WO1995011006A1 - Highly active sulphonyl urea preparations exhibiting rapid or controlled release of the active substance, and method of producing them - Google Patents

Highly active sulphonyl urea preparations exhibiting rapid or controlled release of the active substance, and method of producing them Download PDF

Info

Publication number
WO1995011006A1
WO1995011006A1 PCT/EP1994/003368 EP9403368W WO9511006A1 WO 1995011006 A1 WO1995011006 A1 WO 1995011006A1 EP 9403368 W EP9403368 W EP 9403368W WO 9511006 A1 WO9511006 A1 WO 9511006A1
Authority
WO
WIPO (PCT)
Prior art keywords
preparation
water
alcohol
active ingredient
sulfonylurea
Prior art date
Application number
PCT/EP1994/003368
Other languages
German (de)
French (fr)
Inventor
Kurt H. Bauer
Manfred Keller
Original Assignee
British Technology Group Ltd.
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 British Technology Group Ltd. filed Critical British Technology Group Ltd.
Priority to AU78555/94A priority Critical patent/AU7855594A/en
Priority to EP94929538A priority patent/EP0724427A1/en
Priority to JP7511289A priority patent/JPH09504015A/en
Publication of WO1995011006A1 publication Critical patent/WO1995011006A1/en

Links

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • 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 highly effective preparation forms of sulfonylurea derivatives which are sparingly water-soluble or which release the active ingredient, and to processes for solubilizing sulfonylurea derivatives which are sparingly water-soluble.
  • the effectiveness of a pharmaceutical substance depends to a large extent on its form of application. In general, for a systemic effect, the drug must either be injected directly into the bloodstream or applied in a resorbable form.
  • Absorption of a substance is understood to mean its absorption into the bloodstream or the lymphatic system, from where it is distributed into the whole organism. The rate of absorption and the rate of absorption (ratio of the resorbable portion to the applied amount) depend on numerous factors. Decisive for the effectiveness and bioavailability of many orally or parenterally administered drugs is their solubility in an aqueous medium.
  • a group of drugs, their bioavailability and thus effectiveness strongly depend on their solubility in an aqueous environment are the sulfonylurea derivatives. These substances are currently used to lower blood sugar (diabetes mellitus).
  • glibenclamide Using the example of the best-known representative, glibenclamide (INN), the aim is to show what influence the solubility has on the onset of action, the effectiveness and the dose required for this.
  • Glibenclamide also known as glyburide in American parlance, is a sulfonylurea derivative with the chemical IUPAC name: N-4-2- (5-chloro-2-methoxybenzamido) -ethyl-phenylsulfonyl-N'-cyclohexylurea.
  • the molecular weight is 494.02, the melting point is 172 to 174 ° C (see R. Gröning: drug profiles and bioavailability data of finished drugs, drug monograph Glibenclamid, Deutscher maschinerverlag, Stuttgart, pages 1 to 7, 1987) .
  • Glibenclamide is an odorless, crystalline, white substance which is practically insoluble in water and ether and only moderately soluble in alcohol and chloroform. With alkalis it forms salts which, however, have a very limited solubility in water in comparison to tolbutamide, a substance which also lowers blood sugar.
  • the other therapeutically used sulfonylurea derivatives e.g. Glipizid, Glibornurid, Gliquidon, Glisoxepid and Glimeprid, all similar solubility properties.
  • sulfonylurea derivatives are used worldwide in daily doses of 1-250 mg for the treatment of sugar disease (diabetes mellitus).
  • Two mechanisms can be distinguished in the event of a lowering of blood sugar, namely a pancreatic and an extra pancreatic. effect (see product information from Boehringer Mannheim GmbH and Hoechst AG, Frankfurt / Main, 1984, on Euglucon R N, Semi-Euglucon R N).
  • pancreatic effect leads to an increase in insulin secretion through an increased responsiveness of the beta cells of the pancreas to glucose.
  • glibenclamide is one of the biopharmaceutical problematic medicinal substances.
  • the water solubility is also pH-dependent, in the acidic range glibenclamide is practically insoluble in water.
  • DE-OS 23 48 334 describes a rapidly absorbable form of preparation of glibenclamide and a process for its preparation.
  • Glibenclamide was processed by fine grinding on a large, defined surface or by the finest precipitation from organic solvents in dispersing agents to form easily and quickly absorbable preparations.
  • very fine crystals with a surface area of 3 to 10 m 2 were obtained. Studies have shown that increasing the surface area increases the solubility and dissolution rate, which also improves the bioavailability.
  • DE-OS 23 55 743 lists examples which show that the processing of glibenclamide at elevated temperatures, for example by incorporation into melts of higher molecular weight polyethylene glycols, is detrimental to stability.
  • the active substance is available in vivo, precisely coordinated, as and when required, which can prevent the occurrence of increased or strongly fluctuating blood sugar values.
  • Hyperglycaemia caused by food intake or other influences, can be prevented or quickly normalized.
  • compositions which do not meet these requirements for a rapid release of active substance harbor the risk of hyperglycaemia if an insufficient amount of active substance is available for absorption due to insufficient solubility or release.
  • a prerequisite for rapid absorption is, however, that the active ingredient from the pharmaceutical form is available for release in a dissolved or colloidally dissolved or molecularly dispersed form, if possible. Only if these conditions are met can the active ingredient be rapidly absorbed and thus become effective.
  • the present invention is therefore based on the object of providing a method for improving the solubility of poorly soluble sulfonylurea derivatives. Furthermore, effective, fast or controlled release and thus easily absorbable formulations of poorly soluble sulfonylurea derivatives, such as e.g. Glibenclamid, Glipizid, etc., are provided.
  • the sparingly soluble active ingredients should be brought into solution in a molecularly disperse manner using a simple process and pharmacologically and toxicologically acceptable auxiliaries.
  • the active ingredient should be divided and have good solubility due to the large surface area.
  • the molecularly dispersed active ingredient is to be applied to customary pharmaceutical carrier materials or also embedded therein in order to increase the surface area, so that an active ingredient-auxiliary alloy is obtained.
  • the process for producing the preparation forms according to the invention should be technically simple to carry out, require no complex apparatus and should not have any complicated process steps.
  • the production should be possible with commercially available auxiliaries and simple means.
  • the chemical or physical properties of the active substances or auxiliaries should not be adversely affected by the production process.
  • the required amount of polyethylene glycol can be reduced up to 10 times with reference to Examples 1 and 2 in DE-OS 23 55 743 if the sulfonylurea derivatives are used in an alcohol, one or more polyol (s) and / or in sugar alcohols which have previously been dissolved in water or alcohol-water mixtures, and the mixture is subsequently mixed with 0.5 to 2 mol, preferably 1 mol, of alkali metal hydroxide or ammonia.
  • the manufacturing method according to the invention therefore not only enables a reduction of the required auxiliary substances quantity, but at the same time represents an easy and gentle method for dissolving the poorly soluble sulfonylurea derivatives.
  • the invention relates to highly effective preparation forms of sulfonylurea derivatives which release the active ingredient quickly or in a controlled manner, which are characterized in that they contain one or more sulfonylurea derivative (s) as active ingredient (s), one or more polyol (s) with the exception of polyethylene glycol and / or one or several sugar alcohols, previously dissolved in water or alcohol-water mixtures, contain an alkaline substance and, if appropriate, suitable pharmaceutically acceptable auxiliaries or flavorings and, if appropriate, further pharmaceutically active substances.
  • the invention further relates to a method for producing a highly effective preparation of sulfonylurea derivatives which releases the active ingredient quickly or in a controlled manner, which is characterized in that one or more sulfonylurea derivative (s) are used as active ingredient (s), if appropriate after the previous one Wetting with an alcohol, in an alcohol or one or more polyol (s) except polyethylene glycol and / or one or more sugar alcohol (s), dissolved in water or an alcohol / water mixture, suspended, with an alkali mixed reacting substance and optionally adding other suitable pharmaceutically acceptable auxiliary and flavoring agents and optionally other pharmaceutically active substances until a solid or liquid preparation form is obtained.
  • the preparation forms preferably contain 1 to 1000 parts of propylene glycol, glycerol, hexylene glycol or mixtures thereof and / or 1 to 500 parts of sugar alcohols, dissolved in 2 to 2000 parts of water, in relation to one part of active ingredient. water or alcohol-water mixtures and 0.5 to 3 moles, preferably 1 mole, of an alkaline substance and, if appropriate, 0.01 to 1000 parts of pharmaceutically compatible auxiliaries and flavorings.
  • 1 part of sparingly soluble sulfonylurea derivative is preferably suspended in 3 to 1000 parts of ethanol or polyols such as propylene glycol etc. or sugar alcohols which have previously been dissolved in water or water / ethanol mixtures, with 0.5 to 2 mol, preferably about 1 mole, an alkaline substance and optionally other pharmaceutically acceptable auxiliaries and flavorings are mixed so that a liquid or solid preparation is obtained.
  • the sulfonylurea derivatives can be any sulfonylurea derivatives. They are preferably glibenclamide (glyburide), glipizide, glimeprid, gliquidon, glisoxepid, glibornuride, glicalzide, glisentide, glisolamide, glybuzole, glyclopyramide and glyclamide.
  • glibenclamide glyburide
  • glipizide glimeprid
  • gliquidon glisoxepid
  • glibornuride glicalzide
  • glisentide glisolamide
  • glybuzole glyclopyramide
  • Non-toxic products such as e.g. Glycerin, propylene glycol, hexylene glycol or mixtures thereof, and sugar alcohols, such as e.g. Sorbitol, mannitol, xylitol, isomalt or mixtures thereof in solution in water or alcohol-water mixtures are used.
  • sugar alcohols are preferably dissolved in a concentration of 10% to 70% in water or ethanol-water mixtures.
  • the alkaline substance can be any pharmaceutically acceptable and toxicologically acceptable alkaline substance, such as alkali or alkaline earth metal hydroxides or ammonia, which can form salts with sulfonylureas. It is preferred in a - in ⁇
  • the preparations can furthermore contain pharmaceutically compatible and toxicologically acceptable auxiliaries and flavorings, as are usually used in solid or liquid dosage forms.
  • auxiliaries and flavorings include customary excipients, such as lactose, starch, microcrystalline cellulose, croscarmelose, calcium carbonate, calcium diphosphate, Pluronic polyols, cellulose ethers, alginic acid derivatives, Eudragit, magnesium stearate, silicon dioxide, colorants, sugar substitutes, preservatives, isotropic substances, buffering agents, surface-buffering substances, surface-active substances ⁇ active compounds, flavorings, suppositories, etc., alone or in a mixture, to mention.
  • customary excipients such as lactose, starch, microcrystalline cellulose, croscarmelose, calcium carbonate, calcium diphosphate, Pluronic polyols, cellulose ethers, alginic acid derivatives, Eudragit, magnesium stearate, silicon dioxide, colorants
  • the preparation can also be used as flavoring substances, sugar substitutes, such as fructose, saccharin, aspartame, etc., as well as preservatives, such as e.g. Para-hydroxybenzoic acid esters, benzyl alcohols, sorbic acid or salts thereof in a concentration of 0.1 to 2 wt .-% of the formulation.
  • other pharmaceutically active substances can be added to the preparation form. These are preferably other blood sugar lowering drugs, such as ⁇ -glucosidase inhibitors, such as e.g. Acarbose, miglitol or aldose reductase inhibitors, such as e.g. Alrestatin sodium or Voglibase.
  • These other active ingredients can be formulated either separately from or together with the sulfonylureas.
  • the preparation forms can be in liquid, solid or semi-solid form.
  • Liquid dosage forms are, for example, solutions for oral (juices, drops), nasal (nasal drops, nasal sprays) or parenteral (injection or infusion) application.
  • Solid and semi-solid dosage forms can be, for example, granules (dry juice, sachets), tablets, capsules, pellets, film-coated tablets. be dragées and suppositories.
  • the dosage forms can be formulated in such a way that the entire active ingredient is released either within a very short time or in a time-controlled manner.
  • Liquid dosage forms e.g. Drip solutions have so far not been available for therapy as commercial products.
  • the drip solution allows an individual dosage adapted to the disease state and the food supply. Due to the fact that the active ingredient is present in a molecularly dispersed form in the preparation according to the invention, it is directly available for absorption and thus allows rapid absorption and optimal bioavailability.
  • the alcohol used in each case is preferably ethanol in 94 to 96% pharmaceutical quality and purity according to the requirements of the pharmacopoeia. If necessary, 90% or 70% ethanol can also be used, eg mixtures of 90 parts of ethanol and 10 parts of water. Depending on the solubility of the sulfonylurea derivative used, it may be expedient to first disperse the active ingredient in an alcohol, preferably ethanol, for better wetting, and then with the sugar alcohol, previously in water or an alcohol-water mixture , preferably an ethanol-water mixture, has been suspended. Alcohols other than ethanol can also be used, for example methanol or isopropanol, optionally in dilution with water.
  • a 100 was obtained from glibenclamide tablets which were produced in accordance with the method according to the invention in an in vitro dissolution test (paddle apparatus according to USP XXII, 75 revolutions per minute, buffer pH 7.4, UV measurement at 227 nm) % release of the active ingredient within 5 to 15 minutes, as can be seen in the attached figures.
  • a c m ⁇ C of 189 ng / ml, t max of 1.7 h and an AUC of 635 ng xh / ml were obtained.
  • the reduction in blood glucose determined at the same time proves that very good bioavailability and effectiveness can be achieved with the method according to the invention.
  • FIG. 2 the glibenclamide formulation according to the invention in comparison to Euglucon N.
  • the process for producing liquid dosage forms is simple.
  • the sparingly soluble sulfonylurea derivative, e.g. Glibenclamide is suspended in a stirred kettle in 4 to 1000 parts of propylene glycol, hexylene glycol or sugar alcohols, previously dissolved in water or an ethanol-water mixture with stirring, and as long as with an alkali-reacting substance, e.g. 0.1 molar ammonia solution or sodium hydroxide solution are added until a homogeneous solution is obtained.
  • This solution can then, if necessary, with other suitable auxiliaries, such as Water, sweeteners, flavorings and preservatives are mixed and then used therapeutically to lower blood sugar as a liquid pharmaceutical dosage form (e.g. as a drip solution or juice).
  • an undiluted active ingredient solution is used on tableting aids, e.g. Starch, lactose, mannitol, microcrystalline cellulose or disintegrant, grown in a commercial mixing kettle or fluidized bed granulator. Excess alcohol, ammonia or water can then be removed in the drying cabinet.
  • tableting aids e.g. Starch, lactose, mannitol, microcrystalline cellulose or disintegrant
  • the solution in a very finely divided form on adjuvants customary in pharmacy, such as mannitol, lactose, starch, microcrystalline cellulose or disintegrants persistence agents or mixtures thereof.
  • adjuvants customary in pharmacy such as mannitol, lactose, starch, microcrystalline cellulose or disintegrants persistence agents or mixtures thereof.
  • the molecularly dispersed glibenclamide distributed as a solid solution according to the invention is so finely dispersed and so wettable that a further increase in the rate of solution should theoretically no longer be possible.
  • the active ingredient immediately dissolves with the disintegration of the molecules in a molecularly disperse manner, as has been shown by in-vitro release studies with tablets containing glibenclamide. According to the Noyes-Whitney law, the larger the wettable surface of the particles to be dissolved, the faster the dissolution rate.
  • the sulfonylurea derivatives used according to the invention are usually administered in daily doses of 1 to 250 mg, depending on the sulfonylurea derivative used.
  • This dose can be formulated into single or multiple doses, starting from the sulfonylurea derivatives dissolved according to the invention, according to a method known to the person skilled in the art.
  • the exact dose to be administered can be adjusted by the treating doctor depending on the severity of the condition to be treated and the patient.
  • Example 2 3.5 g of glibenclamide are suspended in 700 g of propylene glycol with stirring and mixed with 7.1 g of 0.1N sodium hydroxide solution.
  • Example 2 3.5 g of glibenclamide are suspended in 700 g of propylene glycol with stirring and mixed with 7.1 g of 0.1N sodium hydroxide solution.
  • glipizide 4.5 g are mixed with stirring in 80 g of hexylene glycol and 20 g of 70% aqueous sorbitol solution and 2% (w / v) ammonia solution is added until a solution is obtained.
  • glimeprid 1 g is stirred in 200 g of propylene glycol and 50 g of 20% aqueous xylitol solution, and 0.1N potassium hydroxide solution is added until a solution is obtained.
  • glisoxepid 8 g are mixed in 1000 g of propylene glycol and 0.5N sodium hydroxide solution is added until a solution is obtained.
  • glipizide 10 g are suspended in 80 g of ethanol and 35 g of 70% sorbent solution and 5% (w / v) ammonia solution is added until a solution is obtained. This is grown on 360 g lactose. After drying and sieving, granules are obtained. This can then be mixed with 100 g of a tabletting auxiliary mixture and pressed into tablets.
  • glibenclamide 5 g are suspended in 50 g of ethanol and 50 g of Karion F (70% sorbitol solution) and 0.5N sodium hydroxide solution is added until a solution is obtained. This is grown on a mixture of 315 g lactose and 50 g corn starch, 20 g microcrystalline cellulose and 72 g acarbose, sieved and granulated. After mixing with 0.5% silicon dioxide and magnesium stearate in each case, 350 mg of powder mixture are filled into hard gelatin capsules.
  • Karion F 50% sorbitol solution

