Base composition for microneedle patch and microneedle patch comprising the same

Abstract

The present invention relates to a base composition for a microneedle patch and a microneedle patch comprising the same. The base composition comprises a first HPMC, a second HPMC and PVP/VA, wherein the viscosity of the first HPMC is greater than that of the second HPMC, the weight ratio of the first HPMC relative to the second HPMC is 1:0.1 to 1:1.2, and the amount of the PVP/VA is 0.25 wt % to 2 wt %. By controlling the constitution of the base composition, the microneedle patch can not only be demolded smoothly during the stage of the production, but also obtain the desired softness, flatness, flexibility, skin adhesion during the stage of use and humidity resistance during the stage of storage.

Claims

1. A base composition, comprising a first hydroxypropyl methylcellulose, a second hydroxypropyl methylcellulose and a polyvinylpyrrolidone/vinyl acetate copolymer, the viscosity of the first hydroxypropyl methylcellulose being 400 centipoises to 10,000 centipoises, and the viscosity of the second hydroxypropyl methylcellulose being 1 centipoise to 100 centipoises, wherein based on a total weight of the base composition, a total amount of the first hydroxypropyl methylcellulose and the second hydroxypropyl methylcellulose is 0.1 wt % to 3 wt %, a weight ratio of the first hydroxypropyl methylcellulose relative to the second hydroxypropyl methylcellulose is 1:0.1 to 1:1.2, and an amount of the polyvinylpyrrolidone/vinyl acetate copolymer is 0.25 wt % to 2 wt %.

2. The base composition as claimed in claim 1, wherein the total amount of the first hydroxypropyl methylcellulose and the second hydroxypropyl methylcellulose is 0.2 wt % to 2.5 wt %.

3. The base composition as claimed in claim 1, wherein the weight ratio of the first hydroxypropyl methylcellulose relative to the second hydroxypropyl methylcellulose is 1:0.2 to 1:1.

4. The base composition as claimed in claim 1, wherein the viscosity of the first hydroxypropyl methylcellulose is 1,000 centipoises to 8,000 centipoises, and the viscosity of the second hydroxypropyl methylcellulose is 2 centipoises to 50 centipoises.

5. The base composition as claimed in claim 3, wherein the viscosity of the first hydroxypropyl methylcellulose is 1,000 centipoises to 8,000 centipoises, and the viscosity of the second hydroxypropyl methylcellulose is 2 centipoises to 50 centipoises.

6. The base composition as claimed in claim 1, wherein a solid content of the base composition is 0.35 wt % to 60 wt %.

7. The base composition as claimed in claim 2, wherein a solid content of the base composition is 0.35 wt % to 60 wt %.

8. The base composition as claimed in claim 3, wherein a solid content of the base composition is 0.35 wt % to 60 wt %.

9. The base composition as claimed in claim 5, wherein a solid content of the base composition is 0.35 wt % to 60 wt %.

10. The base composition as claimed in claim 1, wherein a viscosity of the base composition is 1 centipoise to 200,000 centipoises.

11. The base composition as claimed in claim 1, wherein the surface tension of the base composition is 25 dyne/cm to 50 dyne/cm.

12. The base composition as claimed in claim 1, wherein the base composition consists of the first hydroxypropyl methylcellulose, the second hydroxypropyl methylcellulose, the polyvinylpyrrolidone/vinyl acetate copolymer and water.

13. A microneedle patch, comprising multiple microneedle structures, each microneedle structure having a base and a needle tip formed on the base, wherein the base is made from the base composition as claimed in claim 1.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) Several base compositions for fabricating a microneedle patch are exemplified below to illustrate the implementation of the present invention. One person skilled in the art can easily realize the advantages and effects of the present invention in accordance with the contents disclosed in the specification. Various modifications and variations could be made in order to practice or apply the present invention without departing from the spirit and scope of the invention.

