WO2000040233A1 - Pharmaceutical composition containing metformin, acarbose or glimepiride and optionally poly-(dimethyl)-siloxane - Google Patents

Pharmaceutical composition containing metformin, acarbose or glimepiride and optionally poly-(dimethyl)-siloxane Download PDF

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Publication number
WO2000040233A1
WO2000040233A1 PCT/EP1999/010098 EP9910098W WO0040233A1 WO 2000040233 A1 WO2000040233 A1 WO 2000040233A1 EP 9910098 W EP9910098 W EP 9910098W WO 0040233 A1 WO0040233 A1 WO 0040233A1
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Prior art keywords
pharmaceutical composition
composition according
metformin
siloxane
dimethyl
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PCT/EP1999/010098
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German (de)
French (fr)
Inventor
Thomas Strüngmann
Original Assignee
Hexal Ag
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Priority to AU19824/00A priority Critical patent/AU1982400A/en
Priority to EP99963581A priority patent/EP1140057A1/en
Publication of WO2000040233A1 publication Critical patent/WO2000040233A1/en

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
    • 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
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention relates to a pharmaceutical composition with improved activity and tolerability for the treatment of type II diabetes mellitus, which contains a combination of metformin and / or its pharmaceutically acceptable salts and glimepiride and / or acarbose and optionally poly (dimethyl) siloxane as an effective component .
  • Type II diabetes mellitus non-insulin-dependent diabetes mellitus
  • ⁇ IDDM non-insulin-dependent diabetes mellitus
  • This type of diabetes mainly occurs in adulthood and is divided into type A with normal and type B with increased body weight.
  • This disease has a hereditary basis and is favored by over-caloric nutrition. Weight loss can lead to an improvement in the metabolism (type IIB).
  • the treatment has hitherto been carried out by diet and / or by taking oral antidiabetic agents, in the case of complications and secondary failure by means of the administration of insulin.
  • the object of the present invention is now to provide a pharmaceutical composition for the treatment of type II diabetes mellitus which is improved in efficacy and tolerability and which can be used successfully in the event of secondary failure, complications and unsuccessful diet treatment and improves patient compliance through a lower frequency of ingestion .
  • the combination of metformin and / or its pharmaceutically acceptable salts with glimepiride and / or acarbose and optionally poly (dimethyl) siloxane has superior therapeutic efficacy in the event of secondary failure, complications and / or unsuccessful dietary treatment.
  • the often with the monotherapy of these active ingredients and with the use of the other common antidiabetic gastrointestinal side effects and the risk of hypoglycemia and weight gain are significantly reduced or avoided by using the composition according to the invention, the antidiabetic effect being enhanced.
  • the combination according to the invention ensures simplified, more promising therapy with improved effectiveness, even for more complicated type II diabetes cases.
  • Metformin a 1J-dimethylbiguanide, is an oral anti-diabetic used to treat NIDDM. Metformin reduces the blood sugar level swiftly by inhibiting hepatic gluconeogenesis as well as by reducing glucose absorption and by reducing peripheral insulin resistance. In contrast to the sulfonylureas, which are also used very frequently, metformin does not stimulate the release of insulin from the ß cells in the pancreas, but rather improves the sensitivity of the tissue to insulin. This active ingredient also reduces serum lipid and cholesterol levels. The bioavailability is 50-60%. Gastrointestinal complaints are the usual side effects that occur more or less strongly when taking metformin.
  • Glimepiride is a sulfonylurea used to treat type II diabetes mellitus. It lowers blood sugar levels by reducing insulin release from the ß cells of the pancreas and the glucose transport and metabolism. stimulates in the muscle and fat cells outside the pancreas. Dephosphorylation and activation of the key enzyme of glucose transport and glucose metabolism, caused by the glycosylphosphatidylinositol-specific phospholipase C, is the mechanism of action of glimepiride that takes place outside the pancreas. Hypoglycaemia and weight gain, which occur relatively frequently, and gastrointestinal side effects and gastrointestinal effects.
  • Acarbose acts as an ⁇ -glycosidase inhibitor, ie acarbose delays the enzymatic breakdown of carbohydrates by means of a competitive inhibition of ⁇ -glycosidase. The absorption of glucose from the intestine is thus delayed. Abdominal pain, diarrhea and indigestion are the very common side effects.
  • Poly (mono- or dialkyl) siloxanes in particular poly (dimethyl) siloxane, also known under the name Dimeticon or Simeticon, are considered pharmaceutically acceptable silicone compounds.
  • a pharmaceutical composition for the treatment of type II diabetes mellitus which contains a combination of metformin and / or its pharmaceutically acceptable salts and glimepiride and / or acarbose and optionally poly (dimethyl) siloxane as active ingredient.
  • compositions of metformin are understood to mean acid addition salts. This is obtained by the reaction of metformin, which is in the free
  • Base form is present, with pharmaceutically acceptable acids.
  • Pharmaceutically acceptable acids are inorganic acids (e.g. hydrochloric acid, hydrobromic acid,
  • Sulfuric acid nitric acid, phosphoric acid
  • organic acids e.g. acetic, propionic,
  • solvates with metformin Acid addition salts are called solvates with metformin.
  • Such solvates are e.g.
  • Metformin hydrochloride is preferably used as the salt.
  • the amount of metformin used in the composition according to the invention is between 0.25 and 3.0 g.
  • an amount is used which corresponds to an amount of 0.25-3.0 g of metformin.
  • the amount of glimepiride used in the composition according to the invention is between 0.5 and 10 mg.
  • the amount of acarbose used in the composition according to the invention is between 20 and 400 mg.
  • the amount of poly (dimethyl) siloxane optionally used in the composition according to the invention is between 5 and 1000 mg.
  • the pharmaceutical composition according to the invention can be in the form of tablets, film-coated tablets, effervescent tablets, granules, capsules, dragees, prolonged-release tablets, prolonged-release capsules, chewable tablets, powders, juices, transdermal therapeutic systems, suppositories and solutions.
  • the composition according to the invention can consist of an initial dose and a delayed release component.
  • the initial dose preferably contains glimepiride and / or acarbose and optionally poly (dimethyl) siloxane as powder, granules and / or pellets, each in addition to optional auxiliaries.
  • the active ingredient or combination contained in the initial dose is released immediately after ingestion.
  • the therapeutically effective blood plasma level of the active substance or the active substances is reached very quickly by means of this initial dose, so that a therapeutic effect can be observed shortly after ingestion. Hyperglycaemia caused by food intake is thus counteracted.
  • the delayed-release component contains metformin and / or its pharmaceutically acceptable salts and optionally poly (dimethyl) siloxane as granules and / or pellets, in each case in addition to optional auxiliaries.
  • the granules or the pellets can either contain retarding auxiliaries, which form a controlled release matrix, or can be provided with a controlled release coating.
  • Suitable retarding matrix formers can be hydrophilic or hydrophobic polymers, e.g. Gums, cellulose ethers, cellulose esters, acrylic resins, materials based on proteins, nylon, polyvinyl chloride, starch and polyvinyl pyrrolidone.
  • the water-soluble polymers used include Polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose,
  • Hydroxyalkyl cellulose and / or hydroxypropyl methyl cellulose ether used.
