A transdermal delivery composition acting on the peri-cranial region

Abstract

The present application belongs to the technical field of transdermal drug delivery, and particularly relates to a transdermal delivery composition acting on a pericranial region. The composition comprises a penetration enhancer unit, which comprises a base and microneedles distributed on the base, the height of the microneedles is 0.1-5000 microns, and the shape of the base and the distribution of the microneedles are suitable for adhering to the skin surface of the pericranial region; the penetration enhancer unit is configured to weaken the stratum corneum barrier; and a transdermal preparation containing at least one active substance, the dosage form of the transdermal preparation is configured to adhere to the skin surface of the pericranial region to facilitate the transdermal delivery of the active substance. The composition can effectively overcome the blood-brain barrier, improve the absorption speed of the active substance, and enhance the effective amount, so that the effect of the active substance is accurate, smooth and controllable.

Description

Technical Field

[0001] This invention belongs to the field of transdermal drug delivery technology, and particularly relates to a transdermal delivery composition that acts on the pericranial region. Background Technology

[0002] Neurological disorders (such as insomnia, Parkinson's disease, and Alzheimer's disease) have become a major global health challenge. Statistics show that approximately 300 million people worldwide suffer from sleep-related problems, with working professionals aged 25-45 and the elderly being the most affected. Chronic insomnia not only increases the risk of anxiety disorders but also affects daytime functioning and long-term health, evolving into a hidden health killer that impacts quality of life.

[0003] Limitations of drug delivery methods

[0004] In the clinical treatment of neurological diseases, drug therapy plays a central role. Currently, traditional drug delivery methods mainly rely on oral administration and injection, but these methods have limitations.

[0005] 1. Disadvantages of oral administration:

[0006] Low drug utilization: Orally administered drugs need to be absorbed through the gastrointestinal tract and metabolized by the liver first pass, with less than 5% of the drug actually reaching the brain;

[0007] Unstable drug efficacy: Blood drug concentration fluctuates greatly, peak concentration appears quickly but lasts for a short time, making it difficult to maintain a stable therapeutic effect;

[0008] First-pass effect in the liver, significant side effects: easily causes gastrointestinal reactions (nausea, vomiting, abdominal pain, etc.), and long-term use will burden liver and kidney function;

[0009] Poor adherence: Frequent and regular medication is required, and patients are prone to missing doses or interrupting treatment, especially elderly patients who have even lower adherence.

[0010] 2. Disadvantages of injection administration:

[0011] Traumatic: Requires professional medical personnel to operate, and brings pain and infection risks to patients;

[0012] Limited treatment frequency: Patients need to go to the hospital regularly for injections, which is complicated and costly.

[0013] Inconvenient for long-term medication: It is impossible to self-administer medication, which is inconvenient for patients with chronic diseases;

[0014] Psychological burden: The fear of needles piercing the skin causes some patients (especially children) to develop a resistance to the procedure.

[0015] Blood-brain barrier

[0016] Furthermore, the blood-brain barrier (BBB) ​​is a highly selective semi-permeable boundary between the central nervous system and the systemic circulation, which strictly regulates the exchange of substances between the blood and the central nervous system. Due to the presence of the BBB, more than 98% of small molecule drugs and almost 100% of large molecule drugs (such as proteins and monoclonal antibodies) cannot effectively pass through it, making it difficult for drugs to reach effective therapeutic concentrations in the brain.

[0017] In the treatment of neurological diseases, the challenges are even more severe for drugs that need to act on the central nervous system. The blood-brain barrier, naturally present in the brain, while protecting the central nervous system through its selective permeability mechanism, also blocks many therapeutic drugs, especially large-molecule biological agents. For example, only a very small percentage (less than 0.1%) of some intravenously injected antibody drugs can actually enter brain tissue to exert their effects, resulting in the vast majority of the drug being wasted and potentially causing systemic side effects.

[0018] In existing technologies, the main drug delivery pathways targeting BBB breakthrough include:

[0019] Nasal delivery: bypasses the BBB via the olfactory nerve pathway, but the drug is easily cleared by the nasal mucosa cilia, resulting in limited delivery efficiency;

[0020] Intracranial injection: This involves directly penetrating the skull to enter the brain (such as intracranial injection or stereotactic injection), but it is an invasive procedure with significant trauma and high risks.

[0021] Nanocarrier technology: It utilizes nanocarriers such as targeting peptides and liposomes to enhance BBB penetration, but the preparation is complex and the drug loading capacity is low.

[0022] Chemical penetration enhancers: These enhance skin permeability through surfactants and penetration enhancers, but their penetration-enhancing effect is limited and they can irritate the skin.

[0023] Insomnia

[0024] When it comes to improving sleep quality, patients face more complex needs:

[0025] 1. The need for controllability of onset time:

[0026] Users hope to fall asleep at the expected time (such as 10:00 PM) rather than passively waiting for the medication to take effect;

[0027] A rapid onset of action may cause side effects such as daytime drowsiness and difficulty concentrating in patients;

[0028] If it takes too long to work, it will not be able to meet the user's need to fall asleep within the expected time.

[0029] 2. The need for stable drug efficacy:

[0030] Traditional oral medications exhibit large fluctuations in blood drug concentrations, with significant differences between peak and trough levels;

[0031] Peak concentrations may cause excessive sedation, while trough concentrations may result in insufficient efficacy, leading to fluctuations in sleep quality.

[0032] Long-term use of drugs with fluctuating blood drug concentrations can easily lead to drug resistance or drug dependence.

[0033] 3. Comprehensive requirements for sleep quality:

[0034] Insomnia is not only manifested as difficulty falling asleep, but also includes sleep maintenance disorders, early awakening, and poor sleep quality;

[0035] A single mechanism of action (such as simple sedation) is insufficient to comprehensively improve sleep quality;

[0036] It requires multiple synergistic effects, such as regulating the biological clock, improving sleep structure, and prolonging deep sleep time.

[0037] 4. Long-term security requirements:

[0038] Long-term use of traditional sleeping pills (such as benzodiazepines) may cause side effects such as dependence, tolerance, and memory impairment.

[0039] Long-term, high-dose exogenous melatonin may suppress endogenous secretion rhythms and affect natural sleep regulation;

[0040] There is a need for a sleep aid solution that can be used safely in the long term, without addiction or tolerance.

[0041] 5. Individual differences in user status and environment:

[0042] Insomnia symptoms are affected by a variety of factors, including the user's mental state, stress level, physical exertion, and ambient temperature on the day.

[0043] Traditional fixed-dose dosing methods are difficult to adapt to individual differences;

[0044] There is a need for a dosing regimen that can be precisely adjusted based on the user's status and expected sleep time.

[0045] Taking the treatment of insomnia as an example, sedative-hypnotic drugs such as benzodiazepines are commonly used clinically. However, the efficacy of these traditional drugs varies significantly from person to person. Their onset time, intensity, and duration of action are severely affected by the patient's physical condition, mental state, and whether they have consumed stimulants such as caffeine or tea, making it difficult to achieve a stable and reliable sleep-inducing effect within the patient's expected precise time window. Patients may feel that the medication is "ineffective" due to insufficient dosage, short treatment duration, or insensitivity to the drug. More problematic is that long-term use may lead to drug tolerance, forcing patients to increase the dosage and thus exacerbating the risk of side effects. Common side effects include lingering drowsiness, dizziness, and headache the following day, severely affecting daytime cognitive and motor functions, reducing treatment comfort and patient compliance. Furthermore, the risk of adverse drug interactions during multidrug therapy should not be ignored.

[0046] In summary, existing drug treatments for neurological diseases are limited by the first-pass effect and the blood-brain barrier in terms of drug delivery routes, resulting in low utilization rates of active pharmaceutical ingredients. In specific applications, such as in the treatment of insomnia, they suffer from drawbacks such as uncontrollable onset time, large fluctuations in efficacy, poor user experience, and significant side effects with long-term use. Traditional drug delivery methods generally suffer from numerous problems, including low drug utilization, poor targeting, and difficulty in delivering effective doses to the lesion.

