DESC:Field of Invention
The present invention relates to a drug delivery system for extended release delivery of Trimetazidine for treatment of heart related condition like angina. The invention also relates to a process of preparation of the drug delivery system
Background
Trimetazidine dihydrochloride is used therapeutically in the prophylaxis and treatment of angina pectoris attacks. Trimetazidine, or 1-(2,3,4-trimethoxybenzyl)piperazine, is a compound which, by maintaining the energy metabolism of a cell exposed to hypoxia or ischaemia, avoids the collapse of the intracellular level of adenosine triphosphate (ATP). Trimetazidine has a half-life of 7 to 12 hours. Owing to shorter elimination half-life, the drug is an appropriate candidate for design of extended release formulation.
Various extended-release formulations and drug delivery systems have been developed to improve the dosing regimen and maintain therapeutic levels of Trimetazidine in the patient's bloodstream over an extended period.
US10117838 B2 contains drug in pellets form wherein the core drug pellets are coated with pH-independent polymer ethylcellulose and filled in hard gelatin capsules. However, an alternate and improved approach to extended release capsule approach could be preparation of matrix tablets which may or may not be encapsulated.
EP1108424B2 discloses a matrix tablet for prolonged release of trimetazidine, wherein the prolonged release is controlled by the use of a cellulose derivative polymer present in the matrix. But the subject composition is to be given twice daily to maintain the required efficacy.
EP1195160 discloses a process to prepare a 60mg once a daily composition which is to be prepared through hot-melt extrusion method. Hot melt extrusion process is an expensive and complex process which requires the drug to be granulated at very high temperature of upto 120C.
WO2010/086868 discloses a 70mg once-a-daily matrix tablet composition. Trimetazidine dihydrochloride is a freely water soluble drug and in order to design its compact matrix formulation, a large amount of extended release polymer is required.
Thus there still remains a need for a drug delivery system that provides the convenience of once-daily dosing while achieving the desired delayed release of Trimetazidine.
The present invention discloses a drug delivery system that overcomes the limitations of existing formulations by encapsulating two or more tablet composition within a single capsule, both containing Trimetazidine as the active ingredient, and both tablets are designed to simultaneously release the drugs so as the meet the required pharmacokinetic profile and requiring only once-a-daily consumption.
Summary
The present invention relates to a novel drug delivery system designed to simplify and enhance the treatment of angina. This innovative system comprises a single capsule encapsulating two sustained release tablet composition comprising trimetazidine. Significantly, both the first tablet and the second tablet within the capsule are designed to release the drug simultaneously in a sustained or extended manner. The drug delivery system provides a convenient once daily dosage regimen for the effective treatment of angina.
Detailed Description
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
The term “pharmaceutical composition” refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc.
The term “pharmaceutically acceptable excipient” refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products.
The term “excipients” as used herein means a component of a pharmaceutical product that is not an active ingredient. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
The term “Sustained release” or “extended release” as used herein refers drug delivery system which releases the active agents in sustained or modified or extended for a prolonged period of time.
In an embodiment the present provides a drug delivery system for the sustained delivery of an active ingredient over 24 hours period.
In an embodiment the present invention provides a drug delivery system for the sustained delivery of an active ingredient for a period of 24 hours, wherein the active ingredient is Trimetazidine and wherein the drug delivery system comprised of a capsule encapsulating two or more tablets.
In an embodiment the present invention provides a drug delivery system comprising a capsule, wherein the capsule encapsulates two or more tablets, wherein the tablets comprises of trimetazidine and pharmaceutically acceptable excipient and wherein the drug delivery system enables the delivery of the trimetazidine for a period of 24 hours, thus facilitating once-a-daily intake of the drug for treatment of angina.
In a preferable embodiment the present invention provides a drug delivery system comprising a capsule, wherein the capsule encapsulates two or more tablets, wherein the tablets comprises trimetazidine and pharmaceutically acceptable excipient. The Drug delivery system of the present invention enables the delivery of trimetazidine for a period of 24 hours.
