Patent Grant
10850083
The present invention relates to a microneedle manufacturing method using a biocompatible polymer, and more particularly, to a method of simply and economically manufacturing a microneedle that may realize sufficient hardness and painlessness without causing a loss and degeneration of medicine because the microneedle is manufactured by filling holes, which are formed to be spaced apart from one another in a mold, with a biocompatible polymer solution such as a hyaluronic acid solution by using a stopper capable of applying pressure to the mold, and a fine filling needle and/or a vacuum pump, and then solidifying the biocompatible polymer solution.
A method of injecting medicine in a liquid phase by using a subcutaneous injection needle is widely used as a method of effectively delivering medicine to be applied to a human body. However, there are problems in that a subcutaneous injection needle or an intramuscular injection needle having a diameter of 100 μm or more irritates multiple pain spots existing on skin, thus causing a patient pain which may lead to a phobia to needles, local damage to the skin, and bleeding, a high degree of skill is required to use the needle, and disease infection occurs at an injection site.
To solve the aforementioned problems of the subcutaneous injection needle, researches on a method of transdermally delivering medicine by using a microneedle device just having a diameter and a height of 10 to 100 μm to be applied to a human body are being actively conducted. The microneedle device forms, at one time, multiple channels, which penetrate a skin portion, by using microneedles that penetrate a horny layer of the skin which is a main barrier layer acting against the transdermal delivery of the medicine. A sufficient amount of medicine may reach an epidermal layer or a dermal layer through the channels, and thereafter, the medicine is absorbed through blood vessels and lymph nodes and then delivered into a circulatory system in the human body. In addition, the microneedle may be used for a cosmetic purpose. For example, a bioactive material is applied onto the skin or the microneedles, micro-channels are formed in the skin by the microneedle, and then the bioactive material is transdermally delivered. The method of transdermally delivering an effective material by using the microneedles is very useful, but a microneedle device of a patch type, which is made by simplifying a microneedle device having a complicated structure in the related art, is used more usefully.
A diameter of an upper end of the microneedle is very important in view of having high sharpness since the feature of the microneedle is to penetrate the skin without pain, and the microneedle needs to have sufficient physical hardness since the microneedle needs to penetrate a horny layer of 10 to 20 μm. In addition, an appropriate length of the microneedle, which allows the microneedle to reach capillaries to improve efficiency in delivering medicine, is one of the important elements.
Various types of microneedles including in-plane type microneedles or out-of-plane type microneedles have been developed, an etching method and a photolithographic method are used as a method of manufacturing the microneedles, and a combination of the etching method and the photolithographic method may be used.
U.S. Patent Application Publication No. 2002-138049 discloses a method of manufacturing an out-of-plane type solid microneedle by using an etching method, and this etching method may manufacture a solid silicone microneedle having a diameter of 50 to 100 μm and a length of 500 μm, but it is impossible to penetrate skin without pain, and it is difficult to deliver medicine and a cosmetic ingredient to a target site.
A method of manufacturing a biocompatible solid microneedle by mounting a material manufactured in the form of a capsule by using the photolithographic method is publicly known, and this method has an advantage in freely mounting medicine that may be manufactured in the form of a capsule, but this method has a problem that hardness of the microneedle deteriorates as the amount of mounted medicine is increased, such that this method cannot be applied for medicine required to be injected in a large amount (Jung-Hwan P., et al., Pharmaceutical Research, Vol. 23, No. 5, May 2006).
Japanese Patent Application Laid-Open No. 2005-154321 discloses a method of manufacturing an absorptive microneedle by applying a composition made by mixing maltose and medicine to a mold and solidifying the composition. According to this Japanese Patent Application, the absorptive microneedle is manufactured for the purpose of transdermally absorbing the medicine, but there are problems in that the absorptive microneedle causes pain when penetrating the skin, and because of a technical limitation in manufacturing a mold, it is impossible to manufacture a microneedle which has a diameter at an upper end appropriate to painlessness and a length at a level required for an effective delivery of medicine, that is, a length of 1 mm or more. In addition, the method of manufacturing the microneedle by using the mold requires additional processes that need to manufacture a new mold and a new frame through complicated processes to adjust the diameter and the length of the microneedle, and there are problems in that the process of manufacturing the microneedle by inserting a material into the mold is complicated and requires a large amount of time.
