CN115120555B - Minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery and preparation method thereof - Google Patents
Minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery and preparation method thereof Download PDFInfo
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- CN115120555B CN115120555B CN202210893385.3A CN202210893385A CN115120555B CN 115120555 B CN115120555 B CN 115120555B CN 202210893385 A CN202210893385 A CN 202210893385A CN 115120555 B CN115120555 B CN 115120555B
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- WTJXVDPDEQKTCV-UHFFFAOYSA-N 4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2C1CC1C(N(C)C)C(=O)C(C(N)=O)=C(O)C1(O)C2=O WTJXVDPDEQKTCV-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 229960002421 minocycline hydrochloride Drugs 0.000 title claims abstract description 70
- 239000000017 hydrogel Substances 0.000 title claims abstract description 63
- 238000013268 sustained release Methods 0.000 title claims abstract description 27
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000002716 delivery method Methods 0.000 title description 2
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 36
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 26
- 239000002994 raw material Substances 0.000 claims description 21
- 239000000463 material Substances 0.000 claims description 17
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 14
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 14
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 12
- 239000001110 calcium chloride Substances 0.000 claims description 12
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 12
- 229920001992 poloxamer 407 Polymers 0.000 claims description 12
- 229940044476 poloxamer 407 Drugs 0.000 claims description 12
- 230000000844 anti-bacterial effect Effects 0.000 claims description 11
- 239000003963 antioxidant agent Substances 0.000 claims description 11
- 230000003078 antioxidant effect Effects 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 8
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 8
- 229920001993 poloxamer 188 Polymers 0.000 claims description 8
- 229940044519 poloxamer 188 Drugs 0.000 claims description 8
- 239000000395 magnesium oxide Substances 0.000 claims description 7
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 7
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 7
- 230000000699 topical effect Effects 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 230000008961 swelling Effects 0.000 claims description 6
- 229920001661 Chitosan Polymers 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- 239000003002 pH adjusting agent Substances 0.000 claims description 4
- 239000000473 propyl gallate Substances 0.000 claims description 4
- 229940075579 propyl gallate Drugs 0.000 claims description 4
- 235000010388 propyl gallate Nutrition 0.000 claims description 4
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 3
- 229920003063 hydroxymethyl cellulose Polymers 0.000 claims description 3
- 229940031574 hydroxymethyl cellulose Drugs 0.000 claims description 3
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- 239000003607 modifier Substances 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 40
- 229940079593 drug Drugs 0.000 abstract description 28
- 239000000499 gel Substances 0.000 abstract description 24
- 238000010668 complexation reaction Methods 0.000 abstract description 5
- 206010067484 Adverse reaction Diseases 0.000 abstract description 2
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- 230000007774 longterm Effects 0.000 abstract description 2
- 230000007704 transition Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 48
- 239000008367 deionised water Substances 0.000 description 26
- 229910021641 deionized water Inorganic materials 0.000 description 26
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 12
- 229960004023 minocycline Drugs 0.000 description 12
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 6
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
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- 239000000706 filtrate Substances 0.000 description 3
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- 230000036760 body temperature Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
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- 238000004007 reversed phase HPLC Methods 0.000 description 1
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- 229940126586 small molecule drug Drugs 0.000 description 1
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- 230000002459 sustained effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940072172 tetracycline antibiotic Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- 230000017423 tissue regeneration Effects 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel and a preparation method thereof, and belongs to the technical field of medicine preparation. The hydrogel combines the advantages of metal ion complexation and temperature-sensitive hydrogel, not only utilizes the characteristic that the metal ion and the metal-philic drug complexation can improve the stability, but also combines the unique property of temperature-sensitive gel solution-gel transition and a highly hydrophilic three-dimensional grid structure, so that the drug can be adhered to the administration part, the long-term release of the local drug with high concentration can be maintained, the administration frequency is reduced, the adverse reaction of the drug is reduced to a certain extent, and the utilization rate of the drug is greatly improved.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a minocycline hydrochloride temperature-sensitive hydrogel for local sustained-release delivery and a preparation method thereof.
