FIELD OF THE INVENTION
The present invention relates to novel pharmaceutical compositions comprising at least one poorly soluble active agent preferably a PDE4 inhibitor, at least one carrier(s) present in an amount not less than about 10% by weight of the composition, at least one hydrophilic component(s), optionally a solvent and optionally one or more other pharmaceutically acceptable excipient(s). The present invention also describes process for preparation of such compositions and method of using them.
BACKGROUND OF THE INVENTION
Asthma is a disease which is becoming more prevalent and is the most common disease of childhood. It can be identified by recurrent wheeze and intermittent air flow limitation. Despite many advances in its understanding, said pathology remains a poorly understood and often poorly treated disease. Previously, contraction of airway smooth muscles has been regarded as the most important feature of asthma. Recently there has been a marked change in the way asthma is managed, stemming from the fact that asthma is recognized as a chronic inflammatory disease. Uncontrolled airway inflammation may lead to mucosal damage and structural changes giving irreversible narrowing of the airways and fibrosis of the lung tissue. Therapy should therefore be aimed at controlling symptoms so that normal life is possible and at the same time provide basis for treating the underlying inflammation.
Another respiratory disease whose incidence is steadily increasing throughout the world is chronic obstructive pulmonary disease (COPD). COPD is characterized by airflow obstruction that is generally caused by chronic bronchitis, emphysema, or both. Commonly, the airway obstruction is incompletely reversible but 10-20% of patients do show some improvement in airway obstruction with treatment. In chronic bronchitis, airway obstruction results from chronic and excessive secretion of abnormal airway mucus, inflammation, bronchospasm, and infection. Emphysema is characterized by abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis. COPD can also give rise to secondary pulmonary hypertension. Secondary pulmonary hypertension itself is a disorder in which blood pressure in the pulmonary arteries is abnormally high. In severe cases, the right side of the heart must work harder than usual to pump blood against the high pressure. If this continues for a long period, the right heart enlarges and functions poorly, and fluid collects in the ankles (edema) and belly. Eventually the
left heart begins to fail. Heart failure caused by pulmonary disease is called Cor Pulmonale.
Complicated therapy with different medications and devices may lead to poor compliance of the patients, so to under-treatment and, in turn, negative impact on their quality of life. This is dramatically evident in the case of long-term management of chronic asthma, in particular with prophylactic treatments, such as inhaled steroids, which do not give immediate symptom relief. Recent therapeutic strategy is aimed at both controlling the symptoms and reducing the inflammation by phosphodiesterase inhibitors.
Cyclic nucleotide phosphodiesterases (PDEs) have received considerable attention as anti-asthmatic agents. Cyclic 3',5'-adenosine monophosphate (cAMP) and cyclic 3',5'-guanosine monophosphate (cGMP) are known second messengers that mediate the functional responses of cells to a multitude of hormones, neurotransmitters and autocoids. It has become known that there are multiple, distinct PDE isoenzymes which differ in their cellular distribution. A variety of inhibitors possessing a marked degree of selectivity for one isoenzyme or the other have been synthesized. The PDE enzymes can be grouped into five families according to their specificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds. PDE1 is stimulated by Ca2Vcalmodulin. PDE2 is cGMP-stimulated, and is found in the heart and adrenals. PDES is cGMP-inhibited, and inhibition of this enzyme creates positive inotropic activity. PDE4 is cAMP specific, and its inhibition causes airway relaxation, anti-inflammatory and antidepressant activity. PDES appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDES inhibitors may have cardiovascular activity. Currently, PDE4 inhibitors are being developed for the management of asthma, COPD, rheumatoid arthritis, multiple sclerosis and Crohn's disease. Roflumilast is an oral member of a new class of drug i.e. the phosphodiesterase-4 inhibitors and is undergoing Phase III trials for asthma and COPD. Roflumilast is administered orally at a dose of SOOug once-daily.
US Patent No. 5712298 describes a fluoroalkoxy-substituted benzamide, known as Roflumilast, which is used as cyclic nucleotide phosphodiesterase inhibitors. The inhibition of cyclic nucleotide phosphodiesterase causes a consequent rise in intracellular adenosine 3',5'-monophosphate (cAMP) or guanosine 3',5'-monophosphate
(cGMP) in key cells, and hence very important in the pathophysiology of asthma, which in turn causes smooth muscle relaxation (resulting in bronchodilation) and anti-inflammatory activity. US Patent No. 6713509 discloses a stable controlled release pharmaceutical composition comprising a controlled release excipient, dibasic calcium phosphate, a PDE4 inhibitor in an amount of 10 mg and 60 mg, optionally other excipients, and between about 0.5-2.0% w/w of water.
US Publication No. 2005159492 describes a dosage form in tablet or pellet form for oral administration comprising a slightly soluble PDE4 inhibitor, together with polyvinylpyrrolidone as binder, and one or more other suitable pharmaceutical excipients. PCT Publication No. WO0523225 describes a pharmaceutical composition comprising cilostazol adsorbate and one or more pharmaceutically acceptable inert excipients, wherein the cilostazol adsorbate comprises cilostazol adsorbed on inert carrier. The said compositions specifically comprise a rate controlling polymer and are essentially made as modified release dosage forms. Another PCT Publication No. WO03000238 pertains to a composition comprising a solid adsorbate comprising a low-solubility drug adsorbed onto a substrate, said substrate having a surface area of at least 20 m2/g, wherein at least a major portion of said drug in said adsorbate is amorphous and said adsorbate providing improved concentration of said drug in a use environment relative to a slow-evaporation control composition.
It is known that a solid dispersion prepared by forming a uniform solution or a melt of a poorly soluble compound in a hydrophilic polymer matrix, and then, making the mixture coagulated by cooling or removing a solvent improves the solubility and the absorbability and enhances the bioavailability of a drug. For example, by dispersing griseofulvin in a hydrophilic polymer, polyethylene glycol to obtain the solid dispersion, the solubility thereof is improved (J. Pharm. Sci., 60(9), 1281-1302(1971)). Further, the solid dispersion of sulfathiazole and polyvinylpyrrolidone (J. Pharm. Sci.), 58(5), 538-549(1969)), and the solid dispersion of fisoxazole or sulfamethizole and polyvinylpyrrolidone (Chem. Pharm. Bull., 27(5), 1223-1230(1979)) are known.
