CN114796104B - Cyanomycin temperature-sensitive gel and preparation method thereof - Google Patents
Cyanomycin temperature-sensitive gel and preparation method thereof Download PDFInfo
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- CN114796104B CN114796104B CN202210591630.5A CN202210591630A CN114796104B CN 114796104 B CN114796104 B CN 114796104B CN 202210591630 A CN202210591630 A CN 202210591630A CN 114796104 B CN114796104 B CN 114796104B
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- siramectin
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- poloxamer
- sensitive gel
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- 238000002360 preparation method Methods 0.000 title claims abstract description 69
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- 238000001879 gelation Methods 0.000 title description 3
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Images
Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/14—Ectoparasiticides, e.g. scabicides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a siramectin temperature-sensitive gel and a preparation method thereof. The siramectin temperature-sensitive gel comprises siramectin, poloxamer 407, a penetration enhancer, sodium hyaluronate, a preservative and water; the weight and volume percentages of each component accounting for the siramectin temperature-sensitive gel are as follows: 6-8% of siramectin, 12-20% of poloxamer 407, 0.17-2.45% of penetration enhancer, 0.1-0.2% of sodium hyaluronate, 0-0.15% of preservative and the balance of water. The preparation method comprises the following steps: preparing poloxamer 407 water solution, adding sodium hyaluronate, antiseptic, penetration enhancer, and siramesine, and adding distilled water to sufficient amount. The siramectin temperature-sensitive gel prepared by the invention has better release rate in vitro, good transdermal effect and accumulated permeation quantity up to 12.04mg/cm 2 。
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a siramectin temperature-sensitive gel and a preparation method thereof.
Background
The siramectin is obtained by fermenting a new strain of genetically recombinant streptomyces avermitilis, developed by the American-type pyroxene pharmacy, and is obtained by carrying out chemical synthesis structure modification on the doramectin, and is marketed in the United kingdom for the first time in 7 1999 under the trade name of recourse. The siramectin is white or light yellow crystal powder, the chemical name of the siramectin is 25-cyclohexane-25-des (1-methylpropyl) -5-deoxy-22, 23-dihydro-5- (oximino) -avermectin B1 monosaccharide, and the biggest difference between the siramectin and other avermectin antibiotics is C 5 The substituent on the position is an oxime group, and the oxime has a strong lipophilic group in the molecular structure, so that the oxime has high fat solubility and poor water solubility.
The siramectin is an anti-animal internal and external parasite drug which is first developed by the American-type pyroxene company, has wide inhibition and killing effects on a plurality of parasites, including fleas, mange mites, ticks, hookworms, lice, nematodes, heartworms and the like, and has the advantages of convenient use, better curative effect, low toxicity and the like. Although the sorafenib has poor killing effect on part of nematodes (such as haemonchus contortus) and other avermectin medicines (such as ivermectin and doramectin), the sorafenib has the problems of curative effect and safety deficiency in resisting parasitic infection of mice and rabbits. However, the medicine has better effect on treating fleas (Chlamydia felis and Chlamydia canis), mites, ticks and some in-vivo nematodes (roundworms and hookworms) infection of dogs and cats than other avermectin medicines, and has very good effect on preventing heartworm infection of dogs and cats.
Currently, there are 3 dosage forms for the siramectin formulation: drops, oral preparations and injections. The relatively mature product in the market is siramectin drops for external use produced by the American-type dujie company, the Chinese trade name is 'great favor', and the preparation is dripped on the skin for use, and has the characteristics of broad-spectrum expelling insects in vitro and in vivo, convenient use and the like. However, the common transdermal drops have short residence time on the body surface, so that the medicine is not completely permeated, and the exertion of the medicine effect of the siramectin is affected. Therefore, development of a formulation which has a long contact time with the skin and which can achieve complete or nearly complete penetration of the drug, thereby improving the efficacy of siramectin, is an ongoing research direction for pharmaceutical technicians.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a siramectin temperature-sensitive gel, which comprises siramectin, a matrix, a permeation enhancer, a humectant, a preservative and water.
