FORM 2
THE PATENTS ACT 1970
(39ofl970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"AN IMPROVED CONTROLLED POROSITY OSMOTIC PUMP OF TRIMETAZIDINE DIHYDROCHLORIDE TABLET"
2. APPLICANTS:
I (a) NAME: LYKA LABS LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies Act, 1956
(c) ADDRESS: 101, Shivshakti Industrial Estate, Andheri-Kurla Road,
Andheri (East), Mumbai - 400059, Maharashtra, India.
II (a) NAME: MISRA, AMBIKANANDAN RAJNARAYAN
(b) NATIONALITY: Indian
(c) ADDRESS: Sai-samrpan, E-57, Gokuldham Society, Behind Union Bank,
Sama, Vadodara, Gujarat - 390 008, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be formed:

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an improved Controlled Porosity Osmotic Pump (CPOP) system for water soluble drug such as Trimetazidine dihydrochloride or pharmaceutically acceptable salts thereof, useful for the treatment of angina pectoris. The present invention also relates to the process for preparation of Trimetazidine dihydrochloride controlled release tablets.
BACKGROUND AND PRIOR ART OF THE INVENTION:
Conventional drug delivery systems have little control over their drug release and almost no control over the effective concentration at the target site. This kind of dosing pattern may result in constantly changing, unpredictable plasma concentrations. Drugs can be delivered in a controlled pattern over a long period of time by the process of osmosis. Osmotic devices are the most promising strategy based systems for controlled drug delivery. They are the most reliable controlled drug delivery systems and could be employed as oral drug delivery systems. Osmotic pressure is used as the driving force for these systems to release the drug in a controlled manner.
There are several types of Osmotically Controlled Drug Delivery Systems (OCDDS) such as Elementary osmotic pump (EOP), Multi chambered osmotic pumps, Push-pull osmotic pumps, Osmotic pumps with non-expanding second chamber. There are also some miscellaneous types of Osmotically controlled drug delivery systems such as Controlled-porosity osmotic pumps (CPOP), Modified osmotic pumps for insoluble drugs, Multi particulate delayed release systems, Monolithic osmotic pumps etc.
Among the above different types of drug delivery system, controlled porosity osmotic pump contains water soluble additives in the coating membrane, which after coming in contact with aqueous environment dissolves and results in formation of microporous membrane in situ. A controlled porosity wall can be described as having a sponge like appearance. The resulting membrane is substantially permeable to both water and dissolved solute. (Rathoreet.al. Int. J.Ph.Sci., Sep-Dec 2009, 269-275)

Controlled Porosity Osmotic Drug Delivery System has certain advantages like no special tableting machine required, no need to prepare orifice by drilling technology, easy to prepare etc. Hence, Controlled Porosity Osmotic Pump has been selected for the development of controlled release formulation of water-soluble drug such as Trimetazidine dihydrochloride in the present invention.
Trimetazidine is an anti-ischemic (anti-anginal) metabolic agent, which improves myocardial glucose utilization through inhibition of fatty acid metabolism. It belongs to the category of cardiovascular agents subcategorized as Vasodilators. It acts by directly counteracting all the major metabolic disorders occurring within the ischemic cell. The actions of Trimetazidine include limitation of intracellular acidosis, correction of disturbances of transmembrane ion exchanges, and prevention of excessive production of free radicals. Trimetazidine belongs to BCS (Bio-pharmaceutics Classification System) Class III having high solubility and low permeability. The lowest solubility of Trimetazidine is 1000 mg/ml.
Trimetazidine dihydrochloride has a Chemical Name l-(2, 3, 4 -Trimethoxybenzyl) piperazine dihydrochloride, and is expressed by the formula C14H24Cl2N203 and structure:-

WO International Publication No. 2010015840 discloses a pharmaceutical composition comprising a core which comprises an anti-anginal agent, an osmotic agent and optionally, one or more pharmaceutically acceptable excipients; and a semipermeable membrane surrounding the core, wherein the semipermeable membrane includes at least one aperture through which the anti-anginal agent can be discharged from the pharmaceutical composition to a patient in need thereof. The said publication discloses an Elementary Osmotic Pump (EOP) system which is prepared by laser drilling of semipermeable membrane.

CN Publication No. 1931143 discloses a Trimetazidine osmotic pump controlled release pharmaceutical composition wherein the coating membrane is formed by bilaminar heat exchanger core membrane or monolayer heat exchanger membrane which is made up of one or several components selected from filming material, pore plasticizer, etc.
US Publication No. 20100291208 discloses controlled porous osmotic pump tablets of high permeable drugs such as venlafaxine or metoprolol or pharmaceutically acceptable salts thereof and the preparation process thereof.
US Patent No. 4968507 is directed to an osmotic pump, for the controlled release of a pharmaceutically active agent to an environment of use.
US Patent Publication No. 20070190137 relates to osmotic dosage forms having a controlled release drug layer and a fast release drug layer, and related methods.
Indian Patent No. 226882 discloses Osmotic Pump Controlled Porosity (CPOP) system for drugs having varying solubility characteristics such as diclofenac sodium, pramipexole and nifedipine, in the form of tablets which are intended for achieving controlled release of said drugs over 12-24 hours for the treatment of various chronic therapeutic conditions.
Indian Patent Application No. 2792/DEL/2008 describes a novel oral formulation of Iycopene with enhanced therapeutic efficacy due to enhanced solubility and delayed release of Iycopene.
Indian Patent Application No. 9177/DELNP/2008 describes an oral osmotic pharmaceutical delivery system comprises a highly water-soluble drug exhibiting an erratic or an incomplete release profile when formulated in a elementary osmotic pump delivery system and at least one release enhancing agent.
Chinese Patent Publication No. 1827092 describes osmotic pump type controlled release preparation of tolterodine.

European Patent No. 0300897 describes a controlled release device that provides continuous delivery of an active ingredient in a controlled and particulate composition containing such multiple devices.
An article titled "Formulation and Optimization of Porous Osmotic Pump-based Controlled Release System of Oxybutynin" by Pritam Kanagale et al., published in AAPS Pharm Sci Tech 2007; 8 (3) Article 53, discloses a porous osmotic pump based drug delivery system for controlled release of oxybutynin.
An article titled "Osmotically Controlled Drug Delivery System with Associated Drugs" by Brahma P Gupta et al., published in J. Pharm PharmaceutSci, 13(3) 571 - 588, 2010, discloses new technologies, fabrication and recent clinical research in osmotic drug delivery system for the drug such as Diltiazem HC1, Carbamazepine, Metoprolol, Oxprenolol, Nifedipine, Glipizide etc.
An article titled "Controlled-Porosity Osmotic Pump Tablets-An Overview", by Ch. Ajay Babu.
An article titled "Osmotically Controlled Oral Drug Delivery Systems: A Review", by Rathore Garvendra S et al.
In view of the above disclosure in various prior arts it is apparent that various Osmotic pump delivery systems are known which suffer from drawbacks such as dose dumping, poor drug loading, use of laser drilling for making pores etc., whereas, Controlled Porosity Osmotic Pump (CPOP) systems are easy to formulate with conventional tablet preparation facility and simple in operation, it improves patient compliance with reduced frequency of dosing, it also shows prolonged therapeutic effect with uniform blood concentration and delivery orifice in CPOP is formed by the incorporation of a leachable component so no need of special instruments (laser or manual drilling) for making pore or hole.
Therefore, the main object of the current invention is to develop the controlled porosity osmotic pump tablet which do not need to be drilled by laser, but provides controlled

porosity for drug release by adding a suitable quantity of pore-forming agents into the semipermeable membrane, to thereby avoid a series of defects associated with the preparation of a controlled osmotic pump by laser drilling process. Further, the CPOP of the present invention is designed to achieve higher drug loading prepared by low cost simple process having effective drug release.
Another object of the present invention is to provide the process for preparation of controlled porosity osmotic pump tablet of Trimetazidine dihydrochloride.
SUMMARY OF THE INVENTION:
In accordance with the above objectives, the present invention describes an improved controlled porosity osmotic pump (CPOP) system for water-soluble drug such as Trimetazidine dihydrochloride or pharmaceutically acceptable salts thereof, useful for the treatment of angina pectoris.
In another aspect, the present invention describes the process for preparation of controlled porosity osmotic pump tablets comprising Trimetazidine dihydrochloride or pharmaceutical ly acceptable salts thereof, useful for the treatment of angina pectoris.
BRIEF DESCRIPTION OF FIGURES:
Figure 1: Controlled Porosity Osmotic Pump (CPOP) Tablet Figure 2: Drug Release Profile
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention discloses an improved controlled release porosity osmotic pump (CPOP) system for water-soluble drug such as Trimetazidine dihydrochloride.

The present invention also discloses process for preparation of controlled porosity osmotic pump tablets comprising Trimetazidine dihydrochloride or pharmaceutically acceptable salts thereof, useful for the treatment of angina pectoris.
In a preferred embodiment, the present invention discloses a Controlled Porosity Osmotic Pump (CPOP) system which is in the form of a tablet comprises a core and a semipermeable membrane, useful in the treatment of angina pectoris.
In another preferred embodiment, the present invention disclose a dosage form designed as a tablet, which comprises a core and a semipermeable membrane, wherein the core comprises active ingredient, osmogen, a permeation enhancer and a permeation aid; and the semipermeable membrane comprises a film-forming material, a pore-forming agent and plasticizer. The semipermeable membrane further may or may not be coated with a thin film that comprises a conventional film forming material which is commonly used in the field of tablet preparations. The semipermeable membrane, by weight percent, comprises 20-50% of a film-forming material, 40-50% of pore former and 10-20% of a plasticizer.
The active ingredient Trimetazidine dihydrochloride is present in the range of 30 mg to 40 mg, preferably of 35 mg.
The osmogen in the core is selected from the group consisting of active substance itself, sodium chloride, potassium chloride, mannitol, lactose, sorbitol, and mixtures thereof, preferably active substance itself, mannitol and lactose, in the range of 40 mg to 60 mg.
The permeation aid in the core is selected from the group consisting of microcrystalline cellulose, lactose, alginic acid, alginate, propylene glycol alginate, polyethylene glycol, and mixtures thereof, preferably microcrystalline cellulose in the range of 80 mg to 110 mg.
The binder in the core is selected from the group consisting of maize starch, hydroxy propyl methyl cellulose, Povidone K-30, preferably Povidone K-30, in the range of 10 mg

to 20 mg. The solution used for granulation may be purified water or isopropyl alcohol or. mixture thereof.
The core may further comprise a lubricant and glidants selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, glycerylmonosterate, sodium stearyl fumarate, poiyoxyethylene monostearate, sucrose monolaurate, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium dodecyl sulfate, saponite, talc, colloidal silicon dioxide and mixtures thereof, preferably magnesium stearate, talc and colloidal silicon dioxide in the range of lmg to lOmg.
The film-forming material in the semipermeable membrane is selected from the group consisting of cellulose acetate, ' ethyl cellulose, hydroxypropylmethyl cellulose, polyacrylic resin, and mixtures thereof, preferably cellulose acetate in the range of 35% to 45% of related solid in coating solution.
The pore-forming agent in the semipermeable membrane is selected from the group consisting of polyethylene glycol (having a molecular weight of 200-6000), hydroxypropyl cellulose, micronized sugar, sodium chloride, mannitol, sorbitol, and mixtures thereof, preferably polyethylene glycol and sorbitol in the range of 10% to 65% of related solid in coating solution.
The semipermeable membrane may further comprise a plasticizer selected from the group consisting of triethyl citrate, dibutyl sebacate, phthalates, polyethylene glycol 400, and mixtures thereof, preferably polyethylene glycol 400 as water soluble plasticizer in the range of 10% to 20% of related solids in coating solution.
The above-mentioned auxiliary materials such as osmogen, permeation aid, binder, lubricant, glidants, film-forming material, plasticizer and pore-former may be suitably selected according to the releasing effect and the property and concrete use of the drug etc. After reading the content described in the present invention, a person skilled in the art could determine their suitable amounts by conventional experimentation.

In one of the preferred embodiment, the present invention provides a controlled porosity osmotic pump tablets of Trimetazidine dihydrochloride, consisting of a core and a semipermeable membrane, wherein the core comprises, by weight percent, 10-30% of Trimetazidine dihydrochloride, 30-55% of a osmogen, 30-50% of a permeation aid, 3-9% solid binder and 1.0-3.0% of a lubricants and glidants, the semipermeable membrane comprises, by weight percent, 20-50% of a film-forming material, 40-50% of a pore-forming agent and 10-20% of a plasticizer. The semipermeable membrane is present in an amount of 3-35%, preferably 3-7% by weight of the core.
In one of the specific embodiment of the present invention, controlled porosity osmotic pump tablet of Trimetazidine dihydrochloride comprises the core and semipermeable membrane wherein the core comprises Trimetazidine dihydrochloride, manitol, lactose, microcrystalline cellulose, PVP-K30, magnesium stearate, talc and colloidal silicon dioxide; and the semipermeable membrane material comprises cellulose acetate, water, acetone, polyethylene glycol (400) and D-Sorbitol.
In another embodiment of the present invention, controlled porosity osmotic pump tablet of Trimetazidine dihydrochloride comprises a core which may contain total of 54 wt. % of osmogen and this percentage may or may not include active Trimetazidine dihydrochloride (14 % w/w) in addition to 20 wt. % of Lactose, 20 wt. % of Mannitol and 37.6 wt. % of non-soluble substances such as microcrystalline cellulose and adjuvants. The core is coated with coating solution containing acetone 80% w/w, water 17% w/w and solid 3% w/w., wherein the said solid includes cellulose acetate, D- Sorbitol and PEG 400 in the ratio of 40.579: 46.377: 13.043.
The present invention discloses an improved controlled porosity osmotic release unilamellar system which is economical, easy to prepare single layer tablet that contains core which is coated with semi-permeable membrane. The core component may contain drug, osmogen, binder, diluents, glidents and lubricants etc. The coating may or may not contain osmogen, pores are formed by incorporating the pore forming material in the coating solution. It do not contain separate layer i.e. drug layer and push layer or other multiple excipients or drug layer.

The coating membrane is semipermeable membrane that allows selective entry of gastric liquid followed by restricted exit of solute/drug from the core formulation depending on the concentration of pore forming agent in the semipermeable membrane, wherein, driving force is pressure exerted by osmogen and solution in the core.
The present invention discloses an improved Controlled porosity Osmotic Pump (CPOP) tablets of Trimetazidine dihydrochloride, which do not need to be drilled by laser, but affords controlled porosity for drug release by adding a suitable quantity of pore-forming agents into the semipermeable membrane, thereby avoids a series of defects associated with the prior art preparations of a controlled osmotic pump by laser drilling process.
The inventor has chosen drug i.e. Trimetazidine dihydrochloride having good water solubility and permeability which could be completely released through a semipermeable membrane. The said property of the active ingredient is fully utilizes the solubility and permeability of the drug to prepare a controlled porosity osmotic pump tablet that does not need to be drilled with laser, and thereby saves lots of investment, greatly reduces labor intensity, and increases the safety of the drug.
The recommended daily dosage of the Trimetazidine dihydrochloride is 40 or 60 mg (in 2 or 3 divided doses for conventional release tablets) which should be administered with meals.
In another specific embodiment, the present invention discloses a process for preparing controlled porosity osmotic pump tablets, comprising the steps of:-
(1) mixing active ingredient and auxiliary materials, granulating and tableting the same to prepare the core;
(2) formulating the semipermeable membrane with the materials such as cellulose acetate, D-sorbitol, PEG 400, acetone, water, ethanol or isopropanol, preferably 80% acetone to obtain a coating solution;
(3) placing the core prepared in step (1) in a coating machine, coating the core with the coating solution of step (2) until the semipermeable membrane accounts for 3-35% by weight of the core to obtain a coated tablet and
(4) volatizing the excess solvent till dryness in coating pan by application of hot air.

In the process of coating of semipermeable membrane on core in step (3), the air temperature at the outlet is controlled between 25°C to 55°C, the air temperature at the inlet is controlled between 35°C to 65°C and the material temperature is controlled between 25°C and 60°C.
Further, the present invention optimizes the amount of osmogent to be used in the formulation and to study the effect of osmogent in the core formulation, core tablets were prepared with varying amounts of mannitol. AH the core formulations were coated with similar coating composition containing cellulose acetate and Sorbitol. The coated formulations were studied for in-vitro dissolution studies. The release rate increased as the amount of mannitol increased.
To study the effect of level of pore former, core tablets were coated with coating composition containing varying % (w/w of total solid) of Sorbitol. It was found that the drug release increases with the level of Sorbitol.
For optimizing weight gain percentage of coating solution, same formulations with different weight gain were prepared and the effect of weight gain on drug release was observed to reach to targeted drug release.
Drug Release Profile of Example No. 3:
In-vitro release studies were carried out in the dissolution test apparatus USP Type II. The tests were carried out in 900 ml of 0.1N HC1, pH 1.2 for first hour followed by phosphate buffer pH 6.8 for 8 hrs.at 50 rpm at 37±0.5°C. 5 ml of the aliquot were withdrawn at different predetermined time intervals (1, 2, 4, 8hr.). After each withdrawal 5ml aliquot was replaced by 5 ml of phosphate buffer (pH 6.8) to maintain sink condition. Samples withdrawn were filtered through nylon membrane filter paper (0.45 micron) and analyzed at 270 nm using U.V. spectrophotometer. The percentage drug release was calculated using the equation of calibration curve and this was plotted against function of time to study the pattern of drug release (Refer Figure 2)

Time in Hr. Cumulative % Release Target Average SD RSD
1 40.71 44.29 42.86 37.50 41.79 40.00 25 to 45% 41.19 2.37 5.74
2 60.36 62.86 62.86 52.50 59.64 58.93 43 to 63% 59.52 3.81 6.40
4 80.39 83.59 81.83 81.01 79.64 81.09 60 to 90% 81.26 1.36 1.67
8 96.44 98.19 97.86 97.59 95.75 95.74 NLT 80% 96.93 1.95 2.01
The drug release profile of the Trimetazidine formulation is as follows:-

Time Limit
For 1st hour 25 to 45%
For 2nd hour 43 to 63%
For 4th hour 60 to 90%
For 8th hour NLT 80%
Findings from in-vitro and ex-vivo studies of myocardial ischemia have demonstrated that Trimetazidine found to limits intracellular acidosis limits sodium and calcium accumulation, maintain intracellular ATP levels and reduces creatinephosphakinase release, preserves mitochondrial function, reduces myocardial fatty acid metabolism and increases myocardial glucose metabolism, protects against oxygen free radical induced membrane damage, inhibits neutrophil infiltration by inhibiting fatty acid metabolism and secondarily stimulating glucose metabolism, trimetazidine optimises cardiac metabolism and thus protects the heart against the harmful effects of ischaemia. However, the definitive mechanism of action of trimetazidine has yet to be determined. Consistent with a cytoprotective effect, trimetazidine exhibited anti-ischaemic effects in-vivo. It limited the extent of necrosis in a rat model of myocardial ischaemia and reduced the extent of nephropathy in a rat model of renal ischaemia. In addition, Trimetazidine had a direct anti-ischaemic effect in patients undergoing coronary angioplasty.
The following example, which includes preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of

example and for purpose of illustrative discussion of preferred embodiments of the invention.
EXAMPLES: Example 1:
Composition of Core:

Trimetazidine dihydrochloride 35.00 g
Lactose 50.00 g
Mannitol 50.00 g
Microcrystalline cellulose 94.00 g
PVP K 30 15.00 g
Isopropyl Alcohol (Volatile) q.s.
Magnesium stearate 2.50 g
Talc 2.50 g
Aerosil 1.00 g
Total 250 gm
Composition of Semipermeable Membrane:

Ingredient Weight Relative Solid
Cellulose Acetate 36.000 41.739
D- Sorbitol 39.000 45.217
PEG 400 11.250 13.043
86.250 100.000
Coating Solution:

Acetone 80% w/w
Water 17%w/w
Solid 3% w/w

1000 tablets were prepared according to the following process:
1. Passing Trimetazidine dihydrochioride, lactose, Mannitol, MCC & PVP-K30 through sieve 40# and mixing for 10 minutes;
2. granulating the dry blend with IPA;
3. passing wet mass through sieve 18# and drying at 50°C for 1 hour;
4. passing dried granules through sieve 24# and mixing with Aerosil previously pass through 40#;
5. lubricating the step (4) granules using magnesium stearate and talc previously pass through 40# and
6. compressing lubricated granules using 9 mm S/c punch plain on both side.
Coating Solution Preparation:
1. Dissolving accurately weighed cellulose acetate in acetone;
2. dissolving D-sorbitol in half quantity of water;
3. dissolving PEG in rest of the one fourth of water;
4. mixing step 2 and step 1 with high stirring;
5. mixing step 3 with mixture of step 4;
6. stirring properly the solution of step 5 to have clear solution;
7. dipping the tube of coating solution dispenser in it and
8. coating the tablets till 4 -5% of weight gain is achieved
Example 2:
Composition of Core:

Trimetazidine dihydrochioride 35.00 g
Lactose 50.00 g
Sodium Chloride 50.00 g
Microcrystalline cellulose 94.00 g
PVPK30 15.00 g
Isopropyl Alcohol (Volatile) q.s.
Magnesium stearate 2.50 g
Talc 2.50 g
Aerosil 1.00 g
Total 250 gm

Composition of Semipermeable Membrane:

Ingredient Weight Relative Solid
Cellulose Acetate 35.000 40.579
D- Sorbitol 40.000 46.376
PEG 400 11.250 13.043
86.250 100.000
Coating Solution:

Acetone 80% w/w
Water 17%w/w
Solid 3% w/w
1000 tablets were prepared according to the following process:
1. Passing Trimelazidine dihydrochloride, lactose, Mannitol, MCC & PVP-K30 through sieve 40# and mixing for 10 minutes;
2. granulating the dry blend with IPA;
3. passing wet mass through sieve 18# and drying at 50°C for 1 hour;
4. passing dried granules through sieve 24# and mixing with Aerosil previously pass through 40#;
5. lubricating the step (4) granules using magnesium stearate and talc previously pass through 40# and
6. compressing lubricated granules using 9 mm S/c punch plain on both side.
Coating Solution Preparation:
1. Dissolving accurately weighed cellulose acetate in acetone;
2. dissolving D-sorbitoI in half quantity of water;
3. dissolving PEG in rest of the one fourth of water;
4. mixing step 2 and step 1 with high stirring;
5. mixing step 3 with mixture of step 4;
6. stirring properly the solution of step 5 to have clear solution;

7. dipping the tube of coating solution dispenser in it and
8. coating the tablets till 4 - 5% of weight gain is achieved.
Example 3:
Composition of Core:

Trimetazidine dihydrochloride 35.00 g
Lactose 50.00 g
Mannitol 50.00 g
Microcrystalline cellulose 94.00 g
PVP K 30 15.00 g
Isopropyl Alcohol (Volatile) q.s.
Magnesium stearate 2.50 g
Talc 2-50 g
Aerosil 1.00 g
Total 250 gm
Composition of Semipermeable Membrane:

Ingredient Weight Relative Solid
Cellulose Acetate 35.000 40.579
D- Sorbitol 40.000 46.376
PEG 400 11.250 13.043
86.250 100.000
Coating Solution:

Acetone 80% w/w
Water 17%w/w
Solid 3% w/w
1000 tablets were prepared according to the following process:

1. Passing Trimetazidine dihydrochloride, lactose, Mannitol, MCC & PVP-K30 through sieve 40# and mixing for 10 minutes;
2. granulating the dry blend with IPA;
3. passing wet mass through sieve 18# and drying at 50°C for 1 hour;
4. passing dried granules through sieve 24# and mixing with Aerosil previously pass through 40#;
5. lubricating the step (4) granules using magnesium stearate and talc previously pass through 40# and
6. compressing lubricated granules using 9 mm S/c punch plain on both side.
Coating Solution Preparation:
1. Dissolving accurately weighed cellulose acetate in acetone;
2. dissolving D-sorbitol in half quantity of water;
3. dissolving PEG in rest of the one fourth of water;
4. mixing step 2 and step 1 with high stirring;
5. mixing step 3 with mixture of step 4;
6. stirring properly the solution of step 5 to have clear solution;
7. dipping the tube of coating solution dispenser in it and
8. coating the tablets till 4 to 5% of weight gain is achieved.
The Controlled Porous Osmotic Pump Tablets of the present invention have the following prominent advantages:-
1. Reduced cost: since the producer does not need to purchase expensive laser drilling device for other osmotic system, and does not need to frequently change vulnerable laser tube, and can produce controlled release tablets having good releasing effect by using conventional tableting device and coating device, the cost of device is greatly reduced.
2. Simplified process, reduced labor intensity, and increased reliability of process: since the two procedures of drilling with laser and manually screening are omitted, the process becomes relatively simple, and accordingly the reliability and stability of the process are increased. In the production, the occurrence

probability of unqualified products due to incorrect control of procedures in the process is greatly reduced.
3. Increased safety of preparation: drug is released through multiple pores, which is safer than the release of drug through a single pore drilled with laser; once the controlled porous osmotic pump tablet meets digestive juice when entering into human body, the pore-forming agent automatically generates pores, while the problems including missed drilling, over drilling, insufficient depth of drilling and wrong drilling position associated with the use of a laser device will not occur, and the problem such as invalidation due to blockage of the single pore with foods or sudden release will not occur as well, so that the safety is greatly increased.
4. Drug release is not affected by pH and motility of the GI tract as release of the drug from the formulation is independent of pH and agitation intensity.

We Claim,
1. A Controlled Porosity Osmotic Pump (CPOP) system useful in the treatment of angina pectoris comprising a core and a semipermeable membrane, wherein the core comprises 10-30% of Trimetazidine dihydrochloride, 30-55% of a osmogen, 30-50% of a permeation aid, 3-9% binder and 1.0-3.0% of a lubricants and glidants; and the semipermeable membrane comprises 20-50% of a film-forming material, 40-50%) of a pore-forming agent and 10-20% of a plasticizer.
2. The Controlled Porosity Osmotic Pump (CPOP) system according to claim 1; wherein said osmogen is selected from the group consisting of active substance itself, sodium chloride, potassium chloride, mannitol, lactose, sorbitol, and mixtures thereof; preferably active substance itself, mannitol and lactose in the range of 40 mg to 60 mg.
3. The Controlled Porosity Osmotic Pump (CPOP) system according to claim 1; wherein said permeation aid is selected from the group consisting of microcrystalline cellulose, lactose, alginic acid, alginate, propylene glycol alginate, polyethylene glycol, and mixtures thereof; preferably microcrystalline cellulose in the range of 80 mg to 110 mg.
4. The Controlled Porosity Osmotic Pump (CPOP) system according to claim 1; wherein said binder is selected from the group consisting of maize starch, hydroxy propyl methyl cellulose, Povidone K-30, and mixtures thereof; preferably Povidone K-30, in the range of. 10 mg to 20 mg.
5. The Controlled Porosity Osmotic Pump (CPOP) system according to claim 1; wherein said glidents and lubricants are selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, glycerylmonosterate, sodium stearyl fumarate, polyoxyethylene monostearate, sucrose monolaurate, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium dodecyl sulfate, saponite, talc, colloidal silicon dioxide and mixtures thereof; preferably magnesium stearate, talc and colloidal silicon dioxide in the range of 1 mgto 10 mg.

6. The Controlled Porosity Osmotic Pump (CPOP) system according to claim 1; wherein said film-forming material is selected from the group consisting of cellulose acetate, ethyl cellulose, hydroxypropylmethyl cellulose, polyacrylic resin, and mixtures thereof; preferably cellulose acetate in the range of 35% to 45% of related solid in coating solution.
7. The Controlled Porosity Osmotic Pump (CPOP) system according to claim 1; wherein said pore-forming agent is selected from the group consisting of polyethylene glycol, hydroxypropyl cellulose, micronized sugar, sodium chloride, mannitol, sorbitol, and. mixtures thereof; preferably polyethylene glycol and sorbitol in the range of 10% to 65% of related solid in coating solution.
8. The Controlled Porosity Osmotic Pump (CPOP) system according to claim 1; wherein said plasticizer is selected from the group consisting of triethyl citrate, dibutyl sebacate, phthaiates, polyethylene glycol 400, and mixtures thereof; preferably polyethylene glycol 400 as water soluble plasticizer in the range of 10% to 20% of related solids in coating solution.
9. The Controlled Porosity Osmotic Pump (CPOP) system according to any of the preceding claims; wherein said system is a tablet.

10. The Controlled Porosity Osmotic Pump (CPOP) system according to claim 9; wherein said tablet is prepared by a process comprising;
a) mixing active ingredient and auxiliary materials, granulating and tableting the same to prepare the core;
b) formulating the semipermeable membrane with the materials such as cellulose acetate, D-Sorbitol, PEG 400, acetone, water, ethanol or isopropanol to obtain a coating solution;
c) placing the core prepared in step (a) in a coating machine, coating the core with the coating solution of step (b) until the semipermeable membrane accounts for 3-35% by weight of the core to obtain a coated tablet and
d) volatizing the excess solvent till dryness in coating pan by application of hot air.