CA2173366A1 - 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 themInfo
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- CA2173366A1 CA2173366A1 CA002173366A CA2173366A CA2173366A1 CA 2173366 A1 CA2173366 A1 CA 2173366A1 CA 002173366 A CA002173366 A CA 002173366A CA 2173366 A CA2173366 A CA 2173366A CA 2173366 A1 CA2173366 A1 CA 2173366A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/64—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
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- 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
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- 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
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- 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
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- 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
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- 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
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- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Oil, Petroleum & Natural Gas (AREA)
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Abstract
The invention relates to highly effective preparations of sulphonylurea derivatives which release the active substance rapidly or in a controlled manner. Included here are liquid and rapid-release or modified-release solid pharmaceutical preparations which are characterised in that they contain one or more sulphonylurea derivative(s) as active substance(s), alcohol, one or more polyol(s) with the exception of polyethylene glycol and/or one or more sugar alcohol(s), previously dissolved in water or an alcohol/water mixture, an alkaline substance and optionally suitable pharmaceutically acceptable auxiliary agents and flavourings and optionally further pharmaceutically active substances.
The invention also relates to a process for producing these preparations and their use to treat diabetes (diabetes mellitus).
The invention also relates to a process for producing these preparations and their use to treat diabetes (diabetes mellitus).
Description
~ - ~173~6 Description Highly effective preparations of sulphonylurea which release the active substance rapidly or in a controlled manner and a process for their preparation The invention relates to highly effective preparations of sulphonylurea derivatives which are sparingly soluble in water, which release the active substance rapidly or in a controlled manner and a process for solubilising sulphonylurea derivatives which are sparingly soluble in water.
The efficacy of a medicinal substance depends to a great extent on the form of administration. In general, for a systemic effect, the medicinal substance has to be either injected directly into the bloodstream or administered in a resorbable form. Resorption of a substance means that it is taken up by the bloodstream or the lymphatic system, from where distribution to the entire organism takes place. The rate of resorption and the resorption quota (ratio of resorbable fraction to the amount administered) therefore depend on many factors. In the case of many perorally or parenterally administered drugs, their solubility in an aqueous medium is a critical factor relating to efficacy and bioavailability. One group of drugs whose bioavailability and thus efficacy depends strongly on solubility in an aqueous medium is the group of sulphonylurea derivatives. These substances are currently used to lower blood sugar levels (diabetes mellitus).
As an example of one of the best known members of this group, glibenclamide (INN) will be used to demonstrate the - ~ ~173~6~
effect solubility has on the onset of action, the efficacy and the dose required.
Glibenclamide, also called glyburide in American usage, is a sulphonylurea derivative with the IUPAC chemical name:
N-4-2-(5-chloro-2-methoxybenzamido)-ethyl-phenylsulphonyl-N~-cyclohexylurea. The molecular weight is 494.02, the melting point is 172 to 174C (see R. Groning:
Arzneistoffprofile und Bioverfugbarkeitsdaten von Fertigarzneimitteln, Arzneistoffmonographie Glibenclamid, Deutscher Apothekerverlag, Stuttgart, pages 1 to 7, 1987).
Glibenclamide is an odourless, crystalline, white substance which is virtually insoluble in water and ether and only moderately soluble in alcohol and chloroform. It forms salts with alkalis which, in comparison with tolbutamide, a substance which also lowers blood sugar levels, however, have very limited solubility in water.
Due to the physico-chemical structural relationships, the other therapeutically used sulphonylurea derivatives such as, for instance, glipizide, glibornuride, gliquidone, glisoxepide and glimepride, also all have similar solubility characteristics.
The sulphonylurea derivatives mentioned above are used all over the world in daily doses of 1-250 mg for treating diabetes (diabetes mellitus). Two mechanisms can be differentiated in the process for lowering the blood sugar levels, that is a pancreatic and an extrapancreatic effect (see preparation data sheets from Boehringer Mannheim GmbH
and Hoechst AG, Frankfurt/Main, 1984, on Euglucon~ N, Semi-Euglucon~ N).
The pancreatic effect leads to an increase in insulin secretion due to an increased response to glucose by beta cells in the pancreas.
The efficacy of a medicinal substance depends to a great extent on the form of administration. In general, for a systemic effect, the medicinal substance has to be either injected directly into the bloodstream or administered in a resorbable form. Resorption of a substance means that it is taken up by the bloodstream or the lymphatic system, from where distribution to the entire organism takes place. The rate of resorption and the resorption quota (ratio of resorbable fraction to the amount administered) therefore depend on many factors. In the case of many perorally or parenterally administered drugs, their solubility in an aqueous medium is a critical factor relating to efficacy and bioavailability. One group of drugs whose bioavailability and thus efficacy depends strongly on solubility in an aqueous medium is the group of sulphonylurea derivatives. These substances are currently used to lower blood sugar levels (diabetes mellitus).
As an example of one of the best known members of this group, glibenclamide (INN) will be used to demonstrate the - ~ ~173~6~
effect solubility has on the onset of action, the efficacy and the dose required.
Glibenclamide, also called glyburide in American usage, is a sulphonylurea derivative with the IUPAC chemical name:
N-4-2-(5-chloro-2-methoxybenzamido)-ethyl-phenylsulphonyl-N~-cyclohexylurea. The molecular weight is 494.02, the melting point is 172 to 174C (see R. Groning:
Arzneistoffprofile und Bioverfugbarkeitsdaten von Fertigarzneimitteln, Arzneistoffmonographie Glibenclamid, Deutscher Apothekerverlag, Stuttgart, pages 1 to 7, 1987).
Glibenclamide is an odourless, crystalline, white substance which is virtually insoluble in water and ether and only moderately soluble in alcohol and chloroform. It forms salts with alkalis which, in comparison with tolbutamide, a substance which also lowers blood sugar levels, however, have very limited solubility in water.
Due to the physico-chemical structural relationships, the other therapeutically used sulphonylurea derivatives such as, for instance, glipizide, glibornuride, gliquidone, glisoxepide and glimepride, also all have similar solubility characteristics.
