JPS59206306A - Glibenclamide-containing medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition in the form of gelatin soft caprel containing glibenclamide in a carrier.

The compound 1-(4-['2'-(5-chloro-2-methoxy-benzamido)ethyl]-phenyl-sulfonyl)-3-cyclohexylurea (referred to as "glibenclamide") is produced, for example, by Marjindale 5T
he Extra pl+arlacopoeia
(Pharmacopeia revised edition (separate volume)), 28th edition, 1982, p.
854 and is used in pharmaceutical compositions for the treatment of diabetes.

The therapeutic value and application safety of a drug is likely to be
It is known that complete or even permanent levels of bioavailability of active ingredients depend. A look at the early literature shows that the problems with this perspective were precisely the case with penclamide. For example, the absorption rate upon oral administration was initially reported to be 43% (W.

Rupp, 0. Christ, W. Heptn.
erlArzneilttel -Forshung
/Drug Re5search 19 (19(')9
), 1428-1434). Subsequently, by changing the dosage form and increasing the surface area of the active ingredient, they were able to improve the absorption rate to around 90% (W
, Rupp, O, CI+rist, W, Ful.
berth, ArZlleimittel-FOr
SChLing/DrugResearchb 22 (
1972), 471-473). More recently, the absorption rate of glibenclamide has been further improved, thereby reducing the minimum effective dose, as is evident from DE 2348334 (published tC unexamined patent application). On the other hand, tablets having the properties described in German Published Publication No. 2348334 have been put on the market. In this case, by simultaneously forcibly adding a dispersant, glibenclamide is finely dispersed on a microscopic scale to achieve the desired effect. However, the preparation of finely divided glibenclamide has to be done by various expensive and problematic methods. One of these methods for precipitating the active ingredient from solution is to dissolve the active ingredient, transfer the solution to a receiver with vigorous stirring, and separate and dry the active ingredient. The process involves the consumption of substances and energy and the loss of active ingredients. The method of pulverizing (refining) the second glibenclamide in several steps using a jet mill can only be carried out at the cost of extremely large energy losses and losses of transferred materials. Good too. Furthermore, micronized glibenclamide itself contains considerable problems. That is, in order to maintain a constant qualitative level of the drug, the surface of its particles must be kept constant within narrow limits for each batch of active ingredient;
and it is required to permanently check it. Moreover, in the manufacture of tablets, certain conditions must be strictly maintained. This is because even slight changes in the manufacturing process, such as mixing, compaction pressure, or machine type, can already destroy the particle surface and impair the absorption of glibenclamide. German Publication No. 2355743
No. 1, No. 1, No. 1, No. 2003-2001, glibenclamide formulations containing this active ingredient in the form of salts or at least in the presence of an alkaline substance such as potassium bicarbonate are disclosed. Re-examination of this formulation revealed that glyhenclamide under alkaline conditions or in its salt form degrades so quickly that it is completely unable to achieve the preservative stability required for this type of drug. Ta.

European Publication No. 06468 discloses hard gelatin capsules, in which also glibenclamide is mixed with an alkaline component, dissolved, heated, and if necessary other ingredients are added. It is filled into caprels. The prepared formulation is solid at room temperature. Since alkaline components in the formulation also cause decomposition of glibenclamide, long-term storage stability has not been achieved in this case either.

An object of the present invention is to provide a medicament containing an effective amount of glibenclamide in a carrier, which is easy to manufacture, rapidly exhibits high activity, and can be sufficiently applied for oral administration. It is. Glibenclamide is
It is poorly soluble in normal physiologically compatible solvents. However, in the research carried out to achieve the above purpose while conducting IJX, glibenclamide was found to be a combination of polyalkylene glycol and polyoxyethylene glycerol.
It has been discovered that it can be dissolved to a sufficient extent in physiologically acceptable mixtures with trihydroxystearate. The solution thus obtained can be filled into soft gelatin capsules in a manner known per se. The advantage of this dosage form is that the active ingredient glibenclamide
The advantage is that it can be formulated into formulations without special precautions in its synthesized state.

