CN116115609A - External pharmaceutical composition, liposome and preparation method and application thereof - Google Patents

External pharmaceutical composition, liposome and preparation method and application thereof Download PDF

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Publication number
CN116115609A
CN116115609A CN202211327339.3A CN202211327339A CN116115609A CN 116115609 A CN116115609 A CN 116115609A CN 202211327339 A CN202211327339 A CN 202211327339A CN 116115609 A CN116115609 A CN 116115609A
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mass
parts
liposome
guaiac
antifungal
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王进
李森
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Xi'an Yutai Pharmaceutical Co ltd
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Xi'an Yutai Pharmaceutical Co ltd
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/534—Mentha (mint)
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Abstract

The invention relates to an external pharmaceutical composition, a liposome and a preparation method and application thereof, belonging to the technical field of medicines. The external pharmaceutical composition comprises the following active raw material components: the guaiac blue hydrocarbon and/or sodium azulene sulfonate, antifungal drugs, antibacterial drugs and radix sophorae flavescentis extract, wherein the mass of the guaiac blue hydrocarbon and/or sodium azulene sulfonate is 0.5-2000 wt% of the mass of the antifungal drugs, the mass of the radix sophorae flavescentis extract is 5.0-200 wt% of the mass of the antifungal drugs, and the mass of the antibacterial drugs is 5.0-1000 wt% of the mass of the antifungal drugs; other essential components are also included in the composition. When the pharmaceutical composition or the liposome prepared from the pharmaceutical composition is used for treating dermatophyte infection diseases, the pharmaceutical composition not only can realize antifungal effect, but also can achieve the effects of easing pain, relieving itching and repairing skin tissues of affected parts, and in addition, the recurrence rate of the dermatopathy is low, and the treatment period is short.

Description

External pharmaceutical composition, liposome and preparation method and application thereof
Technical Field
The invention relates to an antifungal drug for skin, belongs to the technical field of medicines, and in particular relates to an external pharmaceutical composition, liposome and a preparation method and application thereof.
Background
Superficial skin fungus infectious diseases occupy a high proportion in skin diseases, generally easy to recur and difficult to cure, and belong to one of intractable skin diseases. Clinically common dermatophyte infectious diseases include tinea manuum, tinea pedis, tinea cruris, tinea corporis, tinea capitis and the like. The symptoms of the skin cream are mainly represented by local skin moist flushing, erosion, soaking blushing or small water bubbles, skin itching is hard, erysipelas, lymphangitis and the like are often caused by secondary infection after scratching, and the skin cream is easy to cornify, desquamate and chap after drying. The current clinical medicines for treating dermatophyte infection mainly comprise imidazoles, triazoles, carotenes cyclooxygenase inhibitors and polyenes. The antifungal agent for external use mainly relates to cream or cream for external use of clotrimazole, miconazole, terbinafine, ciclopirox olamine, butenafine and the like.
The treatment principle of the external antifungal medicine needs to be considered when the external antifungal medicine is selected to treat skin diseases:
(1) The medicine is selected from the following materials: selecting drugs according to etiology, pathological changes, subjective symptoms and the like;
(2) Proper choice of dosage form: the dosage form of the drug is particularly important for the therapeutic effects, and different dosage forms have different physical and absorption effects and may cause adverse effects if the dosage form is improperly selected.
Since itch caused by fungal infection is sometimes severe and is difficult for patients to tolerate, the simple administration of antifungal drugs is to kill fungi and further inhibit the symptoms of itch, so that the initial effect of the antifungal drugs on relieving itch is not obvious, a relatively long process is required, the normal life quality of the patients is influenced, and in addition, the single antifungal drugs are used for treating the technical problems that skin diseases caused by fungal infection are easy to relapse and are difficult to radically cure.
Therefore, the proper compound therapeutic drug is selected, and the drug effect is exerted on the premise of shortening the treatment course as much as possible by means of reasonable dosage forms, and the effects of easing pain, relieving itching, repairing and the like are considered, so that the drug is particularly necessary.
Disclosure of Invention
In order to solve the technical problems, the invention discloses an external pharmaceutical composition, a liposome and a preparation method and application thereof. The external pharmaceutical composition and the liposome prepared from the external pharmaceutical composition not only can realize antifungal effect, but also can play the effects of easing pain, relieving itching and repairing skin tissues of diseased parts, and simultaneously has low recurrence rate and short treatment period.
In order to achieve the technical purpose, the technical scheme provided by the embodiment of the invention is as follows:
in a first aspect, a pharmaceutical composition for external use comprises the following active ingredients:
the anti-fungal drug comprises guaiac blue hydrocarbon and/or sodium azulene sulfonate, an antifungal drug, an antibacterial drug and a radix sophorae flavescentis extract, wherein the guaiac blue hydrocarbon and/or sodium azulene sulfonate accounts for 0.5-2000 wt% of the antifungal drug, the radix sophorae flavescentis extract accounts for 5.0-200 wt% of the antifungal drug, and the antibacterial drug accounts for 5.0-1000 wt% of the antifungal drug;
other essential components are also included in the composition. Other essential components herein include a moisturizing preservative and an antioxidant, and the quality of the moisturizing preservative and the antioxidant meets the use criteria of the composition, and the other essential components also include other components.
As an alternative implementation manner of the embodiment of the invention, when the guaiac blue hydrocarbon and the sodium azulene sulfonate form a mixture, the mass ratio of the guaiac blue hydrocarbon to the sodium azulene sulfonate is (0.01-5), preferably (0.5-5), further preferably (1-5), and most preferably 1:1. Wherein, the guaiac blue hydrocarbon and the sodium azulene sulfonate both belong to sesquiterpene azulene compounds. Guaiac blue oil hydrocarbon belongs to oil solubility, and sodium azulene sulfonate is a water-soluble compound prepared by introducing sulfonic acid groups on the guaiac blue oil hydrocarbon structure. Both have anti-inflammatory and tissue granulation regeneration promoting effects, such as guaiac blue oil hydrocarbon is commonly used for treating burns, scalds, chaps, chilblains, eczema, dermatitis and the like, and sodium azulenesulfonate is commonly used for treating gastric ulcers, oral ulcers and the like. According to the invention, guaiac blue hydrocarbon and/or sodium azulene sulfonate are added into antifungal medicines, so that the skin tissue repair and regeneration can be promoted, and the effects of easing pain and relieving itching can be achieved on the basis of being beneficial to wound healing.
