CN115120555A - Local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel and preparation method thereof - Google Patents
Local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel and preparation method thereof Download PDFInfo
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Images
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- 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
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- 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
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- 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
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- 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
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- 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]
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- 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
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- 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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Abstract
The invention discloses a local sustained-release minocycline hydrochloride temperature-sensitive hydrogel and a preparation method thereof, belonging to the technical field of medicine preparation. The hydrogel disclosed by the invention combines the advantages of metal ion complexation and temperature-sensitive hydrogel, not only utilizes the characteristic that the complexation of metal ions and metal-philic drugs 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 drugs are adhered to the part where the drugs are applied, the long-term release of the local drugs with high concentration can be maintained, the drug administration frequency is reduced, the adverse reaction of the drugs is reduced to a certain extent, and the utilization rate of the drugs is greatly improved.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a local sustained-release minocycline hydrochloride delivery thermosensitive hydrogel and a preparation method thereof.
Background
Minocycline hydrochloride is a tetracycline antibiotic, has the effects of antibiosis, anti-inflammation, neuroprotection, antioxidation, anti-apoptosis, immunoregulation, tissue repair promotion and the like, and is clinically used for treating infection and inflammation. The treatment of many diseases in the clinic requires sustained high concentrations of minocycline hydrochloride, but prolonged systemic administration of high doses of minocycline has been shown to lead to hepatotoxicity and even death in animal experiments. Local administration, while minimizing the side effects of systemic administration, exposes diseased tissue to high concentrations of minocycline. However, because minocycline is a small molecule drug with high water solubility that releases very quickly (less than 24 hours) from hydrophilic drug delivery systems, currently available drug delivery systems are not suitable for delivering bioactive minocycline locally for extended periods of time.
Ion-pairing complexation is a new method for drug release and delivery in recent years, which improves the therapeutic effect by changing the solubility, stability, release, etc. of the drug. Minocycline can complex Ca 2+ 、Mg 2+ The polyvalent metal ions form a complex with positive charges and maintain the antibacterial and anti-inflammatory activities of the complex. However, the complex formed by minocycline and metal ions is powdery, so that the administration of the minocycline on local tissues is inconvenient. The temperature-sensitive hydrogel is also a drug sustained-release delivery mode which is researched more in recent years, is in a solution form at a low temperature, and generates sol-gel transformation after the temperature rises to be close to body temperature, so that the hydrogel can be well adhered to an application part to slowly release the drug. However, due to the defect that minocycline is unstable when meeting water, the sustained-release time is too short, and frequent administration is needed.
Disclosure of Invention
The invention aims to provide a temperature-sensitive hydrogel for local sustained-release delivery of minocycline hydrochloride and a preparation method thereof, which are used for solving the problems in the prior art.
In order to achieve the purpose, the invention provides the following scheme:
one of the technical schemes of the invention is as follows: the local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel comprises the following raw materials in parts by mass: the following raw materials in parts by mass: 0.1-5 parts of minocycline hydrochloride, 20-50 parts of temperature sensitive material, 2-10 parts of temperature regulator, 0.01-2 parts of metal ion complex, 0.01-2 parts of antioxidant and 150-200 parts of water.
Still further, the local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel comprises the following raw materials in parts by mass: 0.1-2 parts of minocycline hydrochloride, 30-50 parts of temperature sensitive material, 4-8 parts of temperature regulator, 0.01-0.1 part of metal ion complex, 0.01-0.1 part of antioxidant and 150-180 parts of water.
Furthermore, the mass ratio of the metal ion complex to the minocycline hydrochloride is 0.1: 1-5.
Further, the mass ratio of the metal ion complex to minocycline hydrochloride is 0.2: 5.
Furthermore, the mass ratio of the antioxidant to the minocycline hydrochloride is 0.1: 1-5.
Further, the mass ratio of the antioxidant to the 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.
Further, the temperature sensitive material is poloxamer 407.
