CN114832226A - Anti-depression sleep-aiding self-soluble microneedle patch and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of medical appliances, and particularly relates to an anti-depression sleep-aiding self-soluble microneedle patch and a preparation method thereof. The self-soluble microneedle patch consists of a water-soluble cannabidiol microcapsule and a microneedle matrix material, wherein the particle size of the water-soluble cannabidiol microcapsule is 200-500 mu m, and the water-soluble cannabidiol microcapsule is formed by wrapping cannabidiol by alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin or hydroxypropyl-beta-cyclodextrin. The microneedle patch prepared by the invention can quickly take effect on a human body, the drug is dissolved out and permeated into the human body from 37min, and the drug effect can be kept for more than 100 min. Therefore, the sleep quality of the depressed patients can be rapidly improved, and the sleep quality comprises the obvious shortening of the sleeping time and the improvement of the continuous sleeping time.

Description

A kind of antidepressant sleep aid autolyzed microneedle patch and preparation method

technical field

The invention belongs to the technical field of medical devices, and in particular relates to an antidepressant and sleep-aiding autolytic microneedle patch and a preparation method.

Background technique

Depressive disorder, also known as depression, is characterized by obvious and long-term low mood. In recent years, the research and development of antidepressants has become one of the hot research fields in psychiatry. Currently commonly used clinical antidepressants include tricyclic antidepressants (TCAs), norepinephrine reuptake inhibitors (NARIs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs) and Dopamine (DA) reuptake inhibitors, etc. Among them, SSRIs have become the first-line treatment for depression, but they take a long period of time and may cause unbearable adverse drug reactions, including sexual dysfunction, weight gain, nausea and headache.

Most patients with depression are often accompanied by various degrees of sleep disturbance, including difficulty falling asleep, early awakening, or altered sleep rhythm, and polysomnography often shows decreased slow wave sleep (SWS), increased rapid eye movement (REM) sleep density or The latency period is shortened, and the proportion of deep sleep is reduced. Most antidepressants such as TCA and SSRI have a modulating effect on REM sleep, but less effective on non-REM sleep, especially SWS. Mianserin and mirtazapine block 5-HT ₂ receptors, which can promote sleep and improve sleep persistence, but have adverse drug reactions such as sleeping and daytime drowsiness. Therefore, there is an urgent need to find a solution that is different from traditional clinical medication and can not only effectively relieve depression, but also reduce adverse drug reactions.

Cannabidiol (CBD) is a natural active ingredient from the stems, leaves, and seeds of the Cannabis genus, an annual herb of the Cannabis family. Sexual diseases have therapeutic and alleviating effects. However, CBD is insoluble in water and needs to be made into a water-soluble form for further utilization. The current common form is to make tablets or drops for oral administration, but the water-soluble CBD microcapsules are easily disintegrated after being corroded by gastric acid, and the CBD inside is not easily absorbed by the intestinal tract and affects the efficacy of the drug. The way of intestinal absorption is also easy to cause adverse drug reactions of gastrointestinal discomfort. On the other hand, oral administration usually requires waiting for the drug to be absorbed into the blood before it can take effect. Therefore, depressed patients with sleep disorders usually need to take hypnotics to solve the problems of difficulty falling asleep, short sleep duration, excessive sleepiness, etc. Wake up early, etc.

To sum up, the present invention proposes an antidepressant and sleep-aiding autolytic microneedle patch scheme, in order to alleviate at least one of the above problems.

SUMMARY OF THE INVENTION

In view of this, the present invention aims to provide a self-dissolving microneedle patch for anti-depression and sleep aid and a preparation method thereof. The specific technical scheme is as follows.

A self-dissolving micro-needle patch for anti-depression and sleep aid, the self-dissolving micro-needle patch is composed of a water-soluble cannabidiol microcapsule and a micro-needle matrix material; the particle size of the water-soluble cannabidiol microcapsule is 200-500 μm; the percentage content of the water-soluble cannabidiol microcapsules in the self-dissolving microneedle patch is 2.5%.