Specifically, the siramectin temperature-sensitive gel comprises siramectin, poloxamer 407, a penetration enhancer, sodium hyaluronate, a preservative and water; the weight and volume percentages of each component accounting for the siramectin temperature-sensitive gel are as follows: 6-8% of siramectin, 12-20% of poloxamer 407, 0.17-2.45% of penetration enhancer, 0.1-0.2% of sodium hyaluronate, 0-0.15% of preservative and the balance of water.
The penetration enhancer is one or two of 1, 2-propylene glycol, polyethylene glycol 400, laurocapram and peppermint oil.
Preferably, the penetration enhancer is 1, 2-propanediol.
The preservative is sodium benzoate, potassium sorbate or a combination thereof.
Further, the invention preferably discloses a siramectin temperature-sensitive gel, wherein the weight and volume percentages of each component in the siramectin temperature-sensitive gel are as follows: 6-8% of sirametin, 15-20% of poloxamer 407, 0.17-0.84% of 1, 2-propylene glycol, 0.1-0.2% of sodium hyaluronate, 0.1-0.15% of preservative and the balance of water.
Further, the invention preferably discloses a siramectin temperature-sensitive gel, wherein the weight and volume percentages of each component in the siramectin temperature-sensitive gel are as follows: 6-8% of sirametin, 15.5-16.0% of poloxamer 407, 0.17-0.84% of 1, 2-propylene glycol, 0.1-0.2% of sodium hyaluronate, 0.1-0.15% of preservative and the balance of water.
Further, the mass ratio of poloxamer 407 to 1, 2-propylene glycol is as follows: 15:1 to 95:1, preferably 95:1 to 50:1 or 20:1 to 15:1, preferably 90 to 95:1 or 18 to 20:1.
The preparation process of the siramectin temperature-sensitive gel provided by the invention comprises the following steps:
(1) Adding poloxamer 407 into distilled water to obtain an aqueous solution of poloxamer 407;
(2) Adding sodium hyaluronate, antiseptic and penetration enhancer into poloxamer 407 water solution, stirring, sealing, and standing to obtain matrix solution;
(3) Adding siramectin into the matrix solution, stirring uniformly, dissolving by ultrasonic, sealing and standing.
(4) Adding distilled water to a certain volume, stirring, and packaging.
The prepared siramectin temperature-sensitive gel has the specification of 0.25ml, and 15mg of the siramectin is contained in each 0.25 ml. The preparation is stored at room temperature.
The experiment takes in vitro release and rat transdermal experiments as research methods, and takes time and in vitro accumulated release percentage and time and accumulated permeation quantity as evaluation indexes respectively.
In vitro drug release test
The experiment uses a vertical diffusion cell, an artificial membrane is fixed between a drug administration cell and a receiving cell, and the effective diffusion area is 1.54cm 2 . The temperature-sensitive gel of the example is weighed by a 1ml syringe and added into a dosing tank respectively, and is uniformly smeared on an artificial membrane, and 4ml of 30% methanol physiological saline is added into a receiving tank to remove bubbles, so that the artificial membrane is connected with the liquid level. Stirring continuously at 37deg.C and 500 (r/min), extracting 4ml of the receiving liquid 1h, 2h, 4h, 6h, 8h, 10h, 12h, and 24h after administration, supplementing fresh receiving liquid with the same volume and the same temperature, filtering the extracted receiving liquid with 0.45 μm filter membrane to obtain subsequent filtrate, measuring ultraviolet absorbance, calculating concentration according to external standard one-point method, and drawing graph of cumulative drug release curve.
The siramectin temperature-sensitive gel prepared by the invention has better release rate in vitro, good transdermal effect and accumulated permeation quantity up to 12.04mg/cm 2 。
Drawings
FIG. 1 is a graph of cumulative drug release for examples 1-6.
FIG. 2 is a graph showing cumulative drug release profiles of examples 1 and 7-12.
Fig. 3 is a graph showing cumulative drug release profiles of examples 1, 7, 8, 13, and 16.
