MXPA00011759A - Controlled release preparations having multi-layer structure - Google Patents

Abstract

Preparations whereby two or more drugs can be released separately at appropriate speeds depending on the disease or the release behaviors of one or more drugs can be precisely controlled, which consist of an outer layer wherein a water-soluble drug is dispersed in a carrier made of a biologically non-degradable and hydrophobic polymer material, and one or more inner layers wherein a water-soluble drug, differing in type or concentration from the one contained in the outer layer, is dispersed in a carrier made of a biologically non-degradable and hydrophobic polymer material, and in which the outer and inner layers are concentrically located in the diametral direction of stick type preparations and both or one of the ends in the axial direction are opened so as to directly come into contact with the environment.

Description

PREPARATION OF CONTROLLED RELEASE THAT HAS A MULTIPLE LAYER STRUCTURE FIELD OF THE INVENTION The present invention relates to a controlled drug release preparation that is useful for the medicine and livestock industry. More specifically, the present invention relates to a controlled drug release preparation having a multilayer structure, by means of which one or more drugs can be released by separating them with a different behavior in vivo, for the purpose of exhibiting effectively the effectiveness of them.

BACKGROUND OF THE INVENTION A drug delivery system has been developed for the purpose of effectively delivering an appropriate amount of drug to the affected site. In order to adopt an individual objective or disorder, a variety of systems have been studied; for example, a controlled drug release preparation which uses as a carrier a hydrophobic polymer material, which is not degradable after being administered in the body. As a method for controlling the release of a drug from said preparation, one is described which uses an additive such as an albumin (Japanese Patent Publication (Tokkohei) No. 61959/1995, and one which forms an outer layer consisting of a Hydrophobic polymer alone (Japanese Patent Publication (Tokkaihei) No. 187994/1995) However, when a preparation contains different drugs, it is impossible to control the release thereof, by these techniques, such that each drug is released with a desired behavior from the preparation The reasons for it are as follows: When a drug, whose release must be controlled, is soluble in water, the powder drug does not dissolve in a vehicle but exists in a dispersed state in the same When this preparation is placed in aqueous media, the powdered drug present on the surface of the preparation dissolves in the surrounding water, and is released. powder drug present around a hole thus formed dissolves to be released. The repetition of said phenomenon results in the formation of a channel by means of which the drug is released sequentially into the interior of the preparation. In this way, the drug's release behavior is influenced by physical characteristics such as the solubility or diffusion rate of the drug in the aqueous surroundings. Accordingly, in a preparation wherein different drugs are dispersed homogeneously in a single vehicle, it is impossible to respectively control the release of each drug as desired because the release of the drug is influenced only by the physical characteristics of the drugs.

Japanese Patent Publication (Tokkohei) No. 78017/1995 discloses an intermittently controlled release preparation, which was designed to intermittently release one or more drugs. In this preparation, it is possible to control for each drug to be released in different periods, but it is not possible to separately control the release of different drugs during the same period. For some diseases, it will be more effective to release one or more drugs with different behavior. However, as stated previously this has never been achieved by a single preparation. On the other hand the US patent 4,351, 337 describes a biodegradable preparation with multiple layer structure wherein a poly-amino acid which is degraded by an enzyme in the body, is used as a vehicle, and where the drug is released by diffusion and degradation of a vehicle. Accordingly, said biodegradable preparation with multiple layer structure has a problem, for example the enzymes in the body can influence its drug release behavior.

OBJECTS OF THE INVENTION The present invention was carried out considering the previously established. It is an object of the present invention to provide a preparation that can release two or more drugs separately at appropriate rates depending on the disease or a preparation wherein the release behaviors of one or more drugs can be controlled accurately. Said problem to be solved was also found by the inventors.

