WO2008157228A1 - Nouveaux procédés de masquage de goût - Google Patents

Nouveaux procédés de masquage de goût Download PDF

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Publication number
WO2008157228A1
WO2008157228A1 PCT/US2008/066701 US2008066701W WO2008157228A1 WO 2008157228 A1 WO2008157228 A1 WO 2008157228A1 US 2008066701 W US2008066701 W US 2008066701W WO 2008157228 A1 WO2008157228 A1 WO 2008157228A1
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WIPO (PCT)
Prior art keywords
poly
api
acid
porous microsphere
pharmaceutical composition
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PCT/US2008/066701
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English (en)
Inventor
Brian Becicka
Erik Michalson
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Cambrex Charles City, Inc.
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Application filed by Cambrex Charles City, Inc. filed Critical Cambrex Charles City, Inc.
Publication of WO2008157228A1 publication Critical patent/WO2008157228A1/fr

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    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a composition and method for the preparation of taste- masked active pharmaceutical ingredients (APIs) for oral delivery.
  • APIs active pharmaceutical ingredients
  • API active pharmaceutical ingredient
  • U.S. 5,075,114 describes a fluidized bed method of coating a pharmaceutical agent for taste-masking purposes.
  • the patent describes the coating as a blend of cellulosic materials, i.e., hydroxypropyl cellulose and either cellulose acetate, cellulose acetate butyrate, or both.
  • a number of drugs are mentioned, including ibuprofen, loperamide, famotidine, cimetidine, and ranitidine.
  • U.S. 5,082,669 describes ethyl cellulose coatings for bitter-tasting drugs. A number of drugs are mentioned as possibilities (at column 3, lines 13-31). The coating is prepared using either a film-forming solution or dispersion, or a spraying technique (column 5, lines 36-50). Based on its Abstract, it appears that JP 57058631 describes coating a granulated API using a combination of an insoluble polymer coating agent, such as ethyl cellulose, and several polymer coating agents of varying solubility characteristics as a way of masking a bitter taste of a drug.
  • an insoluble polymer coating agent such as ethyl cellulose
  • U.S. 5,215,755 describes, in Example VIII, a coating formulation for taste-masking loperamide, supplied as the HCl salt presumably in the form of a powder having a particle size of 40-80 mesh, comprising a blend of hydroxyethyl cellulose and hydroxypropyl cellulose.
  • U.S. 5,489,436 describes a coating formulation for taste-masking loperamide in Example
  • Vi ⁇ comprising a mixture of cellulose acetate, polyvinylpyrrolidone and a copolymer of dimethylaminoethyl methacrylate and neutral methacrylic acid ester.
  • the invention provides a taste-masked pharmaceutical composition suitable for oral administration comprising a granulated mixture of an active pharmaceutical ingredient and a porous microsphere component, wherein the API is incorporated into the pores of the porous microsphere.
  • the invention provides a taste-masked pharmaceutical composition suitable for oral administration comprising a mixture of an active pharmaceutical ingredient and a porous microsphere component, wherein the API is incorporated into the pores of the porous microsphere.
  • the invention provides a taste-masked pharmaceutical composition suitable for oral administration comprising a granulated mixture of an active pharmaceutical ingredient and a porous microsphere component, wherein the API is incorporated into the pores of the porous microsphere, further wherein the porous microsphere component is selected from the group consisting of polyesters, polyamides, polyanhydrides, and polyacrylates, poly(lactic) acid, poly(glycolic) acid, copoly(lactic/glycolic) acid and poly[l,3-bis(-p-carboxyphenoxy)propane- co-sebacic acid], polyglycolic (PGA), polylactic (PLA) acids, copolymers of glycolide and L(- lactide) (PGL), gelatin, agar, starch, arabinogalactan, albumin, collagen, natural and synthetic materials or polymers, such as, poly( ⁇ -caprolactone), poly( ⁇ -caprolactone-CO-lactic acid), poly( ⁇ -caprolactone-CO-glycoli
  • the invention provides a taste-masked pharmaceutical composition suitable for oral administration comprising a granulated mixture of an active pharmaceutical ingredient and a porous microsphere component, wherein the API is incorporated into the pores of the porous microsphere, further wherein the API is selected from antibiotics, antiviral agents, analgesics, anesthetics, anorexics, antiaithritics, antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatory agents, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, H2 antagonists, antitussives, cardiovascular drugs, antiarrhythmics, antihypertensives, ACE inhibitors, diuretics, vasodilators, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics,
  • the invention provides a pharmaceutical composition comprising an API- porous microsphere complex and a sweetener, wherein the sweetener is a member selected from the group consisting of aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose, sucrose, and acesulfame K.
