Claims:WE CLAIM,
1. A solid pharmaceutical composition of Dutasteride comprising Dutasteride or pharmaceutically acceptable salt, polymorph, hydrate, solvate, amorphous form, prodrug, chelate or complex thereof and one or more pharmaceutically acceptable excipients.
2. A solid pharmaceutical composition of Dutasteride according to claim 1, wherein one or more pharmaceutically acceptable excipients are selected from the group comprising of diluents, fillers, binders, disintegrants, glidants, lubricants, plasticizers, rate controlling polymers, solvents, solubilizers, surfactants, anti-oxidants or combination thereof.
3. A solid pharmaceutical composition of Dutasteride according to claim 1 or claim 2, wherein the composition is selected from the group comprising of tablets, capsules, sachets, lozenges, powders, pills or granules.
4. A solid pharmaceutical composition of Dutasteride according to any one of claims 1 to 3 is a tablet.
5. A solid pharmaceutical composition of Dutasteride according to any one of claims 1 to 3 is a capsule in the form of a hard gelatin capsule.
6. A solid pharmaceutical composition of Dutasteride according to any one of claims 1 to 3 is a capsule in the form of a hard gelatin capsule comprising pharmaceutical composition of Dutasteride or pharmaceutically acceptable salt, polymorph, hydrate, solvate, prodrug, chelate or complex thereof and one or more pharmaceutically acceptable excipients as claimed in claim 2.
7. A solid pharmaceutical composition of Dutasteride according to claim 6, wherein the capsule further comprises one or more pharmaceutically acceptable excipients as claimed in claim 2 in the form of a blend mixture.
8. A solid pharmaceutical composition of Dutasteride according to claim 6, wherein the pharmaceutical composition of Dutasteride is selected from the group comprising of powder, pellets, granules, microspheres, micro-/mini-tablets or a tablet.
9. A solid pharmaceutical composition of Dutasteride according to claim 8, wherein the pharmaceutical composition of Dutasteride is tablet.
10. A solid pharmaceutical composition of Dutasteride according to any one of claims 4, 5 or 9, wherein the composition comprises:
(i) Dutasteride or pharmaceutically acceptable salt, polymorph, hydrate, solvate, prodrug, chelate or complex thereof in the proportion comprising between about 0.01% and about 5.0%;
(ii) One or more solubilizers in the proportion comprising between about 0.5% and 40%;
(iii) One or more antioxidants in the proportion comprising between about 0.1% and about 5.0%;
(iv) One or more diluents in the proportion comprising between about 5.0% and about 90%;
(v) One or more binders in the proportion comprising between about 0.5% and about 50%;
(vi) One or more disintegrants in the proportion comprising between about 0.5 and about 50%; and
(vii) One or more lubricants in the proportion comprising between about 0.1% and 10%.
11. A solid pharmaceutical composition of Dutasteride according to claim 7, wherein the blend mixture comprises lubricants in the proportion comprising between about 1.0% and about 90% and disintegrants in the proportion comprising between about 0.1% and about 10%.
12. A solid pharmaceutical composition of Dutasteride according to any one of the preceding claims, wherein Dutasteride or pharmaceutically acceptable salt, polymorph, hydrate, solvate, amorphous form, prodrug, chelate or complex thereof has d90 of the particles between about 10 µm and about 200 µm.
13. A solid pharmaceutical composition of Dutasteride according to any one of the preceding claims, wherein the composition is an immediate release composition or a modified release composition.
14. A solid pharmaceutical composition of Dutasteride according to any one of the preceding claims, wherein the composition is stable for prolonged time when stored under typical storage conditions and/or accelerated conditions characterized in that any individual impurity present in the composition is less than 2.0% and the total impurities present in the composition are less than 5.0%.
15. A solid pharmaceutical composition of Dutasteride according to any one of the preceding claims, wherein the composition has:
(a) a Cmax for Dutasteride, or a salt or derivative thereof, when assayed in the plasma of a mammalian subject following administration that is at least about 50% to about 1900% greater than the Cmax for a Dutasteride marketed or known formulation, administered at the same dose;
(b) an AUC for Dutasteride, or a salt or derivative thereof, when assayed in the plasma of a mammalian subject following administration that is at least about 25% to about 1200% greater than the AUC for a Dutasteride marketed or known formulation, administered at the same dose;
(c) a Tmax for Dutasteride, or a salt or derivative thereof, when assayed in the plasma of a mammalian subject following administration that is less than about 6 hours to about 8 hours; or
(d) any combination of (a), (b), and (c).
16. A solid pharmaceutical composition of Dutasteride according to any one of the preceding claims, wherein the composition further comprises one or more additional therapeutic agents selected from the group comprising of Tamsulosin, Silodosin, Doxazosin, Terazosin, Alfuzosin and Bicalutamide or pharmaceutically acceptable salt, polymorph, hydrate, solvate, prodrug, chelate or complex thereof.
17. A solid pharmaceutical composition of Dutasteride according to any one of the preceding claims in an effective dosage amount for use in the treatment of at least one disease or condition selected from the group comprising of prostatic hyperplasia, prostate cancer, alopecia, alcohol related disorders, nonmalignant neoplasm, urologic diseases, benign prostatic hyperplasia, castration-resistant, metastatic prostate cancer, renal diseases, spinal and bulbar muscular atrophy, hypogonadism, erectile dysfunction, lower urinary tract symptoms, adenocarcinoma of the prostate, androgenetic alopecia, and premenstrual syndrome.
18. Use of a solid pharmaceutical composition of Dutasteride according to any one of the preceding claims in an effective dosage amount for the treatment of at least one disease or condition selected from the group comprising of prostatic hyperplasia, prostate cancer, alopecia, alcohol related disorders, nonmalignant neoplasm, urologic diseases, benign prostatic hyperplasia, castration-resistant, metastatic prostate cancer, renal diseases, spinal and bulbar muscular atrophy, hypogonadism, erectile dysfunction, lower urinary tract symptoms, adenocarcinoma of the prostate, androgenetic alopecia, and premenstrual syndrome.
19. A solid pharmaceutical composition of Dutasteride according to any one of the preceding claims packaged in the pharmaceutically acceptable packaging material selected from the group comprising of high-density polyethylene (HDPE) containers with closure made from polypropylene (PP), polypropylene containers with closure, polystyrene containers with closure and with or without a desiccant; aluminium foil blisters, polychlorotrifluoroethylene blisters, and blisters made of multilayer polymeric foil where different polymeric materials are combined.
20. A process for the preparation of the solid pharmaceutical composition of Dutasteride according to claim 4, wherein the process comprises following steps:
(a) Dissolve API, one or more solubilizer(s) and one or more antioxidant(s) in the solvent;
(b) Disperse one or more diluent(s) in step (a);
(c) Pour the drug coating solution prepared according to step (b) on one or more binder(s);
(d) Drying and milling of the mass obtained in step (c);
(e) Sift one or more diluent(s) and disintegrant(s) through 30#;
(f) Mix blend of step (e) with granules of step (d) in blender;
(g) Sift one or more lubricant(s) through 40#;
(h) Mix one or more lubricant(s) of step (g) with blend of step (f); and
(i) Compress the blend of step (h) into tablet.
wherein, the tablet prepared according to step (i) is filled in the empty capsule for the preparation of the solid pharmaceutical composition of Dutasteride according to claim 5.
21. A process for the preparation of the solid pharmaceutical composition of Dutasteride according to claims 6 to 9, wherein the process comprises following steps:
(a) Dissolve API, one or more solubilizer(s) and one or more antioxidant(s) in the solvent;
(b) Disperse one or more diluent(s) in step (a);
(c) Pour the drug coating solution prepared according to step (b) on one or more binder(s);
(d) Drying and milling of the mass obtained in step (c);
(e) Sift one or more diluent(s) and disintegrant(s) through 30#;
(f) Mix blend of step (e) with granules of step (d) in blender;
(g) Sift one or more lubricant(s) through 40#;
(h) Mix one or more lubricant(s) of step (g) with blend of step (f);
(i) Compress the blend of step (h) into tablet;
(j) Sift one or more lubricant(s) and disintegrant(s) through 30#;
(k) Mix sifted ingredient of step (j) in blender; and
(l) Fill the blend obtained in step (k) and tablet obtained in step (i) in empty hard gelatin capsule.

