TWI633901B - Medical beauty microneedle patch manufacturing method - Google Patents

Medical beauty microneedle patch manufacturing method Download PDF

Info

Publication number
TWI633901B
TWI633901B TW106116174A TW106116174A TWI633901B TW I633901 B TWI633901 B TW I633901B TW 106116174 A TW106116174 A TW 106116174A TW 106116174 A TW106116174 A TW 106116174A TW I633901 B TWI633901 B TW I633901B
Authority
TW
Taiwan
Prior art keywords
needle
layer
needle tip
mixed liquid
holes
Prior art date
Application number
TW106116174A
Other languages
Chinese (zh)
Other versions
TW201800121A (en
Inventor
吳佳育
徐英華
劉大佼
葉修鋒
Original Assignee
怡定興科技股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 怡定興科技股份有限公司 filed Critical 怡定興科技股份有限公司
Priority to TW106116174A priority Critical patent/TWI633901B/en
Priority to CN201710374824.9A priority patent/CN107343984B/en
Publication of TW201800121A publication Critical patent/TW201800121A/en
Application granted granted Critical
Publication of TWI633901B publication Critical patent/TWI633901B/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Medical Informatics (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Media Introduction/Drainage Providing Device (AREA)

Abstract

本創作關於一種醫美微針貼片之製作方法，其係先將含有醫美活性成分之針尖混合液形成於母模之多個孔洞內，將其乾燥成針尖層後，再將針底混合液形成於針尖層上及前述多個孔洞內，而後再將針底混合液乾燥為針底層，藉此令針底層黏合於該針尖層，最後自母模上卸下相互黏合之針尖層和針底層，即製得醫美微針貼片。本創作之方法不僅能克服以往製作微針貼片所面臨之黏接、機台對位與生產成本問題，更能具體節省製程時間、提升量產效率，提供一種適用於大量生產醫美微針貼片之製作方法。This creation relates to a method for making a medical microneedle patch, which first forms a needle tip mixed solution containing medical active ingredients in multiple holes in a master mold, dries it into a needle tip layer, and then mixes the needle base The liquid is formed on the needle tip layer and in the above-mentioned multiple holes, and then the needle bottom mixed liquid is dried into the needle bottom layer, so that the needle bottom layer is adhered to the needle tip layer, and finally the bonded needle tip layer and needle are removed from the mother mold. On the bottom layer, a medical microneedle patch is obtained. The method of this creation can not only overcome the problems of adhesion, machine alignment and production cost faced in the past in the production of microneedle patches, but also can specifically save process time and improve mass production efficiency, and provide a microneedle suitable for mass production of medical beauty How to make a patch.

Description

醫美微針貼片之製作方法Medical beauty microneedle patch manufacturing method

本創作關於一種醫用產品之生產技術，尤指一種醫美微針貼片之製作方法。This creation is about the production technology of a medical product, especially a method of making a medical microneedle patch.

經皮輸藥(transdermal drug delivery)為近年來受到矚目的一種投藥方式，其能利用非侵入性的投藥方式，讓藥物透過皮膚吸收而發揮藥效。經皮輸藥雖能避免口服投藥因消化系統的作用而無法有效控制藥效，同時免除皮下注射所造成之恐懼感及疼痛感，但由於皮膚的角質層同時具有疏水和帶負電荷之性質，故不適合透過經皮輸藥系統傳遞水溶性藥物。Transdermal drug delivery is a drug delivery method that has attracted much attention in recent years. It can utilize non-invasive drug delivery methods to allow drugs to be absorbed through the skin to exert their effects. Although transdermal infusion can prevent oral administration from effectively controlling the effect of the digestive system, and at the same time avoid the fear and pain caused by subcutaneous injection, but because the stratum corneum of the skin is both hydrophobic and negatively charged, It is not suitable for delivery of water-soluble drugs through a transdermal drug delivery system.

針對上述問題，現有技術已發展出一種微針貼片，其基材上佈滿有複數微米等級的微針結構，這些微針結構可刺穿皮膚的角質層，將藥物輸送至表皮層而釋放。利用微針貼片投藥不僅能解決以往口服投藥或皮下注射所存在之諸多問題，更能將欲投遞的藥物類型拓展為脂溶性藥物和水溶性藥物，使前述不同類型的藥物都能透過微針貼片上的微針結構直接輸送至表皮層釋放藥效，而不會有疼痛感產生。In response to the above problems, the prior art has developed a microneedle patch, the substrate of which is covered with a plurality of micron-scale microneedle structures. These microneedle structures can pierce the stratum corneum of the skin and deliver the drug to the epidermal layer for release. . The use of microneedle patch can not only solve many problems in the past oral administration or subcutaneous injection, but also expand the types of drugs to be delivered into fat-soluble drugs and water-soluble drugs, so that the aforementioned different types of drugs can pass through the microneedle The microneedle structure on the patch is directly delivered to the epidermal layer to release the drug effect without pain.

基於微針貼片的諸多優點，目前業界已積極投入微針貼片之開發。如台灣發明專利第201400140A號揭露一種鑲嵌式經皮藥物釋放貼片之製造方法，其一方面需先將包含藥物之生物可分解性高分子膠體灌膜，獲得複數生物可分解性載體，另一方面需先製作形成有複數突狀支持軸的支持基材，並於支持基材預先塗佈黏合劑；而後，再設法對準支持基材表面上之突狀支持軸與前述生物可分解性載體，並將其相互黏接，才能製得鑲嵌式經皮藥物釋放貼片。Based on the many advantages of microneedle patches, the industry has actively invested in the development of microneedle patches. For example, Taiwan Invention Patent No. 201400140A discloses a method for manufacturing a mosaic transdermal drug release patch. On the one hand, a biodegradable polymer colloid containing a drug is firstly perfused to obtain a plurality of biodegradable carriers, and the other On the one hand, it is necessary to first prepare a support substrate having a plurality of protruding support shafts, and apply an adhesive to the support substrate in advance; then, try to align the protruding support shafts on the surface of the support substrate with the aforementioned biodegradable carrier. In order to obtain a mosaic transdermal drug release patch, they can be adhered to each other.

然而，上述製程方法必須額外考慮支持基材上的複數突狀支持軸與複數載體之間的間距及對位問題，增加製程的困難度；且製作過程中另需預先經過塗佈黏合劑的步驟才能黏合支持基材和載體，無不增加製程的複雜度與生產成本。However, the above manufacturing method must additionally consider the spacing and alignment between the plurality of protruding support shafts on the supporting substrate and the plurality of carriers, which increases the difficulty of the process; and in the manufacturing process, an additional step of applying an adhesive is required in advance. In order to adhere the supporting substrate and the carrier, it will increase the complexity of the process and the production cost.

有鑑於上述技術問題，本創作之目的在於解決現有技術製作微針貼片所存在之技術缺陷與不便利性，提供一種有利於量產微針貼片之製作方法。In view of the above technical problems, the purpose of this creation is to solve the technical defects and inconveniences of microneedle patches in the prior art, and to provide a manufacturing method that is beneficial to mass production of microneedle patches.

為達成前述目的，本創作提供一種醫美微針貼片之製作方法，其包括以下步驟： (a) 提供一母模，該母模具有一基準面及複數孔洞，所述多個孔洞由基準面向下凹設成型； (b) 將一針尖混合液形成於該母模之多個孔洞內，藉此令針尖混合液填滿母模之多個孔洞，獲得一裝有針尖混合液之母模，該針尖混合液之液面係與母模之基準面齊平，該針尖混合液中含有醫美活性成分； (c) 將針尖混合液乾燥為針尖層，獲得一具有針尖層之母模，該針尖層之表面低於母模之基準面； (d) 將一針底混合液形成於針尖層上及前述多個孔洞內，藉此令針底混合液覆蓋針尖層及該母模之基準面及多個孔洞中，獲得一裝有針底混合液之母模； (e) 將針底混合液乾燥為針底層，藉此令針底層黏合於該針尖層；以及 (f) 自母模上卸下相互黏合之針尖層和針底層，獲得該醫美微針貼片。In order to achieve the foregoing objective, the present invention provides a method for manufacturing a medical microneedle patch, which includes the following steps: (a) providing a master mold having a reference surface and a plurality of holes, and the plurality of holes are faced by the reference Set down to shape; (b) Form a needle tip mixture into the holes of the master mold, so that the needle tip mixture fills the holes in the master mold to obtain a master mold filled with the needle tip mixture. The liquid level of the needle-point mixed liquid is flush with the reference surface of the master mold, and the needle-point mixed liquid contains medicinal active ingredients; (c) drying the needle-point mixed liquid into a needle-point layer to obtain a mother mold having a needle-point layer, The surface of the needle tip layer is lower than the reference surface of the master mold; (d) forming a needle bottom mixed solution on the needle tip layer and the aforementioned multiple holes, so that the needle bottom mixed solution covers the needle tip layer and the reference of the mother mold And a plurality of holes to obtain a master mold filled with the needle bottom mixed liquid; (e) drying the needle bottom mixed liquid to the bottom layer of the needle, thereby making the bottom layer of the needle adhere to the needle tip layer; and (f) from the master mold The needle tip layer and the needle bottom layer which are adhered to each other are removed to obtain the medical beauty microneedle patch. .

根據本創作醫美微針貼片之製作方法，本創作能無需額外使用黏合劑，於同一母模完成針尖層和針底層之製作。由於本創作醫美微針貼片之製作方法係先令針尖混合液乾燥為針尖層後，再形成針底混合液並令其乾燥，故能利用針尖混合液和針底混合液中高分子材料的高分子作用力從而令經乾燥之針尖層和針底層相互黏合，具體克服以往的製作方法所衍生之黏接、機台對位與生產成本問題，從而節省製程時間、提升量產效率，提供一種適用於大量生產醫美微針貼片之製作方法。According to the production method of this creative medical beauty microneedle patch, the creation can complete the production of the needle tip layer and the needle bottom layer in the same master mold without additional adhesive. Because the method of making this medical and aesthetic microneedle patch is to dry the needle tip mixture into a needle tip layer, and then form the needle bottom mixture and let it dry, it can use the polymer materials in the needle tip mixture and the needle bottom mixture. The polymer force causes the dried needle tip layer and the needle bottom layer to adhere to each other, and specifically overcomes the problems of adhesion, machine alignment and production costs derived from previous manufacturing methods, thereby saving process time and improving mass production efficiency, providing a It is suitable for the manufacturing method of medical micro-needle patch.

於一實施態樣中，所述針尖混合液之水溶性係大於所述針底混合液之水溶性，從而令醫美微針貼片之針尖層的水溶性大於針底層之水溶性。據此，當使用本創作之醫美微針貼片刺穿皮膚時，醫美微針貼片之針尖層將迅速溶解並與針底層脫離，從而在表皮層中迅速地釋放醫美活性成分。於另一實施態樣中，所述針尖混合液之水溶性係小於所述針底混合液之水溶性，從而令醫美微針貼片之針尖層的水溶性小於針底層之水溶性。據此，當使用本創作之醫美微針貼片刺穿皮膚時，醫美微針貼片之針底層會早於針尖層溶解，使針尖層存留於體內，並在表皮層中緩慢地釋放醫美活性成分。是以，本創作醫美微針貼片之製作方法能藉由控制針尖混合液和針底混合液二者的水溶性，依不同需求製造出速溶型醫美微針貼片及緩釋型醫美微針貼片。In one embodiment, the water solubility of the needle-point mixed solution is greater than that of the needle-bottom mixed solution, so that the water-solubility of the tip layer of the medical beauty microneedle patch is greater than that of the bottom layer of the needle. According to this, when the medical beauty microneedle patch of this creation is used to pierce the skin, the needle layer of the medical beauty microneedle patch will quickly dissolve and detach from the needle bottom layer, thereby quickly releasing the medical beauty active ingredients in the epidermal layer. In another embodiment, the water-solubility of the needle-point mixed solution is lower than that of the needle-bottom mixed solution, so that the water-solubility of the tip layer of the medical beauty microneedle patch is less than that of the bottom layer of the needle. According to this, when the medical beauty microneedle patch used in this creation pierces the skin, the needle bottom layer of the medical beauty microneedle patch will dissolve earlier than the needle tip layer, so that the needle tip layer will remain in the body and will be slowly released in the epidermal layer. Medical beauty active ingredients. Therefore, the method for producing the medical micro-needle patch can create the medical micro-needle patch and the slow-release medical micro-needle patch according to different needs by controlling the water solubility of both the needle tip mixed solution and the needle bottom mixed solution. Beautiful micro needle patch.

於本創作醫美微針貼片之製作方法中，前述(b)與(d)步驟可採用濕式塗佈法或印刷法將針尖混合液或針底混合液形成於該母模之多個孔洞內。選用濕式塗佈法塗佈針尖混合液和針底混合液，能有利於控制各微針結構中醫美有效成分的分佈範圍，進而具體控制醫美微針貼片的有效成份之劑量。In the production method of the creative medical beauty microneedle patch, the above steps (b) and (d) can use wet coating method or printing method to form the needle tip mixed solution or the needle bottom mixed solution into a plurality of the master mold. Inside the hole. The wet tip coating method is used to coat the needle tip mixture and the needle bottom mixture, which can help to control the distribution range of the active ingredients of TCM beauty in each microneedle structure, and then specifically control the dose of the active ingredients of the microneedle patch.

較佳的，前述(b)與(d)步驟可各自獨立採用狹縫式塗佈法(slit or slot die coating)、刮刀式塗佈法(blade coating)、斜板式塗佈法(slide coating)、浸漬塗佈法(dip coating)、噴墨印刷法(inkjet printing)或噴嘴印刷法(nozzle printing)將針尖混合液或針底混合液形成於該母模之多個孔洞內，但並非僅限於上述方法。所述(b)步驟將針尖混合液形成於多個孔洞內的方法可與(d)步驟將針底混合液形成於多個孔洞內的方法相同或不同。較佳的，本創作醫美微針貼片之製作方法可採用狹縫式塗佈法或刮刀式塗佈法，將針尖混合液和針底混合液形成於該母模之多個孔洞內。Preferably, the aforementioned steps (b) and (d) can be performed independently using a slit or slot die coating method, a blade coating method, or a slid coating method. The dip coating, inkjet printing, or nozzle printing method forms the needle tip mixture or the needle bottom mixture into the multiple holes of the master mold, but it is not limited to The above method. The method of forming the needle tip mixed liquid in the multiple holes in the step (b) may be the same as or different from the method of forming the needle bottom mixed liquid in the multiple holes in the step (d). Preferably, the production method of the creative medical beauty microneedle patch can adopt a slit coating method or a doctor blade coating method, and the needle tip mixed liquid and the needle bottom mixed liquid are formed in a plurality of holes of the master mold.