  • the invention provides a method of preparing the pharmaceutical composition of comprising combining an API- porous microsphere complex and a sweetener.
  • the invention provides a pharmaceutical unit dosage form comprising an API-porous microsphere complex, wherein the dosage form is coated with a pharmaceutically acceptable coating, wherein the pharmaceutically acceptable coating is a member selected from the group consisting of polyethylene glycols, waxes, cellulose derivatives, and polyacrylate derivatives.
  • the invention provides an oral pharmaceutical unit dosage form comprising an API- porous microsphere complex, wherein the oral dosage form is a member selected from the group consisting of a capsule, a tablet, a wafer, a chewable tablet, a buccal tablet, a sub lingual tablet, a quick-dissolve tablet, an effervescent tablet, a granule, a gum, a pellet, a bead, a pill, a sachet, a sprinkle, a syrup, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an oral suspension, a lozenge, an implant, a powder, a triturate, an enterics/controlled release coated tablet, a thin film, or a strip.
  • the oral dosage form is a member selected from the group consisting of a capsule, a tablet, a wafer, a chewable tablet, a buccal tablet, a sub lingual tablet, a quick-dis
  • the invention provides a method of preparing the oral dosage form, comprising combining an API and a porous microsphere into the oral dosage form.
  • the invention provides a method of making a taste-masked pharmaceutical composition comprising granulating a mixture of an active pharmaceutical ingredient and a porous microsphere component, wherein the porous microsphere component is selected from the group consisting of is selected from the group consisting of polyesters, polyamides, polyanhydrides, and polyacrylates, poly(lactic) acid, poly(glycolic) acid, copoly(lactic/glycolic) acid and poly[l,3-bis(-p-carboxyphenoxy)propane-co-sebacic acid], polyglycolic (PGA), polylactic (PLA) acids, copolymers of glycolide and L(-lactide) (PGL), gelatin, agar, starch, arabinogalactan, albumin, collagen, natural and synthetic materials or polymers, such as, poly( ⁇ - caprolactone), poly( ⁇
  • hydrogels such as poly(hydroxyethyl methacrylate), polyamides (e.g., polyacrylamide), poly(amino acids) (i.e., L-leucine, L-aspartic acid, .beta.-methyl-L- aspartate, ⁇ -benzyl-L-aspartate, glutamic acid and the like), poly(2-hydroxyethyl DL- aspartamide), poly(ester urea), poly(L-phenylalanine/ethylene glycol/1, 6-diisocyanatohexane), poly(methyl methacrylate), SephadexTM, SeparoseTM, and SuperoseTM, TrisacrylTM, UltrogelTM , ACATM media, GF05TM and GF2000TM, SephacrylTM media, SuperdexTM media, such as Superdex 75TM and Superdex 200TM, variants thereof, and combinations thereof.
  • the invention provides that
  • the invention provides a pharmaceutical composition comprising an API- porous microsphere complex and at least one flavorant, wherein the flavorant is a member selected from the group consisting of cherry, strawberry, grape, cream, vanilla, chocolate, mocha, aniseed, eucalyptus, 1 -menthol, carvone, anethole, essential oils such as peppermint or spearmint, cola, and combinations thereof.
  • the invention provides a method of preparing the pharmaceutical composition comprising combining an API- porous microsphere complex and at least one flavorant.
  • the invention provides a pharmaceutical composition comprising an API- porous microsphere complex and further optionally comprising at least one flavorant, and/or at least one sweetener and/or at least one coating.
