CN114073668A - Semi-solid preparation - Google Patents

Semi-solid preparation Download PDF

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CN114073668A
CN114073668A CN202010752507.8A CN202010752507A CN114073668A CN 114073668 A CN114073668 A CN 114073668A CN 202010752507 A CN202010752507 A CN 202010752507A CN 114073668 A CN114073668 A CN 114073668A
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percent
solid formulation
semisolid
compound
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赵玉姣
袁永玲
赵芹
赵志荣
卢智俊
黄慧良
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Regenex Corp
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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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    • 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
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    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P31/12—Antivirals
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Abstract

The invention discloses a semisolid preparation, which comprises a pharmacological active substance and a pharmaceutically acceptable carrier; the pharmacological active substance is 0.01-10% of compound IV, and the pharmaceutically acceptable carrier comprises: 30-90% of solvent, 3-20% of cosolvent, 1-20% of emulsifier, 10-40% of fat-soluble matrix, 10-30% of percutaneous absorption promoter, 0.01-2% of pH regulator, and one or more of the following components: bacteriostatic agent, metal chelating agent, antioxidant, humectant; the weight percentages of the components are as follows: 0-3% of bacteriostatic agent, 0-1% of metal chelating agent, 0-0.2% of antioxidant and 0-10% of humectant; the semisolid preparation is mainly administrated through skin, has good patient compliance, and can avoid the inactivation of the medicament in gastrointestinal tract and the first pass effect of liver; and can stabilize the blood concentration and keep the blood concentration within the effective concentration range for a long time; meanwhile, the irritation of the medicine to the gastrointestinal tract is reduced, and the safety is improved.

Description

Semi-solid preparation
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a semisolid preparation.
Background
The applicant previously granted a patent with publication number CN108676067B, the name of which is a new compound for preventing HIV infection and a preparation method thereof, discloses a structural general formula of the compound IV is shown as formula (IV):
Figure BDA0002610492650000011
r represents the following group:
Figure BDA0002610492650000012
the patent also discloses a specific preparation method of the compound IV, which has the advantages of low preparation cost, simple preparation method, high acyl bromide activity, rapid and thorough reaction with amino, absorption of generated hydrogen bromide by alkali, simple post-treatment and high yield; and the post-treatment is simple, the high-purity target can be obtained by using a recrystallization purification method, column chromatography is not needed, and the method is very suitable for industrial large-scale production. In the meantime, the applicant refers to the test method of patent ZL02807728.8, using HIV strain of type HIV-1IIIB, and conducted in parallel antiretroviral activity and cytotoxicity assays. These assays are based on the survival of MT-4 cells that have been infected with HIV and then exposed to various concentrations of test compounds. After 5 days of MT-4 cell proliferation, the number of viable cells was quantified on a 96-well microplate by the tetrazolium colorimetric-based 3- (4, 5-dimethylthiazol-2-yl) -2, 5-dimethyltetrazolium bromide (MTT) method. The detection result shows that the compound IV has good anti-HIV activity and can effectively prevent HIV infection.
The applicant has made relevant studies on relevant preparations of compound IV based on the existing studies, the compound IV of the present invention belongs to hydrophilic compounds, hydrophilic drugs can be formulated into solution for oral administration or administration by injection or common external preparations, but such drugs often cannot or are difficult to penetrate cell membranes into cells in a passive diffusion manner due to excellent hydrophilicity and poor lipophilicity, so that the drug effect is limited, and part or even most of the drug prototypes are excreted out of the body in the form of drugs. The antiviral drugs in the prior art are mainly in the forms of injections or tablets, capsules, oral liquids and the like, and the administration of the injections or liquid preparations has certain limitations, such as professional personnel required for injection, and difficulty in application of the liquid preparations or the tablets, the capsules and the like to patients with dysphagia. Thus, applicants desire a semisolid formulation that is convenient to administer, fast acting, and highly compliant.
Disclosure of Invention
The invention aims to overcome at least one defect of the prior art and provides a semisolid preparation which has the advantages of convenient administration, good stability and quick response.
The semisolid preparation can be used for preventing and/or treating SARS-CoV, SARS-CoV-2 or MERS-CoV virus infection. Can be used for preventing and/or treating middle east respiratory syndrome, severe acute respiratory syndrome, and novel coronavirus pneumonia.
