WO1994009762A1 - Dispositif d'administration de medicaments - Google Patents

Dispositif d'administration de medicaments Download PDF

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Publication number
WO1994009762A1
WO1994009762A1 PCT/US1993/010640 US9310640W WO9409762A1 WO 1994009762 A1 WO1994009762 A1 WO 1994009762A1 US 9310640 W US9310640 W US 9310640W WO 9409762 A1 WO9409762 A1 WO 9409762A1
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
medicament
coated
carrier core
methanesulfonamide
Prior art date
Application number
PCT/US1993/010640
Other languages
English (en)
Inventor
Robert E. Dempski
Robert C. Olivero
Edward C. Schotz
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP94901276A priority Critical patent/EP0668758A1/fr
Priority to JP6511433A priority patent/JPH08502980A/ja
Priority to AU55926/94A priority patent/AU5592694A/en
Publication of WO1994009762A1 publication Critical patent/WO1994009762A1/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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • Oral dosage forms such as tablets and capsules are convenient for the patient to transport and offer the best chance for patient compliance with the prescribed medication regiment.
  • traditional solid dosage forms utilize powder mixing or dry granulation compressing, these forms represent one of the most difficult and potentially dangerous medicaments to produce.
  • inhalation is considered the primary route of exposure.
  • ingestion by swallowing large inhaled particles which impact on the mucociliary system of the respiratory tract is likely.
  • Ingestion by contamination of hands, dermal contact and transdermal absorption are also possible routes for unintentional receipt of some medicaments.
  • liquid preparations which contain these highly potent compounds are considerably easier to control. Once the active ingredient is dissolved in an appropriate solvent, the chance for accidental contamination, at a level which would cause harm, is dramatically reduced. However, liquid preparations are not as convenient to use, may taste harsh and may result in poor patient compliance.
  • Applicants have created a novel coated dosage form, wherein the active ingredient is contained within a coating, which is applied to a core, in a quantitative and reproducible process.
  • the medicament is contained within a liquid until it has been applied to the carrier core as a film coating.
  • the film coating mixture both fixes the medicament on the surface of the core and seals the surface so that the chance of active ingredient flaking off the dosage form is greatly reduced.
  • the film coated core may be further sealed with an overcoat. This additional coating provides an extra level of protection for those who subsequently handle the dosage form.
  • This invention concerns a dosage form and a method of making the dosage form, for the delivery of highly potent medicaments to humans or other animals comprising:
  • a coating which comprises a highly potent medicament adheres to the surface of the carrier core fixing the medicament to the surface of the core and entraining the medicament.
  • a protective overcoating may be added to the dosage form to provide further protection.
  • the Class III antiarrhythmic drugs metnanesulfonamide, N-[ 1 '-(6-cyano-l ,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro- 4(R)-hydroxyspiro[2H-l-benzopyran-2,4'-pipe ⁇ din]-6-yl]-, (+)-, monohydrochloride, (structure I); methanesulfonamide, N-[l'-(6-cyano-l ,2,3,4-tetrahydronaphth-2-yl)- 3,4-dihydro-4-oxo-spiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-, (+)-, monohydrochloride, (structure II); and methanesulfonamide, N-[ 1 '-[2-(5-
  • Figure 1 shows a block diagram of the process steps utilized in the production of the novel dosage form designed to deliver highly potent drugs.
  • This invention discloses a dosage form and a method of making the dosage form, for the delivery of highly potent drugs to humans or other animals comprising:
  • a coating which comprises a highly potent medicament adheres to the surface of the carrier core fixing the medicament to the surface of the core and entraining the medicament.
