CN112472659B

CN112472659B - Sustained-release microneedle patch and preparation method thereof

Info

Publication number: CN112472659B
Application number: CN201910864485.1A
Authority: CN
Inventors: 邢梦真; 高云华
Original assignee: Zhongke Microneedle Chongqing Technology Co ltd; Zhongke Weizhen Beijing Technology Co ltd
Current assignee: Zhongke Microneedle Chongqing Technology Co ltd; Zhongke Weizhen Beijing Technology Co ltd
Priority date: 2019-09-12
Filing date: 2019-09-12
Publication date: 2022-08-16
Anticipated expiration: 2039-09-12
Also published as: CN112472659A; WO2021047628A1

Abstract

The invention discloses a sustained-release microneedle patch and a preparation method thereof, and relates to the technical field of medicines. The micro-needle patch comprises a needle body and a needle point on the needle body, wherein at least the needle point part comprises a part prepared by needle point preparation liquid capable of realizing gelation in the drying process of the micro-needle patch; the solute of the needlepoint preparation liquid comprises a glycerophosphate compound and a nonionic cellulose ether compound. The glycerophosphate can compete with the cellulose ether compound for water molecules, so that the cloud point of the glycerophosphate is changed, the micro-needle is gelatinized in the drying process, the gel micro-needle with good skin puncture effect is prepared, and the slow release of the entrapped drug in vivo is realized.

Description

Sustained-release microneedle patch and preparation method thereof

Technical Field

The invention relates to the technical field of medicines. And more particularly, to a sustained-release microneedle patch and a method of manufacturing the same.

Background

The sustained-release microneedle is a novel transdermal drug delivery preparation which can realize continuous and gentle delivery of drugs after being applied to the skin, is suitable for long-term drug delivery and narrow-window drug use, has the advantages of reducing drug administration times, improving the drug administration safety and convenience of patients and the like, greatly improves the drug administration compliance of the patients, and plays an important role in the research of novel microneedle drug delivery preparations. The existing sustained-release microneedle is mainly based on (1) a microsphere, a liposome, a solid dispersion and other sustained-release systems; (2) degradable polymer materials such as polylactic acid-glycolic acid copolymer, chitosan and the like; (3) the sol-gel phase-transition material was designed. The introduction of a slow release system leads the preparation process to be more complicated, and the drug-loading rate can be reduced; due to poor water solubility, the degradable polymer material usually needs to use an organic reagent as a solvent, so that organic solvent residue is inevitably caused, and a safety problem is caused.

Currently, few studies on phase-change microneedles are available, including: crosslinked polyvinyl alcohol, polylactic acid-glycolic acid copolymer-polyethylene glycol-polylactic acid-glycolic acid copolymer (PLGA-PEG-PLGA) triblock copolymer, carbomer, poloxamer and the like.

Chinese patent CN102202720A discloses a method for preparing a phase-inversion polymer microneedle by using cross-linked polyvinyl alcohol, which comprises repeatedly freezing at-20 ℃ and thawing at 4 ℃ to make water-soluble polyvinyl alcohol form gel in aqueous solution through micro-crystal construction, thereby realizing sustained release delivery of drugs, but the preparation process is tedious, takes long time, and is not suitable for large-scale industrial production of sustained release microneedles; the phase-change microneedle made of PLGA-PEG-PLGA triblock copolymer has complex raw material synthesis process, poor water solubility of the material, need to introduce organic reagent and has potential safety hazard (Marc Pearton, Chris Allender, Keith Brain, et al Gene Delivery to the Epidermal Cells of Human Skin explantation Using micro-modulated micro-needle and Hydrogel formulation. pharmaceutical research 2008,25 (2): 407-; carbomer and poloxamer gel are widely used as carriers of local treatment drugs in the pharmaceutical industry due to good temperature-sensitive characteristics, and can realize the sustained release of drugs when acting on affected parts such as mucosa or skin, but the two materials have extremely poor mechanical strength and cannot be prepared into microneedles with skin puncture property.

Aiming at the problems, an applicable sol-gel phase conversion material is found, so that the applicable sol-gel phase conversion material has enough mechanical strength and can pierce the stratum corneum of human skin, the process of converting liquid sol into solid gel can be realized in the process of manufacturing the microneedle, and the porous skeleton microneedle which is beneficial to the permeation of the drug is prepared, and the applicable sol-gel phase conversion material has important research significance for promoting the continuous and smooth release of the drug in the skin.