  • Aminoalkyl methacrylate copolymers poly (acrylic acid), poly (methacrylic acid),
  • Methacrylic acid alkylamide copolymers poly (methyl methacrylate),
  • Poly (methyl methacrylate) copolymer, polyacrylamides, aminoalkyl methacrylate copolymers and / or glycidyl methacrylate copolymers are used.
  • digestible, long-chain (C 8 -C 50 , especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols (lauryl, myrestyl, stearyl, cetostearyl, ceryl or cetyl alcohol) can be used as matrix formers.
  • Glycerol esters of fatty acids (Witepsol, glycerol monostearate), mineral and vegetable oils (hydrogenated castor oil) and / or waxes (paraffin waxes, silicone waxes, beeswaxes, castor waxes, carnauba waxes and glycine waxes) can be used.
  • hydrocarbons which have a melting point between 25 ° C and 90 ° C, are particularly suitable.
  • the preferred long-chain hydrocarbons are the fatty alcohols.
  • Other possible matrix formers can be polyalkylene glycols and any combination of the matrix-forming substances listed.
  • a suitable controlled-release matrix form can, in addition to metformin and / or its pharmaceutically acceptable salts and optionally poly (dimethyl) siloxane, known water-soluble auxiliary substances which, like the active substance or active substances, are embedded in a framework formed from water-insoluble, indigestible auxiliary substances included. By removing the soluble components, pores are formed through which the active ingredient (s) diffuse outwards.
  • Polymers such as polyvinyl chloride, polyethylene, polyamide, silicone, ethyl cellulose and / or methacrylic acrylate copolymers can be used as scaffolding substances.
  • the active ingredient / auxiliary mixture is pressed into tablets either directly or after wet granulation with organic solvents or binder solutions, or filled into capsules in pellet form.
  • Such a controlled release matrix can consist of one or more alkyl celluloses and one or more C 12 -C 36 aliphatic alcohols and optionally at least one polyalkylene glycol.
  • metformin and / or its pharmaceutically acceptable salts and optionally poly (dimethyl) siloxane can be combined with known water-soluble auxiliaries and fat-like substances.
  • Degradable mono-, di- and triglycerides glycein monostearate, glycerol monooleate, glycerol tripalmitate
  • erodable fatty alcohols lauryl, myristyl, stearyl, cetyl or ceryl alcohol
  • the active ingredient is released by diffusion and by enzymatic degradation of the lipophilic substances.
  • Embedding metformin and or its pharmaceutically acceptable salts and optionally poly (dimethyl) siloxane in the matrix is carried out by melting, sprinkling, spray drying, granulating or direct tableting.
  • Another matrix form according to the invention can metformin and / or its pharmaceutically acceptable salts and optionally poly (dimethyl) siloxane, in a gel-forming matrix of e.g. Hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, alginate and / or polyacrylic acid embedded.
  • the polymer hydrates and forms a gel-like layer, which slowly erodes and thus releases the active ingredient (s) in a controlled manner.
  • compositions which are common in the art, e.g. Diluents, lubricants, binders, granulation aids, colorants, flavors, detergents, buffers, non-stick agents and / or lubricants can also be contained in the controlled release matrix.
  • composition according to the invention embedded in a controlled-release matrix can also be film-coated with a known, pharmaceutically suitable, non-controlled-release coating agent, an aqueous film coating being preferred.
  • Suitable controlled-release coating agents are water-insoluble waxes and / or polymers (polymethacrylates) and / or water-insoluble cellulose, in particular Ethyl cellulose, optionally water-soluble polymers such as polyvinyl pyrrolidone or water-soluble cellulose such as hydroxypropyl cellulose or hydroxypropyl methyl cellulose.
  • the granules and / or the pellets provided with a delayed-release coating can be obtained in that granules and / or pellets, which were possibly produced for the initial dose, with the corresponding delayed-release ones
  • Metformin increases tissue sensitivity to insulin. Controlled release increases insulin sensitivity over a longer period of time. The frequency of ingestion can thus be significantly reduced and the risk of hyper and hypoglukemia is greatly reduced.
  • Taking this retarding form of the composition according to the invention e.g. before breakfast provides protection against hyper- and hypoglycemia throughout the day.
  • the otherwise usual three times a day intake of antidiabetic substances can be reduced to one or two times a day by means of this retarding form of the composition according to the invention.
  • the patient compliance is thus significantly improved by the composition according to the invention with a simultaneously better effect.
  • the retarding form of the composition according to the invention can be in the form of a capsule, in particular a gelatin capsule, the capsule containing the initial dose and the retarding component, as described above.
  • the initial dose can be in the form of powder, granules and / or pellets.
  • the retarding component can be present as granules and / or pellets.
  • the sustained release form of the composition according to the invention can be in the form of a two-layer tablet.
  • the first layer represents the initial dose which is pressed from the powder, granules and / or pellets described above.
  • the second layer contains the delayed-release component described above, which is pressed from the corresponding granules and / or pellets.
  • the pharmaceutical auxiliaries known according to the prior art such as tablet binders, fillers, Preservatives, tablet disintegrants, flow regulators, plasticizers,
  • wetting agents dispersants, emulsifiers, retardants and / or antioxidants, and / or other known carriers and diluents can be used.

Abstract

The invention relates to a pharmaceutical composition with improved effect and tolerability for the treatment of type II diabetes mellitus. Said composition contains a combination of metformin and/or its pharmaceutically acceptable salts and glimepiride and/or acarbose and optionally poly-(dimethyl)-siloxane as active components.

Description

PHARMAZEUTISCHE ZUSAMMENSETZUNG ENTHALTEND METFORMIN, ACARBOSE ODER GLIMEPIRID UND WAHLWEISE POLY(DIMETHYL)SILOXAN PHARMACEUTICAL COMPOSITION CONTAINING METFORMIN, ACARBOSE OR GLIMEPIRIDE AND ALSO POLY (DIMETHYL) SILOXANE
Die Erfindung betrifft eine pharmazeutische Zusammensetzung mit verbesserter Wirkung und Nerträglichkeit zur Behandlung von Typ-II-Diabetes mellitus, welche eine Kombination von Metformin und/ oder dessen pharmazeutisch unbedenklichen Salzen und Glimepirid und/ oder Acarbose und wahlweise Poly(dimethyl)siloxan als wirksame Komponente enthält.The invention relates to a pharmaceutical composition with improved activity and tolerability for the treatment of type II diabetes mellitus, which contains a combination of metformin and / or its pharmaceutically acceptable salts and glimepiride and / or acarbose and optionally poly (dimethyl) siloxane as an effective component .
Diabetes mellitus Typ II (ΝIDDM = non-insulin-dependent diabetes mellitus) zeigt sich in einer verminderten Insulinwirkung bzw. in einer Insulinunempfindlichkeit. Hauptsächlich tritt diese Diabetes-Form im Erwachsenenalter auf und wird unterschieden in Typ A mit normalem und Typ B mit erhöhtem Körpergewicht. Diese Krankheit hat eine erbliche Grundlage und wird durch überkalorische Ernährung begünstigt. Gewichtsreduktion kann zu einer Verbesserung der Stoffwechsellage führen (Typ IIB). Die Behandlung wird bisher mittels Diät und/ oder Einnahme oraler Antidiabetika, bei Komplikationen und Sekundärversagen mittels der Verabreichung von Insulin durchgeführt.Type II diabetes mellitus (ΝIDDM = non-insulin-dependent diabetes mellitus) manifests itself in a reduced insulin effect or insulin insensitivity. This type of diabetes mainly occurs in adulthood and is divided into type A with normal and type B with increased body weight. This disease has a hereditary basis and is favored by over-caloric nutrition. Weight loss can lead to an improvement in the metabolism (type IIB). The treatment has hitherto been carried out by diet and / or by taking oral antidiabetic agents, in the case of complications and secondary failure by means of the administration of insulin.