A biodegradable microneedle, which is manufactured in a polydimethylsiloxane (PDMS) mold by using a material made by mixing polyvinylpyrrolidone (PVP) and methacrylic acid (MAA), is publicly known (Sean P Sullivan et al., Advanced Materials 2008, 1). In addition, a microneedle is sometimes manufactured by inserting carboxymethylcellulose into a mold having a pyramidal structure (Jeong Woo Lee et al., Biomaterials 2007, 1). However, there is a limitation in that the method of manufacturing the microneedle by using the mold requires additional processes that need to manufacture a new mold and a new frame through complicated processes to adjust the diameter and the length of the microneedle, and there are problems in that the process of manufacturing the microneedle by inserting a material into the mold is complicated and requires a large amount of time.
In addition, U.S. Patent Application Publication No. 20080157421 A1 discloses an apparatus and a method of manufacturing a skin needle by using a pin structure. The method uses a method of pulling a heated or viscous material on a base of a substrate by using a pin by using tensile force. Since this method uses the method of pulling a material, which is melted by heat or has viscosity, by using the pin structure, this method cannot overcome limitations in that a process of newly manufacturing the pin structure in accordance with a desired pattern is required, which causes an increase in production costs, and it is difficult to mount various biological medicines sensitive to heat because of the heating process.
In addition, Korean Patent No. 10-1254240discloses a method of manufacturing a microneedle by forming a bottom layer by applying and drying a viscous material, spotting a viscous composition, bringing a substrate into contact with the viscous composition, and extending and solidifying the composition. This method is performed by dripping an appropriate amount of hyaluronic acid onto a plate and then extending the hyaluronic acid by using another plate or tool, but it is difficult to appropriately adjust a thickness or a length of the hyaluronic acid when extending the hyaluronic acid, viscosity of the hyaluronic acid is not constant because of the nature of the hyaluronic acid, and the hyaluronic acid is greatly affected by an environment, particularly, an exposure temperature and humidity. In addition, it is difficult to expect to obtain a needle having a constant shape and a constant size when cutting the hyaluronic acid while solidifying the hyaluronic acid by using blowing or a temperature after extending the temperature, and there is difficulty in managing process efficiency.
In addition, Korean Patent No. 10-0943157 discloses a mold for manufacturing a fine needle array having fine needle patterns through processes of embossing and dicing fine needle patterns by using a semiconductor etching process. According to the mold for manufacturing an array according to the method, it is difficult to expect to obtain a very fine needle because of the nature of the processing. In particular, the needle has a good external appearance because the mold is used, but because of the limitation of the mold, particularly, a limitation in precision after assembling the needle, there are problems in that it is mechanically difficult to manufacture a needle having a size of 10 to 50 μm, and thus it is difficult to overcome the phobia to needles even though the advantage of this product is to overcome the phobia to needles. In addition, there are many problems when ensuring both stability and effectiveness to apply medicines to the needle. For example, the needle needs to be used aseptically even to perform subcutaneous injection, but because the extension or array type needle often interferes with a person, it is very difficult to implement an aseptic product in the current situation.
The needle needs to supply a sufficient amount of main ingredient having effectiveness only to a necessary site, but there is a limitation in that both of Korean Patent No. 10-1254240 and Korean Patent No. 10-0943157 use and apply the same filling solution or cannot do so.
Accordingly, the present inventors have made an effort to solve the aforementioned problems and completed the present invention after finding out that in a case in which holes formed to be spaced apart from one another in a mold are filled with a biocompatible polymer solution such as a hyaluronic acid solution by using a pressing stopper, a fine filling needle and/or a vacuum pump, it is possible to solve problems of degeneration of medicine, insufficient hardness, and a loss of medicine caused by a complicated process and a long manufacturing time of a solid microneedle manufacturing method in the related art, no pain is incurred when penetrating the skin, the microneedle has a diameter, hardness, and a length that may penetrate into the skin when the microneedle is used for a medicine purpose or sufficiently stimulate the skin when the microneedle is used for a cosmetic purpose, and the microneedle, which has a perfect shape and is based on a biocompatible polymer, may be simply manufactured.
An object of the present invention is to provide a method of manufacturing a microneedle which is easily inserted into skin, may be penetrate deep into the skin, may accurately deliver a substantially necessary main ingredient to a target site in the skin without a degeneration or loss of medicine, may be manufactured aseptically, and has a constant shape and a constant size.
Another object of the present invention is to provide a method of manufacturing a biocompatible polymer-based microneedle which enables a patient to give himself/herself a treatment (injection) at the right time regardless of time and place, and may minimize a shock caused by a rapid injection.
Still another object of the present invention is to provide a method of manufacturing a biocompatible polymer-based microneedle which is more simply manufactured in a short time in comparison with a method of manufacturing a microneedle in the related art.
