CN114099504A - Tacrolimus compound preparation and preparation method thereof - Google Patents

Tacrolimus compound preparation and preparation method thereof Download PDF

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Publication number
CN114099504A
CN114099504A CN202111538702.1A CN202111538702A CN114099504A CN 114099504 A CN114099504 A CN 114099504A CN 202111538702 A CN202111538702 A CN 202111538702A CN 114099504 A CN114099504 A CN 114099504A
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tacrolimus
stirring
compound preparation
percent
emulsifier
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朱丽
薛丹露
黄红红
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Zhuohe Pharmaceutical Group Co ltd
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Zhuohe Pharmaceutical Group Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/436—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 oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Abstract

The invention provides a tacrolimus compound preparation, which comprises the following components in percentage by mass: 0.03% -0.1% of tacrolimus; 0.5 to 2 percent of terbinafine hydrochloride and auxiliary materials. The tacrolimus compound preparation disclosed by the invention is prepared by combining tacrolimus and terbinafine hydrochloride, and has a better curative effect and small side effect when used for treating seborrheic dermatitis.

Description

Tacrolimus compound preparation and preparation method thereof
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a tacrolimus compound preparation and a preparation method thereof.
Background
Tacrolimus (Tacrolimus), also known as FK506, is a fermentation product separated from streptomyces, is a macrolide antibiotic, is a strong novel immunosuppressant, mainly inhibits the release of interleukin-2 (IL-2), comprehensively inhibits T lymphocytes to act as main target cells of the Tacrolimus, and inhibits the immune activity of the T lymphocytes by inhibiting the expression of early lymphocyte-related genes. Tacrolimus acts by binding to the cytoplasmic protein FKBP (forming the FK506 binding protein). At least 4 FKBPs, FKBP-12, FKBP-13, FKBP25, FKBP59, respectively, were present, and the resulting complex reduced the Ca2+ -dependent calcineurin activity. Thus, nuclear factor of activated T cells, the cellular transcription factor (NF-ATC), cannot dephosphorylate, thereby preventing translocation of the translocator into the cell nucleus, which in turn blocks transcription of interleukin 2 factor (IL-2). In addition, tacrolimus also acts to potentiate the action of corticosteroids and progesterone by binding to FKBP to form hormone receptor-containing complexes, preventing their aging. Topical application of tacrolimus may be effected by these mechanisms.
Seborrheic dermatitis is a common clinical superficial inflammatory skin disease, mainly occurs in the positions of a head, a face, a trunk and the like with abundant sebum secretion, wherein the head is the position with the highest incidence rate of seborrheic dermatitis, has great influence on facial beauty of a patient, and can cause serious consequences such as alopecia and the like if the seborrheic dermatitis is not treated in time, so that the seborrheic dermatitis needs to be diagnosed as early as possible and correct treatment measures are taken. The antifungal medicine is a main method for treating the seborrheic dermatitis of the head, and the reasonable use of the antifungal medicine can effectively improve the clinical symptoms of patients, control the seborrheic dermatitis of the head and reduce the recurrence risk. The tacrolimus cream is a common medicine for treating the seborrheic dermatitis of the head, can effectively improve the papule, the macula or the greasy scale symptom of the seborrheic dermatitis of the head, but has limited treatment effect by using a single externally applied medicine. In view of this, a new drug is needed to treat dermatitis.
Disclosure of Invention
The invention aims to disclose a tacrolimus compound preparation, which is prepared by combining tacrolimus and terbinafine hydrochloride, and has better curative effect and small side effect when used for treating seborrheic dermatitis. The preparation method is simple, has low equipment requirement, and is convenient to carry and use and good in curative effect.
In order to realize the aim, the invention provides a tacrolimus compound preparation which comprises the following components in parts by mass:
0.03% -0.1% of tacrolimus; 0.5 to 2 percent of terbinafine hydrochloride and auxiliary materials.
Further, the auxiliary materials comprise 1% -10% of a dissolving agent; 0.5 to 10 percent of freshener; 0.5 to 5 percent of emulsifier; 1% -3% of transdermal penetrating agent; 5% -20% of a thickening agent; 1% -10% of humectant; 0.5 to 3 percent of preservative; 5% -15% of a diluent; 50 to 80 percent of water.
