WO2001049292A1 - Formes posologiques d'apomorphine administree oralement par voie muqueuse - Google Patents

Formes posologiques d'apomorphine administree oralement par voie muqueuse Download PDF

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Publication number
WO2001049292A1
WO2001049292A1 PCT/US2000/034548 US0034548W WO0149292A1 WO 2001049292 A1 WO2001049292 A1 WO 2001049292A1 US 0034548 W US0034548 W US 0034548W WO 0149292 A1 WO0149292 A1 WO 0149292A1
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WO
WIPO (PCT)
Prior art keywords
weight
dextran
apomorphine
percent
tablet
Prior art date
Application number
PCT/US2000/034548
Other languages
English (en)
Inventor
Paul E. Stach
Craig W. Davis
Raymundo A. Sison
Robert K. Mansfield
John D. Bollinger
Pramod K. Gupta
Original Assignee
Tap Holdings, 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
Priority to EP00988174A priority Critical patent/EP1242088A1/fr
Priority to MXPA02006034A priority patent/MXPA02006034A/es
Priority to CA002394297A priority patent/CA2394297A1/fr
Priority to IL15003400A priority patent/IL150034A0/xx
Priority to JP2001549660A priority patent/JP2004501065A/ja
Priority to HU0400495A priority patent/HUP0400495A3/hu
Application filed by Tap Holdings, Inc. filed Critical Tap Holdings, Inc.
Priority to PL00366204A priority patent/PL366204A1/xx
Priority to AU24409/01A priority patent/AU2440901A/en
Priority to BR0012822-8A priority patent/BR0012822A/pt
Publication of WO2001049292A1 publication Critical patent/WO2001049292A1/fr
Priority to NO20023190A priority patent/NO20023190L/no
Priority to HK03101912.0A priority patent/HK1051315A1/zh

