HEAT-RESISTANT IMPLANTABLE POLYMER MICRONEEDLE AND PREPARATION METHOD THEREFOR AND APPLICATION THEREOF

Abstract

Disclosed are a heat-resistant implantable polymer microneedle and a preparation method therefor and an application thereof. The microneedle comprises a needle tip, a needle body, and a base, wherein the needle tip comprises a homogeneous system formed by mixing a biodegradable macromolecular material which has a glass transition temperature of 35-65° C. and is difficultly soluble in water and a macromolecular material having a glass transition temperature higher than that of the biodegradable macromolecular material. The microneedle has good heat resistance and puncture property.

Claims

1. A heat-resistant implantable polymer microneedle, comprising a needle tip, a needle body, and a base, wherein the needle tip comprises a homogeneous system formed by mixing a biodegradable macromolecular material A which has a glass transition temperature of 35-65° C. and is difficultly soluble in water and a macromolecular material B having a glass transition temperature higher than that of the biodegradable macromolecular material A.

2. The microneedle according to claim 1, wherein in the needle tip, the mass ratio of the macromolecular material B to the biodegradable macromolecular material A which is difficultly soluble in water is 0.1:1-0.6:1.

3. The microneedle according to claim 1, wherein the biodegradable macromolecular material A which is difficultly soluble in water is selected from one or more of PLA, PGA, PLGA, PCL, and derivatives thereof.

4. The microneedle according to claim 1, wherein the glass transition temperature of the macromolecular material B is above 130° C.; and optionally, the macromolecular material B is selected from one or more of polyvinylpyrrolidone and derivatives thereof, and cellulose and derivatives thereof.

5. The microneedle according to claim 1, wherein the needle tip further comprises at least one active component; and optionally, the mass ratio of the sum of the biodegradable macromolecular material A and macromolecular material B to the active component is 0.5:1-1000:1.

6. The microneedle according to claim 1, wherein the needle tip further comprises one or more a pore forming agent and a protective agent; optionally, the amount of the added pore forming agent is 0.1%-20% of the total mass of the needle tip; and optionally, the amount of the added protective agent is less than 20% of the total mass of the needle tip.

7. The microneedle according to claim 1, wherein the needle body and the base are independently formed from a matrix comprising a water-soluble macromolecular material; optionally, the water-soluble macromolecular material is selected from one or more of carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl chitosan, chitosan and derivatives thereof, polyvinyl alcohol and derivatives thereof, polyvinyl pyrrolidone and derivatives thereof, sodium hyaluronate, chondroitin sulfate, dextran and derivatives thereof, sodium alginate, poly γ-glutamic acid, pullulan, gelatin, polydopamine, or polyacrylamide; and optionally, the molecular weight of the water-soluble macromolecular material is 10-1000 kDa.

8. A method for preparing a microneedle according to claim 1, comprising the following steps: 1) mixing a biodegradable macromolecular material A which has a glass transition temperature of 35-65° C. and is difficultly soluble in water and a portion of an organic solvent, adding a macromolecular material B, and optionally adding a pore forming agent and a protective agent to obtain a needle tip matrix solution; mixing an active component and the remainder of the organic solvent to obtain a drug solution; and mixing the drug solution and the needle tip matrix solution to obtain a needle tip injection molding solution; or mixing a biodegradable macromolecular material A which has a glass transition temperature of 35-65° C. and is difficultly soluble in water and an organic solvent, adding a macromolecular material B, optionally adding a pore forming agent and a protective agent, and adding an active component to obtain a needle tip matrix solution after mixing; 2) providing an injection molding solution of a needle body and a base; and 3) adding the needle tip injection molding solution to a microneedle mold so that the solution enters a mold cavity under vacuum, performing heating at 30-80° C., and volatilizing the organic solvent, so as to prepare the needle tip; and adding the injection molding solution of the needle body and the base to the microneedle mold so that the solution enters the mold cavity under vacuum, performing drying at the room temperature, and performing demolding, so as to prepare the heat-resistant implantable polymer microneedle.

