CN116983253A - Temperature-sensitive gel carrying indissolvable drugs and preparation method and application thereof - Google Patents
Temperature-sensitive gel carrying indissolvable drugs and preparation method and application thereof Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 58
- 229940079593 drug Drugs 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 239000011159 matrix material Substances 0.000 claims abstract description 12
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000002156 mixing Methods 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 8
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 claims description 66
- 229960003473 androstanolone Drugs 0.000 claims description 64
- 235000013871 bee wax Nutrition 0.000 claims description 10
- 239000012166 beeswax Substances 0.000 claims description 10
- 239000007765 cera alba Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 230000035945 sensitivity Effects 0.000 abstract description 9
- 241000257303 Hymenoptera Species 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 231100000956 nontoxicity Toxicity 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 64
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- BKCJZNIZRWYHBN-UHFFFAOYSA-N Isophosphamide mustard Chemical compound ClCCNP(=O)(O)NCCCl BKCJZNIZRWYHBN-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 238000011068 loading method Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 9
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229920000858 Cyclodextrin Polymers 0.000 description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 7
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 7
- 239000001116 FEMA 4028 Substances 0.000 description 6
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 6
- 229960004853 betadex Drugs 0.000 description 6
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- 238000011835 investigation Methods 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 5
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- 239000003098 androgen Substances 0.000 description 2
- 102000001307 androgen receptors Human genes 0.000 description 2
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- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
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- 230000008195 breast development Effects 0.000 description 1
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- 239000000084 colloidal system Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
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- 150000002576 ketones Chemical class 0.000 description 1
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- 230000003020 moisturizing effect Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003515 testosterones Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
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- 230000007704 transition Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- MLBMCAGVSIMKNT-UHFFFAOYSA-N β-cds Chemical compound O1C(C(C2OS(O)(=O)=O)OS(O)(=O)=O)C(COS(O)(=O)=O)OC2OC(C(C2OS(O)(=O)=O)OS(O)(=O)=O)C(COS(O)(=O)=O)OC2OC(C(C2OS(O)(=O)=O)OS(O)(=O)=O)C(COS(O)(=O)=O)OC2OC(C(C2OS(O)(=O)=O)OS(O)(=O)=O)C(COS(O)(=O)=O)OC2OC(C(OS(O)(=O)=O)C2OS(O)(=O)=O)C(COS(=O)(=O)O)OC2OC(C(C2OS(O)(=O)=O)OS(O)(=O)=O)C(COS(O)(=O)=O)OC2OC2C(OS(O)(=O)=O)C(OS(O)(=O)=O)C1OC2COS(O)(=O)=O MLBMCAGVSIMKNT-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
-
- 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
- A61K47/06—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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention provides a temperature-sensitive gel for carrying insoluble drugs, and a preparation method and application thereof. The preparation method comprises the following steps: mixing isopropyl myristate and white bees, ultrasonically dissolving, and then stirring by a magnetic stirrer; and ultrasonically mixing the solubilizer and the insoluble medicine, adding the prepared gel matrix, and heating in a water bath. The medicine-carrying gel has the advantages of wide sources of raw materials, low price, low preparation cost, high biological safety, no toxicity or harm to human bodies by using 95% ethanol as a solubilizer, low cost, easy obtainment and easy preparation, the medicine-carrying capacity of the gel can reach 2.5%, the medicine-carrying capacity is large, and the medicine-carrying gel has good temperature sensitivity and film forming property.
Description
Technical Field
The invention belongs to the field of temperature-sensitive gel carrying insoluble drugs, and a preparation method and application thereof.
