CN117257726B - Milapine ointment and preparation method and application thereof - Google Patents

Milapine ointment and preparation method and application thereof Download PDF

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Publication number
CN117257726B
CN117257726B CN202311523624.7A CN202311523624A CN117257726B CN 117257726 B CN117257726 B CN 117257726B CN 202311523624 A CN202311523624 A CN 202311523624A CN 117257726 B CN117257726 B CN 117257726B
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parts
mirtazapine
lubricant
ointment
emulsifier
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CN117257726A (en
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杨志坤
李斌
曹相丽
王新东
邹宇云
林洪军
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Jinan Guangshengyuan Biotechnology Co ltd
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Jinan Guangshengyuan Biotechnology 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—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
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to the technical field of medicines, in particular to a mirtazapine ointment and a preparation method and application thereof. Mirtazapine ointment comprising, in parts by weight: mirtazapine: 5-10 parts of a lubricant; an oil phase: 20-30 parts of a lubricant; emulsifying agent: 5-10 parts of a lubricant; auxiliary emulsifier: 5-10 parts of a lubricant; water: 40-50 parts of a lubricant; transdermal enhancer: 5-10 parts of a lubricant; preservative: 0.01-0.5 parts; the oil phase consists of stearic acid, glyceryl monocaprylate, liquid paraffin and vaseline, wherein the mass ratio of the stearic acid to the glyceryl monocaprylate to the liquid paraffin to the vaseline is as follows: 1-2: 1-2: 1-2: 0.5-1; the emulsifier is hydrogenated cardanol polyoxyethylene ether, and has the structure as follows:wherein m is 11 or 13. The mirtazapine ointment provided by the invention has the advantages of light sticky feel, high stability, good safety, high transdermal release rate, higher than 80% transdermal release rate within 24 hours, and better weight increasing effect.

Description

Milapine ointment and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a mirtazapine ointment and a preparation method and application thereof.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Mirtazapine is an antidepressant of noradrenergic and 5-hydroxytryptamine energy, which is a central presynaptic membrane alpha 2 receptor antagonist that enhances adrenergic neurotransmission while blocking the central 5-HT2 and 5-HT3 receptors. Mirtazapine has been widely used in veterinary medicine for its antiemetic and appetite stimulating effects due to its antagonism at the 5HT3 receptor and has been shown to reduce emesis in cats with Chronic Kidney Disease (CKD) and is useful for nutritional support in dogs and cats with acute or chronic diseases.
Currently, topical formulations of mirtazapine have been developed to achieve transdermal administration by application to the inside of the ear of a pet. However, most of the matrixes of the existing mirtazapine ointment are fatty auxiliary materials, such as oleyl alcohol, simethicone, PEG-8 caprylic acid/glyceryl silicate and the like, or the ointment is formed into a water-in-oil ointment, and the problems of heavy sticky feel, poor body feel, difficult cleaning, low transdermal release rate and poor weight increasing effect of the ointment exist.
Disclosure of Invention
Based on the problems existing in the prior art, the invention provides an O/W type mirtazapine ointment for solving the problems of heavy sticky feel, poor body feel, difficult cleaning, low transdermal release rate and poor weight increasing effect of the water-in-oil mirtazapine ointment in the prior art. The O/W mirtazapine ointment of the invention takes stearic acid, glyceryl monocaprylate, paraffin and the like which are cheap and easy to obtain as main oil phase auxiliary materials, takes hydrogenated cardanol polyoxyethylene ether with good suitability with mirtazapine and other auxiliary materials as an emulsifying agent, successfully prepares the mirtazapine ointment with high drug loading capacity, good safety, good stability, high transdermal release rate and good weight increasing effect, and solves the problems of heavy sticky feel, poor body feeling and difficult cleaning of the water-in-oil mirtazapine ointment because the mirtazapine ointment is an oil-in-water ointment.
