Preparation method of jujube seed oil extract in sleeping patch and sleeping patch

Abstract

The present invention relates to the technical field of Chinese jujube seed oil extract, and in particular to a preparation method of Chinese jujube seed oil extract in a sleeping patch and a sleeping patch, comprising the following steps: (1) raw material pretreatment, (2) ultrasound-assisted supercritical CO2 extraction: (3) two-step molecular distillation purification; (4) nano lipid carrier NLC encapsulation; (5) freeze drying, ultrasound-assisted supercritical CO2 extraction combined with two-step molecular distillation purification, this combination can more efficiently extract and enrich the effective ingredients in Chinese jujube seed, while retaining its activity to the greatest extent, the main active ingredients in Chinese jujube seed such as jujube saponin A, flavonoids and unsaturated fatty acids are effectively encapsulated and protected by NLC technology, and the hydrophilic shell on the surface helps the dispersion of the entire system in the hydrogel. NLC has higher encapsulation rate, stability and percutaneous absorption rate, and can better protect and deliver active ingredients.

Description

Technical Field

[0001] The invention relates to the technical field of jujube seed oil extract, and in particular to a preparation method of jujube seed oil extract in a sleeping patch and the sleeping patch. Background Art

[0002] In recent years, transdermal drug delivery systems have attracted widespread attention due to their unique advantages. This drug delivery method can avoid the first-pass effect, reduce gastrointestinal irritation, and achieve slow and sustained drug release. However, existing transdermal drug delivery systems still face many challenges in terms of drug penetration efficiency, release control, and long-term stability.

[0003] As a traditional Chinese medicine for tranquilizing the nerves, the active ingredients of Ziziphus jujuba seed have a significant effect on improving sleep quality. However, due to the large molecular weight and strong hydrophilicity of its active ingredients, it is difficult to effectively penetrate the skin barrier. Currently, the Ziziphus jujuba seed preparations on the market are mainly oral dosage forms, and there are relatively few studies on transdermal administration.

[0004] Although some existing transdermal drug delivery systems attempt to make Chinese jujube seed extract into patches, they often face the following problems: first, the transdermal penetration efficiency of the drug is low, making it difficult to achieve the desired therapeutic effect; second, the drug release is not sustained and uniform enough, making it difficult to maintain a long-term effect; third, the active ingredients are prone to degradation during storage, affecting the stability and shelf life of the product; finally, some patches have poor adhesion properties and are easy to fall off, affecting the user experience. Summary of the invention

[0005] The present invention aims to solve the above technical problems and provides a method for preparing a jujube seed oil extract in a sleeping patch and a sleeping patch.

[0006] The object of the present invention is to provide a method for preparing a jujube seed oil extract for a sleeping patch, comprising the following steps:

[0007] (1) Raw material pretreatment: vacuum drying the seeds of the Chinese date palm at 45-55°C for 10-14 hours to reduce the moisture content to 3-4%, and then crushing the dried seeds to 50-70 mesh at low temperature;

[0008] (2) Ultrasonic-assisted supercritical CO2 extraction: The crushed spiny jujube kernel obtained in step (1) was extracted under the following conditions: pressure 28-32 MPa, temperature 42-48°C, extraction time 2.5-3.5 hours, CO2 flow rate 18-22 L / h, ultrasonic power density 300-400 W / L, and ultrasonic frequency 20-25 kHz;

[0009] (3) Two-step molecular distillation purification: The crude extract obtained in step (2) is subjected to two-step molecular distillation purification, wherein the first step distillation temperature is 120-140°C, the vacuum degree is 0.5-1 Pa, and the distillation time is 20-30 minutes; the second step distillation temperature is 160-180°C, the vacuum degree is 0.1-0.3 Pa, and the distillation time is 40-60 minutes;

[0010] (4) Nanolipid carrier NLC encapsulation: the purified jujube seed oil obtained in step (3) is mixed with solid fat and liquid fat in a weight ratio of 3:5:2, 10-15 parts by weight of a surfactant is added, and the mixture is stirred at 70-80° C., and then 40-50 parts by weight of deionized water is added, and the mixture is homogenized at 80-100 MPa using a high-pressure homogenizer for 8-10 times;

[0011] (5) Freeze drying: The NLC suspension obtained in step (4) is mixed with 5-8 parts by weight of sodium alginate and 3-5 parts by weight of trehalose, and then freeze dried. The freeze drying conditions are: pre-freezing temperature -45°C, 5-7 hours, main drying temperature -35°C to 20°C, 28-36 hours, and post-drying temperature 25-30°C, 5-7 hours.

[0012] Preferably, the solid fat is stearic acid, and the liquid fat is medium-chain triglycerides.

[0013] Preferably, the surfactant is a 1:1 mixture of polyoxyethylene castor oil 40 and soybean lecithin.

[0014] A sleeping patch comprises the following components in parts by weight:

[0015] 20-25 parts of NLC-encapsulated jujube seed oil extract prepared by the method;

[0016] 12-15 parts of propylene glycol;

[0017] 6-8 parts of polyvinylpyrrolidone K90;

[0018] 4-6 parts of hydroxypropyl beta-cyclodextrin;

[0019] 1-2 parts menthol;

[0020] 0.5-1 part lavender essential oil;

[0021] 1-2 parts of γ-aminobutyric acid;

[0022] 1-2 parts glycine;

[0023] Add to 100 parts of deionized water.

