WO2016154313A1 - Compositions pharmaceutiques liquides à forte charge pour administration par voie orale - Google Patents

Compositions pharmaceutiques liquides à forte charge pour administration par voie orale Download PDF

Info

Publication number
WO2016154313A1
WO2016154313A1 PCT/US2016/023783 US2016023783W WO2016154313A1 WO 2016154313 A1 WO2016154313 A1 WO 2016154313A1 US 2016023783 W US2016023783 W US 2016023783W WO 2016154313 A1 WO2016154313 A1 WO 2016154313A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
liquid oral
oral pharmaceutical
loading liquid
composition according
Prior art date
Application number
PCT/US2016/023783
Other languages
English (en)
Inventor
Eric S. Gilbert
Original Assignee
Zywie, Llc
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 Zywie, Llc filed Critical Zywie, Llc
Publication of WO2016154313A1 publication Critical patent/WO2016154313A1/fr

Links

Classifications

    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—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
    • A61K9/14—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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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

Definitions

  • the present invention generally relates to liquid oral pharmaceutical compositions. More particularly, the present invention is directed to a high drug loading liquid oral composition for administering a pharmaceutical active ingredient. Further, the present invention is directed to high loading liquid oral pharmaceutical compositions suitable for administration to persons or animals suffering from a lysosomal storage disorder.
  • Liquid oral dosage forms offer unique advantages over solid dosage forms like tablets and capsules. For example, in many instances, the amount of active ingredient necessary to treat a specific disease or condition requires multiple tablets or capsules one or more times a day. The ingestion of multiple tablets or capsules includes not only the active pharmaceutical ingredient, but multiple doses of excipients which are used to formulate the tablets and capsules. Such excipients, such as oils and alcohols are not well tolerated by many patients and commonly lead to gastric distress.
  • liquid oral dosage forms are more patient compliant than solid dosage forms since delivery of the active pharmaceutical ingredient is achieved in only one or two doses per day. Moreover, liquid oral dosage forms provide rapid absorption of an active pharmaceutical ingredient from the gastro-intestinal tract. Furthermore, liquid oral dosage forms allow the use of flavoring and/or palatability agents, which further promotes patient acceptance and compliance.
  • the Biopharmaceutics Classification System classifies drugs into four groups: Class I: high permeability, high solubility; Class II: high permeability, low solubility; Class III: low permeability, high solubility; and Class IV: low permeability, low solubility.
  • a pharmaceutically active compound is conventionally classified as highly soluble when the largest dose of the compound is soluble in less than 250 mL water over a pH range from 1.0 to 7.5.
  • Soluble compounds have a solubility range of greater than or equal to 33 mg/mL.
  • Sparingly soluble compounds have a range from 10-33 mg/mL, slightly soluble compounds from 1-10 mg/mL, and very slightly soluble compounds from 0.1-1 mg/mL. Compounds with solubilities below 1 mg/mL are classified as practically insoluble.
  • BCS Class I drugs are highly soluble and highly permeable in the gastrointestinal ("GI") tract.
  • BCS Class I drugs include ambroxol hydrochloride, amitriptyline hydrochloride, biperiden hydrochloride, chloroquine phosphate, chlorpheniramine maleate, chlorpromazine hydrochloride, clomiphene citrate, cloxacillin sodium, cyclophosphamide, diazepam, doxycycline, ergotamine tartrate, fluconazole, indinavir sulfate, levamisole hydrochloride, levothyroxine sodium, mefloquine hydrochloride, nelfinavir mesylate, neostigmine bromide, phenytoin sodium, prednisolone, promethazine hydrochloride, proguanil hydrochloride, quinine sulfate, salbutamol, warfarin sodium, caffeine, metoprolol, prop
  • BCS Class II drugs are poorly soluble, but are absorbed in the GI tract.
  • BCS Class II drugs include Albendazole, Acyclovir, Azithromycin, Cefdinir, Cefuroxime axetil, Chloroquine, Clarithromycin, Clofazimine, Diloxanide, Efavirenz, Fluconazparole, Griseofulvin, Indinavir, Itraconazole, Ketoconalzole, Lopinavir, Mebendazole, Nelfinavir, Nevirapine, Niclosamide, Praziquantel, Pyrantel, Pyrimethamine, Quinine, Ritonavir, Bicalutamide, Cyproterone, Gefitinib, Imatinib, Tamoxifen, Cyclosporine, Mycophenolate mofetil, Tacrolimus.
  • CN 1546008A discloses an ambroxol hydrochloride slow release liquid preparation wherein the preparation comprises ambroxol hydrochloride and pharmaceutically acceptable polymers, the auxiliary material with slow release action is cationic ion-exchange resin and cellulose ethyl ether and / or acrylic resin.
  • CN 1546008 has four examples wherein the amount of ambroxol HCl is 75/230 (33% ambroxol HCl); 75/255 (29% ambroxol HCl); 100/250 (40% ambroxol HCl); and 75/240 (31ambroxol HCl), respectively.
  • the highest concentration of ambroxol HCl described in CN 1546008A is 40% by weight which is less than half of the claimed maximum loading amount of 90% by weight as claimed in CN 1546008A.
  • Lysosomal storage disorders are a group of diseases which arise from abnormal metabolism of various substrates, including glycosphingolipids, glycogen, mucopolysaccharides and glycoproteins. More than fifty disorders have been identified that are caused by mutations in metabolic enzymes that are required for the degradation of such compounds. Many of them are neuronopathic and so may produce severe neurological impairment.
  • lysosomal storage disorders include the following: Pompe disease (including infantile and late-onset forms); Gaucher disease (including Type 1 , Type 2 and Type 3 Gaucher disease); Fabry disease; GMI-gangliosidosis; Tay-Sachs disease;
