JPH06321803A - Sustained-release formulation of water-soluble peptide hormone - Google Patents

Abstract

(57) [Summary] (Modified) [Purpose] To provide a sustained-release pharmaceutical preparation for the purpose of reducing the required administration frequency of water-soluble peptide hormones. [Structure] A tubular member having at least one open end having an outer diameter of 10 mm or less, which is composed of an essentially water-insoluble biodegradable polymer, and a water-soluble bioactive substance located in the tubular member. Immersion-type sustained-release preparation comprising a core material containing a peptide hormone. [Effect] 1 The encapsulated drug can be gradually released over a long period of time, for example, from several days to about one month. (2) The material used for the tubular member is biocompatible and biodegradable, and the tubular member is gradually decomposed and metabolized after the completion of drug release, so that an excision operation is unnecessary. 3. The mechanism of sustained release of the water-soluble peptide hormone is dominated by the wetting of the external body fluid from the open end of the tubular member made of the biodegradable polymer and the diffusion rate of the drug inside. It can be adjusted by the shape of the member, the type of polymer constituting the member, and the like.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a sustained-release preparation of a water-soluble peptide hormone. More specifically, the present invention aims to reduce the required number of administrations of a water-soluble peptide hormone, and the drug is placed in a tubular member composed of an essentially water-insoluble biodegradable polymer. Type sustained-release preparation.

[0002]

2. Description of the Related Art Recently, due to the development of genetic engineering, it has become possible to stably supply a large amount of peptide hormones which are present in the living body in a very small amount by using a cell culture method. With such technological development, clinical application of this kind of peptide hormone has progressed, and it has come into practical use in the prevention and treatment of various diseases.

Such a peptide hormone generally has a problem that its half-life is short when administered in vivo. In many cases, continuous administration or continuous administration is required to obtain a sufficient effect. However, in the case of treatments that may extend over a long period of time, frequent drug administration causes physical and psychological distress to the patient, and thus it is desired to reduce the required administration frequency.

[0004] In recent years, home medical care has been advanced and attempts have been made to adapt it in terms of drug administration method. Above all, the construction of a system for safely receiving medical treatment at home has attracted the most attention. Against this background, sustained-release preparations are an area of active development, and early establishment of clinically applicable preparation methods is desired.

However, in the conventional techniques, there are few cases where they are actually used clinically effectively except for special ones.
First of all, these peptide hormones are generally water soluble,
Simply mixing with fats and oils or sparingly soluble substances to control the dissolution rate, or by administering together with a protease inhibitor that has the function of preventing the decomposition of water-soluble peptide hormones, is sufficient No release effect can be obtained. Attempts have been made to obtain a sustained release effect by dispersing peptide hormones in a hydrophobic polymer matrix, but water-soluble peptide hormones have an affinity even when mixed with hydrophobic polymers in organic solvents. However, the sustained release effect has not been obtained yet. The high physiological activity of such peptide hormones and the small amount administered per unit time also make the solution difficult.

JP-A-57-118512 and JP-A-62-20
1861 and Hei 1-155942 disclose a microcapsule obtained from a biodegradable polymer containing a peptide hormone, a sustained release preparation that can be administered by injection, and a method for producing the same. These disclose that a peptide hormone is dispersed in a biodegradable polymer dissolved in an organic solvent, and then the solvent is volatilized and removed to form microcapsules. A sustained-release preparation of LHRH was prepared by this method, and a sustained effect of about 1 month was obtained in a subcutaneous administration animal test.

However, there are various problems in applying such a technique to other peptide hormones.
First, peptide hormones generally have poor stability, and their activity is often lost simply by dispersing them in a polymer matrix. As a cause of such inactivation, when a physiologically active peptide hormone is dispersed in a polymer previously dispersed in an organic solvent, it may be inactivated by contact with the organic solvent at the interface. Further, the activity may be reduced by contact with the surface of the polymer itself. Furthermore, the organic solvent used in the process of preparing such a sustained-release preparation remains in the preparation, and the safety associated with ingestion becomes a problem.

Japanese Unexamined Patent Publication (Kokai) No. 60-185711 discloses a depression-type sustained-release preparation using a cellulose derivative as a base for osmotic delivery and having a function of gradually releasing a drug in a compartment inside the preparation. There is. In this formulation, the drug in solution is injected into the compartment and gradually released from there by utilizing the osmotic pressure difference. However, since the cellulose derivative is not biodegradable, excision operation is required after completion of the release, and its clinical application is difficult.

