CN114042085A - A pharmaceutical composition for treating skin wound and its preparation method - Google Patents

A pharmaceutical composition for treating skin wound and its preparation method Download PDF

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CN114042085A
CN114042085A CN202111342230.2A CN202111342230A CN114042085A CN 114042085 A CN114042085 A CN 114042085A CN 202111342230 A CN202111342230 A CN 202111342230A CN 114042085 A CN114042085 A CN 114042085A
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pharmaceutical composition
fullerene
skin
preservative
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王春儒
赵中普
王晗钰
廖小丹
李慧
甄明明
武万里
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Beijing Fullcan Biotechnology Co ltd
Institute of Chemistry CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/44—Elemental carbon, e.g. charcoal, carbon black
    • 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
    • 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
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation

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Abstract

A pharmaceutical composition containing fullerene for treating skin wound and its preparation method are provided. The fullerene wound medicine composition provided by the disclosure has the advantages of quickly cooling, effectively stopping residual heat at a wound part to continue to damage tissues, and simultaneously promoting the healing of wounds such as skin scald, skin sunburn, mechanical injury, skin ulcer and the like.

Description

A pharmaceutical composition for treating skin wound and its preparation method
Technical Field
The present disclosure relates to the field of chemistry, and in particular, to a novel composition for treating skin wounds and a method for preparing the same.
Background
At present, the medicines for skin wounds are Chinese medicines, such as Chinese medicines and Chinese herbal compound preparations; the western medicines mainly comprise antibacterial medicines, and the main purpose of the external application of the antibacterial medicines is to prevent systemic infection; glycosaminoglycans such as chitosan, heparin, hyaluronic acid have been used for the topical treatment of burns and scalds; biological factor medicines such as basic fibroblast growth factor and epidermal growth factor which are commonly used clinically have the effects of promoting proliferation and division of cells related to wound repair and can accelerate wound healing; local analgesic drugs, burn and scald are often accompanied by severe pain, and analgesic treatment is a very effective treatment measure for reducing or eliminating the stress of the body to pain stimulus and pathophysiological damage; and injection or oral administration of opioids, ketamine, benzodiazepine
Figure BDA0003352586090000011
Class I drugs, etc.
The traditional Chinese medicine preparation for treating skin wounds is powder, cataplasm, ointment and the like. The preparation method is usually to add excipient directly after pulverizing the medicine into powder or add excipient into the fried liquid of the medicine obtained by the frying method, but the obtained preparation is generally coarse, the effective components are not clear and are not collected, and the preparation obtained by the traditional processes has lower curative effect and unstable quality because of the damage of the effective components in the preparation process. And the traditional Chinese medicine has the treatment advantages of burns and scalds below II degree in medium and small areas, and has poor effect in the treatment of large-area and serious burns and scalds.
The western medicine has specific pharmacological actionSome disease symptoms are controlled and relieved more quickly. The skin wound diseases have the characteristic of multiple mechanisms, and western medicines have single action mechanism and lack of comprehensive curative effect, so that better treatment effect is difficult to obtain. Injection or oral administration of opioid, ketamine and benzodiazepine in analgesic drugs
Figure BDA0003352586090000012
Some of them have great side effects and some of them have addiction.
Therefore, the research and development of a product for treating skin wounds (including high-temperature wounds, mechanical injuries, ulcers and the like) with obvious effect, broad spectrum and low cost has important clinical significance.
Fullerene (C60), the third allotrope of carbon. The interior of the molecule is formed into a football-shaped hollow molecule through atoms, the molecule is provided with 60 carbon atoms to form 60 vertexes, 32 faces (comprising 12 regular pentagons and 20 regular hexagons, wherein the pentagons are not connected with each other but are only adjacent to the hexagons) and 30 carbon-carbon double bonds, each carbon atom is connected with three adjacent carbon atoms through an sp2 hybridization orbit, and the rest P orbitals form pi bonds at the periphery and the inner cavity of the C60 molecule.
The present disclosure aims to provide a therapeutic pharmaceutical preparation suitable for skin wounds by improving the solubility of fullerenes using modern pharmaceutical formulation technology.
Disclosure of Invention
The purpose of the present disclosure is to provide a fullerene skin wound pharmaceutical composition and a preparation method thereof. The fullerene skin wound composition can be rapidly cooled, effectively stops 'residual heat' of a wound part to continue to damage tissues, and compared with the conventional skin wound medicine, the fullerene skin wound composition can rapidly cool the wound part, is smeared on an affected part, can play a cold compress role, can form a hydrophobic layer on the affected part, prevents the affected part from being infected, and has the effect of accelerating wound healing.
Specifically, the present disclosure provides:
a pharmaceutical composition comprises active ingredient and adjuvants, wherein the active ingredient is one or more of fullerene or fullerene derivatives, and the adjuvants comprise one or more of oil phase matrix, polymer material, penetration enhancer, antiseptic, antioxidant or pH regulator.
Wherein the fullerene is selected from one or more of hollow fullerene and metal fullerene; optionally, the hollow fullerene is selected from C2nOr one or more of its derivatives; optionally, the metal fullerene is a hollow fullerene with a carbon cage structure enclosing a metal atom or a metal atom cluster, and the metal fullerene is selected from M @ C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2n、MxA3-xN@C2nWherein M and A are respectively and independently selected from Sc, Y and lanthanide metal elements, wherein n is more than or equal to 30 and less than or equal to 60, and x is more than or equal to 0 and less than or equal to 3; optionally, the fullerene derivative is selected from one or more of an amino acid derivative, a hydroxyl derivative, a carboxyl derivative or an amino derivative of the hollow fullerene or the metal fullerene;
optionally, the weight ratio of the active ingredient in the pharmaceutical composition is 0.01-1%, preferably 0.01-0.5%.