As an optional implementation manner of the embodiment of the invention, the antifungal drug is one or two or more of terbinafine hydrochloride, butenafine hydrochloride and miconazole;
the radix Sophorae Flavescentis extract is matrine; the matrine has antibacterial effect, such as inhibiting Streptococcus B, bacillus dysenteriae, bacillus proteus, escherichia coli, staphylococcus aureus, pseudomonas aeruginosa, etc.
The antibacterial drug is any one of chlorhexidine gluconate and chlorhexidine acetate. The antibacterial drug is used together with the kuh-seng extract to synergistically exert antibacterial effect. Wherein the chlorhexidine gluconate is preferably an aqueous solution with a certain concentration. Preferably, the mass percentage of the chlorhexidine gluconate aqueous solution is 20wt%.
As an alternative implementation mode of the embodiment of the invention, the composition comprises the following raw material components in parts by weight:
guaiac blue hydrocarbon and/or sodium azulene sulfonate: 1-1000 parts;
antifungal drug: 50-150 parts;
kuh-seng extract: 10-100 parts;
antibacterial medicine: 10-500 parts;
moisturizing preservative: 10-1000 parts;
antioxidant: 10-100 parts;
essence: 5-50 parts;
fructus Zanthoxyli extract: 1-50 parts.
As an alternative implementation mode of the embodiment of the invention, the moisturizing preservative is one or two of octyl glycol and ethylhexyl glycerol;
the antioxidant is vitamin E acetate;
the essence is peppermint oil; preferably the peppermint oil is of a commercial grade;
the pricklyash peel extract is commercially available pricklyash peel oil.
As an alternative implementation mode of the embodiment of the invention, the moisturizing preservative is two of octyl glycol and ethylhexyl glycerol, and the mass ratio of the octyl glycol to the ethylhexyl glycerol is (3-7).
Wherein, the peppermint oil and the pricklyash peel oil have the functions of relieving pain, relieving itching, eliminating dampness and resisting bacteria on the skin in a synergistic way.
In a second aspect, a method for preparing a pharmaceutical composition for external use comprises mixing the above raw materials according to the first aspect, and making into desired dosage forms.
In a third aspect, a liposome comprising a liposome membrane comprised of lecithin, further comprising the pharmaceutical composition of the first aspect.
As an alternative implementation mode of the embodiment of the invention, the mass of the lecithin is 50-2000 wt% of the mass of the antifungal medicine, and preferably the mass part of the lecithin is 100-1000 parts.
As an alternative implementation manner of the embodiment of the present invention, the liposome further comprises ethanol, and the mass of the ethanol is 500wt% -6000 wt% of the mass of the antifungal drug, preferably, the mass part of the ethanol is 1000-3000 parts, and the liposome further comprises essential water. Preferably, the ethanol is absolute ethanol, the water is purified water, and the purified water is pharmaceutical water prepared by a distillation method, an ion exchange method, a reverse osmosis method or other suitable methods.
In a fourth aspect, a preparation method of the liposome in the third aspect, the preparation method comprises the steps of taking lecithin and ethanol with the weight portions of the formula, uniformly mixing, heating to 45-50 ℃, continuously mixing for a period of time, adding the rest raw material components with the weight portions of the formula, and homogenizing to obtain the liposome. The liposome prepared from lecithin is used as a topical drug carrier, has a similar structure of a biomembrane, is easier to reach a lesion part, and is favorable for exerting drug effect locally.
As an alternative implementation manner of the embodiment of the present invention, the preparation method of the liposome includes the following steps:
(1) Under an inert environment, uniformly mixing lecithin and ethanol in parts by weight of the formula, heating to 45-50 ℃, continuously uniformly mixing for a period of time, adding guaiacum hydrocarbon and/or sodium azulene sulfonate, antifungal drugs, radix sophorae flavescentis extract, moisturizing preservative, antioxidant, essence and pepper extract, and uniformly mixing to form ethanol solution;
(2) Adding antibacterial drugs with formula ratio into water, and uniformly mixing to form an aqueous solution;
(3) And continuously adding the ethanol solution into the water solution under an inert environment, and homogenizing by a homogenizer to obtain the liposome.
The liposome can be subjected to the commercialized processes of subsequent split charging, sealing, packaging and the like.
The inert environment is an inert gas protection condition.
In a fifth aspect, the use of a composition according to the first aspect or a liposome according to the third aspect or a liposome prepared by the method according to the fourth aspect for the preparation of a pharmaceutical formulation for the treatment of a dermatophyte infection disease.
Compared with the prior art, the technical scheme provided by the embodiment of the invention has the following advantages:
1. the external pharmaceutical composition designed by the invention not only can realize antifungal effect, but also can achieve the effects of easing pain, relieving itching and repairing skin tissues of affected parts.
2. The external pharmaceutical composition designed by the invention is beneficial to wound healing on the basis of promoting skin tissue repair and regeneration, and the healed part is moist and smooth, thereby being beneficial to enhancing the subjective feeling of patients in use.
3. The liposome preparation designed by the invention can easily penetrate through the stratum corneum to reach the lesion part, is favorable for targeted drug effect, shortens the treatment period and has low recurrence rate.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the invention and together with the description, serve to explain the principles of the invention.
In order to more clearly illustrate the embodiments of the invention or the technical solutions of the prior art, the drawings which are used in the description of the embodiments or the prior art will be briefly described, and it will be obvious to a person skilled in the art that other drawings can be obtained from these drawings without inventive effort.