The semi-solid formulations of the present invention may also be used for the prevention and/or treatment of infection by HIV.
The semisolid preparation provided by the invention can also be used for preventing and/or treating HPV infection, such as reproductive system related diseases caused by HIV infection.
The semisolid preparation can also be used for preventing and/or treating BV infection, such as bacterial vaginal inflammation caused by BV infection.
The invention provides a semisolid preparation, which comprises a pharmacological active substance and a pharmaceutically acceptable carrier; the pharmacological active substance is 0.01-10% of compound IV, and the pharmaceutically acceptable carrier comprises: 30-90% of solvent, 3-20% of cosolvent, 1-20% of emulsifier, 10-40% of fat-soluble matrix, 10-30% of percutaneous absorption promoter, 0.01-3% of pH regulator, and one or more of the following components: bacteriostatic agent, metal chelating agent, antioxidant, humectant; the weight percentages of the components are as follows: 0-3% of bacteriostatic agent, 0-1% of metal chelating agent, 0-0.2% of antioxidant and 0-10% of humectant;
the solvent is water;
the cosolvent is one or more of ethanol, propylene glycol, glycerol and hexadecanol.
The emulsifier is one or more of polysorbate, glyceryl monostearate, polyoxyethylene (20) lauryl ether and fatty alcohol polyoxyethylene ether.
The fat-soluble matrix is one or more of white vaseline, stearic acid, lanolin, liquid paraffin and beeswax;
the percutaneous absorption enhancer is dimethyl sulfoxide, N-dodecane-2-pyrrolinone, and azone
Figure BDA0002610492650000031
One or more of a ketone;
the pH regulator is one or more of phosphate, tartaric acid and citrate; the pH regulator regulates the pH of the semisolid preparation to 4-9;
wherein the structural formula of the compound IV is shown as the formula (IV):
Figure BDA0002610492650000032
wherein R represents the following group:
Figure BDA0002610492650000033
the compound IV of the invention has good water solubility, and in order to reduce the irritation of the prepared semisolid preparation, the solvent is purified water, but in order to promote the further dissolution of the compound IV, the semisolid preparation of the invention is added with a cosolvent, applicants select one or more of ethanol, propylene glycol, glycerol and hexadecanol from a plurality of selectable cosolvents, preferably, the cosolvent of the invention selects hexadecanol or a mixed solution of ethanol and propylene glycol in a certain ratio, more preferably, the mixed solution of ethanol and propylene glycol in a ratio of 1: 1-5, the dissolubility of the compound IV is guaranteed, the sticky feeling of the semisolid preparation can be reduced, the use comfort of a patient is improved, and the functions of dissolving aid and moisture retention can be realized by propylene glycol.
The invention also discloses another invention point that the selective addition of the percutaneous absorption enhancer, the compound of the invention has good water solubility, and the percutaneous absorption can be absorbed and utilized better only by adding the percutaneous absorption enhancer because the compound of the invention has certain difficulty in the percutaneous absorption, and the invention screens out dimethyl sulfoxide, N-dodecane-2-pyrrolinone and lauryl nitrogen from a plurality of percutaneous absorption enhancers
Figure BDA0002610492650000041
The three components of the ketone can promote the absorption of the drug by skin tissues to a great extent, and simultaneously can not cause great stimulation to the skin tissues. More preferably, the transdermal absorption enhancer is dimethyl sulfoxide, and the applicant has proved through a large number of experiments that dimethyl sulfoxide has less irritation to the skin and can better promote the absorption of the drug.
Another aspect of the present invention is that the applicant selectively adds a pH adjusting agent to improve the stability of the pharmaceutical formulation based on the properties of compound IV. Applicants have found that when the pH of the semisolid formulation of the present invention is controlled to be 4-8, the stability of compound IV and the resulting semisolid formulation is better.
Preferably, the content of the compound IV is 0.05-0.5%.
Preferably, the content of the compound IV is 0.1-5%.
