JPH0129169B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a rapidly absorbing oral drug in the form of granules or tablets containing glibenclamide as a sparingly soluble pharmaceutical active substance, and to a process for producing the same.

It has long been known that the absorption of orally administered poorly soluble pharmaceutical active substances is influenced by particle size, and in such oral drugs, the active ingredient is released after the tablet, coating, or capsule disintegrates. Ru. The finer the particle size, the easier it is to achieve rapid dissolution and absorption of the active substance in the gastrointestinal tract after ingestion. In West German Patent Publication No. 2017495,
It has been described that rapid absorption of sulfonamides can be achieved by incorporating poorly soluble sulfonamides with a particle size of less than 5 μm into galactomannan to form an oral dosage form. It has also been known for a relatively long time that wetting agents improve the solubility and therefore the absorption of such active substances. Therefore, in the case of very sparingly soluble active substances, namely Glibenclamide, active substance particles are present in ultrafine form, with a particle specific surface area of 3 to 10 m ² /g, which can be administered. Preparation forms are described in which the active substance is incorporated in a 2 to 20 times excess of the active substance in a pharmacologically acceptable wetting agent. Non-ionic polyoxyethylene stearate is preferably used as such a wetting agent (as described in West German patent no.
2348334).

However, the production of such finely divided active substances is very expensive. The reason is,
This is because in this case it is necessary to use special grinding equipment or to precipitate the active substance from the solvent in a particularly finely divided form in a unique process step and then to dry it. Also, the wetting agents used in this case have to be used in large excess and can exhibit undesirable side effects, in particular hyperlipidemia, aggregation of red blood cells, hemolysis and allergies.

In the present invention, surprisingly, the poorly soluble pharmaceutical active substance glibenclamide is not in finely divided form, but in the form of ordinary particles with a specific surface area of 0.8-1.4 m ² /g. However, such active substances and the basic compound tris-(hydroxymethyl)-aminomethane (trometamol)
and polyethylene glycol having an average molecular weight of 6,000 to 35,000 were found to be absorbed very well and rapidly when they were intimately mixed together to form granules or tablets. At this time, the mixing ratio should be 1 part of active substance: 1 to 20 parts of trometamol: 5 to 20 parts of polyethylene glycol. Particularly good absorption rates were achieved when equal amounts of trometamol and polyethylene glycol were present, with an optimum effect being found at a component ratio of 1:10:10.

Mixing and granulation of the three components is preferably carried out using a high-speed rotating mixer, for example, a so-called fluid mixer. Since the mixture may be heated during this intensive mixing mode, such heating is controlled by cooling the mixing equipment to keep the mixture temperature as low as possible above the softening temperature of the polyethylene glycol. It is necessary to At this time, granules are produced, which can be administered as they are or after being made into tablets.

Combining the active substance with polyethylene glycol alone does not allow the rate of dissolution and absorption to be improved to the desired degree. It is also possible to dissolve the active substance in polyethylene glycol by making a transparent melt of the active substance in polyethylene glycol heated to a temperature of about 130°C, and then cooling to crystallize out the active substance and reconstitute the polyethylene glycol. When using dosage forms produced by coagulation, it is not possible to obtain useful rapidly absorbing dosage forms. The reason for this is
Apart from the risk of thermal decomposition of the active substance during cooling and storage, the rate of dissolution of such preparations may be reduced, since the active substance crystallizes out in an uncontrolled manner into relatively large crystals or particles. This is because standardization is impossible.

By granulating using a high-speed rotating mixer (Henschel fluid mixer), the ingredients used in the invention are mixed particularly vigorously, so that the temperature rise is lower than or slightly above the softening point of the polyethylene glycol. You need to stop it. This causes the mixture particles to aggregate and form granules. Such granulation methods have been known for a long time, in particular in West German Patent Publications Nos. 1542058 and 2426812.
No. 2426811. In this case, inter alia, so-called filler particles are produced which are then mixed with the active substance and granulated to obtain delayed tablets. Depending on the granulation method used in the case of the combination according to the invention,
The pharmaceutical ingredients, i.e. the water-insoluble active substance, trometamol and polyethylene glycol, are thoroughly mixed with each other to ensure a very rapid absorption of the water-insoluble active substance when the resulting granules or the tablets made therefrom are orally administered.