Detailed Description
The present invention is further illustrated by the following examples, but the present invention is not limited to the following examples. Modifications of the corresponding substitutions or alterations herein, without departing from the spirit and scope of the present invention, are intended to be within the scope of the present invention.
The preparations prepared in the following examples were 100ml, each preparation had a volume of 0.25ml and contained 15mg of drug.
Example 1:
poloxamer 407 | 15.90g | 15.90% |
Sodium benzoate | 0.06g | 0.06% |
Potassium sorbate | 0.08g | 0.08% |
Sodium hyaluronate | 0.13g | 0.13% |
1, 2-propanediol | 0.17g | 0.17% |
Cyanomycin | 6.00g | 6.00% |
Distilled water | To 100ml | Allowance of |
The preparation method comprises the following steps:
(1) Weighing poloxamer 407, and adding poloxamer 407 into 80ml of distilled water to prepare poloxamer 407 aqueous solution;
(2) Precisely weighing potassium sorbate, sodium benzoate, sodium hyaluronate and 1, 2-propylene glycol with the prescribed amount, adding the above solution, stirring uniformly, sealing, and standing in a refrigerator at 4deg.C for 24 hr to obtain gel matrix;
(3) Precisely weighing the prescription amount of the siramectin, adding the siramectin into the gel matrix prepared in the step (2), performing ultrasonic treatment in a low-temperature ultrasonic instrument until the medicine is completely dissolved, and then sealing the mixture and standing the mixture for 24 hours in a refrigerator at the temperature of 4 ℃. Taking out, adding distilled water to 100ml, stirring, and packaging (with specification of 0.25ml and 15mg of siramectin per 0.25 ml) to obtain siramectin temperature-sensitive gel.
The gel state is uniform, the gel is not layered after standing, and the appearance is transparent. 15mg of the preparation (the volume of the preparation is 0.25 ml) containing the drug is taken, the preparation does not gel at room temperature and rapidly gels at body temperature (32 ℃). The in vitro release experiment result shows that the accumulated release of the drug released in vitro for 24 hours reaches 82.49 percent.
Example 2:
poloxamer 407 | 15.90g | 15.90% |
Sodium benzoate | 0.06g | 0.06% |
Potassium sorbate | 0.08g | 0.08% |
Sodium hyaluronate | 0.13g | 0.13% |
Polyethylene glycol 400 | 0.17g | 0.17% |
Cyanomycin | 6.00g | 6.00% |
Distilled water | To 100ml | Allowance of |
The preparation method comprises the following steps:
as in example 1.
The gel state is uniform, the gel is not layered after standing, and the appearance is transparent. 15mg of the preparation (the volume of the preparation is 0.25 ml) containing the drug is taken, the preparation does not gel at room temperature and rapidly gels at body temperature (32 ℃). The in vitro release experiment result shows that the accumulated release of the drug released in vitro for 24 hours reaches 74.11 percent.
Example 3:
poloxamer 407 | 15.90g | 15.90% |
Sodium benzoate | 0.06g | 0.06% |
Potassium sorbate | 0.08g | 0.08% |
Sodium hyaluronate | 0.13g | 0.13% |
Peppermint oil | 0.17g | 0.17% |
Cyanomycin | 6.00g | 6.00% |
Distilled water | To 100ml | Allowance of |
The preparation method comprises the following steps:
as in example 1.
The gel state is uniform, the gel is not layered after standing, and the appearance is transparent. 15mg of the preparation (the volume of the preparation is 0.25 ml) containing the drug is taken, the preparation does not gel at room temperature and rapidly gels at body temperature (32 ℃). The in vitro release experiment result shows that the accumulated release of the drug released in vitro for 24 hours reaches 73.21 percent.
Example 4:
poloxamer 407 | 15.90g | 15.90% |
Sodium benzoate | 0.06g | 0.06% |
Potassium sorbate | 0.08g | 0.08% |
Sodium hyaluronate | 0.13g | 0.13% |
Laurocapram | 0.17g | 0.17% |
Cyanomycin | 6.00g | 6.00% |
Distilled water | To 100ml | Allowance of |
The preparation method comprises the following steps:
as in example 1.