[0024] The preparation method of the sleeping patch comprises the following steps:

[0025] (1) Dissolve polyvinyl pyrrolidone K90 in deionized water and stir evenly;

[0026] (2) dissolving hydroxypropyl β-cyclodextrin, γ-aminobutyric acid and glycine in the solution obtained in step (1) and stirring evenly;

[0027] (3) mixing propylene glycol, menthol and lavender essential oil, and then mixing with the solution obtained in step (2), and ultrasonically treating for 10-15 minutes;

[0028] (4) slowly adding the NLC-encapsulated jujube seed oil extract to the mixture obtained in step (3), and stirring at a low speed at 40-45° C. for 2-3 hours;

[0029] (5) evenly coating the mixture obtained in step (4) on the hydrogel substrate having the microneedle array, with the thickness controlled to be 0.8-1.2 mm;

[0030] (6) Vacuum drying at 45-50° C. for 3-5 hours to obtain a sleeping patch.

[0031] Preferably, the hydrogel substrate is polyacrylamide-sodium carboxymethyl cellulose cross-linked hydrogel.

[0032] Preferably, the microneedle length of the microneedle array is 200-500 μm, and the microneedle density is 100-200 / cm².

[0033] Preferably, the sleeping patch further comprises a layer of waterproof and breathable membrane.

[0034] Preferably, the waterproof and breathable membrane is a polyurethane film or a polytetrafluoroethylene film.

[0035] The present invention has the following beneficial effects:

[0036] In view of the above problems, the present invention proposes an innovative method for preparing a sleep patch, which cleverly combines nano lipid carrier (NLC) technology, microneedle array technology and hydrogel matrix to achieve multiple synergistic effects. First, NLC technology can effectively encapsulate and protect the active ingredients in jujube seed oil, improving its stability and bioavailability. The nano size of NLC (usually in the range of 100-300nm) enables it to penetrate the skin barrier more easily, especially when combined with microneedle array technology, this advantage is more significant.

[0037] The introduction of microneedle array technology creates micron-scale channels (usually between 200-500μm in length) on the skin surface. These microchannels can significantly reduce the barrier effect of the stratum corneum and provide an ideal path for the penetration of NLC. The length and density of the microneedles are carefully designed to ensure sufficient penetration depth without causing obvious pain.

[0038] The choice of hydrogel matrix is ​​also a highlight of the present invention. Polyacrylamide-sodium carboxymethylcellulose cross-linked hydrogel not only has good biocompatibility, but also provides moderate adhesion and air permeability. This matrix can perfectly cooperate with NLC and microneedle technology, which can not only maintain the overall structure of the patch, but also promote the slow release of active ingredients.

[0039] From a molecular perspective, the innovation of this invention is also reflected in the synergistic utilization of various components in the jujube seed oil extract. The main active ingredients in the jujube seed, such as jujuboside A (a triterpenoid compound), flavonoids and unsaturated fatty acids, are effectively encapsulated and protected by NLC technology. The lipid matrix of NLC forms a strong hydrophobic interaction with the hydrophobic parts of these active ingredients, while the hydrophilic shell on the surface helps to disperse the entire system in the hydrogel.

[0040] In addition, the present invention also cleverly introduces γ-aminobutyric acid and glycine as auxiliary ingredients. These two amino acids can not only directly participate in the sleep regulation process, but also produce a synergistic effect with the Chinese date seed extract. γ-aminobutyric acid, as an inhibitory neurotransmitter, can directly promote sleep; while glycine can enhance the effect of γ-aminobutyric acid and also has a mild sedative effect. This design of multiple action mechanisms enables the sleep patch of the present invention to improve sleep quality more comprehensively and effectively.

[0041] Another outstanding advantage of the present invention is the innovation of its preparation process. The application of ultrasound-assisted supercritical CO2 extraction technology not only improves the extraction efficiency, but also retains the effective ingredients in the jujube seed oil to the maximum extent. The two-step molecular distillation purification process further improves the purity and activity of the extract. This refined preparation process lays a solid foundation for the subsequent NLC preparation and sleep patch molding.

[0042] In summary, the present invention has successfully developed an efficient, stable and comfortable sleep patch through the synergistic effect of multiple innovative technologies. This sleep patch not only solves the problems of low penetration efficiency, uneven release, poor stability, etc. faced by traditional transdermal drug delivery systems, but also provides a more comprehensive sleep improvement solution through multiple action mechanisms. The success of the present invention not only provides a new option for the treatment of insomnia, but also provides a new idea and direction for the design of transdermal drug delivery systems, which has broad application prospects and important social significance.

[0043] In addition, the present invention also has the following unexpected technical effects:

[0044] 1. Super synergistic penetration enhancement: The combination of NLC technology and microneedle array is not just a simple superposition effect, but produces a synergistic enhancement that exceeds expectations. The transdermal penetration of Example 3 is more than 100% higher than that of NLC (Comparative Example 2) or microneedles (Comparative Example 1) alone. This significant synergistic effect may be due to the perfect match between the nano-size of NLC and the micro-channels created by the microneedles, which greatly reduces the resistance of the skin barrier.

[0045] 2. All-round stability improvement: NLC technology not only improves the chemical stability of active ingredients, but also unexpectedly improves the physical stability of the entire preparation. This is reflected in the long-term maintenance of the product's appearance stability and adhesion performance under high temperature and high humidity conditions, making it possible for the product to be used under different climatic conditions.

[0046] 3. Nonlinear increase in bioavailability: Although in vitro tests show that the transdermal permeation of Example 3 is about 126.8% higher than that of Comparative Example 1, in animal experiments, the improvement in sedative and hypnotic effects is greater (e.g., the inhibition rate of spontaneous activity is increased by 56.6%). This nonlinear increase may be due to the fact that NLC technology not only increases the permeation of the drug, but also optimizes its distribution and sustained release characteristics in the skin, thereby improving the bioavailability of the drug.

[0047] 4. Improved comfort through synergistic effects of multiple factors: The comfort of a sleeping patch is a complex comprehensive indicator, involving multiple aspects such as adhesion, breathability, and drug release properties. The present invention uses a sophisticated combination of NLC technology, microneedle array, and hydrogel matrix to achieve good breathability and mild drug release properties while ensuring strong adhesion, greatly improving the comfort of use, which is particularly important for sleeping products.

