JPS60215623A - Material containing immobilized physiologically active substance - Google Patents

Abstract

PURPOSE:The titled material useful for closed blood vessel therapy, biopsy, etc., having high activity retention ratio, improved non-dispersibility, being processed into rapidly injectable sol state, obtained by immobilizing a physiologically active substance to a carrier consisting of a specific high polymer substance. CONSTITUTION:A physiologically active substance is immobilized to a carrier of laminae having <=5,000mu, preferably 200-1,000mu longer diameter, <=3,000mu, preferably 200-800mu shorter diameter, and <=2,000mu, preferably <=800mu thickness or fibers having <=30 denier, preferably 0.5-15 denier single fiber fineness, <=3mm., preferably <1mm. fiber length using a high polymer substance having >=50wt% water absorption ratio as a material. Gelatin, chitin, collagen, etc. is preferable used as the material. The material is processed into a rapidly injectable sol state when it is blended with a medium such as water, etc., and it can reduce side effects of the physiologically active substance and be made into aerosol while keeping its activity.

Description

[Detailed description of the invention] The present invention relates to a material on which a physiologically active substance is immobilized.

Bioactive substances such as enzymes, coenzymes, enzyme inhibitors, hormones, various drugs, antigens, and antibodies immobilized on carriers such as polyacrylamide, cellulose, agarose, and cetylane are used as chemical reaction catalysts and specific materials for separation and purification. It is used as an adsorbent.

These immobilization materials are widely used because they are easier to handle and have better ability to retain the activity of physiologically active substances than when using a physiologically active substance alone.

On the other hand, in recent years, therapeutic and diagnostic methods such as vascular occlusion therapy, direct puncture methods, and biopsy methods have become widely used in the medical field. Increasingly, drugs are injected into blood vessels, wound cavities, or tissue gaps. Even in such cases, immobilization materials are often used. In other words, there is a long-awaited material that has a physiologically active substance immobilized thereon, that quickly becomes a sol when mixed with a medium such as water, and that can be easily injected into the body through a syringe needle or catheter.

However, many conventional bioactive substance immobilization materials are difficult to inject into the body through an injection needle or catheter due to the properties of the immobilization carrier.

That is, the shape is too large to be injected, and the compatibility with a medium such as water is poor, so that it cannot be quickly formed into a sol that can be injected. For example, Tokuko Sho 49-4689
In the fI issue, it is used as an identification material for hemostasis *-1! - An example has been disclosed in which Longin is immobilized on a gelatin sponge mass, but this mass is too large to be injected as it is, and it does not form into a vine shape quickly.

On the other hand, in certain clinical settings.

For example, there is currently a strong desire to locally spray hemostatic agents, wound treatment agents, anticancer agents, and the like. That is, in the case of aerosolization of drugs, a patch material is desired because of the advantage of identification rather than using the drug itself. However, aerosolization of bioactive substance immobilization materials is difficult.

It is a technology that has not been neglected in the past because spraying from a hinozzle and maintaining activity during storage were considered to be a national problem.

Aerosol is a general term for packaged products in which a pressure-resistant container is filled with an undiluted solution (or powder) containing an active ingredient and a propellant (a high-pressure liquefied gas with the necessary pressure to eject the undiluted solution). It means that.

In view of the above-mentioned current situation, the present inventors have proposed an anti-cancer substance sustained-release embolic agent previously proposed by the present inventors (Japanese Patent Application Laid-open No. 14001.1/1983), that is, an anti-cancer substance 1 substance. We focused on ■, which is a physiologically active substance immobilization material, which gives the immobilization agent local adhesion and sustained release of anticancer substances by immobilizing it in combination with TMS coagulant. We have investigated similar matters in more detail. the result,
When using a certain type of carrier as a carrier for immobilization, in addition to having the inherent advantages of immobilization even when immobilizing immediate physiologically active substances, it is possible to We found that by mixing it with a medium, it quickly becomes a sol and can be injected into the body, and we also discovered that such a material can be made into an aerosol while retaining its activity. , the invention reached 〒1.

That is, in the present invention, a polymer material having a water absorption rate of 50 weight 1% or more is used as a polymer material, and the major diameter is 5000 microns or less,
Physiologically active substances are immobilized on a carrier that is a thin piece with a short axis of 3000 microns or less and a thickness of 2000 microns or less, or a fiber with a 30 denier or less stringiness and a thread or 3 mm. It is a substance immobilization material.

