FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003
PROVISIONAL / COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION : MODIFIED RELEASE FORMULATION OF TRIMETAZIDINE
2.APPLICANT(S)
(a) NAME : MICRO LABS LIMITED
(b) NATIONALITY: Indian
(c) ADDRESS : MICRO LABS LIMITED
27 .Race Course Road, BANGALORE-560 001 INDIA
3. PREAMBLE TO THE DESCRITION


PROVISIONAL
The following specification describes invention
4. DESCRIPTION (Description shall start from next page)
5. CLAIMS (not applicable for provisional specification. Claims should start with the preamble - "I / We claim" on separate page)
6. DATE AND SIGNATURE (to be given on the last page of specification)
7. ABSTRACT OF THE INVENTION (to be given along with complete specification on the separate page)
Note:
'Repeat boxes in case of more than one entry
*To be signed by the applicant(s)or the authorized registered patent agent
*Name of the applicant should be given in full, family name in the beginning
*Complete address of the applicant should be given stating with postal index no. /code, state and country
*Strike out the column which is/are not applicable


(iii) Declaration by the applicant (s):
I/We, the applicant(s) hereby declare(s) that:
o I am / We are in possession of the above - mentioned invention.
o The provisional/complete specification relating to the invention is filed with this application.
o The invention as disclosed in the specification uses the biological material from India and the
necessary permission from the competent authority shall be submitted by me/us before the
grant of patent to me/us. o There is no lawful ground of objection to the grant of the Patent to me/us. o I am / We are the assignee or legal representative of true & first inventors. o The application or each of the applications, particulars of which are given in Para - 5 was first
application in convertHon countryicountr'ies in respect of my/our invention. o I / We claim the priority from the above mentioned application(s) filed in convention
country/countries and state that no application for protection in respect of the invention had
been made in a convention country before that date by me/us or by any person from which I/We
derive the title.
10. Following are the attachments with the application:
(a) Provisional specification.
(b) Statement and undertaking on Form 3
(c) Power of Authority
(d) Declaration of inventorship on Form 5
Fee Rs. 4000/-in Cash
I / We hereby declare that to the best of my/our knowledge, information and belief the fact and matters stated herein are correct and I/We request that a patent may be granted to me/us for the said invention.
Dated this 20th day of January 2009.

To,
The Controller of Patents
The Patent Office, at Mumbai

PROVISIONAL APPLICATION
MODIFIED RELEASE FORMULATION OF TRIMETAZIDINE
Following is the general description of the present invention:
Field of invention:
The present invention relates to modified release oral formulation of an antianginal drug trimetazidine which releases trimetazidine in a sustained and reproducible manner over prolonged period of time and the method of preparation there of Background of the Invention:
Trimetazidine is a metabolic modulator which has demonstrated anti-ischemic effects in patients with angina. Unlike the conventional classes of antianginal drugs the efficacy of trimetazidine is not dependent on reduction in the heart rate or blood pressure. The efficacy and safety of trimetazidine in the treatment of patients with coronary heart disease and stable angina has been demonstrated in a number of randomized, controlled clinical trials.
Trimetazidine dihydrocloride is administered orally in doses of 40 to 60 mg daily in divided doses as immediate release preparations; usually in practice 20mg preparation is given twice or thrice daily to ensure relatively constant plasma levels. In clinical practice, 35mg. tablets are also often prescribed twice a day. However as the drug is absorbed quickly, immediate release forms tend to give much higher levels immediately after administration and a low level at the time of next dose.

Modified release or sustained release formulations of trimetazidine have been developed to provide relatively constant plasma levels and sustained antianginal and anti ischemic efficacy round the clock .The aim of sustained release formulation is to achieve minimum therapeutic concentrations of drug in the plasma, maintain steady concentration without much fluctuation and increase duration of concentration plateau. It also helps in patient compliance.
European Patent 1195160 describes a sustained release matrix pharmaceutical composition containing active ingredient trimetazidine with hydrocoUoid forming materials and/or hydrophobic polymers and/or other hydrophobic materials as a retardant.
EP 0673649 Bl describes a prolonged release of trimetazidine which is controlled by using a reservoir system in which a mixture of polymer that is insoluble in water and a plasticizer is in the form of a film that coats tablets or mini granules comprising trimetazidine.
EP 1104673A1 deals with a galenic disintegrating agent free pharmaceutical composition of an active principle, notably of an active principle having anti-ischemic action characterized in that it comprises at least one diluting agent comprising a hydrogen carbonate.
US patent 4814176 describes sustained release preparation comprising chitin, chitosan or a mixture of thereof, anionic polymers having carboxyl group or a group capable of providing the same and a pharmaceutical active agent including trimetazidine hydrochloride.
EP 1108424B1 deals with Matrix tablet for the prolonged release of trimetazidine characterized in that the prolonged release is controlled by the use of a cellulose