  • the lysosomal storage disease is selected from: (a) Pompe disease; (b) Gaucher disease; and (c) Fabry disease.
  • Gaucher's disease is the most common of the lysosomal storage diseases. It is a form of sphingolipidosis (a subgroup of lysosomal storage diseases), as it involves dysfunctional metabolism of sphingolipids. The disease is caused by a recessive mutation in a gene located on chromosome 1 and affects both males and females. It is estimated that about one in 100 people in the United States are carriers of the most common type of Gaucher disease.
  • the purpose of the present invention is to provide a high drug loading liquid oral pharmaceutical composition.
  • the oral pharmaceutical composition may be in the form of a suspension or a solution.
  • the high drug loading liquid oral pharmaceutical composition according to the invention may be administered to a subject in a daily dose in portions one or several times per day. In a preferred embodiment, the high drug loading liquid oral pharmaceutical composition is administered once a day.
  • the high drug loading liquid oral pharmaceutical composition comprises (i) an active pharmaceutical ingredient selected from the group consisting of a BCS Class I drug, a BCS Class II drug, a small molecule chaperone, and/or combinations thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the active pharmaceutical ingredient is in the form of granules having a granular core comprising from about 60 to about 97 weight percent of an active pharmaceutical ingredient and from about 3 to about 40 weight percent of the excipient, wherein the weight percent is based on the total weight of the granular core.
  • the high drug loading liquid oral pharmaceutical composition comprises (i) an active pharmaceutical ingredient selected from the group consisting of a BCS Class I drug, a BCS Class II drug, a small molecule chaperone, and combinations thereof; (ii) at least one pharmaceutically acceptable excipient; and (iii) a diluent, wherein the active pharmaceutical ingredient is in the form of granules having a granular core comprising from about 60 to about 97 weight percent of an active pharmaceutical ingredient and from about 3 to about 40 weight percent of the excipient, wherein the weight percent is based on the total weight of the granular core; wherein the granule core is coated with (iv) a water- soluble seal coating in an amount to provide from about 0.5 to about 5 percent weight gain, and (v) an enteric coating in an amount to provide from about 0.5 to about 50 percent weight gain.
  • an active pharmaceutical ingredient selected from the group consisting of a BCS Class I drug, a BCS Class II drug, a small molecule chaperone,
  • the high drug loading liquid oral pharmaceutical composition is prepared by a method comprising:
  • step (c) coating the granules prepared in step (b) with an enteric coating in an amount to provide from about 0.5 to about 50 percent weight gain;
  • step (d) preparing a liquid suspension comprising the enteric coated granules prepared in step (c) and a liquid suspension formulation, wherein the liquid suspension formulation comprises a suspending agent, a vehicle to enhance the stability of the high drug loading liquid oral pharmaceutical composition, and a diluent.
  • the vehicle to enhance the stability of the high drug loading liquid oral pharmaceutical composition is a protective colloid.
  • the high drug loading liquid oral pharmaceutical composition comprises granules prepared according to the invention, microcrystalline cellulose and carboxymethylcellulose sodium; cellulose gum, xanthan gum, and carrageenan; and water.
  • the high drug loading liquid oral pharmaceutical composition is used to treat or alleviate the symptoms of Parkinson's disease.
  • the high drug loading liquid oral pharmaceutical composition is used to treat a lysosomal storage disease is selected from: (a) Pompe disease; (b) Gaucher disease; and (c) Fabry disease.
  • Unexpected advantages of the high drug loading liquid oral pharmaceutical composition according to the invention include at least the following: (1) improved adsorption in the gastrointestinal tract; (2) maintain effective blood concentration over a 24 hour period; (3) reduce undesirable side effects of excipients as compared to solid dosage forms; (4) reduce the number of doses required; and (5) provide an improved taste and mouthfeel qualities.
  • the high drug loading liquid oral pharmaceutical composition comprises an active pharmaceutical ingredient selected from the group consisting of a BCS Class I drug, a BCS Class II drug, a small molecule chaperone, and combinations thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the active pharmaceutical ingredient is in the form of granules having a granular core comprising from about 60 to about 97 weight percent of an active pharmaceutical ingredient and from about 3 to about 40 weight percent of the excipient, wherein the weight percent is based on the total weight of the granular core.
  • the granular core comprises from about 75 to about 97 percent by weight of an active pharmaceutical ingredient and from about 3 to about 25 weight percent of the excipient. More preferably, the granular core comprises from greater than 90 to about 97 weight percent of an active pharmaceutical ingredient and from about 3 to greater than 7 weight percent of the excipient. Most preferably, the granular core comprises greater than 90, greater than 91, greater than 92, greater than 93, greater than 94, greater than 95, greater than 96, or greater than 97 percent by weight of the active pharmaceutical ingredient.
  • the high drug loading liquid oral pharmaceutical composition according to the invention is suitable for drugs categorized as BCS Class I and Class II (i.e., therapeutic agents with a high permeability). Regarding the other two BCS classifications (Class III and Class IV), such drugs are not suitable due to the risk of pharmacokinetic (PK) non-equivalence due to their low permeability.
