WO2005115404A1 - Combinaison de sels de l'acide o-acetylsalicylique et d'inhibiteurs d'alpha-glucosidase - Google Patents

Combinaison de sels de l'acide o-acetylsalicylique et d'inhibiteurs d'alpha-glucosidase Download PDF

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Publication number
WO2005115404A1
WO2005115404A1 PCT/EP2005/005224 EP2005005224W WO2005115404A1 WO 2005115404 A1 WO2005115404 A1 WO 2005115404A1 EP 2005005224 W EP2005005224 W EP 2005005224W WO 2005115404 A1 WO2005115404 A1 WO 2005115404A1
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patients
diabetes
combination according
prevention
combination
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PCT/EP2005/005224
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German (de)
English (en)
Inventor
Wolfram Ledwoch
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Bayer Healtcare Ag
Wolfram Ledwoch
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Publication of WO2005115404A1 publication Critical patent/WO2005115404A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention relates to a combination containing a salt of o-acetylsalicylic acid with a basic amino acid as component A and an alpha-glucosidase inhibitor as component B for the prevention of cardiovascular diseases, medicaments containing this combination and process for their production.
  • Known salts of o-acetylsalicylic acid include salts of o-acetylsalicylic acid with basic amino acids.
  • Oral administration of, for example, the lysine salt of o-acetylsalicylic acid (ASA lysinate) can achieve a flooding of the active ingredient which almost corresponds to the blood level curve of a bolus injection. This is described in the literature [Ch. Raschka, H. J. Koch, Perfusion 6 (2000), 13th year, PERFUSION publishing house, Nuremberg]. The active ingredient dissolves extremely quickly and is immediately absorbed by the body.
  • the low stability of the o-acetylsalicylates is due to a back reaction of the product known to the person skilled in the art to o-acetylsalicylic acid and the corresponding amino acid.
  • the amino acid then reacts with the o-acetylsalicylic acid, splitting off the acetyl group (amidolysis) and releasing salicylic acid.
  • the presence of free salicylic acid in pharmaceutical preparations is undesirable and is therefore to be limited to a low, acceptable value.
  • WO 02/005782 describes salts of o-acetylsalicylic acid with basic amino acids which have increased stability and therefore do not have the disadvantages of o-acetylsalicylates in terms of storage and / or sterilizability.
  • the salts are produced using a special process and are characterized by a certain grain size distribution. They can have a certain content of added glycine and are suitable for the production of pharmaceuticals, for example in the form of tablets, chewable tablets or capsules for oral administration.
  • WO 03/059323 describes an improved processing method for the salts of o-acetylsalicylic acid with basic amino acids in the production of solid
  • Oral dosage forms by adding a flow agent to improve their flow properties and / or subjecting them to a granulation process. According to WO
  • 03/059323 drugs containing salts of o-acetylsalicylic acid with basic amino acids can be used as analgesic, antipyretic, anti-rheumatic, and as non-steroidal anti-inflammatory drugs, for example for the treatment of diseases of the rheumatic type, arthritis, neuralgia, myalgia and / or migraine.
  • they can also be used as platelet aggregation inhibitors in prevention and therapy
  • Cardiovascular and cerebrovascular diseases are used, e.g. for ischemic heart diseases, stroke (stroke), stable and unstable angina pectoris, myocardial infarction (e.g.
  • Compounds of component B are known to the person skilled in the art as substances regulating blood sugar levels. They are alpha-glucosidase inhibitors, which include, for example, acarbose or miglitol. Acarbose has been described in many publications and textbooks as one of the standard therapies for the treatment of type 2 diabetes mellitus. (Lebovitz, et.
  • the present invention relates to a combination comprising a salt of o-acetylsalicylic acid with a basic amino acid as component A and an alpha-glucosidase inhibitor as component B for the prevention of cardiovascular diseases, in particular in patients who have an increased risk of developing cardiovascular disease ill.
  • the invention further relates to a pharmaceutical preparation containing this combination and its preparation.
