CN116173251B - Sterilization method of PHA microsphere injection - Google Patents
Sterilization method of PHA microsphere injection Download PDFInfo
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- CN116173251B CN116173251B CN202211602525.3A CN202211602525A CN116173251B CN 116173251 B CN116173251 B CN 116173251B CN 202211602525 A CN202211602525 A CN 202211602525A CN 116173251 B CN116173251 B CN 116173251B
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- 239000004005 microsphere Substances 0.000 title claims abstract description 101
- 230000001954 sterilising effect Effects 0.000 title claims abstract description 65
- 238000004659 sterilization and disinfection Methods 0.000 title claims abstract description 62
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000002347 injection Methods 0.000 title claims abstract description 16
- 239000007924 injection Substances 0.000 title claims abstract description 16
- 239000003381 stabilizer Substances 0.000 claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000000126 substance Substances 0.000 claims abstract description 11
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 239000006185 dispersion Substances 0.000 claims description 19
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 11
- 229920002674 hyaluronan Polymers 0.000 claims description 11
- 229960003160 hyaluronic acid Drugs 0.000 claims description 11
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
- FHUDZSGRYLAEKR-UHFFFAOYSA-N 3-hydroxybutanoic acid;4-hydroxybutanoic acid Chemical compound CC(O)CC(O)=O.OCCCC(O)=O FHUDZSGRYLAEKR-UHFFFAOYSA-N 0.000 claims description 3
- 229920001661 Chitosan Polymers 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000000661 sodium alginate Substances 0.000 claims description 3
- 235000010413 sodium alginate Nutrition 0.000 claims description 3
- 229940005550 sodium alginate Drugs 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- -1 poly (3-hydroxybutyric acid-3-hydroxyvaleric acid-3-hydroxycaproic acid Chemical compound 0.000 claims description 2
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 claims 2
- IUPHTVOTTBREAV-UHFFFAOYSA-N 3-hydroxybutanoic acid;3-hydroxypentanoic acid Chemical compound CC(O)CC(O)=O.CCC(O)CC(O)=O IUPHTVOTTBREAV-UHFFFAOYSA-N 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 17
- 230000002776 aggregation Effects 0.000 abstract description 7
- 238000004220 aggregation Methods 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000005014 poly(hydroxyalkanoate) Substances 0.000 description 28
- 229920000903 polyhydroxyalkanoate Polymers 0.000 description 27
- 239000007788 liquid Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 4
- 238000005054 agglomeration Methods 0.000 description 3
- 230000036512 infertility Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229920000520 poly(3-hydroxybutyrate-co-3-hydroxyvalerate) Polymers 0.000 description 2
- 229920001432 poly(L-lactide) Polymers 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 239000004632 polycaprolactone Substances 0.000 description 2
- RRWWOSSPAGCJFO-UHFFFAOYSA-N 3-hydroxybutanoic acid;3-hydroxyhexanoic acid Chemical compound CC(O)CC(O)=O.CCCC(O)CC(O)=O RRWWOSSPAGCJFO-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000000464 low-speed centrifugation Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- 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
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0023—Heat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/10—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Abstract
The invention relates to the technical field of biological base material preparations, and in particular discloses a sterilization method of PHA microsphere injection, which comprises the following steps: mixing PHA microsphere, water and stabilizer to obtain gel; wherein the mass ratio of the stabilizer to the microspheres is 1:7-1:20; carrying out damp-heat sterilization on the gel-like substance to obtain sterilized PHA microsphere injection; wherein the temperature of the wet heat sterilization is 102-108 ℃. According to the invention, the PHA microspheres are dispersed and then subjected to damp-heat sterilization, so that the probability of mutual contact of the PHA microspheres is avoided, and the risk of microsphere aggregation is further reduced.
Description
Technical Field
The invention relates to the technical field of biological base material preparations, in particular to a sterilization method of PHA microsphere injection.
Background
Currently, common microsphere materials for injection include poly L-lactic acid (PLLA), polycaprolactone (PCL), poly lactic-co-glycolic acid (PLGA) microspheres and the like, and the microspheres are usually sterilized by irradiation or damp-heat mode to obtain sterile microspheres for medical supplies. Polyhydroxyalkanoate (PHA) microspheres, however, are subjected to irradiation sterilization because PHA has a low heat distortion temperature, and thus, both of the direct wet heat sterilization and the wet heat sterilization after dispersion in water cause a large amount of aggregation of PHA microspheres and are difficult to be effectively dispersed (such aggregation is difficult to be dispersed).