Specifically, the technical scheme of the invention is as follows:
in a first aspect of the present invention, there is provided a mirtazapine ointment comprising, in parts by weight:
mirtazapine: 5-10 parts of a lubricant;
an oil phase: 20-30 parts of a lubricant;
emulsifying agent: 5-10 parts of a lubricant;
auxiliary emulsifier: 5-10 parts of a lubricant;
water: 40-50 parts of a lubricant;
transdermal enhancer: 5-10 parts of a lubricant;
preservative: 0.01-0.5 part;
the oil phase consists of stearic acid, glyceryl monocaprylate, liquid paraffin and vaseline, wherein the mass ratio of the stearic acid to the glyceryl monocaprylate to the liquid paraffin to the vaseline is as follows: 1-2:1-2:0.5-1;
the emulsifier is hydrogenated cardanol polyoxyethylene ether, and has the structure as follows:wherein m is 11 or 13;
in a specific embodiment, the co-emulsifier is polyethylene glycol 400 (PEG 400);
in a specific embodiment, the transdermal enhancer is selected from one or more of isopropyl myristate, trioleate, oleic acid, myristic acid and azone.
In a specific embodiment, the preservative is selected from one or more of sodium benzoate, methylparaben, ethylparaben, propylparaben, benzalkonium bromide, benzyl alcohol.
In a specific embodiment, the mirtazapine ointment comprises, in parts by weight:
mirtazapine: 6-9 parts of a lubricant;
an oil phase: 22-28 parts of a lubricant;
emulsifying agent: 6-9 parts of a lubricant;
auxiliary emulsifier: 6-9 parts of a lubricant;
water: 42-48 parts;
transdermal enhancer: 6-9 parts of a lubricant;
preservative: 0.1 to 0.5 part.
In a specific embodiment, the mass ratio of stearic acid, glyceryl monocaprylate, liquid paraffin and vaseline in the oil phase is: 1:1:1:0.5.
in a second aspect of the present invention, there is provided a method of preparing a mirtazapine ointment according to the first aspect comprising:
(1) Mixing and heating mirtazapine, an oil phase, an emulsifier, a coemulsifier and a transdermal enhancer to 70-90 ℃ to obtain a mixture 1;
(2) Dissolving a preservative in water, and heating to 70-90 ℃ to obtain a mixture 2;
(3) Slowly pouring the mixture 1 obtained in the step (1) into the mixture 2 obtained in the step (2), and stirring and emulsifying to obtain the mirtazapine ointment.
In a specific embodiment, in step (1) and step (2), the heating temperature is 75-85 ℃, preferably 80 ℃.
In a specific embodiment, in the step (3), the temperature of stirring and emulsifying is 50-70 ℃, preferably 55-65 ℃, and more preferably 60 ℃; the stirring time is 1 to 3 hours, preferably 1 to 2 hours.
In a third aspect of the invention, there is provided the use of the mirtazapine ointment of the first aspect in the manufacture of a medicament for the treatment of nausea, vomiting and anorexia in pets.
Preferably, the companion animal is a cat, dog.
The invention has the following beneficial effects:
the mirtazapine ointment is an oil-in-water (O/W) ointment, and solves the problems of heavy sticky feel, poor body feel and difficult cleaning of the water-in-oil mirtazapine ointment.
The mirtazapine ointment provided by the invention has the advantages of high stability, good safety, high transdermal release rate and transdermal release rate higher than 80% within 24 hours.
Compared with the mirtazapine ointment in the prior art, the mirtazapine ointment has better weight increasing effect.
Drawings
FIG. 1 is a time chart of cumulative transdermal rates of the formulations of examples 1-4 and comparative example 1 in the in vitro release test of test example 3 according to the present invention.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
The following examples are intended to illustrate embodiments of the invention and are not to be construed as limiting the invention in any way, and it will be understood by those skilled in the art that various modifications may be made without departing from the spirit and scope of the invention.
The invention takes hydrogenated cardanol polyoxyethylene ether as an emulsifier, which is prepared by polyoxyethylene etherification and hydrogenation of cardanol, wherein the cardanol consists of four side chain alkylphenols with different saturation degrees, and the structure is as follows:
。
the cardanol has the advantages of low price and reproducibility, the cardanol after etherification and hydrogenation is used as an emulsifier, pi-pi interaction of phenyl in hydrogenated cardanol polyoxyethylene ether and benzene ring or aromatic heterocycle in a mirtazapine structure, hydrophobicity of long-chain saturated alkyl and hydrophilicity of a polyoxyethylene chain introduced later are utilized, the solubility of insoluble mirtazapine is greatly increased, and the cardanol as the emulsifier provides stable emulsifying effect in an O/W system, and the cardanol has better effects than conventional emulsifying agents in stability, transdermal release and treatment effects of preparations.