In Japanese Patent Laid-Open No. 63-239212, a drug-containing layer is provided in the center and a solid layer for releasing the drug in a pulsed and continuous manner is provided, and the periphery thereof is coated with silicon to control the drug release. It discloses possible formulation techniques. However, in this case, it is necessary to perform an excision operation of silicon after the administration is completed and the release is completed.

Japanese Patent Publication No. 3-72046 discloses a pellet-type sustained-release preparation in which a biodegradable polymer having low antigenicity such as atelocollagen is used and a drug is dry-molded with the biodegradable polymer. When this was administered in vivo, the drug was released with dissolution of the biodegradable polymer, and a sustained release effect for about 2 days was obtained.

As described above, although many researches have been made up to now and various proposals have been made, a technique which has been satisfied with all points such as safety, practicality and degree of sustained release effect and has been clinically applied has been proposed. rare.

[0012]

In view of the above problems, an object of the present invention is to obtain a water-soluble peptide hormone having a physiological activity in a tubular member composed of a biodegradable polymer. It is intended to provide an embedding type sustained-release preparation capable of sustained-release over a long period of time. In the manufacturing process of such a preparation, it is not always necessary to use an organic solvent or the like, and since the drug to be formulated is not exposed to the environment of high temperature and high pressure, a sustained release preparation with no problems in stability and safety can be obtained. Can be expected.

[0013]

As a result of repeated studies to achieve the above object, the present inventors have found that a water-soluble peptide hormone having physiological activity is mixed with an excipient such as gelatin or hyaluronic acid. In addition, a sustained-release pharmaceutical preparation containing a biodegradable biodegradable polymer, which is essentially water-insoluble, is filled in a tubular member having an outer diameter of 1 mm or less and having at least one open end. did. When such a preparation is infused and administered to a mammalian patient, the external body fluid wets only from the open end, and the release of the dissolved contents is limited to this site. Dissolution of the peptide hormone is delayed and the desired sustained release effect is obtained. The tubular member that remains after the drug is released is gradually decomposed and metabolized, so that an excision operation is unnecessary. Further, the embedding-type sustained-release preparation of the present invention comprises a tubular member on which a core substance containing a water-soluble peptide hormone is to be placed, the thickness, length, treatment of both ends (presence or absence of sealed ends), The sustained release effect can be controlled by appropriately selecting the type and molecular weight of the essentially water-insoluble biodegradable polymer that constitutes the tubular member. Furthermore, in the standard method for producing a sustained-release preparation according to the present invention, the essentially water-insoluble biodegradable polymer and the core substance containing the water-soluble peptide hormone are separately prepared. Therefore, in the conventional formulation technology, the peptide hormone is not subjected to the high temperature / high pressure treatment required at the time of molding, and there is no fear of inactivation. In addition, it can be produced without using an organic solvent or the like, and it is easy to ensure safety when administered in vivo.

Specific examples of the water-soluble peptide hormone formulated according to the present invention include erythropoietin (Japanese Patent Publication No. 2-17156) and G-CSF (Japanese Patent Publication No. 31433).
7) and its derivatives (eg nartograstim), calcitonin (salmon, eel or human), human insulin,
Oxytocin, interferon (α, β or γ), interleukin (I, II, III, IV, V or VI), vasopressin and its derivatives (eg desmopressin), thyroid stimulating hormone (TRH), parathyroid stimulating hormone (PTH). ) And the like.

These water-soluble peptide hormones are once prepared as an aqueous solution, dried and solidified under normal pressure or reduced pressure conditions, and molded into a core substance. At this time, in order to uniformly mix a trace amount of the active ingredient, and for the purpose of further stabilizing the water-soluble peptide hormone and improving the moldability, an appropriate excipient is added to the water-soluble peptide hormone solution and they are added together. It is desirable to solidify. Excipients used here include gelatin, albumin, collagen, fibrin, chondroitin sulfate, hyaluronic acid, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, dextrin, dextran, alginic acid and the like. One kind or two or more kinds of these excipients are used, and the addition amount thereof is in the range of 1 part to 5000 parts with respect to 1 part of the water-soluble peptide hormone.

The core material containing the dried and solidified water-soluble peptide hormone is placed in a tubular member composed of an essentially water-insoluble biodegradable polymer that has been previously melt-compressed and compression-molded. . The shape and size of the core material, and the shape, wall thickness and size of the tubular member differ depending on the administration route. Good, that is, outer diameter 0.5 to
1mm is suitable, and the length is 0.5-2.0cm
It is preferable to cut it to some extent before use. The cross section is usually circular, but it is not always necessary. The outer diameter in the case of non-circular cross section is based on the maximum value. By adopting such a specific form, administration of the impregnated sustained release preparation of the present invention to a living body is significantly simplified. Also, when intraperitoneal administration is performed, a formulation having the same outer diameter and similar length can be used.