The gel state is uniform, the gel is not layered after standing, and the appearance is transparent. 15mg of the preparation (the volume of the preparation is 0.25 ml) containing the drug is taken, the preparation does not gel at room temperature and rapidly gels at body temperature (32 ℃). The in vitro release experiment result shows that the accumulated release of the drug released in vitro for 24 hours reaches 73.64 percent.
Example 5:
poloxamer 407 | 15.90g | 15.90% |
Sodium benzoate | 0.06g | 0.06% |
Potassium sorbate | 0.08g | 0.08% |
Sodium hyaluronate | 0.13g | 0.13% |
Cyanomycin | 6.00g | 6.00% |
Distilled water | To 100ml | Allowance of |
The preparation method comprises the following steps:
as in example 1.
The gel state is uniform, the gel is not layered after standing, and the appearance is transparent. 15mg of the preparation (the volume of the preparation is 0.25 ml) containing the drug is taken, the preparation does not gel at room temperature and rapidly gels at body temperature (32 ℃). The in vitro release experiment result shows that the accumulated release of the drug released in vitro for 24 hours reaches 72.71 percent.
Example 6:
poloxamer 407 | 15.90g | 15.90% |
Sodium benzoate | 0.06g | 0.06% |
Potassium sorbate | 0.08g | 0.08% |
Sodium hyaluronate | 0.13g | 0.13% |
1, 2-propanediol | 0.12g | 0.12% |
Laurocapram | 0.05g | 0.05% |
Cyanomycin | 6.00g | 6.00% |
Distilled water | To 100ml | Allowance of |
The preparation method comprises the following steps:
as in example 1.
The gel state is uniform, the gel is not layered after standing, and the appearance is transparent. 15mg of the preparation (the volume of the preparation is 0.25 ml) containing the drug is taken, the preparation does not gel at room temperature and rapidly gels at body temperature (32 ℃). The in vitro release experiment result shows that the accumulated release of the drug released in vitro for 24 hours reaches 75.44 percent.
The results of examples 1-6 show that under the condition that the components and the dosage in the formula are the same, different permeation enhancers are changed, the release of the medicines is different, and the cumulative release of the medicines can be improved to different degrees by different permeation enhancers. When the permeation enhancer is 1, 2-propanediol, the cumulative drug release at 24 hours is 80% or more, whereas a formulation using polyethylene glycol 400, peppermint oil, laurocapram, 1.2-propanediol in combination with laurocapram as the permeation enhancer is substantially equivalent to the cumulative 24 hour release of a formulation without the addition of the permeation enhancer and is significantly lower than a formulation with 1, 2-propanediol as the permeation enhancer. It can be seen that the same amount of other permeation enhancers does not increase the drug release. Therefore, 1.2-propylene glycol is selected as a permeation enhancer to prepare the siramectin temperature-sensitive gel.
Example 7:
the preparation method comprises the following steps:
as in example 1.
The gel state is uniform, the gel is not layered after standing, and the appearance is transparent. 15mg of the preparation (the volume of the preparation is 0.25 ml) containing the drug is taken, the preparation does not gel at room temperature and rapidly gels at body temperature (32 ℃). The in vitro release experiment result shows that the accumulated release of the medicine reaches 77.48 percent after 24 hours of in vitro release.
Example 8:
poloxamer 407 | 15.90g | 15.90% |
Sodium benzoate | 0.06g | 0.06% |
Potassium sorbate | 0.08g | 0.08% |
Sodium hyaluronate | 0.13g | 0.13% |
1, 2-propanediol | 0.84g | 0.84% |
Cyanomycin | 6.00g | 6.00% |
Distilled water | To 100ml | Allowance of |
The preparation method is the same as in example 1.
The gel state is uniform, the gel is not layered after standing, and the appearance is transparent. 15mg of the preparation (the volume of the preparation is 0.25 ml) containing the drug is taken, the preparation does not gel at room temperature and rapidly gels at body temperature (32 ℃). The in vitro release experiment result shows that the accumulated release of the medicine can reach 90.76% after 24 hours of in vitro release.
