JPH04364120A - Production of collagen and/or gelatin preparation having multi-layer structure - Google Patents

Abstract

PURPOSE:To provide a simplified process for producing a multi-layer type sustained-release preparation containing collagen and/or gelatin as a carrier and having controllable releasing rate, period or behavior of the medicine in the body after administration. CONSTITUTION:The objective collagen and/or gelatin preparation having multi- layer structure is produced by using (A) a collagen and/or gelatin solution having a concentration of 10-40 w/w% and containing one or more kinds of medicines and (B) one or more kinds of collagen and/or gelatin solutions or solution groups having a concentration of 10-40 w/w% and free from medicine or containing medicine having a concentration and/or kind different from those of the component A and simultaneously extruding the components through a multiple die.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing collagen and/or gelatin preparations having a multilayer structure by extrusion molding using multiple nozzles.

0002

[Prior Art] Recently, in drug therapy, various drugs have been developed that can be administered subcutaneously or directly to the lesion and can be released gradually, with the aim of making the drug act efficiently on the lesion and suppressing side effects. Research and development of sustained release formulations is underway. Among these, sustained-release preparations using carriers such as collagen and gelatin, which are biodegradable and have good biocompatibility, are shaped into needles, rods, or plates, and are clinically used as minipellet preparations. is expected to be useful (for example, Japanese Patent Application Laid-Open No. 126217/1983). In addition to regular subcutaneous administration, this mini-pellet can be administered to various parts of the body using fiberscope forceps needles or indwelling needles, so it is possible to devise the administration method and administration site according to the disease. It is a useful pharmaceutical formulation. The term "mini pellet" is not an official academic name nor is it a term commonly used in the industry, but in this specification, it is used for the above purpose and For convenience, a relatively small-sized implant preparation having such a shape will be referred to as a minipellet.

[0003] Collagen and gelatin originally have various properties that make it difficult to make them into mini-pellets. Therefore, there are many problems that must be solved in order to produce minipellets in which the drug is uniformly distributed throughout the collagen or gelatin carrier and the weight, size, etc. are uniform throughout. The present inventors succeeded in manufacturing mini-pellets that overcome these problems (Japanese Patent Application Laid-Open No. 62-228028), and further developed a drying method that enables their industrial production (Japanese Patent Application Laid-Open No. 62-228028). 63-300
No. 766), they succeeded in putting mini pellets into practical use.

[0004] However, rod-shaped, needle-shaped or plate-shaped mini pellet preparations that are industrially formed using these production methods are
Molded bodies composed of a single matrix were not always sufficient to control the release rate, release period, or release behavior of the drug. Therefore, there has been a strong desire for an industrial method for molding mini-pellets with a multilayer structure that allows these to be controlled freely over a wide range.

[0005] Various proposals have been made regarding sustained-release composites having a multilayer structure using natural or synthetic polymeric materials as carriers and methods for producing the same. However, in the conventional manufacturing method of sustained-release composites having a multilayer structure, a molded body of a predetermined shape made of a single matrix is prepared in advance, and this is immersed in a solution containing a polymeric material as a core material. A method has been adopted in which a coating film of a polymeric material is formed on the outer surface of a molded body made of a single matrix by repeating drying. For example, JP-A-56-12061
No. 8 discloses a method for producing spherical and rod-shaped sustained release composites having a multilayer structure using natural or synthetic polymeric substances as carriers, and JP-A-2-142738 discloses
A method for producing a acicular sustained-release composite having a multilayer structure using a poly-α-amino acid as a carrier is disclosed. In both of these methods, a coating film is formed on the outer surface of a molded article by immersion in a solution containing a polymeric material. In such conventional methods, the manufacturing process is generally complicated, and it is difficult to control the thickness of the coating film. Furthermore, since organic solvents are used and press molding is carried out under high temperature and high pressure conditions, it is difficult to implement industrially, and there are also problems in that applicable medical drugs are limited.