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to pharmaceutical formulations suitable for the administration of a therapeutic agent via oral mucosal tissue. More particularly, the present invention concerns tablet dosage forms containing dextran which are particularly suited for prolonged release delivery of apomorphine through oral mucosal tissue.
  • the compound has the structure:
  • Apomorphine has a high affinity for D 2 , D 3 , and D receptors, and is unique in its affinity for Di receptors. It elicits effects similar to those of levodopa and, as such, has been widely used as a treatment for Parkinson's disease. Apomorphine, in higher doses, is a strong emetic, and has been used for a number of years as an agent to induce emesis.
  • United States Patents 5,624,677 and 5,888,534 describe a controlled- release tablet formulation for the sublingual or buccal administration of apomorphine (cf. Prior Art Example below) .
  • the formulation comprises a mixture of a water-insoluble carrier forming a porous structure which is filled, coated, or covered by the active ingredient, an osmotic agent, and a water dispersible polymer, with the mixture being compressed into tablets.
  • biological fluids such as saliva
  • the release of apomorphine is controlled by the competing actions of the water-insoluble carrier and the water-dispersible polymer. Both components undergo changes, with swelling of the water-insoluble carrier providing additional surface area with attendant channeling and fluid penetration.
  • swellable hydrophilic carriers As suitable swellable hydrophilic carriers, the patents teach the use of ethyl cellulose, fumed silica, cross-linked poly(vinylpyrrolidone), microcrystalline cellulose, silica, dicalcium phosphate, and calcium carbonate.
  • Suitable osmotic agents taught by the patents are mannitol, sorbitol, lactose, glucose, fructose, sucrose, mono- and disaccharides, glycerin, polyelectrolytes, urea, sodium chloride, potassium chloride, and other inorganic and organic salts.
  • Suitable polymers include hydroxypropyl cellulose, hydroxymethyl cellulose, gelatin, carboxymethyl cellulose, gum tragacanth, gum acacia, agar gum, sodium alginate, poly(methacrylic acid) poly(acrylic acid), salts of poly(silicic acid), polydactic acid), water soluble starch, carbomers, polycarbophils, poly(vinyl alcohol), poly(ethylene glycol), alkoxy block copolymers, methyl cellulose, polysorbates, and poly(maleic acid).
  • United States Patent 5,770,606 describes compressed tablets for sublingual administration of apomorphine which comprise apomorphine hydrochloride, mannitol, ascorbic acid, citric acid, microcrystalline cellulose(Avicel® PH 1 02), hydroxypropyl methyl cellulose (Methocel® E4M), aspartame, and magnesium stearate.
  • Alternative formulations which are taught replace the microcrystalline cellulose and hydroxypropyl methyl cellulose with ⁇ -cyclodextrin or hydroxypropyl- ⁇ -cyclodextrin.
  • the present invention provides a pharmaceutical formulation for the prolonged-release oral mucosal administration of apomorphine which comprises a therapeuticaUy effective amount of apomorphine or a pharmaceutically acceptable salt or pro-drug thereof in combination with a carrier comprising from about 1 0 percent by weight to about 95 percent by weight dextran, based upon the total weight of the formulation.
  • dextran having a molecular weight in the range between about 5000 Daltons and 1 00,000 Daltons is the sole component of the formulation for prolonging the release of the active drug component.
  • a mixture of microcrystalline cellulose and dextran act as the components to prolong the release of apomorphine.
  • Figure 1 is a graph showing the dissolution profiles for direct compression tablets of the prior art and three examples of the present invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield apomorphine, as for example, by hydrolysis in blood.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Prodrugs as Novel Delivery Systems," Vol. 1 4 of the A.C.S. Symposium Series, American Chemical Society (1 975).
  • esters useful as prodrugs for compounds containing carboxyl groups may be found on pages 14-21 of Bioreversible Carriers in Drug Design: Theory and Application, edited by E.B. Roche, Pergamon Press ( 1 987).
  • prodrug ester group refers to any of several ester-forming groups that are hydrolyzed under physiological conditions. Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art. As used herein, the tern “pharmaceutically acceptable ester” refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters includes formates, acetates, propionates, butryates, acrylates and ethylsuccinates.
  • pharmaceutically acceptable salt refers to those salts which are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are ommensurate with a reasonable benefit/risk ratio.
  • salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1 -1 9 ( 1 977), incorporated herein by reference.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene- sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the preferred salt of apomorphine for use in the formulations of the present invention is the hydrochloride.
  • oral mucosal administration of a pharmaceutical formulation of the present invention is meant the delivery of the drug contained in the formulation through the mucosal tissue located in the oral cavity of a mammal including the tongue, roof of the mouth, inner cheeks (buccal) and under the tongue (sub-lingual).
  • prolonged-release formulation means a formulation which achieves the slow release of the active drug component in the formulation over an extended period of time.
  • “Dextrans” are highly branched glucosans (glucose polymers) produced by the fermentation of sucrose solutions by certain bacteria including
  • Dextrans have been given by infusion as a pre-, per- and postoperative plasma and blood replacement, in the prophylaxis of venous thrombosis and pulmonary embolism, and in the improvement of microcirculation.
  • Dextrans of a number of different molecular weight ranges are commercially available.
  • Dextrans suitable for use in the pharmaceutical formulations of the present invention have average molecular weights ranging from about 5000 Daltons to about 1 00,000 Daltons, with preferred dextrans having average molecular weights in the range of between about 9000 Daltons to about 70,000 Daltons.
  • Particularly preferred dextrans for use in the formulations of this invention are those having average molecular weights (determined by gel filtration) of about 9500 Daltons, 37,500 Daltons, and 69,000 Daltons, respectively, available from Pharmacia Biotech, 800 Centennial Ave. 1 327 Piscataway, NJ 08855-1 327 designated as grades PM 1 0, PM 40 and PM70, respectively.
  • the pharmaceutical formulations of the present invention contain, in addition to the active drug component, one or more grades (i.e. average molecular weights) of dextran as the sole polymeric component for controlling the prolonged release of the drug.
  • the amount of dextran in the formulation ranges from about 80 percent by weight to about 95 percent by weight dextran, based upon the total weight of the formulation.
  • the component for controlling the prolonged release of the active drug may be a mixture of microcrystalline cellulose and dextran.
  • the microcrystalline cellulose comprises up to about 25 weight percent, preferably up to about 20 weight percent of the formulation.
  • the dextran comprises from about 5 weight percent to about 1 5 weight percent of the total weight of the formulation, preferably about 1 0 weight percent.