當(b)步驟使用狹縫式塗佈法塗佈針尖混合液時，其塗佈間隙可控制於1 μm至5000 μm、塗佈速度可控制於1 m/min至100 m/min；上述製程參數可根據所選用之針尖混合液之特性及醫美微針貼片之規格而加以調整。此外，當(d)步驟使用狹縫式塗佈法塗佈針底混合液時，其塗佈間隙可控制於1 μm至3000 μm、塗佈速度可控制於1 m/min至100 m/min；上述製程參數可根據所選用之針底混合液之特性及醫美微針貼片之規格而加以調整。When the needle tip mixture is applied by the slit coating method in step (b), the coating gap can be controlled from 1 μm to 5000 μm, and the coating speed can be controlled from 1 m / min to 100 m / min; the above process The parameters can be adjusted according to the characteristics of the selected needle tip mixture and the specifications of the medical beauty microneedle patch. In addition, when the needle base mixed solution is applied by the slit coating method in step (d), the coating gap can be controlled from 1 μm to 3000 μm, and the coating speed can be controlled from 1 m / min to 100 m / min. The above-mentioned process parameters can be adjusted according to the characteristics of the selected needle-bottom mixture and the specifications of Yimei microneedle patch.

較佳的，於前述(b)步驟中，塗佈間隙可控制於100 μm至5000 μm、塗佈速度可控制於1 m/min至100 m/min；於前述(d)步驟中，塗佈間隙可控制於100 μm至3000 μm、塗佈速度可控制於1 m/min至100 m/min。Preferably, in the step (b), the coating gap can be controlled from 100 μm to 5000 μm, and the coating speed can be controlled from 1 m / min to 100 m / min; in the step (d), the coating The gap can be controlled from 100 μm to 3000 μm, and the coating speed can be controlled from 1 m / min to 100 m / min.

較佳的，前述(b)步驟可進一步包括： 先將針尖混合液形成於該母模上，再令針尖混合液流動至多個孔洞內，藉此令針尖混合液覆蓋於該母模之基準面及多個孔洞中；以及 移除基準面上之針尖混合液，藉此令針尖混合液之液面係與母模之基準面齊平。Preferably, the step (b) may further include: forming the needle-point mixed liquid on the mother mold, and then allowing the needle-point mixed liquid to flow into a plurality of holes, so that the needle-point mixed liquid covers the reference surface of the mother mold. And a plurality of holes; and removing the tip liquid mixture on the reference surface, so that the liquid level of the needle tip liquid is flush with the reference surface of the master mold.

於前述令針尖混合液流動至多個孔洞內之步驟中，其所採用之方法可為真空抽氣法或離心法。於其中一實施態樣，本創作可將針尖混合液和母模置於烘箱中抽氣，藉此令針尖混合液覆蓋於該母模之基準面及多個孔洞中；於另一實施態樣，本創作可將針尖混合液和母模共同離心，藉此令針尖混合液覆蓋於該母模之基準面及多個孔洞。於此，烘箱中的壓力可控制在0.001 torr至90 torr，較佳為0.009 torr至90 torr。而離心步驟之轉速可控制在100 rpm至10000 rpm，較佳為100 rpm至8000 rpm。In the aforementioned step of causing the needle tip mixed liquid to flow into the plurality of holes, the method adopted may be a vacuum suction method or a centrifugation method. In one of the embodiments, the creation can place the needle-point mixture and the master mold in an oven to extract air, so that the needle-point mixture covers the reference surface and multiple holes of the master mold; in the other embodiment, In this creation, the needle tip mixed liquid and the mother mold are centrifuged together, so that the needle tip mixed liquid covers the reference surface and multiple holes of the mother mold. Here, the pressure in the oven can be controlled from 0.001 to 90 torr, preferably from 0.009 to 90 torr. The speed of the centrifugation step can be controlled from 100 rpm to 10000 rpm, preferably from 100 rpm to 8000 rpm.

較佳的，前述(d)步驟可進一步包括：將針底混合液形成於該母模上，再令針底混合液流動至多個孔洞內，藉此令針底混合液覆蓋於針尖層及該母模之基準面及多個孔洞中，獲得一裝有針底混合液之母模。Preferably, the step (d) may further include: forming a needle base mixed liquid on the master mold, and then allowing the needle base mixed liquid to flow into a plurality of holes, so that the needle base mixed liquid covers the needle tip layer and the In the reference plane of the master mold and in a plurality of holes, a master mold containing a mixture of needle bottoms was obtained.

於前述令針底混合液流動至多個孔洞內之步驟中，其所採用之方法可為真空抽氣法或離心法。於其中一實施態樣，本創作可將針底混合液和母模置於烘箱中抽氣，藉此令針底混合液覆蓋於該母模之基準面及多個孔洞中；於另一實施態樣，本創作可將針底混合液和母模共同離心，藉此令針底混合液覆蓋於該母模之基準面及多個孔洞。於此，烘箱中的壓力可控制在0.001 torr至90 torr，較佳為0.009 torr至90 torr。而離心步驟之轉速可控制在100 rpm至10000 rpm，較佳為100 rpm至5000 rpm。In the aforementioned step of causing the needle-bottom mixed solution to flow into the plurality of holes, the method adopted may be a vacuum extraction method or a centrifugation method. In one of the implementations, the creation can place the needle bottom mixture and the master mold in an oven to extract air, so that the needle bottom mixture can cover the reference surface and multiple holes of the master mold; in the other implementation In this way, in this creation, the needle base mixed liquid and the female mold are centrifuged together, so that the needle base mixed liquid covers the reference surface of the female mold and a plurality of holes. Here, the pressure in the oven can be controlled from 0.001 to 90 torr, preferably from 0.009 to 90 torr. The speed of the centrifugation step can be controlled from 100 rpm to 10000 rpm, preferably from 100 rpm to 5000 rpm.

前述(c)和(e)步驟可採用冷凍乾燥或常溫乾燥之方式進行。較佳的，前述(c)和(e)步驟之乾燥溫度可控制在-80°C至160°C；更佳為-80°C至80°C之間；再更佳為-80°C至50°C之間。The steps (c) and (e) can be performed by freeze drying or drying at room temperature. Preferably, the drying temperature in the steps (c) and (e) can be controlled between -80 ° C and 160 ° C; more preferably between -80 ° C and 80 ° C; even more preferably -80 ° C To 50 ° C.

較佳的，前述(e)步驟包括： 將針底混合液置於-80°C至0°C乾燥為針底層，獲得一初次乾燥之針底層及針尖層； 將初次乾燥之針底層及針尖層置於2°C至10°C下，獲得一二次乾燥之針底層及針尖層； 再將該二次乾燥之針底層及針尖層置於室溫下乾燥，藉此令針底層黏合於該針尖層。Preferably, the aforementioned step (e) includes: drying the needle bottom mixed liquid at -80 ° C to 0 ° C to dry the needle bottom layer to obtain a first dried needle bottom layer and the needle tip layer; and drying the first dried needle bottom layer and the needle tip. The layer is placed at 2 ° C to 10 ° C to obtain the dried needle bottom layer and the needle tip layer. The dried needle bottom layer and the needle tip layer are dried at room temperature to make the needle bottom adhere to The tip layer.

更佳的，前述(e)步驟包括： 將針底混合液置於-80°C至0°C乾燥為針底層，獲得一初次乾燥之針底層及針尖層； 將該初次乾燥之針底層及針尖層置於2°C至10°C下乾燥，獲得一二次乾燥之針底層及針尖層； 再令該二次乾燥之針底層及針尖層置於-80°C至0°C下乾燥，獲得一三次乾燥之針底層及針尖層； 再將該三次乾燥之針底層及針尖層置於2°C至10°C下乾燥，獲得一四次乾燥之針底層及針尖層； 再將該四次乾燥之針底層及針尖層置於室溫下乾燥，藉此令針底層黏合於該針尖層。More preferably, the aforementioned step (e) includes: drying the needle bottom mixed liquid at -80 ° C to 0 ° C to dry the needle bottom layer to obtain an initial dried needle bottom layer and a needle tip layer; The needle tip layer is dried at 2 ° C to 10 ° C to obtain the dried needle bottom layer and the needle tip layer. The secondary dried needle bottom layer and the needle tip layer are dried at -80 ° C to 0 ° C. To obtain the dried needle bottom layer and the needle point layer once or three times; then dry the dried needle bottom layer and the needle point layer three times at 2 ° C to 10 ° C to obtain the dried needle bottom layer and the needle point layer one or four times; The four-dried needle bottom layer and the needle tip layer are dried at room temperature, so that the needle bottom layer is adhered to the needle tip layer.

據此，藉由前述反覆冷凍交聯之步驟，能有利於提升醫美微針貼片之機械強度，使醫美微針貼片之微針結構的楊氏模數(Young’s modulus)提升3倍以上。According to this, through the foregoing steps of repeated freeze-crosslinking, the mechanical strength of the medical microneedle patch can be improved, and the Young's modulus of the microneedle structure of the medical microneedle patch can be increased by 3 times. the above.

較佳的，前述初次和三次乾燥步驟的溫度可為-40°C至0°C，更佳為-30°C至-10°C；而前述二次和四次乾燥步驟的溫度可為2°C至6°C。Preferably, the temperature of the foregoing first and third drying steps may be -40 ° C to 0 ° C, more preferably -30 ° C to -10 ° C; and the temperature of the foregoing second and fourth drying steps may be 2 ° C to 6 ° C.

較佳的，於(e)步驟之後，所述(f)步驟可進一步包括： 先將一背層形成於母模及針底層上，藉此令針尖層和針底層夾置於母模和背層之間； 再自具有針尖層和針底層之母模上同時卸下針尖層、針底層和背層，獲得該醫美微針貼片。Preferably, after step (e), the step (f) may further include: first forming a back layer on the mother mold and the needle bottom layer, so that the needle tip layer and the needle bottom layer are sandwiched between the mother mold and the needle bottom layer. Between the layers; the needle tip layer, the needle bottom layer and the back layer are simultaneously removed from the mother mold having the needle tip layer and the needle bottom layer to obtain the medical beauty microneedle patch.

於前述將背層形成於母模及針底層之步驟中，該背層具有黏合性，其可為一膠帶，但並非僅限於此。In the aforementioned step of forming the back layer on the mother mold and the needle base layer, the back layer has adhesiveness, which may be an adhesive tape, but it is not limited thereto.

較佳的，該針尖混合液之黏度低於針底混合液之黏度。所述針尖混合液於於25°C、剪切率(shear rate)為1 S-1 下所測得之黏度較佳為3 釐泊(centipoise，cP)至500000 cP，更佳為5 cP至100000 cP；而該針底混合液於於25°C、剪切率為1 S-1 下所測得之黏度較佳為100 cP至5000000 cP，更佳為10000 cP至500000 cP。當針尖混合液之黏度過高時，針尖混合液將無法如期流至孔洞底部，致使醫美微針貼片中存在結構缺陷，而無法獲得所需之針高以及完整的微針結構；當針底混合液之黏度超出上述範圍時，則無法提供足夠的支撐性，甚而劣化醫美微針貼片的品質。此外，藉由控制針尖混合液和針底混合液之黏度範圍，更能有利於縮短前述(b)及(d)步驟的製程時間，提升量產效率。Preferably, the viscosity of the needle tip mixture is lower than the viscosity of the needle bottom mixture. The viscosity of the needle tip mixture at 25 ° C and a shear rate of 1 S -1 is preferably 3 centipoise (cP) to 500,000 cP, and more preferably 5 cP to 100000 cP; and the viscosity measured at 25 ° C and a shear rate of 1 S -1 is preferably 100 cP to 5000000 cP, and more preferably 10,000 cP to 500,000 cP. When the viscosity of the needle tip mixture is too high, the needle tip mixture will not flow to the bottom of the hole as scheduled, resulting in structural defects in the medical microneedle patch, and the required needle height and complete microneedle structure cannot be obtained; When the viscosity of the bottom mixed solution exceeds the above range, it cannot provide sufficient support, and even deteriorate the quality of the medical beauty microneedle patch. In addition, by controlling the viscosity range of the needle tip mixed solution and the needle bottom mixed solution, it is more conducive to shortening the process time of the aforementioned steps (b) and (d) and improve mass production efficiency.

較佳的，所述針尖混合液之表面張力係小於或等於70 dyne/cm；更佳的，所述針尖混合液之表面張力係大於或等於1 dyne/cm且小於或等於60 dyne/cm。當針尖混合液之表面張力過高時，針尖混合液將無法如期流至孔洞底部，致使醫美微針貼片中存在結構缺陷。較佳的，所述針底混合液之表面張力係小於或等於50 dyne/cm；更佳的，所述針底混合液之表面張力係大於或等於1 dyne/cm且小於或等於40 dyne/cm。當針底混合液之表面張力過高時，將使醫美微針貼片中存在針底層結構不完整、針尖層和針底層無法確實黏合、背層結構存在缺陷(如不平整、有氣泡或凹凸面產生)等問題。Preferably, the surface tension of the needle tip mixture is less than or equal to 70 dyne / cm; more preferably, the surface tension of the needle tip mixture is greater than or equal to 1 dyne / cm and less than or equal to 60 dyne / cm. When the surface tension of the needle tip mixed solution is too high, the needle tip mixed solution cannot flow to the bottom of the hole as scheduled, resulting in structural defects in the medical beauty microneedle patch. Preferably, the surface tension of the needle bottom mixture is less than or equal to 50 dyne / cm; more preferably, the surface tension of the needle bottom mixture is greater than or equal to 1 dyne / cm and less than or equal to 40 dyne / cm. cm. When the surface tension of the mixture at the bottom of the needle is too high, the underlying structure of the needle in the medical beauty microneedle patch is incomplete, the needle tip layer and the needle bottom layer cannot be firmly adhered, and the back layer structure is defective (such as unevenness, air bubbles, or Uneven surface)).

依據本創作，所述針尖混合液和針底混合液皆可為高分子水溶液，而針尖混合液為含有醫美活性成分之高分子水溶液。較佳的，該針尖混合液之濃度小於該針底混合液之濃度。較佳的，該針尖混合液之濃度為5 wt%至50 wt%，該針底混合液之濃度為10 wt%至95 wt%；更佳的，該針尖混合液之濃度為10 wt%至50 wt%，該針底混合液之濃度為15 wt%至95 wt%。藉由控制針尖混合液和針底混合液之濃度範圍，能有利於確保所製得之醫美微針貼片中針尖層和針底層的機械強度，使其能順利通過脫膜步驟，獲得具有完整微針結構的醫美微針貼片。According to this creation, both the needle-point mixed solution and the needle-bottom mixed solution may be a polymer aqueous solution, and the needle-point mixed solution is a polymer aqueous solution containing active medical ingredients. Preferably, the concentration of the needle-point mixed solution is smaller than the concentration of the needle-bottom mixed solution. Preferably, the concentration of the needle tip mixed solution is 5 wt% to 50 wt%, and the concentration of the needle bottom mixed solution is 10 wt% to 95 wt%; more preferably, the concentration of the needle tip mixed solution is 10 wt% to 50 wt%, and the concentration of the needle bottom mixed solution is 15 wt% to 95 wt%. By controlling the concentration range of the needle tip mixed solution and the needle bottom mixed solution, it can be beneficial to ensure the mechanical strength of the needle tip layer and the needle bottom layer in the prepared medical beauty microneedle patch, so that it can smoothly pass through the stripping step and obtain Medical microneedle patch with complete microneedle structure.