Further, the temperature regulator comprises one or more of polyethylene glycol, polyvinyl alcohol, poloxamer 188 (P188).
Still further, the temperature regulating agent 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 bisulfite, propyl gallate and butylated hydroxyanisole.
Still further, the antioxidant is sodium bisulfite.
The second technical scheme of the invention is as follows: a preparation method of the local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel comprises the following steps:
(1) adding the temperature sensitive material into water to swell to obtain a solution 1; adding a temperature regulator into water for swelling to obtain a solution 2; adding minocycline hydrochloride, a metal ion complex and an antioxidant into water, and uniformly mixing to obtain a solution 3;
(2) uniformly mixing the solution 1 and the solution 2 to obtain a solution 4;
(3) and dropwise adding the solution 3 into the solution 4, uniformly stirring, adding a pH regulator to regulate the pH to 3-5, and thus obtaining the local slow-release delivery minocycline hydrochloride temperature-sensitive hydrogel.
Further, in the step (1), the swelling temperature is 4 ℃.
Further, in the step (3), the pH regulator includes one or more of acetic acid, sodium citrate, ethanolamine, and sodium hydroxide.
Still further, the pH adjusting agent is acetic acid.
Further, the pH is 3.8 to 4.2.
The third technical scheme of the invention is as follows: an application of the local sustained-release minocycline hydrochloride temperature-sensitive hydrogel in preparation of antibacterial and anti-inflammatory drugs.
The invention discloses the following technical effects:
the hydrogel disclosed by the invention combines the advantages of metal ion complexing and temperature-sensitive hydrogel, not only utilizes the characteristic that the stability can be improved by complexing metal ions and medicines, but also combines the unique property of temperature-sensitive gel solution-gel conversion and a highly hydrophilic three-dimensional grid structure, so that the medicines are adhered to the part where the medicines are applied, the high-concentration long-acting release of the local medicines can be maintained, the administration frequency is reduced, the adverse reaction of the medicines is reduced to a certain extent, and the utilization rate of the medicines 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 required in the embodiments will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a diagram showing the appearance of a hydrogel prepared in example 1 of the present invention;
FIG. 2 is a microscopic view of the hydrogel prepared in example 1 of the present invention, the left image being at a magnification of 250 times and the right image being at a magnification of 2000 times;
FIG. 3 is a graph showing the results of particle size and Zeta potential measurements of the hydrogel prepared in example 1 of the present invention;
figure 4 is a minocycline hydrochloride standard graph;
FIG. 5 is a liquid chromatogram of the hydrogel prepared in example 1 of the present invention;
FIG. 6 is a graph of the in vitro release rate of the hydrogel and minocycline hydrochloride drug substance prepared according to example 1 of the present invention;
FIG. 7 is a graph of the bacteriostatic effect of the bulk drugs of hydrogel and minocycline hydrochloride prepared in example 1 according to the present invention;
figure 8 is an in vitro bacteriostatic plot of the hydrogel and minocycline hydrochloride drug prepared according to example 1 of the present invention.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but rather as a more detailed description 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. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, 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 to disclose and describe the methods and materials in connection with which they pertain. 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 present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The specification and examples are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.
The "parts" described in the following examples are all "parts by mass".
Example 1
A preparation method of a local slow-release minocycline hydrochloride delivery temperature-sensitive hydrogel comprises the following steps:
the local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel is prepared from the following raw materials in parts by mass: 1 part of minocycline hydrochloride (original drug), 40734 parts of poloxamer, 1886 parts of poloxamer, 0.04 part of calcium chloride, 0.02 part of sodium bisulfite and 160 parts of deionized water.
The pH regulator is acetic acid.
The preparation method comprises the following steps:
(1) poloxamer 407 is added to 60 parts of deionized water and placed in a refrigerator at 4 ℃ for sufficient swelling to obtain solution 1.
(2) Adding poloxamer 188 into 50 parts of deionized water, and placing the mixture in a refrigerator at 4 ℃ for full swelling to obtain a solution 2.