  • the basic amino acid suitable according to the invention as a component of the salt of o-acetylsalicylic acid can occur in the L or D configuration or as a mixture of D and L forms.
  • the term “amino acid” designates in particular the naturally occurring ⁇ -amino acids, but also includes their homologs, isomers and derivatives. Enantiomers can be mentioned as examples of isomers. Derivatives can be, for example, amino acids provided with protective groups. As typical examples For basic amino acids, the following may be mentioned: lysine, arginine, ornithine, diaminobutyric acid, the salt of o-acetylsalicylic acid with lysine is particularly suitable.
  • Protective groups for amino acids are known to the person skilled in the art and are described in TW Greene, PG Wuts, Protective Groups in Organic Synthesis, 3 rd ed., JohnWiley, New York, 1999.
  • Alpha-glucosidase inhibitors are generally within the scope of the invention for everyone The technology classes and substances listed under this term, such as acarbose, miglitol and Voglibose. Acarbose is preferred under this term.
  • primary prevention is the protection of patients from a first cardiovascular disease that results in organ damage.
  • secondary prevention means the protection of patients who have already suffered organ damage as a result of a cardiovascular disease from a new cardiovascular disease.
  • a preferred object of the present invention is a combination containing a salt of o-acetylsalicylic acid with a basic amino acid as component A and an alpha-glucosidase inhibitor as component B for the prevention of cardiovascular diseases in patients who are at increased risk of developing cardiovascular diseases ill.
  • the combination according to the invention shows an unexpected broad and varied spectrum of effects in patients who have an increased risk of developing cardiovascular disease.
  • the patient group at higher risk mentioned here includes, for example, patients with micro- and macroangiopathy, increased blood pressure (hypertension), patients at risk of developing high blood pressure, patients with lipid metabolism disorders such as hyperlipidemia or dyslipidemia, patients with renal dysfunction such as For example, mild renal failure (MRF), which have an increased creatinine level in the blood plasma, patients with diabetes, patients with type 2 diabetes (Non-Insulin Dependent Diabetes Melliuts / NTDDM), patients with an impaired glucose metabolism (pre -diabetic metabolism), patients with impaired glucose tolerance, patients with impaired insulin sensitivity, patients with pre-diabetic insulin resistance syndrome, patients with developing hyperinsulemia, patients with an increased Body Mass Index (BMI), patients; with an increased Homocysteinspi egel, patients who have first-degree relatives who suffer or have suffered from cardiovascular disease and patients who have first-degree relatives who have or have suffered from diabetes.
  • MRF mild renal failure
  • pre -diabetic metabolism pre -diabetic metabolism
  • An increased creatinine level is particularly present at a value of over 1.5 mg / dl in men and 1.4 mg / dl in women.
  • An increased BMI is particularly present at a value of over 25 kg / m 2 .
  • a total cholesterol level of over 200 mg / dl and / or an LDL level (low density lipoprotein) of over 160 mg / dl.
  • pre-diabetic metabolism or renal dysfunction there is an increased risk with a total cholesterol level of over 170 mg / dl and / or an LDL level (low density lipoprotein) of over 120 mg / dl.
  • Patients with elevated blood pressure include, in particular, patients with only slightly elevated blood pressure (120/85 mmHg to 139/90 mmHg) and patients who have insufficiently reduced the elevated blood pressure in the presence of elevated blood pressure (RR> 145/95 mmHg). There is an increased risk with an increased homocysteine level of more than 12 ⁇ mol / 1 in the blood.
  • Patients who have already suffered organ damage as a result of cardiovascular disease also belong to the group of patients with increased risk mentioned here. These patients already had, for example, angioplasty, stroke, bypass surgery, angina pectoris, coronary artery disease, myocardial infarction, abnormal changes in the vessel wall and / or thrombosis.
