HUT74684A - Pharmaceutilal compositions containing highly active sulphonyl urea derivatives exhibiting rapid or controlled release of the active substance, and method of producing them - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to high-potency, fast or controlled release formulations of water-insoluble sulfonylureas and to a process for solubilization of water-insoluble sulfonylureas.

The efficacy of a drug depends largely on the formulation. As a general rule, for systemic action, the active ingredient must be injected directly into the vasculature or be formulated as an absorbable formulation. Resorption, or absorption, of a substance is the entry into the bloodstream or lymphatic system from where it is distributed throughout the body. The rate of resorption and the rate of resorption (ratio of absorbable fraction to total amount administered) are therefore dependent on a large number of factors. The efficacy and bioavailability of many oral and parenteral drugs is determined by their solubility in aqueous media. One class of drugs whose bioavailability, and thus potency, is highly dependent on solubility in aqueous media is the sulfonylurea. These substances are currently used to reduce blood sugar (Diabetes mellitus).

As an example of the effect of solubility on the onset of action, efficacy, and dose required, their most prominent representative is Glibenclamide (INN).

Glibenclamide, also in American terms like Glyburide? -1-, repel, a sulfonylurea derivative with the chemical name according to IUPAC nomenclature: N-4- (5- chloro-2-methoxybenzamido) ethylphenylsulfonyl-N'- cyclohexyl-urea. Molecular weight 494.02, m.p. 172-174 ° C (cf. R Groening: Arzneistoff-profile und B ifferzbarkeitsdaten von Fertigarzneimitteln, Arzneistoffmonographie Glibenclamid, Deutscher Apothekerverlag, Stuttgart, p. 17). Glibenclamide is an odorless, crystalline, white substance which is practically insoluble in water and ether, and only slightly soluble in alcohol and chloroform. It forms salts with alkalis, which, however, have very limited solubility in water when compared to Tolbutamide, which is also a blood glucose lowering agent.

Other therapeutically used sulfonylureas, such as Glipizide, Glibornurid, Gliquidon, Glisoxepid and Glimeprid, all have similar solubility properties based on their physico-chemical structural relationship.

The above-mentioned sulfonylureas are widely used in the treatment of diabetes mellitus at doses of 1-250 mg daily. Two mechanisms may be distinguished in the resultant reduction in blood glucose, namely a pancreatic and an extrapancreatic effect (see Prepare information from Boehringer Mannheim GmbH & Hoechst AG, 1984, Euglucon® N, Semi-Euglucon® N).

The pancreatic effect in response to glucose leads to increased insulin secretion through increased sensitivity of the pancreatic beta cells.

The extrapancreatic effect of insulin resistance is exacerbated by the insulin effect:

- through increased insulin sensitivity and insulin binding capacity of the target tissue:

- direct effect on insulin receptors in sensing growth.

Based on the good efficacy and compatibility of sulfonylurea derivatives, these compositions are currently of major importance in the oral treatment of diabetes.

It is known and proven by studies that not only the active ingredient, but also the pharmaceutical-technological formulation, also called galenic, is of great importance for the achievement of a therapeutic effect (cf. H. Blume et al., Zeer Bioverfügbarkeit und pharmakodynamischen Aktivitat handelsüblicher Glibenclamide). -Fertigarzneimittel / Bioavailability and pharmacodynamic activity of a commercially available Glibenclamide drug,

Announcement 1: Bioequivalenzprüfung an gesunden Probanden unter anon Kohlenhydratbelastung - Bioequivalence Study of Oral Carbohydrate Exposure in Healthy Subjects: Pharm. Ztg., 130, 1062-1069 (1985);

Announcement 2: Untersuchungen Glibenclamidinduzierten Veranderungen hoar Insulin Concentration im Serum und oder Blutglucosewerte an Gesunden Probanden - Investigation of Glibenclamide-Induced Serum Insulin Concentration and Blood Glucose Levels in Healthy Subjects. Ztg., 130, 1070-1078 (1985);

Announcement 3: Bioequivalence of Glucoselösungen Glucoselösung - Bioequivalence Study of Healthy Subjects Undergoing Long-Term Glucose Infusion: Pharm. Ztg., 130, 2606-2610 (1985).

