JPH069388A - Sustained-release oxybutynin hydrochloride preparation - Google Patents

Abstract

(57) [Summary] [Purpose] To provide a sustained-release oxybutynin hydrochloride preparation with long-acting ability that can be orally administered. A sustained-release oxybutynin hydrochloride preparation characterized in that a pharmaceutical composition containing oxybutynin hydrochloride and an acidic substance is mixed with a gel-forming substance such as hydroxypropylmethylcellulose and higher alcohols having 12 or more carbon atoms. [Effects] Controlled release of oxybutynin hydrochloride, lowering the maximum plasma concentration compared to conventional formulations, and obtaining a constant blood concentration for a long time, it is recommended to be taken once or twice a day. can do.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained-release oxybutynin hydrochloride preparation having long-acting orally administered properties.

[0002]

2. Description of the Related Art Sustained-release preparations improve safety by preventing abrupt release of the main drug, improve efficacy by prolonging the action time, and reduce the number of administrations, resulting in troublesome administration by patients. It has advantages such as openness and prevention of non-compliance. In recent years, urinary incontinence of elderly people is becoming a social problem, and the effectiveness of oxybutynin hydrochloride developed as a drug for treatment of frequent urination and urinary incontinence is highly evaluated.

[0003]

However, although oxybutynin hydrochloride is absorbed promptly after administration, its elimination half-life is short, and therefore it has to be taken 3 times a day, which makes the administration complicated. In addition, urinary incontinence patients often have difficulty in going out for a long time due to their symptoms, and frequent urination and
Oxybutynin hydrochloride, which is a drug for treating urinary incontinence, has a long-lasting effect, and there has been a demand for a sustained-release preparation with a sustained-release preparation having the above-mentioned advantages. As a result of intensive studies, the present inventors have completed the present invention by discovering that oxybutynin hydrochloride is mixed with an acidic substance, a gel-forming agent and higher alcohols for sustained release.

[0004]

The sustained-release oxybutynin hydrochloride preparation of the present invention is characterized by including a gel-forming substance and higher alcohols in a pharmaceutical composition containing oxybutynin hydrochloride and an acidic substance. .

The present invention will be further described in detail. Since oxybutynin hydrochloride is a mineral acid salt of an organic base, its solubility in neutral to alkaline is expected to decrease.
Sustained-release preparations will remain in the body for a long time, but for example, the pH in the human gastrointestinal tract is 1 to 3.5 in the stomach,
It is known that pH is 5 to 6 in the duodenum, 6 to 7 in the jejunum, and 8 in the ileum. In order to keep the solubility of the drug constant in the living body where the pH changes in this way, it is necessary to devise a formulation. The present inventors have solved the problem by adding an acidic substance in order to obtain a formulation that is not affected by pH, and were able to obtain the sustained release formulation of the present invention.

Either an inorganic acid or an organic acid can be used as the acidic substance, but an organic acid that is harmless to the human body is desirable. Examples of organic acidic substances include adipic acid, ascorbic acid, erythorbic acid, citric acid, gluconic acid, gluconodeltalactone, succinic acid, tartaric acid, fumaric acid,
Malic acid, aspartic acid, glutamic acid, alginic acid and the like can be mentioned. These organic acids may be used either individually or in combination of two or more, and may also be combined with salts of these organic acids. The amount of the organic acid or its salt used varies depending on the type of the acid and other formulations, but 0.1 to 50 parts by weight is used as the organic acid per 1 part by weight of oxybutynin hydrochloride. In the present invention, tartaric acid, succinic acid, citric acid or salts thereof are preferably used, and when tartaric acid is used, the amount thereof is 0.1 to 50 parts by weight per 1 part by weight of oxybutynin hydrochloride. Is used in an amount of 1 to 10 parts by weight. These additives may be added in the form of powder to the mixture of oxybutynin hydrochloride and a pharmaceutical excipient, but they may be dissolved in water or alcohol and added.

[0006] The gel-forming substance swells with water to give a hydrophilic gel when the formulation is administered, and the diffusion rate of the drug in the gel layer determines the release. As the gel-forming substance, any conventionally known pharmaceutically-acceptable gel-forming substance can be used, for example, gum arabic, guar gum, agar, gelatin, sodium alginate, propylene glycol alginate, polyvinylpyrrolidone, polyvinyl alcohol, Carboxyvinyl polymer, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose and the like can be used. In the present invention, these polymer substances may be used alone or in combination of two or more. Preferably used is hydroxypropyl methylcellulose (HPMC) or HPMC in combination with other gel-forming substances.

The amount of the gel-forming substance to be added depends on the substance, since it is necessary to add a certain amount in order to maintain the gelation of the preparation. A pharmaceutical composition containing oxybutynin hydrochloride 1
It is added in an amount of 10 to 70 parts by weight, preferably 15 to 50 parts by weight in 00 parts by weight.