The particle size of cannabidiol microcapsules is related to water solubility. The smaller the particle size, the better the solubility and dispersibility in water.

Further, the water-soluble cannabidiol microcapsules are formed by encapsulating cannabidiol with a water-soluble material, and the water-soluble material includes α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or hydroxypropyl-β - Cyclodextrin.

The above-mentioned cyclodextrin molecules are hollow cylinders that are wide at the top and narrow at the bottom, open at both ends, and relatively hydrophobic inside the cavity, while all the hydroxyl groups are outside the molecules, which can well coat the CBD molecules. It is also very soluble in water.

Further, the microneedle matrix material is composed of sodium hyaluronate, polyvinylpyrrolidone and water, and its mass percentage is sodium hyaluronate:polyvinylpyrrolidone:water=1-5:1-5:10-15.

As a preference, sodium hyaluronate:polyvinylpyrrolidone:water=2.5:1.5:12, and the microneedles in this ratio have the best toughness and rigidity.

Further, the molecular weight of the sodium hyaluronate is 5000-10000. The sodium hyaluronate within this molecular weight range has better transdermal absorption ability, and the larger the molecular weight, the harder it is to enter the skin.

Further, the self-dissolving microneedle patch contains 100-400 microneedles per square centimeter; the microneedles include triangular conical microneedles and conical microneedles.

The preparation method of the above-mentioned self-dissolving microneedle patch comprises the following steps:

1) Dissolve cannabidiol crystals with a purity higher than 99% with ethanol, heat to above 50°C to accelerate the dissolution if necessary, and cool to room temperature after the dissolution is complete;

2) heating and dissolving any one of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or hydroxypropyl-β-cyclodextrin with pure water or ethanol, after dissolving completely, step ( 1) The solution is added therein and stirred and mixed evenly;

3) Put the mixed solution prepared in step (2) into an airtight container, ultrasonically treat it with an ultrasonic generator for 1-4 hours, ultrasonic power 5000-8000W, temperature 20-60 ° C; after the ultrasonic treatment is completed, carry out decompression concentration and drying dehydration ;

4) The material of step (3) is transferred to the spray dryer, the spray pressure is 100-200 atmospheric pressure, the material is fed at a speed of 300-600ml/h, the hot air inlet flow rate is 0.3-0.8m ³ /min, and the air inlet The temperature is 100-200° C. to obtain water-soluble cannabidiol microcapsules.

Further, sodium hyaluronate and polyvinylpyrrolidone are completely dissolved in water, then the water-soluble cannabidiol microcapsules are added and stirred to form a polymer solution, and the mass ratio of each substance in the polymer solution is water-soluble cannabidiol. Phenol microcapsules: sodium hyaluronate: polyvinylpyrrolidone: water = 0.4:2.5:1.5:12; the polymer solution is introduced into the mold and pressurized in a vacuum environment to push the polymer solution into the mold, causing polymerization The compound solution is filled into the microneedle needle.

Further, the particle size of the water-soluble cannabidiol microcapsules is 200-500 μm.

Further, the molecular weight of the sodium hyaluronate is 5000-10000.

Application of the above-mentioned self-dissolving microneedle patch in the preparation of antipsychotics.

beneficial technical effect

The invention innovatively combines the microneedle patch with water-soluble CBD to prepare a self-dissolving microneedle patch for anti-depression and sleep aid. At present, there is no report of making CBD into the form of microneedle patch. The main reason is that it is difficult for water-soluble CBD to enter the body through the skin lipid bimolecular stratum corneum to exert its curative effect.

