JPS60136509A - Slow-releasing composite having sandwich structure and its preparation - Google Patents

Abstract

PURPOSE:To provide the titled composite capable of releasing the physiologically active component at a constant rate for a long period, by hot-pressing a carrier with a mold, placing a physiologically active substance in the cavity of the molded carrier, covering the substance with the carrier, and again hot-pressing the product. CONSTITUTION:A carrier is charged in a mold having a desired form, and hot- pressed with a convex press to form a cavity to the carrier. A physiologically active substance is placed at the center of the cavity, covered with the carrier, and hot-pressed with a flat press to obtain a slow-releasing composite having sandwich structure. The hot-pressing is carried out preferably at 20-300 deg.C and 50-10,000kg/cm<2> pressure. The releasing rate of the physiologically active substance can be suppressed by irradiating the sandwiched product with light or ionizing radiation after the hot-press with the flat press. The carrier is e.g. amino acid, hemoglavin, etc., and the physiologically active substance is an anti- malignant tumor agent, a hormone preparation, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Background of the Invention A1 Technical Field to Which the Invention Pertains The present invention relates to a sustained-release composite with a novel structure and a method for producing the same. More specifically, the present invention relates to a sustained-release composite comprising a physiologically active substance enclosed in a sandwich-like phase and a method for producing the same.

Explanation of the Prior Art Conventionally, when a physiologically active substance is incorporated into a phase substance that has a property of melting under pressure and heat, a system consisting of simply mixing and dispersing the phase substance and the physiologically active substance is pressurized. Sustained-release composites were manufactured by melting under warm conditions. In the Sawada sustained-release complex produced by this conventional method, the physiologically active substance is encapsulated in the carrier in an apparently dispersed state at the top, and the surface pressure of the carrier is such that the physiologically active substance is exposed.

This means that when jPj contains a physiologically active substance that is easily soluble in water, release of the physiologically active substance from the complex occurs suddenly aVc at the initial step π, and as a result, the physiologically active substance remains for a long period of time. If it is released at a constant rate over a long period of time, there are problems such as durability cannot be expected.

Therefore, there is a need for a sustained-release composite in which the release of a physiologically active substance is sustained at a constant rate over a long period of time, and a method for producing the same.1. was.

SUMMARY OF THE INVENTION As a result of research, the present inventors have discovered that the above-mentioned method can be achieved by creating a sandwich structure in which the center of the carrier ('CgE!l! active substance) that melts under pressure and heating is expanded. The present invention was completed by discovering that the 'Ifj point can be improved compared to the prior art.

Therefore, it is an object of the present invention to provide a sustained-release complex with a desired shape in which a physiologically active f1'' substance is entrapped in the center of a d carrier.

Another object of the present invention is to hot-press a carrier that melts in a specific pressure and temperature range using a mold of a desired shape, place the formed four-part 1rC physiologically active substance, fill the carrier on top, and then press the carrier. An object of the present invention is to provide a method for producing a sustained release composite having a sandwich structure consisting of:

Other objects and advantages of the invention will be highlighted below.

3. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a sustained-release complex in a desired shape in which a physiologically active substance is encapsulated in the center of a carrier.

The release of physiologically active substances from the sustained-release composite having a sandwich structure of the present invention is basically zero-order.
Indicates release. Furthermore, the deactivation of the physiologically active substance contained in the sustained-release composite of the present invention due to U-adhesion was less than that of conventional composites. This is due to the sandwich structure, and is thought to be because the carrier in the outer layer suppresses the deactivation of the physiologically active substance in the center.

The sustained release composite having a sandwich structure of the present invention is 41
A wide variety of shapes can be considered for fp, such as cylinder-shaped, film-shaped, tabular-shaped, spherical, etc., and can be appropriately selected as desired.

The sustained-release composite of the present invention having a sand-inch structure is produced by hot-pressing a carrier that melts at a specific pressure and temperature range using a mold of the desired shape, placing a physiologically active substance on the four parts formed, and then placing the physiologically active substance on the four parts formed. It is manufactured by hot pressing after filling 411 bodies.

After that, a 4Ti body that melts in a specific pressure and temperature range is hot-pressed using a mold of the desired shape, a biologically active substance is placed in the recessed part, and the carrier is filled in the soil part to the desired height, followed by real pressing. However, the present invention also encompasses a method for producing a sustained-release composite that does not form a sandwich 4:f77, which comprises further irradiating with light or ionizing radiation.

Pressure and temperature employed when implementing the present invention
Wh use 4 guns! It is fine as long as the body melts, but 2
For example, the pressure is 50-1o, ooo ky/7. Preferably 100~l0(1(l kg/CT, i range, fortune, degree is 20~:(+lfl''('preferably 30~
9.1) of 15fl'C is good.

The carrier used in the present invention is 50~+(1f10(l kg)
/rnj and at a temperature of 20 to 300° C.9 For example, as a protein, albumin.