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Organic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention concerns highly active sulphonyl urea preparations exhibiting rapid or controlled release of the active substance for use in the treatment of diabetes. Covered are liquid and rapid-release or controlled-release solid pharmaceutical preparations characterized in that they contain one or more sulphonyl urea derivative(s) as the active substance(s), alcohol, one or more polyol(s), with the exception of polyethylene glycol, and/or more sugar alcohol(s), previously dissolved in water or an alcohol/water mixture, an alkaline-reacting substance and, optionally, suitable pharmaceutically tolerated auxiliaries and flavours plus, optionally, other pharmaceutically active substances. The invention also concerns a method of producing such preparations and their use in the treatment of the illness diabetes mellitus.

Description

Beschreibung description
Hochwirksame, den Wirkstoff schnell oder kontrolliert freisetzende Zubereitungsformen von Sulfonylharnstoffen und Verfahren zu deren HerstellungHighly effective forms of preparation of sulfonylureas that release the active ingredient quickly or in a controlled manner and processes for their preparation
Die Erfindung betrifft hochwirksame, den Wirkstoff schnell oder kontrolliert freisetzende Zubereitungsformen von in Wasser schwer löslichen Sulfonylharnstoffderivaten sowie Verfahren zur Solubilisierung von in Wasser schwer lösli¬ chen Sulfonylharnstoffderivaten.The invention relates to highly effective preparation forms of sulfonylurea derivatives which are sparingly water-soluble or which release the active ingredient, and to processes for solubilizing sulfonylurea derivatives which are sparingly water-soluble.
Die Wirksamkeit eines Arzneistoffes hängt zu einem über¬ wiegenden Teil von seiner Applikationsform ab. Generell gilt, daß für eine systemische Wirkung, der Arzneistoff entweder direkt in die Blutbahn injiziert oder in resor¬ bierbarer Form appliziert werden muß. Unter Resorption ei¬ nes Stoffes versteht man dessen Aufnahme in die Blutbahn oder das Lymphgefäßsystem, von wo aus die Verteilung in den Gesamtorganismus erfolgt. Resorptionsgeschwindigkeit und Resorptionsquote (Verhältnis von resorbierbarem Anteil zur applizierten Menge) hängen dabei von zahlreichen Fak¬ toren ab. Entscheidend für die Wirksamkeit und Bioverfüg¬ barkeit vieler peroral oder parenteral applizierter Arz¬ neistoffe ist deren Löslichkeit in wäßrigem Milieu. Eine Gruppe von Arzneistoffen, deren Bioverfügbarkeit und damit Wirksamkeit stark von der Löslichkeit in wäßrigem Milieu abhängig ist, stellen die Sulfonylharnstoffderivate dar. Diese Substanzen werden gegenwärtig zur Blutzuckersenkung (Diabetes mellitus) verwendet.The effectiveness of a pharmaceutical substance depends to a large extent on its form of application. In general, for a systemic effect, the drug must either be injected directly into the bloodstream or applied in a resorbable form. Absorption of a substance is understood to mean its absorption into the bloodstream or the lymphatic system, from where it is distributed into the whole organism. The rate of absorption and the rate of absorption (ratio of the resorbable portion to the applied amount) depend on numerous factors. Decisive for the effectiveness and bioavailability of many orally or parenterally administered drugs is their solubility in an aqueous medium. A group of drugs, their bioavailability and thus effectiveness strongly depend on their solubility in an aqueous environment are the sulfonylurea derivatives. These substances are currently used to lower blood sugar (diabetes mellitus).
Am Beispiel des bekanntesten Vertreters, dem Glibenclamid (INN) soll aufgezeigt werden, welchen Einfluß die Löslich¬ keit auf den Wirkungseintritt, die Wirksamkeit und die hierzu notwendige Dosis hat.Using the example of the best-known representative, glibenclamide (INN), the aim is to show what influence the solubility has on the onset of action, the effectiveness and the dose required for this.
Glibenclamid, im amerikanischen Sprachgebrauch auch als Glyburide bezeichnet, ist ein Sulfonylharnstoffderivat mit der chemischen IUPAC-Bezeichnung: N-4-2-(5-Chlor-2-meth- oxybenzamido)-ethyl-phenylsulfonyl-N'-cyclohexylharnstoff. Das Molekulargewicht beträgt 494,02, der Schmelzpunkt liegt bei 172 bis 174°C (vergl. R. Gröning: Arzneistoff¬ profile und Bioverfügbarkeitsdaten von Fertigarzneimit¬ teln, Arzneistoffmonographie Glibenclamid, Deutscher Apo¬ thekerverlag, Stuttgart, Seite 1 bis 7, 1987). Glibencla¬ mid ist eine geruchlose, kristalline, weiße Substanz, die in Wasser und Ether praktisch unlöslich, in Alkohol und Chloroform nur mäßig löslich ist. Mit Alkalien bildet sie Salze, die jedoch im Vergleich zu Tolbutamid, einer eben¬ falls blutzuckersenkenden Substanz, eine sehr begrenzte Löslichkeit in Wasser besitzen.Glibenclamide, also known as glyburide in American parlance, is a sulfonylurea derivative with the chemical IUPAC name: N-4-2- (5-chloro-2-methoxybenzamido) -ethyl-phenylsulfonyl-N'-cyclohexylurea. The molecular weight is 494.02, the melting point is 172 to 174 ° C (see R. Gröning: drug profiles and bioavailability data of finished drugs, drug monograph Glibenclamid, Deutscher Apothekerverlag, Stuttgart, pages 1 to 7, 1987) . Glibenclamide is an odorless, crystalline, white substance which is practically insoluble in water and ether and only moderately soluble in alcohol and chloroform. With alkalis it forms salts which, however, have a very limited solubility in water in comparison to tolbutamide, a substance which also lowers blood sugar.
Aufgrund der physikalisch-chemischen Strukturverwandt¬ schaft besitzen auch die anderen therapeutisch verwendeten Sulfonylharnstoffderivate, wie z.B. Glipizid, Glibornurid, Gliquidon, Glisoxepid und Glimeprid, alle ähnliche Lös- lichkeitseigenschaften.Due to the physico-chemical structure relationship, the other therapeutically used sulfonylurea derivatives, e.g. Glipizid, Glibornurid, Gliquidon, Glisoxepid and Glimeprid, all similar solubility properties.
Die oben erwähnten Sulfonylharnstoffderivate werden in Ta¬ gesdosen von 1-250 mg weltweit zur Behandlung der Zucker¬ krankheit (Diabetes mellitus) eingesetzt. Bei der eintre¬ tenden Blutzuckersenkung lassen sich zwei Mechanismen un¬ terscheiden, nämlich ein pankreatischer und extrapankrea- tischer Effekt (siehe Präparateinformation der Boehringer Mannheim GmbH und Hoechst AG, Frankfurt/ Main, 1984, zu EugluconR N, Semi-EugluconR N) .The above-mentioned sulfonylurea derivatives are used worldwide in daily doses of 1-250 mg for the treatment of sugar disease (diabetes mellitus). Two mechanisms can be distinguished in the event of a lowering of blood sugar, namely a pancreatic and an extra pancreatic. effect (see product information from Boehringer Mannheim GmbH and Hoechst AG, Frankfurt / Main, 1984, on Euglucon R N, Semi-Euglucon R N).
Die pankreatische Wirkung führt zu einer Verstärkung der Insulinsekretion durch eine erhöhte Ansprechbarkeit der Beta-Zellen des Pankreas auf Glucose.The pancreatic effect leads to an increase in insulin secretion through an increased responsiveness of the beta cells of the pancreas to glucose.
Der extrapankreatische Effekt zeigt sich bei einer Insu¬ linresistenz in einer Verstärkung der Insulinwirkung durch:In the case of insulin resistance, the extrapancreatic effect is shown by an increase in the insulin effect through:
- Erhöhung der Insulinempfindlichkeit und Insulinbindung des Zielgewebes:- Increase in insulin sensitivity and insulin binding of the target tissue:
- direkte Wirkung auf die Insulinrezeptoren im Sinne einer Vermehrung.- Direct effect on the insulin receptors in the sense of an increase.
Aufgrund der guten Wirksamkeit und Verträglichkeit derBecause of the good effectiveness and tolerability of
Sulfonylharnstoffderivate besitzen diese Präparate heute die größte Bedeutung bei der oralen Behandlung der Zucker¬ krankheit.These preparations have the greatest importance today in the oral treatment of sugar disease, sulfonylurea derivatives.
Es ist bekannt und in Untersuchungen belegt, daß zur Er¬ zielung eines therapeutischen Effekts nicht nur die Wirk¬ substanz, sondern auch deren pharmazeutisch-technologische Formulierung, auch als Galenik bezeichnet, von großer Be¬ deutung ist (vergl. H. Blume et al.: Zur Bioverfügbarkeit und pharmakodynamisehen Aktivität handelsüblicher Gliben- cla id-Fertigarzneimittel,It is known and has been proven in studies that not only the active substance, but also its pharmaceutical-technological formulation, also known as galenics, is of great importance for achieving a therapeutic effect (cf. H. Blume et al .: On the bioavailability and pharmacodynamic activity of commercially available finished Gliben-cla id medicinal products,
1. Mitteilung: Bioequivalenzprüfung an gesunden Probanden unter oraler Kohlenhydratbelastung: Pharm. Ztg., 130, 1062-1069, 1985;1st communication: bioequivalence test in healthy volunteers under oral carbohydrate exposure: Pharm. Ztg., 130, 1062-1069, 1985;
2. Mitteilung: Untersuchungen der glibenclamidinduzierten Veränderungen der Insulinkonzentration im Serum und der Blutglucosewerte an gesunden Probanden. Pharm. Ztg., 130, 1070-1078, 1985; 3. Mitteilung: Bioequivalenzprüfung an gesunden Probanden unter Dauerinfusion von Glucoselösung. Pharm. Ztg., 130, 2606-2610, 1985).2nd communication: Investigations of the glibenclamide-induced changes in the insulin concentration in the serum and the blood glucose values in healthy volunteers. Pharm. Ztg., 130, 1070-1078, 1985; 3rd communication: Bioequivalence test on healthy volunteers under continuous infusion of glucose solution. Pharm. Ztg., 130, 2606-2610, 1985).
