NZ721455B2 - Pharmaceutical composition useful for adhesion prevention or hemostasis - Google Patents

Pharmaceutical composition useful for adhesion prevention or hemostasis

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Publication number
NZ721455B2
NZ721455B2 NZ721455A NZ72145512A NZ721455B2 NZ 721455 B2 NZ721455 B2 NZ 721455B2 NZ 721455 A NZ721455 A NZ 721455A NZ 72145512 A NZ72145512 A NZ 72145512A NZ 721455 B2 NZ721455 B2 NZ 721455B2
Authority
NZ
New Zealand
Prior art keywords
pharmaceutical composition
component
viscosity
adhesion
mpa
Prior art date
Application number
NZ721455A
Other versions
NZ721455A (en
Inventor
Tatsuru Fukuda
Hirofumi Tamura
Original Assignee
Otsuka Pharmaceutical Factory Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Otsuka Pharmaceutical Factory Inc filed Critical Otsuka Pharmaceutical Factory Inc
Publication of NZ721455A publication Critical patent/NZ721455A/en
Publication of NZ721455B2 publication Critical patent/NZ721455B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/732—Pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/734—Alginic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/112—Phosphorus-containing compounds, e.g. phosphates, phosphonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/21—Acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/02—Dextran; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/04—Alginic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides

Abstract

Disclosed is a solid pharmaceutical composition comprising: (A) a gelling agent such as sodium alginate; (B) a salt of a divalent metal such as calcium hydrogen phosphate dehydrate and at least one species of acid selected from the group consisting of organic acids and inorganic acids; and (C) polyethylene glycol. The composition offers high water solubility, provides a reasonable range of gelling speeds for gelling agents, and is useful as a medical material for preventing organ and tissue adhesion during surgery on intra-abdominal organs and on tendons, nerves, and joints. Also disclosed is the use of the composition as a hemostatic agent to prevent bleeding during surgery. thylene glycol. The composition offers high water solubility, provides a reasonable range of gelling speeds for gelling agents, and is useful as a medical material for preventing organ and tissue adhesion during surgery on intra-abdominal organs and on tendons, nerves, and joints. Also disclosed is the use of the composition as a hemostatic agent to prevent bleeding during surgery.

Description

DESCRIPTION TITLE OF INVENTION PHARMACEUTICAL COMPOSITION USEFUL FOR PREVENTION OF ADHESION OR FOR HEMOSTASIS This application is a divisional application filed out New Zealand patent application 625851, filed 22 November 2012.
Technical Field
[0001] The present invention relates generally to a pharmaceutical composition effective as a biomedical material for prevention of adhesion or as a hemostatic agent.
Background Art
[0002] Conventionally, gelling agents such as alginates have been used in biomedical materials for use in adhesion prevention, hemostasis, and the like.
Adhesion refers to a state in which organs or tissues that are originally adjacent to, but separate from, each other show unity. Postoperative adhesion at a suture site is a type of artificially generated inflammatory adhesion, and is a complication that is highly likely to be brought about, to various degrees, by an operation. Although adhesion is not problematic when not showing any symptom, adhesion can sometimes cause, for example, stomachache, intestinal obstruction (ileus), and infertility, and therefore, various means have been taken so far to prevent adhesion. Heretofore, reported adhesion preventing biomedical materials that use a gelling agent include a cell blocking membrane containing calcium alginate as a main component (see Patent Literature 1), a composition containing a polysaccharide such as alginic acid, a carboxylic acid group-containing compound, and water (see Patent Literature 2), and the like. When such an adhesion preventing biomedical materials are used (during an operation), the adhesion preventing biomedical material is dissolved in water to allow the gelling agent to gelate, and once a suitable gel strength is reached, the adhesion preventing biomedical material is administered to the affected area.
Such adhesion preventing biomedical materials that use a gelling agent have various gelation rates depending on their compositions, and there are a variety of biomedical materials with which a contact surface promptly undergoes gelation when brought into contact with a gelation accelerator such as calcium and with which gelation takes a considerable amount of time.
Adhesion preventing biomedical materials are required to exhibit viscosity that is suitable for application to the affected area when used. An excessively high or excessively low gelation rate of a gelling agent results in poor handleability. Conventional adhesion preventing biomedical materials that use a gelling agent are problematic in that it is difficult to control the gelation rate and their handleability is poor. In particular, if alginic acid is used as a gelling agent, a motor that revolves at a considerable speed is necessary for dissolving alginic acid in water, and thus a dispersion medium such as ethanol is necessary.
On the other hand, as a biomedical material that takes advantage of a hemostatic action of a gelling agent, for example, a wound dressing in a sheet form or sponge form that contains alginate has been reported (see Patent Literature 3). However, with such a gelling agent-containing biomedical material formed into a sheet or sponge, the wound dressing that has been gelated in advance merely covers the surface of the injured site, and does not stop bleeding by undergoing gelation inside the injured site. Therefore, the hemostatic action is not sufficient.
With such conventional art as background, the development of a pharmaceutical composition that has excellent water solubility, contains a gelling agent having a suitable gelation rate, and is effective as an adhesion preventing biomedical material is desired. Moreover, the development of a pharmaceutical composition that has an excellent hemostatic effect due to a gelling agent is desired.
Citation List Patent Literature Patent Literature 1: JP 11-253547A Patent Literature 2: JP 2003-153999A Patent Literature 3: JP 7-136240A Summary of Invention Technical Problem An object of the present invention is to provide a pharmaceutical composition that has excellent water solubility, contains a gelling agent that has a gelation rate in suitable ranges, and is useful as an adhesion preventing biomedical material and/or to provide a pharmaceutical composition that can demonstrate an excellent hemostatic effect and/or to at least provide the public with a useful choice.
Solution to Problem As a result of having conducted diligent research to solve the foregoing problems, the inventors found that when a gelling agent, a divalent metal salt of an organic acid and/or inorganic acid, and polyethylene glycol are used in combination, a pharmaceutical composition exhibits excellent water solubility, undergoes gelation at a suitable gelation rate when brought into contact with water, and demonstrates properties suitable for an adhesion preventing biomedical material.
Moreover, the inventors found that, when applied in a powder form to an affected part that is accompanied by bleeding, the pharmaceutical composition in which the aforementioned components are used in combination gelates at the affected part and can effectively stop bleeding, and is thus effective as a hemostatic agent. Based on these findings, the inventors conducted further research and accomplished the present invention.
Summary of the Invention [0009a] A powdery pharmaceutical composition comprising (A) a gelling agent which is not in gelated state, (B) a salt of a divalent metal and at least one selected from the group consisting of organic acids and inorganic acids, and (C) polyethylene glycol. [0009b] Use of a powdery pharmaceutical composition comprising (A) a gelling agent which is not in gelated state, (B) a salt of a divalent metal and at least one selected from the group consisting of organic acids and inorganic acids, and (C) polyethylene glycol, for the manufacture of an adhesion preventing biomedical material. [0009c] Certain statements that appear below are broader than what appears in the statements of the invention above. These statements are provided in the interests of providing the reader with a better understanding of the invention and its practice.
The reader is directed to the accompanying claim set which defines the scope of the invention. [0009d] The claims which define the scope of this invention are set out on pages 57-59. Further embodiments described below as a set of numbered embodiments are provided in the interests of providing the reader with a better understanding of the invention and its practice, and are illustrative only.
[0010] That is, disclosed herein are the following embodiments: Item 1. A solid pharmaceutical composition containing (A) a gelling agent, (B) a salt of a divalent metal and at least one selected from the group consisting of organic acids and inorganic acids, and (C) polyethylene glycol.
Item 2. The pharmaceutical composition according to Item 1, further containing (D) an organic acid or an alkali metal salt thereof.
Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the ingredient (A) is alginic acid, a pharmaceutically acceptable alginic acid salt, or pectin.
Item 4. The pharmaceutical composition according to any of Items 1 to 3, wherein the divalent metal in the component (B) is calcium.
Item 5. The pharmaceutical composition according to any of Items 1 to 4, wherein the component (B) is at least one selected from the group consisting of dibasic calcium phosphate and calcium gluconate.
Item 6. The pharmaceutical composition according to any of Items 1 to 5, wherein the component (C) has an average molecular weight of about 1000 to about 20000.
Item 7. The pharmaceutical composition according to any of Items 1 to 6, wherein the component (C) is macrogol 4000.
Item 8. The pharmaceutical composition according to any of Items 1 to 7, wherein the component (D) is gluconic acid or glucono- δ-lactone.
Item 9. The pharmaceutical composition according to any of Items 1 to 8, containing 3 to 50 parts by weight of the component (D) relative to 1 part by weight of the component (B).
Item 10. The pharmaceutical composition according to any of Items 1 to 9, used as an adhesion preventing biomedical material.