From these studies, it was found that Glibenclamide is one of the biopharmaceuticals, due to its low water solubility and dissolution rate. Its water solubility is pH dependent, and in an acidic medium Glibenclamide is practically insoluble in water.

It is also known that the dissolution rate depends on the particle size, i.e. the size of the surface of the particle (cf. H. Borchert et al.). Pharmazeutischen Qualitat von Glibenclamid in Abhangigkeit von dér Teilchengrösse. 3 1, 307309 (1976). Therefore, efforts have been made over the years to correct poor solubility and dissolution rate. It was found that formulations containing micronized, i.e. very finely divided, Glibenclamide (medium particle size> 5 µm), in particular in the presence of surfactants, showed improved release and bioavailability (R. Groening, supra, H. Borchert et al., Supra). ).

No. 2,348,334. In the German patent application, Glibenclamide is described in a quick-release formulation and its preparation. Glibenclamide has been converted into a good and rapidly absorbable formulation by grinding it to a large surface, preferably on a defined surface, or by precipitation from an organic solvent into a dispersant in the form of very fine particles. No. 2,348,334. The fine crystalline material was obtained with a surface area of 3-10 m ² . Studies have shown that surface enhancement increased solubility and dissolution rate, thereby improving bioavailability.

A Glibenclamide tablet (SemiEuglucon ® N) containing 1.75 mg of active ingredient provided the same distribution of Glibenclamide as a tablet containing 2.5 mg of Glibenclamide (Euglucon ® 2.5). Therefore, there is no difference in maximal serum concentrations (c _{max for} both formulations is about 100 ng / ml), whereas at _max (about 1 hour) is about 1.5 hours earlier than with the previous formulation, SemiEuglucon® 2.5 -winter. Thus, from these experiments and comparative studies on the interchangeability of glibenclamide-containing finished drugs, the solubility of Glibenclamide, as determined by seed and surface sizes, is of great importance for the bioavailability and efficacy of different formulations, and not suitable for substitution (cf. H. Blume et al., Untersuchungen zur therapeututischen Relevanz und zur Chargenhomogenität glibenclamidhaltiger Fertigarzneimitt - Tests for the therapeutic identity and batch homogeneity of the glibenclamide-containing pharmaceutical product, p.

Furthermore, it is known that the stability of the active ingredient in the preparation of dosage forms may be affected by the temperature load. No. 2,355,743. In the German Patent Publication there are examples which show that processing of Glibenclamide at elevated temperatures destroys stability, e.g. incorporation into the high molecular weight polyethylene glycol melt.

No. 0,418,553. European Patent Publication No. 3,646,011 relates to high-activity, fast-release formulations of Glibenclamide, characterized in that they consist of a solution of 1 part Glibenclamide, 41,500 parts glycols 76.1-600, preferably propylene glycol, hexylene glycol, relative to Glibenclamide. , tri- or polyethylene glycol, or a mixture thereof, and optionally 0.5 to 3.0 mol, preferably ca. It contains 1 mole of a basic reactant such as alkaline or alkaline earth metal hydroxide or ammonia, and optionally other suitable auxiliary or aromatic substances.

No. 0 086 468. European Patent Application Publication No. 3,646,011 relates to a pharmaceutical composition comprising a rigid case containing an internally short-acting oral antidiabetic sulfonylurea derivative in admixture with a pharmaceutically acceptable liquid carrier, wherein the carrier comprises a hot melt having a melting point of 25 ° C. temperature which would cause thermal damage to the case.