The sulphonylurea derivatives mentioned above are used all over the world in daily doses of 1-250 mg for treating diabetes (diabetes mellitus). Two mechanisms can be differentiated in the process for lowering the blood sugar levels, that is a pancreatic and an extrapancreatic effect (see preparation data sheets from Boehringer Mannheim GmbH
and Hoechst AG, Frankfurt/Main, 1984, on Euglucon~ N, Semi-Euglucon~ N).
The pancreatic effect leads to an increase in insulin secretion due to an increased response to glucose by beta cells in the pancreas.
2~7336G
The extrapancreatic effect is manifested in the case of insulin resistance by increasing the effect of insulin due to:
- an increase in sensitivity to insulin and insulin bonding in the target tissue:
- direct action on the insulin receptors in the sense of a multiplication.
Due to the high efficacy of and tolerance to sulphonylurea derivatives, these preparations now comprise the most important substances for oral treatment of diabetes.
It is known, and has been proven in tests, that in order to produce a therapeutic effect, not only the active substance but also its pharmaceutical/technologiçal formulation, also called the galenic form, is of great importance (see H.
Blume et al.:
zur Bioverfugbarkeit und pharmakodynamischen Aktivitat han-delsublicher Glibenclamid-Fertigarzneimittel, 1st communication: Bioequivalenzprufung an gesunden Probanden unter oraler Kohlenhydratbelastung: Pharm. Ztg., 130, 1062-1069, 1985;
2nd communication: Untersuchungen der glibenclamidinduzierten Veranderungen der Insulinkonzentration in Serum und der Blutglucosewerte an gesunden Probanden. Pharm. Ztg., 130, 1070-1078, 1985;
3rd communication: Bioequivalenzprufung an gesunden Probanden unter Dauerinfusion von Glucoselosung. Pharm.
Ztg., 130, 2606-2610, 1985 .
These tests demonstrated that the use of glibenclamide involves severe biopharmaceutical problems as a result of its low solubility in water ànd low rate of dissoluti~n.
~he solubility in water is also pH-dependent, qlibenclami~
being virtually insoluble in water in the acid region.
- 217~3~6 It is also known that the rate of dissolution depends on the particle size and on the extent of surface area of the particles (see, H. Borchert et al.: Zur pharmazeutischen Qualitat von Glibenclamid in Abhangigkeit von der Teilchengro~e, Pharmazie, 31, 307-309, 1976). Efforts have been made for many years, therefore, to improve the poor solubility and rate of dissolution. It was found that preparations with micronised, that is to say very finely crushed, glibenclamide (average particle size 2 5 ~m) showed an improved release of active substance and bioavailability, especially in the presence of surfactants (R. Groning ibid., H. Borchert et al., ibid).
DE-OS 23 48 334 describes a rapidly resorbable preparation of glibenclamide and a process for its production.
Glibenclamide was processed by very fine milling to a size with as defined as possible a surface area or by very fine precipitation from organic solvents in a dispersant to give effective and rapidly resorbable preparations. Using the method described in DE-OS 23 48 334, very fine crystallites with a surface area of 3 to 10 m2 were obtained. Tests have shown that the solubility and rate of dissolution are increased by enlarging the surface area, which also improves the bioavailability.
Using a glibenclamide tablet (Semi-Euglucon~ N) containing 1.75 mg of active substance, the same level of glibenclamide active substance could be produced as when using a tablet which contains 2.5 mg of glibenclamide (Euglucon~ 2.5). In this case, there was no difference with regard to the maximum serum concentration (cmax for both formulations being about 100 ng/ml), while tmaX (about 1 hour) was achieved 1.5 hours earlier than with the old formulation, Semi-Euglucon~ 2.5. From these tests and from comparative studies on the interchangeability of glibenclamide-containing drug products, it is also obvious that the solubility of glibenclamide, determined by the 21733~
particle size or surface area, is of great importance with respect to the bioavailability and efficacy of different preparations, and certain preparations are not suitable for substitution (see H. Blume et al., Untersuchungen zur therapeutischen Relevanz und zur Chargenhomogenitat glibenclamidhaltiger Fertigarzneimittel, Pharm. Ztg., 132, 23S2-2362, 1987).
It is also known that thermal stress during the production of drug preparations can have a detrimental effect on the stability of the active substance. In the examples provided in DE-OS 23 55 743, it is shown that the processing of glibenclamide at elevated temperatures, for example by incorporating into melts of high molecular weight polyethylene glycol, can be detrimental to the stability.
EP-A-0 418 553 relates to highly effective preparations of glibenclamide which release the active substance rapidly or in a controlled manner, which are characterised in that they comprise a solution consisting of 1 part of glibenclamide, 4-1500 parts of glycols, preferably propylene glycol, hexylene glycol, di, tri or polyethylene glycol with a molecular weight of 76.1 to 600 or mixtures thereof and optionally 0.5 to 3 moles, preferably about 1 mole, of an alkaline substance, such as alkali metal or alkaline earth metal hydroxides or ammonia, with respect to the glibenclamide, and optionally other suitable auxiliary agents or flavourings.
EP-A-0 086 468 relates to a pharmaceutical preparation comprising a rigid plate which consists of an intrinsically quick-acting oral antidiabetic sulphonylurea derivative mixed with a pharmaceutically acceptable liquid carrier, wherein the carrier is a hot-melt with a melting point in the range from 25C to a temperature below that which would cause thermal damage to the plate.
~17336~
Only a few commercial preparations such as, for instance, Euglucon~ N tablets provide relatively rapid in-vitro release of the active substance glibenclamide and as a result adequately rapid and effective resorption or bioavailability in-vivo. Rapid resorption of the active substance from the drug formulation offers the following advantages:
1. For reasons of mental acceptance by patients, the drug formulation can be taken at the same time as food.
2. The active substance is available in-vivo in precise amounts, if required and when required, which can prevent the occurrence of elevated or very variable blood sugar values.
The extrapancreatic effect is manifested in the case of insulin resistance by increasing the effect of insulin due to:
- an increase in sensitivity to insulin and insulin bonding in the target tissue:
- direct action on the insulin receptors in the sense of a multiplication.
Due to the high efficacy of and tolerance to sulphonylurea derivatives, these preparations now comprise the most important substances for oral treatment of diabetes.
It is known, and has been proven in tests, that in order to produce a therapeutic effect, not only the active substance but also its pharmaceutical/technologiçal formulation, also called the galenic form, is of great importance (see H.
