CN116617466A - Injectable gel and preparation method thereof - Google Patents
Injectable gel and preparation method thereof Download PDFInfo
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- CN116617466A CN116617466A CN202310904480.3A CN202310904480A CN116617466A CN 116617466 A CN116617466 A CN 116617466A CN 202310904480 A CN202310904480 A CN 202310904480A CN 116617466 A CN116617466 A CN 116617466A
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- injectable gel
- polycaprolactone
- gel
- polycaprolactone composite
- injectable
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- 238000002360 preparation method Methods 0.000 title abstract description 7
- 238000001879 gelation Methods 0.000 title description 2
- 229920001610 polycaprolactone Polymers 0.000 claims abstract description 68
- 239000004632 polycaprolactone Substances 0.000 claims abstract description 66
- 239000004005 microsphere Substances 0.000 claims abstract description 55
- 239000002131 composite material Substances 0.000 claims abstract description 49
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 21
- 239000008055 phosphate buffer solution Substances 0.000 claims abstract description 14
- 239000000499 gel Substances 0.000 claims description 88
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 30
- 230000003472 neutralizing effect Effects 0.000 claims description 15
- 239000002245 particle Substances 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 10
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 10
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 10
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 10
- 235000011187 glycerol Nutrition 0.000 claims description 10
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 9
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 239000008363 phosphate buffer Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000000839 emulsion Substances 0.000 claims description 7
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 6
- 239000000347 magnesium hydroxide Substances 0.000 claims description 6
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000004140 cleaning Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 238000012216 screening Methods 0.000 claims description 3
- 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 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 102000012422 Collagen Type I Human genes 0.000 claims description 2
- 108010022452 Collagen Type I Proteins 0.000 claims description 2
- 102000001187 Collagen Type III Human genes 0.000 claims description 2
- 108010069502 Collagen Type III Proteins 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 230000001804 emulsifying effect Effects 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000001727 glucose Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 2
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 239000003349 gelling agent Substances 0.000 claims 1
- 238000006731 degradation reaction Methods 0.000 abstract description 21
- 230000015556 catabolic process Effects 0.000 abstract description 20
- 230000002378 acidificating effect Effects 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- 239000007857 degradation product Substances 0.000 abstract description 5
- 208000015181 infectious disease Diseases 0.000 abstract description 5
- 230000008961 swelling Effects 0.000 abstract description 5
- 206010067484 Adverse reaction Diseases 0.000 abstract description 4
- 230000002411 adverse Effects 0.000 abstract description 4
- 230000006838 adverse reaction Effects 0.000 abstract description 4
- 230000007935 neutral effect Effects 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 41
- 230000000052 comparative effect Effects 0.000 description 18
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000004945 emulsification Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229920001432 poly(L-lactide) Polymers 0.000 description 3
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 3
- 239000004926 polymethyl methacrylate Substances 0.000 description 3
- 229940071643 prefilled syringe Drugs 0.000 description 3
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000037303 wrinkles Effects 0.000 description 2
- 108010082858 ArteFill Proteins 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000037394 skin elasticity Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 210000002229 urogenital system Anatomy 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Dispersion Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides an injectable gel, which comprises a polycaprolactone composite microsphere, a gel agent, a regulator and a phosphate buffer solution, wherein the addition amount of the polycaprolactone composite microsphere is 5-50wt%, the addition amount of the gel agent is 0.5-10wt%, the addition amount of the regulator is 0.1-10wt%, and the balance is the phosphate buffer solution, the polycaprolactone composite microsphere consists of polycaprolactone and a neutralizer, and the addition amount of the neutralizer in the polycaprolactone composite microsphere accounts for 10-50% of the total mass of the polycaprolactone composite microsphere. The invention also provides a preparation method of the injectable gel. The injectable gel provided by the invention can maintain a stable pH value close to neutral in a degradation period, solves the problem of adverse reactions such as redness, swelling and infection caused by acidic degradation products of conventional polycaprolactone injectable gel, has mild tissue reaction, can greatly reduce the occurrence rate of adverse events and improve the experience of consumers.
