A sleep aid transdermal patch and its preparation method

Abstract

This invention belongs to the field of patch technology and relates to a sleep-aiding and hypnotic transdermal patch and its preparation method. The sleep-aiding and hypnotic transdermal patch includes a drug-loaded layer, which, by weight, comprises 2-9 parts of active drug and 0.1-7 parts of a penetration enhancer. The penetration enhancer is a combination of menthol and essential oil; the weight ratio of menthol to essential oil is 1-4:0.1-3. This invention, through optimizing the formulation and preparation process, successfully prepares a sleep-aiding and hypnotic transdermal patch with good permeability and stability, enabling slow release and absorption of the drug, solving the problems of insomnia and poor sleep quality; and reducing the probability of side effects while improving the therapeutic effect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of patches, and in particular relates to a sleep-aiding and sleep-improving transdermal patch and a preparation method thereof. BACKGROUND

[0002] Insomnia refers to difficulty falling asleep or difficulty maintaining sleep, resulting in shorter sleep time and shallower sleep, the body cannot get sufficient rest and adjustment, and cannot meet the individual's physiological needs, thereby affecting daily work and life, forming a vicious cycle, i.e., sleep disorder syndrome. Insomnia is mainly divided into two categories: acute insomnia and chronic insomnia. Acute insomnia usually refers to insomnia symptoms lasting no more than 3 months; chronic insomnia is generally caused by external reasons (for example: major setbacks, long-term work or life stress, etc.). If acute insomnia lasts for a long time, it can turn into chronic insomnia. Insomnia can cause many disadvantages: the body condition gradually declines, the immunity decreases, it is difficult to concentrate, the work efficiency decreases, and the person is listless during the day, etc., and the body and mind are harmed to different degrees.

[0003] For insomnia, the "sleeping pills" currently circulating and widely used on the market are mainly divided into ① benzodiazepines, such as triazolam, midazolam, estazolam tablets, alprazolam tablets, diazepam, clonazepam, and lorazepam tablets; ② non-benzodiazepines, such as zolpidem tablets, eszopiclone tablets, and zopiclone tablets; ③ barbiturates, such as phenobarbital tablets and secobarbital sodium capsules; ④ chloral hydrate, and most "sleeping pills" are administered orally. Although they can help people improve sleep to some extent, they often cause many adverse reactions, which are also called side effects, and have different degrees of impact on the user's physical health and quality of life.

[0004] Chinese patent CN115778922A discloses a rapid and efficient melatonin transdermal delivery system. The patch is removed from the protective film and the paste is pasted on the skin with sparse hair. The patch can release throughout the sleep stage, and the patch is removed after waking up. Compared with oral administration, the use of the patch is more convenient, and the patient only needs to paste the drug patch on the skin to achieve slow release and absorption of the drug. However, the sample components of the existing patch are complex, the preparation steps are more, and the preparation time is longer; a single penetration enhancer is used, and the promotion of drug absorption is limited; the reaction situation needs to be monitored at all times during the preparation process. If the reaction time is short, the material may not be completely melted, resulting in particles during subsequent coating, and the patch is uneven. If the reaction time is long, the paste properties will change significantly, resulting in a significant reduction in the sample shelf life.

[0005] Therefore, the sleep-aiding and sleep-improving transdermal patch and the preparation method thereof still need further research. SUMMARY

[0006] The main purpose of the present application is to overcome the defects in the prior art, provide a sleep-aiding and sleep-improving transdermal patch and a preparation method thereof, and the specific technical solutions are as follows:

[0007] The present application provides a sleep-aiding and sleep-improving transdermal patch, which comprises a drug-loaded layer, wherein the drug-loaded layer comprises 2-9 parts of active drug and 0.1-7 parts of penetration enhancer by mass fraction.

[0008] The penetration enhancer is a combination of menthol and essential oil, and the mass ratio of menthol to essential oil is 1-4:0.1-3.

[0009] The sleep-aiding and sleep-improving transdermal patch of the present application is attached to the skin of a patient for transdermal administration, and the active drug is slowly released during transdermal administration, so that the drug dose can be accurately controlled, the release rate of the drug can be better controlled, a better drug permeation rate and stability can be obtained, and the drug concentration is relatively low, thereby reducing the probability of adverse reactions and side effects.

