FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION : A METHOD OF PREPARATION OF AN
ORAL SOLID DOSAGE FORM CONTAINING AN INSOLUBLE 5-ALPHA -
REDUCTASE INHIBITOR AND PHARMACEUTICAL PREPARATIONS
CONTAINING THEREOF
2. APPLICANT(S)
(a) NAME : TITAN LABORATORIES PVT. LTD.
(b) NATIONALITY : An Indian company incorporated under
the Companies Act, 1956
(c) ADDRESS : 102 TITAN HOUSE ,
M.P.VAIDYAMARG, 60 FEET ROAD, GHATKOPAR - EAST, MUMBAI-400 077 MAHARASHTRA INDIA
3. PREAMBLE TO THE DESCRITION
COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of the invention:
The present invention relates to a method of preparation of an instant release oral solid dosage form particularly non-pareil seeds or pellets or beads comprising the active which is an insoluble 5α-reductase inhibitor and pharmaceutical preparations containing thereof.
Background and Prior Art of the invention:
Prostate cancer continues to be a leading cause of cancer death in males worldwide. In the prostate, androgens play a crucial role in both normal and cancerous growth; hence, the androgenic pathway has become a target of therapeutic intervention. Testosterone is converted by 5α-reductase (5aR) isoenzymes to the more potent ligand dihydrotestosterone (DHT), which binds to the androgen receptor (AR) thus promoting proliferation and survival of target tissues, such as the prostate.
5α-reductase inhibitors (or 5-alpha-reductase inhibitors) are a group of drugs with antiandrogenic activity, used in the treatment of benign prostatic hyperplasia and androgenic (or androgenetic) alopecia. These drugs decrease the levels of available 5α-reductase prior to testosterone's binding with the enzyme, thereby reducing levels of dihydrotestosterone that derives from such a bond.

Dutasteride is a 5α-reductase inhibitor a 4 -azasteroid compound that inhibits the conversion of testosterone into dihydrotestosterone. Dutasteride capsules have been approved by the FDA for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate gland. Dutasteride is a dual 5α-reductase inhibitor, blocking both type 1 and type 2 5α-reductase isozymes.
Dutasteride is chemically designated as (5α, 17β)-N-{2, 5-bis (trifluoromethyl) phenyl}-3-oxo-4-azaandrost-l-ene-17-carboxamide. The empirical formula of dutasteride is C27H30F6N2O2, representing a molecular weight of 528.5 with the following structural formula:

Dutasteride is a white to pale yellow powder with a melting point of 242° to 250°C. It is soluble in ethanol (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is insoluble in water.
Dutasteride is commercially available under the trade name AVODART® (GlaxoSmithKline (Research Triangle Park, N.C.))- AVODART® Soft Gelatin

Capsules for oral administration contain 0.5 mg of the active ingredient dutasteride in yellow capsules with red print. Each capsule contains 0.5 mg of dutasteride dissolved in a mixture of mono-di-glycerides of caprylic/capric acid and butylated hydroxytoluene.
Dutasteride belongs to a class of drugs called 5-alpha-reductase inhibitors, which blocks the action of the 5α-reductase enzymes that convert testosterone into dihydrotestosterone (DHT). Finasteride, which is also approved for the treatment of benign prostatic hyperplasia (BPH), in addition to the treatment of male pattern baldness (MPB), belongs to this class of drugs. Dutasteride inhibits both isoforms of 5a-reductase, type I and type II, whereas finasteride only inhibits type II. There are no long-term randomized trials comparing the effects of dutasteride and finasteride in patients with BPH. The EPICS trial, a 12-month clinical study done by GlaxoSmithKline, demonstrated treatment with dutasteride and finasteride resulted in similar decreases in prostate volume, with numerically but not statistically significantly greater improvements in symptom scores for the dutasteride group. Finasteride is marketed by Merck under trademark names Proscar (5 mg/day finasteride) for BPH and Propecia (1 mg/day finasteride) for MPB. Published data from controlled clinical trials demonstrated the 5 mg dose of finasteride did not produce better results than the 1 mg dose.