Item 11. The pharmaceutical composition according to any of Items 1 to 9, used as a hemostatic agent.
Item 12. Use of a solid pharmaceutical composition containing (A) a gelling agent, (B) a salt of a divalent metal and at least one selected from the group consisting of organic acids and inorganic acids, and (C) polyethylene glycol, for the manufacture of an adhesion preventing biomedical material.
Item 13. Use of a solid pharmaceutical composition containing (A) a gelling agent, (B) a salt of a divalent metal and at least one selected from the group consisting of organic acids and inorganic acids, and (C) polyethylene glycol, for the manufacture of a hemostatic agent.
Item 14. An adhesion preventing method including the steps of preparing a solution by mixing an aqueous solvent with a solid pharmaceutical composition containing (A) a gelling agent, (B) a salt of a divalent metal and at least one selected from the group consisting of organic acids and inorganic acids, and (C) polyethylene glycol; and administering the solution to an affected part where adhesion prevention is required.
Item 15. A hemostatic method including the step of administering a solid pharmaceutical composition containing (A) a gelling agent, (B) a salt of a divalent metal and at least one selected from the group consisting of organic acids and inorganic acids, and (C) polyethylene glycol to an affected part where hemostasis is required.
Advantageous Effects of Invention According to the pharmaceutical composition of the present invention, the gelling agent has enhanced solubility, and a gelation reaction can be started while the pharmaceutical composition is in a uniformly dispersed state in a solvent such as water, thereby making it possible to prepare homogeneous gel without generating clumps. Moreover, when the pharmaceutical composition of the present invention is mixed with a solvent such as water, the gelling agent (hereinafter referred to as the component (A)) and a salt of a divalent metal and an organic acid and/or inorganic acid (hereinafter referred to as the component (B)) are uniformly dispersed in the solvent due to polyethylene glycol (hereinafter referred to as the component (C)), and the divalent metal is gradually released from the component (B), thus enabling gradual gelation. That is, with the pharmaceutical composition of the present invention, adjusting the proportion of the component (A) to the component (B) makes it possible to easily and suitably control the gelation rate. Also, with the pharmaceutical composition of the present invention, adjusting the proportion of the component (A) to the component (B) also makes it possible to control the gel strength so as to be a suitable range. Moreover, gel produced by mixing the pharmaceutical composition of the present invention with a solvent can effectively suppresses adhesion of body tissue such as the tendon, nerve, blood vessel, and organs; cerebral nervous system; and the like. As described above, the pharmaceutical composition of the present invention has excellent water solubility and allows the gelation rate of the gelling agent to be suitably adjusted, and therefore demonstrates excellent handleability in medical settings.
Moreover, the pharmaceutical composition demonstrates an excellent adhesion preventing effect on body tissue and is thus effective as an adhesion preventing biomedical material. In particular, the pharmaceutical composition of the present invention is effective as an adhesion preventing biomedical material in the orthopedics field for the tendon, nerve, blood vessel, and the like, and in the digestive surgery field for organs and the like.
In addition, when applied in a powder form to an affected part that is accompanied by bleeding, the pharmaceutical composition of the present invention can demonstrate an excellent hemostatic effect by forming gel at the bleeding site.
In particular, the pharmaceutical composition of the present invention can be applied in a powder form as-is and can thus be applied to and around the affected part where hemostasis is required regardless of the shape of the application site, and moreover, gel can form in a state of tightly adhering to the affected part, thus enabling efficient hemostasis.
Moreover, the pharmaceutical composition of the present invention becomes gel on the affected part to which it is applied, and remains on the affected part for a specific period of time.
Therefore, the pharmaceutical composition of the present invention if blended with a pharmaceutical agent allows the pharmaceutical agent to be gradually released at the affected part. Also, because the pharmaceutical composition of the present invention can be stored in a solid state, the pharmaceutical composition is thus unlikely to be affected by, for example, temperature, and exhibits excellent storage stability.
Brief Description of Drawings is a chart showing the results of measuring the range of motion of the deep digital flexor tendon (difference between bending angles before and after application of load) that is the operative site of each group in Test Example 8. is a photograph showing the operative site (deep digital flexor tendon) of a rat of the control group in Test Example 8. is a photograph showing the operative site (deep digital flexor tendon) of a rat of administration group 1 in Test Example 8. is a chart showing the results of evaluating the total adhesion score of each group in Test Example 9. is a photograph showing the clamped part of a rat over which the powdery pharmaceutical composition of Example has been spread in Test Example 10. is a photograph taken when the gelled pharmaceutical composition was removed minutes after spreading the powdery pharmaceutical composition in Test Example 10. is a photograph taken when sodium alginate power was spread over the clamped part of a rat in Test Example 10. is a chart showing the results of measuring the amount of bleeding in each group in Test Example 11.
Description of Embodiments
[0015] <Pharmaceutical composition> The pharmaceutical composition of the present invention is in a solid form and contains (A) a gelling agent, (B) a salt of a divalent metal and at least one selected from the group consisting of organic acids and inorganic acids, and (C) polyethylene glycol. Below, the pharmaceutical composition of the present invention will now be described in detail. Herein, the unit "w/v %" denotes g/100 mL.
Component (A) The gelling agent (component (A)) used in the present invention is not particularly limited, and is preferably biocompatible or bioabsorbable because it is applied to a living body. Examples include alginic acid, sodium alginate, potassium alginate, propylene glycol alginate, pectin, gellan gum, carrageenan, glucomannan, guar gum, locust bean gum, xanthan gum, glucose, carboxymethyl starch, mannose, galactose, arabinose, fucose, ribose, fructose, dextran, and the like.
Preferable examples include alginic acid, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, pectin, gellan gum, carrageenan, glucomannan, guar gum, and the like.
From the viewpoint of more effectively imparting an effect to control the gelation rate so as to be within suitable ranges and a hemostatic effect, among these gelling agents, alginic acid, pharmaceutically acceptable salts (for example, alkali metal salts) of alginic acid, alginic acid derivatives, and pectin are suitable. Specific examples of such suitable gelling agents include alginic acid, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, and pectin; more preferably, alginic acid, sodium alginate, calcium alginate, potassium alginate, sodium alginate, and pectin; and particularly preferably, sodium alginate.
[0018] Such sodium alginate is commercially available, and examples include Kimica Algin High G-series IL-6G (viscosity of 1 w/v% aqueous solution at 20°C = 50 to 80 mPa ∙s; weight average molecular weight of about 680,000), I-1G (viscosity of 1 w/v% aqueous solution at 20°C = 100 to 200 mPa ∙s; weight average molecular weight of about 720,000), I-3G (viscosity of 1 w/v% aqueous solution at 20°C = 300 to 400 mPa ∙s; weight average molecular weight of about 800,000), and the like; Kimica Algin I-series IL-6 (viscosity of 1 w/v% aqueous solution at 20°C = 50 to 80 mPa ∙s; weight average molecular weight of about 690,000), I-1 (viscosity of 1 w/v% aqueous solution at 20°C = 80 to 200 mPa ∙s; weight average molecular weight of about 860,000), I-3 (viscosity of 1 w/v% aqueous solution at 20°C = 300 to 400 mPa ∙s; weight average molecular weight of about 770,000), I-5 (viscosity of 1 w/v% aqueous solution at 20°C = 500 to 600 mPa ∙s; weight average molecular weight of about 800,000), I-8 (viscosity of 1 w/v% aqueous solution at 20°C = 800 to 900 mPa ∙s; weight average molecular weight of about 790,000), IL-1 (viscosity of 1 w/v% aqueous solution at 20°C = about 15 mPa ∙s; weight average molecular weight of about 260,000), IL-2 (viscosity of 1 w/v% aqueous solution at 20°C = 20 to 50 mPa ∙s; weight average molecular weight of about 580,000), and the like; Kimica Algin ULV-series ULV-5 (viscosity of 10 w/v% aqueous solution at 20°C = 500 to 600 mPa ∙s; viscosity of 1 w/v% aqueous solution at 20°C = about 4 mPa ∙s a; weight average molecular weight of about 80,000), ULV-10 (viscosity of 1 w/v% aqueous solution at 20°C = about 7 mPa ∙s; weight average molecular weight of about 90,000), ULV-20 (viscosity of 1 w/v% aqueous solution at 20°C = about 10 mPa ∙s; weight average molecular weight of about 200,000), and the like (all manufactured by Kimica Corporation). Preferable are I-1G, I-3G, I-1, IL-1, ULV-5, ULV-10, ULV-20, and the like.
[0019] These component (A) ingredents may be used singly or may be used as a combination of two or more.
