JPH04235926A - Sustained release preparation - Google Patents

Abstract

PURPOSE:To easily obtain a sustained release pharmaceutical preparation containing a medicine to be released in sustained state by using poly-beta- hydroxybutyric acid which is a bio-decomposable material having bio- compatibility. CONSTITUTION:The objective sustained release pharmaceutical preparation contains a poly-beta-hydroxybutyric acid having a molecular weight of 50,000-100,000 as a main material and releases a physiologically active substance at a controlled releasing rate.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to a sustained-release preparation in which the release rate of a physiologically active substance in the body is controlled, and more specifically, a sustained-release preparation whose main material is poly-β-hydroxybutyric acid with a molecular weight of 50,000 to 100,000. The present invention relates to a sustained release formulation in which the release rate of a physiologically active substance is controlled.

0002

[Prior Art] In recent drug therapy, drugs are distributed only around the affected area to prevent side effects on normal tissue, and at the same time, polymeric excipients such as resins are used to improve drug efficacy. Research on dosage forms is being actively conducted. As a so-called sustained-release local administration method that continuously supplies an effective concentration of a drug only to the area surrounding the affected area over a long period of time, for example, the drug is placed in a capsule, or a preparation formed into a tablet or pellet is administered around the affected area. Examples include a method of embedding the drug into a microcapsule or microsphere using a polymer coating using a coacervation method or the like, whereby the drug leaches only into the embolized diseased blood vessel. Conventionally, microspheres made using a polymer coating or matrix have been formulated using ethyl cellulose or wax (Japanese Patent Laid-Open No. 54-163).
808) and those formulated into microcapsules or microspheres using polylactic acid, a non-toxic biodegradable polymer (JP-A-54-55717, JP-A-59-
33214) are known. However, polylactic acid has physical property limitations such as a low glass transition temperature and high melt viscosity, making it difficult to obtain uniform microencapsulated microspheres, so this microencapsulated preparation was administered to the affected area. In this case, there is a problem that the drug release rate at the initial stage of administration is very fast and it is difficult to obtain sustained release over a long period of time. As mentioned above, depending on the type of biodegradable polymer used as the coating or matrix of the microspheres,
There are various problems in formulation, and appropriate measures must be taken to achieve favorable pharmacological action of the formulated microspheres.

0003

[Problems to be Solved by the Invention] Poly-β-hydroxybutyric acid (hereinafter abbreviated as PHB), which is easily produced by fermentation, is a biocompatible and biodegradable polymer shown in the structure below. PHB with a molecular weight of 200,000 to 1,000,000 has been studied.

0004

[Chemical formula 1]

PHB is a biodegradable polymer like polyglycolic acid and polylactic acid, but its physical properties differ from polyglycolic acid and polylactic acid in that it has a low glass transition temperature, is brittle, and is difficult to mold. Currently, it is rarely used as a medical polymer material due to problems. In addition, when using conventional PHB as a matrix, it is difficult to formulate microspheres and the sustained release rate of the resulting matrix is extremely low. Yes, I couldn't use it. That is, an object of the present invention is to provide a sustained-release preparation that uses PHB as a matrix and can control the release rate so that the necessary active concentration can be maintained at all times during the period when the drug effect is required.

[0006]

[Means for Solving the Problems] The present inventors conducted intensive research with the aim of developing a microsphere-structure sustained release preparation for injection or implantation using PHB as a matrix, and found that the molecular weight was 5 to 5. The present invention was completed by discovering that a sustained release preparation with a microsphere structure can be obtained by using 100,000 PHB. That is,
The present invention is a sustained release preparation containing poly-β-hydroxybutyric acid with a molecular weight of 50,000 to 100,000. The drugs used in the present invention can be applied to all drugs that are conventionally known as drugs that require sustained release, but are particularly applicable to anticancer drugs, local anesthetics, and insulin whose action is highly time-dependent. These drugs used for prostaglandins are usually preferably contained in an amount of 2 to 50% by weight based on the total weight of the sustained release preparation. The PHB used in the present invention preferably has a molecular weight of 50,000 to 100,000, and if a PHB exceeding 100,000 is used, a sustained release preparation cannot be obtained. The amount of PHB to be used is preferably 50 to 98% by weight based on the obtained sustained-release preparation, and in particular, if it is less than 30% by weight, a sustained-release preparation with desired strength and uniformity cannot be obtained. The sustained release preparation of the present invention comprising PHB with a molecular weight of 50,000 to 100,000 and a drug can be obtained according to a conventional method, for example, by the following method. PH with molecular weight 50,000 to 100,000
Obtained by completely dissolving B in an organic solvent such as chloroform or dichloromethane, dissolving or suspending the drug in this, suspending this dropwise in a gelatin or polyvinyl alcohol solution with stirring, and then removing the solvent by evaporation. The granular microspheres are filtered off from the aqueous medium. Alternatively, PHB having a molecular weight of 50,000 to 100,000 is completely dissolved in an organic solvent such as chloroform, dichloromethane, or methylene chloride, a drug is dissolved or suspended therein, and after the product is shaped, the organic solvent is evaporated. The sustained-release preparation obtained by the present invention has a matrix of PHB with a molecular weight of 50,000 to 100,000, which is homogeneously dispersed with the drug to be released, and a fine particle preparation with a particle size of 10 to 500 μm, or a membrane or thread. , which is a tablet-shaped preparation. Micronized preparations are used for injection, and molded preparations are used for implantation. In the present invention, by appropriately selecting the type of PHB used among PHBs having a molecular weight of 50,000 to 100,000 and the proportion thereof, the release rate of the drug can be controlled, and therefore a constant concentration can be maintained. In addition, since PHB is hydrolyzed by enzymes in the body and does not remain in the body, there is no need to take it out of the body, making it a good sustained-release preparation.

