer/s is selected f rom the g roup b ut n ot l imited to alkyl cellulose, (meth)acrylic acid derivatives. Ethylcellulose, a queous dispersion of Eudragit NE and aqueous dispersion of Eudragit RS are preferred and used as water insoluble polymers alone or in combination. The above-mentioned polymer/s are used in the concentration level of about 1 to about 20% w/w and preferably in the range of about 5 to about 15 % w/w of the drug core. In contrast to the process in the prior art the polymer may be used alone or in combination where drug cores are coated with one polymer (SR I) which is followed by coating with another polymer (SR II) as illustrated in the example below. The antitack agent wherever used is not limited to but preferably is talc and is used in the concentration level of 5 - 40% w/w of the polymer and preferably in the range of about 10 to about 30% w/w.

Plasticizers wherever used are selected but not limited to triethylcitrate, triacetin and are used in the concentration level of about 10 to about 25% w/w and preferably from about 10 to about 20% w/w of the polymer/s used. Water or organic solvents like methanol and methylene chloride (about 2:8 to about 8:2 and preferably about 4:6) can be used for the dissolution of the polymer/s to which plasticizer and antitack agent are added. The solid content of this solution is in the range of about 5 to about 25% w/w and preferably from about 7.5 to about 20% w/w. After this solution is sprayed the sustained release microbeads are dried in the same equipment till the moisture content of the final product is less than 5% w/w and preferably less than 3% w/w. Use of (meth)acrylic acid derivatives involves curing of microbeads in hot air oven at 40°C for 12 hours.

The process parameters for polymer/s sustained release coating involves inlet air temperature of about 20 to about 50°C, outlet air temperature of about 20 to about 40°C, atomization air pressure of about 1.0 - 3.5 bars, fluidization flap open from about 15 to about 90% w/w. This is illustrated with an example below.

SR I

Quantity

Sr. No. Ingredients (mg/capsule)

1 Drug Core 145 2 Ethyl Cellulose 7.25 3 Triacetin 0.75 4 Methylene Chloride QS 5 Methanol QS SR II

Quantity

No. Ingredients (mg/capsule)

1 SR I 153

2 Eudragit NE 30D 10

3 Purified Talc 1.15

4 Water QS

Dissolution Studies:

The test for acceptability of coating level is determined by analysis of the dissolution rate of the finished sustained release microbeads prior to encapsulation. The dissolution procedure followed uses USP apparatus II (paddle) at 50 rpm in 500 ml distilled water at 37°C. Conformance with the dissolution rate given in table I provides 24 hours therapeutic blood levels for the drug component of the sustained release capsule of this invention in capsule form where a given batch of sustained release coated microbeads releases drug too slowly to comply with the desired dissolution rate study, a portion of uncoated (drug coated) or with a lower coating level may be added to the batch to provide, after thorough mixing, a loading dose for rapid increase of the blood drug levels. A batch of sustained release coated microbeads that releases the drug too rapidly may be treated to an additional coat to achieve the desired dissolution profile.

Table I: Acceptable Dissolution Profile for Sustained Release Coated Microbeads

Batches of the Sustained Release Coated Microbeads which have a dissolution profile corresponding to that of table I are filled in pharmaceutically acceptable hard gelatin capsules of size '3' for a dose of 60 mg.

Stability Studies

The polymer coated pellets were encapsulated in size '3' hard gelatin capsules for a dose of 60 mg and subjected to accelerated stability condition at 40°C / 75 %RH and 25°C / 60 % RH. The stability results are as follows.

In-Vivo Bioavailability Studies:

Single dose oral in-vivo bioavailability study shows well-sustained plasma levels of TMZ HCI over 24 hours with AUC₀-26hrs 1602.60 ng.hrs/ml and a C_maχ of 113.78 ng/ml.

Claims

We Claim:

1. A process for the preparation of drug delivery system containing trimetazidine dihydrochloride (TMZ HCI) in novel compositions for Once a day' dosing for 60mg of TMZ HCI exhibiting pH independent invitro release with no latent period, the process comprising:

^■ Dissolving TMZ HCI in aqueous or hydroalcoholic media.

^■ Dispersing and / or dissolving binder in aqueous or hydroalcoholic media.

^■ Mixing of TMZ HCI solution with binder dispersion.

^■ Adding antitack agent and / or glidants to TMZ HCI - binder dispersion

^■ Spraying the dispersion on inert seeds such as sugar spheres followed by drying to obtain drug core.

^■ Sequential coating with one or more water insoluble polymer(s) in aqueous or organic solvents with or without plasticizers and antitack agents followed by drying carried out in a single equipment such as fluid bed processor in a continuous manner followed by curing when necessary to obtain sustained release of TMZ HCI from the formed un-agglomerated microbeads that of uniform shape and size.

2. A process as claimed in claim 1 , wherein, the binder used in the composition is in the range of 5-30% w/w of TMZ HCI, preferably between 7.5 - 20% w/w is selected from but not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrollidone, sodium carboxymethylcellulose, methylcellulose and their mixtures thereof.

