WO2015132708A1 - Composition pharmaceutique de roflumilast - Google Patents

Composition pharmaceutique de roflumilast Download PDF

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Publication number
WO2015132708A1
WO2015132708A1 PCT/IB2015/051513 IB2015051513W WO2015132708A1 WO 2015132708 A1 WO2015132708 A1 WO 2015132708A1 IB 2015051513 W IB2015051513 W IB 2015051513W WO 2015132708 A1 WO2015132708 A1 WO 2015132708A1
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WIPO (PCT)
Prior art keywords
component
roflumilast
subsequent
pharmaceutical composition
composition
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PCT/IB2015/051513
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English (en)
Inventor
Jaya Abraham
Sujay Rajhans
Tapan BUCH
Original Assignee
Torrent Pharmaceuticals Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication of WO2015132708A1 publication Critical patent/WO2015132708A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • Present invention relates to multiparticulate pharmaceutical composition having first inert component comprising one or more pharmaceutical excipients and at least one subsequent component comprising roflumilast, wherein said first inert component is free of roflumilast.
  • invention also relates to process of preparation of said pharmaceutical composition and its use in the treatment of COPD.
  • Roflumilast N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy- benzamide, a phosphodiesterase 4 (PDE-4) inhibitor, is approved in several countries to reduce the risk of chronic obstructive pulmonary disease (COPD), exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. It is available commercially in USA as Daliresp® 500mcg oral immediate release tablet for once a day administration.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • Roflumilast is poorly water soluble drug and has been categorized as BCS class II drug (high permeability, low solubility). Therefore, it is desirable to design a formulation which improves the rate of dissolution and thus improving the bioavailability of the drug. Further, Roflumilast being a potent drug having very low dose formulation, there is a need to develop a robust process with reproducible content uniformity within the batches as well as improve batch to batch consistency.
  • Prior art discloses various techniques to improve dissolution of poorly water soluble drugs, however, selection of suitable technique & excipients largely depends upon the overall characteristics of the molecule, which eventually plays critical role in designing formulation strategy to achieve desired in-vivo dissolution and plasma profile to get the desired therapeutic outcome.
  • US6074670 discloses composition of fenofibrate, a poorly soluble drug, a hydrophilic polymer and a surfactant, wherein API was granulated with solution of hydrophilic polymer such as polyvinylpyrrolidone to have improved dissolution profile.
  • US8431 154 discloses the composition of Roflumilast to improve its release and improved pharmacokinetic profile by using aqueous solution of polyvinylpyrrolidone (PVP) for granulation of roflumilast by preparing solid solution or solid dispersion.
  • PVP polyvinylpyrrolidone
  • US7951398 discloses solid dispersion of poorly soluble drug roflumilast, wherein Roflumilast is dispersed in matrix comprising fatty alcohol, triglyceride and fatty acid ester at high temperature, and then cooling and granulating it with a hydrophilic polymer.
  • Indian patent application 685/DEL/2006 discloses preparation of adsorbate or solid dispersion of Roflumilast and hydrophilic carriers preferably hydroxypropylmethylcellulose to improve dissolution of Roflumilast, in which hydrophilic carrier is dispersed in the mixture of Roflumilast-Solvent resulting in formation of adsorbate or solid dispersion.
  • WO 2013030789 discloses pharmaceutical oral dosage form of Roflumilast with polymeric binders selected from saccharides, protein or synthetic polymers, preferably hydroxylpropylcellulose or hydroxypropylmethylcellulose. The composition prepared by wet granulation using binder solution to granulate Roflumilast.
  • One aspect of the present invention is to provide multiparticulate pharmaceutical composition having first inert component comprising one or more pharmaceutical excipients and at least one subsequent component comprising roflumilast, wherein said first inert component is free of roflumilast.
  • Another aspect of present invention is to provide multiparticulate pharmaceutical composition prepared by granulation process, having first inert component comprising one or more pharmaceutical excipients and at least one subsequent component comprising roflumilast, wherein said first inert component is free of roflumilast.