US7022854 (Dr. Reddy's Laboratories Ltd.) discloses crystalline Form II and process of preparation of crystalline Form I, II and the amorphous form of Dutasteride.
WO 1999/08684 (Glaxo Group Ltd); discloses a pharmaceutical composition of a novel solution of active aza steroid with polyethylene glycol and propylene glycol. In another aspect, the invention discloses a gelatin capsule filled with the novel solution composition of the invention. It claims a soft gelatin capsule.
EP2050436 (Siegfried Generics Int AG) discloses solid pharmaceutical composition for oral administration containing 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 urn (10 micron); method of making said composition and use of the composition in the treatment of benign prostatic hyperplasia (BPH) and alopecia. It further describes that dry or wet standard processes available for mixing dutasteride with excipients. The process for preparing compositions in form of a dry powder blend comprises mixing Dutasteride with excipients, for example in a low-shear mixer or a container blender. Sieving steps can be optionally included in the process to increase homogeneity of the powder blend. Granules can be prepared by dry granulation, e.g. roller compaction. In a wet mixing process the active pharmaceutical ingredient and the excipients are mixed with a liquid to form

a suspension, which is converted into granulates by drying. Wet granulation with water or with an organic solvent is typically carried out in a high shear mixer, in a fluid bed granulator or in any other established equipment. The final pharmaceutical dosage form of the pharmaceutical composition in the form of a powder blend or granules can be filled either in capsules or sachets or can be compressed into tablets on a tablet press, preferably on a rotary tablet press. Optionally dosage forms such as granules, pellets, micro-spheres, micro-tablets, tablets and also filled capsules may be coated by standard coating processes in suitable equipment.
Even though EP 2050436 disclose the pharmaceutical composition containing dutasteride, i.e. the final solid dosage form, can be present as a pharmaceutical dosage form known per se, preferably as a powder, as pellets, as a granulate, as micro-spheres, as micro-tablets, as a tablet, or filled in a capsule, for example in a hard gelatin capsule. It also states that the intermediate formulation which is used to produce the pharmaceutical composition preferably is present for example in the form of a powder comprising dutasteride or as a powder mixture comprising dutasteride in combination with one or more excipients.
US2006204588 (Elan Pharma International Ltd) describes nanoparticulate compositions having an effective average particle size of less than about 2000 nm of finasteride, dutasteride, tamsulosin hydrochloride, or a combination thereof. The

formulations exhibit unexpectedly prolonged release and can be maintained in a depot for release to a patient for a period of up to six months.
US6569463 B2 (PATEL MAHESH V [US]; CHEN FENG-JING [US]) discloses a solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat can include different combinations of pharmaceutical active ingredients, hydrophilic surfactant, lipophilic surfactants and triglycerides. The claims direct to the substrate as a powder or a multiparticulate wherein the multiparticulate is a granule, a pellet, a bead, a spherule, a beadlet, a microcapsule, a millisphere, a nanocapsule, a nanosphere, a microsphere, a platelet, a tablet or a capsule. This prior art does not disclose such a composition for molecules which are insoluble in water.
WO 2005/051344 (Pliva Lachema AS) discloses a method of preparation of an oral solid dosage form with instant release of an active agent containing as the active agent finasteride characterized in that that an aqueous suspension containing 5% to 50% by weight of finasteride, based on the total weight of the suspension, and 0.1% to 50% by weight of at least one anion surfactant, based on the weight of finasteride is milled in order to reach such distribution of particle size of finasteride that the size of 10% of particles does not exceed 2 urn, the size of 50% of particles does not exceed 7µm, and the size of 90 % of particles does not exceed 17µm, then, the obtained aqueous suspension is sprayed to a fluid bed onto a solid particle

hydrophilic carrier having such distribution of particle size that the size of 90% of particles exceeds 40µm and the size of 10% of particles exceeds 200µm,; and the size of 99% of particles does not exceed 300um.
Although prior art teaches the pellet preparation of Finasteride and other less soluble drugs wherein the aqueous drug suspension is sprayed onto the solid carrier no such approaches are tried for water insoluble 5a -reductase inhibitors like Dutasteride.
WO2010092596 (Genepharm India Private Limited); discloses an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising 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 composition upon dilution with aqueous medium forms microemulsion with atleast 95% particles having mean particle size below 200 nm. This invention utilizes the SMEDDS technology.
In above available prior art the drugs need to be dispensed in a particular particle size range, form etc. hence their applicability will be restricted to specific physical and chemical characteristics of the active ingredient namely Dutasteride.

Dutasteride is a water insoluble drug and the commercial availability of Dutasteride is in the form of soft gel capsules. Certain drawbacks of soft gel capsules are that many pharmaceutical companies do not have the equipment necessary to fill soft gelatin capsules and have to transport the drugs to have them processed, adding to the cost. Also soft gelatin capsules are very sensitive to heat and humidity. In hot or humid climates, soft gel caps may stick together or even break open before you have a chance to use them. Unlike soft gelatin capsules hard gelatin capsules are manufactured in one operation and filled in a completely separate operation by means of completely automated operations.
In further contrast to soft gelatin capsules, hard gelatin capsules typically are filled with powders, granules, or pellets. Modified release granules or pellets may be filled without crushing or compaction, thus avoiding disruption of barrier coats or other possible adverse effects on the release mechanism.
In soft gelatin capsules there is a more intimate contact between the shell and its liquid contents than that which exists with dry filled hard gelatin capsules (JP Stanley. Capsules II. Soft gelatin capsules. In: L Lachman, HA Leiberman, JL Kanig, eds. The Theory and Practice of Industrial Pharmacy, 2nd ed. Philadelphia: Lea & Febiger, 1976, pp 404±420.). Drugs can migrate from an oily vehicle into the shell, and this has been related to their water solubility and partition coefficient between water and the non- polar solvent (NA Armstrong, KC James, WKL Pugh.

Drug migration into soft gelatin capsule shells and its effect on the in-vitro availability - J Pharm Pharmacol 36:361± 365, 1984.)
Although the SEDDS/SMEDDS technology has an upper hand in many pharmaceutical dosage forms because of its improved bioavailability and facilitation of solubility of hydrophobic drugs there are certain disadvantages i.e. SEDDS / SMEDDS technology typically comprises of the active, oil, surfactant and a solubilizer and other excipients .Use of oil directs one to the use of oil soluble drugs only also use of oil may lead to toxicity issues if the finished dosage forms are not stored as requirement.
In addition the processes involved in soft gel or liquid or emulsion filled dosage forms of capsules is more complicated than any other solid oral dosage forms.
Prior art discloses pharmaceutical dosage forms of Dutasteride wherein the process involves addition of Dutasteride of particular particle size in powder form or in the form of suspension to formulate the core containing the active Dutasteride.
Emphasizing on the available prior art and drawbacks the inventors have designed a process for a manufacturing pellets of an insoluble 5α-reductase inhibitor particularly Dutasteride (in the form of Dutastefide pellets) where a hydro alcoholic suspension of Dutasteride is sprayed onto the non-pareil seeds or pellets or beads. The oral pharmaceutical dosage form of the pharmaceutical preparation

in the form of seeds or pellets or beads of Dutasteride can optionally, be filled in hard gelatin capsule shells or they can be further formulated in the form of tablets, disintegrating tablets, suspensions etc. which can exhibit a significant therapeutic advantage over single unit dosage form.
Hence the inventor's approach here is to provide a method of preparing a solid oral dosage form of Dutasteride seeds or pellets or beads and the pharmaceutical preparation thereof.
Summary of the invention:
It is an object of the invention to provide Dutasteride pellets.
It is another object of the invention to provide a process for manufacturing Dutasteride pellets wherein the API is loaded onto the non pareil seeds in the form of a hydroalcoholic suspension.
It is yet another object of the invention to provide a finished dosage form of capsule containing the stable pellets of Dutasteride.
In an optional embodiment, the final coated seeds or pellets or beads of Dutasteride can be further filled in hard gelatin capsules or can be further formulated in the form of tablets, disintegrating tablets, suspensions etc as required.

Brief Description of Drawings:
Fig. 1 illustrates a process flowchart for the process for manufacturing of Dutasteride particles of invention.
Detailed Description of the invention:
Core refers to the center portion of a layered or coated drug delivery system. The core portion typically comprises active agent(s), either with or without added excipients, and also includes beads, such as sugar beads or extruded beads, tablets, beads, particles, or capsules impregnated or coated with an active agent.
In an embodiment, the core consists of active ingredient blended with at least one surfactant, at least one binder and at least one anti-adhesive.
In an embodiment, the process for manufacturing core comprises of coating the non-pareil seeds with hydro-alcoholic suspension of active ingredient, that is, Dutasteride.
The hence formed coated cores are further subjected to, optional colour coating, wherein the colour coating solution comprises of a film forming agent, an anti-adhesive agent and pigments and pharmaceutically acceptable colours.

In an embodiment, the coating of hydroalcoholic suspension on non-pareil seeds is carried out by conventional coating method such as fluid bed coating, spray coating, pan coating or powder layering.
In an optional embodiment, the drug coated cores can further be subject to colour coating. The colour coating aids in distinction of the drug pellets, in a situation whereby there is requirement of mixing two or more active ingredients. The process employed for colour coating of the core can be any method conventionally known in art like fluidized bed coating or spray coating.
In an additional embodiment the pellets as formed by process mentioned herein forth can further be formulated in form of capsules or tablets or suspensions or solution, as desired. In case of further processing required for final formulation, any required additional excipients may be added.
In an embodiment, the process of the invention involves the following steps:
1. Preparing of aqueous solution of binder and surfactant;
2. preparing alcoholic solution of active;
3. preparing hydro alcoholic suspension by mixing solutions of step (1) and step
(2);
4. coating the non pareil seeds or pellets or beads with a hydro alcoholic drug suspension of step (3);
5. drying the drug loaded seeds or pellets or beads of step (4) and

6. optionally, colour coating the drug coated non-pareil seeds or pellets or beads of step (5) for product identification.
The invention will now be illustrated with help of example. The aforementioned embodiments and below mentioned examples are for illustrative purpose and are not meant to limit the scope of the invention. Various modifications of aforementioned embodiments and below mentioned examples are readily apparent to a person skilled in the art. All such modifications may be construed to fall within the scope and limit of this invention as defined by the appended claims.
EXAMPLES:
Example 1:
DRUG LOADED PELLETS
The below formula as given in Table 1 was standardized after optimizing the qualitative and quantitative parameters of the excipients and the process. Table 1:

Sr.
No Ingredients %Qty Function
1 Dutasteride 0.605 Active
2 Sodium Lauryl Sulphate 0.4 Surfactant
3 HPMC E-5 2.0 Binder
4 Talc 0.7 Antiadhesive
5 IPA* 35.33 Solvent
6 Water* 48.18 Solvent
7 NPS(18/20#) 96.295 Core

* Note: IPA & Water gets evaporated in the process hence not calculated in the final product. API: 20% overages
Particle size data of API: The particle size of API used in Example 1 is as below; D10: 2.263 µm D50: 14.270 µm D90: 40.370µm
Particle size data of Drug Suspension: The observed particle size of the drug suspension used in example 1 was as below; D10: 5.749 µm D50: 21.914 µm
D90: 42.223 µm
Procedure:
1. Dissolve HPMC E-5 in water. Then add Sodium Lauryl Sulphate
2. Dissolve Dutasteride in Iso Propyl Alcohol.
3. To step (2) add the solution of step (1) under stirring. Then disperse Talc. Keep the solution under stirring throughout the coating.
4. Take the NPS of size 18/20# and load in FBC and start drug loading.
5. Dry the pellets at 45°C for 30 min get LOD NMT 3% checked at 105°C.

6. Store the pellets in double polybag, label properly and keep at temperature 2-8°C
Particle size of finished product:
ASTM 18/25#
Bulk density: 0.7 - 0.9 gm/ml
Processing parameters:
Inlet Temp: 50°C
Spray Rate: Atomization: 0.1-0.3 Kg/cm2
Practical Yield: 98-99%
Processing Condition:
Temperature: NMT 30°C and Humidity: NMT 65%
Use 3M Nose mask, Gloves and cap during processing.
Coating of drug loaded pellets:
Drug loaded particles, as obtained in Example 1 were optionally coated with colour coating solution having composition as per Table 2;

Table 2:

Sr. No. Color coating Standard Quantity
(ing)
1 Drug Pellets 150.0
2 Sunset yellow Lake 0.94
3 Talc 0.129
4 TiO2 0.009
5 HPMC E5 0.126
6 1PA 34.5
7 MDC 34.5
Coated Pellets (18-25#)
Coating Suspension, as presented in Table 2, was prepared using known techniques available in prior art and the Drug loaded pellets of Example 1 were coated, by adopting optimized spraying and coating parameters according to Design Space study protocol as depicted in Table 4.
The formulation of Example 1 was subjected to stability studies and the results obtained are presented in Table 3 below:

Table 3:

Example 1
Stability Condition Initial 40oC/75 % 1 Month
Assay 99.8% 99.2%
Disso 99.8% 98.7%
Design space study:
1. High Spray Rate and Slow spray rate
2. Low bed (100 gm) and High Bed (850 gm)
3. Increased qty of binder
4. Increased qty of water
5. Replacement ofSLS with Tween 80

Table 4:

Sr. Ingredient
No. s Examples (Standard Quantity in mg)
Example
2 (Drug
Suspensio
n for
particle
size Example Example Example

Example Example Example Example Example Example 9 10 11
STAGE DP
3 DP
stage 4 DP stage 5 DP stage 6 DP stage 7 DP
stage 8 DP stage DP stage 300g DP stage 300g DP stage 300g

600g 100g 850g 600g 600g 300g Std. Qty. Std. Qty. Std. Qty.
analysis mg mg mg
1 Dutasteride 0.605 0.605 0.605 0.605 0.605 0.605 0.605 0.605 0.605 *
2 SLS 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4
3 HPMC E5 2 2 2 2 2 2 8 (8%) 6 (6%) 4 (4%) *
4 PVP K30 * * * * * * * * * 2
5 Talc 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7
6 IPA 35.33 35.33 35-33 35.33 35.33 35.33 35.33 35.33 35.33 24.73

7 Water 48.18 48.18 48.18 48.18 48.18 48.18 48.18 48.18 48.18 33.72
8 NPS
(18-20#) * 96.295 96.295 96.295 96.295 96.295 90.295 92.295 94.295 96.4
Total 100 100 100 100 100 100 100 100 100