The physiologically active substance immobilized material of the present invention has the above-mentioned anti-1-1U
9 items: Although it does not have the local adhesive properties of slow-release embolization agents or the special properties brought about by the combination effect of anticancer drugs and immobilizing agents,
In addition to the general advantages of immobilized materials, i.e., high retention of active substances, non-dispersibility, the ability to quickly form a sol that can be injected, and the reduction of side effects of physiologically active substances γi. It also has the advantage of being able to be aerosolized while retaining its activity.

The polymeric substance used as the carrier material in the present invention must have a water absorption rate of 50% by weight or more. If the water absorption rate is less than 50% by weight, it is disadvantageous that when mixed with a medium such as water, a uniform sole shape that can be poured quickly, that is, within 2 to 3 minutes, cannot be formed. on the other hand,
When using a material with a water absorption rate of less than 50%,
In addition to not being able to obtain a sufficient amount of physiologically active substances to be immobilized, there are also concerns that 1. There is a decrease in the activity of physiologically active substances due to air sole formation.

Here, the water absorption rate and υ are determined by the following formula!・It is something that will be used.

In the present invention, the number of months constituting the carrier is as follows.

For example, cellulose, cellulose derivatives, and proteins.

Synthetic polyamino acids, polyamides, polyolefins.

Polymers of dienes, chlorinated polyolefins, polymers of N-vinyl compounds, polymers of aromatic vinyl compounds, polyvinyl alcohol and its aJ4 derivatives, polymers of unsaturated aldehydes, polymers of unsaturated carboxylic acids, unsaturated carphones Polymers of acid esters, polymers of unsaturated carbonic anhydrides, polymers of unsaturated di-Ul, polymers of unsaturated carboxylic acids, chill, silicone resin, polyurecne, natural Rubber and the like disclosed in JP-A-55-58163 can be used.

Among these, it has the advantage that there is no need to remove it after injecting or spraying it into the affected area.

For example, bioabsorbable substances such as collagen, gelatin, chitin, oxidized cellulose, polyglycolic acid, polylactic acid, glycolic acid-lactic acid copolymer, polygeltanic acid, amylose, oxidized amylose such as amylose succinate, especially gelatin, amylose succinate, etc. Chitin, collagen, and oxidized cellulose are preferably used.

The carrier used in the present invention has a major axis of 5000 microns or less,
Preferably 200 to 1000 microns, short axis 3000
000 microns or 200 to 800 microns.

Thin pieces with a thickness of 2000 microns or less, preferably 800 microns or less (including fine particles generally referred to as powder), or single yarn fineness of 30 denier or less, preferably 0.5 to 15 denier, yarn length must be less than 3 mm, preferably less than 1 mm. If these values are exceeded, it is difficult to quickly obtain a uniform sol state using a medium such as water or a propellant in an aerosol.

Sol-like substances do not pass smoothly through injection needles, catheters, and aerosol nozzles and may become clogged.

This is a major drawback, especially when it is required to smoothly pass through a small-diameter injection needle, such as a 23-gauge or 25-gauge injection needle.

The physiologically active substance in the present invention includes, for example, an enzyme.

Various drugs such as Pi+' element, enzyme brightening agents, pro-enzymes, hormones, antibiotics (7) laxatives, anti-cancer agents (5) local anesthetics, etc.

Immunoreactive substances, vitamins. 7LC refers to substances such as amino acids that have an important effect on the physiological functions of animals and plants.

Examples of enzymes include alcohol dehydrogenase.

14# dehydrogenase, glucose-6-phosphate dehydrogenase, talcose oxidase, lucif, lase.

I7-amino acid oxidoreductases such as oxidase, catalase, tyrosinase, peroxidase, transferases such as hexokinase, pyruvate dehydratase, carbamate kinase, acetate kinase, ribonuclease, lipase, acetylcholinesterase, steroid esterase Se.

Amylase, cellulase, dextranase, inherutase, pepsin, renin, trypsin.

Chymotrypsin, papain, ficin, rhombin,
kallikrein, str1/ptokinase, urokinase,
Plasmin, brinolase, asunolakinase 5, hydrolytic enzymes such as urease, penicillin amidase, avirase, glueases such as pyruvate decarpoxylace, alpartase, threonine deaminase, isomerase such as glucose isomerase, tyrosine J-ray TRN
Hesynthetase.

Examples include glue gauze such as acetyl-C08 hensekuse.