Description
Technical Field
The invention relates to the field of medical supplies, in particular to an injectable gel and a preparation method thereof.
Background
With age, various physiological, metabolic and functional changes in the body's various systems, organs and tissues gradually occur, and thus a series of physical sign changes occur. In particular, some changes become more pronounced after the onset of aging. Such as increased wrinkles. As skin elasticity decreases, deep fat and collagen are lost, and skin gaps and lines become more prominent, so that wrinkles are increased; such as the occurrence of urinary incontinence. Aging causes pathological changes in the genitourinary system, affecting the ability to urinate.
At present, various injection products (usually gel) have been developed for specific parts of the human body to improve the appearance or shape of the human body, and to improve the appearance or function of the human body. Such as ArteFill (polymethylmethacrylate microsphere, PMMA), radio (hydroxyapatite microsphere, caHA), sculptra (poly L-lactic acid microsphere, PLLA), ELLANSE (polycaprolactone microsphere, PCL), etc.
However, when the above-mentioned materials are used as microspheres, there are drawbacks such as PMMA, which is a non-degradable microsphere, which once injected will stay permanently in the human body, and although the filling effect thereof can be permanently exerted, concerns about long-term complications (e.g. displacement, granuloma) will also persist. Although PLLA and PCL are degradable materials, the degradation products are acidic, and the occurrence probability of complications such as pain, red swelling, infection, nodules and the like is inevitably increased.
Thus, there remains a need to develop a slowly degradable injection product that can continuously stimulate tissue regeneration over a longer period of time without causing any undesirable tissue reactions in the human body.
In view of this, the present invention has been made.
Disclosure of Invention
Aiming at the defects that degradation products are acidic and are easy to cause adverse reactions such as reddening, swelling and infection in the existing injection products, the invention provides an injectable gel product with neutral degradation process and mild tissue reaction from the aspects of reducing the occurrence rate of adverse events and improving consumer experience.
In order to achieve the above purpose, the invention provides an injectable gel, which comprises polycaprolactone composite microspheres, a gel agent, a regulator and a phosphate buffer solution, wherein the addition amount of the polycaprolactone composite microspheres is 5-50wt%, the addition amount of the gel agent is 0.5-10wt%, the addition amount of the regulator is 0.1-10wt%, and the balance is the phosphate buffer solution, the polycaprolactone composite microspheres consist of polycaprolactone and a neutralizer, and the addition amount of the neutralizer in the polycaprolactone composite microspheres accounts for 10-50% of the total mass of the polycaprolactone composite microspheres.
Preferably or alternatively, the gel is one or more of gelatin, type I collagen, type III collagen, carboxymethyl cellulose, chitosan and sodium alginate.
Preferably or alternatively, the regulator is one or more of glycerol, mannitol, glucose, sodium chloride, potassium chloride.
Preferably or alternatively, the added amount of the polycaprolactone composite microsphere is 20-40wt%, the added amount of the gel is 2-5wt%, the added amount of the regulator is 0.5-5wt%, and the balance is phosphate buffer solution.
Preferably or alternatively, the particle size of the polycaprolactone composite microsphere is 10-100 mu m.
Preferably or alternatively, the particle size of the polycaprolactone composite microsphere is 20-80 mu m.
Preferably or alternatively, the particle size of the polycaprolactone composite microsphere is 30-50 mu m.
Preferably or alternatively, the addition amount of the neutralizing agent in the polycaprolactone composite microsphere accounts for 10-30% of the total mass of the polycaprolactone composite microsphere.
Preferably or alternatively, the neutralizing agent is one or more of hydroxyapatite, tricalcium phosphate, calcium sulfate and magnesium hydroxide.
Preferably or alternatively, the particle size of the neutralising agent is in the range 5 to 50nm.
Preferably or alternatively, the particle size of the neutralising agent is in the range 5 to 30nm.