依據本創作，所述醫美活性成分可為美白成分、保濕成分、抗氧化物、抗皺成分，但並非僅限於此。本創作可選用之美白成分例如：麴酸(kojic acid)、熊果素(arbutin)、維生素C磷酸鈉鹽(sodium ascorbyl phosphate)、維生素C磷酸鎂鹽(magnesium ascorbyl phosphate)、維生素C葡萄醣苷(ascorbyl glycoside)、鞣花酸(ellagic acid)、甘菊萃取物(chamomile ET)、傳明酸十六烷基酯(cetyltranexamate HCl)、4-甲氧基水楊酸鉀鹽(potassium 4-methoxysalicylate)、3-O-乙基抗壞血酸(3-O-ethyl ascorbic acid)、九胜肽(nonapeptide)，但並非僅限於此。本創作可選用之保濕成分例如：神經醯胺(ceramide)、卵磷脂(lecithin)、甘油(glycerol)、多醣類(polysaccharide)、玻尿酸(hyaluronic acid)、玻尿酸鈉(sodium hyaluronate)、蛋白質(protein)、膠原蛋白(collagen)、彈力蛋白(elastin)、胜肽(peptide)、氨基酸(amino acid)、檸檬酸(citrate)、尿酸(uric acid)、尿素(urea)、葡萄糖(glucose)、蔗糖(sucrose)、果糖(fructose)、肝糖(glycogen)、葡萄氨聚糖(glucosamine)、黏多醣(mucopolysaccharides)、乳酸鹽(lactate)、磷酸鹽(phosphate)、吡咯烷酮-5-羧酸乙酯(ethyl-dl-2-pyrrolidone-5-carboxylate)，但並非僅限於此。本創作可選用之抗氧化物例如：葡萄萃取物(grape extract)、綠茶萃取物(green tea extract)、銀杏萃取物(ginkgo extract)、大豆萃取物(soy extract)、石榴萃取物(pomegranate extract)、生薑萃取物(ginger extract)、酵母萃取物(yeast extract)、薏仁萃取物(coix extract)、硫辛酸(R-alpha-lipoic Acid)、葡聚醣(glucan)、輔脢Q10(coenzyme Q10)、超氧化物歧化酶(superoxide dismutase，SOD)、維生素C(vitamine C)及其衍生物、維生素E(Vitamine E)及其衍生物，但並非僅限於此。本創作可選用之抗皺成分例如：維生素A(retinol)及其衍生物、藍銅胜肽(copper peptide，GHK-Cu)、五胜肽(pentapeptide)、六胜肽(hexapeptide)，但並非僅限於此。According to this creation, the medically active ingredients can be whitening ingredients, moisturizing ingredients, antioxidants, and anti-wrinkle ingredients, but it is not limited to this. The whitening ingredients that can be used in this creation are: kojic acid, arbutin, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl glycoside ), Ellagic acid, chamomile ET, cetyltranexamate HCl, potassium 4-methoxysalicylate, 3 -O-ethyl ascorbic acid, nonapeptide, but not limited to this. Moisturizing ingredients that can be used in this creation, such as: ceramide, lecithin, glycerol, polysaccharides, hyaluronic acid, sodium hyaluronate, protein ), Collagen, elastin, peptide, amino acid, citrate, uric acid, urea, glucose, sucrose ( sucrose, fructose, glycogen, glucosamine, mucopolysaccharides, lactate, phosphate, pyrrolidone-5-carboxylic acid ethyl ester -dl-2-pyrrolidone-5-carboxylate), but it is not limited to this. Antioxidants such as grape extract, green tea extract, ginkgo extract, soy extract, pomegranate extract , Ginger extract, yeast extract, coix extract, R-alpha-lipoic Acid, glucan, coenzyme Q10 ), Superoxide dismutase (SOD), vitamin C (vitamine C) and its derivatives, vitamin E (Vitamine E) and its derivatives, but it is not limited to this. Anti-wrinkle ingredients that can be used in this creation, such as: Vitamin A (retinol) and its derivatives, copper peptide (GHK-Cu), pentapeptide, hexapeptide, but not limited to this.

依據本創作，針尖混合液和針底混合液中所含有之高分子材料可為具有溶解性(dissolvable)或澎潤性(swellable)之材料。更具體而言，其高分子材料可為生物可相容(biocompatible)之材料或生物可降解(biodegradable)之材料。該針尖混合物和該針底混合物係各自獨立包含一高分子材料，該針尖混合物中所含之高分子材料可與該針底混合物中所含之高分子材料相同或不同。舉例而言，前述高分子材料可為麥芽糖(maltose)、蔗糖(sucrose)、海藻糖(trehalose)、乳糖(lactose)、糊精(dextrin)、麥芽糊精(maltodextrin)、b-環糊精(b-cyclodextrin)、2-羥丙基-b-環糊精(2-hydroxypropyl-b-cyclodextrin)、葡聚糖(dextran)、支鏈澱粉(amylopectin)、澱粉(starch)、玻尿酸鈉(sodium hyaluronate)、甲基乙烯基醚-馬來酸酐共聚物(poly(methyl vinyl ether-alt-maleic anhydride)，PMVE/MA)、羧甲基纖維素鈉(sodium carboxymethylcellulose，CMC)、甲基纖維素(methylcellulose，MC)、羥丙基甲基纖維素(hydroxypropylmethylcellulose，HPMC)、羥丙基纖維素(hydroxypropyl cellulose，HPC)、明膠(gelatin)、聚乙烯醇(poly(vinyl alcohol)，PVA)、聚乙烯吡咯烷酮(polyvinylpyrrolidone，PVP)、聚乙二醇(polyethylene glycol，PEG)、聚乳酸(polylactic acid，PLA)、聚乙醇酸(poly(glycolic acid)，PGA)、聚乳酸-羥基乙酸共聚物(poly(lactic-co-glycolic acid)，PLGA)、幾丁聚醣(chitosan)或其等之組合，但並非僅限於此。According to this creation, the polymer materials contained in the needle tip mixed liquid and the needle bottom mixed liquid may be dissolvable or swellable materials. More specifically, the polymer material may be a biocompatible material or a biodegradable material. The needle tip mixture and the needle base mixture each independently comprise a polymer material, and the polymer material contained in the needle tip mixture may be the same as or different from the polymer material contained in the needle base mixture. For example, the aforementioned polymer material may be maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, b-cyclodextrin (b-cyclodextrin), 2-hydroxypropyl-b-cyclodextrin, dextran, amylopectin, starch, sodium hyaluronate (sodium hyaluronate), poly (methyl vinyl ether-alt-maleic anhydride) (PMVE / MA), sodium carboxymethylcellulose (CMC), methyl cellulose ( methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, poly (vinyl alcohol, PVA), polyethylene Polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polylactic acid (PLA), poly (glycolic acid, PGA), polylactic acid-glycolic acid copolymer (poly ( lactic-co-glycolic acid), PLGA), chitosan Or a combination thereof, but it is not limited to this.

於其中一實施態樣中，該針底混合液中可含有聚乙烯醇、b-環糊精及海藻糖之水溶液，其針底混合液之濃度為20 wt%至50 wt%之高分子水溶液，即該針底混合液的水含量為50%至80%。以高分子材料為基準，聚乙烯醇之重量比例為30 wt%至80 wt%，b-環糊精之重量比例為小於或等於50 wt%。於此，該針底混合液於於25°C、剪切率為1 S-1 下所測得之黏度較佳為100000 cP至300000 cP。In one embodiment, the needle-bottom mixed solution may contain an aqueous solution of polyvinyl alcohol, b-cyclodextrin and trehalose, and the concentration of the needle-bottom mixed solution is a polymer aqueous solution of 20 wt% to 50 wt%. That is, the water content of the needle bottom mixed liquid is 50% to 80%. Based on the polymer material, the weight ratio of polyvinyl alcohol is 30 wt% to 80 wt%, and the weight ratio of b-cyclodextrin is less than or equal to 50 wt%. Here, the viscosity measured at 25 ° C and a shear rate of 1 S -1 of the needle bottom mixed liquid is preferably 100,000 cP to 300,000 cP.

於另一實施態樣中，該針底混合液中可含有聚乙烯醇及聚乙烯吡咯烷酮之水溶液，其針底混合液之濃度為20 wt%至50 wt%之高分子水溶液。以高分子材料為基準，聚乙烯吡咯烷酮之重量比例為小於或等於50 wt%。於此，該針底混合液於於25°C、剪切率為1 S-1 下所測得之黏度較佳為10000 cP至30000 cP。In another embodiment, the needle-bottom mixed solution may contain an aqueous solution of polyvinyl alcohol and polyvinylpyrrolidone, and the concentration of the needle-bottom mixed solution is a polymer aqueous solution of 20 wt% to 50 wt%. Based on the polymer material, the weight ratio of polyvinylpyrrolidone is 50 wt% or less. Here, the measured viscosity of the needle bottom mixed liquid at 25 ° C and a shear rate of 1 S -1 is preferably 10,000 cP to 30,000 cP.

於其中一實施態樣中，該母模可為硬式母模，其硬式母模之材質可為玻璃、石英、矽晶圓、金屬、金屬氧化物、金屬合金；所述金屬材料可為鋁、銅或鎳，但並非僅限於此。於另一實施態樣中，該母模可為軟式母模，其軟式母模之材質可為高分子、金屬箔(metal foil)或可撓式玻璃；所述高分子為聚二甲基矽氧烷(poly(dimethylsiloxane)，PDMS)、聚甲基丙烯酸甲酯(poly(methyl methacrylate)，PMMA)、聚碳酸酯(polycarbonate，PC)、聚醚碸(polyethersulfone，PES)等，但並非僅限於此。In one embodiment, the master mold may be a hard master mold, and the material of the hard master mold may be glass, quartz, silicon wafer, metal, metal oxide, metal alloy; the metal material may be aluminum, Copper or nickel, but not limited to this. In another embodiment, the master mold may be a soft master mold, and the material of the soft master mold may be a polymer, metal foil or flexible glass; the polymer is polydimethyl silicon Poly (dimethylsiloxane) (PDMS), poly (methyl methacrylate, PMMA), polycarbonate (PC), polyethersulfone (PES), etc., but not limited to this.

依據本創作，所述母模中孔洞的形狀可為圓錐形、方錐形或尖塔型，但並非僅限於此。於所述母模中，此母模具有一基準面及多個孔洞，各孔洞由基準面向下凹設成型。各孔洞之深度介於75 μm至1500 μm，較佳係介於150 μm至1200 μm，更佳係介於175 μm至1000 μm，再更佳係介於200 μm至950 μm。各孔洞之最大寬度為50 μm至600 μm，較佳係介於75 μm至550 μm，更佳係介於100 μm至500 μm，再更佳係介於100 μm至450 μm。According to this creation, the shape of the holes in the master mold may be conical, square, or spire, but it is not limited to this. In the master mold, the master mold has a reference surface and a plurality of holes, and each hole is concavely formed from the reference surface. The depth of each hole is between 75 μm and 1500 μm, preferably between 150 μm and 1200 μm, more preferably between 175 μm and 1000 μm, and even more preferably between 200 μm and 950 μm. The maximum width of each hole is 50 μm to 600 μm, preferably between 75 μm and 550 μm, more preferably between 100 μm and 500 μm, and even more preferably between 100 μm and 450 μm.

於所述醫美微針貼片中，各微針結構之針形可為圓錐形、方錐形或尖塔型，但並非僅限於此。In the medical beauty microneedle patch, the needle shape of each microneedle structure may be a cone shape, a square cone shape, or a spire type, but it is not limited thereto.

於所述醫美微針貼片中，各微針結構之針長可小於1500 μm；較佳係小於1000 μm；再更佳係介於200 μm至950 μm之間。In the medical beauty microneedle patch, the needle length of each microneedle structure may be less than 1500 μm; preferably, it is less than 1000 μm; even more preferably, it is between 200 μm and 950 μm.

於所述醫美微針貼片中，各微針結構之針尖半徑(tip radius)可小於15 μm；較佳係小於11 μm；再更佳可介於5 μm至10 μm之間。此外，所述醫美微針貼片之針尖頂角可小於30°。In the medical beauty microneedle patch, the tip radius of each microneedle structure may be less than 15 μm; preferably, it is less than 11 μm; even more preferably, it may be between 5 μm and 10 μm. In addition, the apex angle of the needle tip of the medical beauty microneedle patch may be less than 30 °.

於所述醫美微針貼片中，所述微針結構之密度可介於每平方公分100針(needles/cm2 )至1000 needles/cm2 ；較佳為150 needles/cm2 至750 needles/cm2 。In the medical beauty microneedle patch, the density of the microneedle structure may be between 100 needles / cm 2 and 1000 needles / cm 2 ; preferably 150 needles / cm 2 to 750 needles / cm 2 .

於應用上，藉由控制醫美微針貼片之針長，該醫美微針貼片於使用時能免於觸及真皮層下方之神經系統，故能降低使用者的恐懼感並且免除其疼痛感。此外，本創作所製得之醫美微針貼片更具有方便操作之優點，更能有利於避免口服投藥時因胃酸作用影響活性成分之效果。In application, by controlling the needle length of the medical beauty microneedle patch, the medical beauty microneedle patch can prevent the nervous system under the dermal layer from being used, so it can reduce the fear of the user and avoid its pain. sense. In addition, the medical beauty microneedle patch produced by this creation has the advantages of convenient operation, and it is more conducive to avoiding the effect of active ingredients due to gastric acid effect during oral administration.

以下列舉數種醫美微針貼片之製作方法作為例示，說明本創作之實施方式；熟習此技藝者可經由本說明書之內容輕易地了解本創作所能達成之優點與功效，並且於不悖離本創作之精神下進行各種修飾與變更，以施行或應用本創作之內容。The following is a list of several methods of making medical microneedle patches as examples to explain the implementation of this creation; those skilled in this art can easily understand the advantages and effects that this creation can achieve through the content of this manual, and it is not inconsistent Various modifications and changes are made in the spirit of this creation to implement or apply the content of this creation.

實施例Examples 11

請配合參閱圖1及圖2所示，本實施例之醫美微針貼片係經由如下所述之方法所製得。Please refer to FIG. 1 and FIG. 2. The medical beauty microneedle patch of this embodiment is prepared by the following method.

首先，如圖1及圖2所示之(a)步驟，準備一母模10，所述母模10具有一基準面11及多個孔洞12，所述多個孔洞12係由基準面11向下凹設成型，且所述多個孔洞12呈矩陣排列凹設於該母模10上。於本實施例中，此母模10之材質為PDMS，母模10上的孔洞密度為289 holes/cm2 ，孔洞陣列範圍為1.5 cm×1.5 cm，各孔洞12之形狀為方錐形，其深度(即孔洞12之末端與基準面11之垂直距離)為750 μm，最大寬度(即孔洞12與基準面11齊平之水平面的最大內徑)為300 μm。First, as shown in step (a) of FIG. 1 and FIG. 2, a master mold 10 is prepared. The master mold 10 has a reference surface 11 and a plurality of holes 12. The concave mold is formed, and the plurality of holes 12 are concavely arranged on the mother mold 10 in a matrix arrangement. In this embodiment, the material of the master mold 10 is PDMS. The hole density on the master mold 10 is 289 holes / cm 2. The hole array range is 1.5 cm × 1.5 cm. The shape of each hole 12 is a square cone. The depth (the vertical distance between the end of the hole 12 and the reference plane 11) is 750 μm, and the maximum width (the maximum inner diameter of the horizontal plane where the hole 12 is flush with the reference plane 11) is 300 μm.