[0048] 5. Synergistic enhancement of broad-spectrum compounds: Although the present invention is mainly aimed at the extract of jujube seed oil, the experimental results show that NLC technology also has good encapsulation and delivery effects on other auxiliary ingredients (such as γ-aminobutyric acid and glycine). This broad spectrum makes the application scope of the present invention far beyond expectations, providing new ideas for the development of various functional transdermal drug delivery systems.

[0049] These unexpected technical effects not only prove the innovation and superiority of the present invention, but also provide new ideas and directions for the design of transdermal drug delivery systems. Through the synergistic effect of multiple technologies, the present invention successfully developed an efficient, stable and comfortable sleep patch. DETAILED DESCRIPTION

[0050] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in conjunction with the specific embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0051] The method of the present invention combines ultrasound-assisted supercritical CO2 extraction with two-step molecular distillation purification. This combination can more efficiently extract and enrich the effective components in the spinach seeds while retaining their activity to the greatest extent.

[0052] Nanolipid carrier (NLC) encapsulation technology, compared with traditional liposomes, NLC has higher encapsulation rate, stability and transdermal absorption rate, and can better protect and deliver active ingredients. Hydroxypropyl β-cyclodextrin can increase the solubility and stability of hydrophobic active ingredients. GABA and glycine, as neurotransmitters, can directly participate in sleep regulation and produce synergistic effects with jujube seed extract. Menthol and lavender essential oil not only enhance the sedative effect, but also promote transdermal absorption. Microneedles can slightly damage the stratum corneum and increase the permeability of active ingredients, while the hydrogel substrate provides good adhesion and comfort.

[0053] The addition of sodium alginate and trehalose can protect the NLC structure and improve product stability and shelf life.

[0054] This optimized preparation method and formula design fully consider the synergistic and complementary effects between the components. NLC technology solves the problem of poor stability of traditional liposomes, and the microneedle array hydrogel matrix overcomes the disadvantage of low transdermal absorption efficiency. At the same time, the careful selection of auxiliary ingredients not only enhances the effect of the main active ingredients, but also improves the stability and bioavailability of the overall formula. This multi-level optimization strategy is expected to significantly improve the sedative and hypnotic effect and user experience of the sleep patch.

[0055] Example 1

[0056] This embodiment provides a method for preparing a jujube seed oil extract in a sleep patch and its application in a sleep patch. The method comprises the following steps:

[0057] First, the raw materials were pretreated. The seeds of the spiny date kernel were vacuum dried at 45°C for 10 hours to reduce the moisture content to 4%. The dried seeds were then crushed to 50 mesh at low temperature.

[0058] Secondly, ultrasonic-assisted supercritical CO2 extraction was performed. The crushed spiny jujube seeds were extracted under the following conditions: pressure 28 MPa, temperature 42°C, extraction time 2.5 hours, CO2 flow rate 18 L / h, ultrasonic power density 300 W / L, and ultrasonic frequency 20 kHz.

[0059] Next, two steps of molecular distillation purification were performed. The first step was distillation temperature of 120°C, vacuum degree of 1 Pa, and distillation time of 20 minutes; the second step was distillation temperature of 160°C, vacuum degree of 0.3 Pa, and distillation time of 40 minutes.

[0060] Then, nanolipid carrier (NLC) encapsulation was performed. The purified jujube seed oil was mixed with stearic acid and medium-chain triglycerides in a weight ratio of 3:5:2, and 10 parts by weight of polyoxyethylene castor oil 40 and soybean lecithin (mixed in a ratio of 1:1) were added and stirred evenly at 70°C. Subsequently, 40 parts by weight of deionized water were added and homogenized 8 times at 80 MPa using a high-pressure homogenizer.

[0061] Finally, freeze drying was performed. The NLC suspension was mixed with 5 parts by weight of sodium alginate and 3 parts by weight of trehalose, and then freeze dried. The freeze drying conditions were pre-freezing temperature -45°C for 5 hours, main drying temperature -35°C to 20°C for 28 hours, and post-drying temperature 25°C for 5 hours.

[0062] The NLC encapsulated jujube seed oil extract prepared based on the above method is used to prepare a sleeping patch. The components and weight portions of the sleeping patch are as follows:

[0063] 20 parts of NLC-encapsulated jujube seed oil extract, 12 parts of propylene glycol, 6 parts of polyvinyl pyrrolidone K90, 4 parts of hydroxypropyl β-cyclodextrin, 1 part of menthol, 0.5 parts of lavender essential oil, 1 part of γ-aminobutyric acid, 1 part of glycine, and 54.5 parts of deionized water.

[0064] The preparation method of the sleeping patch comprises the following steps:

[0065] (1) Dissolve polyvinyl pyrrolidone K90 in deionized water and stir evenly;

[0066] (2) dissolving hydroxypropyl β-cyclodextrin, γ-aminobutyric acid and glycine in the solution obtained in step (1) and stirring evenly;

[0067] (3) mixing propylene glycol, menthol and lavender essential oil, and then mixing with the solution obtained in step (2), and ultrasonically treating for 10 minutes;

[0068] (4) slowly adding the NLC-encapsulated jujube seed oil extract to the mixture obtained in step (3), and stirring at a low speed at 40° C. for 2 hours;

[0069] (5) coating the mixture obtained in step (4) uniformly on a polyacrylamide-sodium carboxymethyl cellulose cross-linked hydrogel substrate having a microneedle array, with a thickness controlled to be 0.8 mm;

[0070] (6) Vacuum drying at 45°C for 3 hours to obtain a sleeping patch.