[0010] Further, the active drug is selected from one or more of ramelteon, agomelatine, valerian extract, spina date seed extract, zopiclone, estazolam, melatonin (MT), oryzanol, zolpidem, trazodone, Wuling capsule, flurazepam, quazepam, temazepam, triazolam, diazepam, midazolam, alprazolam, lorazepam, oxazepam, and clonazepam; preferably, the active drug is selected from melatonin.

[0011] Melatonin, commonly known as sleep hormone, is one of the popular sleep aids and is a common substance for treating insomnia and other problems, and is generally taken orally, and there are few external products, so the market prospect is relatively broad. Compared with the common melatonin patch on the market, the sleep-aiding and sleep-improving transdermal patch of the present application has better permeation rate, better stability and better sleep-aiding effect in combination with the penetration enhancer of the combination of melatonin and essential oil.

[0012] Further, the essential oil is selected from one or more of base essential oil, single essential oil, compound essential oil, traditional Chinese medicine essential oil, massage essential oil, and plant essential oil; the base essential oil includes sweet almond oil, jojoba oil, and wheat germ oil; the single essential oil includes rose essential oil, lavender essential oil, and lemon essential oil; the compound essential oil includes geranium and rose compound essential oil; and the traditional Chinese medicine essential oil includes angelica essential oil, ganoderma lucidum essential oil, and ginseng essential oil.

[0013] Further, 3-10 parts of a stabilizer is further included, and the stabilizer is selected from one or more of glyceryl mono-dicaprylate, glyceryl caprylocaprate, propylene glycol monocaprylate, propylene glycol laurate (II), propylene glycol laurate (I), macrogol-7 stearate, coco-caprylocaprate, glyceryl bis-stearate, propylene glycol dicaprylate, macrogol monostearate (n=10), glyceryl mono-distearte; preferably coco-caprylocaprate and / or propylene glycol dicaprylate.

[0014] Further, 0.1-1 parts of an antioxidant is further included, and the antioxidant is selected from one or more of sulfite, thiourea-ascorbic acid, cysteine, α-tocopherol, butylated hydroxytoluene (BHT), tartaric acid, citric acid, ascorbic acid, diethylenetriaminepentaacetic acid, dimercapto benzimidazole, dimercaprol, propyl gallate, phosphoric acid, citric acid; preferably α-tocopherol and / or butylated hydroxytoluene.

[0015] Further, 30-50 parts of a matrix is further included, and the matrix is selected from one or more of styrene-butadiene-styrene block copolymer, styrene-isoprene-styrene block copolymer, styrene-butadiene copolymer, styrene-butadiene-3-chloropropylene copolymer, polystyrene-methoxypolyethylene glycol, propylene-ethylene block copolymer, polystyrene-polyethylene glycol-polystyrene, glyceryl ester of rosin, hydrogenated glyceryl ester of rosin, natural rubber, synthetic rubber, mixed rubber, polyisobutylene, terpene resin; preferably polyisobutylene and / or styrene-isoprene-styrene block copolymer.

[0016] Further, 27.5-65 parts of a plasticizer is further included, and the plasticizer is selected from one or more of di(2-ethylhexyl)phthalate, dibutyl phthalate, dioctyl phthalate, epoxidized soybean oil, cresyl phosphate, triphenyl phosphate, glycerol, ethylene glycol, sorbitol, liquid paraffin; preferably liquid paraffin.

[0017] Further, a backing layer is further included, and the backing layer is selected from one of non-woven fabric, polyester fabric, knitted fabric; the non-woven fabric includes plaster non-woven fabric, medical backing non-woven fabric, medicinal short fiber non-woven fabric; the polyester fabric includes medicinal polyester fabric, plaster polyester elastic fabric, preferably medicinal polyester fabric.

[0018] Further, an anti-adhesion layer is further included, and the anti-adhesion layer is selected from one of release film, such as medicinal release film, polyester (PET) release film, plaster release film, medicinal polyester release film, preferably plaster release film.