Dated this 14th day of April 2018

[KETANA BABARIA]
IN/PA-660
ATTORNEY FOR THE APPLICANTS , Description:FIELD OF THE INVENTION
The present invention relates to the pharmaceutical field and more precisely to the pharmaceutical compositions of 5-alpha-reductase inhibitor viz. Dutasteride. In particular, the present invention relates to the solid dosage forms of Dutasteride having satisfactory dissolution profile, prolonged stability and desired bioavailability and process for the preparation thereof. The pharmaceutical composition of the present invention, preferably, is in the form of capsule such as hard gelatin capsule. The pharmaceutical composition according to the present invention may be used for treating benign prostatic hyperplasia and/or alopecia.

BACKGROUND OF THE INVENTION
5-alpha-reductase inhibitors are used worldwide for the treatment of benign prostatic hyperplasia. 5-alpha-reductase inhibitors such as Finasteride and Dutasteride reduce the size of the prostate, thereby alleviating the static component of bladder outlet obstruction. Dutasteride, chemically defined as (5a, 17ß)-N-{2, 5-bis (trifluoromethyl) phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide as shown in Figure 1, is a 5-alpha-reductase inhibitor. Dutasteride alone is used to inhibit conversion of testosterone to dihydrotestosterone (DHT), the androgen primarily responsible for the enlargement of prostate gland.

Figure 1
Dutasteride is commercially available as AVODART® soft gelatin capsule which contains 0.5 mg of Dutasteride dissolved in 349.5 mg of a mixture of mono- and di-glyceride of caprylic/capric acid and butylated hydroxy toluene (BHT) leading to larger sized capsules. Development of Dutasteride compositions is subject to many formulation constraints. Dutasteride has poor solubility. These solubility challenges can affect bioavailability, possibly resulting in reduced or unpredictable bioavailability. The choice of excipients is important in order to ensure good solubility and good bioavailability of the pharmaceutically active compound. In order to ensure enhanced bioavailability of Dutasteride dosage forms, solubilizers and permeability enhancers are required to be used in large amounts leading to an increase in the size of the dosage form.

The large-sized capsule may cause low patient compliance due to patient’s inability or unwillingness to swallow the large-sized formulations. In particular, considering that the great majority of benign prostate hyperplasia patients is elderly patients and long-term use of Dutasteride is required for the treatment, the large size of the Dutasteride capsule leads to disadvantages in that taking such large capsule is very inconvenient for elderly patients and thus patient compliance is low. The larger capsule size also poses greater potential safety issues such as choking, formulation arrest, and prolonged transit time, which could result in esophageal injury and/or pain. The larger formulation size also raises product efficacy concerns due to patient’s inability or unwillingness to swallow the larger formulations. Further, a large amount of excipients may lead to undesired side effects.

US 5565467 discloses Dutasteride and its method of use. WO 1999/08666 discloses gelatin capsules filled with a solution comprised of a therapeutically effective amount of a pharmaceutically active aza steroid and a fatty acid ester of glycerol or propylene glycol. WO 1999/08684 discloses a gelatin capsule filled with a therapeutically effective amount of a pharmaceutically active aza steroid, polyethylene glycol, and propylene glycol.

EP 2050436 discloses solid pharmaceutical composition comprising Dutasteride which comprises Dutasteride in powder form, optionally in combination with one or more excipients, wherein the lower limit of the average particle size of Dutasteride is higher than 2.0 µm (>2.0 micron) and the upper limit of the average particle size of Dutasteride is at about 10 µm (10 micron). WO 2010/092596 discloses an oral pharmaceutical composition of Dutasteride which comprises admixture of a) Dutasteride or its pharmaceutically acceptable salt; b) one or more surfactant(s)/co-surfactant(s); c) one or more oil(s); d) optionally antioxidant(s); and e) optionally excipient(s); wherein the admixture may be filled in capsules or the admixture is adsorbed on suitable adsorbent and filled in capsules or compressed into pellets or tablets. WO 2012/076516 discloses a pharmaceutical composition comprising Dutasteride or a pharmaceutically acceptable salt or solvate thereof and a solubilizer wherein solubilizer is selected from the group consisting of propylene glycol esters, medium chain triglycerides, medium chain mono- and diglycerides, long chain mono- and diglycerides, propylene glycol, polyethylene glycols, block copolymers of polyethylene glycol and polypropylene glycol, sucrose fatty acid esters and mixtures thereof. WO 2014/209062 discloses an oral soft capsule formulation comprising a filling material comprising Dutasteride and a soft capsule film containing succinylated gelatin, a plasticizer, and a cross-linking inhibitor wherein the filling material is an emulsion and contains a solvent, a surfactant and a stabilizer. WO 2016/114521 discloses a Dutasteride tablet in which the tablet form Dutasteride composition comprises light anhydrous silicic acid as a stabilizer. WO 2016/126058 discloses a pharmaceutical composition containing Dutasteride in which the solubility of Dutasteride has been increased by preparing an inclusion complex from gamma-cyclodextrin which is good for solidification so as to prepare a solid formulation containing Dutasteride and by preparing a solid dispersion from the inclusion complex and a thickener and/or a surfactant. WO 2017/043913 and WO 2017/116190 discloses a pharmaceutical composition comprising Dutasteride and propylene glycol monolaurate, and a capsule formulation comprising thereof.