Preferably, the pharmaceutical composition according to any of the preceding claims, wherein said active ingredient is selected from C60、C70、C76、C78、C80、C82And C84Or one or more of their derivatives.
In one aspect of the disclosure, a pharmaceutical composition is provided, comprising an active ingredient and an adjuvant, wherein the adjuvant comprises one or more of an oil phase matrix, a penetration enhancer or a preservative.
Optionally, wherein the oil phase matrix is 27-80% by weight of the pharmaceutical composition; the penetration enhancer accounts for 2.5-15% of the weight of the pharmaceutical composition.
Optionally, the oil phase matrix is selected from one or more of paraffin, mineral oil, vegetable oil, lanolin, beeswax, vaseline, stearic acid, sorbitan monostearate, and medium chain triglyceride.
Optionally, the penetration enhancer is selected from one or more of laurocapram, oleum Menthae Dementholatum, Mentholum, oleum Eucalypti, methyl salicylate, ethanol, Borneolum Syntheticum, and L-borneol.
In one aspect of the disclosure, a pharmaceutical composition is provided, which includes an active ingredient and an adjuvant, wherein the adjuvant includes one or more of a polymer material, an antioxidant, a pH adjuster, or a preservative.
Optionally, the weight percentage of the polymer material in the pharmaceutical composition is 0.1-99%, preferably 0.1-5%, 0.4-2%, 20-99%, 20-40% or 50-80%; wherein the antioxidant accounts for 0.01-0.5% of the weight of the pharmaceutical composition, preferably 0.01-0.1%; wherein the pH regulator accounts for 0.01-0.1% of the weight of the pharmaceutical composition.
Optionally, the high molecular material is selected from one or more of carbomer, polyethylene glycol and sodium carboxymethyl cellulose; optionally, the antioxidant is selected from one or more of vitamin C, vitamin E, sodium metabisulfite and BHT; optionally, the pH regulator is selected from one or more of citric acid, sodium citrate, triethanolamine, and arginine.
In one aspect of the disclosure, any one of the pharmaceutical compositions described above, wherein the preservative is present in the pharmaceutical composition at 0.01% to 10% by weight.
Optionally, the preservative is selected from one or more of alcohols, acids, esters, aromatic acids, benzalkonium chloride, phenols and mercuride preservatives; preferably, the preservative is selected from one or more of benzoic acid, sorbic acid, chlorobutanol, methylparaben or ethylparaben.
In another aspect of the present disclosure, there is provided a formulation form of any one of the pharmaceutical compositions as described above, which is a semi-solid formulation.
Preferably, the pharmaceutical composition is formulated in any one of ointment, gel or suppository. More preferably an ointment.
Preferably the ointment is selected from one or more of a cream, salve, paste, salve.
In another aspect of the present disclosure, there is provided a pharmaceutical composition as any one of the preceding, for use in the manufacture of a medicament for treating or reducing skin wounds.
In another aspect of the present disclosure, there is provided a pharmaceutical composition as described in any one of the preceding paragraphs for use in the manufacture of a medicament for treating or alleviating a high temperature wound on the skin. Preferably, the high temperature skin wound comprises burn and scald and sunburn.
In another aspect of the present disclosure, there is provided a pharmaceutical composition as described in any one of the preceding paragraphs for use in the manufacture of a medicament for treating or alleviating mechanical skin injury, drug-induced skin trauma or ulcerative skin trauma.
In another aspect of the present disclosure, there is provided a method of preparing any one of the pharmaceutical compositions as described above, the method of preparing comprising the steps of:
adding corresponding amounts of each component material into a matrix according to the formulation of the pharmaceutical composition; adding one component, stirring until dissolved, adding the other component, and cooling to room temperature to obtain the pharmaceutical composition, wherein the matrix is selected from oil phase matrix or polymer matrix. Preferably, the substrate is a substrate heated at 60-80 degrees celsius.
The pharmaceutical composition disclosed by the invention has the following advantages:
1. the pharmaceutical composition disclosed by the invention can be used for quickly reducing the temperature of an affected part in the early stage of high-temperature skin trauma and relieving the burning pain of the affected part, and can be used for promoting wound healing in later-stage nursing.
2. The pharmaceutical composition disclosed by the invention is used for skin wounds, can play a role of cold compress after being smeared on an affected part, can form a hydrophobic layer on the affected part, prevents the affected part from being infected, and has the function of accelerating wound healing.
3. The preparation process of the pharmaceutical composition disclosed by the invention is simple, and the feeding sequence is not strictly limited.
Drawings
FIG. 1 shows particle size characterization of fullerene paste according to example 8 of the present disclosure;
FIG. 2 shows that the fullerene ointment of the embodiment 9 of the present disclosure can rapidly reduce the temperature of the burnt and scalded skin affected part;
FIG. 3 shows the wound healing rate of rats in each group after 27 days of continuous administration of fullerene ointment and control group according to example 9 of the present disclosure;
FIG. 4 shows the change of the burned area of the back of each group of rats after 27 days of continuous administration in example 9 of the present disclosure;
figure 5 shows dorsal scald status in groups of mice administered for 15 consecutive days of example 10 of the present disclosure;
fig. 6 shows organ coefficients of groups of mice after 15 days of continuous administration in example 10 of the present disclosure;
FIG. 7 shows the change in wound healing rate of skin wounds (chronic ulcers) of rats in groups administered with example 11 of the present disclosure for 15 consecutive days;
FIG. 8 shows the change in area of skin wounds (chronic ulcers) on the back of rats in groups administered for 15 consecutive days in example 11 of the present disclosure;
fig. 9 shows skin wound (chronic ulcer) wound changes of rats in groups of fullerene, excipient and positive drug groups for 15 days after continuous administration according to example 12 of the present disclosure;
FIG. 10 shows the change in the wound healing rate of skin wounds (chronic ulcers) of rats in groups of fullerene group, excipient group and positive drug group administered for 15 days continuously in example 12 of the present disclosure;
fig. 11 shows comparative experiments on repair of uv damaged cells in fullerene group, excipient group, model group and normal group of example 13 of the present disclosure.