FIG. 1 is a photograph showing a liposome prepared in the example of the present invention.
Detailed Description
In order that the above objects, features and advantages of the invention will be more clearly understood, a further description of the invention will be made. It should be noted that, without conflict, the embodiments of the present invention and features in the embodiments may be combined with each other.
The skin diseases caused by fungal infection have severe itching, so that patients cannot tolerate the skin diseases, the initial effect of relieving itching by simply taking antifungal drugs is not obvious, the treatment course is long, and the skin diseases are easy to relapse. If a proper compound therapeutic drug can be selected, and the drug effect can be exerted on the premise of shortening the course of treatment as much as possible by means of reasonable dosage forms, the drug can also have the functions of easing pain, relieving itching, repairing and the like.
In order to solve the above problems or part of the problems, the embodiments of the present invention provide an external pharmaceutical composition, a liposome, and a preparation method and an application thereof. The external pharmaceutical composition and the liposome not only can realize antifungal effect, but also can achieve the effects of easing pain, relieving itching and repairing skin tissues of affected parts, and can also realize the technical purposes of low recurrence rate and short treatment period.
According to a first aspect of the embodiment of the invention, there is provided a pharmaceutical composition for external use, the composition comprising the following active raw material components:
the anti-fungal drug comprises guaiac blue hydrocarbon and/or sodium azulene sulfonate, an antifungal drug, an antibacterial drug and a radix sophorae flavescentis extract, wherein the guaiac blue hydrocarbon and/or sodium azulene sulfonate accounts for 0.5-2000 wt% of the antifungal drug, the radix sophorae flavescentis extract accounts for 5.0-200 wt% of the antifungal drug, and the antibacterial drug accounts for 5.0-1000 wt% of the antifungal drug;
other essential components are also included in the composition. Other essential components herein include a moisturizing preservative and an antioxidant, and the quality of the moisturizing preservative and the antioxidant meets the use criteria of the composition.
Exemplary, the mass of the guaiac hydrocarbon and/or sodium azulene sulfonate is 0.5wt%, 1.0wt%, 5.0wt%, 10wt%, 15wt%, 20wt%, 50wt%, 100wt%, 120wt%, 140wt%, 160wt%, 180wt%, 200wt%, 220wt%, 240wt%, 260wt%, 280wt%, 300wt%, 320wt%, 340wt%, 360wt%, 380wt%, 400wt%, 420wt%, 440wt%, 460wt%, 480wt%, 500wt%, 520wt%, 540wt%, 560wt%, 580wt%, 600wt%, 620wt%, 640wt%, 660wt%, 680wt%, 700wt%, 720wt%, 740wt%, 760wt%, 780wt%, 800wt%, 820wt%, 840wt%, 860wt%, 880wt%, 900wt%, 920wt%, 940wt%, 1100wt%, 1200wt%, 1300wt%, 1500wt%, 1600wt%, 1400wt%, 1800wt%, 960wt%, 2000wt% of the antifungal drug mass.
Preferably, the mass of the guaiac blue hydrocarbon and/or sodium azulene sulfonate is 0.67wt% to 1000wt% of the mass of the antifungal drug, more preferably, the mass of the guaiac blue hydrocarbon and/or sodium azulene sulfonate is 5wt% to 800wt% of the mass of the antifungal drug, still more preferably, the mass of the guaiac blue hydrocarbon and/or sodium azulene sulfonate is 5wt% to 500wt% of the mass of the antifungal drug, and most preferably, the mass of the guaiac blue hydrocarbon and/or sodium azulene sulfonate is 5wt% to 100wt% of the mass of the antifungal drug.
Illustratively, the mass of the kuh-seng extract is 5.0wt%, 8.0wt%, 10wt%, 12wt%, 15wt%, 18wt%, 20wt%, 22wt%, 25wt%, 28wt%, 30wt%, 32wt%, 35wt%, 38wt%, 40wt%, 42wt%, 45wt%, 48wt%, 50wt%, 60wt%, 70wt%, 80wt%, 90wt%, 100wt%, 110wt%, 120wt%, 130wt%, 140wt%, 150wt%, 160wt%, 170wt%, 180wt%, 190wt%, 200wt% of the mass of the antifungal agent. Preferably, the quality of the kuh-seng extract is 5.0-100 wt% of the quality of the antifungal drug, and more preferably, the quality of the kuh-seng extract is 5.0-50 wt% of the quality of the antifungal drug.
The mass of the bacteriostatic drug is, for example, 5.0wt%, 10wt%, 15wt%, 20wt%, 50wt%, 100wt%, 120wt%, 140wt%, 160wt%, 180wt%, 200wt%, 220wt%, 240wt%, 260wt%, 280wt%, 300wt%, 320wt%, 340wt%, 360wt%, 380wt%, 400wt%, 420wt%, 440wt%, 460wt%, 480wt%, 500wt%, 520wt%, 540wt%, 560wt%, 580wt%, 600wt%, 620wt%, 640wt%, 660wt%, 680wt%, 700wt%, 720wt%, 740wt%, 760wt%, 780wt%, 800wt%, 820wt%, 840wt%, 860wt%, 880wt%, 900wt%, 920wt%, 940wt%, 960wt%, 980wt%, 1000wt% of the mass of the antifungal drug. Preferably, the mass of the antibacterial agent is 5.0wt% to 800wt% of the mass of the antifungal agent, more preferably, the mass of the antibacterial agent is 5.0wt% to 500wt% of the mass of the antifungal agent, and most preferably, the mass of the antibacterial agent is 5.0wt% to 200wt% of the mass of the antifungal agent.