In such a treatment, the normal particle size of the active substance particles remains essentially unchanged, but the active substance dissolves rapidly in the gastrointestinal tract since it is intensively mixed with trometamol and polyethylene glycol of the required molecular weight. It was completely unexpected that polyethylene glycol, which is not a humectant, when combined with the basic compound trometamol, significantly accelerates the dissolution and absorption of very sparingly soluble active substances. The reason for this is that such effects do not appear unless trometamol is used in combination. However, with such basic compounds effects are achieved that cannot be achieved with other basic compounds. Incorporation of sodium carbonate into the combination of poorly soluble active substance and polyethylene glycol of a given molecular weight does not achieve the desired solubility improvement.

Contrary to the result in the combination of ultrafinely powdered glibenclamide with a wetting agent as disclosed in DE 2348334, in the combination according to the invention the fineness of the active substance particles is , and therefore has no decisive influence on the absorption rate. However, it is necessary that the average particle size of the sparingly soluble active substance be within a desired range. The reason for this is that improved and facilitated dissolution in the gastrointestinal tract is not achieved. In the case of the combination according to the invention, no increase in solubility occurs even when highly comminuted, finely divided active substances are used.

The novel idea of the present invention is that the solubility of orally administrable, poorly soluble pharmaceutical active substances is improved by combining them with trometamol and polyethylene glycol, which needs to be rapidly absorbed but is difficult to absorb in the gastrointestinal tract when administered orally. It can be applied to a wide variety of pharmacologically active substances that exhibit only low dissolution rates within the tube. It has been found that the combination according to the invention is effective not only in the case of glibenclamide, in which the desired effect is particularly clear, but also in the case of other poorly soluble pharmaceutically active substances. Examples of such active substances are griseofulvin, digoxin (digitoxin), diethylstilbeestrol, prednisolone acetate, spironolactone, indomethacin, sulfathiazole, hydrocortisone, kavain and hexobarbital.

When using the oral medications of the present invention, the rate of absorption is improved so that in many cases the desired therapeutic effect can be achieved at lower doses than previously used or doses that have heretofore been able to achieve the desired therapeutic effect. therapeutic effects can be achieved without any risk of undesirable side effects that can occur with the use of large amounts of humectants and the like.

Next, an example of the present invention using glibenclamide, which is an extremely sparingly soluble effective substance, will be described.

Example 1 1 m ² /g in Henschel fluid mixer FM200
1891 g of glibenclamide having a particle size corresponding to , 16204 g of trometamol, 16204 g of polyethylene glycol (molecular weight 6000),
500~800g of titanium dioxide, which is a white application fee.
Mixing and granulation were carried out at a rotational speed of revolutions per minute, and at this time the temperature of the mixture was controlled at a maximum of 50° C. by cooling.

Next, the produced active substance-containing granules (37000g)
Adding conventional tabletting aids (corn starch, cellulose powder, talc, polyvinylpyrrolidone, silicon dioxide - Aerosil A200 (trade name) - and magnesium stearate) to
This mixture was pressurized to obtain tablets weighing 170 mg containing 3.5 mg of glibenclamide (72 mg of granules containing glibenclamide and 98 mg of tableting aid mixture).

Example 2 Glibenclamide (1 m ² /g) in a Henschel fluid mixer as in Example 1.
946g, trometamol 16677g, and polyethylene glycol (molecular weight 6000) 16677g were mixed.
Granulated. 34,300 g of granules were produced which were then pressed together with tableting aids to obtain tablets weighing 170 mg containing 1.75 mg of glibenclamide. Comparative test on dissolution rate and absorption rate in the gastrointestinal tract The following measurements were performed on two types of tablets containing glibenclamide as a sparingly soluble pharmaceutical active substance: (1) In vitro (in-
(2) plasma glibenclamide concentration, (3) plasma insulin concentration, and (4) plasma glucose concentration.

Two tablets with the following composition were used for these measurements: Tablet A (oral drug of the invention: oramide,
Product name), AI-Hikma
Pharmaceuticals): Obtained according to Example 1.
Tablets containing 3.5 mg of glibenclamide.

Tablet B (conventional oral: Daonil, manufactured by Hoechst AG): Obtained in the same manner as in Example 1, except that trimetamol and polyethylene glycol were not used. Tablet containing 5.0 mg of glibenclamide and a conventional tabletting agent.

(1) Test 1: In vitro dissolution amount of glibenclamide Tablets A and B were each dissolved at 37±1°C in 500ml of phosphate buffer (PH7.5) using a USP dissolution apparatus at 100rpm. Dissolved. 1ml
Aliquots were taken at specific time intervals and analyzed by high performance liquid chromatography.