  • a filler makes up for the decreased amount of dextran in the dextran/microcrystalline cellulose formulations, and may comprise from about 1 0 to about 60 weight percent of the total formulation weight, of the composition.
  • Suitable diluents when needed in the formulations of the present invention include dicalcium phosphate, calcium sulfate, lactose, mannitol, cellulose, kaolin, sodium chloride, dry starch, and powdered sugar.
  • the preferred diluent in the formulations of this invention is mannitol.
  • the formulations may also contain typical binders, lubricants, disintegrants, and coloring, sweetening, and flavoring agents well known to practitioners of the pharmaceutical formulation arts.
  • Suitable sweetening agents include sugars, as well as sugar substitutes including aspartame, acesulfame potassium salt, and saccharin.
  • the sugar substitutes are preferred since they impart adequate sweetness to the formulation without taking up much bulk in the formulation, as would be the case with natural sugars.
  • one or more sugar substitutes is present as a sweetener in amounts ranging between about 1 percent to about 5 percent, preferably about 2 percent, based upon the total weight of the formulation.
  • 5% by weight of the total formulation include sodium benzoate, mixtures of sodium benzoate and sodium acetate, sodium chloride, leucine, Carbowax 4000, magnesium stearate, mixtures of magnesium stearate and sodium lauryl sulfate, and magnesium lauryl sulfate.
  • a preferred lubricant in formulations of the present invention is magnesium stearate.
  • a preferred dosage form of the present invention is a direct compression tablet containing from about 2 to about 10 weight percent apomorphine or a pharmaceutically acceptable salt or pro-drug thereof per tablet, together with a carrier comprising dextran.
  • a particularly preferred unit dosage form of the present invention is a 100 mg tablet containing between about 2 to 1 0 mg of apomorphine hydrochloride. Direct compression tablets are prepared as detailed in the examples given below.
  • apomorphine Slow release of apomorphine to the subject is achieved by oral mucosal administration of the tablet. That is, the tablet is held in the mouth, either on or below the tongue, or against the inner cheek until the tablet has dissolved and the drug is absorbed through the mucosal tissue into the blood stream.
  • the oral mucosal administration of apomorphine permits direct delivery to the blood stream and obviates the elimination of the drug by first pass hepatic metabolism which would otherwise result from ingestion of the tablet.
  • the prolonged release of apomorphine brought about by the presence of dextran prevents the initial rapid rise of apomorphine serum concentration with its attendant undesirable nausea side effects, and ensures effective serum levels over a longer period.
  • the formulations of the present invention contain significantly reduced amounts of microcrystalline cellulose or, in one embodiment of the invention, no microcrystalline cellulose. Thus, the unwanted "gritty" feeling left by this tablet component after dissolution in the mouth is greatly reduced or eliminated.
  • Examples 1 -3 illustrate tablet formulations of apomorphine in which reduced amounts of microcrystalline cellulose are combined with dextrans of varying molecular weights.
  • Examples 4 and 5 illustrate formulations in which dextrans of different molecular weights are employed as the sole polymeric component for prolonging the release of the active drug component.
  • prior art and control formulations are also presente
  • microcrystalline cellulose comprises at least 37.4% of the total weight of each tablet. Since microcrystalline cellulose typically contains about 20% by weight of particles having an average particle size greater than 1 00 ⁇ M, this means that each tablet contains appreciable amounts of this larger particle size water insoluble material which imparts a gritty sensation upon dissolution of the tablet in the mouth.
  • Hydroxypropyl methylcellulose 1 0.00 1 0.00
  • Examples 4 and 5 were; prepared by dry mixing the first portion of dextran, the apomorphine hydrochloride, the flavoring agent (entrapped cool mint orange), and the sweetener (Acesulfame K) . This mixture was then passed through a 20 mesh sieve (0.033 inch, 0.84 mm nominal opening) . The second portion of dextran was then passed through a 20 mesh sieve and added to the mixture of active ingredient, flavoring agent, sweetener, and first portion of dextran. The third portion of dextran was similarly sized through a 20 mesh sieve, added to the previous mixture of ingredients, and dry mixed for twenty minutes. The resulting powdered mixture was compressed into 1 00 mg tablets using a standard one-quarter inch (0.64 cm) concave tableting die. The Control Example and Examples 1 -3 were similarly prepared, with additional mixing steps to accommodate the additional ingredients.
  • Table 1 presents the physical and dissolution properties for tablets prepared in accordance with the various examples. Hardness was measured by the conventional method using the Schleuniger hardness tester (cf.
  • Control Example B illustrates a formulation which was devoid of any polymer ingredient which would function to prolong the release of apomorphine. As a consequence, the drug was essentially completely released within the first ten minutes. In the case of apomorphine such a formulation would administer a "bolus" dose of the drug causing, in some patients, serum levels of the dug to rise above the threshold required to induce nausea. This is, of course, undesirable and a slower release is needed. Such prolonged release formulations are presented in Examples 1 -5. The data for Examples 1 -3 show, for example, complete or almost complete release of apomorphine over a period of 45 minutes.
  • Figure 1 shows release profiles for Examples 1 -3 in comparison with a prior art matrix tablet formulation lacking dextran, but containing a mixture of microcrystalline cellulose and hydroxypropyl methylcellulose as the drug- release controlling ingredients.
  • the drug release profiles for Examples 1 -3 of the present invention more closely approach linearity than does the profile for the prior art formulation.
  • the release of apomorphine from the formulations of Examples 4 and 5, containing dextran as the only polymeric component, were likewise prolonged, reaching 46.4% and 43.8%, respectively at the end of 45 minutes.
  • formulations containing only dextran or a mixture of dextran and reduced levels of microcrystalline cellulose can be "tailor-made" to achieve the desired dissolution profile.
  • the formulations of the present invention thus provide a prolonged- release means for delivering apomorphine by oral mucosal administration which provide a number of advantages.
  • the formulations achieve the desired release profile with fewer ingredients, resulting in savings; the formulations possess increased stability toward oxidative degradation without comparatively high levels of antioxidants; and the formulations are comparatively free of the gritty feeling produced in the mouth by large-particle ingredients employed in prior art matrix tablet formulations.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Epidemiology (AREA)
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  • Neurology (AREA)
  • Biomedical Technology (AREA)
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  • Nutrition Science (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

