WO2014167579A2

WO2014167579A2 - Stable pharmaceutical compositions of tadalafil

Info

Publication number: WO2014167579A2
Application number: PCT/IN2014/000196
Authority: WO
Inventors: Sautik BHATTACHARYA; Ashutosh JAMLOKI; Pavan Kumar M; Ashish SHEGAL
Original assignee: Astron Research Limited
Priority date: 2013-03-28
Filing date: 2014-03-28
Publication date: 2014-10-16
Also published as: IN2013MU01177A; WO2014167579A3

Abstract

The present invention relates to stable pharmaceutical compositions of Tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 μιτι and one or more pharmaceutically acceptable excipients. Further the present invention also discloses the process for the preparation of the said stable pharmaceutical composition.

Description

FIELD OF INVENTION

The present invention relates to stable pharmaceutical compositions of Tadaiafil for oral administration. Further, the present invention also discloses the process for the preparation of the said stable pharmaceutical composition.

BACKGROUND OF THE INVENTION

Tadaiafil, the active ingredient in CIALIS has been used for the treatment of male erectile dysfunction. Tadaiafil has chemical name (6R-trans)-6-(1 ,3-benzodioxol-5-yl)- 2,3,6,7, 12, 12a-hexahydro-2-methyl-pyr-azino[ 1 ',2': 1 ,6] -pyrido[3,4-b] -indole- 1 ,4 dione. The chemical formula of Tadaiafil is C22H1 3O4 representing a molecular weight of 389.41. Tadaiafil chemical structure is:

Tadaiafil

Further, Tadaiafil is practically insoluble in water and is very slightly soluble in some organic solvents. US Patent No.6,841,167 reports that tadaiafil has a water solubility of about 2 μι-ng per mL of water at 25°C. The extremely limited solubility of Tadaiafil poses many major difficulties and challenges when formulating a dosage form that demonstrates acceptable bioavailability.

Pharmacologically, Tadaiafil is a potent and selective inhibitor of the cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase enzyme PDE5. The inhibition of PDE5 increases the amount of cGMP, resulting in smooth muscle relaxation and increased blood flow. Tadalafil is therefore currently used in the treatment of male erectile dysfunction.

The prescribing information for CIALIS® describes this product as film-coated, almond- shaped tablets for oral administration, containing tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose. iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.

Different techniques have been applied in an attempt to overcome the apparent poor water solubility of tadalafil. US Patent No. 5,985,326 involves preparing formulations using "co-precipitates" of tadalafil, wherein an "intimate mixture" of tadalafil and a carrier in a non-aqueous water miscible solvent, and, optionally, water are co-precipitated from the "intimate mixture" using an aqueous "co-precipitation medium" in which the carrier is substantially insoluble. However, this method requires the use of significant amounts of organic solvent, which is environmentally undesirable.

US Patent No. 6,821,975 describes synthesis of tadalafil wherein 90% of the particles have a particle size of less than about 40 microns and a pharmaceutical composition containing this particle size. However, this method requires micronization, which can be time-consuming and also raise safety issues due to fine powder produced thereof.

US Patent No.6,841,167 disclose a soft capsules comprising tadalafil in "free drug" form in admixture with a diluent, lubricant, a hydrophilic binder, and a disintegrant. Soft capsules containing a solution or suspension of tadalafil have been developed in an attempt to prepare formulations of tadalafil with improved bioavailability. From the above background art, it is evident that particle size of tadalafil and extent of solubilization of tadalafil eventually affects the dissolution and bioavailability of the drug. Different techniques known in the art to improve solubility and dissolution rate for Tadalafil like solid dispersions, co-precipitation, milling, hot melt extrusion and other related approaches. However such techniques are of less importance in formulating a bioequivalent product to CIA LIS®

Considering the formulation aspect, it would be highly desirable to produce a stable pharmaceutical composition for oral administration having high dissolution rate of a poorly soluble drug like tadalafil without any need to reduce particle size of the drug (for example, by micronization).

Surprisingly, it has been found out by the inventors of the present invention that the use of coarser particle size above 40 microns with additional excipients like polymer, surfactant and/or solubilizer in the tadalafil composition resulted into higher dissolution rate and achieve bioequivalence with respect to the reference product CIALIS® available in the market.

OBJECT OF THE INVENTION

The object of the present invention is to provide a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 μηι and one or more pharmaceutically acceptable excipients.