To achieve the aforementioned objects, the present invention provides a method of manufacturing a biocompatible polymer-based microneedle, the method including: (a) a primary filling step of covering, by stoppers, upper sides of multiple holes 200 of the mold 100, which are formed to be spaced apart from one another, penetrate a mold 100, and each have a conical shape, and injecting a biocompatible polymer solution containing an appropriate amount of active ingredient by using filling needles 350; (b) a secondary filling step of injecting a biocompatible polymer solution containing an excipient by using the filling needles 350; (c) a step of solidifying the biocompatible polymer solution; and (d) a step of attaching a pad to an upper portion of the mold 100 and then detaching the pad from the mold 100.
The present invention also provides a method of manufacturing a biocompatible polymer-based microneedle, the method including: (a) a primary filling step of covering, by the stoppers, the upper sides of the multiple holes 200, which are formed to be spaced apart from one another, penetrate the mold 100, and each have a conical shape, forming a vacuum at the lower sides of the holes 200, and injecting the biocompatible polymer solution containing an appropriate amount of active ingredient by using the filling needles 350; (b) a secondary filling step of injecting the biocompatible polymer solution containing the excipient by using the filling needle 350; (c) a step of solidifying the biocompatible polymer solution; and (d) a step of attaching the pad to the upper portion of the mold 100 and detaching the pad from the mold 100.
The present invention also provides a method of manufacturing a biocompatible polymer-based microneedle, the method including: (a) a primary filling step of positioning a pad 600 at the lower side of the bottom of the mold 100 having the multiple holes 200, which are formed to be spaced apart from one another, penetrate the mold, and each have a conical shape to seal the lower side of the bottom of the mold, covering, by the vacuum stopper, the upper sides of the holes 200, dripping the biocompatible polymer solution containing an appropriate amount of active ingredient in the vacuum state, releasing the vacuum, and then filling the holes with the biocompatible polymer solution; (b) a secondary filling step of injecting the biocompatible polymer solution containing the excipient by using the filling needles 350; (c) a step of solidifying the biocompatible polymer solution; and (d) a step of attaching the pad 600 to the upper portion of the mold 100 and then detaching the pad from the mold 100.
The present invention also provides a method of manufacturing a biocompatible polymer-based microneedle, the method including: (a) a step of dripping and uniformly applying the biocompatible polymer solution containing an appropriate amount of active ingredient onto the mold 100 having the multiple holes 200 which are formed to be spaced apart from one another, penetrate the mold 100, and each have a conical shape, and injecting the biocompatible polymer solution by connecting the lower sides of the holes 200 of the mold 100 to the vacuum pump; (b) a step of repeating step (a) one to ten times; (c) a step of solidifying the biocompatible polymer solution; and (d) a step of attaching the pad to the upper portion of the mold 100 and then detaching the pad from the mold 100.
Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by the person skilled in the art to which the present invention pertains. In general, the nomenclature used in the specification is well known and commonly used in the present technical field.
The present invention has been completed after finding out that in a case in which a biocompatible polymer-based microneedle is manufactured by filling holes 200 formed to be spaced apart from one another in a mold 100 with a biocompatible polymer solution such as a hyaluronic acid solution by using stoppers 300 and fine filling needles 350 and/or a vacuum pump 400 and solidifying the biocompatible polymer solution, an end of the needle is sharp at a level of 25 to 30%, the microneedle is easily inserted into skin when penetrating the skin such that the needle penetrates deep into the skin, the needle thinly shrinks by about 20% or more in comparison with a case in which a size of a needle is filled in accordance with a method of solidifying the biocompatible polymer solution in the mold 100, no pain is incurred because the needle is thinner than a microneedle in the related art such that feeling is less when the needle is inserted into the skin, and the biocompatible polymer-based microneedle capable of accurately administering medicine to a target site without causing a degeneration or loss of the medicine may be simply manufactured in a short time.
The term “microneedle” used in the present specification means a term including a needle portion and an underlying layer, and the term “needle” means a portion filled with an active ingredient and an excipient that fills an end of the needle.
A method of filling the mold with the biocompatible solution such as the hyaluronic acid according to the present invention will be described below.
(1) The stopper 300 made of various types of materials covers an upper side of the hole 200 of the mold 100 according to the present invention and presses the biocompatible solution to inject a predetermined amount of biocompatible solution, and whether all of the holes 200 are filled with the predetermined amount of injected biocompatible solution is checked by using a vision system.
(2) The stopper 300 covers the upper side of the hole 200 of the mold 100 according to the present invention and presses the biocompatible solution while a vacuum is simultaneously formed at a lower side of the hole 200 to inject a predetermined amount of biocompatible solution, and whether all of the holes 200 are filled with the predetermined amount of injected biocompatible solution is checked by using the vision system.