The microsphere injection is prepared by mixing microsphere materials with auxiliary materials, sterilizing the microsphere materials and the auxiliary materials in the process of preparing the microsphere injection, wherein the microsphere and the auxiliary materials are sterilized respectively, the microsphere adopts irradiation sterilization, the auxiliary materials adopt damp-heat sterilization, and finally the microsphere and the auxiliary materials are mixed aseptically. This sterilization mode has the following drawbacks:
1. for PHA microspheres, irradiation sterilization can also greatly reduce the molecular weight of the material, and has a great influence on the overall performance of the material.
2. From the technical point of view, the microspheres are sterilized and then mixed with auxiliary materials in an aseptic mode, the requirements on the process are high, and the process is complex.
If the microspheres and the auxiliary materials are mixed and sterilized, adhesion is easy, and in order to avoid adhesion, the microspheres with higher content cannot be added.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a sterilization method of PHA microsphere injection. The invention adopts a one-step sterilization method, which not only ensures the sterility of microsphere gel, but also maintains the suspension state of the microspheres.
The invention provides a sterilization method of PHA microsphere injection, which comprises the following steps:
a) Mixing PHA microsphere, water and stabilizer to obtain gel;
wherein the mass ratio of the stabilizer to the PHA microspheres is 1:7-1:20;
b) Carrying out damp-heat sterilization on the gel-like substance to obtain sterilized PHA microsphere injection;
wherein the temperature of the wet heat sterilization is 102-108 ℃.
The sterilization method provided by the invention adopts a one-step sterilization method, the microspheres and the stabilizer are mixed (preferably, the microspheres are dispersed in water to form microsphere dispersion liquid, a certain amount of stabilizer is added to form a milky gel substance with uniformly suspended microspheres, and then the wet heat sterilization is directly carried out. The sterilization temperature is controlled to ensure that the gel-like substance is sterile, and the stabilizer is not destroyed; the proportion of the stabilizer to the microspheres is controlled to keep the suspension state of the microspheres, so that the dispersion is more uniform, and no layering phenomenon occurs.
Regarding step a): the PHA microspheres, water and stabilizer are mixed to obtain a gel-like substance.
Further, step a) comprises:
a1 Dispersing PHA microspheres in water to obtain microsphere dispersion;
wherein, the concentration of the microsphere dispersion liquid is 0.1-300 mg/mL;
a2 Adding a stabilizer into the microsphere dispersion liquid, and fully and uniformly mixing to obtain a gel;
regarding step a 1): the PHA microspheres are dispersed in water to obtain microsphere dispersion.
In the present invention, the PHA microsphere is not particularly limited in the kind of PHA, and may be one or more of poly (3-hydroxybutyrate-3-hydroxyvalerate-3-hydroxyhexanoate) (abbreviated as PHBVHX), poly (3-hydroxybutyrate-3-hydroxyhexanoate) (i.e., P3HB-co-3 HHX) (abbreviated as PHBHHX), poly (3-hydroxybutyrate-4-hydroxybutyrate) (i.e., P3HB-co-4 HB) (abbreviated as P34 HB), or poly (3-hydroxybutyrate-3-hydroxyvalerate) (abbreviated as PHBV), preferably poly (3-hydroxybutyrate-4-hydroxybutyrate).
The particle size of the PHA microspheres is not particularly limited, and may be 20 to 80 microns, preferably 20 to 40 microns; the molecular weight of the PHA microspheres is not particularly limited, and can be 5 to 80 kilodaltons, preferably 10 to 20 kilodaltons.
In the present invention, the water is preferably distilled water or deionized water, more preferably distilled water.
In the invention, the concentration (w/v) of the microsphere dispersion liquid formed by dispersing PHA microspheres in water is 0.1-300 mg/mL; in some embodiments of the invention, the concentration is 0.5mg/mL, 1mg/mL, 5mg/mL, 10mg/mL, 20mg/mL, 50mg/mL, 60mg/mL, 80mg/mL, 100mg/mL, 150mg/mL, 200mg/mL, 250mg/mL, or 300mg/mL. If the concentration is higher than 300mg/mL, the solid content is too high, gel-like microspheres are difficult to prepare, the probability of mutual contact between the microspheres is high, and a small amount of agglomeration occurs after sterilization; preferably 300mg/mL.
Regarding step a 2): adding stabilizer into microsphere dispersion, and mixing completely to obtain gel.
In the invention, the stabilizer comprises one or more of hyaluronic acid and salts thereof, sodium carboxymethyl cellulose, chitosan and derivatives thereof and sodium alginate. Since these substances form a gel-like substance having a certain viscosity after being dissolved in water, the microspheres are dispersed therein to maintain a stable suspended state.
