FORM 2 THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003 Provision
COMPLETE SPECIFICATION
(See section 10 and rule!3)


1. TITLE OF THE INVENTION:
RAPID DISSOLVING COMPOSITIONS CONTAINING TADALAFIL
2. APPLICANT (S):
(a) NAME: AJANTA PHARMA LIMITED.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Ajanta House, Charkop, Kandivalj (West),
Mumbai - 400 067.
Provisional
The following specification describes the invention.

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Field of the Invention:
The present invention discloses a composition containing tadalafil in the form of rapid dissolving film for administering via mucous membranes for the treatment of sexual dysfunction.
Background of the Invention:
Erectile dysfunction (ED) is a common form of male sexual dysfunction.
Tadalafil was developed by Eli Lilly as a treatment for impotence and is currently marketed as Cialis . Tadalafil (Cialis®) is an orally administered phosphodiesterase type-5 (PDE5) inhibitor.
Sexual stimulation causes the local release of nitric oxide, which plays a central role in the vasodilatation of erectile tissues by stimulating guanylyl cyclase activity, consequently raising intracellular concentrations of cyclic guanosine monophosphate (cGMP) and relaxing vascular smooth muscle. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Thus tadalafil is indicated for the treatment of erectile dysfunction.
Chemically tadalafil is (6R,12aR)-,6-(l,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methy]pyrazino-[ 1 \2'\ 1,6]pyrido[3,4-b]indole-1,4-dione (CAS No. 171596-29-5). The chemical structure of tadalafil can be represented as Formula I.
Tadalafil is practically insoluble in water and only slightly soluble in methanol, ethanol and acetone. It does not possess any ionisable groups in the pH range of 1-11 and, subsequently, does not demonstrate any changes in solubility in aqueous buffers in that range. It is freely soluble only in solvents such as dimethylsulfoxide and dimethylformamide.
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(I) Cialis® is a film-coated tablet contains 10 mg or 20 mg of tadalafil as active ingredient. The inactive ingredients present in these tablet formulation are lactose monohydrate, hydroxypropylcellulose, sodium laurylsulfate, croscarmellose sodium, microcrystalline cellulose and magnesium stearate (vegetable source), and Opadry II Yellow.
Published International Patent Application WO 01/08686 discloses tablet and capsule formulations comprising tadalafil as a free drug, in admixture with a diluent, a lubricant, a hydrophilic binder, a disintegrant.
Generally, solid dosage forms such as tablets, pills and capsules which are administrated orally are to be swallowed whole or chewed to deliver the medication with adequate amounts of liquid. Some patients, particularly pediatric and geriatric patients, have difficulty swallowing or chewing solid dosage forms. Traditional tablets and capsules administered with a 200-300 mL of water may be inconvenient or impractical for some patients.
Compounds having low water solubility can have a low rate of dissolution and low bioavailability. See, e.g., Ansel et al.. Pharmaceutical Dosage Forms and Delivery Methods (6th ed., 1995), p. 105, 108.
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Many active agents are poorly absorbed, even after they are dispersed in the stomach, because of low solubility or slow dissolution rate in the gastric fluids. Tablets may be formulated so as to be quick dissolving. These tablets are commonly placed on the tongue and disintegrate rapidly in the oral cavity. However, these tablets may have poor mechanical strength, are fragile and friable, and have insufficient holding capacity for active ingredients (US Patent No. 5,720,974) and may be difficult to store and handle.
Co-precipitation technique has been described in US Patent No. 5,985,326 to improve the solubility of poor water soluble drugs.
US Patent Nos. 5,948,430 and 6,552,024 discloses mucoadhesive film compositions. However, the film described in these patents relies on the use of at least one surfactant.
Traditional oral dosages, such as tablets, are limited in onset time by the rate of absorption in the gastro-intestinal tract. For many types of active agent, fast onset of the therapeutic effect is desirable. The mucoadhesive film when applied in the mouth, lead to faster onset because they target the oral mucosa.
The present invention discloses a surfactant-free composition containing tadalafil in the form of rapid dissolving film for administering via mucous membranes particularly the oral mucosa for the treatment of erectile dysfunction.
Object of the Invention:
One object of the present invention is to provide a pharmaceutical composition containing tadalafil in the form of rapid dissolving film for administering via mucous membranes particularly the oral mucosa.
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Another object of the present invention is to provide a pharmaceutical composition comprising one or more water soluble polymers, and tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof.
Yet another object of the present invention is to provide a process for the preparation of a pharmaceutical composition comprising one or more water soluble polymers, and tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide a pharmaceutical composition in the form of rapid dissolving film comprising one or more water soluble polymers, and tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof, wherein the said film is substantially free from surfactant.
Summary of the Invention:
In one aspect, the present invention relates to a pharmaceutical composition in the form of rapidly dissolving film containing tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof which may adhere to the oral mucosa thereby releasing the active agent.
In another aspect, the present invention relates to a pharmaceutical composition in the form of rapidly dissolving film which comprises of one or more water soluble polymers, and tadalafil or its isomers, enantiomers, pharmaceutical ly acceptable salts thereof.
Another aspect of the invention is to provide a pharmaceutical composition in the form of rapidly dissolving film comprising one or more water soluble polymers, tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.
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Yet another aspect of the invention is to provide a process for the preparation of a pharmaceutical composition in the form of rapidly dissolving film comprising one or more water soluble polymers, tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.
