Microneedle administration method for treating gout

Abstract

The invention provides a microneedle administration method for treating gout, and relates to the field of gout administration, and the microneedle administration method comprises the following steps: S100, preparing a needle tip gel solution: mixing a gout treatment drug with hyaluronic acid, and stirring until the gout treatment drug and hyaluronic acid are completely dissolved to form a drug-loaded needle tip gel solution; s200, preparing a backing gel solution: dissolving hyaluronic acid in an aqueous solvent, and stirring until the hyaluronic acid is completely dissolved to form the backing gel solution. S300, injecting the needle tip gel solution into a needle hole of a microneedle mold, sequentially carrying out vacuum drying and centrifugal treatment to enable the needle hole to be fully filled with the solution, and drying the needle tip for 150 minutes; s400, the surface of a mold is covered with the backing gel solution, vacuum drying is conducted, and a backing layer is formed; and S500, demolding to obtain the drug-loaded microneedle patch, and attaching the drug-loaded microneedle patch to the skin of a patient to deliver a drug. The medicine is directly delivered to the corium layer through the microneedle, the liver first-pass effect and gastrointestinal tract degradation caused by oral administration are avoided, the medicine is released after microneedle puncture, and the medicine is suitable for rapid analgesia in the gout acute attack period, reduction of whole body exposure through local administration, reduction of the gastrointestinal ulcer occurrence rate of NSAIDs medicines and reduction of side effects. The length of the microneedle is 200-800 micrometers, the microneedle only penetrates through the cuticle, nerve endings are prevented from being damaged, the patch is packaged in a sterile aluminum-plastic bubble cap, a patient can attach the patch by himself / herself, and the requirement for frequently seeing a doctor is reduced.

Description

Technical Field

[0001] The present invention relates to the field of gout drug delivery, and in particular to a microneedle drug delivery method for treating gout. Background Art

[0002] The current treatment for gout is mainly oral administration. Although oral administration is convenient and fast, it also has some problems:

[0003] 1. Bioavailability:

[0004] First-pass effect: The drug is metabolized while passing through the liver, resulting in a decrease in the amount of drug entering the blood circulation and reducing the bioavailability of the drug;

[0005] Food effects: Food can affect drug absorption. For example, some drugs need to be taken after a meal, while others need to be taken on an empty stomach.

[0006] Gastrointestinal disorders: Gastrointestinal disorders, such as gastritis or ulcers, can affect drug absorption;

[0007] 2. Dosage control:

[0008] Patient compliance: Patients may forget to take their medication or take the wrong dose;

[0009] Drug dissolution and absorption: Some drugs are difficult to dissolve or absorb from the intestine, resulting in reduced bioavailability;

[0010] 3. Drug stability:

[0011] Gastric fluid environment: Some drugs will be degraded in the acidic gastric fluid environment;

[0012] Enzyme metabolism: Enzymes in the gastrointestinal tract metabolize some drugs, reducing their bioavailability;

[0013] 4. Side effects:

[0014] Gastrointestinal reactions: nausea, vomiting, abdominal pain and other common side effects;

[0015] Drug interactions: Different drugs may interact with each other, affecting drug absorption, metabolism or excretion;

[0016] 5. Drug safety:

[0017] Children and the elderly: Children and the elderly may have different abilities to absorb, metabolize, and excrete drugs, requiring dose adjustment;

[0018] Pregnant and breastfeeding women: Certain drugs pose risks to pregnant and breastfeeding women and need to be used with caution;

[0019] 6. Situations where oral administration is not suitable:

[0020] Poor absorption of oral medications

[0021] Patient is unconscious: Patient cannot take oral medication when unconscious;

[0022] Vomiting or dysphagia: Patients cannot take oral medications if they vomit or have dysphagia;

[0023] Drug irritation: Some drugs can irritate the gastrointestinal tract and should not be taken orally.

[0024] Therefore, we made improvements to this and proposed a microneedle drug delivery method for the treatment of gout. Summary of the Invention

[0025] The purpose of the present invention is to treat gout by Although oral administration is convenient and quick, It also has problems with inconvenience in operation and side effects .

[0026] In order to achieve the above-mentioned purpose of the invention, the present invention provides a microneedle drug delivery method for treating gout to improve the above-mentioned problems.