(3) Adding minocycline hydrochloride, calcium chloride and sodium bisulfite into 50 parts of deionized water, and uniformly mixing by ultrasonic-assisted dissolution to obtain a solution 3.
(4) And uniformly mixing the solution 1 and the solution 2 to obtain a solution 4.
(5) And dropwise adding the solution 3 into the solution 4, stirring at a high speed (1800r/min) at a low temperature (4 ℃), loading the medicine into a gel carrier, adding a pH regulator (acetic acid), and regulating the pH to 4.0 +/-0.2 to obtain the local sustained-release minocycline hydrochloride delivery thermo-sensitive hydrogel.
Example 2
The method is similar to example 1, and is characterized in that the local sustained-release minocycline hydrochloride temperature-sensitive hydrogel is composed of the following raw materials in parts by mass: 1 part of minocycline hydrochloride (technical product), 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 was 10 wt.% sodium hydroxide.
Example 3
The method is similar to example 1, and is characterized in that the local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel is composed of the following raw materials in parts by mass: 1 part of minocycline hydrochloride (original drug), 34 parts of chitosan, 6 parts of polyethylene glycol, 0.04 part of magnesium oxide, 0.02 part of butyl hydroxy anisol and 160 parts of deionized water.
The pH regulator is sodium citrate.
Example 4
The method is similar to example 1, and is characterized in that the local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel is composed of the following raw materials in parts by mass: 1 part of minocycline hydrochloride (technical product), 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 method is similar to example 1, and is characterized in that the local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel is composed of the following raw materials in parts by mass: 1 part of minocycline hydrochloride (original drug), 40734 parts of poloxamer, 1886 parts of poloxamer, 0.04 part of magnesium oxide, 0.02 part of sodium bisulfite and 160 parts of deionized water.
The pH regulator is ethanolamine.
Example 6
A preparation method of a local slow-release minocycline hydrochloride delivery temperature-sensitive hydrogel comprises the following steps:
the local slow-release minocycline hydrochloride delivery thermosensitive hydrogel is prepared from the following raw materials in parts by mass: 1 part of minocycline hydrochloride (original drug), 40730 parts of poloxamer, 5 parts of chitosan, 1885 parts of poloxamer, 0.04 part of calcium chloride, 0.02 part of sodium bisulfite and 160 parts of deionized water.
The pH regulator is acetic acid.
The preparation method comprises the following steps:
(1) poloxamer is added into 50 parts of deionized water, and the mixture is placed in a refrigerator at 4 ℃ for full swelling to obtain a solution 1.
(2) Adding chitosan into 30 parts of deionized water, and heating to dissolve the chitosan to obtain a solution 2.
(3) Poloxamer 188 was added to 30 parts deionized water and placed in a refrigerator at 4 ℃ to fully swell to give solution 3.
(3) Adding minocycline hydrochloride, calcium chloride and sodium bisulfite into 50 parts of deionized water, and uniformly mixing by ultrasonic-assisted dissolution to obtain a solution 4.
(4) And uniformly mixing the solution 1, the solution 2 and the solution 3 to obtain a solution 5.
(5) And dropwise adding the solution 4 into the solution 5, stirring at a high speed (1800r/min) at a low temperature (4 ℃), loading the medicine into a gel carrier, adding a pH regulator (acetic acid), and regulating the pH to 4.0 +/-0.2 to obtain the local sustained-release minocycline hydrochloride delivery thermo-sensitive hydrogel.
Comparative example 1
A preparation method of a local slow-release minocycline hydrochloride delivery temperature-sensitive hydrogel comprises the following steps:
the local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel is prepared from the following raw materials in parts by mass: 1 part of minocycline hydrochloride (original drug), 40715 parts of poloxamer, 1886 parts of poloxamer, 0.04 part of magnesium oxide, 0.02 part of sodium bisulfite and 160 parts of deionized water.
Acetic acid as a pH regulator.