9. A microneedle patch, comprising a microneedle array composed of microneedles according to claim 1 and a back lining.

10. Use of the microneedle patch according to claim 9 in the fields of medicine, health care, and cosmetology.

11. The microneedle according to claim 4, wherein the macromolecular material B is selected from one or more of polyvinylpyrrolidone and derivatives thereof, and cellulose and derivatives thereof.

12. The microneedle according to claim 5, wherein the mass ratio of the sum of the biodegradable macromolecular material A and macromolecular material B to the active component is 0.5:1-1000:1.

13. The microneedle according to claim 6, wherein the amount of the added pore forming agent is 0.1%-20% of the total mass of the needle tip.

14. The micro needle according to claim 6, wherein the amount of the added protective agent is less than 20% of the total mass of the needle tip.

15. The microneedle according to claim 13, wherein the amount of the added protective agent is less than 20% of the total mass of the needle tip.

16. The microneedle according to claim 7, wherein the water-soluble macromolecular material is selected from one or more of carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl chitosan, chitosan and derivatives thereof, polyvinyl alcohol and derivatives thereof, polyvinyl pyrrolidone and derivatives thereof, sodium hyaluronate, chondroitin sulfate, dextran and derivatives thereof, sodium alginate, poly γ-glutamic acid, pullulan, gelatin, polydopamine, or polyacrylamide.

17. The microneedle of claim 7, wherein the molecular weight of the water-soluble macromolecular material is 10-1000 kDa.

18. The microneedle of claim 16, wherein the molecular weight of the water-soluble macromolecular material is 10-1000 kDa.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0048] The implementations of the present application are described in detail below with reference to the drawings.

[0049] FIG. 1 shows side views of a microneedle at 40° C. on (a) Day 0 and (b) Day 2, wherein a needle tip formation is PLGA RG502.

[0050] FIG. 2 shows a structural schematic diagram of a microneedle patch.

[0051] FIG. 3 shows a stereomicroscope photograph of a heat-resistant implantable polymer microneedle patch labeled with a fluorescent dye.

[0052] FIG. 4 shows side views of a heat-resistant implantable polymer microneedle labeled with a fluorescent dye at 40° C. on (A) Day 0, (B) Day 15, and (C) Day 30.

[0053] FIG. 5 shows a stereomicroscope photograph of a heat-resistant implantable polymer microneedle patch labeled with a fluorescent dye that punctures the skin of a pig ear.

[0054] FIG. 6 shows side views of implantable polymer microneedles loaded with levonorgestrel in different formulations which stand at 60° C. for 0 days, 5 days, and 10 days.

[0055] FIG. 7 shows in-vitro cumulative release curves of implantable polymer microneedles loaded with levonorgestrel in different formulations.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0056] In order to describe the present application more clearly, the present application is described below with reference to preferred embodiments and accompanying drawings. Similar components in the drawings are represented by the same reference numeral. Those skilled in the art should understand that the content specifically described below is illustrative rather than restrictive and should not limit the scope of protection of the present application.

Example 1

[0057] Preparation and Heat Resistance Evaluation of a Heat-Resistant Implantable Polymer Microneedle Patch Containing a Fluorescent Dye

[0058] (1) A matrix solution containing 6% (w/w) PLGA (10 KDa, 50/50) and 0.2% (w/w) fluorescent bright-red dye (liposoluble analog drug) was prepared using N-methylpyrrolidone as a solvent, 30% (w/w) (w/w % of the PLGA mass) PVP K90 was added to the matrix solution, and the matrix solution was vortex-mixed and then used as a needle tip injection molding solution.

[0059] (2) A 20% (w/w) PVA solution was prepared by heating and swelling using water as a solvent and polyvinyl alcohol (PVA) as a matrix. A solution containing 20% (w/w) PVP K120 was prepared by swelling at the room temperature using water as a solvent and PVP K120 as a matrix. Then the two solutions were mixed with the mass ratio of PVA:PVP K120 being 1:2, a mixture solution was stirred to mix well, and then centrifugation was performed to remove bubbles, so as to obtain an injection molding solution of a needle body and a base.

