CN113559251A - Soluble micro-needle patch and preparation method and application thereof - Google Patents
Soluble micro-needle patch and preparation method and application thereof Download PDFInfo
- Publication number
- CN113559251A CN113559251A CN202110687960.XA CN202110687960A CN113559251A CN 113559251 A CN113559251 A CN 113559251A CN 202110687960 A CN202110687960 A CN 202110687960A CN 113559251 A CN113559251 A CN 113559251A
- Authority
- CN
- China
- Prior art keywords
- solution
- microneedle
- microneedle patch
- needle body
- molecular polymer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
The invention provides a soluble microneedle patch, a preparation method and application thereof. The microneedle patch comprises a main body support component and sustained-release microspheres, wherein the main body support component consists of a needle body and a base layer. The neurotoxin sustained-release microspheres are prepared from functional components and a biocompatible high polymer material and are coated in the needle body; the needle body is prepared from a hydrophilic high molecular polymer and magnesium particles; the base layer is prepared from antibacterial high polymer materials. The functional component is botulinum toxin A. The microneedle patch disclosed by the invention effectively penetrates the stratum corneum barrier of the skin, and as the hydrophilic high polymer material is quickly dissolved in the skin, the slow-release microspheres containing the effective components are implanted into the dermis layer for long-term effective component slow release, so that long-term treatment of diseases is realized.
Description
Technical Field
The invention belongs to the technical field of noninvasive soluble microneedles, and particularly relates to a soluble microneedle patch and a preparation method and application thereof.
Background
Botulinum toxin is useful in the treatment of a variety of diseases, including hyperhidrosis. Hyperhidrosis generally manifests as a condition of excessive secretion of sweat from the sweat glands. Statistically, 1% to 3% of the world's population suffers from hyperhidrosis. Patients with hyperhidrosis often encounter the following situations in life: drench clothing in formal social situations; the odor is bad due to a lot of sweating in professional occasions, or the embarrassment is caused by the odor brought by over-sweating in armpits when people contact with people at a short distance. According to a sampling survey of 2017 in the united states, about one third of hyperhidrosis patients indicate that spontaneous sweating is almost unbearable and often plagues common daily activities.
The currently common treatment modalities for hyperhidrosis are aluminium antiperspirants and iontophoresis. Aluminum antiperspirants, however, have been tested extensively to demonstrate little antiperspirant effect, but rather to mask body odor by virtue of the perfume ingredients incorporated into the antiperspirant. The iontophoresis method requires a complicated apparatus and a long treatment time, which causes great inconvenience to patients. With the development of therapeutic techniques, in recent years, botulinum toxin a (also referred to as botulinum toxin type a) has come to be widely used for the treatment of hyperhidrosis, and by injecting botulinum toxin a, neurotransmitters between sympathetic nerves and sweat glands are greatly reduced, thereby reducing sweat secretion from sweat glands, with a good antiperspirant effect.
Although botulinum A injection simplifies the procedure compared to iontophoresis, it still requires regular procedures by professional medical personnel. In order to further improve the convenience of handling, the prior art also proposes transdermal administration of botulinum toxin a to an area to be treated using an injection-type hollow microneedle, but on the one hand, it is difficult to achieve both the convenience of handling and the high efficiency of administration. On the other hand, botulinum toxin A, a neurotoxin protein, has a retention property of itself which limits the amount of botulinum toxin A administered per injection, and a therapeutic effect can be obtained in a short period of time, but it is difficult to satisfy the long-term treatment of hyperhidrosis.
In addition to the treatment of hyperhidrosis, botulinum toxin is also commonly used in the cosmetic and plastic industries, and botulinum toxin a is used to treat hypertrophy of the massaged muscles, remove wrinkles, and the like. However, when used in these therapeutic fields, they also have problems of poor convenience, low administration efficiency to the human body, and poor long-lasting therapeutic effect. Under the background, the technical problem to be solved in the field is how to search a convenient, efficient and safe soluble microneedle treatment device for long-acting treatment.
Disclosure of Invention
The invention solves the technical problems that a microneedle device in the prior art is difficult to have both convenience and high efficiency of operation and is not suitable for long-acting treatment, further provides a soluble microneedle patch which is convenient, efficient and safe and can be used for long-acting treatment, and also provides a preparation method and application of the soluble microneedle patch.
