EP0804168A1 - Composition au gout dissimule contenant un complexe medicament/polymere - Google Patents

Composition au gout dissimule contenant un complexe medicament/polymere

Info

Publication number
EP0804168A1
EP0804168A1 EP95903281A EP95903281A EP0804168A1 EP 0804168 A1 EP0804168 A1 EP 0804168A1 EP 95903281 A EP95903281 A EP 95903281A EP 95903281 A EP95903281 A EP 95903281A EP 0804168 A1 EP0804168 A1 EP 0804168A1
Authority
EP
European Patent Office
Prior art keywords
chewable
taste masked
therapeutic agent
complex
polymer
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP95903281A
Other languages
German (de)
English (en)
Inventor
F. SmithKline Beecham Farmaceutici SPA FRANCESE
M. SmithKline Beecham Farmaceutici SPA MANESCHI
D. SmithKline Beecham Farmaceutici SPA OLDANI
Tiziana Crolla
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline SpA
Original Assignee
SmithKline Beecham SpA
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 SmithKline Beecham SpA filed Critical SmithKline Beecham SpA
Publication of EP0804168A1 publication Critical patent/EP0804168A1/fr
Withdrawn legal-status Critical Current

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
    • A61K9/0012—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
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6943—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a pill, a tablet, a lozenge or a capsule