Soft gelatin encapsulation provides the potential to improve the bioavailability of pharmaceutical agents. Relatively insoluble active ingredients can be dispersed in a liquid or gelled carrier to provide faster absorption upon rupture of the capsule. Further, it may be useful to include an antioxidant in the composition so as to prevent oxidation of the pharmaceutically active ingredients in the composition. The other advantages of soft gelatin capsules include superior patient compliance/consumer preference (ease of swallowing, appealing appearance, absence of objectionable taste, and convenience), pharmaceutical elegance, excellent dose uniformity, better tamper evidence (tampering leads to puncturing and visible leakage), and safer handling of highly potent or cytotoxic drug compounds.

Another challenge in formulating compositions comprising Dutasteride is that Dutasteride is prone to oxidation. Therefore, gelatin capsule formulations are preferred as they are much more resistant to oxidation due to the low oxygen permeation of typical gelatin shells, and further have better bioavailability.

Solubilizers which absorb too much water from the ambient air lead to liquefaction of the solid formulation and unwanted crystallization of the active ingredients. A highly hygroscopic solubilizer may also cause problems in processing the dosage forms.

Further, the use of solubilizers might give a negative sensoric effect to the final formulation (tackiness, oiliness, or waxiness, depending on the type and on the used percentage). Additional drawbacks could be related to handling, if the solubilizer needs heating and/or stirring to have a homogeneous product before use, or gel formation that might occur during the production process. Other disadvantages could be strong coloring, bad color, and loss of viscosity.

Some solubilizers may exhibit toxicity when used in large amounts. Hence, the choice of solubilizer and the amount used is critical in formulating a Dutasteride dosage form.
Dutasteride compositions comprising a large amount of solubilizer and permeability enhancer lead to enhanced composition weight, and hence larger size of the final dosage forms, which are not patient compliant. Further, according to AVODART® prescribing information, AVODART® capsules should be swallowed whole. Therefore, there exists a need in the art to develop a more patient-compliant Dutasteride dosage form having smaller size, and yet achieves similar bioavailability.

OBJECTS OF THE INVENTION
The commercially available Dutasteride formulations AVODART® are soft capsules having large capsule size. According to AVODART® prescribing information, AVODART® capsules should be swallowed whole. Since geriatric patients constitute the main patient group for Dutasteride formulations, there exists a need in the art to develop a more patient-compliant dosage form which is smaller in size and easy to administer. The principal object of the present invention is therefore to develop such a Dutasteride formulation that is smaller in size having increased patient acceptability and compliance.

Dutasteride is prone to oxidation. Therefore, gelatin capsule formulations are preferred as they are much more resistant to oxidation due to the low oxygen permeation of typical gelatin shells, and further have better bioavailability. Therefore, a yet another object of the present invention is to develop a gelatin capsule formulations of Dutasteride.

Use of solubilizers is critical in formulating Dutasteride dosage forms. Further, because of poor solubility of Dutasteride, solubilizers and permeability enhancers are required to be used in large amounts leading to an increase in the size of the dosage form. A yet another object of the present invention is therefore to develop such a Dutasteride formulation which does not contain solubilizers and permeability enhancers in larger amounts thereby decreasing the size of the dosage forms, though achieving the desired bioavailability.

A yet another object of the present invention is to provide solid pharmaceutical composition of Dutasteride comprising Dutasteride and one or more pharmaceutically acceptable excipients. A yet another object of the present invention is to provide process for the preparation of solid pharmaceutical compositions of the present invention.

A yet another object of the present invention is to provide solid pharmaceutical compositions of Dutasteride having prolonged stability, desired dissolution profile and improved or comparable pharmacokinetic profile and/or bioavailability as compared to the marketed Dutasteride composition.

A yet another object of the present invention is to provide method for the treatment of at least one diseases or condition selected from the group comprising of prostatic hyperplasia, prostate cancer, alopecia, alcohol related disorders, nonmalignant neoplasm, urologic diseases, benign prostatic hyperplasia, castration-resistant, metastatic prostate cancer, renal diseases, spinal and bulbar muscular atrophy, hypogonadism, erectile dysfunction, lower urinary tract symptoms, adenocarcinoma of the prostate, androgenetic alopecia, premenstrual syndrome and the like comprising administering effective dosage amount of pharmaceutical compositions of the present invention.

A yet another object of the present invention is to use the pharmaceutical compositions of the present invention for the treatment of at least one diseases or condition selected from the group comprising of prostatic hyperplasia, prostate cancer, alopecia, alcohol related disorders, nonmalignant neoplasm, urologic diseases, benign prostatic hyperplasia, castration-restistant, metastatic prostate cancer, renal diseases, spinal and bulbar muscular atrophy, hypogonadism, erectile dysfunction, lower urinary tract symptoms, adenocarcinoma of the prostate, androgenetic alopecia, premenstrual syndrome and the like.

DETAILED DESCRIPTION OF THE INVENTION
In one of the main aspects, the present invention provides solid pharmaceutical compositions of Dutasteride comprising Dutasteride and one or more pharmaceutically acceptable excipients. The solid pharmaceutical compositions according to the present invention include but not limited to tablets, capsules, sachets, lozenges, powders, pills or granules and the like.

In one of the preferred aspects, the solid pharmaceutical compositions of Dutasteride according to the present invention are in the form of tablet formulations. The tablet formulations according to the present invention comprises Dutasteride and one or more pharmaceutically acceptable excipients. A Dutasteride tablet formulation according to the present invention may vary in shape and may be for example round, oblong, oval, polyedric or be present in any other shape. A Dutasteride tablet formulation according to the present invention may be coated or uncoated.

In another preferred aspects, the solid pharmaceutical compositions of Dutasteride according to the present invention are in the form of capsule formulations. Preferably, the capsule formulations of Dutasteride are gelatin capsules. More preferably, the gelatin capsules of Dutasteride are hard gelatin capsules.

In one of the further aspects, the present invention provides hard gelatin capsules comprising pharmaceutical composition of Dutasteride. In one of the further aspects, the composition of Dutasteride is present as powder, granules, pellets, micro-/mini-tablets, micro-spheres or tablets. In one of the further aspects, the hard gelatin capsules of the present invention may further comprise one or more pharmaceutically acceptable excipients. In one of the further aspects of the present invention, two or more pharmaceutically acceptable excipients are present as a blend mixture.

In one of the preferred aspects of the present invention, the hard gelatin capsules of the present invention are filled up with, (i) Dutasteride solid composition such as powder, granules, pellets, micro-/mini-tablets, micro-spheres or tablets; and (ii) Blend mixture. In one of the preferred aspects of the present invention, the Dutasteride solid composition is tablet composition. In one of the preferred aspects, the blend mixture comprises two or more pharmaceutically acceptable excipients. A Dutasteride tablet may vary in shape and may be for example round, oblong, oval, polyedric or be present in any other shape.

In one of the further aspects of the present invention, the capsules of the present invention are of any standard size known to a skilled person. In one of the preferred aspects, the hard gelatin capsules of the present invention are size “2” capsules having locked length approximately 17.60 to 18.0 mm and external diameter approximately 6.35 mm. The final dosage form, hard gelatin capsule may vary in shape and may be for example round, oblong, oval, polyedric or be present in any other shape.