Background
Minocycline hydrochloride is a tetracycline antibiotic with antibacterial, anti-inflammatory, neuroprotective, antioxidant, anti-apoptotic, immunomodulating, tissue repair promoting effects, and is used clinically for treating infection and inflammation. Clinically, the treatment of many diseases requires sustained high concentrations of minocycline hydrochloride, but it has been demonstrated in animal experiments that systemic administration of high doses of minocycline over long periods of time can lead to liver toxicity and even death. Topical administration minimizes the side effects of systemic administration while exposing the diseased tissue to high concentrations of minocycline. However, since minocycline is a highly water-soluble small molecule drug that is released very rapidly (less than 24 hours) from hydrophilic drug delivery systems, currently existing drug delivery systems are not suitable for the topical long-term delivery of bioactive minocycline.
Ion-pairing complexation is a new method for drug release and delivery in recent years, which improves therapeutic effects by changing the solubility, stability, release degree, etc. of the drug. Minocycline can complex multivalent metal ions such as Ca 2+、Mg2+ to form a positively charged complex, and maintain its antibacterial and anti-inflammatory activities. However, the complex formed by minocycline and metal ions is in powder form, which is inconvenient to take in local tissues. The temperature sensitive hydrogel is also a slow release delivery mode of medicines which is researched in a relatively large number in recent years, is in a solution form at low temperature, and is converted into sol-gel after the temperature rises to approach the body temperature, so that the hydrogel can be well adhered to a medicine application position to slowly release the medicines. However, due to the disadvantage that minocycline is unstable when meeting water, the slow release time is too short, and frequent administration is required.
Disclosure of Invention
The invention aims to provide a minocycline hydrochloride temperature-sensitive hydrogel for local slow release delivery and a preparation method thereof, so as to solve the problems in the prior art.
In order to achieve the above object, the present invention provides the following solutions:
One of the technical schemes of the invention is as follows: the minocycline hydrochloride temperature-sensitive hydrogel for local sustained-release delivery comprises the following raw materials in parts by mass: the raw materials with the following mass portions are as follows: 0.1 to 5 parts of minocycline hydrochloride, 20 to 50 parts of temperature sensitive material, 2 to 10 parts of temperature regulator, 0.01 to 2 parts of metal ion complex, 0.01 to 2 parts of antioxidant and 150 to 200 parts of water.
Furthermore, the minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery comprises the following raw materials in parts by weight: 0.1 to 2 parts of minocycline hydrochloride, 30 to 50 parts of temperature sensitive material, 4 to 8 parts of temperature regulator, 0.01 to 0.1 part of metal ion complex, 0.01 to 0.1 part of antioxidant and 150 to 180 parts of water.
Further, the mass ratio of the metal ion complex to minocycline hydrochloride is 0.1:1-5.
Still further, the mass ratio of the metal ion complex to minocycline hydrochloride is 0.2:5.
Further, the mass ratio of the antioxidant to minocycline hydrochloride is 0.1:1-5.
Still further, the mass ratio of the antioxidant to minocycline hydrochloride is 0.1:5.
Further, the temperature sensitive material comprises one or more of hydroxymethyl cellulose, N-isopropyl acrylamide polymer, poloxamer 407 (P407) and chitosan.
Still further, the temperature sensitive material is poloxamer 407.
Further, the temperature regulator comprises one or more of polyethylene glycol, polyvinyl alcohol and poloxamer 188 (P188).
Still further, the temperature modifier is poloxamer 188.
Further, the metal ion complex comprises one or more of magnesium oxide, magnesium chloride and calcium chloride.
Still further, the metal ion complex is calcium chloride.
Further, the antioxidant comprises one or more of sodium bisulphite, propyl gallate and butyl hydroxy anisole.
Still further, the antioxidant is sodium bisulfite.
The second technical scheme of the invention is as follows: the preparation method of the minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery comprises the following steps:
(1) Swelling the temperature sensitive material in water to obtain a solution 1; adding a temperature regulator into water for swelling to obtain a solution 2; minocycline hydrochloride, a metal ion complex and an antioxidant are added into water and uniformly mixed to obtain a solution 3;
(2) Uniformly mixing the solution 1 and the solution 2 to obtain a solution 4;
(3) And (3) dropwise adding the solution 3 into the solution 4, uniformly stirring, adding a pH regulator to regulate the pH to 3-5, and obtaining the local sustained-release delivery minocycline hydrochloride temperature-sensitive hydrogel.