Disclosure of Invention

An object of the present invention is to provide a sustained-release microneedle patch having a good skin piercing effect.

Another object of the present invention is to provide a method of manufacturing a sustained-release microneedle patch.

In order to achieve the purpose, the invention adopts the following technical scheme:

a sustained-release microneedle patch comprises a needle body and a needle point on the needle body, wherein at least the needle point part comprises a part prepared from a needle point preparation liquid capable of realizing gelation in the drying process of the microneedle patch;

the solute of the needlepoint preparation liquid comprises a glycerophosphate compound and a nonionic cellulose ether compound.

Preferably, the glycerophosphate compound is selected from one or more of sodium glycerophosphate, potassium glycerophosphate, magnesium glycerophosphate and calcium glycerophosphate.

Preferably, the nonionic cellulose ether compound is one or a mixture of several of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose and hydroxybutyl methylcellulose.

Preferably, the nonionic cellulose ether compound accounts for 2-40% of the total mass of the preparation liquid.

Preferably, the ratio of the solids content of the nonionic cellulose ether-based compound to the solid content of the glycerophosphate-based compound is from 1:1 to 100:1, more preferably from 5:1 to 50: 1.

Preferably, the solute of the needle tip preparation liquid also comprises a pore-forming agent, and the pore-forming agent accounts for 2% -20% of the total mass of the needle tip preparation liquid.

Preferably, the pore-forming agent is one or more of trehalose, calcium hydrogen phosphate or sodium bicarbonate.

Preferably, the solute of the needle tip preparation solution further comprises at least one active ingredient.

Preferably, the active ingredient is one or more of polypeptide drugs, protein drugs, chemical drugs, skin care active ingredients, health care active ingredients and plant extract ingredients.

Preferably, the microneedle is a unitary microneedle, a layered microneedle, a coated microneedle or a bubble microneedle.

A preparation method of a sustained-release microneedle patch at least comprises the following steps:

weighing a glycerophosphate compound, adding the glycerophosphate compound into ultrapure water, and dissolving to obtain a glycerophosphate aqueous solution;

weighing nonionic cellulose ether compounds, adding the nonionic cellulose ether compounds into a glycerophosphate aqueous solution, adding or not adding a pore-foaming agent, adding or not adding an active ingredient, stirring for dissolving, and removing bubbles to obtain a needle tip preparation solution.

Preferably, the glycerophosphate compound is selected from any one or more of sodium glycerophosphate, potassium glycerophosphate, magnesium glycerophosphate and calcium glycerophosphate; the nonionic cellulose ether compound is one or a mixture of more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose and hydroxybutyl methylcellulose.

The invention has the following beneficial effects:

according to the sustained-release microneedle patch provided by the invention, the needle point preparation liquid comprises the nonionic cellulose ether compound and the glycerophosphate compound additive, in an aqueous solution, glycerophosphate can compete with the cellulose ether compound for water molecules, so that the cellulose ether compound is dehydrated and precipitated when the temperature of the cloud point is lower than the normal temperature, the cloud point of the cellulose ether compound is changed, the microneedles are gelatinized in the drying process, the gel microneedles with good skin puncture effect are prepared, and the slow release of the entrapped drug in vivo is realized. The prescription of the microneedle needle point of the cellulose ether compound containing the glycerophosphate additive has good skin puncture effect, sharp and full needle point and good substrate flexibility, and is suitable for preparing integrated microneedles, layered microneedles, coating microneedles and bubble microneedles.

Drawings

The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.

Fig. 1 is a diagram illustrating a sol-gel phase transition process of a microneedle preparation process in example 1.

Fig. 2 shows a topographic map of the microneedles prepared in example 1 of the present invention.

Fig. 3 is a graph showing the puncture effect of the microneedles prepared in example 1 of the present invention.

Fig. 4 is a graph showing the skin effect of the microneedles prepared in comparative example 1 and example 1 according to the present invention.

Fig. 5 shows a diagram of the intradermal sustained release delivery process for layered microneedles prepared in example 10 of the present invention.

Fig. 6 shows a schematic structural view of coated microneedles prepared in example 11 of the present invention.

