Glyburide containing composition

FIELD: pharmaceutical agents, in particular glyburide containing composition.

SUBSTANCE: claimed composition contains 5-chloro-N-[2-[4-[[(cyclohexylamino) carbonyl]amino]sulfonyl]ethyl]-2-methoxybenzamide, known under generic name as glyburide, and has the next grain-size classification (%): undersize of 3-11 mum - 25; undersize of 6-23 mum - 50 %, and undersize of 15-46 mum - 75 %. Such grain-size classification affords the ability to increase glyburide dissolution rate and provide reproducible biological availability of glyburide.

EFFECT: pharmaceutical composition useful for treatment of II- type diabetes.

11 cl, 2 tbl, 6 ex

 

This invention relates to a physical form known medicinal substance gliburida, also known as glibenclamide, chemical name 5[chloro-N-[2[4-[[[(cyclohexylamino)-carbonyl]amino]sulfonyl]phenyl]ethyl]-2-methoxybenzamide (Merk Index, Tenth Edition, p.642), as well as to pharmaceutical forms such as tablets and capsules, including a specified physical form gliburida.

Specifically, the physical form gliburida which is the subject of the present invention, is a gliburid with a specific particle size distribution. This particle size distribution provides a higher dissolution rate gliburida in comparison with the bulk gliburid and reproducible bioavailability in vivo. Gliburid according to the invention may be included in tablets or it can be placed in the capsule to improve the desired physical and chemical properties (for example, the rate of dissolution and absorption of drug substances). Preferred dissolution rate and absorption of this invention are provided in the initial suction gliburida, however, you can avoid very high and quickly achieved concentrations of drug in plasma (“spike”)that would be created in the case of the use of drugs from the previous technique when attempting to provide suction at the very beginning. Very high and b is quickly achieved concentration may lead to undesirable hypoglycemia. Gliburid in physical form described in this invention allows to achieve this (desired) speed suction at the initial moment, but when saving effects of medicinal substances on the patient (as measured by area under the curve according to the drug concentration against time) and, therefore, maintaining the effectiveness of the drug. Gliburid according to this invention and the products based on it have properties that are particularly suitable for use as an oral means, amplifying secretion before eating.

Gliburid in physical form described in this invention can also be applied to drugs, combining it with other medicinal substances used in the treatment of type II diabetes. Examples include, but without limitation, acarbose or other inhibitors of glucosidase, rosiglitazone, pioglitazone, or other thiazolidinediones, biguanides, such as Metformin fumarate, Repaglinide and other “aginity”. Gliburid with granulometric composition of this invention can especially be applied in those cases in which there are joint products with medicinal substances with high dose and high solubility. An example of such medicinal substances used for the treatment of type II diabetes, is the big and known as Metformin (including it with the Li - fumarate and hydrochloride). Gliburid is an industrial product, is indicated for the treatment of type II diabetes. According to the method steps he is a stimulator of insulin secretion, i.e. it is an agent that stimulates the secretion of insulin in the beta cells of the patient (see U.S. Patent 3426069; 3454635; 3507961 and 3507954). After opening the gliburida were obtained compound gliburida with increased bioavailability compared with the bioavailability obtained initially, and commercially available formulations, for example as described in U.S. patent 3979520 and 4060634. In these patents describes the use of finely ground gliburida or gliburida with a large surface area (e.g., 3-10 m2combined with various pharmaceutically acceptable excipients to obtain increased bioavailability. Another song in the previous technique belongs to the drug finely chopped gliburida with a narrow particle size distribution with dried spray dried lactose. Dried spray dried lactose in the specified composition is a basic excipient (at least 70% of the final composition).

In U.S. patent 5258185 described rapidly absorbed formulation gliburida prepared by dissolving the drug substance in liquid polyethylene glycol and/or alcohol (such as ethanol) with coal is water-alcohol (e.g., sorbitol) and, if necessary, alkalizing agent (e.g., ammonia). This solution is mixed with the appropriate powdered pharmaceutically acceptable excipients, getting the dry granular material suitable for pressing into tablets. Similarly, Ganley (J.Pharm. Pharmac., 36:734-739, 1984) describes the improvement of the drug gliburida by incorporating solid polyethylene glycol in the preparation of capsules, a Shaheen (Int. J.Pharm., 38:123-131, 1987) applies a glycol and an alkaline agent, tromethamine for quick release gliburida of the tablets.