  • Patients with renal dysfunction such as mild renal heart failure (mild renal failure (MRF)) who have an increased creatinine level in the blood plasma, patients with lipid metabolism disorders such as hyperlipidemia or dyslipidemia, and patients with increased blood pressure preferably belong to the patient group mentioned here with increased risk (Hypertension), patients with only slightly increased blood pressure (120/85 rnmHg to 139/90 rnmHg), patients who have reduced the increased blood pressure insufficiently in the presence of increased blood pressure (> 145/95 mmHg), patients with an impaired glucose metabolism ( pre-diabetic metabolism), patients with impaired glucose tolerance, patients with impaired insulin sensitivity, patients with pre-diabetic insulin resistance syndrome, patients with developing hyperinsulinemia, or patients with first-degree relatives who have or have had diabetes without that these patients have diabetes.
  • MRF mild renal heart failure
  • lipid metabolism disorders such as hyperlipidemia or dyslipidemia
  • patients with increased blood pressure preferably belong to the patient group mentioned here with increased risk (Hypertension), patients with only slightly
  • the group of patients with increased risk mentioned here particularly preferably includes patients with a disturbed glucose metabolism (pre-diabetic metabolic situation), patients with impaired glucose tolerance, patients with impaired insulin sensitivity, patients with prediabetic insulin resistance syndrome, patients with developing hyperinsulinemia, ⁇ or patients with first-degree relatives who have or had diabetes without these patients having diabetes.
  • cardiac risk mariangement i.e. in the prophylaxis of cardiovascular diseases that are influenced or caused by more than one risk factor, e.g. Arteriosclerosis, diseases of the coronary arteries of the heart, in particular the arterial coronary arteries, increased serum lipids, hypercholesterolaemia, hypertriglyceridaemia, an increase in both serum cholesterol and serum triglycerides combined with increased VLDL (very low density lipoprotein) and an increase in chylomicrons in plasma and syndrome X
  • Typical risk factors are increased levels of glycerin, decreased levels of HDL, smoking, glucose intolerance and enlarged heart.
  • the risk factors may vary depending on the age and gender of the patient.
  • “Hyperlipidemia” is to be understood as an elevated plasma level of one or more serum lipids.
  • the LDL level is particularly important.
  • values above 130 mg / dl and in patients under 45 are considered as elevated levels Years above 160 mg / dl.
  • dislipidemia is meant either hypertriglyceridemia or hypercholesterolemia, but especially mixed hyperlipidemia, i.e. a disease with high cholesterol (LDL and total cholesterol) and triglyceride. This may be associated with a decrease in plasma HDL (High Density Lipoprotein) cholesterol or a disturbed HDL-C / LDL-C ratio.
  • LDL Low Density Lipoprotein
  • the combination according to the invention proves to be surprisingly advantageous in the prevention of micro- and macroangiopathy, coronary heart diseases, heart failure, impaired brain performance, apoplexy, circulatory disorders, disorders of fat metabolism, high blood pressure or diabetes mellitus.
  • the effect is particularly strong in patients with renal dysfunction, such as mild renal failure (MRF), who have an increased creatinine level in the blood plasma, patients with lipid metabolism disorders such as hyperlipidemia or dyslipidemia, patients with increased blood pressure (hypertension) or Patients with a disturbed glucose metabolism (pre-diabetic metabolism) without these patients having diabetes.
  • MRF mild renal failure
  • lipid metabolism disorders such as hyperlipidemia or dyslipidemia
  • blood pressure hypertension
  • pre-diabetic metabolism pre-diabetic metabolism
  • the combination according to the invention is dosed up to 3 times a day, preference being given to a combination which allows application once or twice a day.
  • the synergistic effect of the combination according to the invention is preferably observed when the combination according to the invention is preferably 0.1 to 20 mg / kg, in particular 0.5 to 5 mg / kg of active ingredient of component A and 0.01 to 20 mg / kg, in particular 0, Contains 1 to 5 mg / kg of active ingredient of component B, based on the patient's kg body weight when administered orally.