BRIEF DESCRIPTION OF THE INVENTION The inventors have studied hard to solve the problem and find that the following is a fundamental key in the release of one or more drugs with different behavior: to form a preparation in the form of a implantable bar in a multilayer structure, and to design it in such a way. so that each layer suits most of the appropriate arrangements and structures. In addition, by using as a carrier a biologically non-degradable hydrophobic polymer that does not degrade in vivo and is not influenced by an enzyme, etc., the preparation of the present invention can stably release the drug in vivo. In this way, the present invention includes the following modalities. (1) A preparation comprising an outer layer wherein a water-soluble drug is dispersed in a vehicle containing a biologically non-degradable hydrophobic polymer material, and one or more inner layers in which a water-soluble drug, which is different or that differs in the concentration thereof of the drug contained in the outer layer, is dispersed in a vehicle containing a biologically non-degradable hydrophobic polymer material, and in which the outer and inner layers are concentrically located in the diametral direction of the preparation in the form of a bar and both or one of the ends in the axial direction are opened to come into direct contact with the environment. (2) A preparation as set forth in item (1) wherein a layer consisting solely of biologically non-degradable hydrophobic polymer material exists between the inner layer in which the water soluble drug is dispersed and the outer layer, or between two inner layers in which a water-soluble drug is dispersed. (3) A preparation as set forth in item (1) or (2) wherein each layer contains a different water soluble drug. (4) A preparation as set forth in item (1) or (2) wherein each layer contains a different concentration of the same water soluble drug. (5) A preparation as set forth in any of the items (1) to (4) wherein at least one of the outer or inner layers contains two or more drugs. (6) A preparation as set forth in any of items (1) to (5) wherein the biologically non-degradable hydrophobic polymer material is silicone.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts cross sections and oblique views of the exemplified preparations of the present invention, and graphs showing the time course of the cumulative release rate of each drug from the preparations. Figure 2 depicts a graph showing the time course of the cumulative release percentage of OVA and IFN of the preparation of Example 1 in experiment 1. Figure 3 shows a graph showing the time course of cumulative release percentage of IL-1 and avidin from the preparation of Example 2 in experiment 2. Figure 4 represents a graph showing the time course and cumulative release percentage of HSA and IFN from the preparation of comparative example 1 in experiment 3. Figure 5 represents a graph showing the time course and cumulative release percentage of HSA and IFN from the preparation of comparative example 2 in experiment 4.

DETAILED DESCRIPTION THE INVENTION In the present specification, an outer layer means the majority of the outer layers in the diametral direction of a rod-shaped preparation, i.e. one that directly contacts the external environment in the diametral direction. The exemplified preparations of the present invention are shown in Figure 1 where a graph is also shown schematically representing the time course of the cumulative release amount of each drug from the respective preparation. In said figure, (a) a preparation is represented where each layer contains a different type of drug respectively, 1 represents a layer containing one or more drugs, and 2 represents a layer containing one or more drugs different from those of 1. (b) Represents a preparation where each layer contains a different type of drug respectively, 4 represents a layer containing one or more drugs, 5 represents a layer containing one or more drugs other than those of 4 and 6, and 6 represents a layer containing one or more drugs different from those of 4 and 5. (c) Represents a preparation wherein each layer contains a different concentration of the same type of drug, 7 represents a layer containing one or more drugs, 8 represents a layer containing the same drug as that of 7 in a different concentration of the drugs in 7 and 9, and 9 represents a layer containing the same drug as that of 7 at a different concentration of the drugs in 7 and 8.

A graph shows the time course of the cumulative released amount that shows a result in case the concentration of the drug in the layer is 7 < 8 < 9 in order. (d) Represents a preparation comprising a layer consisting of biologically non-degradable hydrophobic polymer material only between the drug-containing layers, 0 represents a layer containing one or more drugs, 1. represents a layer consisting of biologically non-degradable hydrophobic polymer material alone, and 2 represents a layer containing the same drug as in 10 at a different concentration than 10, or a layer containing a drug other than 10. Different drug or the different type of water soluble drug used herein includes the mode in which the drugs per se are different from each other, or the modality wherein the combination of a plurality of drugs are different. More specifically, in the aforementioned case, the following modalities are included: (1) Layer 1 contains drug A, and layer 2 contains drug B. (2) Layer 1 contains drug A, and layer 2 contains drug A and B. (3) Layer 1 contains drugs A and B, and layer 2 contains drugs A and C. (4) Layer 1 contains drugs A and B, and layer 2 contains drugs C and D.