[0071] The microneedle array has a microneedle length of 200 μm and a microneedle density of 100 / cm². The sleep patch also includes a layer of polyurethane waterproof and breathable membrane.

[0072] Preferably, in an embodiment of the present invention, NLC technology can improve the stability and transdermal absorption rate of jujube seed oil. Hydroxypropyl β-cyclodextrin can increase the solubility of hydrophobic active ingredients, while γ-aminobutyric acid and glycine as neurotransmitters can directly participate in sleep regulation and produce a synergistic effect with jujube seed extract. The design of the microneedle array helps to improve the permeability of active ingredients, while the hydrogel substrate provides good adhesion and comfort.

[0073] Example 2

[0074] This embodiment provides another method for preparing a jujube seed oil extract in a sleep patch and its application in a sleep patch. The method comprises the following steps:

[0075] First, the raw materials were pretreated. The seeds of the spiny date kernel were vacuum dried at 50°C for 12 hours to reduce the moisture content to 3.5%. The dried seeds were then crushed to 60 mesh at low temperature.

[0076] Secondly, ultrasonic-assisted supercritical CO2 extraction was performed. The crushed spiny jujube seeds were extracted under the following conditions: pressure 30 MPa, temperature 45°C, extraction time 3 hours, CO2 flow rate 20 L / h, ultrasonic power density 350 W / L, and ultrasonic frequency 22.5kHz.

[0077] Next, two steps of molecular distillation purification were performed. The first step was distillation temperature of 130°C, vacuum degree of 0.75 Pa, and distillation time of 25 minutes; the second step was distillation temperature of 170°C, vacuum degree of 0.2 Pa, and distillation time of 50 minutes.

[0078] Then, nano lipid carrier (NLC) encapsulation was performed. The purified jujube seed oil was mixed with stearic acid and medium-chain triglycerides in a weight ratio of 3:5:2, and 12.5 parts by weight of polyoxyethylene castor oil 40 and soybean lecithin (mixed in a ratio of 1:1) were added and stirred evenly at 75°C. Subsequently, 45 parts by weight of deionized water were added and homogenized 9 times at 90 MPa using a high-pressure homogenizer.

[0079] Finally, freeze drying was performed. The NLC suspension was mixed with 6.5 parts by weight of sodium alginate and 4 parts by weight of trehalose, and then freeze dried. The freeze drying conditions were pre-freezing temperature -45°C, 6 hours, main drying temperature -35°C to 20°C, 32 hours, and post-drying temperature 27.5°C, 6 hours.

[0080] The NLC encapsulated jujube seed oil extract prepared based on the above method is used to prepare a sleeping patch. The components and weight portions of the sleeping patch are as follows:

[0081] 22.5 parts of NLC-encapsulated jujube seed oil extract, 13.5 parts of propylene glycol, 7 parts of polyvinylpyrrolidone K90, 5 parts of hydroxypropyl β-cyclodextrin, 1.5 parts of menthol, 0.75 parts of lavender essential oil, 1.5 parts of γ-aminobutyric acid, 1.5 parts of glycine, and 46.75 parts of deionized water.

[0082] The preparation method of the sleeping patch comprises the following steps:

[0083] (1) Dissolve polyvinyl pyrrolidone K90 in deionized water and stir evenly;

[0084] (2) dissolving hydroxypropyl β-cyclodextrin, γ-aminobutyric acid and glycine in the solution obtained in step (1) and stirring evenly;

[0085] (3) mixing propylene glycol, menthol and lavender essential oil, and then mixing with the solution obtained in step (2), and ultrasonically treating for 12.5 minutes;

[0086] (4) slowly adding the NLC-encapsulated jujube seed oil extract to the mixture obtained in step (3), and stirring at a low speed at 42.5° C. for 2.5 hours;

[0087] (5) coating the mixture obtained in step (4) evenly on a polyacrylamide-sodium carboxymethyl cellulose cross-linked hydrogel substrate having a microneedle array, with a thickness controlled to be 1 mm;

[0088] (6) Vacuum drying at 47.5°C for 4 hours to obtain a sleeping patch.

[0089] The microneedle array has a microneedle length of 350 μm and a microneedle density of 150 / cm². The sleep patch also includes a layer of polytetrafluoroethylene waterproof and breathable membrane.

[0090] Preferably, in this embodiment, the content of the NLC-encapsulated jujube seed oil extract is increased to improve the sedative effect of the sleep patch. At the same time, the content of γ-aminobutyric acid and glycine is increased to further enhance the sleep regulation effect. The increase in microneedle length is conducive to the deep penetration of active ingredients, and the increase in microneedle density can increase the drug delivery efficiency.

[0091] Example 3

[0092] This embodiment provides a method for preparing a third type of jujube seed oil extract in a sleep patch and its application in a sleep patch. The method comprises the following steps:

[0093] First, the raw materials were pretreated. The seeds of the spiny date kernel were vacuum dried at 55°C for 14 hours to reduce the moisture content to 3%. The dried seeds were then crushed to 70 mesh at low temperature.

[0094] Secondly, ultrasonic-assisted supercritical CO2 extraction was performed. The crushed spiny jujube kernels were extracted under the following conditions: pressure 32 MPa, temperature 48°C, extraction time 3.5 hours, CO2 flow rate 22 L / h, ultrasonic power density 400 W / L, and ultrasonic frequency 25kHz.

[0095] Next, two steps of molecular distillation purification were performed. The first step was distillation temperature of 140°C, vacuum degree of 0.5 Pa, and distillation time of 30 minutes; the second step was distillation temperature of 180°C, vacuum degree of 0.1 Pa, and distillation time of 60 minutes.

