TWI815406B - Microneedle patch manufacturing process for treating warts and microneedle patch - Google Patents

Abstract

The invention relates to a microneedle patch manufacturing process for treating warts and the microneedle patch. The microneedle patch manufacturing process includes adding an imiquimod solution into a microneedle mold and passing it through the first After the centrifugation process, a gelatin solution is added, and after the second centrifugation process, the microneedle mold is dried, and finally the microneedle mold is removed to obtain the microneedle patch formed therein, and the gelatin solution When forming the needle body of the microneedle patch together with the imiquimod solution, no cross-linking agent is used. In this way, the microneedle patch produced by the microneedle patch of the present invention not only has The ideal mechanical strength can achieve good transdermal drug delivery, improve cell absorption and immune stimulation, and will not cause negative effects of cytotoxicity.

Description

Microneedle patch manufacturing process for treating warts and microneedle patch

The present invention relates to a microneedle patch and its manufacturing process, and particularly refers to a process in which a cross-linking agent is not added to a gelatin solution and an imiquimod solution during the process of making the needle body of the microneedle patch, so that the microneedle patch The needle body of the tablet will not have a cross-linking agent.

According to reports, warts are skin diseases caused by the Human Papillomavirus (HPV). Especially in some medical studies, it has been found that more than 20% of children have been infected with warts, and they can appear throughout the body. It causes different types of infection and negative effects everywhere. For example, warts infected on the face may cause appearance problems; warts infected on the hands may affect hand movements (such as writing); warts on the soles of the feet. You may feel discomfort and pain due to compression. Therefore, in order to effectively solve the problems caused by warts, currently common methods include cryotherapy (Cryotherapy), surgical excision, CO 2 laser therapy (CO ₂ laser therapy), electrodesiccation, external application of drugs or injection interference. However, since most of the above-mentioned treatments are accompanied by side effects such as skin pain or damage to skin tissue, some industry players have designed the use of microneedle patches (MNP) as treatment tools. technical means.

Following the above, the microneedle patch is a transdermal drug delivery system (TDDS) that combines the advantages of transdermal delivery and injection. It uses micron-sized needle tips to directly pierce the stratum corneum of the skin to form A plurality of micropores are used to deliver drugs. At the same time, due to the limited penetration depth of the microneedle patch, it will not touch the nervous system located in the dermis, so no subcutaneous injection will occur. It can deliver peptides, vaccines, macromolecular drugs, etc. through the skin into the human body through the pain sensation.

At present, microneedle patches can be roughly divided into solid microneedle, coated microneedle, hollow microneedle and dissolvable microneedle. Among them, solid microneedle Microneedles are microneedles made of materials such as metal, ceramics or silicon. They are first pierced into the skin to form micropores, and then a drug patch or ointment is applied, so that the drug can be slowly transported into the human body. ; Coated microneedles apply drugs to the surface of the microneedles, so that after the microneedles pierce the stratum corneum of the skin, the drugs are dissolved in the human tissue fluid and transported to the human body; hollow microneedles use the microneedles to deliver the drug through the microneedles The hollow channel is input into the human body; the dissolving microneedle mixes the drug into the microneedle, and after the microneedle pierces the stratum corneum of the skin, the tip of the microneedle melts into the human tissue fluid, thereby dissolving the drug together and injecting it into the human body. into the human body.

However, in actual use, solid microneedles, coated microneedles and hollow microneedles are prone to breakage and stay in the human body. Since the aforementioned needles are usually made of non-biodegradable materials, Can easily cause severe inflammatory reactions. In addition, for coated microneedles, in order to stably attach the drug to the surface of the needle body, it is often necessary to add excipients to the drug during the aforementioned attachment process. Although this situation can stabilize the adhesion state of the drug, But it is easy to reduce drug activity. In addition, although dissolving microneedles do not have the problems caused by the aforementioned types of microneedles, in actual use, dissolving microneedles usually require the addition of additional cross-linking agents (such as glutaraldehyde), which will easily cause cell toxicity. Therefore, how to effectively solve the above problems to provide users with better microneedle products has become an important issue of the present invention.