  • BCS Class I and Class II i.e., therapeutic agents with a high permeability
  • BCS Class I drugs are highly soluble and highly permeable in the gastrointestinal ("GI") tract. Suitable BCS Class I drugs include, but are not limited to, those listed in Kasim et al. MoI. Pharmaceutics 1(1): 85-96 (2004) and Lindenberger et al. Eur. J. Pharm.
  • hydrochloride biperiden hydrochloride, chloroquine phosphate, chlorpheniramine maleate, chlorpromazine hydrochloride, clomiphene citrate, cloxacillin sodium, cyclophosphamide, diazepam, doxycycline, ergotamine tartrate, fluconazole, indinavir sulfate, levamisole hydrochloride, levothyroxine sodium, mefloquine hydrochloride, nelfinavir mesylate, neostigmine bromide, phenytoin sodium, prednisolone, promethazine hydrochloride, proguanil hydrochloride, quinine sulfate, salbutamol, warfarin sodium, caffeine, metoprolol, propranolol, theophylline, verapamil, valacylclovir, diltiazem, gabapentin, levodopa, and di
  • BCS Class II drugs are poorly soluble, but are absorbed in the GI tract. Suitable BCS Class II drugs include, but are not limited to, Ambroxol, Albendazole, Acyclovir,
  • Medroxyprogesterone Pioglitazone, Raloxifene, Mosapride, Orlistat, Cisapride, Rebamipide, Sulfasalazine, Teprenone, Ursodeoxycholic Acid, Ebastine, Hydroxyzine, Loratadine, and Pranlukast.
  • a preferred BCS Class II drug is ambroxol.
  • the active pharmaceutical ingredient may comprise a small molecule chaperone (pharmacoperone) which enters cells and serves as a molecular scaffolding in order to cause otherwise-misfolded mutant proteins to fold and route correctly within the cell.
  • a small molecule chaperone pharmacoperone
  • Mutation of proteins often causes molecular misfolding, which results in protein misrouting within the cell. Accordingly, mutant molecules may retain proper function but end up in parts of the cell where the function is inappropriate, or even deleterious, to cell function.
  • Misfolded proteins are usually recognized by the quality-control system of the cell and retained (and often destroyed or recycled) in the endoplasmic reticulum.
  • Pharmacoperones correct the folding of misfolded proteins, allowing them to pass through the cell's quality-control system and become correctly routed. Since mutations often cause disease by causing misfolding and misrouting, pharmacoperones are potentially therapeutic agents, since they are able to correct this defect.
  • the high drug loading liquid oral pharmaceutical composition comprises an active pharmaceutical ingredient selected from ambroxol, an ambroxol derivative, or a pharmaceutically acceptable salt thereof.
  • ambroxol derivatives include, but are not limited to tribromophenyl propanoate, dibromophenyl benzamide, bromhexine, dibromoanilin, or tribromoaniline or a pharmaceutically acceptable salt thereof.
  • the active pharmaceutical ingredient comprises ambroxol.
  • the active pharmaceutical ingredient comprises ambroxol hydrochloride.
  • the active pharmaceutical ingredient comprises bromhexine.
  • the active pharmaceutical ingredient is preferably in the form of granules which preferably after micronizing have a particle size from about 100 microns to about 500 microns. More preferably, the particle size is from about 200 to about 350 microns. Even more preferably, the particle size is from about 100 to about 200 microns, from about 150 to about 250 microns, from about 200 to about 300 microns, from about 250 to about 350 microns, from about 300 to about 400 microns, from about 350 to about 450 microns, and/or from about 400 to about 500 microns in size.
  • the particle size is from about 100 to about 300 microns, from about 150 to about 350 microns, from about 200 to about 400 microns, from about 250 to about 450 microns, and/or from about 300 to about 500 microns.
  • the present inventors have determined that particle sizes within this range are coatable and provide ease of swallowing without urging the user to bite down.
  • the inventors have found that in preferred embodiments, from about 250 to about 350 microns balances the ability to coat with the ability to avoid the gritty“mouth feel.”
  • the particle size can be determined by laser light scattering for instance using a Malvern
  • Micronization of ambroxol HCl is performed in the dry state using dry mills such as cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills and ball mills.
  • a preferred excipient used to prepare the granular core is a binder.
  • the binder may be any water soluble pharmaceutically acceptable polymer.
  • the active pharmaceutical ingredient is in the form of a powder which the binder necessarily bonds together due to the poor cohesive properties of most powders.
  • the binder is selected from povidone (polyvinylpyrrolidone), copovidone (vinylpyrrolidone-vinylacetate copolymer), microcrystalline cellulose, powdered cellulose, crystalline cellulose, siliconized microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, starch, pregelatinized starch, polymethacrylates, compressible sugars, sucrose and sugar alcohols such as mannitol, sorbitol, maltitol and xylitol and mixtures thereof. More preferably, the binder is hydroxypropyl cellulose (Klucel LF).
  • the high drug loading liquid oral pharmaceutical composition comprises (i) an active pharmaceutical ingredient selected from the group consisting of a BCS Class I drug, a BCS Class II drug, a small molecule chaperone, and combinations thereof; (ii) at least one pharmaceutically acceptable excipient; and (iii) a diluent, wherein the granule core is coated with (iv) a water-soluble seal coating in an amount to provide from about 0.5 to about 5 percent weight gain, and (v) an enteric coating in an amount to provide from about 0.5 to about 50 percent weight gain.