In an embodiment the encapsulated tablets of the present invention comprises trimetazidine in range of 30% to 40% by weight of the tablet.
In an embodiment the encapsulated tablets are present as separated individual units or compressed over one another to form a bilayer tablets. Preferably the encapsulated tablets are single separate units.
In an embodiment the encapsulated tablets are optionally coated with a release retarding pH-independent polymer.
In an embodiment the encapsulated tablets of the present invention further comprises of pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable are release retarding matrix agents, diluent, binders, solvent, glidant, lubricant.
In an embodiment the release retarding matrix forming agents are selected from but not limited to water soluble polymer such as hypromellose (HPMC), xanthan gum, guar gum, sodium alginate, carbomers and hydroxyethyl cellulose, water insoluble polymer such as ethylcellulose and waxes and fats such as glyceryl esters of fatty acids including glyceryl monostearate, glyceryl behenate, fatty acids such as stearic acid, fatty alcohols such as cetyl alcohol, stearyl alcohol, cetosteary alcohol, and the likes.
In a preferred embodiment the release retarding matrix forming agent are hypromellose(HPMC), Glyceral dibehanate, ethyl cellulose or a combination thereof, wherein the matrix forming agents are present in the amount of 35% to 40% by weight of the encapsulated uncoated tablets, preferably in the amount of 38% to 41%, most preferably in the amount of 39%-40% by weight of the encapsulated uncoated tablet
In an embodiment the diluents are selected from but not limited to lactose monohydrate, dibasic calcium phosphate, tribasic calcium phosphate, sorbitol, sucrose, trehalose, isomalt, microcrystalline cellulose, mannitol, starch, sodium carbonate, sodium bicarbonate, dextrose, maltodextrine, calcium carbonate, xylitol or the mixtures thereof. In a preferred embodiment the diluent is Microcrystalline cellulose and present in the amount of 10% to 20%, preferably in the amount of 14%-16% by weight of encapsulated uncoated tablets.
In an embodiment the binders are selected from but are not limited to pregelatinised starch, hydroxypropyl cellulose, sugars, glycose syrups, natural gums, guar gum, gelatins, pullulan, polymetacrylates, collagen, agar, algynate, sodium alginate, hyaluronic acid, pectin, tragacanth gum, carboxymethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate and their copolymers, hydroxypropyl methyl cellulose, carboxy methyl cellulose, methyl cellulose, microcrystalline cellulose, polyvinylalcohol, carrageenan, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, benthonite, laponite, setostearyl alcohol, polyoxyethylene-alkyl ethers, acacia mucilage, polydextrose, polyethylene oxide or the mixtures thereof. In a preferred embodiment the binder is polyvinyl pyrrolidone, HPMC, or a combination thereof, wherein the binder is present in the amount of 1% to 10%, preferably in the amount of 2% to 5% by weight of the tablet.
In an embodiment the solvents are present invention are selected from but not limited to methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof. In a preferred embodiment the solvent is Isopropyl alcohol
In an embodiment the glidants are selected from, but are not limited to colloidal silicon dioxide, stearic acid, talc, aluminum silicate or the mixtures thereof. In a preferred embodiment the glidant is colloidal silicone dioxide. In an embodiment the glidant is present in the amount of 0.5%-5% by weight of the tablet.
In an embodiment the lubricants are selected from, but are not limited to magnesium stearate, sodium stearyl fumarate, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, polyethylene glycol, paraffin or the mixtures thereof, preferably, the lubricant is magnesium stearate and present in the amount of 1% to 5% by weight of the composition.
In an embodiment the encapsulated tablets of the present invention optionally comprises a film coating. In a preferable embodiment the film coating of the present invention comprises of release retardant pH independent polymers, plasticizer and solvents, wherein the release retardant pH independent polymers are selected from Ethyl cellulose, hydroxypropyl methyl cellulose polyvinyl acetate, cellulose acetate, plasticizer is polyethylene glycol and solvents are isopropyl alcohol, methylene choloride or combination thereof.