Preferably, the weight percentages of the components are as follows: 40 to 80 percent of solvent, 8 to 15 percent of cosolvent, 5 to 15 percent of emulsifier, 20 to 30 percent of fat-soluble matrix, 15 to 25 percent of percutaneous absorption enhancer, 0.01 to 0.5 percent of pH regulator, 0.005 to 1 percent of bacteriostatic agent, 0.002 to 0.1 percent of metal chelating agent, 0.005 to 0.1 percent of antioxidant and 1 to 8 percent of humectant.
Preferably, the cosolvent is ethanol and/or propylene glycol; the emulsifier is sodium stearate or polyvinyl alcohol; the fat-soluble matrix is white vaseline or liquid paraffin; the percutaneous absorption enhancer is dimethyl sulfoxide or N-dodecane-2-pyrrolinone.
Preferably, the pH regulator is sodium dihydrogen phosphate, and the pH regulator regulates the pH of the semisolid preparation to be 5-6.
Preferably, the bacteriostatic agent is one or more of parabens, chlorobutanol, sodium benzoate and potassium sorbate.
More preferably, the bacteriostatic agent is sodium phenyl methoxide or ethyl hydroxyphenyl ether or butyl hydroxyphenyl, and the content of the bacteriostatic agent is 0.01-0.1.
Preferably, the antioxidant is one or more of alkyl gallate, vitamin E, ascorbic acid, sulfurous acid, dibutyl hydroxy toluene, etc.
More preferably, the antioxidant is vitamin E, which is an ingredient present in natural foods and is also an essential substance for human body, so that the antioxidant is preferably vitamin E in the ointment of the present invention, which does not cause irritation to the skin and can protect the skin.
Preferably, the humectant is one or more of glycerin or polyethylene glycol or propylene glycol.
As the cosolvent can also be propylene glycol, the propylene glycol can be used as the cosolvent and the humectant to realize dual functions, and the addition of other auxiliary materials is reduced.
Preferably, the metal chelating agent is disodium ethylene diamine tetraacetate, and the content of the metal chelating agent is 0.01 wt% to 0.05 wt%.
The metal chelating agent is added to the ointment, so that the effect of transdermal absorption can be promoted, and the drug effect of the drug can be improved.
Preferably, the semisolid formulation is an oil-in-water ointment; the content of the compound IV is 0.01wt percent to 5wt percent.
Further, the administration route of the semisolid preparation is skin administration.
The semisolid preparation is preferably applied to skin, so that the inactivation of the medicine in the gastrointestinal tract and the first-pass effect of the liver can be avoided; and can stabilize the blood concentration and keep the blood concentration within the effective concentration range for a long time; meanwhile, the irritation of the medicine to the gastrointestinal tract is reduced, the safety is improved, and the patient can stop taking the medicine at any time.
According to the patent CN108676067B, the specific preparation method of the compound IV is as follows:
(1) preparation of compound II: dissolving bromoacyl bromide in an organic solvent, cooling to-60-0 ℃, slowly adding alkali, and then adding a catalyst DMAP to obtain a bromoacyl bromide/alkali/DMAP organic solvent system for later use; dissolving BHA-Lys-Lys2-Lys4-Lys8-Lys16-32TFA in an organic solvent solution, precooling to-40-20 ℃, dropwise adding the solution into an organic solvent system of bromoacyl bromide/alkali/DMAP, and slowly heating to-10 ℃ for reaction; detecting no BHA-Lys-Lys2-Lys4-Lys8-Lys16-32TFA residue in the system, slowly dripping saturated saline solution into the system for quenching reaction, stirring, separating liquid, separating an organic solvent layer, respectively washing with 0.5mol/L diluted hydrochloric acid and the saturated saline solution for the first time, and evaporating the organic solvent under reduced pressure to obtain the compound II.
Preferably, bromoacyl bromide 2 is dissolved in an organic solvent, the temperature is reduced to-40 to-20 ℃, and alkali is slowly added; the molar ratio of the bromoacyl bromide 2, the alkali, the DMAP and the BHA-Lys-Lys2-Lys4-Lys8-Lys16-32TFA is (32-64): (64-128): 0.1: 1; preferably, the molar ratio of bromoacyl bromide, the base, DMAP and BHA-Lys-Lys2-Lys4-Lys8-Lys16-32TFA is (38.4-48): (70.4-80): 0.1: 1; the organic solvent is selected from dichloromethane, trichloromethane, ethyl acetate, isopropyl acetate, toluene or xylene; the base is selected from sodium bicarbonate, sodium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine or pyridine.