Definitions

  • the present invention relates to therapeutic agent/polymer matrix complexes which have improved taste characteristics. Many therapeutically active substances have an unpleasant taste or cause a numbing effect when administered by mouth to a patient.
  • therapeutic agent/polymer combinations are known but the therapeutic agent is coated with the polymer.
  • the problem with such products is that they are liable to be broken when orally administered by the patient, particularly when chewed, thereby allowing the therapeutic agent to be in direct contact with the mouth, thus the taste and/or numbing sensation of the therapeutic agent is no longer effectively masked.
  • a further problem with copolymers of methacrylic acid and methyl methacrylate is that when complexed with therapeutic agents the product formed tends to be a gum.
  • dimenhydrinate is useful for treating the symptoms associated with travel sickness. Dimenhydrinate has a numbing taste.
  • a preferred formulation of dimenhydrinate is in the form of a chewing gum or a chewable tablet which means that the conventional coating techniques using polymers such as anionic copolymers based on methacrylic acid and methylmethacrylate (such as Eudragit), are ineffective in masking the numbing taste because the conventional polymer coated dimenhydrinate complex is broken down when chewed by the patient.
  • polymers such as anionic copolymers based on methacrylic acid and methylmethacrylate (such as Eudragit)
  • paroxetine Another drug, paroxetine, is useful for the treatment of depression, panic disorders and obssessive compulsive disorders.
  • Paroxetine has an unpleasant bitter taste.
  • the present invention provides a therapeutic agent/polymer complex with superior taste masking qualities and can be prepared as a powder which is more easily formulated with other excipients to form conventional formulations. Accordingly, the present invention provides a chewable taste masked formulation comprising a therapeutic agent (or drug) containing at least one basic group or atom optionally in the form of a salt which is reacted with a polymer containing at least one acidic group to form a complex.
  • a preferred therapeutic agent is dimenhydrinate or paroxetine.
  • the term "basic group or atom” is understood to mean a group capable of donating electrons. Such groups include optionally substituted amino groups or optionally substituted thio groups.
  • Suitable salts of therapeutic agents include acid addition salts which are suitably pharmaceutically acceptable salts such as the hydrochloride hemi-hydrate for paroxetine.
  • the drug comprises two active components i.e. a basic one and an acidic one in the form of a salt, such as dimenhydrinate, which is the 8-chlorotheophylline salt of diphenhydramine then the term therapeutic agent in the form of a salt extends to both of these components.
  • Suitable polymers include polymethacrylates such as Eudragit L and S which are copolymers of methacrylic acid and methyl methacrylate and have a mean molecular weight of about 135,000.
  • acidic group is understood to mean a group capable of receiving electrons such as a carboxylic acid group.
  • the complexes of therapeutic agent (including salts thereof) with polymers can be in different weight ratios.
  • the complexes are preferably in a weight ratio of therapeutic agent to polymer of 1:0.8 to 1:1.5.
  • the weight ratio is 1:1.
  • the preparation of complexes of therapeutic agents (including salts thereof) with polymers may suitably be carried out by dissolving the polymer and the therapeutic agent (including salts thereof) in suitable solvents, such as iso-propanol, ethanol or diethyl ether, optionally at elevated temperatures such as 40°C, then for example adding a precipitating solvent such as n-hexane or evaporating the solvent and triturating the residue with a suitable solvent such as acetone.
  • suitable solvent such as acetone
  • such complexes may be prepared by suspending and mixing the therapeutic agent (including salts thereof) and the polymer in water at ambient or elevated temperatures such as 25 to 60°C, preferably 50°C to 60°C, for 5 to 24 hrs.
  • the resulting complex is suitably filtered and dried.
  • Complexes of therapeutic agents (including salts thereof) and polymers may be formulated into conventional chewable dosage forms such as chewable tablets, candies, chewing gums, or soft chewable gelatin capsules using techniques generally known in the art or methods described or analogious to those described in the examples.
  • dimenhydrinate/polymer complexes may be in the form of chewing gums or chewable tablets and paroxetine/ polymer complexes may be in the form of chewable tablets or chewing gums.
  • the Complex of Dimenhydrinate and Copolymer of methacrylic acid and methyl methacrylate was obtained by stepwise dissolving 10 g of Copolymer (Eudragit L) and 10 g of dimenhydrinate in 100 ml of isopropanol, which was heated to 40°C until dissolved then 200 ml of n-hexane were added to precipitate the resulting product which was then filtered and dried.
  • the Complex of Dimenhydrinate and Copolymer of methacrylic acid and methyl methacrylate was obtained by adding 1.5 kg of Dimenhydrinate and 1.5 kg of Copolymer (Eudragit L) to 22.5 litres of water, stirring at room temperature (about 20°C) for 5 hours, heating to 50°C, stirring at 50°C for 4 hours, cooling to room temperature, stirring for 2 hours at room temperature, filtering and drying.
  • Example 3 The following were granulated and admixed in a conventional manner and formed into tablets of 150 mg (Example 3), 300 mg each (Example 4) and 600 mg each (Example 5).
  • Mint flavour (g) 12 The formulation of example No. 6 was prepared by heating the sucrose and the liquid glucose dissolved in purified water, then drying the mass obtained and dispersing in the mass the CDC and the mint flavour. The final dispersion was pressed into candies of 4 g each.
  • Milled gum base is mixed with sorbitol (ca 40% of total amount), menthol (ca 90% of total amount) and aspartame (ca 25% of total amount).
  • the blend is wetted with purified water, kneeded, granulated and then dried at about 40°C.
  • the dried granules are mixed with CDC, mint oil, magnesium stearate and the remaining amounts of sorbitol, menthol and aspartame. This final mixture is pressed into chewing gums of 1230 mg each.
  • the chewing gums can be film coated by conventional film coating procedures.
  • the formulation of the Example 11 is prepared by dissolving the gelatin and glycerol in the purified water heated to 70°C and then, after cooling to 50°C, adding the saccharin sodium, the orange flavour and the CDC. The mass obtained is continually stirred, and processed with a conventional rotary-die process, to obtain soft chewable gelatin capsules of 1850 mg each.
  • the soft gelatin capsules are then dried at 20°C and 20% relative humidity for five days.
  • Example 10 The Complex of paroxetine and Copolymer of methacrylic acid and methyl metacrylate (CPC), was obtained by mixing a solution of 3g of Copolymer (Eudragit L) in 150 ml of ethanol with a solution of 3 g of paroxetine base in 100ml of diethyl ether and stirring at room temperature for 12 hours. The solvent was then evaporated under vacuum and the residue was triturated with acetone. The precipitate was collected by suction filtration, washed with acetone and dried. The 4.6 g of CPC gave the following analytical results.
  • the Complex of paroxetine and Copolymer of methacrylic acid and methyl methacrylate was obtained by adding lOg of paroxetine hydrochloride hemihydrate, lOg of Copolimer (Eudragit L) and 2.3g of sodium hydrogen carbonate to 300 ml of water. The mixture was stirred at room temperature for 12 hours, heated to 60°C and stirred at 60°C for 12 hours. After cooling to room temperature, the precipitate was collected by suction filtration, washed with water and dried.
  • CDC and pregelatinized starch are mixed, wetted with purified water, kneeded, granulated and then dried at about 40°C.
  • the dried granules are mixed with sorbitol, lactose, saccharin sodium, ammonium glycyrrhizinate, mint dried aroma and magnesium stearate, then the final mixture is pressed into tablets of 150 mg, 300 mg or 600 mg.