[0047] Therefore, there is an urgent need in this field to develop a new product or method that can improve drug delivery efficiency, especially to effectively overcome the blood-brain barrier, enhance the efficacy at the target site, control the speed and stability of drug delivery, and achieve precise control of onset time, stable efficacy, few side effects, and a comfortable user experience. Summary of the Invention

[0048] To address the technical problems of uncontrollable onset time of active ingredients, large fluctuations in efficacy, and significant side effects in existing technologies, this invention provides a transdermal delivery composition for use in the pericranial region. The composition comprises: a penetration-enhancing unit including a base and microneedles distributed on the base, the microneedles having a height of 0.1 to 5000 micrometers, and the shape of the base and the distribution of the microneedles being adapted to conform to the skin surface of the pericranial region; the penetration-enhancing unit being configured to weaken the stratum corneum barrier of the skin; and a transdermal formulation containing at least one active ingredient, the dosage form of which is configured to adhere to the skin surface of the pericranial region to facilitate transdermal delivery of the active ingredient.

[0049] The core features of the above technical solution are further explained below.

[0050] 1. Pericranial region: The pericranial region in this technical solution includes the scalp, forehead, periorbital area, nasal alae, cheeks, temporal region (temples), and back of the neck or cheekbone area. The skin surface of the pericranial region refers to the exposed skin surface of the above-mentioned locations, excluding the inside of the nasal cavity and ear canal.

[0051] 2. Microneedles: The height of the microneedles in this technical solution is 0.1 to 5000 micrometers, preferably 50 to 1000 micrometers, and more preferably 100 to 200 micrometers. The shape of the microneedles is conical, pyramidal, or blade-shaped, preferably conical. Conical shapes include cones and pyramids (such as square pyramids or octagonal pyramids). In this technical solution, the conical shape has a sharp top and the base can be set to any shape as needed; the cone shape has a circular base; the pyramidal shape has a polygonal base and triangular sides converging to a top. The material of the microneedles is selected from at least one of inorganic non-metallic materials (such as: single crystal silicon, glass, modified glass, ceramics), metallic materials (such as: titanium alloys), and polymer materials, preferably single crystal silicon.

[0052] 3. Base Shape: In this technical solution, the base shape is selected from at least one of rectangular, elliptical, arc-shaped, circular, and polygonal shapes, preferably rectangular or elliptical. The base shape is selected from planar or curved convex shapes. When the base is curved convex, the microneedles are distributed on one side of the convex surface. The base material is selected from at least one of inorganic non-metallic materials (such as: monocrystalline silicon, glass, modified glass, ceramics), metallic materials (such as: titanium alloys), polymer materials, silicone, polyurethane, polylactic acid, and hyaluronic acid, preferably monocrystalline silicon. Through regional adaptive design, the base can conform to the complex curved surface of the pericranial region, ensuring uniform contact between the microneedle array and the skin surface, improving puncture efficiency and user experience.

[0053] 4. Reciprocating action: The reciprocating action (or reciprocating motion, reciprocating movement, reciprocating unblocking, etc.) in this technical solution refers to the repeated action of the penetration enhancement unit on the skin surface within a certain range. Specifically, it includes longitudinal reciprocating vibration perpendicular to the skin surface, lateral left and right swinging along the skin surface, combinations of the above lateral and longitudinal movements, or other forms of movement such as circular massage.

[0054] The transdermal delivery composition for the pericranial region in this invention has the following innovative features:

[0055] 1) The site of action is specific. This invention selects the pericranial region (including the scalp, forehead, periorbital area, nasal alae, cheek, temporal region (temples), back of the neck, or zygomatic region) as the site of action, enabling the active ingredient to effectively overcome the key physiological barrier of the blood-brain barrier, significantly improving the targeted delivery efficiency of the active ingredient to the brain. This shortens the onset time and reduces the total amount of active ingredient used. Simultaneously, the active ingredient continuously penetrates the body transdermally, achieving stable and continuous drug administration, maintaining a stable blood drug concentration, and resulting in a mild and long-lasting effect.

[0056] 2) Microneedles made of high-strength materials such as monocrystalline silicon have higher puncture strength and more stable structure compared to hollow microneedles or soluble microneedle patches. This avoids the risk of needle breakage and skin damage, ensuring stable and safe application and providing a solid physical basis for subsequent active ingredient delivery.

[0057] 3) The permeation-enhancing unit and the transdermal formulation in this composition can be used in separate steps. The permeation-enhancing unit can be flexibly matched according to the characteristics of the active ingredient (molecular weight, lipid solubility) to meet the delivery needs of various neurological diseases and cosmetic applications.

[0058] The combination of the above innovations can lead to numerous technological advancements: increasing the delivery speed of active ingredients, thereby shortening the onset time; increasing the absorption of active ingredients, thereby reducing the total amount of active ingredients used and reducing side effects; improving the precision of active ingredients, making the onset time more accurate, stable, and controllable; and reducing operational difficulty and user resistance.

[0059] When using this composition, the permeation-enhancing unit needs to be operated to vibrate back and forth, swing left and right, or move in three dimensions on the skin surface. The microneedles weaken the stratum corneum barrier on the skin surface of the pericranial region, allowing the active ingredients to be delivered transdermally into the body.

[0060] The above technical solution will be further optimized and improved below.

[0061] Automatic reciprocating unblocking and delivery function: To further improve user operation convenience and the stability and uniformity of active ingredient delivery, the above technical solution is further improved as follows. The improved composition also includes a driving device configured to drive the penetration-enhancing unit to reciprocate on the skin surface; and a control unit configured to control the driving device to generate a reciprocating motion at a specific frequency. In this improved technical solution, the driving device maintains a specific frequency, driving the penetration-enhancing unit to form a controllable microneedle reciprocating motion on the skin surface. This automatic reciprocating unblocking mechanism can stabilize and control the degree of weakening of the stratum corneum barrier, and the delivery efficiency of the active ingredient can also remain stable and controllable during each user operation. It should be noted that the reciprocating action (reciprocating motion) in this technical solution refers to the penetration-enhancing unit repeatedly acting on the skin surface within a certain amplitude. Specifically, this includes the driving device driving the penetration-enhancing unit to perform longitudinal reciprocating vibration perpendicular to the skin surface, lateral left and right swinging along the skin surface, combinations of the above lateral and longitudinal movements, or other forms of movement such as circular massage.

[0062] The specific vibration frequency range is from 1000 vibrations per minute to 18000 vibrations per minute (i.e., 16.67 Hz to 300 Hz). Preferably, it is 3500 vibrations per minute to 6000 vibrations per minute, and optionally, 4000 vibrations per minute or 5000 vibrations per minute. This specific vibration frequency range can be adjusted according to different skin types, ages, and active ingredient characteristics to achieve an optimal balance between unblocking effect and comfort, effectively improving the user experience.

[0063] Controllable Onset Time Mechanism: In the above technical solution, the starting time point at which the active ingredient exerts its effect is defined as the expected target time point. The transdermal formulation is configured to be administered 0.5 to 1 hour before the expected target time point to achieve precise and controllable intervention of the active ingredient. For example, for insomnia treatment, the expected target time point is 22:00 to 23:00. By administering the transdermal formulation 0.5 to 1 hour before the expected target time point, an effective concentration can be reached at the expected target time point, achieving precise and controllable onset time.

[0064] This technical solution overcomes the blood-brain barrier and shortens the onset time of the active ingredient. Transdermal delivery provides a stable, controllable, and continuous delivery of the active ingredient to the brain. Through a time-effect synergistic mechanism, this solution ensures that the active ingredient reaches an effective concentration when the user needs it, avoiding both premature onset (leading to daytime drowsiness) and delayed onset (failing to meet the expected sleep onset requirements).