Another object of the present invention provides a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 μητ, polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients. Another object of the present invention provides a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 μηι, polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients, wherein the polymer is hydrophilic binder.

Another object of the present invention provides a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 μιη, polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients, wherein the surfactant is non-ionic surfactant..

Another object of the present invention provides a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 μιη, polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients, wherein the solubilizer is lipid in nature.

Another object of the present invention provides a stable pharmaceutical composition for oral administration comprising tadalafil particles having D90 particle size greater than about 40 μιτι, polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients, wherein the polymer is hydrophilic binder, surfactant is non-ionic surfactant and solubilizer is lipid in nature.

Another object of the present invention is to provide a process for the preparation of a stable pharmaceutical composition of tadalafil comprising tadalafil particles having D90 particle size greater than about 40 μηι, polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide, a process for the preparation of granulation blend comprising tadalafil particles having D90 particle size greater than about 40 μιη, polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil for treatment of sexual dysfunction, e.g., male erectile dysfunction and female sexual arousal disorder.

SUMMARY OF THE INVENTION

The present invention relates to a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 μιη, polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients. The said composition provides suitable solubility and dissolution of Tadalafil and achieves bioequivalence with respect , to the reference product CIAL1S®. Furthermore, the present invention provides a suitable method for preparation of the said stable pharmaceutical composition of Tadalafil.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.

The present invention refers to a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafil particles having D90 particle size greater than about 40 μηι and one or more pharmaceutically acceptable excipients, in order to provide suitable solubility and dissolution of Tadalafil and achieve bioequivalence with respect to the reference product CIALIS®. The term "stable composition" refers to assay value of tadala fi l in tadalafi l pharmaceutical composition within the limits of 95% to 1 05% after stabi l ity study according to ICH guidelines which is comparable when compared with reference product CIALIS®.

The compositions known in the prior art util ized m icronized form of Tadalafi l (i.e. particle size below 40 μηι) to achieve desired dissolution and bioavai labi lity. However the present invention avoids the time-consum ing step o f particle size reduction and is successful in achieving improved dissolution with larger particle size of Tadalafi l by incorporation of unconventional excipients in' the Tadalafi l composition. The said composition may contain Tadalafil either in amorphous or crystal l ine form or their combination, and provides an immediate release of Tadalafil .

Γη preferred embodiments, the present invention provides a stable pharmaceutical composition of tadalafil for oral administration comprising tadalafi l particles having D90 particle size greater than about 40 μιη, more preferably between 45 μιη and 80 μιη.

Preferably, the amount of tadalafi l in the present invention is between about 0.2% and about 20%, between about 2%> and about 1 8%o, between about 2.5% and about 1 0%>, or more preferably between about 3%> and about 8% by weight of total composition.

Preferably, tadalafil is in crystalline form. However, amorphous and partial ly amorphous forms of tadalafi l also are contemplated, and are included within the present invention.

Another preferred aspect of the present invention to provide a stable pharmaceutical composition of tadalafi l for oral administration comprising tadalafi l particles having D90 particle size greater than about 40 μηι, polymer, surfactant and/or solubi lizer and one or more pharmaceutical ly acceptable excipients. Further, the inventors of the present invention tried to design composition for oral administration with an aim to provide suitable solubility and bioavailability of Tadalafil, and achieve bioequivalence with respect to the reference product CI A LIS by incorporation of surfactant and/or solubilizer in the composition comprising tadalafil particles having D90 particle size greater than about 40 μηι. However, such compositions have significant limitations in terms of manufacturing due to the poor compressibility and waxy nature of lipid materials and surfactants. The present invention overcomes manufacturing limitations of said composition by incorporation of polymer which helps in achieving free flowing powder material with improved compressibility suitable for compression into tablet dosage form.

The term "polymer" as used herein refers to a pharmaceutically acceptable binder suitable for use in the present invention that includes for example, but is not limited thereto: low-viscosity hydroxypropylmethylce!lulose (HPMC), hydroxypropylcel!ulose (HPC), carboxymethylcellulose (CMC) or methylcellulose (MC), or povidone or starch or gelatin. Preferably, the polymer is a hydrophilic binder such as HPMC.