When the weight average molecular weight of the gelling agent used as the component (A) is excessively high, the pharmaceutical composition of the present invention demonstrates a high viscosity and may not reach throughout the application site and, in addition, the pharmaceutical composition of the present invention may remain longer than the time needed for adhesion prevention or hemostasis. On the other hand, when the weight average molecular weight of the gelling agent used as the component (A) is excessively low, the pharmaceutical composition is unlikely to stay on the affected part. Accordingly, the weight average molecular weight of the gelling agent may be suitably set in consideration of the use, the application site, and the like of the pharmaceutical composition of the present invention.
For example, in the case where sodium alginate is used as a gelling agent and the pharmaceutical composition of the present invention is used as an adhesion preventing agent, in order to impart suitable retentivity on the affected part, it is preferable to use sodium alginate having a weight average molecular weight of 600000 or less, and in order to impart gel strength required for an adhesion preventing effect, it is preferable to use sodium alginate having a weight average molecular weight of 50000 or greater. In the case where sodium alginate is used as a gelling agent and the pharmaceutical composition of the present invention is used as an adhesion preventing agent, more preferably the weight average molecular weight of sodium alginate may be 80000 to 500000.
In the case where sodium alginate is used as a gelling agent and the pharmaceutical composition of the present invention is used as a hemostatic agent, in order to impart viscosity required for a hemostatic effect, it is preferable to use sodium alginate having a weight average molecular weight of 100000 or greater, and more preferably sodium alginate having a weight average molecular weight of 100,000 to 900,000.
Note that, in the case where two or more types of sodium alginate are used in combination, the aforementioned weight average molecular weight of sodium alginate refers to a value calculated from a mixture of the two or more types of sodium alginate.
The component (A) content of the pharmaceutical composition of the present invention may be, for example, 1 to 99 wt% relative to the total weight of the pharmaceutical composition. More specifically, in the case where the pharmaceutical composition is used as an adhesion preventing agent, from the viewpoint of the dispersibility of the component (A) throughout the pharmaceutical composition and the solubility thereof in a solvent, the content may be preferably 1 to 50 wt% and more preferably 5 to 25 wt%. In the case where the pharmaceutical composition is used as a hemostatic agent, the content may be preferably 40 to 99 wt% and more preferably 50 to 80 wt%.
Component (B) The salt of a divalent metal and an organic acid and/or inorganic acid used in the present invention (component (B)) is not particularly limited as long as it is pharmaceutically acceptable.
Examples of the acids that constitute the component (B) include organic acids such as gluconic acid, lactic acid, oxalic acid, citric acid, and acetic acid; and inorganic acids such as sulfuric acid, hydrochloric acid, phosphoric acid, and nitric acid.
Examples of the divalent metal that constitutes the component (B) include barium, magnesium, calcium, iron, and the like. Among these divalent metals, calcium is preferable.
Specific examples of the component (B) include calcium lactate, calcium gluconate, calcium sulfate, calcium citrate, dibasic calcium phosphate (calcium monohydrogen phosphate dihydrate), and the like. Among these components (B), from the viewpoint of more effectively imparting an effect to control the gelation rate so as to be within suitable ranges and a hemostatic effect, salts having low water solubility are suitable. Examples of salts having low water solubility include calcium sulfate, calcium citrate, calcium monohydrogen phosphate dihydrate, and calcium carbonate, and homogeneous gel can be produced using an ionization accelerator or retardant.
Herein, the term "low water solubility" covers the phrases "slightly soluble", "very slightly soluble", and "practically insoluble or insoluble" defined in The Japanese Pharmacopoeia 16th Edition. That is, the term means that 100 mL or more solvent is needed to dissolve 1 g of solute (component (B)).
Suitable examples of the component (B) include dibasic calcium phosphate, calcium monohydrogen phosphate dihydrate, and calcium carbonate.
These component (B) ingredients may be used singly or may be used as a combination of two or more.
The component (B) content of the pharmaceutical composition of the present invention is, for example, 0.1 to 50 wt% relative to the total weight of the pharmaceutical composition, preferably 1 to 20 wt%, and more preferably 1 to 10 wt%.
Regarding the pharmaceutical composition of the present invention, the proportion of the component (A) to the component (B) is not particularly limited. The higher the proportion of the component (B) to the component (A), the higher the gelation rate and the higher the gel strength. Therefore, in consideration of these behaviors, the proportion is suitably set according to the use, the application site, and the like of the pharmaceutical composition. For example, in the case where the pharmaceutical composition is used as an adhesion preventing agent, satisfying the proportion that no more than 1 part by weight of the component (B) is used per part by weight of the component (A) makes it possible to maintain low gel strength from mixing with an aqueous solvent until administration.
From the viewpoint of more effectively imparting an effect to control the gelation rate so as to be within suitable ranges, an adhesion preventing effect, and a hemostatic effect, it is desirable to satisfy that 0.01 to 1 part by weight, preferably 0.02 to 1 part by weight, and more preferably 0.03 to 0.3 parts by weight of the component (B) is used per part by weight of the component (A).
[0034] Component (C) Polyethylene glycol (PEG) (component (C)) used in the present invention is not particularly limited as long as it is pharmaceutically acceptable.
It is desirable that polyethylene glycol used in the present invention is solid at ordinary temperatures, and the average molecular weight thereof may be, for example, about 1000 or greater and preferably about 3000 or greater. Specifically, the average molecular weight may be about 1000 to about 20000 and preferably about 4000 to about 20000. Polyethylene glycol that has an average molecular weight of less than 1000 is not solid at ordinary temperatures, and polyethylene glycol that has an average molecular weight exceeding 20000 has large viscosity, thus making it difficult to handle such polyethylene glycol during production. Here, the average molecular weight of polyethylene glycol refers to a value measured according to the average molecular weight method for "macrogol 400" of The Japanese Pharmacopoeia 16th Edition.
Specific examples of the component (C) include macrogol 1000, macrogol 1500, macrogol 1540, macrogol 3000, macrogol 3350, macrogol 4000, macrogol 6000, macrogol 8000, macrogol 20000, and the like that are referred to in The Japanese Pharmacopoeia 16th Edition and referred to as pharmaceutical raw materials in Japanese Pharmaceutical Excipients. Among these, from the viewpoint of more effectively imparting an effect to control the gelation rate so as to be within suitable ranges and a hemostatic effect, macrogol 3350, macrogol 4000, macrogol 6000, and macrogol 20000 are preferable, and macrogol 3350 and macrogol 4000 are more preferable.
These component (C) ingredients may be used singly or may be used as a combination of two or more.
From the viewpoint of efficiently dispersing/dissolving other components (component (A) and component (B)) and allowing to react uniformly as well as from the viewpoint of more effectively imparting an effect to control the gelation rate so as to be within suitable ranges and a hemostatic effect by taking advantage of the dissolution rate of polyethylene glycol itself, it is desirable that the component (C) is contained in the pharmaceutical composition of the present invention in a form coating at least the component (A).
The component (C) content of the pharmaceutical composition of the present invention varies depending on the use of the pharmaceutical composition, and may be suitably set usually at a range of 1 to 99 wt% relative to the total weight of the pharmaceutical composition. More specifically, in the case where the pharmaceutical composition of the present invention is used as an adhesion preventing biomedical material, the component (C) content is preferably 20 to 99 wt% and more preferably 50 to 80 wt% relative to the total weight of the pharmaceutical composition. Also, in the case where the pharmaceutical composition of the present invention is used as a hemostatic agent, from the viewpoint of simultaneously achieving blood absorptivity and retentivity on the affected part to more effectively impart a hemostatic effect, the component (C) content is preferably 1 to 20 wt% and more preferably 1 to 10 wt% relative to the total weight of the pharmaceutical composition.
Component (D) Moreover, the pharmaceutical composition of the present invention may contain, in addition to the components (A) to (C), an organic acid or an alkali metal salt thereof (component (D)).
Containing the component (D) makes it possible to further enhance the effect to control the gelation rate so as to be within suitable ranges and the hemostatic effect.
The organic acid used in the present invention is not particularly limited, and examples include glucono- δ-lactone, gluconic acid, glucuronic acid, galacturonic acid, oxalic acid, citric acid, acetic acid, and the like. Examples of the organic acid salt include sodium salts, potassium salts, and the like.
Among these, from the viewpoint of more effectively imparting an effect to adjust the gelation rate so as to be within suitable ranges and a hemostatic effect to the pharmaceutical composition of the present invention, glucono- δ-lactone, gluconic acid, and alkali metal salts of gluconic acid are preferable, and sodium gluconate and glucono- δ-lactone are more preferable. Note that glucono- δ-lactone is a compound that is hydrolyzed to gluconic acid when brought into contact with water and shows acidity.
These component (D) ingredients may be used singly or may be used as a combination of two or more.