In some embodiments, when the guaiac blue hydrocarbon and the sodium azulene sulfonate form a mixture, the mass ratio of the guaiac blue hydrocarbon to the sodium azulene sulfonate is (0.01-5), preferably (0.5-5), further preferably (1-5), and most preferably 1:1. Wherein, the guaiac blue hydrocarbon and the sodium azulene sulfonate both belong to sesquiterpene azulene compounds. Guaiac blue oil hydrocarbon belongs to oil solubility, and sodium azulene sulfonate is a water-soluble compound prepared by introducing sulfonic acid groups on the guaiac blue oil hydrocarbon structure. Both have anti-inflammatory and tissue granulation regeneration promoting effects, such as guaiac blue oil hydrocarbon is commonly used for treating burns, scalds, chaps, chilblains, eczema, dermatitis and the like, and sodium azulenesulfonate is commonly used for treating gastric ulcers, oral ulcers and the like. According to the invention, guaiac blue hydrocarbon and/or sodium azulene sulfonate are added into antifungal medicines, so that the skin tissue repair and regeneration can be promoted, and the effects of easing pain and relieving itching can be achieved on the basis of being beneficial to wound healing.
In some embodiments, the antifungal agent is one or two or more of terbinafine hydrochloride, butenafine hydrochloride, miconazole.
In some embodiments, the kuh-seng extract is matrine; the matrine has antibacterial effect, such as inhibiting Streptococcus B, bacillus dysenteriae, bacillus proteus, escherichia coli, staphylococcus aureus, pseudomonas aeruginosa, etc.
In some embodiments, the antibacterial drug is any one of chlorhexidine gluconate and chlorhexidine acetate. The antibacterial drug is used together with the kuh-seng extract to synergistically exert antibacterial effect.
In some embodiments, the composition comprises the following raw material components in parts by weight:
guaiac blue hydrocarbon and/or sodium azulene sulfonate: 1-1000 parts;
antifungal drug: 50-150 parts;
kuh-seng extract: 10-100 parts;
antibacterial medicine: 10-500 parts;
moisturizing preservative: 10-1000 parts;
antioxidant: 10-100 parts;
essence: 5-50 parts;
fructus Zanthoxyli extract: 1-50 parts.
For example, the guaiac blue hydrocarbon or sodium azulene sulfonate may be 1 part by mass, 5 parts by mass, 10 parts by mass, 20 parts by mass, 30 parts by mass, 40 parts by mass, 50 parts by mass, 60 parts by mass, 70 parts by mass, 80 parts by mass, 90 parts by mass, 100 parts by mass, 110 parts by mass, 130 parts by mass, 150 parts by mass, 180 parts by mass, 200 parts by mass, 230 parts by mass, 250 parts by mass, 280 parts by mass, 300 parts by mass, 330 parts by mass, 350 parts by mass, 380 parts by mass, 400 parts by mass, 430 parts by mass, 450 parts by mass, 480 parts by mass, 500 parts by mass.
Illustratively, when the guaiac blue hydrocarbon and the sodium azulene sulfonate form a mixture, the mass ratio of the guaiac blue hydrocarbon to the sodium azulene sulfonate is (0.01-5): (0.01-5), including 0.01:5, 1:1 and 5:0.01.
The antifungal agent may be exemplified by 10 parts by mass, 20 parts by mass, 30 parts by mass, 40 parts by mass, 50 parts by mass, 60 parts by mass, 70 parts by mass, 80 parts by mass, 90 parts by mass, 100 parts by mass, 110 parts by mass, 120 parts by mass, 130 parts by mass, 140 parts by mass, 150 parts by mass.
The kuh-seng extract may be 10 parts by mass, 20 parts by mass, 30 parts by mass, 40 parts by mass, 50 parts by mass, 60 parts by mass, 70 parts by mass, 80 parts by mass, 90 parts by mass, 100 parts by mass.
For example, the antibacterial drug may be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 130, 150, 180, 200, 230, 250, 280, 300, 330, 350, 380, 400, 430, 450, 480, 500 parts by mass.
In some embodiments, the moisturizing preservative is a mixture of caprylyl glycol and ethylhexyl glycerol, and the caprylyl glycol is 10-500 parts and the ethylhexyl glycerol is 10-500 parts. Preferably, the mass ratio of the octyl glycol to the ethylhexyl glycerol is (3-7) to (3-7).
For example, the octylglycol or ethylhexyl glycerol may be 10 parts by mass, 20 parts by mass, 50 parts by mass, 80 parts by mass, 100 parts by mass, 130 parts by mass, 150 parts by mass, 180 parts by mass, 200 parts by mass, 230 parts by mass, 250 parts by mass, 280 parts by mass, 300 parts by mass, 330 parts by mass, 350 parts by mass, 380 parts by mass, 400 parts by mass, 430 parts by mass, 450 parts by mass, 480 parts by mass, 500 parts by mass.
The antioxidant may be exemplified by 10 parts by mass, 20 parts by mass, 30 parts by mass, 40 parts by mass, 50 parts by mass, 60 parts by mass, 70 parts by mass, 80 parts by mass, 90 parts by mass, 100 parts by mass.
The essence may be exemplified by 5 parts by mass, 10 parts by mass, 15 parts by mass, 20 parts by mass, 25 parts by mass, 30 parts by mass, 35 parts by mass, 40 parts by mass, 45 parts by mass, 50 parts by mass.
The pricklyash peel extract may be 1 part by mass, 5 parts by mass, 10 parts by mass, 13 parts by mass, 15 parts by mass, 18 parts by mass, 20 parts by mass, 23 parts by mass, 25 parts by mass, 28 parts by mass, 30 parts by mass, 33 parts by mass, 35 parts by mass, 38 parts by mass, 40 parts by mass, 43 parts by mass, 45 parts by mass, 48 parts by mass, 50 parts by mass.
In some embodiments, the antioxidant is vitamin E acetate.
In some embodiments, the flavor is peppermint oil, preferably the peppermint oil is of a commercially available grade.
In some embodiments, the zanthoxylum bungeanum extract is commercially available zanthoxylum oil.
Wherein, the peppermint oil and the pricklyash peel oil have the functions of relieving pain, relieving itching, eliminating dampness and resisting bacteria on the skin in a synergistic way.
In a second aspect of the embodiment of the present invention, a method for preparing a pharmaceutical composition for external use is provided, which comprises uniformly mixing the above raw materials, and preparing into a desired dosage form, wherein an excipient may be added during the preparation of the desired dosage form.