[0060] (3) The needle tip injection molding solution was drawn and placed on a microneedle mold (the needle height is 700 μm, and the step height is 300 μm), the solution entered a mold cavity under vacuum, the redundant solution was removed, and the remaining solution was heated at 60° C. for 1 hour. Then 30 μL of injection molding solution of the needle body and the base was drawn and placed on the microneedle mold, vacuumizing was performed so that the solution entered the mold cavity, and the solution was dried for 2.5 h at the room temperature, a pressure-sensitive adhesive back lining was pasted on the back of the base, and then demolding was performed, so as to obtain the heat-resistant implantable polymer microneedle patch loaded with a fluorescent dye, having a needle tip height of 300 μm and a total needle height of 700 μm.

[0061] FIG. 2 shows a structural schematic diagram of the prepared polymer microneedle patch.

[0062] Heat resistance evaluation: The prepared microneedle patch is shown in FIG. 3, where there are 117 microneedles on each microneedle patch. The microneedle was sealed and packaged and then placed in an incubator at 40° C. for one month, and was taken out at 0-th, 15-th, and 30-th days, and the side view of the microneedle was observed with an optical microscope. Results are shown in FIG. 4. It can be found that the morphology of the heat-resistant implantable polymer microneedle loaded with a fluorescent dye remained intact after the microneedle stood at 40° C. for one month, and the microneedle still has the puncture property when the ambient humidity exceeds 45% RH.

Example 2

[0063] Skin Puncture and Needle Tip Implantation Test of the Heat-Resistant Implantable Polymer Microneedle Patch

[0064] The microneedle patch in example 1, which stood at 40° C. for one month, was applied to the skin of a fresh pig ear, pressed and held with a self-made needle feeder (30 N/cm2) for 20 s, then placed on agar hydrogel to moisturize for 20 min. Then the microneedle patch was peeled off, to observe, using a stereomicroscope, whether there is an implanted dyed needle tip in the pig ear skin. FIG. 5 shows an implantation photograph of the microneedle tip in the pig ear skin, and it can be clearly seen that the fluorescent bright-red needle tip is left in the skin, with a needle tip implantation rate close to 100%, indicating that the heat-resistant implantable polymer microneedle still has the skin puncture property after stood at 40° C. for one month.

Example 3

[0065] Preparation and Evaluation of Heat Resistance and In-Vitro Release of a Heat-Resistant Implantable Polymer Microneedle Patch Including a Difficultly-Soluble Drug

[0066] (1) A matrix solution containing 4.8% (w/w) PLGA (10 KDa, 50/50) and 3.2% (w/w) levonorgestrel (LNG) was prepared using N, N-dimethylacetamide as a solvent, 0%, 20.0%, 25.0%, and 33.3% (w/w % of the PLGA mass) of hydroxypropyl methyl cellulose (HPMC, 15 cp) were added to the matrix solution respectively, and the matrix solution was vortex-mixed to obtain four needle tip injection molding solutions.

[0067] (2) A 25% (w/w) PVP K120 solution was prepared by swelling at the room temperature using water as a solvent and PVP K120 as a matrix, and used as an injection molding solution for the needle body and the base.

[0068] (3) The four needle tip injection molding solutions were drawn and placed on microneedle molds respectively, the solution entered mold cavity under vacuum, the redundant solution was removed, and the remaining solution was heated at 60° C. for 1 hour. Then 30 μL of injection molding solution of the needle body and the base was drawn and placed on the microneedle mold, vacuumizing was performed so that the solution entered the mold cavity, and the solution was dried for 2.5 h at the room temperature, a pressure-sensitive adhesive back lining was pasted on the back of the base, and then demolding was performed. The model of the microneedle mold used in this example is the same as that in Example 1. Each prepared microneedle patch includes 117 needles, and the total needle height is 700 μm.

[0069] The microneedle patch containing HPMC prepared in this example still has the puncture property when the ambient humidity exceeds 45% RH.