The term “one or more pharmaceutically acceptable excipients” as used herein without limitation includes diluents, disintegrants, solvents, processing aids, buffering agents, colorants, flavorings, coating agents, binders, carriers, glidants, lubricants, granulating agents, gelling agents, polishing agents, sweetening agent, anti-adherents, preservatives, emulsifiers, antioxidants, plasticizers, surfactants, enteric agents, wetting agents, stabilizing agents, solubilizers, bioadhesives, film forming agents, essential oils, emollients, dissolution enhancers, dispersing agents and the like or any combinations thereof.

In one of the preferred aspects of the present invention, one or more pharmaceutically acceptable excipients may be selected from the group comprising of fillers, binders, disintegrants, diluents, lubricants, glidants, plasticizers, surfactants, antioxidants, stabilizers, solvents, solubilizers, preservatives, colorants, sweeteners, flavoring agents and the like or any combinations thereof.

In some of the aspects, the solid pharmaceutical compositions of the present invention may be administered orally or via the oral cavity. In some of the aspects, the solid pharmaceutical compositions of the present invention may also be administered transmucosally, sublingually, via the buccal cavity, via mucosal membranes and/or through the gastrointestinal tract.

In some of the aspects, the solid pharmaceutical compositions of the present invention are in the form of immediate release dosage forms or modified release dosage forms, such as extended release, controlled release, sustained release, prolonged release and delayed release. In some of the aspects, the solid pharmaceutical compositions of the present invention comprise Dutasteride and one or more suitable excipients or additives for the preparation of modified release dosage forms such as rate controlling polymers.

A variety of materials may be used as diluents. Non-limiting examples are spray-dried or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. starch 1500), cellulose (e.g. microcrystalline cellulose; AVICEL®), and others as known in the art. Diluents when present in the compositions of the present invention, may be present in an amount from about 1% to about 99% based on the total weight of the composition.

Fillers which can be used in the present invention are selected without limitation from the group comprising of cellulose and cellulose derivatives like microcrystalline cellulose, powdered cellulose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium silicate, sodium or calcium carboxymethylcellulose, cellulose, dextrin derivatives, dextrin, cyclodextrin, dextrose, fructose, lactitol, lactose, L-HPC, preferably as monohydrate, magnesium carbonate, magnesium trisilicate, magnesium oxide, mannitol, maltol, maltitol, maltodextrins, maltose, sorbitol, starch, pregelatinized starch, sucrose, sugar, xylitol, new composite compounds such as Microcellac®, Cellactose®, Ludipress®, Prosolv®, and related compounds and other materials known to one of ordinary skill in the art or mixture thereof. Fillers when present in the compositions of the present invention, may be present in an amount from about 1% to about 99% based on the total weight of the composition.

Binders or binding agents which can be used in the present invention are selected without limitation from the group comprising of acacia, polyvinyl pyrrolidone, hydroxyl polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, maltodextrins, maltol, maltitol, mannitol, methyl cellulose, ethyl cellulose, starch, pregelatinized starch, modified corn starch, polyacryl amide, poly-N-vinyl amide, sodium or calcium carboxymethyl cellulose, dextrose, fructose, sucrose, sorbitol, xylitol, polyethylene glycol, gelatin, polyethylene oxide, poly propylene glycol, tragacanth, xanthan gum, alginic acid or alginate, and other materials known to one of ordinary skill in the art or mixture thereof. Binders or binding agents when present in the compositions of the present invention, may be present in an amount from about 0.1% to up to about 50% based on the total weight of the composition.

Lubricants or glidants which can be used in the present invention is exemplified without limitation by magnesium stearate, calcium stearate, glyceryl stearate, glycerin monostearate, zinc stearate, talc, polyethylene glycols, hydrogenated vegetable oil, mineral oil, stearic acid, glyceryl behenate, cornstarch, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel, cetostearyl alcohol, stearyl alcohol, sodium stearyl fumarate, glyceryl palmitostearate, glycerol monooleate, stearic acid, docusate sodium, lecithin, potassium benzoate, sorbitan esters, wax and other materials known to one of ordinary skill in the art or mixture thereof. Lubricants or glidants when present in the compositions of the present invention, may be present in an amount from about 0.005% to up to about 10% based on the total weight of the composition.

Disintegrants which can be used in the present invention refer to any material that facilitates the breakup of the granules prepared according to the present invention when placed in contact with an aqueous medium. Suitable disintegrants include, but are not limited to, crospovidone, sodium starch glycolate, hydroxypropyl starch, starch, pregelatinized starch, microcrystalline cellulose, carboxymethylcellulose sodium or calcium, croscarmellose, croscarmellose sodium, carmellose calcium, L-HPC, pregelatinized starch, colloidal silicon dioxide, calcium silicate, polacrilin potassium, low-substituted hydroxypropylcellulose, sodium or calcium alginate, agar, guar gum, chitosan, alginic acid other materials known to one of ordinary skill in the art or mixture thereof. Disintegrants when present in the compositions of the present invention, may be present in an amount from about 0.005% to up to about 50% based on the total weight of the composition.

Non-limiting examples of film forming substances for example are acacia, alginic acid, carboxymethylcellulose, carrageenan, ethylcellulose, hydroxyethylcellulose, hydroxyl propylmethylcellulose, methylcellulose, polyvinyl alcohol, polymethacrylates, povidone, shellac, and related compounds. Glidants or lubricants may also be used as components of the film. The film of optionally coated composition of the invention comprises film forming substances/excipients, glidants or lubricants, or other excipients known to those skilled in the art in a total amount of about 0.005% to up to about 10% by weight of the coating composition.

Suitable solubilizers used in the present invention may be selected from the non-limiting examples such as group consisting of oils such as corn oil, peanut oil, safflower oil, soya bean oil, or Miglyol®812 (neutral oil, triglycerides of medium chain fatty acids); propylene glycol mono- or di-fatty acid esters such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, or propylene glycol caprylic-capric acid diester (e.g. Miglyol® 840); polyalkylene glycol such as polyethylene glycol 400-600; dimethylsulfoxide; or mixtures thereof. Solubilizers when present in the compositions of the present invention, may be present in an amount from about 0.005% to up to about 40% based on the total weight of the composition.

Antioxidants can be compounds that can reduce a drug that has been oxidized, or compounds that are more readily oxidized than the agents they are to protect (oxygen scavengers). Many of the lipid-soluble antioxidants act as scavengers. Antioxidants can also act as chain terminators, reacting with free radicals in solution to stop the free-radical propagation cycle. Mixtures of chelating agents and antioxidants are often used because there appears to be a synergistic effect. This occurs because many of the agents act at differing steps in the oxidative process.