  • the synergistic effect of the combination according to the invention is preferably observed when the combination according to the invention as component A contains the salt of o-acetylsalicylic acid with lysine in a dosage of 25 to 500 mg, preferably in a dosage of 50 to 350 mg, particularly preferably in one Dosage of 75 to 200 mg and as component B acarbose in a dosage of 5 to 500 mg, preferably in a dosage of 30 to 350 mg, particularly preferably in a dosage of 50 to 100 mg.
  • the synergistic effect of the combination according to the invention is preferably observed when components A and B of the combinations according to the invention in a ratio of 1:10 to 10: 1, preferably 1: 5 to 5: 1, particularly preferably 1: 2 to 2: 1 with respect to A and B are present.
  • “Ratio” in the sense of the invention means the weight ratio of the individual components.
  • the combination according to the invention is furthermore distinguished by surprisingly good tolerability.
  • the combination according to the invention is preferably used in human medicine, but is also suitable for veterinary medicine, in particular for the treatment of mammals.
  • “Combination” in the sense of the invention means not only a dosage form which contains all components (so-called fixed combinations) and a combination pack which contains the components separately from one another, but also components applied simultaneously or at different times, provided that they are used for treatment or prophylaxis of the same disease.
  • components A and B can be converted in a known manner into the customary solid formulations, for example tablets, dragées, pills, capsules, powders or granules. Since the combination according to the invention is well tolerated and is effective even in low doses, a wide variety of formulation variants can be implemented. So there is one the possibility of formulating the individual components separately. In this case, the two individual components A and B do not necessarily have to be taken at the same time, but a delayed intake can be advantageous in order to achieve optimal effects. In the case of such a separate administration, it makes sense to combine the formulations of the two individual components, for example tablets or capsules, simultaneously in a suitable primary packaging.
  • the two components are each in separate containers, which can be tubes, vials or blister packs, for example.
  • Such separate packaging of the two components in a common primary packaging is also referred to as a kit.
  • a fixed combination is preferably also suitable as a further formulation variant for the combination according to the invention. “Fixed combination” is to be understood here to mean those dosage forms in which the two components are present together in a fixed quantitative ratio. Such fixed combinations can be implemented, for example, as tablets, dragées, pills, capsules, powders and / or granules.
  • the active ingredients of the components a and B are particularly suitable to be formulated into a fixed combination in the form of a solid oral dosage form.
  • the (fixed oral) dosage form is dependent, so the number of different drugs to be taken separately should be as small as possible (advantage of a fixed combination), and the size and weight of a fixed oral dosage form should be as small as possible with full therapeutic he potency to make the intake as comfortable as possible for the patient.
  • This enables fixed combinations in the form of solid oral pharmaceutical formulations to be implemented with a minimal size and minimal weight.
  • the fixed combination according to the invention accordingly offers the highest possible patient compliance and thereby decisively improves the safety and reliability of a therapy.
  • the functionality can be used to control the release of the active ingredient. For example, by delaying the release of active ingredient (retardation) of a component, the above-mentioned temporal decoupling of the onset of action can also be achieved in fixed combinations.
  • both components A and B can optionally be combined with one or more auxiliaries and tabletted together, granulated, processed into powder, placed in a capsule or pressed into a pill. It is also possible to individually formulate components A and B, for example by granulating both components individually or by processing them into powder and then adding them together in a capsule.
  • the oral dosage forms listed here are manufactured according to the general standard processes and may contain other excipients.
  • Excipients are those that are pharmaceutically accepted and are physiologically harmless, for example: as fillers cellulose derivatives (e.g. microcrystalline cellulose), sugar (e.g. lactose), sugar alcohols (e.g. mannitol, sorbitol), inorganic fillers (e.g. calcium phosphates), binders (e.g.
  • polyvinylpyrrolidone polyvinylpyrrolidone
  • Gelatin starch and cellulose derivatives
  • auxiliaries that are required for the production of pharmaceutical formulations of the desired properties, for example lubricants, release agents, flow agents, disintegrants (for example crosslinked polyvinylpyrrolidone, sodium carboxymethyl cellulose), wetting agents (for example sodium lauryl sulfate), retardants (eg cellulose derivatives, polyacrylic acid derivatives), stabilizers, flavors, color pigments and buffer substances.