Accordingly, one object of the present invention is to provide a pharmaceutical composition in the form of a soft capsule containing glibenclamide in 10 parts, comprising 95 to 80 parts of polyalkylene glycol and poly(alkylene glycol). Oxyethylene glycol? []-Pharmaceutical composition characterized in that it contains 0.5 to 5 parts by weight of cribenclamide dissolved in a mixture with 4.5 to 15 parts by weight of Ru.1-rehydroxystearate. It provides: The present invention also relates to a method for producing the soft capsule.

The relative molecular Φ of polyalkylene glycols can vary between 285 and 2000, while for polyethylene glycol and poly-10 pyrene glycol 380-43
0 is preferable, and in the case of polyoxyethylene polyoxypropylene polymers, 1800 to 2000 is preferable. The ethylene oxide units of the polyoxyethyleneglycerol trihythmyloxystepflate vary from 35 to 65, preferably from 35 to 45.

The following components represent a typical formulation of the solution according to the invention: Glibenclamide 1.0-4.0 g Polyalkylene glycol 94.2-84. OQ polyoxyethylene glycerol/trihydroxystearate 4.8-12.00
Next, the present invention will be explained in detail with reference to Examples.

However, these do not limit the present invention.

Example 1 17.50 g of glibenclamide was mixed with polyoxyethylene glycerol trihydroxystearate (Cre+nophor"-RH40) at 100 to 140°C with stirring.
, 8A'5F), and then this solution was dissolved in polyethylene glycol 400 (l utrol E
(2) Add to 400, BASF>888.550 with stirring at 40-80°C. After cooling to air temperature, the solution is filled into half-sized Geratin soft capsules. Your solution contains 3.50 mg of glibenclamide in 0.200 g.

Support i9L Polyoxyni [tyrene polyoxypropylene polymer (
P 1uronic” L 35, Wyand
otte chemicals CorL)888
．． 55 (l and polyoxyethylene glycerol/l-lyhydroxystearate) (Cremopl+or@-
RH40, BASF) 93.95q
It is prepared under stirring at ~130° C. and at this temperature 17.50 g of glibenclamide are added under stirring. The solution is rapidly cooled to room temperature and filled into soft gelatin capsules of appropriate size. This solution contained 3.50111 g of glibenclamide in 0.20 Oo.

亙１” - Ho') 7D fin＞'I'J] -/L/425 (E,
Merck) 888.55 (+ and polyoxyethylene glycerol trihydroxystearate (Crem
ophor ■-RH40, BASF)93. ．． 951J
Mixed with? II is prepared at 120-140° C. and at this humidity 17.50 CI of glibenclamide is added under stirring.

The solution is rapidly cooled to room temperature and filled into soft gelatin capsules of appropriate size. 0.200 g of this solution contained 3.50 mg of glibenclamide.

The release of glibenclamide from the soft gelatin capsules of the present invention is described in accordance with the United States Pharmacopoeia, 20th Revision (U.

J3-CPa in artificial gastric fluid according to S, P, XX)
Tested using the ddle method. 86 of glibenclamide is U
It was determined from absorption measurements at 2,301 m using the v-spectrophotometric method. The accompanying figures 1 to 1b show that glibenclamide is completely released from the soft capsules according to the invention within a very short time.

In contrast, it has also been shown that the release of the active ingredient from commercially available tablets stops after a short time on the order of about 10%.

The hypoglycemic effect of the gelatin soft capsules of the present invention and commercially available tablets was demonstrated in rabbits (WhiteRUSSian).
S) was tested. Three test groups each consisting of five male animals weighing 2.0 to 2.5 kg were prepared and subjected to the following treatments.

The first test group received glibenclamide in the form of a suspension;
0.1 or 111+(+) per 1 kg of body weight, respectively, was administered via a gastric tube.
．． It was prepared by crushing 5+no tablets in a sufficient amount of water and homogenizing the suspension. The active ingredient content Φ is 0.1111 (+/Q, 2yx/
2 or 1 m(I/O,, adjusted to 2 mg).

The second test group was administered glibenclamide in the form of a solution orally via a gastric tube at 0.1 or 1 m (I)/kg body weight, respectively.
(+Prepared using the contents of a soft gelatin capsule.

The content of active ingredients is 0.11 C each using the original solvent.
11(]10.2πβ or 1mM 0.2cod.

