JPS6025920A - Drug-containing slow-releasing composite and its preparation - Google Patents

Abstract

PURPOSE:To obtain the titled composite, by treating a tissue of a living body with a proteolytic enzyme, and including a drug in the produced tissue carrier. CONSTITUTION:A tissue carrier originated from a living body (e.g. ureter, deferent duct, gullet, trachea, vein, etc. of monkey, rat, dog pig, etc.) is treated with a proteolytic enzyme (e.t. ficin), and a drug (any kind of drugs suitable to be released slowly, e.g. carcinostatic agent, hormone preparation, antihistaminic agent, hypotensor, etc.) is included in the processed tissue to obtain the objective drug-containing slow-releasing composite. The filling of the drug is carried out in dry state attained, e.g. by freeze-drying. A crosslinked structure can be developed in the tissue carrier and the biocompatibility of the tissue can be improved, by irradiating the tissue carrier with light or ionizing radiation. By properly controlling the irradiation dose, a degraded structure is formed in the tissue carrier to effect the digestion of the tissue, and when the tissue is irradiated with radiation having high transmittance, even the inner part of the tissue carrier can be sterilized sufficiently and the inflammation reaction is suppressed.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a drug-containing sustained release complex and a method for preparing the same. Specifically, the present invention relates to a drug-containing sustained-release complex in which a drug is contained in a tissue carrier derived from a living body, and a method for preparing the same.

When biologically derived proteins such as albumin and globulin are used as carriers for artificial organs for implantation in living organisms, these carriers cause relatively strong inflammation (foreign body reaction) to living tissues (e.g. M, Yoshida, M , Δ5ano+1.Ka
etsu, ni, Nakai, II.

Yamanaka, T, 5uzukj, ni, 5hida
+and K, 5uzuki+Biomaterial
On the contrary, collagen carriers have the property of providing a good scaffold for cell proliferation and invasion, and therefore have a high affinity for tissues. Therefore, this carrier has already been put into practical use as a medical carrier in a variety of fields, such as corneal grafts, artificial skin, wound dressing materials, and hemostasis.

Based on the above-mentioned results, the present inventors treated a tissue carrier derived from a living body with ficin to remove protein components, and fabricated a tissue carrier consisting of a collagen component. In addition, in order to impart stronger antithrombotic properties to the tissue carrier, we attempted to suppress amino acid moieties such as lysine in collagen by cross-linking by treatment with glutardehyde (e.g., Yasuharu Noiro, Akio Miyata, Artificial Organs ■ (
6), 966-968 (1982)). When a tissue carrier derived from a living body is used in an implantation experiment as it is, it generally exhibits strong antigenicity. One way to remove this antigenicity is to use ficin.
) processing. Therefore, when using living tissue as a carrier for sustained-release pharmaceuticals, it is considered preferable to remove protein components from the tissue carrier.

Proteolytic enzymes containing ficin would be optimal for removing such components. When a drug is incorporated into a biological tissue carrier mainly composed of collagen components, it is preferable to perform a treatment such as freeze-drying and fill the drug in a dry state. On the other hand, the effects of irradiating a tissue carrier with light or ionizing radiation are: (1) imparting a crosslinked structure to the tissue carrier and increasing its biocompatibility; (2) controlling the irradiation dose to impart a degraded structure to the tissue carrier. (3) To sufficiently sterilize the inside of the tissue carrier using highly penetrating radiation (such as ionizing radiation) and suppress the inflammatory reaction, etc. These (1), (2
) And the effect (3) is an important point in the present invention. Of course, in order to use biological tissue as a sustained-release pharmaceutical carrier, it is also important in the present invention to treat it with a proteolytic enzyme such as ficin and further freeze-dry it.

The drugs used in the present invention include all drugs that generally have the advantage of providing sustained release properties, such as anticancer drugs and hormone drugs, and include, for example, the following: Phleomycin hydrochloride, mitomycin C, carbazylquinone, and lomustine. , ifosfamide, thioinosine,
Cyclabine, fluorouracil, 1-(2-te-1-lahydrofuryl)-5-fluorouracil, midotine, chlorambucil, dibromomannil, thioteba, cyclophosphamide, acetylcholine, noradrenaline, serotonin, kallikrene, gastrin, secretin, adrenaline, Insulin, glucagon, hecumethazone, indomethacin, AC H1 growth hormone,
Gonadotropin, oxytocin, hasopressin, thyroxine, Tsubamaru Bormon, follicular hormone, progesterone, adrenal cortical hormone, prostaglandin, antihistamine, antihypertensive agent, vasodilator, vascular reinforcing agent, stomachic digestive agent, Intestinal regulators, contraceptives, disinfectants for skin, agents for parasitic skin diseases, anti-inflammatory agents, vitamins, various enzyme preparations, vaccines, antiprotozoal agents, etc.