The component (D) content of the pharmaceutical composition of the present invention may be, for example, 1 to 60 wt% and preferably 2 to 50 wt% relative to the total weight of the pharmaceutical composition. More specifically, in the case where the pharmaceutical composition is used as an adhesion preventing agent, the component (D) content may be 3 to 15 wt%, and in the case where the pharmaceutical composition is used as a hemostatic agent, the component (D) content may be 15 to 40 wt%.
The proportion of blending the component (B) and the component (D) in the present invention is not particularly limited, and from the viewpoint of further enhancing the effect to adjust the gelation rate so as to be within to suitable ranges, the adhesion preventing effect, and the hemostatic effect, it is desirable to satisfy that 0.01 to 80 parts by weight, preferably 2 to 50 parts by weight, and more preferably 3 to parts by weight of the component (D) is used relative to 1 part by weight of the component (B). When the component (D) is less than 0.01 parts by weight relative to 1 parts by weight of the component (B), the gelation rate is low, and it is unlikely that the adhesion preventing effect and the hemostatic effect are demonstrated effectively, and when the component (D) exceeds 80 parts by weight, the gelation rate is excessively high, and handleability is likely to be impaired.
Other components The pharmaceutical composition of the present invention may contain, in addition to the aforementioned components, pharmacological components such as bactericidal agents, antibiotics, anti-inflammatory agents, blood circulation improving agents, steroids, enzyme inhibitors, growth factors, and various vitamins as necessary in order to, for example, promote the therapeutic effect and prevent bacterial infections.
Because the pharmaceutical composition of the present invention gelates on the affected part where the composition is applied and remains for a specific period of time, containing the aforementioned pharmacological components makes it possible to use the pharmaceutical composition of the present invention as a type of drug delivery system intended to gradually release the pharmacological components.
Moreover, the pharmaceutical composition of the present invention may contain additives such as excipients, binders, lubricants, pH adjusters, buffers, preservatives, antioxidants, coloring agents, and desiccants as necessary.
Gelation rate The components (A) to (C) and, as necessary, the component (D) are contained in the pharmaceutical composition of the present invention, thus making it possible to adjust the gelation rate so as to be within suitable ranges and also impart an excellent hemostatic effect. Here, the suitable gelation rate refers to a rate that can ensure a sufficient time until the pharmaceutical composition is applied to the affected part, and for example, under 25°C, ω = 3.142 rad/s, and f = 0.5000 Hz conditions in viscoelasticity measurement, the time until reaching a storage elastic modulus G' = a loss rigidity modulus G" may be 1 to 60 minutes, and preferably 3 to 40 minutes.
Measurements of the gelation rate can be carried out using a rheometer.
Form The form of the pharmaceutical composition disclosed herein is not particularly limited as long as the pharmaceutical composition is solid, and the pharmaceutical composition is preferably in a powder form. In the case where the pharmaceutical composition of the present invention is in a powder form, the particle size thereof is not particularly limited, and for example, the particle size measured by a sieving method may be about 200 to 2000 μm and preferably about 355 to 1000 μm.
[0049] Preparation method The pharmaceutical composition of the present invention is prepared by mixing the components (A) to (C) and, as necessary, the component (D) and other pharmacological components and additives and processing the mixture into a desired form. A suitable example of the preparation method of the pharmaceutical composition of the present invention may include the following steps: First step of dissolving the component (C); Second step of admixing the component (A) and the component (B) and, as necessary, the component (D) and other pharmacological components and additives to the solution of the component (C) obtained in the first step; and Third step of solidifying the mixture obtained in the second step and shaping it into a desired form.
[0050] The dissolution of the component (C) in the first step can be carried out by, for example, a method in which the component (C) is thermally dissolved or a method in which the component (C) is dissolved in a solvent. In the case where the component (C) is thermally dissolved, the temperature conditions are suitably set according to the type of the component (C) used, and for example, the temperature may be 50 to 90°C and preferably 60 to 80°C. In the case where the component (C) is dissolved in a solvent, for example, the component (C) may be mixed so as to attain about 5 to 20 wt% with a solvent such as 90 to 99 vol% aqueous ethanol. In the case where the pharmaceutical composition of the present invention is to have a relatively high component (C) content (for example, in the case where the pharmaceutical composition is to be used as an adhesion preventing biomedical material), the first step is preferably carried out by thermal dissolution, and in the case where the pharmaceutical composition of the present invention is to have a relatively low component (C) content (for example, when the pharmaceutical composition is to be used as a hemostatic agent), the first step is preferably carried out by dissolution in a solvent.
In the case where the component (C) is dissolved in a solvent in the first step, the solvent is removed during or after the mixing in the second step. Shaping the mixture into a desired form in the third step can be carried out with a known shaping method such as pulverization or granulation according to the intended shape.
[0052] Because the pharmaceutical composition of the present invention is applied to a living body, it is desirable to subject the pharmaceutical composition to a sterilization treatment.
The sterilizing method is not particularly limited, and examples include EOG sterilization, electron beam sterilization, γ ray sterilization, UV irradiation, and the like, and from the viewpoint of retaining the stability of the gelling agent, electron beam sterilization, EOG sterilization, and γ ray sterilization are preferable.
The pharmaceutical composition of the present invention can be used as an adhesion preventing biomedical material or a hemostatic agent.
In the case where the pharmaceutical composition of the present invention is used as an adhesion preventing biomedical material, the pharmaceutical composition is mixed with a suitable amount of aqueous solvent (such as water or physiological saline) to prepare a solution, and when the mixture exhibits a suitable viscosity, the mixture is administered to the affected part where adhesion prevention is required. Once administered to the affected part where adhesion prevention is required, the pharmaceutical composition of the present invention undergoes gelation on the affected part, and gel with a suitable strength that demonstrates an adhesion preventing function is formed. When a solution of the pharmaceutical composition of the present invention is prepared, the proportion of the aqueous solvent mixed is not particularly limited. For example, the aqueous solvent may be set at about 1 to 99 parts by weight and preferably about 3 to 90 parts by weight per part by weight of the pharmaceutical composition of the present invention. Also, a method for administering a solution of the pharmaceutical composition of the present invention to the affected part is not particularly limited, and the solution may be applied to the affected part using, for example, a syringe, brush, or the like. In the case where the pharmaceutical composition of the prevent invention is used as an adhesion preventing biomedical material, the pharmaceutical composition may be administered in an amount that is suitably set according to the condition of the affected part. For example, gel prepared from the pharmaceutical composition of the present invention may be administered in an amount in the range of about 0.005 to 0.1 g per cm of the affected part where adhesion prevention is required. In the case where the pharmaceutical composition is used as an adhesion preventing biomedical material, a site to which the pharmaceutical composition is applied is not particularly limited. The pharmaceutical composition is suitably used in the field of surgery on the intra-abdominal organs and the like and in the field of orthopedic surgery on the tendon, nerve, and joint.
In the case where the pharmaceutical composition of the present invention is used as a hemostatic agent, a solution in which the pharmaceutical composition is mixed with a suitable amount of water may be applied to the affected part where hemostasis is required or a paste that is formed by gelating the pharmaceutical composition may be applied to the affected part where hemostasis is required, and it is desirable to apply the pharmaceutical composition that is in a solid form as-is to the affected part where hemostasis is required. The pharmaceutical composition of the present invention when administered to the affected part undergoes gelation on the affected part and forms gel with a suitable strength that demonstrates a hemostatic function. Also, in the case where the pharmaceutical composition of the present invention that in a solid form is administered as-is, an aqueous solvent such as water or physiological saline may be spread over the pharmaceutical composition as necessary after the pharmaceutical composition is administered in order to facilitate the gelation of the pharmaceutical composition. A method for administering the pharmaceutical composition of the present invention that is in a solid form to the affected part is not particularly limited, and for example, the pharmaceutical composition of the present invention that has been granulated by spray drying or the like may be administered to the affected part by spreading or the like. In the case where the pharmaceutical composition of the prevent invention is used as a hemostatic agent, the pharmaceutical composition may be administered in an amount that is suitably set according to the condition of the affected part. For example, gel prepared from the pharmaceutical composition of the present invention may be administered in an amount in the range of about 0.01 to 0.1 g per cm of the affected part where hemostatis is required.
Examples The present invention shall be described in detail below by way of examples, but the present invention is not limited to the examples.
Test Example 1. Evaluation 1: Gelation rate of powdery pharmaceutical composition 1 Preparation Sodium alginate (types are indicated in Table 1, all manufactured by Kimica Corporation), calcium hydrogenphosphate dihydrate (manufactured by Wako Pure Chemical Industries, Ltd.), and glucono- δ-lactone (manufactured by Spectrum Chemical Mfg. Corp., USA) were added to macrogol 4000 (manufactured by Sanyo Chemical Industries, Ltd.) that had been dissolved at about 70°C, then sufficiently mixed using a stirring bar, and cooled naturally. Thereafter, the mixture was pulverized, and sifted with a No. 22 sieve defined by The Japanese Pharmacopoeia (a sieve mesh of 710 μm), thus giving a powdery pharmaceutical composition passed through the sieve. The amount of each component is as shown in Table 1 below.