The biologically non-degradable hydrophobic polymer material is not limited as long as it is biocompatible. Silicones are preferred in view of ease of molding, including for example, Silastic ™ Q7-4750 medical grade ETR elastomer or Dow Corning ™ medical grade elastomer MDX-4-4210. The other materials included are ethylene-vinyl acetate copolymers, polyurethanes, polyethylenes, polytetrafluoroethylenes, polypropylenes, polyacrylates, polymethacrylates, etc. Any water soluble drug can be used in the present invention as long as it is soluble in water, and there is no restriction in terms of molecular weight and so on. Drugs are exemplified by, but not limited to, cytokines such as interferons in interleukins; hematopoietic factors such as colony stimulating factors and erythropoietin; hormones such as growth hormone, growth hormone releasing factor, calcitonin, luteinizing hormone, luteinizing hormone-releasing hormone, and insulin; growth factors such as somatomedin, nerve growth factor, neurotrophic factors, fibroblast growth factor, and hepatocyte growth factor; cell adhesion factors; Immunosuppressants; enzymes such as asparaginase, superoxide dismutase, tissue plasminogen activating factor, urokinase, and prourokinase; blood coagulation factors such as blood coagulation factor VIII; proteins involved in the metabolism of bone tissue such as BMP (bone tissue morphogenetic protein); antigens that can be used in a vaccine for humans and / or animals; adjuvants; antigens for carcinoma; nucleic acids; antibodies; antitumor agents such as adriamycin, bleomycin, mitomycin etc .; antibiotics, anti-inflammatory agents, alkylating agents, and the like. The interferon used herein may be a-, β-, or any other interferon, or any combination thereof. The interleukin can also be IL-1, IL-2, and IL-3 or any other, and the colony stimulating factor can be multi-CSF (multipotential CSF), GM-CSF (CSF granulocyte-macrophage), G- CSF (CSF granulocyte), M-CSF (CSF macrophage), or any other. The antigens are exemplified by, but not limited to, toxoid, vaccine and live vaccines per se or a substance derived from them. A layer in which any of the drugs are dispersed homogeneously is located concentrically in the diametral direction in order to obtain a desired release. For example, a drug that is expected to be released at the early stage, must be located in an outer layer, and another, which is expected to produce a sustained release over a prolonged period, should be located much more in the inner layer. Particularly, when sustained release is expected over a prolonged period, the layer in which the drug is dispersed can be located within a layer consisting of a carrier material alone. A layer containing a biologically non-degradable hydrophobic polymer only prevents the infiltration of water and the release of a water soluble drug, and therefore in a layer that exists within it, the infiltration and release of the drug are restricted only in the axial end of the bar-shaped preparation, by means of which the drug will be released continuously at a constant rate over a long period, for the preparation of the present invention, an additive can be used for the purpose of stabilizing or controlling the release of a drug, if necessary. The additive is not critical as long as it is pharmaceutically acceptable, and includes, but is not limited to, salts such as sodium chloride and sodium citrate.; amino acids such as glycine, alanine and um glutamate; sugars such as lactose and mannitol; and proteins such as gelatin, collagen and albumin. The ratio of a drug and an additive dispersed in a vehicle in the total amount of a preparation is not critical as long as dispersion and molding are substantially possible, and preferably, the total amount of drug and additive is less than or equal to 50% by weight based on the weight of the preparation, preferably more than or equal to 5% and less or equal to 40% by weight, and still more preferable greater than or equal to 25% and less than or equal to 35% by weight. The amount of drug contained in the preparation, of course, can vary depending on the type of drug intended, a disorder to be treated, and so on. The preparation of the invention must be in the form of a bar, and comprise two or more layers in the cross section that is at right angles to the axis of the preparation. The layers are located concentrically in the diametral direction, and a type of drug and / or its content in each layer are different from each other. One embodiment of the invention is shown in Figure 1 which is a schematic view of an external appearance and cross section of the preparation of the invention. The size of the preparation of the invention varies depending on the animal to which it is to be administered or of a region of administration, and is preferably less than or equal to 10 mm in diameter and less than or equal to 50 mm in axial length, and still more preferable greater than or equal to 0.5 mm and less than or equal to 5 mm in diameter and greater than or equal to 3 mm and less than or equal to 35 mm in axial length. The thickness of each layer is determined depending on the amount of a drug to be transported or a desired period of sustained release. To prepare the preparation of the