[0019] The application further provides a preparation method of the sleep-aiding and sleep-improving transdermal plaster, comprising the following steps:

[0020] (1) Preparation of dispersion: Mix the active drug, penetration enhancer and stabilizer evenly to obtain a dispersion;

[0021] (2) Mixing process: After mixing the matrix and plasticizer evenly, add the antioxidant and mix evenly; then add the dispersion and mix evenly to obtain the drug-loaded layer;

[0022] (3) Spreading the paste: Apply the drug-carrying layer to the anti-adhesive layer and cover it with the backing layer.

[0023] Furthermore, the preparation method of the sleep-aiding transdermal patch also includes cutting and packaging, cutting to a suitable size, packaging, storing, and storing for later use.

[0024] Compared with the prior art, the present invention has the following significant advantages:

[0025] This invention aims to provide a sleep aid transdermal patch and its preparation method. By optimizing the formulation and preparation process, a sleep aid transdermal patch with good permeability and stability has been successfully prepared, which can achieve slow release and absorption of drugs, solving the problems of insomnia and poor sleep quality; and reducing the probability of side effects while improving the therapeutic effect. Attached Figure Description

[0026] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0027] Figure 1 This is a graph showing the cumulative MT permeability curves of different permeability enhancers in Example 1 of the present invention;

[0028] Figure 2 This is a cumulative permeation rate curve of the sleep-aiding and sleep-inducing transdermal patch MT prepared in Example 1 and Comparative Examples 1-4 of the present invention. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0030] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0031] The active pharmaceutical ingredient used in this embodiment or comparative example is melatonin (MT), the antioxidant is butylated hydroxytoluene, the matrix is ​​polyethylene-butadiene copolymer, the plasticizer is dioctyl phthalate, the anti-adhesive layer is a release film for adhesive plasters, and the backing layer is polyester fiber cloth.

[0032] Example 1

[0033] A sleep aid transdermal patch includes a backing layer, a drug-loaded layer, and an anti-adhesive layer. By weight percentage, the drug-loaded layer includes 5 wt% active drug MT, 3 wt% penetration enhancer menthol, 2.5% lavender essential oil, 0.5 wt% antioxidant, 7 wt% stabilizer propylene glycol dioctyl ester, 50 wt% matrix, and 32 wt% plasticizer.

[0034] The preparation method of the above-mentioned sleep-aiding transdermal patch includes the following steps:

[0035] (1) Preparation of dispersion: Weigh the active drug, penetration enhancer and stabilizer into a mixer and mix them evenly to obtain a dispersion;

[0036] (2) After adding the matrix and plasticizer to the mixer and mixing them evenly, add the antioxidant and mix evenly; then, add the MT dispersion to the mixer and mix evenly to obtain the drug paste.

[0037] (3) Applying the ointment: Apply the ointment to the non-adhesive layer and cover it with the backing layer;

[0038] (4) Cutting and packaging: Cut the finished patch to a suitable size of 3cm×4cm, package it, store it, and use it for later use.

[0039] This embodiment verified the effects of other penetration enhancers using the same method. Specifically, the penetration enhancers used were "menthol 5.5wt%, clove volatile oil 5.5wt%, eugenol 5.5wt%, essential oil 5.5wt%, and propylene glycol 5.5wt%". The remaining components and preparation methods were the same. The cumulative MT permeation rates of the prepared sleep-aiding transdermal patches were compared, as follows: Figure 1As shown, when using a penetration enhancer alone, the 24-hour cumulative MT penetration rate of menthol is significantly higher than that of other penetration enhancers. When menthol is used in combination with essential oils, under the condition of keeping the total amount of penetration enhancer unchanged, IVPT testing is conducted according to the "Technical Guidelines for In Vitro Release and Transdermal Testing of Locally Effective Generic Chemical Drugs" issued by the National Medical Products Administration in 2025. The cumulative MT penetration rate is better than that of using the selected penetration enhancer alone.

[0040] Comparative Example 1

[0041] The difference between this comparative example and Example 1 is that the permeation enhancer in step (1) of Example 1 is replaced with "menthol 3.0wt% and propylene glycol 2.0wt%". The remaining composition and preparation method are the same as in Example 1, and will not be repeated here.