Fig. 7 shows a schematic view of a bubble type microneedle structure prepared in example 12 of the present invention.

Figure 8 shows the in vitro transdermal permeation profile of the microneedles of diclofenac sodium in examples 34-37 of the invention.

Figure 9 shows in vitro transdermal permeation profiles of sustained release layered microneedles containing different amounts of porogens according to examples 38-40 of the present invention.

Detailed Description

In order to more clearly illustrate the invention, the invention is further described below with reference to preferred embodiments and the accompanying drawings. Similar parts in the figures are denoted by the same reference numerals. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.

Aiming at the technical problems in the prior art mentioned in the background technology, the invention firstly provides a sustained-release microneedle patch with good skin puncture effect, which comprises a needle body and a needle point on the needle body, wherein at least the needle point part comprises a part prepared from a needle point preparation liquid capable of realizing gelation in the drying process of the microneedle patch; the solute of the needlepoint preparation liquid comprises a glycerophosphate compound and a nonionic cellulose ether compound. The needle point preparation liquid can form a needle point part of the slow-release microneedle or the whole needle body, and can also form a coating and the like on the surface of the needle point, namely the invention is suitable for preparing the integrated microneedle, the layered microneedle, the coating microneedle and the bubble microneedle.

The nonionic cellulose ether derivative is a product of cellulose macromolecule in which the hydrogen of hydroxyl is replaced by alkyl, and the etherification process enables the originally water-insoluble cellulose to have good water-soluble property, and in addition, the cellulose derivative also has excellent performances of chemical inertness, biocompatibility, biodegradability and the like, so that the cellulose derivative is widely applied in the field of medical preparations, and the material has good mechanical properties and film-forming property, and is suitable for prescription research and application of microneedle preparations.

When the temperature of the aqueous solution of a part of nonionic cellulose ether compound is increased, the flocculation phenomenon of the polymer occurs, and the phase transition process from sol to gel occurs, the phase transition temperature point is called cloud point, and the principle of the gelation property is as follows: in aqueous solutions, there are three interactions between cellulose molecules and water molecules: (1) hydrogen bonding between and within cellulose molecular chains; (2) hydrogen bonding between cellulose molecules and water molecules; (3) hydrophobic interaction between cellulose molecule hydrocarbon groups. When the temperature of the solution is lower, the hydrogen bond interaction force between cellulose molecules and water molecules is dominant, the cellulose shows good water solubility, and when the temperature is raised to the cloud point temperature, the hydrogen bonds between the cellulose and the water molecules are broken, so that the hydrophobic interaction between the cellulose molecules is more dominant, and the flocculation of the cellulose from water is shown to form water-insoluble gel.

The gelation temperature of cellulose ethers is influenced by the molecular weight, degree of substitution, concentration of the material itself, and also by the use of certain additives, such as: salting-out electrolytes (such as phosphate and chloride), polyols (such as glycerol and polyethylene glycol), polyol esters (such as glycerophosphate compounds), and the like. The glycerophosphate compound has both phosphate ions and polyol hydroxyl, so that the glycerophosphate compound has more advantages in the adjustment process of the cloud point of the cellulose ether, and the cloud point temperature of the cellulose ether material can be greatly reduced by adding a small amount of the glycerophosphate compound.

The technical principle of the needle point preparation solution provided by the invention is as follows: in aqueous solution, the glycerophosphate-based compound competes with the cellulose ether compound for water molecules, causing the cellulose ether compound to dehydrate out below the normal cloud point temperature, thereby changing its gelation temperature. The micro-needle formula of the cellulose ether compound containing glycerophosphate has good skin puncture effect, sharp and full needle point and good substrate flexibility.

Preferably, the glycerophosphate-based compound comprises: any one of sodium glycerophosphate, potassium glycerophosphate, magnesium glycerophosphate, and calcium glycerophosphate.

Preferably, the nonionic cellulose ether compound is any one or a mixture of several of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose and hydroxybutyl methylcellulose.

Preferably, the solid content ratio of the nonionic cellulose ether compound to the glycerophosphate compound is 1:1-100: 1.

Further preferably, the solid content ratio of the nonionic cellulose ether compounds to the glycerophosphate compounds is 5:1-50: 1.