  • Another aspect of present invention is to provide multiparticulate pharmaceutical composition having first inert component prepared by granulation process comprising one or more pharmaceutical excipient and at least one subsequent component comprising roflumilast and optionally one or more pharmaceutical excipient, wherein said subsequent component is prepared by granulation of roflumilast and optionally one or more pharmaceutical excipient with said first inert component.
  • Another aspect of present invention is to provide multiparticulate pharmaceutical composition having first inert component and at least one subsequent component prepared by a process comprising the steps:
  • first inert component comprising one or more pharmaceutical excipients, by granulation.
  • step b Optionally adding one or more subsequent components in the mixture/blend of step b.
  • Another aspect of present invention is to provide process of preparing multiparticulate pharmaceutical composition having first inert component and at least one subsequent component comprising the steps:
  • first inert component comprising one or more pharmaceutical excipients, by granulation.
  • step b Optionally adding one or more subsequent components in the mixture/blend of step b.
  • a phosphodiesterase-4 (PDE-4) inhibitor, Roflumilast is known to be effective for reduction in risk of chronic obstructive pulmonary disease (COPD), exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.
  • COPD chronic obstructive pulmonary disease
  • Present invention relates to a novel approach of providing the stable pharmaceutical composition of roflumilast having required content uniformity wherein said composition provides desired dissolution profile and thus a bioequivalent product.
  • Roflumilast free base includes Roflumilast free base, its pharmacologically active metabolites including roflumilast-N-oxide, its pharmaceutically acceptable salt or its polymorphs.
  • Roflumilast is Roflumilast free base.
  • Roflumilast present in the composition according to present invention can be in crystalline form or amorphous form.
  • Particle size distribution (PSD- D90) of roflumilast used according to present invention may vary from 1-25 microns, preferably D90 is less than 10 microns, most preferably D90 is less than 5 microns.
  • multiparticulate means state of matter which is characterized by the presence of particles, pellets, beads or granules irrespective of their size, shape or morphology. Such said multiparticulate may be formulated in the form of compressed tablets, can be filled in a capsule or can be used as such as a pharmaceutical composition.
  • inert component which is free of roflumilast as used herein means a component wherein roflumilast or any other active pharmaceutical ingredient is not added during processing.
  • first inert component means any component which is free of roflumilast and is mixed or added with at least one subsequent component. Meaning of the term should not be construed on the basis of order of preparing or mixing/adding of the components. Thus, any component prepared according to present invention, wherein roflumilast is not added, can be a first inert component irrespective of order of preparation or mixing/adding with subsequent component/s.
  • subsequent component means one or more component other than said first inert component present in the composition. At least one of the said subsequent component comprises roflumilast. Meaning of the term should not be construed on the basis of order of preparing or mixing/adding of the components.
  • D90 means at least 90% of the particles have volume diameter in the specified range when measured by a suitable method for example laser diffraction using a Malvern Mastersizer® laser diffraction instrument.
  • Gramulation means a method used to prepare multiparticulate composition. Said methods include any suitable granulation methods including wet granulation, dry granulation, roller compaction and melt granulation. Preferably wet granulation is used for the preparation of multiparticulate composition.
  • the first embodiment of the present invention provides multiparticulate pharmaceutical composition having first inert component comprising one or more pharmaceutical excipients and at least one subsequent component comprising roflumilast, wherein said first inert component is free of roflumilast.
  • First inert component according to present invention comprises one or more pharmaceutical excipient such as one or more diluent, binder, disintegrant, surfactant or lubricant.
  • pharmaceutical excipient is one or more diluent and/or binder.
  • First inert component according to present invention can be prepared by any known process in the art.
  • first inert component is in the form of granules prepared by wet granulation, which is free of roflumilast. More preferably, first inert component is prepared by aqueous granulation.
  • Subsequent component of said multiparticulate composition prepared according to present invention comprises roflumilast optionally with one or more pharmaceutical excipient, but free of hydrophilic polymeric binder.
  • Said subsequent component is added or mixed with said first inert component.