US Patent No. 4,721,709 describes a pharmaceutical composition for oral administration comprising a hydrophobic practically water-insoluble benzodiazepine drug adsorbed onto a pharmaceutical carrier having an average particle size of less than 40 microns wherein the drug is present in particulate form and the particles of the drug have a mean particle size of less than 10 microns and a particle size distribution such that at least 95% of the particles are less than 15 microns. US Patent No.
5,449,521 discloses amorphous drug absorbed onto a support material. The support material may be crosslinked polymers, linear polymers, water soluble complexing agents, and porous inorganic materials. The drug and support material are co-ground in a mill with its grinding chamber saturated with the vapor of one or more solvents able to solubilize the drug. The resulting product is dried and sieved. The resulting compositions are reported to have a reduced heat of fusion, a reduced melting point, an increased dissolution rate and increased solubilization kinetics.
It is a common observation that when drugs having poor solubility are employed in the preparation of solid dosage forms such as tablets or capsules, their rate of dissolution is rather slow. As a result, their absorption from the gastrointestinal tract into systemic blood circulation is also slow. However, if such drugs are to be administered in oral dosage forms and to be used for clinical indications where a rapid onset of therapeutic activity is desirable, the slow rate of dissolution and slow rate of absorption can put very great limitations on their therapeutic utility. Several attempts to provide oral dosage forms for delivery of poorly soluble active agent have been described previously. However, there still exists a need to develop effective and safe oral dosage form compositions of poorly soluble active agent, which exhibit appreciable in vitro dissolution and solubility and in turn provide better absorption and bioavailability, and that are easier to manufacture and involves a low formulation cost. The inventors of the present invention have now found that formulation of such poorly soluble active agents, particularly PDE4 inhibitors, with suitable carrier(s) provides dosage forms with appreciable rates of dissolution and in turn better bioavailability. The present invention provides such novel compositions.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide a novel pharmaceutical composition comprising at least one PDE4 inhibitor(s) as the active agent, at least one carrier(s) present in an amount not less than 10% by weight of the composition, at least one hydrophilic component(s), optionally a solvent and optionally one or more other pharmaceutically acceptable excipient(s), wherein the carrier(s) and the hydrophilic component(s) is present in a ratio of 0.1:50 to 50:0.1.
It is an objective of the present invention to provide novel pharmaceutical composition comprising roflumilast or its salts, esters, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, derivatives or mixtures thereof as the PDE4 inhibitor, at
least one carrier(s) present in an amount not less than 10% by weight of the composition, at least one hydrophilic component(s), optionally a solvent and optionally one or more other pharmaceutically acceptable excipients, wherein the carrier(s) and the hydrophilic component(s) is present in a ratio of 0.1:50 to 50:0.1.
It is another objective of the present invention to provide process for preparation of such
novel composition which comprises of the following steps:
i) mixing the active agent(s) and carrier(s) together, and optionally adding a solvent,
ii) adding a hydrophilic component(s),
iii) optionally adding one or more other pharmaceutically acceptable excipient(s), and
iv) formulating the mixture into a suitable dosage form.
It is a further objective of the present invention to provide process for the preparation of
such novel composition which comprises of the following steps:
i) dissolving the active agent(s) in a suitable solvent,
ii) adding the carrier(s) and the hydrophilic component(s),
iii) removal of the solvent to obtain a dry material,
iv) milling the dry material to obtain the desired particle size,
v) optionally adding one or more other pharmaceutically acceptable excipient(s), and
vi) formulating the mixture into a suitable dosage form.
It is yet another objective of the present invention to provide process for preparation of
such novel composition which comprises of the following steps:
i) adding the active agent(s) into a molten or a liquid carrier(s) and mixing,
ii) adding a hydrophilic component(s) into the mixture with further mixing,
iii) solidifying the mixture to obtain a dry material,
iv) optionally milling the dry material to obtain the desired particle size,
v) optionally adding one or more other pharmaceutically acceptable excipient(s), and
vi) formulating the mixture into a suitable dosage form.
It is yet another objective of the present invention to provide a method of using such composition which comprises administering to a subject in need thereof an effective amount of the composition.
The novel compositions of the present invention possess appreciable solubility, and in turn provide better absorption and bioavailability of the active agent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel pharmaceutical composition comprising at least one poorly soluble active agent(s) and at least one carrier(s), and optionally one or more other pharmaceutically acceptable excipient(s).
In an embodiment, the present invention describes novel pharmaceutical compositions comprising at least one poorly soluble active agent and at least one carrier, additionally at least one hydrophilic component, and optionally one or more other pharmaceutically acceptable excipients.
In a preferred embodiment, the present invention provides a novel pharmaceutical composition comprising at least one PDE4 inhibitor(s) as the active agent, at least one carrier(s) present in an amount not less than 10% by weight of the composition, at least one hydrophilic component(s), optionally a solvent and optionally one or more other pharmaceutically acceptable excipients, wherein the carrier(s) and the hydrophilic component(s) is present in a ratio of 0.1:50 to 50:0.1.
In an embodiment, the active agent of the present invention is selected from, but not limited to a group comprising antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, leukotriene inhibitors, PDE4 inhibitors, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastic, beta blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, cholesterol-reducing agents, anti-atherosclerotic agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-parkinsonism agents, anti-alzheimer's disease agents, antibiotics, anti-depressants, antiviral agents, glycogen phosphorylase inhibitors, and cholesteryl ester transfer protein inhibitors or the like.