然後，如圖1所示之(b)步驟，利用狹縫式塗佈法，將針尖混合液21′塗佈於該母模10之多個孔洞12內，使該針尖混合液21′填滿母模10之多個孔洞12，直至針尖混合液21′之液面與基準面11齊平，即獲得一裝有針尖混合液之母模10A。具體而言，所述(b)步驟可由依序進行之(b1)至(b4)步驟所完成。如圖2所示之(b1)步驟，利用狹縫式塗佈法，以1000 μm之塗佈間隙、3 m/min之塗佈速度，使針尖混合液21′自狹縫式塗佈頭S1之狹縫噴嘴中擠出並且塗佈於該母模10上。該針尖混合液21′為20 wt%之含有藍銅胜肽及甲基乙烯基醚-馬來酸酐共聚物之水溶液，即針尖混合液21′中含有80 wt%之水與20 wt%之藍銅胜肽與甲基乙烯基醚-馬來酸酐共聚物之混合物，且該針尖混合液21′於25°C、1 S-1 下所測得之黏度為40 cP，其表面張力為30 dyne/cm。接著，如圖2所示之(b2)步驟，將針尖混合液21′和母模10一同置於壓力為20 torr之真空烘箱中抽氣，藉此令針尖混合液21′可自基準面11上經由抽氣流動至母模10之多個孔洞12中，並覆蓋於該母模10之基準面11及所有孔洞12中。然後，如圖2所示之(b3)步驟，使用刮板S2將基準面11上的針尖混合液21′刮除，直至針尖混合液21′之液面與基準面11齊平，獲得一裝有針尖混合液之母模10A，如圖2所示(b4)步驟的狀態。於另一實施態樣中，所述之(b2)步驟亦可採用離心方式完成；例如，將裝有針尖混合液之母模置於離心機中，以3600 rpm之轉速持續離心20分鐘，使針尖混合液可自基準面向下流動並固定在母模之多個孔洞中，並覆蓋於基準面及所有孔洞中。Then, as shown in step (b) of FIG. 1, the needle tip mixed solution 21 ′ is applied to the plurality of holes 12 of the master mold 10 by using a slit coating method to fill the needle tip mixed solution 21 ′. The plurality of holes 12 of the master mold 10 is until the liquid level of the needle tip mixed liquid 21 'is flush with the reference surface 11, and a master mold 10A containing the needle tip mixed liquid is obtained. Specifically, the step (b) can be completed by performing steps (b1) to (b4) in sequence. As shown in step (b1) of FIG. 2, the slit-type coating method is used to make the needle tip mixed liquid 21 ′ from the slit-type coating head S1 at a coating gap of 1000 μm and a coating speed of 3 m / min. A slit nozzle is extruded and coated on the master mold 10. The needle tip mixed solution 21 ′ is a 20 wt% aqueous solution containing blue copper peptide and methyl vinyl ether-maleic anhydride copolymer, that is, the needle tip mixed solution 21 ′ contains 80 wt% water and 20 wt% blue A mixture of copper peptide and methyl vinyl ether-maleic anhydride copolymer. The viscosity of the needle tip mixture 21 ′ at 25 ° C and 1 S -1 is 40 cP, and its surface tension is 30 dyne. / cm. Next, as shown in step (b2) of FIG. 2, the needle tip mixed solution 21 ′ and the master mold 10 are put together in a vacuum oven with a pressure of 20 torr to evacuate, so that the needle tip mixed solution 21 ′ can be drawn from the reference surface 11. The upper part flows into the plurality of holes 12 of the mother mold 10 through air extraction, and covers the reference surface 11 and all the holes 12 of the mother mold 10. Then, as shown in step (b3) of FIG. 2, use the scraper S2 to scrape the needle tip mixed solution 21 ′ on the reference surface 11 until the liquid level of the needle tip mixed solution 21 ′ is flush with the reference surface 11 to obtain a package. The mother mold 10A having the needle tip mixed liquid is in a state of step (b4) shown in FIG. 2. In another embodiment, the step (b2) can also be completed by centrifugation; for example, the mother mold containing the needle tip mixture is placed in a centrifuge, and the centrifuge is continuously centrifuged at 3600 rpm for 20 minutes, so that The needle tip mixture can flow downward from the reference surface and be fixed in multiple holes of the master mold, and cover the reference surface and all holes.

接下來，如圖1及圖2所示之(c)步驟，於30°C之溫度下，持續乾燥該裝有針尖混合液之母模10A長達1小時，藉此令前述針尖混合液21′乾燥為針尖層21，並使針尖層21之表面低於基準面11，獲得一具有針尖層之母模10B。Next, as shown in step (c) in FIG. 1 and FIG. 2, the master mold 10A containing the needle-point mixed solution is continuously dried at a temperature of 30 ° C. for 1 hour, thereby making the aforementioned needle-point mixed solution 21 ′ Dried into the needle tip layer 21 and making the surface of the needle tip layer 21 lower than the reference surface 11 to obtain a female mold 10B having the needle tip layer.

之後，如圖1所示之(d)步驟，將一針底混合液22′形成於針尖層21上及前述多個孔洞12內，藉此令針底混合液22′覆蓋針尖層21、基準面11及多個孔洞12，獲得一裝有針底混合液之母模10C。具體而言，所述(d)步驟可由依序進行之(d1)至(d4)步驟所完成。如圖2所示之(d1)步驟，利用狹縫式塗佈法，以1600 μm之塗佈間隙、3 m/min之塗佈速度，使針底混合液22′自狹縫式塗佈頭S1之狹縫噴嘴中擠出以塗佈於具有針尖層之母模10B上。該針底混合液22′為50 wt%之聚乙烯醇水溶液，即針底混合液22′中含有50 wt%之水與50 wt%之聚乙烯醇，且該針底混合液22′於25°C、1 S-1 下所測得之黏度為200000 cP，其表面張力為37 dyne/cm。接著，如圖2所示之(d2)步驟，將針底混合液22′和具有針尖層之母模10B一同置於壓力為35 torr之真空烘箱中抽氣，藉此令針底混合液22′可自基準面11上經由抽氣流動至母模10之多個孔洞12中，並覆蓋於針尖層21、基準面11及所有孔洞12中。然後，如圖2所示之(d3)步驟，使用刮板S2將基準面11上的針底混合液22′刮除，直至針底混合液22′之液面與基準面11齊平，獲得一裝有針底混合液之母模10C，如圖2所示(d4)步驟的狀態。於另一實施態樣中，所述之(d2)步驟亦可採用離心方式完成；例如，將裝有針底混合液之母模置於離心機中，以3600 rpm之轉速持續離心15分鐘，使針底混合液可自基準面向下流動並固定在母模之多個孔洞中，並覆蓋於針尖層、基準面及所有孔洞中。Thereafter, as shown in step (d) of FIG. 1, a needle-bottom mixed solution 22 ′ is formed on the needle-point layer 21 and in the plurality of holes 12, so that the needle-bottom mixed solution 22 ′ covers the needle-point layer 21 and the reference. The surface 11 and the plurality of holes 12 obtain a female mold 10C filled with a needle bottom mixed liquid. Specifically, the step (d) may be completed by performing the steps (d1) to (d4) in sequence. As shown in step (d1) shown in FIG. 2, the slit-type coating method is used to make the needle bottom mixed solution 22 ′ from the slit-type coating head at a coating gap of 1600 μm and a coating speed of 3 m / min. The slit nozzle of S1 is extruded to apply on a mother die 10B having a needle tip layer. The needle bottom mixed solution 22 ′ is a 50 wt% polyvinyl alcohol aqueous solution, that is, the needle bottom mixed solution 22 ′ contains 50 wt% of water and 50 wt% of polyvinyl alcohol, and the needle bottom mixed solution 22 ′ is at 25%. The measured viscosity at ° C, 1 S -1 is 200,000 cP, and its surface tension is 37 dyne / cm. Next, as shown in step (d2) of FIG. 2, the needle bottom mixed liquid 22 ′ and the female mold 10B having the needle tip layer are put together in a vacuum oven with a pressure of 35 torr to evacuate, so that the needle bottom mixed liquid 22 ′ Can flow from the reference surface 11 into the plurality of holes 12 of the master mold 10 through air extraction, and cover the tip layer 21, the reference surface 11 and all the holes 12. Then, as shown in step (d3) of FIG. 2, the needle-bottom mixed solution 22 ′ on the reference surface 11 is scraped off with a scraper S2 until the liquid level of the needle-bottom mixed solution 22 ′ is flush with the reference surface 11 to obtain A master mold 10C containing a mixture of needle bottoms is shown in step (d4) in FIG. 2. In another embodiment, the step (d2) can also be completed by centrifugation; for example, the mother mold containing the needle bottom mixed solution is placed in a centrifuge and centrifuged at 3600 rpm for 15 minutes, The needle bottom mixed liquid can flow downward from the reference surface and be fixed in a plurality of holes of the master mold, and covers the needle tip layer, the reference surface and all holes.

接著，如圖1及圖2所示之(e)步驟，於30°C之溫度下，持續乾燥該裝有針底混合液之母模10C長達48小時，藉此令針底混合液22′乾燥為針底層22並且黏合於針尖層21上，從而獲得一具有針尖層和針底層之母模10D。Next, as shown in step (e) in FIG. 1 and FIG. 2, the female mold with the needle bottom mixed liquid 10C is continuously dried at a temperature of 30 ° C. for 48 hours, thereby making the needle bottom mixed liquid 22 ′ Is dried to the needle base layer 22 and adhered to the needle tip layer 21 to obtain a female mold 10D having the needle tip layer and the needle base layer.

最後，如圖1所示之(f)步驟，自具有針尖層和針底層之母模10D上卸下針尖層21和針底層22，獲得該醫美微針貼片20。具體而言，所述(f)步驟可由依序進行之(f1)至(f2)步驟所完成。如圖2所示之(f1)步驟，於具有針尖層和針底層之母模10D上形成一背層23，藉此令針尖層21和針底層22夾置於前述母模10D和背層23之間。於本實施例中，該背層23為一透氣膠帶。最後，如圖2所示之(f2)步驟，自具有針尖層和針底層之母模10D上同時卸下針尖層21、針底層22和背層23，即完成本實施例之醫美微針貼片20之製程。Finally, as shown in step (f) of FIG. 1, the needle tip layer 21 and the needle bottom layer 22 are removed from the mother mold 10D having the needle tip layer and the needle bottom layer to obtain the medical beauty microneedle patch 20. Specifically, the step (f) can be completed by performing the steps (f1) to (f2) in sequence. As shown in the step (f1) in FIG. 2, a back layer 23 is formed on the mother mold 10D having the needle tip layer and the needle bottom layer, so that the needle tip layer 21 and the needle bottom layer 22 are sandwiched between the mother mold 10D and the back layer 23. between. In this embodiment, the back layer 23 is a breathable tape. Finally, as shown in step (f2) of FIG. 2, the needle tip layer 21, the needle bottom layer 22, and the back layer 23 are simultaneously removed from the mother mold 10D having the needle tip layer and the needle bottom layer, and the medical microneedles of this embodiment are completed. Manufacturing process of the patch 20.

依據上述製作方法，本實施例先利用狹縫式塗佈法於母模上形成針尖混合液，再利用狹縫式塗佈法於乾燥後的針尖層上塗佈形成針底混合液，故能透過針尖混合液和針底混合液的高分子作用力令經乾燥之針尖層和針底層相互黏合，達到節省製程時間與成本、提升量產效率等功效。此外，利用濕式塗佈技術製作醫美微針貼片更能有利於控制各微針結構中醫美有效成分的劑量，達到有效控制劑量之目的。According to the above manufacturing method, in this embodiment, the needle tip mixed solution is first formed on the master mold by using the slit coating method, and then the needle bottom mixed solution is formed on the dried needle tip layer by using the slit coating method, so that the needle bottom mixed solution can be formed. Through the polymer force of the needle tip mixed liquid and the needle bottom mixed liquid, the dried needle tip layer and the needle bottom layer are adhered to each other, thereby achieving the effects of saving process time and cost, and improving mass production efficiency. In addition, the use of wet coating technology to make the medical beauty microneedle patch is more conducive to controlling the dose of the active ingredients of traditional Chinese medicine beauty in each microneedle structure, and to achieve the purpose of effective dose control.

如圖3所示，經由上述製作方法，本實施例之醫美微針貼片20由下至上依序黏合形成有背層23、針底層22及針尖層21，各相互黏合之針底層22和針尖層21共同構成一方錐形結構，各針底層22相互間隔且矩陣排列於該背層23上。As shown in FIG. 3, through the above-mentioned manufacturing method, the medical beauty microneedle patch 20 of this embodiment is sequentially bonded from bottom to top to form a back layer 23, a needle bottom layer 22, and a needle tip layer 21, each of which is bonded to each other. The needle tip layer 21 collectively constitutes a one-sided tapered structure, and the needle bottom layers 22 are spaced from each other and arranged in a matrix on the back layer 23.

實施例Examples 22

本實施例係大致上採用如前述實施例1所述之方法製備醫美微針貼片，其不同之處主要在於，本實施例改以刮刀式塗佈法塗佈針尖混合液與針底混合液，以離心方式固定針底混合液於多個孔洞中，並且省略刮除針底混合液之步驟。This embodiment uses the method described in Example 1 to prepare a medical microneedle patch. The main difference is that this embodiment uses a doctor blade coating method to coat the tip mixture with the bottom of the needle. The mixture of the needle bottom is fixed in a plurality of holes by centrifugation, and the step of scraping the mixture of the needle bottom is omitted.

具體而言，於(a)步驟之後，利用刮刀式塗佈法進行(b1)步驟，以1000 μm之塗佈間隙、3 m/min之塗佈速度，使針尖混合液塗佈於該母模上；再依序經由如實施例1所述之(b2)至(b4)及(c)步驟，獲得一具有針尖層之母模。該針尖混合液為20 wt%之藍銅胜肽及甲基乙烯基醚-馬來酸酐共聚物之水溶液，且該針尖混合液於25°C、1 S-1 下所測得之黏度為40 cP，其表面張力為30 dyne/cm。以整體針尖混合液之總重為基準，該針尖混合液中含有80 wt%的水及20 wt%之藍銅胜肽與甲基乙烯基醚-馬來酸酐共聚物之混合物。Specifically, after step (a), step (b1) is performed by a doctor blade coating method, and a needle tip mixed solution is applied to the master mold at a coating gap of 1000 μm and a coating speed of 3 m / min. Up; and then sequentially through steps (b2) to (b4) and (c) as described in Example 1, to obtain a master mold with a needle tip layer. The tip mixture was an aqueous solution of 20 wt% blue copper peptide and methyl vinyl ether-maleic anhydride copolymer, and the viscosity measured at 25 ° C and 1 S -1 of the tip mixture was 40. cP, with a surface tension of 30 dyne / cm. Based on the total weight of the entire needle-point mixture, the needle-point mixture contains 80 wt% of water and 20 wt% of a mixture of blue copper peptide and methyl vinyl ether-maleic anhydride copolymer.