present invention, each layer must be prepared separately or simultaneously. For example, the innermost layer is molded into a bar-like shape, which is inserted into a bar-shaped mold with the same diameter as the outer diameter of the second layer by joining their centers. Then, a vehicle material containing a drug that will form the second layer is poured into a mold and cured. After curing, the mold is removed to obtain the preparation of the following invention. The preparation of the present invention can also be obtained by molding the first layer, which layer will be the innermost of the preparation, in a rod-like manner, molding the second layer in a tube-shaped hollow, and then combining the first layer. and the second layer. These methods are used for the preparation of a preparation wherein the first layer is an inner layer and the second layer is an outer layer. The repetition of the same procedures can give a preparation having multiple inner layers. In addition, the preparation of the present invention can also be obtained by extruding into each layer the vehicle material containing a drug, which is prepared separately, from a concentrically located nozzle. The method of the present invention is not limited to those methods. Although it is assumed that the release behavior of a drug present in an outer layer is similar to that of the preparation consisting of an individual layer in view of the mechanism for dissolving a drug and forming a channel as stated above, the behavior of Release of a drug present in an inner layer has not been clear yet. It has been found that in a preparation of the present invention multiple layers placed in the diametral direction of a rod-shaped preparation are comprised, wherein a water-soluble drug is dispersed in a carrier consisting of a biologically non-degradable hydrophobic polymer material. , the drug in the outer layer is released at a rapid rate in the early stage within a short period, and the drug present in the inner layer is released at a slower rate over a long period. When a layer consists solely of a biologically non-degradable hydrophobic polymer, in which the water and the drug are not permeable, there exists between an outer layer and an inner layer in which a water-soluble drug is dispersed, or between two inner layers in which a water-soluble drug is dispersed, the drug in the outer layer is rapidly released in a first-order manner, and the drug in the inner layer can be released slowly in a zero order manner over a long period. A bar-shaped preparation wherein two or more layers containing different concentrations of the same type of drug is located diametrally can freely provide a complex release behavior. The present preparation is useful for example for the treatment of cancer. Bleomycin prolongs the S phase and blocks the G2 phase in a cell cycle, and therefore, when bleomycin is administered to all the mitotic cells are synchronized to the G2 phase. Under this condition, the administration of mitomycin, which is highly sensitive to the G2 phase, makes it possible to kill more mitotic cells. The preparation of the present invention, which contains bleomycin in the outer layer and mitomycin in the inner layer rapidly releases bleomycin at an early stage by which the cells are synchronized, and then leads to the sustained release of mitomycin by which they annihilate the cells in the G2 phase, and therefore, it is expected that a cancer can be treated effectively by a single preparation. As another example of application, there is the treatment of fractures. The fibroblast growth factor (FGF) acts in a relatively early stage of a recovery procedure to promote cartilage proliferation, but shows a suppressive effect in the subsequent cartilage calcification procedure, and therefore, it is not desired that There is FGF in the fracture site for a long time. On the other hand, insulin-like growth factor-1 (IGF-1) has an effect of bone cell maturation. Therefore, the preparation of the present invention, which contains FGF in the outer layer and IGF-1 in the inner layer, rapidly releases FGF at the early stage to promote cartilage growth, and a cartilage cell matures by IGF. -1, so that such individual preparation allows predictably the provision of efficient treatment of a fracture. As another application example, the present invention is useful to be applied to a drug, which shows a therapeutic effect by down-regulation effect, such as LHRH agonist. Thus, the LHRH agonist, when administered in a high dose, causes suppression of sexual hormone secretion by down-regulating receptor, and thereafter, a suppressed sexual hormone secretion condition is maintained by continuous administration of the agonist. A treatment of prostate carcinoma, endometriosis, etc., has been carried out by the method. The preparation of the present invention consisting of the outermost layer containing LHRH agonist, an intermediate layer consisting of a single hydrophobic polymer material, biologically non-degradable, and an inner layer containing LHRH agonist, rapidly releases LHRH agonist into the outermost layer, whereas the LHRH agonist in the inner layer can be continuously released, which leads to the optimal drug release behavior for this treatment.

