Novel mirtazapine external liposome ointment for cats and preparation method of novel mirtazapine external liposome ointment

Abstract

The invention provides a novel mirtazapine external liposome ointment for cats and a preparation method of the novel mirtazapine external liposome ointment. The novel mirtazapine external liposome ointment is prepared by mixing mirtazapine liposome and an ointment matrix, the mirtazapine liposome comprises the following components in percentage by weight: 1.0%-3.0% of mirtazapine, 10.0%-25% of a solvent, 1.0%-15.0% of phospholipid, 0.5%-5.0% of cholesterol and 0.3%-2.0% of a membrane stabilizer, the ointment matrix comprises 0.3%-2.0% of an antioxidant, an excipient and 5.0%-15.0% of a penetration enhancer; the liposome is used as a carrier, so that the miazapine can be effectively promoted to penetrate through the skin barrier of cats, the transdermal absorption rate of the medicine is increased, the concentration of the medicine is remarkably increased, the treatment effect is enhanced, the anorexia symptom of the cats can be effectively improved, and the problem of weight loss can be relieved; the liposome has a long-acting slow-release effect, and can form a drug storage cavern in vivo, slowly release drugs, prolong the action time and reduce the medication frequency. The preparation can maintain the stable and effective blood concentration for 24 hours, can realize the administration frequency once a day or once an alternate day, and reduces the administration burden of an owner.

Description

Technical Field

[0001] This invention relates to the field of resource recycling technology, specifically to a novel mirtazapine topical liposome ointment for cats and its preparation method. Background Technology

[0002] Mirtazapine is a norepinephrine and specific serotonergic antidepressant (NaSSA) originally used primarily to treat depression. Due to its appetite-stimulating side effect, it is now widely used to treat anorexia in cats, especially those with chronic kidney disease (CKD), fatty liver, or those recovering from surgery, to improve their eating habits and alleviate weight loss.

[0003] Currently, the main marketed dosage forms of mirtazapine for cats are oral tablets and regular ointments, but both of these dosage forms have significant drawbacks: Disadvantages of oral administration: Oral administration is difficult and cats are prone to resistance; in addition, mirtazapine is irritating to the gastrointestinal tract and can easily cause side effects such as vomiting, salivation, and dry mouth in cats, which limits its widespread use in clinical treatment.

[0004] Defects of Common Topical Formulations: While transdermal drug delivery can circumvent some of the drawbacks of oral administration, allowing drugs to be absorbed directly into the systemic circulation through the skin, avoiding the first-pass effect, reducing gastrointestinal irritation, and offering convenient administration, existing commercially available topical formulations still have key problems. Firstly, mirtazapine has poor water solubility, making it difficult to penetrate the stratum corneum, a natural barrier of the skin. Ordinary ointments or creams cannot achieve effective transdermal absorption, resulting in low bioavailability, unstable blood drug concentrations, and poor efficacy. Simultaneously, the various solvents used to improve solubility and transdermal absorption also increase the irritation of the base to the skin. Secondly, mirtazapine is prone to the growth of related substances in its liquid and semi-solid states, requiring the addition of appropriate antioxidants to ensure formulation stability.

[0005] Based on the above situation, there is an urgent need in this field for a transdermal ointment for cats that has high penetration efficiency, low irritation, good stability, is easy to use, and can maintain an effective therapeutic blood concentration. Summary of the Invention

[0006] This invention provides a novel mirtazapine topical liposome ointment for cats and its preparation method, aiming to solve the problems mentioned in the background art.

[0007] This invention is achieved by providing a mirtazapine liposome ointment, which is made by mixing mirtazapine liposomes and an ointment base. By weight percentage, the mirtazapine liposomes contain 1.0%-3.0% mirtazapine, 10.0%-25% solvent, 1.0%-15.0% phospholipids, 0.5%-5.0% cholesterol, and 0.3%-2.0% membrane stabilizer. The ointment base contains 0.3%-2.0% antioxidant, 50.0%-70.0% excipients, and 5.0%-15.0% penetration enhancer.