(3) A pad 600 such as a silicone pad or a rubber pad is positioned at a lower side of a bottom of the mold 100 according to the present invention to seal the lower side of the bottom of the mold 100, a vacuum is formed at the upper side of the hole 200 by using a vacuum stopper 310, a predetermined amount of biocompatible solution fills the hole 200 in a vacuum state, and when the vacuum is released after the biocompatible solution is completely injected into the hole 200, the hole 200 is filled with the biocompatible solution as air in the hole is removed. In this case, the pad 600 at the lower side is removed, and whether all of the holes 200 are filled with the amount of injected solution is checked by using the vision system.
The reason why the processes of the present invention are possible is that the polymeric solution does not continuously flow downward due to viscoelasticity of polymeric materials but remains at a position at which the polymeric solution fills the hole. A biocompatible polymer or a biocompatible polymer with a low degree of cross-linking may be used as the polymer, and particularly, hyaluronic acid or cross-linked hyaluronic acid with a low degree of cross-linking (3 to 5%) may be used.
Therefore, one aspect of the present invention relates to a method of manufacturing a biocompatible polymer-based microneedle, the method including: (a) a primary filling step of covering, by the stoppers, the upper sides of the multiple holes 200 of the mold 100, which are formed to be spaced apart from one another, penetrate the mold 100, and each have a conical shape, and injecting the biocompatible polymer solution containing an appropriate amount of active ingredient by using the filling needles 350; (b) a secondary filling step of injecting the biocompatible polymer solution containing an excipient by using the filling needles 350; (c) a step of solidifying the biocompatible polymer solution; and (d) a step of attaching a pad to an upper portion of the mold 100 and then detaching the pad from the mold 100.
As illustrated in
In the manufacturing method, the vacuum may be applied by connecting the lower side of the hole 200 to the vacuum pump 400 when step (a) is performed.
Therefore, another aspect of the present invention relates to a method of manufacturing a biocompatible polymer-based microneedle, the method including: (a) a primary filling step of covering, by the stoppers, the upper sides of the multiple holes 200, which are formed to be spaced apart from one another, penetrate the mold 100, and each have a conical shape, forming a vacuum at the lower sides of the holes 200, and then injecting the biocompatible polymer solution containing an appropriate amount of active ingredient by using the filling needles 350; (b) a secondary filling step of injecting the biocompatible polymer solution containing the excipient by using the filling needle 350; (c) a step of solidifying the biocompatible polymer solution; and (d) a step of attaching the pad to the upper portion of the mold 100 and detaching the pad from the mold 100.
As illustrated in
As illustrated in
In addition, even in a case in which the needle has a small length, an appropriate amount of solution is applied onto the mold 100 having the multiple (several hundreds of) holes 200 which penetrates the mold 100 and each have a conical shape, and then the solution is suctioned from the lower side of the mold 100 by using the vacuum. In this case, for a vacuum suction time and the amount of suctioned solution, the time and a vacuum degree adjusting device may be used by applying a verified method so that the vacuum suction is completed at the moment when the solution forms at the end of the needle.
In addition, still another aspect of the present invention relates to a method of manufacturing a biocompatible polymer-based microneedle, the method including: (a) a primary filling step of positioning the pad at the lower side of the bottom of the mold 100 having the multiple holes 200, which are formed to be spaced apart from one another, penetrate the mold, and each have a conical shape to seal the lower side of the bottom of the mold, covering, by the vacuum stoppers, the upper sides of the holes 200, dripping the biocompatible polymer solution containing an appropriate amount of active ingredient in the vacuum state, releasing the vacuum, and then filling the holes with the biocompatible polymer solution; (b) a secondary filling step of injecting the biocompatible polymer solution containing the excipient by using the filling needles 350; (c) a step of solidifying the biocompatible polymer solution; and (d) a step of attaching the pad to the upper portion of the mold 100 and then detaching the pad from the mold 100.
This method is a method of removing air at a tip and changing a position with a liquid chemical in a case in which the mold 100 is fine such that a very fine needle is made.
As illustrated in
As illustrated in
The process of the method of manufacturing the biocompatible polymer-based microneedle according to the present invention may be performed as follows.
As illustrated in
Therefore, yet another aspect of the present invention relates to a method of manufacturing a biocompatible polymer-based microneedle, the method including: (a) a step of applying, by using the roller 700, an appropriate amount of biocompatible polymer solution onto the mold 100 having the multiple holes 200 which are formed to be spaced apart from one another, penetrate the mold 100, and each have a conical shape, and injecting the biocompatible polymer solution by connecting the lower sides of the holes 200 of the mold 100 to the vacuum pump; (b) a step of repeating step (a) one to ten times; (c) a step of solidifying the biocompatible polymer solution; and (d) a step of attaching the pad to the upper portion of the mold 100 and then detaching the pad from the mold 100.