Die Aufgabe der vorliegenden Erfindung ist es nun, eine in der Wirksamkeit und Verträglichkeit verbesserte pharmazeutische Zusammensetzung zur Behandlung von Typ II Diabetes mellitus bereitzustellen, welche bei Sekundärversagen, Komplikationen und erfolgloser Diätbehandlung mit Erfolg eingesetzt werden kann und die Patienten-Compliance durch eine geringere Einnahmehäufigkeit verbessert.The object of the present invention is now to provide a pharmaceutical composition for the treatment of type II diabetes mellitus which is improved in efficacy and tolerability and which can be used successfully in the event of secondary failure, complications and unsuccessful diet treatment and improves patient compliance through a lower frequency of ingestion .
Es wurde nun überraschenderweise gefunden, daß die Kombination von Metformin und/ oder dessen pharmazeutisch unbedenklichen Salzen mit Glimepirid und/ oder Acarbose und wahlweise Poly(dimethyl)siloxan bei Sekundärversagen, Komplikationen und/ oder einer erfolglosen Diätbehandlung eine überlegene therapeutische Wirksamkeit aufweist. Die häufig bei der Monotherapie dieser Wirkstoffe und bei der Verwendung der anderen gängigen Antidiabetika auftretenden gastrointestinalen Nebenwirkungen sowie die Gefahr der Hypoglykämie und der Gewichtszunahme werden durch Verwendung der erfindungsgemäßen Zusammmensetzung wesentlich verringert bzw. vermieden, wobei die antidiabetische Wirkung verstärkt wird. Gegenüber den, gemäß dem Stand der Technik, bekannten und eingesetzten Antidiabetika wird durch die erfindungsgemäße Kombination eine vereinfachte, erfolgsversprechendere Therapie mit einer verbesserten Wirksamkeit auch für kompliziertere Diabetes-Fälle vom Typ II gewährleistet.It has now surprisingly been found that the combination of metformin and / or its pharmaceutically acceptable salts with glimepiride and / or acarbose and optionally poly (dimethyl) siloxane has superior therapeutic efficacy in the event of secondary failure, complications and / or unsuccessful dietary treatment. The often with the monotherapy of these active ingredients and with the use of the other common antidiabetic gastrointestinal side effects and the risk of hypoglycemia and weight gain are significantly reduced or avoided by using the composition according to the invention, the antidiabetic effect being enhanced. Compared to the antidiabetic agents known and used according to the prior art, the combination according to the invention ensures simplified, more promising therapy with improved effectiveness, even for more complicated type II diabetes cases.
Metformin, ein lJ-Dimethylbiguanid, ist ein orales Antidiabetikum, welches zur Behandlung von NIDDM verwendet wird. Metformin reduziert den Blutzuckerspiegel schwe unktmäßig durch Hemmung der hepatischen Gluconeogenese sowie durch Reduktion der Glucoseresorption und durch Verringerung der peripheren Insulinresistenz. Im Gegensatz zu den ebenfalls sehr häufig verwendeten Sulfonylharnstoffen stimuliert Metformin nicht die Insulinfreisetzung aus den ß-Zellen in der Bauchspeicheldrüse, sondern verbessert die Sensibilität des Gewebes für Insulin. Zusätzlich reduziert dieser Wirkstoff den Lipid- und Cholesterinspiegel im Serum. Die Bioverfügbarkeit beträgt 50-60 %. Gastrointestinale Beschwerden sind die üblichen Nebenwirkungen, die bei der Einnahme von Metformin mehr oder weniger stark auftreten.Metformin, a 1J-dimethylbiguanide, is an oral anti-diabetic used to treat NIDDM. Metformin reduces the blood sugar level swiftly by inhibiting hepatic gluconeogenesis as well as by reducing glucose absorption and by reducing peripheral insulin resistance. In contrast to the sulfonylureas, which are also used very frequently, metformin does not stimulate the release of insulin from the ß cells in the pancreas, but rather improves the sensitivity of the tissue to insulin. This active ingredient also reduces serum lipid and cholesterol levels. The bioavailability is 50-60%. Gastrointestinal complaints are the usual side effects that occur more or less strongly when taking metformin.
Glimepirid ist ein Sulfonylharnstoff, der zur Behandlung von Typ II Diabetes mellitus verwendet wird. Er senkt den Blutzuckerspiegel, indem er die Insulinfreisetzung aus den ß- Zellen der Bauchspeicheldrüse und den Glucosetransport und die Glucosemetabolisierung. in den Muskel- und Fettzellen außerhalb der Bauchspeicheldrüse anregt. Eine Dephosphorylierung und Aktivierung des Schlüsselenzyms des Glucosetransportes und der Glucosemetabolisierung, verursacht durch die Glycosylphosphatidylinositol-spezifische Phospholipase C, stellt den außerhalb der Bauchspeicheldrüse stattfindenden Wirkmechanismus von Glimepirid dar. Relativ häufig tretenden Hypoglykämie und Gewichtszunahme sowie gastrointestinale Beschwerden als Nebenwirkungen auf.Glimepiride is a sulfonylurea used to treat type II diabetes mellitus. It lowers blood sugar levels by reducing insulin release from the ß cells of the pancreas and the glucose transport and metabolism. stimulates in the muscle and fat cells outside the pancreas. Dephosphorylation and activation of the key enzyme of glucose transport and glucose metabolism, caused by the glycosylphosphatidylinositol-specific phospholipase C, is the mechanism of action of glimepiride that takes place outside the pancreas. Hypoglycaemia and weight gain, which occur relatively frequently, and gastrointestinal side effects and gastrointestinal effects.
Acarbose wirkt als α-Glykosidasehemmer, d.h. durch Acarbose wird mittels einer kompetitiven Hemmung der α-Glykosidase die enzymatische Aufspaltung von Kohlehydraten verzögert. Es wird somit die Resorption von Glucose aus dem Darm verzögert. Bauchschmerzen, Durchfälle und Verdauungsstörungen sind die sehr häufig auftretenden unerwünschten Nebenwirkungen.Acarbose acts as an α-glycosidase inhibitor, ie acarbose delays the enzymatic breakdown of carbohydrates by means of a competitive inhibition of α-glycosidase. The absorption of glucose from the intestine is thus delayed. Abdominal pain, diarrhea and indigestion are the very common side effects.
Poly(mono- oder dialkyl)siloxane, insbesondere das Poly(dimethyl)siloxan, auch bekannt unter dem Namen Dimeticon oder Simeticon gelten als pharmazeutisch unbedenkliche Silikonverbindungen.Poly (mono- or dialkyl) siloxanes, in particular poly (dimethyl) siloxane, also known under the name Dimeticon or Simeticon, are considered pharmaceutically acceptable silicone compounds.
