CN114832226B - Anti-depression sleep-aiding autolytic microneedle patch and preparation method thereof - Google Patents
Anti-depression sleep-aiding autolytic microneedle patch and preparation method thereof Download PDFInfo
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- CN114832226B CN114832226B CN202210504559.2A CN202210504559A CN114832226B CN 114832226 B CN114832226 B CN 114832226B CN 202210504559 A CN202210504559 A CN 202210504559A CN 114832226 B CN114832226 B CN 114832226B
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- cyclodextrin
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- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 claims abstract description 52
- 229950011318 cannabidiol Drugs 0.000 claims abstract description 52
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 claims abstract description 52
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 claims abstract description 52
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 15
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Organic Chemistry (AREA)
- Anesthesiology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Medical Informatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of medical instruments, and particularly relates to an anti-depression sleep-aiding autolytic microneedle patch and a preparation method thereof. The self-soluble microneedle patch consists of water-soluble cannabidiol microcapsules and microneedle matrix materials, wherein the particle size of the water-soluble cannabidiol microcapsules is 200-500 mu m, and the water-soluble cannabidiol microcapsules are formed by wrapping cannabidiol with alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin or hydroxypropyl-beta-cyclodextrin. The micro-needle patch prepared by the invention can rapidly take effect on human body, and the medicine can be dissolved and permeated into the human body from 37min, and the efficacy can be maintained for more than 100 min. Thus, the sleep quality of depressed patients can be rapidly improved, including significantly shortening the fall-to-sleep time and improving the duration of sleep.
Description
Technical Field
The invention belongs to the technical field of medical instruments, and particularly relates to an anti-depression sleep-aiding autolytic microneedle patch and a preparation method thereof.
Background
Depressive disorder is also called depression, and is mainly represented by obvious and long-term hypo-mood. In recent years, the development of antidepressants has become one of the hot research fields of psychiatric departments. Currently, clinically used antidepressants include tricyclic antidepressants (TCA), norepinephrine reuptake inhibitors (NARI), monoamine oxidase inhibitors (MAOI), selective 5-hydroxytryptamine reuptake inhibitors (SSRI), dopamine (DA) reuptake inhibitors, and the like. Among them, SSRI has become a first-line therapeutic agent for depression, but its administration period is long, and adverse drug reactions, including sexual dysfunction, body mass increase, nausea and headache, which are intolerable to patients, may occur.
Most depressed patients often experience varying degrees of sleep disturbance, including difficulty falling asleep, early waking, or altered sleep rhythms, polysomnography often manifests as reduced Slow Wave Sleep (SWS), increased Rapid Eye Movement (REM) sleep density, or reduced latency, reduced deep sleep proportions, etc. Most antidepressants such as TCA and SSRI have a modulating effect on REM sleep, but are less effective on non-REM sleep, especially SWS. Pair of 5-HT of mianserin, mirtazapine and the like 2 The receptor blocking effect can promote sleep and improve sleep persistence, but has adverse effects of drugs such as sleepiness in the daytime, and the like. Therefore, it is highly desirable to find a solution which is different from the traditional clinical medicines, and can effectively relieve the depressive disorder and reduce the adverse reaction of medicines.
Cannabidiol (CBD) is a natural active ingredient from the annual herb cannabis sativa stems, leaves, seeds of cannabis sativa of the family cannabinaceae, and has a variety of pharmacological activities, which have been shown to have therapeutic and palliative effects in psychotic disorders such as schizophrenia, depression, anxiety, sleep disorders, etc. However, CBD is insoluble in water and needs to be made in a water-soluble form for further use. The conventional mode is to make into tablets or drops for oral administration, but the water-soluble CBD microcapsules are easy to disintegrate after being corroded by gastric acid, CBD in the water-soluble CBD microcapsules is not easy to be absorbed by intestinal tracts to influence the curative effect of the medicine, and in addition, the oral administration and the intestinal tract absorption mode also easily cause adverse reactions of medicines with gastrointestinal discomfort. On the other hand, the oral administration mode usually needs to take effect after the medicines are absorbed into blood, so that the depressed patients suffering from sleep disorder usually need to take hypnotic medicines in an auxiliary way to solve the problems of difficult falling into sleep, short sleep duration, early waking and the like.