  • lubricants for example crosslinked polyvinylpyrrolidone, sodium carboxymethyl cellulose
  • wetting agents for example sodium lauryl sulfate
  • retardants eg cellulose derivatives, polyacrylic acid derivatives
  • stabilizers flavors, color pigments and buffer substances.
  • a flow agent can be added. This facilitates the flow behavior of the components, preferably the flow behavior of component A, and prevents the components, preferably the component A, from attaching to the pressing tool.
  • flow agents are understood to mean the auxiliaries which are often also called free-flowing aids and which are admixed with pulverulent or granulated, in particular hygroscopic, substances in order to prevent them from clumping or caking and thus to ensure continuous free flow (fluidification).
  • Preferred flow agents are highly disperse silicon dioxide, microcrystalline cellulose and saccharide as well as their mixtures.
  • Particularly preferred flow agents are the saccharides mannitol, sorbitol, xylitol and lactose and their mixtures.
  • the flow agents are usually used in an amount, based on the amount of o-acetyl salicylate, of between 1 and 70% by weight, preferably between 1 and 50% by weight.
  • the amount of superplasticizer can also be larger if necessary.
  • the known, conventional methods are suitable for granulation.
  • Preferred granulation methods are wet and dry granulation, in particular roller compacting.
  • the combination according to the invention or the individual components A or B are accordingly dry granulated in a preferred embodiment and in particular compacted by rollers.
  • Auxiliaries eg binders, solvents, saccharides, polysaccharides
  • both the usual hard gelatin capsules and capsules made of HPMC are suitable for use as capsules.
  • HPMC push-fit capsules can be used directly or after drying.
  • both the combination according to the invention and the individual components A and B are stable not only in the HPMC push-in capsules but also in the hard gelatin push-in capsules. This again demonstrates the stability of the combination and medicament according to the invention.
  • Push-in capsules made from other polymers e.g. starch, cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose lactate, hydroxypropyl cellulose glycolide and hydroxyethyl hydroxypropyl cellulose are also suitable.
  • the combination according to the invention is preferably administered orally.
  • the salt of o-acetylsalicylic acid with a basic amino acid is preferably produced by the method as described in WO 03/059323 ,
  • the invention therefore preferably relates to a combination comprising a salt of o-acetylsalicylic acid with a basic amino acid as component A and an alpha-glucosidase inhibitor as component B, component A having an average particle size distribution measured using a Malvern 2600D device under standard conditions Grain size above "a grain size of 160 microns and a proportion of more than 60% of the particles with a grain size in a range of 100 to 200 microns.
  • component A with a with a Malvern 2600D device below Particle size distribution measured under standard conditions has an average particle size above a particle size of 170 ⁇ m and a proportion of more than 70% of the particles with a particle size in a range from 100 to 200 ⁇ m
  • Component A usually has a residual moisture content of less than 0.4%, preferably less than 0.3% and especially w less than 0.15% water.
  • the low residual moisture content leads to improved stability of component A and consequently also of the combination according to the invention and of the medicament containing this combination.
  • a certain proportion of glycine can be added to component A, as will be explained in detail below regarding the production process.
  • the salt of o-acetylsalicylic acid with a basic amino acid can be prepared by the following procedure. All starting compounds are commercially available.
  • Reactant solutions d. H. o-acetylsalicylic acid and the corresponding amino acid are combined as quickly as possible at a temperature below 30 ° C., preferably from 20 to 25 ° C., under normal pressure and mixed to form a homogeneous phase.
  • Suitable solvents for the reactants are water or water-miscible organic solvents such as alcohols such as methanol, ethanol or isopropanol, in particular ethanol, ethers such as tetrahydrofuran (THF) or ketones such as acetone.
  • the reactants are used in amounts such that the basic amino acid is in a slight excess.
  • a ratio of o-acetylsalicylic acid to amino acid of 1: 1.05 to 1: 1.5 is preferred, with a ratio of o-acetylsalicylic acid to amino acid of 1: 1.05 to 1: 1.2 being particularly preferred.