  • This invention concerns a method for the safe manufacture and delivery to humans and other animals in need thereof, of highly potent medicaments by dispersing the medicament in a coating mixture, spraying the coating mixture on a carrier core and optionally overcoating the coated core with a protective over-coating.
  • the entire coating operation may be conducted within a closed system where the medicament may be contained.
  • dosage form includes, but is not limited to tablets, capsules, spheronized particles, coated non-pareil seeds, boluses, pills, disks, lozenges, controlled delivery devices and any other regularly shaped solid dosage form.
  • this novel dosage form provides for a particularly safe and effective means to deliver highly potent or highly toxic medicaments, defined as those medicaments which have an Exposure Control Limit of about 0.1 mg/m3 or less.
  • medicaments include inorganic and organic compounds without limitation, including medicaments that act on the peripheral nerves, ion channels, nuclear receptors, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles, blood circulatory system, synaptic sites, neuroeffector junctional sites, endocrine and hormone systems, immunological system, reproductive system, skeletal systems, autocoid systems, alimentary and excretory systems, inhibitory and histamine systems, and those materials that act on the central nervous system such as hypnotics and sedatives.
  • beneficial drugs are disclosed in Remington's Pharmaceutical Sciences. 16th Ed., 1980, published by Mack Publishing Co., Eaton, Pa.; and in The Pharmacological Basis of Therapeutics, by Goodman and Gilman, 6th Ed., 1980, published by the MacMillan Company, London; and in The Merck Index. 11th Edition, 1989, published by Merck & Co., Rahway, NJ.
  • the drug can be in various forms, such as charged molecules, charged molecular complexes, ionizable salts or neutral molecules.
  • Acceptable salts include, but are not limited to hydrochlorides, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrate, borate, acetate, maleate, malate, tromethamine, tartrate, oleate, salicylate, salts of metals, and amines or organic cations, for example quaternary ammonium.
  • medicaments such as esters, ethers and amides without regard to their ionization and solubility characteristics can be used alone or mixed with other medicaments.
  • a medicament can be used in a form that upon release from the device, is converted by enzymes, hydrolyzed by body pH or other metabolic processes to the parent form, or to a biologically active form.
  • Exposure Control Limits are based on pharmacological considerations and defined as the time-weighted average concentration for a normal 8 hour workday and 40 hour workweek to which nearly all workers may be repeatedly exposed day after day without adverse effect. To facilitate the derivation of a numerical limit, the equation shown below has been reported. (See E.V. Sargent and G. D. Kirk, “Establishing Airborne Esposure Control Limits in the Pharmaceutical Industry", Am. Ind. Hyg. Assoc. J., 49(6): 309 - 313, 1988, which is hereby specifically incorporated by reference.)
  • ECL (mg m3) NOEL (mg kg/dav x BW (kg
  • NOEL is the no-observable-effect-level
  • BW is the average human body weight (70 kg for males; 50 kg for females);
  • V is the volume of air breathed in an 8 hour day (10 m3/day);
  • S is the time to achieve a plasma steady state;
  • SF is a safety factor; and
  • a is the percent of the compound absorbed.
  • This concept of exposure limits is based on the principle that exposure to a chemical agent may be permitted up to some tolerance limit greater than zero. This assumes a nonlinear dose- response relationship and allows for the estimation of a NOEL. Generally, the NOEL is based on either the therapeutic effect for which the drug is intended or on one or more clinically recognizable side effects which can occur at or below the therapeutic level.
  • the NOEL is determined in populations where it is associated with a certain amount of variability.
  • Individual variability in response to a drug may be due to differences in age, sex, health and nutritional status or genetic factors.