The preparation of the present invention can also be used as a vaccine. A recent study has reported that sustained release of an antigen substance using the DDS technique, leads to a more effective activation of the immune reaction, rather than a usual aqueous injectable solution. To further enhance the effect, an adjuvant can be combined. An adjuvant is a generic term, which shows a substance that acts to reinforce the immunogenicity of an antigen, while it does not have an antigenicity of its own. However, because an adjuvant can cause a strong inflammatory response in the injected region, it is undesirable to release the adjuvant over a long period, as is done with an antigenic substance. According to the present preparation, this can be controlled so that an adjuvant is released rapidly at an early stage and an antigen is released over a long period, which leads to the accumulation of immune cells in a specific region by the adjuvant, and delivery of the antigen substance to said region over a long period. Thus, an effective and safe vaccine preparation can be obtained.

EXAMPLES The present invention is illustrated by the following examples, but is not limited thereto.

EXAMPLE 1 g of an aqueous solution of ovalbumin (OVA) (100 mg / ml) was lyophilized. The lyophilized cake was milled under a nitrogen atmosphere to obtain powder 1. At 386.8 g of an aqueous solution of interferon (IFN) (114 MU / ml), 16.8 g of bovine serum albumin (BSA) were mixed, and the mixture was lyophilized. The lyophilized cake was milled under a nitrogen atmosphere to obtain powder 2. Separately, 1.05 g of component A and 1.05 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was rapidly kneaded with 0.90 g of the above powder 1, and a syringe was filled with this. In addition, 17.5 g of component A and 17.5 of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was quickly kneaded with 15.0 g of the above powder 2, and with this another syringe was filled. Each filled product thus obtained was extruded with pressure through a nozzle with 1.6 mm in diameter and a nozzle with 1.9 mm in diameter, which were located concentrically, so that the product containing OVA and the product containing IFN was They turned inside and outside respectively, and they were left to rest at 25 ° C for 3 days for their healing. This was cut to provide the preparation 1 of the present invention.

EXAMPLE 2 27. 06 g of an aqueous solution of avidin (5 mg / ml), 1.73 g of an aqueous solution of sodium citrate (250 mg / ml), and 5.74 g, of an aqueous solution of mannitol (150 mg / ml) were mixed , and the mixture was lyophilized. The lyophilized cake was milled under a nitrogen atmosphere to obtain powder 3. 57.45 g of an aqueous solution of IL-1β (2 mg / ml) and 10.49 g of an aqueous solution of sodium citrate (250 mg / ml), and 35.01 g of an aqueous solution of mannitol (150 mg / ml) were mixed, and the mixture was lyophilized. The lyophilized cake was milled under a nitrogen atmosphere to obtain powder 4. Separately, 1.05 g of component A and 1.05 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was rapidly kneaded with 0.90 g of the above powder 3, and a syringe was filled therewith. In addition, 8.4 of component A and 8.4 of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was rapidly kneaded with 7.20 g of the above powder 4, and with this another syringe was filled. Each filled product thus obtained was pressed with pressure through a nozzle with a diameter of 1.6 mm and a nozzle with a diameter of 1.9 mm, which were located concentrically, so that the product containing avidin and the product containing IL-1 ß they became internal and external respectively, and they were left to rest at 25 ° C for 3 days for their cure. This was cut to provide the preparation 2 of the present invention.

COMPARATIVE EXAMPLE 1 . 1 g of an aqueous solution of IFN (90 MU / ml), 47.2 g of an aqueous solution of human serum albumin (HSA) (78 mg / ml), 1.05 g of sodium glutamate, and 401.5 g of purified water are they mixed, and the mixture was spray dried. 1.8 g of component A and 1.8 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was quickly kneaded with 2.4 g of the above powder, and a syringe was filled therewith. In addition, 50 g of component A and 50 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed, and another syringe was filled. The filled product thus obtained was pressed through a nozzle with a diameter of 1.6 mm and a nozzle with a diameter of 1.9 mm, which were located concentrically, so that the Silastic containing drug and the Silastic only became interior and outside respectively, and they were left to rest at 37 ° C for a week for their cure. This was cut to provide comparative preparation 1.

COMPARATIVE EXAMPLE 2 To 1493.1 g of an aqueous solution containing at a concentration of 10.6 MU / ml of IFN and 10 mg / ml of HSA, 4.98 g of glycine were added, and the mixture was spray-dried. 0.9 g of component A and 0.9 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was quickly kneaded with 1.2 g of the above powder. With the obtained mixture, a syringe was filled, and pressure was extruded through a hole of 1.6 mm in diameter, and allowed to stand at 37 ° C for one week for its cure. This was cut to provide comparative preparation 2.

