JPH1085318A - Medical material and skin ulcer filling/recovering material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an excellent operability, close-adhesion and filling effect to a wound area at treating decubitus bedsore whose wound surface is not constant, by making a medical material in a paste formed from a mixture containing collagen and polyhydric alcohols. SOLUTION: The medical material in a paste form with collagen as a principal substance suitable for a skin ulcer filling/recovering material, is prepared by containing collagen and polyhydric alcohols. At this time, 0.1-10wt.% of collagen and 0.1-50wt.% of polyhydric alcohols are contained altogether, into which gelatin may be added. Glycerin is best suitable for polyhydric alcohols that may be contained as glycerogelatin together with gelatin. For collagen, atherocollagen, fibrous collagen, bridged collagen and the like are used. This medical material is excellent in operabilty and close adhesion, allowing to be filled into a wound area, and after filling, the base material itself is gradually melting down by a body temperature, finally leaving collagen only.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a paste-like medical material mainly composed of collagen and a material for repairing and repairing skin ulcer.

[0002]

2. Description of the Related Art In recent years, with the aging of life expectancy, the number of bedridden elderly has also increased, and the number of patients suffering from intractable pressure sores and skin ulcers due to bedsores is steadily increasing. Ulcer treatment (material) is on sale. However, there is no definitive treatment, and many are left without any appropriate treatment. III
Surgical treatment using flaps and the like is the most effective means for pressure ulcers and skin ulcers with deep wounds, but it is often impossible due to underlying diseases and the like. Gauze-coated ointments have been applied to affected areas, and conservative ointment treatments have been performed with daily replacement. In recent years, from the concept that wounds heal faster in a moist environment, a hydrocolloid dressing material containing a polymer such as sodium alginate or carboxymethylcellulose as a main component to maintain a moist environment in the wound has been developed. Occlusion therapy with the application of synthetic materials has been practiced in clinical settings.

[0003] However, these preservative ointment treatments and therapeutic agents (materials) do not have a replenishing and repairing effect themselves, require a long period of time until granulation is formed, and are not bioabsorbable. Intensive work is required, and the burden on the patient is large, and there are many problems in terms of treatment. For these reasons, biodegradable materials, such as chitin, chitosan, and collagen, which have a repair effect and are bioabsorbable, have attracted attention. In particular, collagen is widely used in the medical field because of its excellent biocompatibility. Collagen is a protein that is abundantly contained in the dermis, tendons, bones, fascia, etc. of animals. Even if it is derived from a different animal, it can be produced in large quantities because it can reduce immunogenicity by converting it into atelocollagen by enzymatic treatment. It is a useful material that can be obtained relatively inexpensively.

[0004] Since artificial materials using collagen are derived from living organisms, when applied to wounds, they have good tissue affinity and serve as a scaffold for cells themselves, so that cell expansion is promoted at an early stage and granulation tissue is formed. The wound closure is completed in a short time, and the effect of compensation can be expected. In fact, an artificial material comprising a collagen-denatured collagen matrix having good cell invasiveness has also been developed (Japanese Patent Application Laid-Open No. 1-230366), and neutrophils and macrophages can infiltrate early and fibroblasts can invade. . However, since the above-mentioned artificial material is used in the form of a sponge sheet by freeze-drying the suspension or the suspension, the operability of wounds, especially skin ulcers such as pressure ulcers, which are not smooth, is used. There was still room for improvement.

[0005] In order to solve the above-mentioned problems, there has been an attempt to make the collagen viscous. In fact, collagen and sodium alginate are essential components.
An osteogenic material containing calcium phosphate and retaining a tablet shape due to its own viscosity has been disclosed (JP-A-1-07072). Also disclosed is a collagen aqueous solution or aqueous dispersion containing hyaluronic acid (JP-A-1-265970). However, although synthetic polymers such as sodium alginate are highly water-absorbing, they gel themselves and have a replenishing effect, but are not bioabsorbable, so it is considered that long-term in vivo placement is undesirable. In addition, hyaluronic acid is derived from living organisms and is a material having excellent water retention and viscosity, but has a problem that it is not suitable for mass production due to its high cost.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to form a paste mainly from collagen which is bioabsorbable, so that it is easy to operate and can be used for treating wounds, especially pressure ulcers having an irregular wound surface. An object of the present invention is to provide a medical material and a skin ulcer repair / repair material which have excellent adhesion to the skin and have a repair effect.

