FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
ORALLY DISSOLVING COMPOSITIONS OF RHEIN OR DIACEREIN OR
SALTS THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad -431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides an orally dissolving pharmaceutical composition in the form of film or strips, comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutically acceptable excipients.
The following specification particularly describes the invention and the manner in which it is to be performed.


4. Description
The present invention provides an orally dissolving pharmaceutical composition in the form of film or strips, comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutically acceptable excipients.
Chemically, rhein is 9,10-dihydro-4, 5-dihydroxy-9, 10-dioxo-2-anthracene carboxylic acid having a structure of Formula I and diacerein is 4,5-bis (acetyloxy) 9,10-dihydro-4, 5-dihydroxy-9, 10-dioxo-2-anthracenecarboxylic acid having a structure of Formula II. Diacerein is used particularly in the treatment of osteoarthritis. Diacerein has a unique mode of action that differentiates it from non-steroidal anti-inflammatory drugs (NSAIDs) and other conventional forms of drug therapy.

FORMULA I
o
COOH

H3C^^O O O^^CH3

FORMULA II
Diacerein is practically insoluble in the solvents compatible with a pharmaceutical use, such as water, alcohols, acetone, dichloromethane and chloroform. Although diacerein can be administered by oral route but it cannot be completely absorbed by the digestive tract, and this incomplete absorption may result in undesirable side effects such as laxatives effects.
In order to overcome these problems, various derivatives, pharmaceutical compositions and specific galenic forms have been proposed in the literature. For example, European patent, EP 243,968 discloses a potassium salt of diacerein, which is water-soluble and can be used in the preparation of compositions for parenteral administration.
EP904060B1 discloses pharmaceutical compositions of rhein or diacerein, wherein rhein or diacerein is co-micronized with sodium lauryl sulfate.
European Patent Nos. EP263083B1; EP 264989B1 and EP 446753B1 disclose controlled release or delayed release compositions like multiplicity of pellets coated with drug and coating membrane or granules of drug coated with polymers or loading polymeric particles of water swellable cross-linked polymer with drug.
U.S. Patent Nos. 5,225,192 and 5,569,469 describe different poorly soluble medicaments supported on polymeric particles of water swellable cross-linked polymer with drug.
U.S. Patent No. 5,952,383 and European Patent No. EP 862423B1 provide pharmaceutical compositions of diacerein, rhein and their salts along with liquid support systems like oils, suspending agents, homogenizing agents and other excipients.


Current dosing of diacerein is twice a day using immediate release capsule (Art 50). The capsule forms, are however difficult to swallow, especially for geriatric patients. Further, the fear of swallowing, or choking on such solid shaped articles is still a concern in certain populations especially geriatrics. It is estimated that almost 50% of the population have problems of swallowing tablets or capsules (Seager in Journal of Pharmacol. And Pharm. Pages 375-382, 1998). Capsule dosage forms become sticky when wetted by saliva, and if patient experiences difficulty in swallowing on first attempt, then the capsule must often be discarded. Furthermore, if a capsule partially dissolves in patient's mouth, as can result from unsuccessful swallowing or the capsule getting stuck in the orthodontic appliance, the resulting very unpleasant taste can make it difficult to persuade the patient to take another dose. Additionally, these dosage forms are difficult to carry, store and handle. Moreover, the difficulties associated with capsules result in decreased patient compliance. Orally dissolving formulations of rhein or diacerein are beneficial for many reasons. Their characteristic advantage such as administration without liquid, anywhere, anytime lead to their suitability in situations where patients have difficulty in swallowing especially geriatrics and particularly those with neurological disorders.
The concept of oral thin films or strips is of particular advantage over even orally dissolving tablets dosage form due to the special features of thin films or strips such as thin elegant film lead to convenient dosing; thin films or strips are unobstructive hence no risk of choking; and more fast disintegration and hence rapid release.
The concept of oral films comprising certain pharmaceutically active substances is well known in the art since long, e.g. U.S. Pat. No. 4,136,162 (Fuchs and Hilmann, priority 1974). It is therefore remarkable that such oral dosage forms have hardly been commercialized during the last 30 years. Till date, there are no prescription products in market based on oral thin film or strips. This is attributed


