WO2014053974A1 - Compositions pharmaceutiques de sirolimus - Google Patents

Compositions pharmaceutiques de sirolimus Download PDF

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Publication number
WO2014053974A1
WO2014053974A1 PCT/IB2013/058930 IB2013058930W WO2014053974A1 WO 2014053974 A1 WO2014053974 A1 WO 2014053974A1 IB 2013058930 W IB2013058930 W IB 2013058930W WO 2014053974 A1 WO2014053974 A1 WO 2014053974A1
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WIPO (PCT)
Prior art keywords
sirolimus
sugar
pharmaceutical composition
drug
drug overcoat
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PCT/IB2013/058930
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English (en)
Inventor
Varma Srinivasa RUDRARAJU
Ashok Chandra ILLAPAKURTHY
Bharat Kumar BALERAO
Sampath CHARUGUNDLA
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Aizant Drug Research Solutions Private Limited
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Publication of WO2014053974A1 publication Critical patent/WO2014053974A1/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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug

Definitions

  • the present invention relates to pharmaceutical compositions of sirolimus or pharmaceutically acceptable salts thereof for oral administration and process of preparation thereof.
  • Sirolimus which is also known as rapamycin, a macrolide antibiotic produced by Streptomyces hygroscopicus, is an immunosuppressant drug used to prevent rejection in organ transplantation.
  • U.S. Patent No. 3,929,992 discloses rapamycin, its preparation and its antibiotic activity for the first time.
  • U.S. Patent No. 5,100,899 discloses the use of Rapamycin to inhibit transplantation rejection in mammals.
  • U.S. Patent Nos. 5,989,591 and 5,985,325 disclose a solid dosage unit of rapamycin comprising a core, which is over coated with rapamycin, and a sugar coat containing one or more surface modifying agents, one or more sugars and optionally one or more binders.
  • U.S. Patent No. 5,145,684 discloses a nanoparticulate composition comprising particles consisting of a poorly soluble drug having adsorbed onto the surface thereof a non- crosslinked surface stabilizer, wherein effective average particle size of drug substance is less than about 400 nm.
  • U.S. Patent Nos. 5,516,770 and 5,530,006 disclose intravenous sirolimus composition.
  • U.S. Patent Nos. 5,536,729 and 5,559,121 disclose liquid oral sirolimus composition.
  • U.S. Patent Application No. 11/951,910 discloses a nanodispersion of Sirolimus comprising Sirolimus and a surface modifier, wherein the effective average particle size of Sirolimus is more than 400 nm.
  • 12/127,130 discloses a pharmaceutical composition of sirolimus comprising an inert core and a sugar overcoat, wherein said sugar overcoat comprises a) sirolimus; b) poloxamer; c) microcrystalline cellulose; and d) a binder selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methyl cellulose or a mixture thereof; and wherein the poloxamer is not poloxamer 188.
  • U.S. Patent Application No. 12/578,776 discloses a pharmaceutical formulation, comprising a pharmacologically inert core having a coating comprising: (a) sirolimus or a derivative thereof; (b) at least one surface modifying agent; and (c) one or more sugars in an amount less than about 35% of the weight of the sugar overcoat.
  • PCT patent application WO 2011/135580 discloses stable solid pharmaceutical matrix composition comprising sirolimus or pharmaceutically acceptable salts thereof along with one or more sugars.
  • Sirolimus is marketed by Wyeth under the trade name Rapamune ® as 0.5 mg, 1 mg and 2 mg oral tablets for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. It is also available as an oral solution containing 1 mg/ml sirolimus.
  • compositions of sirolimus with conventional excipients show unpredictable dissolution rates, irregular bioavailability profiles, as well as stability problems. There is therefore an existing and continual need for stable and therapeutically equivalent oral solid pharmaceutical compositions of sirolimus.
  • the compositions of the invention overcome all the problems encountered during prior know formulation development process.
  • a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar.
  • a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar and the inert core is a sugar sphere.
  • a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar and the inert core is a mixture of sugar sphere and microcrystalline cellulose spheres.
  • a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar comprising sirolimus and an excipient.
  • a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat devoid of sugar comprises sirolimus and an excipient selected from the group consisting of a binder, a surface active agent and an antioxidant.
  • a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the inert core is a sugar sphere and the drug overcoat devoid of sugar comprises sirolimus, povidone, poloxamer and tocopherol.
  • a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar by employing to the following steps,
  • a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar and wherein the inert coat is a sugar sphere.