Aus diesen Untersuchungen geht hervor, daß Glibenclamid aufgrund seiner geringen Wasserlöslichkeit und Lösungsge¬ schwindigkeit zu den biopharmazeutisch problematischen Arzneisubstanzen zählt. Die Wasserlöslichkeit ist zudem pH-abhängig, im sauren Bereich ist Glibenclamid praktisch wasserunlöslich.From these studies it can be seen that, due to its low solubility in water and speed of dissolution, glibenclamide is one of the biopharmaceutical problematic medicinal substances. The water solubility is also pH-dependent, in the acidic range glibenclamide is practically insoluble in water.
Bekannt ist ebenfalls, daß die Lösungsgeschwindigkeit von der Teilchengröße bzw. von der Ausdehnung der Partikel- Oberfläche abhängt (vergl. H. Borchert et al.: Zur pharma¬ zeutischen Qualität von Glibenclamid in Abhängigkeit von der Teilchengröße, Pharmazie, 3_1, 307-309, 1976). Bereits vor Jahren wurden deshalb Anstrengungen unternommen, die schlechte Löslichkeit und Lösungsgeschwindigkeit zu ver¬ bessern. Gefunden wurde, daß Zubereitungen mit mikroni- siertem, d.h. feinstzerkleinertem Glibenclamid (mittlere Partikelgröße > 5μm) vor allem in Gegenwart von Tensiden eine verbesserte Wirkstofffreisetzung und Bioverfügbarkeit zeigten (R. Gröning ibid., H. Borchert et al., ibid.).It is also known that the dissolution rate depends on the particle size or on the extent of the particle surface (cf. H. Borchert et al .: on the pharmaceutical quality of glibenclamide depending on the particle size, Pharmacy, 3_1, 307-309 , 1976). Efforts were therefore made years ago to improve the poor solubility and dissolution rate. It was found that preparations with micronized, i.e. Finely comminuted glibenclamide (average particle size> 5μm) showed improved active ingredient release and bioavailability, especially in the presence of surfactants (R. Groening ibid., H. Borchert et al., ibid.).
In der DE-OS 23 48 334 wird eine schnell resorbierbare Zu¬ bereitungsform von Glibenclamid und ein Verfahren zu ihrer Herstellung beschrieben. Glibenclamid wurde durch Feinst¬ vermahlung auf eine große, möglichst definierte Oberfläche oder durch feinstes Ausfällen aus organischen Lösungsmit¬ teln in Dispergiermittel zu gut und schnell resorbierbaren Zubereitungen verarbeitet. Mit den in der DE-OS 23 48 334 aufgeführten Methoden wurden Feinstkristallisate mit einer Oberflächengröße von 3 bis 10 m2 erhalten. Untersuchungen haben gezeigt, daß durch eine Oberflächenvergrößerung die Löslichkeit und Lösungsgeschwindigkeit erhöht werden, wo¬ durch auch die Bioverfügbarkeit verbessert wurde. Mit einer Glibenclamid-Tablette (Semi-EugluconR N) mit 1,75 mg Wirkstoffgehalt konnten diesselben Glibenclamid- Wirkstoffspiegel erzielt werden wie mit einer Tablette, die 2,5 mg Glibenclamid enthielt (EugluconR 2,5). Hierbei bestanden keine Unterschiede bezüglich der maximalen Se¬ rumkonzentrationen (cmax für beide Formulierungen ca. 100 ng/ml), während tmax (ca. 1 Stunde) etwa 1,5 Stunden frü¬ her erreicht wurde als mit der alten Formulierung Semi- EugluconR 2,5. Aus diesen Untersuchungen und aus verglei¬ chenden Studien zur Austauschbarkeit von glibenclamidhal- tigen Fertigarzneimitteln ist also ersichtlich, daß die Löslichkeit von Glibenclamid, bestimmt durch die Korn¬ bzw. Oberflächengröße, für die Bioverfügbarkeit und Wirk¬ samkeit der verschiedenen Präparate von großer Bedeutung ist, und bestimmte Präparate zur Substitution nicht ge¬ eignet sind (vergl. H. Blume et al.: Untersuchungen zur therapeutischen Relevanz und zur Chargenhomogenität gli- benclamidhaltiger Fertigarzneimittel, Pharm. Ztg., 132, 2352-2362, 1987).DE-OS 23 48 334 describes a rapidly absorbable form of preparation of glibenclamide and a process for its preparation. Glibenclamide was processed by fine grinding on a large, defined surface or by the finest precipitation from organic solvents in dispersing agents to form easily and quickly absorbable preparations. Using the methods listed in DE-OS 23 48 334, very fine crystals with a surface area of 3 to 10 m 2 were obtained. Studies have shown that increasing the surface area increases the solubility and dissolution rate, which also improves the bioavailability. With a glibenclamide tablet (Semi-Euglucon R N) with 1.75 mg active substance content, the same glibenclamide active substance level could be achieved as with a tablet containing 2.5 mg glibenclamide (Euglucon R 2.5). There were no differences in the maximum serum concentrations (c max for both formulations approx. 100 ng / ml), while t max (approx. 1 hour) was reached approx. 1.5 hours earlier than with the old formulation semi- Euglucon R 2.5. From these studies and from comparative studies on the interchangeability of finished medicinal products containing glibenclamide, it can be seen that the solubility of glibenclamide, determined by the particle size or surface area, is of great importance for the bioavailability and effectiveness of the various preparations. and certain preparations are not suitable for substitution (cf. H. Blume et al .: studies on the therapeutic relevance and the batch homogeneity of finished medicinal products containing gliblamide, Pharm. Ztg., 132, 2352-2362, 1987).
Es ist desweiteren bekannt, daß die Temperaturbelastung bei der Herstellung von Arzneiformen die Wirkstoffstabili¬ tät zu beeinflussen vermag. In der DE-OS 23 55 743 sind Beispiele aufgeführt, die zeigen, daß die Verarbeitung von Glibenclamid bei erhöhten Temperaturen, z.B durch Einar¬ beitung in Schmelzen von höhermolekularen Polyethylengly- kolen der Stabilität abträglich sind.It is also known that the temperature load in the manufacture of pharmaceutical forms can influence the stability of the active ingredient. DE-OS 23 55 743 lists examples which show that the processing of glibenclamide at elevated temperatures, for example by incorporation into melts of higher molecular weight polyethylene glycols, is detrimental to stability.
Nur wenige Handelspräparate, wie z.B. EugluconR N Tablet¬ ten besitzen in-vitro eine relativ schnelle Wirkstoffab¬ gabe von Glibenclamid und demzufolge in-vivo eine hinrei¬ chend rasche und gute Resorption bzw. Bioverfügbarkeit. Eine rasche Resorption des Wirkstoffs aus der Arzneiform bietet folgende Vorteile: 1. Aus Gründen der Einnahmementalität der Patienten kann die Arzneiform gleichzeitig mit der Nahrung verabreicht werden.Only a few commercial preparations, such as, for example, Euglucon R N tablets, have a relatively rapid release of active ingredient of glibenclamide in vitro and, consequently, a sufficiently rapid and good absorption or bioavailability in vivo. Rapid absorption of the active ingredient from the pharmaceutical form offers the following advantages: 1. For reasons of patient mentality, the dosage form can be administered simultaneously with the food.
2. Der Wirkstoff steht, genau abgestimmt, bedarfs- und zeitgerecht in-vivo zur Verfügung, womit das Auftreten von erhöhten oder stark schwankenden Blutzuckerwerten verhin¬ dert werden kann.2. The active substance is available in vivo, precisely coordinated, as and when required, which can prevent the occurrence of increased or strongly fluctuating blood sugar values.
3. Hyperglykämien, bedingt durch Nahrungsaufnahme oder sonstige Einflüsse, können verhindert bzw. rasch normali¬ siert werden.3. Hyperglycaemia, caused by food intake or other influences, can be prevented or quickly normalized.
Arzneiformen, die diesen Ansprüchen nach einer raschen Wirkstofffreisetzung nicht gerecht werden, bergen die Ge¬ fahr von Hyperglykämien, wenn keine ausreichende Menge Wirkstoff, aufgrund unzureichender Löslichkeit bzw. Frei¬ setzung, für die Resorption zur Verfügung steht. Voraus¬ setzung für eine rasche Resorption ist jedoch, daß der Wirkstoff aus der Arzneiform möglichst in gelöster bzw. kolloidal gelöster oder molekulardispers verteilter Form für die Freisetzung zur Verfügung steht. Nur wenn diese Bedingungen erfüllt sind, kann der Wirkstoff rasch resor¬ biert und damit wirksam werden.Pharmaceutical forms which do not meet these requirements for a rapid release of active substance harbor the risk of hyperglycaemia if an insufficient amount of active substance is available for absorption due to insufficient solubility or release. A prerequisite for rapid absorption is, however, that the active ingredient from the pharmaceutical form is available for release in a dissolved or colloidally dissolved or molecularly dispersed form, if possible. Only if these conditions are met can the active ingredient be rapidly absorbed and thus become effective.
Der vorliegenden Erfindung liegt daher die Aufgabe zu¬ grunde, ein Verfahren zur Verbesserung der Löslichkeit von schwerlöslichen Sulfonylharnstoffderivaten bereitzustel¬ len. Ferner sollen wirksame, den Wirkstoff schnell oder kontrolliert freisetzende und somit gut resorbierbare Zu¬ bereitungsformen von schwerlöslichen Sulfonylharnstoffde¬ rivaten, wie z.B. Glibenclamid, Glipizid, etc., bereitge¬ stellt werden.The present invention is therefore based on the object of providing a method for improving the solubility of poorly soluble sulfonylurea derivatives. Furthermore, effective, fast or controlled release and thus easily absorbable formulations of poorly soluble sulfonylurea derivatives, such as e.g. Glibenclamid, Glipizid, etc., are provided.
Die schwerlöslichen Wirkstoffe sollen mit einem einfachen Verfahren und pharmakologisch und toxikologisch unbedenk¬ lichen Hilfsstoffen möglichst molekulardispers in Lösung gebracht werden. Hierdurch soll der Wirkstoff feinst ver- teilt werden und infolge der großen Oberfläche eine gute Löslichkeit besitzen. Der molekulardispers verteilte Wirk¬ stoff soll zur Oberflächenvergrößerung auf übliche pharma¬ zeutische Trägermaterialien aufgezogen oder auch darin eingebettet werden, so daß eine Wirkstoff-Hilfsstoff-Le¬ gierung erhalten wird.The sparingly soluble active ingredients should be brought into solution in a molecularly disperse manner using a simple process and pharmacologically and toxicologically acceptable auxiliaries. The active ingredient should be divided and have good solubility due to the large surface area. The molecularly dispersed active ingredient is to be applied to customary pharmaceutical carrier materials or also embedded therein in order to increase the surface area, so that an active ingredient-auxiliary alloy is obtained.