Reagent and source:
cardanol: 99.5% purchased from Guangdong Bian cashew industries, inc.
Ethylene oxide: 99%, wanzhen chemical materials Co., ltd.
The hydrogenated cardanol polyoxyethylene ether was prepared by the following method in reference Synthesis and application of hydrogenated cardanol polyoxyethylene ether (Materials Science and Engineering, 2019, 592:1-9):
preparation of unsaturated Cardanol polyoxyethylene ether (UCPE-11, UCPE-13): 500g of cardanol is used as a raw material, and the raw material is heated to be 2 multiplied by 10 at 135-140 DEG C 5 ~3×10 5 And (5) carrying out batch ethoxylation in an autoclave of Pa to obtain cardanol polyoxyethylene ether.
Preparation of hydrogenated Cardanol polyoxyethylene ether (CPE-11, CPE-13): weighing 15g of Al-Ni alloy, adding 200ml of deionized water, stirring, taking 30g of sodium hydroxide NaOH, and maintaining the temperature at 60-70 ℃ for treatment to remove aluminum in the Al-Ni alloy, thereby obtaining metallic nickel. The cardanol polyoxyethylene ether 18 g is weighed, then 80 g absolute ethyl alcohol and the metallic nickel obtained by the method are added, and hydrogenation is catalyzed at 25 ℃ to obtain hydrogenated cardanol polyoxyethylene ether (marked as CPE-11 and CPE-13).
The reaction formula is as follows:
example 1 preparation of O/W Milapine ointment
In this embodiment, the O/W mirtazapine ointment comprises the following ingredients in parts by weight:
mirtazapine: 8 parts;
an oil phase: 25 parts of stearic acid, glyceryl monocaprylate, liquid paraffin and Vaseline in a mass ratio of 1:1:1:0.5;
emulsifier CPE-11:8 parts;
co-emulsifier PEG400:8 parts;
water: 45 parts;
transdermal enhancer isopropyl myristate (IPM): 5 parts;
preservative sodium benzoate: 0.2 parts.
The preparation method comprises the following steps:
(1) Mixing and heating the mirtazapine, the oil phase, the emulsifier, the auxiliary emulsifier and the transdermal enhancer in parts by weight to 80 ℃;
(2) Dissolving the preservative in the weight parts into the water and heating to 80 ℃;
(3) Slowly pouring the mixture obtained in the step (1) into the water phase mixture obtained in the step (2), cooling to 60 ℃, stirring for 1h for emulsification, and obtaining the O/W mirtazapine ointment which has uniform color and luster, no granular sensation after being smeared and has no layering discoloration after being centrifuged for 30 min at 3000 r/min.
Example 2 preparation of O/W Milapine ointment
In this embodiment, the O/W mirtazapine ointment comprises the following ingredients in parts by weight:
mirtazapine: 5 parts;
an oil phase: 30 parts of stearic acid, glyceryl monocaprylate, liquid paraffin and Vaseline, wherein the mass ratio of the stearic acid to the glyceryl monocaprylate to the liquid paraffin is 1:1:0.5;
emulsifier CPE-13:10 parts;
co-emulsifier PEG400:5 parts;
water: 45 parts;
transdermal enhancer glycerol trioleate: 5 parts;
preservative sodium benzoate: 0.2 parts.
The preparation method comprises the following steps:
(1) Mixing and heating the mirtazapine, the oil phase, the emulsifier, the auxiliary emulsifier and the transdermal enhancer in parts by weight to 80 ℃;
(2) Dissolving the preservative in the weight parts into the water and heating to 80 ℃;
(3) Slowly pouring the mixture obtained in the step (1) into the water phase mixture obtained in the step (2), cooling to 60 ℃, stirring for 1h for emulsification, and obtaining the O/W mirtazapine ointment which has uniform color, is not layered after standing for 12h, is free from granular feel when being smeared and is free from layered discoloration when being centrifuged.
Example 3 preparation of O/W Milapine ointment
In this embodiment, the O/W mirtazapine ointment comprises the following ingredients in parts by weight:
mirtazapine: 10 parts;
an oil phase: 25 parts of stearic acid, glyceryl monocaprylate, liquid paraffin and Vaseline, wherein the mass ratio of the stearic acid to the glyceryl monocaprylate to the liquid paraffin to the Vaseline is 1:1:1:0.5;
emulsifier CPE-11:5 parts;
co-emulsifier PEG400:10 parts;
water: 45 parts;
transdermal enhancer oleic acid: 5 parts;
preservative methylparaben: 0.2 parts.