Preferably or alternatively, the polycaprolactone has a number average molecular weight of 5000-200000.
Preferably or alternatively, the polycaprolactone has a number average molecular weight of 8000 to 100000.
Preferably or alternatively, the pH of the phosphate buffer is between 6.5 and 8.5.
Preferably or alternatively, the pH of the phosphate buffer is 6.8-7.2.
The invention also provides a preparation method of the injectable gel, which comprises the following steps in sequence:
(1) Dissolving polycaprolactone and a neutralizing agent in dichloromethane to prepare an organic phase;
(2) Taking a polyvinyl alcohol aqueous solution as a water phase, injecting an organic phase into the water phase, and emulsifying at room temperature to obtain emulsion;
(3) Transferring the emulsion into a stirring kettle, volatilizing the solvent, filtering, screening, cleaning with ethanol, and vacuum drying to obtain polycaprolactone composite microspheres;
(4) Mixing polycaprolactone composite microsphere, gel, regulator and phosphate buffer solution, and packaging to obtain injectable gel product.
Advantageous effects
The injectable gel provided by the invention can maintain a stable pH value close to neutral in a degradation period, solves the problem of adverse reactions such as redness, swelling and infection caused by acidic degradation products of conventional polycaprolactone injectable gel, has mild tissue reaction, can greatly reduce the occurrence rate of adverse events and improve the experience of consumers.
Drawings
FIG. 1 is a scanning electron microscope image of polycaprolactone composite microspheres prepared in example 1;
FIG. 2 is an optical microscope photograph of the polycaprolactone composite microsphere prepared in comparative example 1;
FIG. 3 is a graph showing the pH change of the injectable gel prepared in example 2 during the degradation period;
FIG. 4 is a graph showing the pH change of the injectable gel prepared in example 3 during the degradation period;
FIG. 5 is a graph showing the pH change of the injectable gel prepared in comparative example 2 during the degradation period.
FIG. 6 is a graph showing the pH change of the injectable gel prepared in example 4 during the degradation period;
FIG. 7 is a graph showing the pH change of the injectable gel prepared in example 5 during the degradation period;
FIG. 8 is a graph showing the pH change of the injectable gel prepared in example 6 during the degradation period;
FIG. 9 is a graph showing the pH change of the injectable gel prepared in example 7 during the degradation period;
FIG. 10 is a graph showing the pH change during the degradation period of the injectable gel prepared in comparative example 3.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In addition, numerous specific details are set forth in the following description in order to provide a better illustration of the invention. It will be understood by those skilled in the art that the present invention may be practiced without some of these specific details. In some embodiments, materials, elements, methods, means, etc. well known to those skilled in the art are not described in detail in order to highlight the gist of the present invention.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Throughout the specification and claims, unless explicitly stated otherwise, the term "comprise" or variations thereof such as "comprises" or "comprising", etc. will be understood to include the stated element or component without excluding other elements or components.
Example 1
The embodiment provides a preparation method of polycaprolactone composite microspheres.
The polycaprolactone and the neutralizing agent hydroxyapatite were weighed according to a mass ratio of 7:3, respectively, the number average molecular weight of the polycaprolactone used in this example was 20000, the molecular weight distribution was 1.78, and the particle size of the hydroxyapatite used was 10nm.
The above raw materials were put into methylene chloride to prepare an organic phase with a concentration of 15wt%, and sonicated for 3min.
An aqueous polyvinyl alcohol solution with a concentration of 1% was prepared as an aqueous phase. The organic phase was slowly added to the aqueous phase and emulsified at room temperature by shear emulsification at 3000rpm for 15min.
After the emulsification is completed, the prepared emulsion is transferred into a stirring kettle, the solvent is fully volatilized by stirring at a stirring speed of 100rpm for 16 hours, then the emulsion is filtered, screened, then washed by ethanol and dried in vacuum to obtain polycaprolactone composite microspheres, and the polycaprolactone composite microspheres with the particle size of 30-50 mu m prepared in the embodiment account for 43.7 percent.