Some substances prone to oxidation include unsaturated oils/fats, compounds with aldehyde or phenolic groups, colors, flavors, sweeteners, plastics and rubbers, the latter being used in containers for products. Oxidation may manifest as products with an unpleasant odour, taste, appearance, precipitation, discoloration or even a slight loss of activity. The term rancidity refers to many typical off-flavors that result from autoxidation of unsaturated fatty acids that are present in oils and fats, and it affects many oils and fats. The distinct rancid odour may result from short-chain, volatile monomers resulting from the cleavage of the longer chain, less volatile oils and fats. Non-limiting examples of anti-oxidants are a-Tocopherol acetate, Ascorbic acid, Erythorbic acid, Butylated hydroxytoluene (BHT), d-a-Tocopherol natural, Monothioglycerol, Sodium bisulfite, Sodium sulfite, Sodium metabisulfite, Potassium metabisulfite, Acetone sodium bisulfite, Ascorbyl palmitate, Cysteine, d-a-tocopherol synthetic, Nordihydroguaiaretic acid, Sodium formaldehyde sulfoxylate, Sodium thiosulfate, Acetylcysteine, Ascorbyl palmitate, Butylated hydroxyanisole (BHA), Cysteine hydrochloride, Dithiothreitol, Propyl gallate, Thiourea and the like. Antioxidants when present in the compositions of the present invention, may be present in an amount from about 0.005% to up to about 10% based on the total weight of the composition.

Surfactant is a general name for materials that possess surface activity; in solution they tend to orient at the surface of the liquid. There are several general classes of surfactants: anionic, cationic, amphoteric and non-ionic. Surfactants are amphiphilic molecules, i.e. part of the molecule is hydrophilic, and part is lipophilic. This combination of the two opposite affinities in the same molecule causes them to orient to the interface and thereby reduce the interfacial tension between the continuous and disperse phases, such as in emulsions and suspensions. Ionic surfactants work primarily through electrostatic forces, whereas non-ionic surfactants work primarily through steric forces. Non-limiting examples of surfactants are Sodium lauryl sulfate, Docusate sodium, Cocamidopropyl amino betaine, Polyoxyethylene sorbitan fatty acid esters (Polysorbate, Tween®), Polyoxyethylene 15 hydroxystearate (Macrogol 15 hydroxystearate, Solutol HS15®), Polyoxyethylene castor oil derivatives (Cremophor® EL, ELP, RH 40), Polyoxyethylene stearates (Myrj®), Sorbitan fatty acid esters (Span®), Polyoxyethylene alkyl ethers (Brij®), Polyoxyethylene nonylphenol ether (Nonoxynol®) and the like. Surfactants when present in the compositions of the present invention, may be present in an amount from about 0.005% to up to about 10% based on the total weight of the composition.

The term “Dutasteride” as used herein, unless the context requires otherwise, includes Dutasteride, its pharmaceutically acceptable salts and chemical derivatives of Dutasteride such as polymorphs, hydrates, solvates, amorphous forms, prodrugs, chelates, and complexes. The solid pharmaceutical compositions may contain 0.05 mg to 2.0 mg of Dutasteride per dosage unit containing Dutasteride in crystalline or amorphous form.

Dutasteride used for the preparation of the solid pharmaceutical compositions of the present invention comprise particles of Dutasteride, wherein the d90 of the particles of Dutasteride is less than about 1000 µm, or less than about 950 µm, or less than about 900 µm, or less than about 850 µm, or less than about 800 µm, or less than about 750 µm, or less than about 700 µm, or less than about 650 µm, or less than about 600 µm, or less than about 550 µm, or less than about 500 µm, or less than about 450 µm, or less than about 400 µm, or less than about 350 µm, or less than about 300 µm, or less than about 250 µm, or less than about 200 µm, or less than about 150 µm, or less than about 100 µm, or less than about 90 µm, or less than about 80 µm, or less than about 70 µm, or less than about 60 µm, or less than about 50 µm, or less than about 40 µm, or less than about 30 µm, or less than about 20 µm, or less than about 10 µm, or less than about 5 µm, or less than about 2 µm, or less than about 1 µm, or less than about 0.5 µm.

The pharmaceutical composition of the present invention comprises Dutasteride as active pharmaceutical ingredient in amounts of about 0.05 mg to 2.0 mg per dosage unit, preferably 0.1 to 1.5 mg, and for example specifically in 0.05 mg, 0.10 mg, 0.20 mg, 0.50 mg, 0.80 mg, 1.00 mg, 1.50 mg, or 2.0 mg per dosage unit.

The term “pharmaceutical composition” containing/comprising Dutasteride, as used herein, unless otherwise indicated to the contrary, means the final solid dosage form as defined according to the present invention, for example a tablet, or a granulate, or a pellet in the finished dosage form or which is enclosed in a hard gelatin capsule. The tablet or the granules or the pellets, for example, may be coated.

The solid pharmaceutical compositions of the present invention are stable for prolonged time when stored under storage conditions. The term “storage conditions” as used herein without limitation include typical storage conditions such as 2°C-8°C, 40°C±2°C/75±5% RH, 30°C±2°C/65±5% RH, 25°C±2°C/40±5% RH and accelerated conditions such as 40°C±2°C/75±5% RH. The term “prolonged time” as used herein indicates that the pharmaceutical compositions of the present invention are stable for at least 1 month, at least 3 months, at least 6 months or at least 12 months when stored under storage conditions.

As used herein, the terms “stable” or “stability” encompass any characteristic of the solid pharmaceutical compositions which may be affected by storage conditions including, without limitation, potency, total impurities, degradation products, specific optical rotation, optical purity, water content, appearance, viscosity, sterility, and colour and clarity. The storage conditions which may affect stability include, for example, duration of storage, temperature, humidity, and/or light exposure.

In some of the aspects of the present invention, stable solid pharmaceutical compositions or stability of the solid pharmaceutical compositions refer to dosage forms which retain at least about 90%, or about least about 95%, or at least about 96%, or at least about 98%, of the labelled concentration of Dutasteride contained in the said dosage form after storage under typical and/or accelerated conditions. In further aspects, stable solid pharmaceutical compositions or stability of the solid pharmaceutical compositions refer to less than about 15% (area percent), or less than about 10% (area percent), or less than about 7% (area percent), or less than about 5% (area percent), or less than about 2% (area percent) of Dutasteride-related impurities are present after storage under typical and/or accelerated conditions.

In some of the aspects, the pharmaceutical compositions of the present invention contain no more than about 15% (area percent), or no more than about 10% (area percent), or no more than about 7% (area percent), or no more than about 5% (area percent), or no more than about 2% (area percent), or no more than about 1% (area percent), or no more than about 0.5% (area percent), or no more than about 0.2% (area percent), or no more than about 0.1% (area percent) any known or unknown single Dutasteride-related impurity or other impurity after storage under typical and/or accelerated conditions.

In some of the aspects, the pharmaceutical compositions of the present invention contain no more than about 15% (area percent), or no more than about 10% (area percent), or no more than about 7% (area percent), or no more than about 5% (area percent), or no more than about 2% (area percent), or no more than about 1% (area percent), or no more than about 0.5% (area percent), or no more than about 0.2% (area percent), or no more than about 0.1% (area percent) total Dutasteride-related impurities or other impurities after storage under typical and/or accelerated conditions.