The essentially water-insoluble biodegradable polymer used in the present invention is desired to be nontoxic in itself or its metabolites in vivo. Specifically, one or more kinds of polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polymalic acid, polycarbonate and the like, or a copolymer composed of two or more kinds of the above components is used. The weight average molecular weight of these polymers is usually 100 although it depends on the setting conditions of the sustained effect of the sustained-release preparation.
The range is from 00 to 200,000, preferably from 20,000 to 150,000. Among them, polylactic acid / polyglycolic acid copolymer, especially the copolymerization ratio is 50: 5.
0 to 85:15 is preferable.

When the core material is placed on the tubular member, a filler such as lipid is preferably used in order to fill the space between the inner wall of the tubular portion and the core material and to improve the sliding during placement. used. Specifically, lecithin, paraffin, white shellac, Bee wax, stearic acid, stearyl alcohol, polyoxyethylene hydrogenated castor oil, hydrogenated castor oil, palmitic acid, lauric acid, cholesterol, polyethylene glycol 4000, low molecular weight polylactic acid / polylactic acid. A glycolic acid copolymer or the like is considered.

The means for disposing the core member in the tubular member is not particularly limited. As shown in each example, a separately prepared core material is inserted into a tubular member of appropriate length with one end sealed (possibly with the help of a filler), and the other end is left open. Is typical. However, it is also possible to carry out core-sheath composite spinning of both components that constitute the tubular member and the core material, and cut the obtained yarn into an appropriate length. According to the latter method, the productivity in mass production is high, and the thickness can be easily adjusted by incorporating a draft or stretching operation.

The impregnated sustained-release preparation according to the present invention has the following features, for example.

(1) It has a size and shape capable of passing through an injection needle, and is convenient for administration into a living body.

(2) The encapsulated drug can be sustainedly released over a long period of time, for example, from several days to about one month.

(3) A highly active water-soluble peptide hormone that is administered in a trace amount can be uniformly mixed and released.

(4) An organic solvent or the like is not used in the production process, and the water-soluble peptide hormone can be produced without giving a physical impact.

(5) The material used for the tubular member is biocompatible and biodegradable. Both itself and its metabolites are harmless to the human body and are safe.

(6) It is not a preparation effective only for a special peptide hormone, but can be applied to all water-soluble peptide hormones, and exhibits a desired desired sustained release function.

(7) The mechanism of sustained release of the water-soluble peptide hormone is dominated by the wetting of the external body fluid from the open end of the tubular member made of the biodegradable polymer and the drug diffusion rate inside. The speed is adjusted by the shape of the member, the type of the polymer constituting the member, and the like.

[0028]

【Example】

Example 1 5 mg of freeze-dried G-CSF was dissolved in 500 μg of distilled water. To this, 495 mg of low-molecular gelatin (Type B manufactured by Nippi) was added and dissolved. This mixed solution was injection molded through a small hole having a diameter of about 0.3 mm in a low temperature chamber at 4 ° C. Furthermore, this was dried at room temperature overnight to obtain G-C.
An SF-containing gelatin core material was prepared. Dried G-CS
The F-containing gelatin core material was cut to a weight of 2 mg before use.

A biodegradable polymer having an average molecular weight of about 53000, which is a polylactic acid / polyglycolic acid copolymer and has a molecular ratio of polylactic acid to polyglycolic acid of 50:50,
It was placed in a metal tube having an inner diameter of about 1.0 mm and a length of about 1.5 cm, and heated on a hot plate to melt. A stainless needle having a diameter of about 0.5 mm was inserted into this and cooled and solidified as it was. After cooling, the stainless needle was removed and the tubular member was taken out of the metal tube. The obtained member had a tubular shape with one end closed, and was used by cutting it so that the length of the internal cavity was 1 cm.

This member was filled with 1 mg of egg yolk-derived lecithin as a filler. Furthermore, G- that was created earlier
A CSF-containing gelatin core material (2 mg) was inserted to give a filling-type sustained-release preparation.

Example 2 A G-CSF-containing gelatin core material was prepared in the same manner as in Example 1. On the other hand, a cylindrical member was prepared in the same manner as in Example 1 using a polymer having a molecular ratio of polylactic acid and polyglycolic acid of 85:15 and an average molecular weight of 86000. This member was first filled with lecithin in the same manner as in Example 1, and then 2 mg of a gelatin core material containing G-CSF was inserted to give a filled-in type sustained release preparation.