Table: 5

Details Optimized batch Low Bed High bed Fast spray rate Slow spray rate High conc, of HPMC Reduced qty of solvent
Batch No Example 2 Example 4 Example 5 Example 6 Example 7 Example 8 Example 11
Batch size 600 gm 100 gm 850 gm 600 gm 600 gm 300 gm 300 gm
Inlet Temp (°C)(Set/Actual) 50/48-50°C 50/48°C 50/48-50°C 50/50-51°C 50/47.1-49.8°C 50/48.8-49.3°C 50/49°C
Product Temp(°C) (Actual) 47-52°C 49-50°C 48-53°C 48-49.1°C 48.3-49.8°C 47-48°C 48.2-49.8°C
Automization Air Kg/cm2 0.9 0.4 0.9 0.9 0.9 0.9 0.9
Blower RPM 3640-3649 3119-3200 3640-3648 3639-3641 3637-3641 3632-3638 3639-3640
Wurster column Height 3.7 cm 1.5 cm 4.2 cm 3.5 cm 2.7 cm 2.2cm 2.3 cm
Pump RPM 3-5 2-3rpm 3-5 5-12 1-3 3-5 3-4

Spray Rate At 5 rpm: At 3 rpm: At 5 rpm: At 5 rpm: At 2 rpm: 1.67 At 3 rpm: At 3 rpm:
4.36 g/min 2.41 g/min 4.32 g/min 4.36 g/min At 8 rpm: 6.76 g/min g/min
At 3 rpm: 2.48
g/min 1.9g/min 2.1 g/min
Time required 3 hrs 15 min 1 hr 15 min 6 hrs 15 min 1 hr 20 min 7 hrs 40 min 2 hrs 20 min 2 hrs
for coating

Examples 2, 4, 5, 6, 7, 8 were subjected to accelerated conditions of 40°C ±2°C/75% RH ±5% for one month. The results of stability studies are presented in table 6 below.
Table 6:

Example Example Example Example Example Example
2 4 5 6 7 8
Trial Optimum Low High High Low High
Details batch Bed Bed spray rate spray rate conc. Of HPMC
Assay 101.9 110.5 121.5 113.7 109.6 120.7
Disso 98.9 84.2 92.9 110.7 104.9 109.3

Table 6A Stability Data:

Example 2
Stability Condition Initial 40°C/75 % 1 M
Assay 105.4% 102.7
Disso 105.8% 101.8%
Table 6B:
Stability Data:

Example 3
Stability Condition Initial 40°C/75 % 1M
Assay 104.2 102.8
Disso 103.4 101.3
The examples mentioned are illustrative only and does in no way limit the scope of the patent defined unambiguously by the definition of the claims and the contents of the patent description.

We Claim,
1. A hydroalcoholic suspension layering method for preparing pellets comprising an insoluble 5-alpha -reductase inhibitor.
2. The method as claimed in claim 1, wherein the insoluble 5-alpha-reductase inhibitor is Dutasteride.
3. The method as claimed in above claims wherein the pellets comprising Dutasteride are inert cores coated with the suspension containing the active ingredient.
4. The method as claimed in the preceding claims comprising steps of: i. Preparing Drug suspension;
ii. coating the inert cores with the Drug suspension, and iii. optionally, coating the drug loaded cores obtained in step (ii) with colour coating solution.
5. The method as claimed in Claims 1-3, wherein the drug suspension comprises a hydro-alcoholic solvent mixture.
6. The method as claimed in any of above claims wherein the hydroalcoholic mixture comprises of Water and Iso propyl alcohol.
7. The method as claimed in Claim 6, wherein the hydroalcoholic mixture comprising of water and Iso propyl alcohol is in the ratio of 58:42

8. The method as claimed in the preceding claims wherein the drug suspension
comprises
i. Active
ii. Surfactant
iii. Binder
iv. Antiadhesive agent suspended in the hydroalcoholic solvent mixture.
9. The method as claimed in the preceding claims wherein the Active is Dutasteride, the surfactant is Sodium Lauryl Sulphate, the binder is hydroxy propyl methyl cellulose and the Antiadhesive agent is Talc and wherein the resulting pellets are optionally coated.
10. A pharmaceutical formulation comprising immediate -release Dutasteride pellets obtained by the processes of any of claims 1 to 9 above.