In an embodiment of the present invention, the active agent(s) is a PDE4 inhibitor, or its salts, esters, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, derivatives or mixtures thereof. Preferably the PDE4 inhibitor is selected from but not limited to a group comprising denbufylline, rolipram, cipamfylline, arofylline, filaminast, piclamilast, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, cilomilast, 6-[2-(3,4-Diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid, (R)-(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl] pyridine, N-(3,5-Dichloro-4-pyridinyl)-2-[1 -(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide, 9-(2-Fluorobenzyl)-N-6-methyl-2-(trifluoromethyl)
adenine, N-(3,5-Dichloro-4-pyridinyl)-8-methoxy quinoline-5-carboxamide, N-[9-Methyl-4-oxo-
1-phenyl-3,4,6,7-tetrahydro- pyrrolo [3,2,1-jk][1,4] benzodiazepin-3(R)-yl]pyridine-4-
carboxamide,3-[3-(Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino) -8-isopropyl-3H-purine
hydrochloride, 4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-
methoxyethyl)pyridin-2(1H)-one-2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-
difluroromethoxy phenyl)cyclohexan-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-
difluoromethoxyphenyl) cyclohexan-1-ol, and the like used either alone or in combination thereof. In a preferred embodiment, the PDE4 inhibitor is roflumilast, or its salts, esters, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, derivatives or mixtures thereof.
In an embodiment of the present invention, the carrier is selected from but not limited to a group comprising crospovidone, cross-linked polymeric cyclodextrin, dextran, cellulose, alginates, silica gel, titanium dioxide, aluminum oxides; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; starches such as cross-linked sodium carboxymethyl starch, maize, rice, corn and potato starch, polyethylene glycols; sugars, saccharide such as lactose and dextrose; sugar alcohols, such as sorbitol or mannitol; non-pareil seed such as microcrystalline cellulose spherical seed core (celphere®); croscarmellose sodium (Ac-Di-sol®), sodium starch glycolate, polyvinyl alcohol, ascorbic acid, carbopols, polyethylene oxide, mixtures of mono-, di-, and triglycerides with polyethylene glycol (PEG) esters of fatty acids such as Gelucires, and the like or mixtures thereof. In an embodiment, the carrier used in the present invention is inert. In another embodiment of the present invention, the carrier is present in an amount not less than about 10% by weight of the composition, preferably not less than about 25% by weight of the composition. Preferably the carrier used is a saccharide such as lactose or mannitol. Preferably the lactose or mannitol is present in an amount not less than about 10% w/w of the composition, more preferably in an amount of about 15-70% by weight of the composition.
In an embodiment of the present invention, the hydrophilic component(s) is selected from but not limited to a group comprising alkyl celluloses such as methyl cellulose; hydroxyalkyl alkyl celluloses such as hydroxypropyl methylcellulose (HPMC, HPMC E15, HPMC E5, Methocel® K15M); hydroxyalkyl celluloses such as hydroxypropyl cellulose (HPC, Klucel® HF) and hydroxyethyl cellulose (HEC, Natrosol® 250 HX); polyethylene glycols (PEG 6000, PEG 1500, Lutrol® E 1500); copolymers of ethylene oxide with propylene oxide (Poloxamer 407, Poloxamer 188, Poloxamer 407); gelatin; polyvinylpyrrolidone (PVP, Kollidon® 12 PF,
Kollidon® 17 PF); vinylpyrrolidones; vinyl acetates; polyvinylimidazoles; polyvinylpyridine N-oxides; copolymers of vinylpyrrolidone with long-chained alpha-olefins; copolymers of vinylpyrrolidone with vinylimidazole; poly(vinylpyrrolidone/ dimethylaminoethyl methacrylates); copolymers of vinylpyrrolidone/dimethylaminopropyl methacrylamides; copolymers of vinylpyrrolidone/ dimethylaminopropyl acrylamides; quaternised copolymers of vinylpyrrolidones and dimethylaminoethyl methacrylates; terpolymers of vinylcaprolactam/vinylpyrrolidone /dimethylaminoethyl methacrylates; copolymers of vinylpyrrolidone and methacrylamidopropyl-trimethylammonium chloride; terpolymers of caprolactam /vinylpyrrolidone/dimethylaminoethyl methacrylates; copolymers of styrene and acrylic acid; polycarboxylic acids; polyacrylamides; polyvinyl alcohols (PVA, Mowiol® 40-88); hydrolysed polyvinyl acetate; copolymers of ethyl acrylate with methacrylate and methacrylic acid; copolymers of maleic acid with unsaturated hydrocarbons and mixed polymerisation products of the said polymers; polysaccharide gums, both natural and modified (semi-synthetic), including but not limited to xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum; alginic acid; other alginates (i.e. Sodium Alginate HVCR, Propylene glycol Alginate); arabinoglactin; pectin; tragacanth; scleroglucan; dextran; amylase; amylopectin; dextrin; polyethylene glycols; cyclodextrins; hydrophilic polymers; and the like or mixtures thereof.
In another embodiment, the hydrophilic component(s) is present in an amount not less than about 0.25% by weight of the composition. Preferably the hydrophilic component used is hydroxyalkyl alkylcellulose such as hydroxypropyl methylcellulose. Preferably the hydroxypropyl methylcellulose is present in an amount not less than 0.25% w/w of the composition, most preferably about 0.5-10% w/w by weight of the composition. Preferably the hydrophilic component of the present invention is present in such a quantity that is not intended to control or modify the release of the active agent from the dosage form, but instead is incorporated particularly to further improve the solubility preferably by improving the hydrophilicity of the active agent and in turn to aid in improving the dissolution of the poorly soluble active agent. In another embodiment, the ratio of the carrier(s) and the hydrophilic component(s) of the present invention is about 0.1:50 to 50:0.1, preferably about 0.1:35 to 35:0.1 by weight of composition.