  • the granular cores are optionally seal coated with a water-soluble seal coating in an amount to provide from about 0.5 to about 5 percent weight gain, and more preferably from about 0.5 to about 3 percent weight gain, and even more preferably from about 0.5 to about 2 percent weight gain, and even more preferably from about 0.5 to about 1 percent weight gain, and even more preferably from about 1 to about 2 percent weight gain, and even more preferably from about 1 to about 3 percent weight gain, and even more preferably from about 1 to about 4 percent weight gain, and more preferably from about 2 to about 3 percent weight gain, and even more preferably from about 2 to about 4 percent weight gain, and more preferably about 1 percent weight gain, and more preferably about 2 percent weight gain, and more preferably about 3 percent weight gain, and/or more preferably about 4 percent weight gain.
  • a water-soluble seal coating generates a smooth and uniform granule which is more receptive to receiving an enteric coating.
  • Preferred water-soluble polymers include hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethyl hydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon(R) VA64, BASF), gelatine, guar gum, partially hydrolysed starch, alginates and xanthan. Most preferably, the water-soluble polymer is hydroxypropylmethyl cellulose.
  • the seal coating is preferably applied by means of a bottom spray fluidized bed coater equipped with a Wurster column.
  • the granular cores may optionally be coated with an enteric coating directly on the granular core or on a seal coating previously applied to the granular cores.
  • the enteric coating is applied in an amount to provide from about 0.5 to about 50 percent weight gain, from about 1 to about 40 percent weight gain, from about 2 to about 30 percent weight gain, from about 3 to about 20 percent weight gain, or from about 4 to about 10 percent weight gain, based on the total weight of the granular core.
  • the enteric coating is applied in an amount to provide from about 0.5 to about 5 percent weight gain, from about 1 to about 4 percent weight gain, or from about 2 to about 3 percent weight gain, based on the total weight of the granular core.
  • the enteric coating is preferably applied by means of a bottom spray fluidized bed coater equipped with a Wurster column.
  • the enteric coating comprises a polymer selected from an acrylate polymer or an aqueous cellulose dispersion. Combinations of acrylate polymers and/or aqueous cellulose dispersions may also be used.
  • the acrylate polymer is selected from polymethacrylate methylmethacrylate copolymer (Eudragit L-100), polyethylacrylate methylmethacrylate trimethylammonioethyl methacrylate chloride copolymer (Eudragit RL- 100, RS-100), polymethacrylate ethylacrylate copolymer (Eudragit L30D-55), ethylacrylate methylmethacrylate trimethylammonioethyl methacrylate chloride copolymer (Eudragit RL30D), ethylacrylate methylmethacrylate trimethylammonioethyl methacrylate chloride copolymer (Eudragit RL30D), ethylacrylate
  • the acrylate polymer is polymethacrylate ethylacrylate copolymer (Eudragit L30D-55).
  • the enteric coating is preferably applied by means of a bottom spray fluidized bed coater equipped with a Wurster column.
  • the enteric coating increases delivery of the active pharmaceutical ingredient to a region of the gastrointestinal tract of a subject in which the pH is between about 4.5 and about 6.5.
  • the enteric coating also increases delivery of the active pharmaceutical ingredient to the proximal or mid-small intestine or both.
  • the enteric coating increases delivery of the active pharmaceutical ingredient to one or more of the duodenum, jejunum, or mid-ileum.
  • the enteric coating begins to dissolve in an aqueous solution at pH between about 4.5 to about 5.5.
  • the high loading liquid oral pharmaceutical composition is in the form of a solution. In another embodiment, the high loading liquid oral pharmaceutical composition is in the form of a suspension.
  • the enteric coated granules are combined with a liquid suspension formulation.
  • the liquid suspension formulation comprises a suspending agent, a vehicle to enhance the stability of the high drug loading liquid oral pharmaceutical composition, and a diluent.
  • the suspending agent and the vehicle to enhance the stability of the high drug loading liquid oral pharmaceutical composition may be the same or different since many suspending agents also serve as stability enhancers.
  • suspending agents include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, gum tragacanth, and glycerol monostearate. More preferably, the vehicle to enhance the stability of the liquid oral pharmaceutical composition is a protective colloid.
  • protective colloids include, but are not limited to, hydroxymethylcellulose, carboxymethylcellulose sodium, polyvinylalcohol, gelatin, and polyvinyl pyrrolidone. A combination of protective colloids may also be used.
  • a preferred protective colloid is a mixture of cellulose gum, xanthan gum, and carrageenan.
  • diluents include, but are not limited to, water, alcohols (such as for example methyl alcohol, ethyl alcohol, propyil alcohol, i-propyl alcohol etc), acetone, glycerin, oils (such as for example castor oil), any other pharmaceutically acceptable diluent or mixtures thereof. Most preferably water is used as the suspension or solution diluent. In addition, a pH modifier and/or an antioxidant may also be used.
  • the liquid suspension formulation includes microcrystalline cellulose and carboxymethylcellulose sodium (Avicel RC-591); gum (CP Kelco), and water.
  • the liquid suspension formulation includes microcrystalline cellulose and carboxymethylcellulose sodium (Avicel RC-591); cellulose gum, xanthan gum, and carrageenan (Ticaloid Ultrasmooth); and water.