Blume et al.:
zur Bioverfugbarkeit und pharmakodynamischen Aktivitat han-delsublicher Glibenclamid-Fertigarzneimittel, 1st communication: Bioequivalenzprufung an gesunden Probanden unter oraler Kohlenhydratbelastung: Pharm. Ztg., 130, 1062-1069, 1985;
2nd communication: Untersuchungen der glibenclamidinduzierten Veranderungen der Insulinkonzentration in Serum und der Blutglucosewerte an gesunden Probanden. Pharm. Ztg., 130, 1070-1078, 1985;
3rd communication: Bioequivalenzprufung an gesunden Probanden unter Dauerinfusion von Glucoselosung. Pharm.
Ztg., 130, 2606-2610, 1985 .
These tests demonstrated that the use of glibenclamide involves severe biopharmaceutical problems as a result of its low solubility in water ànd low rate of dissoluti~n.
~he solubility in water is also pH-dependent, qlibenclami~
being virtually insoluble in water in the acid region.
- 217~3~6 It is also known that the rate of dissolution depends on the particle size and on the extent of surface area of the particles (see, H. Borchert et al.: Zur pharmazeutischen Qualitat von Glibenclamid in Abhangigkeit von der Teilchengro~e, Pharmazie, 31, 307-309, 1976). Efforts have been made for many years, therefore, to improve the poor solubility and rate of dissolution. It was found that preparations with micronised, that is to say very finely crushed, glibenclamide (average particle size 2 5 ~m) showed an improved release of active substance and bioavailability, especially in the presence of surfactants (R. Groning ibid., H. Borchert et al., ibid).
DE-OS 23 48 334 describes a rapidly resorbable preparation of glibenclamide and a process for its production.
Glibenclamide was processed by very fine milling to a size with as defined as possible a surface area or by very fine precipitation from organic solvents in a dispersant to give effective and rapidly resorbable preparations. Using the method described in DE-OS 23 48 334, very fine crystallites with a surface area of 3 to 10 m2 were obtained. Tests have shown that the solubility and rate of dissolution are increased by enlarging the surface area, which also improves the bioavailability.
Using a glibenclamide tablet (Semi-Euglucon~ N) containing 1.75 mg of active substance, the same level of glibenclamide active substance could be produced as when using a tablet which contains 2.5 mg of glibenclamide (Euglucon~ 2.5). In this case, there was no difference with regard to the maximum serum concentration (cmax for both formulations being about 100 ng/ml), while tmaX (about 1 hour) was achieved 1.5 hours earlier than with the old formulation, Semi-Euglucon~ 2.5. From these tests and from comparative studies on the interchangeability of glibenclamide-containing drug products, it is also obvious that the solubility of glibenclamide, determined by the 21733~
particle size or surface area, is of great importance with respect to the bioavailability and efficacy of different preparations, and certain preparations are not suitable for substitution (see H. Blume et al., Untersuchungen zur therapeutischen Relevanz und zur Chargenhomogenitat glibenclamidhaltiger Fertigarzneimittel, Pharm. Ztg., 132, 23S2-2362, 1987).
It is also known that thermal stress during the production of drug preparations can have a detrimental effect on the stability of the active substance. In the examples provided in DE-OS 23 55 743, it is shown that the processing of glibenclamide at elevated temperatures, for example by incorporating into melts of high molecular weight polyethylene glycol, can be detrimental to the stability.
EP-A-0 418 553 relates to highly effective preparations of glibenclamide which release the active substance rapidly or in a controlled manner, which are characterised in that they comprise a solution consisting of 1 part of glibenclamide, 4-1500 parts of glycols, preferably propylene glycol, hexylene glycol, di, tri or polyethylene glycol with a molecular weight of 76.1 to 600 or mixtures thereof and optionally 0.5 to 3 moles, preferably about 1 mole, of an alkaline substance, such as alkali metal or alkaline earth metal hydroxides or ammonia, with respect to the glibenclamide, and optionally other suitable auxiliary agents or flavourings.
EP-A-0 086 468 relates to a pharmaceutical preparation comprising a rigid plate which consists of an intrinsically quick-acting oral antidiabetic sulphonylurea derivative mixed with a pharmaceutically acceptable liquid carrier, wherein the carrier is a hot-melt with a melting point in the range from 25C to a temperature below that which would cause thermal damage to the plate.
~17336~
Only a few commercial preparations such as, for instance, Euglucon~ N tablets provide relatively rapid in-vitro release of the active substance glibenclamide and as a result adequately rapid and effective resorption or bioavailability in-vivo. Rapid resorption of the active substance from the drug formulation offers the following advantages:
1. For reasons of mental acceptance by patients, the drug formulation can be taken at the same time as food.
2. The active substance is available in-vivo in precise amounts, if required and when required, which can prevent the occurrence of elevated or very variable blood sugar values.
3. Hyperglycaemia, caused by the intake of food or other effects, can be prevented or rapidly normalised.
Drug formulations which do not comply with these requirements for the rapid release of active substance incur the risk of hyperglycaemia if inadequate amounts of active substance are available for resorption due to unsatisfactory solubility or release characteristics. One prerequisite for rapid resorption, however, is that the active substance is available for release from the drug formulation as far as possible in a dissolved or colloidally dissolved form or distributed as a molecular dispersion. Only when these conditions are fulfilled, can the active substance be rapidly resorbed and thus become effective.
The present invention is based on the object of providing a process for improving the solubility of sparingly soluble sulphonylurea derivatives. Furthermore, effective preparations of sparingly soluble sulphonylurea derivatives, such as, for instance, glibenclamide, glipizide, etc., which release the active substance rapidly 21733~
.
or in a controlled manner and thus make it readily resorbable, are intended to be provided.
The sparingly soluble active substance is intended to be brought into solution as far as possible as a molecular dispersion using a simple process and pharmacologically and toxicologically harmless auxiliary agents. As a result, the active substance should be distributed very finely and have a high solubility because of the large surface area. The active substance distributed as a molecular dispersion is intended to be applied to conventional pharmaceutical carriers or even be embedded therein so that an active substance/auxiliary agent composite material is obtained, in order to enlarge the surface area.