Another aspect of the invention is to provide a pharmaceutical composition in the form of rapid dissolving film comprising one or more water soluble polymers, and tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof, wherein the said film is substantially free from surfactant.
Detailed Description of the Invention:
According to one particular aspect of the invention there is provided a pharmaceutical composition in the form of rapidly dissolving film containing tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof which may adhere to the oral mucosa thereby releasing the active agent.
According to a another aspect of the invention there is provided a pharmaceutical composition in the form of rapidly dissolving film which comprises of one or more water soluble polymers, and tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof.
According to yet another aspect of the invention there is provided a pharmaceutical composition in the form of rapidly dissolving film comprising one or more water soluble polymers, tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.
According to a another aspect of the invention there is provided a pharmaceutical composition in the form of rapidly dissolving film which comprises of one or more
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water soluble polymers, and tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof, wherein the said film is substantially free from surfactant.
"Pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable.
According to yet another aspect of the invention there is provided a pharmaceutical composition in the form of rapidly dissolving film comprising one or more water soluble polymers, tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof, and optionally one or more polyalcohols, sweetening agents, thickening or gelling agents, colorants, flavors, flavor enhancers, or taste modifying agents including taste masking agents.
According to yet another aspect of the invention there is provided a process for the preparation of a pharmaceutical composition in the form of rapidly dissolving film comprising one or more water soluble polymers, tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutical^ acceptabJe excipjents.
According to yet another aspect of the invention there is provided a pharmaceutical composition in the form of rapidly dissolving film which is substantially free from surfactants.
The polymers used in the said film include polymers which are hydrophilic and/or water-dispersible, and/or water soluble hydrocollides. Preferred polymers are water-soluble cellulose-derivatives. For example hydroxypropylmethyl cellulose, hydroxyethyl cellulose, or hydroxypropyl cellulose, either alone, or mixtures thereof. Other optional polymers, without limiting the invention, include polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, natural gums like xanthan gum, gum tragacanth, guar gum,
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acacia gum, arabic gum, water-dispersible polyacrylates like polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers.
The polyalcohol used in the present composition comprises of xylitol, sucralose, glycerol, polyethlene glycol, propylene glycol, glycerol monoesters with fatty acids or other pharmaceutically acceptable polyalcohols or mixtures thereof.
The sweetening agents are selected from sugar, dextrose, lactose, mannitol, sucrose, xylitol, malitol, acesulfame potassium, talin, glycyrrhizin, sucralose, aspartame, saccharin, sodium saccharin, sodium cyclamate, honey or mixtures thereof.
Thickening or gelling agents that may be added optionally in the film are selected from, but not limited to Locust bean gum, carrageenen or mixtures thereof.
The flavors which may be added optionally in the composition are selected from the essential oils or water soluble extracts of menthol, wintergreen, peppermint, sweet mint, spearmint, vanillin, cherry, chocolate, cinnamon, clove, lemon, orange, raspberry, rose, spice, violet, herbal, fruit, strawberry, grape, pineapple, peach, kiwi, papaya, mango, coconut, apple, coffee, plum, watermelon, nuts, durean, green tea, grapefruit, banana, butter, camomile. The effect of flavors may be enhanced using flavor enhancers like tartaric acid, citric acid, vanillin, or the like.
Taste masking agents may be incorporated in the said composition whenever taste making is desired. Examples of taste masking agents include resins.
Colorants which may optionally be mixed in the film must be safe in terms of toxicity and should be accepted by the Food and Drug Administration for use in pharmaceutical and cosmetic compositions.
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In another aspect of the invention, there is provided a process for the preparation of a pharmaceutical composition in the form of rapidly dissolving film comprising the steps of
a) blending tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof and one or more water soluble polymers,
b) optionally adding one or more pharmaceutically acceptable excipients,
c) adding one or more suitable solvents to form a slurry,
d) pouring the slurry in strip moulds and
e) drying at suitable temperature to form a film.
In another aspect of the invention, there is provided a process for the preparation of a pharmaceutical composition in the form of rapidly dissolving film comprising the steps of
a) blending tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof and one or more water soluble polymers,
b) optionally adding one or more pharmaceutically acceptable excipients,
c) adding one or more suitable solvents to form a homogeneous mixture,
d) coating the mixture onto a suitable carrier material and
e) drying at suitable temperature to form a film.
The dry film may be cut into pieces of suitable size and shape and packed into suitable container as per the requirement and convenience.
According to another aspect of the invention, the carrier material may be selected from non-siliconized polyethylene film, non-siliconized polyethylene terephthalate film, non-siliconized kraft paper or polyethylene-impregnated kraft paper.
According to another aspect of the invention, the solvent used in the said process is selected from isopropyl alcohol, methylene chloride or mixture thereof.
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According to yet another aspect of the invention, the solvent employed in the said process is selected from ethanol, water or mixture thereof.
According to another aspect of the invention, the drying temperature in the said process is maintained below the boiling point of the solvent employed in the said process. The drying temperature range varies from 10 to 100 °C, preferably 25 to 60 °C.
Example 1
Table 1