In an embodiment, the pharmaceutical composition of the present invention further comprises of a solvent. The solvent used is selected from but not limited to a group comprising alcohols such as methanol, ethanol, propanol, isopropyl alcohol, butanol, monomethoxyethanol, ethylene glycol monomethylether and the like; ethers such as
diethyl ether, dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuran, ethylene glycol and the like; aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile and the like; organic acids such as acetic acid, propionic acid and the like; esters such as ethyl acetate; aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like; ketones such as acetone, methyl ketone and the like; amides such as dimethylformamide, dimethyl acetamide and the like; or suitable mixtures thereof. Among the solvents, the one having a low boiling point such as ketones e.g. acetone, and alcohols e.g. ethanol, is preferable. More preferably the solvent used is ethanol and is in quantity sufficient to dissolve the active agent(s).
In an embodiment, the compositions of the present invention comprise the poorly soluble active agent(s) preferably in the form of an adsorbate or a solid dispersion along with the other pharmaceutically acceptable excipient(s). In a further embodiment, the adsorbate or the solid dispersion can be prepared by mixing the poorly soluble active agent(s) dissolved or dispersed in a solvent alongwith the carrier(s) and a hydrophilic component(s) and/or other pharmaceutically acceptable excipient(s). In an embodiment, the adsorbates may be granulated with the pharmaceutically excipients(s) using any of the conventional methods used in the art including wet granulation, dry granulation, and extrusion-spheronization or the like or directly compacted or compressed to obtain the desired dosage form. In another embodiment, the solid dispersion can be prepared by dissolving or dispersing the active agent in a molten or liquid carrier(s), adding a hydrophilic component with mixing, followed by solidifying the resulting material. Further, a solid dispersion can also be prepared by dissolving or dispersing the active agent in a solvent or a combination of solvents, adding a carrier(s), adding a hydrophilic component with mixing, followed by removal of the solvent by any technique known to the art. In another embodiment, the active agent can exist as a physical mixture with the carrier(s) in the compositions of the present invention. Such physical mixtures can be prepared either by mixing the active agent with the carriers), or dissolving the active agent in a suitable solvent to which a carrier(s) is added followed by removing the solvent.
In an aspect, when the active agent is incorporated as an adsorbate while formulating the composition of the present invention, the active agent is preferably adsorbed to the surface of the carrier(s), and when the active agent is incorporated as a solid dispersion, the active agent preferably interacts with the carrier at molecular level and is preferably coated with a
film or layer formed by the carrier on the surface of the active agent, alongwith a hydrophilic component. In all the processes of preparation of the compositions of the present invention described herein, the form in which the active agent(s) is incorporated while making the compositions is such that the solubility, preferably the aqueous solubility, of the active agent(s), is improved. The pharmaceutically acceptable excipients of the present invention are selected from but not limited to a group comprising diluents, disintegrants, direct compression vehicles, surfactants, binders, fillers, bulking agents, anti-adherants, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, stabilizers, preservatives, lubricants, glidants, chelating agents, and the like known to the art used either alone or in combination thereof. It will be appreciated that certain excipients used in the present composition can serve more than one purpose.
In an embodiment of the present invention, the composition additionally comprises of a surfactant. Suitable surfactants include but not limited to polyoxyethylene-polyoxypropylene block copolymers known as poloxamer; polyglycerin fatty acid ester such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid ester such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate; polyethylene glycol fatty acid ester such as polyoxyethylene monostearate; polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; polyoxyethylene castor oil and hardened castor oil, such as polyoxyethylene hardened castor oil; sucrose ester of fatty acid such as sucrose stearate ester and sucrose palmitate ester; alkyl sulfate salt such as sodium lauryl sulfate and magnesium lauryl sulfate; sodium caproate; sodium glycocholate; soy lecithin; propylene glycol alginate; octyl sulfosuccinate disodium; palmitoyl carnitine; mixtures of mono-, di-, and triglycerides with polyethylene glycol (PEG) esters of fatty acids such as Gelucire®, cationic surfactants such as alkyl trimethyl ammonium bromide; and the like or mixtures thereof.
Suitable diluents include for example pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, saccharides, and/or mixtures of the foregoing. Examples of diluents include microcrystalline celluloses such as Avicel® PH 101, Avicel® PH 102, Avicel® PH 112, Avicel® PH 200, Avicel® PH301 and Avicel® PH 302, lactose such as lactose monohydrate, lactose anhydrous and Pharmatose® DCL21, including anhydrous, monohydrate and spray dried forms; dibasic calcium phosphate such as Emcompress®; mannitol such as Pearlitol® SD 200; starch; sorbitol; sucrose; glucose or the like used alone or in
combination thereof. Suitable direct compression vehicles include for example spray-dried lactose; anhydrous lactose; microcrystalline cellulose; dicalcium phosphate dihydrate; spray-congealed mannitol; combination of sucrose and maltodextrin (Di Pac®); and combination of starch and lactose (Starlac®).
Suitable binders include for example starch, povidone, hydroxypropyl methylcellulose, pregelatinised starch, hydroxypropyl cellulose and/or mixtures of the foregoing. Suitable lubricants, including agents that act on the flowability of the powder to be compressed are, for example, colloidal silicon dioxide such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate, or the like or mixtures thereof. Suitable disintegrants include for example lightly crosslinked polyvinyl pyrrolidone, cornstarch, potato starch, maize starch and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate, or the like or combinations thereof.
In an embodiment, the content of pharmaceutically acceptable excipient(s) in the compositions of the present invention varies depending on a dosage form and an administration method, and is usually 0 to about 99% preferably about 10 to about 99% by weight of the composition. In another embodiment, the content of the adsorbate or the solid dispersion in the composition varies depending on the type of dosage form, the administration method and the like, and is usually about 0.1 to 100% (w/w), preferably about 5 to 80%(w/w), more preferably about 30 to 60%(w/w), relative to the total amount of a preparation.
In an embodiment of the present invention, the composition as disclosed in Example 2 herein provides in-vitro release of not less than about 50% of Roflumilast in about 1 hour; when tested by the USP Apparatus Type II (Paddles) at 75 rpm using 500 ml of different dissolution media maintained at about 37±0.5°C temperature as shown in table-1. The study indicates that the drug release from the said composition is appreciably fast which in turn might lead to good absorption and hence better bioavailability.