Example 9:
poloxamer 407 | 15.90g | 15.90% |
Sodium benzoate | 0.06g | 0.06% |
Potassium sorbate | 0.08g | 0.08% |
Sodium hyaluronate | 0.13g | 0.13% |
1, 2-propanediol | 1.32g | 1.32% |
Cyanomycin | 6.00g | 6.00% |
Distilled water | To 100ml | Allowance of |
The preparation method is the same as in example 1.
The gel state is uniform, the gel does not delaminate after standing, the appearance is transparent, 15mg of the preparation containing the medicine (the volume of the preparation is 0.25 ml) is taken, the gel is not gelled at room temperature, and the gel is rapidly gelled at the body temperature (32 ℃). The in vitro release experiment is carried out, and the result shows that the accumulated release of the drug released in vitro for 24 hours reaches 69.22 percent.
Example 10:
poloxamer 407 | 15.90g | 15.90% |
Sodium benzoate | 0.06g | 0.06% |
Potassium sorbate | 0.08g | 0.08% |
Sodium hyaluronate | 0.13g | 0.13% |
1, 2-propanediol | 1.65g | 1.65% |
Cyanomycin | 6.00g | 6.00% |
Distilled water | To 100ml | Allowance of |
The preparation method is the same as in example 1.
The gel state is uniform, the gel does not delaminate after standing, the appearance is transparent, 15mg of the preparation containing the medicine (the volume of the preparation is 0.25 ml) is taken, the gel is not gelled at room temperature, and the gel is rapidly gelled at the body temperature (32 ℃). The in vitro release experiment is carried out, and the result shows that the accumulated release of the drug released in vitro for 24 hours reaches 72.31 percent.
Example 11:
poloxamer 407 | 15.90g | 15.90% |
Sodium benzoate | 0.06g | 0.06% |
Potassium sorbate | 0.08g | 0.08% |
Sodium hyaluronate | 0.13g | 0.13% |
1, 2-propanediol | 2.13g | 2.13% |
Cyanomycin | 6.00g | 6.00% |
Distilled water | To 100ml | Allowance of |
The preparation method is the same as in example 1.
The gel state is uniform, the gel does not delaminate after standing, the appearance is transparent, 15mg of the preparation containing the medicine (the volume of the preparation is 0.25 ml) is taken, the gel is not gelled at room temperature, and the gel is rapidly gelled at the body temperature (32 ℃). The in vitro release experiment is carried out, and the result shows that the accumulated release of the drug released in vitro for 24 hours reaches 62.33 percent.
Example 12:
the preparation method is the same as in example 1.
The gel state is uniform, the gel does not delaminate after standing, the appearance is transparent, 15mg of the preparation containing the medicine (the volume of the preparation is 0.25 ml) is taken, the gel is not gelled at room temperature, and the gel is rapidly gelled at the body temperature (32 ℃). The in vitro release experiment is carried out, and the result shows that the drug accumulation release reaches 71.02% after 24 hours of in vitro release.
The same formulation is adopted in examples 1 and 7-12, and the dosage of the permeation enhancer is changed, so that the result shows that the dosage of the permeation enhancer affects the accumulated release amount of the medicine. However, the greater the amount of non-permeation enhancer, the greater the cumulative release of drug. The in vitro release result shows that when the weight volume percentage of the 1, 2-propanediol is in the range of 0.1 percent to 1.0 percent, preferably 0.17 percent to 0.84 percent, the accumulated release amount of the medicine can be obviously improved; when the weight volume percentage of the 1, 2-propanediol is 1.32-2.45%, the penetration promoting effect is inhibited, and the excessive addition of the 1, 2-propanediol can possibly reduce the solubility of the medicament.
Example 13:
poloxamer 407 | 15.50g | 15.50% |
Sodium benzoate | 0.06g | 0.06% |
Potassium sorbate | 0.08g | 0.08% |
Sodium hyaluronate | 0.13g | 0.13% |
1, 2-propanediol | 0.84g | 0.84% |
Cyanomycin | 6.00g | 6.00% |
Distilled water | To 100ml | Allowance of |
The preparation method is the same as in example 1.