[0065] Dosage Form Optimization: The transdermal formulation is available in the form of a patch, ointment, cream, gel, liniment, lotion, spray, film, paste, or powder. The dosage form is configured to adhere to the skin surface of the pericranial region to facilitate transdermal delivery of the active ingredient. Patches offer advantages such as ease of use and stable release of the active ingredient; gels provide good adhesion and biocompatibility; creams are easy to apply and absorb; liquids are suitable for rapid release; liniments are suitable for large-area application; and powders are suitable for personalized formulation.

[0066] This technical solution has a wide range of applications; some typical scenarios are listed below.

[0067] One application area is to enhance the delivery efficiency and controllability of sleep-aiding active ingredients. In this application area, the active ingredient is selected from at least one of γ-aminobutyric acid (GABA), melatonin, valerian extract, passionflower extract, lemon balm extract, theanine, and 5-hydroxytryptophan (5-HTP).

[0068] These active ingredients are mostly natural / plant extracts, making them convenient for users to use at home. Compared to current insomnia treatments, this technology systematically integrates a transdermal formulation containing specific sleep-aiding active ingredients with a physical penetration-enhancing unit featuring a microneedle array. This solves problems such as low bioavailability, large fluctuations in blood drug concentration, first-pass effect in the liver, and gastrointestinal irritation associated with traditional oral sleep aids. The system weakens the stratum corneum barrier through the microneedle structure of the penetration-enhancing unit, significantly improving the transdermal absorption efficiency of the sleep-aiding active ingredients, effectively shortening sleep onset time, significantly reducing dosage, achieving a more stable and sustained blood drug concentration, and reducing nighttime awakenings.

[0069] The transdermal formulation in this technology can be made into various dosage forms such as patches, ointments, liquids, liniments, and powders, allowing users to administer the medication themselves. The process is simple and can significantly improve patient adherence, making it particularly suitable for chronic insomnia patients requiring long-term medication. Furthermore, this technology offers high flexibility; users or healthcare professionals can flexibly select and load different types or dosages of sleep-aiding active ingredients based on the specific type of insomnia (e.g., difficulty falling asleep, sleep maintenance disorder) and individual differences, achieving precise and personalized treatment.

[0070] In use, a drive device controls the microneedle array to perform reciprocating puncture movements on the target skin area at a specific frequency (e.g., 4500 times per minute). This reciprocating puncture motion creates numerous temporary micron-sized physical channels on the skin surface, especially in the thinner perianal area, significantly weakening the skin's stratum corneum barrier function. Subsequently, a transdermal formulation (such as a gel, cream, or liquid) containing sleep-aiding active ingredients such as melatonin and gamma-aminobutyric acid (GABA) is directly applied or patched onto the pretreated skin area. At this point, the active ingredients can directly enter the dermis through the microchannels created by the microneedles, bypassing the blood-brain barrier to reach the target and produce an effect.

[0071] Preferably, the content of γ-aminobutyric acid (GABA) in the transdermal formulation is 1% to 20%.

[0072] Preferably, the melatonin content in the transdermal formulation is 0.1% to 5%.

[0073] Preferably, the content of plant extract (on dry weight) in the transdermal formulation is 1% to 15%.

[0074] Preferably, the theanine content in the transdermal preparation is 0.5% to 10%.

[0075] Preferably, the content of 5-hydroxytryptophan (5-HTP) in the transdermal formulation is 0.5% to 5%.

[0076] In addition, the active ingredient in this technical solution may also be selected from at least one of diazepam, alprazolam, lorazepam, zolpidem, eszopiclone, zopiclone, ramelteon, tasimelteon, suvorexant, and leemborexant.

[0077] These active ingredients are mostly chemically synthesized, facilitating targeted care for different types of insomnia, resulting in highly efficient and precise sleep aid. The technical effects of this composition are multifaceted. First, in terms of delivery efficiency, because the active ingredients completely bypass gastrointestinal digestion and the liver's "first-pass effect," their bioavailability is significantly improved. This means that only a much lower dose than oral administration is needed to achieve and maintain an effective therapeutic concentration at the target site, achieving the goal of small and precisely controllable dosage. Second, regarding onset and mechanism of action, the active ingredients overcome the blood-brain barrier, enabling faster distribution to the target site and helping to shorten the onset time. Simultaneously, by selecting appropriate dosage forms (such as sustained-release gels or patches), a stable and continuous release of the active ingredients can be achieved, making the blood drug concentration curve closer to the body's natural secretion rhythm, thereby effectively maintaining sleep throughout the night and reducing nighttime awakenings, especially suitable for insomnia caused by sleep maintenance disorders. Furthermore, in terms of safety, this technical solution fundamentally avoids the hepatic metabolic burden, gastrointestinal irritation, and side effects such as drowsiness and headaches the following day caused by "sudden rises and falls" in blood drug concentration caused by oral administration. Furthermore, selecting the drug delivery site in areas with thinner skin, such as around the eyes, and close to the central nervous system effectively shortens the action distance of the active ingredient, providing a certain locational advantage for its distribution. Finally, the entire system is easy to operate, with high user compliance; the microneedle puncture process is virtually painless; and by controlling the parameters of the driving device (such as frequency and duration of action), the degree of skin barrier weakening can be quantitatively controlled, thus providing a technical basis for personalized and precise drug delivery protocols.

[0078] The transdermal formulation in this composition is preferably a patch, and the content of the active ingredient can be selected from the following ranges.

[0079] Preferably, the transdermal formulation has a drug loading of diazepam per unit area of ​​1 to 40 mg / cm².

[0080] Preferably, the alprazolam loading per unit area in the transdermal formulation is 0.5 to 20 mg / cm².

[0081] Preferably, the drug loading of lorazepam in the transdermal formulation is 0.4 to 16 mg / cm².

[0082] Preferably, the amount of zolpidem loaded per unit area in the transdermal formulation is 0.8 to 30 mg / cm².

[0083] Preferably, the drug loading per unit area of ​​eszopiclone in the transdermal formulation is 0.6 to 24 mg / cm².

[0084] Preferably, the amount of zopiclone loaded per unit area in the transdermal formulation is 0.6 to 24 mg / cm².

[0085] Preferably, the transdermal formulation has a drug loading of ramelteon per unit area of ​​0.3 to 12 mg / cm².

[0086] Preferably, the drug loading per unit area of ​​tasimelteon in the transdermal formulation is 0.4 to 16 mg / cm².

[0087] Preferably, the amount of Suvorexant loaded per unit area in the transdermal formulation is 1 to 40 mg / cm².

[0088] Preferably, the drug loading per unit area of ​​Lemborexant in the transdermal formulation is 1.2 to 44 mg / cm².

[0089] Furthermore, this technical solution can also be used to enhance the effect of eye area skin care, expanding its application potential in the field of skin care. Regarding enhancing the effect of eye area skin care, the active ingredient can be at least one of vitamin K, caffeine, horse chestnut extract, chamomile extract, and daisy extract, used to enhance the improvement of vascular dark circles under the eyes.

[0090] The active ingredients also include at least one of vitamin B3, licorice root extract, arbutin, vitamin C derivative, and Thiamidol, for enhancing the improvement of pigmented dark circles under the eyes.

[0091] The active ingredient also includes at least one of caffeine, peptides, vitamin K, and plant extracts, for enhancing the improvement of structural dark circles under the eyes.

[0092] The active ingredients also include at least one of retinol and its derivatives, hyaluronic acid, polypeptides, and compound plant extracts, for enhancing the overall improvement of skin problems around the eyes.

[0093] The active ingredients also include at least one of the following: sea buckthorn leaf extract, caffeine, acetyl hexapeptide-8, boswellic acid, complex peptides, and plant extracts, for enhancing the improvement of eye bag problems.