Preferably, the BHA-Lys-Lys2-Lys4-Lys8-Lys16-32TFA is prepared by the same method as that of the patent CN 110305188B.
(2) Dissolving the compound II obtained in the step (1) by using anhydrous DMSO, adding alkali and 3, 6-sodium disulfonate-1-naphthol, heating to 40-90 ℃, and stirring for reaction; after the reaction is finished, filtering to remove insoluble substances, slowly dripping the filtrate into an organic solvent to separate out solid precipitate, and filtering; and recrystallizing the solid obtained by filtering by using a mixed solvent of alcohol and water to obtain the compound IV.
Preferably, the molar ratio of the alkali to the 3, 6-sodium disulfonate-1-naphthol in the step (2) is (32-64): (32-64), and preferably, the molar ratio of the alkali to the 3, 6-sodium disulfonate-1-naphthol is (38-48): (35.2-41.6); heating the alkali and 3, 6-sodium disulfonate-1-naphthol to 50-70 ℃, and stirring for reaction; the alkali is selected from sodium bicarbonate, sodium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine or pyridine; the organic solvent is selected from ethyl acetate, isopropyl acetate, acetonitrile, acetone, tetrahydrofuran or isopropanol; the alcohol is selected from methanol, ethanol, n-propanol or isopropanol.
The applicant optimizes the optimal components and the dosage thereof in terms of ointment stability, transdermal absorbability and the like (total 100 g):
compound IV: 0.1g
Ethanol: 3.0g
Propylene glycol: 12.0g
Stearic acid: 8.0g
White vaseline: 10.0g
Liquid paraffin: 5g
Disodium hydrogen phosphate: 0.02g
Butyl hydroxybenzene: 0.05g
Dimethyl sulfoxide: 10.0g
Disodium ethylene diamine tetraacetate: 0.01g
Vitamin E0.01 g
The balance of purified water
The pH value obtained by adjusting is 5-6.
Specifically, the general preparation of the spray containing compound IV of the present invention comprises the following steps:
(1) heating and melting a fat-soluble matrix and an emulsifier in a formula amount in a water bath at 75-85 ℃, and uniformly stirring to obtain an oil phase;
(2) dissolving active ingredients of the medicine in a solvent and/or a part of cosolvent, simultaneously, uniformly mixing ingredients such as a percutaneous absorption enhancer, a pH regulator, a bacteriostatic agent, a metal chelating agent, an antioxidant, a humectant and the like with the other part of cosolvent, then uniformly mixing the two, and heating to 75-85 ℃ to obtain a water phase;
(3) and adding the oil phase into the water phase under the condition of homogenizing and stirring, homogenizing at the speed of 5000rpm for 5-15 min, and finally stirring at the speed of 200rpm until condensation is carried out, thus obtaining the oil phase.
The invention has the beneficial effects that:
(1) the stability of the semi-solid preparation in the pharmaceutical preparation of the compound IV is improved through the interaction of the components in the screened semi-solid preparation prescription, and meanwhile, the inventor screens a proper cosolvent and a proper disease-adjusting pharmaceutical preparation until the pH value is 4-8, so that the stability of the semi-solid preparation can be integrally improved, and the pharmaceutical preparation can be better popularized and applied.
(2) In order to further improve the stability of the semisolid preparation of the present invention, preferably, a metal chelating agent is added to improve the stability of the preparation, the applicant selects disodium edetate from a large amount of metal chelating agents, which can obviously improve the stability of the pharmaceutical preparation of the present invention, and the applicant has surprisingly found that the ointment of the present invention added with the metal ion chelating agent can also promote the transdermal absorption effect and improve the pharmaceutical efficacy, so that the addition of disodium edetate simultaneously plays a dual role in improving the stability of the pharmaceutical preparation and promoting the transdermal absorption.
(3) The compound IV has good water solubility, the main solvent is purified water, the prepared medicinal preparation has small irritation and small side effect, and the safety of skin medication is improved.