The scanning electron microscope of the product prepared by the embodiment is shown in figure 1.
Comparative example 1
The comparative example provides a preparation method of polycaprolactone composite microspheres.
The polycaprolactone and the neutralizing agent hydroxyapatite were weighed according to a mass ratio of 4:6, the number average molecular weight of the polycaprolactone used in this comparative example was 20000, the molecular weight distribution was 1.78, and the particle size of the hydroxyapatite used was 10nm.
The above raw materials were put into methylene chloride to prepare an organic phase with a concentration of 15wt%, and sonicated for 3min.
An aqueous polyvinyl alcohol solution with a concentration of 1% was prepared as an aqueous phase. The organic phase was slowly added to the aqueous phase and emulsified at room temperature by shear emulsification at 3000rpm for 15min.
And after the emulsification is finished, transferring the prepared emulsion into a stirring kettle, stirring at a stirring speed of 100rpm for 16 hours to volatilize the solvent completely, filtering, screening, cleaning with ethanol, and drying in vacuum to obtain the polycaprolactone composite microsphere.
As shown in FIG. 2, the polycaprolactone composite microsphere prepared in the comparative example was observed under an optical microscope, and the obtained product could not maintain a spherical shape due to too high addition amount of the neutralizing agent.
Example 2
The present embodiment provides an injectable gel.
30g of polycaprolactone composite microsphere prepared in example 1, 1.5g of carboxymethyl cellulose, 6.5g of glycerol and 62g of phosphate buffer solution with the pH of 7.0 are taken, the components are uniformly mixed, fully dissolved and then packaged in a prefilled syringe, and the injectable gel product is obtained.
The injectable gel product prepared in this example had a shear viscosity of 150000 mPa.S (0.7 Hz) and a push force of 16.5N (needle 27G,1/2 inch).
Example 3
The present embodiment provides an injectable gel.
30g of polycaprolactone composite microsphere prepared according to the mode in example 1 (except that the addition amount of the neutralizer hydroxyapatite is 20%), 1.5g of carboxymethyl cellulose, 6.5g of glycerol and 62g of phosphate buffer solution with the pH value of 7.0 are taken, and after the components are uniformly mixed and fully dissolved, the mixture is split into pre-filled and sealed syringes, so that an injectable gel product is obtained.
The injectable gel product prepared in this example had a shear viscosity of 150000 mPa.S (0.7 Hz) and a push force of 15.8N (needle 27G,1/2 inch).
Example 4
The present embodiment provides an injectable gel.
30g of polycaprolactone composite microsphere prepared according to the mode in example 1 (except that the addition amount of the neutralizer hydroxyapatite is 10%), 1.5g of carboxymethyl cellulose, 6.5g of glycerol and 62g of phosphate buffer solution with the pH value of 7.0 are taken, and after the components are uniformly mixed and fully dissolved, the mixture is split into pre-filled and sealed syringes, so that an injectable gel product is obtained.
The injectable gel product prepared in this example had a shear viscosity of 150000 mPa.S (0.7 Hz) and a push force of 16.1N (needle 27G,1/2 inch).
Example 5
The present embodiment provides an injectable gel.
30g of polycaprolactone composite microsphere prepared according to the mode in example 1 (except that the addition amount of the neutralizer magnesium hydroxide is 30%), 4.5g of carboxymethyl cellulose, 0.5g of glycerol and 65g of phosphate buffer with the pH of 7.0 are taken, and after the components are uniformly mixed and fully dissolved, the mixture is split into pre-filled and sealed syringes, so that an injectable gel product is obtained.
The injectable gel product prepared in this example had a shear viscosity of 38000 mPa.S (0.7 Hz) and a push force of 25.0N (needle 27G,1/2 inch).
Example 6
The present embodiment provides an injectable gel.