The preparation method comprises the following steps:
(1) poloxamer 407 is added to 60 parts of deionized water and placed in a refrigerator at 4 ℃ for sufficient swelling to obtain solution 1.
(2) Adding poloxamer 188 into 50 parts of deionized water, and placing the mixture in a refrigerator at 4 ℃ for full swelling to obtain a solution 2.
(3) Adding minocycline hydrochloride, calcium chloride and sodium bisulfite into 50 parts of deionized water, and uniformly mixing by ultrasonic-assisted dissolution to obtain a solution 3.
(4) And uniformly mixing the solution 1 and the solution 2 to obtain a solution 4.
(5) And dropwise adding the solution 3 into the solution 4, stirring at a high speed (1800r/min) at a low temperature (4 ℃), loading 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 a local slow-release minocycline hydrochloride delivery temperature-sensitive hydrogel comprises the following steps:
the local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel is prepared from the following raw materials in parts by mass: 1 part of minocycline hydrochloride (technical material), 40740 parts of poloxamer, 0.04 part of calcium chloride, 0.02 part of sodium bisulfite and 160 parts of deionized water.
Acetic acid as a pH regulator.
The preparation method comprises the following steps:
(1) poloxamer 407 is added to 100 parts of deionized water and placed in a refrigerator at 4 ℃ to fully swell to obtain solution 1.
(2) Adding minocycline hydrochloride, calcium chloride and sodium bisulfite into 60 parts of deionized water, and uniformly mixing by ultrasonic-assisted dissolution to obtain a solution 2.
(3) Dropwise adding the solution 1 into the solution 2, stirring at low temperature (4 ℃) at high speed (1800r/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 a gel material.
The gel prepared in this comparative example, which lacks a temperature regulator, is not suitable for administration because it gels at room temperature.
Comparative example 3
A preparation method of a local slow-release minocycline hydrochloride delivery temperature-sensitive hydrogel comprises the following steps:
the local sustained-release minocycline hydrochloride delivery temperature-sensitive hydrogel is prepared from the following raw materials in parts by mass: 1 part of minocycline hydrochloride (original drug), 40734 parts of poloxamer, 1886 parts of poloxamer, 0.04 part of calcium chloride, 0.02 part of sodium bisulfite and 160 parts of deionized water. Acetic acid as a pH regulator.
The preparation method comprises the following steps:
adding minocycline hydrochloride (original drug), poloxamer 407, poloxamer 188, calcium chloride and sodium bisulfite into 160 parts of deionized water, placing in a refrigerator at 4 ℃ for fully swelling for 24h, allowing the drug to enter a gel carrier, taking out, adding a pH regulator (acetic acid), and regulating the pH to 4.0 +/-0.2 to obtain the gel material.
The material prepared by the comparative example cannot well bear the medicine, the prepared gel is turbid, a clear solution cannot be formed, and a uniform grid structure cannot be formed by observation under a scanning electron microscope.
Effect example 1
The hydrogel prepared in example 1 is characterized, and the results are shown in figures 1-3.
FIG. 1 is a schematic diagram of 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 is a light yellow clear solution, has uniform transparency, no drug precipitation, no precipitation, and good temperature-sensitive properties (gelation occurs at 30 ℃).
After the hydrogel prepared in example 1 of the present invention is freeze-dried, it is adhered to a sample tray of a scanning electron microscope by a conductive adhesive, sputtering and gold spraying are performed by an ion sputtering apparatus, and then the structural characterization of the sample is observed by the scanning electron microscope, and the result is shown in fig. 2, wherein the left image is 250 times of magnification, and the right image is 2000 times of magnification.
As can be seen from FIG. 2, the hydrogel prepared in example 1 of the present invention has a three-dimensional grid and hole structure, which is uniformly distributed.
1mL of the hydrogel prepared in the embodiment 1 of the present invention was diluted 100 times with deionized water, sonicated for 30min, stored for further use, and subjected to particle size and Zeta potential detection using a nano-particle size and Zeta potential analyzer (DLS), with the results shown in FIG. 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. + -. 0.54 mA.