[0008] Preferably, the solvent is diethylene glycol monoethyl ether.

[0009] Preferably, the phospholipid is selected from one or more of soybean lecithin, hydrogenated soybean lecithin, egg yolk lecithin, dipalmitoylphosphatidylcholine, distearate phosphatidylcholine, and phosphatidylethanolamine.

[0010] Preferably, the membrane stabilizer is selected from one or more of Span 60, vitamin E, octadecylamine, and phosphatidic acid.

[0011] Preferably, the antioxidant is selected from one or more of the following: a combination of sodium sulfite and disodium edetate, butylated hydroxytoluene, and vitamin E.

[0012] Preferably, the excipient is selected from one or more of polyethylene glycol, liquid paraffin, paraffin wax, and dimethyl silicone oil.

[0013] Preferably, the penetration enhancer is polyethylene glycol glycerol ester (PEG-C-C-C).

[0014] The method for preparing mirtazapine liposome ointment includes the following steps: (1) Mix mirtazapine with a solvent to dissolve it, then stir and mix it with phospholipids, cholesterol and membrane stabilizers dissolved in organic solvents, and evaporate under reduced pressure to remove the organic solvents to form a lipid film; (2) The lipid film is hydrated with an aqueous phase solution to obtain a liposome suspension; (3) The liposome suspension obtained in step (2) is homogenized to obtain liposomes with uniform particle size; (4) Optionally, the liposomes obtained in step (3) are purified to remove unencapsulated drugs; (5) Mix the mirtazapine liposomes obtained in step (3) or (4) with the ointment base in sequence until homogeneous.

[0015] Preferably, the homogenization process in step (3) is performed by thin film extrusion or high-pressure homogenization to control the average particle size of liposomes to 50-200 nm.

[0016] Due to the adoption of the above scheme, the beneficial effects of the present invention are: improved bioavailability and efficacy. Liposomes, as carriers, can effectively promote the penetration of mirtazapine into the cat's skin barrier, improve the transdermal absorption rate of the drug, significantly increase the drug concentration, enhance the therapeutic effect, and effectively improve the cat's anorexia symptoms and alleviate the problem of weight loss.

[0017] With its long-lasting, sustained-release action, the liposomes form a drug reservoir in the body, slowly releasing the drug, prolonging the duration of action, and reducing the frequency of dosing. This formulation can maintain a stable and effective blood drug concentration for up to 24 hours, allowing for once-daily or every-other-day dosing, reducing the burden on the patient.

[0018] It has good biocompatibility and low irritation. The phospholipids and cholesterol used are all endogenous substances that do not irritate cat skin and have good biocompatibility. At the same time, only a very small amount of a single penetration enhancer is needed to achieve ideal transdermal effect, further reducing skin irritation and reducing adverse reactions after cat medication.

[0019] The preparation process is mature, and the film dispersion-extrusion homogenization method is well-established with clear operation steps. It is easy to scale up production and can achieve industrial-scale batch preparation, ensuring the stability and consistency of formulation quality.

[0020] It greatly improves medication compliance. When administering the medication, simply apply a small amount of ointment (about the size of a soybean) to areas with thin skin and no hair, such as the inner ear. The procedure is simple, non-invasive, and stress-free, effectively reducing the cat's resistance and greatly enhancing the treatment experience for both the owner and the pet, as well as long-term medication compliance. Attached Figure Description