The gel state is uniform, the gel does not delaminate after standing, the appearance is transparent, 15mg of the preparation containing the medicine (the volume of the preparation is 0.25 ml) is taken, the gel is not gelled at room temperature, and the gel is rapidly gelled at the body temperature (32 ℃). The in vitro release experiment is carried out, and the result shows that the accumulated release of the drug can reach 80% after 24 hours of in vitro release.
Example 14:
the preparation method is the same as in example 1.
The gel state is uniform, no layering is caused after standing, the appearance is transparent, 15mg of the preparation (the volume of the preparation is 0.25 ml) containing the medicine is taken, the preparation is not gelled at room temperature, the preparation is not gelled at the body temperature (32 ℃), namely, when the dosage of poloxamer 407 is lower than 15.50%, the prepared gel is not gelled at the body temperature (32 ℃).
Example 15:
poloxamer 407 | 16.50g | 16.50% |
Sodium benzoate | 0.06g | 0.06% |
Potassium sorbate | 0.08g | 0.08% |
Sodium hyaluronate | 0.13g | 0.13% |
1, 2-propanediol | 0.84g | 0.84% |
Cyanomycin | 6.00g | 6.00% |
Distilled water | To 100ml | Allowance of |
The preparation method is the same as in example 1.
The gel state is uniform, no layering is caused after standing, the appearance is transparent, 15mg of the preparation containing the medicine (the volume of the preparation is 0.25 ml) is taken, the preparation is gelled after being placed at room temperature for about half an hour, and the gel is quickly gelled at the body temperature (32 ℃), namely, when the dosage of poloxamer 407 is higher than 16.50%, the gel phenomenon can occur at the room temperature.
Example 16:
the release of the drug in the commercial sirolimus drops (great favor) was measured according to the release method described above, and the results indicate that the maximum release was achieved at 2 hours.
The medicine release result shows that the siramectin temperature-sensitive gel can realize slow medicine release, and the commercially available 'great favor' is fast released within 2 hours, so that the siramectin temperature-sensitive gel is more suitable for acting on the body surface for a long time so as to exert the curative effect.
Example 17:
transdermal test of siramectin temperature-sensitive gel
Rat transdermal test
The experiment used a vertical diffusion cell, the rat skin was fixed between the administration cell and the receiving cell, the stratum corneum faced the feeding chamber, the dermis faced the receiving chamber, and the effective diffusion area was 1.54cm 2 . The 15mg dose of the siramectin ethanol solution, example 1, example 7, example 8, example 12, example 13, example 14, example 15 and example 16 commercial "Dachang" siramectin drops were respectively taken and added into a dosing tank, and uniformly smeared on rat skin, and 4ml of 30% methanol physiological saline was added into a receiving tank to remove air bubbles, so that the rat skin was connected with the liquid surface. Stirring was continued at 37℃and 500 (r/min), 4ml of the receiving liquid was withdrawn 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 26h, 28h, 32h after the administration and fresh receiving liquid of the same volume and the same temperature was replenished, the withdrawn receiving liquid was filtered with a 0.45 μm filter membrane to obtain a subsequent filtrate, the ultraviolet absorbance was measured, and the cumulative permeation quantity Q was calculated.
ρn is the mass concentration of siramectin (μg.mL) at the nth sampling point -1 ) V is the sampling volume and A is the penetration area.