(4) The invention screens out the most suitable percutaneous absorption enhancer from various types, can promote the absorption of skin tissues to drugs to a great extent, and does not cause great stimulation to the skin tissues. And the preferable percutaneous absorption enhancer is dimethyl sulfoxide which is used as a universal solvent and can play a role of a bridge that oil phase and water phase are mutually soluble. Further increases the solubility of the drug and improves the dispersion uniformity of the drug in the semisolid preparation.
(5) The active ingredient compound IV is prepared into a semisolid preparation which is mainly administrated through skin, so that the compliance of a patient is good, and the inactivation of the medicine in the gastrointestinal tract and the first pass effect of the liver can be avoided; and can stabilize the blood concentration and keep the blood concentration within the effective concentration range for a long time; meanwhile, the irritation of the medicine to the gastrointestinal tract is reduced, and the safety is improved. The medicine source can be removed at any time due to the withdrawing property of the released medicine; reducing inter-and intra-individual variation of patients; providing a predictable and long action time. In addition, aiming at infectious diseases related to the respiratory system, the patient can also carry out self-administration through skin coating, so that the direct contact between medical personnel and the patient is reduced, and the risk of alternate infection is reduced.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the detailed description and specific examples, while indicating the scope of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The compounds IV in the examples and comparative examples of the present invention were obtained by self-production according to the method disclosed in the previously filed patent CN 108676067B. The pharmaceutically active ingredients in the following examples and comparative examples are all compound IV.
Example 1
The ointment of the pharmaceutical composition of this example had the following formulation (total 100 g): 0.1g of medicinal active ingredients, 15g of white vaseline, 10g of liquid paraffin, 8g of stearic acid, 0.02g of disodium hydrogen phosphate, 0.05% of butyl hydroxybenzoate, and disodium ethylene diamine tetraacetate: 0.01g, vitamin E: 0.01g, 10.0g of dimethyl sulfoxide, 3.0g of ethanol, 12.0g of propylene glycol and the balance of purified water.
The preparation method of the medicinal composition ointment comprises the following steps: (1) heating and melting the white vaseline, the liquid paraffin and the stearic acid in the prescription amount at 80 ℃, and uniformly stirring to obtain an oil phase; (2) dissolving butyl hydroxybenzoate, disodium hydrogen phosphate, disodium ethylene diamine tetraacetate and vitamin E in ethanol, dissolving the active ingredients in propylene glycol and purified water, mixing the two with dimethyl sulfoxide, and heating to 80 deg.C to obtain water phase; (3) and adding the oil phase into the water phase under the condition of homogenizing and stirring, homogenizing at the speed of 5000rpm for 10min, and finally stirring at the speed of 200rpm until condensation is carried out, thus obtaining the ointment with the pH of 5-6.
Example 2
The ointment of the pharmaceutical composition of this example has the following formulation by weight: 0.01g of medicinal active ingredients, 5g of white vaseline, 5g of liquid paraffin, 8g of cetyl alcohol, 20g of fatty alcohol-polyoxyethylene ether, 0.5g of disodium hydrogen phosphate, 0.005g of butyl hydroxybenzoate, 0.1g of alkyl gallate, 0.002g of disodium ethylene diamine tetraacetate, 30.0g of N-dodecane-2-pyrrolinone, 1g of glycerol and the balance of purified water, thus obtaining an ointment with the pH value of 7-8.
The preparation method of the medicinal composition ointment comprises the following steps: (1) heating and melting the white vaseline, the liquid paraffin and the hexadecanol according to the prescription amount at 80 ℃, and uniformly stirring to obtain an oil phase; (2) dissolving the active ingredients in purified water, adding fatty alcohol-polyoxyethylene ether, oxybutylene, alkyl gallate, disodium ethylenediamine tetraacetate, disodium hydrogen phosphate, N-dodecane-2-pyrrolinone and glycerol, mixing, and heating to 80 deg.C to obtain water phase; (3) adding the oil phase into the water phase under homogenizing stirring, homogenizing at 5000rpm for 10min, and stirring at 200rpm for condensation.