derivative polymer present in the matrix selected from hydorxy propyl cellulose, hydroxy ethyl cellulose, hydroxy methyl cellulose, methyl cellulose and hydroxy propyl methyl cellulose.
It is known in the prior art that various grades of hydroxy propyl methyl cellulose are used in the modified release medications The HPMC matrix based system work by the swell and gel technique i.e. they swell by taking in fluids and further gel to provide a matrix which provides sustained effect facilitated by diffusion of the drug . However it is seen that higher viscosity grade HPMC release the drug slowly in the initial phases and the release rate is increased as the time progresses. Exactly the opposite in release is observed when one uses the low viscosity grade HPMC, where in the release is fast in the beginning and slows down as the time progresses.
OBJECTIVES AND SUMMARY OF THE INVENTION:
The object of the present invention is to provide a novel formulation design of a sustained
release formulation of Trimetazidine which is effective and safe and comparable to the
commercially available products.
Another objective of the present invention is to provide a sustained release formulation of
trimetazidine where sustained release is controlled by substances other than polymers
derived from cellulose- which is conventionally used for trimetazidine sustained release
preparations.
The present invention makes use of Polyox™ (Polyethylene oxide) for obtaining
sustained release of the active ingredient trimetazidine in a novel formulation design.

DETAILED DESCRIPTION OF THE PRESENT INVENTION:
The present invention deals with a novel formulation design of a sustained release formulation of trimetazidine which is comparable to the commercially available products like Vastarel MR and its other brands. The design can be complied with using the following approaches.
Approach 1: Comprising essentially of active ingredient trimetazidine dihydrochloride and Polyox™ (Polyethylene oxide) with other excipients and coating ingredients. Polyox ™ Water -Soluble Resins, NF Grade are nonionic poly (ethylene oxide) polymers that meet all the specifications of the United States Pharmacopoeia - National Formulary. They are white, free flowing hydrophilic powders supplied in a wide variety of molecular weight grades, ranging from one hundred thousand to seven million Daltons or amu. Polyox™ are among the fastest hydrating water soluble polymers used in pharmaceutical systems.
Polyox™ is an easily compressible, free flowing and non-hygroscopic powder. It has large swelling capacity relative to other hydrophilic polymers. Polymer concentration, viscosity, particle size can be used as parameters to control the release of drugs. Release of actives is not controlled by pH. Various grades of Polyox™ can be used with different percentages. The matrix technology would form the basis of this approach.
Approach 2: The release pattern of the active ingredient trimetazidine in the sustained release formulation comprising of Polyox™ can be further modified by coating the core

tablets with a combination of water soluble and insoluble polymer coat. Besides contributing to the sustained effects, these polymers used for coating can also help in reducing the quantity of Polyox™ in the core formulation. The water soluble polymer in the film would leach out to form pores thereby forming a permeable blanket or sieve like network with the progress of time and thus serve for the effective sustained release of active ingredient which would in turn leach out in a sustained manner from the matrix and reservoir. The other polymer being water insoluble would retard the drug diffusion into the fluids at the initial instance when the dosage form is in contact with the body fluids .The combination of both the water soluble and insoluble polymers thus would further contribute to the additional sustained action of the drug through the blanket or sieve like network. The reservoir and matrix technology would form the basis of this approach.
Various ratios of water soluble and insoluble polymers can be used to get different release profiles and thus one can target the desired ratio for obtaining the desired release profile. This could also further contribute to the fine tuning of the sustained drug release and reducing the use of sustaining agents used in the core; thus providing the technical advantage over prior art.
The pharmaceutical dosage form, such as tablet, according to the present invention, apart from active drug and sustaining Polymers particularly Polyox™ in the range of 25 -80%, may further contain diluents, binders, lubricants and glidants within acceptable limits in relation to the weight of the pharmaceutical dosage form. The range of the Polyox™ may further be reduced when the sustained effect is obtained in combination with a second polymer as per Approach 2.