Further, in the step (1), the swelling temperature is 4 ℃.
Further, in the step (3), the pH adjuster includes one or more of acetic acid, sodium citrate, ethanolamine and sodium hydroxide.
Still further, the pH adjuster is acetic acid.
Further, the pH is 3.8 to 4.2.
The third technical scheme of the invention: the application of the minocycline hydrochloride temperature-sensitive hydrogel in the preparation of antibacterial and anti-inflammatory drugs.
The invention discloses the following technical effects:
The hydrogel combines the advantages of metal ion complexation and temperature-sensitive hydrogel, not only utilizes the characteristic that the metal ion and drug complexation can improve the stability, but also combines the unique property of temperature-sensitive gel solution-gel transition and a highly hydrophilic three-dimensional grid structure, so that the drug can be adhered to the administration part, the long-acting release of the local drug with high concentration can be maintained, the administration frequency is reduced, the adverse reaction of the drug is reduced to a certain extent, and the utilization rate of the drug is greatly improved.
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 needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a morphology of the hydrogel prepared in example 1 according to the present invention;
FIG. 2 is a microstructure of the hydrogel prepared in example 1 of the present invention, the left drawing is enlarged 250 times, and the right drawing is enlarged 2000 times;
FIG. 3 is a graph showing the particle size and Zeta potential measurement results of the hydrogel prepared in example 1 of the present invention;
FIG. 4 is a minocycline hydrochloride standard curve;
FIG. 5 is a liquid chromatogram of the hydrogel prepared in example 1 of the present invention;
FIG. 6 is a graph showing the in vitro release rates of the hydrogel and minocycline hydrochloride drug substance prepared in example 1 of the present invention;
FIG. 7 is a graph showing the antibacterial effect of the preparation of hydrogel and minocycline hydrochloride drug substance according to example 1 of the present invention;
Fig. 8 is an in vitro bacteriostasis graph of the hydrogel and minocycline hydrochloride drug substance prepared in example 1 of the present invention.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the application described herein without departing from the scope or spirit of the application. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present application. The specification and examples of the present application are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.
The "parts" described in the following examples are all "parts by mass".
Example 1
A preparation method of minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery comprises the following steps:
The minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery comprises the following raw materials in parts by weight: minocycline hydrochloride (raw material) 1 part, poloxamer 407 34 parts, poloxamer 188 parts, calcium chloride 0.04 parts, sodium bisulphite 0.02 parts and deionized water 160 parts.
The pH regulator is acetic acid.
The preparation method comprises the following steps:
(1) Poloxamer 407 was added to 60 parts deionized water and left to swell well in a refrigerator at 4 ℃ to give solution 1.
(2) Poloxamer 188 was added to 50 parts deionized water and left to swell sufficiently in a refrigerator at 4 ℃ to give solution 2.
(3) Minocycline hydrochloride, calcium chloride and sodium bisulphite are added into 50 parts of deionized water, and the solution 3 is obtained after ultrasonic dissolution and uniform mixing.
(4) Solution 1 and solution 2 were mixed well to give solution 4.
(5) And (3) dropwise adding the solution 3 into the solution 4, stirring at a low temperature (4 ℃) at a high speed (1800 r/min), loading the medicine into a gel carrier, and simultaneously adding a pH regulator (acetic acid), and regulating the pH to 4.0+/-0.2 to obtain the minocycline hydrochloride temperature-sensitive hydrogel for local slow release delivery.
Example 2
The difference with the embodiment 1 is that the minocycline hydrochloride temperature-sensitive hydrogel for local slow release delivery consists of the following raw materials in parts by weight: minocycline hydrochloride (raw material), 34 parts of poly-N-isopropyl acrylamide, 6 parts of polyethylene glycol, 0.04 part of magnesium oxide, 0.02 part of propyl gallate and 160 parts of deionized water.
The pH adjuster is 10wt.% sodium hydroxide.
Example 3
The difference with the embodiment 1 is that the minocycline hydrochloride temperature-sensitive hydrogel for local slow release delivery consists of the following raw materials in parts by weight: minocycline hydrochloride (raw material), 34 parts of chitosan, 6 parts of polyethylene glycol, 0.04 part of magnesium oxide, 0.02 part of butyl hydroxy anisole and 160 parts of deionized water.