  • a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar and wherein the drug overcoat is prepared by dispersing or dissolving sirolimus and an excipient in an organic solvent.
  • the present Invention relates to pharmaceutical compositions comprising sirolimus and pharmaceutically acceptable salts thereof, processes for preparing compositions comprising sirolimus, and their methods of use, treatment, and administration.
  • sirolimus inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar.
  • sirolimus includes various forms of sirolimus such as hydrates, solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters, prodrugs, complexes or mixture thereof and all other forms known in the art.
  • Sirolimus can be present in different physical forms, e.g. in an amorphous form, in one or several crystal form (s) (e.g. anhydrous, solvated or hydrated forms), in the form of mixture of different crystal forms (e.g.
  • anhydrous, solvated or hydrated forms or as a mixture of an amorphous form and crystal form (s) (e.g. anhydrous, solvated or hydrated forms).
  • s e.g. anhydrous, solvated or hydrated forms.
  • inert core as used herein comprises a pharmacologically inactive tablet, core, or inert beads or spheres which comprise one or more of soluble or insoluble inert materials and the like, or mixtures thereof.
  • the cores may be optionally seal coated to increase the strength of the core to withstand the mechanical pressures during processing.
  • drug overcoat devoid of sugar as used herein comprises a layer which coats the core. It comprises sirolimus, an excipient but devoid of any sugar.
  • the coating can exist as one or more layers, optionally having one or more separating functional or non- functional layers sandwiched between.
  • pharmaceutical composition refers to a solid dosage form suitable for administration, such as a tablet, capsule, granules, pill, etc.
  • pharmaceutically acceptable salt means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
  • the active ingredient, active agent and drug herein can be interchangeably used.
  • % refers to the weight percent of a substance as it relates to the overall composition unless otherwise indicated.
  • the invention relates to pharmaceutical composition comprising sirolimus, wherein embodiments comprise: a) an inert core; b) a drug overcoat comprising sirolimus and an excipient surrounding the core, wherein the drug overcoat is devoid of sugar.
  • the invention relates to pharmaceutical composition comprising sirolimus, wherein embodiments comprise: a) an inert core, b) optionally, a barrier layer over the inert core, c) a drug overcoat comprising sirolimus and an excipient surrounding the core, wherein the drug overcoat is devoid of sugar.
  • the invention relates to pharmaceutical composition comprising sirolimus, wherein embodiments comprise: a) an inert core, b) optionally, a barrier layer over the inert core, c) a drug overcoat comprising sirolimus and an excipient surrounding the core, wherein the drug overcoat is devoid of sugar and d) optionally, a film coat over the drug overcoat.
  • “Sugar” as used herein includes but not limited to one or more of lactose, mannitol, sorbitol, starch, fructose, xylitol, and sucrose.
  • the inert cores are pharmacologically inert in nature and pharmaceutically compatible.
  • An inert core may be spheres or a placebo tablet, prepared by compressing a mixture of excipients.
  • the inert core is a sugar sphere.
  • a mixture of different spheres with sugar sphere can be used in the present invention.
  • the sugar sphere alone or a mixture of sugar sphere and microcrystalline cellulose sphere as inert core is the most preferred.
  • Non-limiting examples of various substances that can be used for inert cores along with sugar sphere include insoluble inert materials such as particles/beads of silicon dioxide, calcium phosphate dihydrate, dicalcium phosphate, calcium sulfate dihydrate, microcrystalline cellulose, cellulose derivatives, calcium carbonate, dibasic calcium phosphate anhydrous, dibasic calcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, and magnesium oxide, soluble cores such as sugar spheres having sugars like dextrose, lactose, anhydrous lactose, spray-dried lactose, lactose monohydrate, mannitol, starches, sorbitol, and sucrose, insoluble inert plastic materials such as spherical or nearly spherical core beads of polyvinylchloride or polystyrene, and any other pharmaceutically acceptable insoluble synthetic materials, and the like and mixtures thereof.
  • insoluble inert materials such as particles/bea
  • composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat devoid of sugar comprises sirolimus and an excipient selected from the group consisting of a binder, a surface active agent and an antioxidant.
  • composition according to the invention can comprise binders, such as polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures thereof.
  • binders such as polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, poly
  • the excipients include at least one binder selected from hydroxypropyl cellulose and povidone.
  • the binding agent is present in the composition in an amount of from about 0.1% to about 15%, preferably from about 0.1%, to about 10%, more preferably from about 0.5% to about 5%.
