+

WO2009006299A2 - Systèmes à multiples particules - Google Patents

Systèmes à multiples particules Download PDF

Info

Publication number
WO2009006299A2
WO2009006299A2 PCT/US2008/068574 US2008068574W WO2009006299A2 WO 2009006299 A2 WO2009006299 A2 WO 2009006299A2 US 2008068574 W US2008068574 W US 2008068574W WO 2009006299 A2 WO2009006299 A2 WO 2009006299A2
Authority
WO
WIPO (PCT)
Prior art keywords
core
coated
bioadhesive
substance
pharmaceutical composition
Prior art date
Application number
PCT/US2008/068574
Other languages
English (en)
Other versions
WO2009006299A3 (fr
Inventor
Venkateswarlu Vobalaboina
Ezhil Arasan Ramanan
Venkat Arvind Vakati
Deshpande Mangesh
Nookaraju Venkata Sreedharala
Sarveswara Rao Srirama Mandavilli
Original Assignee
Dr. Reddy's Laboratories Ltd.
Dr. Reddy's Laboratories, Inc.
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.)
Filing date
Publication date
Application filed by Dr. Reddy's Laboratories Ltd., Dr. Reddy's Laboratories, Inc. filed Critical Dr. Reddy's Laboratories Ltd.
Publication of WO2009006299A2 publication Critical patent/WO2009006299A2/fr
Publication of WO2009006299A3 publication Critical patent/WO2009006299A3/fr