  • the invention provides a method of preparing the pharmaceutical composition, comprising combining an API- porous microsphere complex optionally with at least one flavorant, and/or at least one sweetener, and/or at least one coating.
  • the invention provides a method of administering a pharmaceutical composition comprising an API- porous microsphere complex to a patient in need thereof, the method comprising providing a unit dose comprising the pharmaceutical composition comprising an API- porous microsphere complex
  • API- porous microsphere complex administering to the patient the unit dosage form, wherein the patient is a mammal.
  • the present invention is directed to a composition and a related method for the preparation of taste-masked active pharmaceutical ingredients (APIs).
  • Taste masking can be defined as the perceived reduction of an undesirable taste commonly associated with a particular API.
  • the present invention obtains the taste masking of an API by conventional granulating (e.g., rotogranulating) techniques.
  • the API is granulated with a porous microsphere component.
  • the granulation of the API with the porous microspheres component loads the API into the pores of the microsphere.
  • the taste of the API is masked by incorporation of the API into the pores of the microsphere.
  • Porous spherical polymer matrices or microspheres having a diameter range between about 1 to about 1000 microns ( ⁇ m) can be prepared.
  • a more preferred range for the spherical polymer matrices of microspheres is between about 0.5 to 150 microns.
  • pore incorporated API is used to define the relative specific location of the agent confined essentially completely inside the pores of the porous microspheres of the invention.
  • API specifically encompasses any diagnostic or pharmacologically active material which would be generally classifiable as a drug suitable for introduction into a human or other animal host, as well as other materials or compositions including, for instance, dyes, antigens, antibodies, enzymes, flavors, comestibles and the like and mixtures thereof.
  • a granular pharmaceutical preparation is produced by mixing an API in a granulating solvent with a porous microsphere component, and granulating the mixture.
  • exemplary granulation solvents include, but are not limited to, alcohols, acetone, ethylacetate and water.
  • the various ingredients that are used are substantially pure and non-toxic.
  • the granulated material so-produced then can be sized, and milled and made into tablets, capsules or a variety of other dosage forms as noted hereinafter.
  • One of the main advantages of the present invention is that by preparing the taste- masked API as a granular composition one is better able to obtain and/or control the particle size of the material destined for use in preparing the final dosage form.
  • the desired polymer or copolymer and the API or other agent(s) are dissolved separately in a suitable solvent.
  • the polymer and drug solutions are mixed together in the appropriate manner with a drug:polymer ratio ranging between about 0.05:1 to 3:1, with the preferred range about 0.8:1.
  • Suitable porous microsphere components microparticles are prepared from any suitable polymeric material, such as polyesters, polyamides, polyanhydrides, and polyacrylates.
  • the polymer is one which will degrade over time in the body, such as poly(lactic) acid, poly(glycolic) acid, copoly(lactic/glycolic) acid and poly[l,3-bis(-p- carboxyphenoxy)propane-co-sebacic acid] and the like materials.
  • polyesters are polyglycolic (PGA) and polylactic (PLA) acids, and copolymers of glycolide and L(-lactide) (PGL).
  • polyesters are particularly suited for the methods and compositions of the present invention by reason of their characteristically low human toxicity and virtually complete biodegradability. It will be understood that the particular polyester or other polymer, oligomer, copolymer, etc., utilized as the microspheric polymer matrix is not critical and a variety of polymers may be utilized as a consequence of the novel processing methods of the invention which yield the desired microspheres of the porosity, consistency, shape and size distribution essentially irrespective of the source of polymer utilized.