  • Surfactant otherwise called surface-active agents or solubilizing agents used to disperse the drug in a particular solvent and also enhance wetting properties of the drug thereby helps either to lower the surface tension of a liquid, allowing easier spreading, and lower the interfacial tension between two liquids or to solubilize the active agent either in composition or in-situ at the site of absorption or action.
  • Non-limiting examples of surfactants include non-ionic, anionic, cationic, amphoteric or zwitterionic or any combination thereof. Non-ionic surfactant is preferable.
  • non-ionic surfactants include ethoxylated triglycerides; fatty alcohol ethoxylates; alkylphenol ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty amine ethoxylates; sorbitan alkanoates; ethylated sorbitan alkanoates; alkyl ethoxylates; alkyl polyglucosides; stearol ethoxylates; and alkyl polyglycosides.
  • Preferred non-ionic hydrophilic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene - polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof.
  • the non- ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; poly glyceryl fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils.
  • the glyceride can be a monoglyceride, diglyceride, triglyceride, or a mixture.
  • non-ionic hydrophilic surfactants that are reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils or sterols. These reaction mixtures are largely composed of the transesterification products of the reaction, along with often complex mixtures of other reaction products.
  • the polyol is preferably glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
  • anionic surfactants include alkylether sulfates; alkylether carboxylates; alkylbenzene sulfonates; alkylether phosphates; dialkyl sulfosuccinates; sarcosinates; alkyl sulfonates; soaps; alkyl sulfates; alkyl carboxylates; alkyl phosphates; paraffin sulfonates; secondary n-alkane sulfonates; alpha-olefin sulfonates; and isethionate sulfonates.
  • Suitable cationic surfactants include fatty amine salts; fatty diamine salts; quaternary ammonium compounds; phosphonium surfactants; sulfonium surfactants; and sulfonxonium surfactants.
  • suitable zwitterionic surfactants include N-alkyl derivatives of amino acids (such as glycine, betaine, aminopropionic acid); imidazoline surfactants; amine oxides; and amidobetaines.
  • compositions may be used. In such mixtures there may be individual components which are liquid, provided that the carrier material overall, is a solid.
  • concentration of surface-active agent in the composition is from range of about 0.01 to about 10.0% (based on the total mass of the pharmaceutical composition), preferably about 0.1 to about 5%, more preferably of about 0.1 to about 2%.
  • the weight ratio of sirolimus to surfactant is from 10: 1 to 1 : 1 (preferably 5: 1 to 1 : 1).
  • Non limiting examples of surfactants are sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate; or sulphosuccinates such as sodium dioctyl sulphosuccinate; or partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, glyceryl monooleate, glyceryl monobutyrate; or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 388, Poloxamer 407 (BASF Wyandotte Corp.); or fatty acid esters of sorbitan such as sorbitan mono laurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan stearate, sorbitan monolaurate etc.
  • Span ® or Arlacel ® such as Span ® or Arlacel ® , Emsorb ® , Capmul ® , or Sorbester ® , Triton X-200 etc.
  • a fatty acid esters of polyhydroxyethylene sorbitan such as polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20) sorbitan monooleate (Tween ® 80), polyoxyethylene (20) sorbitan monostearate (Tween ® 60), polyoxyethylene (20) sorbitan monopalmitate (Tween ® 40), polyoxyethylene (20) sorbitan monolaurate (Tween ® 20); or polyethylene glycol fatty acid esters, e.g.
  • polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor ® EL; BASF Corp.); or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor RH ® 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor RH 60); or sucrose fatty acid esters, such as sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate; or vitamin E and its derivatives such as Vitamin E-TPGS ® (d- alpha-tocopheryl polyethylene glycol 1000 succinate); or phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and
  • acylcarnitines and derivatives N-a-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N-a-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N-a-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof.
  • Each one of these specific surface- active agent constitutes an alternative embodiment of the invention.
  • the composition may further comprise antioxidant, to protect the drug from oxidative degradation.
  • Antioxidants may be selected from group consisting of ascorbic acid, sodium pyrosulphite, glutathione or sorbic acid, tocopherol and the like, in particular tocopherol E-acetate.
  • Weak organic acids like citric acid, tartaric acid, fumaric acid, maleic acid can be used in the drug overcoat to stabilize the formulation.