The technical scheme adopted by the application for solving the technical problems is as follows:
a dissolvable microneedle patch comprising: the main body supporting part comprises a base layer and needle bodies distributed on the base layer; the needle body is prepared from a hydrophilic high molecular polymer, and the hydrophilic high molecular polymer is at least one of monomer polymers or copolymers of polyvinylpyrrolidone and derivatives thereof, trehalose, dextran, carboxymethyl cellulose, chondroitin sulfate, polyvinyl alcohol, silk fibroin and hyaluronic acid; the needle body is distributed with slow release microspheres and magnesium particles; the sustained-release microspheres are prepared from functional components and a biocompatible high-molecular polymer material; the biocompatible high molecular polymer material is at least one of polyvinyl alcohol, polyethylene glycol, polylactic acid, dextran, methylcellulose, carboxymethylcellulose, polyethylene glycol, hypromellose, hydroxymethyl cellulose, hydroxypropyl methylcellulose and gelatin; the functional component is botulinum toxin A.
The molecular weight range of the botulinum toxin A is 150-900 kDa.
The diameter of the magnesium particles is 10-100 mu m.
The base layer is made of antibacterial high polymer materials.
The antibacterial high polymer material is chitosan.
The loading capacity of the botulinum toxin A of each microneedle patch is 220-260U.
The microneedle body is conical and 300-800 mu m in height.
The preparation method of the soluble microneedle patch comprises the following steps of (1) blending the functional components with a microsphere solution, adding the functional components into a water phase to rotate at a high speed, and forming precipitates in the water phase by the slow release microspheres consisting of the biocompatible high polymer material and the functional components; the microsphere solution is a mixed solution prepared from the biocompatible high-molecular polymer material and a solvent, and the concentration of the biocompatible high-molecular polymer material in the mixed solution is 50-400 g/L; the solvent is at least one selected from dioxane, benzene, toluene, pentane, hexane, methanol, ethanol, diethyl ether, ethyl acetate, acetone and carbon tetrachloride; (2) separating the slow release microsphere precipitate, uniformly mixing with magnesium particles, and placing into the groove part of the needle body of the microneedle female die; adding the needle body solution into a needle body groove of the microneedle concave die, firstly carrying out low-speed centrifugation or vacuum drying treatment under the low-temperature condition, then scraping the redundant needle body solution, and then continuously carrying out centrifugation or vacuum drying treatment under the room-temperature condition; the needle body solution is an aqueous solution prepared from the hydrophilic high-molecular polymer and water, and the concentration of the hydrophilic high-molecular polymer in the aqueous solution is 20-200 g/L; (3) adding the base solution into a microneedle female die, carrying out vacuum treatment in a vacuum drier at low temperature, scraping off redundant needle point solution, and drying at 30-40 ℃ for 4-6 hours; (4) and (3) placing the microneedle concave die at normal temperature for drying, and taking out the solidified material in the microneedle concave die to obtain the soluble microneedle patch.
The soluble microneedle patch is used for treating hyperhidrosis or removing wrinkles.
The basic solution is prepared by dissolving bacteriostatic high-molecular polymer materials in acetic acid aqueous solution and performing dialysis and rotary evaporation.
The soluble microneedle patch has the advantages that:
the invention relates to a microneedle or microneedle patch, which is characterized in that a microneedle body is made of hydrophilic high molecular polymer and magnesium particles, a base layer is made of antibacterial high molecular polymer material, a biocompatible high molecular polymer material and slow-release microspheres loaded with functional components and made of botulinum toxin A are used for preparing a soluble microneedle for long-acting treatment, and after the soluble microneedle acts on the skin, the dissolution of the soluble high molecular polymer is accelerated along with the reaction of magnesium and body fluid, so that a needle point is quickly and efficiently separated from the microneedle base layer, and the slow-release microspheres loaded with the functional components are quickly implanted into the skin, so that the microneedle body can efficiently act on a human body, and the administration efficiency is improved. Meanwhile, the slow release microspheres loaded with the botulinum toxin A are implanted into a dermis layer, and the biocompatible high polymer material can be slowly degraded under the skin to release the loaded bioactive components; therefore, the sustained release of the botulinum toxin A can be carried out for a long time, and the botulinum toxin A is irreversibly attached to the presynaptic nerve terminal to inhibit the acetylcholine secretion of the nerve junction part and the sweat secretion of sweat gland, thereby realizing the long-term treatment of the hyperhidrosis.
The dissolvable microneedle patch of the present invention has a variety of uses, including wrinkle removal applications in addition to use in treating hyperhidrosis.
In order to make the technical scheme of the soluble microneedle patch, the preparation method and the application thereof more clear and clear, the invention is further explained with reference to the accompanying drawings and the specific embodiments.