L'invention concerne une formulation pharmaceutique destinée à l'administration orale par voie muqueuse à libération prolongée d'apomorphine. Cette formulation contient une dose efficace d'apomorphine ou un sel ou un promédicament pharmaceutiquement acceptable dudit composé en combinaison avec un support comprenant entre environ 10 % en poids et environ 95 % en poids de dextrane, sur la base du poids total de cette formulation. Dans un mode de réalisation de l'invention, le dextrane présentant un poids moléculaire variant entre 5000 Daltons et 100 000 Daltons est le seul composant de cette formulation qui permet de prolonger la libération du composant médicamenteux actif. Dans un autre mode de réalisation, un mélange de cellulose microcristalline et de dextrane tient lieu de composant prolongeant la libération d'apomorphine.
PCT/US2000/034548 1999-12-30 2000-12-19 Formes posologiques d'apomorphine administree oralement par voie muqueuse WO2001049292A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
MXPA02006034A MXPA02006034A (es) 1999-12-30 2000-12-19 Formas de dosis mucosaloral de apomorfina.
CA002394297A CA2394297A1 (fr) 1999-12-30 2000-12-19 Formes posologiques d'apomorphine administree oralement par voie muqueuse
IL15003400A IL150034A0 (en) 1999-12-30 2000-12-19 Oral mucosal dosage forms of apomorphine
JP2001549660A JP2004501065A (ja) 1999-12-30 2000-12-19 アポモルヒネの口腔粘膜用剤形
HU0400495A HUP0400495A3 (en) 1999-12-30 2000-12-19 Oral mucosal dosage forms of apomorphine, suitable for the administration via oral mucosal tissue
EP00988174A EP1242088A1 (fr) 1999-12-30 2000-12-19 Formes posologiques d'apomorphine administree oralement par voie muqueuse
PL00366204A PL366204A1 (en) 1999-12-30 2000-12-19 Oral mucosal dosage forms of apomorphine
AU24409/01A AU2440901A (en) 1999-12-30 2000-12-19 Oral mucosal dosage forms of apomorphine
BR0012822-8A BR0012822A (pt) 1999-12-30 2000-12-19 Formulação farmacêutica, e, forma de dosagem em tablete
NO20023190A NO20023190L (no) 1999-12-30 2002-07-01 Orale mukosale doseringsformer for apomorfin
HK03101912.0A HK1051315A1 (zh) 1999-12-30 2003-03-14 阿扑嗎啡的口服黏膜劑量形式

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US47584499A 1999-12-30 1999-12-30
US09/475,844 1999-12-30

Publications (1)

Publication Number Publication Date
WO2001049292A1 true WO2001049292A1 (fr) 2001-07-12

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PCT/US2000/034548 WO2001049292A1 (fr) 1999-12-30 2000-12-19 Formes posologiques d'apomorphine administree oralement par voie muqueuse

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Country Link
EP (1) EP1242088A1 (fr)
JP (1) JP2004501065A (fr)
CN (1) CN1414853A (fr)
AU (1) AU2440901A (fr)
BR (1) BR0012822A (fr)
CA (1) CA2394297A1 (fr)
CZ (1) CZ20022245A3 (fr)
HK (1) HK1051315A1 (fr)
HU (1) HUP0400495A3 (fr)
IL (1) IL150034A0 (fr)
MX (1) MXPA02006034A (fr)
NO (1) NO20023190L (fr)
PL (1) PL366204A1 (fr)
WO (1) WO2001049292A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004012702A1 (fr) 2002-08-05 2004-02-12 Pfizer Health Ab Formulations pharmaceutiques a delai d'action rapide contenant un compose pour le dysfonctionnement sexuel contenant de la poudre de cacao et utilisation
JP2006516567A (ja) * 2003-01-24 2006-07-06 マグル ホールディング エービー 経粘膜伝達用組成物材料
US8263121B2 (en) 2004-04-14 2012-09-11 Takeda Pharmaceutical Company Limited Solid pharmaceutical preparation
US8846075B2 (en) 2003-01-24 2014-09-30 Magle Holding Ab Composition material for transmucosal delivery

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0509317D0 (en) * 2005-05-06 2005-06-15 Clarke Anthony Pharmaceutical formulation of apomorphine
US9044475B2 (en) * 2009-06-12 2015-06-02 Cynapsus Therapeutics, Inc. Sublingual apomorphine
WO2020243538A1 (fr) * 2019-05-31 2020-12-03 Primo Pharmatech Llc Forme posologique unitaire pour l'administration transmucosale de médicament d'un ingrédient pharmaceutique actif

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022445A2 (fr) * 1993-03-26 1994-10-13 Merkus Franciscus W H M Compositions pharmaceutiques pour l'administration intranasale de dihydroergotamine, d'apomorphine et de morphine
WO1997006786A1 (fr) * 1995-08-18 1997-02-27 R.P. Scherer Limited Compositions a dissolution rapide et administrees par voie orale, pour agonistes de la dopamine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022445A2 (fr) * 1993-03-26 1994-10-13 Merkus Franciscus W H M Compositions pharmaceutiques pour l'administration intranasale de dihydroergotamine, d'apomorphine et de morphine
WO1997006786A1 (fr) * 1995-08-18 1997-02-27 R.P. Scherer Limited Compositions a dissolution rapide et administrees par voie orale, pour agonistes de la dopamine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004012702A1 (fr) 2002-08-05 2004-02-12 Pfizer Health Ab Formulations pharmaceutiques a delai d'action rapide contenant un compose pour le dysfonctionnement sexuel contenant de la poudre de cacao et utilisation
JP2006516567A (ja) * 2003-01-24 2006-07-06 マグル ホールディング エービー 経粘膜伝達用組成物材料
US8846075B2 (en) 2003-01-24 2014-09-30 Magle Holding Ab Composition material for transmucosal delivery
US8263121B2 (en) 2004-04-14 2012-09-11 Takeda Pharmaceutical Company Limited Solid pharmaceutical preparation

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BR0012822A (pt) 2004-03-09
CN1414853A (zh) 2003-04-30
CZ20022245A3 (cs) 2002-10-16
AU2440901A (en) 2001-07-16
NO20023190D0 (no) 2002-07-01
JP2004501065A (ja) 2004-01-15
EP1242088A1 (fr) 2002-09-25
HK1051315A1 (zh) 2003-08-01
NO20023190L (no) 2002-08-29
CA2394297A1 (fr) 2001-07-12
IL150034A0 (en) 2002-12-01
HUP0400495A2 (hu) 2004-06-28
MXPA02006034A (es) 2004-08-23
PL366204A1 (en) 2005-01-24
HUP0400495A3 (en) 2007-05-02

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