At this time, use a reversed phase ODS (silica gel with chemically bonded octadecylsilyl groups) column (15 x 0.46
cm) and a 55:45 mixture of ammonium sulfate (0.023M) and acetonitrile was used as the mobile phase.

FIG. 1 shows the relationship between the amount of glibenclamide dissolved (mg) and the elapsed time (minutes). As shown in Figure 1, in the case of tablet A, more than 70% of glibenclamide dissolved in the first 10 minutes, 90% dissolved in the first 30 minutes, and complete dissolution was observed within 45 minutes. However, in the case of Tablet B, less than 50% of the glibenclamide was dissolved after 60 minutes and less than 60% after 90 minutes. In the case of tablet B, further
Even after dissolving for 20 minutes at 200 rpm, the dissolution of glibenclamide was not complete.

(2) Test 2: Plasma glibenclamide concentration Six healthy men (age 19-22, weight 61-
Each subject was given a standard breakfast and 150ml of black tea with 3 sugar cubes.
After 15 minutes, one tablet A or B was orally administered with 150 ml of water. A light standard breakfast was given 1.5 hours after dosing, and a standard lunch was given an additional 5 hours after administration.

Blood samples were collected before drug collection and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours after drug collection, centrifuged at 6000 rpm, and stored at -20°C. .

Add 100 μ of internal standard N-(4-
<2-(5-chloro-2-methoxybenzamido)-ethyl>-benzenesulfonyl)N'-cyclohexylurea (0.5 μg/ml) solution and 2
Add ml 0.1M phosphate buffer (PH4.0);
This mixture was extracted with 5 ml of dichloromethane. The organic layer was evaporated to dryness and the residue was dissolved in mobile phase (ammonium sulfate (0.023M) and acetonitrile mixture) (58:42). This dissolution was analyzed by high performance liquid chromatography.

Glibenclamide concentration in plasma (ng/ml)
FIG. 2 shows the relationship between and the elapsed time. As shown in FIG. 2, no significant difference was observed in plasma glibenclamide concentration between tablets A and B over 10 hours after administration.

(3) Test 3: Insulin concentration and glucose concentration in plasma The insulin concentration (U/ml) and glucose concentration (mg/d) of the blood samples collected in Test 2 were measured.

Insulin concentration was measured using the Coat-A-Count solid phase ¹²⁵ I-radioimmunoassay (Diagnostics) for quantitative in vitro measurement of insulin in plasma.
Diagnostic Products
Corp. (California, USA).

Glucose concentrations were measured using a Beckman Actra device for measuring glucose.

As a result of the measurement, no significant difference was observed in insulin concentration and glucose concentration between Tablet A and Tablet B over 10 hours after administration.

From the results of Tests 1 to 3, Tablet A, which uses glibenclamide, a poorly soluble pharmaceutical active substance, in combination with trometamol and polyethylene glycol, has a higher dissolution rate in the gastrointestinal tract and absorption rate than conventional Tablet B. It can be seen that there is a significant improvement and that the amount of glibenclamide required to achieve the same therapeutic effect can be reduced from 5 mg to 3.5 mg.

[Brief explanation of drawings]

FIG. 1 is a graph showing the relationship between the amount of the oral drug of the present invention dissolved in a phosphate buffer solution and the elapsed time, in comparison with the corresponding conventional oral drug. 2 is a graph showing the relationship between the concentration of glibenclamide in plasma and the elapsed time after administration in comparison with a corresponding conventional oral drug.

Claims (1)

[Scope of Claims] 1. A rapidly absorbing oral drug in the form of granules or tablets containing glibenclamide as a poorly soluble pharmaceutical active substance, comprising glibenclamide consisting of particles with a specific surface area of 0.8 to 1.4 m ² /g. and tris-(hydroxymethyl)-aminomethane (trometamol) and average molecular weight
6,000 to 35,000 polyethylene glycol in intimate admixture. 2 The mixing ratio of glibenclamide to trometamol to polyethylene glycol is 1:1 to 20:5 to
20. The oral drug according to claim 1, which is 20. 3. In producing a rapidly absorbing oral drug in the form of granules or tablets containing glibenclamide as a poorly soluble pharmaceutical active substance, the specific surface area is 0.8 to 1.4 m ² /
g of particles of glibenclamide, tris-(hydroxymethyl)-aminomethane (trometamol), and polyethylene glycol with an average molecular weight of 6,000 to 35,000 in a fluid mixer at a temperature lower than the softening point of the polyethylene glycol. A method for producing a rapidly absorbing oral drug, which is characterized by intensive mixing and granulation, and then pressing the resulting granules as required to form tablets.