(II) content determination by reversed-phase high performance liquid chromatography
(1) Chromatographic conditions are as follows: a 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 μ L.
(2) Drawing a standard curve: the minocycline hydrochloride reference substance is precisely weighed, diluted by double distilled water to prepare solutions with mass concentrations of 0.25, 0.5, 1, 2, 4 and 8mg/mL, the serial numbers are marked, the solutions are respectively taken to pass through a 0.22 mu m microporous filter, filtrate 1mL is taken and put into a sample bottle (operation of keeping out of the sun). The standard curve of minocycline was plotted using the peak area as ordinate (Y) and the mass concentration as abscissa (X) as determined by the above chromatographic conditions (see fig. 4).
(3) And (3) determination of sample content: sucking 1mL of prepared minocycline hydrochloride temperature-sensitive gel, placing the minocycline hydrochloride temperature-sensitive gel in a 10mL brown volumetric flask, adding double distilled water to dilute the gel to a scale, filtering the gel by using a 0.22 mu m microporous filter, taking 1mL of filtrate, placing the filtrate in a sample bottle, detecting according to the chromatographic conditions, and recording a chromatogram (see figure 5).
The peak area is substituted into the standard curve by an external standard method to calculate the minocycline hydrochloride content in the temperature-sensitive gel, so that the minocycline hydrochloride content in the hydrogel prepared in the embodiment 1 is 4.9769 +/-0.1 mg/mL.
(III) in vitro Release Rate detection
200mL of PBS (pH7.4) buffer solution was taken and preheated in a shaker at 37 ℃ for use. Precisely sucking 2mL of the hydrogel (5mg/mL) prepared in the embodiment 1 of the invention and the minocycline hydrochloride raw material drug with the same concentration, filling the hydrogel and the minocycline hydrochloride raw material drug into treated dialysis bags, respectively putting the dialysis bags into beakers filled with PBS buffer solution, and performing a release experiment at a constant rate. Sucking 2mL of the solution every 2h (after each taking out, the solution needs to be supplemented with PBS buffer solution with the same volume so as to keep the volume of the buffer solution in the beaker unchanged), filtering the solution by using a 0.22 mu m microporous filter, taking 1mL of filtrate, putting the filtrate into a sample bottle, detecting according to the chromatographic conditions, recording a chromatogram, substituting a peak area into a standard curve to calculate the minocycline hydrochloride content, drawing by taking time as a horizontal coordinate and taking the cumulative release percentage as a vertical coordinate, and comparing the release rates of the two solutions, wherein the result is shown in figure 6.
From fig. 6, it can be seen that the hydrogel (temperature sensitive gel) prepared in example 1 of the present invention has a longer drug release time than the drug release time in the simulated in vitro release process.
(IV) study of antibacterial Effect
(1) And (3) detecting the bacteriostatic effect by an agar punching method: suction with pipette 10 8 Adding 200 mu L of cfu/mL log-phase staphylococcus aureus into an MH agar culture medium plate, uniformly coating the MH agar culture medium plate by using a coating rod, and standing for 3-5 min; using a sterilized 200. mu.L yellow tip, 4 wells were punched in MH agar medium coated with the inoculum, each well being 25mm apart and 15mm apart from the edge of the dish. The gun head is not required to be rotated during punching, so that the situation that the liquid medicine diffusion is influenced to cause the non-uniform inhibition zone due to cracks of the agar round hole is avoided; diluting minocycline hydrochloride temperature-sensitive gel with sterilized deionized water to obtain final medicine-containing concentration: 1mg/mL, 0.5mg/mL, 0.1mg/mL hydrogel as the test sample, 50. mu.L of the sample was added to each well, andsterilizing deionized water as a negative control, and using minocycline raw material solution with the same concentration and a blank gel auxiliary material as a positive control; placing in a constant temperature incubator at 37 deg.C, measuring inhibition zone after overnight, comparing inhibition zone size, and finding the result shown in FIG. 7 (1-temperature sensitive gel, 2-bulk drug, 3-blank gel, 4-sterilized and deionized water).