HPMC is commercially available from Shin-Etsu Chemical Co., Ltd. under the trade name of Metroze in Japan, and there are various types. In the present invention, the Metroze 90SH type or 60
The SH type having an average viscosity of 4000 cps is particularly suitable. The amount of metrolose added to a pharmaceutical composition containing oxybutynin hydrochloride is 10 to 70 parts by weight in 100 parts by weight of the pharmaceutical composition even when combined with other gelling substances, and preferably
15 to 50 parts by weight.

[0009] Metrose may be mixed as a powder with a pharmaceutical composition containing oxybutynin hydrochloride and directly compressed to form a drug product having a desired shape, or may be granulated by a conventional method and then compression-molded. As for the pharmaceutical composition containing oxybutynin hydrochloride, excipients used for usual preparations such as lactose and crystalline cellulose are used. If necessary, the granules or tablets can be coated with a film by a conventional method, and a colorant, a plasticizer, an antioxidant, a stabilizer and the like can be added.

Next, the sustained-release agent thus obtained has a lag time until it forms a sufficient gel upon contact with water. Therefore, when an organic acid is added as in the present invention, these organic agents are added. A large amount of gel-forming substance is required to control the release because the initial elution rate with acid increases. Then, as a result of diligent research to solve such a problem, carbon number of lauryl alcohol, cetanol, stearyl alcohol, oleyl alcohol, lanolin alcohol, etc. is 12
The present inventors have found that when a certain amount or more of the above higher alcohols is added to the formulation, the initial rapid release can be suppressed. These higher alcohols may be used alone or in combination of two or more, and are usually used in the range of 0.5 to 10 parts by weight per 100 parts by weight of the pharmaceutical composition of oxybutynin hydrochloride.

Among the higher alcohols used in the present invention, cetanol or stearyl alcohol is preferably used. The amount used is a pharmaceutical composition of oxybutynin hydrochloride.
0.5 to 10 parts by weight per 100 parts by weight, preferably 1
~ 5 parts by weight are used. These higher alcohols are dissolved in, for example, ethyl alcohol, added to the sustained-release composition of oxybutynin hydrochloride, and uniformly mixed. The sustained-release mixture thus obtained can be used by molding it into a desired dosage form such as a capsule or tablet. Further, the release of the drug can be finely controlled by coating these formulations with a polymer coating agent by a conventional method.

[0012]

ACTION AND EFFECT The thus obtained sustained release oxybutynin hydrochloride tablet of the present invention controls the release of oxybutynin hydrochloride, lowers the maximum plasma concentration as compared with the conventional preparation, and was kept constant for a long time. Because blood concentration can be obtained,
It has become possible to prepare a dosage form that can be taken once or twice.

[0013]

The present invention will be described below by showing Examples according to the present invention. Example 1 Lactose 220 g, crystalline cellulose (trade name: Avicel PH101
Asahi Kasei) 40g and Metroses 60SH4000
(Shin-Etsu Chemical Co., Ltd.) 60 g was mixed. Next, 6 g of oxybutynin hydrochloride, 10 g of stearyl alcohol (Calcol 86, Kao Corporation) and 20 g of citric acid were dissolved in about 100 ml of ethyl alcohol to prepare a solution, which was added little by little to the mixed powder. After drying by a conventional method, 4 g of magnesium stearate was added to the obtained granules, and the mixture was lubricated and compressed into tablets to give 180 mg tablets.

Example 2 Lactose 220 g, crystalline cellulose 40 g and Metrose 60
SH4000 60g was mixed. Then oxybutynin hydrochloride
A solution prepared by dissolving 6 g, 10 g of stearyl alcohol and 20 g of tartaric acid in about 100 ml of ethyl alcohol was prepared and added little by little to the mixed powder. After drying by a conventional method, 4 g of magnesium stearate was added to the obtained granules, and the mixture was lubricated and compressed into tablets to give 180 mg tablets.

Example 3 Lactose 236 g, crystalline cellulose 40 g and Metrose 60
SH4000 60g was mixed. Then oxybutynin hydrochloride
6 g, succinic acid 10 g and stearyl alcohol 10 g
Prepare a solution in which about 100 ml of ethyl alcohol is dissolved,
A small amount was added to the mixed powder. After drying by a conventional method, 4 g of magnesium stearate was added to the obtained granules, and the mixture was lubricated and compressed into tablets to give 180 mg tablets.