30g of polycaprolactone composite microsphere prepared according to the mode in example 1 (except that the addition amount of the neutralizer magnesium hydroxide is 20%), 4.5g of carboxymethyl cellulose, 0.5g of glycerol and 65g of phosphate buffer with the pH of 7.0 are taken, and after the components are uniformly mixed and fully dissolved, the mixture is split into pre-filled and sealed syringes, so that an injectable gel product is obtained.
The injectable gel product prepared in this example had a shear viscosity of 38000 mPa.S (0.7 Hz) and a push force of 24.6N (needle 27G,1/2 inch).
Example 7
The present embodiment provides an injectable gel.
30g of polycaprolactone composite microsphere prepared according to the mode in example 1 (except that the addition amount of the neutralizer magnesium hydroxide is 10%), 4.5g of carboxymethyl cellulose, 0.5g of glycerol and 65g of phosphate buffer solution with the pH value of 7.0 are taken, and after the components are uniformly mixed and fully dissolved, the mixture is split-packed in a prefilled syringe, so that an injectable gel product is obtained.
The injectable gel product prepared in this example had a shear viscosity of 38000 mPa.S (0.7 Hz) and a push force of 25.0N (needle 27G,1/2 inch).
Comparative example 2
This comparative example provides an injectable gel.
30g of polycaprolactone composite microsphere prepared according to the mode in example 1 (except that the addition amount of the neutralizer magnesium hydroxide is 5%), 4.5g of carboxymethyl cellulose, 0.5g of glycerol and 65g of phosphate buffer with the pH of 7.0 are taken, and after the components are uniformly mixed and fully dissolved, the mixture is split into pre-filled and sealed syringes, so that an injectable gel product is obtained.
The injectable gel product prepared in this comparative example had a shear viscosity of 38000 mPa.S (0.7 Hz) and a push force of 25.0N (needle 27G,1/2 inch).
Comparative example 3
This comparative example provides an injectable gel.
30g of polycaprolactone composite microsphere prepared according to the mode in example 1 (except that no neutralizing agent is added), 1.5g of carboxymethyl cellulose, 6.5g of glycerol and 62g of phosphate buffer solution with the pH of 7.0 are taken, the components are uniformly mixed, fully dissolved and then packaged in a prefilled syringe, and the injectable gel product is obtained.
The injectable gel product prepared in this comparative example had a shear viscosity of 150000 mPa.S (0.7 Hz) and a push force of 15.6N (needle 27G,1/2 inch).
Effect examples
The injectable gel products prepared in examples 2 to 7 and comparative examples 2 to 3 were respectively measured for their pH at various time points over a degradation period of 0 to 180 days, and the pH change curves were plotted, with the following results.
Wherein fig. 3 is a pH profile of the injectable gel product provided in example 2 during the period, fig. 4 is a pH profile of the injectable gel product provided in example 3 during the period, fig. 5 is a pH profile of the injectable gel product provided in comparative example 2 during the period, fig. 6 is a pH profile of the injectable gel product provided in example 4 during the period, fig. 7 is a pH profile of the injectable gel product provided in example 5 during the period, fig. 8 is a pH profile of the injectable gel product provided in example 6 during the period, fig. 9 is a pH profile of the injectable gel product provided in example 7 during the period, and fig. 10 is a pH profile of the injectable gel product provided in comparative example 3 during the period.
As can be seen from fig. 3, the injectable gel product prepared in example 2 maintained pH around 6.97 during the degradation period;
as can be seen from fig. 4, the injectable gel product prepared in example 3 maintained pH around 6.82 during the degradation period;
as can be seen from fig. 5, the injectable gel product prepared in comparative example 2 gradually decreased to pH around 6.47 during the degradation period;
as can be seen from fig. 6, the injectable gel product prepared in example 4 maintained pH around 6.75 during the degradation period;
as can be seen from fig. 7, the injectable gel product prepared in example 5 maintained pH around 6.95 during the degradation period;
as can be seen from fig. 8, the injectable gel product prepared in example 6 maintained pH around 6.94 during the degradation period;
as can be seen from fig. 9, the injectable gel product prepared in example 7 maintained pH around 6.81 during the degradation period;
as can be seen from fig. 10, the injectable gel product prepared in comparative example 3 gradually decreased in pH to around 6.61 during the degradation period.