,, By bringing the sparingly soluble sulphonylurea derivatives into solution as a molecular dispersion, they can be rapidly resorbed from the gastro-intestinal tract. In order to avoid hyperglycaemia, therefore, the active substance is immediately available when required or in connection with the taking of food (e.g. the intake of carbohydrates).
The process for producing the preparations in accordance with the invention is intended to be technically simple to perform, requires no expensive equipment and has no complicated process steps. Production is intended to be possible using commercially available auxiliary agents and simple resources. In addition, the method of production should not impair the chemico-physical properties of the active substance and auxiliary agents.
Surprisingly, it was found that the amount of polyethylene glycol required, with reference to examples 1 and 2 in DE-OS 23 55 743, can be reduced by up to 10-fold if the sulphonylurea derivatives are suspended in an alcohol, one or more polyol(s) and in sugar alcohols which have previously been dissolved in water or alcohol/water 21~336~
mixtures and if 0.5 to 2 moles, preferably 1 mole, of alkali metal hydroxide or ammonia is then added to the mixture.
The method of production according to the invention thus enables not only a reduction in the amount of auxiliary agents required but also represents a simple process for dissolving sparingly soluble sulphonylurea derivatives under conditions which are mild with respect to the active substance and the auxiliary agents.
The invention provides highly effective preparations of sulphonylurea derivatives which release the active substance rapidly or in a controlled manner, which are characterised in that they contain one or more sulphonylurea derivative(s) as active substance(s), one or more polyol(s) with the exception of polyethylene glycol and one or more sugar alcohol(s), previously dissolved in water or alcohol/water mixtures, an alkaline substance and optionally suitable pharmaceutically acceptable auxiliary agents or flavourings and optionally further pharmaceutically active substances.
The invention also provides a process for producing a highly effective preparation of sulphonylurea derivatives which releases the active substance rapidly or in a controlled manner, characterised in that one or more sulphonylurea derivative(s) as active substance(s), optionally after prior wetting with an alcohol, is/are suspended in an alcohol or one or more polyol(s) except polyethylene glycol and one or more sugar alcohol(s),.
dissolved in water or an alcohol/water mixture, an alkaline substance is added and optionally further suitable pharmaceutically acceptable auxiliary agents and flavourings and optionally further pharmaceutically active substances are added until a solid or liquid preparation is obtained.
~1733~
The preparations preferably contain, with respect to one part of active substance, 1 to 1000 parts of propylene glycol, glycerine, hexylene glycol or mixtures thereof and 1 to 500 parts of sugar alcohols, dissolved in 2 to 2000 parts of water or alcohol/water mixtures and 0.5 to 3 moles, preferably 1 mole, of an alkaline substance and optionally 0.01 to 1000 parts of pharmaceutically acceptable auxiliary agents and flavourings.
Preferably, in the process according to the invention, 1 part of sparingly soluble sulphonylurea derivative is suspended in 3 to 1000 parts of ethanol or polyols such as propylene glycol etc. or sugar alcohols, which have first been dissolved in water or water/ethanol mixtures, and mixed with 0.5 to 2 moles, preferably about 1 mole, of an alkaline substance and optionally further pharmaceutically acceptable auxiliary agents and flavourings so that a liquid or solid preparation is obtained.
The sulphonylurea derivatives may be any sulphonylurea derivatives. They are preferably glibenclamide (glyburide~, glipizide, glimepride, gliquidone, glisoxepide, glibornuride, glicalzide, glisentide, glisolamide, glybuzole, glyclopyramide and glyclamide.
The polyols used may be pharmaceutically acceptable non-toxic products such as, e.g. glycerine, propylene glycol, hexylene glycol or mixtures thereof, or sugar alcohols such as e.g. sorbitol, mannitol, xylitol, isomaltol or mixtures thereof, dissolved in water or alcohol/water mixtures. The sugar alcohols are preferably dissolved at a concentration of 10 ~ to 70 ~ in water or ethanol/water mixtures.
The alkaline substance may be any of the pharmaceutically acceptable and toxicologically harmless alkaline substances, such as alkali metal or alkaline earth metal hydroxides or ammonia, which can form salts with 21 7336~
sulphonylureas. It is preferably used in an amoun~ of 0.5 to 2 moles, more preferably about 1 mole, with respect to the sulphonylurea derivative.
The preparations may also contain pharmaceutically acceptable and toxicologically harmless auxiliary agents and flavourings such as those which are conventionally used in preparations presented in the solid or liquid form.
Compounds which may be mentioned include conventional 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, buffer substances, isotonic additives, surface active compounds, flavourings, suppository materials, etc., separately or in a mixture. Furthermore, the preparations may also contain as flavourings sugar substitu~es such as fructose, saccharin, aspartam, etc. and preservatives such as e.g. parahydroxybenzoates, benzyl alcohols, sorbic acid or salts thereof at a concentration of 0.1 to 2 wt.~ of the formulation. Furthermore, other pharmaceutically active substances may also be added to the preparations. These are preferably other medicaments for lowering blood-sugar levels such as e.g. ~-glucosidase inhibitors, such as e.g.
acarbose, miglitol, or aldose-reductase inhibitors such as e.g. alrestatin-sodium or voglibase. In this case, these other active substances may be formulated either separately or together with the sulphonylureas.
The preparations may be presented in the liquid, solid or semi-solid form. Liquid forms of presentation are, for instance, solutions for oral (syrups, drops), nasal (nasal drops, nasal sprays) or parenteral (injection or infusion) administration. Solid and semi-solid forms of presentation may be, for example, granules (dried syrup, sachets), tablets, capsules, pellets, film-coated 21733~
tablets, dragees and suppositories. The presentation of the medicament may be formulated so that the entire amount of active substance is released either in a very short time or over a controlled period of time.
Liquid forms of presentation, such as e.g. dropping solutions, have not hitherto been available for therapeutic purposes as commercial products. A dropping solution enables the provision of an individual dosage adjusted to the condition of the illness and the intake of food. Due to the fact that the active substance is present as a molecular dispersion in the preparation according to the invention, it is available immediately for resorption and thus enables rapid resorption and optimum bioavailability.
The particular alcohol used is preferably ethanol in 94 to 96 ~ strength pharmaceutical quality and purity in accordance with the requirements in the pharmacopoeia.
