WO2016042566A1

WO2016042566A1 - Extended release formulation of trimetazidine

Info

Publication number: WO2016042566A1
Application number: PCT/IN2014/000601
Authority: WO
Inventors: Suresh Pareek
Original assignee: Suresh Pareek
Priority date: 2014-09-16
Filing date: 2014-09-16
Publication date: 2016-03-24

Abstract

The present invention relates to a dry ready to use modified release dosage formulation for Trimetazidine dosage forms and its salts and derivatives thereof, a process for preparing extended release tablet using INSTAMODEL (A43 D00046) manufactured by Ideal Cures Private Limited Mumbai India thereof also use thereof as additive to animal feeds, foods and food supplements and also cosmetic and pharmaceutical compositions. Invention also relates to ready-to-use modified release compositions capable of regulating release of Trimetazidine at various dosage strength, a process for production thereof and also use thereof as formulated pharmaceutical compositions.

Description

EXTENDED RELEASE FORMULATION OF TRIMETAZIDINE

Technical Field

The present invention relates to a dry ready to use modified release dosage formulation for Trimetazidine dosage forms and its salts and derivatives thereof, a process for preparing extended release tablet using INSTAMODEL (A43D00046) manufactured by Ideal Cures Private Limited Mumbai India thereof also use thereof as additive to animal feeds, foods and food supplements and also cosmetic and pharmaceutical compositions. Invention also relates to ready-to-use modified release compositions capable of regulating release of Trimetazidine at various dosage strength; a process for production thereof and also use thereof as formulated pharmaceutical compositions.

Background Art

In general Trimetazidine is a metabol ic modulator which has demonstrated ami- ischemic effects in patients with coronary heart disease or angina most wide!) used as anti-anginal and anti-ischemic drug. Trimetazidine is a BCS Class-1 drug and highly soluble and highly permeable. Due to its high water solubility, the form illation of an extended release matrix formulation becomes challenging.

Trimetazidine is administered through solid dosage form orally in unit of 40 to 60 mg daily for immediate release preparations. Generally in practice 20mg preparation is given thrice daily to confirm relatively constant plasma levels. Further in general clinical practice, 35mg tablets of trimetazidine are also often prescribed twice a day. However as the trimetazidine is absorbed quickly, immediate release form general ly make higher peak at the time of administration and gradual ly drug level diminish in blood stream. Salt form of Trimtazidine di hydrochloride is used therapeutical ly in (he long term treatment of angina pectoris and as explained earlier d isplays high solubility in water and is rapidly absorbed by body.

It's well known in the art that Trimetazidine is quickly absorbed and el iminated by the organism and have plasma half-li fe of around 6.0 - 1 .4 hours and Τ_MAX 1 .80 + 0.7 hr. Since trimetazidine has a shorter plasma half-life, in practice 20 mg preparation is given thrice a day in order to ensure relatively constant plasma levels.

In state of the art modified release compositions are developed to provide relati vely constant drug plasma levels and sustained efficacy for longer period of time. Some prior art that discloses extended release compositions of tri metazidine include WO 2006123073, WO 20090663 15 and WO 200903454 1 . I n principle aim of extended and modified release composition is to get required therapeutic concentration of the acti ve in the blood stream and maintain its therapeutic concentration without deviation from strength during specified period.

In state of art various grades of celluiosic polymers are used in the modified release compositions e.g. HPMC polymer. These polymers extend the release of drug by showing osmosis nature in aqueous conditions. Cellulosic matrix based system work by the swelling and gelling function i.e. these polymer swell through influx of liquids and a gel like physical structure is formed which provides extended release effect facilitated by diffusion of the irimetazidine. Some matrix based systems to achieve extended release of trimetazidine are disclosed in WO 200143747, IN 205405 and EP 2386302.

In theory it is known that with high viscosity grade polymer after attaining gelling effect drug release is lower but as time progresses drug release is increased. On the contrary with low viscosity grade polymer after attaining gelling effect drug is released at faster speed due to larger pore sized and concentration of drug decrease as time progresses.

In order to minimize difficulties associated in ratios of polymers, batch lo batch variations, formulating, storing and preserving many loose components of differently textured and sized ingredients means have been desired in industry to make ready to use extended release or modified release composit ion which are convenient to handie.

The object of the present invention was to provide a ready-to-use matrix system and method of preparation for trimetazidine extended release or modified release for mutation.

