Miltazapine composition for pets, transdermal ointment as well as preparation method and application of transdermal ointment

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly provides a mirtazapine composition for pets, transdermal ointment as well as a preparation method and application of the mirtazapine composition and the transdermal ointment. The mirtazapine transdermal composition comprises mirtazapine, a penetration enhancer, a coating agent, an antioxidant and an excipient. Wherein the penetration enhancer is diethylene glycol monoethyl ether, caprylic / capric polyethylene glycol glyceride and oleyl alcohol; the coating agent is dimeticone and cassava starch polymethylsilsesquioxane; the antioxidant is thioglycerol; the excipient is polyethylene glycol 400 and polyethylene glycol 3350. The product is stable in property, good in transdermal property, small in side effect, simple in preparation method and suitable for large-scale production and clinical application.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and specifically provides a mirtazapine composition for pets, a transdermal ointment, and a preparation method and application thereof. Background Art

[0002] Mirtazapine, chemical name is 1,2,3,4,10,14b-hexahydro-2-methylpyrazinyl[2,1-a]pyrido[2,3-c][2]benzazepine It belongs to the piperazine-diazepine class of compounds and is an α2-adrenergic receptor antagonist, noradrenergic and 5-hydroxytryptamine antidepressant. It can enhance both noradrenergic and 5-hydroxytryptamine neurotransmission by antagonizing presynaptic α2-adrenergic receptors and blocking postsynaptic 5-hydroxytryptamine (5-HT2 and 5-HT3) receptors. Currently, it is approved for use in many countries around the world. Early studies have shown that mirtazapine can also cause appetite and weight gain while being used as an antidepressant.

[0003] Cat weight loss and chronic anorexia can lead to many serious complications, such as hepatic lipidosis, low immune function, delayed wound healing, and shortened life span. Therefore, improving appetite is an important guarantee for improving the quality of life of cats. Taking advantage of the side effects of mirtazapine that can cause appetite and weight gain, Kindred Biosciences, Inc. has developed mirtazapine transdermal ointment (trade name: ), is currently the only transdermal preparation approved by FDA and EMA for the management of weight loss in cats. It is used as an appetite stimulant in cats and can significantly increase the weight of cats.

[0004] Giving medication to pets is a tricky thing, especially for pets that are not very cooperative. The wrong medication method may not only cause injury (bites or scratches, etc.), but may also lead to medication failure. Sometimes, the pet may eat the medication, but spit it out later. Especially for dosage forms such as tablets or capsules, it is generally difficult for pets to take the medication actively. Forced medication will cause stress to pets. When pets have a poor appetite or feel unwell, it is even more difficult for them to take the medication actively. This is not an acceptable option for many pet owners. Therefore, transdermal preparations for topical application have natural advantages.

[0005] Patent US10603272B2 discloses a mirtazapine transdermal composition and its preparation method, namely the corresponding product This patent mainly protects the mirtazapine composition and its use method. The preparation method of the mirtazapine composition described in the patent has high requirements for environmental control and process. Because mirtazapine is easily oxidized, nitrogen filling is required throughout the preparation process. In actual operation, it is not easy to fill nitrogen throughout the production process. The equipment needs to be specially customized, and the equipment performance and process control requirements are high. It is not easy to achieve and promote in the industrial production process. At the same time, the market feedback shows that the product has many adverse reactions, mainly manifested as skin irritation, and erythema and edema are prone to occur at the administration site (cat inner ear).

[0006] Therefore, in order to stimulate the appetite of pets, there is an urgent need to provide a transdermal composition and its preparation which has high stability, convenient administration, simple preparation process, few steps, common equipment and low cost, and is easy to industrialize.

[0007] In view of this, the present invention is proposed. Summary of the invention

[0008] The first object of the present invention is to provide a mirtazapine transdermal composition.

[0009] The second object of the present invention is to provide a method for preparing the mirtazapine transdermal composition.

[0010] The third object of the present invention is to provide a mirtazapine transdermal ointment.

[0011] The fourth object of the present invention is to provide a method for preparing mirtazapine transdermal ointment.

[0012] A fifth object of the present invention is to provide a use of the mirtazapine transdermal composition.

[0013] In order to achieve the above object, the present invention particularly adopts the following technical scheme:

[0014] A mirtazapine transdermal composition comprises mirtazapine, a permeation enhancer, a coating agent, an antioxidant and an excipient. The permeation enhancer is diethylene glycol monoethyl ether, caprylic acid capric acid macrogol glyceride and oleyl alcohol; the coating agent is dimethicone and tapioca starch polymethylsilsesquioxane; the antioxidant is thioglycerol; and the excipient is polyethylene glycol 400 and polyethylene glycol 3350.