Methods for determining the stability of the solid pharmaceutical compositions of the present invention with respect to a given parameter are well-known to those of skill in the art. For example, individual impurities and total impurities can be assessed by high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Unless otherwise indicated to the contrary, a percentage amount of any individual impurities (known/unknown), or total impurities reported herein in the pharmaceutical compositions are determined by a peak area percent method using HPLC.

The term “about”, as used herein, when used along with the values assigned to certain measurements and parameters means a variation of up to 10% from such values, or in case of a range of values, means up to a 10% variation from both the lower and upper limits of such ranges.

The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

All percentages mentioned herein, unless otherwise indicated, are on a w/w basis, i.e., as a percentage of the total weight of the composition which may vary within the ranges given.

The specifically mentioned pharmaceutically acceptable excipients in the foregoing lists are intended to be exemplary, not exhaustive, of specific excipients that may be used in the practice of the disclosed invention. It is further understood that more than one of any particular type of excipient may be used in the pharmaceutical compositions described herein. For example, the compositions may include more than one diluent, filler, binder, lubricant, disintegrant, antioxidant, etc. Also, a single excipient may provide multiple functions, as mentioned hereinabove.

The term “comprise/comprises/comprising” as used herein mean that other ingredients, steps, etc. are optionally present. When reference is made herein to a method comprising two or more defined steps, the steps can be carried in any order or simultaneously (except where the context excludes that possibility), and the method can include one or more steps which are carried out before any of the defined steps, between two of the defined steps, or after all of the defined steps (except where the context excludes that possibility).

“Drug-binder solution” or “Drug solution” according to the present invention is a solution of drug and one or more binding agent.

In one of the aspects, the solid pharmaceutical compositions of the present invention are suitable for administration to a subject to treat or prevent a disease or condition. Preferably, the subject is a mammal. More preferably, the mammal is a human. Preferably, the disease or condition is a disease or condition that is treatable by the administration of Dutasteride.

In one of the further aspects, the solid pharmaceutical compositions of the present invention are useful for the human indications of Dutasteride. Preferably, the pharmaceutical compositions disclosed herein are indicated for the treatment of prostate gland enlargement (BPH) and of alopecia. Together with further advantages in terms of satisfactory content uniformity, good stability, long shelf life and simplicity of the processes the compositions of the invention offer considerable advantages over the state of the art.

In one of the further aspects, the present invention is directed to the method for the treatment of at least one disease or condition selected from the group comprising of prostatic hyperplasia, prostate cancer, alopecia, alcohol related disorders, nonmalignant neoplasm, urologic diseases, benign prostatic hyperplasia, castration-resistant, metastatic prostate cancer, renal diseases, spinal and bulbar muscular atrophy, hypogonadism, erectile dysfunction, lower urinary tract symptoms, adenocarcinoma of the prostate, androgenetic alopecia, premenstrual syndrome and the like comprising administering effective dosage amount of pharmaceutical compositions of the present invention.
“Effective dosage amount” as used herein with respect to, for example a Dutasteride pharmaceutical compositions shall mean that dosage that provides the specific pharmacological response for which Dutasteride administered in a significant number of subjects in need of such treatment. It is emphasized that “effective dosage amount”, administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a “effective dosage amount” by those skilled in the art.

In one of the further aspects, the present invention is directed to use of solid pharmaceutical compositions of the present invention for the treatment of a diseases or condition selected from the group comprising of prostatic hyperplasia, prostate cancer, alopecia, alcohol related disorders, nonmalignant neoplasm, urologic diseases, benign prostatic hyperplasia, castration-resistant, metastatic prostate cancer, renal diseases, spinal and bulbar muscular atrophy, hypogonadism, erectile dysfunction, lower urinary tract symptoms, adenocarcinoma of the prostate, androgenetic alopecia, premenstrual syndrome and the like.

In one of the further aspects, the methods of treatment according to the present invention may also comprise administration of one or more additional therapeutic agents selected from the group comprising of Tamsulosin, Silodosin, Doxazosin, Terazosin, Alfuzosin, Bicalutamide and pharmaceutically acceptable salts and solvates thereof. One or more additional therapeutic agents may be administered in single dosage form with Dutasteride or different dosage form. One or more additional therapeutic agents when not administered in single dosage form with Dutasteride, then may be administered concurrently or sequentially.

The solid pharmaceutical compositions of the present invention are proposed to have unexpectedly dramatic dissolution profiles. Rapid dissolution of an administered active agent is preferable, as faster dissolution generally leads to greater bioavailability and faster onset of action. To improve the dissolution profile and bioavailability of Dutasteride it would be useful to increase Dutasteride’s dissolution so that it could attain a level close to 100% dissolution of the drug substance.
The solid pharmaceutical compositions of the present invention comprising Dutasteride, exhibit improved or comparable pharmacokinetic profiles as compared to known Dutasteride compositions, e.g. AVODART®. For example, the Cmax and/or AUC of the solid pharmaceutical compositions of Dutasteride of the present invention can be greater than or substantially equal to the Cmax and/or AUC for known Dutasteride compositions administered at the same dose. In addition, the Tmax of the solid pharmaceutical compositions of Dutasteride of the present invention can be lower than or substantially equal to that obtained for a known Dutasteride compositions, administered at the same dose. In addition, combinations of an improved or comparable Cmax, AUC and Tmax profile can be exhibited by the solid pharmaceutical compositions of Dutasteride of the invention, as compared to known Dutasteride compositions. In further aspects, the solid pharmaceutical compositions of Dutasteride of the present invention may result in minimal different absorption levels when administered under fed as compared to fasting conditions.

In one of the aspects, the solid pharmaceutical compositions comprising Dutasteride or pharmaceutically acceptable salt or derivative thereof exhibits in comparative pharmacokinetic testing with a Dutasteride marketed or known formulation, administered at the same dose, a Tmax not greater than about 90%, not greater than about 80%, not greater than about 70%, not greater than about 60%, not greater than about 50%, not greater than about 30%, not greater than about 25%, not greater than about 20%, not greater than about 15%, not greater than about 10%, or not greater than about 5% of the Tmax exhibited by the marketed or known Dutasteride formulation.

In one of the further aspects, the solid pharmaceutical compositions comprising Dutasteride or pharmaceutically acceptable salt or derivative thereof exhibits in comparative pharmacokinetic testing with a Dutasteride marketed or known formulation, administered at the same dose, a Cmax which is at least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the Cmax exhibited by the marketed or known Dutasteride formulation.

In one of the further aspects, the solid pharmaceutical compositions comprising Dutasteride or pharmaceutically acceptable salt or derivative thereof exhibits in comparative pharmacokinetic testing with a Dutasteride marketed or known formulation, administered at the same dose, an AUC which is at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than the AUC exhibited by the marketed or known Dutasteride formulation.