The term "surfactant" as used herein refers to a pharmaceutically acceptable non-ionic surfactant. Surfactants suitable for use in the present invention include for example, but are not limited thereto: polyoxyethylene alky 1 ethers, polyoxyethylene alkylaryl ethers, polyethylene glycol fatty acid esters (e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate), alkylene glycol fatty acid mono esters (e.g. propylene glycol monolaurate), sucrose fatty acid esters (e.g. sucrose monostearate, sucrose distearate, sucrose monolaurate, sucrose dilaurate) or sorbitan fatty acid mono esters such as sorbitan mono laurate (Span®), sorbitan monooleate, sorbitan monopalmitate, or sorbitan stearate, or mixtures of one or more thereof. Preferably, the surfactant of the present invention is sorbitan stearate. The term "solubilizer" as used herein refers to pharmaceutically acceptable solubilizer which are lipid in nature and suitable for use in the present invention that includes for example, but are not limited thereto: phospholipid, glyceryl acetate, a fatty acid ester of an acetyiated glyceride, lower alcohol fatty acid ester, propylene glycol ester or a combination thereof. Preferably, the solubilizer of the present invention is Capmul MCM (Glycerol Monocaprylocaprate).

In a preferred object, the present invention provides a process for the preparation of granulation blend comprising tadalafil particles having D90 particle size greater than about 40 μιτι, polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients.

"Granulated blend form" according to the present invention is defined as blend comprising tadalafil particles having D90 particle size greater than about 40 μιτι, polymer, surfactant and/or solubilizer and one or more pharmaceutically acceptable excipients manufactured/prepared with organic solvent in a conventional granulator and shall be conveniently converted to capsules or tablets dosage forms.

Granulated blend form according to the present invention is a blend comprising tadalafil particles having D90 particle size greater than about 40 μιη is uniformly covered/embedded involving manufacturing process such as high shear granulator or fluidized bed processor with solubilizer and/or surfactant together dissolved in mixture of organic solvents. Additionally the said blend contains other pharmaceutical excipients known in the art suitably for preparation of tablets or capsule dosage form.

The pharmaceutical composition of the present invention is prepared by standard pharmaceutical manufacturing techniques known in prior art like wet granulation, dry granulation and direct compression, more preferably wet granulation method. Solvents used in wet granulation method are selected from group of isopropyl alcohol, dichloromethane, acetone, ethanol, purified water and mixture thereof, more preferably isopropyl alcohol and dichloromethane are used in this invention.

Further, the composition according to present invention optionally comprises one or more oral, non-toxic, pharmaceutically acceptable excipient such as lactose, gelatin, starch, microcrystalline cellulose, talc, colloidal silicon dioxide, starch,^' magnesium stearate, stearic acid, and croscarmellose sodium.

According to the present invention, solubilizer and/or surfactant may be included additionally along with lubricants and glidants to the obtained granules post drying stage during granulation.

Another object of the present invention is to provide a process for the preparation of tadalafil comprising tadalafil, polymer, surfactant and one or more pharmaceutically acceptable excipients, wherein atleast 90%. of particles of tadalafil having particle size greater than about 40 μιη.

More preferably the stable pharmaceutical composition of the present invention provides a process for the preparation of tadalafil having particle size greater than about 40 μηι comprising the following steps:

(a) sifting of tadalafil, diluents and disintegrant through mesh and transfer to the granulator;

(b) dissolving binder into an organic solvent;

(c) granulating the ingredients of step (a) using the solution of step (b);

(d) dissolving surfactant and/or solubilizer into organic solvent and granulating with components of step (c);

(e) drying the wet granules to get LOD less than 2%;

(f) sifting and lubricating the dried granules to get homogenous blend; (g) compressing the lubricated blend into tablets and/or fi l led in capsule.

Yet another aspect of the present invention is to provide a method of treating sexual dysfunction in patients in need thereof comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising tadalafi l particles having D90 particle size greater than about 40 μιτι and one or more pharmaceutically acceptable excipients.

Examples

The present invention has been described by way of example on ly. It is to be recogn ized that modifications fall ing within the scope and spirit of the claims, which would be obvious to a person skil led in the art based upon the disclosure herein, are also considered to be included within the scope of this invention.

Example 1 :

Brief Manufacturing Process:

1 . Sift tadalafil, MCC, lactose monohydrate and croscarmel lose sodium through 40 mesh and transfer to RMG.

2. Dissolve HPMC into DCM/IPA solvent mixture (60:40 ratio).

3. Granulate Step 1 using Step 2 solution using a laboratory scale rapid m ixer granu lator.

4. Dissolve sorbitan stearate and glycerol monocaprylocaprate into DCM/IPA solvent mixture and granulate step 3.

5. Dry the mass to get LOD less than 2%.

6. Si ft the dried granules through 30 meshes for further improvement of homogenous API distribution.

7. Si ft MCC, lactose monohydrate and croscarmellose sodium through 40 mesh and blend ^' with step 6.

8. Sift magnesium stearate through 40 meshes and lubricate step 7.

9. Compressed the lubricated blend into tablets using a rotary tableting machine to obtain immediate release tablets.

Example 2:

I I Brief Manufacturing Process:

1. Sift tadalafil, MCC, lactose monohydrate and croscarmellose through 40 mesh and transfer to RMG.

2. Dissolve HM.PC into DCM/IPA solvent mixture (60:40 ratio).

3. Granulate Step 1 using Step 2 solution using a laboratory scale rapid mixer granulator.

4. Dissolve sorbitan stearate into DCM/IPA solvent mixture and granulate step 3.

5. Dry the mass to get LOD less than 2%.

6. Sift the dried granules through 30 meshes for further improvement of homogenous API distribution.

7. Sift MCC and lactose monohydrate through 40 meshes and blend with step 6.

8. Sift magnesium stearate through 40 meshes and lubricate step 7.

Dissolution study

Dissolution study of reference product and composition of example I & 2 of the invention were carried with USP dissolution apparatus II at 50 rpm using 1000ml of different medium & given in below tables.

Table 1: Comparable study of dissolution profile in 0.1N HCl with 0.5% SLS, Paddle, 50 rpm, 1000 ml

Table 2: Comparable study of dissolution profile in Purified water with 0.5% SLS, Paddle, 50 rpm, 1000 ml (OGD)

As per the present invention, the pharmaceutical composition of tadalafil having particle size greater than 40 pm exhibits similar dissolution profile of tadalafil when compared with reference product CI A LIS® shown in above table 1 and 2..

In view of the above, it is anticipated that the pharmaceutical composition of tadalafil as per the present invention is also bioequivalent with the reference product CIA LIS®.

Stability Study

Tablet of the above example 1 and 2 were packed and subjected to stability testing at long term (25°C/60% RH) and accelerated (40°C/ 75% RH) for 6 month in a thermostat chamber. HPLC method is used to determine the stability study and found to be stable by showing the assay of tadalafil in the range of 99%.

The invention that is intended to be protected herein, however, is not construed to be limited to the particular forms disclosed because they are to be regarded as illustrative rather than restrictive.

Claims

We claim:

1. A stable pharmaceutical composition of tadalafil comprising tadalafil and one or more pharmaceutically acceptable excipients, wherein atleast 90% of particles of tadalafil having particle size greater than about 40 μιη.

2. A stable pharmaceutical composition of tadalafil comprising tadalafil, polymer, surfactant and one or more pharmaceutically acceptable excipients, wherein atleast 90% of particles of tadalafil having particle size greater than about 40 μιη.

3. The stable pharmaceutical composition according to claim 2, wherein the surfactant is nonionic surfactant.

4. The stable pharmaceutical composition according to claim 3, wherein the non ionic surfactant can be selected from polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyethylene glycol fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid mono esters or mixtures thereof.

5. The stable pharmaceutical composition according to claim 2, wherein the polymer is hydrophilic binder.

6. The stable pharmaceutical composition according to claim 5, wherein the hydrophilic binder can be selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, methyl cellulose or mixture thereof.

7. The stable pharmaceutical composition according to anyone of claim I to 6, further comprising a solubilizer.

8. The stable pharmaceutical composition according to claim 7, wherein the solubilizer is lipid in nature.

9. The stable pharmaceutical composition according to anyone of claim I to 8, wherein the excipients are selected from lactose, gelatin, microcrystalline cellulose, talc, colloidal silicon dioxide, starch, magnesium stearate. stearic acid, and croscarmellose sodium and mixtures thereof.

10. A process for the preparation of stable pharmaceutical composition of tadalafii comprising tadalafii and one or more pharmaceutically acceptable excipients, wherein atleast 90% of particles of tadalafii having particle size greater than about 40 μιη comprising following steps:

(a) sifting of tadalafii and one or more pharmaceutically acceptable excipients through mesh and transfer to the granulator;

(b) dissolving binder into an organic solvent;

(c) granulating the ingredients of step (a) using the solution of step (b);

(e) drying the wet granules;

(0 sifting and lubricating the dried granules to get homogenous blend; (g) compressing the lubricated blend into tablets and/or filled in capsule.