Based on this, the present invention provides a technical solution for preparing a water-soluble microneedle patch with a certain hardness by wrapping a water-soluble CBD with a biodegradable matrix material. In the present invention, the water-soluble CBD microcapsules and the microneedle matrix are fused together, and the water-soluble CBD microcapsules fill the needle body (needle head) part of the microneedle to the maximum extent during manufacture through the mold. When using this product, the patient only needs to stick the microneedle on the skin, and the microneedle adopts the method of physical penetration, firstly penetrating the stratum corneum but not touching the dermis layer to achieve painless delivery of the drug; secondly, the biodegradable matrix material is used. After administration, the drug contained in the needle body is retained in the skin, the needle body is gradually degraded and the drug is released, and the drug is then absorbed by the human body to take effect. The microneedle patch prepared by the invention can quickly take effect on the human body, the medicine starts to dissolve and penetrate into the human body from 37 minutes, and the medicine efficacy is maintained for more than 100 minutes, so the sleep quality of depressed patients can be quickly improved, including significantly shortening the time to fall asleep and Increase the continuous sleep time, the sleep time is extended from the original 2 hours to 6 hours, and the sleep time is shortened from the original 1.6 hours to 0.4 hours. In addition, most oral medicines usually need to be taken every day, and the self-dissolving microneedle patch of the present invention can continuously penetrate the skin of water-soluble CBD microcapsules into the human body within five days to produce an effect, which is persistent and does not require every Take the medicine at the same time and at the same time every day to avoid interruption of treatment due to forgetting and not taking the medicine.

The microneedle patch of the present invention is convenient to use. The patient can take out the patch from the outer packaging bag and stick it on the skin behind the neck before going to bed. The next day, only a little (or no) of the microneedle patch remains. The dissolved matrix material is on the surface of the skin, and the patient only needs to wipe it off, without the need to tear off the pasted non-woven fabric like the traditional non-woven matrix patch, thus avoiding the repeated pulling of the skin.

Description of drawings

In order to illustrate the embodiments of the present invention or the technical solutions in the prior art more clearly, the following briefly introduces the accompanying drawings that are required to be used in the description of the embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention, and for those of ordinary skill in the art, other drawings can also be obtained from these drawings without creative effort.

Fig. 1 is the actual picture of the self-dissolving microneedle patch of the present invention (A: triangular conical microneedle; B: conical microneedle);

Figure 2 is the cumulative release rate curve of the self-dissolving microneedle patch;

Figure 3 is the hardness test of the autolyzed microneedles (N represents pressure).

Detailed ways

In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be described clearly and completely below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are some, but not all, embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

It should be noted that, herein, the terms "comprising", "comprising" or any other variation thereof are intended to encompass non-exclusive inclusion, such that a process, method, article or device comprising a series of elements includes not only those elements, It also includes other elements not expressly listed or inherent to such a process, method, article or apparatus. Without further limitation, an element qualified by the phrase "comprising a..." does not preclude the presence of additional identical elements in a process, method, article or apparatus that includes the element.

As used in this specification, the term "about" is typically expressed as +/- 5% of the stated value, more typically +/- 4% of the stated value, and more typically + /-3%, more typically +/-2% of said value, even more typically +/-1% of said value, even more typically +/-0.5% of said value.

In this specification, certain embodiments may be disclosed in a format that is within a range. It should be understood that this description "within a range" is merely for convenience and brevity and should not be construed as an inflexible limitation on the disclosed scope. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values within that range. For example, a description of a range 1-6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc. , and individual numbers within this range, such as 1, 2, 3, 4, 5, and 6. The above rules apply regardless of the breadth of the range.

Embodiment 1: the preparation method of water-soluble CBD microcapsules

1) Accurately weigh 100g of CBD crystal powder with a purity higher than 99% in 300ml of ethanol aqueous solution, heat at 60°C and stir for 10-30 minutes until completely dissolved, then cool to room temperature for later use.

2) Weigh 200g of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and hydroxypropyl-β-cyclodextrin respectively, add 1000g of first-grade purified water, and stir with or without heating until completely dissolved , and then add the CBD solution dissolved in step (1), and continue to stir with or without heating.