  • solvents used in processes for preparing the drug overcoat include, but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, ⁇ , ⁇ -dimethylformamide, tetrahydrofuran, and mixtures thereof.
  • organic solvents are used to prepare the drug overcoat.
  • Film coating composition usually contains the following components: polymer (s), plasticizer (s), colourant (s) /opacifier (s), vehicle (s).
  • polymer s
  • plasticizer s
  • colourant s
  • opacifier s
  • vehicle s
  • minor quantities of flavours, surfactants and waxes can be used.
  • the majority of the polymers used in film coating are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials.
  • Non limiting examples of cellulose ethers are methylcelluloses, hydroxymethylcelluloses, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethyl ethylcellulose, and sodium carboxymethyl celluloses; acidic cellulose derivatives such as cellulose acetate phthalates, cellulose acetate trimellitates, hydroxypropylmethylcellulose phthalates, polyvinyl acetate phthalates, etc.; insoluble cellulose derivatives such as ethylcelluloses and the like; dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinylalcohols, polyvinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives thereof (e.g., Eudragit ® ), and chitosan and derivatives thereof. Some of them can be further modified to enhance
  • plasticizers can be categorized into three groups: polyols (glycerol, propylene glycol and macrogols), organic esters (phthalate esters, dibutyl sebacetate, citrate esters, triacetin), oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil).
  • a plasticizer is frequently present in amounts ranging from about 5% (w/w) to 30% (w/w) based on the total weight of the film coating.
  • Colourants/opacifiers are classified into several groups: organic dyes and their lakes, inorganic colours, natural colours. Combination of different materials from each group can be combined in defined ratios. Film coating suspensions can be used as ready-to- make preparations which are available on the market.
  • Film coating dispersion can be prepared by using different solvents water, alcohols, ketones, esters, chlorinated hydrocarbons or mixture thereof.
  • Suitable polishing agents include polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (e.g. glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g., carnauba wax, candelilla wax and white wax).
  • surfactants e.g. glycerol monostearate and poloxamers
  • fatty alcohols e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol
  • waxes e.g., carnauba wax, candelilla wax and white wax.
  • polyethylene glycols having molecular weights about 3,000-20,000 are employed.
  • cores/tablets can be coated with conventional materials used for film coating, i. e. as described in "Pharmaceutical Coating Technology", 1995, edited
  • Another embodiment of the invention relates to a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar by employing to the following steps,
  • Another embodiment of the invention relates to a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar by employing to the following steps,
  • Another embodiment of the invention relates to a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar by employing to the following steps,
  • Another embodiment of the invention relates a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat devoid of sugar, wherein the inert coat is a sugar sphere.
  • Another embodiment of the invention relates a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar and wherein the drug overcoat is prepared by dispersing or dissolving sirolimus and an excipient in an organic solvent.
  • the coating steps comprise drug layering techniques or coating techniques known to the skilled artisan.
  • the drug layering or coating techniques may include, but are not limited to, powder coating, spray coating, dip coating, fluidized bed coating with Wurster or top spray or side spray techniques, and modifications thereof.
  • compositions comprising sirolimus, wherein the composition may be in a monolithic form, multiparticulate form, or a combination of both.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, soft and hard gelatin capsules, suppositories etc.
  • the preferred dosage form is tablet.
  • the dosage form is preferably suitable for oral application.
  • compositions are prepared by known technological procedures, e.g. direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients.
  • the active ingredient i.e. drug coated spheres will usually be mixed with an excipient or mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or mixture of excipients which may be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle or medium for the sirolimus.
  • composition preparations of the invention can be produced by compressing a mixture of the drug substance of the invention with excipients.
  • one method for the production includes mixing the sirolimus coated spheres with one or more excipients for the preparation by a suitable mixer, and directly compressing the mixture to tablets.
  • Other methods include a dry granulating step to produce granules for tablets using dry granulating machines or roller compacters, and a wet granulating step to produce granules for tablets using water, ethanol and solutions containing binders.