The preparation method comprises the following steps:
(1) Mixing and heating the mirtazapine, the oil phase, the emulsifier, the auxiliary emulsifier and the transdermal enhancer in parts by weight to 80 ℃;
(2) Dissolving the preservative in the weight parts into the water and heating to 80 ℃;
(3) Slowly pouring the mixture obtained in the step (1) into the water phase mixture obtained in the step (2), cooling to 60 ℃, stirring for 1h for emulsification, and obtaining the O/W mirtazapine ointment which has uniform color, is not layered after standing for 12h, is free from granular feel when being smeared and is free from layered discoloration when being centrifuged.
Example 4 preparation of O/W Milapine ointment
In this embodiment, the O/W mirtazapine ointment comprises the following ingredients in parts by weight:
mirtazapine: 8 parts;
an oil phase: 25 parts of stearic acid, glyceryl monocaprylate, liquid paraffin and Vaseline, wherein the mass ratio of the stearic acid to the glyceryl monocaprylate to the liquid paraffin to the Vaseline is 2:1:1:0.8;
emulsifier CPE-13:8 parts;
co-emulsifier PEG400:8 parts;
water: 45 parts;
transdermal enhancer azone: 5 parts;
preservative sodium benzoate: 0.2 parts.
The preparation method comprises the following steps:
(1) Mixing and heating the mirtazapine, the oil phase, the emulsifier, the auxiliary emulsifier and the transdermal enhancer in parts by weight to 80 ℃;
(2) Dissolving the preservative in the weight parts into the water and heating to 80 ℃;
(3) Slowly pouring the mixture obtained in the step (1) into the water phase mixture obtained in the step (2), cooling to 60 ℃, stirring for 1h for emulsification, and obtaining the O/W mirtazapine ointment which has uniform color, is not layered after standing for 12h, is free from granular feel when being smeared and is free from layered discoloration when being centrifuged.
Comparative example 1
Tween 80 was used as one of the most commonly used O/W emulsifiers, and the inventors found that the O/W mirtazapine ointment with uniform color, no layering of 12h, no graininess of application and no layering discoloration of centrifugation was obtained in the previous study by replacing the emulsifier CPE-11 in example 1 with equal amount of tween-80, the remaining prescription components and amounts, and the preparation method as in example 1 in comparative example 1.
Comparative example 2
Comparative example 2 the co-emulsifier PEG400 was replaced with the same amount of glycerin, the remaining prescription components and amounts, and the preparation method were the same as in example 1, and the resulting preparation was non-uniform in color, layered on standing 12h, smeared with a distinct grainy feel, and centrifuged to separate, indicating that it was not successful in preparing a uniform O/W ointment.
Test example 1 stability test
The following stability tests were performed on the O/W mirtazapine ointments prepared in examples 1-4 and comparative example 1:
(1) Centrifugal test
Placing the ointment into a centrifuge tube, centrifuging at 3000 r/min for 30 min, and observing whether layering and demulsification occur.
(2) Cold resistance test
Placing the ointment into a centrifuge tube, and placing in a refrigerator at-20deg.C for 24-h, and observing whether layering, demulsification, color and uniformity change.
(3) Heat resistance test
Placing the ointment into a centrifuge tube, placing in a 50 ℃ incubator for 6 h, and observing whether layering, demulsification, color and uniformity change and the like occur.
(4) Acceleration test
Placing the ointment into a centrifuge tube, placing the centrifuge tube in a constant temperature incubator with the temperature of 45+/-2 ℃ and the relative humidity of 75%, continuously placing for 3 months, periodically inspecting, and observing the phenomena of layering demulsification, mildew, color change, uniformity change and the like; and the relative content of mirtazapine (namely the percentage of mirtazapine content relative to the current day when the preparation is finished) is measured, and the content measuring method is the method of mirtazapine tablets in the 2020 edition of Chinese pharmacopoeia.