In an embodiment the encapsulated tablets of the present invention comprises of trimetazidine or salts thereof, release retardant matrix forming polymers and pharmaceutically excipients selected from diluents, binders, solvent, glidant, lubricant and optionally a film coating, wherein the film coat comprises of one or more release retardant pH independent polymers, plasticizer and solvents
In an embodiment the encapsulated tablets of the present invention comprises of trimetazidine or its salts thereof in the range of 30% to 50% by weight of the uncoated tablets, an release retardant polymer in the range of 35% to 45% by weight of the uncoated tablets, diluents in the range of 10% to 20% by weight of the uncoated tablets, binders in the range of 1% to 10% by weight of the uncoated tablets, glidant in the range of 0.5% to 2% by weight of the uncoated tablets, lubricant in the range of 1% to 10% by weight of the uncoated tablets.
In an embodiment the present invention provides a drug delivery system comprising a capsule encapsulating
i) a first tablet comprising trimetazidine or its salts thereof in the amount of 30% to 50% and pharmaceutically acceptable excipients,
ii) a second tablet comprising trimetazidine or its salts thereof in the amount of 30% to 50% and pharmaceutically acceptable excipients,
wherein both first and the second tablets exhibits extended drug release profile, wherein both tablets are designed to release the drug simultaneously and wherein both tablets are optionally coated with release retardant pH independent film coating.
In an embodiment the ratio of active ingredient between the first and second tablet is 1:1, 5:3 or 3:5, 1:3 or 3:1, 1:7 or 7:1. Preferably the ratio is 1:1
In an embodiment of the present invention the drug delivery system facilitates the release of the drugs from both first and the second tablets simultaneously to achieve Cmax of 181.35+11.25ng/ml. at timex Tmax of 6.13+ 0.80 hr.
In an embodiment the present invention provides a drug delivery system comprising a capsule, wherein the capsule encapsulates a first tablet comprising trimetazidine in the amount of 30% to 50% and a second tablet comprising trimetazidine in the amount of 30% to 50%, and wherein both first and the second tablets exhibits extended drug release profile and wherein both first and second tablets are designed to release the drugs simultaneously to achieve a Cmax of Cmax of 181.35+11.25ng/ml. at time Tmax of 6.13+ 0.80 hr.
In an embodiment the present invention provides a drug delivery system comprising atleast two tablets encapsulated in hard gelatin capsule, wherein the tablets are designed to provide extended release of the drug to achieve the required efficacy for once-a-day dosing regimen.
Trimetazidine dihydrochloride is a freely water soluble drug and in order to design its compact matrix formulation, a large amount of extended release polymer is required. Servier patent US10117838 B2 contains drug in pellets form wherein the core drug pellets are coated with pH-independent polymer ethylcellulose and filled in hard gelatin capsules.
In an embodiment the present invention is also aimed at formulating matrix tablet which may be optionally coated with a pH-independent release-controlling polymer. The matrix material could be water soluble polymer such as hypromellose, xanthan gum, guar gum, sodium alginate, carbomers and hydroxyethyl cellulose, water insoluble polymer such as ethylcellulose and waxes and fats such as glyceryl esters of fatty acids including glyceryl monostearate, glyceryl behenate, fatty acids such as stearic acid, fatty alcohols such as cetyl alcohol, stearyl alcohol, cetosteary alcohol, and the likes. The matrix tablet may be optionally coated with a polymeric membrane such as ethylcellose, polyvinyl acetate, cellulose acetate, and the likes.
Examples
The scope of the present invention is illustrated by the following examples which are not meant to restrict the scope of the invention in any manner whatsoever.