  • the o-acetylsalicylic acid solution should have a content of 1 to 10% by weight, preferably 5 to 10% by weight and particularly preferably 6 to 8% by weight of o-acetylsalicylic acid.
  • the solution of the basic amino acid should have a content of 10 to 40% by weight, preferably 15 to 35% by weight and particularly preferably 20 to 30% by weight of amino acid.
  • the temperature must not exceed 40 ° C and should preferably be kept below 35 ° C.
  • the homogeneous mixture of the starting products may only be stirred gently.
  • the Stirring energy to be applied should not exceed 0.1 W per liter of reaction medium.
  • an applied stirring energy of 0.04 to 0.06 W per liter of reaction medium is preferred.
  • All conventional, appropriately adjustable stirring devices such as, for example, an agitator container with a baffle, are suitable as stirrers.
  • the solution should not be kept for more than 20 hours under the above conditions for crystallization. According to the invention, a crystallization period of less than 10 hours is preferred under the conditions specified above, a period of 1 to 8 hours being particularly preferred.
  • the o-acetyl salicylate according to the invention can also contain glycine.
  • the amount of glycine is freely selectable. According to the invention, a proportion, based on the total amount of o-acetylsalicylate and glycine, of 5 to 30% by weight, particularly preferably 5 to 15% by weight and particularly preferably 10% by weight glycine, in the reaction solution ,
  • the glycine can be added to the reaction mixture from the reactants as a solution in water or a water-miscible organic solvent, it being possible to use the solvents described above as organic solvents. Glycine is inert towards these reactants. Under the conditions mentioned above, crystallization processes of the two solids (o-acetylsalicylate and glycine) can be carried out from the homogeneous phase (cocrystallization).
  • the glycine can also be added in the form of a suspension to an already crystallized suspension of the o-acetylsalicylate.
  • the glycine suspension can be prepared in a conventional manner. According to the invention, the production of a glycine suspension from a solvent mixture of water and an alcohol such as ethanol is preferred.
  • the type of addition of the glycine has no influence on the properties of the o-acetylsalicylate according to the invention. It should be noted that the addition of glycine to the o-acetylsalicylates according to the invention is not necessary. In particular, the presence of glycine has no influence on the stability of the o-acetylsalicylates according to the invention.
  • the crystals are then isolated in a conventional manner, for example by filtration or centrifugation.
  • the solid is washed several times with organic solvents, alcohols such as ethanol and / or ketones such as acetone or mixtures of alcohols or ketones, for example mixtures of ethanol and acetone, or the use of various solvents of this type being preferred according to the invention.
  • the solid is then dried under reduced pressure.
  • the temperature should be kept below 50 ° C., preferably below 40 ° C. and particularly preferably below 35 ° C.
  • a pressure of less than 50 mbar, preferably less than 30 mbar, should be applied to the solid.
  • the drying process is carried out under conventional conditions, for example in a drying device.
  • the process can also be carried out entirely under sterile conditions.
  • the deviations required for this from the above procedure for example with regard to sterilization of the starting compounds and the apparatus used, are known to the person skilled in the art.
  • a solution of 9.9 kg of o-acetylsalicylic acid in 120 kg of ethanol is added.
  • a solution of 9.0 kg of lysine hydrate in 26.5 kg of water is added in a short time and the solutions are mixed so that a temperature of 30 ° C is not exceeded.
  • 50 g of seed crystals are added and the already crystallizing mixture is mixed with 120 kg of acetone while cooling to 0 ° C.
  • the mixture is left to crystallize for one to eight hours with gentle stirring at 0 ° C.
  • the crystals are isolated on a filter or a centrifuge.
  • the moist product is washed several times with ethanol on a separator.
  • the moist product is transferred to a dryer and dried therein at a pressure of less than 30 mbar at a temperature of not more than 40 ° C.
  • the desired product is obtained in a yield of 89 to 94% with a residual moisture content of 0.10 to 0.15%.