Polyamino acids such as γ-globulin, hemoglobin, and collagen include hemoglabin and collagen.

In addition, polyamino acids (reference) include leucyl-right γ-benzyl, γ-methyl, γ-ether-leyglutamate, β-pendylureasnobutate, etc., and polysaccharides such as ethylene glycol chitin, D(+)- 4 Lycogen, Curulan.

Examples of synthetic polymers such as xylan include polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl chloride, and polyhydroxyethyl methacrylate.

Others dicellulose, sodium carboxycellulose (C
MC), ethercellulose, methylcellulose, texturin, gum arabic, and sanononolose.

Since the present invention relates to a method for producing a sustained release substance by enclosing and immobilizing a physiologically active substance in a carrier, it is not particularly limited to physiologically active substances (specific examples are listed below). .

(1) Antibiotics (!゛): These are classified as follows according to their mechanism of action.

(+1−]; Alkylating agent 9 For example, chlormethine.

Titrodiene mustard-N-oxide, cyclophosphamide, chlorambutyl, thiotepa, etc.

(+)-2; antimetabolite; for example, cytosine arabinonde, 6-mercabutoprine, 5-fluorouracil, etc.

(1)-3; Plant tag nuclear fission greens, such as vinflastine sulfate, temecolsin, etc.

(11-4; Antibiotics; for example, sarcomycin.

actinomycin, mitomycin C, chromomycin A1, etc.

(1)-5; Hormone agents; for example, adrenal corticosteroid hormones, sex hormones, etc.

(1)-6; Other anti-malignant tumor agents; 864 Ill
”, guanyl hydrazone, 1 no asparaginase, P
C113-45, Midotin et al.

(2) Hormone agents (21-T; steroid hormones: for example, steroid metabolic enzymes such as human xylase, isomerase, hydrogenase; sex hormone drugs such as androgens, estrogens, etc.; glococortic acid).

Adrenal skin J^bormon drugs like mineralocorticoids.

(21-2; Peptide hormone; for example, thyrotropin-releasing hormone, luteinizing hormone-releasing hormone,
Parent subbed hormones such as somatostatin; adrenocorticotropic hormone, thyroid stimulating hormone, luteinizing hormone,
Follicle-stimulating hormone, prolactin, intermediate length hormone, pre-pituitary hormone; chromatophore-stimulating hormone; post-pituitary hormone.

Thyroid hormones; parathyroid hormone, calcitonin; insulin, glucagon; gastrointestinal hormones such as gastrin, cholecystokinin, bankleozycin, secretin, motilin: L II -TL]-f, 'I
” l(, I-1, A I) I-T et al.

(2+-3; Catecholamines (2+-1: Insect hormones including ecdysone, juvenile hormone, and brain hormone (2)-5; 3 for plant hormones) Other general medicines listed below;
(ti' sleeping agent; cranial nerve antispasmodic sedative; mental nerve stabilizer; mental nerve activator; autonomic central regulator; antihistamine; sedative 4
1; Agent; Antiemetic; Analgesic; Autonomic nerve blocker; Muscle relaxant;
Muscle tension agent; agent for treating neuralgia and rheumatic diseases; agent for improving uric acid metabolism; anti-inflammatory agent; hypothermic agent; strong 71, · agent; cell activator;
Tube dilator/circulation enhancer: vasopressor; diuretic; depressant;
Anticoagulant; Antitussive; Stomach agent; Peptic ulcer treatment; Anthelmintic; Surfacing agent; Biliary agent; Liver activator; Denaturing agent; Sucrose lowering agent; Anti-aging agent; Vitamins, minerals; Chemotherapy agents; biological preparations; anti-cattle agents 7; agents for eye diseases; agents for otorhinolaryngosis; agents for skin diseases; agents for dental diseases; diagnostic agents; public health agents: various pheromones; narcotics, etc.

The sustained-release composite having a Xandwich structure of the present invention is produced by charging carrier powder in advance into a mold having the desired shape of the composite and applying pressure of 50 to 1000 (lkzo/rnT, temperature of 20 to 3000 kg).
Press with a convex press in the range of 00°C, then charge one or more biologically active substances into the concave center part formed on the carrier, and further charge the carrier powder into the center part, then press flat. Manufactured by hot pressing in a mold press under the above conditions.

Furthermore, the rate of release of the physiologically active substance from the sustained-release composite can be suppressed by applying hot press light using the above-mentioned flat press or irradiation with electrical radiation.

Radiation sources employed in the practice of this invention include visible and ultraviolet light from low-pressure or high-pressure mercury lamps, sunlight, light from photon factories, X-rays, gamma rays, beta-rays, alpha-rays, and electron beams. Either of these is fine. The irradiation dose should be as small as possible because the physiologically active substances in the two layers will be deactivated, but the irradiation dose for 100% curing of the carrier is 1 x 10'1'L or more. is necessary. Therefore, in the case of coarse part P radiation, 1
Preferably 1X1.0' to t, x at a dose rate of 09R/hour
An irradiation dose of 1o'R is required.