Drawings
Fig. 1 is a structure of a dissolvable microneedle patch according to the present invention;
wherein the reference numerals are:
1-a needle body; 2-magnesium particles; 3-sustained release microspheres; 4-base layer.
Detailed Description
The present embodiment provides a dissolvable microneedle patch, which has a structure as shown in fig. 1, and includes a main body supporting portion, the main body supporting portion further includes a base layer and needles distributed on the base layer; the needle body is distributed with slow release microspheres and magnesium particles.
The micro-needle concave die is used in the preparation process of the soluble micro-needle patch in the embodiment and comprises a rectangular sheet-shaped groove body, a plurality of needle body grooves are formed in the bottom surface of the sheet-shaped groove body, and the needle body grooves are conical and are matched with the needle bodies in shape. The height of the needle body groove is 300-800 mu m and is matched with the height of the needle body. In this embodiment, the distribution density of the needle grooves in the microneedle cavity is 20 × 20/cm2. In the present embodiment, the area of each piece is 1cm2The loading amount of the botulinum toxin A of the microneedle patch is 220-260U.
This embodiment further provides methods for preparing various dissolvable microneedle patches by the following examples.
Example 1
The method for preparing the dissolvable microneedle patch described in this embodiment includes the following steps:
(1) blending the functional component botulinum toxin A with the microsphere solution, adding the functional component botulinum toxin A into the water phase, and stirring at a high speed of 450 r/min; wherein the water phase adopts deionized water; the microsphere solution is a mixed solution prepared from polyvinyl alcohol and a solvent, the concentration of the polyvinyl alcohol in the mixed solution is 50g/L, and the solvent is dioxane; after stirring, the slow release microspheres consisting of the polyvinyl alcohol and the functional components form precipitates in the water phase. The molecular weight range of the botulinum toxin A in the embodiment is 150-900 kDa.
(2) Separating the slow release microsphere precipitate generated in the step (1) in a filtering or centrifugal separation mode, uniformly mixing the slow release microsphere and magnesium particles, and placing the mixture into the groove part of the needle body of the microneedle female die; then adding the needle body solution into a needle body groove of the microneedle concave die, and performing vacuum drying treatment at the low temperature of 20 ℃ for 2 hours; and then scraping off the redundant needle body solution, and continuing to perform vacuum drying treatment at room temperature until the needle body is dried.
The diameter of the magnesium particles used in the step is 10-100 mu m, and the mass ratio of the added magnesium particles to the slow-release microspheres is 1: 1.
In this embodiment, the solution of the needle body is an aqueous solution prepared from polyvinylpyrrolidone and water, and the concentration of the polyvinylpyrrolidone in the aqueous solution is 20 g/L.
(3) Adding the base solution into a microneedle concave die, carrying out vacuum drying treatment in a vacuum dryer at low temperature of 21 ℃, scraping redundant needle point solution, and drying for 4-6 hours at 37 ℃;
in this embodiment, the basic solution is prepared by dissolving chitosan, which is an antibacterial high molecular polymer material, in an acetic acid aqueous solution, and then dialyzing and rotary evaporating the solution. The preparation method comprises the following steps: dissolving chitosan in acetic acid water solution with the concentration of 1% V/V to prepare primary chitosan solution with the concentration of 20g/L, and dialyzing the primary chitosan solution at room temperature for 48 hours in ultrapure water to remove excessive acetic acid; after the ultrapure water dialysis is completed, the pH value of the primary chitosan solution is adjusted to 6, and then the primary chitosan solution with the concentration of 100g/L is obtained through rotary evaporation.
(4) And (3) placing the microneedle concave die at normal temperature for drying, and taking out the cured material in the microneedle concave die to obtain the soluble microneedle patch for long-acting treatment of hyperhidrosis.
Example 2
The method for preparing the dissolvable microneedle patch described in this embodiment includes the following steps: (1) mixing the functional component botulinum toxin A with the microsphere solution, then adding the mixture into the water phase, and stirring at a high speed of 850 r/min; wherein the water phase adopts ultrapure water; the microsphere solution is a mixed solution prepared from polyethylene glycol and a solvent, the concentration of the polyethylene glycol in the mixed solution is 100g/L, and the solvent is a toluene solvent; after stirring, the slow release microspheres consisting of the polyethylene glycol and the functional components form precipitates in the water phase. The molecular weight range of the botulinum toxin A in the embodiment is 150-900 kDa.