Durch das molekulardisperse in Lösung bringen, können schwerlösliche Sulfonylharnstoffderivate schnell aus dem Magen-Darm-Trakt resorbiert werden. Zur Vermeidung von Hyperglykämien steht der Wirkstoff somit im Bedarfsfalle oder im Zusammenhang mit der Nahrungsaufnahme (z.B. durch Kohlenhydratzufuhr) sofort zur Verfügung.Due to the molecular dispersion in solution, poorly soluble sulfonylurea derivatives can be quickly absorbed from the gastrointestinal tract. To avoid hyperglycaemia, the active ingredient is immediately available when needed or in connection with food intake (e.g. through carbohydrate intake).
Das Verfahren zur Herstellung der erfindungsgemäßen Zube¬ reitungsformen soll technisch einfach durchzuführen sein, keine aufwendigen Apparaturen benötigen und keine kompli¬ zierten Verfahrensschritte aufweisen. Die Herstellung soll mit handelsüblichen Hilfsstoffen und einfachen Mitteln möglich sein. Darüberhinaus sollen durch das Herstellungs¬ verfahren die Wirk- bzw. Hilfsstoffe in ihren chemisch¬ physikalischen Eigenschaften nicht negativ beeinflußt wer¬ den.The process for producing the preparation forms according to the invention should be technically simple to carry out, require no complex apparatus and should not have any complicated process steps. The production should be possible with commercially available auxiliaries and simple means. In addition, the chemical or physical properties of the active substances or auxiliaries should not be adversely affected by the production process.
Überraschend wurde festgestellt, daß die benötigte Menge Polyethylenglykol unter Bezugnahme auf die Beispiele 1 und 2 in der DE-OS 23 55 743 um das bis zu 10-fache erniedrigt werden kann, wenn man die Sulfonylharnstoffderivate in ei¬ nem Alkohol, einem oder mehreren Polyol(en) und/oder in Zuckeralkoholen, die zuvor in Wasser oder Alkohol-Wasser- Gemischen aufgelöst wurden, suspendiert und das Gemisch nachfolgend mit 0,5 bis 2 Mol, vorzugsweise 1 Mol, Alkali¬ hydroxid oder Ammoniak versetzt.It was surprisingly found that the required amount of polyethylene glycol can be reduced up to 10 times with reference to Examples 1 and 2 in DE-OS 23 55 743 if the sulfonylurea derivatives are used in an alcohol, one or more polyol (s) and / or in sugar alcohols which have previously been dissolved in water or alcohol-water mixtures, and the mixture is subsequently mixed with 0.5 to 2 mol, preferably 1 mol, of alkali metal hydroxide or ammonia.
Das erfindungsgemäße Herstellungsverfahren ermöglicht also nicht nur eine Reduktion der erforderlichen Hilfsstoff- menge, sondern stellt auch gleichzeitig ein Wirkstoff- und hilfsstoffschonendes, einfaches Verfahren zur Lösung der schwerlöslichen Sulfonylharnstoffderivate dar.The manufacturing method according to the invention therefore not only enables a reduction of the required auxiliary substances quantity, but at the same time represents an easy and gentle method for dissolving the poorly soluble sulfonylurea derivatives.
Gegenstand der Erfindung sind hochwirksame, den Wirkstoff schnell oder kontrolliert freisetzende Zubereitungsformen von Sulfonylharnstoffderivaten, die dadurch gekennzeichnet sind, daß sie ein oder mehrere Sulfonylharnstoffderivat(e) als Wirkstoff(e) , ein oder mehrere Polyol(e) ausgenommen Polyethylenglykol und/oder einen oder mehrere Zuckeralko¬ hol(e), zuvor gelöst in Wasser oder Alkohol-Wasser-Gemi¬ schen, eine alkalisch reagierende Substanz und gegebenen¬ falls geeignete pharmazeutisch verträgliche Hilfs- oder Aromastoffe und gegebenenfalls weitere pharmazeutisch wirksame Stoffe enthalten.The invention relates to highly effective preparation forms of sulfonylurea derivatives which release the active ingredient quickly or in a controlled manner, which are characterized in that they contain one or more sulfonylurea derivative (s) as active ingredient (s), one or more polyol (s) with the exception of polyethylene glycol and / or one or several sugar alcohols, previously dissolved in water or alcohol-water mixtures, contain an alkaline substance and, if appropriate, suitable pharmaceutically acceptable auxiliaries or flavorings and, if appropriate, further pharmaceutically active substances.
Die Erfindung betrifft weiterhin ein Verfahren zur Her¬ stellung einer hochwirksamen, den Wirkstoff schnell oder kontrolliert freisetzenden Zubereitungsform von Sulfonyl¬ harnstoffderivaten, das dadurch gekennzeichnet ist, daß man ein oder mehrere Sulfonylharnstoffderivat(e) als Wirk¬ stoff(e), gegebenenfalls nach vorheriger Benetzung mit ei¬ nem Alkohol, in einem Alkohol oder einem oder mehreren Polyol(en) ausgenommen Polyethylenglykol und/oder einem oder mehreren Zuckeralkohol(en) , gelöst in Wasser oder ei¬ nem Alkohol-Wasser-Gemisch, suspendiert, mit einer alka¬ lisch reagierenden Substanz versetzt und gegebenenfalls weitere geeignete pharmazeutisch verträgliche Hilfs- und Aromastoffe und gegebenenfalls weitere pharmazeutisch wirksame Stoffe zusetzt, bis eine feste oder flüssige Zubereitungsform erhalten wird.The invention further relates to a method for producing a highly effective preparation of sulfonylurea derivatives which releases the active ingredient quickly or in a controlled manner, which is characterized in that one or more sulfonylurea derivative (s) are used as active ingredient (s), if appropriate after the previous one Wetting with an alcohol, in an alcohol or one or more polyol (s) except polyethylene glycol and / or one or more sugar alcohol (s), dissolved in water or an alcohol / water mixture, suspended, with an alkali mixed reacting substance and optionally adding other suitable pharmaceutically acceptable auxiliary and flavoring agents and optionally other pharmaceutically active substances until a solid or liquid preparation form is obtained.
Bevorzugt enthalten die Zubereitungsformen in Bezug auf einen Teil Wirkstoff 1 bis 1000 Teile Propylenglykol, Gly- cerin, Hexylenglykol oder Gemische davon und/oder 1 bis 500 Teile Zuckeralkohole, gelöst in 2 bis 2000 Teilen Was- ser oder Alkohol-Wasser-Gemischen sowie 0,5 bis zu 3 Mol, bevorzugt 1 Mol, alkalisch reagierender Substanz sowie ge¬ gebenenfalls 0,01 bis 1000 Teile pharmazeutisch verträgli¬ che Hilfs- und Aromastoffe.The preparation forms preferably contain 1 to 1000 parts of propylene glycol, glycerol, hexylene glycol or mixtures thereof and / or 1 to 500 parts of sugar alcohols, dissolved in 2 to 2000 parts of water, in relation to one part of active ingredient. water or alcohol-water mixtures and 0.5 to 3 moles, preferably 1 mole, of an alkaline substance and, if appropriate, 0.01 to 1000 parts of pharmaceutically compatible auxiliaries and flavorings.
Bevorzugt wird bei dem erfindungsgemäßen Verfahren 1 Teil schwerlösliches Sulfonylharnstoffderivat in 3 bis 1000 Teilen Ethanol oder Polyolen wie Propylenglykol etc. oder Zuckeralkoholen, die zuvor in Wasser oder Wasser-Ethanol- Gemischen gelöst wurden, suspendiert, mit 0,5 bis 2 Mol, vorzugsweise etwa 1 Mol, einer alkalisch reagierenden Sub¬ stanz sowie gegebenenfalls weiteren pharmazeutisch ver¬ träglichen Hilfs- und Aromastoffen so vermischt, daß eine flüssige oder feste Zubereitungsform erhalten wird.In the process according to the invention, 1 part of sparingly soluble sulfonylurea derivative is preferably suspended in 3 to 1000 parts of ethanol or polyols such as propylene glycol etc. or sugar alcohols which have previously been dissolved in water or water / ethanol mixtures, with 0.5 to 2 mol, preferably about 1 mole, an alkaline substance and optionally other pharmaceutically acceptable auxiliaries and flavorings are mixed so that a liquid or solid preparation is obtained.
Die Sulfonylharnstoffderivate können beliebige Sulfonyl¬ harnstoffderivate sein. Sie sind bevorzugt Glibenclamid (Glyburid), Glipizid, Glimeprid, Gliquidon, Glisoxepid, Glibornurid, Glicalzid, Glisentid, Glisolamid, Glybuzol, Glyclopyramid und Glyclamid.The sulfonylurea derivatives can be any sulfonylurea derivatives. They are preferably glibenclamide (glyburide), glipizide, glimeprid, gliquidon, glisoxepid, glibornuride, glicalzide, glisentide, glisolamide, glybuzole, glyclopyramide and glyclamide.
Als Polyole können pharmazeutisch verträgliche nicht to¬ xische Produkte, wie z.B. Glycerin, Propylenglykol, Hexylenglykol oder Gemische davon, sowie Zuckeralkohole, wie z.B. Sorbit, Mannit, Xylit, Isomalt oder Gemische da¬ von gelöst in Wasser oder Alkohol-Wasser-Gemischen einge¬ setzt werden. Die Zuckeralkohole werden bevorzugt in einer Konzentration von 10% bis 70% in Wasser oder Ethanol-Was- ser-Gemischen gelöst.Pharmaceutically acceptable non-toxic products, such as e.g. Glycerin, propylene glycol, hexylene glycol or mixtures thereof, and sugar alcohols, such as e.g. Sorbitol, mannitol, xylitol, isomalt or mixtures thereof in solution in water or alcohol-water mixtures are used. The sugar alcohols are preferably dissolved in a concentration of 10% to 70% in water or ethanol-water mixtures.
Die alkalisch reagierende Substanz kann jede beliebige pharmazeutisch verträgliche und toxikologisch unbedenk¬ liche alkalisch reagierende Substanz sein, wie Alkali¬ bzw. Erdalkalihydroxide oder Ammoniak, die mit Sulfonyl¬ harnstoffen Salze bilden können. Sie wird bevorzugt in ei- - in ¬The alkaline substance can be any pharmaceutically acceptable and toxicologically acceptable alkaline substance, such as alkali or alkaline earth metal hydroxides or ammonia, which can form salts with sulfonylureas. It is preferred in a - in ¬
ner Menge von 0,5 bis 2 Mol, mehr bevorzugt etwa 1 Mol, bezogen auf das Sulfonylharnstoffderivat, eingesetzt.ner amount of 0.5 to 2 mol, more preferably about 1 mol, based on the sulfonylurea derivative used.
