JPH0132205B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing vaginal preparations. More specifically, a carrier such as cellulose is dissolved in an organic solvent, and a solution of prostaglandin and an organic acid dissolved in an organic solvent is added to this solution, mixed uniformly, and then dried. The present invention relates to a method for producing a prostaglandin film vaginal preparation, which is characterized by cyclic release and has high bioavailability. The conventional dosing method, in which the drug is divided into several doses per day and administered as a single dose, is not advantageous for clinical pharmacology, and there are only a few drugs that release the active ingredient in therapeutic concentrations over a long period of time. It has been recognized that multiple administrations are advantageous to both the patient and the clinician. BACKGROUND ART Conventionally, various efforts have been made to create formulations for internal use, mainly for internal use, in order to delay the release of drugs from formulations and thereby maintain the efficacy of the drugs for a long period of time. For example, methods to make it difficult to disintegrate by using large amounts of binders that have no disintegrating effect in the stomach or intestines, methods to coat crystals, granules or tablets of the main drug with oil-based substances such as waxes and waxes, and stearin. A method using a large amount of hydrophobic lubricant such as an acid salt,
Alternatively, there is a method of wrapping the drug in a semipermeable membrane. In addition to these, sustained release preparations are also known in which a poorly soluble or hydrophilic polymer is mixed with a drug to gradually release the drug. For example, the
Publication No. 13092 describes an orally administered sustained-release drug consisting of a drug and a poorly soluble acid-type carboxyvinyl polymer;
Granules or tablets that have a sustained effect in the stomach or intestinal tract and are made of a mixture of a hydrophilic resin such as polyvinyl alcohol or polyacrylic acid and a drug are described. On the other hand, the dosage forms of vaginal suppositories have traditionally been base-type suppositories based on cocoa butter or witepsol, gelatin capsule suppositories based on gelatin, and tablet-type suppositories prepared with mannitrate, glucose, etc. However, all of these have adverse effects on stability due to heating and moisture during production, and the production process is complicated, requiring large-scale equipment and sophisticated technology. In addition, when administered, it hardens, adheres, and deforms due to temperature, and because most of them are round and large, they have the disadvantage of not achieving the expected medicinal effect, such as the feeling of a foreign body in the vagina or not coming into close contact with mucous membranes. Ta. Furthermore,
When long-lasting effects are expected, it is often used as a tablet-shaped suppository, but in this case, the adhesion is not good, and the pattern of disintegration, dissolution, and absorption varies greatly depending on individual differences, so it does not meet expectations. In many cases, the effect is not obtained. In order to improve this adhesion and facilitate disintegration, which is a pre-absorption step, preparations using polyethylene as a carrier have been developed. For example, JP-A-49-133519 discloses a method comprising a thermoplastic, physiologically inert polymer that is soluble in body fluids present in body cavities, such as hydroxypropyl cellulose, polyethylene glycol, etc., and an effective amount of a drug. For example, intravaginally administered contraceptive formulations have been described. The feature of this formulation is that the drug is gradually released as the polymer contained in it dissolves, and therefore the polymer is such that the entire formulation is completely dissolved within 24 hours. Are listed. Furthermore, Japanese Patent Application Publication No. 1973-
44149 also shows an example of the application of 5-FU (5-fluorouracil) suppositories to vaginal cancer. However, all of these require complexity of preparation,
There were problems with stability during heat treatment, and some drugs were not suitable. The present inventors have discovered a sustained-release formulation method that eliminates the drawbacks of these conventional techniques, and at the same time have greatly improved the bioavailability, thereby achieving the present invention. That is, the preparation according to the present invention is a film preparation comprising a cellulose component such as hydroxypropylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone or polyacrylic acid, prostaglandin, and an organic acid. The method for preparing this film preparation involves dissolving a carrier such as hydroxypropyl cellulose in an organic solvent such as alcohol to obtain a transparent solution. Combine the solution with the organic acid and the above carrier solution and stir until homogeneous to form one mixed solution,
This solution is molded into a film by a casting method using a device with appropriate temperature and air volume controls. The air volume depends on the size of the drying container,
Set appropriately depending on the quantity of preparation. Therefore, the above-mentioned formulation according to the present invention has the following characteristics: 1. It has a high bioavailability and has a medicinal effect with a small amount of drug. 2. Since film formation is performed at low temperatures using organic solvents, even unstable substances hardly decompose during the process. Furthermore, the addition of an organic acid can ensure long-term stability of the formulation. 3. It is small in size and does not soften or deform even at relatively high temperatures, making it easy to insert into the vagina. 4. The inserted film adheres closely to the mucous membrane and exhibits a constant drug elution pattern that is independent of individual differences, so the medicinal efficacy has little variation and is sustainable. etc. can be mentioned. The carriers used in the present invention, hydroxypropylcellulose, polyvinylpyrrolidone, or polyacrylic acid, may have any molecular weight and may be used in combination; The viscosity of a 2% aqueous solution at 20℃ is 4~
4000 centipoise is preferably used.
As the organic acid, citric acid is most suitable as shown in the experimental examples below. The active ingredient contained in the preparation of the present invention may be any drug for treating vaginal diseases and for which the therapeutic effect is expected to be further increased than before by sustained release, such as prostaglandin E ₂ , prostaglandin Examples include Grandin F ₂ α and ONO-802 (product name). The present invention will be explained in detail below using Examples and Experimental Examples, but the present invention is not limited thereto. Example 1 199.5 mg of hydroxypropyl cellulose was added to 2 ml of ethanol and stirred until it became transparent. Separately, 1ml of ONO-802 0.2mg and anhydrous citric acid 0.3mg
The above cellulose solution is combined with this solution and stirred until it becomes homogeneous. This solution is dried with air at a low temperature, and a film is formed by a casting method. Example 2 Polyvinylpyrrolidone was used instead of hydroxypropyl cellulose in Example 1, and a film was formed by the same treatment. Example 3 Polyacrylic acid was used instead of hydroxypropyl cellulose in Example 1, and a film was formed by the same treatment. Experimental Example 1 Regarding the ONO-802 hydroxypropyl cellulose film preparation prepared in Example 1 and other dosage forms of Witepsol base and tampon, ONO
The results of a comparison of the uterine contraction activity, which is the pharmacological activity of -802, in rats are shown in Table 1 and the attached drawings (showing changes in duration versus dose in unanesthetized rats).
The film formulation is Willatsol S.
-52 (trade name) It can be seen that the dosage is reduced to less than 1/4 compared to suppositories, and the duration of physiological activity is extended.

[Table] Experimental Example 2 After 4 weeks at a storage temperature of 40°C in the presence of silica gel for the film preparation prepared according to Example 1.
The content of ONO-802 was measured by high performance liquid chromatography and compared. The results are shown in Table 2. It can be seen that the stabilizing effect is maximum when the amount of citric acid added is around 0.3 mg.

【table】 [Brief explanation of drawings]

The figure shows UCA versus dose in unanesthetized rats.
This shows the change in duration.

Claims (1)

[Claims] 1 Cellulose such as hydroxypropylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, or polyacrylic acid as a carrier is dissolved in an organic solvent alone or in combination of two or more, and prostaglandin and prostaglandin are added to this solution. A method for producing a film vaginal preparation, which comprises dissolving citric acid in a molar ratio of 3 to 11 times that of gin and then drying it.