Background
Dihydrotestosterone (DHT), an androgen naturally produced by the human body, is widely distributed in the whole body blood and has a positive effect on the appearance and maintenance of secondary sex characteristics. It is an important steroid hormone produced irreversibly by testosterone (testosterone, T) under 5 a-reductase (5 a-red 1 and 5 a-red 2) conditions, has a higher affinity for the androgen receptor (androgen receptor, AR) and is therefore considered to be a more potent androgen than T. Pediatric DHT treatment of pediatric congenital 5 a-reductase deficiency-induced male pseudoampholytic deformities, such as penile symptoms. 2.5% DHT hydrogel (trade name Andractim) is marketed in France and is an urgent pediatric clinical need. At present, the dihydrotestosterone gel preparation is not approved to be imported in China, cannot be purchased in China, and can only be purchased overseas or purchased instead of by generation. Compared with testosterone and testosterone derivatives on the market at present, the dihydrotestosterone has the advantages that 1, the pharmacological activity is strong, the dihydrotestosterone is the male hormone with the strongest activity generated naturally, and the biological activity in the body is 6 times of that of testosterone; 2. the side effects are small, and compared with ketone and its derivatives, dihydrotestosterone can not be converted into estradiol in vivo, so that the dihydrotestosterone can not produce side effects of breast development of men and women. There are some disadvantages: the use method is not sanitary and inconvenient, the content and the speed of the medicine which is permeated through the skin are limited, the adverse medicine is fully absorbed and takes effect quickly and slowly, the gel selling price is higher, the economic burden of patients is increased, and the patients cannot take medicine for a long time easily.
A temperature-sensitive gel is a special hydrogel that can be transformed from a flowing liquid (sol phase) to a non-flowing hydrogel (gel phase) according to a certain temperature. Because of its characteristics, it has wide application in biomedical and pharmaceutical fields, namely drug delivery, cell culture, tissue engineering, etc.; as the gel is mostly hydrophilic, for insoluble drugs, insufficient drug loading rate easily occurs when preparing the temperature-sensitive gel, or part of the drugs exist in the gel in a suspension form, the dispersion of the drugs is uneven, the release speed is not easy to control, and the exertion of the drug effect is affected. Although some surfactant can be added to increase the drug loading rate of the drug, the addition of the surfactant may bring new problems such as toxic and side effects, and the surfactant cannot solve the problem that the existing medicinal temperature-sensitive gel releases the drug quickly even possibly aggravated.
Disclosure of Invention
In order to solve the technical problems, the invention firstly provides a temperature-sensitive gel for carrying insoluble drugs, which comprises insoluble drugs, a solubilizer, isopropyl myristate and white beeswax, wherein a gel matrix is formed between the isopropyl myristate and the white beeswax, and the solubilizer and the insoluble drugs are mixed and added into the gel matrix.
Preferably, the mass ratio of isopropyl myristate, beeswax, ethanol and insoluble drug is: 79.5:8:10:2.5.
Preferably, the solubilizing agent is 95% ethanol.
Preferably, the poorly soluble drug is dihydrotestosterone.
Based on a general inventive concept, the invention also provides a preparation method of the temperature-sensitive gel carrying the insoluble medicine, which comprises the following steps:
s1, ultrasonically mixing a solubilizer and a poorly soluble drug to dissolve the drug;
s2, mixing isopropyl myristate and white bees, ultrasonically dissolving, stirring by a magnetic stirrer, adding the dissolved medicine prepared in the S1, heating in a water bath, dissolving, cooling at room temperature, and solidifying to obtain the temperature-sensitive gel carrying the insoluble medicine.
Preferably, the temperature of the water bath heating in the step S2 is 75 ℃.
Based on a general inventive concept, the invention also provides application of the temperature-sensitive gel carrying the insoluble medicine in preparing the matrix gel carrying the insoluble medicine.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention provides a gel matrix prepared from isopropyl myristate and white beeswax for carrying insoluble drugs, which has the advantages of wide raw material sources, low price, low preparation cost and high biological safety.
2. The drug-loaded gel provided by the invention has good temperature sensitivity, can maintain the stability of the gel at normal temperature, but can be quickly converted into liquid when contacting the skin surface of a human body, and has good extensibility and easy absorption.