3. A process as claimed in claim 1 , wherein, the antitack agent and / or glidants are selected but not limited to talc, colloidal silicon dioxide, glycerin monostearate, glyceryl behenate in the range of 5 -30% w/w of the TMZ HCI.

4. A process as claimed in claim 1 , wherein, one or more water insoluble polymer/s i s s elected form the g roup of alkylcellulose, (meth)acrylic acid derivatives or both and used in the range of 1 - 20% w/w of the drug core, preferably between 5-15% w/w.

5. A process as claimed in claim land 4 where more than one polymers is sequentially layer-coated on drug core.

6. A process as claimed in claims 1 , 4-5, wherein the alkylcellulose is selected but not limited to ethyl cellulose.

7. A process as claimed in claims 1 , 4-5, wherein, the (meth)acrylic acid derivative is selected from but not limited to aqueous dispersion of Eudragit NE and Eudragit RS.

8. A process as claimed in claim 1 , wherein the plasticizers optionally used are selected but not limited to triacetin and triethylcitrate in the range of 5- 35% w/w of the polymer and preferably between 7.5 - 20%w/w.

9. A process as claimed in claims 1-8 wherein the composition containing TMZ HCI comprises of the binder in the range of 5-30% w/w of TMZ HCI, preferably between 7.5 - 20% w/w, the antitack agent and / or glidants in the range of 5 -30% w/w o f t he T MZ H CI, o ne o r m ore w ater i nsoluble polymer/s in the range of 1 - 20% w/w of the drug core, preferably between 5-15% w/w, and plasticizers optionally used in the range of 5-35% w/w of the polymer, preferably between 7.5 - 20%w/w.

10. A process as claimed in claims 1-9 wherein the composition containing TMZ HCI comprises of the binder in the range of 7.5 - 20% w/w of TMZ HCI, the antitack agent and / or glidants in the range of 5 -30% w/w of the TMZ HCI, one or more water insoluble polymer/s in the range of 5 - 15% w/w of the drug core, and plasticizers optionally used in the range of 7.5 - 20%w/w of the polymer.

11. A process as claimed in claims 1-2, 9-10 wherein the binder is hydroxypropylmethylcellulose in the range of 7.5 - 20% w/w of TMZ HCI.

12. A p rocess as claimed in claims 1 ,4,6, 8-10 wherein the polymer is ethyl cellulose in the range of 5 - 15% w/w of the drug core, and the plasticizer is triacetin in the range of 7.5 - 20%w/w of ethyl cellulose.

13. A process as claimed in claims 1 ,4, 7-10 wherein the polymer is Eudragit RS i n t he range of 5 - 1 5% w/w of the d rug core, a nd the plasticizer is triethylcitrate in the range of 7.5 - 20%w/w of Eudragit RS.

14. A process as claimed in claims 1 ,4,7, 9-10 wherein the polymer is Eudragit NE in the range of 5 - 15% w/w of the drug core.

15. A process of sequential layer-coating as claimed in claims 1 , 4-10 wherein the polymers ethyl cellulose and Eudragit NE are in the range of 5 - 15% w/w of the drug core.

16. A process of sequential layer-coating as claimed in claims 15 wherein the plasticizer is triacetin in the range of 7.5 - 20%w/w of ethyl cellulose.

17. A novel composition as claimed in claims 1-9 wherein the composition containing TMZ HCI comprises of the binder in the range of 7.5 - 20% w/w of TMZ HCI, the antitack agent and / or glidants in the range of 5 -30% w/w of the TMZ HCI, one or more water insoluble polymer/s in the range of 5 - 15% w/w of the drug core, and plasticizer optionally used in the range of 7.5 - 20%w/w of the polymer.

18. A novel composition as claimed in claims 1-2, 9-10 wherein the binder is hydroxypropylmethylcellulose in the range of 7.5 - 20% w/w of TMZ HCI.

19. A novel composition as claimed in claims 1 ,4,6, 8-10 wherein the polymer is ethyl cellulose in the range of 5 - 15% w/w of the drug core, and the plasticizer is triacetin in the range of 7.5 - 20%w/w of ethyl cellulose.

20. A novel composition as claimed in claims 1 ,4, 7-10 wherein the polymer is Eudragit RS in the range of 5 - 15% w/w of the drug core, and the plasticizer is triethylcitrate in the range of 7.5 - 20%w/w of Eudragit RS.

21. A novel composition as claimed in claims 1 ,4,7, 9-10 wherein the polymer is Eudragit NE in the range of 5 - 15% w/w of the drug core.

22. A novel composition of sequential layer-coating as claimed in claims 1 , 4- 10 wherein the polymers ethyl cellulose and Eudragit NE are in the range of 5 - 15% w/w of the drug core.

23. A novel composition of sequential layer-coating a s claimed i n claims 1 5 wherein the plasticizer is triacetin in the range of 7.5 - 20%w/w of ethyl cellulose.

24. Novel composition containing TMZ HCI processed into sustained release microbeads as claimed in claims 1-23 capable of being filled into size 3 capsules for once a day dosage.