Furthermore, the transdermal penetrating agent is one or a mixture of several of propylene glycol, azone and diethylene glycol monoethyl ether in any proportion.
Further, the humectant is sodium hyaluronate, and the sodium hyaluronate is high molecular sodium hyaluronate and/or low molecular sodium hyaluronate.
The invention also provides a preparation method of the tacrolimus compound preparation, which comprises the following steps:
a. respectively dissolving tacrolimus, terbinafine hydrochloride and transdermal penetrant in a dissolving agent for later use;
b. heating the thickening agent, the humectant, the preservative, the diluent and water to 70-85 ℃, stirring and melting until the mixture is clear, preparing a mixed solution and keeping the temperature;
c. heating the emulsifier to 20-40 ℃ until the emulsifier is melted, then adding the emulsifier into the mixed solution obtained in the step b, heating to 70-85 ℃, stirring for emulsification, then slowly cooling while stirring to form a cream matrix, and keeping the temperature;
d. and c, respectively adding the solution obtained in the step a into the cream matrix obtained in the step c, stirring intermittently, stirring for multiple times in a circulating manner, and rapidly cooling to obtain an ointment.
Further, the stirring in the step d is carried out by using a portable high-speed disperser at 70-75 ℃ at 3000 r.min-1Stirring at constant speed (1) for 20s, intermittently, and stirring 8 times in total.
Compared with the prior art, the invention has the beneficial effects that: the preparation is prepared by combining the tacrolimus and the terbinafine hydrochloride, has better curative effect on the seborrheic dermatitis and has small side effect.
Detailed Description
The present invention is described in detail below with reference to various embodiments, but it should be understood that these embodiments are not intended to limit the present invention, and those skilled in the art should be able to make modifications and substitutions on the functions, methods, or structures of these embodiments without departing from the scope of the present invention.
The invention provides a tacrolimus compound preparation, which comprises the following components in percentage by mass: 0.03% -0.1% of tacrolimus; 0.5 to 2 percent of terbinafine hydrochloride and auxiliary materials.
The auxiliary materials comprise 1 to 10 percent of dissolving agent; 0.5 to 10 percent of freshener; 0.5 to 5 percent of emulsifier; 1% -3% of transdermal penetrating agent; 5% -20% of a thickening agent; 1% -10% of humectant; 0.5 to 3 percent of preservative; 5% -15% of a diluent; 50 to 80 percent of water. The transdermal penetrating agent can be one or a mixture of more of propylene glycol, azone and diethylene glycol monoethyl ether in any proportion. The humectant is sodium hyaluronate, and the sodium hyaluronate is high molecular sodium hyaluronate and/or low molecular sodium hyaluronate.
In particular implementations, the dissolution agent may be ethanol or propylene glycol. The algefacient is menthol or menthol. The emulsifier is one or a mixture of more of tween 80, span 80, sodium dodecyl sulfate and polyethylene glycol-7 stearate in any proportion. The thickener is one or more of cetyl alcohol, stearyl alcohol, white vaseline, glyceryl monostearate and stearic acid. The diluent is one or a mixture of more of liquid paraffin, propylene glycol and medium chain triglyceride in any proportion. The preservative is one or a mixture of more of sorbic acid, potassium sorbate, parabens and benzoic acid in any proportion.
The technical solution of the present invention is illustrated by the following specific examples.
Example 1
The tacrolimus compound preparation disclosed by the embodiment comprises the following components:
Figure BDA0003413688420000031
Figure BDA0003413688420000041
the preparation method of the tacrolimus compound preparation comprises the following steps:
a. respectively dissolving tacrolimus, terbinafine hydrochloride and azone in a dissolving agent for later use;
b. heating high-molecular sodium hyaluronate, tween 80 and water to 70-85 deg.C, stirring, melting to clarify, heating Mentholum, stearic acid, propylene glycol and ethylparaben to 70-85 deg.C, stirring, melting to clarify, mixing the two solutions to obtain a mixed solution, and keeping the temperature;
c. heating Tween 80 to 20-40 ℃ until the emulsifier is melted, then adding the Tween 80 into the mixed solution obtained in the step b, heating to 70-85 ℃, stirring for emulsification, then slowly cooling while stirring to form a cream matrix, and keeping the temperature;
d. and c, respectively adding the solution obtained in the step a into the cream matrix obtained in the step c, stirring intermittently, stirring for multiple times in a circulating manner, and rapidly cooling to obtain an ointment. In particular to a portable high-speed disperser at 70-75 ℃ at 3000 r.min-1Stirring at constant speed (1) for 20s, intermittently, and stirring 8 times in total.