  • Example 2 D, L-lysinoacetyl salicylate with 10% glycine
  • a solution of 9.9 kg of o-acetylsalicylic acid in 145 kg of ethanol is placed in a stirrer tank with a baffle.
  • a solution of 9.0 kg of D, L-lysine hydrate and 2.4 kg of glycine in 35 kg of water is added in a short time and the solutions are mixed so that a temperature of 30 ° C is not exceeded , 50 g of seed crystals are added and the already crystallizing mixture is mixed with 120 kg of acetone while cooling to 0 ° C.
  • the mixture is left to crystallize for one to eight hours with gentle stirring at 0 ° C.
  • the crystals are isolated on a filter or a centrifuge.
  • the moist product is washed several times in succession on a separator with ethanol and acetone.
  • the moist product is transferred to a dryer and dried therein at a pressure of less than 30 mbar at a temperature of not more than 40 ° C.
  • Example 3 D, L-lysinoacetyl salicylate with 10% glycine
  • a solution of 9.9 kg of o-acetylsalicylic acid in 120 kg of ethanol is placed in a stirrer tank with a baffle.
  • a solution of 9.0 kg of lysine hydrate in 26.5 kg of water is added in a short time and the solutions are mixed so that a temperature of 30 ° C is not exceeded.
  • 50 g of seed crystals are added and the already crystallizing mixture is mixed with 120 kg of acetone while cooling to 0 ° C. The mixture is left to crystallize for one to eight hours with gentle stirring at 0 ° C.
  • a suspension of 2.1 kg of glycine in 8 kg of water and 25 kg of ethanol is prepared in a separate agitator tank.
  • the crystal mixture is isolated on a filter or a centrifuge.
  • the moist product is washed several times with ethanol on a separator.
  • the moist product is transferred to a dryer and dried therein at a pressure of less than 30 mbar at a temperature of not more than 40 ° C.
  • the desired product is obtained in a yield of 89 to 94% with a residual moisture content of 0.10 to 0.15%.
  • the lysine acetyl salicylate (partial component AI -3) and commercially available Aspisol ® are examined in a Malvern 2600 D measuring device from Malvern under the following standard conditions.
  • the Malvern 2600 measuring device consists of a He / Ne laser, a measuring cuvette with a thermostatically controllable reservoir system, Fourier lenses and a multi-element detector. The measured light intensities are converted into a grain size distribution. The alignment of the laser and lens is set manually before each measurement and the measuring device is checked by a blank measurement. The blank value pulses must not exceed a maximum value of 20 per detector element.
  • the sample to be examined is shaken by hand for approx. 15 s; then a sample is taken with a spatula.
  • the amount of sample depends on the permissible obscuration range (0.1-0.3) of the measuring device.
  • the sample taken is gently predispersed in a beaker with a conventional dispersing agent such as Baysilon MIO ® (Bayer AG) (by stirring with a glass rod) and then poured into the storage container of the measuring device, which is also filled with the dispersing agent.
  • the beaker is completely rinsed out with the dispersant to ensure representative sampling.
  • the measurement is carried out with a set focal length of 300 mm, a thermostat of 20 ° C and a permissible obscuration range of 0.1-0.3.
  • the product is measured after ultrasound times of 0, 15 and 60 seconds.
  • the ultrasonic finger is located in the storage container of the product circulation.
  • the suspension is pumped through the measuring cell in a closed circuit.
  • the signals registered by the detector are evaluated and converted into the grain size distribution.

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Abstract

L'invention concerne une combinaison contenant un sel d'acide o-acétylsalicylique comportant un acide aminé basique en tant que constituant A, et un inhibiteur d'alpha-glucosidase en tant que constituant B, destinée à la prévention de maladies cardio-vasculaires. L'invention concerne également un médicament contenant cette combinaison et des procédés de fabrication de ladite combinaison.