  • a safety factor usually up to 10 fold, can be used.
  • a 10 fold safety factor also can be used when the NOEL has not been identified and the lowest observable effect dose is used.
  • Larger safety factors (100 to 1000 fold) generally are reserved for risk estimated or inconclusive human data or animal data. The larger safety factors may be applied to compounds with carcinogenic or teratogenic potential.
  • the novel dosage form and process of the instant invention may be used to deliver medicament to humans or other animals.
  • animal includes mammals, humans and primates, such as domestic, household, sport or farm animals such as dogs, sheep, goats, cattle, horses and pigs, laboratory animals such as mice, rats and guinea pigs, fish, avians, reptiles and zoo animals.
  • carrier core is meant a nucleus upon which a mixture containing the medicament may be applied.
  • the carrier core may be, for example, a non-pareil seed, a compressed tablet, a triturate, a spheronized particle, an inert bead and slugged material. This list is not meant to be in any way inclusive of the carrier cores which are included within the scope of this invention.
  • the carrier cores may be sized by passing them through a screen which has a pore size at the upper diameter limit and collecting the carrier cores on a screen which has a pore size at the lower diameter limit.
  • the seeds are generally sized by collecting those seeds which pass through a #25 mest size screen and are collected on a #30 mesh size screen. This results in a more uniform particle size for the finished product.
  • the carrier core may be composed of lactose and other excipients such as magnesium stearate, microcrystalline cellulose, starch, stearic acid, calcium phosphate, glycerol monostearate, sucrose, polyvinylpyrrolidone, gelatin, methylcellulose, sodium carboxymethylcellulose, sorbitol, mannitol, polyethylene glycol and other ingredients commonly utilized as stabilizing agents or to aid in the production of tablets, spheronized particles, or other carrier core forms mentioned above.
  • lactose and other excipients such as magnesium stearate, microcrystalline cellulose, starch, stearic acid, calcium phosphate, glycerol monostearate, sucrose, polyvinylpyrrolidone, gelatin, methylcellulose, sodium carboxymethylcellulose, sorbitol, mannitol, polyethylene glycol and other ingredients commonly utilized as stabilizing agents or to aid in the production of tablets, spheronized particles, or other carrier core forms mentioned above
  • the carrier core may also contain, within the core, a second medicament.
  • cardiovascular agents such as Class I antiarrhythmic compounds, anti-anginal compounds, vasodilators, potassium supplements, ⁇ -adrenergic receptor blocking agents, sodium channel blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, A II receptor antagonists, and diuretics may be delivered in combination with the compounds of structures I, II or El, by including them within the carrier core.
  • the coating containing the highly potent medicament may also include hydroxypropylmethylyethylene glycols, sodium carboxymethyl cellulose, carboxymethyl cellulose, methacrylate hydrogels, cellulose acetate phthalate, polyvinyl alcohol, poylacrylic acid, poly N-vinyl pyrrolidone, polyacrylamide, polyethylene oxide, methyUiydroxyethyl cellulose, ethyl cellulose, povidone, shellac, gelatin, wax, acacia, methylcellulose, methacrylic acid, methacrylic acid ester copolymers, titanium dioxide, talc, colorants, plasticizers and other soluble ingredients commonly used in film coatings of pharmaceutical dosage forms.
  • the medicament coating may be prepared as a solution in water or an organic solvent.
  • the medicament coating may also be prepared as a slurry, a suspension, a dispersion and may be partially or completely solubilized prior to application.
  • the medicament may be mixed with a binder, dispersant, lubricants, emulsifier, diluent, wetting agent and colorants.