3. The invention uses 95% ethanol as solubilizer, which is nontoxic and harmless to human body, and has low cost, easy obtaining and easy preparation.
4. The medicine carrying capacity of the gel provided by the invention can reach 2.5%, the medicine carrying capacity is large, and the gel has good temperature sensitivity and film forming property after medicine carrying.
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 shows the effect of different solubilizing agents on drug solubility in Experimental example 2, A being the effect of beta-cyclodextrin and ethanol on DHT dissolution; b is the influence of ethanol, glycerol, IPM,1, 2-propanediol and N, N-dimethylacetamide on the dissolution of DHT;
fig. 2 shows the moldability of four groups of DHT-loaded temperature-sensitive gels of experimental example 4, (1) the experimental group, (2) the experimental group, (3) the experimental group and (4) the experimental group;
fig. 3 shows the temperature sensitivity of two groups of DHT-loaded temperature-sensitive gels at 25 ℃ in experimental example 5, wherein a is the experimental group, and B is the experimental group;
fig. 4 shows the temperature sensitivity of four groups of DHT-loaded temperature-sensitive gels of experimental example 5 at 37 ℃, (1) the experimental group, and (2) the experimental group; (3) the test group is the third test group, and the test group is the fourth test group.
Detailed Description
In order to make the technical problems, technical solutions and advantages to be solved more apparent, the following detailed description will be given with reference to the accompanying drawings and specific embodiments.
The following examples are illustrative of the invention and are not intended to limit the scope of the invention. Modifications and substitutions to methods, procedures, or conditions of the present invention without departing from the spirit and nature of the invention are intended to be within the scope of the present invention.
The technical means used in the examples are conventional means well known to those skilled in the art unless otherwise indicated; the reagents used in the examples were all commercially available unless otherwise specified.
Experimental example 1
Investigation of the viscosity of temperature-sensitive gel matrix with different proportions
3 parts of white beeswax were weighed, 100mg each, placed in 2ml EP tubes, and IPM 800. Mu.L, 1000. Mu.L, 1200. Mu.L were added, respectively. Stirring in 75 deg.C water bath, heating for dissolving, cooling at room temperature, solidifying, and measuring viscosity with DHR-1 rheometer at 25deg.C and shear rate of 5.
As shown in Table 1, the viscosity of the gel matrix formed by isopropyl myristate and white beeswax can reach 7.65-30.60pa.s, when the ratio is 10:1, the rheological property of the low molecular organic gel matrix is good, the average viscosity n (Pa.S) measured by a DHR-1 rheometer is 30.5970, and the matrix has good coating property and is not greasy, so that the ratio of 10:1 is the gel matrix ratio.
TABLE 1 viscosity of gel matrices in different ratios
Experimental example 2
Investigation of the Effect of different solubilizers on the solubility of Dihydrotestosterone drugs
The experiment adopts a single factor investigation mode to respectively examine the solubility of DHT in beta-Cyclodextrin (beta-Cyclodextrin, beta-CD), ethanol (Ethanol, 95%), 1,2, 3-glycerol (glycerol), IPM,1, 2-propanediol and N, N-dimethylacetamide so as to determine the optimal solubilizer, wherein the beta-Cyclodextrin aqueous solution is prepared by dissolving solid beta-CDs in distilled water according to the proportion of 40%, and the experimental group is as follows:
group A: adding 63mg of beta-cyclodextrin and 250mg of DHT into 177 mu L of distilled water for ultrasonic mixing;
group B: adding 125mg of beta-cyclodextrin and 250mg of DHT into 375 mu L of distilled water for ultrasonic mixing;
group C: adding 250mg of DHT into 1ml of ethanol, and mixing by ultrasonic;