to a lot of technical and other obstacles, e.g. stability issues, that had to cleared before one could think of commercializing a said product.
It was a significant challenge to obtain suitable oral films comprising rhein or diacerein according to the invention because quite a number of issues had to be accommodated: High bioavailability of diacerein had to be ensured, high drug loading, the oral film had to be palatable to the patient and its stability, especially the chemical stability of the active substance within the oral film, had to be assured. Moreover, good organoleptic properties, such as an immediate softening of the film to prevent any adverse feeling in the mouth, and sufficient strength to allow for appropriate cutting and packaging operations, were required. The inventors have overcome this challenge by providing rhein or diacerein comprising oral films meeting said requirements.
One of the aspects of the present invention provides an orally dissolving pharmaceutical composition in the form of film or strips, comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutically acceptable excipients.
Another aspect of the present invention provides an orally dissolving pharmaceutical composition in the form of film or strips, comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutically acceptable excipients; wherein the composition exhibits a dissolution profile such that within 30 minutes more than 80% of rhein or diacerein or salts or esters or prodrug thereof is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 75 rpm) using 1000 ml of pH 5.7 phosphate buffer at 37 °C ± 0.5°C.
In another aspect of the present invention, there is provided a process of preparing pharmaceutical composition in the form of film or strips, which process comprises of dissolving or dispersing film-forming polymers and other pharmaceutically acceptable excipients in aqueous medium, mixing rhein or


diacerein or salts or esters or prodrugs thereof in said mixture and finally casting the mixture into films of suitable size.
The film or strips of the invention disintegrate in mouth of patient in less than 45 seconds, preferably in less than 30 seconds.
The films or strips of the invention have a thickness of 1mm or less, preferably of 0.5mm or less. Further, the films of the invention are not limited to any particular size and may be rectangular, square, or round. The film or strips of the invention may or may not be mucoadhesive in nature.
Rhein or diacerein or salts or esters or prodrug thereof are present in the film either in dissolved or uniformly dispersed state.
The films or strips of the invention may be prepared by hot-melt extrusion, solid dispersion extrusion, rolling, semi-solid casting and solvent coating.
The film or strips of the invention comprises of at least one pharmaceutically acceptable film-forming polymer.
Pharmaceutically acceptable polymers may include one or more of film forming polymers such as methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phtalate, cellulose acetate butyrate, amylose, dextran, casein, pullulan, gelatine, pectin, chitin, chitosan, elsiman, zein, gluten, soy protein isolate, whey protein isolate, agar, carrageenan, xanthan gum, tragacanth, guar gum, acacia gum, arabic gum, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, cyclodextrin, carboxyvinyl polymers, polycarbophils, sodium alginate, polyacrylic acid, methylmethacrylate and the like.


The film or strips of the invention comprises of pharmaceutically acceptable excipients wherein excipients may include one or more of plasticizers, emulsifiers, sweeteners, and flavors.
Suitable plasticizer may include one or more of, polyethylene glycol, propylene glycol, glycerin, monoacetin, diacetin, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl titrate, tributyl citrate, triethyl citrate, triethyl acetyl citrate, castor oil, acetylated monoglycerides, sorbitol and the like.
Suitable emulsifiers are those known to ordinary skill in the art and include but not limited to one or more of polyoxyethylene glycerol esters of fatty acids, such as Tagats; polooxylated castor oil, ethylene glycol esters, such as glycol stearate and distearate; propylene glycol esters, such as propylene glycol myristate; glyceryl esters of fatty acids, such as glyceryl stearates and monostearates; sorbitan esters, such as spans and tweens; polyglyceryl esters, such as polyglyceryl 4-oleate; fatty alcohol ethoxylates, such as Brij type emulsifiers; ethoxylated propoxylated block copolymers, such as poloxamers; polyethylene glycol esters of fatty acids, such as Labrafils, Labrafacs, and Labrasols; cremophores; glycerol monocaprylate/caprate, such as Campmul CM 10; Gelucire, Capryol, Captex, Acconon, transcutol, triacetin, vitamin E TPGS and the like.
Suitable sweetener may include one or more of monosaccharides, disaccharides and polysaccharides, e.g. xylose, ribose, glucose, mannose, galactose, fructose, sucrose, maltose, invert sugar, partially hydrolyzed starch, corn syrup solids, mannitol xylitol, D-sorbitol, erythritol, pentitol, hexitol, malitol, dihydrochalcones, monellin, steviosides or glycyrrhizin;. saccharin in free acid form, soluble saccharin salts, e.g. sodium or calcium saccharin salts, cyclamate salts or acesulfame K; dipeptide based sweeteners, such as L-aspartic acid derived sweeteners, e.g. aspartame; water-soluble sweeteners derived from naturally