Links

Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the present invention relates to compositions comprising at least one portion having bioadhesive properties for delivering pharmacologically active substances, processes to prepare such compositions and their methods of use and treatment.
  • the oral route constitutes one of the routes initially favored due to the ease of administration of the dosage form along with high patient compliance. But the active agents administered by the oral route may undergo degradation due to the action of gastrointestinal (“Gl”) enzymes and/or pH of the Gl tract, and/or metabolism in the liver.
  • Gl gastrointestinal
  • a major advantage offered by the mucosal route of administration is bypass of hepatic first-pass metabolism, and of the pH and the enzymes of the gastrointestinal tract. Food effects associated with oral administration are also circumvented.
  • Oral mucosal administration includes buccal, sublingual and gingival routes of administration.
  • Oral mucosa offer a thin, multicellular epithelium, weakly acidic pH and rich vascularization, thus permitting a rapid absorption of drug through the mucosa to the blood stream.
  • Various transmucosal drug delivery systems are known in the art using different techniques such as are disclosed in U.S. Patent Nos.
  • U.S. Patent No. 6,564,092 discloses an autoadhesive oral transmucosal delivery device.
  • U.S. Patent No. 5,908,637 discloses a mucoadhesive drug delivery device comprising a therapeutically effective amount of a hepahnic anticoagulant.
  • U.S. Patent No. 5,780,045 describes a transmucosal drug delivery device in the form of a sheet material containing an acid-containing particulate polymeric resin.
  • U.S. Patent No. 5,762,494 discloses a mucosal applicator for topical anesthetics for insertion into the patient's mouth.
  • U.S. Patent No. 5,516,523 discloses a method for mucosally administering a macromolecular drug to the oral cavity.
  • U.S. Patent No. 5,482,706 discloses a transmucosal composition comprising a peptide or protein, wherein the composition is a liquid dosage form to be administered through nasal or vaginal mucosa.
  • U.S. Patent No. 5,288,498 discloses a transmucosal delivery device for drug delivery to the mouth, pharynx, and esophagus.
  • U.S. Patent No. 4,649,075 discloses a device for delivery of medicaments to epidermal and mucosal surfaces.
  • U.S. Patent Application Publication No. 2005/0142203 discloses a multi- particulate oral dosage form comprising an active pharmaceutical ingredient, a binder comprising polyethylene oxide and a dispersing agent.
  • U.S. Patent No. 5,958,458 describes a pharmaceutical multiple unit particulate formulation in the form of coated cores, and an active substance layered onto their surface.
  • U.S. Patent No. 6,267,990 describes a controlled release pharmaceutical composition comprising an angiotensin converting enzyme ("ACE") inhibitor, wherein the composition has an immediate release (“IR”) and two delayed release (“DR”) components.
  • ACE angiotensin converting enzyme
  • U.S. Patent Application Publication No. 2006/0127484 discloses a pharmaceutical composition comprising two or more pluralities of particles, wherein the particles of each said plurality are coated with different thickness of a pH dissolution dependent polymer. Improved systems for delivering pharmaceutically active agents continue to be needed.
  • the present invention relates to compositions comprising at least one portion having a bioadhesive system for delivering active substances, processes to prepare such compositions and their methods of use and treatment.
  • An aspect of present invention relates to an oral pharmaceutical composition comprising at least two pluralities of particles comprising an active ingredient, wherein the particles of each plurality are coated with a bioadhesive component and further coated with a pH-dependent substance that dissolves under predetermined pH conditions such that the active ingredient is released at different locations in the intestinal tract.
  • the particles of each plurality comprise one or more active ingredients, being the same as, or different from, the active ingredients of another plurality of particles.
  • the particles of different pluralities are coated with a bioadhesive component, and are further coated with one or more pH-dependent substances.
  • the particles of different pluralities further comprise one or more drug release rate-controlling substances, present in a core or in one or more than one layers.
  • Figure 1 is a schematic cross-sectional representation of one unit of a multi-particulate composition wherein active substance, bioadhesive substance, and pH-dependent coating composition are layered onto an inert core.
  • Figure 2 is a schematic cross-sectional representation of one unit of a multi-particulate composition wherein active substance, bioadhesive substance, and pH-dependent coating composition are layered onto an inert core.
  • Figure 3 is a schematic cross-sectional representation of one unit of a multi-particulate composition wherein a core comprises an active substance, and bioadhesive substance and pH-dependent coating compositions are layered onto the core.
  • Figure 4 is a schematic cross-sectional representation of one unit of a multi-particulate composition wherein a core comprises an active substance and a bioadhesive substance and a pH-dependent coating composition are layered onto the core.
  • the present invention relates to compositions comprising at least one portion having bioadhesive, including mucoadhesive, systems for delivering active substances, processes to prepare such compositions and their methods of use and treatment.
  • active or “active agent” or “active substance” or “pharmacologically active agent” or “drug” or “drug substance” or “nutraceutical” may be used synonymously for an active pharmaceutical ingredient that is present in a composition to provide a physiologic effect.
  • particle refers to beads, cores, pellets, granules, aggregates, tablets and the like, without any limitation. Further, a particle comprises one or more pharmaceutical actives, optionally together with one or more pharmaceutically acceptable excipients.