  • the liquid suspension formulation includes from about 0.5% to about 3% of at least one suspending agent; from about 0.5% to about 1% of at least one protective colloid; and about 98% of a diluent, wherein the weight percents are based on the weight of the liquid suspension formulation. More preferably, the protective colloid will be used in an amount of about 0.1 to 0.5 weight percent.
  • the liquid suspension formulation includes about 1.5% of at least one suspending agent; from about 0.2% of at least one protective colloid; and about 98% of a diluent.
  • the high drug loading liquid oral pharmaceutical composition in suspension form has a viscosity less than about 5 Pa s. More preferably, high drug loading liquid oral pharmaceutical composition in suspension form has a viscosity less than about 3 Pa s, and most preferably, less than about 1 Pa s.
  • the high drug loading liquid oral pharmaceutical composition is prepared by a method comprising: (a) preparing granules having a granular core comprising from about 60 to about 97 weight percent of an active pharmaceutical ingredient and from about 3 to about 40 weight percent of at least one pharmaceutically acceptable excipient, wherein the weight percent is based on the total weight of the granular core; (b) coating the granules with a water-soluble seal coating in an amount to provide from about 0.5 to about 5 percent weight gain; (c) coating the granules prepared in step (b) with an enteric coating in an amount to provide from about 0.5 to about 50 percent weight gain; and (d) preparing a liquid suspension comprising the enteric coated granules prepared in step (c) and a liquid suspension formulation, wherein the liquid suspension formulation comprises a suspending agent, a vehicle to enhance the stability of the high drug loading liquid oral pharmaceutical composition, and a diluent.
  • the high loading liquid oral pharmaceutical composition according to the invention will additionally contain a plasticizer.
  • plasticizers are diethyl phthalate, dibutyl phthalate, triethyl citrate, and glycerol.
  • a combination of plasticizers may also be used. More preferably, the plasticizer is triethyl citrate.
  • the granules used in the high loading liquid oral pharmaceutical composition according to the invention are preferably prepared by direct spheronization involving preparing a granular core comprising from about 60 to about 97 weight percent of an active pharmaceutical ingredient, preferably from about 75 to about 97 weight percent, and more preferably from about greater than 90 weight percent to 97 weight percent, and from about 3 to about 40 weight percent of a binder, preferably from about 3 to about 25 weight percent, and more preferably from about 3 to about 10 weight percent, wherein the weight percent is based on the total weight of the granular core.
  • the granulation can be carried out under high shear (mixer granulation) or in a fluidized bed (fluidized bed granulation).
  • the high drug loading oral liquid pharmaceutical composition according to the invention may be administered to a subject in a daily dose in portions one or several times per day. In a preferred embodiment, the high drug loading oral suspension composition is administered once a day.
  • subject (which is to be read to include “individual”, “animal”, “patient” or “mammal” where context permits) defines any subject, particularly a mammalian subject, for whom treatment is indicated. In preferred
  • an“effective amount” or“a therapeutically effective amount” of a compound defines an amount that can be administered to a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, but one that is sufficient to provide the desired effect, e.g. the treatment or prophylaxis manifested by a permanent or temporary improvement in the subject's condition.
  • the amount will vary from subject to subject, depending on the age and general condition of the individual, mode of administration and other factors. Thus, while it is not possible to specify an exact effective amount, those skilled in the art will be able to determine an appropriate "effective" amount in any individual case using routine experimentation and background general knowledge.
  • a therapeutic result in this context includes eradication or lessening of symptoms, reduced pain or discomfort, prolonged survival, improved mobility and other markers of clinical improvement.
  • a therapeutic result need not be a complete cure.
  • a prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • Small molecule chaperones may be effective in treating lysosomal storage disorders. Lysosomal storage disorders (LSDs) are a group of diseases which arise from abnormal metabolism of various substrates, including glycosphingolipids, glycogen,
  • mucopolysaccharides and glycoproteins More than fifty disorders have been identified that are caused by mutations in metabolic enzymes that are required for the degradation of such compounds. Many of them are neuronopathic and so may produce severe neurological impairment.
  • the metabolism of the substrates normally occurs in the lysosome and the process is regulated in a stepwise process by various degradative enzymes. Therefore, a deficiency in any one enzyme activity can perturb the entire process and result in the accumulation of particular substrates.
  • lysosomal storage disorders a number of lysosomal storage disorders and the corresponding defective enzymes:
  • Gaucher disease Acid beta-glucosidase or glucocerebrosidase
  • GMI-gangliosidosis Acid beta-galactosidase
  • Tay-Sachs disease beta-Hexosaminidase A
  • Metachromatic leukodystrophy Arylsulfatase A Hurler-Scheie disease: alpha-L-lduronidase Hunter disease: lduronate-2-sulfatase
  • Morquio disease A N-Acetylgalactosamine-6-sulfate sulfatase
  • Sialidosis Sialidase Schindler-Kanzaki disease: alpha-N-acetylgalactosaminidase
  • the lysosomal storage disease may be selected from any of those diseases as follows: Pompe disease (including infantile and late-onset forms)
  • Gaucher disease (including Type 1 , Type 2 and Type 3 Gaucher disease)