The pH regulator is sodium citrate.
Example 4
The difference with the embodiment 1 is that the minocycline hydrochloride temperature-sensitive hydrogel for local slow release delivery consists of the following raw materials in parts by weight: minocycline hydrochloride (raw material), 24 parts of hydroxymethyl cellulose, 6 parts of polyethylene glycol, 0.04 part of magnesium oxide, 0.02 part of propyl gallate and 160 parts of deionized water.
The pH regulator is ethanolamine.
Example 5
The difference with the embodiment 1 is that the minocycline hydrochloride temperature-sensitive hydrogel for local slow release delivery consists of the following raw materials in parts by weight: minocycline hydrochloride (raw material) 1 part, poloxamer 40734 parts, poloxamer 188 parts, magnesium oxide 0.04 parts, sodium bisulphite 0.02 parts and deionized water 160 parts.
The pH regulator is ethanolamine.
Example 6
A preparation method of minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery comprises the following steps:
The minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery comprises the following raw materials in parts by weight: minocycline hydrochloride (raw medicine) 1 part, poloxamer 407 30 parts, chitosan 5 parts, poloxamer 188 5 parts, calcium chloride 0.04 parts, sodium bisulphite 0.02 parts and deionized water 160 parts.
The pH regulator is acetic acid.
The preparation method comprises the following steps:
(1) Poloxamer was added to 50 parts deionized water and left to swell well in a refrigerator at 4 ℃ to give solution 1.
(2) Chitosan was added to 30 parts of deionized water and heated to dissolve to obtain solution 2.
(3) Poloxamer 188 is added to 30 parts deionized water and left to fully swell in a refrigerator at 4 ℃ to obtain solution 3.
(3) Minocycline hydrochloride, calcium chloride and sodium bisulphite are added into 50 parts of deionized water, and the solution 4 is obtained after ultrasonic dissolution and uniform mixing.
(4) Solution 1, solution 2 and solution 3 were mixed well to give solution 5.
(5) And (3) dropwise adding the solution 4 into the solution 5, stirring at a low temperature (4 ℃) at a high speed (1800 r/min) to load the medicine into a gel carrier, and simultaneously adding a pH regulator (acetic acid) to regulate the pH to 4.0+/-0.2 to obtain the minocycline hydrochloride temperature-sensitive hydrogel for local slow release delivery.
Comparative example 1
A preparation method of minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery comprises the following steps:
The minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery comprises the following raw materials in parts by weight: minocycline hydrochloride (raw material) 1 part, poloxamer 407 15 parts, poloxamer 188 parts, magnesium oxide 0.04 parts, sodium bisulphite 0.02 parts and deionized water 160 parts.
The pH regulator acetic acid.
The preparation method comprises the following steps:
(1) Poloxamer 407 was added to 60 parts deionized water and left to swell well in a refrigerator at 4 ℃ to give solution 1.
(2) Poloxamer 188 was added to 50 parts deionized water and left to swell sufficiently in a refrigerator at 4 ℃ to give solution 2.
(3) Minocycline hydrochloride, calcium chloride and sodium bisulphite are added into 50 parts of deionized water, and the solution 3 is obtained after ultrasonic dissolution and uniform mixing.
(4) Solution 1 and solution 2 were mixed well to give solution 4.
(5) And (3) dropwise adding the solution 3 into the solution 4, stirring at a low temperature (4 ℃) at a high speed (1800 r/min) to load the medicine into a gel carrier, and simultaneously adding a pH regulator (acetic acid) to regulate the pH to 4.0+/-0.2 to obtain the gel material.
The gel prepared by the comparative example has no temperature sensitivity because the content of the temperature sensitive material is too low.
Comparative example 2
A preparation method of minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery comprises the following steps:
The minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery comprises the following raw materials in parts by weight: minocycline hydrochloride (stock) 1 part, poloxamer 407 40 parts, calcium chloride 0.04 parts, sodium bisulphite 0.02 parts and deionized water 160 parts.
The pH regulator acetic acid.
The preparation method comprises the following steps:
(1) Poloxamer 407 was added to 100 parts deionized water and left to swell well in a refrigerator at 4 ℃ to give solution 1.