[0042] Comparative Example 2

[0043] The difference between this comparative example and Example 1 is that the permeation enhancer in step (1) of Example 1 is replaced with "menthol 3.0wt% and eugenol 2.0wt%", and the rest of the composition and preparation method are the same as in Example 1, which will not be repeated here.

[0044] Comparative Example 3

[0045] The difference between this comparative example and Example 1 is that the permeation enhancer in step (1) of Example 1 is replaced with "3.0wt% ethanol and 2.0wt% propylene glycol". The remaining composition and preparation method are the same as in Example 1, and will not be repeated here.

[0046] Comparative Example 4

[0047] The difference between this comparative example and Example 1 is that the penetration enhancer in step (1) of Example 1 is replaced with "menthol 3.0wt% and clove volatile oil 2.0wt%". The rest of the composition and preparation method are the same as in Example 1, and will not be repeated here.

[0048] The 24-hour cumulative transmittance of MT in Example 1 and Comparative Examples 1-4, such as Figure 2 As shown, when menthol is used in combination with essential oils, the cumulative MT permeability over 24 hours is significantly higher than that of the compound formulations in other comparative examples.

[0049] Example 2

[0050] The difference between this embodiment and Example 1 is that the stabilizer in step (1) of Example 1 is replaced with "7wt% of octyl-capric cocoate". The rest of the composition and preparation method are the same as in Example 1, and will not be repeated here.

[0051] Example 3

[0052] The difference between this embodiment and Example 1 is that the stabilizer in step (1) of Example 1 is replaced with "7wt% propylene glycol dioctanoate". The rest of the composition and preparation method are the same as in Example 1, and will not be repeated here.

[0053] Example 4

[0054] The difference between this embodiment and Example 1 is that the stabilizer in step (1) of Example 1 is replaced with “5wt% of coconut oil ester and 2wt% of propylene glycol dioctanoate”. The rest of the composition and preparation method are the same as in Example 1, and will not be repeated here.

[0055] Example 5

[0056] The difference between this embodiment and Embodiment 1 is that the stabilizer in step (1) of Embodiment 1 is replaced with "7wt% glyceryl mono- and dicaprylic / capric triglyceride". The rest of the composition and preparation method are the same as in Embodiment 1, and will not be repeated here.

[0057] Example 6

[0058] The difference between this embodiment and Embodiment 1 is that the stabilizer in step (1) of Embodiment 1 is replaced with “7wt% octanoic acid decanoic acid polyethylene glycol glycerol ester”. The remaining composition and preparation method are the same as in Embodiment 1, and will not be repeated here.

[0059] Example 7

[0060] The difference between this embodiment and Embodiment 1 is that the stabilizer in step (1) of Embodiment 1 is replaced with "7wt% propylene glycol monooctanoate". The rest of the composition and preparation method are the same as in Embodiment 1, and will not be repeated here.

[0061] Example 8

[0062] The difference between this embodiment and Embodiment 1 is that the stabilizer in step (1) of Embodiment 1 is replaced with "propanediol laurate (II) 7wt%", and the rest of the composition and preparation method are the same as in Embodiment 1, which will not be repeated here.

[0063] Example 9

[0064] The difference between this embodiment and Example 1 is that the stabilizer in step (1) of Example 1 is replaced with "propanediol laurate (Ⅰ) 7wt%", and the rest of the composition and preparation method are the same as in Example 1, which will not be repeated here.

[0065] Example 10

[0066] The difference between this embodiment and Example 1 is that the stabilizer in step (1) of Example 1 is replaced with "polyethylene glycol-7 stearate 7wt%", and the rest of the composition and preparation method are the same as in Example 1, which will not be repeated here.

[0067] Example 11

[0068] The difference between this embodiment and Embodiment 1 is that the stabilizer in step (1) of Embodiment 1 is replaced with "7wt% glyceryl distearate". The rest of the composition and preparation method are the same as in Embodiment 1, and will not be repeated here.

[0069] Under high temperature and light conditions, the MT content was detected at corresponding time points (according to the "Technical Guidelines for In Vitro Release and Transdermal Testing of Topically Effective Generic Chemical Drugs" issued by the National Medical Products Administration in 2025). The results are shown in Table 1.