Only a few commercially available formulations, such as Euglucon® N tablets, exhibit a relatively rapid release of Glibenclamide in vitro, followed by in vivo rapid and good absorption and bioavailability. The benefits of rapid absorption from the formulation are:

1. Patients should take the medicine at the same time as meal, according to their usual diet.

2. The active substance is available in vivo in a well-defined manner, calculated on the basis of need and duration, to prevent the occurrence of elevated or severely decreasing blood glucose levels.

3. Hyperglycemia, which depends on food intake or other influences, can be avoided or quickly normalized.

Formulations that do not meet these needs after a rapid release of the drug have the inherent risk of hyperglycemia if there is insufficient amount of the drug due to insufficient solubility or release that is available for absorption. However, a rapid absorption is expected when the active ingredient is available in the form of a formulation, preferably dissolved or colloidally dissolved or dispersed in a molecular dispersion. Only when these conditions are met can the active ingredient be rapidly absorbed and thus act.

It is therefore an object of the present invention to provide a process for increasing the solubility of poorly soluble sulfonylureas. It is a further object of the present invention to provide effective, rapid and controlled release formulations of poorly soluble sulfonylureas such as Glibenclamide, Glipizide, and the like, which are readily absorbed.

The sparingly soluble active substances should be dissolved in solution, preferably in a molecularly dispersed form, by a simple process and with pharmacologically and toxicologically acceptable excipients. It is through this that the active ingredient is finely dispersed and consequently the large surface area provides good solubility. The active ingredient dispersed in the molecular dispersion should be applied to, or rather embedded in, conventional pharmaceutical carriers to increase the surface area to form an active ingredient excipient alloy.

Due to the solution dispersion by molecular dispersion, the poorly soluble sulfonylureas are able to be rapidly absorbed from the gastrointestinal tract. To avoid hyperglycaemia, the active ingredient is therefore readily available when needed or in connection with food intake (eg carbohydrate transport).

The process for preparing the compositions of the present invention must be technically easy to carry out, require no costly apparatus, and must not involve any complicated process steps. Production must be feasible with commercially available excipients and simple means. In addition, the chemical and physical properties of the active ingredients and excipients cannot be adversely affected during the manufacturing process.

Surprisingly, it has been found that U.S. Patent No. 2,355,743 is incorporated herein by reference. The required amount of polyethylene glycol as given in Examples 1 and 2 of the German Patent Application can be reduced to 10 times if the sulfonylureas are suspended in an alcohol, one or more polyols and sugar alcohols previously and the resulting mixture is mixed with 0.5-2.0 mol, preferably 1 mol, of alkali hydroxide or ammonia.

The preparation process of the present invention not only reduces the amount of excipient required, but also provides an active and excipient-friendly, simple process for the dissolution of poorly soluble sulfonylureas.

SUMMARY OF THE INVENTION The present invention relates to high-potency, rapid and controlled release pharmaceutical formulations of sulfonylureas, characterized in that one or more sulfonylureas as active ingredient, one or more polyols other than polyethylene glycol, and one or more sugar alcohols, previously dissolved in water or an alcohol-water mixture, containing an alkaline reactant and optionally suitable pharmaceutically acceptable excipients and flavoring agents and optionally further pharmaceutically active substances.

The present invention also relates to the preparation of high-potency, rapid and controlled release formulations of sulfonylureas which comprise the step of providing one or more sulfonylureas as an active ingredient, optionally in an alcohol or in one or more polyols other than polyethylene glycol, and in one or more sugar alcohols previously dissolved in water or alcoholic urine, mixed with a basic reacting agent, and optionally further suitable pharmaceutically acceptable excipients and flavoring agents, and optionally further pharmaceutically active substances are added to form a solid or liquid preparation.

The compositions according to the invention preferably contain from 1 to 1000 parts of propylene glycol, glycerol, hexylene glycol or a mixture thereof and from 1 to 500 parts of sugar alcohol dissolved in 2 to 2000 parts water or alcohol-water, and 0.5- 3.0 moles, preferably 1 mole, of an alkaline reactant and optionally 0.01 to 1000 parts of pharmaceutically acceptable excipients and flavorings.