Example 4 Lactose 80 g, crystalline cellulose 80 g, Metrose 60 SH
4000 80 g and sodium alginate (trade name: Kimitsu Algin I-5, Kimitsu Chemical Industry) 80 g were mixed. Next, 6 g of oxybutynin hydrochloride, 20 g of tartaric acid and 10 g of stearyl alcohol were added to about 100 parts of ethyl alcohol.
A solution dissolved in ml was prepared and added little by little to the mixed powder. After drying by a conventional method, 4 g of magnesium stearate was added to the obtained granules, and the mixture was lubricated and compressed into 1 tablet.
180 mg tablets were obtained.

Comparative Example 6 g of oxybutynin hydrochloride was mixed with 314.4 g of lactose and 36 g of crystalline cellulose, and magnesium stearate was further added.
After lubricating with 3.6 g, a tablet was compressed into 180 mg to give a plain tablet.

Test Example With respect to the sustained-release tablets and plain tablets prepared in the above-mentioned Examples and Comparative Examples, the release property (dissolution rate) and the blood concentration at the time of administration were measured. 1) The dissolution rate of oxybutynin hydrochloride from each tablet was measured according to the dissolution test method of the Japanese Pharmacopoeia. Eluent is first
Solution (pH 1.2) or phosphate buffer (pH 6.8) 900
Add ml to a flask and keep it at 37 ℃, and paddle to 100
Stir on rotation. The test solution was collected over time at 2, 4, 6, 8 and 10 hours, and immediately the same amount as the sampling amount was replenished to keep the liquid amount constant. On the other hand, the amount of oxybutynin hydrochloride in the collected liquid was quantified by high performance liquid chromatography. 2) In addition, in order to measure changes in plasma concentration during human administration, 0.25, 0.5, 1, 2, 3, 4, 6,
Blood was collected for 8, 10, and 12 hours, the blood was centrifuged, and the drug concentration in plasma was measured.

3) Test Results FIGS. 1 to 4 show the results of dissolution tests from the preparations obtained in Examples and Preparation Examples. FIG. 1 shows the results of dissolution tests of plain tablets obtained in Comparative Example and tablets obtained in Example 1 at pH 1.2 and pH 6.8. It was shown that oxybutynin hydrochloride of a plain tablet was easily dissolved and the dissolution rate was 100% within a few minutes, but the tablet of Example 1 showed sustained release and was hardly affected by pH. 2 is a second embodiment, FIG. 3 is a third embodiment, and FIG.
Shows the results of each tablet of Example 4, and all of Examples 1
It shows sustained release and pH stability similar to that of the above formulation. Next, FIG. 5 shows changes in plasma concentration of oxybutynin hydrochloride when the plain tablets (3 mg × 2 tablets) obtained in Comparative Example or the sustained release tablets (3 mg × 2 tablets) obtained in Example 1 were administered to 4 volunteers. Shown in. Sustained-release tablets have Tmax of 4 compared to ordinary tablets
2 times, Cmax was 1/4 times, and it was confirmed to have a sustained effect.

[Brief description of drawings]

FIG. 1 is a graph showing the results of dissolution tests of plain tablets and tablets of Example 1 at various pHs.

FIG. 2 is a graph showing the results of a dissolution test on tablets of Example 2.

FIG. 3 is a graph showing the results of a dissolution test on tablets of Example 3.

FIG. 4 is a graph showing the results of a dissolution test on tablets of Example 4.

FIG. 5 is a graph showing changes in plasma concentration of oxybutynin hydrochloride when a plain tablet and the sustained release tablet of Example 1 were administered.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Takako Igarashi 957-5 Wanagaya, Matsudo-shi, Chiba Kodama Co., Ltd., Institute for Biological Sciences (72) Inventor Katsuyoshi Yasaka 326-3 Obishi, Sakai-cho, Ibaraki Prefecture Miyanishi Small Ball Science Research Institute

Claims (5)

[Claims] 1. A sustained-release oxybutynin hydrochloride preparation, which comprises a gel-forming substance and higher alcohols mixed with a pharmaceutical composition containing oxybutynin hydrochloride and an acidic substance. 2. The sustained-release oxybutynin hydrochloride preparation according to claim 1, which contains 0.1 to 50 parts by weight of an acidic substance with respect to 1 part by weight of oxybutynin hydrochloride. 3. The sustained-release oxybutynin hydrochloride preparation according to claim 1, wherein the gel-forming substance is hydroxypropylmethylcellulose (HPMC) or a combination of HPMC and another gel-forming substance. 4. The amount of HPMC or the combined amount of HPMC and other gel-forming substance in 100 parts by weight of a pharmaceutical composition containing oxybutynin hydrochloride is 10 to 70 parts by weight. The sustained-release oxybutynin hydrochloride preparation according to item 3. 5. The sustained-release oxybutynin hydrochloride preparation according to claim 1, wherein the amount of the higher alcohols in 100 parts by weight of the pharmaceutical composition containing oxybutynin hydrochloride is 1 to 20 parts by weight.