Detailed Description
Based on the above disclosure, other modifications, substitutions and alterations can be made without departing from the basic technical concept of the present disclosure as it is known and customary in the art.
The foregoing and other aspects of the present disclosure are achieved by the following detailed description of the embodiments. It should not be understood that the scope of the above-described subject matter of the present disclosure is limited to the following examples. All the technologies realized based on the above contents of the present disclosure belong to the scope of the present disclosure.
I. Definition of
Throughout the specification and claims, unless explicitly stated otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or component but not the exclusion of any other element or component.
The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, disorder or condition being treated.
The terms "reduce", "inhibit", "reduce" or "decrease" are used relative to a control. One skilled in the art will readily determine the appropriate control for each experiment. For example, a decreased response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with a compound.
As used herein, the term "effective amount" or "therapeutically effective amount" refers to a dose sufficient to treat, inhibit or alleviate one or more symptoms of the disease state being treated or to otherwise provide a desired pharmacological and/or physiological effect. The precise dosage will vary depending on a variety of factors, such as the subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder, and the treatment being administered. The effective amount of the effect may be relative to a control. These controls are known in the art and discussed herein, and may be, for example, the condition of the subject prior to or without administration of the drug or drug combination, or in the case of a drug combination, the effect of the combination may be compared to the effect of administration of only one drug.
The terms "adjuvant" and "excipient" are used herein to include any other compound that is not a therapeutic or biologically active compound that may be contained in or on the microparticles. Thus, the excipient should be pharmaceutically or biologically acceptable or relevant, e.g., the excipient is generally non-toxic to the subject. "excipient" includes a single such compound, and is also intended to include multiple compounds.
The term "pharmaceutical composition" means a composition comprising an aminofullerene derivative and at least one pharmaceutically acceptable ingredient selected from the group consisting of, depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrating agents, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, penetration enhancers, oil phase bases, and the like.
The term "semi-solid formulation" refers to a form of composition formulation, which may include ointments, oculentums, gels, suppositories, and the like. "ointment" refers to a semisolid external preparation having a certain consistency prepared by uniformly mixing a drug with a suitable base. Ointments may include creams, salves, pastes, salves, and the like.
As used herein, the term "penetration enhancer" refers to a percutaneous absorption enhancer having an effect of enhancing the release of a drug from a system and enhancing the percutaneous absorption of the drug. Has high safety, no systemic toxicity, no irritation, no sensitization, no phototoxicity and no acne-causing effect; it has stable chemical properties, and can be combined with other raw materials in the preparation.
As used herein, the term "preservative" refers to an additive having bacteriostatic action in a pharmaceutical formulation, and preservatives may include, but are not limited to, alcoholic preservatives such as ethanol, isopropanol, chlorobutanol, phenyl-p-chlorophenylpropanediol, phenoxyethanol, propylene glycol, bromonitropropanediol, and the like; acid preservatives such as benzoic acid, sorbic acid, dehydroacetic acid, propionic acid, cinnamic acid and the like; ester preservatives such as methyl paraben, ethyl paraben, propyl paraben, glyceryl caprylate and the like; aromatic acid preservatives such as anisole, citronellal, clove powder, vanillin esters, and the like; and other preservatives, such as benzalkonium chloride, phenols, mercurides, and other preservatives conventionally used in pharmaceutical formulations.
As used herein, the term "fullerene" is a series of spheroidal cluster molecules consisting of an even number of carbon atoms, 12 five-membered rings, with the remainder being six-membered rings. Fullerenes include hollow fullerenes, metal fullerenes, or other variants.
The terms "metallofullerene", "endohedral fullerene" refer to a class of compounds having particular structures and properties, generally referred to as endohedral fullerenes, generally represented by the form M @ C2n, wherein M represents a metallic element, enclosed within the carbon cage structure of the fullerene by various metal or metal atom clusters.
As used herein, the term "fullerene derivative" refers to a fullerene derivative obtained by chemically modifying a fullerene body, wherein the modified fullerene body may be one or a mixture of hollow fullerenes and metallic fullerenes.
The term "fullerene aminated derivative" refers to a fullerene derivative having an amino group at the end of a modifying group attached to the fullerene body, and optionally includes, but is not limited to, ethylenediamine, propylenediamine, butylenediamine, etc. derivatives having amino groups at both ends are bonded to fullerene during the synthesis process, wherein the amino group at one end is attached to fullerene, and the amino group at the other end is exposed. The modified fullerene body can be one or a mixture of hollow fullerene and metal fullerene.
The term "fullerene carboxylated derivative" refers to a fullerene derivative having a carboxyl group at the end of a modifying group attached to a fullerene body, wherein the modified fullerene body can be one or a mixture of hollow fullerene and metal fullerene.
The term "fullerene hydroxylated derivative" refers to a fullerene derivative whose fullerene body is connected with a modifying group with a hydroxyl end, wherein the modified fullerene body can be one or a mixture of hollow fullerene and metal fullerene.
As used herein, the term "skin wound" includes, but is not limited to, high temperature wounds, mechanical injuries and drug induced skin wounds, ulcerative skin wounds and the like. "high temperature wound" refers to skin wound caused by high temperature, including but not limited to burns, scalds, sunburn, etc. Burns and scalds are tissue injuries generally caused by hot liquids (water, soup, oil, etc.), steam, high-temperature gas, flames, hot metal liquids or solids (such as molten steel and steel ingots), and mainly comprise tissue injuries of skin, mucous membranes and the like. Sunburn generally refers to a skin wound caused by intense ultraviolet radiation, and the affected skin is red, swollen, burning, painful, and even has the symptoms of blister, burning pain, desquamation of the skin, etc.