According to the results, the technical scheme provided by the invention is that the polycaprolactone composite microsphere comprising the neutralizing agent with a specific proportion is prepared, and the polycaprolactone composite microsphere is adopted to prepare the injectable gel, so that the prepared injectable gel product maintains a stable pH value close to neutral in a degradation period, the problem of adverse reactions such as redness, swelling and infection caused by acidic degradation products of the conventional polycaprolactone injectable gel is solved, and the injectable gel provided by the invention has mild tissue reaction, can greatly reduce the occurrence rate of adverse events and promote the experience of consumers.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; 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: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (16)
1. The injectable gel is characterized by comprising polycaprolactone composite microspheres, a gel agent, a regulator and a phosphate buffer solution, wherein the addition amount of the polycaprolactone composite microspheres is 5-50wt%, the addition amount of the gel agent is 0.5-10wt%, the addition amount of the regulator is 0.1-10wt%, and the balance is the phosphate buffer solution, the polycaprolactone composite microspheres consist of polycaprolactone and a neutralizer, and the addition amount of the neutralizer in the polycaprolactone composite microspheres accounts for 10-50% of the total mass of the polycaprolactone composite microspheres.
2. The injectable gel of claim 1, wherein the gelling agent is one or more of gelatin, type I collagen, type III collagen, carboxymethyl cellulose, chitosan, sodium alginate.
3. The injectable gel of claim 1, wherein the modulator is one or more of glycerol, mannitol, glucose, sodium chloride, potassium chloride.
4. The injectable gel of claim 1, wherein the polycaprolactone composite microsphere is added in an amount of 20-40wt%, the gel is added in an amount of 2-5wt%, the regulator is added in an amount of 0.5-5wt%, and the balance is phosphate buffer.
5. The injectable gel of claim 1, wherein the polycaprolactone composite microsphere has a particle size of 10-100 μm.
6. The injectable gel of claim 5, wherein the polycaprolactone composite microsphere has a particle size of 20-80 μm.
7. The injectable gel of claim 6, wherein the polycaprolactone composite microsphere has a particle size of 30-50 μm.
8. The injectable gel of claim 1, wherein the amount of neutralizing agent added to the polycaprolactone composite microsphere is 10-30% of the total mass of the polycaprolactone composite microsphere.
9. The injectable gel of claim 8, wherein the neutralizing agent is one or more of hydroxyapatite, tricalcium phosphate, calcium sulfate, magnesium hydroxide.
10. The injectable gel of claim 9 wherein the neutralizing agent has a particle size of 5-50nm.
11. The injectable gel of claim 10 wherein the neutralizing agent has a particle size of 5-30nm.
12. The injectable gel of claim 1, wherein the polycaprolactone has a number average molecular weight of 5000-200000.
13. The injectable gel of claim 12, wherein the polycaprolactone has a number average molecular weight of 8000-100000.
14. The injectable gel of claim 1, wherein the phosphate buffer has a pH of 6.5-8.5.
15. The injectable gel of claim 14, wherein the phosphate buffer has a pH of 6.8-7.2.
16. A method of preparing an injectable gel according to any one of claims 1 to 15, wherein the method is carried out in sequence by the steps of:
(1) Dissolving polycaprolactone and a neutralizing agent in dichloromethane to prepare an organic phase;
(2) Taking a polyvinyl alcohol aqueous solution as a water phase, injecting an organic phase into the water phase, and emulsifying at room temperature to obtain emulsion;
(3) Transferring the emulsion into a stirring kettle, volatilizing the solvent, filtering, screening, cleaning with ethanol, and vacuum drying to obtain polycaprolactone composite microspheres;
(4) Mixing polycaprolactone composite microsphere, gel, regulator and phosphate buffer solution, and packaging to obtain injectable gel product.
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