Disclosure of invention

Summary of Invention

Accordingly, the present invention provides hydrophilic matrix system based ready to use technology for Modified or Extended Release Formulation of Trimetazidine Hy drochloi ide using INST AMODEL (A43D00046) manufactured by Idea! Cures -Private Limited Mumbai India.

Accordingly, the present invention also provides method for making ready to use

Trimetazidine modified or extended release formulation, involving steps of aqueous granulation, drying, lubrication and punching of tablets.

In another aspect, present invention also provides twice a day i rimetazidine table dosage form.

Extended release or modified release tablet formulation can be in the form of single or multilayer tablets, capsule shaped oral dosage form, caplet, granules, disc, pellets, granules in capsule, mini-tablets in oral dosage form and other possible oral dosage form mean thereof.

In yet another embodiment, the solid oral dosage form can optionally include one or more pharmaceutically acceptable excipients.

The details of one or more embodiments in the practice of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.

Detailed Inscription Below description specify various scientific terms unless stated with context, 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 invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

Unless stated to the contrary. The feature 'ready-to-use', in the context of the present invention, is taken to mean the property that the composition according to the invention can be used directly for its purposes by the user by simply dispersing it in required quantity of water.

The term 'modified release' is in context of the invention as a way of active drug delivery where the rate of release of the active drug from the composition is not exclusively dependent on the concentration of active drug remaining in the dosage form and / or the solubility of the active drug in the liquid surrounding the composition, and where the time course with or without respective location of release of active drug from itn oral dosage form are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms. For the purpose of invention active drug is selected from Trimetazidine, its intermediates and derivatives thereof.

The term Trimetazidine' is in context of the invention includes its polymorphic forms, the pharmaceutically acceptable salts, including salts esters and pother chemical derivatives or intermediates etc. The solid pharmaceutical composition comprises Trimetazidine from 1 to 50 w/w % of dosage form.

The term 'dosage', 'solid pharmaceutical composition' may include one or more of tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet and the like. The solid pharmaceutical composition also includes multilayer tablets. The solid pharmaceutical compositions are meant for oral administration.

The term 'tablet' includes pharmaceutical compositions of all shapes and sizes, whether coated or uncoated.

The term 'Lubricant' in the context of the present invention, is taken to mean that an ingredient added to prevent the adhesion of tablet materials to the punches and dies, reduce inter-particle friction and facilitate the ejection of oral dosage forms from the die cavity. Lubricant of present invention includes but not limited to talc, magnesium stearate, stearic acid, sodium stearyl fumarate and there derivatives thereof.

The term 'Glidant' in the context of the present invention, is taken to mean that an ingredient which enhance product flow by reducing inter-particulate friction. Glidant can be used in present invention includes but not limited to silicon di-oxide. colloidal silicon dioxide and there derivatives thereof. It is available undei several brand names like AEROSIL® and CAB-O SiL®.

The term 'Solvent' in the context of the present invention, is taken to mean in- gredient that facilitate mixing of components in wel granulation process. Solvent can be used in present invention includes but not limited to Acetone, ethanol, methylene di chloride, isopropyl alcohol, water or their mixture thereof.

The term 'Binder' or 'Binding agent' in the context of the present invention, is taken to mean ingredient that facilitate binding of components in wet granulation process. Solvent can be used in present invention includes but not limited to polyvinyl polymers, Polyvinyl pyrrolidone K.30 (PVP K.30) and there derivatives thereof

The ready to use polymeric composition Instamodel A43D00046 for extended and modified release formulation was supplied by Ideal Cures Private Limited, Mumbai, www.idealcures.co.in . This product was used to create inventive dosage form having ideal modified release profile for twice a day administration.

According to inventors it was surprisingly found that extended release solid oral dosage form for trimetazidine can be created with ready to use Instamodel

(A43D00046) system and dosage form have advantageous modified release properties

The ready to use composition in accordance with present invention comprise INSTAMODEL.. (A43D00046). In one of the embodiment of present invention

Trimetazidine is formulated with ready to use composition to prepare modified release dosage form In accordance with present invention di fferent .salts, derivatives, polymorphs of trimetazidine could be combined to achieve ready-to-use composition to achieve extended or modified release dosage form.