Press, the chemical formula of imiquimod is C ₁₄ H ₁₆ N ₄ , which has a good therapeutic effect on warts. Therefore, the applicant adheres to the research spirit of excellence and finally developed it after a long period of hard research and experiments. A microneedle patch manufacturing process for treating warts and a microneedle patch are developed according to the present invention. It is expected that the advent of the present invention can provide users with a better usage experience and gain market favor.

One object of the present invention is to provide a microneedle patch manufacturing process for treating warts. First, a gelatin powder is added to a deionized water and heated to a first temperature for a first period, so that the gelatin The powder is completely dissolved in the deionized water to form a gelatin solution, and then an imiquimod solution is added to a plurality of needle channel grooves of a microneedle mold, where the ratio of the imiquimod solution is ml of dimethyl styrene aqueous solution contains 2 mg of imiquimod, and the microneedle mold is subjected to a first centrifugation process so that the imiquimod solution in the needle channel groove is compacted. In a needle tip cavity of the needle channel groove, the gelatin solution is added to the microneedle mold, and the microneedle mold is subjected to a second centrifugation process to remove the gelatin in each needle channel groove. The solution together with the corresponding imiquimod solution is at least compacted in each needle channel groove. Finally, after the microneedle mold is subjected to a drying process, the microneedle mold is removed to form a microneedle patch, and the When the gelatin solution and the imiquimod solution jointly form the needle body of the microneedle patch, no cross-linking agent is used. In this way, the microneedle patch produced by the microneedle patch of the present invention, It not only has ideal mechanical strength and can achieve good transdermal drug delivery effects, but also can improve cell absorption and immune stimulation without causing negative effects of cytotoxicity.

Optionally, the first temperature is 45 degrees Celsius to 55 degrees Celsius, and the first period is 15 minutes to 25 minutes.

Optionally, the weight percentage of the gelatin powder and the deionized water is 1:0.5~5.

Optionally, the amount of imiquimod solution added to the microneedle mold is 70 microliters to 90 microliters.

Optionally, the time of the first centrifugation procedure is 3 minutes to 7 minutes.

Optionally, the amount of gelatin solution added to the microneedle mold is 70 microliters to 90 microliters.

Optionally, the second centrifugation procedure lasts from 25 minutes to 35 minutes.

Optionally, the drying procedure is to leave the microneedle mold at room temperature for 20 to 28 hours.

Optionally, the microneedle mold material is silicone resin, and the microneedle patch formed by the microneedle mold is provided with a 10x10 array of needles, and the longitudinal length of each needle is 230 microns (µm ) to 580 microns.

Another object of the present invention is to provide a microneedle patch for treating warts, which is made by the microneedle patch manufacturing process for the aforementioned purpose, and the needle material formed by the microneedle patch includes Gelatin with imiquimod, but no cross-linking agent is used.

In order to facilitate the review committee to have a further understanding of the purpose, technical features and effects of the present invention, the detailed description is as follows:

In order to make the purpose, technical content and advantages of the present invention more clear, the disclosed embodiments of the present invention will be further described in detail below in conjunction with specific implementation modes and with reference to the accompanying drawings. Those skilled in the art can understand the advantages and effects of the present invention from the contents disclosed in this specification, and the present invention can be implemented or applied through other different specific embodiments, and various details in this specification can also be based on different viewpoints and applications. , various modifications and changes can be made without departing from the concept of the present invention. In addition, it should be stated in advance that the drawings of the present invention are only simple schematic illustrations and are not drawn according to actual dimensions. In addition, unless the context clearly indicates or defines otherwise, the meanings of "a" and "the" in the present invention include the plural. In addition, the following embodiments will further describe the relevant technical content of the present invention in detail, but the disclosed content is not intended to limit the scope of the present invention.