[0057] Gelation rate measurement The gelation rate of the powdery pharmaceutical composition obtained above was measured. Specifically, 0.3 g of the powdery pharmaceutical composition was added to 3 mL of purified water and stirred for 30 sec, and 1 min after preparation, the gelation time was measured with a viscosity/viscoelasticity measuring apparatus (rheometer) (HAAKE MARS III: manufactured by Thermo Fisher Scientific Inc.) under 25°C conditions. Specific measurement conditions were as follows.
Temperature control unit: Peltier plate Measurement geometry: Parallel plate with 35 mm diameter Gap: 1 mm Sample amount: 1 mL Applied stress: 11.90 Pa Frequency: 0.5000 Hz Angular velocity: 3.142 rad/s
[0058] The point at which a storage elastic modulus G' and a loss rigidity modulus G" overlapped (crossover point) was regarded as a gel point, and the time until the gel point was reached was regarded as a gel time. Results are also shown in Table 1 below.
Table 1 Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Na alginate I-1G I-1G I-1G I-1G I-1G I-1 I-3G I-8 (upper row: type 、lower 10 15 20 25 5 5 5 row: content) 90 80 70 60 50 90 90 90 Macrogol 4000 Calcium hydrogenphosp 2.5 5 7.5 10 12.5 2.5 2.5 2.5 hate dihydrate Glucono- δ-lac 2.5 5 7.5 10 12.5 2.5 2.5 2.5 tone Gelation time (min) 6.475 5.341 2.882 2.012 <1 >10 4.066 4.631 Note 1: The unit of the content of each component is "wt%".
Note 2: In the table, Na alginate is as follows: I-1G denotes Kimica Algin High G-series I-1G having a viscosity of 100 to 200 mPa ∙s and weight average molecular weight of about 680,000, I-1 denotes Kimica Algin I-series I-1 having a viscosity of 80 to 200 mPa ∙s and weight average molecular weight of about 860,000, I-3G denotes Kimica Algin High G-series I-3G having a viscosity of 300 to 400 mPa ∙s and weight average molecular weight of about 800,000, and I-8 denotes Kimica Algin I-series I-8 having a viscosity of 800 to 900 mPa ∙s and weight average molecular weight of about 790,000. Here, viscosity refers to the viscosity of a 1 w/v% aqueous solution at 20°C.
It was confirmed that in Examples 1 to 8, the solubility in water was enhanced, thus making it possible to form homogeneous gel without generating clumps. On the other hand, a test carried out in the same manner using a pharmaceutical composition having the same composition as Example 1 except that macrogol 4000 was not blended showed that the pharmaceutical Component composition did not disperse in a uniform manner, forming clumps when the pharmaceutical composition was dissolved in water, and it was difficult to prepare homogeneous gel. Also, a test carried out in the same manner using a pharmaceutical composition having the same composition as Example 1 except that calcium hydrogenphosphate dihydrate was not blended showed that it was not possible to impart sufficient gel strength.
It was also confirmed from the results of Examples 1 to that the greater the macrogol 4000 content, the shorter the gelation time. Moreover, it was confirmed from the results of Examples 6 to 8 that the greater the viscosity of sodium alginate, the shorter the gelation time. Although the measured values of the gel strengths of the pharmaceutical compositions of Examples 5 to 8 are not shown, the gel strengths of the pharmaceutical compositions of Examples 1 to 8 (in particular, Examples 2 to 8) were in a range favorable to demonstrate an adhesion preventing effect.
It is clear from the results provided above that combining sodium alginate (a gelling agent), calcium hydrogenphosphate dihydrate (a salt of an acid and a divalent metal), and macrogol 4000 (polyethylene glycol) enhances the solubility of sodium alginate (a gelling agent) in water, thus allowing homogeneous gel to be prepared without generating clumps. Also, it is clear that suitably configuring the proportions of sodium alginate (a gelling agent), calcium hydrogenphosphate dihydrate (a salt of an acid and a divalent metal), and macrogol 4000 (polyethylene glycol) makes it possible to achieve a desired gelation rate. From these results, it was confirmed that the pharmaceutical compositions of Examples 1 to 8 had properties suitable as adhesion preventing biomedical materials.
[0063] Test Example 2. Evaluation 2: Gelation rate of powdery pharmaceutical composition Preparation Sodium alginate (Kimica Algin I-series IL-6, viscosity of 1 w/v% aqueous solution at 20°C = 50 to 80 mPa ∙s, weight average molecular weight of about 690,000, manufactured by Kimica Corporation), calcium hydrogenphosphate (manufactured by Wako Pure Chemical Industries, Ltd.), and glucono- δ-lactone (manufactured by Spectrum Chemical Mfg. Corp., USA) were added to macrogol 4000 (manufactured by Sanyo Chemical Industries, Ltd.) that had been dissolved at about 70°C, then sufficiently mixed using a stirring bar, and cooled naturally. Thereafter, the mixture was pulverized, and sifted with a No. 30 sieve defined by The Japanese Pharmacopoeia (a sieve mesh of 500 μm), thus giving a powdery pharmaceutical composition passed through the sieve. The amount of each component is as shown in Table 2 below.
Gelation rate measurement The gelation rate of the powdery pharmaceutical composition obtained above was measured. Specifically, 0.25 g of the powdery pharmaceutical composition was added to 5 mL of purified water and stirred for 10 sec, and 1 min after preparation, the gelation time was measured with a viscosity/viscoelasticity measuring apparatus (rheometer) (HAAKE MARS III: manufactured by Thermo Fisher Scientific Inc.) under 37°C conditions. Specific measurement conditions were as follows.
Temperature control unit: Peltier plate Measurement geometry: Parallel plate with 35 mm diameter Gap: 1 mm Sample amount: 1 mL Applied stress: 1 Pa Frequency: 0.5000 Hz Angular velocity: 3.142 rad/s The point at which G' and G" overlapped (crossover point) was regarded as a gel point, and the time until the gel point was reached was regarded as a gel time. The values of the storage elastic modulus (G') and the loss rigidity modulus (G") at the crossover point, the gelation time, the viscosity at the crossover point (| η*|) are also shown in Table 2.
Table 2 Example 9 10 11 12 13 14 15 Na alginate 5 10 15 20 25 30 50 1 2 3 4 5 6 10 hydrogenphosphate Glucono- δ-lactone 3 6 9 12 15 18 30 Macrogol 4000 91 82 73 64 55 46 10 84.89 72.26 38.58 25.12 16.68 12.91 7.25 Gelation time (min) G',G" (Pa) at crossover 0.195 0.865 1.228 2.356 4.175 4.195 12.53 point Viscosity | η*| (mPa ∙s) at 88 374 578 1038 1972 1906 5970 crossover point Note: The unit of the content of each component is "wt%".
It was confirmed from the results presented above that the larger the sodium alginate content, the shorter the gelation time and the higher the viscosity. That is, it is clear that adjusting the sodium alginate concentration makes it possible to control the gelation time and the gel strength attained after the pharmaceutical composition is brought into contact with water.
[0068] Test Example 3. Evaluation 3: Gelation rate of powdery pharmaceutical composition Preparation Sodium alginate (Kimica Algin I-series IL-1, viscosity of 1 w/v% aqueous solution at 20°C = about 15 mPa ∙s, weight average molecular weight of about 260,000, manufactured by Kimica Corporation), calcium hydrogenphosphate (manufactured by Wako Pure Chemical Industries, Ltd.), and glucono- δ-lactone Component (manufactured by Spectrum Chemical Mfg. Corp., USA) were added to macrogol 4000 (manufactured by Sanyo Chemical Industries, Ltd.) that had been dissolved at about 70°C, then sufficiently mixed using a stirring bar, and cooled naturally. Thereafter, the mixture was pulverized, and sifted with a No. 30 sieve defined by The Japanese Pharmacopoeia (a sieve mesh of 500 μm), thus giving a powdery pharmaceutical composition passed through the sieve. The amount of each component is as shown in Table 3 below.
[0069] Gelation rate measurement The gelation rate of the powdery pharmaceutical composition obtained above was measured. Specifically, the powdery pharmaceutical composition was added to purified water so as to attain the concentrations shown in Table 3 and then stirred for 10 sec, and 1 min after preparation, the gelation time was measured with a viscosity/viscoelasticity measuring apparatus (rheometer) (HAAKE MARS III: manufactured by Thermo Fisher Scientific Inc.) under 37°C conditions. Specific measurement conditions are the same as in Test Example 2. The obtained results are shown in Table 3.