  • the term “adding” “added” “mixing” or “mixed” as used herein are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply mixing, adding, granulating of one of the said components with other component to form mixture or blend.
  • Said subsequent component is either present as a separate component in any physical form such as powder, granules, beads and the like or can be granulated with said first inert component.
  • subsequent component can be coated over said first component.
  • subsequent component is granulated with first inert component using wet granulation, more preferably using non-aqueous granulation.
  • a part of first inert component is granulated with said subsequent component.
  • about 90-96% of total first inert component is granulated with said subsequent component.
  • Granulation can be performed using any of the known method such as rapid mixer granulation or fluid bed granulation. It is preferable that all the said components are dried before addition of other component.
  • non-aqueous granulation means granulation to prepare any of the components of multiparticulate composition according to present invention wherein organic or inorganic solvent is used for granulation, preferably organic solvent is used for granulation, which is substantially free of water.
  • substantially free means less than 10% of water is present in the organic solvent. Preferably, less than 5%, most preferably less than 1% of water is preset in the solvent.
  • a further embodiment of present invention provides a multiparticulate pharmaceutical composition having first inert component comprising one or more pharmaceutical excipients and at least one subsequent component comprising roflumilast, wherein said first inert component is free of roflumilast and said subsequent component is free of hydrophilic polymeric binder.
  • free of hydrophilic polymeric binder means any subsequent component which comprises roflumilast, wherein roflumilast is not mixed with any hydrophilic polymeric binder, preferably aqueous solution of hydrophilic polymeric binder, during the preparation of said subsequent component.
  • compositions may further comprise one or more subsequent components.
  • Such said subsequent component/s may or may not comprise roflumilast.
  • composition prepared according to present invention not only provides consistent content uniformity but also provides a stable product with desired characteristics such as hardness and/or dissolution profile. It is noteworthy that composition according to present invention does not require any complex process or use of polymeric binder solution to modify API characteristics, but still provides desired dissolution profile, which provides bioequivalent product. Additionally, multiparticulate composition prepared by the process according to present invention has acceptable flow properties.
  • first inert component comprising one or more pharmaceutical excipients, by granulation.
  • step b Optionally adding one or more subsequent components in the mixture/blend of step b.
  • first inert component comprising one or more pharmaceutical excipients, by granulation.
  • step b Optionally adding one or more subsequent components in the mixture/blend of step b.
  • composition according to present invention is prepared by a process comprising:
  • first inert component comprising one or more diluent, binder, disintegrant, surfactant or lubricant, by granulation.
  • step b Optionally adding one or more diluent, disintegrant, surfactant or lubricant in the mixture/blend of step b.
  • step d Optionally adding one or more diluent, disintegrant, surfactant or lubricant in the granules of step d.
  • step e Optionally adding one or more diluent, disintegrant, surfactant or lubricant in the granules of step d.
  • step e Preparing a pharmaceutical composition from the mixture or blend of step e.
  • Diluent, disintegrant, surfactant or lubricant used in each of the preceding steps can be same or different.
  • Another embodiment of present invention provides multiparticulate pharmaceutical composition having first inert component comprising one or more pharmaceutical excipient and at least one subsequent component comprising roflumilast, wherein at least one of the said components is prepared by wet granulation and said first inert component is free of roflumilast.
  • Another embodiment of present invention provides multiparticulate pharmaceutical composition having first inert component comprising one or more pharmaceutical excipient and at least one subsequent component comprising roflumilast, wherein said first inert component and at least one subsequent component are prepared by wet granulation and said first inert component is free of roflumilast.
  • said first inert component is prepared by the wet granulation using aqueous granulation and at least one subsequent component is prepared by wet granulation using non-aqueous granulation.
  • Solvent used for non-aqueous granulation of roflumilast to prepare pharmaceutical composition according to present invention include acetone, methylene chloride, isopropyl alcohol, ethanol, chloroform, dichloromethane, ether methanol and the like or combination thereof.
  • compositions according to present invention comprises diluent, binder, disintegrant, surfactant, lubricant and the like.