Due to the low solubility gliburida in water, the dissolution rate of the medicinal substances in the form of a dosage form, is the controlling factor in determining the rate and extent of absorption of drug substances. The dissolution rate depends on the particle size (or surface area of particles, which can be related to particle size). Borchert (Pharmazie, 31:307-309, 1976) showed the importance of this in vivo when in studies on rats showed more intense absorption gliburida in comparison with coarser material, when this drug was administered in the form of a suspension. Amqvist et al (ann. Clin. Res., 15:21-25, 1983) showed that it is possible finely chop gliburid to such an extent that the reduced particle size gliburida provide the supports, in comparison with the known formulation, a higher maximum serum concentration and a larger area under the curve concentration in the serum is the time after administration of the dose in the form of tablets containing low quantities of medicinal substances.

In none of these studies, however, have not shown how to determine the limits of the granulometric properties, is needed in order to ensure adequate bioavailability of the solid dosage form containing gliburid. It has been found that a suitable bioavailability gliburida get when reducing the size of particles gliburida control in such a way as to not get something that is classic “fine” material, but is still small enough to provide the desired dissolution rate. Achieving appropriate bioavailability contributes to the choice of excipients used in the formulation. Preferred excipients known in the prior art are such that allow drug release, almost without affecting the rate of dissolution and hence absorption of drug substances. Such excipients should be well soluble in water and therefore are quickly dissolved when the medicinal substance is in the water environment. This is the case of poorly soluble gliburid is released in the form of a thin slurry. Dissolution gliburida in the slurry, the speed of which is regulated by the particle size distribution is a prerequisite suction. Therefore, suction characteristics are determined by the grain size gliburida. Thus, when modeling the in vivo tests, the preferred dosage form is rapidly turning into a suspension of particles gliburida when it is swallowed. Poorly soluble excipients can give slowly disintegrating dosage form. For example, dosage forms, prepared from insoluble excipients a dicalcium phosphate, slow to break down and, therefore, slow release gliburid. In some currently available drugs gliburida, for example, Micronase™use such excipients, and as a result, they slowly release gliburid in the solution. Tablets and capsules prepared according to this invention with the use of soluble excipients, allocate 805 contained in them gliburida in for 20 minutes in an environment with phosphate buffer pH 6.4 with 1 wt.% sodium dodecyl sulfate under stirring with a stirrer at 50 rpm

When appropriate bioavailability gliburida possible to avoid rapid formation of very high maximum (“spike”) to the drug concentration in the blood plasma. Very high the th concentration can cause a patient's susceptibility to unwanted hypoglycemia. In addition, suitable (appropriate) bioavailability gliburida provides an adequate degree of absorption of the medicinal substance, such that the area under the curve “concentration of drug substances-time saves effectiveness. Not pushing any theory, the authors suggest that, apparently, it is this combination, i.e. early onset of absorption gliburida without the formation of exceptionally high maximum concentration of drug substance in plasma, however, while maintaining the exposure of the patient with the drug substance, makes it possible to apply gliburid according to the invention as oral contraceptives, causing the secretion before eating.

Other medicinal substances can also be prepared in the form of a combined preparation with gliburid, and they will continue to provide adequate bioavailability gliburida. In particular covered by the combined pill or capsules for complex drug therapy of diabetes.

Studies of tablets Metformin hydrochloride/gliburid made from gliburida with different granulometric characteristics help to identify the correlation between grain size gliburida and efficiency in vivo. The following table shows the properties of the parties gliburida used in the series is a combination of what's tablets. The specified particle size distribution can be obtained by sieving or, preferably, by grinding on vostokstrojj mill and to determine the method of laser scattering, table 1.

Table 1.

The particle size gliburida (microns)
Party pills25% lower fraction50% lower fraction75% lower fraction
Combo 1

Combo 2

Combo 3

Combo 4
15

28

10

6
33

58

25

11
62

88

52

19

The following pharmacokinetic parameters obtained in the analysis of curves of concentration gliburida in plasma over time for the four batches of tablets Metformin hydrochloride gliburid 500/2 .5 mg, prepared from these parties gliburida and introduced in the form of doses to patients; table 2.

Table 2

Pharmacokinetic parameters gliburida
Party pillsThe gusto (ng/ml creom.)AUC (ng/ml/h, Srem)The gusto (ng/ml sraam)AUC (ng/ml/HR, AVG aifm)
Combo 17147876493
Combo 25234554339
Combo 36451367531
Combo 48864293716

You can set a reasonable correlation between particle size and the maximum geometric mean concentration value of gliburida in plasma, Relish and also the geometric mean area under the curve concentration gliburida in the plasma - time AUC.

From these correlations computed desirable limits of particle size gliburida that could give calculated values of the Gusto and AUC 25% from the average for parties specified drug gliburida, Micronase™used in in vivo studies.

Applying these requirements to the Taste and AUC obtained the desired limits of particle size:

Limits to 25% lower fractionLimits to 50% lower fractionLimits to 75% lower fraction
3-micron6-mokran15-mokran

When measuring particles by the method of laser scattering using a medicinal substance dispersed in liquid paraffin, for introduction into the measuring cell. Based on the above data and use the I this methodology, it is found that for reliable reproducibility of the solubility and bioavailability preferred the following particle sizes:

25% lower (podkrkonosi) fractions 4-7 microns

50% lower fractions 7-13 microns

and 75% lower fractions 17-23 microns.

Especially preferred are the following particle size gliburida (particle size):

25% lower fraction of not more than 6 microns

50% lower fractions of size not more than 7 to 10 µm, and

75% lower fractions of size not more than 21 microns.

Gliburid must comply with these limits for steady reproducibility and appropriate bioavailability every time when preparing the drug and used in the form of tablets or capsules.

Gliburid with such granulometric composition has a surface area of about 1.7-2.2 m2g-1determined by adsorption of nitrogen. This is another difference gliburida in this invention from gliburida from the previous technique. Required gliburida in the previous technique, the surface area of the powder is more than 3 m2g-1(preferably 5-10 m2g-lin order to achieve its appropriate bioavailability. Gliburid with particle size distribution are presented in detail in this description, has in the human body suitable bioavailability.

When PR is expansion of gliburida tablets or capsules preferably incorporated in the composition of the drug corresponding amount soluble in the water of the excipients. The solubility of such excipients in water is usually from 50 mg/ml to 300 mg/ml can be used separately or in combination, and they can range in weight 45-90% by weight of the preparation. Such material used in tablets or capsules, completely dissolves within 5-10 minutes when testing for selection of drug substance in vitro, thus freed suspension gliburida. The preparation can also contain a binder such as povidone or hypromellose, low viscosity, lubricant such as magnesium stearate or stearyl fumarate magnesium. It was found that it is highly desirable to include a substance that promotes grinding for fast destruction of the dosage form when released into the aquatic environment. Relevant disintegrant include sodium-croscarmellose and alkaline starch. The drug, if necessary, may include other excipients, such as substances that promote ingestion, antiadhesive, dyes, flavorings, components for film coating (including polymers such as hypromellose, wetting agents such as Polysorbate 20, plasticizers such as polyethylene glycol 200), and other substances commonly used in the preparation of tablets and capsules and well-known specialists in this field of technology.

Fit well Astoriya in water excipients also include. Without limitation, carbohydrate alcohols, such as mannitol, sorbitol and xylitol; sugars such as sucrose, lactose, maltose and glucose; oligosaccharides, such as maltodextrins.

Example 1

Gliburid

Bulk gliburid served in vozduhonosnye mill (Esco Strahlmuele) through a hopper with a screw feed, the feed rate is 20-30 kg/hour. The mill operates under a nitrogen pressure of about 1.5 atmospheres and the pressure in the micron colloidal chamber 4 to the atmosphere. Not allowed to decrease the size gliburida, usually described as fine. The mill shut down and out of her unload the medicinal substance. Sample gliburida with reduced particle size are examined by the method of particle size analysis using laser diffraction beam. The following results are obtained:

D 25% 5 μm, D 50% 9 microns, D 75% 21 microns.

(Note: This method of grinding in the mill is usually carried out to obtain industrial finely ground material. Test industrial finely ground sample by the method of particle size analysis gives the following results:

D 25% to 2.8 μm, D 50% 4.5 microns, D 75% to 7.3 microns.

Therefore, the material of this example is different from the subject of an industrial design fine gliburida).

Example 2

Prepare medication gliburida, the composition of single doses which is presented below:

Ingredientmg tablet
Mannitol

Gliburid example 1

Sodium croscarmellose

Microcrystalline cellulose

Povidone

Magnesium stearate
150,0

5,0

6,25

75,0

12,5

0,2-2,5

Gliburid mixed with sodium croscarmellose and this mixture is mixed with mannitol. Then carry out a wet granulation of the mixture, using povidone dissolved in an appropriate amount of purified water. The obtained granules are dried to the desired residual moisture, mixed with microcrystalline cellulose, plastificator, mixing with magnesium stearate and pressed into tablets containing 5 mg gliburida.

Method in vitro dissolution of tablets determine the speed with which gliburid released from the tablets. The tablet is placed in a medium for dissolution of phosphate buffer pH 6.4 with 1 wt.% sodium dodecyl sulfate and stirred with a paddle stirrer at 50 rpm 80% of the drug substance tablet is dissolved within 20 minutes.

Example 3

Ingredientmg pills
Mannitol

Gliburid example 1

Sodium croscarmellose

Microcrystalline cellulose

On icon

Magnesium stearate

Film coating (if necessary)
250,0

1,25

7,0

28,25

10,0

of 0.6 to 6.0

of 4.5 to 12.0

In a process similar to the process described in example 2, get tablets containing 1.25 mg gliburida. Tablets if necessary, cover the shell of the proper composition for film coating, such as OPADRY using the form to cover with side branches.

Example 4

Ingredient

Lactose monohydrate

Gliburid example 1

Sodium croscarmellose

Microcrystalline cellulose
mg tablet 250,0

250,0

5,0

7,0

28,25
Povidone10,0
Magnesium stearateof 0.6 to 6.0

By a method similar to the method described in Example 2, get tablets containing 5.0 mg gliburida.

Example 5

From gliburida according to the invention can be prepared in combination with other drugs lekarstvennymi substances for the treatment of type II diabetes. This simplifies the treatment of patients who have shown combination therapy when treatment with a single drug does not allow adequate control of their disease. Such agents may include, but without limitation, acarbose or friend who e glycosidase inhibitors, rosiglitazone, pioglitazone or other thiazolidinediones, biguanides, such as Metformin fumarate, Repaglinide or other “aginity”.

The example of maleate of rosiglitazone
Ingredientmg tablet
Mannitol

Rosiglitazone maleate

Gliburid example 1

Sodium croscarmellose

Microcrystalline cellulose

Povidone

Magnesium stearate

- (equivalent to 2 mg of rosiglitazone
250,0

2,65

1,25

7,0

28,25

10,0

of 0.6 to 6.0

By a method similar to that described in example 2, two medicinal substance is first mixed with sodium croscarmellose, and then add the remaining ingredients for the preparation of tablets, each containing 1.25 mg gliburida and 2 mg rosiglitazone (as maleate).

Specialist in the art will appreciate that the presented variants of the invention can be modified, without departing from the essence and scope of the invention.

1. 5-chloro-N-[2-[4-[[(cyclohexylamino)-carbonyl]amino]sulfonyl]ethyl]-2-methoxybenzamide having the following particle size characteristics:

25% lower (podkrkonosi) fraction with a particle size of 3 to 11 μm,

50% lower fraction with a particle size 6-23 μm and

75% bottom FR who work with particle size 15-46 microns.

2. The substance according to claim 1, having the following particle size characteristics:

25% lower fraction with a particle size of 4-7 microns, 50% lower fraction with a particle size of 7 to 13 microns and 75% lower fraction with a particle size 17-23 microns.

3. The substance according to claim 2, having the following particle size characteristics:

25% lower (podkrkonosi) fraction with a particle size of not more than 6 μm,

50% lower fraction with a particle size of not more than 7 to 10 µm and

75% of the bottom fraction with a particle size of not more than 21 µm.