[0015] Furthermore, the mirtazapine transdermal composition comprises 0.5% to 4% w / w mirtazapine, 30% to 40% w / w penetration enhancer, 2% to 7% w / w coating agent, 0.05% to 1% w / w antioxidant and 55% to 65% w / w excipient.

[0016] Furthermore, the mass ratio of polyethylene glycol 400 to polyethylene glycol 3350 is 3:2 to 5:2.

[0017] Further, the mirtazapine transdermal composition comprises 2% w / w mirtazapine, 19% w / w diethylene glycol monoethyl ether, 6% w / w caprylic acid capric acid macrogol glyceride, 5% w / w oleyl alcohol, 0.05% w / w thioglycerol, 1.5% w / w dimethicone, 1.45% w / w tapioca starch polymethylsilsesquioxane, 45% w / w polyethylene glycol 400 and 20% w / w polyethylene glycol 3350.

[0018] Further, the mirtazapine transdermal composition comprises 2% w / w mirtazapine, 22.4% w / w diethylene glycol monoethyl ether, 7.5% w / w caprylic acid capric acid macrogol glyceride, 5% w / w oleyl alcohol, 0.1% w / w thioglycerol, 3% w / w dimethicone, 4% w / w tapioca starch polymethylsilsesquioxane, 40% w / w polyethylene glycol 400 and 16% w / w polyethylene glycol 3350.

[0019] Further, the mirtazapine transdermal composition comprises 2% w / w mirtazapine, 25% w / w diethylene glycol monoethyl ether, 5% w / w caprylic acid capric acid macrogol glyceride, 10% w / w oleyl alcohol, 1.0% w / w thioglycerol, 1% w / w dimethicone, 1% w / w tapioca starch polymethylsilsesquioxane, 33% w / w polyethylene glycol 400 and 22% w / w polyethylene glycol 3350.

[0020] The preparation method of the above-mentioned mirtazapine transdermal composition comprises:

[0021] Step (1): heating polyethylene glycol 400 and polyethylene glycol 3350 at 70°C to 80°C to melt until clear, stirring and cooling to 40°C to 50°C for later use;

[0022] Step (2): diethylene glycol monoethyl ether, caprylic acid capric acid polyethylene glycol glyceride, dimethicone, oleyl alcohol, and thioglycerol are stirred and mixed; then mirtazapine is added and stirred until dissolved; finally, tapioca starch polymethylsilsesquioxane is added and stirred and mixed;

[0023] Step (3): Add the active phase obtained in step (2) to the polyethylene glycol matrix obtained in step (1), shear for 5 to 40 minutes using an emulsifier, and stir until cooled to obtain a mirtazapine transdermal composition.

[0024] Preferably, after step (3), the method further comprises placing the mirtazapine transdermal composition into a filling and sealing machine, and packaging the composition into mirtazapine transdermal ointment using an aluminum medicinal ointment tube.

[0025] A mirtazapine transdermal ointment comprises the mirtazapine transdermal composition of the present invention, and a traditional Chinese medicine extract and / or a flavor enhancer. The traditional Chinese medicine extract is prepared by extracting at least one of lithospermum officinale, siler, schizonepeta and angelica dahurica, and the flavor enhancer is rosemary oil.

[0026] Preferably, the content of the traditional Chinese medicine extract is 1% to 5% w / w.

[0027] The preparation method of the mirtazapine transdermal ointment comprises the following steps: uniformly mixing the mirtazapine transdermal composition, the traditional Chinese medicine extract and / or the flavor enhancer, and putting the mixture into a filling and sealing machine, and then packaging the mixture into the mirtazapine transdermal ointment using an aluminum medicinal ointment tube.

[0028] The invention discloses an application of the mirtazapine transdermal composition in preparing a medicine for stimulating cat appetite and controlling cat weight loss.

[0029] Compared with the prior art, the technical effects of the present invention are:

[0030] The present invention optimizes and selects the auxiliary materials of the mirtazapine external dosage form, so that the transdermal composition or scalp ointment has good clinical effects. At the same time, the preparation method is simpler than the prior art: only the active phase and the matrix need to be sheared and mixed; the preparation process does not require nitrogen filling protection, which is convenient for industrialization. The active ingredients of the mirtazapine transdermal composition or ointment are in a dissolved state in the preparation; it contains a variety of penetration enhancers to synergistically promote the active ingredients to penetrate the skin and enter the blood to exert their effects; it is preferred to use the synergistic and complementary effects of traditional Chinese medicine and Western medicine to exert the efficacy of mirtazapine in stimulating cat appetite while reducing side effects and reducing erythema and edema at the medication site. The product quality is stable: the accelerated test (30°C ± 2°C, RH65% ± RH5%) shows that the properties are stable and not stratified for 6 months, and the increase of related substances is small.