The foregoing and other aspects of the present disclosure are achieved by the following detailed description of the embodiments. It should not be understood that the scope of the above-described subject matter of the present disclosure is limited to the following examples. All the technologies realized based on the above contents of the present disclosure belong to the scope of the present disclosure.
Detailed description of the preferred embodiments
One aspect of the disclosure relates to a pharmaceutical composition, comprising an active ingredient and an adjuvant, wherein the active ingredient is one or more of fullerene or fullerene derivatives; wherein the auxiliary materials comprise one or more of an oil phase matrix, a high polymer material, a penetration enhancer, a preservative, an antioxidant or a pH regulator.
In one embodiment, the active ingredient fullerene is selected from one or more of an empty fullerene, a metallofullerene, preferably, the empty fullerene is selected from C2nOr one or more of its derivatives; preferably, the metal fullerene is a hollow fullerene with a carbon cage structure wrapped with metal atoms or metal atom clusters, and the metal fullerene is selected from M @ C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2n、MxA3-xN@C2nOne ofOr a plurality of the compounds, wherein M and A are respectively and independently selected from Sc, Y and lanthanide series metal elements, wherein n is more than or equal to 30 and less than or equal to 60, and x is more than or equal to 0 and less than or equal to 3.
In one embodiment, the fullerene derivative comprises one or more of an amino acid derivative, a hydroxyl derivative, a carboxyl derivative, an amino derivative of the hollow fullerene or the metallic fullerene.
In a particular embodiment, the fullerene is preferably C60、C70、C76、C78、C80、C82、C84Or one or more of their derivatives. More preferably C60、C70、C82Or one or more of their derivatives.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an auxiliary material, wherein the active ingredient accounts for 0.01-1% of the composition by weight, and the active ingredient is selected from one or more of fullerene or fullerene derivatives.
In a specific embodiment, the pharmaceutical composition comprises an active ingredient and an auxiliary material, wherein the active ingredient is preferably 0.01-0.5% by weight of the pharmaceutical composition.
In a particular embodiment, the pharmaceutical composition comprises fullerene C2nAnd auxiliary materials, wherein 2n is the number of carbon atoms, and n is more than or equal to 30 and less than or equal to 60; wherein the fullerene C2nThe weight ratio of the medicine composition is 0.01-0.5%.
In a specific embodiment, the pharmaceutical composition comprises fullerene and an auxiliary material, wherein the fullerene is C60、C70、C76、C78、C80、C82、C84Or one or more of the derivatives thereof, wherein the weight ratio of the fullerene in the pharmaceutical composition is 0.01-0.5%.
In a specific embodiment, the pharmaceutical composition comprises metal fullerene and auxiliary materials, wherein the metal fullerene accounts for 0.01-0.5% of the pharmaceutical composition by weight; the metal fullerene is selected from M @ C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2n、MxA3-xN@C2nWherein M and A are respectively and independently selected from Sc, Y and lanthanide metal elements, and x is more than or equal to 0 and less than or equal to 3.
In a specific embodiment, the pharmaceutical composition comprises a fullerene derivative and an auxiliary material, wherein the fullerene derivative accounts for 0.01-0.5% of the pharmaceutical composition by weight; the fullerene derivative comprises one or more of amino acid derivatives, hydroxyl derivatives, carboxyl derivatives and amino derivatives of the hollow fullerene or the metal fullerene.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an adjuvant comprising one or more of an oil phase matrix, a penetration enhancer, or a preservative. Wherein the oil phase matrix comprises one or more of hydrocarbons, lipids, and greases.
The hydrocarbon matrix is selected from one or more of vaseline, solid paraffin, liquid paraffin, and silicone.
The lipid matrix is selected from one or more of lanolin, beeswax and spermaceti wax.
The oil and fat matrix is selected from vegetable oil, mineral oil, animal and vegetable higher fatty acid glyceride or their mixture.
In a specific embodiment, the oil phase base is selected from one or more of paraffin, mineral oil, vegetable oil, lanolin, beeswax, vaseline, stearic acid, sorbitol monostearate, and medium chain triglyceride.
In a particular embodiment, the oil phase base is preferably selected from one or more of petrolatum, beeswax, lanolin, paraffin wax.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an adjuvant comprising one or more of an oil phase matrix, a penetration enhancer, or a preservative. Wherein the penetration enhancer comprises one or more of alcohols, fatty acids, fatty acid esters, terpenes, azone and homologues thereof.
The alcohol penetration enhancer is selected from one or more of ethanol, propylene glycol, oleyl alcohol, lauryl alcohol and cetyl alcohol.
The fatty acid penetration enhancer is one or more selected from oleic acid, lauric acid, linoleic acid, and salicylic acid.
The fatty acid ester penetration enhancer is selected from one or more of isopropyl palmitate, lanolin, and methyl salicylate.
The terpenes penetration enhancer is selected from one or more of oleum Eucalypti, menthol, oleum Menthae Dementholatum, Mentholum, Camphora, Borneolum Syntheticum, and L-Borneolum Syntheticum.
The penetration enhancer is selected from laurocapram.
In a specific embodiment, the penetration enhancer is selected from one or more of laurocapram, peppermint oil, menthol, eucalyptus oil, methyl salicylate, ethanol, borneol and levoborneol.