  • the lysosomal storage disease is selected from: (a) Pompe disease; (b) Gaucher disease; and (c) Fabry disease.
  • the lysosomal disease is selected from Type 1, Type 2 and Type 3 Gaucher disease.
  • Gaucher’s disease is a genetic disease in which fatty substances (sphingolipids) accumulate in cells and certain organs.
  • the disorder is characterized by bruising, fatigue, anemia, low blood platelets, and enlargement of the liver and spleen. It is caused by a hereditary deficiency of the enzyme glucocerebrosidase.
  • This enzyme acts on the glycolipid glucocerebroside.
  • glucosylceramide accumulates, particularly in white blood cells, most often macrophages (mononuclear leukocytes). Glucosylceramide can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.
  • the subject that is treated with the oral pharmaceutical composition has a mutation in a glucocerebrosidase.
  • the subject having a mutation in a beta glucocerebrosidase also has either Gaucher’s and/or Parkinson’s Disease.
  • the subject that is treated with the oral pharmaceutical composition of the present invention has a mutation in a beta glucocerebrosidase.
  • the patient having a mutation in a beta glucocerebrosidase has Parkinson’s disease and/or Gaucher’s Disease.
  • the mutation in beta glucocerebrosidase is selected from:
  • the high drug loading oral liquid pharmaceutical composition may be given to a subject who is also receiving enzyme replacement therapy (e.g., combination therapy).
  • enzyme replacement therapy include, but are not limited to recombinant glucocerebrosidase, such as, for example, Imiglucerase, Velaglucerase,
  • Taliglucerase alfa (Elelyso), and/or Eliglustat (Cerdelga).
  • the high drug loading oral liquid pharmaceutical composition may be administered simultaneously, sequentially or at different times with the enzyme replacement therapy.
  • the high drug loading oral liquid pharmaceutical composition comprises ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof for treating a patient having a misfolded and/or erroneously transported glucocerebrosidase.
  • the high drug loading oral liquid pharmaceutical composition comprises ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof for treating or preventing a patient having a lysosomal storage disorder.
  • the high drug loading oral liquid pharmaceutical composition comprises ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof for treating a patient having a mutation in a glucocerebrosidase.
  • the high drug loading oral liquid pharmaceutical composition comprises ambroxol, an ambroxol derivative or a
  • the high drug loading oral liquid pharmaceutical composition comprises ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof for treating a patient suffering from Gaucher’s disease.
  • the high drug loading oral liquid pharmaceutical composition comprises ambroxol, an ambroxol derivative or a pharmaceutically acceptable salt thereof for treating a patient suffering from Parkinson’s Disease.
  • disease is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms.
  • the term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired. It therefore encompasses conditions arising from infection, trauma, injury, surgery, radiological ablation, poisoning or nutritional deficiencies.
  • treatment refers to an intervention (e.g. the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s) (for example, the reduction in accumulation of pathological levels of lysosomal enzymes).
  • the term is used synonymously with the term “therapy”.
  • treatment refers to an intervention (e.g. the administration of an agent to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population.
  • treatment is used synonymously with the term “prophylaxis”.
  • pharmaceutical acceptable excipient refers to additives useful for converting active pharmaceutical ingredients into pharmaceutical dosage forms which are suitable for administration to patients.
  • Suitable excipients include surfactants, solubilizers, binders, antifoaming agents, stabilizers, plasticizers, pH modifiers, colouring agents etc.
  • Dimethylpolysiloxane (dimeticone) or other antifoaming agent can be used to prevent foaming of the granulation liquid.
  • Polyethylene glycols, triethylcitrate, tributylcitrate, triacetine, dibutylsebacate etc. can be used as plasticizers.
  • titanium dioxide, iron oxides and other coloring agents can also be applied.
  • a sweetener may likewise be used.
  • sweeteners are mannitol, glucose, maltose, starch syrup, malt extract, maltitol, sorbitol, sucrose, unrefined sugar, fructose, lactose, honey, xylitol, hydrangea tea, saccharin, aspartyl phenylalanine ester and other malto-oligo saccharides, and oligo sacchaxzdes such as maltosyl sucrose, isomaltyrose of reduced type and raffinose.
  • Pharmaceutical preparations containing these additives may be prepared according to any method known in this field, currently used ones or ordinary ones depending on the specific high drug loading oral suspension according to the invention.
  • “and/or” is to be taken as specific disclosure of each of the two specified features or components with or without the other.
  • “A and/or B” is to be taken as specific disclosure of each (i) A, (ii) B and (iii) A and B, just as if each is set out individually.
  • the term“about” is used to refer to an amount that is approximately, nearly, almost, or in the vicinity of being equal to or is equal to a stated amount.
  • Example 1 A better understanding of the present invention may be obtained through the following examples which set forth to illustrate, but are not to be construed as to limit the present invention.
  • Example 1 A better understanding of the present invention may be obtained through the following examples which set forth to illustrate, but are not to be construed as to limit the present invention.
  • the resulting sphere contained 97% by weight of ambroxol HCl and 3% by weight of HPC.