之後，再利用刮刀式塗佈法進行(d1)步驟，以1600 μm之塗佈間隙、3 m/min之塗佈速度，使針底混合液塗佈於母模上；接著，將裝有針底混合液之母模置於離心機中，以3600 rpm之轉速持續離心15分鐘，使針底混合液可自基準面向下流動並固定在母模之多個孔洞中，並覆蓋於針尖層、基準面及所有孔洞中；再依序經由如實施例1所述之(e)步驟，獲得一具有針尖層和針底層之母模。該針底混合液為50 wt%之聚乙烯醇/b-環糊精/海藻糖水溶液，且該針底混合液於25°C、1 S-1 下所測得之黏度為230000 cP，其表面張力為37 dyne/cm。以整體針底混合液之總重為基準，該針底混合液中含有50 wt%的水及50 wt%之聚乙烯醇、b-環糊精與海藻糖之混合物。以聚乙烯醇、b-環糊精及海藻糖之總重為基準，聚乙烯醇之含量為40 wt%，b-環糊精之含量不大於50 wt%。After that, the step (d1) is performed by a doctor blade coating method to apply the needle-bottom mixture to the master mold at a coating gap of 1600 μm and a coating speed of 3 m / min; The mother mold of the bottom mixed liquid is placed in a centrifuge, and the centrifugation is continued at 3600 rpm for 15 minutes, so that the needle bottom mixed liquid can flow downward from the reference surface and fixed in a plurality of holes of the mother mold, and is covered in the needle tip layer, The reference plane and all holes; and then sequentially through step (e) as described in Example 1, a master mold having a needle tip layer and a needle bottom layer is obtained. The needle bottom mixture is a 50 wt% polyvinyl alcohol / b-cyclodextrin / trehalose aqueous solution, and the viscosity measured at 25 ° C and 1 S -1 of the needle bottom mixture is 230,000 cP. The surface tension was 37 dyne / cm. Based on the total weight of the entire needle base mixed liquid, the needle base mixed liquid contains 50 wt% of water and 50 wt% of a mixture of polyvinyl alcohol, b-cyclodextrin and trehalose. Based on the total weight of polyvinyl alcohol, b-cyclodextrin and trehalose, the content of polyvinyl alcohol is 40 wt%, and the content of b-cyclodextrin is not more than 50 wt%.

於本實施例中，所述之針底層可藉由材料本身之高分子作用力黏合於針尖層；因此，於(e)步驟之後，能直接自具有針尖層和針底層之母模上同時卸下相互黏合之針尖層和針底層，完成(f)步驟，獲得本實施例之醫美微針貼片。In this embodiment, the needle bottom layer can be adhered to the needle tip layer by the high polymer force of the material itself; therefore, after step (e), the needle bottom layer can be directly removed from the mother mold having the needle tip layer and the needle bottom layer simultaneously. The needle tip layer and the needle bottom layer which are adhered to each other are completed, and step (f) is completed to obtain the medical beauty microneedle patch of this embodiment.

實施例Examples 33

本實施例係大致上採用如前述實施例1所述之方法製備醫美微針貼片，其不同之處主要在於，本實施例改以刮刀式塗佈法塗佈針尖混合液與針底混合液，另變換母模之結構與省略刮除針底混合液之步驟。此外，本實施例所選用之針尖混合液之組成亦有別於實施例1之針尖混合液之組成。本實施例之詳細製作流程請參閱圖4所示，以下將配合圖1及圖4說明本實施例之製作方法。This embodiment uses the method described in Example 1 to prepare a medical microneedle patch. The main difference is that this embodiment uses a doctor blade coating method to coat the tip mixture with the bottom of the needle. In addition, the structure of the master mold is changed and the step of scraping off the mixed liquid at the bottom of the needle is omitted. In addition, the composition of the needle-point mixture used in this embodiment is also different from the composition of the needle-point mixture in Example 1. Please refer to FIG. 4 for the detailed manufacturing process of this embodiment. The manufacturing method of this embodiment will be described below with reference to FIGS. 1 and 4.

首先，如圖1及圖4所示之(a)步驟，準備一母模10，該母模10具有一基準面11及多個孔洞12。於本實施例中，此母模10之材質為PDMS，母模10上的孔洞密度為289 holes/cm2 ，孔洞陣列範圍為1.0 cm×1.0 cm，各孔洞12之形狀為圓錐形，其深度(即孔洞12之末端與基準面11之垂直距離)為600 μm，直徑 (即孔洞12與基準面11齊平之水平面的最大內徑)為300 μm。First, as shown in step (a) of FIGS. 1 and 4, a master mold 10 is prepared. The master mold 10 has a reference surface 11 and a plurality of holes 12. In this embodiment, the material of the master mold 10 is PDMS, the hole density on the master mold 10 is 289 holes / cm 2 , the hole array range is 1.0 cm × 1.0 cm, and the shape of each hole 12 is conical and its depth (That is, the vertical distance between the end of the hole 12 and the reference surface 11) is 600 μm, and the diameter (that is, the maximum inner diameter of the horizontal plane where the hole 12 is flush with the reference surface 11) is 300 μm.

然後，如圖1所示之(b)步驟，利用刮刀式塗佈法，將針尖混合液21′塗佈於該母模10之多個孔洞12內，使該針尖混合液21′填滿母模10之多個孔洞12，直至針尖混合液21′之液面與基準面11齊平，即獲得一裝有針尖混合液之母模10A。具體而言，如圖4所示之(b1)步驟，本實施例之(b1)步驟係利用刮刀式塗佈法，以800 μm之塗佈間隙、3 m/min之塗佈速度，利用刮刀S1A使針尖混合液21′塗佈於該母模10上，再依序經由如實施例1所述之(b2)至(b4)及(c)步驟，獲得一具有針尖層之母模10B。於此，針尖混合液21′為10 wt%之含有羧甲基纖維素鈉/玻尿酸/聚氧乙烯單月桂酸去水山梨酯(polyoxyethylene sorbitan monolaurate，polysorbate 20，tween 20)之水溶液，且該針尖混合液21′於25°C、1 S-1 下所測得之黏度為45 cP，其表面張力為35 dyne/cm。以該針尖混合液總重為基準，該針尖混合液中含有90 wt%的水及10 wt%之羧甲基纖維素鈉、玻尿酸與聚氧乙烯單月桂酸去水山梨酯之混合物。以羧甲基纖維素鈉、玻尿酸與聚氧乙烯單月桂酸去水山梨酯之總重為基準，羧甲基纖維素鈉之含量不大於50 wt%，聚氧乙烯單月桂酸去水山梨酯之含量為0.5 wt%。Then, as shown in step (b) of FIG. 1, the needle tip mixed solution 21 ′ is applied to the plurality of holes 12 of the master mold 10 by a doctor blade coating method, so that the needle tip mixed solution 21 ′ fills the mother. A plurality of holes 12 of the mold 10 is used until the liquid level of the needle tip mixed liquid 21 'is flush with the reference surface 11 to obtain a female mold 10A filled with the needle tip mixed liquid. Specifically, as shown in step (b1) shown in FIG. 4, step (b1) of this embodiment uses a doctor blade coating method with a coating gap of 800 μm and a coating speed of 3 m / min, using a doctor blade. S1A applies the needle tip mixed solution 21 'on the master mold 10, and then sequentially proceeds through steps (b2) to (b4) and (c) as described in Example 1 to obtain a master mold 10B having a needle tip layer. Here, the tip mixture 21 ′ is a 10 wt% aqueous solution containing sodium carboxymethylcellulose / hyaluronic acid / polyoxyethylene monolaurate desorbate (polyoxyethylene sorbitan monolaurate, polysorbate 20, tween 20), and the tip The viscosity of the mixed solution 21 ′ measured at 25 ° C and 1 S -1 was 45 cP, and its surface tension was 35 dyne / cm. Based on the total weight of the needle tip mixture, the needle tip mixture contains 90 wt% water and 10 wt% sodium carboxymethyl cellulose, a mixture of hyaluronic acid and polyoxyethylene monolaurate desorbate. Based on the total weight of sodium carboxymethylcellulose, hyaluronic acid, and polyoxyethylene monolaurate sorbitan, the content of sodium carboxymethylcellulose is not more than 50 wt%, and polyoxyethylene monolaurate sorbitan Its content is 0.5 wt%.

之後，如圖1所示之(d)步驟，將一針底混合液22′形成於針尖層21上及前述多個孔洞12內，藉此令針底混合液22′覆蓋針尖層21、基準面11及多個孔洞12，獲得一裝有針底混合液之母模10C。具體而言，如圖4所示之(d1)步驟，本實施例之(d1)步驟也利用刮刀式塗佈法，以1000 μm之塗佈間隙、3 m/min之塗佈速度，利用刮刀S1A使針底混合液22′塗佈於具有針尖層之母模10B上。接著，如圖4所示之(d2)步驟，將針底混合液22′和具有針尖層之母模10B一同置於壓力為30 torr之真空烘箱中抽氣，藉此令針底混合液22′可自基準面11上經由抽氣流動至多個孔洞12中，獲得一裝有針底混合液之母模10C。於此，針底混合液為50 wt%之聚乙烯醇/b-環糊精/海藻糖水溶液，且該針底混合液於25°C、1 S-1 下所測得之黏度為230000 cP，其表面張力為37 dyne/cm。以該針底混合液總重為基準，該針底混合液中含有50 wt%的水及50 wt%之聚乙烯醇、b-環糊精與海藻糖之混合物；以聚乙烯醇、b-環糊精及海藻糖之總重為基準，聚乙烯醇之含量為40 wt%，b-環糊精之含量不大於50 wt%。Thereafter, as shown in step (d) of FIG. 1, a needle-bottom mixed solution 22 ′ is formed on the needle-point layer 21 and in the plurality of holes 12, so that the needle-bottom mixed solution 22 ′ covers the needle-point layer 21 and the reference. The surface 11 and the plurality of holes 12 obtain a female mold 10C filled with a needle bottom mixed liquid. Specifically, as shown in step (d1) shown in FIG. 4, step (d1) of this embodiment also uses a doctor blade coating method, with a coating gap of 1000 μm and a coating speed of 3 m / min, using a doctor blade. In S1A, the needle bottom mixed solution 22 'is applied on a mother mold 10B having a needle tip layer. Next, as shown in step (d2) of FIG. 4, the needle bottom mixed liquid 22 ′ and the female mold 10B having the needle tip layer are put together in a vacuum oven at a pressure of 30 torr to evacuate the needle bottom mixed liquid 22. ′ Can be flowed from the reference surface 11 into a plurality of holes 12 through suction to obtain a female mold 10C filled with a needle bottom mixed liquid. Here, the needle bottom mixed solution is a 50 wt% polyvinyl alcohol / b-cyclodextrin / trehalose aqueous solution, and the viscosity measured at 25 ° C and 1 S -1 of the needle bottom mixed solution is 230,000 cP. , Its surface tension is 37 dyne / cm. Based on the total weight of the needle-bottom mixture, the needle-bottom mixture contains 50 wt% of water and 50 wt% of a mixture of polyvinyl alcohol, b-cyclodextrin and trehalose; based on polyvinyl alcohol, b- Based on the total weight of cyclodextrin and trehalose, the content of polyvinyl alcohol is 40 wt%, and the content of b-cyclodextrin is not more than 50 wt%.

接著，如圖1及圖4所示之(e)步驟，於30°C之溫度下，持續乾燥該裝有針底混合液之母模10C長達12至16小時，藉此令針底混合液22′乾燥為針底層22A並且黏合於針尖層21上，從而獲得一具有針尖層和針底層之母模10D，所述之針底層22A係同時黏合於該針尖層21並且覆蓋於該基準面11；最後再依序進行如實施例1所述之(f1)及(f2)步驟，即完成本實施例之醫美微針貼片20A之製程。Next, as shown in step (e) in FIG. 1 and FIG. 4, the female mold with the needle bottom mixed liquid 10C is continuously dried at a temperature of 30 ° C. for 12 to 16 hours, so that the needle bottom is mixed. The liquid 22 ′ is dried into a needle base layer 22A and adhered to the needle tip layer 21 to obtain a female mold 10D having a needle tip layer and a needle base layer. The needle base layer 22A is simultaneously adhered to the needle tip layer 21 and covers the reference surface. 11; Finally, the steps (f1) and (f2) as described in Example 1 are sequentially performed to complete the manufacturing process of the medical beauty microneedle patch 20A of this embodiment.

請參閱圖5所示，所述醫美微針貼片20A由下至上依序黏合形成有背層23、針底層22A及針尖層21，各相互黏合之針底層22A和針尖層21共同構成一圓錐形結構，各針底層22係互相連接形成於該背層23上，而各圓錐形結構係以間隔且呈矩陣之方式排列。Please refer to FIG. 5, the medical beauty microneedle patch 20A is sequentially bonded from bottom to top to form a back layer 23, a needle bottom layer 22A, and a needle tip layer 21, and each of the needle bottom layers 22A and the needle tip layer 21 bonded together form a In the conical structure, the needle bottom layers 22 are connected to each other and formed on the back layer 23, and the conical structures are arranged in a spaced and matrix manner.

實施例Examples 44

本實施例係大致上採用如前述實施例1所述之方法製備醫美微針貼片，其不同之處主要在於，本實施例變換母模之結構、改以刮刀式塗佈法塗佈針尖混合液與針底混合液以及省略刮除針底混合液之步驟。This embodiment uses the method described in Example 1 to prepare a medical microneedle patch. The main difference is that in this embodiment, the structure of the master mold is changed and the needle tip is coated by a doctor blade coating method. Mixing the liquid with the needle bottom and omitting the step of scraping the needle bottom mixed liquid.

具體而言，於(a)步驟中，所選用之母模具有基準面及多個孔洞，母模上的孔洞密度為289 holes/cm2 ，孔洞陣列範圍為1 cm×1 cm，各孔洞之形狀為方錐形，其深度為600 μm，最大寬度為300 μm。Specifically, in step (a), the selected master mold has a reference plane and a plurality of holes. The hole density on the master mold is 289 holes / cm 2 , and the hole array range is 1 cm × 1 cm. The shape is a square cone with a depth of 600 μm and a maximum width of 300 μm.