90 ~ strength or 70 ~ strength ethanol may optionally be used, i.e. for instance mixtures of 90 parts of ethanol and 10 parts of water. Depending on the solubility of the sulphonylurea derivative used, it may be expedient to first disperse the active substance in an alcohol, preferably ethanol, for better wetting, and then to suspend it in the sugar alcohol which has been previously dissolved in water or an alcohol/water mixture, preferably an ethanol/water mixture. Alcohols other than ethanol may also be used, e.g. methanol or isopropanol, optionally diluted with water. Due to physiological intolerance however, it must be ensured that these alcohols can be completely removed during the course of the manufacturing process. Ethanol is toxicologically harmless and is therefore preferred because, in contrast to other alcohols, it may also be present in the final product.
~17336~
Blume et al. (Ph. Ztg. 132, 39, 2352/101-2362/111, 1987) have demonstrated, in comparative in-vitro/in-vivo tests, that the bioavailability and effect depend directly on the rate of dissolution of the active substance and that the active substance becomes more rapidly available the more rapidly it is released in-vitro. In 3 batches of the generic preparation glycolande N with in-vitro dissolution rates of less than 80 ~ within 30 minutes, the pharmacokinetic parameter for tmaX was spread over 2.3 to 3.3 hours and for cmax over 120 to 133 ng/ml x h. In 1992 Blume et al. published, in Pharmazeutischen Zeitung no. 40, 137th year, tests on the pharmaceutical quality of glibenclamide-containing ready-to-use drugs, comparing 3.5 mg commercially available German preparations with products available in other Ec member states. From the in-vitro dissolution curves for the different preparations, it was shown that only a very few preparations had adequate in-vitro rates of release of active substance.
By way of example, using glibenclamide tablets which had been prepared in accordance with the process according to the invention, a 100 ~ release of the active substance occurred within 5 to 15 minutes in the in-vitro dissolution test (paddle apparatus in accordance with USP
XXII, 75 revs. per minute, buffer pH 7.4, W measurement at 227 nm), as can be seen from the accompanying diagrams. In a pharmacokinetic test using 12 volunteers, a cmax of 189 ng/ml, tmax f 1.7 h and an AUC of 653 ng x h/ml were obtained. The lowering of blood glucose level, measured at the same time, proved that very good bioavailability and efficacy can be produced using the process according to the invention.
The invention is explained in more detail by means of the accompanying figures. These show ~1~33~
Figure 1: a curve for in-vitro dissolution of different glibenclamide preparations in accordance with the Pharmazeutischen Zeitung reference cited above;
Figure 2: the glibenclamide formulation according to the invention compared with Euglucon N.
The method of production according to the invention is explained in more detail in the following.
The process for producing liquid forms of presentation is simple. The sparingly soluble sulphonylurea derivative, such as e.g. glibenclamide, is suspended in a stirred vessel 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 an alkaline substance such as, for instance, 0.1 molar ammonia solution or caustic soda solution, is added until a homogeneous solution is obtained. This solution can then optionally be mixed with other suitable auxiliary agents such as, for instance, water, sweeteners, flavourings and preservatives, and then used as a liquid pharmaceutical form of presentation (e.g. as a dropping solution or as a syrup) for lowering blood sugar levels.
To produce solid forms of presentation, an undiluted solution of active substance can be applied to tablet-producing auxiliary agents such as, for instance, starch, lactose, mannitol, microcrystalline cellulose or disintegrant, in a commercial mixing tank or fluidised bed granulator. Excess alcohol, ammonia or even water can then be removed in a drying cabinet.
Preferably, the solution is applied in a finely divided form to customary pharmaceutical auxiliary agents such as, for instance, mannitol, lactose, starch, 21733~
microcrystalline cellulose or disintegrant or dispersant or mixtures thereof. Using this type of procedure, the active substance is distributed as a quasi molecular dispersion or as an active substance composite material over a large surface area.
The glibenclamide applied as a solid solution and distributed as a molecular dispersion according to the invention, is so finely dispersed and so readily wettable that a further rise in the rate of dissolution should theoretically be no longer possible. The active substance goes into solution as a molecular dispersion immediately the tablet disintegrates, as can be shown by means of in-vitro release tests using glibenclamide-containing tablets. According to the Noyes-Whitney Law, the rate of dissolution is faster the greater is the wettable surface area of the particle to be dissolved.
The sulphonylurea derivatives used according to the invention are normally administered in daily doses of 1 to 250 mg, depending on the sulphonylurea derivative used. This dosage can be formulated as single doses or multiple doses using the dissolved sulphonylurea derivatives according to the invention, by a procedure known to a person skilled in the art. The exact dose to be administered can be adjusted by the doctor treating the patient, depending on the severity of the condition being treated and the patient.
The invention is explained in more detail by means of the following examples.
` -- 2~7336~
Example 1 4.5 g of glipizide are mixed, with stirring, with 80 g of hexylene glycol and 20 g of 70 ~ strength aqueous sorbitol solution and 2 ~ (w/v) strength ammonia solution is added until a solution is obtained.
Example 2 1 g of glimepride is stirred in 200 g of propylene glycol and 50 g of 20 ~ strength aqueous xylitol solution and 0.1 N caustic potash solution is added until a solution is obtained.
Drug formulations which do not comply with these requirements for the rapid release of active substance incur the risk of hyperglycaemia if inadequate amounts of active substance are available for resorption due to unsatisfactory solubility or release characteristics. One prerequisite for rapid resorption, however, is that the active substance is available for release from the drug formulation as far as possible in a dissolved or colloidally dissolved form or distributed as a molecular dispersion. Only when these conditions are fulfilled, can the active substance be rapidly resorbed and thus become effective.
The present invention is based on the object of providing a process for improving the solubility of sparingly soluble sulphonylurea derivatives. Furthermore, effective preparations of sparingly soluble sulphonylurea derivatives, such as, for instance, glibenclamide, glipizide, etc., which release the active substance rapidly 21733~
.
or in a controlled manner and thus make it readily resorbable, are intended to be provided.
The sparingly soluble active substance is intended to be brought into solution as far as possible as a molecular dispersion using a simple process and pharmacologically and toxicologically harmless auxiliary agents. As a result, the active substance should be distributed very finely and have a high solubility because of the large surface area. The active substance distributed as a molecular dispersion is intended to be applied to conventional pharmaceutical carriers or even be embedded therein so that an active substance/auxiliary agent composite material is obtained, in order to enlarge the surface area.
