WO2012127495A2

WO2012127495A2 - A pharmaceutical composition and process for preparation thereof

Info

Publication number: WO2012127495A2
Application number: PCT/IN2012/000129
Authority: WO
Inventors: Piyush B. SHAH; Sampada H. TUPE; Chetan B. CHURE
Original assignee: Titan Laboratories Pvt. Ltd.
Priority date: 2011-02-28
Filing date: 2012-02-24
Publication date: 2012-09-27
Also published as: WO2012127495A3

Abstract

The present invention provides a pharmaceutical composition comprising, an inner core; a coating layer comprising insoluble 5-alpha-reductase inhibitor as an active ingredient; and optionally, a colouring layer and process for the pharmaceutical preparation thereof, wherein insoluble 5-alpha-reductase inhibitor is Dutasteride.

Description

A PHARMACEUTICAL COMPOSITION AND PROCESS FOR PREPARATION

THEREOF

Technical field of the invention:

The present invention provides a pharmaceutical composition, comprising an inner core, coated with an active ingredient, i.e. an insoluble 5a-reductase inhibitor, optionally coated with the colouring agent and process for the pharmaceutical preparations 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 5 a-reductase (5 a R) 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.

5a-reductase inhibitors (or 5-alpha-reductase inhibitors) are a group of drugs such as Alfatradiol, Dutasteride or Finasteride with antiandrogenic activity, used in the treatment of benign prostatic hyperplasia and androgenic (or androgenetic) alopecia. These drugs decrease the levels of available 5a-reductase prior to testosterone's binding with the enzyme, thereby reducing levels of dihydrotestosterone that derives from such a bond.

Dutasteride is a 5a-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 5a-reductase inhibitor, blocking both type 1 and type 2, 5a-reductase isozymes.

Dutasteride is chemically designated as (5a, 17β)-Ν-{2, 5-bis (trifluoromethyl) phenyl}- 3-oxo-4-azaandrost-l-ene-17-carboxamide. The empirical formula of dutasteride is C₂7H3oF6N₂0₂, 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 5a-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 5oc-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 soft gelatin capsule filled with the novel solution composition of the invention.

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 μπι (>2.0 micron) and the upper limit of the average particle size of Dutasteride is at about 10 μηι (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 the 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. Although EP 2050436 discloses 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 said pharmaceutical composition preferably is present in the form of a powder comprising Dutasteride as defined above, or as a powder mixture comprising Dutasteride as defined above 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 directed 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 μπι, the size of 50% of particles does not exceed 7μιη, and the size of 90 % of particles does not exceed 17μιη, 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 40μηι and the size of 10% of particles exceeds 200μιη,; and the size of 99% of particles does not exceed 300μηι.

Although prior art teaches the pellet preparation of Finasteride and other less soluble drugs however, the inner core coated with drug suspension of water insoluble 5a- reductase inhibitors like Dutasteride is not tried.

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 at least 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 per 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 pharmaceutical composition, comprising, an inner core coated with an insoluble 5a- reductase inhibitor, particularly Dutasteride and a process for a manufacturing the same, where a hydro alcoholic suspension of Dutasteride is sprayed onto the inner cores are selected from non-pareil seeds, 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. The pharmaceutical composition of the instant invention provides a cost-effective and convenient process for the preparation of the same. Further, the pharmaceutical composition may be provided in different dosage forms with uniform drug content.

Summary of the invention:

In a preferred aspect, the invention provides pharmaceutical composition comprising, an inner core and coating layer containing an insoluble 5-alpha-reducatse inhibitor (Dutasteride). The composition is optionally coated with a coloring layer;

According to the invention, the core refers to the center portion of a layered or coated drug delivery system. The core portion may comprises active agent(s), either with or without added excipients, and also includes beads, such as sugar beads or extruded beads, pellets, seeds, tablets, particles, or capsules impregnated or coated with an active agent.

In another aspect, the invention provides pharmaceutical composition comprising, an insoluble 5-alpha-reducatse inhibitor, particularly, Dutasteride coated non-pareil seeds or pellets or beads which are optionally, coated with pharmaceutically acceptable colours.

In a further aspect, the invention provides a pharmaceutical composition comprising, an insoluble 5-alpha-reducatse inhibitor, particularly^ Dutasteride core with or without excipients, optionally coated with pharmaceutically acceptable colours.

In yet another aspect, the present invention provides a process for manufacturing, an insoluble 5-alpha-reducatse inhibitor i.e Dutasteride coated non-pareil seeds or pellets or beads, wherein the API or drug is loaded onto the non-pareil seeds or pellets or beads in the form of hydroalcoholic drug suspension using conventional methods.