4. Tablet or capsule, stimulating insulin secretion containing substance according to claim 1 and a second drug substance, applicable for the treatment of type II diabetes and selected from the group consisting of acarbose, rosiglitazone, Metformin fumarata and Repaglinide.

5. Tablet or capsule, stimulating insulin secretion containing substance according to claim 1 and at least one soluble in water excipient.

6. Tablet or capsule according to claim 5, characterized in that at least one soluble in water excipient is 45-90 wt.% the total weight of the preparation.

7. Tablet or capsule, stimulating insulin secretion containing substance according to claim 1.

8. Tablet or capsule, stimulating insulin secretion that contains a combination of Metformin and gliburida having the following particle size characteristics:

50% lower fraction with a particle size 6-23 μm and

75% of the bottom fraction with a particle size 15-46 microns.

9. The tablet or capsule of claim 8, wherein gliburid has the following particle size characteristics:

25% lower fraction with a particle size of 4-7 microns, 50% lower fraction with a particle size of 7 to 13 microns and 75% lower fraction with a particle size 17-23 microns.

10. The tablet or capsule of claim 8, wherein gliburid has the following particle size characteristics:

25% lower (podkrkonosi) fraction with a particle size of not more than 6 μm,

50% lower fraction with a particle size of not more than 7 to 10 µm and

75% of the bottom fraction with a particle size of not more than 21 µm.

11. A method of treating type II diabetes, which consists in the introduction in need of such treatment to the patient a therapeutically effective amount of a substance according to claim 1.



 

Same patents:

The invention relates to the derivatives of benzosulfimide formula (I):

< / BR>
where X represents a nitro-group, a cyano or halogen; Y1represents a secondary or tertiary amino group; Y2represents nitrogen or NH group; Z represents oxygen, sulfur, -N-CN or CH-NO2; and R1and R2that may be the same or different, are each independently saturated or unsaturated linear or branched alkyl group containing from 2 to 12 carbon atoms, saturated or unsaturated alicyclic group containing from 3 to 12 carbon atoms, phenyl, unsubstituted or substituted by one or more substituents, which represents a1-C4alkyl group, nitro, cyano, trifluoromethyl, carboxy and halogen, benzyl group or phenylethylene group, or Y1means tertiary amino group and R1form a morpholine or homopiperazin and Y2represents nitrogen and R2forms homopiperazin, except for derivatives, for which X is a nitro-group, Y1represents a secondary amino group (-NH-), Y2represent the group, includes m-toluyl, phenyl and cyclooctyl, and with the exception of N-[(2-cyclooctylamino-5-cyanobenzoyl)sulfonyl] N'-Isopropylamine, or its pharmacologically acceptable salt

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ArSO2NHCONHR',

where R = ArCONHCH2CH2, HtCONHCH2CH2, R' = cycloalkyl, cycloalkenyl, including substituted cycloalkyl or cycloalkenyl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

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16 cl, 1 tbl, 86 ex

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where: R represents hydrogen;

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R3and R4

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-CN;

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The invention relates to organic chemistry, in particular to the compounds representing amide of the formula I:

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< / BR>
where X represents a nitro-group, a cyano or halogen; Y1represents a secondary or tertiary amino group; Y2represents nitrogen or NH group; Z represents oxygen, sulfur, -N-CN or CH-NO2; and R1and R2that may be the same or different, are each independently saturated or unsaturated linear or branched alkyl group containing from 2 to 12 carbon atoms, saturated or unsaturated alicyclic group containing from 3 to 12 carbon atoms, phenyl, unsubstituted or substituted by one or more substituents, which represents a1-C4alkyl group, nitro, cyano, trifluoromethyl, carboxy and halogen, benzyl group or phenylethylene group, or Y1means tertiary amino group and R1form a morpholine or homopiperazin and Y2represents nitrogen and R2forms homopiperazin, except for derivatives, for which X is a nitro-group, Y1represents a secondary amino group (-NH-), Y2represent the group, includes m-toluyl, phenyl and cyclooctyl, and with the exception of N-[(2-cyclooctylamino-5-cyanobenzoyl)sulfonyl] N'-Isopropylamine, or its pharmacologically acceptable salt

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