Table 3 Ex. 16 Ex. 17 Ex. 18 Ex. 19 Ex. 20 Ex. 21 Ex. 22 Ex. 23 Ex. 24 Ex. 25 Ex. 26 Ex. 27 Na alginate 20 20 20 20 20 20 20 20 20 20 20 10 78.8 77.6 76 74 72 70 68 64 60 60 40 40 Macrogol 4000 Ca hydrogen- 0.2 0.4 0.67 1 1.3 1.7 2 4 6 10 20 40 phosphate Glucono- δ- 1 2 3.33 5 6.7 8.3 10 12 14 10 20 10 lactone Concentration in 20 20 10 10 10 10 10 10 10 10 10 purified water (g/100 mL) Gelation time 130.20 74.11 51.78 78.93 64.91 37.13 25.52 12.98 7.77 8.58 4.72 3.72 (min) G',G" (Pa) at 4.525 5.386 5.539 1.246 0.999 0.887 1.135 1.623 1.406 1.704 1.257 0.496 crossover point Viscosity | η*| (mPa ∙s) at 2024 2412 2510 562 450 402 505 724 619 752 557 222 crossover point Note: The unit of the content of each component is "wt%".
Component It was confirmed from the results presented above that the larger the proportion of calcium hydrogenphosphate to sodium alginate, the shorter the gelation time and the higher the viscosity. That is, it is clear that adjusting the proportion of sodium alginate to calcium hydrogenphosphate makes it possible to control the gelation time and the gel strength attained after the pharmaceutical composition is brought into contact with water.
Test Example 4. Evaluation 4: Gelation rate of powdery pharmaceutical composition Preparation Sodium alginate (Kimica Algin I-series IL-1, viscosity of 1 w/v% aqueous solution at 20°C = about 15 mPa ∙s, weight average molecular weight of about 260,000, manufactured by Kimica Corporation), calcium hydrogenphosphate (manufactured by Wako Pure Chemical Industries, Ltd.), and glucono- δ-lactone (manufactured by Spectrum Chemical Mfg. Corp., USA) were added to macrogol 4000 (manufactured by Sanyo Chemical Industries, Ltd.) that had been dissolved at about 70°C, then sufficiently mixed using a stirring bar, and cooled naturally. Thereafter, the mixture was pulverized, and sifted with a No. 30 sieve defined by The Japanese Pharmacopoeia (a sieve mesh of 500 μm), thus giving a powdery pharmaceutical composition passed through the sieve. The amount of each component is as shown in Table 4 below.
Gelation rate measurement The gelation rate of the powdery pharmaceutical composition obtained above was measured. Specifically, 1 g of the powdery pharmaceutical composition was added to 10 mL of purified water and stirred for 10 sec, and 1 min after preparation, the gelation time was measured with a viscosity/viscoelasticity measuring apparatus (rheometer) (HAAKE MARS III: manufactured by Thermo Fisher Scientific Inc.) under 37°C conditions. Specific measurement conditions are the same as in Test Example 2. The obtained results are shown in Table 4.
Table 4 Ex. 28 Ex. 29 Ex. 30 Ex. 31 Ex. 32 Ex. 33 Ex. 34 Ex. 35 Ex. 36 Ex. 37 Ex. 38 20 20 20 20 20 20 20 20 20 10 Na alginate 69.9 69.5 69 60 74 69 49 29 19 9 9 Macrogol 4000 10 10 10 1 1 1 1 1 1 1 hydrogenphosphate Glucono- δ-lactone 0.1 0.5 1 10 5 10 30 50 60 70 80 Ca hydrogenphosphate : 1 ：0.01 1 ：0.05 1 ：0.1 1 ：1 1 ：5 1 ：10 1 ：30 1 ：50 1 ：60 1 ：70 1 ：80 glucono- δ-lactone Na alginate : Ca 1 ：0.5 1 ：0.5 1 ：0.5 1 ：0.5 1 ：0.05 1 ：0.05 1 ：0.05 1 ：0.05 1 ：0.05 1 ：0.05 1 ：0.1 hydrogenphosphate Gelation time (min) 158.9 48.10 40.37 35.25 63.63 12.80 10.23 7.033 5.113 3.175 2.013 G',G" (Pa) at crossover 4.493 2.347 2.731 0.8822 1.311 1.607 1.010 0.8837 0.9616 1.595 1.304 point Viscosity | η*| (mPa ∙s) 2103 1034 1254 377.6 607.7 745.9 409.1 375.5 367.8 426.7 375.8 at crossover point Note: The unit of the content of each component is "wt%".
Component It was confirmed from the results presented above that the greater the proportion of glucono- δ-lactone to calcium hydrogenphosphate, the shorter the gelation time. That is, it is clear that adjusting the proportion of glucono- δ-lactone to calcium hydrogenphosphate makes it possible to control the gelation time attained after the pharmaceutical composition is brought into contact with water.
Test Example 5. Evaluation 5: Gelation rate of powdery pharmaceutical composition Preparation Sodium alginate, calcium hydrogenphosphate (manufactured by Wako Pure Chemical Industries, Ltd.), and glucono- δ-lactone (manufactured by Spectrum Chemical Mfg.
Corp., USA) were added to macrogol 4000 (manufactured by Sanyo Chemical Industries, Ltd.) that had been dissolved at about 70°C, then sufficiently mixed using a stirring bar, and cooled naturally. Thereafter, the mixture was pulverized, and sifted with a No. 30 sieve defined by The Japanese Pharmacopoeia (a sieve mesh of 500 μm), thus giving a powdery pharmaceutical composition passed through the sieve. The amount of each component is as shown in Tables 5 to 9 below. In Tables 5 to 9, the types of Na alginate are as follows.
A: a mixture of 90 parts by weight of Kimica Algin ULV-series ULV-5 (10 w/v% aqueous solution, viscosity of 500 to 600 mPa ∙s at 20°C, manufactured by Kimica Corporation) and 10 parts by weight of Kimica Algin I-series I-1 (viscosity of 1 w/v% aqueous solution at 20°C = 80 to 200 mPa ∙s, weight average molecular weight of about 860,000, manufactured by Kimica Corporation), B: ULV-10 (viscosity of 1 w/v% aqueous solution at 20°C = about 7 mPa ∙s, weight average molecular weight of about 90,000, manufactured by Kimica Corporation) C: ULV-20 (viscosity of 1 w/v% aqueous solution at 20°C = about mPa ∙s, weight average molecular weight of about 200,000, manufactured by Kimica Corporation) D: Kimica Algin High G-series IL-1 (viscosity of 1 w/v% aqueous solution at 20°C = about 15 mPa ∙s, weight average molecular weight of about 260,000, manufactured by Kimica Corporation) E: Kimica Algin I-series IL-6 (viscosity of 1 w/v% aqueous solution at 20°C = 50 to 80 mPa ∙s, weight average molecular weight of about 690,000, manufactured by Kimica Corporation) Gelation rate measurement The gelation rate of the powdery pharmaceutical composition obtained above was measured. Specifically, the powdery pharmaceutical composition was added to purified water so as to attain the concentrations shown in Tables 5 to 9 and then stirred for 10 sec, and 1 min after preparation, the gelation time was measured with a viscosity/viscoelasticity measuring apparatus (rheometer) (HAAKE MARS III: manufactured by Thermo Fisher Scientific Inc.) under 37°C conditions.
Moreover, the viscosity (| η*|) at the beginning of measurement was also measured. Specific measurement conditions are the same as in Test Example 2. The obtained results are shown in Table 5.
Table 5 Ex. 28 Ex. 29 Ex. 30 Ex. 31 Ex. 32 Ex. 33 Ex. 34 Type A B C D D E D alginate Content 20 20 20 20 20 20 20 68 68 68 68 64 64 68 Macrogol 4000 2 2 2 2 4 4 2 hydrogenphosphate Glucono- δ-lactone 10 10 10 10 12 12 10 Concentration in 10 25 10 25 10 25 10 25 10 10 purified water(g/100 Viscosity | η*| (mPa ∙s) at beginning of 15 22 160 22 140 28 298.4 42 1482 308.8 2 measurement Gelation time (min) 69.50 31.74 7.30 43.23 8.48 35.16 7.41 15.09 1.15 2.98 25.52 G',G" (Pa) at crossover 0.374 0.890 2.669 0.991 2.870 1.113 3.798 0.872 6.655 2.765 1.135 point Viscosity | η*| (mPa ∙s) 168 416 1212 428 1249 488 1653 383 2907 1250 505 at crossover point Note: The unit of the content of each component is "wt%".