Preferably, the pore-forming agent is one of trehalose, calcium hydrogen phosphate or sodium bicarbonate, and the three pore-forming agents have a remarkable pore-forming effect in the sustained-release microneedle patch provided by the invention, so that the cumulative permeation quantity of the drug can be up to 80%, and the bioavailability of the drug is improved.

Preferably, the solute of the needle tip preparation solution further comprises at least one active ingredient; preferably, the active ingredient is one or more of polypeptide drugs, protein drugs, chemical drugs, skin care active ingredients, health care active ingredients and plant extract ingredients, and specifically can be diclofenac sodium, interferon, captopril, hexapeptide and the like.

weighing a glycerophosphate compound, adding the glycerophosphate compound into ultrapure water for dissolving to obtain a glycerophosphate aqueous solution;

weighing nonionic cellulose ether compounds, adding the nonionic cellulose ether compounds into glycerophosphate solution, adding or not adding a pore-foaming agent, adding or not adding active ingredients, stirring for dissolving, and removing bubbles to obtain a needle tip preparation solution.

The skilled person can perform the corresponding subsequent preparation steps, such as preparing the supporting microneedle, molding a mold, etc., according to the type of the microneedle to be prepared, and can refer to the following specific examples.

Preferably, the glycerophosphate compound is any one of sodium glycerophosphate, calcium glycerophosphate, potassium glycerophosphate and magnesium glycerophosphate; the nonionic cellulose ether compound is one or a mixture of more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose and hydroxybutyl methylcellulose.

Preferably, the solid content ratio of the nonionic cellulose ether compound to the glycerophosphate compound is 1:1-100: 1; further preferably, the solid content ratio of the nonionic cellulose ether compounds to the glycerophosphate compounds is 5:1-50: 1.

In order to more clearly illustrate the invention, the invention is further described below with reference to preferred embodiments and the accompanying drawings. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.

Example 1

The sustained-release microneedle patch was prepared as follows:

(1) according to the formula of example 1 in table 1, using a pipette to pipette 5.525mL of ultrapure water into a centrifuge tube, precisely weighing 0.075g of sodium glycerophosphate by using an electronic balance, adding the sodium glycerophosphate into the centrifuge tube for dissolution, then weighing 2.4g of hydroxypropyl cellulose, adding the hydroxypropyl cellulose into the centrifuge tube, stirring, and removing bubbles in the solution by using a centrifugal method after the solution is completely dissolved to obtain a microneedle preparation solution;

(2) the prepared microneedle preparation liquid is used for preparing microneedles by adopting a PDMS mold method, the microneedle mold is subjected to negative pressure vacuumizing treatment through an air pump, the solution is ensured to completely enter a pinhole, and then ventilation equipment is opened to accelerate drying and molding of the microneedles.

TABLE 1 microneedle preparation formulations of comparative example 1 and examples 1-6

	Ultrapure water (mL)	Sodium glycerophosphate (g)	Hydroxypropyl cellulose (g)
				Comparative example 1	5.6	0	2.4
Example 1	5.525	0.075	2.4
				Example 2	5.48	0.12	2.4
Example 3	5.44	0.16	2.4
				Example 4	5.145	0.185	2.4
Example 5	5.36	0.24	2.4
				Example 6	5.12	0.48	2.4

Example 2

The sustained-release microneedle patch was prepared by the preparation method of example 1, except that the formulation of the microneedle preparation solution was the formulation of example 2 in table 1, namely: 5.48mL of ultrapure water, 0.12g of sodium glycerophosphate and 2.4g of hydroxypropyl cellulose.

Example 3

The sustained-release microneedle patch was prepared by the preparation method of example 1, except that the formulation of the microneedle preparation solution was the formulation of example 3 in table 1, namely: 5.44mL of ultrapure water, 0.16g of sodium glycerophosphate and 2.4g of hydroxypropyl cellulose.

Example 4

The sustained-release microneedle patch was prepared by the preparation method of example 1, except that the microneedle preparation solution was prepared according to the method of example 4 in table 1, that is: 5.145mL of ultrapure water, 0.185g of sodium glycerophosphate and 2.4g of hydroxypropyl cellulose.