In the above test items (1) to (3), the ointments prepared in examples 1 to 4 and comparative example 1 were free from delamination, demulsification and change in color and uniformity. The preparation prepared in comparative example 2 had the phenomena of delamination and increased granular feel in the centrifugation, cold-resistance and heat-resistance test.
Thus, the ointments of examples 1 to 4 and comparative example 1 were examined for acceleration test, and the results are shown in Table 1.
Table 1.
The results show that the ointments prepared in examples 1-4 show superior stability in an accelerated test for 3 months, no layering, demulsification and color and uniformity change, and no obvious change of mirtazapine content in the preparation. In the accelerating test of the first two months, the ointment prepared in the comparative example 1 has no layering, demulsification, color and uniformity change, but in the 3 rd month, stability changes such as layering and the like occur, and the content of the active ingredients is obviously reduced. This indicates that tween-80 used in comparative example 1 was poorly compatible with the other components in the formulation.
Test example 2 safety test
White healthy rabbits weighing (2.5+ -0.2) kg were taken, and each half of the rabbits was divided into a blank group and ointment administration groups prepared in examples 1-4 and comparative example 1, each group being 5. Shaving the rabbit ears. Uniformly smearing corresponding ointment on the ear hair-removing area of the rabbit of each administration group, once a day, 1 g; the blank control group was coated with 1 mL normal saline. The administration was continued for 7 days, and the presence or absence of erythema and edema was observed within 48 hours of the removal of the drug.
As a result, the ointments prepared in examples 1 to 4 and comparative example 1 showed no erythema or edema, which proved to be excellent in safety.
Test example 3 in vitro Release test
Preparation of ex-vivo skin: the white rabbits of 6 months old were euthanized, the back hair was shaved, the back skin was peeled off, and the subcutaneous fat was removed, washed with physiological saline, and stored therein for later use.
In vitro transdermal test: the isolated skin is sheared into a circular sheet with the diameter of about 2.8 cm, the external bare part of the epidermis is upward, the upper chamber and the lower chamber of a vertical Franz diffusion cell are arranged in the middle, the stratum corneum is upward, 6.5 mL of 30% ethanol physiological saline is added into a receiving cell to be used as receiving liquid, 0.5 g meter of azone ointment is uniformly coated on the stratum corneum, the epidermis of the skin is contacted with the receiving liquid, magnetic stirring is carried out for 200 r/min, a constant-temperature water bath is arranged at 32 ℃, and 1.5 mL receiving liquid is taken as a sample to be detected by 2, 4, 6, 8, 12 and 24h after the transdermal test is started, and the same amount of fresh 30% ethanol physiological saline is immediately replenished. The sample to be tested was taken out and filtered through a 0.22 μm filter and the mirtazapine content was determined by HPLC. The cumulative transdermal quantity Q was calculated according to the following formula n And cumulative transdermal rate L n ：
Q n =Cn×V+；
L n = Q n /W×100%；
Q n To accumulate transdermal flux, C n For the concentration of the sample at the nth time point, V is the receiving pool volume, C i For the concentration of the sample at the ith time point, V 0 For each sampled volume, L n For cumulative transdermal rate, W is the mirtazapine content of the ointment sample.
Cumulative transdermal rate results at each sampling time point figure 1.
FIG. 1 is a time chart of cumulative transdermal rates of the formulations of examples 1-4 and comparative example 1 in the in vitro release test of test example 3 according to the present invention. As can be seen from fig. 1, examples 1 to 4 using hydrogenated cardanol polyoxyethylene ether as an emulsifier had a transdermal release rate of more than 80% in 24 hours, whereas comparative example 1 using tween-80 as an emulsifier had a transdermal release rate of only 52.4%.
Test example 4 clinical trials
Test animals: cats with obvious weight loss or anorexia in recent years are clinically examined to be older than 1 year old, have a body weight of 2 kg, and are divided into 2 treatment groups and 1 control group, wherein each group is larger than 30.
Preparation: mirataz mirtazapine ointment (available from Kindred Biosciences) and mirtazapine ointment prepared in example 1 according to the invention.
The test method comprises the following steps:
control group: smearing 1 mL normal saline on inner auricle of cat;
treatment group: taking Mirataz mirtazapine ointment and the O/W mirtazapine ointment prepared in example 1 according to the mirtazapine 2 mg, uniformly smearing the samples on the auricles of cats, alternately using the left and right ears, continuously applying the medicines for 14 days, and recording the weight gaining effect and adverse reaction of the samples. The results are shown in Table 2 below.