  • biodegradable or bioerodable polymers or copolymers evidencing the necessary low degree of toxicity suitable for use in the present invention include, for example, gelatin, agar, starch, arabinogalactan, albumin, collagen, natural and synthetic materials or polymers, such as, poly( ⁇ -caprolactone), poly( ⁇ -caprolactone-CO- lactic acid), poly( ⁇ -caprolactone-CO-glycolic acid), poly( ⁇ -hydroxy butyric acid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate), (e.g., methyl, ethyl, butyl, etc.), hydrogels such as poly(hydroxyethyl methacrylate), polyamides (e.g., polyacrylamide), poly(amino acids) (i.e., L-leucine, L-aspartic acid, .beta.-methyl-L-aspartate, ⁇ -benzyl-L- as
  • size exclusion media examples include, but are not limited to, SephadexTM, SeparoseTM, and SuperoseTM, by Amersham Biosciences, and TrisacrylTM and UltrogelTM by Pall Corporation, , ACATM media, such as ACA 34TM, ACA 44TM, ACA 54TM, and ACA 200TM (commercially available from BioSepra, Inc., Marlborough, Mass. USA), GF05TM and GF2000TM (commercially available from BioSepra, Inc., Marlborough, Mass. USA),
  • SephacrylTM media such as S400TM, S500TM, and S- 1000TM (commercially available from Pharmacia Biotech, Uppsala, Sweden), SuperdexTM media, such as Superdex 75TM and Superdex 200TM (commercially available from Pharmacia Biotech, Uppsala, Sweden), and the like. Processes for forming such particles will be apparent to the skilled artisan and include, but are not limited to, spray drying of the polymeric material to generate substantially spherical particles or freeze drying followed by ball milling to produce randomly shaped particles .
  • APIs include, without being limiting, antibiotics, antiviral agents, analgesics, anesthetics, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatory agents, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, H2 antagonists, antitussives, cardiovascular drugs, antiarrhythmics, antihypertensives, ACE inhibitors, diuretics, vasodilators, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetics, psychostimulants, sedatives, antimigrane agents antituberculosis agents, tranquilizers vitamins and mineral supplements.
  • antibiotics such as tetracycline, penicillin V, or neomycin
  • hypnotics such as the barbiturates, methaqualone or mecloqualone
  • oral antidiabetics such as sulf amides or biguanides
  • antihistamines such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, or promethazine
  • bronchodilators such as theophylline or hydroxyethyl theophylline
  • vasoconstrictors such as ephedrine or isoprenaline or naphazoline
  • antitussants such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, and chlophedianol hydrochloride.
  • the active ingredients suitable for use in the pharmaceutical compositions and methods of the present invention are not particularly limited, as the compositions are surprisingly capable of effectively delivering a wide variety of active ingredients.
  • the active ingredient can be hydrophilic, lipophilic, amphiphilic or hydrophobic, and can be solubilized, dispersed, or partially solubilized and dispersed.
  • Such active ingredients can be any compound or mixture of compounds having therapeutic or other value when administered to an animal, particularly to a mammal, such as drugs, nutrients, cosmeceuticals, diagnostic agents, nutriceuticals, nutritional agents, and the like.
  • Suitable APIs are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, antihelmimthics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malariale, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, .beta.
  • -Blockers cardiac inotropic agents, corticosteroids, diuretics, antiparkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
  • suitable APIs are: acetretin, albendazole, albuterol, 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
  • APIs are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, antihelminthics, anti-arrhythmic agents, anti- bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti- epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, antimigraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, .beta.-Blockers, cardiac inotropic agents, corticosteroids, diuretics, antiparkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, levo
  • the API can be a cytokine, a peptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid, or a mixture thereof.
  • suitable APIs also include: acarbose; acyclovir; acetyl cysteine; acetylcholine chloride; alatrofloxacin; alendronate; aglucerase; 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; bleomnycin sulfate; calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate
  • standard granulating equipment and drying apparatus can be used to produce pharmaceutical compositions of the API - microsphere complex, or taste masked API - microsphere complexes of the present invention.
  • Such equipment and apparatus are well known to those skilled in the art.
  • pan granulators and rotor granulators along with spray drying and drum drying procedures may be suitable.
  • Preferred ways of performing the original salt/complex formation and subsequent granulation thereof may include use of paddle dryers or fluidized bed plow mixers.
  • Tilt-A-Mix mixer available from Processall, hie. Dosage Forms
  • An advantage of the techniques used in practicing the present invention is that one can produce granules having a uniform distribution of the API - microsphere complex, or the taste masked API - microsphere complex. In this way, one can be confident that when these granules are used to prepare the ultimate oral dosage form, whether in the form of a film (such as a fast melt film), a tablet (including chewable tablets and fast dissolving tablets), a capsule, an oral suspension, a gum, a lozenge, or the like dosage forms, one is precisely providing the desired quantity of the API, and not an undesired lower or higher amount of the API.