group D: DHT 25mg was added to 100 μl ethanol sonicated mix/group E: adding 25mg of DHT into 1000 mu L of ethanol, and mixing by ultrasonic;
group F: DHT 25mg was added to 100 μl glycerol sonicated mix/G group: DHT 25mg was added to 1000 μl of glycerin and mixed by sonication;
group H: DHT 25mg was added to the ultrasonic mix/group I100 μl ipm: adding 25mg of DHT into 1000 muLIPM, and mixing by ultrasonic;
group J: DHT 25mg was added to 100 μl of 1, 2-propanediol sonicated mix/K group: DHT 25mg was added to 1000 μl of 1, 2-propanediol and mixed sonically;
l groups: DHT 25mg was added to 100 μln, ultrasonic mix in N-dimethylacetamide/M group: DHT 25mg was added to 1000 μln and mixed sonically with N-dimethylacetamide;
as a result, as shown in FIG. 1, it was observed from FIG. 1A that the solutions were pale yellow or milky white and oily, respectively, and the layering phenomenon was remarkable and the solubility was poor when cyclodextrin was added. In contrast, the dihydrotestosterone can be completely dissolved in ethanol, the dissolution speed is high, and the solution is clear and transparent; observations from fig. 1B find that: 25 mg/100. Mu.L of ethanol is partially dissolved, 25mg/1ml is completely dissolved; glycerol is too viscous, neither ratio DHT is soluble and aggregates to sink; the main medicine is dispersed into tiny particles in the IPM at two proportions, but is almost insoluble; propylene glycol, although slightly lower than glycerol, also results in a small bulk distribution of the main drug, which is almost insoluble; n, N-dimethylacetamide can completely dissolve the main drug only at 25mg/100 mu L, and the dissolution speed is high, even stirring is not needed. It follows that DHT has better solubility in ethanol and N, N-dimethylacetamide.
The above experiment gives a certain reference to the solubilizer of DHT, but since N, N-dimethylacetamide is found to be a slightly toxic compound, which has strong irritation to eyes, skin and mucous membrane, it is not suitable as a component of an external preparation from the viewpoint of safety.
Thus, ethanol is a preferred DHT solubilizing agent.
Experimental example 3
Investigation of the effect of drug loading on gel viscosity
Three groups of 1.25%, 2.5% and 5% of different drug loading were designed for single factor experiments, and viscosity was analyzed using a cone-plate rheometer to investigate the upper and lower drug loading limits, with the following groups:
drug loading 1.25%: 25mg of the solution is dissolved in 100 mu L of ethanol, added into a mixture of 1.704mL of IPM and 171mg of beeswax, stirred in a water bath at 75 ℃, heated and dissolved, cooled at room temperature, solidified to obtain DHT-loaded temperature-sensitive gel, and the viscosity is measured by a DHR-1 rheometer under the conditions of 25 ℃ and a shearing rate of 5.
Drug loading 2.5%: 50mg of the solution is dissolved in 200 mu L of ethanol, added into a mixture of 1.591mL of IPM and 159mg of beeswax, stirred in a water bath at 75 ℃, heated and dissolved, cooled at room temperature, solidified to obtain DHT-loaded temperature-sensitive gel, and the viscosity is measured by a DHR-1 rheometer at 25 ℃ and a shearing rate of 5.
Drug loading rate 5%: 100mg of the solution is dissolved in 400 mu L of ethanol, added into a mixture of 1.364mL of IPM and 136mg of beeswax, stirred in a water bath at 75 ℃, heated and dissolved, cooled at room temperature, solidified to obtain DHT-loaded temperature-sensitive gel, and the viscosity is measured by a DHR-1 rheometer under the conditions of 25 ℃ and a shearing rate of 5.
The results are shown in Table 2,
TABLE 2 viscosity of gels with different drug loadings
| Drug loading rate | 1.25％ | 2.5％ | 5％ |
| Viscosity pa.s (average) | 15.8284 | 22.7519 | 8.1099 |
As shown in the table, the low molecular weight organic gel of dihydrotestosterone can be formed when the drug loading rates are 1.25%, 2.5% and 5% respectively, and the average viscosity is 15.8284, 22.7519 and 8.1099n (Pa.S) respectively.