Examples of coenzymes include 3, such as Piritki to luphosphoric acid.

Examples include nicotine adenine dinucleotide.

Examples of enzyme inhibitors include 2, such as ohomucoid Kun i
tz soybean trypsin inhibitor, aprotinin, antitropin ■, α2-macrogrin, α1-antitrypsin, α1-antiplasmin.

Examples include plasminogen antiactivator and heparin.

Examples of proenzymes include plasminogen.

Fibrinogen, prothromtin, tin liquid coagulation No.
l'II stator etc. are opened.

For hormones and L2, for example] Lutison, Testolone,
Estrone, estradiol, estrogen, synthetic estrogen, progesterone, inci1. Examples include phosphorus, tomastatin, gonado-1-robin, adrenaline, luadrenaline, gestano-1, and gastrin.

Examples of antibiotics include cloxacillin, cycloxacillin, flucloxacillin, ampicillin, hexcillin, talampicillin, cyclacillin, amoxicillin,
Penicillins such as pibmecillinum and piperagiline, cephaloridine, cephaloglycin, cephalexin, 1!
Cephalosporins such as fazolin, cephapirin, cefrazine, cefradul, cefoxytin, cefatridine, streptomycin, kanama icin, frasiomycin, paromomycin, kentamycin.

Bekanamycin, lipostamycin, dihekacin.

Aminoglycosides such as amikacin, tobramycin, and speculum, oxytetocycline. Tetracycline, dimethylchlortetracycline, methacycline, doxycycline.

Tetracycline systems such as methacycline, macrolides such as erythromycin, kitasamycin, oleandomycin, spiramycin, josamycin, midecamycin, lincomycins such as lincomycin and talindamycin, anti-inflammatory drugs such as micamicin, gramicidin S, and gramicidin. Gram-positive bacteria, colistin, polymyxins such as I?IJ Me!'-Syn B, biomycin, cabreomycin, enbiomycin,
Anti-succulentium amyloids such as cycloserine, l
= Polyene macrolides such as Te1noson B and pimaricin.

Rifampicin, virolnidoline, mitomycin C
, acnanomycin. Examples include pleomycin, daunorubicin, doxorubicin, neocarzinostatin, and the like.

Examples of disinfectants include dyes such as acrinol and acrylflavin, furan agents such as coflazone, quaternary ammonium salts such as henzalkonium chloride and henzetonicum chloride, guanidium salts such as chlorhexincin, and povidone-iodine. Examples include iodine complexes and amphoteric surfactants such as alkyldiaminoethylglycine hydrochloride.

Examples of anticancer drugs include nitroken mustard.

Nitromine, chlorambucil, cyclophosphamide, melphalan, caratul mustard, mannomustine, Dohan, RCNIl, l-lyethylene melamine, thio 4PP8, 8z', a-, TI':PΔ,
Trenimon.

Alkylating agents such as inprocuon, fusulfan, Tsume Senlumi I/Ran, vivosulfan, ethoglucide, epoxypropicine, epoxypiperazine, hexamethylmelamine, dibromomannitol, pivobroman, etc.2folic acid, aminopriten methotrexate, guanine, 8 - Azaganin, 6-mercabutoprine, azathioprine, uracil, 5-fluorouracil, cytarabine, azaserine.

Antimetabolites such as diazomycin, actinomycin Antimetabolites such as diazomycin, actinomycin D, zacromycin, mitomycin C, downmycin, pleomycin, chromomycin.

Antibiotics such as cardinophilin 94', 5-11P, +o
Synthetic agents such as -1, cyclophosphatide, plant ingredients such as doxorubicin, da1'7 norubicin, neocartinoscun, 11B-hematoporphyrin, C.

Examples include -pro1-porphyrin, stilhestrolhydroxourea, procarbazine, methylglycoxalubisguanylhydrazone, -asharaginase, and the like.

Local anesthetics include 2, such as tropicacocaine.

Cocaine, procoin, marcaine, chlorcaine, tetracaine, xylocaine, naebain, butacaine, etc. can be mentioned.

An immunoreactive substance is a substance that can form an immunological bond, such as an antigen or an antibody. An antigen is a substance that can induce an antigen-antibody reaction, and is generally a peptide,
These include proteins, polysaccharides, glucoproteins, and steroids. Antibodies are forces produced within the body by antigen stimulation.1. anti-j3
;” and l)! , 11'1, and its scientific substance is an immunoglobulin. Such immunoreactive substances and L7 include microorganisms such as filaments, yeasts, bovines, viruses, their immunologically active components, and antibodies, serum components, and toxins isolated from humans and animals. .