[0094] The active ingredient also includes at least one of retinol, retinoic acid derivatives, acetyl hexapeptide-8, palmitoyl tetrapeptide-7, conopeptide, hexapeptide, palmitoyl pentapeptide, L-ascorbic acid, vitamin C derivatives, and trifluoroacetyl isobutylamino dipeptide-42, for enhancing the improvement of skin wrinkles.

[0095] The active ingredients may also include plant extracts, such as valerian extract, passionflower extract, lemon balm extract, jujube seed extract, ganoderma extract, schisandra extract, polygonum multiflorum vine extract, polygala extract, paeonol, chamomile extract, ashwagandha extract, hops extract, lavender oil, sandalwood oil, neroli oil, and bergamot oil.

[0096] The active ingredients may also include minerals and small molecules, such as magnesium (magnesium glycine, magnesium citrate), vitamin B6, vitamin B12, folic acid, and adenosine.

[0097] The active ingredients may also include neurotransmitter / receptor regulatory active ingredients, such as γ-aminobutyric acid (GABA), L-theanine, zolpidem, eszopiclone, zaleplon, leemborexant, suvorexant, melatonin, L-tryptophan, 5-hydroxytryptophan (5-HTP), doxylamine succinate, diphenhydramine HCl, doxepin, and gabapentin.

[0098] The compositions of this invention enable the direct and efficient delivery of the aforementioned active ingredients to the target skin layer, reducing the distribution of the active ingredient in non-target areas and lowering the risk of irritation to sensitive skin around the eyes. Using this technical solution can improve the utilization rate of the active ingredient and reduce its consumption. Detailed Implementation

[0099] This technical solution aims to provide a transdermal delivery composition for the pericranial region. The microneedles and active ingredient work synergistically to deliver the active ingredient from a specific area to overcome the blood-brain barrier, thereby enhancing the absorption efficiency of the active ingredient and achieving control over its absorption rate and stability. The technical solution is further illustrated below with some embodiments, but the scope of protection of this invention is not limited to these embodiments.

[0100] Example 1

[0101] This embodiment provides a transdermal delivery composition for use in the pericranial region, comprising:

[0102] The infiltration unit includes a rectangular monocrystalline silicon substrate and an array of solid monocrystalline silicon microneedles distributed on the substrate. The microneedles are pyramidal in shape, with a height of 100 micrometers and an array density of 473 microneedles per square centimeter. The monocrystalline silicon microneedles are fabricated using 3D photolithography etching technology to form a 100-micrometer-high array of microneedles on the silicon substrate.

[0103] The drive unit, including a miniature vibration motor, is configured to generate 5,000 reciprocating motions per minute.

[0104] This transdermal formulation is a gel containing γ-aminobutyric acid (GABA) as the active ingredient. The GABA content is 10% (100 mg), the sodium hyaluronate content is 2%, and purified water is the balance. Preparation of the transdermal formulation: Dissolve sodium hyaluronate in purified water to form a 2% solution, and stir for 2 hours until completely dissolved; add GABA powder to the sodium hyaluronate solution to a final concentration of 10%, and stir for 30 minutes until uniformly dispersed; fill the gel into aluminum-plastic bags, each bag containing 100 mg of GABA, and seal the packaging.

[0105] The base is shaped to fit the skin surface of the temporal region, which is the skin surface above the ear and in the projection area of ​​the temporal bone, including areas such as the temples.

[0106] Experimental protocol

[0107] 1. Experimental Objective This study aims to evaluate the efficacy, safety, and advantages (such as onset speed and duration of action) of a combination of "microneedle penetration enhancement + GABA transdermal gel" acting on the temporal region in improving sleep quality in insomnia patients compared with traditional oral medications.

[0108] 2. Experimental Design

[0109] Participants: Ninety adult patients aged 18-65 years who met the diagnostic criteria for insomnia disorder according to the International Classification of Sleep Disorders (ICSD-3) were recruited. They were randomly assigned to three groups of 30 each.

[0110] Grouping and Intervention:

[0111] Experimental group: Microneedle penetration enhancement + 10% GABA transdermal gel.

[0112] Positive control group: Oral administration of equal doses of GABA tablets, containing 100 mg GABA per dose.

[0113] Blank control group: Microneedle-enhanced transdermal gel (containing only matrix: 2% sodium hyaluronate solution) without GABA. The transdermal gels (containing the drug / blank) had the same appearance and odor.

[0114] Test equipment: A medical-grade polysomnography (PSG) device or a high-precision wearable sleep monitor of the same model. Wearable sleep monitoring instruments, such as Huawei smartwatches or Apple watches of the same model, are also acceptable.

[0115] 3. Active ingredient delivery methods

[0116] The user used the active ingredient at 9:30 PM, with the expected target time being 10:00 PM.

[0117] Procedures for the experimental group and the blank control group:

[0118] • Step 1: Clean the skin in the temporal area (temples and above the ears) with a cotton ball soaked in medical alcohol and wait for the alcohol to evaporate.

[0119] • Step 2: Place the penetration enhancement unit onto the temporal region, turn on the drive device, and control the penetration enhancement unit to perform vertical reciprocating dredging on the skin for 30 seconds, with a specific vibration frequency of 5000 times / minute.

[0120] • Step 3: Turn off the drive unit and remove the permeation unit.

[0121] • Step 4: Immediately apply the transdermal preparation (gel) to the unblocked area and spread it evenly.

[0122] Positive control group: Oral administration of equal doses of GABA tablets.

[0123] 4. Experimental Procedure and Observation Time Points The total cycle is 4 weeks, as detailed below:

[0124] Baseline period (W0, one week before medication): All subjects received no intervention and only used sleep diaries and wearable devices to record baseline sleep data.

[0125] Treatment period (W1, one week of medication): Each group received the designated intervention, administered at a fixed time each day for 7 consecutive days. Sleep data were continuously recorded.

[0126] Washout / follow-up period (W2, one week after the end): Stop all interventions and observe whether the efficacy continues or rebounds.

[0127] Reassessment period (W3, one week after intervention): In the second week after intervention is discontinued, sleep status is reassessed to examine long-term effects.

[0128] 5. Key evaluation indicators (measured using a standardized wearable sleep monitoring device)

[0129] Sleep latency period;

[0130] Total sleep duration;

[0131] Percentage of deep sleep (N3 stage);

[0132] Number of times you wake up at night.

[0133] 6. Data and Results

[0134]

[0135] 7. Data Analysis

[0136] The above experimental data show that, compared with oral GABA and the blank control, the "microneedle penetration enhancer + GABA transdermal gel" combination acting on the temporal region exhibits significant and comprehensive superiority in all core indicators of improving insomnia. Specifically, it is reflected in:

[0137] Significantly faster onset of sleep: During the treatment period (W1), the sleep latency was shortened by 60% (from 45 minutes to 18 minutes), a much greater improvement than that in the oral group (32%) and the blank group (19%).

[0138] Sleep duration and structure optimization: Total sleep duration increased by 29% (to 7.5 hours), and the proportion of deep sleep increased significantly by 115% (from 13% to 28%). Both of these indicators were significantly better than the control group.

[0139] Improved sleep continuity: The number of nighttime awakenings decreased by 60% (from 5 to 2), indicating improved sleep maintenance.

[0140] The therapeutic effect was sustained: During the washout period (W2) and reassessment period (W3) after the intervention was stopped, most indicators in the experimental group (such as sleep latency and total sleep duration) declined slightly, but were still significantly better than the baseline period and better than the other two groups at the same time, suggesting that the therapeutic effect had good sustainability rather than an immediate rebound.

[0141] In summary, the "microneedle penetration enhancer + GABA transdermal gel" composition acting on the temporal region in this embodiment can significantly enhance the absorption efficiency of the active ingredient and shorten the onset time; at the same time, it has a longer duration of efficacy.

[0142] Example 2

[0143] This embodiment provides a transdermal delivery composition for use in the pericranial region, comprising:

[0144] The permeation-enhancing unit includes an arc-shaped base and an array of solid stainless steel microneedles distributed on the base. The microneedles are blade-shaped, with a height of 100 micrometers and an array density of 473 microneedles per square centimeter.

