WO2016042569A1

WO2016042569A1 - Extended release formulation of diclofenac

Info

Publication number: WO2016042569A1
Application number: PCT/IN2014/000604
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 Diclofenac dosage forms and its salts and derivatives thereof, a process for preparing extended release tablet using INSTAMODEL (A43D00040) 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 Diclofenac at various dosage strength, a process for production thereof and also use thereof as formulated pharmaceutical compositions.

Description

EXTENDED RELEASE FORMULATION OF DICLOFENAC

Technical Field

[1] The present invention relates to a dry ready to use modified release dosage formulation for Diclofenac dosage forms and its salts and derivatives thereof, a process for preparing extended release tablet using INSTAMODEL (A43D00040) 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 Diclofenac at various dosage strength, a process for production thereof and also use thereof as formulated pharmaceutical compositions.

Background Art

[2] In general Diclofenac are indicated for use as non-steroidal anti-inflammatory drug

(NSAID). Diclofenac is a non-steroidal anti-inflammatory agent (NSAID) with predominantly analgesic actions. Diclofenac sodium is a benzeneacetic acid derivative. It is used for the relief of pain and inflammation in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. It is a cytokine inhibitor. Diclofenac works by blocking the action of a substance in the body called cyclo-oxygenase. Cyclo-oxygenase is involved in the production of prostaglandins (chemicals in the body) which cause pain, swelling and inflammation. It belongs to class II of the biopharmaceutical classification (BCS) in which dissolution rate is the controlling step in daig absorption. Diclofenac is known for Anti-inflammatory and Analgesic action. It is poorly soluble in water leading to erratic dissolution, oral absorption and therefore poor bioavailability is also observed.

[3] Diclofenac is administered through solid dosage ranges from 100 mg to 75 mg daily. In standard doses of 100 mg is taken in daily. Prescription of Diclofenac recommend that it should be taken with meals if possible and daily. Dosage generally should not exceed 100 mg daily.

[4] It is generally known that diclofenac sodium migrates into blood within 30 minutes and reaches the maximum concentration in blood within 2 hours after oral administration and the blood concentration half-life is as short as 1.3 hours. Since diclofenac sodium is quickly absorbed in and excreted from blood, it is difficult to maintain in blood for a long time. For this reason, currently commercially available diclofenac sodium tablets must be taken three times a day. In addition, it has been reported that oral administration of diclofenac sodium would often induce various side effects including gastroenteritis. Therefore, there is a strong need for a long acting preparation which can sustain the action of diclofenac sodium in safe over an extended period of time. In state of the art modified release compositions are developed to provide relatively constant drug plasma levels and sustained efficacy for longer period of time. In principle aim of extended and modified release composition is to get required therapeutic concentration of the active in the blood stream and maintain its therapeutic concentration without deviation from strength during specified period. US 4968505, US 2002051817, WO 199702017, WO 199524188 and WO 201 10361 14 are some of the prior art documents disclosing modified release compositions of diclofenac for its release over a long time.

In state of art various grades of cellulosic 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 Diclofenac.

In theory it is known that with high viscosity grade polymer after attaining gelling effect daig 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 to 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 composition which are convenient to handle.

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

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 Diclofenac Hydrochloride using INSTAMODEL (A43D00040) manufactured by Ideal Cures Private Limited Mumbai India.

Accordingly, the present invention also provides method for making ready to use Diclofenac modified or extended release formulation, involving steps of aqueous granulation, drying, lubrication and punching of tablets.

In another aspect, present invention also provides Once a day Diclofenac 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 Discription

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 an 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 Diclofenac, its intermediates and derivatives thereof.

The term 'Diclofenac' 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 Diclofenac 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 under several brand names like AEROSIL® and CAB-O-SIL®.

The term 'Solvent' in the context of the present invention, is taken to mean ingredient that facilitate mixing of components in wet granulation process. Solvent can be used in present invention includes but not limited to Acetone, ethano!, 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 dextrin and their derivatives, maltodextrin, polyvinyl polymers, Polyvinyl pyrrolidone K30 (PVP K30) and there derivatives thereof.

The ready to use polymeric composition Instamodel A43D00040 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 Once a day administration.

According to inventors it was surprisingly found that extended release solid oral dosage form for Diclofenac can be created with ready to use Instamodel (A43D00040) system and dosage fonn have advantageous modified release properties. The ready to use composition in accordance with present invention comprise INSTAMODEL (A43D00040). In one of the embodiment of present invention Diclofenac is formulated with ready to use composition to prepare modified release dosage form. In accordance with present invention different salts, derivatives, polymorphs of Diclofenac 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 Diclofenac is blended with the ready to use polymer and aqueous granulated further the granulated 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 Diclofenac and INSTAMODEL 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 Diclofenac and INSTAMODEL 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 fonn appropriate dosage form and optionally coated. [31 ] 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.

[32] Inventive dosage form may be prepared by blending Diclofenac, their derivatives or combination thereof along with ready to use composition. Therefore inventive formulation r>rf>naratinn cnmnritip stens ης·-

[33]

1. Blending of ready to use formulation Instamodel (A43D00040) with Diclofenac .

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

[34] According to one of the embodiment inventive dosage form is prepared by

blending ready to use composition (Instamodel A43D00040), process blending is performed by conventional dry blender or a food processor or 'V-blender' or a similar function device. Further Diclofenac 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 oral dosage form.