  • compositions according to present invention may optionally further comprises one or more glidant, coloring agent, flavoring agent, preservatives, antioxidants and the like.
  • glidant coloring agent, flavoring agent, preservatives, antioxidants and the like.
  • suitable amount of said excipient is known to a skilled person or as given in Handbook of pharmaceutical excipients (sixth edition, 2009).
  • a diluent according to present invention include powdered cellulose, microcrystallme cellulose, silicified microcrystallme cellulose, starch, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate; sugars such as dextrose, lactose or sucrose; sugar alcohols such as mannitol, sorbitol, xylitol or erythritol; or mixtures thereof.
  • diluent is lactose, starch or mixture thereof.
  • Pharmaceutical composition comprises diluent in the amount of 50-98% w/w of the total composition.
  • a binder according to present invention include polyvinyl alcohol, starch, pregelatinised starch; cellulose derivatives such as cellulose powder, microcrystallme cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose; gelatin, zein, polymethacrylates, sodium alginate, gums, synthetic resins or mixtures thereof.
  • binder is polyvinyl alcohol.
  • Pharmaceutical composition comprises binder in the amount of 2- 30% w/w of the total composition.
  • a disintegrant according to present invention include carboxymethyl cellulose and its salt including sodium or calcium salt, cross-linked carboxymethyl cellulose sodium, cross-linked carboxymethyl cellulose calcium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, pregelatinized starch, low substituted hydroxypropyl cellulose, and mixtures thereof.
  • disintegrant is carboxymethylcellulose calcium.
  • Pharmaceutical composition comprises disintegrant in the amount of 0.6 - 8.0 w/w of the total composition.
  • a surfactant according to present invention is selected from one or more non-ionic or ionic (i. e., cationic, anionic and Zwitterionic) surfactants suitable for use in pharmaceutical compositions.
  • Suitable surfactants include mono fatty acid esters of polyoxyethylene sorbitan such as those sold under the brand name Tween ® ; sodium lauryl sulfate, polyoxyethylene castor oil derivatives such as those sold under the brand name Cremophor ® , polyethoxylated fatty acids and their derivatives, propylene glycol fatty acid esters, sterol and sterol derivatives; sorbitan fatty acid esters and their derivatives, sugar esters, polyoxyethylene-polyoxypropylene block copolymers such as those sold under the brand name Poloxamer ® , soy lecithin, or mixtures thereof.
  • Pharmaceutical composition comprises surfactant in the amount of 0.01-7 % w/w of the total composition.
  • a lubricant according to present invention include talc, metallic stearate such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, magnesium trisilicate or mixtures thereof.
  • lubricant is magnesium stearate.
  • Pharmaceutical composition comprises lubricant in the amount of 0.2-2% w/w of the total composition.
  • compositions prepared according to present invention comprises roflumilast in the amount of 0.01-2%, preferably 0.1-1%, most preferably 0.6 - 0.9% w/w of the total composition.
  • First inert component according to present invention can be present in the amount of 70 to 99% w/w of the total composition.
  • first inert component is present in the amount of 90-99% w/w of the total composition, most preferably, it is 95-99% w/w of the total composition.
  • Particle size (D90) of first inert component can be less than 400 microns.
  • particle size (D90) of first inert component is less than 300 microns, more preferably particle size(D90) is less than 200 microns.
  • One or more subsequent components according to present invention can be present in the amount of 1 to 30% w/w of the total composition.
  • one or more subsequent components are present in the amount of 1-10% w/w of the total composition; most preferably, it is 1-5% w/w of the total composition.
  • a pharmaceutical composition according to present invention is a solid composition for immediate release for oral or nasal administration and it can be in the form of tablet, powder or capsule. Preferably, said composition is in the form of tablet or capsule for oral administration.
  • a pharmaceutical composition according to present invention may be a nasal composition for immediate release, suitable for inhalation.
  • Said composition is in the form of powder.
  • a multiparticulate pharmaceutical composition of the present invention when formulated for nasal administration, the particle size of each component is critical. Desired particle size of the components can be obtained by suitable technique i.e milling, homogenization or any other technique known in the art.