Interferon inducers, anthelmintics, fish disease drugs, pesticides, auxincyhererin, cytokinin, absincinic acid, insect pheromones, etc. Biological tissue carriers include ureter,
Vas deferens, girdle, amniotic membrane, esophagus, intestinal tract, trachea, veins, arteries,
Examples include skin waste, etc., and its origin (for example, monkey, rat, dog, pig, horse, etc.) does not matter at all.

Proteolytic enzymes are typified by ficin, but any type can be used as long as the tissue carrier is a collagen component.

Freeze-drying is generally used to dry the tissue carrier, but any drying method may be used as long as it does not impair the flexibility of the carrier itself.

Conditions for irradiating light or ionizing radiation (dose, temperature,
(atmosphere, etc.) is not limited in the present invention.

However, if it is necessary to limit the conditions, the radiation dose may be 1xlO" to 1xlO'rad, jp, 1°C to +50°C, and the atmosphere may be nitrogen, vacuum, carbon dioxide gas, etc.

The shape of the tissue carrier is generally a tube (such as a ureter). Both ends of the tissue carrier in a drug-filled state are tied indirectly with surgical sutures, or both ends are tied (directly) using the carrier itself. Or J, 13
Use a method such as embedding the carrier with both ends bent appropriately without pressing the carrier.

When using the crotch (amniotic membrane), one example is a method in which the drug is sandwiched between the crotch and the membrane.

The elution of the drug from the tissue carrier is controlled by (1) the thickness of the tissue carrier, (2) the type of tissue carrier (e.g. urine, trachea, etc.), and (3) the digestion (degradation) of the tissue carrier in the Inviν0 experiment. , (4) forming a pinball on the tissue carrier, etc. Furthermore, the daily elution amount can be controlled by changing the filling rate.

The elution test for drugs from tissue carriers is generally 0.1
M phosphate buffer (pH 7.4) was used at 37° C. while shaking 100 times per minute (using an Erlenmeyer flask).
The amount of drug eluted into the phosphate buffer solution was determined by UV method. In this case, the medium was replaced with a new medium every measurement day.

Examples are shown below.

Ureter removed from a pig (Example 1), vas deferens (Example
2), trachea (Example 3), food 3M (Example 4), and intestinal tract (Example 5) were treated with 0.05% ficin'1B solution (
p+(7,4) for 2 days at room temperature. Thereafter, it was treated with 1% glutardehyde solution 1FK (pH 7,4) at room temperature for 6 hours.Furthermore, freeze-drying was performed.
20 mg of H-RH was charged. An example of the charge@ operation is shown in Figure 1. One end of the tubular tissue carrier 1 is tied with thread, and the other end is filled with a drug and then tied with thread 3. The size of this carrier is 2 cm between the threads at both ends, and the thickness of the tube is 0.5 cm.
~l cm. In from this drug-containing tissue carrier
The elution behavior of L H-RI-1 in Vitro is shown in FIG. In the figure, the number 111 on the right is the number of the example.

Once the target was defeated, monkeys (Example 6), dogs (Example 7), rats (Example 8)
The test was carried out under the same conditions as in Example 1 using the ureter removed from ). In vitr at that time.

Figure 3 shows the elution amount of L H-RH per day. The number α1 (j) on the right in the figure is the example number.

Disaster side 1 In Example 1, in the pig ureter of freeze-dried jij
γ-rays from a Co ray source at 1 x 1' Orad/hr
It was irradiated for 4 hours. The other works are based on Example 1. Tnνi per day of L H-RH from this carrier
The amount of tro melt is about 1.5 times greater than that of Example 1.

This drug-containing carrier was transferred to WiStar-based Rano)' (00g
When implanted in the lower back skin, the carrier itself decreased to 10% at 4 weeks after implantation, 30% at 8 weeks, and 50% at 122 weeks.
% weight loss (7 minutes of digestion) W).

Due to the weight reduction of the carrier itself, the elution of the drug in vitro is also accelerated, 12i! ! Visually, 78% of the charged drug amount was eluted (for comparison, Inv
42% for i tro).