It is to be understood that the terms used herein generally have their ordinary meanings in the art and that in case of conflict, any definitions given herein shall control. Since the same thing can be said in many ways, alternative words and synonyms may be used for any term discussed or described herein without special qualification as to whether a term is stated or discussed herein, and the use of one or more synonyms does not exclude other synonyms. . The embodiments used anywhere in the description of the present invention, including the use of any terms, are only illustrative and in no way limit the scope and meaning of the present invention or any terms. Likewise, the present invention is not limited to the various embodiments disclosed in the specification. Although the terms first, second, third, etc. may be used herein to describe various elements, each element should not be limited by the foregoing terms. The foregoing terms are mainly used to distinguish one element from another element and should not be used in any way. components impose no substantial limitations and should not limit the order in which the individual components may be assembled or arranged in a practical application.

Furthermore, the terms "substantially" or "approximately" used in this article may refer to a value within a range of deviations from a specific value that can be recognized or determined by those skilled in the art. Or the average of complex values, including taking into account certain specific errors that may occur when measuring the specific value due to the limitations of the measurement system or equipment. For example, the value mentioned substantially can include A range of ±5%, ±3%, ±1%, ±0.5%, ±0.1% and one or more standard deviations of that particular value.

The present invention is a microneedle patch manufacturing process for treating warts and the microneedle patch. In one embodiment, please refer to Figures 1 and 2. The microneedle patch 1 includes a base 11 and a plurality of branches. Needle body 12, wherein the base body 11 can be in the shape of a flat plate, and its material is at least composed of gelatin, and the needles are also arranged on one side of the base body 11 (the bottom surface in Figure 1) Body 12, these needle bodies 12 are spaced apart from each other, and the needle tip 121 of each needle body 12 is at least composed of imiquimod (imiquimod) or a mixture of imiquimod and gelatin, and the remaining needle body 12 parts are made of imiquimod (imiquimod) or a mixture of imiquimod and gelatin. The product needs to be made of the same material as the needle tip 121, or at least made of gelatin. During the forming process of the microneedle patch 1, the gelatin and imiquimod will not be doped or cross-linking agents will be used to promote the gelatin. The needle body 12 is formed by cross-linking with imiquimod. In this way, when the user attaches the microneedle patch 1 to the skin surface, the needles 12 (or at least the needle tip portion 121) can penetrate the stratum corneum of the skin, and the medicine (i.e., microphone) located in the needle tip portion 121 imiquimod) can be accompanied by the needle tip 121 to penetrate deep into the epidermal tissue under the stratum corneum to produce a drug reaction under the skin, so that imiquimod can be imported into the human body to achieve the medical treatment of warts. need.

Please refer to Figures 1 to 3. In a preferred embodiment of the present invention, the microneedle patch manufacturing process includes the following steps:

Preparing gelatin solution (step (201)): The present invention can first add gelatin powder to deionized water, then heat the aforementioned deionized water to a first temperature (such as: 45 degrees Celsius to 55 degrees Celsius), and heat A first period (such as: 15 minutes to 25 minutes) is reached, so that the gelatin powder can be completely dissolved in the deionized water, thereby forming a gelatin solution, wherein the weight percentage of the gelatin powder and the deionized water is 1: 0.5~5, and according to the process requirements, as the weight percentage of gelatin powder and deionized water changes, the industry can adjust the value of the first temperature and/or the value of the first period to form a gelatin solution that can be used , in a preferred embodiment of the present invention, the first temperature can be 50 degrees Celsius, and the first period can be 20 minutes.

Add the imiquimod solution to the microneedle mold (step (202)): Please refer to Figure 1 and Figure 4, wherein Figure 4 is the partial structure of the microneedle mold 3 of the present invention, especially here It should be mentioned that the microneedle mold 3 described in the present invention is only for the convenience of illustrating the process of the present invention. Therefore, only the structure of the microneedle mold 3 used in the process will be described, but it is not limited to the structure and state shown in Figure 4. In this way, as long as the microneedle mold 3 is sufficient to produce the microneedle patch 1 referred to in the present invention. In addition, the microneedle mold 3 is provided with a forming space, which includes a base groove 31 and a plurality of needle track grooves 32, wherein the needle track grooves 32 are located below the base groove 31 (in the direction of Figure 4 ), and the longitudinal section shows a tapered state with a wide top and narrow bottom.