[0070] Heat resistance evaluation: The prepared four types of microneedles were sealed and packaged and then placed in an incubator at 60° C. for 10 days, and were taken out at 0-th, 5-th, and 10-th days, and the side view of the microneedle was observed with an optical microscope. Results are shown in FIG. 6. It can be found that, the needle tip of the implantable polymer microneedle loaded with LNG containing no HPMC obviously melted and deformed after the microneedle stood at 60° C. for 10 days, while the morphologies of the drug-loaded heat-resistant implantable polymer microneedles containing different amounts of HPMC remained intact after the microneedles stood at 60° C. for 10 days.

[0071] Drug loading amount test: One piece of microneedle was placed into a centrifuge tube, 0.7 mL acetonitrile was added, then 0.3 mL ultrapure water was added after vortex dissolution, centrifugation was performed after vortex mixing, and centrifuged supernatant was analyzed by means of liquid chromatography. The drug loading amount tests were performed on the four types of microneedles respectively. In the tests, 5 microneedles were tested in parallel, and it was measured that the drug loading amount of each microneedle was 72±4.3 μg.

[0072] In-vitro release evaluation: The needle tip of the microneedle was scraped off with a scalpel and sealed in a dialysis bag, where a receptor fluid was 25% (v/v) ethanol-PBST. Samples were taken every 12 h in the first 7 days and every day in the next 14 days, where a sampling manner is total sampling, and the same amount of fresh receptor fluid was added. Drug concentration in the receptor fluid at each sampling point was measured by means of liquid chromatography, and results are shown in FIG. 7. It can be seen from the figure that the in-vitro cumulative release rates of the drug-loaded microneedles with needle tips containing 0%, 20.0%, 25.0%, and 33.3% (w/w % of the PLGA mass) of HPMC in 21 days were 72.8±4.3%, 75.3±4.0%, 77.5±4.9%, and 83.8±5.1%, respectively. With the increase of HPMC content in the needle tip, the cumulative release rate of LNG increases gradually, indicating that the addition of HPMC can not only enhance the heat resistance of the microneedle, but also help to improve the bioavailability of the difficultly-soluble LNG

Examples 4-8

[0073] Refer to Example 1 for a preparation method, where parameters of various components in Examples 4-8 are shown in Table 1.

TABLE-US-00001 TABLE 1 Proportions and Process Parameters of the Components Example 4 Example 5 Example 6 Example 7 Example 8 Needle tip 100 mg/mL PLGA 150 mg/mL 80 mg/mL PLA (25 120 mg/mL PGA (20 90 mg/mLPCL (30 KDa) + 50 injection (10 KDa, PLA (25 KDa) + 20 mg/mL KDa) + 36 mg/mL mg/mL hydroxybutylcellulose molding 75/25) + 10 mg/mL KDa) + 20 hydroxypropyl HPMC (15 cp) + 50 (15 cp) + 5 mg/mL solution PVP K17 + 45 mg/mL HPMC cellulose (30 mg/mL norethisterone diacetate mg/mL leuprorelin (30 cp) + 60 cp) + 40 mg/mL p-nitroacetanilide acetate mg/mL progesterone etonogestrel Injection Total solid content Total solid Total solid content PVA (6.0 cp) solution Hydroxypropylmethylcellulose molding is 40%, where content is 30%, is 30%, where with 25% solid content (50 cp) with 25% solid content solution of carboxymethyl where PVA (6.0 sodium the needle chitosan (50 cp):PVP K90 is carboxymethyl body and KDa):PVP K90 is 2:1 cellulose (200 base 1:1 KDa):dextran (70 kDa) is 1:1 Heating 65° C., 1.5 h 70° C., 1 h 60° C., 1 h 50° C., 1.5 h 75° C., 0.5 h temperature and time of the needle tip Heat Stable storage at Stable storage Stable storage at Stable storage at 40° C. Stable storage at 40° C. resistance of 40° C. for more than at 40° C. for 40° C. for more than for more than 1.5 for more than 3 months the 0.5 month more than 1 2 months months microneedle month Skin puncture Yes Yes Yes Yes Yes property

[0074] Microneedle patches prepared in Examples 4-8 still have the puncture property when the ambient humidity exceeds 45% RH.