JP-A No. 57-55146 discloses a central portion in which atelocollagen or gelatin contains a drug at a relatively high concentration, and a central portion in which atelocollagen or gelatin contains a drug in a relatively high concentration, and Pharmaceutical carriers have been described, each having a shell containing a relatively low concentration of a pharmaceutical or an outer shell containing no pharmaceutical. The manufacturing method is to make the center sphere in a split mold, crosslink it for 4 days after air drying, then place the center sphere approximately in the center of the split mold for the outer shell, and fill it with the mixture for the outer shell to make a two-layered sphere. After air drying, crosslinking is performed, and this manufacturing method is complicated and difficult to implement industrially.

[0007]

SUMMARY OF THE INVENTION The present invention was devised in view of the above, and its purpose is to improve the release rate, release period, and release rate of drugs released in vivo after administration. The object of the present invention is to provide a simpler method for producing a multilayer sustained release preparation using collagen and/or gelatin as a carrier whose behavior can be controlled.

[0008]

[Means for Solving the Problems] The present inventors have conducted extensive research in order to develop a method for industrially producing sustained release preparations with a multilayered structure using collagen and/or gelatin as carriers in high yields. As a result, by extruding two or more 10 to 40 w/w % collagen and/or gelatin solutions with different drug concentrations or types of drugs through multiple nozzles, a desired multilayer sustained release product can be obtained. It has been found that a formulation can be obtained. The present invention was completed based on this knowledge.

[0009] The fact that a multilayer sustained release preparation can be obtained by extrusion molding from multiple nozzles is surprising in light of the complexity of the manufacturing method of the conventional multilayer sustained release preparation mentioned above. The key to success is based primarily on the fact that 10-40% w/w collagen and/or gelatin solutions are used as carriers. That is, the collagen and/or gelatin solution of 10 to 40 w/w% is gel-like to the extent that it can be extruded from a nozzle, and is gel-like to the extent that it can maintain its shape after extrusion molding. It has this advantageous characteristic. On the other hand, the multilayer preparation according to the present invention is manufactured and used mainly for the purpose of sustained drug release, but is not necessarily limited to this purpose. For example, it is of course possible to use it as a means to keep multiple drugs isolated from each other. Further, this multilayered preparation is usually formed into the minipellet shape mentioned above, but it can also be formed into a larger shape other than rod-like, needle-like, or plate-like.

[0010] For this reason, in this specification, a preparation produced by extrusion molding from multiple nozzles according to the method of the present invention is referred to as a "collagen and/or gelatin preparation having a multilayer structure." shall be.

[0011] As understood from the foregoing, the present invention provides 10 to 10 drugs containing one or more drugs.
40 w/w % collagen and/or gelatin solution (A) and drug free or (A
), one or more 10-40 w/w % collagen and/or gelatin solutions or solution group (B) with different concentrations and/or types of drugs are simultaneously extruded using multiple nozzles. The present invention provides a method for producing a collagen and/or gelatin preparation having a multilayer structure, which is characterized by molding. The present invention will be explained in more detail below.

[0012] In this specification, the term "multilayer structure" refers to a molded article composed of two or more matrices. The matrix here refers to a system in which one or more drugs and/or additives are homogeneously dispersed in a carrier, but it also includes a system consisting only of a carrier containing neither drugs nor additives. It is a matrix. Therefore,
Collagen and/or gelatin preparations having a multilayered structure are preparations that are composed of multiple matrices, and each matrix has a concentration of the drug contained therein (including cases where the concentration is 0) and/or drug concentration. or the concentration of additives and/or the type of additives. The content of the drug is preferably 0 to 50 w/w%, preferably 0 to 30 w/w%, and more preferably 3 to 20 w/w%.

[0013] 10-40 w/w% collagen and/or
Or gelatin solution means an aqueous solution containing collagen and/or gelatin defined below in a proportion of 10 to 40% by weight.