According to a third aspect of embodiments of the present invention, there is provided a liposome comprising a liposome membrane material composed of lecithin, and further comprising the pharmaceutical composition.
In some embodiments, the mass of the lecithin is 50wt% to 2000wt% of the mass of the antifungal agent, and preferably the mass fraction of the lecithin is 100 to 1000 parts.
In some embodiments, the lecithin comprises any one of soy lecithin, egg yolk lecithin, hydrogenated soy lecithin, hydrogenated egg yolk lecithin.
In some embodiments, the liposome further comprises ethanol, the mass of the ethanol is 500-6000 wt% of the mass of the antifungal drug, the mass fraction of the ethanol is 1000-3000 parts, and the liposome further comprises essential water. Preferably, the ethanol is absolute ethanol, the water is purified water, and the purified water is pharmaceutical water prepared by a distillation method, an ion exchange method, a reverse osmosis method or other suitable methods.
Illustratively, the mass of lecithin is 50wt%, 100wt%, 150wt%, 200wt%, 250wt%, 300wt%, 350wt%, 400wt%, 500wt%, 600wt%, 700wt%, 800wt%, 900wt%, 1000wt%, 1200wt%, 1400wt%, 1600wt%, 1800wt%, 2000wt%, 2200wt%, 2400wt%, 2600wt%, 2800wt%, 3000wt% of the mass of the antifungal agent.
Exemplary, the mass parts of the lecithin are 100 parts, 200 parts, 300 parts, 400 parts, 500 parts, 600 parts, 700 parts, 800 parts, 900 parts, 1000 parts.
Illustratively, the mass of the ethanol is 500wt%, 1000wt%, 1500wt%, 2000wt%, 2500wt%, 3000wt%, 3500wt%, 4000wt%, 4500wt%, 5000wt%, 5500wt%, 6000wt% of the mass of the antifungal agent.
Exemplary, the ethanol is 1000 parts by mass, 1200 parts by mass, 1400 parts by mass, 1600 parts by mass, 1800 parts by mass, 2000 parts by mass, 2200 parts by mass, 2400 parts by mass, 2600 parts by mass, 2800 parts by mass, 3000 parts by mass.
According to a fourth aspect of the embodiment of the invention, a preparation method of the liposome is provided, and the preparation method comprises the steps of taking lecithin and ethanol which are in parts by weight of a formula, uniformly mixing the lecithin and the ethanol, heating the mixture to 45-50 ℃, continuously mixing the mixture for a period of time, adding the rest raw material components in parts by weight of the formula, and homogenizing the mixture to obtain the liposome.
As an alternative implementation manner of the embodiment of the present invention, the preparation method of the liposome includes the following steps:
(1) Under an inert environment, uniformly mixing lecithin and ethanol in parts by weight of the formula, heating to 45-50 ℃, continuously uniformly mixing for a period of time, adding guaiacum hydrocarbon and/or sodium azulene sulfonate, antifungal drugs, radix sophorae flavescentis extract, moisturizing preservative, antioxidant, essence and pepper extract, and uniformly mixing to form ethanol solution;
(2) Adding antibacterial drugs with formula ratio into water, and uniformly mixing to form an aqueous solution;
(3) And continuously adding the ethanol solution into the water solution under an inert environment, and homogenizing by a homogenizer to obtain the liposome.
The liposome can be subjected to the commercialized processes of subsequent split charging, sealing, packaging and the like.
The inert environment is an inert gas protection condition.
In a fifth aspect, the present embodiment provides an application of an external pharmaceutical composition or liposome in preparing a pharmaceutical preparation for treating dermatophyte infection diseases. The external pharmaceutical composition or the liposome acts on dermatophyte infection diseases, not only can realize antifungal effects, but also can achieve the effects of easing pain, relieving itching and repairing skin tissues of affected parts, and can also realize the technical purposes of low recurrence rate and short treatment period.
The dermatophyte infection diseases include, but are not limited to, tinea pedis, tinea corporis, tinea cruris and the like.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced otherwise than as described herein; it will be apparent that the embodiments in the specification are only some, but not all, embodiments of the invention.
Example 1
The composition comprises the following raw material components in parts by weight, and is added into an ointment base to prepare an ointment paste with the total weight of 10000 parts;
wherein, guaiac blue oil hydrocarbon: 1 part;
terbinafine hydrochloride: 100 parts;
kuh-seng extract: 10 parts;
20wt% chlorhexidine gluconate aqueous solution: 100 parts;
octyl glycol: 70 parts;
ethylhexyl glycerol: 30 parts;
vitamin E acetate: 30 parts;
peppermint oil: 10 parts;
fructus Zanthoxyli extract: 10 parts.
The following table 1 shows the raw material components contained in the compositions exemplified in examples 1 to 16, and comparative examples 1 to 3.
Table 1 list of raw material components disclosed in examples 1 to 16 and comparative examples 1 to 3
Figure BDA0003912387190000081
Figure BDA0003912387190000091
The preparation method of the external pharmaceutical composition provided in the embodiment 1 to the embodiment 16 comprises the steps of uniformly mixing all the components in the formula, adding other essential components, and preparing any dosage form.