Example 2
Figure BDA0003413688420000042
Figure BDA0003413688420000051
The preparation method of the tacrolimus compound preparation comprises the following steps:
a. respectively dissolving tacrolimus, terbinafine hydrochloride and azone in a dissolving agent for later use;
b. heating low-molecular sodium hyaluronate, high-molecular sodium hyaluronate, tween 80 and water to 70-85 ℃, stirring and melting to be clear, heating menthol, stearic acid, propylene glycol and ethylparaben to 70-85 ℃, stirring and melting to be clear, mixing the two to prepare a mixed solution, and keeping the temperature;
c. heating Tween 80 to 20-40 ℃ until the emulsifier is melted, then adding the Tween 80 into the mixed solution obtained in the step b, heating to 70-85 ℃, stirring for emulsification, then slowly cooling while stirring to form a cream matrix, and keeping the temperature;
d. and c, respectively adding the solution obtained in the step a into the cream matrix obtained in the step c, stirring intermittently, stirring for multiple times in a circulating manner, and rapidly cooling to obtain an ointment. In particular to a portable high-speed disperser at 70-75 ℃ at 3000 r.min-1Stirring at constant speed (1) for 20s, intermittently, and stirring 8 times in total.
Specific experiments are as follows:
establishing a model:
12 SPF-grade Kunming mice of 6 weeks old were used. Mice were shaved on their backs the day before the experiment and had an area of approximately 2.5cm by 2.5 cm. Mice were sensitized on the back by applying 100 μ L of 0.5% DNCB on day 1 and day 2 of the experiment. At 3-6 days, mice were not treated at all. At day 8-16, mice were first treated on their backs and ears with 4% SDS to remove the barrier function of the skin and stratum corneum. After drying for 3 hours, 100 μ L of 0.5% DNCB was applied for excitation treatment, and modeling was successful.
And (3) comparing the curative effects:
mice successfully modeled were randomly divided into two groups, and the control group was applied with tacrolimus ointment on the affected part, the experimental group was applied with the ointment prepared in example 2 of the present application twice a day for 15 days, and the rash condition and the dry skin condition of the applied part were visually observed and recorded.
TABLE 1 adverse reaction index Standard Table
Figure BDA0003413688420000061
TABLE 2 adverse reaction evaluation Table
Rash Dry skin
Experimental group 10 12
Control group 15 26
p 0.027 0.014
Adverse reactions were evaluated and scored for each experimental mouse according to table 1, and the sum of the values for each group of adverse reactions was the value in table 2. The results in the table show that the ointment prepared by the invention can effectively improve the adverse reaction.
The observation indexes of the curative effect are as follows: the behavior of scratching is that the mice are placed independently, the times of scratching the back of the mice within 10min are observed, and one time of scratching is counted continuously. ② expressing the skin damage, namely observing the expression condition of the skin damage of each group of mice. And thirdly, detecting the concentrations of IL-4, IFN-gamma and IgE in the serum, namely after the model is successfully established, anesthetizing mice in a model group and a control group by injecting 10% chloral hydrate (1ml/kg) into the abdominal cavity, removing right eyeballs to take blood, standing for 30min at 37 ℃, centrifuging for 15min at 3500r/min, collecting the serum, applying an enzyme-linked immunosorbent assay, using the IL-4, IFN-gamma and IgE ELISAKit of the mice, and operating according to the instruction of a specification.
TABLE 3 therapeutic efficacy criteria
Figure BDA0003413688420000071
TABLE 4 comparison of serum expression levels of IL-4, IFN-. gamma.and IgE between the experimental and control groups
Group of Number of examples IL-4(pg/mL) IFN-γ(pg/mL) IgE(ng/mL)
Experimental group 6 67.367±17.266 55.681±9.451 20.687±13.339
Control group 6 73.320±13.897 60.744±8.159 27.196±46.997
p 0.044 0.035 0.042
The results show that the compound preparation has better curative effect on dermatitis, small side effect and developability. In addition, the production process is simple, the production equipment is universal, and the cost is low.
The above-listed detailed description is only a specific description of a possible embodiment of the present invention, and they are not intended to limit the scope of the present invention, and equivalent embodiments or modifications made without departing from the technical spirit of the present invention should be included in the scope of the present invention.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.