[0096] Then, nano lipid carrier (NLC) encapsulation was performed. The purified jujube seed oil was mixed with stearic acid and medium-chain triglycerides in a weight ratio of 3:5:2, and 15 parts by weight of polyoxyethylene castor oil 40 and soybean lecithin (mixed in a ratio of 1:1) were added and stirred evenly at 80°C. Subsequently, 50 parts by weight of deionized water were added and homogenized 10 times at 100 MPa using a high-pressure homogenizer.

[0097] Finally, freeze drying was performed. The NLC suspension was mixed with 8 parts by weight of sodium alginate and 5 parts by weight of trehalose, and then freeze dried. The freeze drying conditions were pre-freezing temperature -45°C, 7 hours, main drying temperature -35°C to 20°C, 36 hours, and post-drying temperature 30°C, 7 hours.

[0098] The NLC encapsulated jujube seed oil extract prepared based on the above method is used to prepare a sleeping patch. The components and weight portions of the sleeping patch are as follows:

[0099] 25 parts of NLC-encapsulated jujube seed oil extract, 15 parts of propylene glycol, 8 parts of polyvinylpyrrolidone K90, 6 parts of hydroxypropyl β-cyclodextrin, 2 parts of menthol, 1 part of lavender essential oil, 2 parts of γ-aminobutyric acid, 2 parts of glycine, and 39 parts of deionized water.

[0100] The preparation method of the sleeping patch comprises the following steps:

[0101] (1) Dissolve polyvinyl pyrrolidone K90 in deionized water and stir evenly;

[0102] (2) dissolving hydroxypropyl β-cyclodextrin, γ-aminobutyric acid and glycine in the solution obtained in step (1) and stirring evenly;

[0103] (3) mixing propylene glycol, menthol and lavender essential oil, and then mixing with the solution obtained in step (2), and ultrasonically treating for 15 minutes;

[0104] (4) slowly adding the NLC-encapsulated jujube seed oil extract to the mixture obtained in step (3), and stirring at a low speed at 45° C. for 3 hours;

[0105] (5) coating the mixture obtained in step (4) uniformly on a polyacrylamide-sodium carboxymethyl cellulose cross-linked hydrogel substrate having a microneedle array, with a thickness controlled to be 1.2 mm;

[0106] (6) The mixture was vacuum dried at 50°C for 5 hours to obtain a sleeping patch.

[0107] The microneedle array has a microneedle length of 500 μm and a microneedle density of 200 / cm². The sleep patch also includes a layer of polyurethane waterproof and breathable membrane.

[0108] Preferably, in this embodiment, the content of the jujube seed oil extract encapsulated by NLC reaches the highest level, which can achieve the strongest sedative effect. At the same time, the content of menthol and lavender essential oil also reaches the highest level, which can provide better aromatherapy effects and further promote transdermal absorption. The increase in microneedle length and density can maximize the drug delivery efficiency.

[0109] Example 4

[0110] This embodiment provides a fourth method for preparing the jujube seed oil extract in a sleep patch and its application in a sleep patch. The method comprises the following steps:

[0111] First, the raw materials were pretreated. The seeds of the spiny date kernel were vacuum dried at 52.5°C for 13 hours to reduce the moisture content to 3.2%. The dried seeds were then crushed to 65 mesh at low temperature.

[0112] Secondly, ultrasonic-assisted supercritical CO2 extraction was performed. The crushed spiny jujube seeds were extracted under the following conditions: pressure 31 MPa, temperature 46°C, extraction time 3.2 hours, CO2 flow rate 21 L / h, ultrasonic power density 375 W / L, and ultrasonic frequency 23.5 kHz.

[0113] Next, two steps of molecular distillation purification were performed. The first step was distillation temperature of 135°C, vacuum degree of 0.6 Pa, and distillation time of 27 minutes; the second step was distillation temperature of 175°C, vacuum degree of 0.15 Pa, and distillation time of 55 minutes.

[0114] Then, nano lipid carrier (NLC) encapsulation was performed. The purified jujube seed oil was mixed with stearic acid and medium-chain triglycerides in a weight ratio of 3:5:2, and 13.5 parts by weight of polyoxyethylene castor oil 40 and soybean lecithin (mixed in a ratio of 1:1) were added and stirred evenly at 77°C. Subsequently, 47 parts by weight of deionized water were added and homogenized 9 times at 95 MPa using a high-pressure homogenizer.

[0115] Finally, freeze drying was performed. The NLC suspension was mixed with 7 parts by weight of sodium alginate and 4.5 parts by weight of trehalose, and then freeze dried. The freeze drying conditions were pre-freezing temperature -45°C, 6.5 hours, main drying temperature -35°C to 20°C, 34 hours, and post-drying temperature 28°C, 6.5 hours.

[0116] The NLC encapsulated jujube seed oil extract prepared based on the above method is used to prepare a sleeping patch. The components and weight portions of the sleeping patch are as follows:

[0117] 23 parts of NLC-encapsulated jujube seed oil extract, 14 parts of propylene glycol, 7.5 parts of polyvinyl pyrrolidone K90, 5.5 parts of hydroxypropyl β-cyclodextrin, 1.7 parts of menthol, 0.8 parts of lavender essential oil, 1.7 parts of γ-aminobutyric acid, 1.7 parts of glycine, and 44.1 parts of deionized water.

[0118] The preparation method of the sleeping patch comprises the following steps:

[0119] (1) Dissolve polyvinyl pyrrolidone K90 in deionized water and stir evenly;

[0120] (2) dissolving hydroxypropyl β-cyclodextrin, γ-aminobutyric acid and glycine in the solution obtained in step (1) and stirring evenly;

[0121] (3) mixing propylene glycol, menthol and lavender essential oil, and then mixing with the solution obtained in step (2), and ultrasonically treating for 13 minutes;

[0122] (4) slowly adding the NLC-encapsulated jujube seed oil extract to the mixture obtained in step (3), and stirring at a low speed at 43° C. for 2.7 hours;

[0123] (5) coating the mixture obtained in step (4) uniformly on a polyacrylamide-sodium carboxymethyl cellulose cross-linked hydrogel substrate having a microneedle array, with a thickness controlled to be 1.1 mm;

[0124] (6) Vacuum drying at 48°C for 4.5 hours to obtain a sleeping patch.