Preferably, the process of the present invention comprises suspending 1 part of a poorly soluble sulfonylurea in 3 to 1000 parts of ethanol or polyols, such as propylene glycol, etc., or sugar alcohols previously dissolved in water or a mixture of water and ethanol. 0.5 to 2.0 moles, preferably 1 mole, of a basic reacting agent and optionally other pharmaceutically acceptable excipients and flavorings ι

mixing to form a liquid or solid composition.

The sulfonylurea derivatives may be any sulfonylurea derivative, preferably Glibenclamide (Glyburid), Glipizide, Glimeprid, Gliquidon, Glisoxepid, Glibornuride, Glicalzid, Glisentid, Glisolamide, Glybuzol, Glyclopyramide.

As a polyol, pharmaceutically acceptable non-toxic products, e.g. glycerol, propylene glycol, hexylene glycol, or a mixture thereof; and sugar alcohols, e.g. sorbitol, mannitol, xylitol, isomaltose, or a mixture thereof, dissolved in water or a mixture of alcohol and water. Preferably, the sugar alcohols are dissolved in water or ethanol-water at a concentration of 10% to 70%.

The alkaline reactant may be any pharmaceutically acceptable basic reactant such as alkali or alkaline earth metal hydroxides or ammonia which can form salts with sulfonylureas. They are preferably present in an amount of 0.5 to 2.0 moles, more preferably about 0.5 to 2.0 moles relative to the sulfonylurea derivative. 1 mole.

The compositions may also contain pharmaceutically acceptable and toxicologically inert excipients and flavoring agents as they are commonly used in solid or liquid dosage forms. These include customary binders such as lactose, starch, microcrystalline cellulose, croscarmelose, calcium carbonate, calcium diphosphate, Pluronic polyols, cellulose ether, alginic acid derivatives, Eudragit, magnesium stearate, silicon dioxide, colorants, substances, preservatives, buffers, isotonic additives, surfactants, flavorings, suppository masses, etc., alone or in a mixture, to name a few. Further, the composition may contain fructose, saccharin, aspartame, etc. as sugar-substituting flavoring agents, and as a preservative, a concentration of 0.1 to 2.0% by weight of the composition, of para-hydroxybenzoic acid ester, benzyl alcohol, citric acid or salts thereof. Further, further pharmaceutically active substances may be added to the compositions of the invention. These may preferably be other blood glucose lowering drugs, such as α-glucosidase inhibitors such as Acarbose, Miglitol; or aldose reductase inhibitors, e.g. Alrestatin-Sodium or Voglibase. These other active ingredients may be formulated either separately or together with the sulfonylureas.

The compositions may be in liquid, solid or semi-solid form. Liquid formulations include, for example, solutions for oral administration (solutions, drops), nasal (nasal drops, nasal spray) or parenteral (injection or infusion) formulations. Solid and semi-solid formulations include granules (dried syrups, powders), tablets, capsules, pills, film-coated tablets, dragees and suppositories. The dosage forms may therefore be formulated so that all active ingredients are absorbed in a controlled manner within the shortest time or time.

Liquid formulations such as droplets have not been available as a commercial product until now. The drops allow individual dosing, adapted to the disease state and food intake. Due to the fact that the active ingredient is dissolved in a molecular dispersion in the composition according to the invention, it is directly available for absorption, thereby enabling rapid absorption and bioavailability.

The alcohol used is preferably ethanol, 94-96%, of pharmaceutical grade and purity according to the Pharmacopoeia. Optionally, 90% or 70% ethanol may be used, i.e. a mixture of 90 parts ethanol and 10 parts water. Depending on the solubility of the sulfonylurea used, it may be desirable to first disperse the active ingredient in an alcohol, preferably ethanol, and then suspend with the sugar alcohol previously dissolved in water or alcoholic urine. Alcohols other than ethanol may be used, such as methanol or isopropanol, optionally diluted with water. However, based on physiological intolerance, it should be stated that these alcohols must be completely removed during the manufacturing process. Ethanol is toxicologically insignificant and is therefore advantageous because, unlike other alcohols, it can be present in the final product.