  • a film such as a fast melt film
  • a tablet including chewable tablets and fast dissolving tablets
  • a capsule an oral suspension, a gum, a lozenge, or the like dosage forms
  • the invention provides an oral dosage form which may be a capsule, a tablet, a wafer, a chewable tablet, a buccal tablet, a sub-lingual tablet, a quick-dissolve tablet, an effervescent tablet, a granule, a gum, a pellet, a bead, a pill, a sachet, a sprinkle, a syrup, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an oral suspension, a lozenge, an implant, a powder, a triturate, an enterics/controlled release coated tablet, a thin film, or a strip.
  • any of the wide variety of excipients commonly used in making pharmaceutical preparations can be used.
  • disintegrants, coloring agents, flavoring agents, lubricants, fillers and the like materials can be employed with the inventive granular composition of this invention.
  • the present invention is not to be limited to any specific set of excipients.
  • Suitable pharmaceutical excipients include but are not limited to, polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavoring agents, pharmaceutical grade dyes or pigments, and viscosity agents, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, lactose, mannitol, sorbitol, tribasic calcium phosphate, dibasic calcium phosphate, compressible sugar, starch, calcium sulfate, dextro and microcrystalline cellulose, acacia, tragacanth, hydroxypropylcellulose, pregelatinized starch, gelatin, po
  • the invention provides extended release formulations for the therapeutically active agent.
  • the pharmaceutical composition of the invention includes a controlled release, sustained release, or timed release dosage formulation for the therapeutically active agent.
  • the extended release formulation as described herein can provide continuous and non-pulsating therapeutic levels of the therapeutically active agent to a mammal in need of such treatment over a period of time, such as a six-hour period or longer, e.g., a twelve-hour to twenty-four hour period.
  • Such an extended release, controlled release, sustained release, or timed release dosage formulation employs a mixture of organic acid and water-soluble polymers, e.g., a high molecular weight hydroxypropyl methylcellulose and polyvinylpyrrolidone .
  • the invention provides pharmaceutical unit dosage forms, wherein the dosage form is coated with a pharmaceutically acceptable coating.
  • the pharmaceutically acceptable coating material includes, but is not limited to, a rapid-disintegrating coating material, a colorant, an enteric polymer, a plasticizer, a water-soluble polymer, a water-insoluble polymer, a dye, a pigment, other disintegrants, combinations thereof, and polymorphic forms thereof, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose succinate, carboxymethylethylcellulose, cellulose acetophthalate.
  • plasticizers include polyethylene glycol (PEG), propylene glycol, and others
  • water-soluble polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene oxide, and others.
  • the invention provides pharmaceutically acceptable coating of bulk active material.
  • the invention provides pharmaceutically acceptable coating of bulk material comprising microsphere complexes of APIs.
  • the invention provides pharmaceutically acceptable coating of bulk active material, wherein the material is taste masked.
  • the invention provides pharmaceutically acceptable coating of bulk material comprising microsphere complexes of APIs, wherein the material is taste masked.
  • the pharmaceutically acceptable coating material includes, but is not limited to, a rapid-disintegrating coating material, a colorant, an enteric polymer, a plasticizer, a water-soluble polymer, a water-insoluble polymer, a dye, a pigment, other disintegrants, combinations thereof, and polymorphic forms thereof, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose succinate, carboxymethylethylcellulose, cellulose acetophthalate.
  • plasticizers include polyethylene glycol (PEG), propylene glycol, and others
  • water-soluble polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene oxide, and others.
  • the step of providing the pharmaceutically active agent with the coating includes a treatment for coating onto portions of the pharmaceutically active agent.
  • the drying includes applying heat the bottom of the carrier surface. Moreover, the drying may include applying microwave energy to the film.
  • Useful methods for providing the pharmaceutically active agent with the coating include fluidized bed coating, spray congealing coating, agglomeration or granulation coating, entrapment coating, coaccervation coating, infusion coating, spin coating, ion exchange coating of the pharmaceutically active agent.