Composition Quantity per strip in mg Quantity (% on dry weight basis)
Tadalafil 10 1.0
Xylitol 310 31.0
Sucralose 150 15.0
Menthol 1 0.1
Locust bean gum 9.8 0.98
Carrageenan 9.8 0.98
Citric acid monohydrate 50 5.0
HPMC(MethocelE-15) 100 10
Polyethylene glycol 400 247.4 24.74
Peppermint oil 100 10
Quinoline yellow 6 0.6
Brilliant Blue 6 0.6
Isopropyl alcohol q. s. q. s.
Methylene chloride q. s. q.s.
Total Weight of strip 1000 100
All ingredients except menthol were sifted through sieve no. 60 and mixed with menthol in polyethylene glycol 400 to form a coherent mass. Methylene chloride and isopropyl alcohol were added and mixed thoroughly. Then quinoline yellow
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and brilliant blue were added. The slurry was passed through colloidal mill and finally peppermint oil was mixed. The slurry was poured in strip moulds by using semiautomatic liquid filling machine and dried at about 40 °C up to 10 hours. The dried strips were wrapped in aluminium lined paper.
Example 2
Table 2

Composition Quantity per strip in mg Quantity (% on dry weight basis)
Tadalafil 20 2.0
Xylitol 300 30.0
Sucralose 150 15.0
Menthol 1 0.1
Locust bean gum 9.8 0.98
Carrageenan 9.8 0.98
Citric acid monohydrate 50 5.0
HPMC(MethocelE-15) 100 10
Polyethylene glycol 400 247.4 24.74
Peppermint oil 100 10
Quinoline yellow 6 0.6
Brilliant Blue 6 0.6
Isopropyl alcohol q.s. q.s.
Methylene chloride q.s. q.s.
Total Weight of strip 1000 100
Procedure for the preparation of strips is same as descried in Example 1.
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Example 3
Table 3

Composition Quantity per strip in mg Quantity (% on dry weight basis)
Tadalafil 20 4
HPMC(MethocelE15) 300 60
Peppermint oil 50 10
Propylene glycol 400 59 11.8
Aspartame 50 10
Citric acid 12.5 2.5
Benzoic acid 2.5 0.5
Quinoline yellow 3 0.6
Brilliant Blue 3 0.6
Ethanol q. s. q. s.
Water q. s. q.s.
Total weight of strip 500 100
The ingredients as indicated in Table 3 were mixed to form a homogeneous mixture. This mixture was degassed in a vacuum chamber and coated on the non-siliconized side of a polyester film. It was dried in a hot air circulating oven to form a self supporting non-tacky and flexible film. The film was then cut into strips and the resulting strips were wrapped in aluminium lined paper.
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Claim:
1. A pharmaceutical composition in the form of rapidly dissolving film comprising one or more water soluble polymers, tadalafil or its isomers, enantiomers, pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.
2. A pharmaceutical composition according to claim 1, wherein the water soluble polymer is selected from hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol sodium alginate, polyethylene glycol, natural gums like xanthane gum, tragacantha, guar gum, acacia gum, arabic gum, water-dispersible polyacrylates like polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers or mixtures thereof.
3. A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipients are selected from polyalcohols, sweetening agents, thickening or gelling agents, colorants, flavors.
4. Polyalcohol according to claim 3, is selected from xylitol, sucralose, glycerol, polyethlene glycol, propylene glycol, glycerol monoesters with fatty acids or other pharmaceutically acceptable polyalcohols or mixtures thereof.
5. Sweetening agent according to claim 3, is selected from sugar, dextrose, lactose, mannitol, sucrose, xylitol, malitol, acesulfame potassium, talin, glycyrrhizin, sucralose, aspartame, saccharin, sodium saccharin, sodium cyclamate and honey or mixtures thereof.
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6. Thickening or gelling agent according to claim 3, is selected from Locust bean gum, carrageenen or mixtures thereof.
7. A process for the preparation of a pharmaceutical composition in the form of rapidly dissolving film comprising the steps of

a) blending tadalafil or its isomers, enantiomers, pharmaceuticaily acceptable salts thereof and one or more water soluble polymers,
b) optionally adding one or more pharmaceuticaily acceptable excipients,
c) adding one or more suitable solvents to form a mixture,
d) pouring the mixture in strip moulds or coating the mixture onto a suitable carrier material, and
e) drying at suitable temperature to form a film.

(Dr. Eswaran K Iyer) GM- Intellectual Property For Ajanta Pharma Limited
8. According to claim 7, the carrier material may be selected from non-siliconized polyethylene film, non-siliconized polyethylene terephthalate film, non-siliconized kraft paper or polyethylene-impregnated kraft paper.
9. According to claim 7, the solvent may be selected from isopropyl alcohol, methylene chloride, ethanol, water or mixture thereof.
10. According to claim 7, the drying temperature varies from 10 to 100 °C, preferably 30-60 °C.
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