Example 1
Preparing DHT-loaded temperature-sensitive gel with different proportions, wherein the reaction temperature is designed to be 75 ℃ and 85 ℃; the ratio of 95% ethanol/DHT was designed to be 200. Mu.l/50 mg, 400. Mu.l/50 mg, and four experimental groups were designed as follows:
the method comprises the following steps: dissolving 50mg in 200 mu L of ethanol, adding into 1591 mu L of mixture of IPM and 159mg of beeswax, stirring in 75 ℃ water bath, heating to dissolve, cooling at room temperature, and solidifying to obtain DHT-loaded temperature-sensitive gel A;
the following: dissolving 50mg in 400 mu L of ethanol, adding into 1409 mu L of mixture of IPM and 141mg of beeswax, stirring in 75 ℃ water bath, heating to dissolve, cooling at room temperature, and solidifying to obtain DHT-loaded temperature-sensitive gel B;
the following steps: dissolving 50mg in 200 mu L ethanol, adding into 1409 mu L mixture of IPM and 141mg beeswax, stirring in water bath at 85deg.C, heating to dissolve, cooling at room temperature, and solidifying to obtain DHT-loaded temperature-sensitive gel C;
and (3) taking: 50mg of the DHT-loaded thermosensitive gel D is dissolved in 400 mu L of ethanol, added into 1409 mu L of a mixture of IPM and 141mg of beeswax, stirred in a water bath at 85 ℃, heated for dissolution, cooled at room temperature, and solidified.
Experimental example 4
Examination of film Forming Property of four groups of DHT-loaded temperature-sensitive gels of example 1
And (3) respectively taking four groups of small amounts of dihydrotestosterone organogels in the embodiment 1, spreading and smearing the four groups of small amounts of dihydrotestosterone organogels in a cell culture dish, drying the cell culture dish in a baking oven at 37 ℃, and observing whether a layer of film is formed on the surface of the cell culture dish, if so, proving that the prepared dihydrotestosterone low-molecular organogel has film forming property.
As shown in fig. 2, a white film can be formed on the surface of the cell culture dish by four groups, which proves that the prepared dihydrotestosterone low-molecular organic gel has film forming property, and the coating of the DHT temperature-sensitive gel is more uniform.
Experimental example 5
Examination of the temperature sensitivity of example 1 four groups of DHT-loaded temperature-sensitive gels
(1) Taking two groups of small amounts of dihydrotestosterone organogels in 50ml beakers respectively, placing the beakers in a constant-temperature water bath kettle at 25 ℃ and observing the solid-liquid state of the organogels;
(2) And (3) respectively taking four groups of small amounts of dihydrotestosterone organogel in the preparation method of the embodiment 1, namely, the preparation method and the application method, putting the four groups of small amounts of dihydrotestosterone organogel in a 50ml beaker, putting the beaker in a constant-temperature water bath kettle at 37 ℃ and observing the solid-liquid state of the organogel.
As shown in fig. 3, by observing the solid-liquid state of the gel, two groups of gel states at 25 ℃ can be found to be semi-solid, and fig. 4 shows that four groups of gels are rapidly converted into liquid from the original semi-solid gel state in the environment of human body temperature close to 37 ℃ and the phase change time is rapid, so that the prepared dihydrotestosterone low-molecular organic gel has good temperature sensitivity and is easy to absorb after being applied to the skin surface. When the cream is actually smeared on the skin surface, the cream-white semitransparent gel is rapidly liquid when contacting the skin surface, is uniform and fine, has good spreadability and good temperature sensitivity.
Experimental example 6
Investigation of the viscosity of four groups of DHT-loaded temperature-sensitive gels of example 1
In the experiment, a DHR-1 rheometer is adopted, the rheological properties of four groups of DHT temperature-sensitive gels in an orthogonal experiment are studied in an oscillation mode, so that the optimal prescription and conditions are screened, and the viscosities of four groups of dihydrotestosterone low-molecular organic gels in the example 1 are respectively measured by adopting the DHR-1 rheometer under the conditions of 25 ℃ and a shear rate of 5.