[0031] In addition, the production equipment used in the preparation method of the present invention is a liquid preparation tank, an emulsification tank and a filling and sealing machine commonly used in the formulation process, which does not require special customization and is easier to implement and promote in the industrialization process, thereby indirectly reducing the production cost. DETAILED DESCRIPTION

[0032] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] The mirtazapine transdermal composition provided by the invention comprises mirtazapine as an active ingredient and a penetration enhancer, a coating agent, an antioxidant and an excipient as auxiliary materials.

[0034] The product has stable properties, good skin permeability, few side effects, and a simple preparation method, making it suitable for large-scale production and clinical application.

[0035] The penetration enhancer is a combination of diethylene glycol monoethyl ether, caprylic / capric macrogol glycerides, and oleyl alcohol.

[0036] In some embodiments, the penetration enhancer accounts for 30% to 40% w / w of the mirtazapine transdermal composition, for example, but not limited to, 30% w / w, 31% w / w, 32% w / w, 33% w / w, 34% w / w, 35% w / w, 36% w / w, 37% w / w, 38% w / w, 39% w / w or 40% w / w.

[0037] In the mirtazapine transdermal composition, diethylene glycol monoethyl ether accounts for 17% to 25% w / w of the mirtazapine transdermal composition, for example, but not limited to, 17% w / w, 17.5% w / w, 18% w / w, 18.5% w / w, 19% w / w, 19.5% w / w, 20% w / w, 20.5% w / w, 21% w / w, 21.5% w / w, 22% w / w, 22.5% w / w, 23% w / w, 23.5% w / w, 24% w / w, 24.5% w / w or 25% w / w. Caprylic capric acid macrogol glyceride accounts for 5% to 10% w / w of the mirtazapine transdermal composition, for example, but not limited to, 5% w / w, 5.5% w / w, 6% w / w, 6.5% w / w, 7% w / w, 7.5% w / w, 8% w / w, 8.5% w / w, 9% w / w, 9.5% w / w or 10% w / w. Oleyl alcohol accounts for 5% to 10% w / w of the mirtazapine transdermal composition, for example, but not limited to, 5% w / w, 5.5% w / w, 6% w / w, 6.5% w / w, 7% w / w, 7.5% w / w, 8% w / w, 8.5% w / w, 9% w / w, 9.5% w / w or 10% w / w.

[0038] The coating agent is dimethicone and tapioca starch polymethylsilsesquioxane.

[0039] In some embodiments, the coating agent accounts for 2% to 7% w / w of the mirtazapine transdermal composition, for example, but not limited to, 2% w / w, 2.5% w / w, 3% w / w, 3.5% w / w, 4% w / w, 4.5% w / w, 5% w / w, 5.5% w / w, 6% w / w, 6.5% w / w or 7% w / w.

[0040] In the mirtazapine transdermal composition, dimethicone accounts for 0.5% to 3% w / w of the mirtazapine transdermal composition, such as but not limited to 0.5% w / w, 1% w / w, 1.5% w / w, 2% w / w, 2.5% w / w or 3% w / w. Tapioca starch polymethylsilsesquioxane accounts for 0.5% to 5% w / w of the mirtazapine transdermal composition, such as but not limited to 0.5% w / w, 1% w / w, 1.5% w / w, 2% w / w, 2.5% w / w, 3% w / w, 3.5% w / w, 4% w / w, 4.5% w / w or 5% w / w.

[0041] The antioxidant is monothioglycerol.

[0042] In some embodiments, the antioxidant accounts for 0.05% to 1% w / w of the mirtazapine transdermal composition, which can be but is not limited to 0.05% w / w, 0.1% w / w, 0.15% w / w, 0.2% w / w, 0.25% w / w, 0.3% w / w, 0.35% w / w, 0.4% w / w, 0.45% w / w, 0.5% w / w, 0.55% w / w, 0.6% w / w, 0.65% w / w, 0.7% w / w, 0.75% w / w, 0.8% w / w, 0.85% w / w, 0.9% w / w, 0.95% w / w or 1% w / w.

[0043] The excipients are polyethylene glycol 400 and polyethylene glycol 3350.

[0044] In some embodiments, the excipient accounts for 55% to 65% w / w of the mirtazapine transdermal composition, for example, but not limited to, 55% w / w, 55.5% w / w, 56% w / w, 56.5% w / w, 57% w / w, 57.5% w / w, 58% w / w, 58.5% w / w, 59% w / w, 59.5% w / w, 60% w / w, 60.5% w / w, 61% w / w, 61.5% w / w, 62% w / w, 62.5% w / w, 63% w / w, 63.5% w / w, 64% w / w, 64.5% w / w or 65% w / w.