(2) Description of Reagents 1. First hydroxypropyl methylcellulose (first HPMC): (1) 65SH-400, viscosity: 400 cP, purchased from Shin-Etsu Chemical Co., Ltd.; (2) 65SH-1500, viscosity: 1,500 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd.; (3) 90SH-4000, viscosity: 4,000 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd.; (4) 90SH-4000SR, viscosity: 4,000 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd.; (5) 65SH-4000, viscosity: 4,000 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd.; (6) 60SH-4000, viscosity: 4,000 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd.; (7) 60SH-10000, viscosity: 10,000 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd. 2. Second hydroxypropyl methylcellulose (Second HPMC): (1) PHARMACOAT 603, viscosity: 3 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd.; (2) SB-4, viscosity: 4 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd.; (3) PHARMACOAT 645, viscosity: 4.5 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd.; (4) PHARMACOAT 606, viscosity: 6 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd.; (5) PHARMACOAT 615, viscosity: 15 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd.; (6) METOLOSE 65SH-50, viscosity: 50 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd.; (7) METOLOSE 60SH-50, viscosity: 50 cP (@20 C., 2% aqueous solution), purchased from Shin-Etsu Chemical Co., Ltd. 3. Polyvinyl alcohol, purchased from Nippon Synthetic Chemical Industry Co., Ltd. 4. Polyvinylpyrrolidone/vinyl acetate copolymer, product name: Kollidon, purchased from BASF Corporation. 5. Trehalose, product name: TREHA, purchased from Hayashibara Co., Ltd. 6. Carboxymethyl cellulose (CMC), purchased from Sigma-Aldrich. 7. -cyclodextrin (-CD), product name: -cyclodextrin, purchased from Yiyang Industrial Co., Ltd.

(3) Preparation of Base Solution

(4) Base solution of Examples and Comparative Examples were each obtained by mixing the aforementioned reagents according to the constitution shown in the following Table 1 with water.

(5) TABLE-US-00001 TABLE 1 The constitution of the base solution of Examples (E1 to E4) and Comparative Examples (C1 to C9). First Component Second Component Third Component Type Amount Type Amount Type Amount E1 First 1 wt % Second 0.25 wt % PVP/VA 2 wt % HPMC HPMC E2 First 1 wt % Second 0.5 wt % PVP/VA 1 wt % HPMC HPMC E3 First 1 wt % Second 0.5 wt % PVP/VA 0.5 wt % HPMC HPMC E4 First 1 wt % Second 0.5 wt % PVP/VA 0.25 wt % HPMC HPMC C1 PVA 16.8 wt % TREHA 16.8 wt % -CD 8.4 wt % C2 Second 2 wt % TREHA 4 wt % HPMC C3 PVP/VA 8 wt % TREHA 2 wt % C4 Second 1 wt % CMC 9 wt % HPMC C5 PVP/VA 8 wt % CMC 2 wt % C6 Second 2 wt % -CD 3 wt % HPMC C7 First 2 wt % PVP/VA 1 wt % HPMC C8 First 1 wt % Second 1 wt % HPMC HPMC C9 First 1 wt % Second 0.5 wt % PVP/VA 4 wt % HPMC HPMC

(6) In the above table, the first HPMC and second HPMC of Examples 1 to 4 may be any of the reagents exemplified above. Specifically, the first HPMC may be 60SH-4000, and the second HPMC may be PHARMACOAT 645; the viscosity of the selected first HPMC is greater than that of the selected second HPMC, regardless of the combination of the first HPMC and second HPMC. By contrast, the first HPMC in Comparative Examples 7 to 9 may also be any of the reagents exemplified above. Specifically, the first HPMC is 60SH-4000. The second HPMC in Comparative Examples 2, 4, and 7-9 may also be any of the reagents exemplified above. Specifically, the second HPMC is PHARMACOAT 645.

(7) The solid content, viscosity and surface tension of the base solution in each of Examples and Comparative Examples are shown in Table 2 below. The viscosity of each of the base solutions is measured by using a viscometer (instrument model: MCR302, purchased from Anton Paar) at 25 C. with a shear rate of 1 s.sup.1. The surface tension of each of the base solutions is measured at 25 C. by using FACE Automatic Surface Tensiometer (instrument model: CBVP-A3) through the wilhelmy plate method.