Claims (6)

1. The tacrolimus compound preparation is characterized by comprising the following components in parts by mass:
0.03% -0.1% of tacrolimus; 0.5 to 2 percent of terbinafine hydrochloride and auxiliary materials.
2. The tacrolimus compound preparation according to claim 1, wherein the auxiliary material comprises a dissolving agent 1-10%; 0.5 to 10 percent of freshener; 0.5 to 5 percent of emulsifier; 1% -3% of transdermal penetrating agent; 5% -20% of a thickening agent; 1% -10% of humectant; 0.5 to 3 percent of preservative; 5% -15% of a diluent; 50 to 80 percent of water.
3. The tacrolimus compound preparation according to claim 2, wherein the transdermal penetrating agent is one or a mixture of more of propylene glycol, azone and diethylene glycol monoethyl ether in any proportion.
4. The tacrolimus compound preparation according to claim 3, wherein the humectant is sodium hyaluronate, and the sodium hyaluronate is high-molecular sodium hyaluronate and/or low-molecular sodium hyaluronate.
5. A preparation method of a tacrolimus compound preparation is characterized by comprising the following steps:
a. respectively dissolving tacrolimus, terbinafine hydrochloride and transdermal penetrant in a dissolving agent for later use;
b. heating the thickening agent, the humectant, the preservative, the diluent and water to 70-85 ℃, stirring and melting until the mixture is clear, preparing a mixed solution and keeping the temperature;
c. heating the emulsifier to 20-40 ℃ until the emulsifier is melted, then adding the emulsifier into the mixed solution obtained in the step b, heating to 70-85 ℃, stirring for emulsification, then slowly cooling while stirring to form a cream matrix, and keeping the temperature;
d. and c, respectively adding the solution obtained in the step a into the cream matrix obtained in the step c, stirring intermittently, stirring for multiple times in a circulating manner, and rapidly cooling to obtain an ointment.
6. The method for preparing the tacrolimus compound preparation according to claim 5, wherein the stirring in the step d is performed by using a portable high-speed disperser at 70-75 ℃ and 3000 r-min-1Stirring at constant speed (1) for 20s, intermittently, and stirring 8 times in total.
CN202111538702.1A 2021-12-15 2021-12-15 Tacrolimus compound preparation and preparation method thereof Pending CN114099504A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098463A1 (en) * 2001-06-05 2002-12-12 The New Industry Research Organization Antifungal compositions
US20120277193A1 (en) * 2009-09-21 2012-11-01 President And Fellows Of Harvard College Synergistic Combination Therapy
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CN108079074A (en) * 2018-02-02 2018-05-29 佛山市南海东方澳龙制药有限公司 Compound hydrochloric acid terbinafine emulsifiable paste and preparation method thereof
CN108210449A (en) * 2018-02-02 2018-06-29 佛山市南海东方澳龙制药有限公司 Dog Terbinafine hydrochloride emulsifiable paste and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098463A1 (en) * 2001-06-05 2002-12-12 The New Industry Research Organization Antifungal compositions
US20120277193A1 (en) * 2009-09-21 2012-11-01 President And Fellows Of Harvard College Synergistic Combination Therapy
CN105663027A (en) * 2016-04-01 2016-06-15 中国人民解放军广州军区武汉总医院 External preparation containing sirolimus as well as preparation method and application thereof
CN108079074A (en) * 2018-02-02 2018-05-29 佛山市南海东方澳龙制药有限公司 Compound hydrochloric acid terbinafine emulsifiable paste and preparation method thereof
CN108210449A (en) * 2018-02-02 2018-06-29 佛山市南海东方澳龙制药有限公司 Dog Terbinafine hydrochloride emulsifiable paste and preparation method thereof

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Title
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舒畅: "盐酸特比萘芬乳膏治疗面部脂溢性皮炎的临床疗效观察", 实用皮肤病学杂志, vol. 9, no. 3, pages 183 - 185 *

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