Example 5

The sustained-release microneedle patch was prepared by the preparation method of example 1, except that the formulation of the microneedle preparation solution was the formulation of example 5 in table 1, namely: 5.36mL of ultrapure water, 0.24g of sodium glycerophosphate and 2.4g of hydroxypropyl cellulose.

Example 6

The sustained-release microneedle patch was prepared by the preparation method of example 1, except that the formulation of the microneedle preparation solution was the formulation of example 6 in table 1, namely: 5.12mL of ultrapure water, 0.12g of sodium glycerophosphate and 2.4g of hydroxypropyl cellulose.

Comparative example 1

The sustained-release microneedle patch was prepared as follows:

(1) according to the prescription of comparative example 1 in table 1, using a pipette to pipette 5.6mL of ultrapure water into a centrifuge tube, weighing 2.4g of hydroxypropyl cellulose into the centrifuge tube, stirring, and removing bubbles in the solution by using a centrifugal method after the solution is completely dissolved to obtain a microneedle preparation solution;

Test example 1 Observation of Properties

(1) Cloud point temperatures of microneedle preparation solutions of different formulations:

7 tubes of microneedle preparation solutions prepared in the steps (1) of examples 1 to 6 and comparative example 1 were sequentially placed in constant temperature stability chambers set at different temperatures, wherein the set temperatures include: 37 ℃, 35 ℃, 33 ℃, 31 ℃, 29 ℃, 26 ℃, 23 ℃, 20 ℃ and 4 ℃. The solution was allowed to stand in a constant temperature stability chamber for 2 hours to stabilize the temperature of the solution, and then taken out to observe the condition of the solution, and the results are summarized in Table 2.

TABLE 2 solution state of comparative example 1 and examples 1 to 6 after leaving for 2 hours under different temperature conditions

Storage temperature

Comparative example 1

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

37℃

Clear and transparent

Turbid and whitish

35℃

Clear and transparent

Turbid and whitish

33℃

Clear and transparent

Turbid and whitish

31℃

Clear and transparent

Turbid and whitish

29℃

Clear and transparent

Turbid and whitish

26℃

Clear and transparent

Turbid and whitish

23℃

Clear and transparent

Turbid and whitish

20℃

Clear and transparent

Turbid and whitish

4℃

Clear and transparent

The cloud point temperatures of the hydroxypropyl cellulose microneedle preparation solutions containing different amounts of sodium glycerophosphate in examples 1-6 and comparative example 1 were obtained experimentally and documented as shown in table 3 below.

TABLE 3 cloud Point temperatures of microneedle preparation solutions in examples 1-6 and comparative example 1

	Cloud point of solution
		Comparative example 1	About 40 deg.C (documented)
Example 1	33-35℃
		Example 2	31-33℃
Example 3	29-31℃
		Example 4	26-29℃
Example 5	20-23℃
		Example 6	Lower than 20 deg.C

The above results show that the cloud point of hydroxypropyl cellulose can be significantly changed by adding different doses of sodium glycerophosphate additive.

(2) Sol-gel phase transition process of microneedle fabrication process

As shown in FIG. 1, FIG. 1(a) shows a sol state after sample application, and FIG. 1(b) shows a gel state during drying. Microneedles are prepared by a mold method at room temperature (25 ℃), wherein the turbidity point of the microneedle solution of the example 1 is higher than the room temperature, and the solution is in a clear and transparent sol state; in the drying process, the concentration of the sodium glycerophosphate is gradually increased along with the volatilization of water, so that the cloud point of the microneedle solution is gradually reduced, and when the temperature is lower than the room temperature, the solution is flocculated and is in a turbid and whitish gel state.

(3) Shape and skin puncture effect of prepared microneedle

The shape of the microneedle prepared in example 1 of the present invention is shown in fig. 2, and the puncture effect of the microneedle prepared in example 1 is shown in fig. 3. After the microneedle patch prepared by the method is completely dried, the substrate is flat, the flexibility is good, and the needle point is sharp and full. After the skin puncture experiment of pig ears is carried out, a complete microneedle pinhole array is left on the skin after trypan blue staining, and the microneedle patch prepared by the method is proved to have good skin puncture effect.