Continuing with the above, please refer to Figures 1 and 4. The imiquimod solution can be added to at least the plurality of needle channel grooves 32 of the microneedle mold 3. In this embodiment, the imiquimod solution is added to the microneedle mold 3. The quantity of the imiquimod solution in the mold 3 is 70 microliters to 90 microliters (but not limited to this). The imiquimod solution is made by dissolving imiquimod in dimethyl sulfoxide (Dimethylsulfoxide). sulfoxide (DMSO for short), the ratio is 2 mg of imiquimod per milliliter of dimethylsulfoxide aqueous solution (2 mg/mL). In this embodiment, the microneedle mold 3 can also be made of silicone, and the transverse cross-section of the base 11 of the microneedle patch 1 formed by the microneedle mold 3 is square. With a side length of 200 microns (µm), the microneedle patch 1 can also have a 10x10 array of needles 12 (ie, 100 needles 12), and the longitudinal length of each needle 12 is from 230 microns to 580 Microns. In this embodiment, in order to form the aforementioned microneedle patch 1, the longitudinal length of the needle channel groove 32 of the microneedle mold 3 can be substantially 250 microns to 620 microns (preferably 600 microns). , so as to produce the needle body 12 of the required length.

The first centrifugation process (step (203)): Referring again to Figures 1 and 4, the microneedle mold 3 will be placed in a centrifugal equipment to perform centrifugation operations on the microneedle mold 3. The aforementioned step The centrifugation operation time of a centrifugation program is 3 minutes to 7 minutes (but not limited to this), and after the centrifugation operation, the imiquimod solution in the needle channel groove 32 can be compacted in each of the In a needle tip cavity 321 of the needle channel groove 32, in other words, the imiquimod solution will be accumulated and compacted toward the area of the needle tip cavity 321 due to the influence of centrifugal force.

Add the gelatin solution to the microneedle mold (step (204)): Referring again to Figures 1 and 4, the gelatin solution can be added to the microneedle mold 3, and the gelatin solution can be placed in each needle channel concave The amount of imiquimod solution in the groove 32, the gelatin solution can at least be added to the base groove 31, or the base groove 31 and each needle channel groove 32, in this embodiment, added to the The amount of gelatin solution in the microneedle mold 3 is 70 microliters to 90 microliters (but not limited to this).

Second centrifugation process (step (205)): Please refer to Figures 1 and 4 again. The microneedle mold 3 will be placed into the centrifuge equipment again to perform centrifugation operations on the microneedle mold 3. As mentioned above The centrifugation operation time of the second centrifugation procedure is 25 minutes to 35 minutes (but not limited to this). Moreover, after the centrifugation operation, the gelatin solution in the microneedle mold 3 together with the corresponding imiquimod solution can be at least is compacted in each needle channel groove 32. During the aforementioned process, part of the gelatin solution will be mixed with the imiquimod solution. However, due to the influence of centrifugal force, both the gelatin solution and the imiquimod solution will move toward the needle tip cavity 321. The area direction is stacked and compacted. Therefore, all or a large amount of imiquimod will still exist in the solution in the needle tip cavity 321 .

Drying procedure (step (206)): Refer again to Figures 1 and 4. The microneedle mold 3 can be left to dry at room temperature for 20 to 28 hours. In this embodiment, the optimal drying time is one day. , after that, the microneedle mold 3 is removed (ie, demoulding operation), and the microneedle patch 1 can be obtained. For example, adhesive tape is used to affix it to the base 11 of the microneedle patch 1, so that the microneedle patch 1 is The sheet 1 is pulled away from the microneedle mold 3, and as shown in Figure 2, at least the needle tip 121 of the microneedle patch 1 can have imiquimod. Therefore, when the microneedle patch 1 is used as a tool for treating warts, It can deliver imiquimod into the human body to complete the role and efficacy of transdermal drug delivery.