[0014] Collagen used in the present invention is a main protein in animal connective tissues, and as a protein with low antigenicity, it is a safe substance that is already frequently used in surgical systems, hemostatic agents, etc. In the present invention, for the purpose of increasing safety, atelocollagen with extremely low antigenicity may be used by removing telopeptide, which is the main antigenic site of collagen. Furthermore, it goes without saying that in the method of the present invention, chemically modified succinylated collagen or methylated collagen can also be used. On the other hand, gelatin is heat-denatured collagen and is a completely safe substance medically. Gelatin can also be chemically modified in the same way as collagen. In the present invention, collagen, gelatin, or the above-mentioned derivatives thereof can be used alone or in combination in appropriate proportions. In this specification, for convenience, collagen or its derivatives, gelatin or its derivatives, each alone, or a mixture thereof will be referred to as "collagen and/or gelatin". All collagen, gelatin and derivatives thereof can be obtained and used commercially.

[0015] There are no particular limitations on the drugs to be contained in the preparation of the present invention, but examples thereof include prostaglandins, prostacyclin, various hormones, antibiotics, chemotherapeutic agents, anti-inflammatory agents, anticancer agents, and the like. Furthermore, since the production method of the present invention is carried out under extremely mild conditions without steps such as heating or organic solvent treatment, it is particularly suitable for producing preparations of drugs that are generally unstable to heat. Examples of heat-labile drugs include peptide and protein physiologically active substances.

[0016] As peptide/protein physiologically active substances,
Examples include cytokines, endocrine-related substances, protein hormones, growth factors, nutritional factors, enzymes, etc. that have immunomodulatory effects. More specific examples are shown below. Examples of physiologically active substances having immunomodulatory effects include IFN,
interleukin (IL), colony stimulating factor (CSF)
), macrophage activating factor (MAF), and the like. It should be noted that the IFN referred to here may be any of α, β, γ, and other IFNs, or a combination thereof. Similarly, IL is IL-1, IL
-2 or IL-3, or any other, CSF
is multi-CSF (multipotent CSF), GM-CSF
(granulocyte-monocyte-macrophage CSF), G-CSF (
It may be granulocyte-CSF) or M-CSF (monocyte-macrophage CSF) or any other CSF, or a mixture thereof. Furthermore, the physiologically active substance used in the present invention does not depend on its manufacturing method, and may be any substance extracted from a living body, an artificially synthesized substance, or one obtained by genetic recombination, cell culture, or the like.

[0017] The present invention has a multilayer structure with two or more layers, and two or more types of collagen and/or gelatin solutions containing different substances are supplied to each layer independently. Ordinary multiple nozzles can be used. As a specific example of the multiple nozzle, for example, the double structure nozzle shown in FIG. 1 can be used.

To carry out the present invention, collagen and/or gelatin are first kneaded with water. At this time,
Optionally, one or more drugs and/or additives are added. In order to knead each ingredient uniformly, JP-A-6
It is preferable to follow the method described in Japanese Patent No. 2-228028. Specifically, it is preferable to use one of the following methods. b) Under acidic conditions with a pH of 5 or less, reduce the salt concentration of the mixed solution to the fiber-forming concentration or less. Under such conditions, even if the concentration of collagen and/or gelatin is high, they will not become fibrous and a homogeneous mixed solution will be obtained. b) Using collagen and/or gelatin that has been chemically modified such as succinylation or methylation. This method is effective when it is necessary to adjust the pH of the mixed solution from the viewpoint of drug stability. c) Add glucose to the mixed solution. Addition of glucose increases the solubility of collagen and/or gelatin, so this method is particularly effective when the mixture is approximately neutral. The mixture of two or more liquids thus obtained is extruded into gas (usually air) through multiple nozzles (dry molding). At this time, each layer comes into contact with each other, and each layer is extruded into an integrated state. Next, the molded body is dried by an appropriate method. At this time, in order to maintain the shape of the molded body almost as it is, the method described in JP-A-63-300766 is used, in other words, a part or all of the molded body is brought into contact with a hydrophobic porous membrane having continuous pores. It is preferable to carry out drying treatment.