(4) After microneedle action on skin

The effects of the microneedles prepared in comparative example 1 and example 1 after 8 hours and the microneedles prepared in example 1 after 72 hours were applied to the skin are shown in fig. 4. Comparative example 1 the state of the microneedle after 8 hours of skin application is shown as mark a, and the state of the skin is shown as mark 1, it can be seen that the tip of the microneedle has been dissolved completely in the skin after 8 hours of skin application, and no solution remains on the skin after the substrate is removed; example 1 the state of the microneedle after 8 hours of action on the skin is shown as mark b-1, and the state of the skin is shown as mark 2, wherein the microneedle of b-1 has swelling property due to the addition of sodium glycerophosphate, the needle point absorbs water, swells and softens in the skin to form gel, and when the substrate is removed, white gel residue is left on the skin, which indicates that the microneedle has a certain slow release effect; the microneedle state after 72 hours on the skin of the microneedle of example 1 is shown as a mark b-2, and the skin state is shown as a mark 3, and it is found that the microneedle is further swollen, but no gel remains on the skin after 72 hours, indicating that the microneedle has been completely absorbed by the skin after about 72 hours of decomposition and release.

Example 7

The sustained-release microneedle patch was prepared by the preparation method of example 1, except that the formulation of the microneedle preparation solution was the formulation of example 7 in table 3, that is: 5.3mL of ultrapure water, 0.3g of sodium glycerophosphate and 2.4g of hydroxypropyl methylcellulose.

Example 8

The sustained-release microneedle patch was prepared by the preparation method of example 1, except that the formulation of the microneedle preparation solution was the formulation of example 8 in table 3, that is: 5.2mL of ultrapure water, 0.4g of sodium glycerophosphate and 2.4g of hydroxypropyl methylcellulose.

Example 9

The sustained-release microneedle patch was prepared by the preparation method of example 1, except that the formulation of the microneedle preparation solution was the formulation of example 8 in table 3, that is: 5mL of ultrapure water, 0.6g of sodium glycerophosphate and 2.4g of hydroxypropyl methylcellulose.

Test example 2

The cloud point temperatures of the microneedle preparation liquids of examples 7 to 9 measured according to the method of test example 1 are shown in table 4 below.

Table 4 examples 7-9 microneedle preparation formulations and cloud point temperatures of microneedle solutions

	Ultrapure water (mL)	Sodium glycerophosphate (g)	Hydroxypropyl methylcellulose (g)	Cloud point of solution
					Example 7	5.3	0.3	2.4	30-32℃
Example 8	5.2	0.4	2.4	25-27℃
					Example 9	5	0.6	2.4	20-22℃

Example 10

Layered microneedles were prepared according to the following steps:

(1) preparing a microneedle tip: a microneedle tip preparation solution was prepared according to the formulation method and recipe of example 1.

(2) Using a dissolvable material as the microneedle substrate: microneedle substrate solutions were prepared according to the formulation method and recipe of comparative example 1.

(3) Firstly, using a needle point solution, adding a sample on a PDMS mold, adding a substrate solution after the solution is dried to form a film, and blowing until the whole microneedle is completely dried and molded.

The diagram of the intradermal sustained release delivery process of layered microneedles is shown in figure 5. The design of layering micropin can make the micropin act on the skin after, utilizes the phase transition of needle point to realize the slow release of medicine, and the basement can take place to dissolve after acting for a period to realize the subcutaneous embedding of medicine carrying needle point, the micropin back sheet can be taken off from the skin, avoids long-term the skin irritation and the inconvenience of applying and bringing for the patient, has further improved patient's compliance and security of using medicine.

Example 11

Preparation of coated microneedles

(1) Preparation of coating solution: weighing 6.2mL of ultrapure water by using a pipette gun, adding the ultrapure water into a centrifuge tube, precisely weighing 0.2g of sodium glycerophosphate by using an electronic balance, adding the sodium glycerophosphate into the centrifuge tube, dissolving, weighing 1.6g of hydroxypropyl cellulose, adding the hydroxypropyl cellulose into the centrifuge tube, and stirring and dissolving to obtain the microneedle coating solution.

(2) Preparation of supporting microneedles: transferring 6.92mL of ultrapure water by using a liquid transfer gun, adding the ultrapure water into a centrifugal tube, precisely weighing 0.08g of magnesium chloride hexahydrate by using an electronic balance, adding the magnesium chloride hexahydrate into the centrifugal tube for dissolving, then weighing 3g of polyvinyl alcohol into the centrifugal tube, heating and dissolving at 80 ℃ after stirring, removing bubbles in the solution by using a centrifugal method to obtain a microneedle preparation solution, and preparing a formed microneedle as a supporting microneedle by using a mold method.