The results are shown in Table 3,
table 3 viscosity of four sets of DHT-loaded temperature-sensitive gels
From the above table, although four groups of dihydrotestosterone have temperature sensitivity and film forming property, the rheological property of the groups is better than that of the experimental groups. The increase of the ethanol content in the two-by-two control can affect the rheological viscosity of the low molecular organic gel, the reaction temperature is 75 ℃ which is the phase transition point of the low molecular organic gel, and the beeswax is difficult to be completely dissolved in the organic solvent IPM below the reaction temperature, and the gel viscosity is affected to a certain extent above the reaction temperature.
Experimental example 7
Investigation of Heat resistance, cold resistance, film Forming Property and moisture-retaining Property of example 1 DHT-loaded thermosensitive gel
Heat resistance: keeping the temperature at 37+/-1 ℃ for 24 hours, and detecting the oil-water separation phenomenon of the colloid after the temperature is restored to the room temperature;
cold resistance: under the condition of (-8+/-1 ℃) for 24 hours, after the room temperature is restored, whether the shape difference is obvious from that before the test is detected;
film forming property: spreading a small amount of gel in a culture dish, drying in a baking oven at 37 ℃, and detecting whether a film is formed or not;
moisture retention, the product was left at 37.+ -. 1 ℃ for 24 hours, and weight loss was measured.
The results are shown in Table 4:
TABLE 4 Heat resistance, cold resistance, film Forming Property, moisturizing Property of DHT-loaded thermosensitive gel
Experimental results show that the DHT-loaded temperature-sensitive gel has no problems in use and coating, has better stability under high-cold and dry environments, but has a certain oil-water separation phenomenon under the condition of high heat, and the oil-water separation phenomenon occurs due to the fact that the DHT-loaded temperature-sensitive gel has temperature-sensitive characteristics and the space structure of the low-molecular organic gel is destroyed under the condition of high heat, so that water crosslinked into the space structure is lost, and the oil-water separation phenomenon occurs.
The above embodiments are only preferred embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to apply equivalents and modifications according to the technical solution and the concept of the present invention within the scope of the present invention.
Claims (7)
1. The temperature-sensitive gel for carrying the insoluble medicine is characterized by comprising the insoluble medicine, a solubilizer, isopropyl myristate and white beeswax, wherein a gel matrix is formed between the isopropyl myristate and the white beeswax, and the solubilizer and the insoluble medicine are mixed and added into the gel matrix.
2. The temperature-sensitive gel according to claim 1, wherein the mass ratio of isopropyl myristate, beeswax, ethanol and poorly soluble drug is 79.5:8:10:2.5.
3. The temperature-sensitive gel of claim 1, wherein the solubilizing agent is 95% ethanol.
4. The temperature-sensitive gel of claim 1, wherein the poorly soluble drug is dihydrotestosterone.
5. A method of preparing a poorly soluble drug-loaded temperature-sensitive gel as claimed in any one of claims 1 to 4, comprising the steps of:
s1, ultrasonically mixing a solubilizer and a poorly soluble drug to dissolve the drug;
s2, mixing isopropyl myristate and white beeswax, ultrasonically dissolving, stirring in a magnetic stirrer, adding the dissolved medicine prepared in the step S1, heating in a water bath, dissolving, cooling at room temperature, and solidifying to obtain the temperature-sensitive gel carrying the insoluble medicine.
6. The method according to claim 5, wherein the water bath heating temperature in the step S2 is 75 ℃.
7. Use of a poorly soluble drug-loaded temperature-sensitive gel as claimed in any one of claims 1 to 4 or prepared by a preparation method as claimed in any one of claims 5 to 6 for the preparation of a poorly soluble drug-loaded temperature-sensitive gel.
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