1;110-12 ~Ureter removed from a pig was treated with 0.05% pepsin p111.
．． 8 (Example 10), 0.05% trypsin solution, pl
+7.8 (Example 1), ), 0.05% chymotrypsin solution, pl+7.8 (Example 12), treated in the same manner as in Example 1, and loaded with drug. FIG. 4 shows the in vitro Lro'G release behavior of L H-RH from this carrier. The number at the right end of the figure is Example No.'#.

Testosterone (Example 13), 5-fluorouracil (Example 14), and pleomycin hydrochloride (Example 15) were used in place of L H-RH in Example 1.

FIG. 5 shows the daily amount of drug dissolved in vitro. The numbers at the right end of the figure are the example numbers.

Implementation - Earthwork In Example 13, 20 holes with a diameter of 0.2 mm were drilled in the carrier. The daily elution amount of testosterone from this carrier was accelerated five times compared to Example 13.

[Brief explanation of the drawing]

FIG. 1 shows an overview of the operation of loading a drug into a tubular tissue carrier in the present invention; FIG. 2 shows the in vitro elution of L H-RH from drug-containing tissue carriers in Examples 1 to 5. Figure 3 shows the LH-RH elution behavior of the LJ studs in Examples 6 to 8; Figure 4 shows the similar LH-RH elution behavior in Examples 10 to 12. Figure 5 shows In Vit of the drugs in Examples 13-15.
does not show the elution behavior of L H-RH in ro; In Figures 2 to 5, the horizontal axis is elution time (days) and the vertical axis is 1
This is the daily elution amount (887 days). Patent Applicant: Japan Atomic Energy Research Institute, Volume 3 (Fig. 4, Ground: 5) dQ 4 (/ 50 60 Continued from page 1) 0 Inventor: Masaharu Asano 2-15-19 Kataoka-cho, Takasaki City 0 Inventor: Isao Kaetsu 170-1 Namienoki-cho, Takasaki City 0 author Hidetoshi Yamanaka 1-14-22 Maebashi Cartaka Hanadai 0 author Katsuyuki Nakai 4-7 Shimoyo-cho, Maebashi City 0 author Keizo Shida 3-Showa-cho, Maebashi City 38-27 Damage to procedural amendment (spontaneous) September 7, 1980 Kazuo Wakasugi, Commissioner of the Patent Office1, Indication of the case: Patent Application No. 132818, filed in 19812, Name of the invention: Drug-containing sustained-release complex and Cleavage method 3, relationship with the case of the person making the amendment Patent applicant address: 2-2-2 Uchisaiwai-cho, Chiyoda-ku, Tokyo Name (
409) Japan Atomic Energy Research Institute 4, Agent■104 Address: 8-15 Ginza, Chuo-ku, Tokyo Rai I10 Gin I! Dia Heights No. 410 drawings and power of attorney 6, details of amendments are as follows.

Claims (9)

[Claims] (1) A sustained-release drug-containing complex comprising a drug contained in a biological tissue carrier treated with a proteolytic enzyme. (2) The drug-containing sustained-release complex according to item 1, wherein the biological tissue carrier is tubular and has both ends tied or bent. (3) A method for preparing a sustained-release drug-containing complex, which comprises treating a tissue carrier of biological origin with a proteolytic enzyme, drying it, and then incorporating the drug therein. (4) The tissue carrier derived from the transformed body is a monkey, a rat, a dog, a pig,
Ureter, vas deferens, ligament, amniotic membrane, esophagus, intestinal tract of horses, cows, etc.
3. The method for preparing a sustained release complex containing a drug selected from the trachea, veins, arteries, skin, etc. (5) The method for preparing a sustained-release drug-containing complex according to item 3, wherein the proteolytic enzyme is ficin. (6) The method for preparing a sustained-release drug-containing complex according to item 3, wherein the drying is lyophilization. (7) The method for preparing a sustained-release drug-containing complex according to item 3, which comprises further treating with glutaldehyde after treatment with the proteolytic enzyme. (8) The method for cleaving a drug-containing sustained release complex according to item 3, which comprises irradiating with light or ionizing radiation before the drying. (9) If the radiation is irradiated, the dose is 1xlO to 1x10'ra
d, 7i degrees -100°C to +50°C 1 The method for preparing a drug-containing sustained-release complex according to item 8, which is carried out in a nitrogen or carbon dioxide atmosphere or in a vacuum. α0) The method for cleaving a sustained-release drug-containing complex according to item 3, in which the tissue carrier derived from a living body is tubular and one end is tied or bent, and after filling with the drug, the other end is tied or bent to encapsulate the drug. .