Example 3
The ointment of the pharmaceutical composition of this example has the following formulation by weight: 10g of medicinal active ingredient, 10g of white vaseline, 20g of liquid paraffin, 10g of white beeswax, 1g of polyoxyethylene (20) lauryl ether, 8g of glyceryl monostearate, 0.02g of tartaric acid, 1.0g of ethylparaben, 0.1g of sulfurous hydrochloric acid, 1.0g of disodium ethylenediamine tetraacetic acid and laurocapram
Figure BDA0002610492650000081
20.0g of ketone, 8.0g of propylene glycol and the balance of purified water to obtain an ointment with the pH value of 4-5.
The preparation method of the medicinal composition ointment comprises the following steps: (1) heating and melting the prescribed amount of white vaseline, liquid paraffin, white beeswax and glyceryl monostearate in a water bath at 80 ℃, and uniformly stirring to obtain an oil phase; (2) dissolving the active ingredients in propylene glycol and purified water, and adding polyoxyethylene (20) lauryl ether, ethylparaben, tartaric acid, sulfurous hydrochloric acid, disodium edetate, and azone
Figure BDA0002610492650000091
Mixing ketone uniformly, heating to 80 deg.C to obtain water phase; (3) adding the oil phase into the water phase under homogenizing stirring, homogenizing at 5000rpm for 10min, and stirring at 200rpm for condensation.
Example 4
The ointment of the pharmaceutical composition of this example has the following formulation by weight: 1g of medicinal active ingredients, 12g of white vaseline, 7g of stearyl alcohol, 806 g of polysorbate, 4.6g of glycerin monostearate, 0.02g of disodium hydrogen phosphate, 0.3g of sodium benzoate, 10g of dimethyl sulfoxide, 12g of glycerol and the balance of purified water.
The preparation method of the medicinal composition ointment comprises the following steps: (1) heating and melting the white vaseline, the stearyl alcohol and the glyceryl monostearate in the formula amount in a water bath at 80 ℃, and uniformly stirring to obtain an oil phase; (2) dissolving the active ingredients in purified water, adding polysorbate 80, sodium benzoate, disodium hydrogen phosphate, dimethyl sulfoxide and glycerol, mixing, and heating to 80 deg.C to obtain water phase; (3) adding the oil phase into the water phase under homogenizing stirring, homogenizing at 5000rpm for 10min, and stirring at 200rpm for condensation.
Comparative example 1
This comparative example is different from example 1 in that the cosolvent of ethanol and propylene glycol are not added in this example, and the remaining ingredients are the same as example 1, and an ointment is prepared.
Comparative example 2
This comparative example is different from example 1 in that dimethyl sulfoxide, a percutaneous absorption enhancer, was not added in this example, and an ointment was prepared in the same manner as in example 1 except for the remaining components.
Comparative example 3
This comparative example is different from example 1 in that disodium ethylenediaminetetraacetate, a metal chelating agent, was not added in this example, and the remaining ingredients were the same as in example, to prepare an ointment.
Comparative example 4
The difference between the comparative example and example 1 is that the pH regulator added in the example is sodium hydroxide, and the pH of the prepared ointment is 9.0-10.0.
Comparative example 5
The difference between the comparative example and example 1 is that the pH regulator added in the example is tartaric acid, and the pH of the prepared ointment is 2.5-3.5.
General quality assessment of ointments
(1) And (3) appearance character investigation: the whiteness and fineness of each ointment, and the consistency and spreadability of the ointment when applied to the back of the hand after being observed by visual observation, and the results are shown in table 1.
Table 1: appearance character
Figure BDA0002610492650000101
(2) Droplet size and distribution inspection
A small amount of the ointment prepared in each example and comparative example was applied to a glass slide, pressed uniformly with a glass cover, and observed under a microscope for the size and distribution of the droplets in each prescription, and the results are shown in Table 2.
Table 2: droplet size and distribution
Figure BDA0002610492650000102
Secondly, stability test of ointment
(1) General stability investigation, centrifugal test, heat resistance test, cold resistance test.
And (3) centrifugal test: taking 10g of the above 9 prescriptions of ointment, placing into a graduated centrifuge tube, placing into a centrifuge, centrifuging at 3000r/min for 30min, taking out, and observing whether layering phenomenon exists.
Heat resistance test: placing 15g of each of the 9 prescriptions in a test tube, placing in an oven at constant temperature (55 deg.C), taking out after 6 hr, cooling to room temperature, and observing whether the ointment is coarse, thin and soft, and layered.