,, By bringing the sparingly soluble sulphonylurea derivatives into solution as a molecular dispersion, they can be rapidly resorbed from the gastro-intestinal tract. In order to avoid hyperglycaemia, therefore, the active substance is immediately available when required or in connection with the taking of food (e.g. the intake of carbohydrates).
The process for producing the preparations in accordance with the invention is intended to be technically simple to perform, requires no expensive equipment and has no complicated process steps. Production is intended to be possible using commercially available auxiliary agents and simple resources. In addition, the method of production should not impair the chemico-physical properties of the active substance and auxiliary agents.
Surprisingly, it was found that the amount of polyethylene glycol required, with reference to examples 1 and 2 in DE-OS 23 55 743, can be reduced by up to 10-fold if the sulphonylurea derivatives are suspended in an alcohol, one or more polyol(s) and in sugar alcohols which have previously been dissolved in water or alcohol/water 21~336~
mixtures and if 0.5 to 2 moles, preferably 1 mole, of alkali metal hydroxide or ammonia is then added to the mixture.
The method of production according to the invention thus enables not only a reduction in the amount of auxiliary agents required but also represents a simple process for dissolving sparingly soluble sulphonylurea derivatives under conditions which are mild with respect to the active substance and the auxiliary agents.
The invention provides highly effective preparations of sulphonylurea derivatives which release the active substance rapidly or in a controlled manner, which are characterised in that they contain one or more sulphonylurea derivative(s) as active substance(s), one or more polyol(s) with the exception of polyethylene glycol and one or more sugar alcohol(s), previously dissolved in water or alcohol/water mixtures, an alkaline substance and optionally suitable pharmaceutically acceptable auxiliary agents or flavourings and optionally further pharmaceutically active substances.
The invention also provides a process for producing a highly effective preparation of sulphonylurea derivatives which releases the active substance rapidly or in a controlled manner, characterised in that one or more sulphonylurea derivative(s) as active substance(s), optionally after prior wetting with an alcohol, is/are suspended in an alcohol or one or more polyol(s) except polyethylene glycol and one or more sugar alcohol(s),.
dissolved in water or an alcohol/water mixture, an alkaline substance is added and optionally further suitable pharmaceutically acceptable auxiliary agents and flavourings and optionally further pharmaceutically active substances are added until a solid or liquid preparation is obtained.
~1733~
The preparations preferably contain, with respect to one part of active substance, 1 to 1000 parts of propylene glycol, glycerine, hexylene glycol or mixtures thereof and 1 to 500 parts of sugar alcohols, dissolved in 2 to 2000 parts of water or alcohol/water mixtures and 0.5 to 3 moles, preferably 1 mole, of an alkaline substance and optionally 0.01 to 1000 parts of pharmaceutically acceptable auxiliary agents and flavourings.
Preferably, in the process according to the invention, 1 part of sparingly soluble sulphonylurea derivative is suspended in 3 to 1000 parts of ethanol or polyols such as propylene glycol etc. or sugar alcohols, which have first been dissolved in water or water/ethanol mixtures, and mixed with 0.5 to 2 moles, preferably about 1 mole, of an alkaline substance and optionally further pharmaceutically acceptable auxiliary agents and flavourings so that a liquid or solid preparation is obtained.
The sulphonylurea derivatives may be any sulphonylurea derivatives. They are preferably glibenclamide (glyburide~, glipizide, glimepride, gliquidone, glisoxepide, glibornuride, glicalzide, glisentide, glisolamide, glybuzole, glyclopyramide and glyclamide.
The polyols used may be pharmaceutically acceptable non-toxic products such as, e.g. glycerine, propylene glycol, hexylene glycol or mixtures thereof, or sugar alcohols such as e.g. sorbitol, mannitol, xylitol, isomaltol or mixtures thereof, dissolved in water or alcohol/water mixtures. The sugar alcohols are preferably dissolved at a concentration of 10 ~ to 70 ~ in water or ethanol/water mixtures.
The alkaline substance may be any of the pharmaceutically acceptable and toxicologically harmless alkaline substances, such as alkali metal or alkaline earth metal hydroxides or ammonia, which can form salts with 21 7336~
sulphonylureas. It is preferably used in an amoun~ of 0.5 to 2 moles, more preferably about 1 mole, with respect to the sulphonylurea derivative.
The preparations may also contain pharmaceutically acceptable and toxicologically harmless auxiliary agents and flavourings such as those which are conventionally used in preparations presented in the solid or liquid form.
Compounds which may be mentioned include conventional 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, buffer substances, isotonic additives, surface active compounds, flavourings, suppository materials, etc., separately or in a mixture. Furthermore, the preparations may also contain as flavourings sugar substitu~es such as fructose, saccharin, aspartam, etc. and preservatives such as e.g. parahydroxybenzoates, benzyl alcohols, sorbic acid or salts thereof at a concentration of 0.1 to 2 wt.~ of the formulation. Furthermore, other pharmaceutically active substances may also be added to the preparations. These are preferably other medicaments for lowering blood-sugar levels such as e.g. ~-glucosidase inhibitors, such as e.g.
acarbose, miglitol, or aldose-reductase inhibitors such as e.g. alrestatin-sodium or voglibase. In this case, these other active substances may be formulated either separately or together with the sulphonylureas.
The preparations may be presented in the liquid, solid or semi-solid form. Liquid forms of presentation are, for instance, solutions for oral (syrups, drops), nasal (nasal drops, nasal sprays) or parenteral (injection or infusion) administration. Solid and semi-solid forms of presentation may be, for example, granules (dried syrup, sachets), tablets, capsules, pellets, film-coated 21733~
tablets, dragees and suppositories. The presentation of the medicament may be formulated so that the entire amount of active substance is released either in a very short time or over a controlled period of time.
Liquid forms of presentation, such as e.g. dropping solutions, have not hitherto been available for therapeutic purposes as commercial products. A dropping solution enables the provision of an individual dosage adjusted to the condition of the illness and the intake of food. Due to the fact that the active substance is present as a molecular dispersion in the preparation according to the invention, it is available immediately for resorption and thus enables rapid resorption and optimum bioavailability.