(8) The viscosity of the base solution of Comparative Example 1 was too high, so the surface tension thereof could not be measured. In addition, precipitated crystals were observed in the base solution of Comparative Example 6 through the naked eye, so the viscosity and the surface tension thereof were not further measured, either.

(9) Preparation of Microneedle Patch

(10) In the production process, a microneedle patch was made from the base solution of each of Examples and Comparative Examples mentioned above through the method described below.

(11) First of all, many needle holes of the PDMS master mold were coated by using the blade or slot die coating with the coating gap of 1,000 m and at the coating speed of 3 m/min. The needle tip solution was 20 wt % aqueous solution of copper peptide and poly(methyl vinyl ether-alt-maleic anhydride), i.e., the needle tip solution contained 80 wt % of water as well as 20 wt % of mixture of copper peptide and poly(methyl vinyl ether-alt-maleic anhydride). The viscosity of the needle tip solution measured at a shear rate of 1 s.sup.1 at 25 C. was 40 cP, and the surface tension thereof was 30 dyne/cm. Next, the PDMS master mold coated with the needle tip solution was placed in a vacuum oven at a pressure of 20 torr and evacuated, so that the needle tip solution was filled into the needle holes of the master mold. The density of the needle holes on the master mold was 289 holes/cm.sup.2; the array of the holes was 1.5 cm1.5 cm; the shape of the holes was pyramidal; the depth thereof was about 600 m; and the maximum width thereof was about 300 m. Then, the solution of the needle tip composition was dried at 30 C. and under the relative humidity of 30% to 50% for 1 hour, thereby making the needle tip solution dry and form into needle tips.

(12) Afterwards, the base solutions in the aforementioned Examples and Comparative Examples were respectively chosen to fill into many needle holes of the PDMS master mold using the blade or slot die coating with the coating gap of 1,600 m and at the coating speed of 3 m/min. Next, the PDMS master mold coated with the base solution was placed in a vacuum oven at a pressure of 35 torr and evacuated, so that the base solution was filled into the needle holes of the master mold. Then, the base solution was dried at 30 C. and the relative humidity of 45% to 75% for 1 hour, thereby making the base solution dry and form into the base with the water amount less than 20%. Then, the microneedle structure with a base and a needle tip formed on the base can be demolded from the PDMS master mold, and the production of the microneedle patch was completed.

(13) The microneedle patches of Examples and Comparative Examples were respectively subjected a compressive test with the displacement set to 10 mm, the speed set to 66 mm/min, and 500 compressive stress values received per second at the same time by using a universal material testing machine (instrument model 3343, purchased from INSTRON) to measure the mechanical strengths of the microneedle patches.

(14) In the preparation of the microneedle patch by using the base solution of Comparative Example 4, deformation of the microneedle patch occurred during demolding, so the mechanical strength of the microneedle patch could not be further measured. In the preparation of the microneedle patch by using the base solution of Comparative Example 5, the microneedle patch was broken because of its brittle base during demolding, so the mechanical strength thereof could not be further measured, either. Therefore, only the mechanical strengths of the microneedle patches produced by using the base solution of Examples 1 to 4, Comparative Examples 1 to 3 and Comparative Examples 6 to 9 were listed in Table 2 below.

(15) TABLE-US-00002 TABLE 2 The properties of the base solution of Examples and Comparative Examples and the mechanical strength of the microneedle patches produced therefrom. Microneedle Patch Base Solution Mechanical Solid Content Viscosity Surface Tension Strength (wt %) (cP) (dyne/cm) (N/needle) E1 3.25 235.8 43.6 0.15 E2 2.5 230.7 43.9 0.14 E3 2 242.3 43.8 0.13 E4 1.75 199.2 43.4 0.13 C1 42 250000 0.014 C2 6 7.2 44.2 0.065 C3 10 2.4 43.8 0.25 C4 10 3803.9 43.9 C5 10 27.5 44.1 C6 5 0.003 C7 3 125.7 44.5 0.17 C8 2 241.2 43.9 0.1 C9 5.5 257.3 43.4 0.16