In summary, the present invention proposes an anti-depression sleep-aiding self-soluble microneedle patch scheme for alleviating at least one of the above problems.
Disclosure of Invention
In view of the above, the invention aims to provide an anti-depression sleep-aiding self-soluble microneedle patch and a preparation method thereof, and the specific technical scheme is as follows.
An anti-depression sleep-aiding autolytic microneedle patch, which consists of a water-soluble cannabidiol microcapsule and a microneedle matrix material; the particle size of the water-soluble cannabidiol microcapsule is 200-500 mu m; the water-soluble cannabidiol microcapsule accounts for 2.5% of the self-soluble microneedle patch.
The particle size of the cannabidiol microcapsule is related to water solubility, and the smaller the particle size is, the better the solubility and dispersibility of the cannabidiol microcapsule in water are.
Further, the water-soluble cannabidiol microcapsules are formed by encapsulating cannabidiol with a water-soluble material comprising alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, or hydroxypropyl-beta-cyclodextrin.
The cyclodextrin molecules are hollow cylindrical objects with wide upper part and narrow lower part and two open ends, the inside of the cavity is relatively hydrophobic, and all hydroxyl groups are outside the molecules, so that CBD molecules can be well coated, and meanwhile, the cyclodextrin molecules can be well dissolved in water.
Further, the microneedle matrix material consists of sodium hyaluronate, polyvinylpyrrolidone and water, and the mass percentage of the microneedle matrix material is sodium hyaluronate: polyvinylpyrrolidone: water = 1-5:1-5:10-15.
As a preference, sodium hyaluronate: polyvinylpyrrolidone: water = 2.5:1.5:12, the microneedles at this ratio had the best toughness and rigidity.
Further, the molecular weight of the sodium hyaluronate is 5000-10000, the sodium hyaluronate in the molecular weight range has better transdermal absorption capacity, and the larger molecular weight can lead to difficult entering into skin.
Further, the self-soluble microneedle patch contains 100-400 microneedles per square centimeter; the microneedles include triangular tapered microneedles and conical microneedles.
The preparation method of the autolytic microneedle patch comprises the following steps:
1) Dissolving cannabidiol crystal with purity higher than 99% with ethanol, heating to above 50deg.C to accelerate dissolution if necessary, and cooling to room temperature after dissolution;
2) Heating and dissolving any one of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin or hydroxypropyl-beta-cyclodextrin with pure water or ethanol, adding the solution obtained in the step (1) after the dissolution is completed, and stirring and mixing uniformly;
3) Placing the mixed solution prepared in the step (2) into a closed container, performing ultrasonic treatment for 1-4h by using an ultrasonic generator, wherein the ultrasonic power is 5000-8000W, and the temperature is 20-60 ℃; concentrating under reduced pressure and drying to remove water after ultrasonic treatment;
4) Transferring the material obtained in the step (3) into a spray dryer, wherein the spraying pressure is 100-200 atm, the material is fed at the speed of 300-600ml/h, and the hot air inlet flow is 0.3-0.8m 3 And/min, wherein the air inlet temperature is 100-200 ℃, and the water-soluble cannabidiol microcapsule is obtained.
Further, completely dissolving sodium hyaluronate and polyvinylpyrrolidone in water, then adding the water-soluble cannabidiol microcapsules, and uniformly stirring to form a polymer solution, wherein the mass ratio of each substance in the polymer solution is that the water-soluble cannabidiol microcapsules: sodium hyaluronate: polyvinylpyrrolidone: water = 0.4:2.5:1.5:12; introducing the polymer solution into a mold and pressurizing under vacuum conditions forces the polymer solution into the mold, causing the polymer solution to fill the microneedle tips.
Further, the particle size of the water-soluble cannabidiol microcapsule is 200-500 μm.
Further, the molecular weight of the sodium hyaluronate is 5000-10000.
The self-soluble microneedle patch is applied to preparation of anti-mental depression drugs.