Example 1- Formulation details of Encapsulated tablet
S.N. Ingredients Amount per tablet
1 Trimetazidine Dihydrochloride 36.22%
2 HPMC (Hypromellose K200 M) 39.57%
3 Microcrystalline cellulose 15.96%
4 Povidone 3.1%
5 Silicon dioxide 1.3%
6 Magnesium stearate 3.04%
7 Isopropyl alcohol (Solvent) As reqd.
Wt of Uncoated tablet 100%
Film coating
7 Ethylcellulose 20.8 mg
8 HPMC (Hypromellose E5) 12.0mg
9 Polyethylene glycol 2.24mg
10 Isopropyl alcohol (Solvent) As reqd.
11 Methylene chloride (Solvent) As reqd.

Example 2 – Formulation details of encapsulated tablet
S.N. Ingredients Mg per tablet
1 Trimetazidine Dihydrochloride 35%
2 Glyceryl dibehanate (Compritol 888 ATO) 40%
3 Microcrystalline cellulose 16.94%
4 Povidone 4.2%
5 Magnesium stearate 2.96%
6 Isopropyl alcohol As required
Wt of Uncoated tablet 100%
Film coating
6 Ethylcellulose 20.8
7 Talc 20.8
8 Solvent As required
Example 3 – Formulation details of encapsulated tablet
S.N. Ingredients Mg per tablet
1 Trimetazidine Dihydrochloride 38.94%
2 Ethylcellulose 50 cps 39.27%
3 Microcrystalline cellulose 14.77%
4 HPMC (Hypromellose) 3.74%
5 Magnesium stearate 3.27%
Wt of Uncoated tablet 100%
Film coating
6 Ethylcellulose 20.8
7 Talc 20.8

Example 4– Process of preparation
Step 1- Sifting of API & Excipients - Trimetazidine HCL, Microcrystalline cellulose and ethyl cellulose were sifted and sieve integrity were checked (Humidity: NMT 60%; Temp: NMT 25oC). The sifted material was then dry mixed in RMG for 10 minutes ate slow speed. Separately a transparent Binder solution was prepared by mixing PVP with isopropyl alcohol.
The dried mixture of Trimetazidine, MCC and ethyl cellulose was then granulated by slowly pouring the binder solution to the dried mixture in an RMG for 2-3 minutes at Impeller On & Chopper off. Additional quantity of isopropyl alcohol can be added, if required. Again, run RMG at slow speed of impeller and fast speed of chopper for 3-5 min or to get dough like consistency.
The wet dough is then passed through multi-mill at slow speed and knives forward using 8.0 mm screen & collect the wet coarse granules in fluidized bed dryer (FBD/FBP) bowl. The wet milled granules were then dried in the FBD/FBP, initially through air drying for 10 minutes then at temperature between 50oC-60oC (with intermittent raking after every 20 minutes for 5 minutes) and outlet temperature between 32oC-42oC or till the value of moisture content obtained between LOD 2.0% to 3.0% w/w at 105oC.
The dried granules are then sifted through sieve#20 fitted with mechanical sifter and pass the retained granules through multimill at slow speed and knives forward using 1.0mm screen. Again sift the milled granules through sieve#20 fitted with vibro sifter. The sifted granules are then taken for lubrication and colloidal silicon dioxide is added and charge them into a octagonal blender/rotocube mixer and mixed for 10minutes. Then magenesium sterate is added and mixed for 5 minutes.
The lubricated mixture are then compressed into tablets which are further (opitional) flim coated. The film coat is prepared by mixing ethyl cellulose with HPMC, PEG, IPA and MDC. The compressed tablets were then encapsulated in gelatin capsules.
