JP2646170B2 - Sustained-release oxybutynin hydrochloride preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained-release sustained-release oxybutynin hydrochloride preparation which can be orally administered.

[0002]

2. Description of the Related Art Sustained-release preparations improve safety by preventing rapid release of the active ingredient, improve efficacy by extending the duration of action, and complicate administration of patients by reducing the number of administrations. It has advantages such as openness and prevention of non-compliance. In recent years, while urinary incontinence of the elderly has become a social problem, the effectiveness of oxybutynin hydrochloride, which has been developed as a therapeutic agent for pollakiuria and urinary incontinence, has been highly evaluated.

[0003]

However, although oxybutynin hydrochloride is absorbed immediately after taking it, it has to be taken three times a day due to its short elimination half-life, so that taking it is complicated. In addition, urinary incontinence patients often have difficulty going out for a long time due to their symptoms.
There has been a demand for sustained release of a drug for the treatment of urinary incontinence, oxybutynin hydrochloride, which has a long-lasting effect and has the above-mentioned advantages. The present inventors have conducted intensive studies, and as a result, have found that a sustained release can be achieved by adding an acidic substance, a gel former and a higher alcohol to oxybutynin hydrochloride, thereby completing the present invention.

[0004]

The sustained-release oxybutynin hydrochloride preparation of the present invention comprises a pharmaceutical composition containing oxybutynin hydrochloride and an acidic substance mixed with a gel-forming substance and a higher alcohol. .

[0005] Further, the present invention will be described in detail. Since oxybutynin hydrochloride is a mineral salt of an organic base, it is expected that the solubility in neutral to alkaline is reduced.
Sustained-release preparations will be present in the body for a long time. For example, the pH in the human gastrointestinal tract is pH 1-35 in the stomach,
It is known that the duodenum has a pH of 5 to 6, the jejunum has a pH of 6 to 7, and the ileum has a pH of 8. In order to keep the solubility of the drug constant in the living body where the pH changes as described above, it is necessary to devise a formulation. The present inventors have solved the problem by adding an acidic substance in order to obtain a preparation which is not affected by pH, and have obtained a sustained-release preparation of the present invention.

[0005] As the acidic substance, either an inorganic acid or an organic acid can be used, but an organic acid which is harmless to the human body is desirable. Organic acidic substances include, for example, 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 can be used alone or in combination of two or more, and further can be combined with salts of these organic acids. The amount of the organic acid or its salt used varies depending on the kind of the acid and other compounds, but is used as the organic acid in an amount of 0.1 to 50 parts by weight per 1 part by weight of oxybutynin hydrochloride. In the present invention, tartaric acid, succinic acid, citric acid or salts thereof are preferably used. When tartaric acid is used, for example, the amount is preferably 0.1 to 50 parts by weight with respect to 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 a powder form to a mixture of oxybutynin hydrochloride and a pharmaceutical excipient, or may be added after being dissolved in water or alcohol.

The gel-forming substance swells with water to form a hydrophilic gel when the formulation is administered, and the rate of diffusion of the drug in the gel layer limits release. As the gel-forming substance, any 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 polymers, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose and the like can be used. In the present invention, these polymer substances can be used alone or in combination of two or more. Preferably, hydroxypropyl methylcellulose (HPMC) or HPMC is used in combination with other gel-forming substances.

The compounding amount of the gel-forming substance needs to be added in a certain amount in order to maintain the gelation of the preparation, and varies depending on the substance. However, 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 based on 00 parts by weight.

[0008] In Japan, HPMC is commercially available from Shin-Etsu Chemical under the trade name of METROZ, and there are various types.
SH types with an average viscosity of 4000 cps are particularly suitable. The amount of metroze added to the pharmaceutical composition containing oxybutynin hydrochloride is 10 to 70 parts by weight in combination with other gelling substances in 100 parts by weight of the pharmaceutical composition, preferably
15 to 50 parts by weight.

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

[0010] Next, the sustained-release agent thus obtained has a lag time until a sufficient gel is formed upon contact with water. Since the initial dissolution rate by the acid is increased, more gel-forming substances are required to control the release. Accordingly, the present inventors conducted intensive research to solve such a problem, and found that carbon atoms of 12 such as lauryl alcohol, cetanol, stearyl alcohol, oleyl alcohol, and lanolin alcohol were used.
The present inventors have found that when a certain amount or more of the above higher alcohol is added to the preparation, the initial rapid release can be suppressed. These higher alcohols can be used alone or in combination of two or more, and usually used in the range of 0.5 to 10 parts by weight based on 100 parts by weight of the pharmaceutical composition of oxybutynin hydrochloride.

Of the higher alcohols used in the present invention, cetanol or stearyl alcohol is preferably used. Its use amount is a pharmaceutical composition of oxybutynin hydrochloride
0.5 to 10 parts by weight for 100 parts by weight, preferably 1 to 10 parts by weight.
To 5 parts by weight. 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 shaping it into a desired dosage form such as a capsule or a tablet. In addition, these preparations can be coated with a polymer film agent by a conventional method to finely control the release of the drug.