  • An aspect of the present invention relates to oral pharmaceutical compositions comprising at least two pluralities of particles comprising an active ingredient, wherein the particles of each plurality are coated with a bioadhesive component and further coated with a pH-dependent substance that dissolves under predetermined pH conditions, such that the active ingredient is released at different locations in the intestinal tract.
  • the particles of each plurality comprise one or more active ingredients, being the same as or different from the active ingredients of another plurality of particles.
  • the particles of different pluralities are coated with a bioadhesive component, and are further coated with one or more pH-dependent substances.
  • compositions of the present invention comprise multi-particulate systems comprising one or more active substances coated over an inert core, with or without binder, and then coated with bioadhesive coating compositions, or one or more active substances are coated over an inert core, with or without binder and one or more bioadhesive substances, or a core is prepared along with an active substance and then coated with a bioadhesive coating composition.
  • compositions of the present invention comprise multi-particulate systems as different portions wherein each portion starting material may be commercially available inert cores, or prepared inert cores, or cores prepared along with at least one active substance with or without binder and other pharmaceutically acceptable excipients, or cores prepared along with at least one active substance and at least one bioadhesive substance with or without binder and other pharmaceutically acceptable excipients or combinations thereof, and are further coated with bioadhesive compositions and pH dependent coating compositions. Cores, or one or more than one layer, may contain the same or different active substances. Compositions of the present invention may further comprise one or more rate-controlling substance, present in a core, or one or more than one layers.
  • the invention includes pharmaceutical compositions comprising at least one of: a) a pharmaceutically active agent coated onto a core, which is further coated with a bioadhesive component; b) a pharmaceutically active agent in a core, and a bioadhesive component coated onto at least a portion of the core; c) a pharmaceutically active agent and a bioadhesive component in an uncoated core; or d) a pharmaceutically active agent and a bioadhesive component coated onto a core; wherein at least one of a), b), c) and d) is further coated with a substance that dissolves under predetermined pH conditions.
  • the above a), b), c) and d) are coated with two or more substances which dissolve under different pH conditions.
  • the above a), b), c) and d) further comprise one or more rate-controlling substances, present in a core or in one or more than one layers.
  • the invention includes pharmaceutical compositions comprising a pharmaceutically active agent coated onto a core, which is further coated with a bioadhesive component, and then further coated with a substance that dissolves under predetermined pH conditions.
  • the invention includes pharmaceutical compositions comprising a pharmaceutically active agent in a core, a bioadhesive component coated onto at least a portion of the core, and a further coating with a substance that dissolves under predetermined pH conditions.
  • the invention includes pharmaceutical compositions comprising a pharmaceutically active agent and a bioadhesive component in an uncoated core, which is further coated with a substance that dissolves under predetermined pH conditions.
  • the invention includes pharmaceutical compositions comprising a pharmaceutically active agent and a bioadhesive component coated onto a core, which is further coated with a substance that dissolves under predetermined pH conditions.
  • Figure 1 shows a cross-sectional view of particle 10 according to one embodiment of the invention.
  • Inert core 11 is surface coated with composition 12 comprising an active substance with or without binder and other pharmaceutically acceptable excipients, further coated with composition 13 comprising one or more bioadhesive substances with or without other pharmaceutically acceptable excipients, and having an outer coating composition 14 comprising pH dependent polymers with or without other pharmaceutically acceptable excipients.
  • Figure 2 shows a cross-sectional view of particle 20 according to one embodiment of the invention.
  • Inert core 21 is surface coated with composition 22 comprising active substance and bioadhesive substance, with or without binder and other pharmaceutically acceptable excipients, and further coated with a coating composition 23 comprising a pH dependent polymer, with or without other pharmaceutically acceptable excipients.
  • Figure 3 shows a cross-sectional view of particle 30 according to one embodiment of the invention.
  • Core 31 has active substance and is surface coated with composition 32 comprising a bioadhesive substance with or without binder and other pharmaceutically acceptable excipients, and is further coated with a coating composition 33 comprising a pH dependent polymer, with or without other pharmaceutically acceptable excipients.
  • Figure 4 shows a cross-sectional view of particle 40 according to one embodiment of the invention.
  • Core 41 has an active substance and bioadhesive substance and is surface coated with composition 42 comprising a pH dependent polymer, with or without other pharmaceutically acceptable excipients.
  • the inert cores that can be used in context of the present invention include but are not limited to water-soluble and water-insoluble cores.
  • Water-soluble cores include sugar spheres, lactose and the like; water-insoluble cores include microcrystalline cellulose, silicon dioxide, calcium carbonate, dicalcium phosphate anhydrous, dicalcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like, or the inert cores are prepared using pharmaceutically acceptable excipients by various techniques.