Example 17
Disclosed is a method for producing a liposome comprising a liposome membrane material composed of lecithin, comprising ethanol, and further comprising the composition provided in the example 2, wherein the total mass of the liposome is 10000g;
the preparation method comprises the following steps:
weighing 2.0kg of absolute ethyl alcohol, placing the absolute ethyl alcohol into a container protected by inert gas, adding 200g of soybean lecithin, uniformly stirring, heating to about 45 ℃, stirring for about 30min, and continuously adding 5g of guaiac blue oil hydrocarbon, 100g of terbinafine hydrochloride, 25g of matrine, 70g of octaethylene glycol, 30g of ethylhexyl glycerol, 30g of vitamin E acetate, 10g of peppermint oil and 10g of pepper extract, wherein any adding sequence and mode of the guaiac blue oil hydrocarbon, the terbinafine hydrochloride, the matrine, the octaethylene glycol, the ethylhexyl glycerol, the vitamin E acetate, the peppermint oil and the pepper extract are all within the protection scope of the invention; after the addition is finished, stirring uniformly to form ethanol mixed solution;
taking 7.42kg of purified water, adding 100g of 20wt% chlorhexidine gluconate aqueous solution into the purified water, and uniformly mixing to form an aqueous solution;
mixing the ethanol mixed solution and the water solution, and homogenizing by a homogenizer to form a blue emulsion shown in figure 1; the blue emulsion can be subjected to subsequent commercial packaging, such as subpackaging, sealing, packaging and the like.
Example 18
Disclosed is a method for producing a liposome comprising a liposome membrane material composed of lecithin, comprising ethanol, and further comprising the composition provided in the example 3, wherein the total mass of the liposome is 10000g;
the preparation method comprises the following steps:
weighing 2.0kg of absolute ethyl alcohol, placing the absolute ethyl alcohol into a container protected by inert gas, adding 200g of soybean lecithin, uniformly stirring, heating to about 40 ℃, stirring for about 30min, and continuously adding 10g of guaiac blue oil hydrocarbon, 100g of terbinafine hydrochloride, 25g of matrine, 70g of octaethylene glycol, 30g of ethylhexyl glycerol, 30g of vitamin E acetate, 10g of peppermint oil and 10g of pepper extract, wherein any adding sequence and mode of the guaiac blue oil hydrocarbon, the terbinafine hydrochloride, the matrine, the octaethylene glycol, the ethylhexyl glycerol, the vitamin E acetate, the peppermint oil and the pepper extract are all within the protection scope of the invention; after the addition is finished, stirring uniformly to form ethanol mixed solution;
taking purified water, adding 100g of 20wt% chlorhexidine gluconate aqueous solution into the purified water, and uniformly mixing to form an aqueous solution;
mixing the ethanol mixed solution and the water solution, homogenizing by a homogenizer, and carrying out subsequent commercial packaging such as split charging, sealing, packaging and the like.
Example 19
Disclosed is a method for producing a liposome comprising a liposome membrane material composed of lecithin, comprising ethanol, and further comprising the composition provided in the example 6, wherein the total mass of the liposome is 10000g;
the preparation method comprises the following steps:
weighing 2.0kg of absolute ethyl alcohol, placing the absolute ethyl alcohol into a container protected by inert gas, adding 200g of soybean lecithin, uniformly stirring, heating to about 45 ℃, stirring for about 30min, and continuously adding 5g of guaiac blue oil hydrocarbon, 100g of butenafine hydrochloride, 25g of matrine, 70g of octaethylene glycol, 30g of ethylhexyl glycerol, 30g of vitamin E acetate, 10g of peppermint oil and 10g of pepper extract, wherein any adding sequence and mode of the guaiac blue oil hydrocarbon, the butenafine hydrochloride, the matrine, the octaethylene glycol, the ethylhexyl glycerol, the vitamin E acetate, the peppermint oil and the pepper extract are all within the protection scope of the invention; after the addition is finished, stirring uniformly to form ethanol mixed solution;
taking purified water, adding 100g of 20wt% chlorhexidine gluconate aqueous solution into the purified water, and uniformly mixing to form an aqueous solution;
mixing the ethanol mixed solution and the water solution, homogenizing by a homogenizer, and carrying out subsequent commercial packaging such as split charging, sealing, packaging and the like.
Example 20
Disclosed is a method for producing a liposome comprising a liposome membrane material composed of lecithin, comprising ethanol, and further comprising the composition provided in the example 7, wherein the total mass of the liposome is 10000g;
the preparation method comprises the following steps:
weighing 2.0kg of absolute ethyl alcohol, placing the absolute ethyl alcohol into a container protected by inert gas, adding 200g of soybean lecithin, uniformly stirring, heating to about 45 ℃, stirring for about 30min, and continuously adding 5g of guaiac blue oil hydrocarbon, 100g of miconazole, 25g of matrine, 70g of octaethylene glycol, 30g of ethylhexyl glycerol, 30g of vitamin E acetate, 10g of peppermint oil and 10g of pricklyash peel extract under the stirring state, wherein any adding sequence and mode of the guaiac blue oil hydrocarbon, the miconazole, the matrine, the octaethylene glycol, the ethylhexyl glycerol, the vitamin E acetate, the peppermint oil and the pricklyash peel extract are all in the protection scope of the invention; after the addition is finished, stirring uniformly to form ethanol mixed solution;
taking purified water, adding 100g of 20wt% chlorhexidine gluconate aqueous solution into the purified water, and uniformly mixing to form an aqueous solution;
mixing the ethanol mixed solution and the water solution, homogenizing by a homogenizer, and carrying out subsequent commercial packaging such as split charging, sealing, packaging and the like.
Example 21
Disclosed is a method for producing a liposome comprising a liposome membrane material composed of lecithin, comprising ethanol, and further comprising the composition provided in the example 10, wherein the total mass of the liposome is 10000g;
the preparation method comprises the following steps:
weighing 2.0kg of absolute ethyl alcohol, placing the absolute ethyl alcohol into a container protected by inert gas, adding 200g of soybean lecithin, uniformly stirring, heating to about 45 ℃, stirring for about 30min, and continuously adding 5g of guaiac blue oil hydrocarbon, 100g of terbinafine hydrochloride, 100g of matrine, 70g of octaethylene glycol, 30g of ethylhexyl glycerol, 30g of vitamin E acetate, 10g of peppermint oil and 10g of pepper extract, wherein any adding sequence and mode of the guaiac blue oil hydrocarbon, the terbinafine hydrochloride, the matrine, the octaethylene glycol, the ethylhexyl glycerol, the vitamin E acetate, the peppermint oil and the pepper extract are all within the protection scope of the invention; after the addition is finished, stirring uniformly to form ethanol mixed solution;
taking purified water, adding 20g of chlorhexidine acetate aqueous solution into the purified water, and uniformly mixing to form an aqueous solution;
mixing the ethanol mixed solution and the water solution, homogenizing by a homogenizer, and carrying out subsequent commercial packaging such as split charging, sealing, packaging and the like.