EXPERIMENT 1 A preparation of Example 1, which was cut to 1 cm in length, was placed in 2 ml of phosphate buffer (pH 7.4) containing 0.3% Tween 20 and 0.01% sodium azide and allowed to stand; from here, OVA and IFN released were determined by ELISA and RIA respectively, and then the cumulative released ratio was obtained. The results are shown in figure 2.

EXPERIMENT 2 A preparation of Example 2, which was cut to 1 cm in length, was placed in 2 ml of phosphate pH regulator (pH 7.4) containing 0. 3% Tween 20 and 0.01% sodium azide and allowed to stand; from here the liberated avidin and IL-β were determined by ELISA respectively, and then the cumulative released ratio was obtained. The results are shown in figure 3.

EXPERIMENT 3 A preparation of comparative example 1, which was cut to 1 cm in length, was placed in 2 ml of phosphate buffer (pH 7.4) containing 0.5% BSA and 0.01% sodium azide and allowed to stand; from here HSA and IFN released were determined by ELISA and RIA respectively, and then the cumulative released ratio was obtained. The results are shown in figure 4.

EXPERIMENT 4 A preparation of comparative example 2, which was cut to 1 cm in length, was placed in 10 ml of phosphate buffer (pH 7.4) containing 0.5% BSA and 0.01% sodium azide and allowed to stand; from here HSA and IFN released were determined by ELISA and RIA respectively, and then the cumulative released ratio was obtained. The results are shown in Figure 5. The preparation of the present invention allowed a separate control of the release behavior for IFN and OVA. Thus, the release of a drug present in the outer layer (IFN in Example 1 and IL-β in Example 2) concluded at an early stage, while a drug present in the inner layer ((OVA in Example 1 and avidin in Example 2) showed a sustained release during the period for determination (Figures 2 and 3) On the other hand, the preparations of Comparative Examples 1 and 2 released IFN and HSA in the same standard.

EXAMPLE 3 A mixture of OVA and Silastic ™, Silastic ™ alone, and a mixture of IFN, BSA and Silastic ™, obtained in Example 1, were extruded with a nozzle pressure of 5 mm outside diameter, which has a concentric structure, so that each of these ingredients formed the innermost layer, the middle layer and the outermost layer, which were allowed to stand at 25 ° C for 3 days for healing. This was cut to provide the preparation 3 of the present invention.

EXAMPLE 4 3. 62 g of an aqueous IFN solution (50 MU / ml), 1 g of HSA powder and 15.38 ml of purified water were mixed, and the mixture was lyophilized. The lyophilized cake was milled under a nitrogen atmosphere to obtain powder 5. 1. 05 g of component A and 1.05 g of component B of medical grade EPR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was rapidly kneaded with 0.90 g of powder 5. 56.0 ml of an aqueous solution of interferon (IFN) (50 MU / ml) and 1 g of HSA powder were mixed, and the mixture was lyophilized. The lyophilized cake was milled under a nitrogen atmosphere to obtain powder 6. 1.05 g of component A and 1.05 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was rapidly kneaded with 0.90 g of powder 6. 347 ml of an aqueous solution of interferon (IFN) (100 MU / ml and 0.6 g of HSA powder were mixed, and the mixture was lyophilized. lyophilized was milled to obtain powder 7. 0.35 g of component A and 0.35 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed in. After mixing, the mixture was rapidly kneaded with 0.30 g of the above powder 7 A mixture of powder 7 and Silastic ™, a mixture of powder 6 and Silastic ™ and a mixture of powder 5 and Silastic ™, were extruded with pressure through a nozzle of 2 mm outside diameter, which has a concentric structure , so that these ingredients formed the innermost layer, the middle layer and the outermost layer respectively, which were allowed to stand at 25 ° C for 3 days for their cure.This was cut to provide preparation 4 of the present invention .