  • the cores containing active substance are prepared by mixing active substance with one or more pharmaceutically acceptable excipients.
  • the bioadhesive systems of the present invention can be formulated with or without pharmaceutically acceptable excipients in the form of tablets, minitablets, pellets (extruded or fluidized) or beads or spheres or cores that are either encapsulated in capsules or formed into tablets or minitablets, capsules encapsulating minitablets or pellets (extruded or fluidized), microcapsules or microspheres and the like.
  • the substance(s) used for providing the modified or delayed release can either be coated as a layer or coating onto the core or admixed or blended or adsorbed onto the core. The coating can be done by various techniques such as spray coating, dip coating, fluidized bed coating, and the like.
  • compositions of the present invention by powder coating or spray coating onto inert particles.
  • the resulting materials may be optionally mixed or blended or adsorbed with pharmaceutically acceptable excipient(s) to be either encapsulated or compressed into tablets or minitablets.
  • the bioadhesive systems may be formulated using matrix or reservoir, or combinations of matrix and reservoir principles, and further may be presented as monolithic or as multi-particulate compositions.
  • Matrix portions of compositions of the present invention may be prepared by direct blending, dry granulation or wet granulation of active substance with one or more rate controlling substances and then are filled into capsules, or formed, such as by compression, into tablets, or layered on to inert beads and then such beads are filled into capsules or formed into tablets.
  • compositions of the present invention may be prepared by coating the powders or granules or pellets or tablets or cores with one or more rate controlling substances and they may be filled into capsules.
  • Matrix-reservoir portions of compositions of the present invention may be prepared by first preparing the matrix portion as mentioned in the previous paragraphs and subsequently coating the matrix composition with one or more rate controlling substances.
  • Bioadhesive substances that can be used include, but are not limited to: polyacrylic polymers such as carbomers and derivatives like polycarbophil, carbopol; poly(acrylic acid) (PAA), N-isopropylacrylamide, PAA copolymehzed with polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP); polyvinyl alcohol (PVA), polyvinyl alcohol/polyvinylpyrrolidone, poly lactic acid/polyethylene glycol, dextran, hydroxyethylmethacrylate/methacrylic acid, ethylene oxide and its derivatives, cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) and sodium carboxy
  • Bioadhesive substances that can be used also include new- generation polymers such as cationic thiomers like chitosan-cysteine, chitosan- thiobutylamidine as well as chitosan-thioglycolic acid and the anionic thiomers like poly(acylic acid)-cysteine, poly(acrylic acid)-cysteine, carboxy-methylcellulose- cysteine and alginate-cysteine
  • new- generation polymers such as cationic thiomers like chitosan-cysteine, chitosan- thiobutylamidine as well as chitosan-thioglycolic acid and the anionic thiomers like poly(acylic acid)-cysteine, poly(acrylic acid)-cysteine, carboxy-methylcellulose- cysteine and alginate-cysteine
  • Ratios of active substance to bioadhesive substance may vary from about 1 :0.1 to 1 :25, by weight.
  • Rate-controlling substances that can be used include but are not limited to: hydrophilic substances such as carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC); homopolymers or copolymers of N-vinylpyrrolidone; vinyl and acrylic polymers; polyacrylic acid and the like; hydrophobic substances such as celluloses like ethyl cellulose, low substituted hydroxyl propyl cellulose (L-HPC), cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate; polyalkyl methacrylates; polyalkyl acrylates; polyvinyl acetate (PVA); chitosan; crosslinked vinylpyrrolidone polymers; hydrogenated castor oil
  • weight ratios of rate- controlling substance to active ingredient can range from about 1 :5 to about 5:1 , or from about 1 :3 to about 3:1 , or from about 1 :2 to about 2:1.
  • one or more pH-dependent dissolution substances can be employed in the multi-particulate compositions.
  • pH-dependent dissolution substances include materials those are insoluble or have a limited solubility at gastric pH values, and provide pH dependent release of the active in the intestinal regions.
  • Nonlimiting examples of such pH-dependent dissolution substances include cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate thmellitate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose succinate, natural resins such as zein, shellac and copal collophohum, carboxymethyl ethylcellulose, polyalkyl methacrylates, polyalkyl acrylates, and the like and mixtures thereof.
  • HPMCP hydroxypropyl methylcellulose phthalate
  • PVAP polyvinyl acetate phthalate
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • natural resins such as zein
  • Polymethacrylates (copolymers of acrylic acid and acrylic acid esters) that have been found useful include EUDRAGIT ® or mixtures of its various grades such as Eudragit ® L-100, Eudragit ® S-100.
  • Eudragit ® is a family of anionic copolymers based on methacrylic acid and methyl methacrylate. The ratio of the free carboxyl groups to the free ester groups is approximately 1 :1 in Eudragit ® L-100 and 1 :2 in Eudragit ® S-100.
  • enteric polymers are Eudragit ® L 12.5, L100, or Eudragit ® S 12.5, S100, and enteric dispersion systems like Eudragit ® L 3OD 55, Eudragit ® FS 3OD, Eudragit ® L100-55 (Rohm Pharma); Kollicoat ® MAE30D and 30DP (BASF), Estacryl ® 3OD (Eastman Chemical), Aquateric ® and Aquacoat ® CPD30 (FMC).
  • one or more pH-dependent dissolution substances which dissolve in specific pH ranges can be selected to target the release of the active ingredient to the desired site of gastrointestinal tract.