[0021] Figure 1 For pharmacodynamic evaluation, blood drug concentration-time curves were obtained for the control group (commercially available mirtazapine ointment) and the liposome ointment group of the present invention. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0023] A novel mirtazapine topical liposome ointment for cats and its preparation method are disclosed. The mirtazapine liposome ointment of this invention comprises mirtazapine liposomes and an ointment matrix. The specific components, by weight percentage, are as follows: mirtazapine liposome components: active ingredient mirtazapine 1.0% - 3.0%, solvent 10.0% - 25%, liposome carrier (phospholipids 1.0% - 15.0% + cholesterol 0.5% - 5.0%), and membrane stabilizer 0.3% - 2.0%. The solvent is preferably diethylene glycol monoethyl ether; the phospholipids are selected from one or more of soybean lecithin, hydrogenated soybean lecithin, egg yolk lecithin, dipalmitoylphosphatidylcholine (DPPC), distearate phosphatidylcholine (DSPC), and phosphatidylethanolamine (PE), preferably soybean lecithin or hydrogenated soybean lecithin; the membrane stabilizer is selected from one or more of Span 60, vitamin E, octadecylamine, and phosphatidic acid, preferably Span 60 and vitamin E. • Ointment base components: antioxidant 0.3% - 2.0%, excipients 50.0% - 70.0%, penetration enhancer 5.0% - 15.0%. The antioxidant is selected from one or more of sodium sulfite and disodium edetate, butylated hydroxytoluene (BHT), and vitamin E, preferably a combination of sodium sulfite and disodium edetate; the excipient is preferably polyethylene glycol (such as a combination of polyethylene glycol 400 and polyethylene glycol 3350); the penetration enhancer is preferably polyethylene glycol glycerol ester (caprylic / capric acid).

[0024] Preparation method of mirtazapine liposome ointment The preparation method includes the following steps: (1) Preparation of lipid membrane: Mirtazapine was dissolved in diethylene glycol monoethyl ether and mixed with phospholipids, cholesterol and membrane stabilizer solution dissolved in an appropriate amount of organic solvent (such as anhydrous ethanol, chloroform). The mixture was then evaporated under reduced pressure in a water bath at 40-60℃ on a rotary evaporator to remove the organic solvent and form a uniform lipid film on the bottle wall.

[0025] (2) Hydration: Add water for injection or buffer salt solution preheated to 50-65℃ to the flask containing the lipid membrane, and hydrate by rotating at a constant temperature for 30-60 minutes to fully hydrate and swell the lipid membrane to form a multi-compartment liposome suspension.

[0026] (3) Homogenization: The above multi-compartment liposome suspension is passed through a microporous filter membrane or subjected to multiple extrusion homogenizations using a high-pressure homogenizer to obtain small single-compartment liposomes (SUV) or large single-compartment liposomes (LUV) with uniform particle size distribution, preferably with a particle size range of 50 nm - 200 nm.

[0027] (4) Purification: Unencapsulated free drug and impurities are removed by dialysis, gel chromatography or ultracentrifugation to obtain purified mirtazapine liposomes.

[0028] (5) Formulation: Add antioxidant to liposomes and stir to dissolve. Mix thoroughly with pre-melted ointment base and penetration enhancer at a suitable temperature (preferably 50-60°C) and cool to room temperature to obtain mirtazapine liposome ointment.

[0029] (6) Filling: The ointment cooled to room temperature is filled into suitable ointment tubes under aseptic conditions.

[0030] Example 1: Preparation of mirtazapine liposomes 1. Formula (based on 20 mL of liposome suspension): Mirtazapine 100 mg, diethylene glycol monoethyl ether 900 mg, hydrogenated soybean lecithin 1000 mg, cholesterol 200 mg, phosphatidic acid 50 mg, phosphate-buffered saline (PBS, pH 7.4) added to 20 mL. 2. Preparation steps: (1) Accurately weigh the above-mentioned amounts of hydrogenated soybean lecithin, cholesterol and Span 60, dissolve them in 20 mL of anhydrous ethanol to obtain a liposome carrier solution.

[0031] (2) Accurately weigh mirtazapine and diethylene glycol monoethyl ether, stir until completely dissolved, and slowly add them to the above liposome carrier solution while continuously stirring, and mix evenly.

[0032] (3) Transfer the mixed solution to a 100mL round-bottom flask, place it on a rotary evaporator, and perform vacuum rotary evaporation under a 50℃ water bath (100rpm, vacuum degree -0.09MPa). After the organic solvent is completely removed, a uniform lipid film is formed on the flask wall.