In a dosage form according to the invention trimetazidine is aqueous granulated and blended with the ready to use polymer and the mixture is compressed to produce a solid formulation. The ingredients are blended to form a uniform powder and then compressed with means generally known to skilled in the art.

In yet another embodiment of present invention Trimetazidine and I NSTAMODEL are blended together with binding agent and thereafter wet granulated and dried. These dried granules are then processed in presence of lubricant and glidant, and thereafter compressed to form appropriate dosage form and finally coated.

In yet another embodiment of present invention Trimetazidine and I NSTAMODEL are blended together with binding agent and thereafter wet granulated and dried. T hese dried granules are then processed in presence of lubricant and glidant. and thereafter compressed to form appropriate dosage form and optionally coated.

This system of formulation uses simple and economic polymers hence cost effective to the customer. Another advantage of the present formulation is its robust and reproducible results for extended release dose form without batch to batch variations. Further by using aqueous solvent system for granulation dosage form does not have any residual solvent or hazardous effect found in many organic solvent based formulations.

Inventive dosage form may be prepared by blending Trimetazidine, their derivatives or combination thereof along with ready to use composition. Therefore inventive formulation preparation comprise steps as:-

1. Blending of ready to use formulation Instamodel (A43D00046) with

Trimetazidine.

2. Thorough mixing to form dry powder

3. Wet granulation with active drug and solvent

4. Sieving through appropriate size

5. Tray drying or fluidized bed drying

6. Optionally addition of lubricant

7. Final tablet compression

8. Optional film coating

According to one of the embodiment inventive dosage form is prepared by blending ready to use composition (Instamodel A43D00046), process blending is performed by conventional dry blender or a food processor or 'V-blender' or a similar function device. Further Trimetazidine are processed using aqueous solvent with binder through wet granulation or a similar wet mixing method to generate dosage formulation. Dosage formulation is further dried, sieved and compressed optionally with addition of lubricant, binder, glidant to form modified release or dosage form.

In one of the embodiment of present invention, inventive dosage formulations are prepared by blending Trimetazidine along with Instamodel (A43D00046). Initially all components are blended by conventional dry blending in a food processor or 'V- b lender' or a similar function device. Other solid oral dosage formulation components like binders, lubricants, glidants, detackifier, excipients can be added to create inventive formulation. Further mixture is then processed with appropriate quantity of aqueous solvent with binder and wet granulated. Obtained sieved granulated is then uniformly mixed with premeasured amount of the lubricant to improve industrial acceptability and oral dosage compression quality. Subsequently uniform mixed inventive formulation is compressed in standard pharmacopoeial. equipment to gel a controlled release oral dosage formulation of the correct desired weight and strength.

According to one of the main embodiment wherein hardness of tablets produced is in range of 7 Kg/cm- to 1 1 Kg/cm². In one of the embodiment oral dosage forms produced by inventive composition having human administrate active ingredient is suitable for human use. Alternatively drug suitable for veterinary purpose formulated in accordance with present composition will be suitable for veterinary use.

According to the objective of present invention Trimetazidine is formulated in oral dosage form for modified or extended release delivery. Inventive composition comprising 10, 35, 40 mg or 50 mg of in plurality of dosage formulations. Controlled release formulation can have combination of one or more additional drugs.

Suitable APIs that can be used with the present invention include, but are not limited to: andrenergic blocking agent; acetyl-chol in- esterase inhibitor; analgesic or antipyretics; angiotensin modulator; anthelmintic agents; anti anxiety agent; antibacterial; antibiotic; anticoagulant; anticonvulsant; antidepressant; antifungal; antihistamine; antimalarial; antimicrobial agent; antipsychotic agent; Antiviral agents: blood glucose lowering drug; calcium channel modulator; diuretic; erectile dysfunction; gastric acid secretion inhibitor; histamine H2-receptor antagonist; inhibitor of steroid Type II 5[alpha]- reductase including: lipid regulating agents; selective Hl- receptor antagonist; vasodilator; vitamins.

Following examples are offered to more fully illustrate the invention, but are not to be construed as limiting the scope thereof.

Mode for Invention

Example 1 .