  • a polymer like Eudragit ® L30D-55, which dissolves at about pH 5.5-6 is useful for targeting the duodenum, i.e., to release the drug in the upper intestines.
  • a polymer that dissolves at increasing pH generally targets lower sections of the intestine, where near the colon, for example, Eudragit ® FS30D which dissolves at about pH 7 and releases the drug in the lower intestine and colon.
  • Using combinations of these polymers in various ratios makes it possible to manipulate drug release within a 5.5-7 pH range, and is also within the scope of the present invention.
  • one or more pharmaceutically acceptable excipients may optionally be used.
  • useful pharmaceutically acceptable excipients include but are not limited to: diluents such as microcrystalline cellulose (MCC), silicified MCC (e.g.
  • ProsolvTM HD 90 microfine cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like; binders such as acacia, guar gum, alginic acid, dextrin, maltodextrin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL ® ), hydroxypropyl methylcellulose (e.g.
  • METHOCEL ® carboxymethyl cellulose sodium, povidone (various grades of KOLLIDON ® , PLASDONE ® ) starch and the like; disintegrants such as carboxymethyl cellulose sodium (e.g. Ac-Di-Sol ® , Primellose ® ), crospovidone (e.g. Kollidon ® , Polyplasdone ® ), povidone K-30, polacrilin potassium, starch, pregelatinized starch, sodium starch glycolate (e.g.
  • surfactants which can include anionic surfactants such as chenodeoxycholic acid, 1 -octanesulfonic acid sodium salt, sodium deoxycholate, glycodeoxycholic acid sodium salt, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, sodium cholate hydrate, sodium lauryl sulfate (SLS) and sodium dodecyl sulfate (SDS); cationic surfactants such as cetylpyhdinium chloride monohydrate and hexadecyltrimethylammonium bromide; nonionic surfactants such as N-decanoyl- N-methylglucamine, octyl a-D-glucopyranoside, n-Dodecyl b-D-maltoside (DDM), polyoxyethylene sorbitan esters like polysorbates and the like; plasticizers such as acetyltributyl citrate
  • Solvents that may be used in processing steps such as granulation, layering, and coating include, without limitation: water; organic solvents such as alcohols like ethanol and isopropyl alcohol, acetone, methylene chloride, dichloromethane, ethyl acetate; and mixtures thereof. Water alone, or in a mixture with organic solvents, can be used.
  • compositions of the present invention may further include excipients such as but not limited to pharmaceutically acceptable glidants, lubricants, opacifiers, sweeteners, flavors, preservatives, colorants and other commonly used excipients.
  • excipients such as but not limited to pharmaceutically acceptable glidants, lubricants, opacifiers, sweeteners, flavors, preservatives, colorants and other commonly used excipients.
  • the pharmaceutical compositions of the present invention can be manufactured as described below.
  • the granules or cores can be prepared by sifting the active and excipients through a desired mesh size sieve and then mixed using a rapid mixer granulator, planetary mixer, mass mixer, ribbon mixer, fluid bed processor or any other suitable device.
  • the blend optionally can be granulated by dry or wet granulation. In wet granulation, the granulate can be dried using a tray drier, fluid bed drier, rotary cone vacuum drier and the like. The granulate particles are sieved and then mixed with lubricants and disintegrants and compressed into tablets or filled into capsules.
  • the manufacture of granules may be done by direct compression with the use of directly compressible excipients using a suitable device, such as a multi-station rotary machine to form compressed slugs or by roller compaction to form slugs, which are passed through a multimill, fluid energy mill, ball mill, colloid mill, roller mill, hammer mill and the like, equipped with a suitable screen.
  • the milled slugs are then lubricated and compressed into tablets or pellets and are coated with a rate controlling substance. Coated pellets are further filled into capsules or compressed as tablets or mini tablets, which are optionally further coated and then are filled into capsules.
  • the pharmaceutically active agents that are used can include but are not limited to hydrophilic, hydrophobic, and amphiphilic substances that may be solubilized, dispersed, partially solubilized or partially dispersed, or any combination of these states.
  • Such pharmaceutically active agents may be drugs or pharmaceuticals or nutraceuticals and may be formulated as a compound or mixture of compounds having therapeutic or nutritional value when administered to animals, particularly to mammals such as humans.
  • the pharmaceutically active agents can include but are not limited to members of the following classes of actives: analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anticoagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malahals, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, glucosidase inhibitors, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, beta- blockers, cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-ang
  • the pharmaceutical active agents include but are not limited to: acarbose; acetaminophen; acyclovir; acetyl cysteine; acetylcholine chloride; alatrofloxacin; alendronate; alglucerase; amantadine hydrochloride; ambenomium; amifostine; amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human); antihemophilic factor (porcine); antihemophilic factor (recombinant); aprotinin; asparaginase; atenolol; atracurium besylate; atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomycin sulfate; calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sul
  • the pharmaceutical active agents further include but are not limited to: aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethasone, benezepril, benzonatate, betamethasone, bicalutanide, budesonide, bupropion, busulfan, butenafine, calcifediol, calcipotriene, calcitriol, camptothecin, candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivastatin, cetirizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene, clomipramine,clonazepam,