3. And (3) coating the completely dried polyvinyl alcohol soluble microneedle by using the coating solution to obtain the polyvinyl alcohol coated microneedle. The structural schematic diagram of the coated microneedle is shown in fig. 6. The obtained microneedle patch has good slow release effect.

EXAMPLE 12 preparation of bubble type microneedle

(1) Preparation of a needle tip solution: weighing 6.2mL of ultrapure water by using a pipette gun, adding the ultrapure water into a centrifuge tube, precisely weighing 0.2g of potassium glycerophosphate by using an electronic balance, adding the potassium glycerophosphate into the centrifuge tube, dissolving, weighing 1.6g of hydroxypropyl cellulose, adding the hydroxypropyl cellulose into the centrifuge tube, and stirring and dissolving to obtain a needle tip solution.

(2) Preparation of fast dissolving base solution: using a pipette to transfer 15.6mL of ultrapure water into a centrifuge tube, precisely weighing 0.4g of polyvinylpyrrolidone K1200.4 g by using an electronic balance, adding into the centrifuge tube for dissolving, then weighing 4g of hydroxyethyl cellulose into the centrifuge tube, stirring for dissolving, and removing bubbles in the solution by using a centrifugal method to obtain the microneedle substrate solution.

(3) And (3) adding a low-concentration needle point solution on the PDMS mould, adding an instant substrate solution after the solution is dried completely to form a film, and drying by blowing until the microneedle is completely molded. The schematic structure of the obtained bubble type microneedle is shown in fig. 7. The obtained microneedle patch has good slow release effect.

Examples 13-15 preparation of sustained-Release microneedles containing a porogen

The sustained release microneedle patch was prepared by the preparation method of example 1, except that a pore-forming agent was further added to the tip preparation solution according to the components shown in the following table. The obtained microneedle patch also has a good slow release effect, and the existence of the pore-forming agent can promote the release of the drug to a certain extent, thereby playing a role in controlling the slow release time.

Table 5 prescription design table of sustained release microneedle containing different kinds of porogenic agent

Examples 16-21 preparation of sustained-Release microneedles encapsulating Polypeptides, protein drugs

A sustained release microneedle patch was prepared by the preparation method of example 1, except that active ingredients were further added to the tip preparation solution according to the ingredients shown in the following table. The obtained microneedle patch also has a good slow release effect, and the active ingredients can well exert the active effect.

Table 6 table for designing sustained release microneedle formulation encapsulating polypeptide and protein drugs

Examples 22-27 preparation of sustained-Release microneedles encapsulating chemical-based drugs

Table 7 prescription design table of sustained release micro-needle for entrapping chemical drugs

Examples 28-33 preparation of sustained-Release microneedles encapsulating skin-Care drugs

Table 8 prescription design table of sustained release microneedle encapsulating skin care drug

Examples 34-37 in vitro transdermal drug delivery Effect of sustained-Release Integrated microneedles encapsulating diclofenac sodium

(1) Preparing a microneedle solution: microneedle solutions containing 75mg/mL diclofenac sodium and different porogens were prepared in an amount of 8mL each according to the design in table 9, and dried and molded microneedles were obtained according to the preparation method in example 1.

(2) Evaluation of in vitro transdermal sustained-release effects of microneedles containing different additives

An in-vitro percutaneous permeation experiment is carried out by using a full-automatic transdermal instrument, the skin of the pig ear after skin grafting is taken as a transdermal material, the temperature is controlled to be 37 +/-0.5 ℃, the receiving solution is 0.01M phosphate buffer solution (pH is 7.4), the sampling mode is full sampling, the receiving solution with the same volume is automatically added after each sampling, and the sampling time is 0h, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h and 72 h. The in vitro transdermal permeation curves of the sustained release microneedles containing different additives are shown in fig. 8.