[0007]

The present invention to achieve the above object is as follows. (1) A paste-like medical material containing collagen and polyhydric alcohols. (2) The medical material according to (1), comprising 0.1 to 10% by weight of collagen and 0.1 to 50% by weight of polyhydric alcohols. (3) The medical material according to the above (1) or (2), wherein the collagen and the polyhydric alcohol contain gelatin. (4) The medical material according to any one of (1) to (3), wherein the polyhydric alcohol is glycerin, and is contained as glycerogelatin together with gelatin.

(5) The medical material according to (1) to (4), comprising 0.1 to 10% by weight of collagen and 0.1 to 50% by weight of glycerogelatin. (6) The medical material according to (1) or (2), wherein the polyhydric alcohol is polyethylene glycol (macrogol). (7) The collagen is atelocollagen, fibrotic collagen, fibrotic atelocollagen, cross-linked collagen,
The medical material according to any one of (1) to (6), which is at least one of crosslinked atelocollagen. (8) The medical material according to any one of (1) to (7), which contains a physiologically active substance, and the physiologically active substance is gradually released. (9) A material for repairing and repairing skin ulcer, comprising the medical material according to any one of (1) to (8).

[0009] The medical material of the present invention has an appropriate consistency when filled into the wound, and can be filled into the wound with good operability and adhesiveness. After filling, the base material itself gradually dissolves at body temperature and finally dissolves. Contains only bioabsorbable collagen. The paste form referred to in the present invention is similar to an ointment generally used in pharmaceuticals and the like which has a suitable consistency and is made into a semi-solid form of uniform quality.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The collagen used in the present invention is not particularly limited, but includes dermis, tendons, bones, and the like of animals such as cows, pigs, and chickens.
Using tissue rich in collagen such as fascia as a raw material,
It is preferable to use atelocollagen from which the telopeptide region, which is the main antigenic site of collagen, has been removed. Further, a fibrillar collagen obtained by adding a neutral buffer solution of pH 7 to 8 to an acidic solution of collagen, heating at 37 ° C. for 1 to 8 hours, and concentrating is preferable, and further, atherocollagen is similarly fibrillated. It is preferable to use fibrous atherocollagen from the viewpoint of antigenicity.

[0011] The above-mentioned collagen is preferably used after cross-linking from the physical aspect such as resistance to enzymes such as collagenase. The cross-linking treatment is obtained by introducing chemical cross-linking into the fibrous collagen with a chemical such as isocyanate or glutaraldehyde, or by introducing cross-linking by a radical generated by a Fenton reaction-like mechanism such as an ascorbic acid-copper solution. Can be Also,
It is preferable to use crosslinked atelocollagen from the viewpoint of antigenicity.

In the present invention, collagen is made to contain polyhydric alcohols for imparting viscosity. As polyhydric alcohols, glycerin and macrogol can be particularly preferably used. Further, other water-soluble base materials can be contained, and gelatin and the like can be contained. Further, in the present invention, it is preferable to mix both glycerin and gelatin as glycerogelatin.

Glycerogelatin is used as a base material for anal or vaginal suppositories because it is a soft lump obtained by mixing gelatin in water and glycerin and heat-dissolving it, and gradually dissolves in secretion fluid. Gelatin here is a water-soluble protein produced by adding water or acid to crude collagen obtained by treating animal bones, skin, ligaments or tendons with acid or alkali, and then heating and extracting it. Since collagen does not fibrillate and thus has different properties from collagen, it is defined in the present invention as being different from collagen and gelatin. In addition, 37
Denatured collagen obtained by heat denaturation at a temperature in the range of up to 90 ° C. has similar properties and is therefore defined as gelatin in the present invention.

Also, its characteristic is its sol-gel conversion ability, and when gelatin powder is swollen in water and then heated to 37 ° C. or higher, gelatin dissolves into a viscous sol depending on the concentration. When this is cooled, it becomes an elastic gel, and when heated above 37 ° C., it returns to a sol again. The conversion of gelatin from gel to sol is rapid and easily melts and decomposes when applied to a living body, so that it is difficult to impart viscosity to collagen with gelatin alone from the viewpoint of operability. Therefore, the conversion time from gel to sol is extended by using glycerogelatin, and it is excellent in operability because it is gradually dissolved.

[0015] Gelatin and glycerin are not particularly limited, and those generally commercially available can be used. As the concentration of gelatin, 10 to 50% shows an appropriate consistency, but 20% is most appropriate. The ratios of water: glycerin: gelatin are 0: 4: 1, 0.5: 3.5: 1, and 1:
3: 1, 2: 2: 1 is preferred, but 0.5: 3.5: 1 or 1: 3: 1 is more preferred.