[0145] The drive unit, including a miniature vibration motor, is configured to generate 4,000 reciprocating motions per minute.

[0146] Transdermal formulation: a melatonin gel, each 1g gel contains 2.0mg of melatonin.

[0147] The base is shaped to fit the skin surface of the eye and cheekbone areas.

[0148] Experimental protocol

[0149] 1. Experimental Objective

[0150] This study aims to evaluate the comprehensive advantages of microneedle-melatonin compositions acting on the periorbital and zygomatic regions compared with traditional oral melatonin formulations in improving sleep quality, onset speed, duration of action, and reducing side effects such as next-day drowsiness in patients with anxiety-induced insomnia.

[0151] 2. Experimental Design

[0152] Subjects: Ninety adult patients aged 18-60 years who met the diagnostic criteria for comorbid anxiety disorder and insomnia according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) were recruited. Patients with allergies to benzodiazepines, a history of drug abuse, or severe liver or kidney dysfunction were excluded.

[0153] Grouping and Intervention (randomly divided into 3 groups, 30 people in each group):

[0154] Experimental group: Microneedle penetration enhancement + melatonin transdermal gel (one gel was applied to each of the bilateral target areas, each containing 2.0 mg of melatonin).

[0155] Positive control group: Oral administration of the same dose of melatonin tablets, containing 4mg of melatonin per dose.

[0156] Blank control group: microneedle penetration enhancement + blank gel matrix without melatonin (the composition is the same as the experimental group gel, except that it does not contain melatonin).

[0157] Testing equipment: A medical-grade polysomnography (PSG) device or a high-precision wearable sleep monitor of the same model, or a wearable sleep monitoring instrument, such as a Huawei smartwatch or Apple Watch of the same model; used for objective sleep index collection; and the Insomnia Severity Index (ISI) is used for subjective assessment.

[0158] 3. Active ingredient delivery methods

[0159] The intervention was performed 30 minutes before bedtime each night.

[0160] Procedures for the experimental group and the blank control group:

[0161] • Cleansing: Use a gentle cleansing product to cleanse the skin around the eyes and cheekbones (from the outer corner of the eyebrow to the outer corner of the eye, and the bony area around the eye socket), then wipe with sterile saline-soaked cotton pads and let it air dry.

[0162] • Administration: Take a measured amount of melatonin gel or blank gel and apply it evenly to the area around the eyes and cheekbones on both sides.

[0163] • Penetration Enhancement: Immediately use the drive unit to control the penetration enhancement unit to repeatedly touch the skin surface where the gel is applied, apply gentle vertical pressure and hold for 5 seconds.

[0164] Positive control group: Oral administration of the same dose of melatonin tablets.

[0165] 4. Experimental Procedure and Observation Time Points

[0166] The total cycle is 4 weeks, including:

[0167] Baseline period (W0): One week after enrollment, no medication intervention was administered, and baseline sleep and anxiety data were recorded.

[0168] Treatment period (W1-W2): 14 consecutive days of intervention, performed at a fixed time each evening.

[0169] Washout / follow-up period (W3): All interventions are discontinued, and the persistence of efficacy and withdrawal response are observed.

[0170] Treatment efficacy reassessment period (W4): The second week after the intervention is discontinued, a reassessment is conducted.

[0171] 5. Key Evaluation Indicators

[0172] Objective sleep indicators (PSG / wearable devices): sleep latency, total sleep duration, and percentage of deep sleep (N3 stage).

[0173] Subjective scale score: Insomnia Severity Index (ISI) total score.

[0174] Safety indicator: Sleepiness level the following morning (Visual Analogue Scale, VAS).

[0175] 6. Data and Results

[0176]

[0177] 7. Data Analysis

[0178] The experimental data above show that, compared with traditional oral administration, the microneedle-melatonin combination acting on the periorbital and zygomatic regions can effectively shorten the sleep latency, reduce drug efficacy fluctuations, maintain a stable and sustained effect, and reduce side effects.

[0179] The experimental data above showed that the sleep latency in the experimental group was shortened by 60%, far superior to the 31% in the oral administration group. This is attributed to the fact that microneedling technology instantly weakens the skin's stratum corneum barrier through physical means, allowing the melatonin gel to bypass the gastrointestinal absorption and first-pass metabolism processes required for oral administration. The active ingredients directly overcome the blood-brain barrier and diffuse rapidly, achieving a rapid onset of action. Its advantage in shortening sleep latency is extremely prominent, which is of great significance for patients with insomnia who have difficulty falling asleep.

[0180] Meanwhile, the experimental group experienced a 20% improvement in sleep efficiency and a significant reduction in nighttime awakenings. The composition, acting on a specific site, achieved continuous and controllable release of the active ingredient, avoiding the "peak-trough" fluctuations in blood drug concentration that occur after oral administration, characterized by a rapid rise followed by a rapid fall. This stable delivery of the active ingredient effectively reduced sleep interruptions caused by nighttime drops in blood drug concentration, ensuring the continuity of sleep throughout the night.

[0181] Furthermore, during the washout period (W3) after intervention cessation, although the sleep indicators (such as sleep latency and sleep efficiency) in the experimental group slightly decreased, they were still significantly better than those in the baseline period and the oral group at the same time, indicating that its efficacy has better sustainability. Meanwhile, the second-day sleepiness score in the experimental group (3.0) was significantly lower than that in the oral group (5.5). This suggests that this combination not only prolongs the effective duration of action but also avoids the excessive sedation and sleepiness side effects caused by excessively high peak blood drug concentrations after oral administration, thereby improving both efficacy and medication safety and daytime quality of life.

[0182] Potential synergistic effects of targeted drug delivery: Selecting the periorbital and zygomatic regions, which are rich in nerves and acupoints, can not only overcome the blood-brain barrier and improve the absorption efficiency of active ingredients, but also produce a calming and soothing effect similar to acupuncture through the slight physical stimulation of microneedles.

[0183] In summary, this embodiment, through the innovative combination of microneedles and melatonin active ingredients for targeted drug delivery in the periorbital and zygomatic regions, can effectively improve the speed and stability of transdermal absorption of the active ingredients.

[0184] Example 3

[0185] This embodiment provides a transdermal delivery composition for use in the pericranial region, comprising:

[0186] The permeation unit includes a circular base and an array of solid monocrystalline silicon microneedles distributed on the base. The microneedles are cone-shaped, with a height of 100 micrometers and an array density of 500 microneedles per square centimeter.

[0187] The drive unit, including a miniature vibration motor, is configured to generate 4,000 reciprocating motions per minute.

[0188] Transdermal preparation: Diazepam patch. Contains 2.5 mg of diazepam per patch.

[0189] The base is shaped to fit the skin surface of the temples and the area around the eyes, including the recessed area between the outer edge of the eye socket and the front edge of the ear.

[0190] Experimental protocol

[0191] 1. Experimental Objective

[0192] This study aims to evaluate the improvement of microneedle-diazepam combination applied to the temple and periocular area in terms of controllability, predictability, and stability of sleep onset time in insomnia patients compared to traditional oral diazepam formulations.

[0193] 2. Experimental Design

[0194] Subjects: Ninety adult patients (aged 18-50 years) diagnosed with "difficulty falling asleep type insomnia" were recruited. Key inclusion criteria: Based on baseline monitoring during the first week, their natural sleep latency was consistently greater than 45 minutes, with a daily fluctuation (standard deviation) greater than 15 minutes.

[0195] Grouping: Divided into 3 groups, with 30 people in each group.

[0196] Experimental group: 400μm single crystal silicon microneedle pretreatment + diazepam transdermal patch (one patch on each temple).

[0197] Positive control group: Oral administration of equal doses of diazepam tablets, containing 5 mg of diazepam.