Landscapes

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

Abstract

Une formulation, au goût dissimulé, pouvant être mâchée, comprend un agent thérapeutique (ou médicament) contenant au moins un groupe ou atome basique se présentant éventuellement sous la forme d'un sel qui est mis en réaction avec un polymère contenant au moins un groupe acide pour former un complexe.
EP95903281A 1993-12-03 1994-11-24 Composition au gout dissimule contenant un complexe medicament/polymere Withdrawn EP0804168A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITMI932540 1993-12-03
ITMI932540A IT1274241B (it) 1993-12-03 1993-12-03 Complessi agente terapeutico/matrice polimerica dotati di migliorate caratteristiche di sapore e composizioni farmaceutiche che li contengono
PCT/EP1994/003903 WO1995015155A1 (fr) 1993-12-03 1994-11-24 Composition au gout dissimule contenant un complexe medicament/polymere

Publications (1)

Publication Number Publication Date
EP0804168A1 true EP0804168A1 (fr) 1997-11-05

Family

ID=11367288

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95903281A Withdrawn EP0804168A1 (fr) 1993-12-03 1994-11-24 Composition au gout dissimule contenant un complexe medicament/polymere

Country Status (9)

Country Link
EP (1) EP0804168A1 (fr)
JP (1) JPH09505818A (fr)
CN (1) CN1145586A (fr)
AU (1) AU693144B2 (fr)
CA (1) CA2177721A1 (fr)
IT (1) IT1274241B (fr)
NZ (1) NZ277238A (fr)
WO (1) WO1995015155A1 (fr)
ZA (1) ZA949567B (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU748804B2 (en) * 1995-07-20 2002-06-13 Smithkline Beecham Plc Paroxetine controlled release compositions
GB9514842D0 (en) * 1995-07-20 1995-09-20 Smithkline Beecham Plc Novel formulation
US6548084B2 (en) * 1995-07-20 2003-04-15 Smithkline Beecham Plc Controlled release compositions
CA2206592A1 (fr) * 1996-05-30 1997-11-30 Shu-Zhong Wang Methode de preparation de chlorhydrate de paroxetine amorphe
US5965555A (en) * 1996-06-07 1999-10-12 Hoechst Aktiengesellschaft Xanthine compounds having terminally animated alkynol side chains
DE19631084A1 (de) * 1996-08-01 1998-02-05 Basf Ag Verwendung von (Meth)acrylsäure-Copolymeren zur Erhöhung der Permeabilität der Schleimhaut
US6638948B1 (en) 1996-09-09 2003-10-28 Pentech Pharmaceuticals, Inc. Amorphous paroxetine composition
EP1078925A1 (fr) 1997-06-10 2001-02-28 Synthon B.V. Composés 4-phenylpiperidine
US5955475A (en) * 1997-06-30 1999-09-21 Endo Pharmaceuticals Inc. Process for manufacturing paroxetine solid dispersions
PL197989B1 (pl) * 1997-12-19 2008-05-30 Smithkline Beecham Corp Sposób wytwarzania szybko rozpraszających się tabletek do podawania doustnego, szybko rozpraszający się preparat farmaceutyczny w postaci tabletek i szybko rozpraszająca się, farmaceutycznie dopuszczalna, tabletka do podawania doustnego
IT1298732B1 (it) * 1998-03-13 2000-02-02 Recordati Chem Pharm Composizioni farmaceutiche orali assumibili senza liquidi,contenenti complessi di inclusione
CH689805A8 (fr) * 1998-07-02 2000-02-29 Smithkline Beecham Plc Méthanesulfonate de paroxétine, procédé pour sa préparation et compositions pharmaceutiques le contenant.
EP1161241B1 (fr) 1999-03-12 2005-12-07 Aesica Pharmaceuticals Ltd. Forme galenique pharmaceutique stable pour anhydrate de paroxetine
JP2005501066A (ja) * 2001-08-09 2005-01-13 スミスクライン　ビーチャム　パブリック　リミテッド　カンパニー パロキセチンおよび医薬上許容されるグリチルリチン酸塩を含む組成物
GB0119467D0 (en) * 2001-08-09 2001-10-03 Smithkline Beecham Plc Novel compound
EP2802311B1 (fr) * 2011-10-25 2018-12-12 Expermed S.A. Composition pharmaceutique sublinguale contenant un antihistaminique et procédé de préparation associé

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU589991B2 (en) * 1985-08-26 1989-10-26 G.D. Searle & Co. Taste masking compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9515155A1 *

Also Published As

Publication number Publication date
ZA949567B (en) 1995-10-10
ITMI932540A1 (it) 1995-06-03
JPH09505818A (ja) 1997-06-10
CN1145586A (zh) 1997-03-19
AU693144B2 (en) 1998-06-25
NZ277238A (en) 1998-04-27
AU1219895A (en) 1995-06-19
ITMI932540A0 (it) 1993-12-03
WO1995015155A1 (fr) 1995-06-08
IT1274241B (it) 1997-07-15
CA2177721A1 (fr) 1995-06-08

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