[35] In one of the embodiment of present invention, inventive dosage formulations are prepared by blending Diclofenac along with Instamodel (A43D00040). Initially all components are blended by conventional dry blending in a food processor or 'V- blender' 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 get a controlled release oral dosage formulation of the correct desired weight and strength.

[36] According to one of the main embodiment wherein hardness of tablets produced is in range of 5 Kg/cm² to 15 Kg/cm². In one of the embodiment oral dosage forms produced by inventive composition having human administrable 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 Diclofenac is formulated in oral dosage form for modified or extended release delivery. Inventive composition comprising 50, 75, 100 mg or 200 mg of Diclofenac in plurality of dosage formulations. Controlled release formulation can haye 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; acety!-cho!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.

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

Mode for Invention

[40] Example 1 .

[41] Preparation of Diclofenac modified release tablets (100 mg)

[42] The dosage formulation for 100,000 (30.00 kg) Tablets of Diclofenac is prepared using composition as stated in table:- 1 wherein Diclofenac is 10.0 kg and 19.70 kg of Instamodel (A43D00040) are weighed, sifted in rapid mixture granulator 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 Diclofenac with above ingredients is granulated using 80 parts of IP A in 20 parts of water as granulating solvent in rapid mixture granulator (RMG) . It is recommended that RMG should be at slow speed for 15 min followed by high speed for 3-5 mins. Granulation step requires proper optimization of water quantity and continuous monitoring to avoid heavy granulation. If required extra water can be added gradually under continuous observation (to avoid heavy wet mass). Generated wet mass is sieved using 4mm screen (Multi-mill/ Fitzmill) dried in tray drier (or Fluidized bed dryer) at temperature not more than 50°C-55°C keeping loss on drying at 1 -2%.

Subsequently sift the dried granule using #30 mesh sieve on vibratory sifter and again sift on 1.0 mm screen at slow speed.

Table 1 Quantity for Batch size

Formulation Composition

of 100,000 Tabs.

ingredients

% /w mg/ tablet Kg

Diclofenac 33.33% 100.0 10.00

Instamodel

65.67 % 197.0 19.70

(A43D00040) IH

EPA : Water :: 80 : 20 q. s. q.s. 21.00

Magnesium S tea rate,

1.00 % 3.0 00.30

USPNF/BP/Eur. Ph

Total 100.00 300.0 30.00

To promote efficient tablet punching further 0.30 kg of magnesium stearate sieved through 60 mesh screen is added to above dried blended formulation in blender for subsequent 5 minutes. Final screened granules are compressed using 10.0 mm (for 300 mg average weight) circular, standard concave circular punches using Karnavati Tablet Compression M/C-17 Stn. GMP machine at hardness not less than 10- 15 kg/cm². Generated dosage form tablets are then subjected to film coating using Instacoat Universal. Coating composition is weighed in accordance with table 1 and 1 1% coating suspenstion is prepared in water with stirrer and mixed for about 45 minutes subsequently it is passed through 80 mesh screen.¹ Coating is preformed on dosage form using INSTACOAT Pharma RnD coater (6' pan) at 25 rpm with inlet temperature being 53 °C and bed temperature at 40 °C. coating was done using 1 mm nozzle sprayer with peristaltic pump injecting coating suspension at the rate of l ml/min. Coated tablets are then dried and packed as per pharmacopoieal guidelines.

Example 2

Dissolution Profile Evaluation of Diclofenac tablet

Diclofenac 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: 0.05 M Phosphate buffer pH 7.5; 900 ml Time interval: 1 , 4 and 8 hour

Table 2

It was observed that it shows maximum absorbance at 284 nm on Double Beam UV-VIS Spectrophotometer (UV 2700- Thermo Fisher Scientific).

DICLOFENAC IN VITRO % DRUG RELEASE USING INSTAMODEL (Α43Ρ0004(Γ) DISSOLUTION COMPARISON

Dissolution Comparison study for Voveran SR 100 Tablets v/s Prololnged Release DiclofenacTablets 100 m g using Instam odel

0 1 2 3 4 5 6 7 8 9 10

Time in Hrs

The drug dissolved profile of the Reference products and Diclofenac having dose strength of 100 mg using Instamodel (A43D00040) formulations are compared. The release exponents for the Reference and formulated Diclofenac 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 Diclofenac, In- stamodel (A43D00040), solvent, binder, lubricant, glidant optionally opacifiers, colorants.

The solid pharmaceutical composition of claim 1 , wherein Diclofenac can be in form of salt, polymorphic form, its derivatives or mixture thereof.

The solid pharmaceutical composition of claim 1 , wherein binder is selected from polyvinyl polymers, Polyvinyl pyrrolidone K30 (PVP K30) and like.

The solid pharmaceutical composition of claim 1 , wherein solvent is selected from water, isopropyl alcohol and like.

The solid pharmaceutical composition of claim 1 , wherein lubricant is selected from talc, magnesium stearate, 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 Diclofenac tablet according to claim 1 comprising

a. Blending Instamodel (A43D00040) with Diclofenac.

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 Diclofenac tablet according to claim 1 comprising

a. Blending Instamodel (A43D00040) with Diclofenac.

_. d. Addition of lubricant and glidant

e. Final tablet compression.

f. Optional film coating.