  • the pharmaceutically acceptable polymers of the instant invention include, but are not limited to, water-soluble hydrophilic polymers, maltodextrin, natural gums, arabic gum, guar gum, xanthan gum, tragacanth gum, agar, gellan gum, kayara gum, alginic acids, pectins, pre-gelatinized starch, dextrin, maltodextrin, and blends of these polymers, combinations thereof, and polymorphic forms thereof.
  • water-soluble polymers examples include polyvinylpyrrolidone, hydroxypropyl cellulose (HPC; Klucel), hydroxypropyl methylcellulose (HPMC; Methocel), nitrocellulose, hydroxypropyl ethylcellulose, hydroxypropyl butylcellulose, hydroxypropyl pentylcellulose, methyl cellulose, ethylcellulose (Ethocel), hydroxyethyl cellulose, various alkyl celluloses and hydroxyalkyl celluloses, various cellulose ethers, cellulose acetate, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, vinyl acetate/crotonic acid copolymers, poly-hydroxyalkyl methacrylate, hydroxymethyl methacrylate, methacrylic acid copolymers, polymethacrylic acid, polymethylmethacrylate, maleic anhydride/methyl vinyl ether copolymers, poly vinyl alcohol, sodium and calcium polyacrylic acid, polyacrylic acid, acidic carboxy
  • Suitable examples of pharmaceutically acceptable sweeteners for the oral formulations include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose, sucrose, Acesulfame potassium, Alitame, Aspartame, and Aspartame- Acesulfame Salt, Cyclamate, Neohesperidine dihydrochalcone, Neotame, Saccharin, Sucralose, Stevia, Tagalose.
  • Suitable sweeteners include both natural and artificial sweeteners.
  • suitable sweeteners include, e.
  • water- soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, dihydrochalcones, monellin, steviosides, and glycyrrhizin; water-soluble artificial sweeteners such as the soluble saccharin salts, i.
  • dipeptide based sweeteners such as L-aspartic acid derived sweeteners, such as L-aspartyl-L-phenylalanine methyl ester (aspartame), L-alpha-aspartyl- N- (2, 2,4, 4- tetramethyl-3-thietanyl)-D-alaninamide hydrate, methyl esters of L-aspartyl-L- phenylglycerin and L-aspartyl-L-2, 5, dihydrophenylglycine,
  • L-aspartic acid derived sweeteners such as L-aspartyl-L-phenylalanine methyl ester (aspartame), L-alpha-aspartyl- N- (2, 2,4, 4- tetramethyl-3-thietanyl)-D-alaninamide hydrate, methyl esters of L-aspartyl-L- phenylglycerin and L-aspartyl-L-2, 5, dihydropheny
  • water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as a chlorinated derivatives of ordinary sugar (sucrose), known, for example, under the product description of sucralose; and protein based sweeteners such as thaurnatoccous danielli (Thaumatin I and II).
  • Flavorants may also be used to improve the flavor of the composition and, as with the sweeteners, the pleasant flavor of the flavorant is not altered or reduced by the taste- masking component of the present invention. Flavorants may be used singly or in combination. Flavorants may be both natural and synthetic flavors.
  • flavorants include, but are not limited to, cherry, strawberry, grape, cream, vanilla, chocolate, mocha, aniseed, eucalyptus, 1 -menthol, carvone, anethole, citrus oils, essential oils such as peppermint, spearmint, or methyl salicylate (oil of wintergreen), cola, and the like.
  • the API - microsphere complex of the instant invention may optionally comprise a film-forming agent which can be selected from known pharmaceutical coating agents, many of which are polymeric materials and include cellulose-based coating agents; methacrylate- based coating agents, and polyvinyl acetate phthalate-based coating agents.
  • Suitable cellulose-based coating agents include methyl, ethyl and propyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose, hydroxypropylcellulose, hydroxypropyl ethyl cellulose, cellulose acetate, cellulose acetate butyrate, and nitrocellulose.