Macrogol has an average molecular weight of 100
Less than 0 (200, 300, 400, 600
Etc.) are liquid, and those of 1000 or more (1000, 150
0, 1540, 4000, 6000 etc.) are solid,
These macrogol can be appropriately mixed to prepare a substrate having an appropriate consistency. In the present invention, macrogol 400 and macrogol 4000 are defined as 1: 1, 2:
Those mixed at a mixing ratio of 3 or 3: 2 are preferably used.

In the present invention, the mixing ratio of collagen and the above-mentioned base material can be adjusted as appropriate, but is based on a medical material containing 0.1 to 10% by weight, preferably 1 to 3% by weight of collagen. The proportion of the base material is preferably 0.1 to 50% by weight, and particularly preferably 20 to 50% by weight in terms of operability.

The general method for preparing the medical material of the present invention is not particularly limited, and may be a method for producing an ordinary paste-form preparation. Mix well to make a paste.

In the medical material of the present invention, glycerogelatin and macrogol are soft lumps having a semi-solid consistency at ordinary temperature, but gradually dissolve at 37 ° C. corresponding to body temperature, so Only collagen that is sex,
Collagen is used as a scaffold for cells to replace the living body. In addition, when the medical material of the present invention is applied to a wound, particularly a skin ulcer such as a pressure ulcer or the like in which the wound surface is not smooth, the adhesiveness to the wound surface is good, and the wound can be healed at an early stage. It can be used effectively as a restoration material.

In the medical material and the skin ulcer repair / repair material of the present invention, since glycerogelatin and macrogol gradually dissolve, if necessary, a drug is added to these base materials so that the drug can be combined with the base material. It is possible to increase the therapeutic effect by sustained release. Although there is no particular limitation on the type of drug, various antibiotics, chemotherapeutics, biologicals,
Anti-aging agents, cell growth factors, anti-inflammatory agents and the like.

[0021]

The present invention will be described in more detail with reference to the following examples. Example 1 Atelocollagen powder (Koken Co., Ltd.)
3 (w / v)% of the phosphate buffer was added to the hydrochloric acid solution of pH2~3 containing in content, final concentration of 0.27 (w / v)% _{atelocollagen, 30mM Na 2 HPO 4, 100mM} NaCl, pH7 ~
Eight collagen solutions were prepared. This collagen solution was immersed in a thermostat at 37 ° C. for 4 hours to obtain a suspension of fibrillated atelocollagen. Each final concentration of this suspension is 0.1.
A cupric chloride solution and an ascorbic acid solution were added to 1 mM, and immersed in a thermostat at 37 ° C. for another 1 hour.
A TA solution (final concentration 5 mM) was added. This suspension is
By centrifuging at 00 rpm for 15 minutes, the mixture was concentrated to a final concentration of 4 (w / v)% to obtain a suspension concentrate of crosslinked fibrillated atelocollagen. Next, 20% of purified water, 60% of glycerin and 20% of gelatin were mixed and dissolved by heating on a water bath to prepare a glycerogelatin substrate. Before this base material was completely hardened, the above-mentioned crosslinked fibrillated atelocollagen concentrate was mixed in equal amounts to obtain a paste-like medical material.

Example 2 Atelocollagen powder (Koken Co., Ltd.)
Was added to a hydrochloric acid solution having a pH of 2 to 3 containing 0.3% (w / v)% and a final concentration of 0.27 (w / v)% atelocollagen, 30 mM Na _2. HPO ₄ , 100 mM NaC
1. A collagen solution having a pH of 7 to 8 was prepared. A cupric chloride solution and an ascorbic acid solution were added to this collagen solution so that the final concentrations were 0.1 mM, and the collagen solution was immersed in a thermostat at 37 ° C. for 4 hours to obtain a translucent hydrogel suspension. Was. After adding an EDTA solution (final concentration: 5 mM) to the suspension, the suspension was centrifuged at 3000 rpm for 15 minutes to concentrate the suspension to a final concentration of 2 (w / v)%. A cloudy concentrate was obtained. The hydrogel suspension concentrate and the glycerogelatin substrate obtained in the same manner as in Example 1 were mixed in equal amounts to obtain a paste-like medical material.

Example 3 An equal amount of both Macrogol 400 and Macrogol 4000 were taken at 65 ° C. on a water bath.
After heating and melting and mixing, the mixture was stirred at room temperature until it hardened to prepare a substrate. This substrate and the crosslinked fibrillated atelocollagen concentrate obtained by the same method as in Example 1 were mixed in equal amounts to obtain a paste-like medical material.