The particular alcohol used is preferably ethanol in 94 to 96 ~ strength pharmaceutical quality and purity in accordance with the requirements in the pharmacopoeia.
90 ~ strength or 70 ~ strength ethanol may optionally be used, i.e. for instance mixtures of 90 parts of ethanol and 10 parts of water. Depending on the solubility of the sulphonylurea derivative used, it may be expedient to first disperse the active substance in an alcohol, preferably ethanol, for better wetting, and then to suspend it in the sugar alcohol which has been previously dissolved in water or an alcohol/water mixture, preferably an ethanol/water mixture. Alcohols other than ethanol may also be used, e.g. methanol or isopropanol, optionally diluted with water. Due to physiological intolerance however, it must be ensured that these alcohols can be completely removed during the course of the manufacturing process. Ethanol is toxicologically harmless and is therefore preferred because, in contrast to other alcohols, it may also be present in the final product.
~17336~
Blume et al. (Ph. Ztg. 132, 39, 2352/101-2362/111, 1987) have demonstrated, in comparative in-vitro/in-vivo tests, that the bioavailability and effect depend directly on the rate of dissolution of the active substance and that the active substance becomes more rapidly available the more rapidly it is released in-vitro. In 3 batches of the generic preparation glycolande N with in-vitro dissolution rates of less than 80 ~ within 30 minutes, the pharmacokinetic parameter for tmaX was spread over 2.3 to 3.3 hours and for cmax over 120 to 133 ng/ml x h. In 1992 Blume et al. published, in Pharmazeutischen Zeitung no. 40, 137th year, tests on the pharmaceutical quality of glibenclamide-containing ready-to-use drugs, comparing 3.5 mg commercially available German preparations with products available in other Ec member states. From the in-vitro dissolution curves for the different preparations, it was shown that only a very few preparations had adequate in-vitro rates of release of active substance.
By way of example, using glibenclamide tablets which had been prepared in accordance with the process according to the invention, a 100 ~ release of the active substance occurred within 5 to 15 minutes in the in-vitro dissolution test (paddle apparatus in accordance with USP
XXII, 75 revs. per minute, buffer pH 7.4, W measurement at 227 nm), as can be seen from the accompanying diagrams. In a pharmacokinetic test using 12 volunteers, a cmax of 189 ng/ml, tmax f 1.7 h and an AUC of 653 ng x h/ml were obtained. The lowering of blood glucose level, measured at the same time, proved that very good bioavailability and efficacy can be produced using the process according to the invention.
The invention is explained in more detail by means of the accompanying figures. These show ~1~33~
Figure 1: a curve for in-vitro dissolution of different glibenclamide preparations in accordance with the Pharmazeutischen Zeitung reference cited above;
Figure 2: the glibenclamide formulation according to the invention compared with Euglucon N.
The method of production according to the invention is explained in more detail in the following.
The process for producing liquid forms of presentation is simple. The sparingly soluble sulphonylurea derivative, such as e.g. glibenclamide, is suspended in a stirred vessel 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 an alkaline substance such as, for instance, 0.1 molar ammonia solution or caustic soda solution, is added until a homogeneous solution is obtained. This solution can then optionally be mixed with other suitable auxiliary agents such as, for instance, water, sweeteners, flavourings and preservatives, and then used as a liquid pharmaceutical form of presentation (e.g. as a dropping solution or as a syrup) for lowering blood sugar levels.
To produce solid forms of presentation, an undiluted solution of active substance can be applied to tablet-producing auxiliary agents such as, for instance, starch, lactose, mannitol, microcrystalline cellulose or disintegrant, in a commercial mixing tank or fluidised bed granulator. Excess alcohol, ammonia or even water can then be removed in a drying cabinet.
Preferably, the solution is applied in a finely divided form to customary pharmaceutical auxiliary agents such as, for instance, mannitol, lactose, starch, 21733~
microcrystalline cellulose or disintegrant or dispersant or mixtures thereof. Using this type of procedure, the active substance is distributed as a quasi molecular dispersion or as an active substance composite material over a large surface area.
The glibenclamide applied as a solid solution and distributed as a molecular dispersion according to the invention, is so finely dispersed and so readily wettable that a further rise in the rate of dissolution should theoretically be no longer possible. The active substance goes into solution as a molecular dispersion immediately the tablet disintegrates, as can be shown by means of in-vitro release tests using glibenclamide-containing tablets. According to the Noyes-Whitney Law, the rate of dissolution is faster the greater is the wettable surface area of the particle to be dissolved.
The sulphonylurea derivatives used according to the invention are normally administered in daily doses of 1 to 250 mg, depending on the sulphonylurea derivative used. This dosage can be formulated as single doses or multiple doses using the dissolved sulphonylurea derivatives according to the invention, by a procedure known to a person skilled in the art. The exact dose to be administered can be adjusted by the doctor treating the patient, depending on the severity of the condition being treated and the patient.
The invention is explained in more detail by means of the following examples.
` -- 2~7336~
Example 1 4.5 g of glipizide are mixed, with stirring, with 80 g of hexylene glycol and 20 g of 70 ~ strength aqueous sorbitol solution and 2 ~ (w/v) strength ammonia solution is added until a solution is obtained.
Example 2 1 g of glimepride is stirred in 200 g of propylene glycol and 50 g of 20 ~ strength aqueous xylitol solution and 0.1 N caustic potash solution is added until a solution is obtained.
Claims (14)
1. A highly effective preparation of sulphonylurea derivatives which release the active substance rapidly or in a controlled manner, characterised in that it contains one or more sulphonylurea derivative(s) as active substance(s), one or more polyol(s) and sugar alcohol(s) with the exception of polyethylene glycol, previously dissolved in water or alcohol/water mixtures, an alkaline substance and optionally suitable pharmaceutically acceptable auxiliary agents and flavourings and optionally further pharmaceutically active substances.
2. A preparation according to Claim 1, characterised in that it contains 1 to 1000 parts of polyol(s) and 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 auxiliary agents and flavourings, with respect to 1 part of medicinal substance.
3. A preparation according to Claim 1 or 2, characterised in that it contains, as a sulphonylurea derivative, glibenclamide (glyburide), glipizide, glimepride, gliquidone, glisoxepide, glibornuride, glicalzide, glisentide, glisolamide, glybuzole, glyclopyramide or glyclamide.