(2) Minocycline hydrochloride, calcium chloride and sodium bisulphite are added into 60 parts of deionized water, and the solution 2 is obtained after ultrasonic dissolution and uniform mixing.
(3) And (3) dropwise adding the solution 1 into the solution 2, stirring at a low temperature (4 ℃) at a high speed (1800 r/min) to load the medicine into a gel carrier, and simultaneously adding a pH regulator (acetic acid) to regulate the pH to 4.0+/-0.2 to obtain the gel material.
The gel prepared in this comparative example, because of the lack of temperature regulator, can gel at room temperature, which is disadvantageous for administration.
Comparative example 3
A preparation method of minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery comprises the following steps:
The minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery comprises the following raw materials in parts by weight: minocycline hydrochloride (raw material) 1 part, poloxamer 407 34 parts, poloxamer 188 parts, calcium chloride 0.04 parts, sodium bisulphite 0.02 parts and deionized water 160 parts. The pH regulator acetic acid.
The preparation method comprises the following steps:
minocycline hydrochloride (raw medicine), poloxamer 407, poloxamer 188, calcium chloride and sodium bisulphite are added into 160 parts of deionized water, the mixture is placed in a refrigerator at 4 ℃ to be fully swelled for 24 hours, the medicine is put into a gel carrier, the mixture is taken out, a pH regulator (acetic acid) is added, and the pH is regulated to 4.0+/-0.2, so that the gel material is obtained.
The material prepared by the comparative example cannot well bear medicines, the prepared gel is turbid, cannot form clear solution, and cannot form a uniform grid structure when observed under a scanning electron microscope.
Effect example 1
The hydrogels prepared in example 1 were characterized and the results are shown in FIGS. 1-3.
FIG. 1 is a schematic view showing the appearance of the hydrogel prepared in example 1 of the present invention;
as can be seen from FIG. 1, the hydrogel prepared in example 1 of the present invention has a pale yellow clear solution, uniform transparency, no precipitation or precipitation of the drug, and good temperature-sensitive property (gelation can occur at 30 ℃).
After the hydrogel prepared in the embodiment 1 of the invention is freeze-dried, the hydrogel is adhered on a scanning electron microscope sample disc by using a conductive adhesive, sputtering and metal spraying are performed by using an ion sputtering instrument, and then structural characterization of the sample is observed by using the scanning electron microscope, and the result is shown in fig. 2, the left graph is enlarged 250 times, and the right graph is enlarged 2000 times.
As can be seen from fig. 2, the hydrogel prepared in example 1 of the present invention has a three-dimensional mesh-like pore structure, which is uniformly distributed.
1ML of the hydrogel prepared in the embodiment 1 of the invention is diluted by 100 times with deionized water, is subjected to ultrasonic treatment for 30min, is stored for standby, and is subjected to particle size and Zeta potential detection by using a nano-particle size and Zeta potential analyzer (DLS), and the result is shown in figure 3.
As can be seen from FIG. 3, the hydrogel prepared in example 1 of the present invention had a particle size of 11.25.+ -. 1.85nm and a zeta potential of-23.8.+ -. 0.54mA.
(II) reversed-phase high performance liquid chromatography for content determination
(1) Chromatographic conditions: chromatographic column: ultimate XB-C18 liquid chromatography column, mobile phase: acetonitrile: pure water (38:62), flow rate: 1mL/min, wavelength 350nm, column temperature 30 ℃, sample injection: 20. Mu.L.
(2) Drawing a standard curve: precisely weighing minocycline hydrochloride reference substance, diluting with double distilled water to obtain solutions with mass concentration of 0.25, 0.5, 1,2, 4, 8mg/mL, labeling serial numbers, respectively taking the solutions, passing through 0.22 μm microporous filter, taking 1mL of filtrate, and placing into a sample bottle (light-shielding operation). The standard curve of minocycline was plotted (see figure 4) using peak area as ordinate (Y) and mass concentration as abscissa (X) as determined by the chromatographic conditions described above.
(3) Determination of sample content: 1mL of the prepared minocycline hydrochloride temperature-sensitive gel is sucked, placed in a 10mL brown volumetric flask, diluted to a scale by double distilled water, filtered by a 0.22 mu m microporous filter, 1mL of filtrate is taken and placed in a sample bottle, detection is carried out according to the chromatographic conditions, and a chromatogram is recorded (see figure 5).