[0045] In some embodiments, the mass ratio of polyethylene glycol 400 to polyethylene glycol 3350 is 3:2 to 5:2, for example, but not limited to, 3:2, 7:4, 2:1, 9:4 or 5:2.

[0046] In some embodiments, mirtazapine accounts for 0.5% to 4% w / w of the mirtazapine transdermal composition, for example, but not limited to, 0.5% w / w, 1% w / w, 1.5% w / w, 2% w / w, 2.5% w / w, 3% w / w, 3.5% w / w or 4% w / w.

[0047] A method for preparing a mirtazapine transdermal composition, the preparation method comprising:

[0048] Step (1): Heat polyethylene glycol 400 and polyethylene glycol 3350 at 70°C to 80°C to melt until clear, stir and cool to 40°C to 50°C for use.

[0049] Step (2): diethylene glycol monoethyl ether, caprylic acid capric acid polyethylene glycol glyceride, dimethicone, oleyl alcohol, and thioglycerol are stirred and mixed; then mirtazapine is added and stirred until dissolved; finally, tapioca starch polymethylsilsesquioxane is added and stirred and mixed.

[0050] Step (3): adding the active phase obtained in step (2) to the polyethylene glycol matrix obtained in step (1), shearing with an emulsifier for 5 to 40 minutes, stirring until cooled, and obtaining a mirtazapine transdermal composition. The mirtazapine transdermal composition prepared by this method is easy to apply and has good transdermal properties.

[0051] Furthermore, the above-mentioned mirtazapine transdermal composition can be optionally mixed with a Chinese medicine extract and / or a flavoring agent to obtain a mirtazapine transdermal ointment. For example, the transdermal composition obtained in the above step (3) is mixed with an appropriate amount of a Chinese medicine extract and a flavoring agent, mixed evenly, put into a filling and sealing machine, and packaged into a mirtazapine transdermal ointment using an aluminum medicinal ointment tube. The Chinese medicine extract is extracted from one or more of Lithospermum officinale, Saposhnikovia divaricata, Nepeta tenuifolia, and Angelica dahurica; and the flavoring agent is rosemary oil.

[0052] The Chinese medicine extract is obtained by combining lithospermum, siler, schizonepeta and angelica after being extracted in a certain ratio, wherein lithospermum is 3 parts, siler, 1 part, schizonepeta and 1 part. The compatibility includes lithospermum, lithospermum + siler, lithospermum + schizonepeta, lithospermum + angelica, lithospermum + siler + schizonepeta, lithospermum + siler + angelica, lithospermum + siler + schizonepeta + angelica, lithospermum + siler + schizonepeta + angelica. The above composition ratios are all extracted by ethanol, 8 times the amount of ethanol is added for the first soaking for 1 hour, the extraction is performed 3 times, each time for 2 hours, the filtrates are combined, concentrated, centrifuged, dried, and crushed to pass through a 100-mesh sieve to obtain the product.

[0053] The above product can be used to prepare medicines for stimulating cat appetite and controlling cat weight loss.

[0054] The present invention is further described below by way of examples. Unless otherwise specified, the materials in the examples are prepared according to existing methods or directly purchased from the market.

[0055] Example 1 Exemplary Formulations 1 to 7 of Mirtazapine Transdermal Compositions

[0056] The compositions of mirtazapine transdermal composition formulas 1 to 7 are shown in Table 1:

[0057] Table 1 Formula composition of the mirtazapine transdermal composition of the present application (W / W)

[0058] The inventors investigated the dosage of penetration enhancers (diethylene glycol monoethyl ether, caprylic acid capric acid macrogol glyceride, oleyl alcohol) while ensuring that the total amount of the formula was 100% w / w. The dosage mainly affects the transdermal properties of the product. In vitro transdermal tests were performed on mirtazapine transdermal composition formulas 1 to 5 (the test method is the same as that of Example 5).

[0059] According to the above formulas 1 to 5, transdermal ointments 1 to 5 were prepared according to the preparation method of Example 3 below, and the evaluation results are shown in Table 4. When the amount of penetration enhancer was in the range of 30% to 40% w / w (Formula 2, Formula 3, Formula 5), ​​the maximum transdermal rate and cumulative transdermal amount were comparable to those of foreign products. The 90% confidence interval ratio is within the acceptance interval of 80.00% to 125.00%, and the transdermal curve can be well fitted with it. When the penetration enhancer dosage is 41.5% w / w (formulation 1), the overall transdermal penetration is fast; when the penetration enhancer dosage is 29% w / w (formulation 4), the dissolution is slow. The 90% confidence interval ratios of the maximum transdermal rate and cumulative transdermal amount of Formula 1 and Formula 4 did not all fall within the acceptance interval of 80.00% to 125.00%.