[0125] The microneedle array has a microneedle length of 400 μm and a microneedle density of 175 / cm². The sleep patch also includes a layer of polytetrafluoroethylene waterproof and breathable membrane.

[0126] Preferably, in this embodiment, the content of each component and the preparation parameters are selected to be intermediate values ​​to achieve a balance of various properties. This formulation design can ensure a good sedative effect while taking into account drug delivery efficiency and comfort of use. In particular, the medium level of microneedle length and density can improve drug penetration while minimizing skin irritation.

[0127] Through the above four embodiments, it can be seen that the preparation method of the sleep patch of the present invention has strong flexibility and adjustability. By adjusting various parameters, sleep patches with different effect strengths can be prepared for different degrees of insomnia. For example, the formula in Example 3 is suitable for patients with severe insomnia, while the formula in Example 1 is more suitable for patients with mild insomnia.

[0128] In addition, the preparation method of the present invention fully considers the synergistic effect between the components. For example, NLC technology not only improves the stability of jujube seed oil, but also can be combined with microneedle array technology to significantly improve the transdermal absorption efficiency of drugs. At the same time, γ-aminobutyric acid and glycine, as auxiliary ingredients, can directly participate in sleep regulation, form a synergistic effect with jujube seed extract, and further enhance the overall effect of the sleep patch.

[0129] In general, the present invention has successfully developed an efficient, safe and easy-to-use sleeping patch through the combination of multiple innovative technologies, providing a new treatment option for insomnia patients.

[0130] Comparative Example 1 (corresponding to Example 1)

[0131] This comparative example provides a method for preparing a jujube seed oil extract without using NLC encapsulation technology and its application in a sleep patch. The method comprises the following steps:

[0132] First, the raw materials were pretreated. The seeds of the spiny date kernel were vacuum dried at 45°C for 10 hours to reduce the moisture content to 4%. The dried seeds were then crushed to 50 mesh at low temperature.

[0133] Secondly, conventional solvent extraction was performed, using ethanol as the extraction solvent, and reflux extraction was performed at 60°C for 3 hours, and the extract was concentrated under reduced pressure to obtain the jujube seed oil extract.

[0134] Next, the jujube seed oil extract was directly used to prepare a sleeping patch. The components and weight portions of the sleeping patch were the same as those in Example 1, except that the jujube seed oil extract wrapped in NLC was replaced by the jujube seed oil extract directly extracted.

[0135] The preparation method of the sleeping patch is the same as that of Example 1, but the NLC encapsulation step is omitted.

[0136] Preferably, in this comparative example, due to the lack of NLC encapsulation technology, the stability and transdermal absorption rate of the jujube seed oil extract may be reduced, which may result in the overall effect of the sleeping patch being inferior to that of the product in Example 1.

[0137] Comparative Example 2 (corresponding to Example 2)

[0138] This comparative example provides a method for preparing a sleep patch without using a microneedle array. The steps for preparing the jujube seed oil extract in this method are the same as those in Example 2, but in the preparation process of the sleep patch, a common hydrogel substrate is used instead of a microneedle array hydrogel substrate.

[0139] The components and weight proportions of the sleeping patch are the same as those in Example 2, and the preparation method is also basically the same, but in step (5), the mixture is evenly coated on a common polyacrylamide-sodium carboxymethyl cellulose cross-linked hydrogel substrate, and the thickness is controlled to be 1 mm.

[0140] Preferably, in this comparative example, due to the lack of a microneedle array structure, the transdermal penetration of the active ingredient may be limited. This may result in a prolonged onset of the sleep patch and reduced overall efficacy. By comparison with Example 2, the importance of microneedle array technology in improving drug delivery efficiency can be highlighted.

[0141] Comparative Example 3 (corresponding to Example 3)

[0142] This comparative example provides a method for preparing a sleeping patch without adding γ-aminobutyric acid and glycine. The method for preparing the jujube seed oil extract is the same as that in Example 3, but in the sleeping patch formula, γ-aminobutyric acid and glycine are removed, and the content of deionized water is increased accordingly.

[0143] The components and weight proportions of the sleeping patch are as follows:

[0144] 25 parts of NLC-encapsulated jujube seed oil extract, 15 parts of propylene glycol, 8 parts of polyvinyl pyrrolidone K90, 6 parts of hydroxypropyl beta-cyclodextrin, 2 parts of menthol, 1 part of lavender essential oil, and 43 parts of deionized water.

[0145] The preparation method of the sleeping patch is basically the same as that of Example 3, but the process of adding γ-aminobutyric acid and glycine is omitted in step (2).

[0146] Preferably, in this comparative example, due to the lack of γ-aminobutyric acid and glycine, two neurotransmitters directly involved in sleep regulation, the sedative effect of the sleep patch may be reduced. By comparison with Example 3, it can be demonstrated that these two auxiliary ingredients are important in enhancing the sleep regulation effect of the spiny jujube seed extract.

[0147] Comparative Example 4 (corresponding to Example 4)

[0148] This comparative example provides a method for preparing a jujube seed oil extract by encapsulating it with common liposomes instead of NLC. The preliminary steps of the method (raw material pretreatment, ultrasound-assisted supercritical CO2 extraction, and two-step molecular distillation purification) are the same as those in Example 4, but in the encapsulation step, conventional liposome technology is used.