於(b1)步驟中，以400 μm之塗佈間隙、3 m/min之塗佈速度，利用刮刀 式塗佈法將針尖混合液塗佈於母模上；再依序經由如實施例1所述之(b2)至(b4)步驟，並於(c)步驟中以30°C之溫度下持續乾燥該裝有針尖混合液之母模3小時，獲得一具有針尖層之母模。該針尖混合液為20 wt%之含有玻尿酸/2-羥丙基-b-環糊精/聚氧乙烯單月桂酸去水山梨酯之水溶液，且該針尖混合液於25°C、1 S-1 下所測得之黏度為13500 cP，其表面張力為30 dyne/cm。以該針尖混合液總重為基準，該針尖混合液中含有80 wt%的水及20 wt%之玻尿酸、2-羥丙基-b-環糊精、聚氧乙烯單月桂酸去水山梨酯之混合物。以玻尿酸、2-羥丙基-b-環糊精、聚氧乙烯單月桂酸去水山梨酯之總重為基準，2-羥丙基-b-環糊精之含量不大於50 wt%，聚氧乙烯單月桂酸去水山梨酯之含量為0.5 wt%。In (b1) step, a coating gap of 400 μm, 3 m / min the coating speed, using a doctor knife coating mixture is applied to the needle tip on the master mold; and then sequentially through as in Example 1 In the steps (b2) to (b4), and in step (c), the master mold with the needle tip mixed liquid is continuously dried at a temperature of 30 ° C for 3 hours to obtain a master mold having a needle tip layer. The tip of mixture containing 20 wt% of the hyaluronic acid / 2-hydroxypropyl cyclodextrin -b- / monolaurate polyoxyethylene polysorbate solution to water mountains, and the mixed solution at the needle tip 25 ° C, 1 S - The viscosity measured at 1 was 13,500 cP and its surface tension was 30 dyne / cm. Based on the total weight of the needle tip mixture, the needle tip mixture contains 80 wt% water and 20 wt% hyaluronic acid, 2-hydroxypropyl-b-cyclodextrin, polyoxyethylene monolaurate desorbate Of a mixture. Based on the total weight of hyaluronic acid, 2-hydroxypropyl-b-cyclodextrin and polyoxyethylene monolaurate desorbate, the content of 2-hydroxypropyl-b-cyclodextrin is not more than 50 wt%, The content of polyoxyethylene monolaurate desorbate was 0.5 wt%.

於(d1)步驟中，以1000 μm之塗佈間隙、3 m/min之塗佈速度，利用刮刀式塗佈法將針底混合液塗佈於母模上。接著，於(d2)步驟，將針底混合液和母模一同置於壓力為50 torr之真空烘箱中抽氣，藉此令針底混合液可自基準面上經由抽氣流動至母模之多個孔洞中，獲得一裝有針底混合液之母模。該針底混合液為50 wt%之聚乙烯醇/聚乙烯吡咯烷酮水溶液，且該針底混合液於25°C、1 S-1 下所測得之黏度為18000 cP，其表面張力為37 dyne/cm。以該針底混合液總重為基準，該針底混合液中含有50 wt%的水及50 wt%之聚乙烯醇與聚乙烯吡咯烷酮之混合物。以聚乙烯醇與聚乙烯吡咯烷酮之總重為基準，聚乙烯吡咯烷酮之含量不大於50 wt%。In step (d1), a needle-bottom coating method is applied to the master mold at a coating gap of 1000 μm and a coating speed of 3 m / min by a doctor blade coating method. Next, in step (d2), the needle bottom mixed liquid and the mother mold are put together in a vacuum oven with a pressure of 50 torr to evacuate, so that the needle bottom mixed liquid can flow from the reference plane to the mother mold through suction. Among the plurality of holes, a master mold containing a mixture of needle bottoms was obtained. The needle bottom mixed solution is a 50 wt% polyvinyl alcohol / polyvinylpyrrolidone aqueous solution, and the measured viscosity of the needle bottom mixed solution at 25 ° C and 1 S -1 is 18000 cP, and its surface tension is 37 dyne / cm. Based on the total weight of the needle bottom mixed solution, the needle bottom mixed solution contains 50 wt% of water and 50 wt% of a mixture of polyvinyl alcohol and polyvinylpyrrolidone. Based on the total weight of polyvinyl alcohol and polyvinylpyrrolidone, the content of polyvinylpyrrolidone is not more than 50 wt%.

於(e)步驟中，於30°C之溫度下，持續乾燥該裝有針底混合液之母模長達48小時，藉此令針底混合液乾燥為針底層並且黏合於針尖層上，從而獲得一具有針尖層和針底層之母模。In step (e), at 30 ° C, the female mold with the needle bottom mixed liquid is continuously dried for 48 hours, so that the needle bottom mixed liquid is dried to the bottom of the needle and adhered to the needle tip layer. Thus, a female mold having a needle tip layer and a needle bottom layer was obtained.

於本實施例中，所述之針底層可藉由材料本身之高分子作用力黏合於針尖層；因此，於(e)步驟之後，能直接自具有針尖層和針底層之母模上同時卸下相互黏合之針尖層和針底層，完成(f)步驟，獲得本實施例之醫美微針貼片。In this embodiment, the needle bottom layer can be adhered to the needle tip layer by the high polymer force of the material itself; therefore, after step (e), the needle bottom layer can be directly removed from the mother mold having the needle tip layer and the needle bottom layer simultaneously. The needle tip layer and the needle bottom layer which are adhered to each other are completed, and step (f) is completed to obtain the medical beauty microneedle patch of this embodiment.

實施例Examples 55

本實施例係大致上採用如前述實施例4所述之方法製備醫美微針貼片，其不同之處主要在於，(e)步驟乾燥針底混合液之方法以及針底混合液之組成。This embodiment uses the method described in the previous Example 4 to prepare a medical microneedle patch. The main difference is that the method of step (e) dries the needle base mixed solution and the composition of the needle base mixed solution.

於此，針底混合液為濃度15 wt%之聚乙烯醇及聚乙烯吡咯烷酮，該聚乙烯醇相對於聚乙烯吡咯烷酮之重量比例為4：1，且該針底混合液於25°C、1 S-1 下所測得之黏度為11000 cP，其表面張力為37 dyne/cm。Here, the needle-bottom mixed solution is 15% by weight of polyvinyl alcohol and polyvinylpyrrolidone, the weight ratio of the polyvinyl alcohol to the polyvinylpyrrolidone is 4: 1, and the needle-bottom mixed solution is at 25 ° C, 1 The measured viscosity at S -1 was 11,000 cP, and its surface tension was 37 dyne / cm.

於(e)步驟中，本實施例係於室溫下乾燥24小時，令針底層黏合於該針尖層。最後，經由如實施例4所述之(f1)及(f2)步驟，製得該醫美微針貼片。In step (e), the embodiment is dried at room temperature for 24 hours, so that the needle bottom layer is adhered to the needle tip layer. Finally, through the steps (f1) and (f2) described in Example 4, the medical beauty microneedle patch is prepared.

實施例Examples 66

本實施例係大致上採用如前述實施例4所述之方法製備醫美微針貼片，其不同之處主要在於，(e)步驟乾燥針底混合液之方法以及針底混合液之組成。This embodiment uses the method described in the previous Example 4 to prepare a medical microneedle patch. The main difference is that the method of step (e) dries the needle base mixed solution and the composition of the needle base mixed solution.

具體而言，針底混合液為濃度為15 wt%之聚乙烯醇及聚乙烯吡咯烷酮，該聚乙烯醇相對於聚乙烯吡咯烷酮之重量比例為4：1，且該針底混合液於25°C、1 S-1 下所測得之黏度為11000 cP，其表面張力為37 dyne/cm。Specifically, the needle-bottom mixed solution is 15% by weight of polyvinyl alcohol and polyvinylpyrrolidone. The weight ratio of the polyvinyl alcohol to the polyvinylpyrrolidone is 4: 1, and the needle-bottom mixed solution is at 25 ° C. The measured viscosity at 1 S -1 is 11000 cP, and its surface tension is 37 dyne / cm.

於(e)步驟中，本實施例係於-20°C之溫度下，持續乾燥該裝有針底混合液之母模長達15分鐘，先獲得初次乾燥之針底層及針尖層；再將其置於4°C下乾燥15分鐘，獲得二次乾燥之針底層及針尖層；而後再放回-20°C之環境下乾燥15分鐘，獲得三次乾燥之針底層及針尖層；再將其置於4°C下乾燥15分鐘，獲得四次乾燥之針底層及針尖層；最後再將該四次乾燥之針底層及針尖層置於室溫下乾燥24小時，即可完成(e)步驟，令針底層黏合於該針尖層。最後，經由如實施例4所述之(f1)及(f2)步驟，製得該醫美微針貼片。In step (e), this example is to continuously dry the mother mold with the needle bottom mixed liquid at a temperature of -20 ° C for 15 minutes, and obtain the needle bottom layer and the needle tip layer which are dried for the first time; It is dried at 4 ° C for 15 minutes to obtain the secondary dried needle bottom and needle tip layer; then it is returned to the -20 ° C environment and dried for 15 minutes to obtain the three dried needle bottom and needle tip layer; Dry at 4 ° C for 15 minutes to obtain four dried needle bottoms and needle tip layers. Finally, dry the four dried needle bottoms and needle tip layers at room temperature for 24 hours to complete step (e). So that the bottom of the needle is adhered to the tip layer. Finally, through the steps (f1) and (f2) described in Example 4, the medical beauty microneedle patch is prepared.

實施例Examples 77

本實施例係大致上採用如前述實施例1所述之方法製備醫美微針貼片，其不同之處主要在於，針尖混合液為25 wt%之含有藍銅胜肽/羧甲基纖維素鈉/麥芽糖/聚氧乙烯單月桂酸去水山梨酯之水溶液，且該針尖混合液於25°C、1 S-1 下所測得之黏度為1500 cP，其表面張力為35 dyne/cm。This example uses the method described in Example 1 to prepare a medical microneedle patch. The main difference is that the needle tip mixture is 25 wt% of blue copper peptide / carboxymethyl cellulose. An aqueous solution of sodium / maltose / polyoxyethylene monolaurate desorbate, and the measured viscosity of the needle tip mixture at 25 ° C, 1 S -1 was 1500 cP, and its surface tension was 35 dyne / cm.

比較例Comparative example 11

本比較例係大致上採用如前述實施例1所述之方法製備醫美微針貼片，其不同之處主要在於，針尖混合液為3 wt%之含有藍銅胜肽/羧甲基纖維素鈉/聚氧乙烯單月桂酸去水山梨酯之水溶液，且該針尖混合液於25°C、1 S-1 下所測得之黏度為31 cP，其表面張力為35 dyne/cm。This comparative example uses the method described in Example 1 to prepare a medical microneedle patch. The main difference is that the needle tip mixture is 3 wt% of blue copper peptide / carboxymethyl cellulose. An aqueous solution of sodium / polyoxyethylene monolaurate dehydrated sorbate, and the measured viscosity of the needle tip mixture at 25 ° C, 1 S -1 was 31 cP, and its surface tension was 35 dyne / cm.

試驗例Test example 11

為分析實施例5及實施例6之醫美微針貼片的機械強度，本試驗例分別製作二種等厚度之平面膜。其中平面膜1(模擬實施例5之醫美微針貼片)和平面膜2(模擬實施例6之醫美微針貼片)皆係由15 wt%之聚乙烯醇/聚乙烯吡咯烷酮水溶液作為塗佈液所製得，該聚乙烯醇相對於聚乙烯吡咯烷酮之重量比例為4：1。In order to analyze the mechanical strength of the medical beauty microneedle patches of Examples 5 and 6, two types of flat films of the same thickness were made in this test example. Among them, the flat film 1 (simulating the medical beauty microneedle patch of Example 5) and the flat film 2 (simulating the medical beauty microneedle patch of Example 6) are both coated with a 15 wt% aqueous solution of polyvinyl alcohol / polyvinylpyrrolidone. The weight ratio of the polyvinyl alcohol to the polyvinylpyrrolidone obtained by the cloth liquid is 4: 1.

而於乾燥製程中，平面膜1係於室溫下乾燥24小時，即完成平面膜1之乾燥步驟；平面膜2則係先置於-20°C之溫度下乾燥15分鐘，再於4°C下乾燥15分鐘，而後再放回-20°C之環境下乾燥15分鐘，再於4°C下乾燥15分鐘，最後於室溫下乾燥24小時，即完成平面膜2之乾燥步驟。In the drying process, the flat film 1 is dried at room temperature for 24 hours, and the drying step of the flat film 1 is completed; the flat film 2 is first dried at -20 ° C for 15 minutes, and then dried at 4 ° Dry at 15 ° C for 15 minutes, then return to -20 ° C for 15 minutes, then dry at 4 ° C for 15 minutes, and finally dry at room temperature for 24 hours to complete the drying step of flat film 2.

針對前述平面膜1及平面膜2，本試驗例皆採用ASTM D882試驗方法分析後，得到平面膜1之楊氏模數為32.8 MPa，而平面膜2之楊氏模數明顯提升至81.5 MPa，大約提升3.2倍。For the aforementioned flat film 1 and flat film 2, the test examples are analyzed by the ASTM D882 test method. The Young's modulus of the flat film 1 is 32.8 MPa, and the Young's modulus of the flat film 2 is significantly increased to 81.5 MPa. About 3.2 times.

由此可見，藉由特定的乾燥步驟，實施例6之醫美微針貼片能具有較高的機械強度，而獲得較佳的微針貼片品質。It can be seen that, through a specific drying step, the medical beauty microneedle patch of Example 6 can have higher mechanical strength and obtain better microneedle patch quality.

試驗例Test example 22

為分析實施例7及比較例1之醫美微針貼片的針尖溶解度，本試驗例分別製作二種等厚度之平面膜。其中平面膜3(模擬實施例7之醫美微針貼片)係由25 wt%之含有藍銅胜肽/羧甲基纖維素鈉/麥芽糖/聚氧乙烯單月桂酸去水山梨酯之水溶液作為塗佈液所塗佈而成，平面膜4(模擬比較例1之醫美微針貼片)係由3 wt%之含有藍銅胜肽/羧甲基纖維素鈉/聚氧乙烯單月桂酸去水山梨酯之水溶液所塗佈而成，平面膜3和平面膜4之厚度相等，且二者皆材切為2 cm×2 cm的尺寸大小。In order to analyze the needle tip solubility of the medical beauty microneedle patch of Example 7 and Comparative Example 1, two kinds of flat films of the same thickness were made in this test example. The flat film 3 (a medical microneedle patch of Example 7) is a 25 wt% aqueous solution containing blue copper peptide / sodium carboxymethyl cellulose / maltose / polyoxyethylene monolaurate desorbate Coated as a coating liquid, the flat film 4 (simulating the medical beauty microneedle patch of Comparative Example 1) is made of 3 wt% blue copper peptide / sodium carboxymethyl cellulose / polyoxyethylene monolaurate Coated with an aqueous solution of sorbitan, the thickness of the flat film 3 and the flat film 4 are equal, and both materials are cut to a size of 2 cm × 2 cm.