Die Zubereitungen können weiterhin pharmazeutisch verträg¬ liche und toxikologisch unbedenkliche Hilfs- und Aroma¬ stoffe enthalten, wie sie üblicherweise in festen oder flüssigen Darreichungsformen eingesetzt werden. Darunter sind übliche Excipientien, wie Lactose, Stärke, mikrokri¬ stalline Cellulose, Croscarmelose, Calciumcarbonat, Calci- umdiphosphat, Pluronic-Polyole, Celluloseether, Alginsäu- rederivate, Eudragit, Magnesiumstearat, Siliciumdioxid, Farbstoffe, Zuckeraustauschstoffe, Konservierungsstoffe, Puffersubstanzen, Isotonisierungszusätze, oberflächenak¬ tive Verbindungen, Aromastoffe, Zäpfchenmassen, etc., al¬ lein oder im Gemisch, zu erwähnen. Ferner kann die Zube¬ reitung als Aromastoffe Zuckeraustauschstoffe, wie Fruc- tose, Saccharin, Aspartam, etc., sowie Konservierungs- stoffe, wie z.B. Para-Hydroxybenzoesäureester, Benzylalko- hole, Sorbinsäure oder Salze davon in einer Konzentration von 0,1 bis 2 Gew.-% der Formulierung enthalten. Ferner können der Zubereitungsform noch weitere pharmazeutisch wirksame Stoffe zugesetzt werden. Dies sind bevorzugt weitere blutzuckersenkende Medikamente, wie z.B. α-Gluco- sidase-Inhibitoren, wie z.B. Acarbose, Miglitol oder Al- dose-Reductase-Inhibitoren, wie z.B. Alrestatin-Natrium oder Voglibase. Dabei können diese weiteren Wirkstoffe entweder getrennt von oder zusammen mit den Sulfonylharn- stoffen formuliert werden.The preparations can furthermore contain pharmaceutically compatible and toxicologically acceptable auxiliaries and flavorings, as are usually used in solid or liquid dosage forms. These include customary excipients, such as lactose, starch, microcrystalline cellulose, croscarmelose, calcium carbonate, calcium diphosphate, Pluronic polyols, cellulose ethers, alginic acid derivatives, Eudragit, magnesium stearate, silicon dioxide, colorants, sugar substitutes, preservatives, isotropic substances, buffering agents, surface-buffering substances, surface-active substances ¬ active compounds, flavorings, suppositories, etc., alone or in a mixture, to mention. The preparation can also be used as flavoring substances, sugar substitutes, such as fructose, saccharin, aspartame, etc., as well as preservatives, such as e.g. Para-hydroxybenzoic acid esters, benzyl alcohols, sorbic acid or salts thereof in a concentration of 0.1 to 2 wt .-% of the formulation. Furthermore, other pharmaceutically active substances can be added to the preparation form. These are preferably other blood sugar lowering drugs, such as α-glucosidase inhibitors, such as e.g. Acarbose, miglitol or aldose reductase inhibitors, such as e.g. Alrestatin sodium or Voglibase. These other active ingredients can be formulated either separately from or together with the sulfonylureas.
Die Zubereitungsformen können in flüssiger, fester oder halbfester Form vorliegen. Flüssige Darreichungsformen sind z.B. Lösungen zur oralen (Säfte, Tropfen), nasalen (Nasentropfen, Nasensprays) oder parenteralen (Injektion oder Infusion) Applikation. Feste und halbfeste Darrei¬ chungsformen können beispielsweise ein Granulat (Trocken¬ saft, Sachets), Tabletten, Kapseln, Pellets, Filmtablet- ten, Dragees und Zäpfchen sein. Die Arzneiformen können hierbei so formuliert werden, daß der gesamte Wirkstoff entweder innerhalb kürzester Zeit oder zeitkontrolliert freigesetzt wird.The preparation forms can be in liquid, solid or semi-solid form. Liquid dosage forms are, for example, solutions for oral (juices, drops), nasal (nasal drops, nasal sprays) or parenteral (injection or infusion) application. Solid and semi-solid dosage forms can be, for example, granules (dry juice, sachets), tablets, capsules, pellets, film-coated tablets. be dragées and suppositories. The dosage forms can be formulated in such a way that the entire active ingredient is released either within a very short time or in a time-controlled manner.
Flüssige Darreichungsformen, wie z.B. Tropflösungen sind bislang für die Therapie als Handelsprodukte nicht erhält¬ lich. Die Tropflösung erlaubt eine individuelle, dem Krankheitszustand und der Nahrungszufuhr angepaßte Dosie¬ rung. Aufgrund der Tatsache, daß in der erfindungsgemäßen Zubereitung der Wirkstoff molekulardispers gelöst vor¬ liegt, steht er für die Resorption direkt zur Verfügung und erlaubt dadurch eine rasche Resorption und optimale Bioverfügbarkeit.Liquid dosage forms, e.g. Drip solutions have so far not been available for therapy as commercial products. The drip solution allows an individual dosage adapted to the disease state and the food supply. Due to the fact that the active ingredient is present in a molecularly dispersed form in the preparation according to the invention, it is directly available for absorption and thus allows rapid absorption and optimal bioavailability.
Der jeweils verwendete Alkohol ist bevorzugt Ethanol in 94 bis 96%iger pharmazeutischer Qualität und Reinheit gemäß den Anforderungen des Arzneibuchs. Gegebenenfalls können auch 90%iger oder 70%iger Ethanol verwendet werden, d.h. z.B. Gemische aus 90 Teilen Ethanol und 10 Teilen Wasser. Je nach der Löslichkeit des verwendeten Sulfonylharnstoff- derivats kann es zweckmäßig sein, den Wirkstoff zur besse¬ ren Benetzung zuerst in einem Alkohol, bevorzugt Ethanol, zu dispergieren und danach mit dem Zuckeralkohol, der zu¬ vor in Wasser oder einem Alkohol-Wasser-Gemisch, bevorzugt einem Ethanol-Wasser-Gemisch, gelöst wurde, zu suspendie¬ ren. Es können auch andere Alkohole als Ethanol verwendet werden, z.B. Methanol oder Isopropanol, gegebenenfalls in Verdünnung mit Wasser. Aufgrund der physiologischen Unver¬ träglichkeit muß jedoch sichergestellt werden, daß diese Alkohole im Laufe des Herstellungsverfahrens gänzlich ent¬ fernt werden können. Ethanol ist toxikologisch unbedenk¬ lich und wird deshalb bevorzugt verwendet, weil er - im Gegensatz zu den anderen Alkoholen - auch im Endprodukt enthalten sein kann. Blume et al. (Ph. Ztg. 132, 39, 2352/101-2362/111, 1987) belegten in vergleichenden in-vitro/in-vivo Untersuchun¬ gen, daß die Bioverfügbarkeit und Wirkung direkt von der Auflösungsgeschwindigkeit des Wirkstoffes abhängt und der Wirkstoff um so rascher verfügbar ist, je schneller er in- vitro freigesetzt wird. Bei 3 Chargen des generischen Prä¬ parates Glykolande N mit in-vitro Dissolutionsraten von weniger als 80% innerhalb von 30 min streuten die pharma- kokinetischen Parameter für tmaϊC von 2,3 bis 3,3 h und für craax von 120 bis 133 ng/ml x h. Blume et al. publizierten 1992 in der Pharmazeutischen Zeitung Nr. 40, 137. Jahrgang Untersuchungen zur pharmazeutischen Qualität glibenclamid- haltiger Fertigarzneimittel von in Deutschland handelsüb¬ lichen 3,5 mg Präparaten im Vergleich zu den in anderen EG-Mitgliedstaaten verfügbaren Produkten. Aus den in-vitro Dissolutionskurven der verschiedenen Präparate geht her¬ vor, daß nur sehr wenige Präparate eine hinreichende in- vitro Wirkstofffreisetzung aufweisen.The alcohol used in each case is preferably ethanol in 94 to 96% pharmaceutical quality and purity according to the requirements of the pharmacopoeia. If necessary, 90% or 70% ethanol can also be used, eg mixtures of 90 parts of ethanol and 10 parts of water. Depending on the solubility of the sulfonylurea derivative used, it may be expedient to first disperse the active ingredient in an alcohol, preferably ethanol, for better wetting, and then with the sugar alcohol, previously in water or an alcohol-water mixture , preferably an ethanol-water mixture, has been suspended. Alcohols other than ethanol can also be used, for example methanol or isopropanol, optionally in dilution with water. Due to the physiological incompatibility, however, it must be ensured that these alcohols can be removed completely in the course of the production process. Ethanol is toxicologically harmless and is therefore preferred because - unlike the other alcohols - it can also be contained in the end product. Blume et al. (Ph. Ztg. 132, 39, 2352 / 101-2362 / 111, 1987) demonstrated in comparative in-vitro / in-vivo investigations that the bioavailability and activity depend directly on the dissolution rate of the active ingredient and the active ingredient all the more the faster it is released, the faster it is released in vitro. In 3 batches of the generic preparation Glykolande N with in vitro dissolution rates of less than 80% within 30 min, the pharmacokinetic parameters for t maϊC varied from 2.3 to 3.3 h and for c raax from 120 to 133 ng / ml x h. Blume et al. published in 1992 in the Pharmaceutical Newspaper No. 40, 137th year, studies on the pharmaceutical quality of glibenclamide-containing finished medicinal products of 3.5 mg preparations commercially available in Germany compared to the products available in other EC member states. From the in vitro dissolution curves of the various preparations, it can be seen that only very few preparations have a sufficient in vitro release of active ingredient.
Beispielsweise erfolgte aus Glibenclamid-Tabletten, die entsprechend dem erfindungsgemäßen Verfahren hergestellt wurden, im in-vitro Dissolutionstest (Paddle-Apparatur ge¬ mäß USP XXII, 75 Umdrehungen pro Minute, Puffer pH 7,4, UV-Messung bei 227 nm) eine 100%ige Freisetzung des Wirk¬ stoffes innerhalb von 5 bis 15 min, wie den beigefügten Abbildungen entnommen werden kann. In einer pharmakokine- tischen Untersuchung an 12 Freiwilligen erhielt man eine cmβϊC von 189 ng/ml, tmax von 1,7 h und eine AUC von 635 ng x h/ml. Die gleichzeitig ermittelte Senkung der Blutglu- cose beweist, daß mit dem erfindungsgemäßen Verfahren eine sehr gute Bioverfügbarkeit und Wirksamkeit erzielt werden kann.For example, a 100 was obtained from glibenclamide tablets which were produced in accordance with the method according to the invention in an in vitro dissolution test (paddle apparatus according to USP XXII, 75 revolutions per minute, buffer pH 7.4, UV measurement at 227 nm) % release of the active ingredient within 5 to 15 minutes, as can be seen in the attached figures. In a pharmacokinetic study on 12 volunteers, a c mβϊC of 189 ng / ml, t max of 1.7 h and an AUC of 635 ng xh / ml were obtained. The reduction in blood glucose determined at the same time proves that very good bioavailability and effectiveness can be achieved with the method according to the invention.