Examples include hormones, enzymes, alkaloids, capsules, silk extracts, blood cells, bone marrow cells, and lectins.

Examples of vitamins include vitamin A, vitamin B, vitamin C, vitamin D, and vitamin A.

In the present invention, these physiologically active substances may be used individually or in combination.

The physiologically active substances used in the present invention can be bound or adsorbed to the r'+ii complex, or can be immobilized by encapsulation. One example of binding a physiologically active substance to a carrier is O, Z (rh o r s
k y +Immobilized Er+zyme
Conventionally known covalent bonding methods and ionic bonding methods such as those described in J.S. CRC Press, 1973 can be employed.

When producing the physiologically active substance immobilized material of the present invention, the physiologically active substance can be bound to the carrier in the following manner, for example. In other words, when a physiologically active substance has a functional group capable of forming a covalent bond or an ionic bond, such as an amino group or a carboxyl group, a solution containing the functional group that can form a covalent bond or an ionic bond with these functional groups is added. Immobilization by binding for two purposes can be achieved by treating a carrier with groups. In addition, if the carrier does not have any functional groups that can covalently or ionically bond with the functional groups of the physiologically active substance, after introducing those functional groups into the carrier through a chemical reaction, The substance can be bound to its carrier. If a physiologically active substance does not have a functional group, it is possible to use it after introducing a functional group through a chemical reaction as described above, but in many cases, it is possible to introduce a functional group through a chemical reaction as described above. This method is not preferably employed because the properties of the physiologically active substance will be impaired. For covalent bonding, use dicyclohexylcarposiimide.

1-cyclohexyl-3-(2-morpholinoethyl)-
It is preferred to use a dehydration condensation agent such as carposiimide-meth-p-toluenesulfonate.

In addition, when manufacturing the physiologically active substance immobilized material of the present invention, the physiologically active substance can be adsorbed onto the carrier by a physical adsorption method, entrapment method, etc. in the following manner. That is, the physiologically active substance can be physically adsorbed by dissolving or suspending the physiologically active substance in a solvent that can wet the carrier and treating the carrier with this solution. The entrapment method is a method in which physiologically active substances are wrapped in a fine lattice of Kel so that they cannot be released.This adsorption method and entrapment method are effective for any physiologically active substance and silk combination of carriers. can be,
Since it is simple and often does not impair its properties as a physiologically active substance, it is preferably employed in wood inventions.

In order to produce the physiologically active substance immobilized material of the wood invention, in addition to the method of binding or adsorbing the physiologically active substance to a carrier as described above, it is necessary to first bind the physiologically active substance to the material itself before processing it into a carrier. It can also be produced by binding or adsorbing a physiologically active substance, and then processing the material to which the physiologically active substance is bound or adsorbed into a carrier. For example, the material of the present invention can be produced by obtaining a carrier using a polymeric substance bound or coated with a physiologically active substance in advance.

The immobilization material of the present invention is used in the following manner. For example, for materials where local anesthetics are immobilized in gelatin powder or oxycellulose cotton.

By injecting this into a blood vessel through a catheter as an embolic agent during vascular occlusion therapy, it is possible to simultaneously suppress the symptoms of "pain" that frequently occur after this therapy. Regarding materials on which a hemostatic agent is immobilized, 1. For example, at the time of biopsy, immediately after removing the inner cylinder of the biopsy needle, a syringe containing the material of the present invention in the form of a sol is attached to the outer cylinder of the biopsy needle, and the outer cylinder is removed. By slowly withdrawing and injecting, rapid hemostasis is achieved. If this material is used, it will become possible to perform the biopsy even in cases where it was predicted based on the results of preoperative tests that the bleeding tendency would be large and it was judged that the biopsy could not be performed. In addition, with regard to kA agents containing fixed hormones such as estrogen, if this agent is injected near the affected area in the same manner as after scorched earth surgery, for example, by intramuscular injection, repeated injections may be troublesome and side effects may be caused to the progress of the disease. It is possible to reduce the

If the immobilization material of the present invention is filled into a syringe and used, it is easy to use because it can be directly injected by simply sucking a medium such as water into the syringe. be.

The present invention will be explained in more detail with reference to Examples below.