EXAMPLE 5 ml of influenza A antigen (Chemicon, catalog No. AG-845), 1.87 g of an aqueous solution of sodium citrate (250 mg / ml), 6.22 g of aqueous solution of mannitol (150 mg / ml) and g of purified water were mixed, and the mixture was lyophilized. The lyophilized cake was milled under a nitrogen atmosphere to obtain powder 8. 29.63 g of an aqueous solution of IL-2 (1 mg / ml), 10.63 g of an aqueous solution of sodium citrate (250 mg / ml), 35.42 g of an aqueous solution of mannitol (150 mg / ml) and 110.45 g of purified water were mixed, and the mixture was lyophilized. The lyophilized cake was milled under a nitrogen atmosphere to obtain powder 9. 1.05 g of component A and 1.05 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the metal was quickly kneaded with 0.90 g of powder 8, and a syringe was filled with this. 8.4 g of component A and 8.4 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was quickly kneaded with 7.20 g of powder 9, and with this another syringe was filled. The filled products thus obtained were extruded with pressure through a 1.6 mm diameter nozzle and a 1.9 mm diameter nozzle, which were located concentrically, so that the product containing influenza and the product containing IL-2 They formed inner and outer layers respectively, which were left to rest at 25 ° C for 3 days for their healing. This was cut to provide the preparation 5 of the present invention.

EXAMPLE 6 Bleomycin chloride powder was milled under nitrogen atmosphere to obtain powder 10. Mitomycin C powder was milled under nitrogen atmosphere to obtain powder 11. 8.4 g of component A and 8.4 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was rapidly kneaded with 7.2 g of the above powder 10, and a syringe was filled therewith. Then 8.4 g of component A and 8.4 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was quickly kneaded with 7.2 g of powder 11, and with this another syringe was filled. The filled products thus obtained were extruded with pressure through a nozzle of 1.9 mm in diameter and a nozzle of 2.3 mm in diameter, which were located concentrically, so that the product containing mitomycin C and the product containing chloride of Bleomycin formed inner and outer layers respectively, which were left to stand at 25 ° C for 3 days for healing. This was cut to provide the preparation 6 of the present invention.

EXAMPLE 7 . 17 ml of insulin-like growth factor (IGF-1), 1.84 g of an aqueous solution of sodium citrate (250 mg / ml), 6.13 g of a . *, & Aqueous mannitol solution (150 mg / ml) and 25 g of purified water were mixed, and the mixture was lyophilized. The lyophilized cake was milled under a nitrogen atmosphere to obtain powder 35.90 mg of basic fibroblast growth factor (bFGF), 1.82 g of an aqueous solution of sodium citrate (250 mg / ml), 6.06 g of an aqueous solution of mannitol (150 mg / ml) and 24.67 g of purified water were mixed, and the mixture was lyophilized. The lyophilized cake was milled under a nitrogen atmosphere to obtain powder 13. 1.05 g of component A and 1.05 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was quickly kneaded with 0.90 g of the powder 12, and a syringe was filled with this. 1.05 g of component A and 1.05 g of component B of medical grade ETR elastomer Silastic ™ Q7-4750 were mixed. After mixing, the mixture was quickly kneaded with 0.90 g of powder 13, and this was filled with another syringe. The filled products thus obtained were extruded with pressure through a 1.6 mm diameter nozzle and a 1.9 mm diameter nozzle, which were disposed concentrically, so that the product containing IGF-1 and the product containing bFGF They formed inner and outer layers respectively, which were left to rest at 25 ° C for 3 days for their healing. This was cut to provide the preparation 7 of the present invention.

Claims (6)

NOVELTY OF THE INVENTION CLAIMS

1. - A preparation that includes an outer layer, wherein a soluble drug with water is dispersed in a vehicle that includes a biologically non-degradable hydrophobic polymer material, and one or more internal layers in which a water-soluble drug, which is different or different in concentration to the drug contained in the outer layer, it is dispersed in a vehicle which includes a biologically non-degradable hydrophobic polymer material, and in which the inner and outer layers are concentrically located in the diametral direction of a bar-shaped preparation , and both or one of the sides in axial direction are opened so that they come into direct contact with the environment.

2. A preparation according to claim 1, further characterized in that a layer consisting solely of biologically non-degradable hydrophobic polymer material, exists between the inner layer, in which a soluble drug with water is dispersed, and the outer layer , or between two inner layers in which a water-soluble drug is dispersed.

3. A preparation according to claim 1 or 2, further characterized in that each layer contains a different drug soluble with water.

4. - A preparation according to claim 1 or 2, further characterized in that each layer contains a different concentration of the same soluble drug with water.

5. A preparation according to any of claims 1-4, further characterized in that at least one of the outer or inner layers contains two or more drugs.

6. A preparation according to any of claims 1-5, further characterized in that the biologically non-degradable hydrophobic polymer material is silicone.