Beneficial technical effects
The invention creatively combines the microneedle patch with the water-soluble CBD to prepare the anti-depression sleep-aiding autolytic microneedle patch. The CBD has not been reported to be in the form of a microneedle patch at present, and the main reason is that the water-soluble CBD is difficult to penetrate into the body through the lipid bilayer of the skin to exert curative effect.
Based on the above, the invention provides a technical scheme that a biodegradable matrix material wraps a water-soluble CBD to prepare a water-soluble microneedle patch with certain hardness. In the present invention, the water-soluble CBD microcapsules are fused with the microneedle substrate, and the water-soluble CBD microcapsules are filled with the needle body (needle head) portion of the microneedle to the maximum extent at the time of manufacture by a mold. When the product is used by a patient, only the micro needle is stuck on the skin, and the micro needle firstly penetrates through the stratum corneum but does not touch the dermis layer in a physical permeation promoting manner so as to realize painless drug delivery; secondly, by utilizing the biocompatibility of the biodegradable matrix material, the drug carried by the needle body is retained in the skin after administration, the needle body is gradually degraded and releases the drug, and then the drug is absorbed by the human body for efficacy. The micro-needle patch prepared by the invention can rapidly take effect on a human body, and the medicine can be dissolved and permeated into the human body from 37min, and the medicine effect can be maintained for more than 100min, so that the sleep quality of a depressed patient can be rapidly improved, the sleep time is obviously shortened and the continuous sleep time is prolonged from original 2 hours to 6 hours, and the sleep time is shortened from original 1.6 hours to 0.4 hour. In addition, most of oral administration is usually required to be taken every day, and the self-soluble micro-needle patch can be continuously provided with the water-soluble CBD microcapsules to enter a human body in five days, so that the self-soluble micro-needle patch has a lasting effect, does not need to be taken at fixed points every day, and avoids treatment interruption caused by forgetting to take the medicine.
The microneedle patch provided by the invention is convenient to use, a patient takes the patch out of the outer packaging bag and sticks the patch to the skin behind the neck before sleeping, only a little (or no) undissolved matrix material is left on the skin surface of the microneedle patch in the next day, and the patient only needs to erase the patch, and the patch with the traditional non-woven fabric matrix is not required to tear off the stuck non-woven fabric, so that repeated pulling of the skin is avoided.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It will be apparent to those of ordinary skill in the art that the drawings in the following description are of some embodiments of the invention and that other drawings may be derived from these drawings without inventive faculty.
FIG. 1 is a physical view of the self-soluble microneedle patch of the present invention (A: triangular pyramid shaped microneedles; B: conical microneedles);
FIG. 2 is a graph of the cumulative release rate of an autolytic microneedle patch;
FIG. 3 is a self-soluble microneedle hardness test (N stands for pressure).
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
It should be noted that, in this document, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising one … …" does not exclude the presence of other like elements in a process, method, article, or apparatus that comprises the element.
As used in this specification, the term "about" is typically expressed as +/-5% of the value, more typically +/-4% of the value, more typically +/-3% of the value, more typically +/-2% of the value, even more typically +/-1% of the value, and even more typically +/-0.5% of the value.
In this specification, certain embodiments may be disclosed in a format that is within a certain range. It should be appreciated that such a description of "within a certain range" is merely for convenience and brevity and should not be construed as a inflexible limitation on the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all possible sub-ranges and individual numerical values within that range. For example, the description of ranges 1-6 should be considered to have specifically disclosed subranges 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., as well as individual numbers within this range, e.g., 1,2,3,4,5, and 6. The above rule applies regardless of the breadth of the range.
Embodiment one: preparation method of water-soluble CBD microcapsule
1) 100g of CBD crystal powder with purity higher than 99% is accurately weighed in 300ml of ethanol water solution, heated to 60 ℃ and stirred for 10-30 minutes until the CBD crystal powder is completely dissolved, and then cooled to room temperature for standby.
2) 200g of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin and hydroxypropyl-beta-cyclodextrin are respectively weighed, 1000g of primary purified water is respectively added, stirring is performed with or without heating until the primary purified water is completely dissolved, then the CBD solution dissolved in the step (1) is added, and stirring is continued with or without heating.