為分析前述平面膜3及平面膜4之溶解特性，本試驗例採用相同方法對平面膜3及平面膜4進行分析。具體而言，使用PBS緩衝溶液模擬人體體液環境，並將尺寸相等的平面膜3及平面膜4分別浸泡於37°C下含已知重量之PBS緩衝溶液的培養皿中持續15分鐘。接著，將濾紙置放於連接有抽氣裝置之布氏漏斗上，分別抽氣過濾前述培養皿中浸有平面膜3之緩衝溶液及浸有平面膜4之緩衝溶液，再以103°C烘乾殘餘於濾紙上之平面膜，直至重量不再變化後，即得殘餘平面膜之重量。再計算浸泡前之平面膜與浸泡後殘餘平面膜之重量差，所述重量差即平面膜溶解重量，將平面膜溶解重量除以起始PBS緩衝溶液重量，即可比較得知平面膜3及平面膜4之溶解特性。In order to analyze the dissolution characteristics of the aforementioned planar film 3 and planar film 4, the same method is used to analyze the planar film 3 and the planar film 4 in this test example. Specifically, the PBS buffer solution was used to simulate the human body fluid environment, and the flat films 3 and 4 of the same size were immersed in a petri dish containing a known weight of PBS buffer solution at 37 ° C for 15 minutes. Next, the filter paper was placed on a Buchner funnel connected to a suction device, and the buffer solution impregnated with the flat membrane 3 and the buffer solution impregnated with the flat membrane 4 in the aforementioned petri dishes were suction-filtered, and then dried at 103 ° C. Dry the flat film remaining on the filter paper until the weight does not change any more to obtain the weight of the remaining flat film. Then calculate the weight difference between the flat film before immersion and the remaining flat film after immersion. The difference in weight is the dissolved weight of the flat film. Divide the dissolved weight of the flat film by the weight of the initial PBS buffer solution. Dissolution characteristics of the flat film 4.

實驗結果顯示，平面膜3經由前述測試方法所測得之溶解度為0.41 wt%，平面膜4經由前述測試方法所測得之溶解度為0.026 wt%；可見使用25 wt%之含有藍銅胜肽/羧甲基纖維素鈉/麥芽糖/聚氧乙烯單月桂酸去水山梨酯之水溶液作為針尖混合液所製得之醫美微針貼片(實施例7)的溶解性較比較例1之醫美微針貼片的溶解性佳。The experimental results show that the solubility of Planar Film 3 measured by the aforementioned test method is 0.41 wt%, and the solubility of Planar Film 4 measured by the aforementioned test method is 0.026 wt%; it can be seen that the use of 25 wt% blue copper peptide / The medical beauty microneedle patch (Example 7) prepared by the aqueous solution of carboxymethylcellulose sodium / maltose / polyoxyethylene monolaurate desorbate as a needle-point mixture was more soluble than the medical beauty of Comparative Example 1. The microneedle patch has good solubility.

此外，比較實施例7及比較例1之醫美微針貼片的製作過程可知，選用合適的針尖混合液製作醫美微針貼片，能確保實施例7之醫美微針貼片獲得較佳之溶解度，故能傳遞足量之醫美活性成分；相較之下，由於比較例1之醫美微針貼片的針尖層溶解度不佳，致使成品無法確保針尖層溶解而傳遞足量之醫美活性成分或達成其功效。In addition, it can be seen from the manufacturing process of the medical beauty microneedle patch of Comparative Example 7 and Comparative Example 1 that the use of a suitable needle tip mixture to make the medical beauty microneedle patch can ensure that the medical beauty microneedle patch of Example 7 can obtain a better quality. Good solubility, so it can pass a sufficient amount of medical beauty active ingredients; in contrast, due to the poor solubility of the needle tip layer of the medical beauty microneedle patch of Comparative Example 1, the finished product can not ensure that the needle tip layer is dissolved and enough medicine is delivered. Beauty active ingredients or achieve their effect.

試驗例Test example 33

為確定本創作醫美微針貼片之製作方法所製得之成品確實能應用於醫美用途，本試驗例選用已除毛的豬皮作為穿刺對象，進行體外穿刺試驗，以觀察醫美微針貼片的穿刺深度。In order to confirm that the finished product made by the method of creating the medical beauty microneedle patch can indeed be used for medical beauty, this test example selects the depilated pigskin as the puncture object and conducts an in vitro puncture test to observe the medical beauty The depth of puncture of the needle patch.

於本試驗例中，選用前述實施例2之醫美微針貼片為代表性例子，將醫美微針貼片貼合於自製治具上，並壓在已除毛的豬皮約5分鐘，將經穿刺的豬皮染色，觀察豬皮上是否出現醫美微針貼片的穿刺點。In this test example, the medical beauty microneedle patch of the aforementioned Example 2 is selected as a representative example. The medical beauty microneedle patch is attached to a self-made jig, and pressed against the depilated pigskin for about 5 minutes. , Stain the punctured pig skin and observe whether the puncture point of the medical beauty microneedle patch appears on the pig skin.

接著，將經穿刺的豬皮浸泡於福馬林中，進行組織固定、切片與染色，以光學顯微鏡觀察經穿刺的豬皮中穿刺點的深度，其結果請參閱圖6所示。Next, the punctured pig skin was immersed in formalin, and the tissue was fixed, sliced, and stained. The depth of the puncture point in the punctured pig skin was observed with an optical microscope. The results are shown in FIG. 6.

如圖6所示，實施例2之醫美微針貼片的穿刺深度約100 μm；有此可見，前述製作方法所製得之醫美微針貼片確實能穿刺具有隔離屏障之角質層，並且到達表皮層及真皮層的上方，使醫美微針貼片中的醫美活性成分於體內發揮所期望的效果。As shown in FIG. 6, the puncture depth of the medical beauty microneedle patch of Example 2 is about 100 μm; it can be seen that the medical beauty microneedle patch prepared by the foregoing manufacturing method can indeed penetrate the stratum corneum with an isolation barrier. And it reaches above the epidermal layer and the dermal layer, so that the medical beauty active ingredients in the medical beauty microneedle patch can exhibit desired effects in the body.

試驗例Test example 44

為確定本創作醫美微針貼片之製作方法所製得之成品確實能應用於醫美用途，本試驗例選用週齡6週的小鼠(品系為Balb/C)為穿刺對象，進行活體穿刺試驗，以觀察醫美微針貼片的穿刺情形。In order to confirm that the finished product produced by the method of creating the medical beauty microneedle patch can indeed be used for medical beauty, this test example uses a 6-week-old mouse (strain Balb / C) as the puncture object for living body Puncture test to observe the puncture situation of Yimei microneedle patch.

於本試驗例中，選用如前述實施例2之醫美微針貼片為代表性例子，將醫美微針貼片貼合於自製治具上。In this test example, the medical beauty microneedle patch as in the foregoing Example 2 is selected as a representative example, and the medical beauty microneedle patch is attached to a self-made jig.

於活體穿刺試驗前二天，先使用除毛膏將小鼠上預定進行穿刺試驗的區域進行除毛，以作為醫美微針貼片的觀察對象。在進行活體穿刺試驗時，將小鼠麻醉，將實施例2之醫美微針貼片壓在小鼠已除毛的區域約1分鐘，再將醫美微針貼片持續貼於鼠皮約1小時，再觀察鼠皮上是否出現醫美微針貼片的穿刺點；如圖7所示，實施例2之醫美微針貼片確實已如預期在鼠皮上產生微針孔洞陣列。Two days before the biopsy test, the hair was removed from the area intended for the biopsy test on the mouse by using a hair removal cream, as the observation object of the medical beauty microneedle patch. During the biopsy test, the mice were anesthetized, and the medical beauty microneedle patch of Example 2 was pressed against the hair-removed area of the mouse for about 1 minute, and then the medical beauty microneedle patch was continuously attached to the mouse skin. After 1 hour, observe whether the puncture point of the medical beauty microneedle patch appears on the rat skin; as shown in FIG. 7, the medical beauty microneedle patch of Example 2 has indeed produced a microneedle hole array on the mouse skin as expected. .

此外，本試驗例另使用光學顯微鏡觀察穿刺前、穿刺後醫美微針貼片上微針結構之高度變化。請參閱圖8A所示，於穿刺前，醫美微針貼片之針高為750 μm；請參閱圖8B所示，於穿刺後，醫美微針貼片之針高為260 μm。In addition, in this test example, an optical microscope was used to observe the change in the height of the microneedle structure on the medical microneedle patch before and after the puncture. Please refer to FIG. 8A. Before the puncture, the needle height of the medical beauty microneedle patch is 750 μm. Please refer to FIG. 8B. After the puncture, the needle height of the medical beauty microneedle patch is 260 μm.

由於實施例2之醫美微針貼片的針尖層中含有醫美活性成分，可見醫美微針貼片之醫美活性成分已如預期傳遞至小鼠體內，並且溶解於其中發揮所期望之醫美效果。As the needle tip layer of the medical beauty microneedle patch of Example 2 contains the medical beauty active ingredient, it can be seen that the medical beauty active ingredient of the medical beauty microneedle patch has been passed into mice as expected, and dissolved in it to exert the desired effect. Medical beauty effect.

10‧‧‧母模10‧‧‧master

10A‧‧‧裝有針尖混合液之母模10A‧‧‧Master with mixed tip

10B‧‧‧具有針尖層之母模10B‧‧‧Master with needle tip layer

10C‧‧‧裝有針底混合液之母模10C‧‧‧Master with mixed liquid at the bottom of the needle

10D‧‧‧具有針尖層和針底層之母模10D‧‧‧Master with needle tip layer and needle bottom layer

11‧‧‧基準面11‧‧‧ datum

12‧‧‧孔洞12‧‧‧ Hole

20、20A‧‧‧醫美微針貼片20, 20A‧‧‧Medical Microneedle Patch

21‧‧‧針尖層21‧‧‧ Needle Tip Layer

21′‧‧‧針尖混合液21′‧‧‧ Needle tip mixture

22、22A‧‧‧針底層22, 22A‧‧‧ Needle bottom

22′‧‧‧針尖混合液22′‧‧‧ Needle tip mixture

23‧‧‧背層23‧‧‧Back layer

S1‧‧‧狹縫式塗佈頭S1‧‧‧Slit-type coating head

S1A‧‧‧刮刀S1A‧‧‧Scraper

S2‧‧‧刮板S2‧‧‧Scraper

圖1為本創作醫美微針貼片之製作方法的流程圖。 圖2為說明實施例1之醫美微針貼片之製作方法的示意圖。 圖3為實施例1之製作方法所製得之醫美微針貼片的示意圖。 圖4為說明實施例3之醫美微針貼片之製作方法的示意圖。 圖5為實施例3之製作方法所製得之醫美微針貼片的示意圖。 圖6為實施例2之醫美微針貼片穿刺豬皮後的照片圖。 圖7為實施例2之醫美微針貼片穿刺鼠皮後的照片圖。 圖8A及圖8B分別為實施例2之醫美微針貼片於穿刺小鼠前、穿刺小鼠後的照片圖。FIG. 1 is a flowchart of a method for creating a medical microneedle patch. FIG. 2 is a schematic diagram illustrating a method for manufacturing a medical microneedle patch of Example 1. FIG. FIG. 3 is a schematic diagram of a medical beauty microneedle patch prepared by the manufacturing method of Example 1. FIG. FIG. 4 is a schematic diagram illustrating a method for manufacturing the medical beauty microneedle patch of Embodiment 3. FIG. FIG. 5 is a schematic diagram of a medical beauty microneedle patch prepared by the manufacturing method of Embodiment 3. FIG. FIG. 6 is a photograph of the medical beauty microneedle patch of Example 2 after puncturing pig skin. FIG. 7 is a photograph of the medical beauty microneedle patch of Example 2 after puncturing mouse skin. 8A and 8B are photographs of the medical beauty microneedle patch of Example 2 before and after puncturing the mice.

無。no.

Claims (19)