Example 3 A G-CSF-containing gelatin core material and a tubular member were prepared in the same manner as in Example 2. Polyoxyethylene hydrogenated castor oil was hot melted and filled into this tubular member. 2m to this
g of a G-CSF-containing gelatin core material was inserted to give a filled-in type sustained-release preparation.

Example 4 A G-CSF-containing gelatin core material and a tubular member were prepared in the same manner as in Example 2. This tubular member was first filled with a polylactic acid / polyglycolic acid copolymer having a molecular ratio of 50:50 and an average molecular weight of about 1000. 2m to this
g of a G-CSF-containing gelatin core material was inserted to give a filled-in type sustained-release preparation.

Example 5 10 mg of a freeze-dried product of erythropoietin was dissolved in 500 μl of distilled water. To this, 490 mg of low-molecular gelatin (Type B, manufactured by Nippi) was added and dissolved. In a low temperature room at 4 ° C., a small hole having a diameter of about 0.3 mm was used in Example 1.
Injection molding was performed in the same manner as in 1. and dried overnight at room temperature to prepare a gelatin core material containing erythropoietin. 1 mg of the gelatin core material containing erythropoietin was cut out, and this was inserted into the tubular member prepared in Example 2 using lecithin as a filler.

Example 6 An erythropoietin-containing gelatin core material was prepared in the same manner as in Example 5. Low molecular weight gelatin (Nippi,
This was carried out in Example 2 using a 50% aqueous solution of type B).
It was inserted into the tubular member prepared in. This was dried in a desiccator overnight at room temperature to give a fill-in type sustained release preparation.

Example 7 1 mg of a freeze-dried product of erythropoietin was dissolved in 3.0 ml of a 15% sodium hyaluronate aqueous solution. This mixed solution was injection-molded through a small hole having a diameter of 0.3 mm. This was dried at room temperature to prepare an erythropoietin-containing hyaluronic acid core material. After drying, one piece was cut into 1 mg to obtain a core material.

In the same manner as in Example 1, a biodegradable polymer of polylactic acid / polyglycolic acid copolymer having a molecular ratio of 85:15 and a molecular weight of 86000 was melted by heat. The melted polymer was filled in a metallic tube having an inner diameter of about 0.8 mm and a length of 1.5 cm, and a stainless needle having a diameter of about 0.4 mm was inserted therein and cooled as it was. After cooling, the stainless needle was removed and the tubular member was taken out of the metal tube.

This member was filled with a 50% aqueous solution of low-molecular gelatin (type B, manufactured by Nippi Co.) as a filler, the hyaluronic acid core material prepared above was inserted, and the mixture was dried overnight in a desiccator at room temperature. A sustained release type sustained release preparation was obtained.

Example 8 An erythropoietin-containing hyaluronic acid core material was prepared in the same manner as in Example 7. A biodegradable polymer with a ratio of polylactic acid to polyglycolic acid of 65:35 and an average molecular weight of about 1
A cylindrical member made from 100,000 is used as a filler.
A hyaluronic acid core was inserted using 0% polyethylene glycol (molecular weight about 4000). This was dried in a desiccator at room temperature overnight to obtain a filled-in type sustained release preparation.

Example 9 Synthetic freeze-dried salmon calcitonin (200 μg)
It was dissolved in μl of distilled water. 80m low molecular weight gelatin
g was added and dissolved. Injection molding was carried out in a low temperature chamber in the same manner as in Example 1 to prepare a salmon calcitonin-containing gelatin core material. A cylindrical member prepared in the same manner as in Example 2 was filled with lecithin in advance, and a salmon calcitonin-containing gelatin core material cut into 1 mg was inserted thereinto.

Example 10 Human-derived interferon-α 400 μg of lyophilized product
Was dissolved in 120 μl of distilled water. To this, 120 mg of low molecular weight gelatin was added and dissolved. In the same manner as in Example 1, injection molding was performed in a low temperature chamber and drying was performed to prepare an interferon-α-containing gelatin core material. First, a cylindrical member prepared in the same manner as in Example 2 was filled with a polylactic acid / polyglycolic acid copolymer having a molecular ratio of 50:50 and an average molecular weight of about 1,000. Furthermore, the interferon-α containing gelatin core material cut into 1 mg was inserted into this,
An embedding type sustained release preparation was prepared.

Example 11 5 mg of lyophilized naltograstim was dissolved in 500 μl of distilled water. To this, 495 mg of low-molecular gelatin (Type B manufactured by Nippi) was added and dissolved. In the same manner as in Example 1, the material was molded into a core material by injection molding in a low temperature room. This was cut into a core material having a weight of 2 mg. The naltograstim-containing gelatin core material previously prepared by using lecithin as a filler was inserted into a cylindrical member made of the same polymer as that prepared in Example 7 to prepare an embedding-type sustained-release preparation. .