The third test group had a body weight of 11 (0.69% saline per 0.2
Cod was administered orally to serve as a pair of fish.゛To measure the sugar content in the blood, before application and every hour after application,
Blood was collected from the ear marginal vein for 7 or 24 hours, respectively. The measurement is ]:.

H, 3 Chmidt et al. (;l, K fin, Ch
em, 13 iochem.

(J', entrifichem
3. Protein was removed in system 400, and the protein was removed using the kinetic hexokinase method.
, t-IKH method). Low test in which the measured blood sugar concentration was statistically compared with each blood sugar level of test substance release + fff>. The reduction value is at least 1 of the previous value
When it reached 0 to 15%, it was considered that the test substance caused a significant decrease in blood glucose ω in terms of fc'EI. Figure 2 and Figure 3 show the blood levels of rabbits when the glibenclamide preparation was administered. i represents the concentration. The average value of the measured values for each of the five animals was recorded. Furthermore, the AUC value (area under the curve) was calculated from each of these average values. F, t1. Dost (Qrundlagen
derl)l+a+nakokineNk, Q
eorg Thieme Verlag, S
According to Tutthart (1968), the area surrounded by one time axis of blood glucose level is a measure of the amount of the test substance present in the body. They were calculated and the following values were obtained indicating a greater reduction in blood sugar compared to the control: Gelatin soft capsules 32.0% (7 hours) (Example 1) Geratin soft capsules 24.2% (24 time)<
Example 2) City 1llll! Formulation: 20.1% (7 hours) Commercial preparation: 17.8% (24 hours) Shows excellent utilization efficiency.

[Brief explanation of the drawing]

FIG. 1, FIG. 18 and FIG. 1b are graphs showing changes over time in the release rate (%) of glibenclamide from 3.5 mg [Latin soft capsules of the present invention in comparison with commercially available tablets, respectively in Example 1. , 2 and 3 formulations. <[In the figure, the capsules of the present invention are indicated by ○...○, and the commercially available tablets are indicated by .... Figures 2 and 3 show glibenclamide administration to rabbits at 7 or 24 +1.
Figure 2 is a graph showing the change in blood glucose level (mn + ol/πβ) over time between 1 and 2 days. In the figure, Δ-△ indicates the control (Group 3), e-• indicates the commercially available tablets (Group 1), and ○-○ indicates the soft gelatin capsules of Example 1 (Group 2). ) Corresponds to - Ruru 1゜ Patent Applicant Drorgi - 1 Gezershi [・F I ~ Mitsut Beschlenkter Hafrang Run 1-・Company Commandet Gezershi + 7ft

Claims (5)

[Claims] (1) A pharmaceutical composition in the form of a soft gelatin capsule containing an effective amount of glibenclamide in a carrier, comprising 95 to 80 parts by weight of polyalkylene glycol and 4 parts by weight of polyoxyethylene glycerol trihydroxystearate.
．． A pharmaceutical composition characterized in that it contains 0.5 to 5 parts by weight of glibenclamide dissolved in a mixture with 5 to 15 parts by weight. (2) The relative molecular weight of polyalkylene glycol is 28
5-630. The pharmaceutical composition according to item 1. (3) The relative molecular weight of polyalkylene glycol in the form of polyoxyethylene polyoxypropylene polymer is 15
2. The pharmaceutical composition according to item 1, wherein the pharmaceutical composition has a molecular weight of 00 to 2000. (4) The pharmaceutical composition according to any one of items 1 to 3, wherein the polyoxyethylene glycerol trihydroxystearate contains 35 to 65 ethylene oxide units. (5) A method for producing a pharmaceutical composition containing glibenclamide in the form of a soft gelatin capsule, the method comprising: glibenclamide 0
．． 5 to 5 parts by weight of polyoxyethylene glycerol trihydroxystearate to 4.5 to 15 parts by weight of 100
Dissolve under heating at ~140°C and heat the solution at 40-80°C.
80-95
Alternatively, add 0.5 to 5 parts by weight of glibenclamide to a mixture of 80 to 95 parts by weight of polyalkylene glycol and 4.5 to 15 parts by weight of polyoxyethylene glycerol trihydroxystearate with stirring. and dissolved under heating at 100 to 140°C,
A method characterized by cooling the solution obtained by any of these methods and filling it into soft gelatin capsules.