Blume et al. (Ph. Ztg. 132, 39, 2352 / 101-2362 / 1111, 1987) demonstrated that bioavailability and activity are directly dependent on the dissolution rate of the active ingredient, and the faster the active ingredient is available, the faster it is released in vitro. In 3 batches of generic Glykolande N formulations with in vitro dissolution rates of less than 80%, pharmacokinetic parameters were diffused within 30 minutes, t _max 2.3 - 3.3 h and c _max 120 - 133 ng / ml x h ( Blume et al., Pharmazeutische Zeitung 40, 137 (1992). Over the years, studies have been carried out on the pharmaceutical quality of finished medicinal products containing 3.5 mg of glibenclamide as commercially available in Germany, compared to products available in other EC Member States. The in vitro dissolution curve of the different formulations shows that only a few formulations exhibit sufficient in vitro release.

For example, Glibenclamide tablets prepared according to the method of the present invention were successful in the in vitro dissolution test (Paddle apparatus USP XXII, 75 rpm, buffer pH 7.4, UV measurement at 227 nm). 100% release of drug within 15 minutes as shown in the accompanying drawings. In a pharmacokinetic study in 12 volunteers, c _max was 189 ng / ml, t _raax 1.7 hours and AUC 635 ng xh / ml. The concurrent reduction in blood glucose demonstrates that the process of the present invention has achieved very good bioavailability and efficacy.

The invention is illustrated in more detail by the accompanying drawings, in which:

Figure 1 of the Pharmazeutische Zeitung a.a.O. shows the in vitro dissolution curve for various Glibenclamide formulations according to the invention; the

Figure 2: Glibenclamide formulation of the invention compared to Euglucon N.

The preparation methods of the present invention are described in more detail below.

The process for preparing liquid formulations is simple. A poorly soluble sulfonylurea derivative such as Glibenclamide is suspended in a stirring vessel with 4-1000 parts of propylene glycol, hexylene glycol or sugar alcohols previously dissolved in water or ethanol-water with stirring, and a such as 0.1M ammonia solution or caustic soda until a homogeneous solution is obtained. This solution may then optionally be mixed with other suitable excipients, such as water, sweeteners, flavoring and preservatives, and thereafter therapeutically used as a liquid pharmaceutical formulation (e.g., as drops or as a solution) to lower blood glucose levels.

For the preparation of solid dosage forms, the undiluted active ingredient solution is formulated in a commercially available conventional mixing vessel or vortex granulator for tabletting auxiliaries, e.g.

starch, lactose, mannitol, microcrystalline cellulose or carrier, are applied.

κ «

It is preferable to apply the solution very finely divided to the pharmaceutically acceptable excipients, e.g. mannitol, lactose, starch, microcrystalline cellulose or carrier, dispersant or mixture thereof. As such, the active ingredient is quasi-molecularly dispersed or dispersed over a large surface area as an active ingredient alloy.

The Glibenclamide dispersed as a solid solution dispersed in the molecular dispersion of the present invention is so finely dispersed and so wettable that it is theoretically impossible to further increase the dissolution rate. The active ingredient immediately dissolves into a solution of the molecule in molecular dispersion as shown by in vitro release studies with Glibenclamide-containing tablets. According to Noyes-Whitney law, the faster the dissolution rate is, the greater the wettable surface of the particle to be dissolved.

The sulfonylureas used in the present invention are usually administered in a daily dose of 1 to 250 mg, depending on the sulfonylurea used. This dose may be a single or multiple dose release of the sulfonylurea derivatives of the present invention formulated according to methods known to those skilled in the art. The exact dosage to be administered may be adjusted by the attending physician according to the severity of the condition being treated and the patient.