Example 1 A thin piece of bioabsorbable gelatin (a thin piece with a major axis of 1500 mm or less, a short axis of 900 microns or less, and a thickness of 200 microns or less), 200 mR of thrombin, and a powdered physiological saline solution [concentrated dried pear powder of human thrombin] (manufactured by Green Cross) in which 1 bottle (500 units) was dissolved in 5 ml of water] for 5 minutes at room temperature.

Freeze-drying was carried out at -30'C for 15 hours to obtain fixed gelatin slices on which thrombin was fixed.

When 2 ml of 2% calcium chloride aqueous solution was added to 100 mg of this product, it became a uniform sol in about 10 seconds, and the resulting sol smoothly passed through a 23G injection needle. In addition, 10ml of distilled water was added to the remaining 100mg of 7, stirred and left to stand for 1 hour, and the thrombin concentration in the distilled water was determined by the thrombin time measurement method.15
unit/ml, indicating that a considerable amount of thrombin was present in the immobilized product without being dispersed. On the other hand, after adding 10 ml of distilled water to 1 bottle of thrombin powder and stirring and leaving it to stand for 1 hour, the thrombin concentration in the distilled water was 48 uni.
t/ml, and almost the entire amount was dispersed.

In addition, the water absorption rate of bioabsorbable gelatin is 3200i'tj
The amount was %.

Comparative Example 1 Gelathrombin (tissue-absorbable hemostatic agent, 2X6Xl cm
, made by Green Cross), the longer diameter is 5500 microns, the shorter length is 4
A section of -3500 microns and 3000 microns thick was cut, and the force 5 was collected to prepare a small amount of carrier of 100 mg.

When 2 ml of distilled water was added to this material, it did not form a uniform sol and could not pass through 19G injection.
Six].

Example 2.3 20 mg of oxycellulose cotton (absorbent oxidized cellulose cotton type, Sankyo Co., Ltd.) was formed in 20 mL of a 0.5N aqueous calcium acetate solution for 2 hours at room temperature, then washed with water and air-dried. Neutralized Oxycel cotton was obtained. This is a fiber with a single yarn fineness of 3 denier or less! It was a delicate aggregate with a diameter of 11,500 microns and a water absorption rate of 65% by weight. After this, 100B each was given to 10 Cefac tablets (conjugated estrogen drug, manufactured by Yamanouchi Pharmaceutical Co., Ltd.) or 10 mFX of Sutocaine (1'! acid tetracaine).

10 mg bottle, manufactured by Kyorin Pharmaceutical Co., Ltd.) dissolved in 5 ml of physiological saline for 100 minutes at 7°C, A stage, -30°.
Freeze-drying was performed at C to obtain Nistrokene-immobilized neutralized Oxycel cotton and tetracaine-immobilized neutralized Oxycel cotton.

When I added 2ml of physiological saline to these things, it was about 1
It became a uniform sol in 0 seconds, and the obtained sol smoothly passed through a 23G injection needle.

Comparative Example 2 Tetocaine-immobilized Oxycell cotton and estrogen-immobilized Oxycell cotton were prepared in the same manner as in Example 2, except that oxycellulose cotton with a fiber length of about 5 mm was used and the neutralization operation with calcium acetate was not performed. I got it.

When the same syringe needle passage experiment as in Example 2 was conducted using this 4), a uniform sol could not be obtained, and passage through an 18G needle was not easy.

Examples 4 and 5 Meibanoku (temporary emergency dressing for skin defects, medical atelocolaken fiber aggregate, manufactured by Meiji Seika) was finely ground with a homogenizer, and the daughter thread count was 10 deniers or less and the fiber length was 200 mg of fiber aggregate with a diameter of 2.5 mm or less was obtained.

The water absorption rate of this product was 98% by weight. 1 of this
0 (ImF!) was immersed in 2 ml of a 500 μg/ml (potency) aqueous solution of dihekacin sulfate or chlorhexidine hydrochloride for 5 minutes at room temperature, and then lyophilized at -30"C for 15 hours to remove sulfuric acid. Dibekacin-immobilized atelocollagen fiber aggregates and chlorhexidine-immobilized atelocollagen fiber aggregates were obtained.