[0060] The results showed that the dosage of penetration enhancer would affect the in vitro transdermal penetration of the drug, and the preferred dosage of penetration enhancer (diethylene glycol monoethyl ether, caprylic acid capric acid macrogol glyceride, oleyl alcohol) in the final formulation was 30% to 40% w / w.

[0061] The inventors investigated the dosage of the coating agent (dimethicone, tapioca starch polymethylsilsesquioxane) while ensuring that the total amount of the formula was 100% w / w. The dosage mainly affects the properties and ductility of the product. The physical properties of the mirtazapine transdermal composition formulas 1 to 5 are evaluated below. When the dosage of the coating agent is in the range of 2% to 7% w / w (Formula 2, Formula 3, Formula 5), ​​each sample is a white ointment with a fine gloss and good ductility, and is easy to apply and clean; when the dosage of the coating agent is 7.49% w / w (Formula 1), the ductility of the paste is poor and it is not easy to push; when the dosage of the coating agent is 1% w / w (Formula 4), the color of the paste is dark and grayish white.

[0062] The results show that the amount of coating agent will affect the properties and ductility of the ointment. The preferred amount of coating agent (dimethicone, tapioca starch polymethylsilsesquioxane) in the final formula is 2% to 7% w / w.

[0063] The inventors investigated the dosage of antioxidant (thioglycerol) and excipient (polyethylene glycol 400, polyethylene glycol 3350) and the ratio of the two components of the excipient while ensuring that the total amount of the formula was 100% w / w. The dosage mainly affects the stability of the product. The following stability tests were conducted on mirtazapine transdermal composition formulas 1 to 7 (the test method is the same as that of Example 6).

[0064] According to the above-mentioned formulas 1 to 7, transdermal ointments 1 to 7 were prepared according to the preparation method of the following Example 3, and the evaluation results are shown in Table 5. Wherein the amount of antioxidant was 0.05% to 1% w / w, the amount of excipient was 55% to 65% w / w, and the mass ratio of polyethylene glycol 400 to polyethylene glycol 3350 was 3:2 to 5:2 (formula 2, formula 3, and formula 5). The sample properties were the best, easy to apply, and there was no significant increase in impurities in the accelerated test (30°C ± 2°C, RH 65% ± RH 5%) for 6 months. When the amount of antioxidant is lower than 0.05% w / w, the amount of excipient is lower than 55% w / w (Formula 1) and the amount of excipient is higher than 65% w / w (Formula 4), it has a greater impact on the amount of penetration enhancer. On the one hand, it makes the ointment thicker or thinner, affecting the subsequent product filling, and on the other hand, it affects the in vitro transdermal penetration of the product. At the same time, the accelerated test (30℃±2℃, RH65%±RH5%) for 6 months shows a significant increase in impurities, especially oxidative impurities. The dosage of antioxidant is 0.05% to 1% w / w, and the dosage of excipient is 55% to 65% w / w. However, when the mass ratio of polyethylene glycol 400 to polyethylene glycol 3350 is lower than 3:2 (Formula 6) and higher than 5:2 (Formula 7), the product properties are affected to a certain extent. The ointment is thick or thin, which affects the subsequent product filling. At the same time, the impurities in the accelerated test (30℃±2℃, RH65%±RH5%) for 6 months increased significantly, especially the oxidized impurities. The reason for the increase of impurities under this condition should be related to the ointment properties caused by different excipient ratios. The paste is thin, and local sedimentation or stratification will occur during the sample placement process, resulting in uneven distribution of antioxidants and severe local oxidation; the paste is thick, and the air introduced during the shearing process is not easy to be discharged, forming small bubbles in the paste, which promotes the oxidation of mirtazapine.

[0065] The results show that the amount of antioxidant, the amount of excipient and the ratio of the two components of the excipient will affect the properties and stability of the drug. The preferred amount of antioxidant (thioglycerol) in the final formula is 0.05% to 1% w / w, and the amount of excipient (polyethylene glycol 400, polyethylene glycol 3350) is 55% to 65% w / w, among which the preferred mass ratio of polyethylene glycol 400 to polyethylene glycol 3350 is 3:2 to 5:2.

[0066] Example 2 Exemplary formulations of mirtazapine transdermal ointment 8 to 10

[0067] The composition of mirtazapine transdermal ointment formula 8-10 is shown in Table 2:

[0068] Table 2 The formula composition of the mirtazapine transdermal ointment of this application (W / W)

[0069] The inventors investigated the added Chinese herbal extracts while ensuring that the total amount of the formula was 100% w / w. The type and amount of the added extracts mainly affected the irritation of the product. The irritation of mirtazapine transdermal ointment formulas 8 to 10 was evaluated below (the test method was the same as that of Example 7).