The method according to the present invention is a method in which the stoppers 300 cover the upper sides of the multiple conical holes 200 formed to be spaced apart from one another in the mold 100 and then press the solution, a method in which the stoppers cover the upper sides of the holes 200 of the mold 100 and the lower sides of the holes 200 are connected to the vacuum pump, or a method in which the pad is positioned at the lower portion of the bottom of the mold 100 to seal the lower portion of the bottom of the mold 100, the vacuum stoppers cover the upper sides of the holes 200, the upper sides of the holes 200 are connected to the vacuum pump, the biocompatible polymer solution containing an appropriate amount of active ingredient is dripped in the vacuum state, and the vacuum is released, such that a predetermined amount of solution is injected, in which the primary filling injects the solution containing the main ingredient first, the secondary filling applies the excipient to accurately move the main ingredient to the end of the needle, and finally, the biocompatible polymer solution having a larger molecular weight is sufficiently applied onto the mold or an underlying layer capable of being attached to the pad is made.
Design is performed such that an accurate amount of biocompatible polymer solution is injected so that the main ingredient in the biocompatible polymer solution is accurately positioned at the end of the needle. The method of the present invention may be applied to medicine, particularly, biological medicine.
The number of times of application is determined depending on the amount of polymeric solution which is applied once, and the number of times of application may also vary depending on viscosity of the solution. The higher the viscosity, the larger the number of times, and the number of times may be 1 to 10.
The mold 100, which is filled with the solution injected and solidified to manufacture the biocompatible polymer-based microneedle, is tested by the vision system (medicine) or with the naked eye, such that whether the mold 100 is appropriately filled is checked, and then the mold is moved to the chamber to solidify the solution. When the solution is appropriately solidified, the pad is attached to the mold 100 and simultaneously detached from the mold 100. In this case, other methods may be used in accordance with products. Whether the pad is completely attached is checked. Additional solidification or drying is performed so that the needle is not contaminated and strength and hardness of the needle do not deteriorate for an effective period of time. In the case of a very sensitive product, freeze-drying is performed to adjust the amount of moisture to 3% or less. The needle is primarily packaged by blistering or thermal forming so that the needle is not lost, and the needle is secondarily packaged by using an aluminum pouch and a dehumidifying agent. The needle is finally packaged by using a carton box above the needle, and the package is completed by imparting a manufacturing number and a manufacturing date.
According to the present invention, the microneedle is manufactured by the aforementioned manufacturing method by using a biocompatible polymer, particularly, sodium hyaluronic acid, such that the microneedle delivers a main substance required for cosmetics and medicines to an appropriate position.
The microneedle of the present invention applied to cosmetics is a short needle having a size suitable to apply the cosmetics to the extent that the cosmetics stimulate skin, and the microneedle may exhibit an improvement on wrinkles, whitening, skin activation, and other functionality. In particular, in the case in which the cross-linked hyaluronic acid is used, the effect continues for a significant period of time, and other functional substances are slowly released in a sustained release manner, such that there is an advantage in that the cross-linked hyaluronic acid acts while remaining for a long period of time.
In addition, in the case in which the microneedle is used for a medicine purpose, the phobia to needles may be avoided, the microneedle is simply carried, and anyone may easily inject medicine. In particular, in a case of a patient who gets an injection every day, stiff and deformed muscle as well as the phobia to needles may be caused, but the microneedle may solve the inconvenience to the patient who needs to go to the hospital for prescriptions and treatments. Therefore, a patient may give himself/herself a treatment (injection) at the right time regardless of time and place. In addition, it can be said that there is an effect in that a shock caused by a rapid injection may be minimized. Regarding a difference from a microneedle product in the related art, since the end of the needle is sharp at a level of 25 to 30%, the needle is easily inserted deep into skin, such that the needle sufficiently exhibits its own effect, and since the needle is relatively thin, a patient feels less the needle when the needle is inserted into the skin. In addition, the product in the related art cannot administer an accurate amount of main ingredient of medicine into a desired site, but the microneedle according to the present invention may administer medicine significantly accurately to a necessary site.
In the present invention, the biocompatible polymer may be, but not limited to, a soluble substance derived from a body which is at least one of hyaluronic acid (HA), gelatin, chitosan, collagen, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), polylysine, carboxymethylchitin, fibrin, agarose, pullulan, and cellulose; or a biocompatible polymer or a cross-linked biocompatible polymer which is at least one of polyvinylpyrrolidone (PVP), polyethyleneglycol (PEG), polyvinylalcohol (PVA), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose sodium, polyalcohol, arabic gum, alginate, cyclodextrin, dextrin, glucose, fructose, starch, trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melezitose, dextran, sorbitol, xylitol, palatinit, polylactic acid, polyglycolic acid, polyethylene oxide, polyacrylic acid, polyacrylic amide, polymethacrylic acid, and polymaleic acid, preferably, hyaluronic acid or cross-linked hyaluronic acid, gelatin, or cross-linked gelatin. A molecular weight of the biocompatible polymer is within a range of 10,000 to 4,000,000 Da.