The shape of the molded product obtained by the method of the present invention is usually rod-like, needle-like, or plate-like, but there are no restrictions on its cross-sectional shape; for example, it can be circular, triangular, square, trapezoidal, etc. Applicable. Particularly preferable shapes of the molded product obtained by the method of the present invention include one composed of two or more rod-shaped matrices layered concentrically as shown in FIG. Examples include those composed of a plate-like matrix having more than one layer. At this time, by changing the dimensions of the nozzle, it is possible to form layers of various thicknesses, and the thickness of the layers can be easily controlled. In addition, in a molded body composed of two or more rod-shaped matrices layered concentrically,
If the carrier component is not extruded from the central nozzle, a hollow pipe or tube-shaped preparation can be produced. Further, by arranging two or more nozzles in one outer cylindrical nozzle, it is also possible to manufacture a multi-structure matrix with a cross section as shown in FIG. 4.

[0020]

EXAMPLES The present invention will be explained in more detail below using experimental examples and examples, but these examples are not intended to limit the present invention.

Example 1 45 g of 2 w/w% atelocollagen aqueous solution and 5.6 m of α-type interferon (64 million international units/ml)
l and human serum albumin aqueous solution (71 mg/ml) 1
．． 41 ml was mixed well and freeze-dried. 2.3 ml of water was added to this freeze-dried product, and after swelling in the refrigerator overnight, it was sufficiently kneaded in a mortar to obtain a homogeneous mixed solution (liquid A).
Atelocollagen 26w/w% aqueous solution).

Separately, 90 g of a 2 w/w% atelocollagen aqueous solution and a human serum albumin aqueous solution (71 mg/ml) 2
．． 82 ml was mixed well and freeze-dried. 4.3 ml of water was added to this freeze-dried product, and after swelling in the refrigerator overnight, it was sufficiently kneaded in a mortar to obtain a homogeneous mixed solution (solution B) (26% w/w aqueous solution of atelocollagen). Transfer each of mixed solutions A and B to plastic syringes and centrifugally defoam them using a high-speed centrifuge. Mixed liquids A and B are each set as a syringe into a special double structure nozzle so that liquid A is supplied to the center and liquid B is supplied to the outer layer. This dedicated double structure nozzle has a volume ratio of 1:2 between the center and the outer layer, and the diameters of the outer layer and the center are 2.0 mm and 1.0 mm, respectively.
It is 0mm. The material is stainless steel SUS, which can withstand autoclave or dry heat sterilization and has excellent chemical resistance.
-316. The extrusion speed of both liquids A and B is 1:2
When extruded at the same time at the rate, both liquids A and B come into contact at the nozzle opening and are formed into an integrated rod. this,
The mixture was left standing in a desiccator kept at a relative humidity of 75% with an inclination, dried in a refrigerator for 72 hours, and then further dried in a desiccator containing silica gel for 24 hours. By cutting this into an appropriate length, α-type interferon 100
A molded article having a two-layer structure with a diameter of about 1.1 mm and containing 10,000 international units was obtained.

Example 2 45 g of 2 w/w% atelocollagen aqueous solution and 5.6 m of α-type interferon (64 million international units/ml)
1 and interleukin 2 (2x103U/ml) 2ml
and human serum albumin aqueous solution (71 mg/ml)1.
41 ml was mixed well and freeze-dried. After adding 2.3 ml of water to this freeze-dried product and swelling it in the refrigerator for a day and night,
The mixture was sufficiently kneaded in a mortar to obtain a uniform mixed solution (solution A) (26% w/w aqueous solution of atelocollagen). Transfer this A solution and B solution obtained in Example 1 to a syringe,
Centrifuge to defoam using a high-speed centrifuge. Mixed liquids A and B are placed in the syringe using a special double structure nozzle, with liquid A in the center and liquid B in the center.
The liquid was set so as to be supplied to the outer layer, and treated in the same manner as in Example 1 to produce a molded body having a two-layer structure with a diameter of 1.1 mm containing α-type interferon and interleukin 2 in the center. I got it.