The invention is further illustrated by the following examples.

* · «·· ·« • ♦♦

Example 1

Glipizide (4.5 g) was mixed with 80 g of hexylene glycol and 20 g of 70% aqueous sorbitol solution with stirring and mixed with 2% (w / v) ammonia until a solution was obtained.

Example 2 Glimepride (g) is mixed with 200 g of propylene glycol and 50 g of a 20% aqueous solution of xylitol, and 0.1 N potassium hydroxide is added until a solution is obtained.

Claims (14)

Claims CLAIMS 1. An effective, rapid and controlled release formulation of a sulfonylurea, characterized in that one or more sulfonylurea derivatives have been previously dissolved in water or alcoholic urine, with the exception of polyethylene glycol, an alkaline reactant and optionally suitable pharmaceutically acceptable excipients and flavoring agents and optionally further pharmaceutically active substances. Composition according to Claim 1, characterized in that from 1 to 1000 parts of polyol and sugar alcohol dissolved in from 2 to 2000 parts in water or alcohol-water mixture, from 0.5 to 3.0 moles of alkali-reacting agent, 0.01 to 1000 parts are pharmaceutically acceptable excipients and flavorings. Composition according to claim 1 or 2, characterized in that the sulfonylurea derivative is Glibenclamide (Glyburid), Glipizide, Glimeprid, Gliquidon, Glisoxepid, Glibornurid, Glicalzid. Glisentid, Glisolamide, Glybuzol, Glyclopyramide or Glyclamide. 4. A composition according to any one of claims 1 to 5, characterized in that the sugar alcohol contains 70% sorbitol solution of craving glycol. • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · To to k to · to 5. A composition according to any one of claims 1 to 3, characterized in that it is in the form of a liquid formulation. 6. Composition according to any one of claims 1 to 3, characterized in that it is in the form of a solid solution or an alloy. A process for the preparation of a highly effective, rapid and controlled release formulation of a sulfonylurea, characterized in that one or more sulfonylurea derivatives as an active ingredient, optionally after preheating with alcohol, in one or more polyols other than polyethylene glycol, and suspended in a sugar alcohol previously dissolved in water or a mixture of alcohol and water, mixed with a basic reacting agent and optionally further suitable pharmaceutically acceptable excipients and flavoring agents and optionally further pharmaceutically active substances, and a solid or liquid preparation. we get. 8. The process of claim 7, wherein 1 part of the active ingredient is suspended in 1 to 1000 parts of polyol and sugar alcohol dissolved in 2 to 2000 parts of water or alcoholic water and 0.5 to 3 moles of a basic reactant. and optionally mixed with other suitable pharmaceutically acceptable excipients and flavorings to form a liquid or solid composition. 9. A process according to claim 7 or 8, characterized by? ·····? The sulfonylurea derivative is Glibenclamide (Glyburid), Glipizide, Glimeprid, Gliquidon, Glisoxepid, Glibornurid, Glicalzid, Glisentide, Glisolamide, Glybuzol, Glyclopyramid or Glyclamide. 10. A process according to any one of claims 1 to 4, wherein the sugar alcohol is a 70% sorbitol solution or glycol. 11. A process according to any one of claims 1 to 4, wherein a liquid composition is prepared. 12. A 7-11. A process according to any one of claims 1 to 3, characterized in that a solid solution or alloy is prepared in solid or semi-solid form for use. 13. A sulfonylurea derivative of at least one of claims 1-6. Use of a rapidly absorbable pharmaceutical composition according to any one of claims 1 to 3, optionally together with further pharmaceutically active substances, for the treatment of diabetes mellitus. 14. A sulfonylurea derivative having at least one of claims 1-6. Use of a rapidly absorbable composition according to any one of claims 1 to 6, optionally together with other pharmaceutically active substances, for the manufacture of a medicament for the treatment of diabetes mellitus.