It is yet another aspect of the present invention to provide a finished dosage form of capsule, containing the stable non-pareil seeds or pellets or beads of Dutasteride.

In an another aspect, the final coated non-pareil 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. The non-pareil seeds or pellets or beads of Dutasteride may be provided either as immediate release or sustained release or controlled release by suitably altering the release profile with the use of suitable polymers. Brief Description of Drawings:

Fig. 1 illustrates a process flowchart for the manufacturing of drug loaded core of present invention for example (Dutasteride pellets).

Detailed Description of the invention:

The present invention describes, a pharmaceutical composition, comprising, a) an inner core; b) a coating layer comprising insoluble 5-alpha-reductase inhibitor as an active ingredient and c) optionally, a colouring layer.

Core refers to the center portion of a layered or coated drug delivery system. The core portion may comprises active agent, 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.

The Non-Pareil Seeds (NPS)s are spherical particles of uniform diameter within different grades. They are white, uniform granules that are practically inert, odorless and tasteless. In an embodiment of the present invention, the inner core is selected from non-pareil seeds, pellets or beads or may comprise active ingredient, which is coated with a coating layer, comprising an active ingredient i.e insoluble 5-alpha-reductase inhibitor and other pharmaceutically acceptable excipients such as surfactant, binder, antiadhesive agent, solvents and colours.

In another embodiment, the core consists of, active ingredient, wherein active ingredient is Dutasteride, blended with at least one surfactant, at least one binder and at least one anti-adhesive.

According to above embodiments, the core of the present invention having diameter in the range of from 0.5mm to 2 mm. Further the core comprising about 0.2 % to 1.5 % by weight of active ingredient i.e. Dutasteride. In an embodiment, the process for preparation of pharmaceutical composition of 5-alpha- reductase inhibitor involves the following steps:

1. preparing the hydro-alcoholic drug suspension, which comprises an insoluble 5-alpha- reductase inhibitor, surfactant, binder, antiadhesive agent and other pharmaceutically acceptable excipients;

2. coating the inner core with drug suspension;

3. drying the drug coated core at temp range 30°C-60°C ; and

4. optionally, colour coating to the drug coated core for product identification.

In an another embodiment, the coating of hydroalcoholic drug suspension, consisting an active ingredient on non-pareil seeds or beads or pellets, is carried out by conventional coating method such as fluid bed coating, spray coating, pan coating or powder layering.

In yet another embodiment, the hydro-alcoholic drug suspension can be prepared by the following steps;

a) preparing aqueous solution of binder and surfactant,

b) preparing alcoholic solution of active ingredient,

c) adding solution of step a) to the solution of step b); followed by dispersing the anti- adhesive agent to the hydro-alcoholic mixture to obtain hydro-alcoholic drug suspension.

Accordingly, the drug loaded cores such as non-pareil seeds or pellets or beads are dried at temperature range 30°C-60°C, preferably 45°C, whereas time required for the drying is 10-60 minutes, preferably 30 min, The loss on drying is tested by using conventional method to get result not more than 3.0%.

In accordance to the process described hereinabove, the aqueous solution contains water as a solvent, whereas the alcoholic solution contains an alcohol such as isopropyl alcohol as a solvent. Further the binder used in the hydro-alcoholic suspension is selected from polymers such as hydroxyl propyl methyl cellulose (HPMC), Polyvinylpyrrolidone (PVP); the surface active agents or surfactants are selected from the group consisting of cationic, anionic, nonionic, and ampholytic surface-active agents such as sodium lauryl sulphate (SLS), polysorbate or Tween 80; and the antiadhesive agents are selected from Talc, Kaoline, colloidal silica, preferably Talc; optionally the colouring agents used for coating are selected from pigments such as Ti0₂, Sunset yellow lake etc.

In an optional embodiment, the drug coated cores can further be subjected to colour coating, wherein the colour coating solution comprises of a film forming agent, an anti- adhesive agent and pigments and pharmaceutically acceptable colours. 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 drug loaded cores as formed by process mentioned herein forth can further be formulated in the form of capsules or tablets or suspensions or solution, with additional pharmaceutically acceptable excipients.

The invention will now be illustrated with help of examples. 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 core i.e Dutasteride loaded Non-pareil seeds (without colour coating)

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:

NPS (18/20#): Non-pareil seeds with 18-20 mesh sieve (850-1000μηι)

* Note: IPA & Water gets evaporated in the process hence not calculated in the final product.