Die der Erfindung zugrundeliegende Aufgabe wird nun durch eine pharmazeutische Zusammensetzung zur Behandlung von Typ II Diabetes mellitus gelöst, welche eine Kombination von Metformin und/ oder dessen pharmazeutisch unbedenklichen Salzen und Glimepirid und/ oder Acarbose und wahlweise Poly(dimethyl)siloxan als aktiven Bestandteil enthält.The object on which the invention is based is now achieved by a pharmaceutical composition for the treatment of type II diabetes mellitus, which contains a combination of metformin and / or its pharmaceutically acceptable salts and glimepiride and / or acarbose and optionally poly (dimethyl) siloxane as active ingredient.
Unter pharmazeutisch unbedenklichen Salzen des Metformins werden Säureadditionssalze verstanden. Diese erhält man durch die Reaktion von Metformin, welches in der freienPharmaceutically acceptable salts of metformin are understood to mean acid addition salts. This is obtained by the reaction of metformin, which is in the free
Basenform vorliegt, mit pharmazeutisch unbedenklichen Säuren. Pharmazeutisch unbedenkliche Säuren sind anorganische Säuren (z.B. Salzsäure, Bromwasserstoffsäure,Base form is present, with pharmaceutically acceptable acids. Pharmaceutically acceptable acids are inorganic acids (e.g. hydrochloric acid, hydrobromic acid,
Schwefelsäure, Salpetersäure, Phosphorsäure) oder organische Säuren (z.B. Essig-, Propion-,Sulfuric acid, nitric acid, phosphoric acid) or organic acids (e.g. acetic, propionic,
Hydroxyessig-, Milch-, Brenztrauben-, Oxal-, Malein-, Malon-, Bernstein-, Fumar-, Äpfel-, Wein-, Citronen-, Methansulfon-, Ethansulfon-, Benzolsulfon-, p-Toluolsulfon-,Hydroxyacetic, milk, pyruvate, oxal, maleic, malonic, amber, fumaric, apple, wine, lemon, methane sulfone, ethane sulfone, benzenesulfone, p-toluenesulfone,
Cyclohexansulfamin-, Salicyl-, p-Aminosalicyl- und Pamoasäure). Ebenso alsCyclohexanesulfaminic, salicylic, p-aminosalicylic and pamoic acid). As well as
Säureadditionssalze werden Solvate mit Metformin bezeichnet. Derartige Solvate sind z.B.Acid addition salts are called solvates with metformin. Such solvates are e.g.
Hydrate, Alkoholate und dergleichen. Bevorzugt wird Metformin Hydrochlorid als Salz verwendet.Hydrates, alcoholates and the like. Metformin hydrochloride is preferably used as the salt.
Die in der erfindungsgemäßen Zusammensetzung eingesetzte Menge an Metformin liegt zwischen 0,25 und 3,0 g. Bei Verwendung eines Salzes wird eine Menge eingesetzt, die einer Menge von 0,25- 3,0 g Metformin entspricht.The amount of metformin used in the composition according to the invention is between 0.25 and 3.0 g. When using a salt, an amount is used which corresponds to an amount of 0.25-3.0 g of metformin.
Die in der erfindungsgemäßen Zusammensetzung eingesetzte Menge an Glimepirid liegt zwischen 0,5 und 10 mg. Die in der erfindungsgemäßen Zusammensetzung eingesetzte Menge an Acarbose liegt zwischen 20 und 400 mg.The amount of glimepiride used in the composition according to the invention is between 0.5 and 10 mg. The amount of acarbose used in the composition according to the invention is between 20 and 400 mg.
Die in der erfindungsgemäßen Zusammensetzung wahlweise eingesetzte Menge an Poly(dimethyl)siloxan liegt zwischen 5 und 1000 mg.The amount of poly (dimethyl) siloxane optionally used in the composition according to the invention is between 5 and 1000 mg.
Die erfindungsgemäße pharmazeutische Zusammensetzung kann in Form von Tabletten, Filmtabletten, Brausetabletten, Granulaten, Kapseln, Dragees, Retardtabletten, Retardkapseln, Kautabletten, Pulvern, Säften, transdermalen therapeutischen Systemen, Suppositorien und Lösungen vorliegen.The pharmaceutical composition according to the invention can be in the form of tablets, film-coated tablets, effervescent tablets, granules, capsules, dragees, prolonged-release tablets, prolonged-release capsules, chewable tablets, powders, juices, transdermal therapeutic systems, suppositories and solutions.
Die erfindungsgemäße Zusammensetzung kann aus einer Initialdosis und einer verzögert freisetzenden Komponente bestehen. Die Initialdosis beinhaltet vorzugsweise Glimepirid und/ oder Acarbose und wahlweise Poly(dimethyl)siloxan als Pulver, Granulat und/oder Pellets, jeweils neben fakultativen Hilfsstoffen. Der in der Initialdosis enthaltende Wirkstoff bzw. die Kombination wird sofort nach der Einnahme freigesetzt. Der therapeutisch wirksame Blutplasmaspiegel des Wirkstoffes bzw. der Wirkstoffe wird mittels dieser Initialdosis sehr schnell erreicht, so daß kurz nach der Einnahme eine therapeutische Wirkung zu verzeichnen ist. Einer durch die Nahrungsaufnahme verursachten Hyperglykämie wird somit entgegengewirkt. Die verzögert freisetzende Komponente enthält Metformin und/ oder dessen pharmazeutisch unbedenklichen Salze und wahlweise Poly(dimethyl)siloxan als Granulat und/ oder Pellets, jeweils neben fakultativen Hilfsstoffen. Das Granulat oder die Pellets können entweder retardierende Hilfsstoffe enthalten, welche eine kontrolliert freisetzende Matrix bilden, oder mit einer kontrolliert freisetzenden Beschichtung versehen sein.The composition according to the invention can consist of an initial dose and a delayed release component. The initial dose preferably contains glimepiride and / or acarbose and optionally poly (dimethyl) siloxane as powder, granules and / or pellets, each in addition to optional auxiliaries. The active ingredient or combination contained in the initial dose is released immediately after ingestion. The therapeutically effective blood plasma level of the active substance or the active substances is reached very quickly by means of this initial dose, so that a therapeutic effect can be observed shortly after ingestion. Hyperglycaemia caused by food intake is thus counteracted. The delayed-release component contains metformin and / or its pharmaceutically acceptable salts and optionally poly (dimethyl) siloxane as granules and / or pellets, in each case in addition to optional auxiliaries. The granules or the pellets can either contain retarding auxiliaries, which form a controlled release matrix, or can be provided with a controlled release coating.