[0033] (4) Add 20 mL of phosphate buffer (PBS, pH 7.4) preheated to 55 °C to the flask containing the lipid film, and continue to rotate and hydrate in a 55 °C constant temperature water bath for 45 minutes to fully hydrate and swell the lipid film to form a multi-compartment liposome suspension.

[0034] (5) The obtained multi-chambered liposome suspension was passed through polycarbonate membranes with pore sizes of 0.8 μm, 0.45 μm and 0.22 μm in sequence and extruded multiple times in an extruder to obtain small single-chambered liposomes with a particle size of about 150 nm.

[0035] (6) The above liposomes were separated and purified using a dextran gel column (Sephadex G-50) to remove unencapsulated free drug and finally obtain purified mirtazapine liposomes.

[0036] Example 2: Preparation of Mirtazapine Liposome Ointment Take the mirtazapine liposomes prepared in Example 1 (equivalent to 2g of mirtazapine), add sodium sulfite and disodium edetate (antioxidant), and stir until completely dissolved; at the same time, heat polyethylene glycol 400 and polyethylene glycol 3350 (excipients) to melt at 60°C, and add octanoic acid-capric acid-polyethylene glycol glycerol ester (penetration enhancer) and mix evenly; then, mix the liposomes containing antioxidants with the above-mentioned melted ointment base and penetration enhancer, and continue stirring at 60°C until completely homogeneous, cool to room temperature and homogenize, and finally dispense to obtain a liposome ointment with a mirtazapine content of about 2.0%.

[0037] Example 3: Pharmacodynamic Evaluation Experimental design: Twelve healthy adult domestic cats were selected and randomly divided into two groups of six each.

[0038] Experimental group: The mirtazapine liposome ointment prepared in Example 1 of this invention was applied to the cats, and the application site was the inner side of the auricle; Control group: Cats were given commercially available mirtazapine ointment, with the same application site and dosage as the experimental group.

[0039] Sampling and detection: Blood samples were collected from cats before administration (0 hours) and at 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours after administration. The concentration of mirtazapine in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS / MS).

[0040] Test results: as attached Figure 1 As shown, the control group (commercially available mirtazapine ointment) had a shorter time to peak concentration (Tmax), about 2 hours, and the blood drug concentration decreased rapidly; while the liposome ointment group of the present invention had a longer time to peak concentration (Tmax), about 8 hours, a moderate peak blood drug concentration (Cmax), and was able to maintain a blood drug level higher than the minimum effective concentration even 24 hours after administration, showing obvious sustained-release characteristics.

[0041] Conclusion: The mirtazapine transdermal ointment described in this invention can be safely and effectively absorbed through the cat's skin into the systemic circulation, providing a sustained and stable blood drug concentration. It can be administered once a day and is very suitable for clinical use in the treatment of anorexia in cats to alleviate the problem of weight loss in cats.

[0042] Example 4: Evaluation of transdermal absorption rate 1. Experimental Methods: The transdermal absorption characteristics of the mirtazapine liposome ointment prepared in Example 1 and the commercially available mirtazapine ointment were evaluated in vitro using the Franz diffusion cell method. Using isolated SD rat skin as a barrier, a 24-hour transdermal test was conducted at a constant temperature of 37±0.5℃. Receiving fluid was collected at preset time points (1, 2, 4, 6, 8, 12, and 24 hours). The concentration of mirtazapine in the receiving fluid was determined by high-performance liquid chromatography (HPLC), and its cumulative permeation was calculated.

[0043] 2. Experimental Results: The cumulative permeability (Q_n) at different time points is shown in Table 1: Table 1 3. Conclusion: The experimental results show that, under the same experimental conditions, the cumulative penetration of mirtazapine liposome ointment at each time point is higher than that of commercially available mirtazapine ointment, proving that the liposomes and ointment matrix selected in this invention can effectively promote the transdermal penetration of mirtazapine. Theoretically, this transdermal rate can reach the administration rate required for treating feline anorexia.