4. A preparation according to one of Claims 1 to 3, characterised in that it contains a 70 % strength sorbitol solution as a sugar alcohol or glycols.
5. A preparation according to one of Claims 1 to 4, characterised in that it is presented in the form of a liquid preparation.
6. A preparation according to one of Claims 1 to 4, characterised in that it is presented in the form of a solid solution or composite material.
7. A process for preparing a highly effective preparation of sulphonylurea derivatives which release the active substance rapidly or in a controlled manner, characterised in that one or more sulphonylurea derivative(s) as active substance(s), optionally after prior wetting with an alcohol, is suspended in one or more polyol(s) and sugar alcohol(s) with the exception of polyethylene glycol, which have previously been dissolved in water or an alcohol/water mixture, an alkaline substance is added and optionally suitable pharmaceutically acceptable auxiliary agents and flavourings and optionally further pharmaceutically active substances are added until a solid or liquid preparation is obtained.
8. A process according to Claim 7, characterised in that 1 part of active substance is suspended in 1 to 1000 parts of polyol(s) and sugar alcohol(s) dissolved in 2 to 2000 parts of water or alcohol/water mixtures and 0.5 to 3 moles of an alkaline substance are added and optionally further suitable pharmaceutically acceptable auxiliary agents and flavourings are admixed so that a liquid or solid preparation is obtained.
9. A process according to Claim 7 or 8, characterised in that the sulphonyl urea derivative is glibenclamide (glyburide), glipizide, glimepride, gliquidone, glisoxepide, glibornuride, glicalzide, glisentide, glisolamide, glybuzole, glyclopyramide or glyclamide.
10. A process according to one of Claims 7 to 9, characterised in that 70 % sorbitol solution as a sugar alcohol or glycols are used.
11. A process according to one of Claims 7 to 10, characterised in that a liquid preparation is produced.
12. A process according to one of Claims 7 to 11, characterised in that a solid solution or composite material is produced for use in solid or semi-solid forms of presentation.
13. Use of a rapidly resorbable preparation of sulphonylurea derivatives according to at least one of Claims 1 to 6, optionally together with further pharmaceutically active substances, for treating diabetes (diabetes mellitus).
14. Use of a rapidly resorbable preparation of sulphonylurea derivatives according to at least one of Claims 1 to 6, optionally together with further pharmaceutically active substances, for producing a medicinal substance for treating diabetes (diabetes mellitus).
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)
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|---|---|
| CA2173366A1 true CA2173366A1 (en) | 1995-04-27 |
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|---|---|---|---|
| CA002173366A Abandoned CA2173366A1 (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 |
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|---|---|
| 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 (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6174543B1 (en) | 1998-07-29 | 2001-01-16 | Shiseido Company, Ltd. | Antidiabetic external skin application composition |
| EP2181705A1 (en) | 2008-10-31 | 2010-05-05 | Disphar International B.V. | Sustained-release formulation of gliclazide |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AP1243A (en) * | 1999-02-01 | 2004-02-02 | Servier Lab | Core tablet for controlled release of gliclazide after oral administration. |
| AU2004273911B2 (en) | 2003-09-17 | 2010-04-15 | Board Of Regents, The University 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 |
| DE102005008044A1 (en) | 2005-02-19 | 2006-08-31 | Degussa Ag | Polymer powder with Blockpolyetheramid, use in a molding process and molding, made from this polymer powder |
| DE102005033379A1 (en) | 2005-07-16 | 2007-01-18 | Degussa Ag | Use of cyclic oligomers in a molding process and molding made by this process |
| DE102006015791A1 (en) | 2006-04-01 | 2007-10-04 | Degussa Gmbh | Polymer powder, process for the preparation and use of such a powder and molded articles 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 |
| 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 |
| DE102011078719A1 (en) | 2011-07-06 | 2013-01-10 | Evonik Degussa Gmbh | Powder containing polymer-coated 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 |
| DE102011078722A1 (en) | 2011-07-06 | 2013-01-10 | Evonik Degussa Gmbh | Powder containing polymer-coated inorganic particles |
| DE102011078721A1 (en) | 2011-07-06 | 2013-01-10 | Evonik Degussa Gmbh | Powder containing polymer-coated polymeric core particles |
| DE102012205908A1 (en) | 2012-04-11 | 2013-10-17 | Evonik Industries Ag | Polymer powder with adapted melting behavior |
| WO2017196358A1 (en) | 2016-05-13 | 2017-11-16 | Hewlett-Packard Development Company, L.P. | Material sets |
| WO2017196364A1 (en) | 2016-05-13 | 2017-11-16 | 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2118040A (en) * | 1982-02-15 | 1983-10-26 | Hoechst Uk Ltd | Oral anti-diabetic preparation |
| DE3927882A1 (en) * | 1989-08-23 | 1991-02-28 | Bauer Kurt Heinz | HIGHLY EFFECTIVE, QUICK-ABSORBABLE PREPARATION FORMS OF GLIBENCLAMIDE, METHOD FOR THE PRODUCTION AND USE THEREOF |
-
1993
- 1993-10-22 DE DE4336159A patent/DE4336159A1/en not_active Withdrawn
-
1994
- 1994-10-12 EP EP94929538A patent/EP0724427A1/en not_active Withdrawn
- 1994-10-12 CA CA002173366A patent/CA2173366A1/en not_active Abandoned
- 1994-10-12 HU HU9600956A patent/HUT74684A/en unknown
- 1994-10-12 WO PCT/EP1994/003368 patent/WO1995011006A1/en not_active Application Discontinuation
- 1994-10-12 AU AU78555/94A patent/AU7855594A/en not_active Abandoned
- 1994-10-12 NZ NZ274501A patent/NZ274501A/en unknown
- 1994-10-12 JP JP7511289A patent/JPH09504015A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6174543B1 (en) | 1998-07-29 | 2001-01-16 | Shiseido Company, Ltd. | Antidiabetic external skin application composition |
| EP2181705A1 (en) | 2008-10-31 | 2010-05-05 | Disphar International B.V. | Sustained-release formulation of gliclazide |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995011006A1 (en) | 1995-04-27 |
| DE4336159A1 (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 |
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