TABLE 2
Average weight gain Standard deviation of
Control group (35) 0.32% 4.21%
Milapine ointment group (42) 5.61% 5.36%
Mirataz (39) 4.86% 5.24%
As can be seen from Table 2, the O/W mirtazapine ointment prepared by the invention has better weight increasing effect than the reference preparation.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (8)

1. An ointment of mirtazapine, characterized in that it comprises, in parts by weight:
mirtazapine: 5-10 parts of a lubricant;
an oil phase: 20-30 parts of a lubricant;
emulsifying agent: 5-10 parts of a lubricant;
auxiliary emulsifier: 5-10 parts of a lubricant;
water: 40-50 parts of a lubricant;
transdermal enhancer: 5-10 parts of a lubricant;
preservative: 0.01-0.5 parts;
the oil phase consists of stearic acid, glyceryl monocaprylate, liquid paraffin and vaseline, wherein the mass ratio of the stearic acid to the glyceryl monocaprylate to the liquid paraffin to the vaseline is as follows: 1-2: 1-2: 1-2: 0.5-1;
the emulsifier is hydrogenated cardanol polyoxyethylene ether, and has the structure as follows:wherein m is 11 or 13;
the auxiliary emulsifier is polyethylene glycol 400;
the transdermal enhancer is one or more selected from isopropyl myristate, trioleate, oleic acid, myristic acid and azone.
2. The mirtazapine ointment of claim 1, wherein the preservative is selected from one or more of sodium benzoate, methylparaben, ethylparaben, propylparaben, benzalkonium bromide, benzyl alcohol.
3. Mirtazapine ointment according to claim 1, characterized in that it comprises, in parts by weight:
mirtazapine: 6-9 parts of a lubricant;
an oil phase: 22-28 parts of a lubricant;
emulsifying agent: 6-9 parts of a lubricant;
auxiliary emulsifier: 6-9 parts of a lubricant;
water: 42-48 parts;
transdermal enhancer: 6-9 parts of a lubricant;
preservative: 0.1 to 0.5 part.
4. Mirtazapine ointment according to claim 1, wherein the mass ratio of stearic acid, glyceryl monocaprylate, liquid paraffin and petrolatum in the oil phase is: 1:1:1:0.5.
5. a process for the preparation of mirtazapine ointment according to any one of claims 1 to 4, comprising the steps of:
(1) Mixing and heating mirtazapine, an oil phase, an emulsifier, a coemulsifier and a transdermal enhancer to 70-90 ℃ to obtain a mixture 1;
(2) Dissolving a preservative in water, and heating to 70-90 ℃ to obtain a mixture 2;
(3) Slowly pouring the mixture 1 obtained in the step (1) into the mixture 2 obtained in the step (2), and stirring and emulsifying to obtain the mirtazapine ointment.
6. The method according to claim 5, wherein in the step (1) and the step (2), the heating temperature is 75 to 85 ℃.
7. The method according to claim 6, wherein in the step (3), the temperature of the stirring and emulsification is 50 to 70 ℃ and the stirring time is 1 to 3 hours.
8. Use of a mirtazapine ointment according to any one of claims 1 to 4 and/or a mirtazapine ointment prepared by a method according to any one of claims 6 to 7 for the manufacture of a medicament for the treatment of nausea, vomiting, anorexia in pets.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0453603A1 (en) * 1990-04-26 1991-10-30 Sagitta Arzneimittel Gmbh Piroxicam containing pharmaceutical compositions for topical application
CN112107584A (en) * 2020-07-17 2020-12-22 上海信元动物药品有限公司 Mizapine preparation composition for treating nausea, vomiting and anorexia of pets and process thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9855243B2 (en) * 2013-10-30 2018-01-02 Qurient Co., Ltd. Topical anti-inflammatory pharmaceutical composition with zileuton cream formulation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0453603A1 (en) * 1990-04-26 1991-10-30 Sagitta Arzneimittel Gmbh Piroxicam containing pharmaceutical compositions for topical application
CN112107584A (en) * 2020-07-17 2020-12-22 上海信元动物药品有限公司 Mizapine preparation composition for treating nausea, vomiting and anorexia of pets and process thereof

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Inventor after: Yang Zhikun

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