Preferably, the stabilizer is Hyaluronic Acid (HA), the molecular weight of the hyaluronic acid is 100-140 ten thousand daltons, and the average molecular weight is 120 ten thousand daltons.
In the invention, the mass ratio of the stabilizer to the PHA microspheres is 1:7-1:20; in some embodiments of the invention, the mass ratio is 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, or 1:20. Preferably, the mass ratio of the stabilizer to the PHA microspheres is 1:10-1:12. In the range, the microspheres can be stably dispersed after sterilization by using hyaluronic acid and salts thereof, sodium carboxymethyl cellulose, chitosan and derivatives thereof and sodium alginate, and maintain a good suspension state, and the microspheres are unstable to disperse beyond the proportion, so that layering or agglomeration can occur.
Further, the concentration of the stabilizer (the ratio of the mass of the stabilizer to the volume of the dispersion) in the present invention is 15 to 40mg/mL, preferably 20 to 35mg/mL, more preferably 25 to 30mg/mL (1:10 to 12); the concentration is lower than 25mg/mL (1:12), the microspheres cannot be stably dispersed after sterilization, and a small amount of layering occurs after the microspheres are placed for 30 min; when the concentration is higher than 30mg/mL (1:10), the viscosity becomes too high, and it becomes difficult to mix the mixture into a gel-like substance.
By adjusting the ratio of the microspheres to the stabilizing agent (e.g., hyaluronic acid), the stability of the gel-like material can be ensured after sterilization is completed without any delamination.
In the invention, the stabilizer is added into the microsphere dispersion liquid and then fully and uniformly mixed by adopting a mechanical stirring mode, and the speed and the time of the mechanical stirring are not particularly limited, so that a uniform gel-like substance can be formed.
Further, after the dispersion of the microspheres is added with the stabilizer and fully and uniformly mixed, bubbles can be removed by low-speed centrifugation, the centrifugation speed can be 1500rpm, and the centrifugation time can be 2min.
Regarding step b): and carrying out damp-heat sterilization (namely high-pressure steam sterilization with a certain temperature) on the gel-like substance to obtain the sterilized PHA microsphere injection.
In the invention, the temperature of moist heat sterilization (high pressure steam temperature) is controlled to be 102-108 ℃, preferably 105-108 ℃, and bacteria are detected when the temperature is lower than 102 ℃; when the temperature is higher than 108 ℃ and lower than 110 ℃, the stabilizer is damaged by a small amount, and a small amount of layering occurs; the stabilizer is destroyed in a large amount at a temperature higher than 110 ℃, and the microspheres are agglomerated.
The sterilization temperature is controlled to be slightly lower than the traditional wet heat sterilization temperature, so that the microspheres are prevented from being deformed or agglomerated due to high temperature, and the stabilizer (such as hyaluronic acid gel) is prevented from being damaged due to the high temperature, so that the viscosity is reduced, and the effect of stabilizing the microspheres cannot be achieved.
Preferably, the time of the wet heat sterilization is 20 to 30min, preferably 20min.
Sterilizing at 102-108 deg.c for 20-30 min to ensure sterility of the injection.
The beneficial effects are that:
(1) the method has the advantages that sterilization is realized by a one-step method, the risk of secondary bacteria infection by traditional sterilization and compounding and mixing is avoided, and meanwhile, the process difficulty is reduced.
(2) The wet heat sterilization process effectively avoids the damage of materials and ensures the stability of products.
(3) And after the PHA microspheres are dispersed, carrying out damp-heat sterilization, so that the probability of mutual contact of the PHA microspheres is avoided, and the risk of microsphere aggregation is further reduced.
(4) The invention mixes PHA microsphere with a special stabilizer to form gel with uniformly suspended microsphere, then directly carries out damp-heat sterilization, and controls sterilization temperature and stabilizer/microsphere proportion to ensure the sterility of microsphere gel, simultaneously maintains the suspension state of microsphere, and has more uniform dispersion and no layering and agglomeration phenomenon.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 shows, in order from left to right, photographs of samples of dispersions of microspheres of examples 1-6 after sterilization with a stabilizer;
fig. 2 shows, in order from left to right, x 10-fold photographs under a sample microscope of a sterilized dispersion of microspheres of examples 1, 2, 3, 6, 7 mixed with a stabilizer;
fig. 3 shows, in order from left to right, photographs of samples of dispersions after sterilization of the microspheres of examples 8, 9, 10, 7 mixed with a stabilizer.