[0075] It should be noted that the needle body and base in the above examples not only correspond to one example, but also can be combined with a needle tip in other examples, where the heating temperature and time of the needle tip and the heat resistance of the microneedle are determined by the composition of the needle tip injection molding solution.

Examples 9-14

[0076] Refer to Example 1 for a preparation method, where parameters of various components in Examples 9-14 are shown in Table 2.

TABLE-US-00002 TABLE 1 Proportions and Process Parameters of the Components Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Needle tip 200 mg/mL 80 mg/mL 100 mg/mL 100 mg/mL 60 mg/mL 45 mg/mL injection PLGA (30 KDa, PLGA (30 KDa, PGA (15 KDa) + PGA (15 KDa) + PCL (25 KDa) + PLA (10 KDa) + molding 85/15) + 65/35) + 15 mg/mL 15 mg/mL 8 mg/mL 20 mg/mL solution 32 mg/mL 30 mg/mL hydroxypropylcellulose hydroxypropylcellulose hydroxybutylcellulose HPMC (50 cp) + PVP K30 + PVP K90 + (15 cp) + 36 mg/mL (15 cp) + 15 mg/mL (30 cp) + 2 mg/mL 18 mg/mL 2 mg/mL 10 mg/mL Finasteride trehalose + hydroxypropyl- sucrose + Goserellin diacerein 36 mg/mL β-cyclodextrin + 10 mg/mL Finasteride 12 mg/mL Exenatide Paliperidone Injection Total solid content is 25%, where PVA (6.0 cp):PVP K90 is 1:1 molding solution of the needle body and base Heating 70° C., 0.5 h 75° C., 0.5 h 65° C., 1 h 65° C., 2 h 75° C., 1 h 40° C., 3 h temperature and time of the needle tip Heat Stable storage Stable storage Stable storage Stable storage Stable storage Stable storage resistance at 60° C. at 60° C. at 50° C. at 50° C. at 50° C. at 40° C. of the for more than for more than for more than for more than for more than for more than microneedle 15 days 1 month 10 days 10 days 1 month 1 month Skin Yes Yes Yes Yes Yes Yes puncture property

[0077] Microneedle patches prepared in Examples 9-14 still have the puncture property when the ambient humidity exceeds 45% RH.

Comparative Example 1

[0078] Example 1 was repeated, with a difference that the mass ratio of PLGA to PVP K90 in the needle tip is 1:0.8, where the other conditions remain unchanged, so as to prepare a microneedle and a microneedle patch. The sealed and packaged microneedle was placed in an incubator at 40° C. for one month, and taken out at 0-th, 15-th, and 30-th days. It was found that the microneedle of this formulation lost the puncture property when the ambient humidity exceeds 45% RH.

Comparative Example 2

[0079] Example 1 was repeated, with a difference that the mass ratio of PLGA to PVP K90 in the needle tip is 1:0.05, where the other conditions remain unchanged, so as to prepare a microneedle and a microneedle patch. The sealed and packaged microneedle was placed in an incubator at 40° C. for one month, and taken out at 0-th, 15-th, and 30-th days. It was found that the needle tip of the microneedle of this formulation fully melted and deformed after the microneedle stood at 40° C. for 15 days.

Comparative Example 3

[0080] Example 1 was repeated, with a difference that PVP K90 is replaced with HHPC, where the other conditions remain unchanged, so as to prepare a microneedle and a microneedle patch. The sealed and packaged microneedle was placed in an incubator at 40° C. for one month, and taken out at 0-th, 15-th, and 30-th days. It was found that the microneedle of this formulation has no puncture property.

[0081] Obviously, the above embodiments of the present application are only examples for clearly describing the present application rather than limiting the embodiments of the present application. Those of ordinary skilled in the art could make other different forms of changes or modifications on the basis of the above description. It is impossible to enumerate all the embodiments herein, and any obvious change or modification derived from the technical solution of the present application still falls within the scope of protection of the present application.