Experimental Example 1 The impregnated sustained-release preparation containing 20 μg of G-CSF obtained in Examples 1 and 2 was applied to the back of 11-week-old male Wistar Imamichi rat using a 17G-implanted needle. It was administered subcutaneously. After the administration, venous blood was collected from the jugular vein over time, and potassium cyanide was added to prepare a sample. This sample is an automatic hematology analyzer (Toa Medical Electronics,
The white blood cell count was measured using Sysmex F-300).

The white blood cell count in FIG. 1 was obtained by averaging the results obtained from 3 rats. In the control experiment, a gelatin core material containing 20 μg of G-CSF was administered.

Experimental Example 2 The impregnated sustained-release preparation containing 400 U of erythropoietin obtained in Example 7 was injected using an 18G injection needle.
It was subcutaneously administered to the back of 7-week-old male Wistar ST-SLC rats. After administration, venous blood was collected from the jugular vein over time, and the hematocrit value was measured using an automatic blood cell counter (Toa Medical Electronics, Sysmex E-2500). The specific activity of erythropoietin is 180,000 U /
Calculated as mg.

FIG. 2 shows the average of the results obtained from 3 rats. In the control experiment, 400 U of erythropoietin aqueous solution was similarly administered, and the effect was observed.

[Brief description of drawings]

FIG. 1 shows the use results of the impregnated sustained release preparation of the present invention containing G-CSF.

FIG. 2 shows the use results of the impregnated sustained release preparation of the present invention containing erythropoietin.

Continuation of the front page (51) Int.Cl. ⁵ Identification code Reference number within the agency FI Technical display area A61K 37/30 8314-4C 37/36 8314-4C 37/66 H 8314-4C 47/34 D 7433-4C 47 / 36 B 7433-4C 47/42 B 7433-4C

Claims (14)

[Claims] 1. A cylindrical member having at least one open end having an outer diameter of 1 mm or less, which is composed of an essentially water-insoluble biodegradable polymer, and a physiological activity located in the cylindrical member. Immersion type sustained release preparation comprising a core material containing a water-soluble peptide hormone. 2. The impregnated sustained-release preparation according to claim 1, wherein the water-soluble peptide hormone having physiological activity is further mixed with an excipient to form the core material. 3. The excipient is gelatin, albumin,
The infill-type sustained-release preparation according to claim 2, which is one or more selected from the group consisting of collagen, fibrin, hyaluronic acid, chondroitin sulfate, alginic acid, gum arabic, and dextrin. 4. The method of claim 3, wherein the excipient is gelatin.
The filling-type sustained-release preparation described. 5. The impregnated sustained-release preparation according to claim 2, wherein the excipient is present in an amount of 1 to 5000 times by weight with respect to the physiologically active water-soluble peptide hormone to form the core material. 6. The one end of the tubular member is sealed,
The impregnated sustained-release preparation according to claim 1, wherein the other end is open and the core material is exposed. 7. The impregnated sustained release preparation according to claim 1, wherein the tubular member is cut to a length of 2 cm or less. 8. The essentially water-insoluble biodegradable polymeric substance is one or more selected from the group consisting of polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polymalic acid and polycarbonate, Alternatively, the impregnated sustained release preparation according to claim 1, which is a copolymer composed of two or more kinds of the above components. 9. The essentially water-insoluble biodegradable polymeric substance has a weight average molecular weight of 10,000 to 200,000.
The impregnated sustained-release preparation according to claim 8, which is within the range. 10. The essentially water-insoluble biodegradable polymeric substance has a weight average molecular weight of 20,000 to 15,000.
The impregnated sustained release preparation according to claim 9, which is in the range of 0. 11. The impregnated sustained-release preparation according to claim 8, wherein the essentially water-insoluble biodegradable polymer substance is a polylactic acid / polyglycolic acid copolymer. 12. The impregnated sustained-release preparation according to claim 11, wherein the copolymerization ratio of the polylactic acid / polyglycolic acid copolymer is 50:50 to 85:15. 13. The impregnated sustained-release preparation according to claim 1, wherein a filler is further present in the tubular member. 14. The water-soluble peptide hormone having physiological activity is one or more selected from the group consisting of erythropoietin, G-CSF, insulin, calcitonin, growth hormone, interferon and interleukin. Item 10. The impregnated sustained release preparation according to Item 1.