In the present invention the pharmaceutical composition, through Approach 1 may be produced by dry mixing of active substance with Polymer and diluents or any other granulation technique known to the person skilled in art. This could also include various wet and dry granulation techniques using aqueous or non aqueous solvents, fluid bed granulation techniques etc.
This mix is further lubricated with the glidants and lubricants to aid in the smooth compression run and produce quality dosage forms.
In the present invention for Approach 2, the cores may be prepared as per Approach 1 or any other techniques as discussed for Approach 1. These cores are further coated with polymers which contribute to the sustained release effect of the drug in combination to the sustained effect produced by Polyox™ alone.
The cores of Approach 1 and 2 can be coated with a film using standard coating processes and methods such as a conventional coating pan or any other coating techniques known to a person skilled in art using In-house coating mixtures or readymade coating mix.
The sustained release tablets according to the present invention release trimetazidine dihydrochloride in a controlled manner which provide an effect over a time period up to 12 hours.
The tablets thus obtained have a dissolution profile comparable to that of Vastarel MR Tablets and its various brands as available.

Approach 1: Example
In one of the embodiments, the coating composition comprised of Opadry pink (03G84583).
The preferred composition of this formulation is as follows:
Ingredients Mg/Tab
Dry mix
Trimetazidine dihydrochloride 35.00
Polyethylene oxide 110.00
Microcrystalline cellulose 53.00
Lubrication
Magnesium stearate 2.00
Core weight (mg) 200.00
Coating
Opadry pink 03G84583 4.00
Isopropyl alcohol —
Methylene chloride —
Coated tablet weight (mg) 204.00
Manufacturing process of the above formula:
The Direct compression method is used where the dry blend comprising the active is
mixed and lubricated.
This lubricated blend is compressed using the necessary tooling to get the compressed
cores.
The compressed tablets are then coated to the desired weight gain to get the coated
tablets.

Comparative dissolution profile of Trimetazidine dihydrochloride MR tablets 35mg,
(Apparatus- Basket, RPM-100, Media-pH 6.8 buffer, Volume-900ml) with that of the
innovator is given below:
Time (hr) Vastarel 35mg, B.No.805942 Approach 1 (Coated)

% release % release
0 0.00 0.00
1 38.07 38.45
4 80.11 80.15
8 94.54 95.07
12 99.90 99.94
Approach 2: Example

Ingredients Mg/Tab
Dry mix
Trimetazidine dihydrochloride 35.00
Polyethylene oxide 80.00
Microcrystalline cellulose 20.00
Lubrication
Magnesium stearate 2.00
Core weight (nig) 137.00
The coating comprises of Hypromellose, ethyl cellulose, titanium dioxide, Macrogol 6000, red iron oxide; the preferred concentration of the various ingredients used is given
below:
Coating Mg/Tab
Hypromellose 5 cps 15.525
Ethyl cellulose (20 cps) 7.475
Titanium dioxide 3.00
Macrogol 6000 1.97
Red iron oxide 0.03
Isopropyl alcohol —
Methylene chloride —
Coated tablet weight 165.00

Manufacturing process of the above formula:
The Direct compression method is used where the dry blend comprising the active is
mixed and lubricated. This lubricated blend is compressed using the necessary tooling to
get the compressed cores.
The compressed tablets are then coated to the desired weight gain to get the coated
tablets.
Comparative dissolution profile of Trimetazidine dihydrochloride MR tablets 35mg, (Apparatus- Basket, RPM-100, Media-pH 6.8 buffer, Volume-900ml) with that of the innovator is given below:

Time (hr) Vastarel 35nig, B.No.805942 Approach 2 (Coated)

% release % release
0 0.00 0.00
1 38.07 29.92
4 80.11 85.57
8 94.54 99.01
12 99.90 101.63
The compositions discussed above are given only as some of the examples of the present invention and this in no way restricts the scope and flexibility of the invention. Various modifications and the use of different concentrations of the ingredients are possible and are used to achieve the identical (to that of the innovator) or similar dissolution profile and /or bioequivalence results. It is emphasized that the essence and the uniqueness of the present invention is the novel use of Polyox™, at various concentrations worked out in the invention for achieving desired sustained release of trimetazidine- with or without the polymer coating; at defined ratios further helping in reducing the concentration of Polyox™ in the formulation.

The modified release tablets of the present invention could be of any desired strength but preferably containing - 35mg of the active ingredient as it is the presently commercially available strength. The modified release tablets according the present invention releases tnmetazidine dihydrochloride in a controlled manner which would provide an effect over prolonged period; such sustained release tablets of 35mg.strength can be orally administered twice a day to achieve therapeutic effects for 24 Hrs.