To sum up, when the gelatin solution and the imiquimod solution jointly form the needle body 12 of the microneedle patch 1 produced by the process of the present invention, no cross-linking agent ( Such as: glutaraldehyde), therefore, the problem of cell toxicity can be avoided, and at the same time, the needle body 12 can also have the expected mechanical strength, enough to pierce the skin without breaking, so that the needle body 12 The gelatin and imiquimod on 12 can be dissolved in human tissue fluid, thereby allowing imiquimod to be imported into the human body. In other words, the microneedle patch 1 is a dissolvable microneedle, and because gelatin is Biodegradable material, so it will not cause serious inflammatory reactions.

In particular, please refer to Figures 1 to 4. The step of preparing the gelatin solution of the present invention is not limited to being the first step to be completed, as long as it is completed before step (204); In addition, after the first centrifugation process is completed, the staff can first remove the imiquimod solution on the surface of the microneedle mold 3. For example, use a pipette to suck up the imiquimod solution on the surface of the microneedle mold 3 that does not enter the grooves of the needle channels. 32% of the imiquimod solution to achieve the removal of the imiquimod solution. In this way, the imiquimod solution can be prevented from remaining in the formed base 11, so that the imiquimod solution can be accurately coated on the needle. into the needle tip 121 of the body 12, and then proceed to step (204). Furthermore, since the gelatin will gradually shrink as water evaporates during the drying process, the length of the needle body 12 of the microneedle patch 1 is usually smaller than the longitudinal length of the needle channel groove 32 , therefore, in order to produce an ideal length of the needle body 12 to achieve better transdermal drug delivery effect, please refer to Figure 5A, where the weight percentage of gelatin powder and deionized water is 1:1, 1 : 1.5, 1:2, 1:2.5 and other four ratios to produce the needle body 12, and after measurement, the weight percentage of gelatin powder and deionized water is 1:2, 1:2.5 and other two ratios, The length of the needle body 12 is ideal. Also, please refer to Figure 5B. After the mechanical strength of the needles made from the two aforementioned ratios (1:2, 1:2.5) is measured with a texture analyzer, for example, The piece vertically presses the needle tip of the needle body 12 until the needle tip is damaged. The mechanical strength (force = Newton/microneedle patch) of the needle body 12 with a ratio of 1:2 can be higher than that of the needle body 12 with a ratio of 1:2.5. It has good mechanical strength. It can be seen that the needle body 12 made with the weight percentage of gelatin powder and deionized water as 1:2 has better mechanical strength and length to effectively penetrate the needle body 12. The skin enters the dermis layer, thereby achieving good transdermal drug delivery effect.

Referring again to Figures 1 to 4, the gelatin solution formed by using the aforementioned gelatin powder and deionized water in a weight percentage of 1:2 is combined with the microneedle patch process of the present invention to form a microneedle patch. Tablet 1 (that is, the needle body 12 contains imiquimod), the aforementioned needle body 12 containing imiquimod (dashed line in Figure 6A), and the needle body 12 with only gelatin (solid line in Figure 6A (line) after the mechanical strength test, as shown in Figure 6A, as the pressure applied by the test piece increases (that is, the displacement distance of the test piece pressing the needle body 12 increases), the breaking point timing of the two aforementioned needle bodies 12 is approximately The force appears at 17 Newtons (as shown in Figure 6B). In other words, the microneedle patch 1 produced through the microneedle patch process of the present invention still has the mechanical strength expected by the industry after adding imiquimod. .

In addition, in order to prove that the microneedle patch 1 of the present invention has a positive effect on the treatment of warts, RAW-Blue™ cells (derived from mouse RAW 264.7 macrophages) were used to evaluate "imiquimod" and "imiquimod". The effect of the mixture with gelatin (i.e., the needle 12 material of the present invention) on the immune response, and the QUANTI-Blue™ detection method can detect and quantify SEAP activity (according to the absorbance at 630 nm) ), as shown in Figure 7, as the concentration of imiquimod increases, the "imiquimod and gelatin mixture" of the present invention is better than the simple "imiquimod" in improving cell absorption and immune stimulation. "Special", therefore, in the microneedle patch 1 of the present invention, the needle body 12 formed by mixing gelatin with imiquimod, in actual use, gelatin can achieve a stabilizer effect and help improve cell absorption and Immune stimulation and other effects.