Die Erfindung wird anhand der beigefügten Figuren näher erläutert. Darin zeigt Figur 1 eine Kurve zur in-vitro Dissolution von verschie¬ denen Glibenclamid-Präparaten gemäß der Pharmazeutischen Zeitung a.a.O. ;The invention is explained in more detail with reference to the attached figures. In it shows 1 shows a curve for the in vitro dissolution of various glibenclamide preparations according to the Pharmaceutical Newspaper loc. Cit.;
Figur 2 die erfindungsgemäße Glibenclamid-Formulierung im Vergleich zu Euglucon N.FIG. 2 the glibenclamide formulation according to the invention in comparison to Euglucon N.
Nachstehend wird das erfindungsgemäße Herstellungsverfah¬ ren näher erläutert.The production method according to the invention is explained in more detail below.
Das Verfahren zur Herstellung flüssiger Darreichungsformen ist einfach. Das schwerlösliche Sulfonylharnstoffderivat, wie z.B. Glibenclamid, wird in einem Rührkessel in 4 bis 1000 Teilen Propylenglykol, Hexylenglykol oder Zuckeralko¬ holen, zuvor gelöst in Wasser oder einem Ethanol-Wasser- Gemisch unter Rühren, suspendiert und solange mit alka¬ lisch reagierender Substanz, wie z.B. 0,1 molarer Am¬ moniaklösung oder Natronlauge versetzt, bis eine homogene Lösung erhalten wird. Diese Lösung kann dann gegebenen¬ falls mit weiteren geeigneten Hilfsstoffen, wie z.B. Was¬ ser, Süß-, Aroma- und Konservierungsstoffen, gemischt wer¬ den und dann als flüssige pharmazeutische Darreichungsform (z.B. als Tropflösung oder Saft) therapeutisch zur Blut¬ zuckersenkung verwendet werden.The process for producing liquid dosage forms is simple. The sparingly soluble sulfonylurea derivative, e.g. Glibenclamide is suspended in a stirred kettle in 4 to 1000 parts of propylene glycol, hexylene glycol or sugar alcohols, previously dissolved in water or an ethanol-water mixture with stirring, and as long as with an alkali-reacting substance, e.g. 0.1 molar ammonia solution or sodium hydroxide solution are added until a homogeneous solution is obtained. This solution can then, if necessary, with other suitable auxiliaries, such as Water, sweeteners, flavorings and preservatives are mixed and then used therapeutically to lower blood sugar as a liquid pharmaceutical dosage form (e.g. as a drip solution or juice).
Zur Herstellung fester Darreichungsformen wird eine unver¬ dünnte Wirkstofflösung auf Tablettierhilfsstoffe, wie z.B. Stärke, Lactose, Mannit, mikrokristalline Cellulose oder Sprengmittel, in einem handelsüblichen Mischkessel oder Wirbelschichtgranulator aufgezogen. Überschüssiger Alko¬ hol, Ammoniak oder auch Wasser können anschließend im Trockenschrank entfernt werden.To produce solid dosage forms, an undiluted active ingredient solution is used on tableting aids, e.g. Starch, lactose, mannitol, microcrystalline cellulose or disintegrant, grown in a commercial mixing kettle or fluidized bed granulator. Excess alcohol, ammonia or water can then be removed in the drying cabinet.
Bevorzugt ist es, die Lösung feinstverteilt auf pharmazeu¬ tisch gebräuchliche Hilfsstoffe, wie z.B. Mannit, Lactose, Stärke, mikrokristalline Cellulose oder Sprengmittel, Dis- persionsmittel oder Gemische davon aufzuziehen. Mit einem solchen Vorgehen wird der Wirkstoff quasi molekulardispers bzw. als Wirkstofflegierung auf einer großen Oberfläche verteilt.It is preferred to distribute the solution in a very finely divided form on adjuvants customary in pharmacy, such as mannitol, lactose, starch, microcrystalline cellulose or disintegrants persistence agents or mixtures thereof. With such a procedure, the active substance is distributed in a quasi-molecularly dispersed manner or as an active substance alloy on a large surface.
Das erfindungsgemäß molekulardispers verteilte, als feste Lösung aufgezogene Glibenclamid ist so fein dispergiert und so gut benetztbar, daß eine weitere Steigerung der Lö¬ sungsgeschwindigkeit theoretisch nicht mehr möglich sein sollte. Der Wirkstoff geht sofort mit dem Tablettenzerfall molekulardispers in Lösung, wie anhand von in-vitro Frei¬ setzungsuntersuchungen mit Glibenclamid-haltigen Tabletten gezeigt werden konnte. Nach dem Noyes-Whitney-Gesetz ist die Lösungsgeschwindigkeit umso schneller, je größer die benetzbare Oberfläche der zu lösenden Partikel ist.The molecularly dispersed glibenclamide distributed as a solid solution according to the invention is so finely dispersed and so wettable that a further increase in the rate of solution should theoretically no longer be possible. The active ingredient immediately dissolves with the disintegration of the molecules in a molecularly disperse manner, as has been shown by in-vitro release studies with tablets containing glibenclamide. According to the Noyes-Whitney law, the larger the wettable surface of the particles to be dissolved, the faster the dissolution rate.
Die erfindungsgemäß verwendeten Sulfonylharnstoffderivate werden üblicherweise in Tagesdosen von 1 bis 250 mg in Ab¬ hängigkeit von dem eingesetzten Sulfonylharnstoffderivat verabreicht. Diese Dosis kann zu Einfach- oder Mehrfachdo¬ sen, ausgehend von den erfindungsgemäß gelösten Sulfonyl¬ harnstoffderivaten, nach einem dem Fachmann bekannten Ver¬ fahren formuliert werden. Die genau zu verabreichende Do¬ sis kann von dem behandelnden Arzt je nach der Schwere des zu behandelnden Zustands und dem Patienten eingestellt werden.The sulfonylurea derivatives used according to the invention are usually administered in daily doses of 1 to 250 mg, depending on the sulfonylurea derivative used. This dose can be formulated into single or multiple doses, starting from the sulfonylurea derivatives dissolved according to the invention, according to a method known to the person skilled in the art. The exact dose to be administered can be adjusted by the treating doctor depending on the severity of the condition to be treated and the patient.
Die Erfindung wird anhand der nachstehenden Beispiele nä¬ her erläutert.The invention is illustrated by the examples below.
B e i s p i e l 1Example 1
3,5 g Glibenclamid werden in 700 g Propylenglykol unter Rühren suspendiert und mit 7,1 g 0,1N Natronlauge ver¬ setzt. B e i s p i e l 23.5 g of glibenclamide are suspended in 700 g of propylene glycol with stirring and mixed with 7.1 g of 0.1N sodium hydroxide solution. Example 2
4,5 g Glipizid werden unter Rühren in 80 g Hexylenglykol und 20 g 70%iger wäßriger Sorbitlösung gemischt und so¬ lange mit Ammoniaklösung 2%ig (G/V) versetzt, bis eine Lösung erhalten wird.4.5 g of glipizide are mixed with stirring in 80 g of hexylene glycol and 20 g of 70% aqueous sorbitol solution and 2% (w / v) ammonia solution is added until a solution is obtained.
B e i s p i e l 3Example 3
1 g Glimeprid wird in 200 g Propylenglykol und 50 g 20%iger wäßriger Xylitlösung gerührt und solange mit 0,1N Kalilauge versetzt, bis eine Lösung erhalten wird.1 g of glimeprid is stirred in 200 g of propylene glycol and 50 g of 20% aqueous xylitol solution, and 0.1N potassium hydroxide solution is added until a solution is obtained.
B e i s p i e l 4Example 4
8 g Glisoxepid werden in 1000 g Propylenglykol gemischt und solange mit 0,5N Natronlauge versetzt, bis eine Lösung erhalten wird.8 g of glisoxepid are mixed in 1000 g of propylene glycol and 0.5N sodium hydroxide solution is added until a solution is obtained.
B e i s p i e l 5Example 5
10 g Glipizid werden in 80 g Ethanol und 35 g 70%iger Sor¬ bitlösung suspendiert und solange mit Ammoniaklösung 5%ig (G/V) versetzt, bis eine Lösung erhalten wird. Diese wird auf 360 g Lactose aufgezogen. Nach dem Trocknen und Sieben wird ein Granulat erhalten. Dies kann anschließend mit 100 g einer Tablettierhilfsstoffmischung versetzt und zu Ta¬ bletten verpreßt werden.10 g of glipizide are suspended in 80 g of ethanol and 35 g of 70% sorbent solution and 5% (w / v) ammonia solution is added until a solution is obtained. This is grown on 360 g lactose. After drying and sieving, granules are obtained. This can then be mixed with 100 g of a tabletting auxiliary mixture and pressed into tablets.
B e i s p i e l 6Example 6
10 g Glibornurid werden in 60 g 80%igem Isopropanol sus¬ pendiert, mit 100 g Sorbitlösung 70% vermischt und solange mit Ammoniaklösung 5%ig (G/V) versetzt, bis eine Lösung erhalten wird. Diese wird dann auf eine Mischung aus 50 g mikrokristalliner Cellulose, 350 g Lactose und 50 g Mais¬ stärke aufgezogen und nach dem Sieben und Trocknen unter Zugabe von 50 g Sprengmittel und jeweils 1% Magnesiumstea- rat und Siliciumdioxid verpreßt.10 g of glibornuride are suspended in 60 g of 80% isopropanol, mixed with 100 g of 70% sorbitol solution and 5% (w / v) ammonia solution is added until a solution is obtained. This is then drawn onto a mixture of 50 g of microcrystalline cellulose, 350 g of lactose and 50 g of corn starch and, after sieving and drying, under Add 50 g disintegrant and 1% magnesium stearate and silicon dioxide each.
B e i s p i e l 7Example 7
5 g Glibenclamid werden in 50 g Ethanol und 50 g Karion F (70%ige Sorbitlösung) suspendiert und solange mit 0,5N Na¬ tronlauge versetzt, bis eine Lösung erhalten wird. Diese wird auf eine Mischung aus 315 g Lactose und 50 g Mais¬ stärke, 20 g mikrokristalliner Cellulose und 72 g Acarbose aufgezogen, gesiebt und granuliert. Nach Vermischen mit jeweils 0,5% Siliciumdioxid und Magnesiumstearat werden jeweils 350 mg Pulvermischung in Hartgelatinekapseln abge¬ füllt. 5 g of glibenclamide are suspended in 50 g of ethanol and 50 g of Karion F (70% sorbitol solution) and 0.5N sodium hydroxide solution is added until a solution is obtained. This is grown on a mixture of 315 g lactose and 50 g corn starch, 20 g microcrystalline cellulose and 72 g acarbose, sieved and granulated. After mixing with 0.5% silicon dioxide and magnesium stearate in each case, 350 mg of powder mixture are filled into hard gelatin capsules.