In one of the further aspects, the Tmax of Dutasteride or salt thereof, when assayed in the plasma of the mammalian subject, is less than about 6 to about 8 hours. In other aspects of the invention, the Tmax of Dutasteride or salt thereof is less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or less than about 30 minutes after administration.

In some aspects, the solid pharmaceutical compositions of Dutasteride of the present invention exhibit improved or comparable bioavailability as compared to known Dutasteride compositions, e.g. AVODART®.

The solid pharmaceutical compositions of the present invention are suitable for administration to all types of patients’ population. In particular, solid pharmaceutical compositions of the invention are suitable for geriatric patients.

In one of the further aspects, a pharmaceutical composition according to the present invention may further comprises at least one second active ingredient selected from the group consisting of alpha-1-adrenoreceptors, anti-androgens and pharmaceutically acceptable salts and solvates thereof. Examples of suitable alpha-1-adrenoreceptors include Tamsulosin, Silodosin, Doxazosin, Terazosin and Alfuzosin. Bicalutamide is an example of a suitable anti-androgen. Thus, the composition according to the present invention may further comprise at least one second active ingredient selected from the group consisting of Tamsulosin, Silodosin, Doxazosin, Terazosin, Alfuzosin, Bicalutamide and pharmaceutically acceptable salts and solvates thereof.

In one of the further aspects, the pharmaceutical composition of the present invention may be administered in combination with other active ingredients in the same dosage form or different dosage forms. The other active ingredients are those effective in the treatment of benign prostatic hyperplasia, and include but are not limited to, alpha-1-adrenoreceptors, anti-androgens and pharmaceutically acceptable salts and solvates thereof. Examples of suitable alpha-1-adrenoreceptors include Tamsulosin, Silodosin, Doxazosin, Terazosin and Alfuzosin. Bicalutamide is an example of a suitable anti-androgen.

In one of the further aspects, the present invention also encompasses a pharmaceutical composition comprising a capsule dosage form of Dutasteride in combination with a second dosage form of an additional active ingredient. The additional active ingredients are those effective in the treatment of benign prostatic hyperplasia, and include but are not limited to, alpha-1-adrenoreceptors, anti-androgens and pharmaceutically acceptable salts and solvates thereof in an immediate-release or a modified-release form. Examples of suitable alpha-1-adrenoreceptors include Tamsulosin, Silodosin, Doxazosin, Terazosin and Alfuzosin. Bicalutamide is an example of a suitable anti-androgen.

In one of the further aspects, the composition comprises a solid pharmaceutical composition of Dutasteride combined with a solid composition containing the second active ingredient. The solid composition of Dutasteride can be in the form of granules, pellets, tablets, micro-/mini-tablets or microspheres. The solid composition containing the second active ingredient can be in the form of granules, pellets, micro-/mini-tablets, tablets or microspheres. Both compositions can be combined into a solid dosage form, e.g. by filling both compositions into hard gelatin capsules.

It has surprisingly been found that the pharmaceutical composition according to the invention is a stable composition showing a suitable dissolution profile of Dutasteride and a satisfactory bioavailability of Dutasteride. The composition can be prepared by an easy and quick process. In particular, there is no need to provide a micro-emulsion comprising Dutasteride nor is there a need to micronize Dutasteride and, therefore, harmful fine powders of Dutasteride can be avoided. Furthermore, there are no special requirements as to the polymorphic form or the particle size of the Dutasteride. Excellent content homogeneities can be obtained by the pharmaceutical composition according to the present invention.

The pharmaceutical compositions of the present invention can also be prepared using other active agents showing similar therapeutic activities, that Dutasteride shows and belong to the similar therapeutic class, that Dutasteride belongs. Such other agents for example are Finasteride, Tamsulosin and the like or pharmaceutically acceptable salts thereof or derivatives thereof. Such pharmaceutical compositions comprising above mentioned therapeutic agents are also encompassed within the scope of the present invention.

The pharmaceutical compositions according to the present invention can be packed into a primary packaging having decreased permeability for water such as high-density polyethylene (HDPE) containers with closure, such as polypropylene (PP) closure, and with or without a desiccant; aluminium foil blisters; polychlorotrifluoroethylene blisters or any other suitable water vapor low permeable packaging such as blisters made of multilayer polymeric foil where different polymeric materials are combined. The pharmaceutical compositions of the present invention may also be packed into containers made from polypropylene, polystyrene and the like with closure, and with or without desiccant. The pharmaceutical compositions of the present invention may also be packed into blister packing such as polyvinyl chloride blisters, polychloro-trifluoro-ethylene blisters, cyclic olefin copolymers blisters; strip packaging such consisting one or two plies, made from regenerated cellulose, paper, plastic, foil or combination thereof. The pharmaceutical compositions of the present invention may also be packed into low-density polyethylene (LDPE) pouches or aluminum pouches.

The pharmaceutical compositions of the present invention can be described as following general formula:
Table-1: General formula of the pharmaceutical compositions of the present invention
Sr. No. Ingredient % w/w
Part-1: Dutasteride Tablet
Drug Solution
1 Dutasteride 0.01-5
2 Solubilizer(s) 0.5-40
3 Anti-oxidant(s) 0.1-5
4 Diluent(s) 5-90
5 Solvent(s) Q.S.
Base material
6 Binder 0.5-50
Extra granular material
7 Diluent(s) 5-90
8 Disintegrant(s) 0.5-50
9 Lubricant(s) 0.1-10
Part-2: Blend mixture
10 Lubricant(s) 0-90
11 Disintegrant(s) 0-10

In one of the further aspects, the present invention provides process for the preparation of the pharmaceutical compositions of Dutasteride. The process comprises following steps:
(a) Dissolve API, one or more solubilizer(s) and one or more antioxidant(s) in the solvent;
(b) Disperse one or more diluent(s) in step (a);
(c) Pour the drug coating solution prepared according to step (b) on one or more binder(s);
(d) Drying and milling of the mass obtained in step (c);
(e) Sift one or more diluent(s) and disintegrant(s) through 30#;
(f) Mix blend of step (e) with granules of step (d) in blender;
(g) Sift one or more lubricant(s) through 40#;
(h) Mix one or more lubricant(s) of step (g) with blend of step (f); and
(i) Compress the blend of step (h) into tablet;
(j) Sift one or more lubricant(s) and disintegrant(s) through 30#;
(k) Mix sifted ingredient of step (j) in blender; and
(l) Fill the blend obtained in step (k) and tablet obtained in step (i) in empty hard gelatin capsule.

Those who are skilled in the art can understand that some variations in the process described herein can be adopted. A skilled person may omit use of some pharmaceutical excipients as described herein. A skilled person may also alternatively use some or all pharmaceutical excipients as described herein from the same excipient classes. Such variations are well within the scope of the present invention. A skilled person can also change and/or omit steps of their sequences of the herein described process for the purposes of suitability and convenience where one or more pharmaceutically acceptable excipients may or may not be used without affecting and diminishing the quality and characteristics of the resulting product. For example, when the pharmaceutical compositions according to the present invention are tablet compositions, steps (j) to (l) may be omitted. Such variations/changes/omissions/additions are well within the scope of the present invention.