In a specific embodiment, the penetration enhancer is preferably selected from one or more of menthol, borneol, peppermint oil, laurocapram and ethanol.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an auxiliary material, wherein the auxiliary material comprises one or more of an oil phase matrix, a penetration enhancer and a preservative, and the oil phase matrix accounts for 27-80% of the weight.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an auxiliary material, wherein the auxiliary material comprises one or more of an oil phase matrix, a penetration enhancer and a preservative, and the penetration enhancer accounts for 2.5-15% of the weight of the pharmaceutical composition.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an auxiliary material, wherein the auxiliary material comprises one or more of a high molecular material, an antioxidant, a pH regulator or a preservative, and the high molecular material is one or more selected from carbomer, polyethylene glycol and sodium carboxymethylcellulose.
In a specific embodiment, the polymer material is preferably selected from one or more of carbomer 940, carbomer 981, polyethylene glycol 400 and polyethylene glycol 4000.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an auxiliary material, wherein the auxiliary material comprises one or more of a high molecular material, an antioxidant, a pH regulator or a preservative, and the antioxidant is selected from one or more of vitamin C, vitamin E, sodium metabisulfite and BHT.
In a particular embodiment, the antioxidant is preferably BHT.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an auxiliary material, wherein the auxiliary material comprises one or more of a high molecular material, an antioxidant, a pH regulator or a preservative, and the pH regulator is one or more selected from citric acid, sodium citrate, triethanolamine and arginine.
In a particular embodiment, the pH adjusting agent is preferably triethanolamine.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an adjuvant, wherein the adjuvant comprises one or more of a polymer material, an antioxidant, a pH regulator or a preservative, wherein the polymer material accounts for 0.1-99% by weight of the pharmaceutical composition, preferably 0.1-5%, 0.4-2%, 20-99%, 20-40% or 50-80%.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an auxiliary material, wherein the auxiliary material comprises one or more of a polymer material, an antioxidant, a pH regulator or a preservative, wherein the antioxidant accounts for 0.01-0.5% by weight of the pharmaceutical composition, preferably 0.01-0.1%.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an auxiliary material, wherein the auxiliary material comprises one or more of a high molecular material, an antioxidant, a pH regulator or a preservative, and the pH regulator accounts for 0.01-0.1 wt% of the pharmaceutical composition.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an adjuvant comprising one or more of an oil phase matrix, a polymeric material, a penetration enhancer, a preservative, an antioxidant, or a pH adjuster. Wherein the preservative comprises one or more of alcohols, acids, esters, aromatic acids, benzalkonium chloride, phenols and mercuride preservatives.
The alcohol antiseptic is selected from one or more of ethanol, isopropanol, chlorobutanol, phenyl-p-chlorophenylpropanediol, phenoxyethanol, propylene glycol, and bromonitropropanediol.
The acid preservative is selected from one or more of benzoic acid, sorbic acid, dehydroacetic acid, propionic acid and cinnamic acid.
The ester antiseptic is selected from one or more of methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, and glyceryl caprylate.
The aromatic acid antiseptic is selected from one or more of anisole, citronellal, clove powder, and vanillic acid ester.
In a particular embodiment, the preservative is preferably selected from one or more of benzoic acid, sorbic acid, chlorobutanol, methylparaben or ethylparaben.
In one embodiment, the pharmaceutical composition comprises an active ingredient and an auxiliary material, wherein the auxiliary material comprises one or more of an oil phase matrix, a high molecular material, a penetration enhancer, a preservative, an antioxidant or a pH regulator, wherein the preservative accounts for 0.01-10% of the weight of the pharmaceutical composition.
In one embodiment of the present disclosure, the pharmaceutical composition includes an active ingredient and an auxiliary material, wherein the active ingredient is one or more of fullerene or fullerene derivatives; wherein the auxiliary materials comprise one or more of oil phase matrix, penetration enhancer and preservative; wherein the oil phase matrix is selected from one or more of paraffin, mineral oil, vegetable oil, lanolin, beeswax, vaseline, stearic acid, sorbitol monostearate, and medium chain triglyceride; wherein the penetration enhancer is selected from one or more of laurocapram, oleum Menthae Dementholatum, Mentholum, oleum Eucalypti, methyl salicylate, ethanol, Borneolum Syntheticum, and L-Borneolum Syntheticum; wherein the preservative comprises one or more of alcohols, acids, esters, aromatic acids, benzalkonium chloride, phenols and mercuride preservatives, and the preservative is preferably selected from one or more of benzoic acid, sorbic acid, chlorobutanol, methyl hydroxybenzoate or ethylparaben.
In another embodiment of the present disclosure, the pharmaceutical composition comprises an active ingredient and an adjuvant, wherein the active ingredient is one or more of fullerene or fullerene derivatives; wherein the auxiliary materials comprise one or more of high molecular materials, antioxidants, pH regulators or preservatives; wherein the high molecular material is selected from one or more of carbomer, polyethylene glycol 400 and polyethylene glycol 4000; wherein the antioxidant is selected from the group consisting of BHT; wherein the pH adjusting agent is selected from triethanolamine; wherein the preservative comprises one or more of alcohols, acids, esters, aromatic acids, benzalkonium chloride, phenols and mercuride preservatives, and the preservative is preferably selected from one or more of benzoic acid, sorbic acid, chlorobutanol, methyl hydroxybenzoate or ethylparaben.
Another aspect of the present disclosure relates to a formulation of any one of the aforementioned pharmaceutical compositions, which is a semi-solid formulation.
In one embodiment, the semi-solid formulation is selected from any one of an ointment, an ophthalmic ointment, a gel, or a suppository.
In a specific embodiment, the formulation of any of the aforementioned pharmaceutical compositions is an ointment.
In a specific embodiment, the formulation of any one of the aforementioned pharmaceutical compositions is selected from one or more of a cream, an ointment, a paste, and an ointment.