A cross-linking agent used to cross-link the cross-linked biocompatible polymer may be 1,2,7,8-diepoxyoctane, divinyl sulfone (DVS), glutaraldehyde, 1,4-butanediol diglycidyl ether (BDDE), vinyl sulfide, or polyethylene oxide. Preferably, BDDE is used, but the present invention is not limited thereto.
A process of manufacturing the mold 100 according to the present invention as illustrated in
The conical penetrating holes 200 are formed in all iron plates including stainless steel or all available plastic materials such as polycarbonate or polypropylene by using a drill or a laser.
For impregnation of cosmetics, a length (depth) of a hole in a plate or a die-casting hole is 50 to 270 μm, a diameter of a large hole is 30 to 80 μm, a diameter of a small hole is 10 to 50 μm, and the small hole is adjusted in accordance with the large hole. Nutrients and active ingredients need to be supplied to a site immediately before a horny layer, a transparent layer, an isolation layer, a stratum spinosum, and an underlying layer, and as a result, the microneedle needs to be mainly designed to be applied to epidermal tissue.
A length of the microneedle for impregnation of medicine is 600 μm or less, and the microneedle needs to be designed such that the active ingredient is supplied from a lower end of the underlying layer except for the horny layer, the transparent layer, the isolation layer, and the stratum spinosum, and as a result, the microneedle needs to be designed such that the active ingredient accurately exists to the end of the needle from a point spaced, by about 50 μm (0.1 mm), apart from an underlying portion of the microneedle and the active ingredient may be measured. This configuration may vary depending on an ingredient of medicine and a degree of obesity of a patient. At a portion of the conical hole where the active ingredient exists, similar to the microneedle for a cosmetic purpose, a diameter of a large hole is 30 to 80 μm, and a diameter of the end of the microneedle, which comes into contact with the skin, may be adjusted within a range of 10 to 70 μm. The mold 100 has various shapes modified as necessary.
The main feature of the present invention is that in the case of the microneedle used for a medicine purpose, the microneedle needs to be designed such that all active ingredients may be injected. In this production system, all of the holes 200 are related directly to an injection amount of active ingredients, such that a sufficient number of holes are manufactured to include a total amount of main ingredients, sub-ingredients, and solvents so that the holes are filled with a necessary amount of main ingredients, sub-ingredients, and solvents and the main ingredients and the sub-ingredients are solidified. In the case of the microneedle for a cosmetic purpose, since the active ingredient is applied to an overall length of the needle and skin care is important, the cosmetic needs to have a thickness equal to or smaller than a thickness of the needle, and the thickness and the length need to be maintained so that the time it takes for the cosmetic to melt is limited to at most 30 minutes so that there is no inconvenience within a zone of life.
In the case of the microneedle for a medicine purpose, the microneedle is required not to exceeds the aforementioned dimension so that the microneedle is free from the phobia to needles in a situation in which the maximum advantage of the microneedle is to overcome the phobia to needles, the overall time it takes for the medicine to melt needs to be adjusted to at most 30 minutes to several hours, and the microneedle needs to be designed so that a hypodermic injection effect occurs in stratum spinosum, conium, and subcutaneous tissue.
A melting speed may vary depending on mixtures or proportions of low molecular components and high molecular components of the hyaluronic acid and a cross-linking method.
The length and the thickness of the microneedle needs to be determined in sufficient consideration of a shrinking phenomenon that occurs during the solidification.
In the case of the microneedle according to the present invention for a biological or medicine product, a necessary amount of solution is injected first by using the stoppers 300. Then, the amount of solution, which is to be attached to the patch, is additionally injected. A method according to the present invention is as follows.
(1) As a method of filling the holes doubly, the solution containing the active ingredient is applied first, and then the portion to be attached to the patch is applied secondarily or multiple times. This method applies an accurate amount of solution such that the active ingredient is positioned at the end of the needle and the remaining solution is maintained in a sub-form, or the method additionally applies the solution to be attached to the pad in consideration of the amount of solution that shrinks.
(2) As a tube-in-tube filling method, the active ingredient enters a center.
In this case, the mold may be used regardless of whether the holes 200 penetrate the mold.