The peak area is substituted into a standard curve by an external standard method to calculate the minocycline content in the temperature-sensitive gel, so that the minocycline hydrochloride content in the hydrogel prepared in the embodiment 1 of the invention is 4.9769 +/-0.1 mg/mL.
(III) in vitro Release Rate detection
200ML of PBS (pH 7.4) buffer solution was taken and placed in a shaker at 37℃for pre-heating. Precisely sucking the hydrogel (5 mg/mL) prepared in the embodiment 1 of the invention and minocycline hydrochloride bulk drug with the same concentration, respectively filling 2mL into treated dialysis bags, respectively placing the dialysis bags into beakers filled with PBS buffer solution, and carrying out release experiments at a constant rate. 2mL of PBS buffer solution with the same volume is sucked every 2h (the buffer solution in the beaker is required to be supplemented after each taking out, the volume of the buffer solution in the beaker is kept unchanged), a microporous filter with 0.22 mu m is used for filtering, 1mL of filtrate is taken and put into a sample bottle, detection is carried out according to the chromatographic conditions, a chromatogram is recorded, the peak area is substituted into a standard curve to calculate the minocycline hydrochloride content, the time is plotted on the abscissa, the cumulative release percentage is plotted on the ordinate, and the release rates of the two are compared, so that the result is shown in figure 6.
From fig. 6, it can be seen that the time for releasing the drug in the simulated in vitro release process of the hydrogel (temperature sensitive gel) prepared in example 1 of the present invention is longer than that of the drug.
(IV) study of antibacterial Effect
(1) And (3) detecting the bacteriostasis effect of the agar perforation method: 200 mu L of staphylococcus aureus in a logarithmic phase of 10 8 cfu/mL is sucked by a pipette and added into a MH agar culture medium plate, uniformly coated by a coating rod, and kept stand for 3-5 min; 4 wells were punched in MH agar medium coated with the bacterial solution using a sterilized 200. Mu.L yellow gun head, with a distance of 25mm between each well and 15mm from the edge of the dish. The gun head is not required to be rotated during punching, so that cracks are prevented from occurring in the agar round holes, and the diffusion of the liquid medicine is influenced, so that the bacteriostasis zone is uneven; diluting minocycline hydrochloride temperature-sensitive gel with sterilized deionized water, wherein the final drug concentration is as follows: 1mg/mL, 0.5mg/mL and 0.1mg/mL of hydrogel are taken as detection samples, 50 mu L of sample is added into each hole, meanwhile, sterilized deionized water is taken as negative control, and the minocycline bulk drug solution with the same concentration and blank gel auxiliary materials are taken as positive control; placing in a constant temperature incubator at 37deg.C overnight, measuring the antibacterial zone, and comparing the size of the antibacterial zone, wherein the results are shown in FIG. 7 (1-temperature sensitive gel, 2-raw material medicine, 3-blank gel, and 4-sterilized deionized water).
As can be seen from fig. 7, the antibacterial ability of the hydrogel is not reduced compared with that of the bulk drug under the same concentration condition, and the antibacterial effect is good.
(2) Drawing an in-vitro bacteriostasis curve: 10 6 cfu/mL of staphylococcus aureus bacterial liquid in a log phase is mixed with hydrogel and minocycline bulk drugs respectively to obtain drug-containing bacterial liquids with the concentration of 1/2-MIC (0.125 mu g/mL) and MIC (0.25 mu g/mL), the drug-containing bacterial liquids are added into a 48-pore plate, and a non-drug-containing broth culture medium is used as a positive control, so that three parallel controls are arranged. The bacterial count was measured with a high throughput real-time microbial growth meter, and the bacteriostasis curves of 1/2-MIC and MIC drug concentration against Staphylococcus aureus were plotted on the time point as coordinates, with the results shown in FIG. 8.
As can be seen from fig. 8, the antibacterial time of the hydrogel compared with the minocycline bulk drug is obviously prolonged under the same concentration.
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.