Another aspect of the disclosure relates to the use of any one of the aforementioned pharmaceutical compositions in the manufacture of a medicament for treating or reducing skin wounds.
In a particular embodiment, the skin wound comprises any one of a high temperature wound, a mechanical injury, a drug induced skin wound, a skin ulcer.
In a particular embodiment, the use of a pharmaceutical composition as described hereinbefore for the manufacture of a medicament for the treatment or alleviation of cutaneous high temperature wounds. The high temperature wound is selected from burn, scald and sunburn.
In a particular embodiment, the use of a pharmaceutical composition as described hereinbefore for the preparation of a medicament for the treatment or alleviation of ulcerative skin wounds.
In one embodiment, the pharmaceutical composition as described above can rapidly lower the temperature of the high temperature wound skin, preventing continued damage to the skin tissue.
In one embodiment, the pharmaceutical composition as described above has the effect of promoting wound healing.
In one embodiment, the pharmaceutical composition as described above may form a hydrophobic layer at the site of the skin wound, having an infection preventing effect.
In another aspect of the present disclosure, a method for preparing a pharmaceutical composition is provided, the method comprising the steps of: adding corresponding amounts of each component material into a matrix according to the formulation of the pharmaceutical composition; adding one component each time, stirring continuously until the other component is dissolved, adding the other component, and cooling to room temperature to obtain the pharmaceutical composition.
In one embodiment, the preparation method comprises the following steps: according to the formula of the pharmaceutical composition, adding corresponding amounts of the materials of each component into a molten oil phase matrix (heated and dissolved at 60-80 ℃), continuously stirring each component until the components are dissolved, adding the other component, and finally cooling to room temperature to obtain the pharmaceutical composition.
Example III
The disclosure is further illustrated with reference to the following examples. The description of the specific exemplary embodiments of the present disclosure has been presented for purposes of illustration and description. It is not intended to limit the disclosure to the precise form disclosed, and obviously many modifications and variations are possible in light of the teaching of the present disclosure. The exemplary embodiments were chosen and described in order to explain certain principles of the disclosure and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the disclosure and various alternatives and modifications thereof.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Preparation of the pharmaceutical composition:
the fullerene used in the formulations of the following examples, unless otherwise specified, may be any fullerene or fullerene derivative material, such as C60、C70、C76、C78、C80、C82、C84Or derivatives thereof, and the like.
The preservatives used in the formulations of the following examples may be any of those which are pharmaceutically acceptable, such as benzoic acid, sorbic acid, chlorobutanol, methylparaben, ethylparaben, and the like, unless otherwise specified.
Example 1: preparation of fullerene ointment
The formula comprises the following components in percentage by mass:
Figure BDA0003352586090000121
the process comprises the following steps: according to the above formula, adding corresponding amount of each component material into molten oil phase matrix (medium chain triglyceride, vaseline, lanolin and beeswax) which is heated and dissolved at 60-80 deg.C; adding antiseptic, penetration enhancer (Mentholum, L-Borneolum, and methyl salicylate), mineral oil, and fullerene, adding one component, stirring to dissolve, adding the other component, and cooling to room temperature to obtain fullerene ointment.
Example 2: preparation of fullerene ointment
The formula comprises the following components in percentage by mass:
Figure BDA0003352586090000131
the process comprises the following steps: according to the above formula, adding corresponding amount of each component material into molten oil phase matrix (medium chain triglyceride, paraffin, lanolin, sorbitol monostearate and beeswax) which is heated and dissolved at 60-80 deg.C; adding antiseptic, penetration enhancer (Mentholum, L-Borneolum, and methyl salicylate), vegetable oil, and fullerene, adding one component, stirring to dissolve, adding the other component, and cooling to room temperature to obtain fullerene ointment.
Example 3: preparation of fullerene ointment
The formula comprises the following components in percentage by mass:
Figure BDA0003352586090000132
the process comprises the following steps: according to the formula, adding corresponding amount of each component material into a molten oil phase matrix (medium chain triglyceride, vaseline and beeswax) which is heated and dissolved at 60-80 ℃; adding antiseptic, penetration enhancer (Mentholum, L-Borneolum, and methyl salicylate), and fullerene, adding one component, stirring to dissolve, adding the other component, and cooling to room temperature to obtain fullerene ointment.
Example 4: preparation of fullerene ointment
The formula comprises the following components in percentage by mass:
Figure BDA0003352586090000141
the process comprises the following steps: according to the above formula, adding corresponding amount of each component material into molten oil phase matrix (medium chain triglyceride, stearic acid, lanolin, sorbitol monostearate and beeswax) which is heated and dissolved at 60-80 deg.C; adding antiseptic, penetration enhancer (Mentholum, L-Borneolum, and methyl salicylate), mineral oil, and fullerene, adding one component, stirring to dissolve, adding the other component, and cooling to room temperature to obtain fullerene ointment.
Example 5: preparation of fullerene ointment
The formula comprises the following components in percentage by mass:
Figure BDA0003352586090000142
Figure BDA0003352586090000151
the process comprises the following steps: according to the formula, adding corresponding amount of each component material into molten oil phase matrix (medium chain triglyceride, white vaseline and beeswax) which is heated and dissolved at 60-80 ℃; adding antiseptic, penetration enhancer (ethanol, Mentholum, L-Borneolum, and methyl salicylate), and fullerene, adding one component, stirring to dissolve, adding the other component, and cooling to room temperature to obtain fullerene ointment.
Example 6: preparation of fullerene gel
The formula comprises the following components in percentage by mass:
Figure BDA0003352586090000152
the process comprises the following steps: according to the formula, adding the corresponding amount of each component material into a high polymer material (carbomer) at the temperature of 60-80 ℃; adding antiseptic, antioxidant (BHT), pH regulator (triethanolamine), and fullerene, adding another component after stirring to dissolve each component, adding purified water, and cooling to room temperature to obtain the fullerene gel.