3) Placing the mixed solution prepared in the step (2) into a closed container, performing ultrasonic treatment for 1-4h by using an ultrasonic generator, wherein the ultrasonic power is 5000-8000W, and the temperature is 20-60 ℃; after the ultrasonic treatment, the mixture was concentrated under reduced pressure using a rotary evaporator to remove most of the solvent and water. Transferring the treated material into a vacuum drying oven, and vacuum drying for 60-120h at a vacuum degree of-0.08 MPa and a temperature of 35-75 ℃.
4) Transferring the material obtained in the step (3) into a spray dryer, wherein the spraying pressure is 100-200 atm, the material is fed at the speed of 300-600ml/h, and the hot air inlet flow is 0.3-0.8m 3 Air intake per minThe temperature is 100-200 ℃.
5) And (5) testing the water solubility of the cannabidiol microcapsules obtained by embedding.
And weighing equal amounts of CBD microcapsules wrapped by different materials by taking purified water as a solvent, and testing the solubility of the CBD microcapsules in water for 5 min. The results are shown in the following table.
TABLE 1 solubility test of microcapsules made with different media
Embodiment two: preparation method of antidepressant microneedle
The water-soluble CBD micron-sized capsule prepared in example three was mixed with sodium hyaluronate, polyvinylpyrrolidone and water in the ratio of water-soluble CBD: sodium hyaluronate: polyvinylpyrrolidone: water = 0.4:2.5:1.5:12. all polymer solutions were centrifuged at 5000rpm for 5 minutes to remove air bubbles. Each micro-mold consisted of 100 (10 x 10) conical (conical, triangular pyramid) needles, and a polymer solution was introduced into the mold, then a pressure (0.1 MPa) was applied under vacuum for about 10 minutes to facilitate the polymer to enter the mold, the mold was removed, and the microneedle mold was centrifuged at 4500rpm for 30 minutes to remove trapped air bubbles, and the polymer solution was filled into the microneedles. Next, the mold was dried at 25 ℃ for 48 hours. Finally, the microneedle is taken out after the drying is finished.
Embodiment III: microneedle performance test
1) Needle content: when observed by a microscope, it is preferable to reach 100%, and it is preferable to reach 80%, and it is inferior to 80%.
2) Mechanical properties: the evaluation criteria were that the aluminum foil paper was successfully penetrated and that the aluminum foil paper was not penetrated.
3) Hygroscopicity: the evaluation criteria were that the microneedle hygroscopicity was good, in which the microneedle was able to successfully pass through more than 2 layers of aluminum foil paper after being placed in a high humidity environment for 12 hours, the microneedle was only able to pass through 1 layer of aluminum foil paper, and the microneedle was not able to pass through the aluminum foil paper, and the hygroscopicity was poor.
4) Degree of release: transdermal diffusion cell with FranzThe in vitro release performance of the prepared CBD autolytic microneedle patch was evaluated. The CBD autolytic microneedle patch is fixed at the mouth of a diffusion cell, phosphate Buffer (PBS) with pH of 7.4 is used as a receiving medium, the sample adding amount of each cell is 4ml, the temperature of the diffusion cell is (32+/-1) DEG C, and the rotating speed of a stirrer is 300r/min. 1ml was sampled at 5, 15, 30, 45, 60 and 90min, while 1ml blank PBS was supplemented. Samples at each time point were filtered through a 0.22 μm filter membrane, and the peak area was detected by HPLC sample injection, and the concentration (P) was calculated by an external standard method n ) The cumulative release percentage (R is calculated according to the following formula n )。
Experimental results: the rapid release is carried out for the first 30min, the release rate is obviously slowed down after 30min, the CBD is basically completely released from the autolytic microneedle patch by 60min, the release amount is not obviously increased after 90min, and the cumulative release percentage reaches (98.60 +/-1.99)%. The faster release rate of the drug from the matrix indicates that the microneedle matrix has good drug release performance.