Claims (7)
1. The minocycline hydrochloride temperature-sensitive hydrogel for local sustained release delivery is characterized by comprising the following raw materials in parts by weight: 0.1 to 5 parts of minocycline hydrochloride, 20 to 50 parts of temperature sensitive material, 2 to 10 parts of temperature regulator, 0.01 to 0.04 part of metal ion complex, 0.01 to 2 parts of antioxidant and 150 to 200 parts of water;
the preparation method of the minocycline hydrochloride temperature-sensitive hydrogel for local sustained-release delivery comprises the following steps:
(1) Swelling the temperature sensitive material in water to obtain a solution 1; adding a temperature regulator into water for swelling to obtain a solution 2; minocycline hydrochloride, a metal ion complex and an antioxidant are added into water and uniformly mixed to obtain a solution 3;
(2) Uniformly mixing the solution 1 and the solution 2 to obtain a solution 4;
(3) Adding the solution 3 drop into the solution 4, uniformly stirring, adding a pH regulator to regulate the pH to 3-5, and obtaining the local sustained-release delivery minocycline hydrochloride temperature-sensitive hydrogel;
The metal ion complex comprises one or more of magnesium oxide, magnesium chloride and calcium chloride.
2. The topical sustained release delivery minocycline hydrochloride temperature-sensitive hydrogel of claim 1, wherein the temperature-sensitive material comprises one or more of hydroxymethyl cellulose, N-isopropyl acrylamide-based polymer, poloxamer 407, chitosan.
3. The topical sustained release delivery minocycline hydrochloride temperature-sensitive hydrogel of claim 1, wherein said temperature modifier comprises one or more of polyethylene glycol, polyvinyl alcohol, poloxamer 188.
4. The topical sustained release delivery minocycline hydrochloride temperature-sensitive hydrogel of claim 1, wherein said antioxidant comprises one or more of sodium bisulfite, propyl gallate, butyl hydroxy anisole.
5. The topical sustained release delivery minocycline hydrochloride temperature-sensitive hydrogel of claim 1, wherein in step (1) the swelling temperature is 4 ℃.
6. The topical sustained release delivery minocycline hydrochloride temperature-sensitive hydrogel of claim 1, wherein in step (3) the pH adjusting agent comprises one or more of acetic acid, sodium citrate, ethanolamine, sodium hydroxide.
7. Use of the topical sustained release delivery minocycline hydrochloride temperature-sensitive hydrogel of any one of claims 1-6 in the preparation of antibacterial, anti-inflammatory drugs.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109568262A (en) * | 2019-01-04 | 2019-04-05 | 华南农业大学 | A kind of Doxycycline Temperature-sensitive in situ gel uterus perfusion and preparation method thereof for sow |
| KR20200072322A (en) * | 2018-12-12 | 2020-06-22 | 주식회사 리엔젠 | Method for manufacturing controlled releasable DDS device using thermosensitive hydrogel |
| WO2021036058A1 (en) * | 2019-08-28 | 2021-03-04 | 深圳翰宇药业股份有限公司 | Teriparatide sustained release gel injection solution and preparation method therefor |
| CN113797160A (en) * | 2021-10-28 | 2021-12-17 | 沈阳药科大学 | Minocycline hydrochloride nano sustained-release gel and preparation method and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20200072322A (en) * | 2018-12-12 | 2020-06-22 | 주식회사 리엔젠 | Method for manufacturing controlled releasable DDS device using thermosensitive hydrogel |
| CN109568262A (en) * | 2019-01-04 | 2019-04-05 | 华南农业大学 | A kind of Doxycycline Temperature-sensitive in situ gel uterus perfusion and preparation method thereof for sow |
| WO2021036058A1 (en) * | 2019-08-28 | 2021-03-04 | 深圳翰宇药业股份有限公司 | Teriparatide sustained release gel injection solution and preparation method therefor |
| CN113797160A (en) * | 2021-10-28 | 2021-12-17 | 沈阳药科大学 | Minocycline hydrochloride nano sustained-release gel and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| "Metal ion-assisted self-assembly of complexes for controlled and sustained release of minocycline for biomedical applications";Zhiling Zhang等;《Biofabrication》;第7卷;文献编号015006第1-13页 * |
| "Temperature-sensitive hydrogel loaded with minocycline hydrochloride complex for accelerating infected wound healing";Tianyang Wang等;《Journal of Drug Delivery Science and Technology》;第88卷;文献编号104961第1-13页 * |
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