  • composition of sirolimus comprising an inert core coated with a drug overcoat devoid of sugar and one or more excipients such as binders, diluents, lubricant/glidants, disintegrating agents, surfactants, solvents, and coloring agents.
  • excipients such as binders, diluents, lubricant/glidants, disintegrating agents, surfactants, solvents, and coloring agents.
  • Excipients such as diluents, lubricants and glidants commonly used in pharmaceutical composition may be used and reference is made to the extensive literature on suitable substances [see in particular "Handbook of Pharmaceutical Excipients” edited by Raymond C Rowe, Paul J Sheskey & Sian C Owen (2006)] the content of which is incorporated herein by reference.
  • excipients are also used in the preparation of the pharmaceutical composition like diluents such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof.
  • a preferred further diluent that also causes reduced sticking properties of tablets to the equipment used for tabletting is silica, preferably colloidal or fumed silica.
  • the excipients include at least one diluent selected from microcrystalline cellulose and lactose monohydrate.
  • Non-limiting examples of binders include one or more of gum acacia, cholesterol, tragacanth, stearic acid, gelatin, casein, lecithin (phosphatides), carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcelluloses, hydroxy ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalates, microcrystalline celluloses, noncrystalline celluloses, polyvinylpyrrolidones (povidones or PVP), cetostearyl alcohol, cetyl alcohol, cetyl esters wax, dextrates, dextrin, lactose, dextrose, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyoxyethylene alkyl ethers, polyethylene glycols, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polyvinylalcohols, and mixtures thereof.
  • binders include one or more of gum
  • Non-limiting examples of disintegrants include starches, modified starches, croscarmellose sodium, crospovidones, and sodium starch glycolate.
  • the composition according to the invention can also comprise lubricants, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof. It is preferred that the excipients include at least one lubricant, selected from stearic acid, magnesium stearate, calcium stearate and sodium lauryl sulphate, more preferably from stearic acid, magnesium stearate and calcium stearate.
  • the composition can also comprises glidants such as colloidal silica (e. g. Aerosil ), magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • Useful coloring agents include FDA approved colorants and examples are iron oxides, lake of tartrazine, allura red, lake of quinoline yellow, and lake of erythrosine.
  • additives may be selected and used by the skilled artisan having regard to the particular desired properties of the pharmaceutical composition by routine experimentation and without any undue burden.
  • the absolute amounts of each additive and the amounts relative to other additives is similarly dependent on the desired properties of the pharmaceutical composition and may also be chosen by the skilled artisan by routine experimentation without undue burden.
  • the composition prepared can be packaged using appropriate packaging materials such as containers and closures composed of polyethylene (high density polyethylene or low density polyethylene), polypropylene, glass, stainless steel, etc. Also useful are various blisters or strips composed of aluminum or high-density polypropylene, or polyvinyl chloride, or polyvinyl chloride (PVC) coated with polyvinylidene dichloride (PVDC), generally termed PVC/PVDC.
  • PVC/PVDC polyvinylidene dichloride
  • at least 60 % of drug are dissolved from the pharmaceutical composition in a 0.4% SLS in water in 30 minutes, when dissolution is performed using a basket apparatus according to Ph. Eur.
  • the drug release rate of the composition of the invention is more than 40% in 15 minutes, above 60% in 30 minutes, and above 75% in 45 minutes.
  • the exact dose of active agent and the particular formulation to be administered depend on a number of factors, e. g. the condition to be treated, the desired duration of the treatment and the rate of release of the active agent.
  • the amount of the active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.
  • Another embodiment of the invention relates to methods of using pharmaceutical compositions of the present invention for the known indications of the particular active agent incorporated therein including prophylaxis of organ rejection especially in renal transplantation.
  • Another embodiment of the invention relates to methods of using pharmaceutical composition of the present invention may include co-administration of cyclosporine and/or corticosteroids, as required for particular patients.
  • a pharmaceutical composition comprising sirolimus or a pharmaceutically acceptable salt thereof of the invention has a comparable bioavailability to commercial form of sirolimus.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Preparation (AREA)
  • General Chemical & Material Sciences (AREA)
  • Transplantation (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Chemistry (AREA)