Example 7: preparation of fullerene pharmaceutical composition preparation
The formula comprises the following components in percentage by mass:
Figure BDA0003352586090000153
Figure BDA0003352586090000161
the process comprises the following steps: according to the formula, adding corresponding amounts of each component material into high molecular materials (PEG400 and PEG4000) at 60-80 ℃; adding antiseptic, antioxidant (BHT), and fullerene, adding another component after each component is dissolved, and cooling to room temperature to obtain the fullerene pharmaceutical composition.
Example 8: particle size testing of Fullerene ointments
The method comprises the following steps: the fullerene ointment (example 3) was dissolved in toluene and after 15 minutes of sonication, particle size analysis was performed using a Nano-particle size potential analyzer (DLS, Malvern, Nano-ZS90, UK). As shown in fig. 1, the fullerene paste of the present disclosure has a uniform particle size distribution, mainly centered around 1 μm.
Example 9: experiment for treating rat burn and scald by fullerene ointment
Scalding the rat model: 12 male SD rats were randomly divided into 2 groups, a fullerene group (sample prepared in example 3), an ointment matrix control group, 6 rats in each group, depilatory cream for back depilation, and the temperature of the back skin was measured and recorded as normal skin temperature, after anesthesia of the rats using Mahjong, the rats were scalded for 5 seconds by using a YLS-5Q desk type super temperature control scalding instrument # 4 ironing head after being heated to 100 ℃, then the skin temperature was immediately measured and recorded as the skin temperature after scald, and after administration, the skin temperature was measured and recorded as the skin temperature after drug application. The whole process is completed in 20 seconds. The results are shown in FIG. 2. Subsequently, the application was performed 1 time per day, and the area of healed wounds due to scald was counted by photographing every 2 days, and the results are shown in fig. 3 and 4.
And (4) conclusion: it can be seen that the healing speed of the back scald area of the rat in the fullerene treatment group is obviously higher than that of the control group, and the wound healing rate of the fullerene treatment group reaches 91.10% on the 27 th day, while the wound healing rate of the control group is only 73.88%.
Example 10: experiment for treating burn and scald of mice by using fullerene ointment
Scalding the mouse model: male C57 mice were taken 24 and randomized into 3 groups: normal group, adjuvant control group, treatment group (sample prepared in example 3), 8 mice per group, and 2 groups other than the normal group were shaved on their backs, and then depilated with depilatory cream, which was washed clean with physiological saline. The next day, after anaesthetizing the air mahjong mice, the table type super temperature control scalding instrument 1# is used for ironing the heads, and after the temperature is heated to 80 ℃, the backs of the mice are scalded for 10 s. After scald, the treatment group is coated with fullerene burn and scald ointment, and the auxiliary material group is coated with blank auxiliary materials. The administration is carried out continuously for 15 days, the wound condition of the back of the mouse is observed and recorded every day, the scald condition of the back of the mouse is tested and recorded every other day after the administration is started, the figure 5 shows, then the mouse is euthanized by carbon dioxide, the weight of organs such as heart, liver, spleen, lung and kidney is taken, the organ coefficient is recorded, and the result shows in figure 6.
And (4) conclusion: the recovery speed of the scald and wound of the fullerene treatment group is faster than that of the auxiliary material control group. After 15 days of treatment, the fullerene treated group had healed substantially completely, while the adjuvant control group had a larger wound. Moreover, the organ coefficients of the fullerene treatment group and the auxiliary material control group are not obviously different from those of the normal group, which shows that the fullerene and the auxiliary material thereof have no obvious toxicity to the main organs.
Example 11: experiment for treating rat skin wound by fullerene ointment
Rat skin wound (chronic ulcer) model: randomly dividing 16 male SD rats into 2 groups, fullerene group (sample prepared in example 3) and adjuvant group, 8 rats in each group, depilating the back of depilatory cream, anesthetizing with air Mahjong rats, drawing 1 x 1cm square with mark on the back, and making 1cm area 2100 microliters of 0.75mg/mL mitomycin C solution was injected intramuscularly at the center point, after 30 minutes, the entire skin was cut off along the edge of the score, the wound area was recorded and recorded as the initial wound area, and the next day, once a day, the application was performed. The wound healing was recorded by taking pictures on days 3, 6, 9, 12 and 15, and the wound healing rate was counted, and the results are shown in fig. 7 and 8.
And (4) conclusion: the fullerene burn and scald ointment has a treatment effect on a rat skin wound model caused by high-temperature scald, mechanical injury and medicines, has a function of quickly cooling the burn and scald affected part, prevents residual heat from continuously damaging skin tissues, and has a function of promoting wound healing on the wound caused by three factors.
Example 12: experiment for treating rat skin wound by fullerene pharmaceutical composition preparation
Rat skin wound (chronic ulcer) model: the 24 male SD rats were randomly divided into 3 groups, a fullerene group (sample prepared in example 6), an excipient group (containing only auxiliary materials and no fullerene), a positive drug group (recombinant fibroblast growth factor), 8 rats in each group, the back of the depilatory cream was depilated, and after anaesthesia was performed on the rats using air Mahjong, the back was drawn with a mark to form a square with a side length of 1.8 x 1.8cm and an area of 3.24cm 2100 microliters of 0.75mg/mL mitomycin C solution was injected intramuscularly at the center point, after 30 minutes, the entire skin was cut off along the edge of the score, the wound area was recorded and recorded as the initial wound area, and the next day, once a day, the application was performed. The wound healing was recorded by taking pictures on days 3, 6, 9, 11 and 13, and the wound healing rate was counted, and the results are shown in fig. 9 and 10.