Preparation of Trimetazidine modified release tablets (35mg)

The dosage formulation for 100,000 (21.00 kg) Tablets of Trimetazidine is prepared using composition as stated in table:- I wherein Trimetazidine is 3.50 kg and weighed accordingly, subsequently sieved to get uniformly granulated powder .through 40 mesh screen. It is noted that other size screen could be used to get similar results. Sieved Trimetazidine is blended with 16.40 kg of ready to use (nstamodel

(A43D00046) in blender for 15 minutes (e.g. RMG granulator). Solvent system for wot granulation is prepared by taking 0.84 kg PVP K -30 in 3.50 kg of I PA , in RMG granulator in low to medium speed in the duration of 10 minutes followed by 2 - 3 minutes of high speed. Further if process requires more IPA then in can be added in wet granulation step.

Table 1

Generated wet mass is sieved using 1.0 mm screen (Multi-mill/ Filzmill) dried in tray drier (or Fluidized bed dryer) at temperature not more than 45°C keeping loss on drying ar 1 -2%. To promote efficient tablet pouching further 0. 12 ky of Colloidal silicon dioxide and 0.14 kg of magnesium, stearate sieved through 40 mesh screen is added to above dried blended formulation in blender for subsequent > minutes. Final screened granules are compressed using 8 mm (for 210 mg strength at 300 mg average weight) circular, standard concave punches using Karnavati Tablet Compression Ml C-17 Stn. GMP machine at hardness not less than 8- 10 kg/cm- Generated dosage form tablets are then subjected to film coating using Instacoat Universal. Coating composition is weighed in accordance with table I and 1 1% coating suspension is prepared in water with stirrer and mixed for about 45 minutes subsequently it is passed through 80 mesh screen. Coating is preformed on dosage form using INSTACOAT Pharma RnD coater (6' pan) at 25 rpin with inlet temperature being 53 °C and bed tem perature at 40 °C. coating was done using I mm nozzle sprayer with peristaltic pump injecting coating suspension at the rate of I ml/min. Coated tablets are then dried and packed as per pharmacopoieal guidelines.

Example 2

Dissolution Profile Evaluation of 1 rimetaztdine tablet

Trimetazidine dose form dissolution study was performed. Drug dissolution profiles of tablet prepared are measured by USP 35 dissolution test of rotating basket method <71 1>. It is evident from standard state of the art that active ingredient may have its own dissolution testing parameters which can be found in their respective monographs. The active ingredient content for present invention is standardized for sustained release profile is as per table 2:-

Medium: Phosphate buffer pH 6.8; 500 ml

Time interval: 1, 2, 6, and 10 hour

Table 2

It was observed that it shows maximum absorbance at 27/0.4 rim on Double Beam U V-V!S Spectrophotometer (UV 2700- Thermo Fisher Scientific).

Following are the absorbance value obtained for the above mentioned standard plot: .

[57] IN VITRO DISSOLUTION COMPARISON

[58]

The drug dissolved profile of the Reference products and Trimetazidine having dose strength of 35 mg using Instamodei (A43D00046) formulations are compared. The release exponents for the Reference and formulated trimetazidine is found to be having similar modified release profile indicating a predominantly diffusion based drug release mechanism.

Claims

A modified release solid pharmaceutical composition comprising Trimetazidine, Instamodel (A43D00046), binder, lubricant, glidant optionally opacifiers, colorants.

The solid pharmaceutical composition of claim I , wherein Trimetazidine can be in form of salt, hydrochloride, polymorphic form, its derivatives or mixture thereof.

The solid pharmaceutical composition of claim I , wherein binder is selected from polyvinyl polymers, Polyvinyl pyrrolidone K.30 (PVP K.30) and like. The solid pharmaceutical composition of claim 1 , wherein lubricant is selected from talc, magnesium stearale, stearic acid, sodium stearyl fumarate and combination thereof.

The solid pharmaceutical composition of claim 1 , wherein glidant is selected from silicon di-oxide, colloidal silicon dioxide and there derivatives thereof. A process for preparing trimetazidine tablet according to claim 1 comprising a. Blending Instamodel (A43D00046) with Trimetazidine.

b. Thorough mixing and Wet granulation with binder and solvent c. Sieving and drying

d. Addition of lubricant and glidant

e. Final tablet compression

f. Optional film coating

The solid pharmaceutical composition prepare using process for preparing trimetazidine tablet according to claim 1 comprising

a. Blending Instamodel (A43D00046) with Trimetazidine.

b. Thorough mixing and Wet granulation with binder and solvent c Sieving and drying

d. Addition of lubricant and glidant

e. Final tablet compression

f. Optional film coating