  • Another preferred embodiment of present invention provides a multiparticulate pharmaceutical composition suitable for nasal administration, having first inert component comprising one or more pharmaceutical excipients and at least one subsequent component comprising roflumilast, wherein said first inert component is free of roflumilast and particle size (D90) of said components is less than 10 microns.
  • particle size (D90) of said components is less than 5 microns, more preferably particle size (D90) is less than 2 microns.
  • Another embodiment of present invention provides a multiparticulate pharmaceutical composition suitable for nasal administration, having first inert component comprising one or more pharmaceutical excipients and at least one subsequent component comprising roflumilast comprising the steps of:
  • first inert component comprising one or more pharmaceutical excipients, by granulation.
  • step (b) Milling or homogenizing the granules obtained in step (a) to obtain the first inert component having particle size (D90) of less than 10 microns.
  • step b Adding at least one subsequent component comprising roflumilast with the component prepared according to step b.
  • step c Optionally adding one or more subsequent components in the mixture/blend of step c.
  • a multiparticulate pharmaceutical composition suitable for nasal administration prepared according to present invention can be filled in a capsule or in any suitable nasal or inhalation device for administration of it through nasal route.
  • Such said nasal device and its use is generally known in the art.
  • a pharmaceutical composition according to present invention may optionally comprise a coating.
  • Coating according to present invention may be functional or non-functional coating, preferably coating is non-functional coating.
  • Non- functional coating comprises a film forming polymer and one or more excipients suitable for said coating.
  • Another embodiment of present invention provides a composition comprising roflumilast prepared according to present invention, wherein at least one subsequent component may comprise one or more active ingredient other than roflumilast.
  • Said other active ingredient is preferably selected from bronchodilators such as salmeterol, formoterol, indacaterol, bambuterol, tiotropium, ipratropium, theophylline, levosalbutamol, pirbuterol, epinephrine, ephedrine, terbutaline, or leukotriene antagonist selected from montelukast, zafirlukast, pranlukast and zileuton and pharmaceutically acceptable salts thereof.
  • bronchodilators such as salmeterol, formoterol, indacaterol, bambuterol, tiotropium, ipratropium, theophylline, levosalbutamol, pirbuterol, epinephrine, ephedrine, terbutaline, or leukotriene antagonist selected from montelukast, zafirlukast, pranluk
  • Another embodiment of present invention provides use of the composition prepared according to present invention for reducing the risk of chronic obstructive pulmonary disease (COPD), exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.
  • COPD chronic obstructive pulmonary disease
  • Lactose monohydrate and maize starch were co-sifted through 40# and mixed in FBP (Fluid bed processor).
  • step b PVA was dissolved in water and blend of step a was granulated with PVA solution. Obtained granules were dried and sized to get first inert component.
  • step b First inert component prepared in step b were charged in RMG (Rapid mixer granulator) and mixed with Roflumilast and Ca CMC.
  • Blend obtained in step c was granulated with acetone. Wet mass was then dried and sized through 0.5 mm sieve.
  • step d Granules obtained in step d were blended with Ca CMC and than lubricated using magnesium stearate.
  • Blend obtained in step e was compressed to form a tablet.
  • Dissolution profile Dissolution of tablets prepared according to example 1 was checked in 500 ml of media comprising 0.1 N HCL+0.1 % SLS or Acetate buffer pH 4.5+1% SLS, at 50 rpm.
  • Lactose monohydrate and maize starch were co-sifted through 40# and mixed in FBP.
  • step b PVA was dissolved in water and blend of step a was granulated with PVA solution. Obtained granules were dried and sized to get first inert component.
  • step c First inert component prepared in step b were charged in RMG and mixed with Roflumilast.
  • Blend obtained in step c was granulated with acetone. Wet mass was then dried and sized through 0.5 mm sieve.
  • step d Granules obtained in step d were blended with Ca CMC and then lubricated using magnesium stearate.
  • Blend obtained in step e was compressed to form a tablet.