[0027] The specific application is as follows:

[0028] The following steps are involved:

[0029] S100, preparing a needle tip gel solution: mixing a gout treatment drug with hyaluronic acid, and stirring until completely dissolved to form a drug-loaded needle tip gel solution;

[0030] S200, preparing a backing gel solution: dissolving hyaluronic acid in an aqueous solvent and stirring until completely dissolved to form a backing gel solution;

[0031] S300, injecting the needle tip gel solution into the pinholes of the microneedle mold, sequentially performing vacuum drying and centrifugation to allow the solution to fully fill the pinholes, and performing vacuum drying to form a needle tip layer;

[0032] S400, covering the backing gel solution on the mold surface and vacuum drying to form a backing layer;

[0033] S500: After demoulding, the drug-loaded microneedle patch is obtained and attached to the patient's skin to deliver the drug.

[0034] As a preferred technical solution of the present application, the gout treatment drug is selected from at least one of the following: non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, glucocorticoids, uricase or IL-1β inhibitors (loxoprofen ointment, Babu ointment, Shuxiaoyao patch).

[0035] As a preferred technical solution of the present application, the molecular weight of the hyaluronic acid is 200,000-400,000, the mass concentration of hyaluronic acid in the needle tip gel solution is 10%-30%, and the mass concentration of hyaluronic acid in the backing gel solution is 5%-15%.

[0036] As the preferred technical solution of this application, the needle body length of the microneedle mold is 200-800 microns, the needle tip diameter is 50-200 microns, and the array density is 50-200 needles / cm 2 .

[0037] As the preferred technical solution of this application, the vacuum drying conditions are: vacuum degree 0.09-0.1MPa, temperature 37-45°C, time 150 minutes; centrifugal conditions are speed 3000-5000rpm, time 2-5 minutes.

[0038] As a preferred technical solution of the present application, at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose (CMC) or sodium alginate is further added to the needle tip gel solution or the backing gel solution to adjust the mechanical strength of the gel.

[0039] As a preferred technical solution of the present application, the microneedle mold is made of polydimethylsiloxane (PDMS), polylactic acid (PLA) or metal, and the mold surface is plasma treated to enhance solution wettability.

[0040] As a preferred technical solution of the present application, the backing layer of the drug-loaded microneedle patch further contains a penetration enhancer, including menthol, azone or liposomes, for enhancing the transdermal penetration efficiency of the drug.

[0041] As a preferred technical solution of the present application, the microneedle patch is sterilized by gamma rays before use and packaged in a sterile aluminum-plastic blister package.

[0042] As the preferred technical solution of this application, the microneedle patch applies 0.1-0.5N / cm 2 The pressure is maintained for 5-30 minutes to complete drug delivery.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] In the scheme of this application:

[0045] 1. The drug is delivered directly to the dermis through microneedles, avoiding the first-pass liver effect and gastrointestinal degradation of oral administration. The drug is released after microneedle puncture, significantly shortening the time to peak blood drug concentration. It is suitable for rapid analgesia during acute gout attacks. Local administration reduces systemic exposure, reduces the incidence of gastrointestinal ulcers of NSAIDs, and minimizes side effects. The microneedles are 200-800 microns in length and only penetrate the stratum corneum to avoid damage to nerve endings. The patch is encapsulated in a sterile aluminum-plastic blister, which patients can apply by themselves, reducing the need for frequent medical treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 A schematic diagram of the microneedle drug delivery method for treating gout provided in this application;

[0047] Figure 2 Schematic diagram of the morphology of the meltable microneedles under an electron microscope for the microneedle drug delivery method for treating gout provided in this application Figure 1 ;

[0048] Figure 3 Schematic diagram of the morphology of the meltable microneedles under an electron microscope for the microneedle drug delivery method for treating gout provided in this application Figure 2 . DETAILED DESCRIPTION

[0049] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of the present invention.

[0050] As described in the background art, gout is treated by Although oral administration is convenient and quick, it also has operational difficulties. Problems with bowel movements and side effects .

[0051] In order to solve this technical problem, the present invention provides a microneedle drug delivery method for treating gout, which is applied to Gout drug delivery .

[0052] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0053] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features and technical solutions therein may be combined with each other.

[0054] It should be noted that similar reference numerals and letters denote similar items in the following drawings, and therefore, once an item is defined in one drawing, it does not need to be further defined or explained in subsequent drawings.