(Table Removed)
In an embodiment of the present invention, the compositions can be made as immediate release dosage forms, modified release dosage forms, or a combination of both wherein the dosage form comprises at least two fractions which releases a fraction of the active agent immediately and a fraction of the active agent in a controlled manner.
In an embodiment of the present invention is provided a process for preparation of such
novel composition which comprises of the following steps:
i) mixing the active agent(s) and carrier(s) together, and optionally adding a solvent,
ii) adding a hydrophilic component(s),
iii) optionally adding one or more other pharmaceutically acceptable excipient(s), and
iv) formulating the mixture into a suitable dosage form.
In a further embodiment of the present invention, the process for the preparation of such
novel composition comprises of the following steps:
i) dissolving the active agent(s) in a suitable solvent,
ii) adding the carrier(s) and the hydrophilic component(s),
iii) removal of the solvent to obtain a dry material,
iv) milling the dry material to obtain the desired particle size,
v) optionally adding one or more other pharmaceutically acceptable excipient(s), and
vi) formulating the mixture into a suitable dosage form.
In a further embodiment of the present invention, the process for the preparation of such
novel composition comprises of the following steps:
i) adding the active agent(s) into a molten or a liquid carrier(s) and mixing,
ii) adding a hydrophilic component(s) into the mixture with further mixing,
iii) solidifying the mixture to obtain a dry material,
iv) optionally milling the dry material to obtain the desired particle size,
v) optionally adding one or more other pharmaceutically acceptable excipient(s), and
vi) formulating the mixture into a suitable dosage form.
In a further embodiment of the present invention, the process for the preparation of such novel composition comprises of the following steps:
i) mixing the active agent(s) and carrier(s) together to obtain a solid solution,
ii) adding a hydrophilic component(s) with mixing,
iii) solidifying the mixture to obtain a dry material,
iv) optionally milling the dry material to obtain the desired particle size,
v) optionally adding one or more other pharmaceutically acceptable excipient(s), and
vi) formulating the mixture into a suitable dosage form.
In a further embodiment, the composition of the present invention is preferably in the form solid dosage forms such as tablets, capsules, pellets, granules, powder, or the like, preferably as tablets. The tablets can be prepared by either wet granulation, direct compression, or by compaction granulation. The tablets can be prepared by either wet granulation, direct compression, or by dry compression (slugging). In a preferred embodiment of the present invention, the oral composition is prepared by direct compression. In an embodiment, the compositions of the present invention are in the form of compressed tablets, moulded tablets, mini-tablets, capsules, pellets, granules and products prepared by extrusion or film cast technique, and the like. The dosage forms, particularly tablets, may be optionally coated with a functional or nonfunctional coating based on the desired design of the dosage form and its intended purpose. The tablets/minitablets may be optionally filed into capsules.
In another embodiment of the present invention is provided a method of using such novel composition which comprises administering to a patient in need thereof an effective amount of the composition. The compositions comprising PDE4 inhibitor as the active agent are useful particularly for management of asthma and chronic obstructive pulmonary disease and/or other associated respiratory disorders.
The examples given below serve to illustrate embodiments of the present invention. However they do not intend to limit the scope of present invention.
EXAMPLES
Example 1
S. No. Ingredient mg/tablet
1. Roflumilast 0.5
2. Lactose 50.0
3. Ethanol q.s. (lost in processing)
4. Sodium lauryl sulphate 1.0
5. Microcrystalline cellulose (Avicel® PH 102) 16.0
6. Combination of starch and lactose (Starlac®) 30.0
7. Magnesium stearate 0.5
8. Sodium starch glycolate 2.0
Procedure:
i) Roflumilast was dissolved in ethanol to form a solution.
ii) Lactose was added to the solution of step i) with stirring.
iii) The solvent contained in the material of step ii) was evaporated and the dried
material so obtained was milled, iv) Sodium lauryl sulphate, Microcrystalline cellulose, Combination of starch and
lactose, Sodium starch glycolate and Magnesium stearate were sifted through
mesh # 40 sieve and mixed with the material of step iii). v) The blend of step iv) was compressed into tablet.
Example 2
a) Adsorbate
S. No. Ingredient mg/tablet
1. Roflumilast 0.5
2. Mannitol 50.0
3. Hydroxypropyl methylcellulose (HPMC E5) 1.5
4. Ethanol q.s. (lost in processing)
b) Tablet
5. Roflumilast adsorbate 52.0
6. Sodium lauryl sulphate 1.0
7. Microcrystalline cellulose (Avicel® PH 102) 14.5
8. Combination of starch and lactose (Starlac®) 30.0
9. Magnesium stearate 0.5
10. Sodium starch glycolate 2.0
Procedure:
i) Roflumilast was dissolved in ethanol to form a solution.
ii) Hydroxypropyl methylcellulose was added to the solution of step i) followed by the
addition of Mannitol with stirring,
iii) The solvent contained in the material of step ii) was evaporated and the dried
adsorbate so obtained was milled, iv) Sodium lauryl sulphate, Microcrystalline cellulose, Combination of starch and
lactose, Sodium starch glycolate and Magnesium stearate were sifted through mesh 40 sieve and mixed with the material of step iii). v) The blend of step iv) was compressed into tablet.
Example 3
S. No. Ingredient mg/capsule
1. Roflumilast 0.5
2. Hydroxypropyl methylcellulose 11.5
3. Ethanol q.s. (lost in processing)
4. Microcrystalline cellulose (Avicel® PH102) 50.0
5. Magnesium stearate 0.5
6. Sodium starch glycolate 2.0
Procedure:
i) Roflumilast was dissolved in ethanol to form a solution.
ii) Hydroxypropyl methylcellulose was added to the solution of step i) with stirring.
iii) The solvent contained in the material of step ii) was evaporated and the dried
material so obtained was milled. iv) Microcrystalline cellulose, Sodium starch glycolate and Magnesium stearate were
sifted through mesh # 40 sieve and mixed with the material of step iii). v) The blend of step iv) was compacted using a Roller Compactor to obtain compacts, vi) The compacts were filled into a hard gelatin capsule.