The method of the present invention will be specifically explained in the following VC, '-J Example'.

The elution test of ?1tll reagent from the fried polymer composition in j(eyes)\+1tro was carried out using a medium of 10100O (jllll 1'V+ ''' water) once a month, and the number of basket rotations was 10 ( Lrl)mn181s:37°(
゛TeT,] ST' X l X l/CX I? Row ivy.

Example 1) Poly γ-benzylu L ~ Glutamate 1007'l!
Fill & into a cylindrical tube with an inner diameter of 10 π and 100 zo/C11
Hot pressed for 5 seconds at +00°C under pressure of
Friend.

It was molded into a concave shape with a depth of 1.5 mm. Then, in advance at room temperature, 9/c-r to 100 was added to the recessed hole.
Really breathed under pressure of /1, diameter 7, thickness 1.5+
u + weight 5 (HntBf) natural Lulcinizin
g hormone rclc-as i nghO ηr) 1] c (I) II - [t, TI) is charged, and the upper part E 5 (l m//poly-γ-benzyl monoglutamate is charged). + 2 (1 (11g)
/Cn'i Press at 100°q for 5 seconds to form a circle with a diameter of 10 rnm + a thickness of 3 ynm (A=, i
Jl is a flat-bottomed cylindrical hard composite with a sandwich structure in which physiologically active substances with a diameter of 7mm and a thickness of 15mm are encased in the center of the Jζζ rod.

T from the obtained sandwich type 4J bottom cylindrical crosspiece,
The in vitro release behavior Ij of 11-1 and I-1 is shown in FIG.

Example 2) γ-globulin 10m9 in glass with an inner diameter of 1.6 mm%
y (Filled to 400!9/i, hot pressed at 60°C for 5 seconds to form a concave shape with a diameter of 10 mm and a depth of 5 mm/
(.

Thereafter, 6 m9 of mitomycin was charged into the recessed hole, and 5 m9 of γ-globulin was added to the top of the mitomycin. A hard sword-shaped composite having a sandwich structure in which a physiologically active substance with a diameter of LO mm and a height of 5 mm was enclosed in the center of a 6 mm needle-shaped carrier was obtained.

FIG. 2 shows the in vitro release behavior of mitomycin C from the obtained Sand Inch needle-like complex.

Example 3) The composite prepared in Example 2) was treated with CO- in a nitrogen atmosphere.
['l (from 1 cara]rw) was irradiated with 1 Mrad.

1() of mitomycin C from the complex
The release behavior of ilro is shown in FIG. 2 by -e-■-.

Sukokai 111 row 4) Polyvinyl chloride powder was hot pressed at 500 kg/i at 100°C for 1 () seconds to prepare a mold consisting of three elements A, +3 and C as shown in Figure 4. .

Elements A and C are 10 strips wide, 30 mm long and 05 mm thick.
Element B is 6 mm wide, 26 mm long, and J
[It is 0.5 dragons in size and has a frame-like shape.

This mold was used to mill a composite having a sandwich structure. In other words, element B is superimposed on element C to form a 9th order VC element] FC5-Fluorouracil (5-I't+)
1 g of element A was placed on top of element B, and the whole was hot-pressed at 100°C for 10 seconds at 5'00 kg/i to form a film-like hard sand-inch structure slow-moving composite. I got a body.

? In vitro analysis of 5-Fu from the complex
Figure 3 shows the release behavior.

[Brief explanation of the drawing]

1 to 3 are graphs showing the release behavior of physiologically active substances from sustained release composites prepared according to the present invention. Fourth
The figure is a sketch of the mold used in Example 4. Patent applicant: Japan Atomic Energy Research Institute N.I. Representative: Patent attorney: Kyo Yuasa 31-■1. i (4 others) U 10 20 30 40 50 60 days

Claims (1)

[Scope of Claims] Sustained release 1 having a sandwich structure comprising 11 kinds or 2 or more physiologically active substances enclosed in the middle part VC of a carrier.
7th υ combination. A carrier was charged in advance into a mold suitable for a sustained-release composite with a shape of 2.9 mm, and hot pressed with a convex press for 4'H.
The body is molded into a concave shape, and one or two types of
A method for producing a sustained-release composite having a sandwich structure, which comprises charging one or more physiologically active substances and then charging a carrier on top of the carrier (hot pressing with a 3-flat press. 10.000 kll/ /c
3. A method according to claim 2, carried out at a pressure of ITl and a temperature range of 20 to 300'C. 4. A carrier is charged in advance into a template yc suitable for the complex into the sustained release enzyme of the desired shape, hot pressed with a convex press to form the carrier into a concave shape, and one or more species are placed in the center of the four parts of the carrier. A sustained-release composite with a sandwich structure is produced by charging a physiologically active substance, then charging a carrier on top of the carrier, hot-pressing it with a flat press, and irradiating it with halo reeds or ionizing radiation. how to.