[0070] According to the above formulas 8 to 10, transdermal ointments 8 to 10 were prepared according to the preparation method of Example 3 below, and the evaluation results are shown in Table 7. The results show that the added Chinese herbal extract has a significant improvement effect on the skin irritation caused by mirtazapine transdermal ointment, and can significantly reduce the erythema and edema at the administration site. The final formula preferably uses 1% to 5% w / w of the Chinese herbal extract, wherein the Chinese herbal extract is extracted from one or more of Lithospermum officinale, Saposhnikovia divaricata, Nepeta tenuifolia and Angelica dahurica.

[0071] Example 3 Preparation method of mirtazapine transdermal composition and ointment

[0072] The preparation method of the mirtazapine transdermal composition of the present application comprises:

[0073] Step (1): heating polyethylene glycol 400 and polyethylene glycol 3350 at 70°C to 80°C to melt until clear, stirring and cooling to 40°C to 50°C for later use;

[0074] Step (2): diethylene glycol monoethyl ether, caprylic acid capric acid polyethylene glycol glyceride, dimethicone, oleyl alcohol, and thioglycerol are stirred and mixed; then mirtazapine is added and stirred until dissolved; finally, tapioca starch polymethylsilsesquioxane is added and stirred and mixed;

[0075] Step (3): adding the active phase obtained in step (2) to the polyethylene glycol matrix obtained in step (1), shearing with an emulsifier for 5 to 40 minutes, stirring until cooled, and obtaining a mirtazapine transdermal composition. The mirtazapine transdermal composition prepared by this method is easy to apply and has good transdermal properties.

[0076] The preparation method of the mirtazapine transdermal ointment of the present application comprises: adding an appropriate amount of a Chinese herbal extract and a flavoring agent to the transdermal composition obtained in step (3) of the preparation method of the transdermal composition, mixing, putting into a filling and sealing machine, and packaging into the mirtazapine transdermal ointment using an aluminum medicinal ointment tube. The Chinese herbal extract is extracted from one or more of Lithospermum officinale, Saposhnikovia divaricata, Nepeta tenuifolia and Angelica dahurica; and the flavoring agent is rosemary oil.

[0077] Compared with the method disclosed in patent US10603272B2, the preparation method used in this application has a simpler preparation process: only the active phase and the matrix need to be sheared and mixed; the preparation process does not require nitrogen protection, which is convenient for industrialization. The clinical effect of the transdermal ointment of this application is excellent: the active ingredient is in a dissolved state in the preparation; it contains a variety of penetration enhancers, which synergistically promote the active ingredient to penetrate the skin and enter the blood to exert its effect; it utilizes the synergistic and complementary effects of traditional Chinese medicine and Western medicine to exert the efficacy of mirtazapine in stimulating cat appetite while reducing side effects and reducing erythema and edema at the medication site. The quality of the transdermal ointment is stable: the accelerated test (30℃±2℃, RH65%±RH5%) shows that the properties are stable and not stratified for 6 months, and the increase of related substances is small. In addition, the production equipment used in the preparation method of this application is the common liquid preparation tank, emulsification tank and filling and sealing machine in the preparation process, which does not require special customization, is easier to implement and promote in the industrialization process, and indirectly reduces the production cost.

[0078] Example 4 Comparative Example Mirtazapine transdermal ointment

[0079] According to the active ingredient ratio of 2% w / w of the mirtazapine transdermal composition disclosed in this application, a similar formula T composition disclosed in patent US10603272B2 was selected for sample preparation. The preparation method was referred to Example 3, and nitrogen was not charged during the whole process.

[0080] Table 3 US10603272B2 patent formula T

[0081] Example 5 In vitro skin permeation test

[0082] For topical transdermal preparations, in vitro transdermal testing is an important means of evaluating the performance of the preparation, which can preliminarily determine the transdermal conditions and in vivo bioavailability of the drug in vivo; for generic drug products, in vitro transdermal testing is generally consistent with the original reference preparation, which can increase the probability of in vivo bioequivalence with the reference preparation. The mirtazapine transdermal ointment prepared in this application is a generic product, and the reference preparation is a foreign product. Therefore, conducting an in vitro permeation comparison test between the self-developed preparation and the reference preparation is of great significance for in vivo bioequivalence. Among them, the maximum permeation rate and cumulative permeation amount are parameters for measuring the permeation similarity of products. According to the guidelines of EMA and FDA, the 90% confidence interval ratio of the reference preparation and the self-developed preparation is within the acceptance interval of 80.00% to 125.00%, proving that the in vitro permeation behavior of the two is consistent. If it exceeds the acceptance interval of 80.00% to 125.00%, it is considered that the in vitro permeation behavior of the two is inconsistent.