Component Table 6 Ex. 35 Ex. 36 Ex. 37 Ex. 38 Type A A A A alginate 20 20 20 Content Macrogol 4000 68 70 72 74 Ca hydrogenphosphate 2 1.7 1.3 1 Glucono- δ-lactone 10 8.3 6.7 5 Concentration in purified 7 14 10 14 10 14 10 14 water(g/100 mL) Viscosity | η*| (mPa ∙s) at 46 25 44 24 37.28 25 42 beginning of measurement 43.52 10.24 29.37 13.4 41.49 26.02 63.51 47.54 Gelation time (min) G',G" (Pa) at crossover 0.7153 1.306 0.8877 1.193 0.8167 1.012 0.9244 1.021 point Viscosity | η*| (mPa ∙s) at 319.6 569 403.9 549.4 366.5 452.8 415.2 458.5 crossover point Note: The unit of the content of each component is "wt%".
Component Table 7 Ex. 39 Ex. 40 Ex. 41 Ex. 42 Type B B B B alginate 20 20 20 Content Macrogol 4000 68 70 72 74 Ca hydrogenphosphate 2 1.7 1.3 1 Glucono- δ-lactone 10 8.3 6.7 5 Concentration in purified 14 10 14 10 14 10 14 water(g/100 mL) Viscosity | η*| (mPa ∙s) at 22 37 18 33 18 33 20 34 beginning of measurement 43.23 20.96 48.97 22.55 63.01 43.18 78.47 65.72 Gelation time (min) G',G" (Pa) at crossover 0.991 1.22 0.9263 1.023 0.755 0.9921 0.864 1.01 point Viscosity | η*| (mPa ∙s) at 427.6 547.8 416.4 460 338.2 447.1 388.6 463 crossover point Note: The unit of the content of each component is "wt%".
Component Table 8 Ex. 43 Ex. 44 Ex. 45 Ex. 46 Type C C C C alginate 20 20 20 Content Macrogol 4000 68 70 72 74 Ca hydrogenphosphate 2 1.7 1.3 1 Glucono- δ-lactone 10 8.3 6.7 5 Concentration in purified 14 10 14 10 14 10 14 water(g/100 mL) Viscosity | η*| (mPa ∙s) at 28 43.89 19.01 45 23 42 25 46 beginning of measurement .16 23.44 48.96 27.3 59.11 37.75 76.87 60.86 Gelation time (min) G',G" (Pa) at crossover 1.113 1.205 0.9645 1.253 1.177 1.353 1.203 1.288 point Viscosity | η*| (mPa ∙s) at 487.6 530 434 557 534 606.9 542.5 582.4 crossover point Note: The unit of the content of each component is "wt%".
Component Table 9 Ex. 47 Ex. 48 Ex. 49 Ex. 50 type D D D D alginate 20 20 20 content Macrogol 4000 68 70 72 74 Ca hydrogenphosphate 2 1.7 1.3 1 Glucono- δ-lactone 10 8.3 6.7 5 Concentration in purified 14 10 14 10 14 10 14 water(g/100 mL) Viscosity | η*| (mPa ∙s) at 42 84 - - - - - - beginning of measurement .09 9.358 Gelation time (min) - - - - - - G',G" (Pa) at crossover 0.872 2.395 - - - - - - point Viscosity | η*| (mPa ∙s) at 383 1075 - - - - - - crossover point Note: The unit of the content of each component is "wt%".
Note: “-” denotes “not determined” Component The pharmaceutical compositions of Examples 28 to 50 all had gelling rates and gel strengths within suitable ranges and sufficiently satisfied properties required as adhesion preventing biomedical materials.
[0084] Test Example 6. Preparation of powdery pharmaceutical composition Preparation Sodium alginate (Kimica Algin High G-series I-1G, viscosity of 1 w/v% aqueous solution at 20°C = 100 to 200 mPa ∙s, weight average molecular weight of about 720,000, manufactured by Kimica Corporation), calcium hydrogenphosphate dihydrate (manufactured by Wako Pure Chemical Industries, Ltd.), and glucono- δ-lactone (manufactured by Spectrum Chemical Mfg.
Corp., USA) were sufficiently mixed with each other, then added to a 5 wt% solution of macrogol 4000 (water was used as a solvent), and kneaded using an agate mortar while being exposed to warm air, thus giving a mixture. Thereafter, the mixture was pulverized, and sifted with a No. 22 sieve defined by The Japanese Pharmacopoeia (a sieve mesh of 710 μm), thus giving a powdery pharmaceutical composition. The amount of each component is as shown in Table 10 below. These powdery pharmaceutical compositions had properties suitable as hemostatic agents.
Table 10 Ex. 51 Ex. 52 Ex. 53 Ex. 54 Ex. 55 Ex. 56 Ex. 57 Ex. 58 Ex. 59 Ex. 60 Ex. 61 Ex. 62 Na alginate 2 2 2 2 2 2 2 2 2 4 4 4 Macrogol 4000 0.25 0.5 1 0.25 0.5 1 0.1 0.2 0.5 0.2 0.3 0.4 hydrogenphosphate 0.8 0.8 0.8 0.4 0.4 0.4 0.2 0.2 0.2 0.2 0.2 0.2 dihydrate Glucono- δ-lactone 4 4 4 2 2 2 1 1 1 1 1 1 Total 7.05 7.3 7.8 4.65 4.9 5.4 3.3 3.4 3.7 5.4 5.5 5.6 Note: The unit of the content of each component is "g".
Test Example 7. Evaluation 6: Gelation rate of powdery pharmaceutical composition A powdery pharmaceutical composition was obtained in the same manner as in Test Example 5 except that pectin (SM-666 and Vistop D-1382, both manufactured by San-Ei Gen F.F.I., Inc.) was used in place of sodium alginate. The amount of each component is as shown in Table 11 below. The gelation rates were measured in the same manner as in Test Example 5 using the resulting powdery pharmaceutical compositions. Results are shown in Table 11 below.
Table 11 Ex. 63 Ex. 64 Type SM-666 Vistop® D-1382 Pectin Content 20 20 Component Calcium hydrogenphosphate 2 2 10 Glucono- δ-lactone 68 68 Macrogol 4000 Concentration in purified water(g/100 mL)10 10 Viscosity | η*| (mPa ∙s) at beginning of 9516 24 measurement Gelation time (min) 1.49 4.73 G',G" (Pa) at crossover point 3.900 3.096 Viscosity | η*| (mPa ∙s) at crossover point1727 1339 Note: The unit of the content of each component is "wt%".
The pharmaceutical compositions of Examples 63 and 64 both had gelling rates and gel strengths within suitable ranges and sufficiently satisfied properties required as adhesion preventing biomedical materials.
Test Example 8. Adhesion preventing effect 1: Tendon An adhesion preventing effect on the tendon was evaluated using male rats (Crlj:WI) (obtained from Charles River Laboratories Japan, Inc.). Specifically, first, the synovial tendon sheath in the plantar part of a rat was longitudinally incised, the deep digital flexor tendon was then exposed and cut to a halfway point so as to prepare a tendon-injured model rat. Next, the test substances shown in Table 12 were each administered in 50 μL amounts to the operative site where the tendon was cut to the halfway point and its surroundings. Then, in order to prevent the tendon that had been cut to the halfway point from rupturing caused by the rat's own movement, the sciatic nerve was cut to limit motility of the rat, and the rat was reared for 4 weeks. After 4 weeks, the foot of each rat was removed at the ankle so as to have only the long flexor muscle.
A 60 g load was applied to the long flexor muscle of the removed foot, and the angle of the metatarsophalangeal joint (MTP) and the angle of the proximal interphalangeal joint (PIP) of the second finger before and after the application of the load were measured. According to the expression below, the difference between the bending angles before and after the application of the load was calculated. For comparison, the difference between the bending angles of a normal finger in which the deep digital flexor tendon was not cut to a halfway point was also measured before and after the application of a load.
Expression 1 Difference between bending angles before and after application of load (°) = (Angle of MTP after application of load + angle of PIP after application of load) - (Angle of MTP before application of load + angle of PIP before application of load)
[0091] Table 12 Test substance Control group Physiological saline Administration The pharmaceutical composition of Example 28 was group 1 added to physiological saline so as to attain 10 g/100 mL and stirred for 10 seconds, and the solution within 1 minute from preparation was used for administration.
Administration The pharmaceutical composition of Example 28 was group 2 added to purified water so as to attain 25 g/100 mL and stirred for 10 seconds, and the solution within 1 minute from preparation was used for administration.
Administration The pharmaceutical composition of Example 34 was group 3 added to physiological saline so as to attain 10 g/100 mL and stirred for 10 seconds, and the solution within 1 minute from preparation was used for administration.
Administration The pharmaceutical composition of Example 22 was group 4 added to physiological saline so as to attain 10 g/100 mL and stirred for 10 seconds, and the solution within 1 minute from preparation was used for administration.
Administration The pharmaceutical composition of Example 23 was group 5 added to purified water so as to attain 25 g/100 mL and stirred for 10 seconds, and the solution within 1 minute from preparation was used for administration.