In the case in which the active ingredient is a cosmetically active ingredient, a length of the microneedle from the lower end of the underlying layer to the end of the needle is 50 to 270 μm, a diameter of the lower end of the underlying layer is 30 to 80 μm, a diameter of the end of the needle is 10 to 50 μm, and a cosmetically active ingredient, an excipient, and a patch attachment portion including a biocompatible polymer matrix may be sequentially applied from the end of the needle.
In addition, in the case in which the active ingredient is medicine, a length from the lower end of the underlying layer to the end of the needle is 600 μm or less, a diameter of the lower end of the underlying layer is 100 to 400 μm, a diameter of the end of the needle is 10 to 70 μm, and a pharmaceutically active ingredient, an excipient, and a patch attachment portion including a biocompatible polymer matrix may be sequentially applied from the end of the needle.
With this structure, the active ingredient may be injected to a maximally perfectly accurate position without pain.
After the filling, the microneedle according to the present invention may be solidified by blowing air at a temperature of 5 to 30° C. or blowing air at a temperature of 80° C. or more, or by rapid freeze drying.
A hole is formed in a portion (attachment portion) of the patch or the pad, on which the microneedle is placed to facilitate the solidification, and the hole allows a user to have an air blowing effect so that the microneedle is prevented from being deformed.
Solidification methods include, but not limited to, a method of blowing air by adjusting a temperature to 5 to 30° C. for a biological product, a method of blowing air at a temperature of 80° C. or more to a general chemical product, particularly, a product having no heat sensitivity, a solidification method using a temperature of 65 to 90° C. and a method simultaneously using air blowing or a combination of these two methods, and a method of maintain a significantly low moisture content through rapid freeze drying.
The application range of the microneedle according to the present invention corresponds to all of a patch type filler, a patch type botox, remicade and a biosimilar thereof, Enbrel and a biosimilar thereof, Humira and a biosimilar thereof, small molecule protein, for example, a biological protein product with a low capacity such as insulin, human growth hormone, parathyroid hormone (PTH), granulocyte colony-stimulating factor (GCSF), interferon A′R, and follicle-stimulating hormone (FSH). In addition, the application range also includes vaccine, antibiotics with a low capacity, anti-cancer drug, and chemical products.
Therefore, another aspect of the present invention relates to a cross-linked hyaluronic acid-based microneedle in which a length from the lower end of the underlying layer to the end of the needle is 600 μm or less, a diameter of the lower end of the underlying layer is 100 to 400 μm, a diameter of the end of the needle is 10 to 70 μm, and a cross-linked hyaluronic acid matrix, which contains a pharmaceutically active ingredient and an excipient and has a degree of cross-linking of 1 to 10%, is sequentially applied from the end of the needle.
In addition, still another aspect of the present invention relates to a cross-linked hyaluronic acid-based microneedle in which a length from the lower end of the underlying layer to the end of the needle is 50 to 270 μm, a diameter of the lower end of the underlying layer is 30 to 80 μm, a diameter of the end of the needle is 10 to 50 μm, and a cross-linked hyaluronic acid matrix, which contains a cosmetically active ingredient and an excipient and have a degree of cross-linking of 1 to 10%, is sequentially applied from the end of the needle.
The cross-linked hyaluronic acid-based microneedle means a microneedle using cross-linked hyaluronic acid. The degree of cross-linking of the cross-linked hyaluronic acid may be 1 to 10%, preferably, 3 to 6%, and productivity is excellent within this range. A cross-linking agent used to cross-link the cross-linked hyaluronic acid may be 1,2,7,8-diepoxyoctane, divinyl sulfone (DVS), glutaraldehyde, 1,4-butanediol diglycidyl ether (BDDE), vinyl sulfide, or polyethylene oxide. Particularly, BDDE is used, but the present invention is not limited thereto.
Hereinafter, the present invention will be described in more detail through Examples. The Examples are provided only to describe the present invention and may be selectively changed in accordance with substances or chemicals, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to the Examples.
Hyaluronic acid and a main ingredient (insulin) was inputted into a tank after measuring the hyaluronic acid and the main ingredient. The hyaluronic acid and the main ingredient were mixed until the entire solution became homogeneous such that the preparation was completed, and then the solution was inputted into a filling tank.
In accordance with the processes illustrated in
The needle was primarily packaged by blistering or thermal forming so that the needle was not lost, and the needle was secondarily packaged by using an aluminum pouch and a dehumidifying agent. The needle was finally packaged by using a carton box above the needle, and the package was completed by imparting a manufacturing number and a manufacturing date.