Claims

Ansprüche Expectations
1. Hochwirksame, den Wirkstoff schnell oder kontrolliert freisetzende Zubereitungsform von Sulfonylharnstoffderiva¬ ten, dadurch g e k e n n z e i c h n e t, daß sie ein oder mehrere Sulfonylharnstoffderivat(e) als Wirkstoff(e) , ein oder mehrere Polyol(e) und/oder Zuckeralkohol(e) ausgenommen Polyethylenglykol, zuvor gelöst in Wasser oder Alkohol-Wasser-Gemischen, eine alkalisch reagierende Sub¬ stanz und gegebenenfalls geeignete pharmazeutisch verträg¬ liche Hilfs- und Aromastoffe und gegebenenfalls weitere pharmazeutisch wirksame Stoffe enthält.1. Highly effective form of preparation of sulfonylurea derivatives, which releases the active ingredient quickly or in a controlled manner, characterized in that it contains one or more sulfonylurea derivative (s) as active ingredient (s), one or more polyol (s) and / or sugar alcohol (s) with the exception of polyethylene glycol , previously dissolved in water or alcohol-water mixtures, contains an alkaline substance and, if appropriate, suitable pharmaceutically acceptable auxiliaries and flavorings and, if appropriate, further pharmaceutically active substances.
2. Zubereitungsform nach Anspruch 1, dadurch g e ¬ k e n n z e i c h n e t, daß sie 1 bis 1000 Teile Poly- ol(e) und/oder Zuckeralkohol(e) , gelöst in 2 bis 2000 Teilen Wasser oder Alkohol-Wasser-Gemischen, 0,5 bis 3 Mol einer alkalisch reagierenden Substanz, 0,01 bis 1000 Teile pharmazeutisch verträgliche Hilfs- und Aromastoffe, bezo¬ gen auf 1 Teil Arzneistoff, enthält.2. Form of preparation according to claim 1, characterized ge ¬ indicates that it 1 to 1000 parts of polyol (s) and / or sugar alcohol (s), dissolved in 2 to 2000 parts of water or alcohol-water mixtures, 0.5 to 3 moles of an alkaline substance, 0.01 to 1000 parts of pharmaceutically acceptable auxiliaries and flavorings, based on 1 part of drug.
3. Zubereitungsform nach Anspruch 1 oder 2, dadurch g e k e n n z e i c h n e t, daß sie als Sulfonylharn- stoffderivat Glibenclamid (Glyburid), Glipizid, Glimeprid, Gliquidon, Glisoxepid, Glibornurid, Glicalzid, Glisentid, Glisolamid, Glybuzol, Glyclopyramid oder Glyclamid ent¬ hält.3. Form of preparation according to claim 1 or 2, characterized in that it is used as a sulfonylurea derivative glibenclamide (glyburide), glipizide, glimeprid, gliquidon, glisoxepid, glibornuride, glicalzide, glisentide, glisolamide, glybuzolide or glyclopyid, glyclopyid, or glyclopylol.
4. Zubereitungsform nach einem der Ansprüche 1 bis 3, dadurch g e k e n n z e i c h n e t, daß sie als Zucker¬ alkohol eine 70%ige Sorbitlösung oder Glykole enthält.4. Form of preparation according to one of claims 1 to 3, characterized in that it contains a 70% sorbitol solution or glycols as sugar alcohol.
5. Zubereitungsform nach einem der Ansprüche 1 bis 4, dadurch g e k e n n z e i c h n e t, daß sie in Form ei¬ ner flüssigen Darreichungsform vorliegt. 5. Form of preparation according to one of claims 1 to 4, characterized in that it is in the form of a liquid dosage form.
6. Zubereitungsform nach einem der Ansprüche 1 bis 4, dadurch g e k e n n z e i c h n e t, daß sie in Form ei¬ ner festen Lösung bzw. Legierung vorliegt.6. Form of preparation according to one of claims 1 to 4, characterized in that it is in the form of a solid solution or alloy.
7. Verfahren zur Herstellung einer hochwirksamen, den Wirkstoff schnell oder kontrolliert freisetzenden Zuberei¬ tungsform von Sulfonylharnstoffderivaten, dadurch g e ¬ k e n n z e i c h n e t, daß man ein oder mehrere Sulfo¬ nylharnstoffderivat(e) als Wirkstoff(e) , gegebenenfalls nach vorheriger Benetzung mit einem Alkohol, in einem oder mehreren Polyol(en) und/oder Zuckeralkohol(en) ausgenommen Polyethylenglykol, die zuvor in Wasser in Wasser oder ei¬ nem Alkohol-Wasser-Gemisch gelöst wurden, suspendiert, mit einer alkalisch reagierenden Substanz versetzt und gegebe¬ nenfalls weitere geeignete pharmazeutisch verträgliche Hilfs- und Aromastoffe und gegebenenfalls weitere pharma¬ zeutisch wirksame Stoffe zusetzt, bis eine feste oder flüssige Zubereitungsform erhalten wird.7. A process for the preparation of a highly effective preparation of sulfonylurea derivatives which releases the active ingredient quickly or in a controlled manner, characterized in that one or more sulfonylurea derivative (s) are used as active ingredient (s), if appropriate after prior wetting with an alcohol, suspended in one or more polyol (s) and / or sugar alcohol (s), with the exception of polyethylene glycol, which had previously been dissolved in water in water or an alcohol-water mixture, mixed with an alkaline substance and, if appropriate, other suitable substances Add pharmaceutically acceptable auxiliary and flavoring substances and optionally other pharmaceutically active substances until a solid or liquid preparation form is obtained.
8. Verfahren nach Anspruch 7, dadurch g e k e n n ¬ z e i c h n e t, daß man 1 Teil Wirkstoff in 1 bis 1000 Teilen Polyol(e) und/oder Zuckeralkohol(en) gelöst in 2 bis 2000 Teilen Wasser oder Alkohol-Wasser-Gemischen sus¬ pendiert und 0,5 bis 3 Mol einer alkalisch reagierenden Substanz zusetzt und gegebenenfalls mit weiteren geeigne¬ ten pharmazeutisch verträglichen Hilfs- und Aromastoffen so vermischt, daß eine flüssige oder feste Zubereitungs¬ form erhalten wird.8. The method according to claim 7, characterized in that 1 part of active ingredient in 1 to 1000 parts of polyol (s) and / or sugar alcohol (s) in 2 to 2000 parts of water or alcohol-water mixtures is suspended and suspended 0.5 to 3 mol of an alkaline substance is added and, if necessary, mixed with other suitable pharmaceutically acceptable auxiliaries and flavorings in such a way that a liquid or solid preparation is obtained.
9. Verfahren nach Anspruch 7 oder 8, dadurch g e ¬ k e n n z e i c h n e t, daß das Sulfonylharnstoffderivat Glibenclamid (Glyburid), Glipizid, Glimeprid, Gliquidon, Glisoxepid, Glibornurid, Glicalzid, Glisentid, Glisolamid, Glybuzol, Glyclopyramid oder Glyclamid ist. 9. The method according to claim 7 or 8, characterized ge ¬ indicates that the sulfonylurea derivative glibenclamide (glyburide), glipizide, glimeprid, gliquidon, glisoxepid, glibornuride, glicalzide, glisentide, glisolamide, glybuzole, glyclopyramide or glyclamide.
10. Verfahren nach einem der Ansprüche 7 bis 9, dadurch g e k e n n z e i c h n e t, daß als Zuckeralkohol eine 70%ige Sorbitlösung oder Glykole verwendet werden.10. The method according to any one of claims 7 to 9, characterized in that a 70% sorbitol solution or glycols are used as the sugar alcohol.
11. Verfahren nach einem der Ansprüche 7 bis 10, dadurch g e k e n n z e i c h n e t, daß eine flüssige Zuberei¬ tung hergestellt wird.11. The method according to any one of claims 7 to 10, characterized in that a liquid preparation is produced.
12. Verfahren nach einem der Ansprüche 7 bis 11, dadurch g e k e n n z e i c h n e t, daß eine feste Lösung bzw. Legierung zur Verwendung in festen oder halbfesten Darrei¬ chungsformen hergestellt wird.12. The method according to any one of claims 7 to 11, characterized in that a solid solution or alloy is produced for use in solid or semi-solid dosage forms.
13. Verwendung einer schnell resorbierbaren Zubereitungs¬ form von Sulfonylharnstoffderivaten nach mindestens einem der Ansprüche 1 bis 6 gegebenenfalls zusammen mit weiteren pharmazeutisch wirksamen Stoffen zur Behandlung der Zuckerkrankheit (Diabetes mellitus). 13. Use of a rapidly absorbable preparation form of sulfonylurea derivatives according to at least one of Claims 1 to 6, optionally together with other pharmaceutically active substances for the treatment of diabetes (diabetes mellitus).
PCT/EP1994/003368 1993-10-22 1994-10-12 Highly active sulphonyl urea preparations exhibiting rapid or controlled release of the active substance, and method of producing them WO1995011006A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU78555/94A AU7855594A (en) 1993-10-22 1994-10-12 Highly active sulphonyl urea preparations exhibiting rapid or controlled release of the active substance, and method of producing them
EP94929538A EP0724427A1 (en) 1993-10-22 1994-10-12 Highly active sulphonyl urea preparations exhibiting rapid or controlled release of the active substance, and method of producing them
JP7511289A JPH09504015A (en) 1993-10-22 1994-10-12 Highly effective sulfonylurea formulations that release active substances in a rapid or controlled manner and methods for their preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4336159.5 1993-10-22
DE4336159A DE4336159A1 (en) 1993-10-22 1993-10-22 Highly effective forms of preparation of sulfonylureas that release the active ingredient quickly or in a controlled manner and processes for their preparation

Publications (1)

Publication Number Publication Date
WO1995011006A1 true WO1995011006A1 (en) 1995-04-27

Family

ID=6500829

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/003368 WO1995011006A1 (en) 1993-10-22 1994-10-12 Highly active sulphonyl urea preparations exhibiting rapid or controlled release of the active substance, and method of producing them

Country Status (8)