  • compositions of the present invention are particularly useful for active ingredients having specific absorption sites (i.e., absorption windows) in the gastrointestinal (Gl) tract.
  • the absorption of the drug from the Gl tract is influenced by the location of the dosage form in the Gl tract and the Gl contents. Some drugs are more efficiently absorbed from the upper part of Gl tract while others are absorbed from the lower parts of the Gl tract. Therefore, in instances where the drug is not absorbed uniformly over the Gl tract, the rate of drug absorption may not be constant in spite of the drug delivery system delivering the drug at a constant rate into Gl tract fluids.
  • the drug may not be completely absorbed when administered in the form of a typical controlled-release drug delivery system.
  • drugs having an absorption window in the stomach or upper small intestine are acyclovir, bisphosphonates, captopril, trospium, furosemide, metformin, gabapentin, levodopa, baclofen, ciprofloxacin, etc.
  • the compositions of the present invention not only deliver the drug at a controlled rate, but also retain the drug at absorption site in the gastrointestinal tract for an extended period of time.
  • the pharmaceutically active agent can be a cytokine, a peptide mimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid, and the like.
  • Useful nutraceuticals include but are not limited to: vitamins such as carotenoids, vitamin E, vitamin D, vitamin C, thiamine, riboflavin, niacin, folic acid, pyridoxine, biotin, pantothenic acid, cyanocobalamin and the like; minerals such as magnesium, manganese, zinc, selenium, chromium, copper and the like; nutritional elements such as alpha lipoic acid, lutein, beta carotenoids; and the like.
  • compositions with bioadhesive systems are prepared by a process comprising: a) coating inert cores with a solution or dispersion of at least one active agent with or without binder and other pharmaceutically acceptable excipients in an aqueous or non aqueous or mixture thereof solvents, using semiautomatic or automatic coating systems or fluid bed coaters; b) drying drug loaded cores and sifting through a sieve and further coating with one or more bioadhesive substances in aqueous or non aqueous solvents, or mixtures thereof, using semiautomatic or automatic coating systems or fluid bed coaters; c) drying bioadhesive layered cores and sifting through a sieve, then dividing into two or more portions, each portion being coated with a solution or dispersion of different pH-sensitive coating substances in aqueous or nonaqueous solvents, or mixtures thereof, using semiautomatic or automatic coating systems or fluid bed coaters; d) drying pH-sensitive coated portions
  • compositions with bioadhesive systems are prepared by a process comprising: a) coating inert cores with a solution or dispersion of at least one active agent, with or without binder, one or more bioadhesive substance and other pharmaceutically acceptable excipients in an aqueous or nonaqueous solvent, or a mixture thereof, using semiautomatic or automatic coating systems or fluid bed coaters; b) sifting dried bioadhesive layered cores through a sieve and dividing into two or more portions, each portion being coated with a solution or dispersion of different pH-sensitive coating substances, in aqueous or nonaqueous solvents, or mixtures thereof, using semiautomatic or automatic coating systems or fluid bed coaters; c) drying different pH-sensitive coated portions and mixing in calculated proportions; d) filling blended pellets into capsules or compressing as tablets along with one or more pharmaceutically acceptable excipients; and e) optionally, coating compressed tablets with film coating compositions.
  • compositions with bioadhesive systems are prepared by a process comprising: a) preparing cores including at least one active substance and one or more pharmaceutically acceptable excipients by dry granulation, wet granulation, or spheronization, using granulation equipment, a fluid bed granulator or processor, or an extruder-spheronizer; b) sifting drug-containing cores through a sieve and further coating with one or more bioadhesive substances in aqueous or nonaqueous solvents, or mixtures thereof, using, semiautomatic or automatic coating systems or fluid bed coaters; c) sifting dried bioadhesive layered cores through a sieve and dividing into two or more portions, each portion being coated with a solution or dispersion of different pH-sensitive coating substances in aqueous or nonaqueous solvents, or mixtures thereof, using semiautomatic or automatic coating systems or fluid bed coaters; d) drying different pH-sensitive
  • compositions with bioadhesive systems are prepared by a process comprising: a) preparing cores including at least one active substance, one or more bioadhesive substances and one or more pharmaceutically acceptable excipients by dry granulation, wet granulation, or spheronisation, using granulation equipment, a fluid bed granulator or processor, or an extruder-spheronizer; b) sifting dried drug and bioadhesive substance-containing cores through a sieve and dividing into two or more portions, each portion being coated with a solution or dispersion of different pH sensitive coating substances in aqueous or nonaqueous solvents, or mixtures thereof, using semiautomatic or automatic coating systems or fluid bed coaters; c) drying different pH-sensitive coated portions and mixing in calculated proportions; d) filling blended pellets into capsules or compressing as tablets along with one or more pharmaceutically acceptable excipients; and e) optionally, coating compressed tablets with film coating
  • modified-release polymers are incorporated in the active-containing cores or mixed together with a bioadhesive substance in desired amounts as one of the ingredients in the core preparation, or coated over the active containing core, and further divided into portions and each portion is coated with different pH-dependent substances.
  • compositions are used for local, systemic, transmucosal drug delivery, or combinations thereof, as immediate release or delayed release, or modified release of one active or more than one active, or one active as immediate release and others as delayed or modified release, formulations.