Cold resistance test: 15g of the 9 prescriptions of ointment are respectively put into test tubes, put into a refrigerator at (-15 ℃) for 24h, taken out, and observed after the temperature is cooled to room temperature.
The test results are shown in Table 3.
TABLE 3 results of centrifugal, Cold and Heat resistance tests
Figure BDA0002610492650000111
(2) Long term stability study
Referring to the requirement of stability of pharmaceutical preparations in the national pharmacopoeia 2015 edition, the ointments of examples 1-4 and comparative examples 1-5 were subjected to stability test at 40 + -2 deg.C, room temperature (25 + -2 deg.C) and refrigerated storage at 4 + -1 deg.C for 6 months, and then sampled at 0, 1, 2, 3 and 6 months, and the content (%) of compound IV was determined by HPLC.
The test results are shown in Table 4.
Table 4 long term stability experimental data
Figure BDA0002610492650000112
Figure BDA0002610492650000121
From the test results shown in tables 3 and 4, it is understood that the ointments containing compound IV prepared in examples 1 to 4 of the present invention are colorless and transparent white and fine ointments after 6 months of stability test at (40 ± 2) ° c, room temperature (25 ± 2 ℃) and refrigerated storage at (4 ± 1) ° c, respectively, and the reduction of compound IV as the pharmaceutical active ingredient is controlled to be between 0 and 2, so that the pharmaceutical preparations and compound IV are highly stable. In contrast, in comparative examples 1 to 5, the stability is significantly deteriorated, after accelerated for 6 months, the active ingredient compound IV is reduced by up to 32%, and particularly, as can be seen from comparative examples 4 and 5, the pH value has a significant effect on the stability of the pharmaceutical preparation of the present invention, and therefore, the pharmaceutical preparation of the present invention preferably has a pH within 4 to 8, which can significantly improve the stability of the pharmaceutical preparation.
On the other hand, the stability of the ointment can be obviously improved by adding the cosolvents of ethanol and propylene glycol, and the inventor analyzes that the cosolvents are absent in the comparative example 1, the medicine is not uniformly dispersed, obvious layering can occur after a certain time, the sampling uniformity cannot be realized, and the obvious difference of sample content measurement is caused. Similarly, comparative example 2 mainly lacks the transdermal absorption enhancer, namely dimethyl sulfoxide, which may also cause the problem of the uniformity of the ointment sample of the product, while comparative example 3 lacks the metal chelating agent, which has a certain influence on the stability of the ointment, and particularly has an obvious influence under the condition of higher temperature. Therefore, it is preferable to add a suitable cosolvent, percutaneous absorption enhancer, and metal chelator in order to improve the stability of the ointment of the present invention. In conclusion, the optimized prescription and preparation process are stable and feasible.
It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the technical solutions of the present invention, and are not intended to limit the specific embodiments of the present invention. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention claims should be included in the protection scope of the present invention claims.

Claims (18)

1. A semi-solid formulation comprising a pharmacologically active substance and a pharmaceutically acceptable carrier; the pharmacological active substance is 0.01-10% of compound IV, and the pharmaceutically acceptable carrier comprises: 30-90% of solvent, 3-20% of cosolvent, 1-20% of emulsifier, 10-40% of fat-soluble matrix, 10-30% of percutaneous absorption promoter, 0.01-2% of pH regulator, and one or more of the following components: bacteriostatic agent, metal chelating agent, antioxidant, humectant; the weight percentages of the components are as follows: 0-3% of bacteriostatic agent, 0-1% of metal chelating agent, 0-0.2% of antioxidant and 0-10% of humectant;
the solvent is water;
the cosolvent is one or more of ethanol, propylene glycol, glycerol and hexadecanol.
The emulsifier is one or more of polysorbate, glyceryl monostearate, polyoxyethylene (20) lauryl ether and fatty alcohol polyoxyethylene ether.