3) Put the mixed solution prepared in step (2) into an airtight container, ultrasonically treat it with an ultrasonic generator for 1-4h, ultrasonic power 5000-8000W, temperature 20-60°C; after ultrasonic treatment, use a rotary evaporator to decompress Concentrate to remove most of the solvent and moisture. Transfer the processed material to a vacuum drying box, vacuum dry for 60-120h, vacuum degree -0.08MPa, temperature 35-75℃.

4) The material of step (3) is transferred to the spray dryer, the spray pressure is 100-200 atmospheric pressure, the material is fed at a speed of 300-600ml/h, the hot air inlet flow rate is 0.3-0.8m ³ /min, and the air inlet Temperature 100-200℃.

5) Water solubility test of cannabidiol microcapsules obtained by embedding.

Using purified water as a solvent, weigh equal amounts of CBD microcapsules wrapped with different materials, and test their solubility in water for 5 minutes. The results are shown in the table below.

Table 1 Solubility test of microcapsules prepared by different media

Embodiment 2: the preparation method of antidepressant microneedle

The water-soluble CBD micro-scale capsules prepared in Example 3 are mixed with sodium hyaluronate, polyvinylpyrrolidone and water, and the ratio is water-soluble CBD: sodium hyaluronate: polyvinylpyrrolidone: water=0.4:2.5:1.5: 12. All polymer solutions were centrifuged at 5000 rpm for 5 minutes to remove air bubbles. Each micro mold consists of 100 (10*10) conical (cone, triangular cone) needles, the polymer solution is introduced into the mold, and then in a vacuum environment, pressure (0.1MPa) is applied for about 10 minutes to promote polymerization The microneedle mold was centrifuged at 4500 rpm for 30 minutes to remove trapped air bubbles and the polymer solution was filled into the microneedle tips. Next, the molds were dried at 25°C for 48 hours. Finally, the microneedles are removed after drying.

Example 3: Microneedle Performance Test

1) Needle content: observed under a microscope, it is good if it reaches 100%, good if it reaches 80%, and poor if it is less than 80%.

2) Mechanical properties: The evaluation standard is that it can pass through the aluminum foil paper as good, and cannot pass through the aluminum foil paper as poor.

3) Hygroscopicity: The evaluation standard is that the hygroscopicity of microneedles that can pass through more than 2 layers of aluminum foil paper smoothly after being placed in a high-humidity environment for 12 hours is good, and the hygroscopicity of microneedles that can only pass through 1 layer of aluminum foil paper is medium, and cannot The hygroscopicity of the microneedles passing through the aluminum foil was poor.

4) Release: Franz transdermal diffusion cell was used to evaluate the in vitro release performance of the prepared CBD autolytic microneedle patch. Fix the CBD autolyzed microneedle patch at the mouth of the diffusion cell, pH 7.4 phosphate buffered saline (PBS) as the receiving medium, the sample volume of each cell is 4ml, the temperature of the diffusion cell is (32±1) ℃, and the speed of the stirring bar is is 300r/min. 1 ml was sampled at 5, 15, 30, 45, 60 and 90 min and supplemented with 1 ml of blank PBS. The samples at each time point were filtered through a 0.22 μm filter membrane and then injected with HPLC to detect the peak area. The concentration (P _n ) was calculated by the external standard method, and the cumulative release percentage (R _n ) was calculated according to the following formula.

Experimental results: the first 30min was released rapidly, and the release rate slowed down significantly after 30min. By 60min, the CBD had been basically completely released from the autolyzed microneedle patch. At 90min, the release amount did not increase significantly, and the cumulative release percentage reached (98.60±1.99 )%. The faster drug release rate from the matrix indicated that the microneedle matrix had good drug release performance.

Embodiment 4

Twenty volunteers were recruited, including 15 females and 5 males, aged 25-50 years. On the first night, each volunteer’s voluntary sleep-onset time and sleep duration were recorded, and the antidepressant microneedle patch of the present invention was applied to the back of the neck on the second night, and went to bed at the same time as the first night, and the sleep-onset time and duration were recorded. sleep duration. The results are shown in the table below.