Abstract

La présente invention concerne une composition pharmaceutique de sirolimus ou des sels pharmaceutiquement acceptables de celui-ci pour une administration par voie orale et un procédé de préparation associé. La composition pharmaceutique de sirolimus comprend un cœur inerte et un médicament, l'enrobage du médicament ne comprenant pas de sucre.
PCT/IB2013/058930 2012-10-01 2013-09-27 Compositions pharmaceutiques de sirolimus WO2014053974A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN4101/CHE/2012 2012-10-01
IN4101CH2012 2012-10-01

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WO2014053974A1 true WO2014053974A1 (fr) 2014-04-10

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021088507A (ja) * 2019-12-02 2021-06-10 ノーベルファーマ株式会社 シロリムス含有顆粒製剤、及びその製造方法
WO2022023414A3 (fr) * 2020-07-29 2022-07-14 Biotronik Ag Compositions pharmaceutiques de microsphères et procédés

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101361703A (zh) * 2008-09-24 2009-02-11 宋洪涛 西罗莫司缓控释制剂及其制备方法
US20090068266A1 (en) * 2007-09-11 2009-03-12 Raheja Praveen Sirolimus having specific particle size and pharmaceutical compositions thereof
US20090130210A1 (en) * 2007-09-11 2009-05-21 Raheja Praveen Pharmaceutical compositions of sirolimus
US20100098770A1 (en) * 2008-10-16 2010-04-22 Manikandan Ramalingam Sirolimus pharmaceutical formulations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090068266A1 (en) * 2007-09-11 2009-03-12 Raheja Praveen Sirolimus having specific particle size and pharmaceutical compositions thereof
US20090130210A1 (en) * 2007-09-11 2009-05-21 Raheja Praveen Pharmaceutical compositions of sirolimus
CN101361703A (zh) * 2008-09-24 2009-02-11 宋洪涛 西罗莫司缓控释制剂及其制备方法
US20100098770A1 (en) * 2008-10-16 2010-04-22 Manikandan Ramalingam Sirolimus pharmaceutical formulations

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021088507A (ja) * 2019-12-02 2021-06-10 ノーベルファーマ株式会社 シロリムス含有顆粒製剤、及びその製造方法
JP7492723B2 (ja) 2019-12-02 2024-05-30 ノーベルファーマ株式会社 シロリムス含有顆粒製剤、及びその製造方法
WO2022023414A3 (fr) * 2020-07-29 2022-07-14 Biotronik Ag Compositions pharmaceutiques de microsphères et procédés

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