Example 4
a) Adsorbate
S. No. Ingredient mg/tablet
1. Roflumilast 0.5
2. Maltitol 15.5
3. Ethanol q.s. (lost in processing)
Procedure:
i) Roflumilast was dissolved in ethanol to form a solution.
ii) To the solution formed in step i), Maltitol was added and dispersed by stirring.
iii) The dispersion of step ii) was layered on non-pareil sugar (NPS) beads using
Wurster coating apparatus, iv) The layered beads were then dried, milled and passed through mesh #60 sieve to
obtain Roflumilast adsorbate material.
b) Tablet

S. No. Ingredient mg/tablet
1. Roflumilast adsorbate material 16.0
2. Sodium glycocholate 1.5
3. Dibasic calcium phosphate 14.0
4. Lactose monohydrate 30.0
5. Isopropyl alcohol q.s. (lost in processing)
6. Magnesium stearate 0.5
7. Croscarmellose sodium 2.0
Procedure:
i) Roflumilast adsorbate material was mixed with Sodium glycocholate, Dibasic calcium phosphate and Lactose monohydrate and sifted through mesh #40 sieve.
ii) The material of step i) was granulated with isopropyl alcohol, dried and sifted through mesh #30 sieve.
iii) Magnesium stearate and Croscarmellose sodium were sifted through mesh #40 sieve and added to the material of step ii) and mixed together.
iv) The blend of step iii) was compressed into tablet.
Example 5
a) Solid dispersion (SD)
S. No. Ingredient mg/tablet
1. Roflumilast 0.5
2. Hydroxypropyl methylcellulose (HPMC E5) 1.5
3. Lactose 50.0
4. Ethanol q.s. (lost in processing)
b) Tablet
5. Roflumilast (SD) 52.0
6. Sodium glycocholate 1.5
7. Dibasic calcium phosphate (Emcompress®) 14.0
8. Combination of starch and lactose (Starlac®) 30.0
9. Magnesium stearate 0.5
10. Crospovidone 2.0
Procedure:
i) Roflumilast was dissolved in ethanol to form a solution.
ii) Hydroxypropyl methylcellulose was added to the step i) solution and was allowed to swell for 5 minutes.

iii) Lactose was added to the dispersion of step ii) with stirring.
iv) The excess solvent was evaporated from the material of step iii) and resulted
material was milled to get the solid dispersion, v) Sodium glycocholate, Dibasic calcium phosphate, Combination of starch and
lactose, Crospovidone and Magnesium stearate were added to the solid dispersion
of step iv) and were mixed together, vi) The blend of step v) was compressed into tablet.
Example 6
a) Adsorbate
S. No. Ingredient mg/capsule
1. Rolipram 1.0
2. Polyethylene glycol (PEG 6000) 2.0
3. Mannitol 49.0
4. Ethanol q.s. (lost in processing)
b) Capsule
5. Rolipram adsorbate 52.0
6. Polyoxyethylene sorbitan monostearate 1.5
7. Lactose anhydrous (Pharmatose® DCL21) 14.0
8. Combination of sucrose and maltodextrin (Di Pac®) 30.0
9. Sodium stearyl fumarate 0.5
Procedure:
i) Rolipram was dispersed in Ethanol to form a homogeneous dispersion.
ii) Mannitol and Polyethylene glycol were added to the step i) solution to form dough.
iii) The excess solvent of the dough of step ii) was evaporated and the resulted
material was milled to get the adsorbate. iv) Polyoxyethylene sorbitan monostearate, Lactose anhydrous, Combination of
sucrose and maltodextrin, and Sodium stearyl fumarate were added to adsorbate of
step iii) and were mixed together, v) The blend of step iv) was filled into hard gelatin capsule.
Example 7
a) Solid dispersion (SD)
S. No. Ingredient mg/capsule
1. Risperidone 2.0
2. Hydroxypropyl methylcellulose (HPMC E15) 2.0

3. Mannitol 50.0
4. Ethanol q.s. (lost in processing)
b) Capsule
5. Risperidone (SD) 54.0
6. Sorbitan monooleate 2.0
7. Lactose anhydrous (Pharmatose® DCL21) 45.0
8. Sodium stearyl fumarate 1.0
9. Sodium starch glycolate 2.0
Procedure:
i) Risperidone was dissolved in Ethanol to form a solution.
ii) Hydroxypropyl methylcellulose was added to the step i) solution with stirring.
iii) Mannitol was added to the dispersion of step ii).
iv) The excess solvent was evaporated and resulted material was milled to get the solid
dispersion, v) Sorbitan monooleate, Lactose anhydrous, Sodium starch glycolate and Sodium
stearyl fumarate were added to the solid dispersion of step iv) and were mixed
together, vi) The blend of step v) was filled into hard gelatin capsule.
Example 8
a) Solid dispersion (SD)
mg/tablet
5.0
2.0 53.0 q.s. (lost in processing)
60.0
2.0 15.0 30.0
1.0
2.0
S. No. Ingredient
1. Roflumilast
2. Hydroxypropyl beta-cyclodextrin
3. Dextrose
4. Ethanol
b) Tablet
5. Roflumilast (SD)
6. Magnesium lauryl sulfate
7. Microcrystalline cellulose (Avicel PH102)
8. Dicalcium phosphate dihydrate
9. Glyceryl behenate
10. Sodium starch glycolate
Procedure:
i) Roflumilast was dissolved in Ethanol to form a solution.

ii) Dextrose and Hydroxypropyl beta-cyclodextrin were added to the solution of step i). iii) The excess solvent was evaporated and resulted material was milled to get the solid
dispersion, iv) Magnesium lauryl sulfate, Microcrystalline cellulose, Dicalcium phosphate
dihydrate, Sodium starch glycolate and Glyceryl behenate were added to the solid
dispersion of step iii) and were mixed together, v) The blend of step iv) was compressed into tablet.