Hyaluronic acid was cross-linked by mixing and incubating the hyaluronic acid and a cross-linking agent In this case, the hyaluronic acid cross-linked by 3 to 5% was used. The process is performed aseptically. Patch type cross-linked hyaluronic acid (HA) (a substitute of a filler) and a main ingredient were inputted into a tank after measuring the patch type cross-linked hyaluronic acid and the main ingredient. The hyaluronic acid and the main ingredient were mixed until the entire solution became homogeneous such that the preparation was completed, and then the solution was transferred into a filling tank.
In accordance with the processes illustrated in
The needle was primarily packaged by blistering or thermal forming so that the needle was not lost, and the needle was secondarily packaged by using an aluminum pouch and a dehumidifying agent. The needle was finally packaged by using a carton box above the needle, and the package was completed by imparting a manufacturing number and a manufacturing date.
As illustrated in
Hyaluronic acid was cross-linked by mixing and incubating the hyaluronic acid and a cross-linking agent. In this case, the hyaluronic acid cross-linked by 3 to 5% was used. The process is performed aseptically. Patch type cross-linked hyaluronic acid (HA) (a substitute of a filler) and a cosmetically active ingredient (Group A: sterilized adenosine, copper peptide, hexapeptide, EGF, glyceryl glucoside (GG) propolis, dipotassium glycyrrhizate, glycyrrhiza extract, and allantoin; and Group B: sterilized adenosine, niacinamide, vitamin E acetate, vitamin C, propolis, dipotassium glycyrrhizate, glycyrrhiza extract, allantoin, and green tea extract) were inputted into a tank after measuring the patch type cross-linked hyaluronic acid and the cosmetically active ingredient. The hyaluronic acid and the main ingredient were mixed until the entire solution became homogeneous such that the preparation was completed, and then the solution was inputted into a filling tank.
A predetermined amount of the cross-linked hyaluronic acid solution, which was completely prepared according to the process illustrated in
The needle was primarily packaged by blistering or thermal forming so that the needle was not lost, and the needle was secondarily packaged by using an aluminum pouch and a dehumidifying agent. The needle was finally packaged by using a carton box above the needle, and the package was completed by imparting a manufacturing number and a manufacturing date.
Images of commercially available microneedles for a cosmetic purpose from Companies A, B, and C were captured by a microscope and compared with that of Example 2 of the present invention.
As illustrated in
In contrast, the microneedle in the related art never had a shape of the microneedle and did not have a diameter, hardness, and a length that may be used for a cosmetic purpose.
The end of the needle of the biocompatible polymer-based microneedle manufactured according to the present invention is sharp at a level of 25 to 30% in comparison with that of the needle in the related art, such that the needle is easily inserted into skin and penetrate deep into the skin, and since the needle is thinner than the microneedle in the related art, a patient feels less the microneedle when the microneedle is inserted into the skin, and the microneedle may accurately inject medicine to a target site without causing a degeneration or loss of the medicine. The microneedle in the related art cannot be manufactured aseptically, and it is difficult to accurately position the main ingredient only at a necessary site, and as a result, there is a limitation in using the microneedle in the related art for a medicine purpose.
In addition, it is possible to solve the problem of a phobia to needles and stiff and deformed muscle caused by the microneedle in the related art, and to solve the inconvenience to the patient who needs to go to the hospital for prescriptions and treatments, such that the patient may give himself/herself a treatment (injection) at the right time regardless of time and place, there is an effect in that a shock caused by a rapid injection may be minimized, and the microneedle is more simply manufactured in a short time in comparison with a method of manufacturing the microneedle in the related art.
Although the specific part of the present invention has been described in detail, it will be obvious to those skilled in the art that such a specific description is just a preferred embodiment and the scope of the present invention is not limited thereby. Accordingly, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10-2016-0015785 | Feb 2016 | KR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/KR2016/009330 | 8/23/2016 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2017/138682 | 8/17/2017 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 8088321 | Ferguson | Jan 2012 | B2 |
| 20080088066 | Ferguson | Apr 2008 | A1 |
| 20090326415 | Lim | Dec 2009 | A1 |
| 20130144217 | Ross | Jun 2013 | A1 |
| 20150141910 | Francis et al. | May 2015 | A1 |
| 20170080196 | Lee | Mar 2017 | A1 |
| 20170333691 | Kodama | Nov 2017 | A1 |
| 20200009767 | Li | Jan 2020 | A1 |
| Number | Date | Country |
|---|---|---|
| 1020100129958 | Dec 2010 | KR |
| 1020140051648 | May 2014 | KR |
| 1020140141360 | Dec 2014 | KR |
| 2007080427 | Jul 2007 | WO |
| 2015010599 | Jan 2015 | WO |
| Entry |
|---|
| International Search Report for PCT/KR2016/009330 dated Nov. 1, 2016. |
| Number | Date | Country | |
|---|---|---|---|
| 20190030309 A1 | Jan 2019 | US |