Referring to the attached figure 8 of the invention, the result shows that each tablet of the sustained-release microneedle patch loaded with about 2.1mg of diclofenac sodium can realize stable drug release lasting for 72 hours after administration, and the addition of the pore-forming agent can obviously improve the drug release amount of the microneedles, wherein the pore-forming effect of the trehalose pore-forming agent and the calcium hydrogen phosphate pore-forming agent is more obvious, the accumulated permeation amount of the drugs reaches more than 85 percent, and the bioavailability of the drugs is improved.

Table 9 prescription design table of slow-release micro-needle entrapping diclofenac sodium

EXAMPLES 38 to 40 in vitro transdermal drug delivery Effect of Tranexamic acid-entrapped sustained Release layered microneedles

(1) Preparing a microneedle tip solution: 8mL of microneedle solution containing 50mg/mL tranexamic acid and different contents of trehalose is prepared according to the design of Table 10, and the layered microneedle with the substrate capable of being rapidly dissolved and broken and the drug-loaded needle tip embedded in the skin to realize slow drug release is obtained according to the preparation method of the example 10.

(2) Evaluation of in-vitro transdermal sustained release effect of layered microneedle containing different content of pore-forming agent

An in vitro percutaneous penetration experiment is carried out by using a full-automatic transdermal instrument, the skin of the pig ear after skin grafting is used as a transdermal material, the temperature is controlled to be 37 +/-0.5 ℃, the receiving solution is 0.01M phosphate buffer solution (pH is 7.4), the sampling mode is full sampling, the receiving solution with the same volume is automatically added after each sampling, and the sampling time is 0h, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h and 72 h. The in vitro transdermal permeation curves of the sustained release layered microneedles containing different amounts of porogens are shown in fig. 9.

Referring to fig. 9 of the drawings, the results show that each sustained-release layered microneedle patch carrying about 0.4mg of tranexamic acid removes the backing layer after 1 hour of drug administration, and the drug-loaded needle tip embedded in the skin can realize stable drug release lasting for 72 hours, and the microneedle release speed is obviously accelerated along with the increase of the addition amount of the pore-forming agent trehalose, thereby realizing the controlled release of the drug.

TABLE 10 sustained-release layered microneedle prescription design table with tranexamic acid

It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention, and it will be obvious to those skilled in the art that other variations or modifications may be made on the basis of the above description, and all embodiments may not be exhaustive, and all obvious variations or modifications may be included within the scope of the present invention.

Claims

1. A sustained release microneedle patch, which comprises a needle body and a needle point on the needle body, and is characterized in that: at least the needle point part comprises a part prepared from a needle point preparation liquid capable of realizing gelation in the drying process of the microneedle patch;

solutes of the needlepoint preparation liquid comprise glycerophosphate compounds and nonionic cellulose ether compounds;

the glycerophosphate compound is selected from one or more of sodium glycerophosphate, potassium glycerophosphate, magnesium glycerophosphate and calcium glycerophosphate;

the nonionic cellulose ether compound is one or a mixture of more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose and hydroxybutyl methylcellulose;

the nonionic cellulose ether compound accounts for 2-40% of the total mass of the preparation liquid;

the solid content ratio of the nonionic cellulose ether compound to the glycerophosphate compound is 1:1-100: 1.

2. The sustained-release microneedle patch according to claim 1, wherein the ratio of the solid contents of the nonionic cellulose ether-based compound and the glycerophosphate-based compound is 5:1 to 50: 1.

3. The sustained-release microneedle patch according to claim 1, wherein a solute of the needle tip preparation liquid further comprises a pore-forming agent, and the pore-forming agent accounts for 2-20% of the total mass of the needle tip preparation liquid.

4. The sustained-release microneedle patch according to claim 3, wherein the pore-forming agent is one or more of trehalose, calcium hydrogen phosphate, or sodium hydrogen carbonate.

5. The sustained-release microneedle patch according to claim 1, wherein the solute of the needle tip preparation liquid further comprises at least one active ingredient.

6. The sustained-release microneedle patch according to claim 5, wherein the active ingredient is one or more of a polypeptide drug, a protein drug, a chemical drug, a skin care active ingredient, a health care active ingredient, and a plant extract ingredient.

7. The sustained-release microneedle patch according to claim 1, wherein the microneedles are one-piece microneedles, layered microneedles, coated microneedles or bubble microneedles.

8. A method of manufacturing a sustained-release microneedle patch according to any one of claims 1 to 7, comprising at least the steps of: