WO2013030789A1

WO2013030789A1 - Pharmaceutical oral solid dosage form containing a poorly water soluble pde - iv inhibitor

Info

Publication number: WO2013030789A1
Application number: PCT/IB2012/054476
Authority: WO
Inventors: Vikas Batra; Sumit Gupta; Anupam Trehan; Vinod Kumar Arora
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2011-08-30
Filing date: 2012-08-30
Publication date: 2013-03-07
Anticipated expiration: 2014-02-28

Abstract

The present invention relates to a pharmaceutical solid oral dosage form of a poorly water-soluble phosphodiesterase₄ selective inhibitor (PDE-IV inhibitor) as an active ingredient, in particular roflumilast, and processes of preparation thereof.

Description

PHARMACEUTICAL ORAL SOLID DOSAGE FORM CONTAINING A POORLY WATER

SOLUBLE PDE - IV INHIBITOR

Field of Invention

Background of the Invention

Phosphodiesterase inhibitors are the drugs that block one or more of the five subtypes of the enzyme phosphodiesterase (PDE) and prevent the inactivation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype. PDE-IV is the major cAMP-metabolizing enzyme found in inflammatory and immune cells. This has generated great interest in PDE-IV as a potential target to treat lung inflammatory diseases. PDE-IV inhibitors have proven potential as anti-inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), and rhinitis. The selective targeting of PDE-IV has been actively pushed as a novel

therapeutic approach in the treatment of respiratory diseases associated with inflammatory diseases. However, in general, these PDE-IV inhibitors suffer from a problem of low aqueous solubility. Roflumilast, a potential PDE-IV inhibitor disclosed in U.S. Patent No. 5,712,298, has a solubility of only 0.53 milligram/Litre (mg/L) at 21°C. The low aqueous solubility thus becomes the limiting factor, resulting in reduced bioavailability.

There always remains a challenge to the pharmaceutical developers to formulate this class of drugs into suitable pharmaceutical dosage forms so as to have enhanced water-solubility and thus increased bioavailability.

In general, the prior arts teach a number of approaches like particle size reduction, lyophilization, complexation, solvent deposition, solvate formation, and solid dispersion to formulate poorly water-soluble drugs into pharmaceutical dosage forms so as to have an enhanced water-solubility and thus achieve an increase in bioavailability.

U.S. Patent No. 6,677,362, assigned to Warner-Lambert Company, discloses a solid dispersion of water-insoluble drugs and the process for its preparation in which water-insoluble drugs were combined with a carrier polymer such as polyvinylpyrrolidone (PVP) without the need of any organic solvents and/or high fusion temperatures.

U.S. Patent No. 7,407,670, assigned to Janssen Pharmaceutica, N.V., also discloses solid dispersions of bioactive compounds for enhancing dissolution and solubility of the bioactive compounds by using various carrier polymers.

U.S. Patent No. 7,951,397, assigned to Nycomed GmbH, discloses a process for producing solid oral dosage forms of poorly water-soluble PDE-IV inhibitors having improved solubility and dissolution. The process comprises granulating the active compound with an aqueous solution of polyvinylpyrrolidone (PVP).

However, there still exists a need of alternative pharmaceutical solid oral dosage forms of poorly water-soluble PDE-IV inhibitors having desired in-vitro and in-vivo release profiles which can be economically and commercially manufactured. In the present invention, the inventors have successfully developed such a pharmaceutical solid oral dosage form of a poorly water-soluble PDE-IV inhibitor, particularly roflumilast, having improved solubility and dissolution and which does not make use of specialized expensive and time-consuming techniques.

The present invention is summarized and described in detail below.

Summary of the Invention

In one of the general aspects, the present invention provides a pharmaceutical solid oral dosage form of a poorly water-soluble PDE-IV inhibitor, comprising:

(a) a poorly water-soluble PDE-IV inhibitor;

(b) one or more of binders; and

(c) one or more of pharmaceutically acceptable excipients

wherein the binder is selected from a group consisting of a saccharide, protein or synthetic polymer.

Embodiments of the invention may include one or more of the following features. For example, the poorly water-soluble PDE-IV inhibitor may be roflumilast. The PDE-IV inhibitor may be present in an amount of from about 0.1% to about 10% by weight of the solid dosage form. The poorly water-soluble PDE-IV inhibitor and the binder may be present in a weight ratio of from about 1 : 1 to about 1 :20.

The binder may be a saccharide such as sucrose, lactose, starches, microcrystalline cellulose, low- viscosity hydroxypropyl cellulose and/or a hydroxypropylmethyl cellulose. The low- viscosity hydroxypropyl cellulose may have a viscosity of less than about 1000 cPs. The protein may be a gelatin and the synthetic polymer may be one or more of polyethylene glycol, polyvinyl acetate, polyvinyl alcohol and propylene glycol. The binder may be present in an amount of from about 0.1% to about 10% by weight of the solid dosage form.

The pharmaceutically acceptable excipient may include diluents, disintegrants, lubricants, surfactants, coloring agents, flavoring agents and preservatives. For example, the diluent may be lactose, the disintegrant may be croscarmellose sodium, the lubricant may be magnesium stearate and the surfactant may be polyethylene glycol. The diluent may be present in an amount of from about 50% to about 85% by weight of the solid dosage form. The disintegrant may be present in an amount of from about 5% to about 30%, while the lubricant may be in an amount of from about 0.1% to about 2% by weight of the solid dosage form, respectively.

In another general aspect, the invention provides a process for the preparation of a pharmaceutical solid oral dosage form of poorly water-soluble PDE-IV inhibitor comprising:

(a) a poorly water-soluble PDE-IV inhibitor;

(b) one or more of binders; and

(c) one or more of pharmaceutically acceptable excipients

wherein the binder is selected from a group consisting of a saccharide, protein, or synthetic polymer, wherein the process comprises the steps of:

i. blending the PDE-IV inhibitor and one or more of the binders with one or more of the pharmaceutically acceptable excipients;

ii. optionally granulating the blend;

iii. further blending the granules/blend of step (ii) with one or more

pharmaceutically acceptable excipients; and

iv. processing the final blend into a suitable solid oral dosage form. In yet another general aspect, the invention provides a method of treating chronic obstructive pulmonary disease (COPD), which comprises administering the

pharmaceutical solid oral dosage form of a poorly water-soluble PDE-IV inhibitor to a mammal in need thereof.

The details of various embodiments of the invention are set forth in the description below. Other features and advantages of the invention will also be apparent from the description.

Detailed Description of the Invention

The term "poorly water-soluble PDE-IV inhibitor", as used herein, includes PDE- IV inhibitors with a solubility in water of less than or equal to 100 mg/L, particularly with a solubility in water of less than or equal to 1 mg/L, at a temperature of 15°C to 25°C, more particularly at 21°C.

Examples of poorly water-soluble PDE-IV inhibitors include, but are not limited to, roflumilast, rolipram, ibudilast, piclamilast, cilomilast, and in particular roflumilast. The term "roflumilast", as used herein, includes roflumilast, its enantiomers,

diastereomers, metabolites, prodrugs, analogues or a pharmaceutically acceptable salt thereof.

The poorly water-soluble PDE-IV inhibitor, in particular romflumilast, may be present in an amount of from about 0.1% to about 10% weight by weight (w/w) based on the total weight of the dosage form. Further, the roflumilast used in the present invention has a D₅o value in the range of from about 2 μιη to about 15 μιη and D90 value in the range of from about 5 μιη to about 40 μιη.

The pharmaceutical dosage form of the present invention comprises a binder selected from a group consisting of a saccharide, protein or synthetic polymer. The binder may be present in an amount of from about 0.1% to about 10% (w/w) based on the total weight of the dosage form.

The term "saccharide", as used herein, includes disaccharides and their derivatives such as sucrose and lactose; polysaccharides and their derivatives such as starches selected from starch, corn starch, preswollen starch, pregelatinized starch; cellulose or modified cellulose such as microcrystalline cellulose; cellulose ethers such as methyl cellulose, hydroxypropyl cellulose (HPC) and hydroxypropylmethyl cellulose (HPMC); agar;

tragacanth; plasdone; alginic acid and its derivatives such as sodium alginate; gum arabic; and sugar alcohols such as xylitol, sorbitol and maltitol. Particularly preferred saccharides are hydroxypropyl cellulose and hydroxypropylmethyl cellulose.

Hydroxypropyl cellulose is a non-ionic water-soluble cellulose ether that is formed by reaction with propylene oxide. It has a longstanding history of safe and effective use in the pharmaceutical industry. Hydroxypropyl cellulose is commercially available from Aqualon and Nippon Soda Co., under the brand names Klucel® and HPC®. It provides a remarkable set of physical properties for tablet binding, modified-release and film-coating.

Based on the requirement and the role it has to play in the pharmaceutical dosage form, hydroxypropyl cellulose of a desired viscosity range may be selected. Broadly, the viscosity ranges and corresponding hydroxylpropyl celluloses are classified as low-, medium- and high- viscosity hydroxypropyl celluloses. Examples of low- viscosity hydroxypropyl cellulose include Klucel® EF, Klucel® LF, Klucel® IF and Klucel® OF. The 2% w/w aqueous solutions of these low- viscosity hydroxypropyl celluloses have viscosities of less than about 1000 cPs. Other examples are HPC®-SL, HPC®-L, and HPC®-M. The 2% w/w aqueous solutions of these polymers have viscosities of 3-6, 6-10, and 150-400 cPs, respectively. In particular, HPC®-L may be used.

Hydroxypropylmethyl cellulose is a methylcellulose modified with a small amount of propylene glycol ether groups attached to the anhydroglucose of the cellulose. HPMCs vary in the chain length of their cellulosic backbone and consequently in their viscosity as measured, for example, at a 2% by weight concentration in water. HPMCs which can be used in the present invention are illustratively available under the brand names Methocel® of Dow Chemical Co. and Metolose® of Shin-Etsu Chemical Co. Examples of particularly suitable HPMCs having low- and medium-viscosities include Methocel® E5 which has a viscosity of 2% w/w in water, of about 5 cPs.

Further, the poorly water-soluble PDE-IV inhibitor, in particular roflumilast, and low- viscosity hydroxypropyl cellulose and/or hydroxypropylmethyl cellulose are present in a weight ratio of from about 1 : 1 to about 1 :20, in particular about 1 : 10.

The term "protein", as used herein, includes gelatin. The term "synthetic polymer", as used herein, includes polyethylene glycol, polyvinyl acetate, polyvinyl alcohol and propylene glycol.

The term "pharmaceutical dosage form", as used herein, includes solid dosage forms such as powder, tablet, granule, pellet, spheroid, capsule, caplet, bead,

multiparticulate, powders for suspension and unit dosage packages.

The term "pharmaceutically acceptable excipients", as used herein, may include diluents, disintegrants, lubricants, surfactants, coloring agents, flavoring agents, and preservatives.

Preferred examples of diluents may include, but are not limited to, calcium phosphate - dibasic, calcium carbonate, lactose, glucose, levulose, sucrose, cellulose - microcrystalline, cellulose - powdered, silicified microcrystalline cellulose, calcium silicate, kaolin, corn starch, potato starch, wheat starch, starch pregelatinized, polyols such as mannitol, sorbitol, xylitol, maltitol and sucrose. The pharmaceutical dosage form may comprise from about 50% to about 85% of the diluent, w/w based on the total weight of the dosage form.

Preferred examples of disintegrants may include, but are not limited to, croscarmellose sodium, sodium starch glycolate, sodium carboxymethylcellulose, hydroxypropylcellulose, xanthan gum, alginic acid, alginates and carbopols. The pharmaceutical dosage form may comprise from about 5% to about 30% of the disintegrant, w/w based on the total weight of the dosage form.

Preferred examples of lubricants may include, but are not limited to, sodium lauryl sulfate, talc, magnesium stearate, sodium stearyl fumarate, stearic acid, glycerylbehenate, hydrogenated vegetable oil, or zinc stearate, and suitable glidants may include colloidal silicon dioxide and talc. The pharmaceutical solid dosage form may comprise from about 0.1% to about 2% of lubricant, w/w based on the total weight of the dosage form.

Preferred examples of surfactants may include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical compositions. These include polyethylene glycols, e.g., Macrogol 4000, Macrogol 3350 and Macrogol 6000; polyethoxylated fatty acids and its derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4-150 mono dilaurate, polyethylene glycol-20 glyceryl stearate; alcohol-oil transesterification products, for example, polyethylene glycol-6 corn oil; polyglycerized fatty acids, for example, polyglyceryl-6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol-20 sorbitanmonooleate and sorbitanmonolaurate; polyethylene glycol alkyl ether or phenols, for example, polyethylene glycol-20 cetyl ether, polyethylene glycol- 10-100 nonyl phenol; sugar esters, for example, sucrose monopalmitate; polyoxyethylene- polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example, sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octylsulfosuccinate disodium and palmitoylcarnitine.

Preferred examples of coloring agents may include, but are not limited to, water- soluble FD&C dyes and mixtures thereof with lakes and direct compression sugars such as Di-Pac®. In addition, colored dye migration inhibitors such as tragacanth, acacia or attapulgite talc may be added. Specific examples include calcium carbonate, chromium- cobalt-aluminium oxide, ferric ferrocyanide, ferric oxide, iron ammonium citrate, iron (III) oxide hydrated, iron oxides, magnesium carbonate and titanium dioxide.

Preferred examples of flavoring agents may include, but are not limited to, saccharin, aspartame, cyclamate sodium and maltol.

Preferred examples of preservatives may include, but are not limited to, potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of para- hydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quartemary compounds such as benzalkonium chloride.

These solid dosage forms may be further coated with one or more functional and/or non- functional coating layers comprising film- forming polymers with or without coating additives.

The "coating additives" may comprise one or more of plasticizers, glidants or lubricants, opacifiers and lubricants. Examples of "film- forming polymers" may include cellulose derivatives such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzed polyvinyl alcohol, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; or methacrylic acid polymers such as Eudragit® RL and Eudragit® RS.

Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry®, may also be used for coating.

Suitable examples of plasticizers may include, but are not limited to, phosphate esters; phthalate esters; mineral oils; fatty acids and esters; fatty alcohols, vegetable oils and hydrogenated vegetable oils including acetylated hydrogenated cottonseed glyceride and acetylated hydrogenated soybean oil glycerides; acetyl tributyl citrate; acetyl triethyl citrate; castor oil; diacetylated monoglycerides; dipropylene glycol salicylate glycerin; glycerylcocoate; mono- and di-acetylated monoglycerides; phthalylglycolate; diocyl phthalate; sorbitol; sorbitol glyceryltricitrate; sucrose octaacetate; a-tocopheryl polyethylene glycol succinate; phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols; and fatty alcohols including cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol and myristyl alcohol; methyl abietate; acetyl tributyl citrate; acetyl triethyl citrate; diisooctyladipate; amyl oleate; butyl ricinoleate; benzyl benzoate; butyl and glycol esters of fatty acids; butyl diglycol carbonate; butyloleate; butyl stearate; di(beta-methoxyethyl) adipate; dibutylsebacate; dibutyl tartrate;

diisobutyladipate; dihexyladipate; triethylene glycol di(beta-ethyl butyrate); polyethylene glycol; diethylene glycol monolaurate; monomeric polyethylene ester; hydrogenated methyl ester of rosin; methoxyethyloleate; butoxyethyl stearate; butyl phthalyl butyl glycolate; glycerol tributyrate; and triethylene glycol.

The pharmaceutical acceptable excipients and/or film-forming polymers and coating additives may be selected to provide an immediate-release profile or a modified- release profile.

Examples of solvents used as granulating fluid or for preparing a

solution/dispersion of the coating composition may include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, chloroform, ether and water, or combinations thereof. The granulating fluid is removed using techniques known in the art such as tray drying, fluid bed drying, microwave drying and vacuum drying prior to compression of the bulk material into tablets.

Coating may be performed by applying film- forming polymer(s), with or without other pharmaceutically inert excipients, as a solution/suspension using any conventional coating technique known in the art such as spray coating in a conventional coating pan or fluidized bed processor, dip coating, or compression coating.

The pharmaceutical solid oral dosage forms of the invention may be prepared by following the process of wet granulation, direct compression or dry granulation.

In one embodiment, the pharmaceutical oral solid dosage form of a poorly water- soluble PDE-IV inhibitor may be prepared by a process comprising the steps of:

(a) blending the PDE-IV inhibitor and low-viscosity hydroxypropyl cellulose with one or more intragranular pharmaceutically acceptable excipients;

(b) passing the blend of step (a) through a roller compactor to form a compacted mass;

(c) reducing the compacted mass into granules of suitable size;

(d) blending the granules of step (c) with extragranular pharmaceutically

acceptable excipients;

(e) compressing the blend of step (d) into tablets using a suitable tooling; and

(f) optionally coating the tablets with one or more layers of film-forming

polymer(s) and coating additive(s).

In another embodiment, the pharmaceutical oral solid dosage form of a poorly water-soluble PDE-IV inhibitor may be prepared by a process comprising the steps of:

(b) compressing the blend of step (a) in a heavy tabletting press to form slugs;

(c) reducing the slugs of step (b) into granules of suitable size;

(d) blending the granules of step (c) with extragranular pharmaceutically

acceptable excipients; (e) compressing the blend of step (d) into tablets using a suitable tooling; and

(f) optionally coating the tablets with one or more layers of film-forming

polymer(s) and coating additive(s).

(a) blending the PDE-IV inhibitor and low-viscosity hydroxypropyl cellulose with one or more pharmaceutically acceptable excipients;

(b) directly compressing the blend of step (a) into tablets using a suitable tooling; and

(c) optionally coating the tablets with one or more layers of film-forming

polymer(s) and coating additive(s).

(a) blending the PDE-IV inhibitor with one or more intragranular

pharmaceutically acceptable excipients;

(b) dissolving low- viscosity hydroxypropyl cellulose in a solvent to form

granulating fluid;

(c) granulating the blend of step (a) with the granulating fluid of step (b);

(d) blending the granules of step (c) with extragranular pharmaceutically

acceptable excipients;

(f) optionally coating the tablets with one or more layers of film-forming

polymer(s) and coating additive(s).

(a) blending one or more intragranular pharmaceutically acceptable excipients;

(b) dissolving low- viscosity hydroxypropyl cellulose in a solvent to form

granulating fluid;

(c) dissolving the PDE-IV inhibitor in the granulating fluid of step (b);

(d) granulating the blend of step (a) with the solution of step (c); (e) blending the granules of step (d) with extragranular pharmaceutically acceptable excipients;

(f) compressing the blend of step (e) into tablets using a suitable tooling; and

(g) optionally coating the tablets with one or more layers of film-forming polymer(s) and coating additive(s).

(a) blending one or more intragranular pharmaceutically acceptable excipients;

(b) dissolving low- viscosity hydroxypropyl cellulose in a solvent to form a granulating fluid;

(c) dispersing the PDE-IV inhibitor in the granulating fluid of step (b);

(d) granulating the blend of step (a) with the dispersion of step (c);

(e) blending the granules of step (d) with extragranular pharmaceutically

acceptable excipients;

(b) passing the blend of step (a) through a hot melt extruder to form extrudes;

(c) sizing the extrudes of step (b);

(d) blending the extrudes of step (c) with one or more pharmaceutically

acceptable excipients;

(f) optionally coating the tablets with one or more layers of film-forming polymer(s) and coating additive(s).

In another embodiment, the pharmaceutical oral solid dosage form of a poorly water-soluble PDE-IV inhibitor may be prepared by a process comprising the steps of: (a) dissolving or dispersing the PDE-IV inhibitor in a solvent;

(b) dissolving hydroxypropylmethyl cellulose in a solvent and mixing with solution or dispersion of step (a);

(c) blending one or more pharmaceutically inert excipients;

(d) granulating the blend of step (c) with the solution or dispersion of step (b);

(e) blending the granules of step (d) with one or more pharmaceutically inert excipients;

(g) optionally coating the tablets with one or more layers of film-forming

polymer(s) and coating additive(s).

Alternatively, granulation may be done by shear granulators, rapid mixer granulators, fluidized bed granulators, spray driers or by spheronizers or pelletizers.

The invention may be further illustrated by the following examples, which are for illustrative purpose only and should not be construed as limiting the scope of the invention in any way.

Example 1 a: Wet Granulation Method

Brief Manufacturing Procedure:

1. Roflumilast and lactose monohydrate were mixed in a geometric manner using sieve size # 44 BSS.

2. HPC®-L was dissolved in purified water to prepare a binder solution.

3. The mixture of step (1) was granulated with the binder solution of step (2).

4. The wet granules of step (3) were dried in the fluid bed dryer.

5. The dried granules were shifted through sieve size # 22 BSS.

6. Starch was shifted through sieve size # 44 BSS.

7. The material of step (6) was added to the dried granules of step (5) and mixed.

8. Magnesium stearate was shifted through sieve size # 44 BSS.

9. The blend of step (7) was mixed with the lubricant of step (8).

10. The blend of step (9) was compressed with appropriate punch and toolings. 1 1. A coating solution was prepared and core tablets were coated in a suitable coating pan to get an appropriate w/w build up.

Example lb: Wet Granulation Method

Brief Manufacturing Procedure:

2. HPC®-L was dissolved in purified water to prepare a binder solution.

3. The mixture of step (1) was granulated with the binder solution of step (2).

4. The wet granules of step (3) were dried in the Fluid Bed dryer.

5. The dried granules of step (4) were shifted through sieve size # 22 BSS.

6. Starch was shifted through sieve size # 44 BSS.

7. The material of step (6) was added to the dried granules of step (5) and

mixed.

8. Magnesium stearate was shifted through sieve size # 44 BSS.

9. The blend of step (7) was mixed with the lubricant of step (8).

10. The blend of step (9) was compressed into tablets with appropriate punch and toolings. 1 1. A coating solution was prepared and core tablets were coated in a suitable coating pan to get an appropriate w/w build up.

Example 2: Dry Granulation/Roller Compaction Method

Brief Manufacturing Procedure:

1. Roflumilast, lactose monohydrate, HPC®-L and starch were mixed in a geometric manner using sieve size # 44 BSS and mixed well for 15 minutes.

2. Magnesium stearate was shifted through sieve size # 44 BSS.

3. The blend of step (1) was lubricated with the material of step (2).

4. The material of step (3) was compacted and the compacts were crushed in a multi-mill and passed through sieve size # 22 BSS.

5. Magnesium stearate was sifted through sieve size #44 BSS and mixed with the material of step (4).

6. The blend of step (5) was compressed into tablets with appropriate punch and toolings.

7. A coating solution was prepared and the core tablets were coated in a suitable coating pan to get an appropriate w/w build up. Example 3 : Direct Compression Method

Brief Manufacturing Process:

1. Roflumilast, lactose, HPC®-L and starch were mixed in a geometric manner using sieve size # 44 BSS and mixed well for 15 minutes.

2. Magnesium stearate was shifted through # 44 BSS.

3. The blend of step (1) was lubricated with the material of step (2).

4. The blend of step (3) was compressed into tablets with appropriate punch and toolings.

5. A coating solution was prepared and core tablets were coated in a suitable coating pan to get an appropriate w/w build up.

Example 4: Rapid Mixer Granulator (RMG Process

Brief manufacturing Process:

1. HPMC 5 cPs was dissolved in purified water under continuous stirring.

2. Roflumilast was dissolved in acetone and mixed with the solution of step (1) to get a clear solution.

3. Lactose was sifted through mesh # 30 BSS and granulated with the solution of step (2) in RMG.

4. The granules of step (3) were dried and passed through mesh # 22 BSS.

5. Maize starch was sifted through mesh # 44 BSS and mixed with the granules of step (4) in a blender.

6. Magnesium stearate was sifted through mesh # 44 BSS and mixed with the blend of step (5).

7. The Lubricated granules of step (6) were compressed into tablets using appropriate punch and toolings.

8. A coating solution was prepared and core tablets were coated in a suitable coating pan to get an appropriate w/w build up. Example 5a: Fluid Bed Processor (FBP Granulation Method

Brief Manufacturing Process:

1. HPC®-L and Macrogol were dissolved in purified water and then roflumilast was dispersed under continuous stirring.

2. Lactose and maize starch were sifted through mesh # 30 BSS.

3. The material of step (2) was granulated with the dispersion of step (1) in a fluid bed processor.

4. The granules of step (3) were dried and passed through mesh # 25 BSS.

5. Extragranular lactose and maize starch were sifted through mesh # 30 BSS and mixed with the granules of step (4) in a blender.