And (4) conclusion: the fullerene pharmaceutical composition preparation has a therapeutic effect on a chronic ulcer type rat skin wound model, has an effect of promoting wound healing on an injured wound, and has an effect superior to an excipient group without fullerene and a treatment group with a reconstituted fibroblast growth factor.
Example 13: fullerene pharmaceutical composition preparation for cell repair experiment of ultraviolet ray damage
The cell suspension in logarithmic growth phase is inoculated into a 96-well cell culture plate (about 5 ten thousand cells are inoculated in each well), the cell suspension is divided into a normal group, a model group, an excipient group (an auxiliary material in example 6) and a fullerene group (a sample in example 6 and no preservative is added), after 24 hours of culture, the energy of 8J/cm2 is used for irradiating other cells except the normal group with ultraviolet rays with the irradiation distance of 15cm for 20 minutes, then the culture solution is sucked out, the normal group and the model group are replaced by normal cell culture solution, the fullerene and the excipient group are cultured by the prepared culture solution respectively containing a fullerene sample and an excipient, and after 24 hours, the cell activity is detected by CCK-8. The results of the experiment are shown in FIG. 11.
And (4) conclusion: the fullerene pharmaceutical composition preparation has a protective effect on cell damage caused by ultraviolet rays, and the effect is superior to that of an excipient group without adding fullerene and that of a model group.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solutions of the present disclosure, not to limit them; although the present disclosure has been described in detail with reference to the foregoing embodiments, it should be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present disclosure.

Claims (10)

1. A pharmaceutical composition comprises active ingredient and adjuvants, wherein the active ingredient is one or more of fullerene or fullerene derivatives, and the adjuvants comprise one or more of oil phase matrix, polymer material, penetration enhancer, antiseptic, antioxidant or pH regulator; characterized in that the fullerene is selected from one or more of hollow fullerene and metal fullerene; optionally, the hollow fullerene is selected from C2nOr one or more of its derivatives; optionally, the metal fullerene is a hollow fullerene with a carbon cage structure enclosing a metal atom or a metal atom cluster, and the metal fullerene is selected from M @ C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2n、MxA3-xN@C2nWherein M and A are respectively and independently selected from Sc, Y and lanthanide metal elements, wherein n is more than or equal to 30 and less than or equal to 60, and x is more than or equal to 0 and less than or equal to 3; optionally, the fullerene derivative is selected from one or more of an amino acid derivative, a hydroxyl derivative, a carboxyl derivative or an amino derivative of the hollow fullerene or the metal fullerene;
wherein the weight ratio of the active ingredient in the pharmaceutical composition is 0.01-1%, preferably 0.01-0.5%.
2. The pharmaceutical composition of claim 1, wherein the adjuvant comprises an oil phase matrix, a penetration enhancer and a preservative, wherein the oil phase matrix accounts for 27-80% of the pharmaceutical composition; the penetration enhancer accounts for 2.5-15% of the weight of the pharmaceutical composition.
3. The pharmaceutical composition according to any one of claims 1 or 2, characterized in that the oily phase base is selected from one or more of paraffin, mineral oil, vegetable oil, lanolin, beeswax, vaseline, stearic acid, sorbitan monostearate, medium chain triglycerides; optionally, the penetration enhancer is selected from one or more of laurocapram, oleum Menthae Dementholatum, Mentholum, oleum Eucalypti, methyl salicylate, ethanol, Borneolum Syntheticum, and L-borneol.
4. The pharmaceutical composition of claim 1, wherein the excipients comprise a polymeric material, an antioxidant, a pH modifier, and a preservative; wherein the weight percentage of the high molecular material in the pharmaceutical composition is 0.1-99%, preferably 0.1-5%, 0.4-2%, 20-99%, 20-40% or 50-80%; wherein the antioxidant accounts for 0.01-0.5% of the weight of the pharmaceutical composition, preferably 0.01-0.1%; wherein the pH regulator accounts for 0.01-0.1% of the weight of the pharmaceutical composition.
5. The pharmaceutical composition according to any one of claims 1 or 4, wherein the polymeric material is selected from one or more of carbomer, polyethylene glycol, sodium carboxymethylcellulose; optionally, the antioxidant is selected from one or more of vitamin C, vitamin E, sodium metabisulfite and BHT; optionally, the pH regulator is selected from one or more of citric acid, sodium citrate, triethanolamine, and arginine.
6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the preservative is present in the pharmaceutical composition in a percentage by weight comprised between 0.01% and 10%; optionally, the preservative is selected from one or more of alcohols, acids, esters, aromatic acids, benzalkonium chloride, phenols and mercuride preservatives; preferably, the preservative is selected from one or more of benzoic acid, sorbic acid, chlorobutanol, methylparaben or ethylparaben.
7. The pharmaceutical composition according to any one of claims 1-6, for use in the preparation of a pharmaceutical formulation, wherein the pharmaceutical formulation is a semi-solid formulation; preferably, the pharmaceutical formulation is any one of an ointment, a gel or a suppository.
8. The pharmaceutical composition according to any one of claims 1 to 7, for use in the manufacture of a medicament for treating or reducing skin wounds.
9. The pharmaceutical composition according to any one of claims 1 to 8, for use in the manufacture of a medicament for treating or alleviating burns and scalds of the skin, sunburn of the skin, mechanical damage of the skin, drug-induced skin wounds or ulcerative skin wounds.
10. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 9, comprising the steps of: adding corresponding amounts of each component material into a matrix according to the formulation of the pharmaceutical composition; adding one component into the mixture, continuously stirring the mixture until the mixture is dissolved, adding the other component into the mixture, and finally cooling the mixture to room temperature to obtain the pharmaceutical composition; wherein the matrix is selected from any one of an oil phase matrix or a polymer material matrix.
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Citations (2)

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