[0198] Blank control group: 400μm monocrystalline silicon microneedle pretreatment + placebo transdermal patch (excluding diazepam, other components are the same as the experimental group patch).

[0199] Testing equipment: A medical-grade polysomnography (PSG) device of the same model or a high-precision wearable sleep monitor.

[0200] 3. Active ingredient delivery methods

[0201] The intervention was performed 30 minutes before bedtime each night.

[0202] Procedures for the experimental group and the blank control group:

[0203] • Cleansing: Use a gentle cleansing product to wash the skin around the temples and eyes, then wipe with sterile saline-soaked cotton pads and let it air dry.

[0204] • Penetration Enhancement: The drive unit controls the penetration enhancement unit to reciprocate horizontally and vertically on the skin surface of the target area, and vertically press and lift for 10 seconds to promote penetration.

[0205] • Administration: Apply diazepam patch or placebo patch to the temples and periorbital area after microneedling pretreatment. Leave the patch on until the following morning.

[0206] Positive control group: Oral administration of equal doses of diazepam tablets.

[0207] 4. Experimental Procedure and Observation Time Points

[0208] Baseline period (W1): lasting 1 week. Without any drug or device intervention, subjects wore only a high-precision wearable sleep monitor (such as an EEG-based sleep headband) to record their daily natural sleep latency to assess their inherent variability in sleep latency.

[0209] Treatment period (W2): lasting 1 week. Each group received the designated intervention at a fixed time each night (e.g., 22:30).

[0210] Washout period (W3): lasts for 1 week. All interventions are discontinued, and the monitor is continued to be worn to observe natural changes in sleep latency, assess the persistence of efficacy, and whether the baseline fluctuation pattern has returned.

[0211] 5. Key evaluation indicators (measured using a standardized wearable sleep monitoring device)

[0212] Mean sleep latency ± standard deviation (minutes).

[0213] 6. Data and Results

[0214]

[0215] 7. Data Analysis

[0216] The experimental data above show that, compared with oral diazepam and the blank control group, the microneedle-diazepam combination applied to the temples and periocular area can release the active ingredient in a slow and controlled manner, achieving precise and stable control of the time to fall asleep.

[0217] The data from the experimental group during the treatment period (sleep latency of 31±4 minutes) provides strong evidence for "precise and controllable" results. For example, if a user wants to fall asleep at the target time T, a simple procedure of "microneedle pretreatment + patch application" 30 minutes after T can reliably control the sleep onset time to near the target time, much like setting an alarm clock. The small standard deviation (±4 minutes) in the experimental data indicates that this effect is highly reproducible across different individuals and nights. This experiment demonstrates that the "microneedle + patch" regimen can provide a highly stable and reproducible sleep-inducing effect, addressing the biggest clinical challenge of oral therapies—the unpredictability of efficacy.

[0218] Traditional oral diazepam is significantly affected by gastrointestinal absorption differences and the first-pass effect in the liver, resulting in slow peak plasma concentration and large fluctuations, leading to unpredictable clinical effects (oral group data: 43±16 minutes). In contrast, this regimen uses microneedles to physically enhance penetration and instantly open transdermal channels, allowing the active ingredient to directly enter the circulation and avoiding the first-pass effect; at the same time, the sustained-release design of the patch ensures a more stable release of the active ingredient.

[0219] In summary, this experiment quantitatively verified, from two dimensions—"mean value close to the target" and "minimal fluctuation range"—that the microneedle-diazepam combination applied to the temples and periocular area has significant advantages over traditional oral administration in addressing the clinical pain point of uncontrollable sleep onset time.

[0220] It should be noted that, depending on the type and content of the active ingredient, the composition in this embodiment can be applied between 0.5 h and 1 h before the expected target time point to achieve precise control over the time to fall asleep.

[0221] Example 4

[0222] This embodiment provides a transdermal delivery composition for use in the pericranial region, comprising:

[0223] The permeation-enhancing unit includes an arc-shaped base and an array of solid monocrystalline silicon microneedles distributed on the base. The microneedles are conical in shape, with a height of 100 micrometers and an array density of 473 microneedles per square centimeter. The base material contains hyaluronic acid.

[0224] The drive unit, including a miniature vibration motor, is configured to generate 3,500 reciprocating motions per minute.

[0225] Transdermal formulation: Rametamide patch, patch size 4cm², each patch contains 2mg / cm² of rametamide.

[0226] The base is shaped to fit the skin surface of the nasal alar area on both sides.

[0227] Experimental protocol

[0228] 1. Experimental Objective

[0229] This study aimed to evaluate the advantages of a microneedle-ramelteamide composition acting on the nasal ala compared to conventional oral medication in improving sleep onset speed, sleep stability (reducing nighttime awakenings), and overall predictability of therapeutic efficacy in insomnia patients. The focus was on validating that the nasal ala-acting composition could overcome the blood-brain barrier, achieving faster and more stable delivery of the active ingredient.

[0230] 2. Experimental Design

[0231] Subjects: Ninety adult patients (aged 18-50 years) meeting the DSM-5 diagnostic criteria for "chronic insomnia disorder - difficulty falling asleep" were recruited. Key inclusion criteria: Based on baseline monitoring during the first week, their natural sleep latency was consistently greater than 45 minutes, and they had an average of ≥2 awakenings per night.

[0232] Grouping: The participants were randomly and single-blindly divided into 3 groups of 30 people each.

[0233] Experimental group: Microneedling pretreatment of the skin on both sides of the nose + application of rameltein gel.

[0234] Hand control group: Microneedling pretreatment of the skin on the inner forearm of the hand + application of rameltein gel.

[0235] Oral control group: Oral administration of an equal dose of ramelteamide tablets (8 mg).

[0236] Testing equipment: A medical-grade polysomnography (PSG) device of the same model or a high-precision wearable sleep monitor (capable of accurately monitoring sleep latency, number of awakenings, and sleep stages).

[0237] 3. Formulation and Delivery Methods

[0238] Users perform this 30 minutes before bedtime each night:

[0239] Procedures for the experimental group and the hand control group:

[0240] • Cleansing: Use a gentle cleansing product to wash the skin on both sides of the nose or the skin on the hands, then wipe with sterile saline cotton pads and let it air dry.

[0241] • Administration: Take a measured amount of ramelteamide gel and apply it evenly to the skin on both sides of the nose or the skin area of ​​the hand.

[0242] • Penetration Enhancement: Use the drive device to control the penetration enhancement unit to treat the skin surface of the target area in a circular motion, and apply vertical pressure for 15 seconds to promote penetration.

[0243] Oral control group: Oral administration of an equivalent dose of rametidamide tablets 8mg.

[0244] 4. Experimental Procedure and Observation Time Points

[0245] Baseline period (W1): lasting 1 week. No intervention, only wearing monitoring devices to record natural sleep parameters.

[0246] Treatment period (W2): lasts for 1 week. Receive the prescribed intervention at a fixed time each evening.

[0247] Washout period (W3): lasts for 1 week. All interventions are discontinued, and monitoring continues to assess residual effects and rebound.

[0248] 5. Key Evaluation Indicators

[0249] Sleep latency: The time (in minutes) from "lights out, ready to sleep" to the onset of the first stage of sleep. Calculate the mean and standard deviation for the treatment period.

[0250] Nighttime awakenings: The number of times each awakening lasts longer than 5 minutes during sleep.

[0251] Total sleep time.

[0252] 6. Data and Results

[0253] 7. Data Analysis and Conclusions

[0254] The experimental data above show that, compared with oral ramelteamide and hand-delivered ramelteamide, the microneedle-ramelteamide composition applied to the nasal ala can effectively bypass the blood-brain barrier and improve the absorption efficiency and stability of the active ingredient in the sleep center.