Example 22
Disclosed is a method for producing a liposome comprising a liposome membrane material composed of lecithin, comprising ethanol, and further comprising the composition provided in the example 12, wherein the total mass of the liposome is 10000g;
the preparation method comprises the following steps:
weighing 2.0kg of absolute ethyl alcohol, placing the absolute ethyl alcohol into a container protected by inert gas, adding 200g of soybean lecithin, uniformly stirring, heating to about 45 ℃, stirring for about 30min, and continuously adding 5g of sodium azulene sulfonate, 100g of terbinafine hydrochloride, 25g of matrine, 70g of octaethylene glycol, 30g of ethylhexyl glycerol, 30g of vitamin E acetate, 10g of peppermint oil and 10g of pepper extract, wherein any adding sequence and mode of the guaiac blue oil hydrocarbon, the terbinafine hydrochloride, the matrine, the octaethylene glycol, the ethylhexyl glycerol, the vitamin E acetate, the peppermint oil and the pepper extract are all within the protection scope of the invention; after the addition is finished, stirring uniformly to form ethanol mixed solution;
taking purified water, adding 100g of 20wt% chlorhexidine gluconate aqueous solution into the purified water, and uniformly mixing to form an aqueous solution;
mixing the ethanol mixed solution and the water solution, homogenizing by a homogenizer, and carrying out subsequent commercial packaging such as split charging, sealing, packaging and the like.
Example 23
Disclosed is a method for producing a liposome comprising a liposome membrane material composed of lecithin, comprising ethanol, and further comprising the composition provided in the example 14, wherein the total mass of the liposome is 10000g;
the preparation method comprises the following steps:
weighing 2.0kg of absolute ethyl alcohol, placing the absolute ethyl alcohol into a container protected by inert gas, adding 200g of soybean lecithin, uniformly stirring, heating to about 45 ℃, stirring for about 30min, and continuously adding 5g of sodium azulene sulfonate, 5g of guaifenesin, 100g of terbinafine hydrochloride, 25g of matrine, 70g of octaethylene glycol, 30g of ethylhexyl glycerol, 30g of vitamin E acetate, 10g of peppermint oil and 10g of pricklyash peel extract, wherein any adding sequence and mode of the guaifenesin, the terbinafine hydrochloride, the matrine, the octaethylene glycol, the ethylhexyl glycerol, the vitamin E acetate, the peppermint oil and the pricklyash peel extract are all in the protection scope of the invention; after the addition is finished, stirring uniformly to form ethanol mixed solution;
taking purified water, adding 100g of 20wt% chlorhexidine gluconate aqueous solution into the purified water, and uniformly mixing to form an aqueous solution;
mixing the ethanol mixed solution and the water solution, homogenizing by a homogenizer, and carrying out subsequent commercial packaging such as split charging, sealing, packaging and the like.
Comparative example 4
Disclosed is a method for preparing a liposome comprising a liposome membrane material composed of lecithin, ethanol, and the composition provided in comparative example 1, wherein the total mass of the liposome is 10000g.
Comparative example 5
Disclosed is a method for preparing a liposome comprising a liposome membrane material composed of lecithin, ethanol, and the composition provided in comparative example 2, wherein the total mass of the liposome is 10000g.
Comparative example 6
A method for preparing a liposome comprising a liposome membrane material composed of lecithin, ethanol, and the composition provided in comparative example 3 is disclosed, wherein the total mass of the liposome is 10000g.
Test example 1
Bacteriostasis test:
1.1 activating strains and preparing bacterial suspensions: culturing Trichophyton rubrum in potato dextrose agar medium at 28deg.C until good conidium is formed, collecting in sterile physiological saline, and concentrating the bacterial suspension with hemocytometerThe degree is adjusted to 2 multiplied by 10 6 CFU/ml。
1.2 in vitro bacteriostasis test: selecting a standard sterile culture dish with the diameter of 9cm, adding 20ml of a melting culture solution, manufacturing a potato dextrose agar plate, balancing for 30min at 35 ℃ before use, uniformly coating bacterial suspension on the surface of the culture medium plate, punching 3 holes (with the diameter of 7 mm) on the culture medium after bacteria coating by using a sterile puncher, adding an equal volume (0.2 ml/hole) of a medicine solution one by one after agar removal, culturing for 7 days at the temperature of 28 ℃, repeating the test for 3 times for each sample, placing the plate on a blue background, observing the size of a bacteriostasis ring around each sample, and recording the diameter value of the bacteriostasis ring, wherein the diameter of the bacteriostasis ring is the average number of the maximum diameter and the minimum diameter (or the average number of the maximum diameter and the minimum diameter is represented by multiplied by 2).
1.3 data analysis: the results were repeated for each sample in the form of mean ± standard deviation. All data were analyzed using SPSS24.0 software.
Table 2 diameter (mm) of inhibition ring of examples and comparative examples against trichophyton rubrum
Figure BDA0003912387190000131
/>
Figure BDA0003912387190000132
Figure BDA0003912387190000141
Test example 2
Clinical trial:
the products of examples 17 to 23 and comparative examples 1 to 6 were used for clinical trials;
2.1 screening of assays:
2.1a, the disease condition of the patient accords with relevant diagnosis standards of tinea pedis clinically;
2.1b, patient was not using any drug for treating skin for two consecutive weeks.
2.2 grouping of patients:
the patients were randomly divided into groups, including test and control groups; 50 patients in each group, and the average age of each group of patients, the male and female proportion has no statistical significance (P > 0.05), and the patients are comparable. And the statistics of clinical symptoms erosion, pain, itching and other symptoms of each group of patients are shown in the following table 3.