The results of the rat transdermal test for 32 hours show that: the average value of the drug accumulated permeation quantity of 3 batches of test samples of the blank drugs is 6.82mg/cm 2 The method comprises the steps of carrying out a first treatment on the surface of the The average value of the cumulative permeation amounts of the drugs in the 3 batches of test pieces of example 1 was 7.57mg/cm 2 The method comprises the steps of carrying out a first treatment on the surface of the The average value of the cumulative permeation amounts of the drugs in the 3 batches of test pieces of example 7 was 8.68mg/cm 2 The method comprises the steps of carrying out a first treatment on the surface of the Example 8 batch 3The average value of the accumulated permeation quantity of the medicine of the test sample is 12.04mg/cm 2 The method comprises the steps of carrying out a first treatment on the surface of the The average value of the cumulative permeation amounts of the drugs in the 3 batches of test pieces of example 12 was 8.92mg/cm 2 The method comprises the steps of carrying out a first treatment on the surface of the The average value of the cumulative permeation amounts of the drugs in the 3 batches of test pieces of example 13 was 10.29mg/cm 2 The method comprises the steps of carrying out a first treatment on the surface of the The average value of the cumulative permeation amounts of the drugs in the 3 batches of test pieces of example 14 was 9.33mg/cm 2 The method comprises the steps of carrying out a first treatment on the surface of the The average value of the cumulative permeation amounts of the drugs in the 3 batches of test pieces of example 15 was 10.01mg/cm 2 The method comprises the steps of carrying out a first treatment on the surface of the The average value of the accumulated permeation quantity of 3 batches of samples sold in the market of 'great favor' is 8.34mg/cm 2 . From the results, the drug permeability of the temperature-sensitive gel preparation is obviously higher than that of a drug solution and higher than that of the commercial 'great favor', and particularly the drug accumulated permeability of the gel of the example 8 is the highest.
Example 18:
gel time determination of siramectin temperature sensitive gel: 0.25ml of the example gel was taken into a glass tube at room temperature, at which point the formulation was in the sol state. The glass test tube is placed in a water bath kettle with the temperature of 32 ℃, timing is started, the glass test tube is inverted from time to observe the gel time of the sol, namely the gel time of the siromycin temperature-sensitive gel, each example is measured three times, and the average value is calculated.
Examples | Gel time(s) |
1 | 4.4 |
2 | 3.2 |
3 | 3.0 |
4 | 4.3 |
5 | 3.8 |
6 | 4.4 |
7 | 3.9 |
8 | 3.3 |
9 | 3.6 |
10 | 3.2 |
11 | 3.5 |
12 | 3.7 |
13 | 3.0 |
14 | Non-gelling |
15 | Room temperature gelation |
From the above results, in example 14, the addition amount of poloxamer 407 was small, so that the temperature-sensitive gel matrix could not be produced; the poloxamer 407 in example 15 was added in a large amount to directly form a gel.
Claims (7)
1. The siramectin temperature-sensitive gel is characterized by comprising the following components in percentage by weight and volume: 6-8% of sirametin, 15.5-16.0% of poloxamer 407, 0.17-0.84% of 1, 2-propylene glycol, 0.1-0.2% of sodium hyaluronate, 0-0.15% of preservative and the balance of water, wherein the mass ratio of the poloxamer 407 to the 1, 2-propylene glycol is as follows: 20:1-15:1.
2. The siramectin temperature-sensitive gel of claim 1, wherein said preservative is sodium benzoate, potassium sorbate, or a combination thereof.
3. The siramectin temperature-sensitive gel as set forth in claim 2, wherein the preservative is a combination of sodium benzoate and potassium sorbate, and the preservative accounts for 0.1-0.15% by weight of the siramectin temperature-sensitive gel.
4. The siramectin temperature-sensitive gel according to claim 1, wherein the mass ratio of poloxamer 407 to 1, 2-propanediol is 18-20:1.
5. The method for preparing the siramectin temperature-sensitive gel according to claim 1, comprising the steps of:
(1) Adding poloxamer 407 into distilled water to obtain an aqueous solution of poloxamer 407;
(2) Adding sodium hyaluronate, antiseptic and 1, 2-propylene glycol into poloxamer 407 water solution, stirring, sealing, and standing to obtain matrix solution;
(3) Adding siramectin into the matrix solution, stirring uniformly, dissolving by ultrasonic, sealing and standing;
(4) Adding distilled water to a certain volume, stirring, and packaging.
6. Use of a siramectin temperature-sensitive gel according to any one of claims 1 to 4 for the preparation of a medicament for the inhibition and killing of parasites.
7. The use according to claim 6 wherein the parasite is a flea, scabies, tick, hookworm, lice, nematode or heartworm.
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