[0255] The experimental group had the shortest mean sleep latency (28 minutes) and a very small standard deviation (±5 minutes) during the treatment period, demonstrating its "rapid and stable" sleep-inducing properties. The advantage of the experimental group lies in the fact that the active ingredient enters the body transdermally via the nasal ala, bypassing the blood-brain barrier, allowing it to act quickly and efficiently on the body and produce its effects. In contrast, the hand-administered control group had a slightly slower onset of action and less stable results (±12 minutes). In this delivery method, the active ingredient needs to undergo systemic circulation and blood circulation to take effect, significantly reducing the onset time and efficacy. The oral control group had the slowest onset of action and the most unpredictable effect (±18 minutes), which is entirely consistent with the known characteristics of oral ramelteamide, which is greatly affected by food, first-pass metabolism in the liver, and individual CYP450 enzyme differences.

[0256] Furthermore, the experimental group experienced significantly fewer nighttime awakenings than the other two groups, and their total sleep time was significantly longer. This indicates that the microneedle-ramelteamide composition applied to the nasal ala not only helps with rapid sleep onset but also enhances sleep continuity and depth. This composition allows the active ingredients to act more directly on the sleep center, optimizing the regulation of sleep structure.

[0257] Example 5

[0258] This embodiment provides a transdermal delivery composition for use in the pericranial region, comprising:

[0259] The permeation-enhancing unit includes a base and microneedles arrayed on the base. The base is circular, elliptical, or crescent-shaped, and can be planar or curved, such as having a curved convex surface. The base material includes hyaluronic acid. In some processes, the base material includes at least one of inorganic non-metallic materials (such as monocrystalline silicon, glass, modified glass, ceramics), metallic materials (such as titanium alloys), polymer materials, silicone, polyurethane, polylactic acid, and hyaluronic acid, preferably monocrystalline silicon.

[0260] The microneedles are conical in shape; alternatively, they are pyramidal in shape. The solid microneedles have a height of 150 micrometers; alternatively, they have a height of 200 micrometers.

[0261] The drive unit includes a housing, a miniature vibration motor, a transmission rod, and a connecting base. The penetration-enhancing unit is mounted on the connecting base, and the drive unit can drive the penetration-enhancing unit to produce reciprocating motions of 1000 to 18000 times per minute (i.e., 16.67 Hz to 300 Hz). It is easily understood that in some composition types, the reciprocating motion of the penetration-enhancing unit can be manually controlled, thus eliminating the need for a drive unit. It should be noted that users can hold the drive unit to perform various care movements such as circular massage, vertical point lifting massage perpendicular to the skin, and horizontal reciprocating massage, and can also adopt other suitable three-dimensional reciprocating care movements according to their usage habits.

[0262] In this embodiment, the transdermal formulation is a gel, cream, or liquid, wherein the active ingredient comprises one or more of the following: gamma-aminobutyric acid (GABA), melatonin, valerian extract, passionflower extract, lemon balm extract, theanine, and serotonin (5-HTP). In some transdermal formulations, the content of gamma-aminobutyric acid (GABA) is 1% to 20%. In some transdermal formulations, the content of melatonin is 0.1% to 5%. In some transdermal formulations, the content of plant extracts (on a dry weight basis) is 1% to 15%. In some transdermal formulations, the content of theanine is 0.5% to 10%. In some transdermal formulations, the content of serotonin (5-HTP) is 0.5% to 5%.

[0263] In this embodiment, the shape of the base is suitable for fitting onto the skin surface of the forehead, temples, around the eyes, nose, and cheekbones.

[0264] Example 6

[0265] This embodiment provides a transdermal delivery composition for use in the pericranial region, comprising:

[0266] The permeation-enhancing unit includes a substrate and microneedles arrayed on the substrate; wherein the substrate is polygonal, rectangular, or elliptical, and the substrate material includes monocrystalline silicon. In some processes, the substrate material is selected from at least one of inorganic non-metallic materials (e.g., glass, modified glass, ceramics), metallic materials (e.g., titanium alloys), polymer materials, silicone, polyurethane, polylactic acid, and hyaluronic acid. The microneedles are selected from monocrystalline silicon, stainless steel, polymers, or titanium. The microneedles are conical in shape; alternatively, they are blade-shaped or pyramidal. The height of solid microneedles is 300-1500 micrometers; in some combinations, the microneedle height is 1000 micrometers.

[0267] The drive unit includes a housing, an elastic element, a transmission rod, and a connecting seat. The penetration-enhancing unit is mounted on the connecting seat, and the user manually controls the drive unit to reciprocate and press against the skin, causing the penetration-enhancing unit to weaken the stratum corneum barrier.

[0268] In this embodiment, the transdermal formulation is a patch, gel, cream, liquid, liniment, or powder. The active ingredient comprises one or more of diazepam, alprazolam, lorazepam, zolpidem, eszopiclone, zopiclone, ramelteon, tasimelteon, suvorexant, and leemborexant. In some compositions, the drug loading of diazepam is 1 to 40 mg / cm². In some compositions, the drug loading of alprazolam is 0.5 to 20 mg / cm². In some compositions, the drug loading of lorazepam is 0.4 to 16 mg / cm². In some compositions, the drug loading per unit area of ​​zolpidem is 0.8 to 30 mg / cm². In some compositions, the drug loading per unit area of ​​eszopiclone is 0.6 to 24 mg / cm². In some compositions, the drug loading per unit area of ​​zopiclone is 0.6 to 24 mg / cm². In some compositions, the drug loading per unit area of ​​ramelteon is 0.3 to 12 mg / cm². In some compositions, the drug loading per unit area of ​​tasimelteon is 0.4 to 16 mg / cm². In some compositions, the drug loading per unit area of ​​suvorexant is 1 to 40 mg / cm². In some compositions, the drug loading per unit area of ​​leemborexant is 1.2 to 44 mg / cm².

[0269] In this embodiment, the base is shaped to fit onto the skin surface of the scalp, forehead, around the eyes, nose, cheeks, temporal region (temples), back of the neck, or cheekbone.

[0270] Example 7

[0271] This embodiment provides a transdermal delivery composition for use in the pericranial region, comprising:

[0272] The permeation-enhancing unit includes a substrate and an array of microneedles distributed on the substrate; wherein the substrate is polygonal, rectangular, or elliptical, and the substrate material includes monocrystalline silicon. In some processes, the substrate material includes metals, titanium alloys, or polymers. The microneedles are selected from monocrystalline silicon, stainless steel, polymers, or titanium. The microneedles are conical in shape; alternatively, the microneedles are blade-shaped or pyramidal. The height of solid microneedles ranges from 50 micrometers to 200 micrometers, and in some combinations, the microneedle height is 150 micrometers.

[0273] In this embodiment, the transdermal preparation is a patch, ointment, cream, gel, liniment, lotion, spray, film, paste, or powder. The active ingredients include one or more of the following: vitamin K, caffeine, horse chestnut extract, chamomile extract, daisy extract, vitamin B3, licorice root extract, arbutin, vitamin C derivatives, Thiamidol, peptides, retinol and its derivatives, hyaluronic acid, polypeptides, compound plant extracts, sea buckthorn leaf extract, caffeine, acetyl hexapeptide-8, boswellia carterii, complex peptides, and plant extracts. It should be noted that the above active ingredients can also be used in combination with any of the active ingredients in Examples 1 to 6 to achieve multiple effects such as sleep aid and skin improvement.

[0274] In this embodiment, the base is shaped to fit onto the skin surface of the scalp, forehead, around the eyes, nose, cheeks, temporal region (temples), back of the neck, or cheekbone.

[0275] Example 8

[0276] This embodiment provides a transdermal delivery composition for use in the pericranial region, comprising:

[0277] The permeation-enhancing unit includes a substrate and an array of microneedles distributed on the substrate; wherein the substrate is polygonal, rectangular, or elliptical, and the substrate material includes monocrystalline silicon. In some processes, the substrate material includes metals, titanium alloys, or polymers. The microneedles are selected from monocrystalline silicon, stainless steel, polymers, or titanium. The microneedles are conical in shape; alternatively, the microneedles are blade-shaped or pyramidal. The height of solid microneedles ranges from 50 micrometers to 500 micrometers; in some combinations, the microneedle height is 150 micrometers.