[0044] Example 5: Stability Evaluation 1. Experimental design: The mirtazapine liposome ointment prepared in Example 1 and the commercially available mirtazapine ointment were subjected to accelerated stability tests (test conditions: 30℃, relative humidity 65%) to investigate the changes in related substances (impurity A, total impurities) of the two ointments at different time points (0 months, 1 month, 3 months, 6 months).

[0045] 2. Test Results: The test results for related substances are shown in Table 2 below: Table 2 3. Conclusion: The above results show that, in the accelerated testing after 6 months, impurity A was not detected in the mirtazapine liposome ointment of this invention, and the total impurity content was only 0.42%; while in the commercially available mirtazapine ointment, the impurity A content reached 0.45% and the total impurity content reached 0.79% in the accelerated testing after 6 months. This proves that the formulation design of the mirtazapine liposome ointment of this invention is more reasonable, the stability is better, and the clinical use is safer and more effective.

[0046] The above description of the embodiments is intended to enable those skilled in the art to understand and use the present invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments. Improvements and modifications made by those skilled in the art based on the principles of the present invention without departing from the scope of the invention should be within the protection scope of the present invention. The above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A mirtazapine liposome ointment, characterized in that, It is prepared by mixing mirtazapine liposomes and an ointment base; by weight percentage, the mirtazapine liposomes contain 1.0%-3.0% mirtazapine, 10.0%-25% solvent, 1.0%-15.0% phospholipids, 0.5%-5.0% cholesterol, and 0.3%-2.0% membrane stabilizer; the ointment base contains 0.3%-2.0% antioxidant, 50.0%-70.0% excipients, and 5.0%-15.0% penetration enhancer.

2. The mirtazapine liposome ointment according to claim 1, characterized in that, The solvent is diethylene glycol monoethyl ether.

3. The mirtazapine liposome ointment according to claim 1, characterized in that, The phospholipid is selected from one or more of soybean lecithin, hydrogenated soybean lecithin, egg yolk lecithin, dipalmitoylphosphatidylcholine, distearate phosphatidylcholine, and phosphatidylethanolamine.

4. The mirtazapine liposome ointment according to claim 1, characterized in that, The membrane stabilizer is selected from one or more of Span 60, vitamin E, octadecylamine, and phosphatidic acid.

5. The mirtazapine liposome ointment according to claim 1, characterized in that, The antioxidant is selected from one or more of the following: a combination of sodium sulfite and disodium edetate, butylated hydroxytoluene, and vitamin E.

6. The mirtazapine liposome ointment according to claim 1, characterized in that, The excipient is selected from one or more of polyethylene glycol, liquid paraffin, paraffin wax, and dimethyl silicone oil.

7. The mirtazapine liposome ointment according to claim 1, characterized in that, The preferred penetration enhancer is polyethylene glycol glycerol ester (caprylic / capric acid ethyl ester).

8. A method for preparing mirtazapine liposome ointment as described in any one of claims 1-7, characterized in that, Includes the following steps: (1) Mix mirtazapine with a solvent to dissolve it, then stir and mix it with phospholipids, cholesterol and membrane stabilizers dissolved in organic solvents, and evaporate under reduced pressure to remove the organic solvents to form a lipid film; (2) The lipid film is hydrated with an aqueous phase solution to obtain a liposome suspension; (3) The liposome suspension obtained in step (2) is homogenized to obtain liposomes with uniform particle size; (4) Optionally, the liposomes obtained in step (3) are purified to remove unencapsulated drugs; (5) Mix the mirtazapine liposomes obtained in step (3) or (4) with the ointment base in sequence until homogeneous.

9. The preparation method according to claim 8, characterized in that, The homogenization process described in step (3) uses a thin film extrusion method or a high-pressure homogenization method to control the average particle size of liposomes to 50-200 nm.

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