As can be seen from FIG. 7, the hydrogel has no decrease in bacteriostatic ability compared with the bulk drug at the same concentration, and has good bacteriostatic effect.
(2) Drawing an in-vitro bacteriostasis curve: will 10 6 The cfu/mL log-phase staphylococcus aureus liquid is respectively mixed with the hydrogel and the minocycline raw material medicine to be drug-containing liquid with the concentrations of 1/2-MIC (0.125 mug/mL) and MIC (0.25 mug/mL), the drug-containing liquid is added into a 48-well plate, a drug-free bacteria-containing broth culture medium is used as a positive control, and three parallel controls are arranged. The bacterial number is detected by a high-throughput real-time microorganism growth instrument, an 1/2-MIC and MIC drug concentration versus Staphylococcus aureus bacteriostasis curve is drawn by taking the bacterial number as a vertical coordinate and a time point as a coordinate, and the result is shown in figure 8.
As can be seen from FIG. 8, the water gel has obviously prolonged bacteriostasis time compared with minocycline bulk drug under the same concentration condition.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.
Claims (9)
1. The local slow-release minocycline hydrochloride delivery thermosensitive hydrogel is characterized by comprising the following raw materials in parts by mass: 0.1-5 parts of minocycline hydrochloride, 20-50 parts of temperature sensitive material, 2-10 parts of temperature regulator, 0.01-2 parts of metal ion complex, 0.01-2 parts of antioxidant and 150-200 parts of water.
2. The thermo-sensitive hydrogel for local sustained-release delivery of minocycline hydrochloride according to claim 1, wherein the temperature sensitive material comprises one or more of hydroxymethyl cellulose, N-isopropylacrylamide polymer, poloxamer 407, chitosan.
3. The topical sustained-release delivery minocycline hydrochloride temperature-sensitive hydrogel according to claim 1, wherein the temperature modifier comprises one or more of polyethylene glycol, polyvinyl alcohol, poloxamer 188.
4. The topical sustained-release minocycline hydrochloride temperature-sensitive hydrogel according to claim 1, wherein the metal ion complex comprises one or more of magnesium oxide, magnesium chloride, calcium chloride.
5. The topical sustained-release delivery minocycline hydrochloride temperature-sensitive hydrogel according to claim 1, wherein the antioxidant comprises one or more of sodium bisulfite, propyl gallate, butyl hydroxyanisole.
6. A preparation method of the local slow-release minocycline hydrochloride temperature-sensitive hydrogel according to any one of claims 1 to 5, characterized by comprising the following steps:
(1) adding the temperature sensitive material into water to swell to obtain a solution 1; adding a temperature regulator into water for swelling to obtain a solution 2; adding minocycline hydrochloride, a metal ion complex and an antioxidant into water, and uniformly mixing to obtain a solution 3;
(2) uniformly mixing the solution 1 and the solution 2 to obtain a solution 4;
(3) and dropwise adding the solution 3 into the solution 4, uniformly stirring, adding a pH regulator to regulate the pH to 3-5, and thus obtaining the local slow-release delivery minocycline hydrochloride temperature-sensitive hydrogel.
7. The method for preparing the minocycline hydrochloride temperature-sensitive hydrogel according to claim 1, wherein the swelling temperature in step (1) is 4 ℃.
8. The preparation method of the local sustained-release minocycline hydrochloride temperature-sensitive hydrogel according to claim 1, wherein in the step (3), the pH regulator comprises one or more of acetic acid, sodium citrate, ethanolamine and sodium hydroxide.
9. The application of the local slow-release minocycline hydrochloride temperature-sensitive hydrogel according to any one of claims 1 to 5 in preparation of antibacterial and anti-inflammatory drugs.
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