[0278] In this embodiment, the transdermal formulation is a patch, ointment, cream, gel, liniment, lotion, spray, film, paste, or powder. The active ingredient includes one or more of the following: retinol, retinoic acid derivatives, acetyl hexapeptide-8, palmitoyl tetrapeptide-7, conocapeptide, hexapeptide, palmitoyl pentapeptide, L-ascorbic acid, vitamin C derivatives, and trifluoroacetyl isobutylamino dipeptide-42. It should be noted that the above active ingredients can also be used in combination with any of the active ingredients in Examples 1 to 6 to achieve multiple effects such as sleep aid and skin improvement.

[0279] In this embodiment, the base is shaped to fit onto the skin surface of the scalp, forehead, around the eyes, nose, cheeks, temporal region (temples), back of the neck, or cheekbone.

Claims

1. A transdermal delivery composition for use in the pericranial region, characterized in that, include: A penetration enhancement unit includes a base and microneedles distributed on the base, the microneedles having a height of 0.1 to 5000 micrometers, and the shape of the base and the distribution of the microneedles are adapted to conform to the skin surface of the pericranial region; the penetration enhancement unit is configured to weaken the skin stratum corneum barrier; as well as A transdermal formulation comprising at least one active ingredient, wherein the dosage form of the transdermal formulation is configured to adhere to the skin surface of the pericranial region to facilitate transdermal delivery of the active ingredient.

2. The transdermal delivery composition for the pericranial region according to claim 1, characterized in that, The pericranial region includes the scalp, forehead, temporal region, periorbital region, cheek, nasal alae, back of the neck, or cheekbone area.

3. The transdermal delivery composition for the pericranial region according to claim 1, characterized in that, The active ingredient takes effect at a time point that is the expected target time point, and the transdermal formulation is configured to be administered 0.5 h to 1 h before the expected target time point.

4. The transdermal delivery composition for the pericranial region according to claim 1, characterized in that, The dosage form of the transdermal preparation is a patch, ointment, cream, gel, liniment, ointment, spray, film, paste, or powder.

5. The transdermal delivery composition for the pericranial region according to claim 1, characterized in that, Also includes: A driving device configured to drive the penetration-enhancing unit to reciprocate against the skin surface; as well as A control unit is configured to control the drive device to generate reciprocating motion at a specific frequency.

6. The transdermal delivery composition for the pericranial region according to claim 5, characterized in that, The specific frequency range is from 1,000 vibrations per minute to 18,000 vibrations per minute.

7. The transdermal delivery composition for the pericranial region according to claim 1, characterized in that, The microneedles are cone-shaped, pyramidal, or blade-shaped.

8. The transdermal delivery composition for use in the pericranial region according to claim 1, characterized in that, The microneedles are made of at least one of inorganic non-metallic materials, metallic materials, and polymeric materials.

9. The transdermal delivery composition for use in the pericranial region according to claim 1, characterized in that, The active ingredient is selected from at least one of γ-aminobutyric acid (GABA), melatonin, valerian extract, passionflower extract, lemon balm extract, theanine, and 5-hydroxytryptophan (5-HTP).

10. The transdermal delivery composition for the pericranial region according to claim 9, characterized in that, The transdermal formulation contains 1% to 20% γ-aminobutyric acid (GABA).

11. The transdermal delivery composition for use in the pericranial region according to claim 9, characterized in that, The melatonin content in the transdermal formulation is 0.1% to 5%.

12. The transdermal delivery composition for use in the pericranial region according to claim 9, characterized in that, The transdermal formulation contains 1% to 15% plant extract (on a dry weight basis).

13. The transdermal delivery composition for the pericranial region according to claim 9, characterized in that, The theanine content in the transdermal preparation is 0.5% to 10%.

14. The transdermal delivery composition for use in the pericranial region according to claim 9, characterized in that, The transdermal formulation contains 0.5% to 5% ...

15. The transdermal delivery composition for use in the pericranial region according to claim 1, characterized in that, The active ingredient is selected from at least one of diazepam, alprazolam, lorazepam, zolpidem, eszopiclone, zopiclone, ramelteon, tasimelteon, suvorexant, and leemborexant.

16. The transdermal delivery composition for use in the pericranial region according to claim 15, characterized in that, The transdermal formulation contains 1 to 40 mg / cm² of diazepam per unit area.

17. The transdermal delivery composition for use in the pericranial region according to claim 15, characterized in that, The alprazolam loading per unit area in the transdermal formulation is 0.5 to 20 mg / cm².

18. The transdermal delivery composition for use in the pericranial region according to claim 15, characterized in that, The transdermal formulation contains lorazepam at a loading capacity of 0.4 to 16 mg / cm².

19. The transdermal delivery composition for use in the pericranial region according to claim 15, characterized in that, The transdermal formulation has a drug loading of zolpidem per unit area of ​​0.8 to 30 mg / cm².

20. The transdermal delivery composition for use in the pericranial region according to claim 15, characterized in that, The transdermal formulation contains 0.6 to 24 mg / cm² of eszopiclone.

21. The transdermal delivery composition for use in the pericranial region according to claim 15, characterized in that, The transdermal formulation contains 0.6 to 24 mg / cm² of zopiclone per unit area.

22. The transdermal delivery composition for use in the pericranial region according to claim 15, characterized in that, The transdermal formulation has a drug loading of ramelteon per unit area of ​​0.3 to 12 mg / cm².

23. The transdermal delivery composition for use in the pericranial region according to claim 15, characterized in that, The transdermal formulation contains 0.4 to 16 mg / cm² of tasimelteon per unit area.

24. The transdermal delivery composition for use in the pericranial region according to claim 15, characterized in that, The transdermal formulation contains 1 to 40 mg / cm² of Suvorexant per unit area.

25. The transdermal delivery composition for use in the pericranial region according to claim 15, characterized in that, The transdermal formulation has a drug loading of leemborexant of 1.2 to 44 mg / cm².

26. The transdermal delivery composition for the pericranial region according to claim 1, characterized in that, The active ingredients also include at least one of vitamin K, caffeine, horse chestnut extract, chamomile, and daisy extract.

27. The transdermal delivery composition for the pericranial region according to claim 1, characterized in that, The active ingredients also include at least one of vitamin B3, licorice root extract, arbutin, vitamin C derivatives, and Thiamidol.

28. The transdermal delivery composition for use in the pericranial region according to claim 1, characterized in that, The active ingredients also include at least one of caffeine, polypeptides, vitamin K, and plant extracts.

29. The transdermal delivery composition for use in the pericranial region according to claim 1, characterized in that, The active ingredients also include at least one of retinol and its derivatives, hyaluronic acid, polypeptides, and compound plant extracts.

30. The transdermal delivery composition for use in the pericranial region according to claim 1, characterized in that, The active ingredients also include at least one of the following: sea buckthorn leaf extract, caffeine, acetyl hexapeptide-8, bosine, complex polypeptides, and plant extracts.

31. The transdermal delivery composition for use in the pericranial region according to claim 1, characterized in that, The active ingredient also includes at least one of retinol, retinoic acid derivatives, acetyl hexapeptide-8, palmitoyl tetrapeptide-7, conopeptide, hexapeptide, palmitoyl pentapeptide, L-ascorbic acid, vitamin C derivatives, and trifluoroacetyl isobutylamino dipeptide-42.

32. The transdermal delivery composition for use in the pericranial region according to claim 1, characterized in that, The active ingredients include plant extracts.

33. The transdermal delivery composition for use in the pericranial region according to claim 1, characterized in that, The active ingredients include minerals and small molecules.

34. The transdermal delivery composition for use in the pericranial region according to claim 1, characterized in that, The active ingredients include neurotransmitter / receptor regulatory active ingredients.

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