The fat-soluble matrix is one or more of white vaseline, stearic acid, lanolin, liquid paraffin and beeswax;
the percutaneous absorption enhancer is dimethyl sulfoxide, N-dodecane-2-pyrrolinone, and azone
Figure FDA0002610492640000013
One or more of a ketone;
the pH regulator is one or more of phosphate, tartaric acid and citrate; the pH regulator regulates the pH of the semisolid preparation to 4-8;
wherein the structural formula of the compound IV is shown as the formula (IV):
Figure FDA0002610492640000011
wherein R represents the following group:
Figure FDA0002610492640000012
2. the semi-solid formulation of claim 1, wherein the compound IV is present in an amount of 0.05% to 1%.
3. The semi-solid formulation of claim 1, wherein the compound IV is present in an amount of 0.5% to 3%.
4. The semi-solid formulation of claim 1, wherein the weight percentages of the components are: 40 to 80 percent of solvent, 8 to 15 percent of cosolvent, 5 to 15 percent of emulsifier, 20 to 30 percent of fat-soluble matrix, 15 to 25 percent of percutaneous absorption enhancer, 0.01 to 0.5 percent of pH regulator, 0.005 to 1 percent of bacteriostatic agent, 0.002 to 0.1 percent of metal chelating agent, 0.005 to 0.1 percent of antioxidant and 1 to 8 percent of humectant.
5. The semi-solid formulation of claim 1, wherein the co-solvent is ethanol and/or propylene glycol; the emulsifier is sodium stearate or polysorbate 80; the fat-soluble matrix is white vaseline and/or liquid paraffin; the percutaneous absorption enhancer is dimethyl sulfoxide or N-dodecane-2-pyrrolinone.
6. The semi-solid formulation of claim 1, wherein the pH adjusting agent is sodium dihydrogen phosphate, and the pH adjusting agent adjusts the pH of the semi-solid formulation to 5-6.
7. The semi-solid formulation of claim 1, wherein the bacteriostatic agent is one or more of parabens, chlorobutanol, sodium benzoate, and potassium sorbate.
8. The semisolid preparation according to claim 7, wherein the bacteriostatic agent is sodium phenyl methoxide, ethyl hydroxyphenyl ether or butyl hydroxyphenyl, and the content of the bacteriostatic agent is 0.01-0.1%.
9. The semi-solid formulation of claim 1, wherein the antioxidant is one or more of alkyl gallate, vitamin E, ascorbic acid, sulfurous acid, dibutylhydroxytoluene.
10. The semi-solid formulation of claim 1, wherein the humectant is one or a mixture of glycerin, propylene glycol, or polyethylene glycol.
11. The semi-solid formulation of claim 1, wherein the metal chelating agent is disodium ethylenediaminetetraacetic acid; the content of the metal chelating agent is 0.01 wt% -0.05 wt%.
12. The semisolid formulation according to any one of claims 1 to 11, wherein the semisolid formulation is an ointment or a gel or a suppository.
13. The semisolid formulation according to claim 12, characterized in that the semisolid formulation is an oil-in-water ointment; the content of the compound IV is 0.01wt percent to 5wt percent.
14. The semisolid formulation according to any one of claims 1 to 11, wherein the administration route of the semisolid formulation is dermal administration.
15. Use of a semisolid formulation according to any one of claims 1 to 11 for the prevention and/or treatment of a SARS-CoV, SARS-CoV-2 or MERS-CoV virus infection.
16. Use of a semi-solid formulation according to any one of claims 1 to 11 for the prevention and/or treatment of HIV infection.
17. Use of a semi-solid formulation according to any of claims 1 to 11 for the prevention and/or treatment of HPV infections.
18. Use of a semi-solid formulation according to any one of claims 1 to 11 for the prevention and/or treatment of BV infection.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108676067A (en) * 2018-03-23 2018-10-19 广州朗圣药业有限公司 A kind of noval chemical compound and preparation method thereof of pre- preventing HIV infection
CN109528917A (en) * 2017-09-21 2019-03-29 延边山宝科技发展有限公司 A kind of preparation method towards hospital's composition and its cream for treating rheumatoid arthritis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109528917A (en) * 2017-09-21 2019-03-29 延边山宝科技发展有限公司 A kind of preparation method towards hospital's composition and its cream for treating rheumatoid arthritis
CN108676067A (en) * 2018-03-23 2018-10-19 广州朗圣药业有限公司 A kind of noval chemical compound and preparation method thereof of pre- preventing HIV infection

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