[0055] Example 1, please refer to Figure 1-Figure 3 , a microneedle drug delivery method for treating gout, comprising the following steps:

[0056] S100, preparing a needle tip gel solution: mixing a gout treatment drug with hyaluronic acid, and stirring until completely dissolved to form a drug-loaded needle tip gel solution;

[0057] S200, preparing a backing gel solution: dissolving hyaluronic acid in an aqueous solvent and stirring until completely dissolved to form a backing gel solution;

[0058] S300, injecting the needle tip gel solution into the pinholes of the microneedle mold, sequentially performing vacuum drying and centrifugation to allow the solution to fully fill the pinholes, and performing vacuum drying to form a needle tip layer;

[0059] S400, covering the backing gel solution on the mold surface and vacuum drying to form a backing layer;

[0060] S500, after demoulding, the drug-loaded microneedle patch is obtained and attached to the patient's skin to deliver the drug;

[0061] By preparing the needle tip and backing gel solution step by step, combined with vacuum drying and centrifugation processes, the drug is ensured to be precisely distributed at the microneedle tip, avoiding drug waste, significantly increasing the local drug concentration, and reducing side effects caused by systemic exposure. At the same time, the mechanical strength of the microneedle is supported by the backing layer, ensuring skin puncture efficiency.

[0062] The gout treatment drugs are selected from at least one of the following: non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, glucocorticoids, uricase or IL-1β inhibitors (loxoprofen ointment, Babu ointment, Shuxiaoyao patch). The selected drugs cover different stages of gout (acute inflammatory stage and chronic uric acid-lowering treatment), are adapted to the physicochemical properties of microneedle delivery (such as molecular weight, solubility), and directly deliver anti-inflammatory or uric acid-lowering drugs to the lesions through microneedles, avoiding the first-pass effect and gastrointestinal irritation of oral administration, and improving treatment safety.

[0063] The molecular weight of the hyaluronic acid is 200,000-400,000, the mass concentration of hyaluronic acid in the needle tip gel solution is 10%-30%, and the mass concentration of hyaluronic acid in the backing gel solution is 5%-15%. Too low a molecular weight (<200,000) will lead to a loose microneedle structure, while too high a molecular weight (>400,000) will reduce the solubility; the concentration gradient design ensures a balance between the hardness of the needle tip and the flexibility of the backing. The high concentration of hyaluronic acid at the needle tip provides sufficient mechanical strength to penetrate the skin, and the low concentration of hyaluronic acid on the backing enhances the flexibility of the patch to avoid breakage during use.

[0064] The microneedle mold has a needle body length of 200-800 microns, a needle tip diameter of 50-200 microns, and an array density of 50-200 needles / cm 2 The needle length covers the epidermis to the superficial dermis, which is suitable for patients with different skin thicknesses; the needle tip diameter is optimized to the balance point between penetration resistance and drug carrying capacity, ensuring that the drug is delivered to the capillary area of ​​the dermis and improving bioavailability. At the same time, the high-density array design increases the single dose.

[0065] The vacuum drying conditions are: vacuum degree 0.09-0.1MPa, temperature 37-45°C, and time 150 minutes; the centrifugation conditions are rotation speed 3000-5000rpm and time 2-5 minutes. Vacuum drying removes bubbles and accelerates solvent volatilization, and centrifugation forces the solution to penetrate into the needle hole. The two work together to avoid needle tip void defects. In actual production, after the process parameters are optimized, the microneedle forming rate reaches more than 95%, and the drug distribution uniformity error is <5%, significantly improving batch consistency.

[0066] The microneedle mold is made of polydimethylsiloxane (PDMS), polylactic acid (PLA) or metal, and the mold surface is plasma treated to enhance solution wettability. The PDMS mold is low-cost and easy to demold, the PLA mold is biodegradable and environmentally friendly, and the metal mold is suitable for high-temperature and high-pressure sterilization. Plasma treatment reduces the mold contact angle from 110° to 20°, increases the solution filling rate by 30%, and reduces raw material waste.

[0067] The backing layer of the drug-loaded microneedle patch also contains a penetration enhancer, including menthol, azone or liposomes, which is used to enhance the efficiency of drug transdermal penetration. The penetration enhancer temporarily disrupts the lipid arrangement of the stratum corneum, reduces the skin barrier resistance, and combines microneedle physical puncture with chemical penetration enhancement to increase the drug transdermal rate by 2-3 times. It is particularly suitable for large molecule drugs (such as uricase).

[0068] The microneedle patch is sterilized by gamma rays before use and packaged in a sterile aluminum-plastic blister package. Gamma rays have strong penetrability and leave no residue. The aluminum-plastic blister blocks moisture and oxygen, and the shelf life can reach 24 months. The bacterial endotoxin content after sterilization is <0.25EU / mg, which meets the requirements of the pharmacopoeia, and the portable packaging is suitable for patients to use at home.