Geeignete retardierende Matrixbildner können hydrophile oder hydrophobe Polymere, wie z.B. Gummis, Celluloseether, Celluloseester, Acrylharze , Materialen, die auf Proteinen basieren, Nylon, Polyvinylchlorid, Stärke und Polyvinylpyrrolidon darstellen. Als wasserlösliche Polymere werden u.a. Polyvinylpyrrolidon, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Hydroxyethylcellulose, Hydroxymethylcellulose,Suitable retarding matrix formers can be hydrophilic or hydrophobic polymers, e.g. Gums, cellulose ethers, cellulose esters, acrylic resins, materials based on proteins, nylon, polyvinyl chloride, starch and polyvinyl pyrrolidone. The water-soluble polymers used include Polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose,
Poly(vinylalkohole), Alginate, Polydextrose, Carboxymethylen, hydriertePoly (vinyl alcohols), alginates, polydextrose, carboxymethylene, hydrogenated
Hydroxyalkylcellulose und/ oder Hydroxypropylmethylcelluloseether verwendet. Als wasserunlösliche Polymere werden Polyvinylchlorid, Ethylcellulose, Methylcellulose, Carboxymethylcellulose (teilweise wasserlöslich, je nach mittleren Substitutionsgrad), Celluloseacetate, Celluloseacetatphthalate, Ethylenvinylalkohol, Alginsäure und/ oder deren Derivate, Acrylsäure- und/ oder Methacrylsäure-Copolymere, Methylmethacrylat- Copolymere, Ethoxyethylmethacrylat-Copolymere, Cyanoethylmethacrylate,Hydroxyalkyl cellulose and / or hydroxypropyl methyl cellulose ether used. Polyvinyl chloride, ethyl cellulose, methyl cellulose, Carboxymethyl cellulose (partially water-soluble, depending on the average degree of substitution), cellulose acetates, cellulose acetate phthalates, ethylene vinyl alcohol, alginic acid and / or their derivatives, acrylic acid and / or methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate copolymers, cyanoethyl methacrylates,
Aminoalkylmethacrylat-Copolymere, Poly(acrylsäure), Poly(methacrylsäure),Aminoalkyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid),
Methacrylsäurealkylamid-Copolymere, Poly(methylmethacrylate),Methacrylic acid alkylamide copolymers, poly (methyl methacrylate),
Poly(methacrylsäureanhydride), Methylmethacrylate, Polymethacrylate,Poly (methacrylic anhydrides), methyl methacrylates, polymethacrylates,
Poly(methylmethacrylat)-Copolymer, Polyacrylamide, Aminoalkylmethacrylat-Copolymere und/ oder Glycidylmethacrylat-Copolymere verwendet.Poly (methyl methacrylate) copolymer, polyacrylamides, aminoalkyl methacrylate copolymers and / or glycidyl methacrylate copolymers are used.
Ebenso können als Matrixbildner verdauliche, langkettige (C8 -C50, insbesondere C12 -C40), substituierte oder unsubstituierte Kohlenwasserstoffe, wie z.B. Fettsäuren, Fettalkohole (Lauryl-, Myrestyl-, Stearyl-, Cetostearyl-, Ceryl- oder Cetylalkohol), Glycerinester von Fettsäuren (Witepsol, Glycerinmonostearat), Mineral- und Pflanzenöle (hydriertes Rizinusöl) und/ oder Wachse (Paraffϊnwachse, Silikonwachse, Bienenwachse, Rizinuswachse, Carnaubawachse und Glycowachse) verwendet werden. Die Kohlenwasserstoffe, die einen Schmelzpunkt zwischen 25 °C und 90 °C aufweisen, sind besonders geeignet. Die bevorzugten langkettigen Kohlenwasserstoffe stellen die Fettalkohole dar. Weitere mögliche Matrixbildner können Polyalkylenglykole sowie jegliche Kombinationen der aufgeführten matrixbildenden Stoffe sein.Likewise digestible, long-chain (C 8 -C 50 , especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols (lauryl, myrestyl, stearyl, cetostearyl, ceryl or cetyl alcohol) can be used as matrix formers. , Glycerol esters of fatty acids (Witepsol, glycerol monostearate), mineral and vegetable oils (hydrogenated castor oil) and / or waxes (paraffin waxes, silicone waxes, beeswaxes, castor waxes, carnauba waxes and glycine waxes) can be used. The hydrocarbons, which have a melting point between 25 ° C and 90 ° C, are particularly suitable. The preferred long-chain hydrocarbons are the fatty alcohols. Other possible matrix formers can be polyalkylene glycols and any combination of the matrix-forming substances listed.
Eine geeignete kontrolliert freisetzende Matrixform kann neben Metformin und/ oder dessen pharmazeutisch unbedenklichen Salzen und wahlweise Poly(dimethyl)siloxan bekannte, wasserlösliche Hilfsstoffe, welche, genauso wie der Wirkstoff bzw. die Wirkstoffe, in ein Gerüst, gebildet aus wasserunlöslichen, unverdaulichen Hilfsstoffen, eingebettet sind, enthalten. Durch Herauslösen der löslichen Bestandteile entstehen Poren, durch die der bzw. die Wirkstoff(e) nach außen diffundieren. Als gerüstbildende Substanzen können Polymere wie Polyvinylchlorid, Polyethylen, Polyamid, Silicone, Ethylcellulose und/ oder Methacryl- Acrylat-Copolymere eingesetzt werden. Das Wirkstoff-Hilfsstoff-Gemisch wird entweder direkt oder nach dem Feuchtgranulieren mit organischen Lösungsmitteln bzw. Bindemittellösungen zu Tabletten verpreßt oder in Pelletform in Kapseln gefüllt. Eine derartige kontrolliert freisetzende Matrix kann aus einer oder mehreren Alkylcellulosen und einem oder mehreren C12 -C36 aliphatischen Alkoholen sowie wahlweise mindestens einem Polyalkylenglykol bestehen.A suitable controlled-release matrix form can, in addition to metformin and / or its pharmaceutically acceptable salts and optionally poly (dimethyl) siloxane, known water-soluble auxiliary substances which, like the active substance or active substances, are embedded in a framework formed from water-insoluble, indigestible auxiliary substances included. By removing the soluble components, pores are formed through which the active ingredient (s) diffuse outwards. Polymers such as polyvinyl chloride, polyethylene, polyamide, silicone, ethyl cellulose and / or methacrylic acrylate copolymers can be used as scaffolding substances. The active ingredient / auxiliary mixture is pressed into tablets either directly or after wet granulation with organic solvents or binder solutions, or filled into capsules in pellet form. Such a controlled release matrix can consist of one or more alkyl celluloses and one or more C 12 -C 36 aliphatic alcohols and optionally at least one polyalkylene glycol.
Bei einer weiteren erfindungsgemäßen Matrixform kann Metformin und/ oder dessen pharmazeutisch unbedenklichen Salzen und wahlweise Poly(dimethyl)siloxan mit bekannten wasserlöslichen Hilfsstoffen und fettähnlichen Stoffen kombiniert werden. Als lipophile Stoffe können abbaubare Mono-, Di- und Triglyceride (Glyceinmonostearat, Glycerolmonooleat, Glycerintripalmitat), aber auch erodierbare Fettalkohole (Lauryl-, Myristyl-, Stearyl-, Cetyl- oder Cerylalkohol) mit einem Schmelzpunkt von 30-80 °C verwendet werden. Die Wirkstoffabgabe erfolgt durch Diffusion und durch enzymatischen Abbau der lipophilen Stoffe. Das Einbetten von Metformin und oder dessen pharmazeutisch unbedenklichen Salzen und wahlweise Poly(dimethyl)siloxan in die Matrix erfolgt durch Schmelzen, Sprüherstarren, Sprühtrocknen, Granulieren oder Direkttablettieren.In a further matrix form according to the invention, metformin and / or its pharmaceutically acceptable salts and optionally poly (dimethyl) siloxane can be combined with known water-soluble auxiliaries and fat-like substances. Degradable mono-, di- and triglycerides (glycein monostearate, glycerol monooleate, glycerol tripalmitate), but also erodable fatty alcohols (lauryl, myristyl, stearyl, cetyl or ceryl alcohol) with a melting point of 30-80 ° C can be used as lipophilic substances . The active ingredient is released by diffusion and by enzymatic degradation of the lipophilic substances. Embedding metformin and or its pharmaceutically acceptable salts and optionally poly (dimethyl) siloxane in the matrix is carried out by melting, sprinkling, spray drying, granulating or direct tableting.