  • the overcoat may include hydroxypropylmethyl- cellulose, hydroxypropylcellulose, polyethylene glycols, sodium carboxymethyl cellulose, carboxymethyl cellulose, methacrylate hydrogels, cellulose acetate phthalate, polyvinyl alcohol, poylacrylic acid, poly N-vinyl pyrrolidone, polyacrylamide, polyethylene oxide, methyUiydroxyethyl cellulose, ethyl cellulose, povidone, shellac, gelatin, wax, acacia, methylcellulose, methacrylic acid, methacrylic acid ester copolymers, titanium dioxide, talc, colorants, plasticizers and other soluble ingredients commonly used in film coatings of pharmaceutical dosage forms.
  • the overcoat may be prepared as a solution in water, an aqueous solution or an organic solvent.
  • the overcoating may also be prepared as a slurry, suspension, dispersion and may be partially or completely solubilized prior to application.
  • the film coating mixture is prepared by mixing a solution containing from about 1 mg to about 500 mg of the highly potent compound and about 140 ml of water with about 0.6 to about 10 grams of hydroxypropylmethylcellulose in about 50 ml of water.
  • more or less concentrated solutions of the highly potent compound or the hydroxypropylmethylcellulose are within the scope of this invention.
  • the medicament coating and the overcoat may be applied to the dosage form core using any coating procedure including the use of a fluidized bed film coating device, including a roto-processor, a pan coater or a baffled pan coater or any air suspension process.
  • the film coating mixture may also be manually added to the carrier cores while they are mixed in the presence of a heated stream of air or inert gas.
  • the medicament coating and the overcoat may be applied to any thickness desired.
  • a coating thickness of from about 1 to about 1000 mm is generally applied to the surface of the dosage form core.
  • a coating thickness of from about 5 to about 100 mm is applied depending upon the concentration of medicament to be included on each carrier core.
  • the film coating thickness generally ranges from about 25 to about 500 mm, depending upon the concentration of medicament to be included on each carrier core.
  • a portion, 44 g, of the binder solution was weighed into a clean, tared 250 ml erlenmeyer flask. This solution was diluted with 110 g of purified water with mixing. The resulting diluted solution was covered and stored at room temperature until needed.
  • a quantity of non-pareil seeds were sized between #25 and #30 mesh sieves. From the sized non-pareil seeds, 452.8 g were transferred to a holding container. Magnesium stearate was bolted through a #60 screen. One gram was transferred to a suitable storage container until needed.
  • the coating column conditions were as follows: Preheat column for about 10 minutes Atomization Pressure set to about 1.1 Bar Inlet Temperature set to about 70°C Outlet Temperatue set to about 34°C Air Flow set to about 80 m3/hour Inner Partition Height set to about 0.5 inches Application Rate set to about 5.0 g/min. Next, 452.8 g of the sized non-pareil seeds were loaded into the coating column and the polymeric/drug solution was applied. The pellets were dryed for 10 minutes in the column.
  • the overcoat was applied.
  • the binder solution was sprayed onto the coated pellets using the same coating conditions used to apply the drug containing coat. Following application of the overcoat, the pellets were dried for 15 minutes in the column.
  • the dried coated non-pareils were transferred into a double plastic bag containing 1 g of the bolted magnesium stearate.
  • the bag was sealed after allowing a head space of air and then vigorously shaken to sufficiently lubricate the coated pellets.
  • the lubricated pellets were then encapsulated using a Bonapace Hand Fill Encapsulator. The weight of pellets in each capsule was based on a laboratory analysis of the pellets after coating.
  • Placebo tablet can be used as carrier cores, in place of non ⁇ pareil seeds.
  • Tablets can be prepared from dry blending a mixture of about 35% microcrystalline cellulose, about 50% lactose and about 14% pregelatinized starch. This mixture is then lubricated with magnesium stearate (about 1 % of final tablet weight) and directly compressed into the core tablet using a standard tableting machine.
  • These tablets may then be transferred to a film coating processor where the medicament coating and if desired the overcoat is added.