occurring water-soluble sweeteners, e.g. sucralose; and protein based sweeteners, e.g. thaumatococcus danielli (Thaumatin I and II) and the like.
Suitable flavoring agents may include those known to the skilled artisan, such as natural, "natural-like" and artificial flavors. These flavors may be chosen e.g. from synthetic flavor oils, flavoring aromatics, oleo-resins and extracts derived e.g. from plants, leaves, flowers or fruits.
Representative flavors may include one or more of spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, vanilla, chocolate, coffee, cocoa and citrus oil, lemon, orange, cherry, grape, lime or grapefruit, and fruit essences, e.g. apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple or apricot; mints such as peppermint (including menthol, especially levomenthol), aldehydes and esters, e.g. cinnamyl acetate, cinnamaldehyde, citral, diethylacetal, dihydrocarvyl acetate, eugenyl formate or p-methylanisol; alpha-citral (geranial) and beta-citral (neral); decanal; ethyl vanillin; piperonal (heliotropine); vanillin; alpha-amyl cinnamaldehyde; butyraldehyde; valeraldehyde; citronellal; decanal; aldehyde C-8; aldehyde C-9; aldehyde C-12; 2-ethyl butyraldehyde; hexenal, i.e. trans-2; tolyl aldehyde; veratraldehyde; 2,6-dimethyl-5-heptenal (melonal); 2-6-dimethyloctanal; 2-dodecenal and the like.
Moreover, the films of the invention optionally include usual auxiliaries known in the art such as saliva stimulating agents like citric acid, lactic acid, malic acid, succinic acid, ascorbic acid, adipic acid, fumaric acid, tartaric acids; cooling sensation agents like maltitol, monomenthyl succinate, ultracool; fillers like saccharose, glucose, fructose, maltose, maltitol, mannitol, dextrins such as maltodextrins; xylitol, sorbitol, microcrystalline cellulose, titanium dioxide; stabilizers like gums, agar; coloring agents like titanium dioxide, natural food colors, dyes suitable for food, drug and cosmetic applications; disintegration agents like croscarmellose sodium; preservatives like alpha-tocopherol, citric


acid, butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, fumaric acid, malic acid, sodium ascorbate or ascorbic acid palmitate or pH regulators like sodium bicarbonate, sodium carbonate; antitacking agents like talc, magnesium stearate, sodium stearyl fumarate, stearic acid etc.
The pharmaceutical film composition of the invention may be prepared by dissolving film-forming polymers and other pharmaceutically acceptable excipients, mixing rhein or diacerein or salts or esters or prodrugs thereof in said mixture and finally casting the mixture into films or strips of suitable size.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.


Example 1
Table 1 provides the composition of batches of the present invention.
Table 1

S. No. Ingredient % w/w
1. Diacerein 5-20
2. Pullulan 5-15
3. HPMC 5-15
4. Luster clear 5-15
5. Carrageenan 0.1-5
6. Xanthan Gum 0.1-5
7. Locust Bean Gum 0.1-5
8. Maltodextrin 5-15
9. Xylitol 5-15
10. Propylene Glycol 0.5-5
11. Glycerin 0.5-5
12. Tween 80 0.5-5
13. Olive Oil 0.5-5
14. Sucralose 5-10
15. Acesulfame potassium 0.5-5
16. Peppermint flavor 10-25
17. Menthol 0.5-5
18. Orange-vanilla flavor 0.5-5
19. Water q.s.
Procedure: Pullulan, HPMC, lusterclear, carrageenan, locust bean gum & xanthan gum were added to purified water with continuous stirring and allowed to dissolve completely. Sucralose, xylitol, acesulfame potassium, maltodextrin, orange vanilla flavor & peppermint flavor were added to above mixture and stirred for few minutes. Tween-80, propylene glycol, glycerin, olive oil and menthol were mixed and added to above mixture and stirred for few minutes. Diacerein was added to above mixture and stirred for few minutes. The final mixture thus obtained was casted into films of suitable size.


Example 2
Table 2 provides the composition of batches of the present invention.

s.No. Ingredients (% w/w)
1 Diacerein 5-20
2 Xanthan gum 0.1-5
3 Locust bean gum 0.1-5
4 Carrageenan 0.1-5
5 HPMC 5-15
6 CMC Sodium 1-5
7 Pro sweet 1-5
8 Sucralose 5-10
9 Mannitol 5-15
10 Water q.s.
11 Maltitol 5-15
12 Menthol 0.5-5
13 Mixed Fruit Flavour 0.5-5
14 Polysorbate 80 0.5-5
15 Vitamin E TPGS 0.5-5
16 Glycerin 0.5-5
17 Olive oil 0.5-5
Procedure: Vitamin E TPGS was added to water having temp 40-50°c and stirred for few minutes. ProSweet, sucralose, xanthan gum, locust bean gum and carrageenan, HPMC, CMC Sodium were added to TPGS solution under continuous stirring. The mixture was stirred for few minutes. Diacerein was added to above mixture and the above mixture was allowed to stir for few minutes (Mixture A). Glycerin was heated to about 40-50°C and menthol was added to it and allowed to dissolve by stirring (Mixture B). Olive oil, mixed fruit flavour and polysorbate 80 were added to mixture B to form mixture C. Mixture C was added to mixture A under continuous stirring (Mixture D). Mixture D was casted into films of suitable size.