Example 9
a) Solid dispersion (SD)
S. No. Ingredient mg/capsule
1. Cilomilast 15.0
2. Hydroxypropyl cellulose 2.0
3. Sorbitol 53.0
4. Ethanol q.s. (lost in processing)
b) Capsule
5. Cilomilast (SD) 70.0
6. Polyoxyethylene castor oil 2.0
7. Microcrystalline cellulose (Avicel PH102) 15.0
8. Dicalcium phosphate dihydrate 30.0
9. Calcium stearate 1.0
Procedure:
i) Cilomilast was dissolved in Ethanol to form a solution.
ii) Hydroxypropyl cellulose was added to the step i) solution with stirring.
iii) Sorbitol was added to the dispersion of step ii) with stirring.
iv) The excess was evaporated and resulted material was milled to get the solid
dispersion, v) Polyoxyethylene castor oil, Microcrystalline cellulose, Dicalcium phosphate
dihydrate, and Calcium stearate were sifted through mesh #40 sieve and added to
the solid dispersion of step iv) followed by mixing, vi) The blend of step v) was filled into hard gelatin capsule.
Example 10
a) Adsorbate
S. No. Ingredient mg/tablet
1. Cisapride 10.0

2. Lactose 50.0
3. Acetone q.s. (lost in processing)
b) Tablet
4. Cisapride adsorbate 60.0
5. Corn starch 13.0
6. Hydroxypropyl cellulose 2.5
7. Purified water q.s.
8. Sodium lauryl sulphate 1.5
9. Calcium stearate 0.5
10. Dicalcium phosphate dihydrate 10.0
11. Sodium starch glycolate 2.5
Procedure:
i) Cisapride was dissolved in Acetone to form a solution, ii) Lactose was added to the step i) solution with stirring, iii) The excess solvent was evaporated and the material was milled to get solid
dispersion, iv) Corn starch, Dicalcium phosphate dihydrate, Sodium lauryl sulphate and Sodium
starch glycolate were sifted through mesh 30 sieve and mixed together, v) Hydroxypropyl cellulose was dissolved in purified water, vi) The material of step iv) was granulated with the material of step v) and the granules
thus obtained were dried and sifted through mesh 20 sieve, vii) Calcium stearate was sifted through mesh 40 sieve and added to the material of
step vi) followed by mixing, viii) The blend of step vii) was compressed into tablets.
Example 11
a) Adsorbate
S. No. Ingredient mg/tablet
1. Roflumilast 0.5
2. Sodium alginate 1.5
3. Mannitol 50.0
4. Ethanol q.s. (lost in processing)
b) Tablet
5. Roflumilast adsorbate 52.0

6. Sodium lauryl sulphate 1.0
7. Microcrystalline cellulose (Avicel PH102) 44.5
8. Magnesium stearate 0.5
9. Sodium starch glycolate 2.0
Procedure:
i) Roflumilast was dissolved in ethanol to form a solution.
ii) Lactose and Sodium alginate were mixed together.
iii) Solution of step i) was adsorbed on the material of step ii).
iv) The excess solvent was evaporated and resulted material was milled to get the
adsorbate. v) Sodium lauryl sulphate, Microcrystalline cellulose, Sodium starch glycolate and
Magnesium stearate were added to the adsorbate of step iv) and mixed together, vi) The blend of step v) was compressed into tablet.
Example 12
S. No. Ingredient mg/tablet
1. Roflumilast 0.5
2. Polyvinyl pyrrolidone 1.5
3. Maltose 60.0
4. Ethanol q.s. (lost in processing)
5. Poloxamer 1.5
6. Croscarmellose sodium 3.0
7. Colloidal silicon dioxide 0.5

8. Hydrogenated vegetable oil (Lubritab®) 0.5
Procedure:
i) Roflumilast was dissolved in ethanol to form a solution.
ii) Poloxamer was added to the solution of step i) to form a solution with stirring to
obtain a uniform dispersion, iii) Polyvinyl pyrrolidone, Maltose and Croscarmellose sodium were sifted through #30
mesh sieve and mixed together, iv) The mixture of step iii) was granulated with the dispersion of step ii); then the
granules were sifted through # 18 mesh sieve followed by drying to obtain the dried
granules, v) Hydrogenated vegetable oil and Colloidal silicon dioxide were sifted through 40
mesh sieve and mixed together.
vi) The material of step v) was added to the material of step iv) and mixed, vii) The blend of step vi) was compressed into tablets.

We Claim:
1. A novel pharmaceutical composition comprising at least one PDE4 inhibitor(s) as
the active agent, at least one carrier(s) present in an amount not less than 10% by
weight of the composition, at least one hydrophilic component(s), optionally a
solvent and optionally one or more other pharmaceutically acceptable excipient(s),
wherein the carrier(s) and the hydrophilic component(s) is present in a ratio of
0.1:50 to 50:0.1.
2. The composition as claimed in claim 1, wherein the PDE4 inhibitor is selected from
a group comprising denbufylline, rolipram, cipamfylline, arofylline, filaminast,
piclamilast, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, cilomilast,
6-[2-(3,4-Diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid, (R)-(+)-4-[2-(3-
Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine, N-(3,5-Dichloro-4-
pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide, 9-(2-
Fluorobenzyl)-N-6-methyl-2-(trifluoro methyl) adenine, N-(3,5-Dichloro-4-pyridinyl)-
8-methoxyquinoline-5-carboxamide, N-[9-Methyl-4-oxo-1-phenyl-3,4,6,7-
tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3(R)-yl]pyridine-4-carboxamide ,3-[3-
(Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine
hydrochloride, 4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-
methoxyethyl)pyridin-2 (1 H)-one-2-carbomethoxy-4-cyano-4-(3-
cyclopropylmethoxy-4-difluroromethoxyphenyl) cyclohexan-1 -one, cis[4-cyano-4-(3-
cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 -ol, or its
pharmaceutically acceptable salts, hydrates, polymorphs, esters, and derivatives
thereof.