According to the above, the above are only preferred embodiments of the present invention. However, the scope of rights claimed by the present invention is not limited thereto. According to those who are familiar with the art, based on the technical content disclosed in the present invention, they can Equivalent changes that can be easily imagined should not depart from the scope of protection of the present invention.

[customary knowledge] without [Invention] 1: Microneedle patch 11: base body 12: Needle body 121: Needle tip 201~206: Steps 3: Microneedle mold 31: Seat body groove 32: Needle groove 321: Needle tip cavity

[Figure 1] is a schematic three-dimensional cross-sectional view of the microneedle patch of the present invention; [Figure 2] is a partial enlarged view of the microneedle patch of the present invention; [Figure 3] is a flow chart of the microneedle patch manufacturing process of the present invention; [Fig. 4] is a partial cross-sectional view of the microneedle mold of the present invention; [Figure 5A] The weight percentage of gelatin powder and deionized water of the present invention is 1:1. Schematic diagram of the length of the needle formed by four ratios: 1:1.5, 1:2, 1:2.5; [Figure 5B] The weight percentage of the gelatin powder and deionized water of the present invention is 1:2. Schematic diagram of the mechanical strength of a needle body formed with a ratio of 1:2.5; [Figure 6A] is a schematic diagram showing a needle formed from a gelatin solution and a needle formed from gelatin mixed with imiquimod, which are subjected to pressure for mechanical strength testing; [Figure 6B] is a schematic diagram of the timing of the breaking points of the two types of needles in Figure 6A; and [Figure 7] is a schematic diagram of the QUANTI-Blue™ detection method for imiquimod and a mixture of imiquimod and gelatin.

201~206: Steps

Claims (9)

A method for manufacturing a microneedle patch for treating warts, including: adding a gelatin powder to a deionized water, and heating it to a first temperature for a first period, so that the gelatin powder is completely dissolved in the deionized water. water to form a gelatin solution; an imiquimod solution is added to a plurality of needle channel grooves of a microneedle mold, wherein the ratio of the imiquimod solution is that each milliliter of the dimethyl sulfoxide aqueous solution contains 2 mg of imiquimod; perform the first centrifugation process on the microneedle mold, so that the imiquimod solution in the needle channel groove is compacted in a needle tip cavity of the needle channel groove; Add the gelatin solution to the microneedle mold; perform a second centrifugation process on the microneedle mold, so that each gelatin solution and the corresponding imiquimod solution in each needle channel groove are at least compacted in each needle channel groove; and after the microneedle mold is subjected to a drying process, the microneedle mold is removed to form a microneedle patch, and the gelatin solution and the imiquimod solution jointly form the microneedle patch. No cross-linking agent is used when inserting the needle body of the patch. The method for manufacturing a microneedle patch according to claim 1, wherein the first temperature is 45 degrees Celsius to 55 degrees Celsius, and the first period is 15 minutes to 25 minutes. The method for manufacturing a microneedle patch according to claim 1, wherein the weight percentage of the gelatin powder and the deionized water is 1:0.5~5. The method for manufacturing a microneedle patch according to claim 1, wherein the amount of imiquimod solution added to the microneedle mold is 70 microliters to 90 microliters. The method for manufacturing a microneedle patch according to claim 1, wherein the first centrifugation procedure lasts from 3 minutes to 7 minutes. The microneedle patch manufacturing method as described in claim 4, wherein the amount of gelatin solution added to the microneedle mold is 70 microliters to 90 microliters. The microneedle patch manufacturing method as described in claim 5, wherein the second centrifugation process lasts from 25 minutes to 35 minutes. The microneedle patch manufacturing method as described in claim 1, wherein the drying procedure is to allow the microneedle mold to be left to dry at room temperature for 20 to 28 hours. The method for manufacturing a microneedle patch according to any one of claims 1 to 8, wherein the microneedle mold material is silicone resin, and the microneedle patch formed by the microneedle mold is provided with a 10x10 array. The number of needles, and the longitudinal length of each needle is 230 microns to 580 microns.

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