Country Link
EP (1) EP0724427A1 (en)
JP (1) JPH09504015A (en)
AU (1) AU7855594A (en)
CA (1) CA2173366A1 (en)
DE (1) DE4336159A1 (en)
HU (1) HUT74684A (en)
NZ (1) NZ274501A (en)
WO (1) WO1995011006A1 (en)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018373A1 (en) * 1999-02-01 2000-04-06 Adir Et Compagnie Core tablet for controlled release of gliclazide after oral administration
EP1693415A2 (en) 2005-02-19 2006-08-23 Degussa GmbH Polymer powder with blockpolyetheramide, and the use in a process and moulding produced from this polymer powder
EP1743759A1 (en) 2005-07-16 2007-01-17 Degussa GmbH Use of cyclic oligomers in a forming process and object produced by this process
EP1982816A1 (en) 2007-04-20 2008-10-22 Evonik Degussa GmbH Composite powder, its use in a moulding method and moulds made of this composite powder
EP2103643A1 (en) 2008-03-19 2009-09-23 Evonik Degussa GmbH Copolyamide powder and its production, its use in a moulding method and object made of this copolyamide powder
US7611693B2 (en) 2003-09-17 2009-11-03 Board Of Regents, The Univerisity Of Texas System Mechanism-based targeted pancreatic beta cell imaging and therapy
EP2543457A1 (en) 2011-07-06 2013-01-09 Evonik Degussa GmbH Powder containing core particles coated with polymer containing metals, metal oxides, metal nitrides or half metal nitrides
EP2543696A1 (en) 2011-07-06 2013-01-09 Evonik Degussa GmbH Powder containing core particles coated with polymer
EP2543701A1 (en) 2011-07-06 2013-01-09 Evonik Degussa GmbH Powder containing inorganic particles coated with polymer
EP2543700A1 (en) 2011-07-06 2013-01-09 Evonik Degussa GmbH Powder containing particles coated with polymer
EP2650106A1 (en) 2012-04-11 2013-10-16 Evonik Industries AG Polymer powder with adapted melt behaviour
US8865053B2 (en) 2004-05-14 2014-10-21 Evonik Degussa Gmbh Process for the production of moldings
EP1840155B1 (en) 2006-04-01 2016-12-28 Evonik Degussa GmbH Polymer powder, method for manufacturing and utilising such a powder and moulded parts made thereof
US10710301B2 (en) 2016-05-13 2020-07-14 Hewlett-Packard Development Company, L.P. Material sets
US10717232B2 (en) 2016-05-13 2020-07-21 Hewlett-Packard Development Company, L.P. Material sets
DE202022000644U1 (en) 2022-03-15 2022-04-21 Evonik Operations Gmbh Powder for processing in a layer-by-layer process with visible and near-infrared lasers
EP4245506A1 (en) 2022-03-15 2023-09-20 Evonik Operations GmbH Powder for processing in a layer-by-layer method with lasers in the visible and near infrared range

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4064574B2 (en) 1998-07-29 2008-03-19 株式会社資生堂 Anti-diabetic topical skin preparation
EP2181705A1 (en) 2008-10-31 2010-05-05 Disphar International B.V. Sustained-release formulation of gliclazide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0086468A2 (en) * 1982-02-15 1983-08-24 Hoechst Uk Limited Oral anti-diabetic preparation
EP0418553A1 (en) * 1989-08-23 1991-03-27 Kurt H. Prof. Dr. Bauer High potency, rapidly resorbable glibenclamide preparations, process for their preparation and their use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0086468A2 (en) * 1982-02-15 1983-08-24 Hoechst Uk Limited Oral anti-diabetic preparation
EP0418553A1 (en) * 1989-08-23 1991-03-27 Kurt H. Prof. Dr. Bauer High potency, rapidly resorbable glibenclamide preparations, process for their preparation and their use

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2788981A1 (en) * 1999-02-01 2000-08-04 Adir MATRIX TABLET FOR THE EXTENDED RELEASE OF GLICLAZIDE AFTER ORAL ADMINISTRATION
AP1243A (en) * 1999-02-01 2004-02-02 Servier Lab Core tablet for controlled release of gliclazide after oral administration.
WO2000018373A1 (en) * 1999-02-01 2000-04-06 Adir Et Compagnie Core tablet for controlled release of gliclazide after oral administration
US7611693B2 (en) 2003-09-17 2009-11-03 Board Of Regents, The Univerisity Of Texas System Mechanism-based targeted pancreatic beta cell imaging and therapy
DE102004024440B4 (en) 2004-05-14 2020-06-25 Evonik Operations Gmbh Polymer powder with polyamide, use in a shaping process and molded body made from this polymer powder
US10005885B2 (en) 2004-05-14 2018-06-26 Evonik Degussa Gmbh Polymer powder with polyamide, use in a shaping process, and moldings produced from this polymer powder
US8865053B2 (en) 2004-05-14 2014-10-21 Evonik Degussa Gmbh Process for the production of moldings
EP1693415A2 (en) 2005-02-19 2006-08-23 Degussa GmbH Polymer powder with blockpolyetheramide, and the use in a process and moulding produced from this polymer powder
DE202005021503U1 (en) 2005-02-19 2008-07-24 Evonik Degussa Gmbh Polymer powder with Blockpolyetheramid, use in a molding process and molding, made from this polymer powder
US7491792B2 (en) 2005-02-19 2009-02-17 Degussa Ag Polymer powder with block polyetheramide, use in a shaping process, and moldings produced from this polymer powder
EP1743759A1 (en) 2005-07-16 2007-01-17 Degussa GmbH Use of cyclic oligomers in a forming process and object produced by this process
EP1840155B1 (en) 2006-04-01 2016-12-28 Evonik Degussa GmbH Polymer powder, method for manufacturing and utilising such a powder and moulded parts made thereof
DE102007019133A1 (en) 2007-04-20 2008-10-23 Evonik Degussa Gmbh Composite powder, use in a molding process and molding made from this powder
EP1982816A1 (en) 2007-04-20 2008-10-22 Evonik Degussa GmbH Composite powder, its use in a moulding method and moulds made of this composite powder
DE102008000755B4 (en) 2008-03-19 2019-12-12 Evonik Degussa Gmbh Copolyamide powder and its preparation, use of copolyamide powder in a molding process and molding, made from this copolyamide powder
DE102008000755A1 (en) 2008-03-19 2009-09-24 Evonik Degussa Gmbh Copolyamide powder and its preparation, use of copolyamide powder in a molding process and molding, made from this copolyamide powder
EP2103643A1 (en) 2008-03-19 2009-09-23 Evonik Degussa GmbH Copolyamide powder and its production, its use in a moulding method and object made of this copolyamide powder
DE102011078722A1 (en) 2011-07-06 2013-01-10 Evonik Degussa Gmbh Powder containing polymer-coated inorganic particles
EP2543696A1 (en) 2011-07-06 2013-01-09 Evonik Degussa GmbH Powder containing core particles coated with polymer
DE102011078719A1 (en) 2011-07-06 2013-01-10 Evonik Degussa Gmbh Powder containing polymer-coated particles
EP2543700A1 (en) 2011-07-06 2013-01-09 Evonik Degussa GmbH Powder containing particles coated with polymer
US10787559B2 (en) 2011-07-06 2020-09-29 Evonik Operations Gmbh Powder comprising polymer-coated glass particles
DE102011078720A1 (en) 2011-07-06 2013-01-10 Evonik Degussa Gmbh Powder comprising polymer-coated core particles containing metals, metal oxides, metal or metalloid nitrides
US9428610B2 (en) 2011-07-06 2016-08-30 Evonik Degussa Gmbh Powder comprising polymer-coated inorganic particles
DE102011078721A1 (en) 2011-07-06 2013-01-10 Evonik Degussa Gmbh Powder containing polymer-coated polymeric core particles
EP2543701A1 (en) 2011-07-06 2013-01-09 Evonik Degussa GmbH Powder containing inorganic particles coated with polymer
US10479733B2 (en) 2011-07-06 2019-11-19 Evonik Degussa Gmbh Powder comprising polymer-coated core particles comprising metals, metal oxides, metal nitrides or semimetal nitrides
EP2543457A1 (en) 2011-07-06 2013-01-09 Evonik Degussa GmbH Powder containing core particles coated with polymer containing metals, metal oxides, metal nitrides or half metal nitrides
EP2650106A1 (en) 2012-04-11 2013-10-16 Evonik Industries AG Polymer powder with adapted melt behaviour
DE102012205908A1 (en) 2012-04-11 2013-10-17 Evonik Industries Ag Polymer powder with adapted melting behavior
US10710301B2 (en) 2016-05-13 2020-07-14 Hewlett-Packard Development Company, L.P. Material sets
US10717232B2 (en) 2016-05-13 2020-07-21 Hewlett-Packard Development Company, L.P. Material sets
DE202022000644U1 (en) 2022-03-15 2022-04-21 Evonik Operations Gmbh Powder for processing in a layer-by-layer process with visible and near-infrared lasers
EP4245506A1 (en) 2022-03-15 2023-09-20 Evonik Operations GmbH Powder for processing in a layer-by-layer method with lasers in the visible and near infrared range
WO2023174990A1 (en) 2022-03-15 2023-09-21 Evonik Operations Gmbh Powder for use in a layerwise process with lasers in the visible and near-infrared range

Also Published As

Publication number Publication date
DE4336159A1 (en) 1995-04-27
CA2173366A1 (en) 1995-04-27
AU7855594A (en) 1995-05-08
EP0724427A1 (en) 1996-08-07
HU9600956D0 (en) 1996-06-28
JPH09504015A (en) 1997-04-22
NZ274501A (en) 1997-03-24
HUT74684A (en) 1997-01-28

Similar Documents

Publication Publication Date Title
EP1858490B1 (en) Pharmaceutical forms with improved pharmacokinetic properties
WO1995011006A1 (en) Highly active sulphonyl urea preparations exhibiting rapid or controlled release of the active substance, and method of producing them
EP1067905B1 (en) Fizzy formulations
DE3915347C2 (en) Harzadsorbate, process for their preparation and pharmaceutical preparations containing them
EP0128482B1 (en) Galenic forms of oral antidiabetics and process for their preparation
DE69924710T2 (en) PHARMACEUTICAL PREPARATION FOR APPLICATION IN ANTIASTHMATHERAPY
EP0481294B2 (en) Solid fast-dissolving pharmaceutical preparation containing N-acetyl-cysteine
EP1410793B1 (en) Delivery form of sodium ibuprofen
EP2061436B1 (en) Ibuprofen-effervescent preparation having a high dissolution rate and method for the production thereof
EP2334284B1 (en) Compacted cinacalcet
DD224216A5 (en) PROCESS FOR PREPARING ORAL ANTI-DIABETICALLY ACTUATING PREPARATIONS
EP0759296A1 (en) Rapidly disintegrating formulation comprising tramadol or a tramadol salt
DE60225686T2 (en) PARACETAMOL CONTAINING TABLET
DE10153934A1 (en) Process for the crystallization of profenes
WO2010105822A2 (en) Dry processing of retigabine
DE102009058321A1 (en) Orodispersible tablet containing dapoxetine
EP1077684B1 (en) Effervescent preparations
EP1309319B1 (en) Pharmaceutical, effervescent formulation containing ramipril
DE60319802T2 (en) SEDIEREN NON BENZODIAZEPINE FORMULATIONS
DD249186A1 (en) METHOD OF MANUFACTURING A NEW GLIBENCLAMID MEDICAMENT WITH HIGHER BIODEGRADABILITY
WO2007093168A2 (en) Rapid release irbesartan-containing pharmaceutical composition
EP0418553A1 (en) High potency, rapidly resorbable glibenclamide preparations, process for their preparation and their use
EP1589944B1 (en) Pharmaceutical preparations and a method for their production
DE112007000920T5 (en) Pharmaceutical compositions of cefixime
EP0559702B1 (en) Retarded-action urapidil formulation

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 94194299.6

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CN HU JP NZ US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2173366

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 274501

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 1994929538

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 1996 628734

Country of ref document: US

Date of ref document: 19960723

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 1994929538

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1994929538

Country of ref document: EP