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

Abstract

Un procédé de traitement et d'administration à un patient de médicaments dont les limites d'exposition sont égales ou inférieures à 0,1 mg/m3 assure la protection de ceux qui préparent la forme de dosage, du patient et du personnel médical qui entre en contact avec le produit.
PCT/US1993/010640 1992-11-05 1993-11-04 Dispositif d'administration de medicaments WO1994009762A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP94901276A EP0668758A1 (fr) 1992-11-05 1993-11-04 Dispositif d'administration de medicaments
JP6511433A JPH08502980A (ja) 1992-11-05 1993-11-04 薬剤配送装置
AU55926/94A AU5592694A (en) 1992-11-05 1993-11-04 Drug delivery device

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US97188292A 1992-11-05 1992-11-05
US971,882 1992-11-05

Publications (1)

Publication Number Publication Date
WO1994009762A1 true WO1994009762A1 (fr) 1994-05-11

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/010640 WO1994009762A1 (fr) 1992-11-05 1993-11-04 Dispositif d'administration de medicaments

Country Status (5)

Country Link
EP (1) EP0668758A1 (fr)
JP (1) JPH08502980A (fr)
AU (1) AU5592694A (fr)
CA (1) CA2147862A1 (fr)
WO (1) WO1994009762A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0803250A1 (fr) * 1996-04-24 1997-10-29 American Home Food Products, Inc. Libération programmée de stéroides à partir d'enrobages de sucre
US5997905A (en) * 1998-09-04 1999-12-07 Mcneil-Ppc Preparation of pharmaceutically active particles
WO2001087272A2 (fr) * 2000-05-18 2001-11-22 Therics, Inc. Procede et forme d'un dispositif d'administration de medicament, par exemple enrober un noyau toxique a l'interieur d'une zone non toxique en forme posologique orale
FR2837100A1 (fr) * 2002-03-18 2003-09-19 Flamel Tech Sa Comprimes a bases de microcapsules a liberation modifiee
WO2006097361A1 (fr) * 2005-03-18 2006-09-21 Ethypharm Comprime sublingual enrobe
FR2920308A1 (fr) * 2007-09-05 2009-03-06 Unither Dev Soc Par Actions Si Forme pharmaceutique pour l'administration par voie orale de principes actifs.
CN103006604A (zh) * 2013-01-16 2013-04-03 南京正宽医药科技有限公司 一种头孢呋辛酯片及其制备方法
CN103110603A (zh) * 2013-01-31 2013-05-22 浙江华立南湖制药有限公司 一种头孢克洛分散片及其制备方法
US9814684B2 (en) 2002-04-09 2017-11-14 Flamel Ireland Limited Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US9877921B2 (en) 2005-09-09 2018-01-30 Nova Southeastern University Epinephrine nanoparticles, methods of fabrication thereof, and methods for use thereof for treatment of conditions responsive to epinephrine
US10159656B2 (en) 2005-09-09 2018-12-25 Nova Southeastern University Methods for use of epinephrine fine particles for treatment of conditions responsive to epinephrine
US10251849B2 (en) 2012-06-15 2019-04-09 Nova Southeastern University Sublingual compositions including epinephrine nanoparticles
US10568836B2 (en) 2011-10-21 2020-02-25 Nova Southeastern University Epinephrine nanoparticles encapsulated with chitosan and tripolyphosphate, methods of fabrication thereof, and methods for use thereof for treatment of conditions responsive to epinephrine
US10682316B2 (en) 2005-09-09 2020-06-16 Nova Southeastern University Methods for fabrication of epinephrine bitartrate nanoparticles and epinephrine bitartrate nanoparticles fabricated thereby
US11229613B2 (en) 2013-03-22 2022-01-25 Nova Southeastern University Compositions including epinephrine microcrystals

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5082669A (en) * 1989-07-20 1992-01-21 Dainippon Pharmaceutical Co., Ltd. Rapid-releasing oral particle pharmaceutical preparation with unpleasant taste masked
US5215989A (en) * 1989-12-08 1993-06-01 Merck & Co., Inc. Nitrogen-containing heterocyclic compounds as class III antiarrhythmic agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5082669A (en) * 1989-07-20 1992-01-21 Dainippon Pharmaceutical Co., Ltd. Rapid-releasing oral particle pharmaceutical preparation with unpleasant taste masked
US5215989A (en) * 1989-12-08 1993-06-01 Merck & Co., Inc. Nitrogen-containing heterocyclic compounds as class III antiarrhythmic agents