Example 3
Table 3 provides the composition of batches of the present invention.

S.No. Ingredients (% w/w)
1 Diacerein 5-20
2 HPMC 5-15
3 Sucralose 5-10
4 Water q.s.
5 Ethanol q.s.
6 Menthol 0.5-5
7 Mixed Fruit Flavour 0.5-5
8 Peppermint Flavour 0.5-5
9 PEG 400 0.5-5
10 Vitamin E TPGS 0.5-5
11 Glycerin 0.5-5
Procedure: Vitamin E TPGS was added to water having temp 40-50°c under continuous stirring. The mixture was stirred for few minutes (Mixture A). Sucralose, peppermint flavour and HPMC were added to ethanol under continuous stirring. The mixture was stirred for few minutes (Mixture B). Mixture B was added to Mixture A under continuous stirring (Mixture C). Diacerein was added to Mixture C and allowed to stir for few minutes (Mixture D). Glycerin was heated to about 40-50°C and menthol crystals were added to it and allowed to dissolve by stirring (Mixture E). Mixed fruit flavour and PEG 400 were added to the mixture E (Mixture F). Mixture F was added to Mixture B under continuous stirring and stirred for few minutes (Mixture G). Mixture G was casted into films of suitable size.


WE CLAIM:
1) An orally dissolving pharmaceutical composition in the form of film or strips comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutically acceptable excipients.
2) An orally dissolving pharmaceutical composition in the form of film or strips comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutically acceptable excipients; wherein the composition exhibits a dissolution profile such that within 30 minutes more than 80% of rhein or diacerein or salts or esters or prodrug thereof is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 75 rpm) using 1000 ml of pH 5.7 phosphate buffer at 37 °C ± 0.5°C.

3) The film of claim 1 or 2, wherein the film comprises at least one pharmaceutically acceptable film forming polymer.
4) The film of claim 3, wherein the pharmaceutically acceptable film forming polymer comprises one or more of methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phtalate, cellulose acetate butyrate, amylose, dextran, casein, pullulan, gelatine, pectin, chitin, chitosan, elsiman, zein, gluten, soy protein isolate, whey protein isolate, agar, carrageenan, xanthan gum, tragacanth, guar gum, acacia gum, arabic gum, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, cyclodextrin, carboxyvinyl polymers, sodium alginate, polyacrylic acid, and methylmethacrylate.


4) The film of claim 1 or 2, wherein the said film disintegrates in mouth of patient in less than 45 seconds.
5) The film of claim 1or 2, wherein the said film has a thickness of 1mm or less.
6) The film of claim 1 or 2, wherein the other pharmaceutically acceptable excipients comprises one or more of plasticizers, emulsifiers, sweeteners, and flavors.
7) The film of claim 6, wherein plasticizer comprises one or more of polyethylene glycol, propylene glycol, glycerin, glycerol, monoacetin, diacetin, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl titrate, tributyl citrate, triethyl citrate, triethyl acetyl citrate, castor oil, acetylated monoglycerides, and sorbitol.
8) The film of claim 6, wherein the emulsifiers comprises one or more of polyoxyethylene glycerol esters of fatty acids, polooxylated castor oil, ethylene glycol esters, propylene glycol esters, glyceryl esters of fatty acids, sorbitan esters, polyglyceryl esters, fatty alcohol ethoxylates, ethoxylated propoxylated block copolymers, polyethylene glycol esters of fatty acids, glycerol monocaprylate/caprate, Gelucire, Capryol, Captex, Acconon, transcutol, vitamin E TPGS and triacetin.
9) A process of preparing pharmaceutical composition, in the form of film or strips comprising rhein or diacerein, or salts or esters or prodrug thereof, which process comprises of dissolving or dispersing film-forming polymers and other pharmaceutically acceptable excipients, mixing rhein or diacerein or salts or esters or prodrugs thereof in said mixture and casting the said mixture into films or strips of suitable size.


10) An orally dissolving pharmaceutical composition substantially as herein described.

ABSTRACT
The present invention provides an orally dissolving pharmaceutical composition in the form of film or strips, comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutical ly acceptable excipients. The invention also relates to the process of preparation of such compositions.