  • the invention specifically contemplates pharmaceutical products, such as capsules or tablets, containing an active that is formulated in a bioadhesive system as described above, and also containing the same active and/or another active that is not formulated in a bioadhesive system.
  • pharmaceutical products such as capsules or tablets
  • an active that is formulated in a bioadhesive system as described above, and also containing the same active and/or another active that is not formulated in a bioadhesive system.
  • the following examples are provided only to further illustrate certain specific aspects and embodiments of the invention in greater detail, and should not be construed as limiting the scope of the invention in any manner.
  • EXAMPLES 1-2 Multiparticulate systems comprising metformin hydrochloride using inert cores.
  • Celphere is 100% microcrystalline cellulose spherical seed core manufactured by Asahi Kasei of Japan.
  • Aquacoat is a 30% aqueous dispersion of ethylcellulose, also containing sodium lauryl sulphate and cetyl alcohol, and manufactured by FMC Biopolymer Inc.
  • Eudragit products are anionic polymers of methacrylic acid and methacrylates from Rohm GmbH & Co. KG, Germany.
  • the ratio of the free carboxyl groups to the free ester groups is approximately 1 :1 in Eudragit ® L-100 and 1 :2 in Eudragit ® S-100.
  • HPMC coated pellets of stage 2 100 grams were coated with a dispersion of Eudragit L100, Eudragit S100, and dibutyl phthalate in isopropyl alcohol and methylene chloride, using a fluid bed processor.
  • the final coated pellets passed through a ASTM #20 mesh sieve and were retained on a ASTM #25 mesh sieve.
  • 100 grams of drug-bioadhesive coated pellets from stage 1 were coated with a dispersion of Eudragit L100, Eudragit S100, and dibutyl phthalate in isopropyl alcohol and methylene chloride, using a fluid bed processor.
  • the final coated pellets passed through a ASTM #20 mesh sieve and were retained on a ASTM #25 mesh sieve.
  • EXAMPLE 3 Multiparticulate system comprising metformin hydrochloride cores.
  • DCP Dibasic calcium phosphate
  • Metformin hydrochloride, HPMC, ethylcellulose and DCP were sifted through a ASTM #60 mesh sieve and mixed for 5 minutes in a mixer.
  • Povidone was dispersed in methylene chloride, isopropyl alcohol was added, and the solution was used to granulate the above dry blend in a mixer, then the granules were dried at 75 0 C.
  • Stage 2 50 grams of drug-bioadhesive granules of Stage 1 were coated with a dispersion of Eudragit L100, Eudragit S100, and dibutyl phthalate in isopropyl alcohol and methylene chloride using a fluid bed processor.
  • EXAMPLE 4 Controlled-release pellets comprising miglitol.
  • Miglitol was dissolved in water, and HPMC was dispersed in this solution under stirring.
  • step 2 The dispersion of step 1 was coated onto Celphere pellets using a fluid bed coater.
  • Drug-coated particles of step 2 (300 g) were further coated with a dispersion of ethyl cellulose and dibutyl phthalate in isopropyl alcohol and methylene chloride, using a fluid bed coater.
  • Controlled-release pellets of step 3 (300 g) were further coated with a dispersion of HPMC and propylene glycol in water, using a fluid bed coater.
  • EXAMPLE 5 Controlled-release pellet composition comprising miglitol.
  • Bioadhesive pellets of Example 4 were further coated with a dispersion of either Eudragit L 100 in isopropyl alcohol (Portion A) or Eudragit S 100 and diethyl phthalate in isopropyl alcohol (Portion B), using a fluid bed coater.
  • Portion A and Portion B were mixed in a weight ratio of 1 : 1.
  • the pellet mixture was analyzed for its in vitro release profile under the following conditions: Media: 0.1 N hydrochloric acid, pH 1.2 (initial 2 hours) and then either a pH
  • EXAMPLE 6 Bioadhesivity of controlled-release pellet composition comprising miglitol.
  • Method 1 A pellet mixture from Example 5 was suspended in 5 ml of pH 5.8 phosphate buffer, contained in an artificial stomach under stirring for 15 minutes.
  • the artificial stomach was a glass chamber having an inlet connected to a peristaltic pump and an outlet attached to rat intestine having a total length of about 86 cm.
  • the volume of the glass chamber was 5 ml.
  • the lengths of duodenum, small intestine and large intestine were about 10 cm, 60 cm and 16 cm, respectively, with a total intestine length of about 86 cm.
  • pH 5.8 phosphate buffer was circulated at a flow rate of 1 ml/minute using a peristaltic pump.
  • Celphere is 100% microcrystalline cellulose spherical seed core manufactured by Asahi Kasei in Japan.
  • Eudragit products are anionic polymers of methacrylic acid and methacrylates from Rohm GmbH & Co. KG, Germany.
  • step 1 Miglitol was dissolved in water, and HPMC was dispersed in this solution under stirring. 2. Dispersion of step 1 was coated onto Celphere pellets using a fluid bed coater.
  • Drug coated particles of step 2 (300 g) were further coated with a dispersion of ethyl cellulose and dibutyl phthalate in isopropyl alcohol and methylene chloride, using a fluid bed coater.
  • step 3 Particles of step 3 (300 g) were further coated with a dispersion of HPMC, and propylene glycol in water, using a fluid bed coater.
  • step 4 Particles of step 4 (300 g) were further coated with a dispersion of Eudragit L 100-55, Eudragit RSPO, and diethyl phthalate in isopropyl alcohol, using a fluid bed coater.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur des compositions pharmaceutiques orales qui comprennent une pluralité de particules comprenant un ingrédient actif, les particules étant enrobées par ou contenant un composant bioadhésif et ayant des enrobages externes comprenant une substance qui se dissout dans des conditions de pH prédéterminées.
PCT/US2008/068574 2007-06-29 2008-06-27 Systèmes à multiples particules WO2009006299A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US94702007P 2007-06-29 2007-06-29
US60/947,020 2007-06-29
US95000007P 2007-07-16 2007-07-16
US60/950,000 2007-07-16