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0803250A1 (fr) * 1996-04-24 1997-10-29 American Home Food Products, Inc. Libération programmée de stéroides à partir d'enrobages de sucre
US5997905A (en) * 1998-09-04 1999-12-07 Mcneil-Ppc Preparation of pharmaceutically active particles
US6149943A (en) * 1998-09-04 2000-11-21 Mcneil-Ppc, Inc. Microcrystalline cellulose particles having active core
US7875290B2 (en) 2000-05-18 2011-01-25 Massachusetts Institute Of Technology Method and form of a drug delivery device, such as encapsulating a toxic core within a non-toxic region in an oral dosage form
WO2001087272A2 (fr) * 2000-05-18 2001-11-22 Therics, Inc. Procede et forme d'un dispositif d'administration de medicament, par exemple enrober un noyau toxique a l'interieur d'une zone non toxique en forme posologique orale
WO2001087272A3 (fr) * 2000-05-18 2002-04-18 Therics Inc Procede et forme d'un dispositif d'administration de medicament, par exemple enrober un noyau toxique a l'interieur d'une zone non toxique en forme posologique orale
US7276252B2 (en) 2000-05-18 2007-10-02 Massachusetts Institute Of Technology Method and form of a drug delivery device, such as encapsulating a toxic core within a non-toxic region in an oral dosage form
FR2837100A1 (fr) * 2002-03-18 2003-09-19 Flamel Tech Sa Comprimes a bases de microcapsules a liberation modifiee
WO2003077888A2 (fr) * 2002-03-18 2003-09-25 Flamel Technologies Comprimes a base de microcapsules a liberation modifiee
WO2003077888A3 (fr) * 2002-03-18 2004-04-15 Flamel Tech Sa Comprimes a base de microcapsules a liberation modifiee
US8507003B2 (en) 2002-03-18 2013-08-13 Flamel Technologies Compressed tablets comprising microcapsules with modified release
US9814684B2 (en) 2002-04-09 2017-11-14 Flamel Ireland Limited Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US10004693B2 (en) 2002-04-09 2018-06-26 Flamel Ireland Limited Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US8709479B2 (en) * 2005-03-18 2014-04-29 Ethypharm Sublingual coated tablet of fentanyl
KR101239926B1 (ko) * 2005-03-18 2013-03-07 에띠팜 설하용 코팅정
WO2006097361A1 (fr) * 2005-03-18 2006-09-21 Ethypharm Comprime sublingual enrobe
NO338771B1 (no) * 2005-03-18 2016-10-17 Ethypharm Sa Sublingual belagt tablett
FR2883179A1 (fr) * 2005-03-18 2006-09-22 Ethypharm Sa Comprime enrobe
US10159656B2 (en) 2005-09-09 2018-12-25 Nova Southeastern University Methods for use of epinephrine fine particles for treatment of conditions responsive to epinephrine
US9877921B2 (en) 2005-09-09 2018-01-30 Nova Southeastern University Epinephrine nanoparticles, methods of fabrication thereof, and methods for use thereof for treatment of conditions responsive to epinephrine
US10682316B2 (en) 2005-09-09 2020-06-16 Nova Southeastern University Methods for fabrication of epinephrine bitartrate nanoparticles and epinephrine bitartrate nanoparticles fabricated thereby
FR2920308A1 (fr) * 2007-09-05 2009-03-06 Unither Dev Soc Par Actions Si Forme pharmaceutique pour l'administration par voie orale de principes actifs.
WO2009044056A3 (fr) * 2007-09-05 2009-06-11 Unither Dev Dispositif pour l'administration par voie orale de principes actifs
US10568836B2 (en) 2011-10-21 2020-02-25 Nova Southeastern University Epinephrine nanoparticles encapsulated with chitosan and tripolyphosphate, methods of fabrication thereof, and methods for use thereof for treatment of conditions responsive to epinephrine
US10251849B2 (en) 2012-06-15 2019-04-09 Nova Southeastern University Sublingual compositions including epinephrine nanoparticles
US11246843B2 (en) 2012-06-15 2022-02-15 Nova Southeastern University Method for increasing plasma concentration of epinephrine in a subject having a condition responsive to epinephrine
CN103006604A (zh) * 2013-01-16 2013-04-03 南京正宽医药科技有限公司 一种头孢呋辛酯片及其制备方法
CN103110603B (zh) * 2013-01-31 2014-07-02 浙江华立南湖制药有限公司 一种头孢克洛分散片及其制备方法
CN103110603A (zh) * 2013-01-31 2013-05-22 浙江华立南湖制药有限公司 一种头孢克洛分散片及其制备方法
US11229613B2 (en) 2013-03-22 2022-01-25 Nova Southeastern University Compositions including epinephrine microcrystals

Also Published As

Publication number Publication date
JPH08502980A (ja) 1996-04-02
AU5592694A (en) 1994-05-24
CA2147862A1 (fr) 1994-05-11
EP0668758A1 (fr) 1995-08-30

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