The present invention is further exemplified by the following non-limiting examples.

BEST MODE OF CARRYING OUT THE INVENTION

EXAMPLES
The solid pharmaceutical compositions of the present invention are explained in more detail with reference to the following examples. These examples are provided by way of illustration only and should not be construed as to limit the scope or spirit of the claims in any manner.
Example-1: Preparation of Pharmaceutical Composition of Dutasteride according to the Present Invention
Sr. No. Ingredient Quantity (mg/capsule)
Part-1: Dutasteride Tablet
Drug Solution
1 Dutasteride 0.5
2 Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) 3.0
3 Butylated Hydroxy Toluene (BHT) 0.1
4 Butylated Hydroxy Anisole (BHA) 0.1
5 Lactose anhydrous 3.3
6 Ethanol Q.S.
Base material
7 Hydroxy Propoyl Methyl Cellulose 10.0
Extra granular material
8 Lactose anhydrous 52.0
9 Crospovidone (Poly plasdone ultra 10) 19.5
10 Magnesium stearate (Ligamed MF 3V) 1.5
Total weight of Part-1 90.0
Part-2: Blend mixture
11 Lactose anhydrous 172.0
12 Crospovidone (Poly plasdone ultra 10) 8.0
Total weight of Part-2 180.0
Capsule Filling
13 Part-1: Dutasteride tablet 90.0
14 Part-2: Blend mixture 180.0
15 Size “2” empty hard gelatin capsule 1 unit (63.0 mg)

Method of Preparation:
Part-1: Preparation of Dutasteride Tablet
Steps:
1. Dissolve Dutasteride, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), Butylated hydroxy toluene and Butylated hydroxy anisole in anhydrous ethanol;
2. Disperse Lactose anhydrous in solution obtained in step (1);
3. Pour the drug coating solution on base material i.e. Hypromellose E5;
4. Dry the dough mass obtained in step (3) under vaccum;
5. Mill the dried mass obtained in step (4);
6. Sift Lactose anhydrous and Crospovidone (Poly palsdone Ultra 10) through 30#;
7. Mix blend of step (6) with granules of step (5) in blender;
8. Sift Magnesium stearate through 40#;
9. Mix sifted Magnesium stearate of step (8) with blend of step (7); and
10. Compress the blend of step (9) into tablet with suitable tooling.

Part-2: Preparation of Blend mixture
Steps:
11. Sift Lactose anhydrous and Crospovidone (Polypalsdone Ultra 10) through 30#; and
12. Mix sifted ingredient of step 11 in blender.

Part-3: Filling up capsule
13. Fill the blend of step 12 and tablet of step 10 in empty hard gelatin capsule.

Those who are skilled in the art can understand that for the preparation of tablet compositions according to the present invention, steps (11) to (13) may be omitted.

Example-2: Dissolution rate of the pharmaceutical composition of the present invention
The rate of dissolution of the resulting formulations were measured according to the following method.
Dissolution Method
Apparatus Paddle
Temperature 37.5°±0.5°C
Volume of dissolution medium 900 mL
Stirring speed 50 RPM
Sampling time 5, 10, 15, 20, 30, 45, 60 min.
Dissolution medium 0.1 N HCl with 2% SLS

Results of the dissolution tests performed are summarized in the table below.
Time
(in minutes) EU RLD-Lot No.: AA2427
Pilot BE Reference) DUTC1028 (EG in Capsule)
Pilot BE Test
5 8.1% 66%
10 37.2% 90.2%
15 50.8% 91.7%
20 72.9% 93.7%
30 82.6% 94.8%
45 87.8% 95.4%
60 91.8% -
Whole capsule Test product

Example-3: Stability studies of the pharmaceutical composition of the present invention
Stability of the pharmaceutical compositions of the present invention were tested under different storage conditions. It was surprisingly found that the capsule dosage forms according to the present invention are stable at least for two months when stored under storage conditions. The stability study results are provided in the table below.
Test Results
Initial 40°C ± 2°C/75 ± 5 RH
1 month 2 months
Description Opaque blue colour, Size “2” hard gelatin capsule, imprinted with thick black band on cap and yellow thick band on body, containing white tablet and off-white powder
Assay of Dutasteride 102.2% 100.5% 103.0%
Assay of Butylated Hydroxy Anisole 100.4% 98.0% 100.6%
Assay of Butylated Hydroxy Toluene 100.6% 98.0% 91.9%
Dissolution (15 mins.) 92.0 91.0% 92.0%
Related Substances
Any individual impurity (NMT 0.5%) 0.21% 0.20% 0.21%
Total impurities (NMT 5.0%) 0.21% 0.20% 0.21%
NMT = Not More Than

Example-4: Bioequivalence study of the pharmaceutical composition of the present invention
An open label, balanced, randomized, two-treatment, single-period, single-dose, parallel groups oral bioequivalence study of Dutasteride capsules 0.5 mg of the present invention (Test Product) and AVODART® 0.5 mg soft capsules (Reference Product) of GlaxoSmithkline UK Limited was conducted in normal, healthy, adult, male human subjects under fasting conditions. The results are summarized in table below.

Bioequivalence study results summary (Cmax)
Treatment N Mean SD Geometric LSM Ratio 90% CI
Test Product (T) 6 3042.2867 1272.23274 2868.945 87.46 56.06, 136.47
Reference Product ® 6 3603.3108 1626.07077 3280.157
Inter-subject CV: 44.51, Power: 19.38
P-value for test of treatment effect: 0.5972
Geometric LSM = Geometric least-squares mean (back-transformed from the log scale)
SD = back-transformed between-subject standard deviation
Ratio = Least-squares mean ratio (Test/Reference)*100

Bioequivalence study results summary (AUC0-72)
Treatment N Mean SD Geometric LSM Ratio 90% CI
Test Product (T) 6 66232.9397 22299.1855 62729.197 110.92 71.15, 172.92
Reference Product ® 6 61772.9114 27572.5849 56553.028
Inter-subject CV: 44.41, Power: 19.42
P-value for test of treatment effect: 0.6812
Geometric LSM = Geometric least-squares mean (back-transformed from the log scale)
SD = back-transformed between-subject standard deviation
Ratio = Least-squares mean ratio (Test/Reference)*100

Above mentioned data shows that the pharmaceutical compositions of the present invention are suitable for the treatment or conditions where the Dutasteride is an effective therapy and can be a better choice over existing Dutasteride formulations (e.g. soft capsules-AVODART®) where geriatric patients and other patients have problem of swallowing large sized capsules. Such patients can be benefited by the administration of small sized gelatin capsules of the present invention.

It should be understood that various changes and modifications to the presently preferred embodiments and examples described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.