(2) Separating the slow release microsphere precipitate generated in the step (1) in a filtering or centrifugal separation mode, uniformly mixing the slow release microsphere and magnesium particles, and placing the mixture into the groove part of the needle body of the microneedle female die; then adding the needle body solution into a needle body groove of the microneedle concave die, and firstly carrying out low-speed centrifugal treatment at the low temperature of 5 ℃ for 6 hours; and then scraping off the redundant needle body solution, and continuing to perform low-speed centrifugation treatment at room temperature until the needle body is dry. The rotation speed when the low-speed centrifugation treatment is carried out is 4000 r/min.
The diameter of the magnesium particles used in the step is 10-100 mu m, and the mass ratio of the added magnesium particles to the slow-release microspheres is 2: 3.
In the embodiment, the needle body solution is an aqueous solution prepared from trehalose and water, and the concentration of the trehalose in the aqueous solution is 200 g/L.
(3) Adding the base solution into a microneedle concave die, carrying out vacuum drying treatment in a vacuum dryer at low temperature of 21 ℃, scraping redundant needle point solution, and drying for 4-6 hours at 37 ℃;
in this embodiment, the basic solution is prepared by dissolving chitosan, which is an antibacterial high molecular polymer material, in an acetic acid aqueous solution, and then dialyzing and rotary evaporating the solution. The specific preparation method is the same as that of example 1.
(4) And (3) placing the microneedle concave die at normal temperature for drying, and taking out the cured material in the microneedle concave die to obtain the soluble microneedle patch for long-acting treatment of hyperhidrosis.
Example 3
The method for preparing the dissolvable microneedle patch described in this embodiment includes the following steps:
(1) blending the functional component botulinum toxin A with the microsphere solution, then adding the mixture into the water phase, and stirring at a high speed of 550 r/min; wherein the water phase adopts deionized water; the microsphere solution is a mixed solution prepared from polylactic acid and a solvent, the concentration of the polylactic acid in the mixed solution is 400g/L, and the solvent is methanol; after stirring, the slow release microspheres consisting of the polylactic acid and the functional components form precipitates in a water phase. The molecular weight range of the botulinum toxin A in the embodiment is 150-900 kDa.
(2) Separating the slow release microsphere precipitate generated in the step (1) in a filtering or centrifugal separation mode, uniformly mixing the slow release microsphere and magnesium particles, and placing the mixture into the groove part of the needle body of the microneedle female die; then adding the needle body solution into a needle body groove of the microneedle concave die, and performing vacuum drying treatment at 21 ℃ for 3 hours; and then scraping off the redundant needle body solution, and continuing to perform vacuum drying treatment at room temperature until the needle body is dried.
The diameter of the magnesium particles used in the step is 10-100 mu m, and the mass ratio of the added magnesium particles to the slow-release microspheres is 1: 3.
In this embodiment, the needle body solution is an aqueous solution prepared from hyaluronic acid and water, and the concentration of hyaluronic acid in the aqueous solution is 100 g/L.
(3) Adding the base solution into a microneedle concave die, carrying out vacuum drying treatment in a vacuum dryer at the low temperature of 20 ℃, scraping redundant needle point solution, and drying at 37 ℃ for 4-6 hours;
in this embodiment, the basic solution is prepared by dissolving chitosan, which is an antibacterial high molecular polymer material, in an acetic acid aqueous solution, and then dialyzing and rotary evaporating the solution. The preparation method comprises the following steps: dissolving chitosan in acetic acid water solution with the concentration of 1% V/V to prepare primary chitosan solution with the concentration of 20g/L, and dialyzing the primary chitosan solution at room temperature for 48 hours in ultrapure water to remove excessive acetic acid; after the ultrapure water dialysis is completed, the pH value of the primary chitosan solution is adjusted to 6, and then the primary chitosan solution with the concentration of 100g/L is obtained through rotary evaporation.
(4) And (3) placing the microneedle concave die at normal temperature for drying, and taking out the cured material in the microneedle concave die to obtain the soluble microneedle patch for long-acting treatment of hyperhidrosis.
In the soluble microneedle patch prepared in examples 1 to 3 of this embodiment, when in use, the needle tip side of the patch is tightly attached to the skin, and after the needle body acts on the skin, the dissolution of the soluble high molecular polymer can be accelerated along with the reaction of magnesium and body fluid, so that the needle tip and the microneedle base layer are separated quickly and efficiently, the sustained release microspheres loaded with botulinum toxin a are implanted into the dermis layer, so that the sustained release of botulinum toxin a can be carried out for a long time, the corrosion inhibition time can be as long as 12 months, and the sustained release effect is very excellent. Botulinum toxin A inhibits sympathetic nerve activity and neurotransmitters between sympathetic nerves and sweat glands are greatly reduced, thereby enabling long-term treatment of hyperhidrosis. In addition to being used to treat hyperhidrosis, the dissolvable microneedle patch of this embodiment may also be used to remove wrinkles.