3. The composition as claimed in claim 2, wherein the PDE4 inhibitor is roflumilast or
pharmaceutically acceptable salts, hydrates, polymorphs, esters, and derivatives
thereof.
4. The composition as claimed in claim 1, wherein the carrier is selected from a group
comprising crospovidone, cross-linked polymeric cyclodextrin, dextran,
polyvinylpyrrolidone, cellulose, alginates, silica gel, titanium dioxide, aluminum
oxides; cellulose derivatives, starches, sugars, sugar alcohols, croscarmellose
sodium, sodium starch glycolate, polyvinyl alcohol, ascorbic acid, carbopols,
polyethylene oxide, and mixtures of mono-, di-, & triglycerides with polyethylene
glycol (PEG) esters of fatty acids, saccharide selected from lactose and mannitol,
used either alone or in combination thereof.
5. The composition as claimed in claim 1, wherein the hydrophilic component is
selected from a group comprising alkyl celluloses; hydroxyalkyl alkyl celluloses;
hydroxyalkyl celluloses; polyethylene glycols; copolymers of ethylene oxide with
propylene oxide; gelatin; polyvinylpyrrolidone; vinylpyrrolidones; vinyl acetates;
polyvinylimidazoles; polyvinylpyridine N-oxides; copolymers of vinylpyrrolidone with
long-chained alpha-olefins; copolymers of vinylpyrrolidone with vinylimidazole;
poly(vinylpyrrolidone/dimethylaminoethyl methacrylates); copolymers of
vinylpyrrolidone/dimethylaminopropyl methacrylamides; copolymers of
vinylpyrrolidone/dimethylaminopropyl acrylamides; quaternised copolymers of
vinylpyrrolidones and dimethylaminoethyl methacrylates; terpolymers of
vinylcaprolactam/vinylpyrrolidone/dimethylaminoethyl methacrylates; copolymers of
vinylpyrrolidone and methacrylamidopropyl-trimethylammonium chloride;
terpolymers of caprolactam/vinylpyrrolidone/dimethylaminoethyl methacrylates;
copolymers of styrene and acrylic acid; polycarboxylic acids; polyacrylamides;
polyvinyl alcohols; hydrolysed polyvinyl acetate; copolymers of ethyl acrylate with
methacrylate and methacrylic acid; copolymers of maleic acid with unsaturated
hydrocarbons and mixed polymerisation products of the said polymers;
polysaccharide gums; alginic acid; alginates; arabinoglactin; pectin; tragacanth;
scleroglucan; dextran; amylase; amylopectin; dextrin; polyethylene glycols;
cyclodextrins, or mixtures thereof.
6. The composition as claimed in claim 5, wherein the hydrophilic component(s) is
hydroxypropyl methylcellulose present in an amount not less than 0.25% by weight
of the composition.
7. The composition as claimed in claim 1, wherein the solvent is selected from a
group comprising methanol, ethanol, propanol, isopropyl alcohol, butanol,
monomethoxyethanol, ethylene glycol monomethylether; ethers such as diethyl
ether, dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuran, ethylene glycol;
aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane; aromatic
hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile;
organic acids such as acetic acid, propionic acid; esters such as ethyl acetate;
aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane,
chloroform; ketones such as acetone, methyl ketone; amides such as
dimethylformamide, dimethyl acetamide; used either alone or in combination
thereof.
8. The composition as claimed in claim 1, wherein active agent is in the form of an
adsorbate or a solid dispersion.
9. The composition as claimed in claim 1, wherein the pharmaceutically acceptable
excipient(s) are selected from a group comprising diluents, disintegrants, direct
compression vehicles, surfactants, binders, fillers, bulking agents, anti-adherants,
anti-oxidants, buffering agents, colorants, flavoring agents, coating agents,
plasticizers, stabilizers, preservatives, lubricants, glidants, chelating agents used
either alone or in combination thereof.
10. A process of preparation of the composition as claimed in claim 1, which comprises
of the following steps:
i) mixing the active agent(s) and carrier(s) together, and optionally adding a solvent,
ii) adding a hydrophilic component(s),
iii) optionally adding one or more other pharmaceutically acceptable excipient(s),
and iv) formulating of the mixture into a suitable dosage form.
11. A process for the preparation of the composition as claimed in claim 1, which
comprises of the following steps:
i) dissolving the active agent(s) in a suitable solvent,
ii) adding the carrier(s) and the hydrophilic component(s),
iii) removal of the solvent to obtain a dry material,
iv) milling the dry material to obtain the desired particle size,
v) optionally adding one or more other pharmaceutically acceptable excipient(s), and
vi) formulating the mixture into a suitable dosage form.
12. A process for the preparation of the composition as claimed in claim 1, which
comprises of the following steps:
i) adding the active agent(s) into a molten or a liquid carrier(s) and mixing,
ii) adding a hydrophilic component(s) into the mixture with further mixing,
iii) solidifying the mixture to obtain a dry material,
iv) optionally milling the above dry material to obtain the desired particle size,
v) optionally adding one or more other excipient(s), and
vi) formulating the mixture into a suitable dosage form.
13. A process for the preparation of the composition as claimed in claim 1, which
comprises of the following steps:
i) mixing the active agent(s) and carrier(s) together to obtain a solid solution,
ii) adding a hydrophilic component(s) with mixing,
Hi) solidifying the mixture to obtain a dry material,
iv) optionally milling the dry material to obtain the desired particle size,
v) optionally adding one or more other excipient(s), and
vi) formulating the mixture into a suitable dosage form.
14. A composition as claimed in claim 1, which is useful for the management of asthma
and chronic obstructive pulmonary disease and/or other associated respiratory
disorders.
15. The pharmaceutical composition and process for the preparation of pharmaceutical
composition substantially as herein described and illustrated by the examples.