7. The lubricated granules of step (6) were compressed into tablets using

appropriate punch and toolings.

8. A coating solution was prepared and the core tablets were coated in a suitable coating pan to get an appropriate w/w build up. Example 5b: Fluid Bed Processor (FBP Granulation Method

Brief Manufacturing Process:

1. HPMC was dissolved in purified water under continuous stirring.

3. Lactose was sifted through mesh # 30 BSS.

4. The lactose of step (3) was granulated with the solution of step (2) in a fluid bed processor.

5. The granules of step (4) were dried and passed through mesh # 22 BSS.

6. Maize starch was sifted through mesh # 44 BSS and mixed with the granules of step (5) in a blender.

7. Magnesium stearate was sifted through mesh # 44 BSS and mixed with the maize starch of step (6).

8. The lubricated granules of step (7) were compressed into tablets using

appropriate punch and toolings.

9. A coating solution was prepared and core tablets were coated in a suitable coating pan to get an appropriate w/w build up. Example 6: Hot Melt Extrusion Method

Brief Manufacturing Process:

1. Roflumilast was mixed with HPC®-L and sifted through mesh # 30 BSS.

2. Lactose was mixed with the blend of step (1) and sifted through mesh # 30 BSS.

3. The blend of step (2) was extruded using a hot-melt extruder.

4. Molten extrudes were spread on a chiller unit.

5. The cooled extrudes of step (4) were sized through a multi mill and then passed through mesh # 25 BSS.

6. Lactose and maize starch were sifted through mesh # 44 BSS and mixed in a blender with the sized extrudes of step (5).

7. Magnesium stearate was sifted through mesh # 44 BSS and mixed with the blend of step (6).

8. The lubricated granules of step (7) were compressed into tablets using

appropriate punch and toolings.

9. A coating solution was prepared and core tablets were coated in a suitable coating pan to get an appropriate w/w build up.

Claims

We Claim:

1. A pharmaceutical solid oral dosage form of a poorly water-soluble PDE-IV inhibitor, comprising:

(a) a poorly water-soluble PDE-IV inhibitor;

(b) one or more of binders; and

(c) one or more of pharmaceutically acceptable excipients

wherein the binder is selected from a saccharide, protein or synthetic polymer.

2. The pharmaceutical solid oral dosage form according to claim 1, wherein the PDE- IV inhibitor is present in an amount of from about 0.1% to about 10% by weight of the solid dosage form.

3. The pharmaceutical solid oral dosage form according to claim 1, wherein the PDE- IV inhibitor and the binder are present in a weight ratio of from about 1 : 1 to about 1 :20.

4. The pharmaceutical solid oral dosage form according to claim 1, wherein the binder is present in an amount of from about 0.1% to about 10% by weight of the solid dosage form.

5. The pharmaceutical solid dosage form according to claim 1, wherein the pharmaceutically acceptable excipient is selected from diluents, disintegrants, lubricants, surfactants, coloring agents, flavoring agents and preservatives.

6. The pharmaceutical dosage form according to claim 5, wherein the diluent is present in an amount of from about 50% to about 85% by weight of the solid dosage form.

7. The pharmaceutical dosage form according to claim 5, wherein the disintegrant is present in an amount of from about 5% to about 30% by weight of the solid dosage form.

8. The pharmaceutical dosage form according to claim 5, wherein the lubricant is present in an amount of from about 0.1% to about 2% by weight of the solid dosage form.

9. A process for the preparation of a pharmaceutical solid oral dosage form of poorly water-soluble PDE-IV inhibitor comprising:

(a) a poorly water soluble PDE-IV inhibitor;

(b) one or more of binders; and

(c) one or more of pharmaceutically acceptable excipients

wherein the binder is selected from a saccharide, protein or synthetic polymer, and wherein the process comprises the steps of: i. blending the PDE-IV inhibitor and one or more of the binders with more of the pharmaceutically acceptable excipients; ii. optionally granulating the blend;

iii. further blending the granules/blend of step (ii) with one or more pharmaceutically acceptable excipients; and

iv. processing the final blend into a suitable solid oral dosage form.

10. A method for the treatment of COPD comprising the administration of a pharmaceutical solid oral dosage of claim 1.