The obtained results are shown in It was confirmed from the results that administration groups 1 to 5 showed greater differences in values between the bending angles before and after the application of the load than that of the control group, and thus the range of motion of the deep digital flexor tendon at the operative site was increased, and postoperative adhesion was effectively suppressed. shows the operative site (deep digital flexor tendon) 4 weeks after the operation on a rat of the control group, and shows the operative site (deep digital flexor tendon) 4 weeks after the operation on a rat of administration group 1. As is clear from , in the control group administered with physiological saline, strong adhesion between scar tissue attached to the tendon and surrounding tissue was observed. On the other hand, as is clear from , in administration group 1 administered with the pharmaceutical composition of Example 28 together with physiological saline, almost no scar tissue was present in the tendon, and adhesion was considerably suppressed.
Test Example 9. Adhesion preventing effect 2: Peritoneum-cecum A preventing effect on adhesion of the sidewall and the cecum was evaluated using male rats (Crlj:WI) (obtained from Charles River Laboratories Japan, Inc.). Specifically, first, a 1×4 cm piece of a rat's right peritoneal external oblique muscle and internal oblique muscle was excised to prepare a sidewall. Next, the inside of the sidewall was rubbed with gauze. Also, the cecum was removed from the rat, and the entire cecum was rubbed with gauze and then left to stand for 20 minutes at room temperature while being exposed to air. Thereafter, the cecum was washed with a lactated Ringer's solution (manufactured by Otsuka Pharmaceutical Factory, Inc.), and the test substances shown in Table 13 were each administered to the entire area of the cecum. Next, the cecum that had been treated in the above-described manner was attached to the sidewall part and brought back inside the peritoneal cavity, then the abdomen was closed, and the rat was reared for 1 week. Laparotomy was performed 1 week later to observe adhesion of the sidewall and the cecum. Adhesion was evaluated according to the criteria shown below to yield an adhesion site score and an adhesion severity score, and these scores were added up to give a total adhesion score. <Adhesion site score> Score: State 0: No adhesion 1: Adhesion observed only in sidewall removed site 2: Adhesion observed in both sidewall removed site and inside of sidewall <Adhesion severity score> Score: state 1: Mild adhesion; adhesion easily removable by hand 2: Moderate adhesion; adhesion requiring blunt dissection and removable 3: Severe adhesion; adhesion requiring blunt dissection and not removable without tissue damage Table 13 Test substance Control group A None Control group B Lactated Ringer's solution (manufactured by Otsuka Pharmaceutical Factory, Inc.) Administration The pharmaceutical composition of Example 28 group A was added to purified water so as to attain 14 g/100 mL and stirred for 10 seconds, and the solution within 1 minute from preparation was used for administration.
Administration The pharmaceutical composition of Example 22 group B was added to purified water so as to attain 14 g/100 mL and stirred for 10 seconds, and the solution within 1 minute from preparation was used for administration.
The obtained results are shown in According to the results, all 6 subjects administered with the lactated Ringer's solution in the control group B developed adhesion, whereas adhesion was not developed in 5 subjects out of 6 subjects in administration group A, and adhesion was not observed in 4 subjects out of 6 subjects in administration group B. It is clear from the results presented above that use of the pharmaceutical composition of the present invention makes it possible to effectively inhibit adhesion of organs.
Test Example 10. Hemostatic effect 1 <Method A: Evaluation of hemostatic effect on non-continuous bleeding Laparotomy was performed on male rats (Crlj:WI) (obtained from Charles River Laboratories Japan, Inc.) to expose the left kidney, then the left renal artery and vein were clamped, blood oozing therefrom was removed, 0.3 g of the powdery pharmaceutical composition of Example 57 was spread on the clamped site, and pressure was applied thereto for 1 minute with wet gauze that had been dampened with physiological saline.
Thereafter, the clamp was removed, and presence or absence of bleeding was visually checked for 5 minutes. As a comparative example, sodium alginate power was spread, and measurement was carried out in the same manner. <Method B: Evaluation of hemostatic effect on continuous bleeding> A test was carried out in the same manner as in method A except that the clamp was removed before spreading the composition.
In method A, the powdery pharmaceutical composition of Example 57 was spread. The state reached 5 minutes after clamp removal is shown in , the state after removing the gelled pharmaceutical composition of Example 57 is shown in , and the state reached 5 minutes after clamp removal following spreading the comparative example (sodium alginate powder) is shown in . As shown in in the case where the powdery pharmaceutical composition of Example 57 was spread, no bleeding was visible at 5 minutes after clamp removal. Also, bleeding was not visible even when the gelled composition was removed. On the other hand, in the comparative example (in which sodium alginate powder was spread), overt bleeding continued even at 5 minutes after clamp removal, and thus no hemostatic effect was observed. Also, in method B, the powdery pharmaceutical composition of Example 57 showed a nearly identical hemostatic effect, but no hemostatic effect was observed with the sodium alginate powder of the comparative example.
Test Example 11. Hemostatic effect 2 The hemostatic effect was evaluated using male rats (Crlj:WI) (obtained from Charles River Laboratories Japan, Inc.). Specifically, the left renal artery and vein of a rat were clamped, and 1/3 of the kidney was excised. Next, oozing blood was removed, the test substances shown in Table 14 were administered to the excision site of the kidney. Then, about 2 mL of physiological saline was spread using a syringe equipped with a spray nozzle on the test substance administered to the excision site of the kidney, and left to stand for 1 minute.
The clamp was then removed. For 5 minutes from clamp removal, the blood from the excision site of the kidney was absorbed into medical gauze, and the difference between the weights of the gauze before and after absorption was calculated as the amount of bleeding.
Table 14 Test substance Control group I None Control group II Sodium alginate (Kimica Algin I-series I-1, viscosity of 1 w/v% aqueous solution at 20°C = 80 to 200 mPa ∙s, manufactured by Kimica Corporation); administered in an amount of 45.0±7.1 mg Administration Powdery pharmaceutical composition group I containing 60.6 wt% of sodium alginate (Kimica Algin I-series I-1, viscosity of 1 w/v% aqueous solution at 20°C = 80 to 200 mPa ∙s, manufactured by Kimica Corporation), 3.0 wt% of macrogol 4000, 6.1 wt% of calcium hydrogenphosphate (manufactured by Wako Pure Chemical Industries, Ltd.), and 30.3 wt% of glucono- δ-lactone (manufactured by Spectrum Chemical Mfg. Corp., USA) (prepared in the same manner as in Example 1); administered in an amount of 60.0±14.1 mg The obtained results are shown in It was confirmed from the results that the amount of bleeding in administration group I was significantly smaller than in control groups I and II, and thus the pharmaceutical composition of the present invention has an excellent hemostatic effect.
In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention.
Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
The term “comprising” as used in this specification and claims means “consisting at least in part of”. When interpreting statements in this specification, and claims which include the term “comprising”, it is to be understood that other features that are additional to the features prefaced by this term in each statement or claim may also be present. Related terms such as “comprise” and “comprised” are to be interpreted in similar manner.

Claims (12)

1. A powdery pharmaceutical composition comprising (A) a gelling agent which is not in gelated state, (B) a salt of a divalent metal and at least one selected from the group 5 consisting of organic acids and inorganic acids, and (C) polyethylene glycol.
2. The pharmaceutical composition according to claim 1, further comprising (D) an organic acid or an alkali metal salt 10 thereof.
3. The pharmaceutical composition according to claim 1 or claim 2, wherein the component (A) is alginic acid, a pharmaceutically acceptable alginic acid salt, or pectin.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the divalent metal in the component (B) is calcium. 20
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the component (B) is at least one selected from the group consisting of dibasic calcium phosphate and calcium gluconate. 25
6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the component (C) has an average molecular weight of about 1000 to about 20000.
7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the component (C) is macrogol 4000.
8. The pharmaceutical composition according to any one of 5 claims 2 to 7, comprising 3 to 50 parts by weight of the component (D) relative to 1 part by weight of the component (B).
9. Use of a powdery pharmaceutical composition comprising (A) a gelling agent which is not in gelated state, (B) a salt
10 of a divalent metal and at least one selected from the group consisting of organic acids and inorganic acids, and (C) polyethylene glycol, for the manufacture of an adhesion preventing biomedical material. 15 10. Use of a powdery pharmaceutical composition containing (A) a gelling agent which is not in gelated state, (B) a salt of a divalent metal and at least one selected from the group consisting of organic acids and inorganic acids, and (C) polyethylene glycol, for the manufacture of a hemostatic agent.
11. A powdery pharmaceutical composition as defined in claim 1 substantially as herein described, and optionally with reference to any example thereof. 25
12. A use as defined in claim 9 or claim 10 substantially as herein described, and optionally with reference to any example thereof.
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