[0149] The steps of liposome encapsulation are as follows:

[0150] The purified jujube seed oil and soybean lecithin were mixed in a weight ratio of 1:2 and stirred at 60° C. Then 47 parts by weight of deionized water were added and homogenized 5 times at 50 MPa using a high-pressure homogenizer.

[0151] The subsequent freeze-drying step is the same as in Example 4.

[0152] The components and weight proportions of the sleeping patch are the same as those in Example 4, except that the NLC-encapsulated jujube seed oil extract is replaced with the liposome-encapsulated jujube seed oil extract. The preparation method is also basically the same.

[0153] Preferably, in this comparative example, due to the use of ordinary liposomes instead of NLC, the encapsulation efficiency and stability of the jujube seed oil extract may be reduced. This may result in a shortened shelf life of the sleep patch and insufficient continuous and uniform release of the active ingredient during use. By comparison with Example 4, the advantages of NLC technology in improving drug stability and controlling release can be highlighted.

[0154] Comparative Example 5 (for microneedle length and density)

[0155] This comparative example provides a method for preparing a sleep patch using shorter microneedles and lower density. The preparation method of the jujube seed oil extract is the same as that of Example 1, and the components and weight portions of the sleep patch are also the same as those of Example 1.

[0156] The preparation method is basically the same, but in step (5), the microneedle length of the microneedle array hydrogel substrate used is 100 μm and the microneedle density is 50 / cm².

[0157] Preferably, in this comparative example, due to the short length and low density of the microneedles, the active ingredient may not be able to effectively penetrate the skin barrier, resulting in insufficient drug absorption. By comparison with Example 1, it can be verified that appropriate microneedle length and density are important for improving drug delivery efficiency.

[0158] Comparative Example 6 (for preparation process parameters)

[0159] This comparative example provides a method for preparing a jujube seed oil extract using supercritical CO2 extraction at a relatively low pressure and in a relatively short time. The other steps are the same as those in Example 2, but the conditions for supercritical CO2 extraction are as follows:

[0160] The pressure was 20 MPa, the temperature was 40 °C, the extraction time was 1.5 h, the CO2 flow rate was 15 L / h, the ultrasonic power density was 250 W / L, and the ultrasonic frequency was 18 kHz.

[0161] The components, weight parts and preparation method of the sleeping patch are the same as those in Example 2.

[0162] Preferably, in this comparative example, due to the relatively mild extraction conditions, the effective components may not be fully extracted, thus affecting the sedative effect of the final product. By comparison with Example 2, it can be demonstrated that the importance of optimized supercritical CO2 extraction process parameters for improving the quality of the jujube seed oil extract can be improved.

[0163] The above six comparative examples fully cover the core innovations of the present invention, including NLC encapsulation technology, microneedle array technology, synergistic effects of auxiliary components, and optimization of key process parameters. These comparative examples will help highlight the superiority of the present invention in improving drug stability, percutaneous absorption efficiency, and overall sedative effect, thereby strongly supporting the creativity of the present invention.

[0164] Next, the present invention will design a series of test experiments to evaluate the effectiveness of the present invention and provide detailed test results and analysis.

[0165] The evaluation experiment was designed as follows:

[0166] In order to comprehensively evaluate the performance of the sleep patch of the present invention, the following test experiments were designed:

[0167] 1. In vitro release experiment

[0168] Objective: To evaluate the release characteristics of jujube seed oil extract from sleep patches.

[0169] Methods: Franz diffusion cell method was used, pH 7.4 phosphate buffer was used as the receiving solution, and the release experiment was carried out at 37℃ for 24 hours. The cumulative release amount of jujuboside A was determined by high performance liquid chromatography (HPLC).

[0170] 2. In vitro percutaneous permeation test

[0171] Objective: To evaluate the transdermal permeability of jujube seed oil extract.

[0172] Methods: Ex vivo pig skin was used as a skin model, and the Franz diffusion cell method was used to conduct a permeation experiment at 37°C for 48 hours. The cumulative amount of jujuboside A that permeated the skin was determined by HPLC.

[0173] 3. Stability test

[0174] Objective: To evaluate the stability of sleep patches under different storage conditions.

[0175] Methods: The sleeping patches were stored at 25℃ / 60%RH and 40℃ / 75%RH for 6 months, and the content and appearance changes of jujuboside A were tested regularly.

[0176] 4. Adhesion test

[0177] Objective: To evaluate the adhesive properties of sleep patches.

[0178] Methods: The 90° peel test was used to test the adhesion strength of the sleep patch on the artificial skin.

[0179] 5. Evaluation of sedative and hypnotic effects (animal experiments)

[0180] Objective: To evaluate the sedative and hypnotic effects of sleep patches.

[0181] Methods: The spontaneous activity test and sodium pentobarbital-induced sleep test were conducted on mice to evaluate the inhibitory effect of the sleep patch on the activity of mice and its effect on the sleep latency and sleep time.

[0182] The experimental results are as follows:

[0183] Table 1. In vitro release test results (24-hour cumulative release rate, %)

[0184]

[0185] Table 2. In vitro percutaneous permeation test results (48-hour cumulative permeation, μg / cm²)

[0186]

[0187] Table 3. Stability test results (Jujuboside A content retention rate, %)

[0188]

[0189] Table 4. Adhesion test results (90° peel strength, N / 25mm)

[0190]

[0191] Table 5. Evaluation results of sedative and hypnotic effects

[0192]

[0193] The results and discussion are as follows:

[0194] 1. In vitro release characteristics: The sleep patches of Examples 1-4 showed ideal sustained release characteristics, with a 24-hour cumulative release rate between 85% and 93%. In contrast, Comparative Example 1 (without NLC encapsulation) showed a trend of rapid initial release, while Comparative Example 2 (without microneedle array) and Comparative Example 5 (short microneedles) showed a slower release rate. This shows that the synergistic effect of NLC encapsulation technology and microneedle array can achieve sustained and stable release of drugs.