When 1.5 ml of physiological saline was added to each of these at 75 mP, a uniform sol was formed using a Q trowel for about 15 seconds, and the resulting sol smoothly passed through a 23 G injection needle. In addition, 10 ml of distilled water was added to each 10 mg of these, and the titer of dibekacin sulfate or chlorhexidine hydrochloride in the distilled water after stirring and standing for 1 hour and after standing for 3 days was determined for the former. Bacillus
s Subtilis ATCC 6633, and Staphylococcus aureus AT for the latter.
When measured using the cylindrical plate method using CC 6538-P as a test bacterium, the former was found to be 4 μg/ml and 8 μg/ml.
/ml, and 3 μg/ml and 8.5 μg/m for the latter.
The value of l was obtained.

For reference, 10 ml of distilled water was added to 100 μg of dibekacin sulfate or 100 μg of chlorhexidine, and the titer was measured in the same manner as in Examples 4 and 5. The titer of the former was 9.8 μg/ml. 6μg
/ml, 9.5 μg/ml and 6.5 μg for the latter.
/ml values were obtained.

The low titer at the first hour of the immobilized materials obtained in Examples 4 and 5 indicates low dispersibility, and the high titer at the third day indicates a high activity retention rate. This is considered to indicate that

Examples 6, 7, 8 500 ml of bioabsorbable seratin flakes used in Example 1
each, a fibrogamine aqueous solution [one bottle of human blood coagulation factor Preparation (made by Green Cross) 1 bottle (
50 mg) dissolved in 5 ml of water] or thrombin aqueous solution [1 bottle (500 units) dissolved in 5 ml of water] for 3 minutes at room temperature, and then freeze-dried at -30°C for 10 hours. , FXIII, fibrinogen or thrombin were immobilized on three types of immobilized gelatin slices.

This stuff has a propellant of Freon 12/Freon 11 = 40
39.5 g of a mixture of /60 (weight ratio) was added, and an aerosol having an internal pressure of 3.2 kg/cm2 (25°C) was obtained by a conventional method. All three types of aerosols became uniform sol-forms by simply shaking several times, and spraying from the valve could also be performed in sequence. In addition, immediately after the aerosol was created, 100 mg of the physiologically active substance sprayed from the obtained aerosol was collected and the activity of FXIII, fibrinogen, or thrombin was measured. No deactivation due to aerosolization was observed.

In addition, the activity of FXIII was performed as follows.

That is, a predetermined weight of FXIII-immobilized gelatin slice was collected, and the same weight of physiological saline was incubated at 37°C for 15 minutes, the immobilized product was extracted, and the dilution ratio of 1 was extracted from the extracted water.
Create a dilution series of /1, 1/5, 1/10, 1/20, and 1/40, collect 50 μl of each, and add calcium chloride aqueous solution adjusted to 0.025 mol/l and 1/1 to the collected solution. Kaolin water suspension adjusted to .9 wt% (
100 μg of an equal volume mixed solution of kaolin (Ishizu Pharmaceutical FXtra Pure) was added, and 10 μl of a 1.3 wt% physiological saline solution of fibrinogen (Human Plasma, Green Cross) not containing FXIII was added. After incubating the mixture at 37°C for 10 minutes, 3 ml of 5w/v% monochloroacetic saline solution was added and incubated at 37°C for 2 minutes to observe the purified insoluble clots and to determine the dilution of the insoluble clots. Changes in activity were judged by changes in degree.

Furthermore, fibrinogen activity was measured by measuring the activity of FXIII contained in fibrinogen.

Thrombin activity was measured by a conventional method of measuring thrombin time.

Comparative Examples 3, 4, 5 Single yarn fineness 3 denier, fiber length 2 mm, water absorption rate 25% by weight
Three types of immobilized silk threads on which FXIII, fibrinogen, or thrombin were immobilized were obtained in exactly the same manner as in Examples 6 to 8, except that fiber aggregates made of silk threads were used.

Using this material, an attempt was made to produce an aerosol in the same manner as in Examples 6 to 8, but there was little uniform sol formation with the propellant, and valve clogging was often observed. Furthermore, when the same activity measurements as in Examples 6 to 8 were performed, it was found that FXIII, fibrinogen, or thrombin were all inactivated by aerosolization.
Admitted.

Patent applicant: Unitika Co., Ltd.

Claims (1)

[Claims] (1) Made of a polymer material with a water absorption rate of 50% by weight or more, and the major axis is 5000 microns or less and the minor axis is 300 microns.
0 micron or less, a thin piece with a thickness of 2000 microns or less, or a single yarn fineness of 30 denier or less, and a yarn length of 3 mm
A physiologically active substance immobilization material in which a physiologically active substance is immobilized on a carrier which is the following fiber.