TABLE 3 statistical forms of clinical symptoms for patients
Figure BDA0003912387190000142
The treatment method comprises the following steps: each of the test and control groups in table 3 was treated with the samples prepared in each of the examples and comparative examples in such a manner that the preparation was uniformly applied to the affected part for 2 times/day for two weeks.
And (3) observing the indexes: each group of patients observed their therapeutic effect after stopping the drug and stopping the drug for 1 month, and the results of the fungal test were carried out. The clinical symptoms of patients with pain and itching symptoms were followed up on the third day of medication. The recovery of the skin of the affected part of the patient with erosion symptoms is observed when stopping the medicine for two weeks continuously.
Curative effect judgment criteria: the treatment effect is classified into 4 grades of invalid, effective, obvious effect and recovery, wherein the invalid refers to that the clinical symptoms of patients are not improved at all, and the result of fungus test is positive; effective means that the clinical symptoms of the patient are improved, and the result of the fungus test is weak positive or weak negative; the obvious effect means that the clinical symptoms of the patient are obviously improved, and the result of fungus test is negative: recovery refers to the disappearance of clinical symptoms in the patient, which is negative as a result of the fungal test. The judgment criteria of the clinical symptoms of pain, itch and erosion are pain and itch symptom relief, and the healing of the erosion part is observed and the skin is smooth.
Statistical methods: the data in this study were processed using SPSS24.0 statistical software. P <0.05 indicates that the difference is statistically significant.
Table 4 comparison of clinical efficacy of each group
Figure BDA0003912387190000151
Comparison of clinical symptoms for each group is shown in table 5;
table 5 list of clinical symptom comparisons for each group
Figure BDA0003912387190000152
/>
Figure BDA0003912387190000161
In conclusion, when the external pharmaceutical composition and the liposome are clinically used, the antifungal effect can be realized, and the effects of easing pain, relieving itching and repairing skin tissues of affected parts can be achieved.
After stopping the medicine for 1 month, the invalid cases are removed, and the follow-up results show that the disease recurrence rate of 1-3 patients in the test group patients is 2.0-6.0%, and the disease recurrence rate of 12 patients in the control group 1 patients is 30%. Of the patients in control group 4, 8 had recurrent disease, the recurrent rate of the disease was 19.0%, and the recurrent rate of the disease was lower in the patients in test group than in the patients in control group 1, 4, the difference was statistically significant (P < 0.05).
Therefore, the external pharmaceutical composition and the liposome can also realize the technical purposes of low recurrence rate and short treatment period.
It should be noted that, in this document, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising one … …" does not exclude the presence of other like elements in a process, method, article, or apparatus that comprises the element.
The foregoing is only a specific embodiment of the invention to enable those skilled in the art to understand or practice the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown and described herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (10)

1. A pharmaceutical composition for external use, characterized in that the composition comprises the following active raw material components:
the anti-fungal drug comprises guaiac blue hydrocarbon and/or sodium azulene sulfonate, an antifungal drug, an antibacterial drug and a radix sophorae flavescentis extract, wherein the guaiac blue hydrocarbon and/or sodium azulene sulfonate accounts for 0.5-2000 wt% of the antifungal drug, the radix sophorae flavescentis extract accounts for 5.0-200 wt% of the antifungal drug, and the antibacterial drug accounts for 5.0-1000 wt% of the antifungal drug;
other essential components are also included in the composition.
2. The composition according to claim 1, wherein the mass ratio between the guaiac blue hydrocarbon and the sodium azulene sulfonate when the guaiac blue hydrocarbon and the sodium azulene sulfonate form a mixture is (0.01-5), preferably (0.5-5), more preferably (0.5-5), still more preferably (1-5) and (1-5).
3. The composition according to claim 1, wherein the antifungal agent is one or two or more of terbinafine hydrochloride, butenafine hydrochloride, miconazole;
the radix Sophorae Flavescentis extract is matrine;
the antibacterial drug is any one of chlorhexidine gluconate and chlorhexidine acetate.
4. The composition according to claim 1, wherein the composition comprises the following raw material components in parts by mass:
guaiac blue hydrocarbon and/or sodium azulene sulfonate: 1-1000 parts;
antifungal drug: 50-150 parts;
kuh-seng extract: 10-100 parts;
antibacterial medicine: 10-500 parts;
moisturizing preservative: 10-1000 parts;
antioxidant: 10-100 parts;
essence: 5-50 parts;
fructus Zanthoxyli extract: 1-50 parts.
5. The composition of claim 4, wherein the moisturizing preservative is one or both of octylglycol and ethylhexyl glycerol;
the antioxidant is vitamin E acetate;
the essence is peppermint oil.
6. A liposome comprising a liposome membrane material comprising lecithin, and further comprising the pharmaceutical composition of any one of claims 1-5.
7. Liposome according to claim 6, characterized in that the mass of lecithin is 50-2000% of the mass of antifungal drug, preferably the mass fraction of lecithin is 100-1000.
8. Liposome according to claim 6, characterized in that the liposome further comprises ethanol, and the mass of the ethanol is 500-6000 wt% of the mass of the antifungal drug, preferably the mass fraction of the ethanol is 1000-3000 parts, and the liposome further comprises essential water.
9. A method for preparing a liposome according to any one of claims 6 to 8, which is characterized in that the preparation method comprises the steps of taking lecithin and ethanol which are the components of the formula in parts by weight, uniformly mixing the lecithin and the ethanol, heating the mixture to 45 to 50 ℃, continuously mixing the mixture for a period of time, adding the components of the rest raw materials in parts by weight, and homogenizing the mixture to prepare the liposome.
10. Use of a composition according to any one of claims 1 to 5 or a liposome according to any one of claims 6 to 8 or a liposome obtainable by a method according to claim 9 for the preparation of a pharmaceutical formulation for the treatment of a dermatophyte infection.
CN202211327339.3A 2022-10-27 2022-10-27 External pharmaceutical composition, liposome and preparation method and application thereof Pending CN116115609A (en)

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