Detailed Description
For a further understanding of the present invention, preferred embodiments of the invention are described below in conjunction with the examples, but it should be understood that these descriptions are merely intended to illustrate further features and advantages of the invention, and are not limiting of the claims of the invention.
Unless otherwise indicated, all materials, reagents, methods and the like used in the examples are those conventionally used in the art.
PHA microsphere is produced by Beijing blue crystal microorganism technology Co., ltd, has particle diameter of 20-40 micrometers, and molecular weight of 10-20 ten thousand daltons.
Hyaluronic acid is commercially available, and has a molecular weight of 100-140 kilodaltons and a molecular weight average of 120 kilodaltons.
Example 1
A sterilization method of PHA microsphere injection for subcutaneous injection, comprising the following steps:
dispersing 300mg PHA microspheres in 1mL of water to obtain a microsphere dispersion of 300mg/mL; adding 30mg of hyaluronic acid, mechanically stirring for 0.5h, centrifuging at 1500rpm for 2min to remove bubbles, and forming uniform gel; sterilizing the gel at 117 deg.C for 20min.
Examples 2 to 10
Examples 2-10 differ from example 1 in the following table.
Different sterilization temperatures are adopted in examples 1-7, fig. 1 shows the sterilized state of examples 1-6, fig. 2 shows the microsphere photographs of the samples under the microscope after the sterilization of examples 1, 2, 3, 6 and 7, and as shown in fig. 1 and 2, the sterilization temperatures are higher than 108 ℃ and can be layered to different degrees, so that the sterilization temperatures lower than 108 ℃ are better. The microspheres are dispersed more uniformly at the sterilization temperature below 108 ℃, and the sterilization effect (for example, the bacterial count is 0 under the sterilization condition of 105 ℃ and 20 min) can be satisfied after the microspheres are maintained for a certain time at the sterilization temperature of 102-108 ℃ through detection.
In examples 7 to 10, the proportions of the stabilizer and the microspheres are different, and fig. 3 shows the sterilized states of examples 8, 9, 10 and 7 (the proportions in the figures represent the mass ratio of the stabilizer to the microspheres), and as shown in fig. 3, after the mass ratio of the stabilizer to the microspheres reaches 1:12, almost no layering phenomenon occurs after sterilization, and after the mass ratio of the stabilizer to the microspheres reaches 1:10, no layering phenomenon occurs after sterilization, so that the mass ratio of the stabilizer to the microspheres is preferably 1:10 to 1:12.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limited thereto. Although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some or all of the technical features thereof, without departing from the spirit and scope of the present invention as defined in the claims; and such modifications or substitutions are intended to be within the scope of the present invention as defined by the claims.
Claims (6)
1. A sterilization method of PHA microsphere injection, which is characterized by comprising the following steps:
a) Mixing PHA microsphere, water and stabilizer to obtain gel;
wherein the stabilizer is one or more selected from hyaluronic acid and salts thereof, sodium carboxymethyl cellulose, chitosan and derivatives thereof, and sodium alginate; the mass ratio of the stabilizer to the PHA microspheres is 1:10-1:12; the ratio of PHA microsphere to water is 0.1-300 mg:1mL;
b) Carrying out damp-heat sterilization on the gel-like substance to obtain sterilized PHA microsphere injection;
wherein the temperature of the wet heat sterilization is 102-108 ℃.
2. Sterilization process according to claim 1, characterized in that step a) comprises:
a1 Dispersing PHA microspheres in water to obtain microsphere dispersion;
a2 Adding stabilizer into microsphere dispersion, and mixing completely to obtain gel.
3. The sterilization process according to claim 1 or 2, wherein the PHA microspheres are one or more selected from poly (3-hydroxybutyric acid), poly (3-hydroxybutyric acid-3-hydroxyvaleric acid-3-hydroxycaproic acid), poly (3-hydroxybutyric acid-4-hydroxybutyric acid) or poly (3-hydroxybutyric acid-3-hydroxyvaleric acid).
4. The sterilization process according to claim 1 wherein the stabilizing agent is hyaluronic acid.
5. The sterilization method according to claim 1, wherein the temperature of the wet heat sterilization is 105 to 108 ℃.
6. The sterilization method according to claim 1, wherein the time of the wet heat sterilization is 20 to 30 minutes.
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| WO2020021499A1 (en) * | 2018-07-26 | 2020-01-30 | Azista Industries Pvt Ltd | Haemostatic gel composition and its process of preparation |
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