[0069] After the microneedle patch is attached, 0.1-0.5N / cm is applied to the skin. 2 The pressure lasts for 5-30 minutes to complete drug delivery. The pressure is achieved through an elastic bandage or self-adhesive backing to avoid bending of the microneedles due to excessive pressure. The pressure drives the microneedles deep into the skin, and the short-term attachment reduces the risk of skin irritation and contact dermatitis.

[0070] In the present invention, unless otherwise specified or limited, the terms "installed," "connected," "connect," "fixed," etc. should be understood in a broad sense. For example, they can refer to fixed connection, detachable connection, or integration; mechanical connection, electrical connection, or communication; direct connection or indirect connection through an intermediate medium; internal communication between two elements or interaction between two elements, unless otherwise specified. Those skilled in the art will understand the specific meanings of the above terms in the present invention based on specific circumstances.

[0071] Obviously, the embodiments described above are only some embodiments of the present invention, rather than all embodiments. The preferred embodiments of the present invention are given in the accompanying drawings, but they do not limit the patent scope of the present invention. The present invention can be implemented in many different forms. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive. Although the present invention has been described in detail with reference to the aforementioned embodiments, for those skilled in the art, it is still possible to modify the technical solutions described in the aforementioned specific embodiments, or to make equivalent replacements for some of the technical features therein. Any equivalent structure made using the contents of the present invention specification and drawings, directly or indirectly used in other related technical fields, is also within the scope of patent protection of the present invention.

Claims

1. A microneedle drug delivery method for treating gout, characterized in that: The following steps are involved: S100, preparing a needle tip gel solution: mixing a gout treatment drug with hyaluronic acid, and stirring until completely dissolved to form a drug-loaded needle tip gel solution; S200, preparing a backing gel solution: dissolving hyaluronic acid in an aqueous solvent and stirring until completely dissolved to form a backing gel solution; S300, injecting the needle tip gel solution into the pinhole of the microneedle mold, performing vacuum drying and centrifugation in sequence to allow the solution to fully fill the pinhole, and performing vacuum drying; S400, covering the backing gel solution on the mold surface and vacuum drying to form a backing layer; S500: After demoulding, the drug-loaded microneedle patch is obtained and attached to the patient's skin to deliver the drug.

2. A microneedle drug delivery method for treating gout according to claim 1, characterized in that: The gout treatment drug is selected from at least one of the following: non-steroidal anti-inflammatory drugs, colchicine, glucocorticoids, uricase or IL-1β inhibitors (including loxoprofen ointment, Babu ointment, and Shuxiaoyao patch).

3. A microneedle drug delivery method for treating gout according to claim 2, characterized in that: The molecular weight of the hyaluronic acid is 200,000-400,000, the mass concentration of the hyaluronic acid in the needle tip gel solution is 10%-30%, and the mass concentration of the hyaluronic acid in the backing gel solution is 5%-15%.

4. A microneedle drug delivery method for treating gout according to claim 3, characterized in that: The microneedle mold has a needle body length of 200-800 microns, a needle tip diameter of 50-200 microns, and an array density of 50-200 needles / cm 2 .

5. A microneedle drug delivery method for treating gout according to claim 4, characterized in that: The vacuum drying conditions are: vacuum degree 0.09-0.1 MPa, temperature 37-45° C., time 150 minutes; and centrifugal conditions are rotation speed 3000-5000 rpm, time 2-5 minutes.

6. A microneedle drug delivery method for treating gout according to claim 5, characterized in that: At least one of polyvinyl alcohol, carboxymethyl cellulose or sodium alginate is further added to the needle tip gel solution or the backing gel solution to adjust the mechanical strength of the gel.

7. A microneedle drug delivery method for treating gout according to claim 6, characterized in that: The microneedle mold is made of polydimethylsiloxane, polylactic acid or metal, and the mold surface is plasma treated to enhance solution wettability.

8. A microneedle drug delivery method for treating gout according to claim 7, characterized in that: The backing layer of the drug-loaded microneedle patch also contains a penetration enhancer, including one of menthol, azone or liposome, for enhancing the transdermal penetration efficiency of the drug.

9. A microneedle drug delivery method for treating gout according to claim 8, characterized in that: The microneedle patch is sterilized by gamma ray before use and packaged in a sterile aluminum-plastic blister package.

10. A microneedle drug delivery method for treating gout according to claim 9, characterized in that: After the microneedle patch is attached, 0.1-0.5N / cm is applied to the skin. 2 The pressure is maintained for 5-30 minutes to complete drug delivery.

Images