[0083] Apparatus: Franz diffusion apparatus, the drug delivery area in the diffusion cell is 3.14cm 2, the volume of the receiving chamber is 7ml.

[0084] Transdermal method: The receiving medium is a pH 5.8 phosphate buffer containing 0.005% gentamicin (prepared according to the pharmacopoeia method, prepared and used immediately), and the skin of the nude mouse is preferably in contact with the liquid surface; the dosage of mirtazapine transdermal ointment is 100 mg, and it should be applied as evenly as possible; the temperature is 37°C ± 0.3°C; the magnetic stirrer continuously stirs the receiving liquid at a speed of 300r / min; the sampling time points are 1h, 2h, 4h, 6h, 8h, and 10h; the sampling is 1ml / time; the receiving liquid (permeate sample) is passed through a 0.45μm organic microporous filter membrane for liquid phase content determination and analysis.

[0085] Table 4 In vitro skin permeation test results of samples

[0086] Take ointment 1 to ointment 5 and foreign products In vitro transdermal tests were performed, and the results are shown in Table 4. The results show that the mirtazapine transdermal ointment 2, ointment 3, and ointment 5 prepared in the present application are comparable to foreign products. The in vitro transdermal behaviors of the reference preparation and the self-developed preparation were consistent, and the 90% confidence interval ratios of the reference preparation and the self-developed preparation were both within the acceptance interval of 80.00% to 125.00%.

[0087] Example 6 Stability Test

[0088] Ointment 1 to Ointment 7 and the mirtazapine transdermal preparation prepared in Example 4 were packaged in aluminum medicinal ointment tubes and placed under accelerated conditions (30°C ± 2°C, RH 75% ± RH 5%) for 6 months to observe the stability of the samples. The results are shown in Table 5.

[0089] Table 5 Stability test results of samples

[0090] As shown in Table 5, the mirtazapine transdermal ointment 2, ointment 3 and ointment 5 prepared in the present application have good stability under accelerated conditions for 6 months, and there is no significant change in quality compared with 0 days; the mirtazapine transdermal preparation (comparative example) prepared in Example 4 has a significant increase in related substances under accelerated conditions for 6 months. This shows that the mirtazapine transdermal ointment prepared in the present application has good stability.

[0091] Example 7 Skin irritation test

[0092] The mirtazapine transdermal preparations prepared in Ointment 8 to Ointment 10 and Example 4 were subjected to skin irritation tests with target animal cats as research subjects. The test screened 24 healthy cats, aged 5 to 8 months, half male and half female, and divided into 4 groups, 6 in each group. This test selected the inner auricle of the cat for administration, and adopted the self-control method of the left and right sides of the same body, with the ointment applied to the left ear and the right ear as a blank control. The drug was evenly applied to the inner auricle, administered once a day for 7 consecutive days, and the animals were caged after administration. One hour after the last administration, the general symptoms of the test cats were observed: mental state, behavioral activities, respiratory status, diet and other visible adverse reactions, and the skin irritation reaction at the administration site was observed at the same time.

[0093] The skin irritation judgment standard is formulated according to the "Technical Guidelines for Drug Irritation, Allergy and Hemolysis Research" issued by the State Food and Drug Administration (CFDA) in May 2014. The degree of erythema and edema is divided into 5 levels for irritation evaluation. According to the different degrees of irritation, the degree of erythema and edema reaction can be divided into: none, mild, moderate, severe, and serious. The skin irritation reaction scoring standard is shown in Table 6.

[0094] Table 6 Skin irritation response scoring criteria

[0095] The skin irritation test results of Ointment 8 to Ointment 10 and the mirtazapine transdermal preparation prepared in Example 4 are shown in Table 7.

[0096] Table 7 Cat skin irritation test and general symptom observation results of samples

[0097] As shown in Table 7, the mirtazapine transdermal ointment 8 to 10 prepared in the present application were used on cats for 7 consecutive days without erythema and edema, and the mental state, behavioral activity, respiratory state, etc. of the cats were not affected, and the diet increased; the mirtazapine transdermal preparation (comparative example) prepared in Example 4 was used on cats for 7 consecutive days, and 4 cats had mild erythema, with an incidence of 67% (4 / 6), and 2 cats had edema, with an incidence of 33% (2 / 6). It shows that the mirtazapine transdermal ointment prepared in the present application has low irritation.

[0098] Note that the above are only preferred embodiments of the present invention and the technical principles used. Those skilled in the art will understand that the present invention is not limited to the specific embodiments described herein, and that various obvious changes, readjustments and substitutions can be made by those skilled in the art without departing from the scope of protection of the present invention. Therefore, although the present invention has been described in more detail through the above embodiments, the present invention is not limited to the above embodiments, and may also include more other equivalent embodiments without departing from the technical concept of the present invention, all of which belong to the protection scope of the present invention.