[0007]

[Examples] The present invention will be explained in more detail below with reference to Examples. Example 1 50 mg of poly-β-hydroxybutyric acid was added to 1 part of dichloromethane.
ml with stirring, then add mitomycin C.
10 mg was dissolved. Separately treated gelatin with alkali (manufactured by Miyagi Chemical Co., Ltd., jelly strength 250 bloom)
0.9 g was added to 89.1 g of water and dissolved by heating at 50°C to prepare a 1% aqueous gelatin solution. Transfer the 1% aqueous gelatin solution into a 100 ml beaker and add poly-β to it.
A dichloromethane solution containing -hydroxybutyric acid and mitomycin C was added and emulsified, and the dichloromethane was evaporated while stirring at 500 rpm for 25 minutes. After confirming that the dichloromethane had completely disappeared, microsphere formation was completed. This solution was filtered using a G4 glass filter, washed with purified water, and then dried under reduced pressure for 18 hours to obtain purple spherical microspheres. In addition, poly-β-hydroxybutyric acid has a molecular weight of 65,000 (hereinafter referred to as PHB6).
5K), 70,000 (hereinafter referred to as PHB70K), 90,000 (hereinafter referred to as PHB90K), and 1
30,000 (hereinafter referred to as PHB130K) were used to obtain four types of microspheres. The content of mitomycin C in each of the microspheres prepared was 3.7% for PHB65K, 4.5% for PHB70K, 6.3% for PHB90K, and PHB1.
In the case of 30K, it was 6.3%. Using the above four types of microspheres, a mitomycin C release experiment was conducted in the following manner, and the results shown in FIG. 1 were obtained. PHB65K, P
Release of mitomycin C was observed in HB70K and PHB90K, but almost no release was observed in PHB130K. Furthermore, the amount of mitomycin C released after one week was 99.8% for PHB65K and 98% for PHB70K.
．． 9% and 99.1% for PHB90K, while P
In HB130K, the amount was significantly lower at 4.7%.

(Drug release experiment) Microsphere 5m
g into 10 ml of pH 8.0 phosphate buffer containing 0.01% Teen80, shaken in a constant temperature shaking tank at 37°C, collected the released liquid over time, and prepared a drug-free solution. In addition, the volume of the ejected liquid was always kept constant. The amount of drug in the obtained released liquid was determined by liquid chromatography (HPLC) or by measuring absorbance in ultraviolet light. (HPLC measurement conditions) Column: Lichrospher 5 μm RP-
18, 250 mm x 4 mm Mobile phase: methanol: 0.01M phosphate buffer (pH 6
)=2:3 Detector: UV detector (350nm)

Example 2 25 mg of poly-β-hydroxybutyric acid was dissolved in dichloromethane 0
．． After dissolving in 5 ml with stirring, add mitomycin C.
10 mg was dissolved. Separately, 0.3 g of alkali-treated gelatin (manufactured by Miyagi Chemical Co., Ltd., Jelly Strength 250 Bloom) was added to 29.7 g of water and dissolved by heating at 50° C. to prepare a 1% aqueous gelatin solution. Transfer the 1% aqueous gelatin solution into a 50 ml beaker, add poly-β-hydroxybutyric acid and mitomycin C-containing dichloromethane solution to emulsify it, and evaporate dichloromethane while stirring at 50 rpm for 25 minutes until dichloromethane completely disappears. I finished making microspheres after confirming what I had done. This solution was filtered using a G4 glass filter, washed with purified water, and then dried under reduced pressure for 18 hours.
Purple spherical microspheres were obtained. In addition, poly-β-
Hydroxybutyric acid has a molecular weight of 65,000 (hereinafter referred to as PHB).
Three types of microspheres were obtained using microspheres of 65K), 70,000 (hereinafter referred to as 70K), and 130,000 (hereinafter referred to as 130K), respectively. The content of mitomycin C in each of the microspheres prepared was 16.2% for PHB65K, 17.2% for PHB70K, and 19.0% for PHB130K. Using the three types of microspheres mentioned above,
A mitomycin C release experiment was conducted in the same manner as in Example 1, and the results shown in FIG. 2 were obtained. PHB65K and PH
Release of mitomycin C was observed in B70K, but P
It was hardly seen in HB130K. Also, 1
The amount of mitomycin C released after a week was 59.7% for PHB65K and 92.3% for PHB70K, while it was significantly lower at 4.5% for PHB130K.