Example IV
20 volunteers were recruited, 15 of which were females, 5 of which were males, aged 25-50 years. The autonomous sleeping time and the sleeping duration of each volunteer are recorded first in the first night, and the sleeping time and the sleeping duration are recorded after the anti-depression microneedle patch is stuck to the neck at night the second night and at the same time as the first night. The results are shown in the following table.
Table 2 anti-depressive microneedle sleep monitoring
Monitoring by sleep time, wherein the original sleep time is 2 hours, and gradually prolonging to 6 hours after pasting; the original sleeping time is 1.6 hours, and the time is gradually shortened to 0.4 hour after the plaster is applied.
The embodiments of the present invention have been described above with reference to the accompanying drawings, but the present invention is not limited to the above-described embodiments, which are merely illustrative and not restrictive, and many forms may be made by those having ordinary skill in the art without departing from the spirit of the present invention and the scope of the claims, which are to be protected by the present invention.
Claims (6)
1. An anti-depression sleep-aiding autolytic painless microneedle patch is characterized by comprising a water-soluble cannabidiol microcapsule and a microneedle matrix material; the microneedle matrix material consists of sodium hyaluronate, polyvinylpyrrolidone and water, wherein the molecular weight of the sodium hyaluronate is 5000-10000; the autolytic painless microneedle patch delivers the drug by adopting a physical penetration promotion mode penetrating through the stratum corneum but not contacting the dermis layer; 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 with a water-soluble material; the water-soluble cannabidiol microcapsule is arranged at the needle part of the self-soluble painless microneedle patch, and the self-soluble painless microneedle patch accounts for 2.5 percent.
2. The autolytic painless microneedle patch of claim 1, wherein the water soluble material comprises an alpha cyclodextrin, a beta cyclodextrin, a gamma cyclodextrin, or a hydroxypropyl-beta cyclodextrin.
3. The self-dissolving painless microneedle patch of claim 1, wherein the mass percentages of sodium hyaluronate, polyvinylpyrrolidone and water are: polyvinylpyrrolidone: water = 1-5:1-5:10-15.
4. The autolytic painless microneedle patch of claim 1, wherein the autolytic painless microneedle patch comprises 100-400 microneedles per square centimeter, the microneedles comprising triangular-cone-shaped microneedles and conical-shaped microneedles.
5. The method for preparing the autolytic painless microneedle patch according to any one of claims 1 to 4, comprising the steps of:
(1) Dissolving cannabidiol crystal with purity higher than 99% with ethanol, heating to above 50deg.C to accelerate dissolution if necessary, and cooling to room temperature after dissolution;
(2) Heating and dissolving any one of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin or hydroxypropyl-beta-cyclodextrin with pure water or ethanol, adding the solution obtained in the step (1) after the dissolution is completed, and stirring and mixing uniformly;
(3) Placing the mixed solution prepared in the step (2) into a closed container, performing ultrasonic treatment for 1-4h by using an ultrasonic generator, wherein the ultrasonic power is 5000-8000W, and the temperature is 20-60 ℃; concentrating under reduced pressure and drying to remove water after ultrasonic treatment;
(4) Transferring the material obtained in the step (3) into a spray dryer, wherein the spraying pressure is 100-200 atm, the material is fed at the speed of 300-600ml/h, the air inlet flow rate of hot air is 0.3-0.8 m/min, and the air inlet temperature is 100-200 ℃, so as to obtain the water-soluble cannabidiol microcapsule;
(5) Completely dissolving sodium hyaluronate and polyvinylpyrrolidone with molecular weight of 5000-10000 in water, then adding the water-soluble cannabidiol microcapsule, and uniformly stirring to form a polymer solution, wherein the mass ratio of each substance in the polymer solution is that the water-soluble cannabidiol microcapsule: sodium hyaluronate: polyvinylpyrrolidone: water = 0.4:2.5:1.5:12; introducing the polymer solution into a mold and pressurizing under vacuum conditions forces the polymer solution into the mold, causing the polymer solution to fill the microneedle tips.
6. The method of claim 5, wherein the water-soluble cannabidiol microcapsules have a particle size of 200-500 μm.
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