  • the sphere had a particle size (x 50 ) of 346.08 microns and a density of 0.71 g/ml.
  • Micronized ambroxol HCl in the form of a powder was placed into a rotor granulator (GXR-35 Rotor Granulator, Freund-Vector Corporation) and a binder solution of hydroxypropylcellulose (HPC-Klucel LF) was sprayed onto the ambroxol HCl powder to form a granular core. Additional ambroxol HCl powder was then co-sprayed with the binder solution to grow the spheres. As layers of ambroxol HCl were added, the particles became more spherical. The resulting sphere contained 97% by weight of ambroxol HCl and 3% by weight of HPC. The sphere had a particle size (x50) of 264.49 microns and a density of 0.71 g/ml Example 3
  • the ambroxol HCl granules prepared in Example 1 were seal coated to generate a smooth and uniform substrate using a bottom-spray fluidized bed coater equipped with a Wurster column. Batch size was approximately 750 grams.
  • the seal coating contained 9.1% by weight of hypromellose (HPMC); 0.9% by weight of triethyl citrate (TEC); and 90% by weight of water.
  • the ambroxol HCl spheres were seal coated to 2% weight gain.
  • the seal coated ambroxol HCl granules prepared in Example 3 were enteric coated using a bottom-spray fluidized bed coater equipped with a Wurster column. Batch size was approximately 750 grams.
  • the enteric coating contained 58.0 % by weight of Eudragit L30D55; 0.9% by weight of triethyl citrate (TEC); 8.7% by weight of Plasacryl T20; and 32.5% by weight of water.
  • the seal coated ambroxol HCl spheres were enteric coated to 35% weight gain.
  • Ambroxol HCl granules were prepared according to the procedure set forth in Example 1.
  • the ambroxol HCl spheres are water-soluble seal coated to a 2% weight gain by the procedure set forth in Example 3.
  • the seal coated ambroxol HCl spheres were enteric coated using a bottom-spray fluidized bed coater equipped with a Wurster column. Batch size was approximately 750 grams.
  • the enteric coating contained 58.0 % by weight of Eudragit L30D55; 0.9% by weight of triethyl citrate (TEC); 8.7% by weight of Plasacryl T20; and 32.5% by weight of water.
  • the enteric coating weight gains are set forth in Table 1. TABLE 1
  • Ambroxol HCl granules are prepared according to the procedure set forth in Example 1.
  • the ambroxol HCl spheres are water-soluble seal coated to a 2% weight gain by the procedure set forth in Example 3.
  • the seal coated ambroxol HCl spheres are enteric coated using a bottom-spray fluidized bed coater equipped with a Wurster column. Batch size was approximately 750 grams.
  • the enteric coating contains 58.0 % by weight of Eudragit L30D55; 0.9% by weight of triethyl citrate (TEC); 8.7% by weight of Plasacryl T20; and 32.5% by weight of water.
  • the enteric coating weight gains are set forth in Table 2. TABLE 2
  • a stable oral suspension of the coated ambroxol HCl granules was prepared by adding microcrystalline cellulose and carboxymethylcellulose sodium (Avicel RC-591) to water while homogenizing at 7500 rpm. Mixing was continued for 30-60 seconds. The mixture was transferred to an overhead mixer and gum (CP Kelco) was added and mixing was continued for 10-60 minutes. Citric acid was added to adjust the pH of the mixture and a protective colloid was added. The protective colloid contained cellulose gum, xanthan gum, and carrageenan (Ticaloid Ultrasmooth). The suspension composition is set forth in Table 4. TABLE 4
  • An oral suspension of the coated ambroxol HCl granules was prepared by adding microcrystalline cellulose and carboxymethylcellulose sodium (Avicel RC-591) to water while homogenizing at 7500 rpm. Mixing was continued for 30-60 seconds. The mixture was transferred to an overhead mixer and gum (CP Kelco) was added and mixing was continued for 10-60 minutes. Citric acid was added to adjust the pH of the mixture and a protective colloid was added. The protective colloid contained gum arabic. The suspension quickly settled.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique liquide à forte charge pour administration par voie orale qui comprend (i) un ingrédient pharmaceutique actif sélectionné au sein du groupe constitué par un médicament de classe I du système de classification biopharmaceutique (BCS, pour "Biopharmaceutics Classification System"), un médicament de classe II du BCS, une petite molécule chaperonne, et des combinaisons de ces derniers ; (ii) au moins un excipient pharmaceutiquement acceptable ; et (iii) un diluant, l'ingrédient pharmaceutique actif se présentant sous forme de granules ayant un noyau granulaire comprenant entre environ 60 et environ 97 pour cent en poids d'un ingrédient pharmaceutique actif et entre environ 3 et environ 40 pour cent en poids de l'excipient, le pourcentage en poids étant basé sur le poids total du noyau granulaire ; le noyau du granulé étant enrobé (iv) d'un enrobage isolant hydrosoluble en une quantité permettant d'obtenir une augmentation de poids comprise entre environ 0,5 et environ 5 pour cent, et (v) un enrobage gastro-résistant en une quantité permettant d'obtenir une augmentation de poids comprise entre environ 0,5 et environ 50 pour cent. Les avantages inattendus de la composition pharmaceutique liquide à forte charge pour administration par voie orale de l'invention comprennent au moins les avantages suivants : (1) une meilleure absorption dans le tractus gastro-intestinal ; (2) le maintien d'une concentration sanguine efficace sur une période de 24 heures ; (3) une diminution des effets secondaires indésirables des excipients en comparaison à des formes posologiques solides ; (4) une diminution du nombre de doses requises ; et (5) l'apport de meilleures qualités gustatives et d'une meilleure sensation en bouche.
PCT/US2016/023783 2015-03-24 2016-03-23 Compositions pharmaceutiques liquides à forte charge pour administration par voie orale WO2016154313A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562137726P 2015-03-24 2015-03-24
US62/137,726 2015-03-24