Example 4 An equal amount of both Macrogol 400 and Macrogol 4000 were taken at 65 ° C. on a water bath.
After heating and melting and mixing, the mixture was stirred at room temperature until it hardened to prepare a substrate. This base material and the hydrogel suspension concentrate obtained in the same manner as in Example 2 were mixed in equal amounts to obtain a paste-like medical material.

Comparative Example 1 A cross-linked fibrilated atelocollagen concentrate obtained in the same manner as in Example 1 was mixed with 10 (W /
v) An equal amount of an aqueous solution of sodium carboxymethylcellulose (Wako Pure Chemical) was mixed to obtain a paste-like material.

(Test Example 1) 1 g of the paste-like material obtained in Examples 1 to 4 and Comparative Example 1 was used as a dye solution (0.0
By placing on 2 cm square meroline (Smith & Nephew) filled with 1% patent blue (saline) and incubating at 37 ° C., the absorption of the dye into the paste material and the dissolution of the substrate added to the collagen were determined. Examined. The glycerogelatin and macrogol base materials added in the paste materials of Examples 1 to 4 all eluted within 30 minutes after the incubation, and only collagen remained on meroline. On the other hand, in the paste material of Comparative Example 1, sodium carboxymethylcellulose added to collagen absorbed water and swelled, and 30 minutes after incubation, remained on meroline in a state of being mixed with collagen. In addition, the dye solution permeated uniformly in all paste materials.

(Test Example 2) In order to examine the operability and wound healing effect of the paste-like materials obtained in Examples 1 to 4 and Comparative Example 1, application to a full-thickness skin defect wound on the back of a guinea pig was examined. Tried. The back skin of a Hartley guinea pig weighing around 450 g was gradually haired under Nembutal anesthesia, and a 2 × 2 cm skeletal muscle fascia was created on the back skin, and a 100-fold diluted phosmin (Daiichi Pharmaceutical Co., Ltd.) was prepared. Was used to stop bleeding. When the pet-like material obtained in Examples 1 to 4 was applied to the defective wound, the wound could be filled with good operability and the adhesion to the wound surface was good. Several days after application, the base material added as a thickener was completely dissolved, and only collagen remained in the wound. In addition, as a result of observing the tissue specimen of the wound on the 10th day after application, good infiltration of fibroblasts and capillaries without a strong inflammatory reaction or excessive proliferation of granulation tissue was observed. On the 10th day, the wound area was reduced to about 50% of the initial.

On the other hand, when the paste material obtained in Comparative Example 1 was applied to a defective wound, the wound was filled with good operability. However, a few days after the application, the added base material was swollen with a leachate, and it became thick. Then, it flowed out together with the collagen, and no collagen remained in the wound. Also,
On day 10, the wound area increased slightly from the beginning.

[0029]

As described above, the medical material according to the present invention has an appropriate consistency and excellent operability by mixing collagen and polyhydric alcohol, and impairs the biocompatibility and replenishment effect of collagen. It has the effect of being useful for tissue repair without the need. As the polyhydric alcohol, glycerin and macrogol are particularly preferable, and glycerin is preferably used as glycerogelatin together with gelatin. In addition, the medical material of the present invention, when applied to a wound, particularly a skin ulcer having a non-smooth wound such as a pressure ulcer, has good adhesion to the wound and has a characteristic of healing the wound early, so that the skin ulcer can be repaired and repaired. It can be used effectively as a material.

Claims (9)

[Claims] 1. A paste-like medical material containing collagen and polyhydric alcohols. 2. The composition according to claim 1, comprising 0.1 to 10% by weight of collagen and 0.1 to 50% by weight of polyhydric alcohols.
2. The medical material according to claim 1. 3. The collagen according to claim 1, wherein the collagen and the polyhydric alcohol contain gelatin.
2. The medical material according to claim 1. 4. The medical material according to claim 1, wherein the polyhydric alcohol is glycerin, and is contained as glycerogelatin together with gelatin. 5. The composition according to claim 1, comprising 0.1 to 10% by weight of collagen and 0.1 to 50% by weight of glycerogelatin.
5. The medical material according to any one of items 1 to 4. 6. The medical material according to claim 1, wherein the polyhydric alcohol is polyethylene glycol. 7. The medical material according to claim 1, wherein the collagen is at least one of atelocollagen, fibrotic collagen, fibrotic atelocollagen, cross-linked collagen, and cross-linked atelocollagen. 8. The medical material according to claim 1, further comprising a physiologically active substance, wherein the physiologically active substance is gradually released. 9. A material for repairing and repairing skin ulcer, comprising the medical material according to claim 1.