  • Suitable methacrylate-based coating agents include anporous microsphere polymers of methacrylic acid and methacrylates with a COOH group, catporous microsphere polymers with a dimethylaminoethyl ammonium group, copolymers of acrylate and methacrylates with quaternary ammonium groups, copolymers of acrylate and methacrylates with quaternary ammonium group in combination with sodium carboxymethylcellulose, waxes and the like materials.
  • a film-forming agent that is insoluble in water but soluble in an organic solvent.
  • a film forming agent would embrace the alkyl derivatives of cellulose, preferably cellulose ethers such as methyl, ethyl and propyl cellulose, which are insoluble in water and soluble in organic solvents; cellulose esters such as cellulose acetate and cellulose acetate butyrate; nitrocellulose; poly(meth)acrylates, polyvinyl acetate, polyvinyl chloride, waxes and the like.
  • One preferred film-forming agent (B) comprises ethyl cellulose.
  • the film-forming agent can be supplied to the granulating process dissolved in an organic solvent, such as ethanol, which then can provide at least a portion of the granulating liquid.
  • the film-forming agent is provided as a water-based dispersion and comprises an aqueous dispersion of ethyl cellulose.
  • a suitable ethyl cellulose aqueous dispersion will normally have a concentration of water-insoluble ethyl cellulose of 3 to 40 wt. %, more usually 10 to 35 wt. %.
  • the ethyl cellulose aqueous dispersion is preferably used in combination with at least one physiologically compatible lipophilic diester of (i) a C6-C40 and preferably a C 10-Cl 6 aliphatic or aromatic dicarboxylic acid and (ii) a C1-C8 and preferably a C2-C5 aliphatic alcohol, as a plasticizer.
  • Suitable plasticizers include dibutyl phthalate, diethyl phthalate, dibutyl sebacate and diethyl sebacate.
  • the quantity of plasticizer is from 5 to 50 wt. % and preferably 10 to 40 wt. %, relative to ethyl cellulose.
  • the aqueous ethyl cellulose dispersion may be a commercial product such as, for example, sold under the names Aquacoat® or Surelease®. Such dispersions, such as for example Surelease®, may already contain the necessary plasticizer. Alternatively, it is possible to incorporate the plasticizers into the aqueous ethyl cellulose dispersion, possibly with the assistance of a surfactant or an emulsif ⁇ er as needed.
  • the film-forming agent generally constitutes from 3 to 40 percent (%) by weight of the API-containing granule, preferably from 5 to 25 weight percent of the API-containing granule and more preferably from about 5 to 10 weight percent of the API-containing granule.
  • the API - microsphere complex of the instant invention may optionally comprise a water soluble binder.
  • suitable ingredients for use as the water soluble binder include organic polyols (typically non-toxic hydrocarbons having two or more hydroxyls) such as 1,3- dihydroxypropane, hexylene glycol, glycerine, sorbitol, inositol and carbohydrates such as glucose and sucrose; polyethylene glycol; hydroxypropyl cellulose; hydroxypropyl methylcellulose; hydroxyethyl cellulose; polyvinyl alcohol; polyvinylpyrrolidone; carboxymethylcellulose and the like materials.
  • a suitable water soluble binder material may be a PEG having a molecular weight of 500 or more (preferably between 1000 and 6000) or a polyvinylpyrrolidone having a molecular weight of at least 10000 (preferably between 10000 and 360,000).
  • the preferred binder material is polyethylene glycol (PEG), particularly PEGs having a number average molecular weight of 3000 to 4000.
  • an API includes reference to one or more APIs (drugs), and the like.
  • Example 1 Preparation of taste-masked Diphenhydramine HCl.
  • An aqueous mixture is prepared from a diphenhydramine acid salt (the HCl salt), which is dissolved in water.
  • Sephadex G- 10 25 g is added to the solution, and the solution is stirred for 12 hours.
  • the mixture is then concentrated to dryness under vacuum using external heat with a temperature of 60 0 C.
  • the dried product is milled and sieved to yield the taste-masked Diphenhydramine HCl - Sephadex complex.
  • Example 2 Preparation of taste-masked Diphenhydramine HCl.
  • Sample Evaluation method Routine organoleptic screening can be used to identify satisfactorily taste masked compositions from those that are not.
  • a suitable screening test for evaluating the suitability of the methods of the present invention for taste masking a specific API involves preparing a solution or suspension of about 4 mmol of the taste masked API in 13 ml of water. The mixture is then agitated for about 1-2 hours and then an approximate 5 ⁇ L sample of the mixture is tasted. The taste of an aqueous solution or suspension of the untreated API at the same concentration should be evaluated contemporaneously.
  • the relative taste of the taste masked API can be rated on a scale of 1 to 4, where 4 signifies that the taste of the untreated API is the same as the taste masked sample and 1 signifies that the taste masked API has no significant taste.
  • 4 signifies that the taste of the untreated API is the same as the taste masked sample
  • 1 signifies that the taste masked API has no significant taste.

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Abstract

L'invention concerne une composition pharmaceutique au goût masqué apte à être administrée oralement, qui comprend un mélange granulé d'un ingrédient pharmaceutique actif et d'un composant à microsphère poreuse, l'ingrédient pharmaceutique actif étant introduit dans les pores de la microsphère poreuse.
PCT/US2008/066701 2007-06-13 2008-06-12 Nouveaux procédés de masquage de goût WO2008157228A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102988546A (zh) * 2012-11-21 2013-03-27 徐曼丽 用于提神醒脑的中药香囊
CN105866308A (zh) * 2016-05-10 2016-08-17 芜湖雨耕山食品检测有限公司 利用气相色谱检测食品中甜蜜素的方法
CN107083180A (zh) * 2017-05-25 2017-08-22 江南大学 一种基于草莓型微球的自清洁反射涂层及其制备方法
US9822257B2 (en) 2012-07-23 2017-11-21 Crayola Llc Dissolvable films and methods of using the same
US9872838B2 (en) * 2016-05-30 2018-01-23 Sun Pharmaceutical Industries Limited Raloxifene sprinkle composition
CN112315944A (zh) * 2020-12-08 2021-02-05 黄山中皇制药有限公司 一种穿琥宁肠溶干混悬剂的制备方法

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US6740310B2 (en) * 1996-05-24 2004-05-25 Massachusetts Institute Of Technology Porous particles comprising excipients for deep lung delivery
WO2005013944A1 (fr) * 2003-08-11 2005-02-17 Merck Frosst Canada Ltd. Formulation pharmaceutique a gout masque et aromatisee, obtenue par un procede d'enrobage en une etape

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6740310B2 (en) * 1996-05-24 2004-05-25 Massachusetts Institute Of Technology Porous particles comprising excipients for deep lung delivery
WO2005013944A1 (fr) * 2003-08-11 2005-02-17 Merck Frosst Canada Ltd. Formulation pharmaceutique a gout masque et aromatisee, obtenue par un procede d'enrobage en une etape

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9822257B2 (en) 2012-07-23 2017-11-21 Crayola Llc Dissolvable films and methods of using the same
CN102988546A (zh) * 2012-11-21 2013-03-27 徐曼丽 用于提神醒脑的中药香囊
CN105866308A (zh) * 2016-05-10 2016-08-17 芜湖雨耕山食品检测有限公司 利用气相色谱检测食品中甜蜜素的方法
US9872838B2 (en) * 2016-05-30 2018-01-23 Sun Pharmaceutical Industries Limited Raloxifene sprinkle composition
US10092522B2 (en) 2016-05-30 2018-10-09 Sun Pharmaceutical Industries, Ltd. Raloxifene sprinkle composition
US10335376B2 (en) 2016-05-30 2019-07-02 Sun Pharmaceutical Industries Limited Raloxifene sprinkle composition
CN107083180A (zh) * 2017-05-25 2017-08-22 江南大学 一种基于草莓型微球的自清洁反射涂层及其制备方法
CN112315944A (zh) * 2020-12-08 2021-02-05 黄山中皇制药有限公司 一种穿琥宁肠溶干混悬剂的制备方法
CN112315944B (zh) * 2020-12-08 2022-09-02 黄山中皇制药有限公司 一种穿琥宁肠溶干混悬剂的制备方法

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