Eine weitere erfindungsgemäße Matrixform kann Metformin und/ oder dessen pharmazeutisch unbedenklichen Salze und wahlweise Poly(dimethyl)siloxan, in eine gelbildende Matrix aus z.B. Hydroxymethylcellulose, Hydroxyethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Alginat und/ oder Polyacrylsäure eingebettet, enthalten. Das Polymer hydratisiert und bildet eine gelartige Schicht, welche langsam erodiert und so den bzw. die Wirkstoff(e) kontrolliert freisetzt.Another matrix form according to the invention can metformin and / or its pharmaceutically acceptable salts and optionally poly (dimethyl) siloxane, in a gel-forming matrix of e.g. Hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, alginate and / or polyacrylic acid embedded. The polymer hydrates and forms a gel-like layer, which slowly erodes and thus releases the active ingredient (s) in a controlled manner.
Andere pharmazeutisch geeignete Hilfsstoffe, welche nach dem Stand der Technik üblich sind, wie z.B. Verdünnungsmittel, Schmiermittel, Bindemittel, Granulierungshilfsmittel, Farbstoffe, Aromastoffe, Detergenzien, Puffer, Antihaftmittel und/ oder Gleitmittel können zudem in der kontrolliert freisetzenden Matrix enthalten sein.Other pharmaceutically acceptable excipients which are common in the art, e.g. Diluents, lubricants, binders, granulation aids, colorants, flavors, detergents, buffers, non-stick agents and / or lubricants can also be contained in the controlled release matrix.
Die in eine kontrolliert freisetzende Matrix eingebettete erfindungsgemäße Zusammensetzung kann noch mit einem bekannten, pharmazeutisch geeigneten, nicht kontrolliert freisetzenden Überzugsmittel filmbeschichtet werden, wobei ein wässeriger Filmüberzug bevorzugt wird.The composition according to the invention embedded in a controlled-release matrix can also be film-coated with a known, pharmaceutically suitable, non-controlled-release coating agent, an aqueous film coating being preferred.
Geeignete kontrolliert freisetzende Überzugsmittel sind wasserunlösliche Wachse und/ oder Polymere (Polymethacrylate) und/ oder wasserunlösliche Cellulose, insbesondere Ethylcellulose, wahlweise wasserlösliche Polymere wie Polyvinylpyrrolidon oder wasserlösliche Cellulose, wie Hydroxypropylcellulose oder Hydroxypropylmethylcellulose.Suitable controlled-release coating agents are water-insoluble waxes and / or polymers (polymethacrylates) and / or water-insoluble cellulose, in particular Ethyl cellulose, optionally water-soluble polymers such as polyvinyl pyrrolidone or water-soluble cellulose such as hydroxypropyl cellulose or hydroxypropyl methyl cellulose.
Zudem können bei Bedarf noch andere wasserlösliche Agenzien wie Polysorbat hinzugefugt werden. Das mit einer verzögert freisetzenden Beschichtung versehene Granulat und/ oder die Pellets können dadurch erhalten werden, daß Granulat und/ oder Pellets, die gegebenenfalls für die Initialdosis hergestellt wurden, mit der entsprechenden verzögert freisetzendenIf necessary, other water-soluble agents such as polysorbate can also be added. The granules and / or the pellets provided with a delayed-release coating can be obtained in that granules and / or pellets, which were possibly produced for the initial dose, with the corresponding delayed-release ones
Beschichtung versehen werden.Coating.
Metformin erhöht die Sensibilität der Gewebe für Insulin. Durch die kontrollierte Freisetzung wird eine erhöhte Insulinsensibilität über einen längeren Zeitraum erreicht. Die Einnahmehäufigkeit kann somit wesentlich verringert werden und die Gefahr einer Hyperund Hypoglukämie wird stark gesenkt. Die Einnahme dieser retardierenden Form der erfindungsgemäßen Zusammensetzung z.B. vor dem Frühstück gewährleistet einen Schutz vor Hyper- und Hypoglykämie während des ganzen Tages. Die sonst übliche dreimal tägliche Einnahme von antidiabetisch wirksamen Stoffen kann mittels dieser retardierenden Form der erfindungsgemäßen Zusammensetzung auf ein- bis zweimal täglich reduziert werden. Die Patienten-Compliance wird somit durch die erfindungsgemäße Zusammensetzung wesentlich verbessert bei gleichzeitig besserer Wirkung.Metformin increases tissue sensitivity to insulin. Controlled release increases insulin sensitivity over a longer period of time. The frequency of ingestion can thus be significantly reduced and the risk of hyper and hypoglukemia is greatly reduced. Taking this retarding form of the composition according to the invention e.g. before breakfast provides protection against hyper- and hypoglycemia throughout the day. The otherwise usual three times a day intake of antidiabetic substances can be reduced to one or two times a day by means of this retarding form of the composition according to the invention. The patient compliance is thus significantly improved by the composition according to the invention with a simultaneously better effect.
Die retardierende Form der erfindungsgemäßen Zusammensetzung kann in Form einer Kapsel, insbesondere einer Gelatinekapsel vorliegen, wobei die Kapsel die Initialdosis und die retardierende Komponente, wie oben beschrieben, beinhaltet. Die Initialdosis kann als Pulver, Granulat und/ oder Pellets vorliegen. Die retardierende Komponente kann als Granulat und/ oder Pellets vorliegen.The retarding form of the composition according to the invention can be in the form of a capsule, in particular a gelatin capsule, the capsule containing the initial dose and the retarding component, as described above. The initial dose can be in the form of powder, granules and / or pellets. The retarding component can be present as granules and / or pellets.
Die retardierende Form der erfindungsgemäßen Zusammensetzung kann in Form einer Zweischichttablette vorliegen. Die erste Schicht stellt die Initialdosis dar, welche aus dem oben beschriebenen Pulver, Granulat und/ oder Pellets gepreßt wird. Die zweite Schicht beinhaltet die oben beschriebene verzögert freisetzende Komponente, welche aus dem entsprechenden Granulat und/ oder Pellets gepreßt wird.The sustained release form of the composition according to the invention can be in the form of a two-layer tablet. The first layer represents the initial dose which is pressed from the powder, granules and / or pellets described above. The second layer contains the delayed-release component described above, which is pressed from the corresponding granules and / or pellets.