PCT/EP2005/005224 2004-05-25 2005-05-13 Combinaison de sels de l'acide o-acetylsalicylique et d'inhibiteurs d'alpha-glucosidase WO2005115404A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004025535A DE102004025535A1 (de) 2004-05-25 2004-05-25 Kombination von Salzen der o-Acetylsalicylsäure und Alpha-Glucosidase-Inhibitoren
DE102004025535.0 2004-05-25

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WO2005115404A1 true WO2005115404A1 (fr) 2005-12-08

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006128600A2 (fr) * 2005-06-02 2006-12-07 Bayer Healthcare Ag Complexe actif stable de sels de l'acide o-acetylsalicylique contenant des acides amines basiques et de la glycine
WO2023131645A1 (fr) * 2022-01-05 2023-07-13 Aspiair Gmbh Synthèse améliorée de particules d'acétylsalicylate de lysine · glycine

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997027847A1 (fr) * 1996-02-02 1997-08-07 Merck & Co., Inc. Methode de traitement du diabete et d'etats pathologiques associes
WO2000010610A2 (fr) * 1998-08-19 2000-03-02 Theramark Limited Ciblage de medicament
WO2003059323A2 (fr) * 2002-01-18 2003-07-24 Bayer Healthcare Ag Sels stables d'acide o-acetylsalicylique contenant des acides amines ii basiques
WO2003088962A1 (fr) * 2002-04-16 2003-10-30 Merck & Co., Inc. Therapie combinatoire faisant appel a un agoniste de ppar alpha/gamma
WO2004105771A1 (fr) * 2003-05-28 2004-12-09 Bayer Healthcare Ag Association d'acide acetylsalicylique et d'inhibiteurs de l'alpha-glucosidase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997027847A1 (fr) * 1996-02-02 1997-08-07 Merck & Co., Inc. Methode de traitement du diabete et d'etats pathologiques associes
WO2000010610A2 (fr) * 1998-08-19 2000-03-02 Theramark Limited Ciblage de medicament
WO2003059323A2 (fr) * 2002-01-18 2003-07-24 Bayer Healthcare Ag Sels stables d'acide o-acetylsalicylique contenant des acides amines ii basiques
WO2003088962A1 (fr) * 2002-04-16 2003-10-30 Merck & Co., Inc. Therapie combinatoire faisant appel a un agoniste de ppar alpha/gamma
WO2004105771A1 (fr) * 2003-05-28 2004-12-09 Bayer Healthcare Ag Association d'acide acetylsalicylique et d'inhibiteurs de l'alpha-glucosidase

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MODESTE A-B ET AL: "Bullous pemphigoid induced by spironolactone", ANNALES DE DERMATOLOGIE ET DE VENEREOLOGIE 2002 FRANCE, vol. 129, no. 1, 2002, pages 56 - 58, XP009052732, ISSN: 0151-9638 *
SCHEEN A J: "Management of the metabolic syndrome.", MINERVA ENDOCRINOLOGICA. JUN 2004, vol. 29, no. 2, June 2004 (2004-06-01), pages 31 - 45, XP009052755, ISSN: 0391-1977 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006128600A2 (fr) * 2005-06-02 2006-12-07 Bayer Healthcare Ag Complexe actif stable de sels de l'acide o-acetylsalicylique contenant des acides amines basiques et de la glycine
WO2006128600A3 (fr) * 2005-06-02 2007-04-26 Bayer Healthcare Ag Complexe actif stable de sels de l'acide o-acetylsalicylique contenant des acides amines basiques et de la glycine
AU2006254429B2 (en) * 2005-06-02 2011-11-10 Bayer Intellectual Property Gmbh Stabile active ingredient complex of salts of the o-acetylsalicylic acid with basic amino acids and glycine
US8063243B2 (en) 2005-06-02 2011-11-22 Bayer Pharma Aktiengesellschaft Stable active compound complex of salts of o-acetylsalicylic acid with basic amino acids and glycine
WO2023131645A1 (fr) * 2022-01-05 2023-07-13 Aspiair Gmbh Synthèse améliorée de particules d'acétylsalicylate de lysine · glycine

Also Published As

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