一種醫美微針貼片之製作方法，其包括以下步驟： (a) 提供一母模，該母模具有一基準面及複數孔洞，所述多個孔洞由基準面向下凹設成型； (b) 將一針尖混合液形成於該母模之多個孔洞內，藉此令針尖混合液填滿母模之多個孔洞，獲得一裝有針尖混合液之母模，該針尖混合液之液面係與母模之基準面齊平，該針尖混合液中含有醫美活性成分； (c) 將針尖混合液乾燥為針尖層，獲得一具有針尖層之母模，該針尖層之表面低於母模之基準面； (d) 將一針底混合液形成於針尖層上及前述多個孔洞內，藉此令針底混合液覆蓋針尖層及該母模之基準面及多個孔洞中，獲得一裝有針底混合液之母模； (e) 將針底混合液乾燥為針底層，藉此令針底層黏合於該針尖層；以及 (f) 自母模上卸下相互黏合之針尖層和針底層，獲得該醫美微針貼片。A method for manufacturing a medical microneedle patch includes the following steps: (a) providing a master mold having a reference surface and a plurality of holes, the plurality of holes are concavely formed from the reference surface; (b) ) Forming a needle-point mixed liquid in a plurality of holes in the master mold, thereby filling the needle-point mixed liquid in the holes in the master mold to obtain a master mold containing the needle-point mixed liquid, and the liquid level of the needle-point mixed liquid It is flush with the reference plane of the master mold, and the needle tip mixture contains medicinal active ingredients; (c) The needle tip mixture is dried into a needle tip layer to obtain a master mold with a needle tip layer, the surface of the needle tip layer is lower than that of the mother die. (D) forming a needle base mixed liquid on the needle tip layer and the plurality of holes, so that the needle base mixed liquid covers the needle tip layer and the reference surface and multiple holes of the master mold to obtain A female mold containing the needle bottom mixed liquid; (e) drying the needle bottom mixed liquid into the needle bottom layer, thereby making the needle bottom layer adhere to the needle tip layer; and (f) removing the adhesive needle point layer from the mother mold. And the needle bottom layer to obtain the medical beauty microneedle patch. 如請求項1所述之製作方法，其中該針尖混合液之黏度係低於該針底混合液之黏度。The manufacturing method according to claim 1, wherein the viscosity of the needle tip mixed liquid is lower than the viscosity of the needle bottom mixed liquid. 如請求項2所述之製作方法，其中該針尖混合液之黏度為3釐泊至500000釐泊。The manufacturing method as described in claim 2, wherein the viscosity of the needle tip mixed liquid is 3 centipoise to 500,000 centipoise. 如請求項2所述之製作方法，其中該針底混合液之黏度為100 釐泊至5000000 釐泊。The manufacturing method as described in claim 2, wherein the viscosity of the needle base mixed liquid is 100 centipoise to 5000000 centipoise. 如請求項1所述之製作方法，其中該針尖混合液之濃度為5 wt%至50 wt%。The manufacturing method according to claim 1, wherein the concentration of the needle tip mixed solution is 5 wt% to 50 wt%. 如請求項1所述之製作方法，其中該針底混合液之濃度為10 wt%至95 wt%。The manufacturing method according to claim 1, wherein the concentration of the needle bottom mixed liquid is 10 wt% to 95 wt%. 如請求項1所述之製作方法，其中該針尖混合液之表面張力係小於或等於70 dyne/cm。The manufacturing method according to claim 1, wherein the surface tension of the needle tip mixed liquid is less than or equal to 70 dyne / cm. 如請求項1所述之製作方法，其中該針底混合液之表面張力係小於或等於50 dyne/cm。The manufacturing method according to claim 1, wherein the surface tension of the needle bottom mixed liquid is less than or equal to 50 dyne / cm. 如請求項1所述之製作方法，其中前述(c)及(e)步驟使用冷凍乾燥或常溫乾燥之方式進行。The production method according to claim 1, wherein the steps (c) and (e) are performed by freeze-drying or drying at room temperature. 如請求項1所述之製作方法，其中前述(c)及(e)步驟之乾燥溫度為-80°C至160°C。The method according to claim 1, wherein the drying temperature in the steps (c) and (e) is -80 ° C to 160 ° C. 如請求項1所述之製作方法，其中前述(e)步驟包括： 將針底混合液置於-80°C至0°C乾燥為針底層，獲得一初次乾燥之針底層及針尖層； 將初次乾燥之針底層及針尖層置於2°C至10°C下，獲得一二次乾燥之針底層及針尖層；以及 再將該二次乾燥之針底層及針尖層置於室溫下乾燥，藉此令針底層黏合於該針尖層。The manufacturing method according to claim 1, wherein the step (e) includes: drying the needle bottom mixed liquid at -80 ° C to 0 ° C to dry the needle bottom layer to obtain an initial dried needle bottom layer and the needle tip layer; The first dried needle bottom layer and the needle tip layer are placed at 2 ° C to 10 ° C to obtain the secondary dried needle bottom layer and the needle tip layer; and the second dried needle bottom layer and the needle tip layer are dried at room temperature. In this way, the bottom of the needle is adhered to the needle tip layer. 如請求項1所述之製作方法，其中於前述(e)步驟之後，該(f)步驟包括： 將一背層形成於該母模及該針底層上，藉此令該針尖層和該針底層夾置於該母模和該背層之間；以及 自具有該針尖層和該針底層之母模上同時卸下該針尖層、該針底層和該背層，獲得該醫美微針貼片。The manufacturing method according to claim 1, wherein after step (e), the step (f) includes: forming a back layer on the master mold and the needle bottom layer, thereby making the needle tip layer and the needle The bottom layer is sandwiched between the mother mold and the back layer; and the needle tip layer, the needle bottom layer and the back layer are simultaneously removed from a mother mold having the needle tip layer and the needle bottom layer to obtain the medical beauty microneedle patch sheet. 如請求項1所述之製作方法，其中前述(b)步驟包括： 將針尖混合液形成於該母模上，再令針尖混合液流動至多個孔洞內，藉此令針尖混合液覆蓋於該母模之基準面及多個孔洞中；以及 移除基準面上之針尖混合液，藉此令針尖混合液之液面係與母模之基準面齊平。The manufacturing method according to claim 1, wherein the step (b) comprises: forming the needle-point mixed liquid on the mother mold, and then flowing the needle-point mixed liquid into a plurality of holes, thereby covering the needle-point mixed liquid on the mother. The reference surface of the mold and a plurality of holes; and removing the needle tip mixed liquid on the reference surface, so that the liquid level of the needle tip mixed liquid is flush with the reference surface of the mother mold. 如請求項13所述之製作方法，其中令針尖混合液流動至多個孔洞內之方法包括真空抽氣法及離心法。The production method according to claim 13, wherein the method for causing the needle tip mixed liquid to flow into the plurality of holes includes a vacuum evacuation method and a centrifugation method. 如請求項1所述之製作方法，其中前述(d)步驟包括：將針底混合液形成於該母模上，再令針底混合液流動至多個孔洞內，藉此令針尖混合液覆蓋於針尖層及該母模之基準面及多個孔洞中，獲得該裝有針底混合液之母模。The manufacturing method according to claim 1, wherein the step (d) includes forming the needle base mixed liquid on the master mold, and then allowing the needle base mixed liquid to flow into a plurality of holes, thereby covering the needle tip mixed liquid on the master mold. The needle tip layer and the reference plane of the mother mold and a plurality of holes obtain the mother mold filled with the needle bottom mixed liquid. 如請求項15所述之製作方法，其中令針底混合液流動至多個孔洞內之方法包括真空抽氣法及離心法。The manufacturing method according to claim 15, wherein the method of causing the needle bottom mixed liquid to flow into the plurality of holes includes a vacuum evacuation method and a centrifugation method. 如請求項1至16中任一項所述之製作方法，其中前述(b)步驟中將該針尖混合液形成於該母模之多個孔洞內之方法包括狹縫式塗佈法、刮刀式塗佈法、斜板式塗佈法、浸漬塗佈法、噴墨印刷法或噴嘴印刷法；前述(d)步驟將針底混合液形成於針尖層上及前述多個孔洞內之方法包括狹縫式塗佈法、刮刀式塗佈法、斜板式塗佈法、浸漬塗佈法、噴墨印刷法或噴嘴印刷法。The production method according to any one of claims 1 to 16, wherein the method of forming the needle tip mixed liquid in the plurality of holes of the master mold in the step (b) includes a slit coating method and a doctor blade method Coating method, swash plate coating method, dip coating method, inkjet printing method or nozzle printing method; the method of forming the needle bottom mixed liquid on the needle tip layer in the step (d) and the plurality of holes includes a slit Coating method, doctor blade coating method, swash plate coating method, dip coating method, inkjet printing method, or nozzle printing method. 如請求項1至16中任一項所述之製作方法，其中該醫美活性成分係包含麴酸、熊果素、維生素C磷酸鈉鹽、維生素C磷酸鎂鹽、維生素C葡萄醣苷、維生素C及其衍生物、維生素E及其衍生物、維生素A及其衍生物、鞣花酸、甘菊萃取物、傳明酸十六烷基酯、4-甲氧基水楊酸鉀鹽、3-O-乙基抗壞血酸、神經醯胺、卵磷脂、甘油、多醣類、玻尿酸、玻尿酸鈉、蛋白質、膠原蛋白、彈力蛋白、藍銅胜肽、五胜肽、六胜肽、九胜肽、氨基酸、檸檬酸、尿酸、尿素、葡萄糖、蔗糖、果糖、肝糖、葡萄氨聚糖、黏多醣、乳酸鹽、磷酸鹽、吡咯烷酮-5-羧酸乙酯、葡萄萃取物、綠茶萃取物、銀杏萃取物、大豆萃取物、石榴萃取物、生薑萃取物、酵母萃取物、薏仁萃取物、硫辛酸、葡聚醣、輔脢Q10、超氧化物歧化酶或其等之組合。The manufacturing method according to any one of claims 1 to 16, wherein the medical beauty active ingredient comprises gallic acid, arbutin, vitamin C phosphate sodium salt, vitamin C magnesium phosphate salt, vitamin C glucoside, vitamin C, and Derivatives, Vitamin E and its derivatives, Vitamin A and its derivatives, ellagic acid, camomile extract, cetyl tranexamate, potassium 4-methoxysalicylate, 3-O- Ethyl ascorbic acid, neuraminamine, lecithin, glycerin, polysaccharides, hyaluronic acid, sodium hyaluronate, protein, collagen, elastin, blue copper peptide, pentapeptide, hexapeptide, nonapeptide, amino acid, lemon Acid, uric acid, urea, glucose, sucrose, fructose, liver sugar, glucosaminoglycan, mucopolysaccharide, lactate, phosphate, ethyl pyrrolidone-5-carboxylate, grape extract, green tea extract, ginkgo extract, Soy extract, pomegranate extract, ginger extract, yeast extract, coix seed extract, lipoic acid, dextran, cocoid Q10, superoxide dismutase or a combination thereof. 如請求項1至16中任一項所述之製作方法，其中該針尖混合物和該針底混合物係各自獨立包含一高分子材料，該高分子材料係選自於下列所組成之群組：麥芽糖、蔗糖、海藻糖、乳糖、糊精、麥芽糊精、b-環糊精、2-羥丙基-b-環糊精、葡聚糖、支鏈澱粉、玻尿酸鈉、甲基乙烯基醚-馬來酸酐共聚物、羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、羥丙基纖維素、明膠、聚乙烯醇、聚乙烯吡咯烷酮、聚乙二醇、聚乳酸、聚乙醇酸、聚乳酸-羥基乙酸共聚物、幾丁聚醣及其組合物。The manufacturing method according to any one of claims 1 to 16, wherein the needle tip mixture and the needle bottom mixture each independently comprise a polymer material selected from the group consisting of maltose , Sucrose, trehalose, lactose, dextrin, maltodextrin, b-cyclodextrin, 2-hydroxypropyl-b-cyclodextrin, dextran, amylopectin, sodium hyaluronate, methyl vinyl ether -Maleic anhydride copolymer, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, polylactic acid , Polyglycolic acid, polylactic-co-glycolic acid copolymer, chitosan and combinations thereof.
TW106116174A 2017-05-16 2017-05-16 Medical beauty microneedle patch manufacturing method TWI633901B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
TW106116174A TWI633901B (en) 2017-05-16 2017-05-16 Medical beauty microneedle patch manufacturing method
CN201710374824.9A CN107343984B (en) 2017-05-16 2017-05-24 Method for manufacturing medical micro-needle patch

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
TW106116174A TWI633901B (en) 2017-05-16 2017-05-16 Medical beauty microneedle patch manufacturing method

Publications (2)

Publication Number Publication Date
TW201800121A TW201800121A (en) 2018-01-01
TWI633901B true TWI633901B (en) 2018-09-01

Family

ID=60253307

Family Applications (1)

Application Number Title Priority Date Filing Date
TW106116174A TWI633901B (en) 2017-05-16 2017-05-16 Medical beauty microneedle patch manufacturing method

Country Status (2)

Country Link
CN (1) CN107343984B (en)
TW (1) TWI633901B (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108078880B (en) * 2017-11-20 2020-12-18 广州暨南大学医药生物技术研究开发中心有限公司 Whitening composition containing coix seed fermentation liquor
CN109833224A (en) * 2017-11-27 2019-06-04 苏州纳通生物纳米技术有限公司 A kind of transdermal rush infiltration beautifying skin method
JP7008144B2 (en) * 2018-09-26 2022-01-25 富士フイルム株式会社 Manufacturing method of transdermal absorption sheet
CN110202635B (en) * 2019-07-05 2024-05-24 无锡元旭生物技术有限公司 Cutting and assembling device for soluble microneedle patch
CN110507559A (en) * 2019-09-29 2019-11-29 卢沁梅 A kind of beautifying nourishing liquid
CN111375124A (en) * 2020-03-19 2020-07-07 上海缓释新材料科技有限公司 Anti-aging slow-release soluble microneedle based on polylactic acid compound and preparation method thereof
CN111408047B (en) * 2020-04-17 2020-11-17 南京鼓楼医院 Conductive microneedle patch for wound repair and preparation method thereof
CN114376569B (en) * 2022-01-19 2023-10-13 浙江大学 Glucagon-carrying wearable device for treating hypoglycemia
TWI794035B (en) * 2022-03-07 2023-02-21 怡定興科技股份有限公司 Anti-wrinkle composition, anti-wrinkle microneedle patch and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW512067B (en) * 1999-06-09 2002-12-01 Procter & Gamble Method of manufacturing an intracutaneous microneedle array
TW544438B (en) * 2002-10-25 2003-08-01 Ind Tech Res Inst Method for manufacturing 3D high aspect-ratio microneedle array device
TW201703809A (en) * 2015-06-30 2017-02-01 Nissha Printing Microneedle sheet and method for producing same

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2691388T3 (en) * 2008-10-07 2018-11-27 Tuo Jin Polymeric phase transition microneedles
US20140066842A1 (en) * 2011-03-07 2014-03-06 3M Innovative Properties Company Microneedle devices and methods
CN103429222B (en) * 2011-03-07 2015-09-09 3M创新有限公司 Microneedle devices and method
CN104780967B (en) * 2012-11-13 2017-04-12 富士胶片株式会社 Method for manufacturing transdermal-absorption sheet
EP3024530A4 (en) * 2013-07-22 2017-04-19 Tuo Jin Fabrication process of phase-transition microneedle patch
US20150141910A1 (en) * 2013-11-14 2015-05-21 University Medical Pharmaceuticals Corporation Microneedles for therapeutic agent delivery with improved mechanical properties
CN103800998B (en) * 2014-02-24 2016-03-30 苏州大学 A kind of Silk fibroin gel microneedle device and preparation method thereof
CN204092839U (en) * 2014-09-30 2015-01-14 陈宁生 Eye mask colloidal particle micropin
CN104706626B (en) * 2015-03-25 2018-02-23 北京化工大学 A kind of microneedle patch for being easy to animal vaccine to be administered and preparation method thereof
CN105498081A (en) * 2015-09-04 2016-04-20 李媚 Sterile microstructure body and preparation method thereof
CN105078880A (en) * 2015-09-12 2015-11-25 北京化工大学 Macromolecular soluble microneedle used for cutaneous penetration of polypeptide and protein medicines and preparation method of macromolecular soluble microneedle
CN105411997A (en) * 2015-12-30 2016-03-23 李媚 Degradable microstructure body and preparation method thereof
CN106474620A (en) * 2016-09-22 2017-03-08 北京化工大学 A kind of polymer micro needle of medicine controlled release, preparation method and microneedle patch

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW512067B (en) * 1999-06-09 2002-12-01 Procter & Gamble Method of manufacturing an intracutaneous microneedle array
TW544438B (en) * 2002-10-25 2003-08-01 Ind Tech Res Inst Method for manufacturing 3D high aspect-ratio microneedle array device
TW201703809A (en) * 2015-06-30 2017-02-01 Nissha Printing Microneedle sheet and method for producing same

Also Published As

Publication number Publication date
TW201800121A (en) 2018-01-01
CN107343984A (en) 2017-11-14
CN107343984B (en) 2021-02-02

Similar Documents

Publication Publication Date Title
TWI633901B (en) Medical beauty microneedle patch manufacturing method
TWI629073B (en) Microneedle patch manufacturing method
CN104069585B (en) Detachable microneedle device and its manufacture method
US9919141B2 (en) Needle-shaped body and method for manufacturing needle-shaped body
JP2020203127A (en) Microarray for delivering therapeutic agent, use method, and manufacturing method
US20110152792A1 (en) Microneedle array using porous substrate and production method thereof
EP2990072B1 (en) Production method for acicular body
CN110151736A (en) Patch and preparation method thereof
TWI759712B (en) Microneedle device and method for making the same
CN204352374U (en) A kind of detachable microneedle device
JP6714319B2 (en) Needle-like body manufacturing method
CN216497013U (en) Medicine-carrying microneedle patch
JP2019006798A (en) Acicular body
CN116212215A (en) Microneedle patch with multilayer structure and manufacturing method thereof
TWI783807B (en) Multi-layered microneedle patch and method of manufacturing the same
JP2009195583A (en) Method and apparatus for manufacturing sheet with microneedle-shaped projection drug product accumulated therein
TWI794035B (en) Anti-wrinkle composition, anti-wrinkle microneedle patch and preparation method thereof
JP2017121315A (en) Method and apparatus for manufacturing stylet
WO2023227003A1 (en) Method for preparing microneedle patch, forming mold, and alignment fit device
JP2017023511A (en) Stylet
TWI688405B (en) Biodegradable microneedle array
JP2008303162A (en) Method for producing patch having conical projections of several hundred micrometers
TWM643895U (en) Microneedle patch
CN116899093A (en) Novel plaster microneedle patch and preparation method thereof
JP2017158937A (en) Manufacturing method of percutaneous absorption device