Example 5 – Stability studies
a) Dissolution profile
Test Acceptance Criteria Initial testing After 3 months After 6 months After 9 months After 12 months After 18 months
Dissolution (By HPLC)
After 2 hours Not more than 20% Min. 0.24% 0.01% 0.02% 0.02% 0.07% 0.00%
Max. 2.24% 0.02% 0.28% 0.03% 0.16% 0.00%
Avg. 0.92% 0.02% 0.07% 0.02% 0.10% 0.00%
After 8 hours Between 25% to 65% Min. 26.87% 33.82% 37.15% 30.95% 26.24% 28.40%
Max. 30.14% 44.23% 44.57% 39.47% 31.92% 35.74%
Avg. 28.62% 38.94% 40.88% 35.83% 29.33% 32.11%
After 2 hours Between 45% to 85% Min. 49.43% 72.07% 65.29% 76.27% 61.82% 74.72%
Max. 66.75% 82.38% 84.01% 81.35% 62.32% 82.39%
Avg. 56.75% 77.38% 77.88% 78.09% 62.14% 78.94%
After 24 hours Not less than 70% Min. 81.40% 94.64% 98.89% 98.73% 92.50% 102.81%
Max. 91.21% 104.03% 101.33% 101.04% 104.72% 105.41%
Avg. 86.78% 99.25% 100.02% 100.02% 98.23% 104.48%

b) Impurity profile
Test Acceptance Criteria Initial Testing After 3 months After 6 months After 9 months After 12 months After 18 months
Related substances (By HPLC)
Trimctazidine impurity (I) at RRT (About) 0.21 Not more than 1.0% Not Detected Not Detected Not Detected Not Detected Not Detected Not Detected
Trimetazidine impurity (H) at RRT (About) 0.24 Not more than 1.0% Not Detected Not Detected Not Detected Not Detected Not Detected Not Detected
Trimetazidine impurity (D) at RRT (A bout) 0.45 Not more than 1.0% Not Detected Not Detected Not Detected Not Detected Not Detected Not Detected
Trimetazidine impurity (C) at RRT (About) 0.71 Not more than 1.0% 0.010% 0.005% Not Detected Not Detected 0.011% Not Detected

Trimetazidine impurity (B) at RRT (About) 0.90 Not more than 1.0% Not Detected Not Detected Not Detected Not Detected 0.016% Not Detected
Trimetazidine impurity (A) at RRT (About) 0.95 Not more than 1.0% Not Detected 0.013% Not Detected Not Detected 0.021% Not Detected
Trimetazidine impurity (E) at RRT (About) 0.98 Not more than 1.0% Not Detected 0.043% 0.083% 0.115% 0.123% 0.117%

Single maximum Impurity Not more than 0.5% 0.085% 0.039% 0.052% 0.046% 0.030% 0.062%
Total impurities (Excluding known impurities ) Not more than 2.0% 0.150% 0.136% 0.239% 0.097% 0.044% 0.062%

Example 6 – Bioequivalence studies
1. AIMS AND OBJECTIVES
The aim and the objective of the present study was to evaluate the pharmacokinetic parameters and to compare the bioequivalence of Trimetazidine HCI Extended Release (ER) Capsules 80mg (each hard gelatin ER capsule contains Trimetazidine HCI IP 80mg), with Vastarel MR 80 mg Capsule in 24 healthy human volunteers in a randomized, two way complete crossover design.
2. SUBJECTS:
Subjects were adult, human, healthy male volunteers, the mean age 32.81+ 5.43 years and mean weight 59.15+4.52 kg selected from the panel of volunteers. Volunteers were screened for inclusion in the study within 2l days before the commencement of the study.
They fulfilled the selection criteria as per the protocol submitted earlier (Annexure III). Before admission to the study each subject was informed of the nature and the risks of the study and a written informed consent was obtained from the volunteers. They were allocated to the treatment Al or A2
3. MATERIALS AND METHODS:
3.1 STUDY DESIGN:
This was a single dose, randomized; two treatments and two-way cross over study, with at least a washout period of 7 days between the two dosing sessions. In each dosing session, volunteers received either of the Test preparation as per the present invention (as film coated tablets), or the reference preparation, Vastarel MR 80 mg Capsule, only on the study day at a fixed times.