[0070] Table 1. MT Content Detection Results

[0071]

[0072] Note: The result is the ratio to the indicated value.

[0073] Table 1 shows that, when using stabilizers alone, compared with other stabilizers, coconut oil ester (caprylic / capric acid ester) exhibits the least decrease in MT content under high temperature and light conditions, indicating the best stability. When coconut oil ester and propylene glycol dicaprylyl ester are used in combination, while maintaining the total amount constant, the combined use of coconut oil ester and propylene glycol dicaprylyl ester results in significantly higher MT content under high temperature and light conditions compared to other single stabilizers.

[0074] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A sleep-aiding sleep-inducing transdermal patch, characterized by, The drug-loaded layer comprises 2-9 parts of active drug, 0.1-7 parts of penetration enhancer, and 3-10 parts of stabilizer by mass fraction; The penetration enhancer is a combination of menthol and essential oil; the mass ratio of the menthol to the essential oil is 1-4:0.1-3; The active drug is selected from melatonin; the essential oil is selected from lavender essential oil; and the stabilizer is selected from coco-caprylate / caprate and / or propylene glycol dicaprylate.

2. The sleep-aid sleep-improving transdermal patch according to claim 1, characterized by, The antioxidant is selected from one or more of sulfite, cysteine, alpha-tocopherol, butylated hydroxytoluene, tartaric acid, citric acid, ascorbic acid, diethylenetriaminepentaacetic acid, dimercapto benzimidazole, dimercaprol, propyl gallate, and phosphoric acid.

3. The sleep-aid sleep-improving transdermal patch of claim 2, characterized by, The antioxidant is selected from alpha-tocopherol and / or butylated hydroxytoluene.

4. The sleep-aid sleep-improving transdermal patch according to claim 1 or 2, characterized by, The matrix is selected from natural rubber or synthetic rubber.

5. The sleep-aid sleep-inducing transdermal patch according to claim 4, characterized by, The matrix is selected from one or more of styrene-butadiene-styrene block copolymer, styrene-isoprene-styrene block copolymer, styrene-butadiene copolymer, polystyrene-methoxypolyethylene glycol, propylene-ethylene block copolymer, polystyrene-polyethylene glycol-polystyrene, glyceryl ester of rosin, hydrogenated glyceryl ester of rosin, polyisobutylene, terpene resin.

6. The sleep-aid sleep-improving transdermal patch according to claim 5, characterized by, The matrix is selected from polyisobutylene and / or styrene-isoprene-styrene block copolymer.

7. The sleep-aid sleep-inducing transdermal patch according to any one of claims 1 to 3, wherein The plasticizer is selected from one or more of di(2-ethylhexyl) phthalate, dibutyl phthalate, epoxidized soybean oil, tricresyl phosphate, triphenyl phosphate, glycerol, ethylene glycol, sorbitol, and liquid paraffin.

8. The sleep-aid sleep-inducing transdermal patch according to claim 7, characterized by, The plasticizer is selected from liquid paraffin.

9. The sleep-aid sleep-inducing transdermal patch according to claim 7, characterized by, The backing layer is selected from non-woven fabric.

10. The sleep-aid sleep-inducing transdermal patch of claim 9, wherein, The backing layer is selected from knitted fabric.

11. The sleep-aid sleep-improving transdermal patch according to claim 9 or 10, characterized by, The backing layer is selected from polyester fabric.

12. The sleep-aid sleep-inducing transdermal patch of claim 9, wherein The release layer is selected from release film.

13. A process for the preparation of a sleep-aiding hypnotic transdermal patch according to any one of claims 1-12, characterized by, The method comprises the following steps: (1) dispersion liquid preparation: uniformly mixing and stirring the active drug, the penetration enhancer, and the stabilizer to prepare a dispersion liquid; (2) mixing process: uniformly mixing and stirring the matrix and the plasticizer, then adding the antioxidant and uniformly mixing and stirring, and then adding the dispersion liquid and uniformly mixing and stirring to obtain the drug-loaded layer; (3) paste spreading: coating the drug-loaded layer on the release layer and covering with the backing layer.

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