Zur Herstellung der oben genannten Dosierungsformen können die nach dem Stand der Technik bekannten pharmazeutischen Hilfsstoffe, wie Tablettenbinder, Füllstoffe, Konservierungsmittel, Tablettensprengmittel, Fließregulierungsmittel, Weichmacher,To produce the dosage forms mentioned above, the pharmaceutical auxiliaries known according to the prior art, such as tablet binders, fillers, Preservatives, tablet disintegrants, flow regulators, plasticizers,
Netzmittel, Dispergiermittel, Emulgator, Retardierungsmittel und/ oder Antioxidantien, und/ oder sonstige bekannte Träger- und Verdünnungsmittel verwendet werden. Wetting agents, dispersants, emulsifiers, retardants and / or antioxidants, and / or other known carriers and diluents can be used.

Claims

Patentansprücheclaims
1. Pharmazeutische Zusammensetzung, gekennzeichnet durch eine Kombination von Metformin und/ oder dessen pharmazeutisch unbedenklichen Salzen und Glimepirid und/ oder Acarbose und wahlweise Poly(dimethyl)siloxan als aktive Bestandteile.1. Pharmaceutical composition, characterized by a combination of metformin and / or its pharmaceutically acceptable salts and glimepiride and / or acarbose and optionally poly (dimethyl) siloxane as active ingredients.
2. Pharmazeutische Zusammensetzung nach Anspruch 1 zur Verwendung bei der Behandlung von Typ II Diabetes mellitus.2. A pharmaceutical composition according to claim 1 for use in the treatment of type II diabetes mellitus.
3. Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch Säureadditionssalze des Metformins, insbesondere das Hydrochlorid.3. Pharmaceutical composition according to one of the preceding claims, characterized by acid addition salts of metformin, in particular the hydrochloride.
4. Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch eine Menge an Metformin von 0,25-3,0 g. 5. Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch eine Menge an Metformin-Salz(en), die einer Menge von 0,25-3,0 g4. Pharmaceutical composition according to one of the preceding claims, characterized by an amount of metformin of 0.25-3.0 g. 5. Pharmaceutical composition according to one of the preceding claims, characterized by an amount of metformin salt (s), an amount of 0.25-3.0 g
Metformin entspricht. 6. Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch eine Menge an Glimepirid von 0,5-10 mg. 7. Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch eine Menge an Acarbose von 20-400 mg.Metformin corresponds. 6. Pharmaceutical composition according to one of the preceding claims, characterized by an amount of glimepiride of 0.5-10 mg. 7. Pharmaceutical composition according to one of the preceding claims, characterized by an amount of acarbose of 20-400 mg.
8. Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch eine Menge an Poly(dimethyl)siloxan von 5-1000 mg.8. Pharmaceutical composition according to one of the preceding claims, characterized by an amount of poly (dimethyl) siloxane of 5-1000 mg.
9. Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche in der Form von Tabletten, Filmtabletten, Brausetabletten, Granulaten, Kapseln, Dragees,9. Pharmaceutical composition according to one of the preceding claims in the form of tablets, film-coated tablets, effervescent tablets, granules, capsules, coated tablets,
Retardtabletten, Retardkapseln, Kautabletten, Pulvern, Säften, transdermalen therapeutischen Systemen, Suppositorien und Lösungen. lO.Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche, welche folgende Komponenten umfaßt oder aus ihnen besteht: a) eine Wirkstoffinitialdosis, die Glimepirid und/ oder Acarbose und wahlweise Poly(dimethyl)siloxan als aktive Bestandteile neben fakultativen Hilfsstoffen enthält b) eine verzögert freisetzende Komponente, welche Metformin und/ oder dessen pharmazeutisch unbedenklichen Salze und wahlweise Poly(dimethyl)siloxan als aktive Bestandteile neben fakultativen Hilfsstoffen enthält.Prolonged-release tablets, prolonged-release capsules, chewable tablets, powders, juices, transdermal therapeutic systems, suppositories and solutions. 10. Pharmaceutical composition according to one of the preceding claims, which comprises or consists of the following components: a) an initial dose of active substance which contains glimepiride and / or acarbose and optionally poly (dimethyl) siloxane as active constituents in addition to optional auxiliaries b) a delayed-release component Which contains metformin and / or its pharmaceutically acceptable salts and optionally poly (dimethyl) siloxane as active ingredients in addition to optional auxiliaries.
11.Pharmazeutische Zusammensetzung nach Anspruch 10, dadurch gekennzeichnet, daß bei der Initialdosis die aktiven Bestandteile in Form von Pulver, Granulat und/ oder Pellets vorliegen 12.Pharmazeutische Zusammensetzung nach Anspruch 10, dadurch gekennzeichnet, daß bei der verzögert freisetzenden Komponente die aktiven Bestandteile in Form von Granulat und/ oder Pellets vorliegen. 13. Pharmazeutische Zusammensetzung nach Anspruch 10 oder 12, gekennzeichnet durch die11.Pharmaceutical composition according to claim 10, characterized in that at the initial dose the active ingredients are in the form of powder, granules and / or pellets. 12.Pharmaceutical composition according to claim 10, characterized in that the active ingredients in the delayed release component Form of granules and / or pellets are present. 13. Pharmaceutical composition according to claim 10 or 12, characterized by the
Einbettung einer therapeutisch wirksamen Menge an Metformin und/ oder dessen pharmazeutisch unbedenklichen Salzen und wahlweise Poly(dimethyl)siloxan in eineEmbedding a therapeutically effective amount of metformin and / or its pharmaceutically acceptable salts and optionally poly (dimethyl) siloxane in one
Matrix, welche die kontrollierte Freisetzung gewährleistet. 14.Pharmazeutische Zusammensetzung nach Anspruch 10, 12 oder 13, gekennzeichnet durch eine kontrolliert freisetzende Matrix, die hydrophile und/ oder hydrophobe Polymere, insbesondere Gummi, Celluloseether, Acrylharze und/ oder Materialen auf Proteinbasis, und/ oder verdauliche langkettige, substituierte oder unsubstituierte Kohlenwasserstoffe, insbesondere Fettalkohole, Fettsäuren, Glycerinester von Fettsäuren, Mineral- und/ oderMatrix that ensures controlled release. 14.Pharmaceutical composition according to claim 10, 12 or 13, characterized by a controlled release matrix, the hydrophilic and / or hydrophobic polymers, in particular rubber, cellulose ethers, acrylic resins and / or protein-based materials, and / or digestible long-chain, substituted or unsubstituted hydrocarbons , in particular fatty alcohols, fatty acids, glycerol esters of fatty acids, mineral and / or
Pflanzenöle sowie Wachse und/ oder Polyalkylenglykole als Retardierungsmittel enthält. 15. Pharmazeutische Zusammensetzung nach Anspruch 10 oder 12, gekennzeichnet durch eine normal freisetzende Matrix und ein kontrolliert freisetzender Überzug als verzögert freisetzende Komponente. lO.Pharmazeutische Zusammensetzung nach Anspruch 15, gekennzeichnet durch wasserunlösliche Wachse und Polymere und/ oder wasserunlösliche Cellulose und/ oder wasserlösliche Polymere und/ oder wasserlösliche Cellulose und wahlweise Polysorbat als geeignete kontrolliert freisetzende Überzugsmittel. 17.Pharmazeutische Zusammensetzung nach Anspruch 16, gekennzeichnet durchContains vegetable oils and waxes and / or polyalkylene glycols as a retardant. 15. Pharmaceutical composition according to claim 10 or 12, characterized by a normally releasing matrix and a controlled releasing coating as a delayed releasing component. 10. Pharmaceutical composition according to claim 15, characterized by water-insoluble waxes and polymers and / or water-insoluble cellulose and / or water-soluble polymers and / or water-soluble cellulose and optionally polysorbate as suitable controlled-release coating agents. 17.Pharmaceutical composition according to claim 16, characterized by
Polymethaycrylat und/ oder Ethylcellulose und/ oder Hydroxypropylcellulose Hydroxypropylmethylcellulose und/ oder Polyvinylpyrrolidon als kontrolliert freisetzendePolymethyl acrylate and / or ethyl cellulose and / or hydroxypropyl cellulose Hydroxypropylmethylcellulose and / or polyvinylpyrrolidone as controlled release
Überzugsmittel. 18. Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche in Form einer Kapsel, insbesondere einer Gelantinekapsel, wobei die Kapsel die Initialdosis und die verzögert freisetzende Komponente enthält.Coating agent. 18. Pharmaceutical composition according to one of the preceding claims in the form of a capsule, in particular a gelatin capsule, the capsule containing the initial dose and the delayed-release component.