Table 2 Antidepressant microneedle sleep monitoring

By monitoring the sleep time, the original sleep time was 2 hours, which was gradually extended to 6 hours after the patch; the original sleep time was 1.6 hours, and it was gradually shortened to 0.4 hours after the patch.

The embodiments of the present invention have been described above in conjunction with the accompanying drawings, but the present invention is not limited to the above-mentioned specific embodiments, which are merely illustrative rather than restrictive. Under the inspiration of the present invention, without departing from the scope of protection of the present invention and the claims, many forms can be made, which all belong to the protection of the present invention.

Claims (10)

1. a self-dissolving micro-needle patch for anti-depression and sleep aid, is characterized in that, described self-dissolving micro-needle patch is made up of water-soluble cannabidiol microcapsules and microneedle matrix material; Described water-soluble cannabidiol The particle size of the microcapsules is 200-500 μm; the percentage content of the water-soluble cannabidiol microcapsules in the self-dissolving microneedle patch is 2.5%. 2. The self-dissolving microneedle patch of claim 1, wherein the water-soluble cannabidiol microcapsules are formed by wrapping cannabidiol with a water-soluble material, and the water-soluble material comprises α-cyclodextrin , β-cyclodextrin, γ-cyclodextrin or hydroxypropyl-β-cyclodextrin. 3. The self-dissolving microneedle patch of claim 1, wherein the microneedle matrix material is composed of sodium hyaluronate, polyvinylpyrrolidone and water, and its mass percentage is sodium hyaluronate: polyethylene Pyrrolidone:water=1-5:1-5:10-15. 4. The self-dissolving microneedle patch according to claim 3, wherein the molecular weight of the sodium hyaluronate is 5000-10000. 5. The self-dissolving microneedle patch of claim 1, wherein the self-dissolving microneedle patch contains 100-400 microneedles per square centimeter, and the microneedles comprise triangular pyramidal microneedles and Conical microneedles. 6. the preparation method of the self-dissolving microneedle patch described in any one of claim 1-5, is characterized in that, comprises the steps: 1) Dissolve cannabidiol crystals with a purity higher than 99% with ethanol, heat to above 50°C to accelerate the dissolution if necessary, and cool to room temperature after the dissolution is complete; 2) heating and dissolving any one of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or hydroxypropyl-β-cyclodextrin with pure water or ethanol, after dissolving completely, step ( 1) The solution is added therein and stirred and mixed evenly; 3) Put the mixed solution prepared in step (2) into an airtight container, ultrasonically treat it with an ultrasonic generator for 1-4 hours, ultrasonic power 5000-8000W, temperature 20-60 ° C; after the ultrasonic treatment is completed, carry out decompression concentration and drying dehydration ; 4) The material of step (3) is transferred to the spray dryer, the spray pressure is 100-200 atmospheric pressure, the material is fed at a speed of 300-600ml/h, the hot air inlet flow rate is 0.3-0.8m ³ /min, and the air inlet The temperature is 100-200° C. to obtain water-soluble cannabidiol microcapsules. 7. preparation method as claimed in claim 6 is characterized in that, sodium hyaluronate and polyvinylpyrrolidone are completely dissolved in water, then add described water-soluble cannabidiol microcapsules and stir to form polymer solution, described The mass ratio of each substance in the polymer solution is water-soluble cannabidiol microcapsules: sodium hyaluronate: polyvinylpyrrolidone: water = 0.4: 2.5: 1.5: 12; the polymer solution is introduced into the mold and placed in a vacuum environment Pressurization forces the polymer solution into the mold, causing the polymer solution to fill the microneedle needles. 8. The preparation method according to claim 6, wherein the particle size of the water-soluble cannabidiol microcapsules is 200-500 μm. 9. The preparation method of claim 7, wherein the molecular weight of the sodium hyaluronate is 5000-10000. 10. The application of the self-dissolving microneedle patch of claim 1 in the preparation of antipsychotics.

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