Test Example 1: Demolding Evaluation

(16) This test example aimed to observe the situation that the microneedle structures each having a base and a needle tip formed thereon were demolded from the PDMS master mold. In the stage of producing a microneedle patch, if the microneedle structure could be smoothly demolded from the PDMS master mold without damaging the structure of the base, mark in Table 3 below. If the microneedle structure could not be demolded from the PDMS master mold smoothly or the base was brittle and broken or damaged during demolding, mark x in Table 3 below.

Test Example 2: Properties Evaluation of a Microneedle Patch

(17) In this test example, the softness and skin adhesion of each microneedle patch were evaluated by 5 people with visual observation and the actual experience after completion of the production of a microneedle patch, and the observation and sensory responses from these people were also listed in Table 3 below.

(18) In addition, in the evaluation of the flatness of a microneedle patch, after cutting off the excess edge material from the demolded microneedle patch, the demolded microneedle patch was laid flat on a flat marble platform and then shot with a camera that was laid flat on the platform to observe whether the microneedle patch was flat on the marble platform. If a microneedle patch was flat on the marble platform and the microneedle structure was not observed to be warped or partially warped, the flatness of the microneedle patch was determined to be good and then marked in Table 3 below. On the contrary, if a microneedle patch was observed that it was unable to be flat on the marble platform and was warped or partially warped, the flatness of the microneedle patch was determined to be poor and then marked x in Table 3 below.

(19) Further, in the evaluation of the flexibility of a microneedle patch, the microneedle patch was bent into a radius of curvature of 7.5 mm and was observed whether it was broken or deformed. If the microneedle patch was not broken or deformed after bending, the flexibility of the microneedle patch was determined to be good and then marked in Table 3 below. On the contrary, if the microneedle patch was broken or deformed after bending, the flexibility of the microneedle patch was determined to be poor and then marked x in Table 3 below.

(20) The humidity resistance described in Table 3 below was evaluated whether the microneedle patch maintained 90% of the original mechanical strength after being placed in an environment of the ambient temperature of 25 C. and the relative humidity of 60% for 5 days. The mechanical strength was measured as described above. If the microneedle patch maintained 90% of the original mechanical strength after being placed in the aforementioned environment for 5 days, it was indicated that the humidity resistance of the microneedle patch was good and marked in Table 3 below. On the contrary, if the mechanical strength of the microneedle patch was below 90% of the original mechanical strength after being placed in the aforementioned environment for 5 days, it was indicated that humidity resistance of the microneedle patch was poor and marked x in Table 3 below.

(21) TABLE-US-00003 TABLE 3 The results of the microneedle patches prepared by base solutions of Examples 1 to 4 and Comparative Examples 1 to 9 at the stages of production, use and storage Stage of Stage of Production Stage of Use Storage Demolding Skin Humidity Evaluation Softness Flatness Flexibility adhesion Resistance E1 E2 E3 E4 C1 x x x x C2 x C3 x x x x C4 x x x x x C5 x x x x x C6 x x C7 x x x C8 x x C9 x x x

(22) Since the stability of the base solution of Comparative Example 1 was relatively poor, the problem of surface drying and unevenness was liable to occur, which resulted in difficult demolding. In addition, by using the base solution of Comparative Example 1, the hygroscopicity of the base of the microneedle patch was relatively high, resulting in failure to store the microneedle patch for a long time and adversity for use in the industry. Further, for Comparative Example 1, the base of the microneedle patch was not as soft as expected and the flatness was insufficient, so the microneedle patch manufactured therefrom was still unfavorable for use.

(23) Regarding the experimental results corresponding to Comparative Example 2 and Comparative Example 3, even if PVA was replaced by either HPMC or PVP/VA, the hygroscopicities of the bases of the microneedle patches were not effectively improved, which also resulted in failure to store these microneedle patches for a long time. In addition, for Comparative Example 3, an external force was further required during the demolding process, and the structure of the base of the microneedle patch was too soft and easily deformed, which resulted in poor softness and flatness of the microneedle patch.