19.Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche in Form einer Zweischichttablette, wobei die Tablette als erste Schicht die Initialdosis und als zweite Schicht die verzögert freisetzende Komponente enthält. 20.Pharmazeutische Zusammensetzung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch Tablettenbinder, Füllstoffe, Konservierungsmittel,19.Pharmaceutical composition according to one of the preceding claims in the form of a two-layer tablet, the tablet containing the initial dose as the first layer and the delayed-release component as the second layer. 20.Pharmaceutical composition according to one of the preceding claims, characterized by tablet binders, fillers, preservatives,
Tablettensprengmittel, Fließregulierungsmittel, Weichmacher, Netzmittel,Tablet disintegrants, flow regulators, plasticizers, wetting agents,
Dispergiermittel, Emulgator, Retardierungsmittel und/ oder Antioxidantien und/ oder sonstige bekannte Träger- und Verdünnungsmittel als Hilfsstoffe. 21.Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 1-20, bei dem man die aktiven Bestandteile Metformin und/ oder dessen pharmazeutisch unbedenklichen Salze und Glimepirid und/ oder Acarbose und wahlweiseDispersants, emulsifiers, retardants and / or antioxidants and / or other known carriers and diluents as auxiliaries. 21. A method for producing a pharmaceutical composition according to any one of claims 1-20, in which the active ingredients metformin and / or its pharmaceutically acceptable salts and glimepiride and / or acarbose and optionally
Poly(dimethyl)siloxan mit mindestens einem pharmazeutisch annehmbaren Träger vereint. Poly (dimethyl) siloxane combined with at least one pharmaceutically acceptable carrier.
PCT/EP1999/010098 1998-12-30 1999-12-16 Pharmaceutical composition containing metformin, acarbose or glimepiride and optionally poly-(dimethyl)-siloxane WO2000040233A1 (en)

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* Cited by examiner, † Cited by third party
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EP1258249A1 (en) * 1999-12-28 2002-11-20 Ajinomoto Co., Inc. Oral preparations for diabetes
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EP1258249A4 (en) * 1999-12-28 2003-03-19 Ajinomoto Kk Oral preparations for diabetes
EP1258249A1 (en) * 1999-12-28 2002-11-20 Ajinomoto Co., Inc. Oral preparations for diabetes
US7022339B2 (en) 1999-12-28 2006-04-04 Ajinomoto Co., Inc. Antidiabetic preparation for oral administration
US8197850B2 (en) 2000-11-17 2012-06-12 Flamel Technologies Medicine based on anti-hyperglycaemic microcapsules with prolonged release and method for preparing same
EP1349531A1 (en) * 2001-01-12 2003-10-08 Sun Pharmaceuticals Industries Ltd. Spaced drug delivery system
EP1738751A3 (en) * 2001-01-12 2007-01-17 Sun Pharmaceutical Industries Limited Spaced drug delivery system
WO2002094285A1 (en) * 2001-05-23 2002-11-28 Flamel Technologies Single-daily-dose antidiabetic oral pharmaceutical form comprising a biguanide and at least another active principle
FR2825023A1 (en) * 2001-05-23 2002-11-29 Flamel Tech Sa ANTIDIABETIC ORAL PHARMACEUTICAL FORM "ONE TAKEN PER DAY" INCLUDING BIGUANIDE AND AT LEAST ONE OTHER ACTIVE INGREDIENT
WO2003061643A1 (en) * 2002-01-25 2003-07-31 Laboratorios Silanes, S.A. De C.V. Pharmaceutical composition that is used to control blood glucose in patients with type 2 diabetes
US9045438B2 (en) 2002-01-25 2015-06-02 Silanes S.A. De C.V. Pharmaceutical composition containing glimepiride and metformin hydrochloride
EP1469838A1 (en) * 2002-02-01 2004-10-27 DepoMed, Inc. Manufacture of oral dosage forms delivering both immediate release and sustained release drugs
EP1469838A4 (en) * 2002-02-01 2009-03-25 Depomed Inc Manufacture of oral dosage forms delivering both immediate release and sustained release drugs
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)
US8911781B2 (en) 2002-06-17 2014-12-16 Inventia Healthcare Private Limited Process of manufacture of novel drug delivery system: multilayer tablet composition of thiazolidinedione and biguanides
US6830759B2 (en) 2002-06-28 2004-12-14 Ajinomoto Co., Inc. Antidiabetic preparation for oral administration
WO2004012700A2 (en) 2002-08-05 2004-02-12 Torrent Pharmaceuticals Limited Dosage form comprising high dose high soluble active ingredient as modified release and low dose active ingredient as immediate release
WO2004012700A3 (en) * 2002-08-05 2004-04-01 Torrent Pharmaceuticals Ltd Dosage form comprising high dose high soluble active ingredient as modified release and low dose active ingredient as immediate release
WO2004045622A1 (en) * 2002-11-15 2004-06-03 Ranbaxy Laboratories Limited Pharmaceutical dosage forms of biguanide-sulfonylurea combinations
SG129278A1 (en) * 2003-03-05 2007-02-26 Usv Ltd A solid oral dosage form of metformin and glyburide and the method of preparation thereof
WO2005065639A3 (en) * 2003-11-21 2005-09-01 Torrent Pharmaceuticals Ltd Novel pharmaceutical compositions
WO2005065639A2 (en) * 2003-11-21 2005-07-21 Torrent Pharmaceuticals Limited Novel pharmaceutical compositions
CN1296050C (en) * 2003-12-10 2007-01-24 浙江海正药业股份有限公司 Acarbose enteric coated tablets and its prepn. method
WO2005102273A3 (en) * 2004-04-22 2006-05-18 Ranbaxy Lab Ltd Pharmaceutical compositions of a biguanide and a sulfonylurea
WO2005102273A2 (en) * 2004-04-22 2005-11-03 Ranbaxy Laboratories Limited Pharmaceutical compositions of a biguanide and a sulfonylurea
WO2005107717A3 (en) * 2004-05-11 2006-05-18 Ranbaxy Lab Ltd Oral dosage form for the extended release of biguanide and sulfonylurea
WO2005107717A2 (en) * 2004-05-11 2005-11-17 Ranbaxy Laboratories Limited Oral dosage form for the extended release of biguanide and sulfonylurea

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