  • Dissolution profile Dissolution of tablets prepared according to example 2 was checked in 500 ml of media comprising 0.1 N HCL+0.1 % SLS or Acetate buffer pH 4.5+1% SLS, at 50 rpm.
  • Lactose monohydrate and maize starch were co-sifted through 40# and mixed in FBP.
  • step b PVA was dissolved in water and blend of step a was granulated with PVA solution. Obtained granules were dried and sized to get first inert component.
  • step b First inert component prepared in step b were charged in RMG and mixed with Roflumilast and Ca CMC.
  • Blend obtained in step c was granulated with acetone. Wet mass was then dried and sized through 0.5 mm sieve.
  • step d Granules obtained in step d were lubricated using magnesium stearate.
  • Blend obtained in step e was compressed to form a tablet.
  • Dissolution profile Dissolution of tablets prepared according to example 3 was checked in 500 ml of media comprising 0.1 N HCL+0.1% SLS at 50 rpm.
  • Example 3 42 67 86 93 93
  • step a Lactose monohydrate and maize starch were co-sifted through 40# and mixed in FBP b.
  • PVA was dissolved in water and blend of step a was granulated with PVA solution. Obtained granules were dried and sized to get 64.37 mg of first inert component.
  • step b c. 61.07 mg of first inert component prepared in step b were charged in RMG and mixed with Roflumilast and Ca CMC.
  • Blend obtained in step c was granulated with acetone. Wet mass was then dried and sized through 0.5 mm sieve.
  • step d 3.3 mg of first inert component prepared in step b were mixed with granules obtained in step d.
  • step e Granules obtained in step e were lubricated using magnesium stearate.
  • Blend obtained in step e was compressed to form a tablet.
  • Dissolution profile Dissolution of tablets prepared according to example 4 was checked in 500 ml of media comprising 0.1 N HCL+0.1 % SLS at 50 rpm.
  • composition of Example 4 was packed in HDPE container with silica gel canister and kept for 6 months under the conditions 25°C/60% RH and 40°C/75% RH . Assay and dissolution results of composition are summarized in table 1.
  • compositions prepared according to present invention shows good stability and dissolution, even after storage at various conditions.

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Abstract

La présente invention se rapporte à une composition pharmaceutique multiparticulaire comportant un premier constituant inerte comprenant un ou plusieurs excipients pharmaceutiques et au moins un autre constituant comprenant du roflumilast, ledit premier constituant inerte étant exempt de roflumilast. L'invention porte également sur un procédé de préparation de ladite composition pharmaceutique et son utilisation dans le traitement de la broncho-pneumopathie chronique obstructive (BPCO).
PCT/IB2015/051513 2014-03-07 2015-03-02 Composition pharmaceutique de roflumilast WO2015132708A1 (fr)

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IN782MU2014 2014-03-07

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9884050B1 (en) 2017-06-07 2018-02-06 Arcutis, Inc. Inhibition of crystal growth of roflumilast
WO2019060379A1 (fr) 2017-09-22 2019-03-28 Arcutis, Inc. Compositions pharmaceutiques de roflumilast dans des mélanges aqueux de solvants pharmaceutiquement acceptables miscibles à l'eau
US11129818B2 (en) 2017-06-07 2021-09-28 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half life
WO2023044502A1 (fr) * 2021-09-20 2023-03-23 Iolyx Therapeutics, Inc. Compositions pharmaceutiques ophtalmiques de roflumilast
WO2024058848A1 (fr) 2022-09-15 2024-03-21 Arcutis Biotherapeutics, Inc. Compositions pharmaceutiques de roflumilast et de solvants capables de dissoudre des quantités élevées de médicament
US11992480B2 (en) 2018-11-16 2024-05-28 Arcutis Biotherapeutics, Inc. Method for reducing side effects from administration of phosphodiesterase-4 inhibitors
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US11793796B2 (en) 2017-06-07 2023-10-24 Arcutis Biotherapeutics, Inc. Inhibition of crystal growth of roflumilast
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US12005051B2 (en) 2017-06-07 2024-06-11 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half life
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