(24) Regarding Comparative Example 4 and Comparative Example 5, if HPMC or PVP/VA was used in combination with CMC, the problem of too high hygroscopicity could be overcome by using the base solutions of Comparative Example 4 and Comparative Example 5. However, the film-forming property of the base solution of Comparative Example 4 was poor. The base prepared by using the base solutions of Comparative Example 4 and Comparative Example 5 cannot be demolded without an external pulling force, unfortunately, the microneedle patch of Comparative Example 4 was deformed during the demolding process, and the microneedle patch of Comparative Example 5 was even broken during the pulling process. These problems severely degraded the qualities of the microneedle patches. In addition, as the bases of the microneedle patches manufactured by using the base solution of Comparative Example 4 and Comparative Example 5 were both too hard, the softness, flatness, flexibility and skin adhesion of the microneedle patches of Comparative Example 4 and Comparative Example 5 did not qualify for use.

(25) Similarly, even if the problem of too high hygroscopicity could be overcome by using the base solution of Comparative Example 6 formulated by combining a single HPMC and -CD, the problems of hard structures and brittleness also existed in Comparative Example 6 as described in Comparative Example 5, which resulted in poor softness. Further, crystals were precipitated in the base solution of Comparative Example 6, which further resulted in that the microneedle patch manufactured therefrom has defects of structural unevenness.

(26) In addition, if a single HPMC and PVP/VA were combined to formulate the base solution of Comparative Example 7, the base manufactured therefrom could be demolded smoothly in the production process. However, problems of warped structures and extremely soft base were liable to occur due to compression. On the other hand, if only two HPMCs with different viscosities were combined and formulated into the base solution of Comparative Example 8, as described in Comparative Example 7, problems of warped structures and soft microneedles were liable to occur due to compression. Accordingly, regardless of the base solution of Comparative Example 7 or that in Comparative Example 8, the microneedles manufactured therefrom both failed to obtain the desired softness and flatness. In particular, the microneedle patch manufactured by using the base solution of Comparative Example 7 had the problem of too high hygroscopicity and could not be stored for a long time.

(27) Further, if PVP/VA was further added to the combination of two HPMCs with different viscosities to formulate the solution of the base composition in Comparative Example 9, the base manufactured therefrom was hard because of too high content of PVP/VA, which resulted in problems of failing to withstand external forces and being prone to breaking. Therefore, even if two HPMCs and PVP/VA were mixed to formulate the base solution, the softness, flexibility and skin adhesion of the microneedle patch could not be improved.

(28) In contrast with Example 1 to Example 4, the base solutions were formulated by combining appropriate amount of the first HPMC, the second HPMC, and the PVP/VA, the base of microneedle patch could withstand external forces without being brittle and broken, and the microneedle patch manufactured therefrom could maintain high mechanical strength. Moreover, the base of the microneedle patch of each of Example 1 to Example 4 could also have good softness, flatness, flexibility and skin adhesion, as well as good humidity resistance.

(29) Based on the above test results, by using appropriate amount of the first HPMC, the second HPMC and PVP/VA in combination, the microneedle patch can be demolded smoothly during preparation, and the base of the microneedle patch can have desired softness, flatness, flexibility, skin adhesion and humidity resistance without having problems of hard structures and being brittle and prone to breakage. Therefore, the base manufactured from the base solution can be demolded smoothly during the stage of production without being liable to break; in the meantime, it can provide sufficient support as well as good softness, flatness, flexibility and skin adhesion during the stage of use, and prolong the storage time of microneedle patches.

(30) Even though numerous characteristics and advantages of the present invention have been set forth in the foregoing description, together with details of the structure and features of the invention, the disclosure is illustrative only. Changes may be made in the details, especially in matters of shape, size, and arrangement of parts within the principles of the invention to the full extent indicated by the broad general meaning of the terms in which the appended claims are expressed.