3.2 PRODUCT INFORMATION:
Reference Preparation (Al): Vastarel MR 80 mg Capsule (each hard gelatin modified -release capsule contains Trimetazidine 80mg pellets)
Test Preparation of the present Invention (A2): Trimetazidine HCI Extended Release (ER) Capsules 80mg Trimetazidine HCI IP 80mg) (as film coated tablets)
3.3 DOSE
With the reference preparation, the dose was one Vastarel MR 80 mg Capsule and with the test preparation, the dose was one Trimetazidine HCI Extended Release (ER) Capsules 80mg (Tablet 40mg + Tablet 40mg)
3.4 BLOOD COLLECTION:
All the volunteers assembled in CPU ward at 5.00 a.m. on the study day of each session, after overnight fasting of 10 hrs. Their TPR, BP was recorded and an indwelling intravenous catheter was introduced with strict aseptic precautions in the suitable vein for blood collection. They received either of the study preparations according to their code no at 7.32 a.m in period I & 8.00a.m in period II.
A total of 25 blood samples of each volunteer were collected at 0 hr. (before drug administration) and 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5,4.0, 4.5, 5.0, 6.0, 6-5, 7.0, 8.0, 10.0, 12.0, 12.5, 13.0, l4.0, 16.0, 24.0, 48.0, and 12.0 hrs. (after drug administration) in the test tubes with EDTA at each time point.
Lunch, snacks and dinner were provided after 4 hrs, 8 hrs., and 14 hrs. respectively after drug ingestion. On the study days volunteers were permitted normal activities, excluding strenuous exercise.
Collected blood samples were centrifuged immediately & plasma was separated and stored frozen at -200C with appropriate labeling of volunteer code no with study date and collection time. Abnormal signs/symptoms were monitored, during the study period and for one week after the study period and if noticed, their details were entered in the case report sheets and tabulated at the end of the study.
4. LCMS/MS ANALYSIS
Samples were analysed by LCMS/MS after extracting the drug from plasma and injecting it on the LCMS/MS column for chromatographic analysis. The blood plasma concentration of the volunteers for Reference and Test preparations were tabulated
5. PHARMACOKINETIC VARIABLES STUDIED
Plasma levels of Trimetazidine for every volunteer at each time point were plotted to obtain Time-Plasma concentration curves for the study preparations. The mean of primary pharmacokinetic parameters of Bioavailability for this single dose study were: -
Cmax - (Maximum Plasma Concentration)
Tmax - (Time to Maximum Plasma Concentration)
AUC(0-t) - (The area under plasma concentration time curve)
AUC(0-inf) - (The area under plasma concentration time curve 0 to infinity)
T1/2-(Elimination half life)
Kel-(Elimination rate constant)
6. PHARMACOKINETIC PARAMETERS
Administration of the Reference preparation, one Vastarel MR 80 mg capsule, as a single dose in the fasting state produced the maximum plasma concentration of 192.10 + 11.99 ng/ml (Cmax) at the time 6.3g+0.49hr (tmax) whereas administration of the Test preparation, Trimetazidine HCI Extended Release (ER) Capsules 80mg, as a single dose in the fasting state produced the maximum plasma concentration 181.35+11.25 ng/ml (Cmax) at the time 6.13 + 0.80hr (tmax)
Administration of the Reference preparation produced the area under plasma concentration time curve (AUC0-t) 2605.22+198.30ng.hr/ml, whereas administration of the Test preparation produced the area under plasma concentration curve (AUC0-t) 2370.45+ 282.04 ng.hr/ml.
When administered as a single dose, in the fasting state, the Reference preparation, produced the area under plasma concentration time curve up to infinity (AUC0-t) 2887.85+ 294.08 ng.hr/ml, whereas administration of the Test preparation, produced area under plasma concentration time curve up to infinity (AUC0-a) 2554.51+ 427.42 ng.hr/ml.
Administration of the Reference preparation produced the plasma elimination half life, (t1/2) 16.15 + 2.39 hr whereas administration of the Test preparation produced the plasma elimination half-life (t1/2) 14.50 + 2.81 hr. Administration of the Reference preparation, produced the plasma elimination constant (Kel 0.044 + 0.006 hr-1, whereas administration of the Test preparation produced the plasma elimination constant (Kel) 0.049 + 0.008 hr-l.
On the basis of comparison of the AUC0-t of Trimetazidine, after single dose administration, the relative bioavailabitity & log transformed relative bioavailability of the test preparation, Trimetazidine HCI Extended Release (ER) Capsules 80mg, were 90.99% & 98.80% respectively with that of the reference preparation, Vastarel® MR 80 mg Capsule.
6.2 ADVERSE REACTIONS:
In phase I of the study, volunteer 4 complained about mild headache.
7. DISCUSSION:
The single dose bioequivalence study of Trimetazidine HCI Extended Release (ER) Capsules 80mg was conducted in 24 adult healthy, human, male volunteers with two preparations of Trimetazidine. Values of Cmax, tmax and AUCo-t were comparable for the reference and the test preparation in the fasting state. Trimetazidine was detected in plasma from 0.25 to 12.0 hrs for both the preparations peak plasma levels of Trimetazidine were achieved between 5.0 to 7.0 hrs for both the preparations.
The mean peak plasma levels of Trimetazidine with Reference preparation, Vastarel® MR 80 mg Capsule, on the study day ranged between 170.56 - 207.32 ng/ml. While the Test preparation, Trimetazidine HCl Extended Release (ER) Capsules 80mg, ranged between 164.49 -202.92 ng/ml. On the basis of comparison of the AUCo-t for Trimetazidine after single dose administration, the relative bioavailability & log transformed relative bioavailability of the test preparation, Trimetazidine HCI Extended Release (ER) Capsules 80mg, were 90.99% & 98.80% respectively with that of the reference preparation, Vastarel® MR 80 mg Capsule.
8. CONCLUSION:
On the basis of the pharmacokinetic parameters studied, it can be concluded that the Test preparation of the present invention is bioequivalent with the Reference preparation.
,CLAIMS:1. A drug delivery system comprising a capsule consisting of a first tablet comprising Trimetazidine within the interior of the capsule and a second tablet comprising Trimetazidine within the interior of the same capsule, wherein the ratio of the amount of Trimetazidine in the first tablet and second tablet are 1:1, 5:3 or 3:5, 1:3 or 3:1, wherein both first and second tablet exhibits delayed drug release profile, and wherein the first tablet and second tablet are designed to release the active ingredient simultaneously to achieve a Cmax of 181+11.25 ng/ml at the time 6.13+0.80 hrs (Tmax) and once daily dosing and optionally wherein the first and second tablets are coated with release retarding pH independent polymers.
2. The first and the second tablet according to claim 1 are extended release matrix tablet, wherein the matrix tablet comprises Trimetazidine in the amount of 35% to 40% by weight of the uncoated tablet and pharmaceutical acceptable excipients.
3. The pharmaceutically acceptable excipients according to claim 2 are release-retarding excipients, diluents, binders, solvent, glidant, lubricants and film coating
4. The release retarding excipients according to claims 3 are selected from water swellable polymers, water insoluble polymers and hydrophobic waxes, fat and oils or mixtures thereof.
5. The composition according to claim 3, wherein the release-retarding excipient is ethyl cellulose and present in the amount of 35% to 45%, preferably in the amount of 39% to 40% by weight of the uncoated tablet.
6. The composition according to claim 3, wherein the diluents is microcrystalline cellulose and present in the amount of 10% to 20%, preferably in the amount of 14% to 16% by weight of the uncoated tablet
7. The composition according to claim 3, wherein the binder is polyvinyl pyrrolidone and present in the amount of 1% to 10%, preferably in the amount of 2% to 4% by weight of the uncoated tablet.
8. The composition according to claim 3 wherein the glidant is colloidal silicon dioxide and lubricant is magnesium stearate, and present in the amount of 1%-5% by weight of the tablet.
9. The composition according to claim 3 wherein the film coating comprises of film formers, plasticizer and solvents, wherein the film formers are Ethyl cellulose and HPMC, wherein the plasticizer is polyethylene glycol and solvents are Isopropyl alcohol and methylene chloride.