Publications (1)

Publication Number Publication Date
WO2016154313A1 true WO2016154313A1 (fr) 2016-09-29

Family

ID=55806753

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/023783 WO2016154313A1 (fr) 2015-03-24 2016-03-23 Compositions pharmaceutiques liquides à forte charge pour administration par voie orale

Country Status (1)

Country Link
WO (1) WO2016154313A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112773779A (zh) * 2021-02-04 2021-05-11 上海交通大学医学院附属新华医院 氨溴索、千金藤和汉防已在治疗酸性鞘磷脂酶缺乏症中的应用
US11103596B2 (en) 2015-05-11 2021-08-31 Ucl Business Plc Fabry disease gene therapy
CN114129514A (zh) * 2021-11-15 2022-03-04 华萃国际生物科技(广东)有限公司 一种混悬滴剂及其制备方法和应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2318511A (en) * 1996-10-23 1998-04-29 Eurand Int Process for the preparation of a pharmaceutical composition for rapid suspension in water
WO1999059544A2 (fr) * 1998-05-18 1999-11-25 Takeda Chemical Industries, Ltd. Comprimes se desintegrant dans la bouche
WO2001072284A1 (fr) * 2000-03-28 2001-10-04 Biochemie Gesellschaft M.B.H. Particules granulees a masquage de gout
CN1546008A (zh) 2003-12-02 2004-11-17 沈阳药科大学 盐酸氨溴索液体缓释制剂及其制备方法
WO2014181390A1 (fr) * 2013-05-08 2014-11-13 全星薬品工業株式会社 Particule revêtue d'un film polymère fonctionnel ayant une grande teneur en médicament, comprimé la contenant, et procédés de production associés

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2318511A (en) * 1996-10-23 1998-04-29 Eurand Int Process for the preparation of a pharmaceutical composition for rapid suspension in water
WO1999059544A2 (fr) * 1998-05-18 1999-11-25 Takeda Chemical Industries, Ltd. Comprimes se desintegrant dans la bouche
WO2001072284A1 (fr) * 2000-03-28 2001-10-04 Biochemie Gesellschaft M.B.H. Particules granulees a masquage de gout
CN1546008A (zh) 2003-12-02 2004-11-17 沈阳药科大学 盐酸氨溴索液体缓释制剂及其制备方法
WO2014181390A1 (fr) * 2013-05-08 2014-11-13 全星薬品工業株式会社 Particule revêtue d'un film polymère fonctionnel ayant une grande teneur en médicament, comprimé la contenant, et procédés de production associés

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KASIM ET AL., MOL. PHARMACEUTICS, vol. 1, no. 1, 2004, pages 85 - 96
LINDENBERGER ET AL., EUR. J. PHARM. BIOPHARM., vol. 58, no. 2, 2004, pages 265 - 78

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11103596B2 (en) 2015-05-11 2021-08-31 Ucl Business Plc Fabry disease gene therapy
CN112773779A (zh) * 2021-02-04 2021-05-11 上海交通大学医学院附属新华医院 氨溴索、千金藤和汉防已在治疗酸性鞘磷脂酶缺乏症中的应用
CN112773779B (zh) * 2021-02-04 2022-08-16 上海交通大学医学院附属新华医院 氨溴索、千金藤和汉防已在治疗酸性鞘磷脂酶缺乏症中的应用
CN114129514A (zh) * 2021-11-15 2022-03-04 华萃国际生物科技(广东)有限公司 一种混悬滴剂及其制备方法和应用

Similar Documents

Publication Publication Date Title
EP1940361B1 (fr) Formes de dosage pharmaceutique possedant des proprietes de liberation controlee et/ou immediate
US6576260B2 (en) Sustained-release form of administration containing tramadol saccharinate
ES2150889T3 (es) Combinacion de glibenclamida-metformina para el tratamiento de la diabetes mellitus tipo ii.
US8663694B2 (en) Taste masked dosage form containing roflumilast
DK1919458T5 (en) Enteric-coated cysteamine, cystamine and derivatives thereof
ES2649063T3 (es) Formulaciones farmacéuticas que contienen rifaximina, procedimientos para su obtención y método de tratamiento de la enfermedad intestinal
US20130273157A1 (en) Orally disintegrating tablet
US20040219212A1 (en) Single-daily dose antidiabetic oral pharmaceutical form comprising a biguanide and at least another active principle
US20110268808A1 (en) Dual-release pharmaceutical suspension
WO2010127345A2 (fr) Compositions de comprimé à désintégration orale comportant les combinaisons de médicaments à dose élevée et faible
JP2000344660A (ja) 速崩壊性固形製剤
US11433041B2 (en) Palatable compositions including sodium phenylbutyrate and uses thereof
BRPI0621633A2 (pt) composição farmacêutica, método para tratar distúrbio de déficit de atenção por hiperatividade (adhd) e composição farmacêutica de liberação sustentada
ES2703874T3 (es) Psicoestimulante que contiene una composición farmacéutica
WO2016154313A1 (fr) Compositions pharmaceutiques liquides à forte charge pour administration par voie orale
US20070281019A1 (en) Phenylephrine pulsed release formulations and pharmaceutical compositions
EP0393747A2 (fr) Forme de dosage de mebeverine
US20210290557A1 (en) Multi-particulate pharmaceutical composition, immediate release pellets, sustained release pellets, enteric release pellets and use thereof
US20120064155A1 (en) Oral pharmaceutical composition for use in respiratory diseases
JP2003512311A (ja) Ｃｎｓ介在性障害を治療するための持続放出製剤
AU2006236052B2 (en) Oral pulsed dose drug delivery system

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: 16718048

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16718048

Country of ref document: EP

Kind code of ref document: A1