Example 3 50 mg of poly-β-hydroxybutyric acid was added to 1 m of methylene chloride.
1 with stirring, 3',5'-dipentanoyl-5-fluoro-2'-deoxyuridine (hereinafter F
10 mg (denoted as UdR-C5) was dissolved. Separately acid-treated gelatin (manufactured by Miyagi Chemical Co., Ltd., jelly strength 250)
Bloom) was added to 89.1 g of water and dissolved by heating at 50°C to prepare a 1% aqueous gelatin solution. 100
Transfer the 1% aqueous gelatin solution into a ml beaker, emulsify the methylene chloride solution containing poly-β-hydroxybutyric acid and FUdR-C5, and evaporate the methylene chloride while stirring at 500 rpm for 25 minutes. After confirming that the particles had completely disappeared, the process of forming microspheres was completed. This solution was filtered using a G4 glass filter, washed with purified water, and then dried under reduced pressure for 18 hours.
White spherical microspheres were obtained. In addition, poly-β-
Hydroxybutyric acid has a molecular weight of 65,000 (hereinafter referred to as PHB).
65K), 130,000 (hereinafter referred to as PHB130K)
Three types of microspheres were obtained using PHB456K (hereinafter referred to as PHB456K) and PHB456,000 (hereinafter referred to as PHB456K). FUd in each microsphere created
-C5 content is 16.6% for PHB65K, PH
It was 14.2% for B130K and 15.3% for PHB456K. Using the three types of microspheres mentioned above, a FUdR-C5 release experiment was conducted in the same manner as in Example 1, and the results shown in FIG. 3 were obtained. In addition, F.U.
The amount of dR-C5 was determined by measuring absorbance at 268 nm.

Example 4 50 mg of poly-β-hydroxybutyric acid was added to 1 m of methylene chloride.
8.3 mg of dibucaine was dissolved in the solution with stirring. The 0.1% polyvinyl alcohol aqueous solution was placed in a 100 ml beaker, and a methylene chloride solution containing poly-β-hydroxybutyric acid and dibucaine was added thereto to emulsify it, and the methylene chloride was evaporated while stirring at 500 rpm for 25 minutes. After confirming that the particles had completely disappeared, we finished converting them into microspheres. This solution was filtered using a G4 glass filter, washed with purified water, and then dried under reduced pressure for 18 hours to obtain white spherical microspheres. Two types of microspheres were obtained using poly-β-hydroxybutyric acid having a molecular weight of 63,000 (hereinafter referred to as PHB63K) and 73,000 (hereinafter referred to as PHB73K). The content of dibucaine in each microsphere prepared is P
Both HB63K and PHB73K were 9.6%. Using the above two types of microspheres, a dibucaine release experiment was conducted in the same manner as in Example 1,
The results shown in Figure 4 were obtained. Dibucaine release was observed in both PHB63K and PHB73K microspheres. Note that dibucaine was quantified by measuring absorbance at 326 nm.

Example 5 Poly-β-hydroxybutyric acid 10 with a molecular weight of 73,000
1 mg, 2.6 mg, or 4.2 mg of aclarubicin hydrochloride were dissolved in 1 ml of chloroform, dropped onto a circular cover glass with a diameter of 15 mm, and the chloroform was evaporated at 4°C in a petri dish to create three types of membranes. . Using these three types of membranes, a release experiment of aclarubicin hydrochloride was conducted in the same manner as in Example 1. 12 of each membrane
The amount of aclarubicin hydrochloride released after 0 hours was 1.3% for the membrane using 1 mg of aclarubicin hydrochloride, 6.3% for the membrane using 2.6 mg of aclarubicin hydrochloride, and 6.3% for the membrane using 4.2 mg of aclarubicin hydrochloride. , 2.3%
, and release from the membrane was observed. Note that aclarubicin hydrochloride was quantified by measuring absorbance at 258 nm.

[0013]

[Effects of the Invention] According to the present invention, it is possible to easily obtain a sustained-release preparation containing a drug for which sustained release is desired using poly-β-hydroxybutyric acid, which is a biocompatible biodegradable substance. I can do it.

[Brief explanation of the drawing]

FIG. 1 shows the release of drugs into a phosphate buffer from four types of sustained-release preparations containing poly-β-hydroxybutyric acid with different molecular weights.

FIG. 2 shows the release of drugs into a phosphate buffer from three types of sustained-release preparations containing poly-β-hydroxybutyric acid with different molecular weights.

FIG. 3 shows the release of drugs into a phosphate buffer from three types of sustained-release preparations containing poly-β-hydroxybutyric acid with different molecular weights.

FIG. 4 shows the release of drugs into a phosphate buffer from two types of sustained-release preparations containing poly-β-hydroxybutyric acid with different molecular weights.

Claims (1)

[Claims] 1. A sustained release preparation containing poly-β-hydroxybutyric acid with a molecular weight of 50,000 to 100,000.