Claims

1. A mirtazapine transdermal composition, characterized in that: The mirtazapine transdermal composition comprises mirtazapine, a penetration enhancer, a coating agent, an antioxidant and an excipient; The penetration enhancer is diethylene glycol monoethyl ether, caprylic acid capric acid macrogol glyceride and oleyl alcohol; The coating agent is dimethicone and tapioca starch polymethylsilsesquioxane; The antioxidant is thioglycerol; The excipients are polyethylene glycol 400 and polyethylene glycol 3350.

2. The mirtazapine transdermal composition according to claim 1, characterized in that: The mirtazapine transdermal composition comprises 0.5% to 4% w / w mirtazapine, 30% to 40% w / w penetration enhancer, 2% to 7% w / w coating agent, 0.05% to 1% w / w antioxidant and 55% to 65% w / w excipient.

3. The mirtazapine transdermal composition according to claim 2, characterized in that: The mass ratio of polyethylene glycol 400 to polyethylene glycol 3350 is 3:2 to 5:

2.

4. The mirtazapine transdermal composition according to claim 1, characterized in that The mirtazapine transdermal composition includes 2% w / w mirtazapine, 19% w / w diethylene glycol monoethyl ether, 6% w / w caprylic acid capric acid macrogol glyceride, 5% w / w oleyl alcohol, 0.05% w / w thioglycerol, 1.5% w / w dimethicone, 1.45% w / w tapioca starch polymethylsilsesquioxane, 45% w / w polyethylene glycol 400 and 20% w / w polyethylene glycol 3350.

5. The mirtazapine transdermal composition according to claim 1, characterized in that: The mirtazapine transdermal composition includes 2% w / w mirtazapine, 22.4% w / w diethylene glycol monoethyl ether, 7.5% w / w caprylic acid capric acid macrogol glyceride, 5% w / w oleyl alcohol, 0.1% w / w thioglycerol, 3% w / w dimethicone, 4% w / w tapioca starch polymethylsilsesquioxane, 40% w / w polyethylene glycol 400 and 16% w / w polyethylene glycol 3350.

6. The mirtazapine transdermal composition according to claim 1, characterized in that: The mirtazapine transdermal composition includes 2% w / w mirtazapine, 25% w / w diethylene glycol monoethyl ether, 5% w / w caprylic acid capric acid macrogol glyceride, 10% w / w oleyl alcohol, 1.0% w / w thioglycerol, 1% w / w dimethicone, 1% w / w tapioca starch polymethylsilsesquioxane, 33% w / w polyethylene glycol 400 and 22% w / w polyethylene glycol 3350.

7. The method for preparing the mirtazapine transdermal composition according to any one of claims 1 to 6, characterized in that: The preparation method comprises: Step (1): heating polyethylene glycol 400 and polyethylene glycol 3350 at 70°C to 80°C to melt until clear, stirring and cooling to 40°C to 50°C for later use; Step (2): diethylene glycol monoethyl ether, caprylic acid capric acid polyethylene glycol glyceride, dimethicone, oleyl alcohol, and thioglycerol are stirred and mixed; then mirtazapine is added and stirred until dissolved; finally, tapioca starch polymethylsilsesquioxane is added and stirred and mixed; Step (3): adding the active phase obtained in step (2) to the polyethylene glycol matrix obtained in step (1), shearing for 5 to 40 minutes using an emulsifier, and stirring until cooled to obtain a mirtazapine transdermal composition; Preferably, after step (3), the method further comprises placing the mirtazapine transdermal composition into a filling and sealing machine, and packaging the composition into mirtazapine transdermal ointment using an aluminum medicinal ointment tube.

8. A mirtazapine transdermal ointment, characterized in that: A mirtazapine transdermal composition comprising the mirtazapine transdermal composition according to any one of claims 1 to 6, and a traditional Chinese medicine extract and / or a flavor enhancer, wherein the traditional Chinese medicine extract is extracted from at least one of Lithospermum officinale, Saposhnikovia divaricata, Nepeta tenuifolia and Angelica dahurica, and the flavor enhancer is rosemary oil; Preferably, the content of the traditional Chinese medicine extract is 1% to 5% w / w.

9. The method for preparing the mirtazapine transdermal ointment according to claim 8, characterized in that: The mirtazapine transdermal composition, the Chinese medicinal extract and / or the flavor enhancer are mixed and put into a filling and sealing machine, and are packaged into mirtazapine transdermal ointment using an aluminum medicinal ointment tube.

10. Use of the mirtazapine transdermal composition according to any one of claims 1 to 6 in the preparation of a drug for stimulating cat appetite and controlling cat weight loss.

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