[0012]

[Action and Effect] The sustained-release oxybutynin hydrochloride tablet of the present invention thus obtained controls the release of oxybutynin hydrochloride, reduces the maximum plasma concentration as compared with conventional preparations, and maintains the same for a long time. Because blood levels can be obtained, one day,
It has become possible to obtain a dosage form preparation that can be taken once or twice.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below by showing embodiments according to the present invention. Example 1 Lactose 220 g, crystalline cellulose (trade name: Avicel PH101)
(Asahi Kasei Kogyo) 40g and Metro's 60SH4000
(Shin-Etsu Chemical Co., Ltd.) 60 g was mixed. Next, a solution prepared by dissolving 6 g of oxybutynin hydrochloride, 10 g of stearyl alcohol (Calcol 86, Kao Corporation) and 20 g of citric 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, the obtained granules were lubricated by adding 4 g of magnesium stearate, and tabletted to obtain a tablet of 180 mg per tablet.

Example 2 Lactose 220 g, crystalline cellulose 40 g and Metrolose 60
60 g of SH4000 were mixed. Next, oxybutynin hydrochloride
A solution prepared by dissolving 6 g, stearyl alcohol 10 g and tartaric acid 20 g in about 100 ml of ethyl alcohol was prepared and added little by little to the mixed powder. After drying by a conventional method, the obtained granules were lubricated by adding 4 g of magnesium stearate, and tabletted to obtain a tablet of 180 mg per tablet.

Example 3 Lactose 236 g, microcrystalline cellulose 40 g and Metrolose 60
60 g of SH4000 were mixed. Next, oxybutynin hydrochloride
6g, succinic acid 10g and stearyl alcohol 10g
To a solution of about 100 ml of ethyl alcohol,
A small portion was added to the mixed powder. After drying by a conventional method, the obtained granules were lubricated by adding 4 g of magnesium stearate, and tabletted to obtain a tablet of 180 mg per tablet.

Example 4 Lactose 80 g, crystalline cellulose 80 g, Metrolose 60 SH
80 g of 4000 and 80 g of sodium alginate (trade name: Kimitsu Algin I-5, Kimitsu Chemical Industry) 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 31 g of lactose and 36 g of crystalline cellulose were mixed with 6 g of oxybutynin hydrochloride.
After lubricating with 3.6 g, it was compression-molded into 180 mg per tablet to obtain plain tablets.

Test Example The release (dissolution rate) and the blood concentration at the time of administration were measured for the sustained release tablets and the ordinary tablets prepared in the above Examples and Comparative Examples. 1) The dissolution rate of oxybutynin hydrochloride from each tablet was measured according to the dissolution test method of the Japanese Pharmacopoeia method. The eluate is the first
Solution (pH 1.2) or phosphate buffer (pH 6.8) 900
Put the mixture in a flask and keep it at 37 ° C.
Stir with rotation. The test solution was sampled at 2, 4, 6, 8, and 10 hours with time, and the same amount of solution was immediately replenished to keep the solution volume constant. On the other hand, the amount of oxybutynin hydrochloride in the collected liquid was determined by high performance liquid chromatography. 2) In addition, to measure changes in plasma concentration at the time of human administration, 0.25, 0.5, 1, 2, 3, 4, 6, 6
Blood was collected for 8, 10, and 12 hours, and the blood was centrifuged, and then 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 a dissolution test at pH 1.2 and pH 6.8 of the plain tablet obtained in the comparative example and the tablet obtained in Example 1. The oxybutynin hydrochloride of the ordinary tablet easily dissolves and reaches a dissolution rate of 100% in a few minutes, but the tablet of Example 1 shows sustained release and is hardly affected by pH. FIG. 2 is Embodiment 2, FIG. 3 is Embodiment 3, FIG.
Shows the results of each tablet of Example 4, and all the results are shown in Example 1.
Shows sustained release and stability to pH as in the case of the preparation. Next, the change in the plasma concentration of oxybutynin hydrochloride when the normal tablet (3 mg × 2 tablets) obtained in Comparative Example or the sustained release tablet (3 mg × 2 tablets) obtained in Example 1 was administered to four volunteers is shown in FIG. Shown in Sustained-release tablets have a Tmax of 4 compared to plain tablets
And Cmax were reduced by a factor of 4 and it was confirmed that they had a long-lasting effect.

[Brief description of the drawings]

FIG. 1 is a graph showing the results of a dissolution test of each of a normal tablet and a tablet of Example 1 at each pH.

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

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

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

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

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication A61K 47/12 A61K 47/12 A J 47/38 47/38 F (72) Inventor Takako Igarashi Chiba 957-5 Wagaya, Matsudo Prefecture, Japan Kodama Co., Ltd.Biological Science Research Institute (72) Inventor Katsuyoshi Yasaka 326-3 Miyanishi, Oho, Sakaimachi, Sarushima-gun, Ibaraki Pref. Kodama Co., Ltd.

Claims (5)

(57) [Claims] 1. A sustained-release oxybutynin hydrochloride preparation comprising a gel composition and a higher alcohol 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 per 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 composition according to claim 1, wherein the amount of HPMC or a combination of HPMC and another gel-forming substance in 100 parts by weight of the pharmaceutical composition containing oxybutynin hydrochloride is 10 to 70 parts by weight. 4. The sustained-release oxybutynin hydrochloride preparation according to claim 3. 5. The sustained-release oxybutynin hydrochloride preparation according to claim 1, wherein the amount of the higher alcohol in 100 parts by weight of the pharmaceutical composition containing oxybutynin hydrochloride is 1 to 20 parts by weight.