[0195] 2. Transdermal permeation performance: The transdermal permeation performance of Examples 1-4 is significantly better than that of each comparative example. In particular, Example 3 has a cumulative permeation amount of 68.5 μg / cm² in 48 hours, which is 126.8% higher than that of Comparative Example 1 (without NLC encapsulation). This result fully demonstrates the significant advantages of NLC encapsulation technology combined with microneedle array in improving drug transdermal absorption.

[0196] 3. Stability: The NLC-encapsulated formulas (Examples 1-4) showed excellent stability under different storage conditions. In particular, under accelerated test conditions (40°C / 75%RH), the retention rate of jujuboside A after 6 months was still between 91-93%, much higher than that of Comparative Examples 1 and 4. This shows that NLC technology can effectively protect active ingredients and extend the shelf life of products.

[0197] 4. Adhesion: The adhesion performance of Examples 1-4 is better than that of most comparative examples, especially the peel strength of Example 3 reaches 3.3 N / 25 mm. This may be due to the fact that the NLC technology improves the rheological properties of the formula and enhances the interaction with the skin.

[0198] 5. Sedative and hypnotic effect: Examples 1-4 all showed significant effects in terms of autonomic activity inhibition, sleep latency reduction and sleep time extension, especially Example 3, all indicators were the best. This result verifies the excellent performance of the present invention in improving sleep quality.

[0199] Comprehensive analysis shows that Example 3 exhibits the best comprehensive performance and can be regarded as the best embodiment of the present invention.

[0200] The above description is only an embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent substitution, improvement, etc. made within the spirit and principle of the present invention should be included in the scope of the claims of the present invention.

Claims

1. A sleeping patch, characterized in that: The composition comprises the following components in parts by weight: 20-25 parts of NLC-encapsulated jujube seed oil extract; 12-15 parts of propylene glycol; 6-8 parts of polyvinylpyrrolidone K90; 4-6 parts of hydroxypropyl beta-cyclodextrin; 1-2 parts menthol; 0.5-1 part lavender essential oil; 1-2 parts of γ-aminobutyric acid; 1-2 parts glycine; Add to 100 parts of deionized water; The method for preparing the NLC-encapsulated jujube seed oil extract comprises the following steps: (1) Raw material pretreatment: vacuum drying the seeds of the Chinese date palm at 45-55°C for 10-14 hours to reduce the moisture content to 3-4%, and then crushing the dried seeds to 50-70 mesh at low temperature; (2) Ultrasonic-assisted supercritical CO2 extraction: The crushed spiny jujube kernel obtained in step (1) was extracted under the following conditions: pressure 28-32 MPa, temperature 42-48°C, extraction time 2.5-3.5 hours, CO2 flow rate 18-22 L / h, ultrasonic power density 300-400 W / L, and ultrasonic frequency 20-25 kHz; (3) Two-step molecular distillation purification: The crude extract obtained in step (2) is subjected to two-step molecular distillation purification, wherein the first step distillation temperature is 120-140°C, the vacuum degree is 0.5-1 Pa, and the distillation time is 20-30 minutes; the second step distillation temperature is 160-180°C, the vacuum degree is 0.1-0.3 Pa, and the distillation time is 40-60 minutes; (4) Nanolipid carrier NLC encapsulation: the purified jujube seed oil obtained in step (3) is mixed with solid fat and liquid fat in a weight ratio of 3:5:2, 10-15 parts by weight of a surfactant is added, and the mixture is stirred at 70-80° C., and then 40-50 parts by weight of deionized water is added, and the mixture is homogenized at 80-100 MPa using a high-pressure homogenizer for 8-10 times; (5) Freeze drying: the NLC suspension obtained in step (4) is mixed with 5-8 parts by weight of sodium alginate and 3-5 parts by weight of trehalose, and then freeze dried. The freeze drying conditions are pre-freezing temperature of -45°C for 5-7 hours, main drying temperature of -35°C to 20°C for 28-36 hours, and post-drying temperature of 25-30°C for 5-7 hours. The solid fat is stearic acid, and the liquid fat is medium chain triglyceride; The surfactant is a 1:1 mixture of polyoxyethylene castor oil 40 and soybean lecithin.

2. The sleeping patch according to claim 1, characterized in that: The preparation method of the sleeping patch comprises the following steps: (1) Dissolve polyvinyl pyrrolidone K90 in deionized water and stir evenly; (2) dissolving hydroxypropyl β-cyclodextrin, γ-aminobutyric acid and glycine in the solution obtained in step (1) and stirring evenly; (3) mixing propylene glycol, menthol and lavender essential oil, and then mixing with the solution obtained in step (2), and ultrasonically treating for 10-15 minutes; (4) slowly adding the NLC-encapsulated jujube seed oil extract to the mixture obtained in step (3), and stirring at a low speed at 40-45° C. for 2-3 hours; (5) evenly coating the mixture obtained in step (4) on the hydrogel substrate having the microneedle array, with the thickness controlled to be 0.8-1.2 mm; (6) Vacuum drying at 45-50° C. for 3-5 hours to obtain a sleeping patch.

3. The sleeping patch according to claim 2, characterized in that: The hydrogel substrate is polyacrylamide-sodium carboxymethyl cellulose cross-linked hydrogel.

4. The sleeping patch according to claim 2, characterized in that: The microneedle length of the microneedle array is 200-500 μm, and the microneedle density is 100-200 / cm².

5. The sleeping patch according to any one of claims 2 to 4, characterized in that: The sleeping patch also includes a layer of waterproof and breathable membrane.

6. The sleeping patch according to claim 5, characterized in that: The waterproof and breathable membrane is a polyurethane film or a polytetrafluoroethylene film.

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