API: 20% overages

The process for the preparation of Dutasteride loaded non-pareil seeds involve following steps:

1. dissolving HPMC E-5 in water, then addition of sodium lauryl sulphate,

2. dissolving Dutasteride in iso-propyl alcohol,

3. adding the solution of step 1) to the solution of step 2) under stirring, followed by dispersing the Talc with continuous stirring, throughout the coating,

4. taking the non-pareil seeds of mesh size 18/20#, subsequently loading the seeds in fluidized bed coating (FBD) for drug loading,

5. drying the drug coated seeds/pellets eads at 45°C for 30 min, and getting the LOD, NMT 3.0% at 105°C,

6. Further, storing the dried seeds/pellets/beads in properly labeled, double polybag, at temperature 2-8°C. Further the pharmaceutical composition comprising an insoluble 5 -alpha- inhibitor i.e. Dutasteride is prepared in accordance to the optimized batch parameters as given in Table 5.

Particle size data of API (Dutasteride): The particle size of API used in Example 1 is as below;

Dio: 2.263 μηι

D₅₀: 14.270 μπι

D₉₀: 40.370μπι

Particle size data of Drug Suspension: The observed particle size of the drug suspension used in Example 1 was as below;

Di₀: 5.749 μηι

D₅₀: 21.914 μηι

D₉₀: 42.223 μηι

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.

Colour coating to the drug loaded cores:

Drug loaded cores, as obtained in Example 1, were optionally coated with colour coating solution having composition as per Table 2;

Table 2: Standard Quantity

Sr. No. Color coating

(in g)

1 Drug Pellets 150. 0

2 Sunset yellow Lake 0.94

3 Talc 0.129

4 Ti0₂ 0.009

5 HPMC E5 0.126

6 IPA 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.

The drug loaded cores of Example 1, were coated, by adopting optimized spraying and coating parameters according to Design Space study protocol as depicted in Table 4.

The composition of Example 1, was subjected to stability studies and the results obtained are presented in Table 3 below:

Table 3:

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 of SLS with Tween 80 Table 4:

Table: 5

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:

The composition of Example 2 and Example 3, was subjected to Stability studies at accelerated conditions (40°C ±2°C/75% RH ±5%). The results of the stability studies are presented in Table 6A and 6B respectively.

Table 6A:

Stability Data:

Example 2

Stability 40°C/75 %

Initial

Condition 1 M

Assay 105.4% 102.7

Disso 105.8% 101.8%

Table 6B:

Stability Data:

The examples mentioned are illustrative only and does in no way limit to the scope of the invention defined unambiguously by the definition of the claims and the contents of the patent description.

Claims

We Claim,

1. A pharmaceutical composition comprising, a) an inner core; b) a coating layer comprising an insoluble 5-alpha-reductase inhibitor and optionally, a colouring layer.

2. The pharmaceutical composition according to claim 1, wherein the insoluble 5- alpha-reductase inhibitor is Dutasteride.

3. The pharmaceutical composition according to claim 1, wherein, inner core is selected from non-pareil seeds or pellets or beads or active ingredient(s) with or without added excipients.

4. The pharmaceutical composition according to claim 1, wherein coating layer comprising; an insoluble 5-alpha-reductase inhibitor; surfactant; binder; anti- adhesive agent and solvents.

5. The pharmaceutical composition, according to claim 1, wherein said composition can be formulated into a dosage form selected from the group consisting of capsules, tablets, suspension or solution.

6. The pharmaceutical composition, according to claim 5, wherein said dosage form can be formulated as immediate release or sustained release or controlled release dosage forms.

7. A process for the preparation of pharmaceutical composition of 5-alpha- reductase inhibitor comprising steps of ;

a) preparing drug suspension, which comprises insoluble 5-alpha-reductase inhibitor, surfactant, binder, solvents and anti-adhesive agent;

b) coating the inner cores with drug suspension;

c) drying the drug loaded cores, and d) optionally, coating the drug loaded cores, with colouring agent.

8. The process for pharmaceutical composition, according to claim 7, wherein inner cores, coated with a drug suspension containing an insoluble 5-alpha- reductase inhibitor i.e. Dutasteride.

9. The process for pharmaceutical composition, according to claim 7, wherein the solvent is hydro-alcoholic solvent.

10. The process for pharmaceutical composition, according to claim7, wherein the hydro-alcoholic solvent mixture, comprising of water and isopropyl alcohol in the ratio of 58:42

11. The process for pharmaceutical composition, according to claim 7, wherein an insoluble 5-alpha-reductase inhibitor is Dutasteride; the surfactant is Sodium Lauryl Sulphate; the binder is hydroxy propyl methyl cellulose (HPMC) and the antiadhesive agent is Talc and wherein the resulting drug loaded core is optionally coated with pharmaceutically acceptable colours.

12. The process for the preparation of pharmaceutical composition, wherein an insoluble 5-alpha-reductase inhibitor is Dutasteride and is prepared in accordance to the optimized batch process parameters as given in Table 5.