In the soluble microneedle patch of examples 1 to 3 in this embodiment, in addition to the polyvinylpyrrolidone, trehalose, and hyaluronic acid in the above examples, the hydrophilic polymer in the needle body may be at least one of a copolymer of polyvinylpyrrolidone, a monomer polymer or copolymer of a polyvinylpyrrolidone derivative, dextran, carboxymethyl cellulose, chondroitin sulfate, polyvinyl alcohol, and silk fibroin. The biocompatible high molecular polymer material in the slow release microspheres can also be selected from at least one of dextran, methylcellulose, carboxymethylcellulose, polyethylene glycol, hypromellose, hydroxymethyl cellulose, hydroxypropyl methylcellulose and gelatin.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the claims.
Claims (9)
1. A dissolvable microneedle patch, comprising:
the main body supporting part comprises a base layer and needle bodies distributed on the base layer;
the needle body is prepared from a hydrophilic high molecular polymer, and the hydrophilic high molecular polymer is at least one of monomer polymers or copolymers of polyvinylpyrrolidone and derivatives thereof, trehalose, dextran, carboxymethyl cellulose, chondroitin sulfate, polyvinyl alcohol, silk fibroin and hyaluronic acid;
the needle body is distributed with slow release microspheres and magnesium particles; the sustained-release microspheres are prepared from functional components and a biocompatible high-molecular polymer material; the biocompatible high molecular polymer material is at least one of polyvinyl alcohol, polyethylene glycol, polylactic acid, dextran, methylcellulose, carboxymethylcellulose, polyethylene glycol, hypromellose, hydroxymethyl cellulose, hydroxypropyl methylcellulose and gelatin; the functional component is botulinum toxin A.
2. The soluble microneedle patch according to claim 1, wherein said botulinum toxin a has a molecular weight in the range of 150-900 kDa.
3. The dissolvable microneedle patch according to claim 1, wherein said magnesium particles are 10-100 μ ι η in diameter.
4. The dissolvable microneedle patch according to claim 1, wherein the base layer is made of bacteriostatic high molecular polymer material.
5. The dissolvable microneedle patch according to claim 4, wherein the bacteriostatic polymeric material is chitosan.
6. The dissolvable microneedle patch according to any one of claims 1-5, wherein each microneedle patch has a botulinum loading of 220- > 260U.
7. The dissolvable microneedle patch according to any one of claims 1-6, wherein said microneedle body is tapered having a height of 300-800 μm.
8. The method of preparing a dissolvable microneedle patch according to claim 1, comprising the steps of:
(1) blending the functional components with a microsphere solution, adding the mixture into a water phase, and rotating at a high speed, wherein the slow release microspheres composed of the biocompatible high polymer material and the functional components form precipitates in the water phase; the microsphere solution is a mixed solution prepared from the biocompatible high-molecular polymer material and a solvent, and the concentration of the biocompatible high-molecular polymer material in the mixed solution is 50-400 g/L; the solvent is at least one selected from dioxane, benzene, toluene, pentane, hexane, methanol, ethanol, diethyl ether, ethyl acetate, acetone and carbon tetrachloride;
(2) separating the slow release microsphere precipitate, uniformly mixing with magnesium particles, and placing into the groove part of the needle body of the microneedle female die; adding the needle body solution into a needle body groove of the microneedle concave die, firstly carrying out low-speed centrifugation or vacuum drying treatment under the low-temperature condition, then scraping the redundant needle body solution, and then continuously carrying out centrifugation or vacuum drying treatment under the room-temperature condition; wherein the needle body solution is an aqueous solution prepared from the hydrophilic high molecular polymer and water, and the concentration of the hydrophilic high molecular polymer in the aqueous solution is 20-200 g/L;
(3) adding the base solution into a microneedle female die, carrying out vacuum treatment in a vacuum drier at low temperature, scraping off redundant needle point solution, and drying at 30-40 ℃ for 4-6 hours;
(4) and (3) placing the microneedle concave die at normal temperature for drying, and taking out the solidified material in the microneedle concave die to obtain the soluble microneedle patch.
9. Use of the dissolvable microneedle patch of claims 1-7 for treating hyperhidrosis or removing wrinkles.
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