Example 3 90 g of 2 w/w % atelocollagen aqueous solution, 2 ml of interleukin 2 (2×10 3 U/ml) and 2.82 ml of human serum albumin aqueous solution (71 mg/ml) were thoroughly mixed and freeze-dried. Add 4.3 liters of water to this freeze-dried product.
ml and swelled in a refrigerator for a day and night, and then sufficiently kneaded in a mortar to obtain a uniform mixed solution (solution B) (26 w/w % aqueous solution of atelocollagen). This B solution and the A solution obtained in Example 1 are each transferred to a syringe and centrifugally defoamed using a high-speed centrifuge. Mixed liquid A,
Place each of B in the syringe into the special double structure nozzle A.
The solution was set so that the liquid was supplied to the center and the B solution was supplied to the outer layer, and the same treatment as in Example 1 resulted in a 1.1 mm diameter product containing α-type interferon in the center and interleukin 2 in the outer layer. A molded article having a double type structure was obtained.

Experimental Example 1 The minipellets having a two-layered structure prepared in Example 1 and the control minipellets were each subcutaneously administered to mice, and the time course of the blood concentration was observed by radioimmunoassay. Three mice were used for each, and the dose was 1 million international units per mouse. The results are shown in Figure 5. In Figure 5, the vertical axis is the blood concentration of α-interferon (average of 3 animals, unit: unit/ml
), and the horizontal axis represents time (unit: days). ○ represents a mini-pellet having a double-layer structure (invention), and ● represents a single-layer mini-pellet (control).

[0026] A control mini-pellet was prepared as follows. 2w/w% atelocollagen aqueous solution 54g
and α-type interferon (64 million international units/ml)
2.68ml and human serum albumin aqueous solution (71mg
/ml) were mixed well and lyophilized. 2.8 ml of water was added to this freeze-dried product, and after swelling in the refrigerator overnight, it was thoroughly kneaded in a mortar to obtain a homogeneous mixture (
Atelocollagen 26w/w% aqueous solution). The series of steps from extrusion to drying was performed in the same manner as in Example 1 except for using a nozzle with a single structure.
A molded body (control) having a single structure with a diameter of about 1.1 mm containing 00,000 international units was obtained.

As is clear from FIG. 5, the initial peak of the minipellets of the present invention is suppressed, and they tend to persist for a longer period of time, with almost constant blood concentrations maintained up to 7 days after administration. , showed a more controlled release behavior.

[Brief explanation of the drawing]

FIG. 1 is a cross-sectional view of a multiple nozzle used in the present invention.

FIG. 2 is a perspective view of a multilayer molded product obtained by the present invention.

FIG. 3 is a perspective view of a multilayer molded product obtained by the present invention.

FIG. 4 is a perspective view of a multilayer molded article obtained by the present invention.

FIG. 5 is a graph showing the time course of the blood concentration when the double-layer molded product obtained by the present invention and the single-layer molded product as a control were subcutaneously administered to mice.

Claims (6)

[Claims] Claim 1: (A) 10-40% w/w collagen and/or containing one or more drugs;
or gelatin solution, and (B) 10 to 40 w/w of one or more drugs that do not contain any drug or have a different concentration and/or type of drug than (A).
1. A method for producing a collagen and/or gelatin preparation having a multilayered structure, characterized by simultaneously extruding a collagen and/or gelatin solution or a group of solutions of 1.5% by weight using multiple nozzles. 2. The manufacturing method according to claim 1, wherein the molded product extruded by extrusion molding is extruded into a gas. 3. The manufacturing method according to claim 1, wherein extrusion molding is performed using multiple nozzles forming concentric layers. 4. The manufacturing method according to claim 1, wherein extrusion molding is performed using multiple nozzles having a laminated structure. [Claim 5] Solution (A) and solution or solution group (B)
2. The manufacturing method according to claim 1, wherein only the drug concentration differs from that of the drug. [Claim 6] Solution (A) and solution or solution group (B)
The manufacturing method according to claim 1, wherein the types of drugs are different from each other.