Publications (2)

Publication Number Publication Date
WO2009006299A2 true WO2009006299A2 (fr) 2009-01-08
WO2009006299A3 WO2009006299A3 (fr) 2009-02-19

Family

ID=40226782

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/068574 WO2009006299A2 (fr) 2007-06-29 2008-06-27 Systèmes à multiples particules

Country Status (1)

Country Link
WO (1) WO2009006299A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130273120A1 (en) * 2010-04-15 2013-10-17 Shin Nippon Biomedical Laboratories, Ltd. Methods and compositions for intranasal delivery
CN103565751A (zh) * 2013-10-17 2014-02-12 广州帝奇医药技术有限公司 一种长效缓释微丸及其制备方法
JP2015124195A (ja) * 2013-12-27 2015-07-06 株式会社三和化学研究所 ミグリトール含有コーティング製剤
WO2022200402A1 (fr) * 2021-03-23 2022-09-29 Substipharm Formulation par voie orale d'ivermectine et utilisations

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997003670A1 (fr) * 1995-07-20 1997-02-06 Smithkline Beecham P.L.C. Compositions de paroxetine a liberation controlee
WO2001052816A2 (fr) * 2000-01-19 2001-07-26 Carlsbad Technology, Inc. Formulations pharmaceutiques de derives benzimidazole administrees par voie orale et procede de preparation de ces dernieres
WO2003013480A1 (fr) * 2001-08-06 2003-02-20 Dr. Reddy's Laboratories Ltd. Preparation enterique de fluoxetine
WO2004045589A1 (fr) * 2002-11-15 2004-06-03 Elan Pharmaceuticals, Inc. Composition a liberation modifiee comprenant un hypnotique a action breve, destinee au traitement des troubles du sommeil
WO2004056336A2 (fr) * 2002-12-20 2004-07-08 Ranbaxy Laboratories Limited Systemes d'administration de medicaments a unites multiples et a liberation controlee
WO2005044240A2 (fr) * 2003-10-31 2005-05-19 Dexcel, Ltd. Formulation stable contenant du lansoprazole

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997003670A1 (fr) * 1995-07-20 1997-02-06 Smithkline Beecham P.L.C. Compositions de paroxetine a liberation controlee
WO2001052816A2 (fr) * 2000-01-19 2001-07-26 Carlsbad Technology, Inc. Formulations pharmaceutiques de derives benzimidazole administrees par voie orale et procede de preparation de ces dernieres
WO2003013480A1 (fr) * 2001-08-06 2003-02-20 Dr. Reddy's Laboratories Ltd. Preparation enterique de fluoxetine
WO2004045589A1 (fr) * 2002-11-15 2004-06-03 Elan Pharmaceuticals, Inc. Composition a liberation modifiee comprenant un hypnotique a action breve, destinee au traitement des troubles du sommeil
WO2004056336A2 (fr) * 2002-12-20 2004-07-08 Ranbaxy Laboratories Limited Systemes d'administration de medicaments a unites multiples et a liberation controlee
WO2005044240A2 (fr) * 2003-10-31 2005-05-19 Dexcel, Ltd. Formulation stable contenant du lansoprazole

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130273120A1 (en) * 2010-04-15 2013-10-17 Shin Nippon Biomedical Laboratories, Ltd. Methods and compositions for intranasal delivery
US9687536B2 (en) 2010-04-15 2017-06-27 Shin Nippon Biomedical Laboratories, Ltd. Methods and compositions for intranasal delivery
US10463723B2 (en) * 2010-04-15 2019-11-05 Shin Nippon Biomedical Laboratories, Ltd. Methods and compositions for intranasal delivery
CN103565751A (zh) * 2013-10-17 2014-02-12 广州帝奇医药技术有限公司 一种长效缓释微丸及其制备方法
JP2015124195A (ja) * 2013-12-27 2015-07-06 株式会社三和化学研究所 ミグリトール含有コーティング製剤
WO2022200402A1 (fr) * 2021-03-23 2022-09-29 Substipharm Formulation par voie orale d'ivermectine et utilisations

Also Published As

Publication number Publication date
WO2009006299A3 (fr) 2009-02-19

Similar Documents

Publication Publication Date Title
US20090252787A1 (en) Granular pharmaceutical compositions
KR100657779B1 (ko) 활성 물질의 방출이 조절되는 피복된 약물 제형
ES2209240T3 (es) Formas de dosificacion farmaceutica oral de liberacion por pulsos.
AU772168B2 (en) Timed pulsatile drug delivery systems
WO2007018943A2 (fr) Supports solides permettant une meilleure administration de principes actifs dans des compositions pharmaceutiques
US20080014257A1 (en) Oral dosage forms
CN101132769A (zh) 用于药物的跨黏膜给药的药物组合物
US20130171199A1 (en) Controlled release pharmaceutical composition
JP2012116863A (ja) 薬学的組成物における活性成分の改善された送達のための固体キャリア
TWI649100B (zh) 延遲釋放型半胱胺珠粒調配物，以及其製備及使用方法
ES2838816T3 (es) Composición farmacéutica o nutracéutica con resistencia contra la influencia de etanol
US20090317465A1 (en) Composition and method of preparation of release systems for constant (zero-order) release of active agents
HU231030B1 (hu) Többszörös bevonattal ellátott gyógyszer dózisforma
US8268356B2 (en) Aqueous film coating solution, film coated granule and tablet using the same
WO2012001705A2 (fr) Compositions pharmaceutiques de (r)-lansoprazole
KR101390695B1 (ko) 약리 활성 물질의 흡수성이 개선된 의약 조성물
WO2006117803A2 (fr) Systemes d'administration transmucosale de medicaments
WO2009006299A2 (fr) Systèmes à multiples particules
WO2008157228A1 (fr) Nouveaux procédés de masquage de goût
JP2013531059A (ja) マルチユニット錠剤組成物
KR20160076928A (ko) 푸마르산 에스테르를 함유하는 미니-정제 형태의 약제학적 제제
EP1830849A1 (fr) Formes galeniques a liberation rapide pour antibiotiques
CN101478958A (zh) 包含哌啶烷醇和减充血剂的组合的药物组合物
CN107648231B (zh) 右兰索拉唑药物制剂
ZA200502318B (en) Controlled release preparation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08772161

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 7392/CHENP/2009

Country of ref document: IN

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08772161

Country of ref document: EP

Kind code of ref document: A2

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载