KR102560152B1 - Microneedle for accelerating percutaneous absorption - Google Patents

Abstract

The present invention relates to a microneedle in which the stability of an active ingredient is improved and the percutaneous absorption rate of the active ingredient is improved at the same time. Such effects can be achieved by containing the active ingredient in a specific liquid crystal and including it in the microneedle. The liquid crystal of the present invention does not lose its intended effect during the manufacturing process of the microneedle, and can achieve the objectives of improving the stability and transdermal absorption of the active ingredient even when administered in a form present inside the microneedle.

Description

Microneedle for accelerating percutaneous absorption}

The present invention relates to a technology capable of increasing the stability of an active ingredient included in a microneedle and administered to the skin. In particular, the present invention relates to a microneedle application technology that does not affect the percutaneous penetration rate of an active ingredient in the microneedle even when used simultaneously with the microneedle technology, and that secures its stability during the manufacturing process of the microneedle. More preferably, the present invention relates to a technology capable of improving the stability of an active ingredient contained in a microneedle and simultaneously increasing the speed of transdermal administration of the active ingredient.

The microneedle is a promising technology for the absorption of active ingredients that are difficult to absorb through the skin without skin invasion. It is less painful than conventional injections and can significantly increase the absorption of active ingredients that are difficult to absorb into the skin compared to external compositions such as conventional creams and lotions.

Administration of various active ingredients has been attempted to these microneedles, but there are many limitations in developing them into actual products. For example, the manufacturing process of the microneedle is often accompanied by a warming process, and physical forces such as centrifugation and vacuum are also applied to this, which affects the stability of many components included in the microneedle, including the active ingredient.

Meanwhile, many active ingredients are unstable in temperature, light, heat, moisture, additives, excipients, etc., and various studies are being conducted to stabilize these active ingredients. For example, techniques such as chemically binding a derivative to an active ingredient to prepare a more stable derivative or encapsulating the active ingredient to protect it from external stimuli have been applied. In the case of this stabilization technology, the original degree of absorption of the active ingredient in the body is changed, and in general, it also inhibits the transdermal administration of the active ingredient. For example, when an active ingredient is encapsulated to protect it or derivatized to increase solubility, the transdermal administration speed may be slowed down.

Therefore, it is practically difficult to maintain or improve absorption in the body while improving stability.

Republic of Korea Patent Registration No. 10-0793615 (2008. 1. 10. Notice) International Patent Application Publication WO 02/064193 (published on August 22, 2002)

Therefore, an object to be solved by the present invention is to provide a microneedle-related technology capable of improving the stability of the active ingredient included in the microneedle, at the same time not being affected by various harsh conditions applied during the manufacturing process of the microneedle, and maintaining or improving the skin penetration rate of the active ingredient.

In order to solve the above problems, the present invention provides a microneedle for accelerating absorption of an active ingredient, characterized in that the active ingredient is contained in a liquid crystal and contained in the microneedle. More preferably, the present invention provides a microneedle for promoting absorption of an active ingredient, characterized in that the active ingredient is included in a liquid crystal containing a lipid component and contained in the microneedle.

The present invention also provides a patch for delivering a drug or cosmetic active ingredient comprising such a microneedle.

While carrying out various studies, the present inventors included the active ingredient in a liquid crystal containing a lipid component, more preferably a liquid crystal made of a mixture of ceramide, cholesterol, surfactant, higher alcohol, oil and polyol, and impregnating the microneedle to improve the percutaneous penetration rate of the active ingredient and also dramatically improve the stability of the active ingredient. The present invention was completed by confirming that the above objects are efficiently achieved even when administered in a form present in a needle.

That is, the liquid crystal gel composed of the active ingredient according to the present invention, that is, the lipid component containing the functional active ingredient, is impregnated into the needle and applied to the skin, so that the microneedle penetrates into the skin without pain, and the microneedle is decomposed by moisture in the skin. Or, while dissolving, the liquid crystal containing the functional active ingredient can be delivered into the skin.

In the present invention, "liquid crystal" is generally an intermediate state between a solid and a liquid, and it usually refers to a system in which organic molecules having both a hydrophilic part and a lipophilic part are regularly arranged with each other to form a lamellar structure consisting of several layers.

Preferably, the active ingredient that can be used in the present invention is vitamin C or its derivatives (eg, magnesium ascorbyl phosphate, ascorbyl glucoside, sodium ascorbyl phosphate, aminopropyl ascorbyl phosphate, 3-o-ethoxy-ascorbic acid), niacinamide, retinol or retinol derivatives (eg, retinyl acetate, retinyl palmitate), arbutin, adenosine. , kojic acid, caffeine, white chive oil, diosmetin, macerignan, asiaticoside, polydatin, ginsenoside, prangenidine, hydroxyproline, etc., but these ingredients are preferred active ingredients and the present invention is not limited to these active ingredients.

The length of the microneedle according to the present invention is not limited to a specific size. However, for the purpose of the present invention, the upper and lower length of the microneedle is preferably 0.05 mm to 2.5 mm, more preferably 0.1 mm to 2 mm.

In order to achieve the desired effect of the present invention, the material forming the microneedle is dissolved in the skin, and when the microneedle is applied to the skin, the microneedle is dissolved or collapsed, thereby releasing the liquid crystal containing the active ingredient contained in the microneedle.

The microneedle according to the present invention may be manufactured using materials and manufacturing methods described in, for example, Korean Patent Registration No. 10-0793615, International Patent Application Publication No. WO 02/064193, and Korean Patent Publication No. 10-2011-0065361.

More specifically, for the transdermal administration of the liquid crystal according to the present invention, the microneedle is preferably made of a material that dissolves in the skin, and such ingredients include hyaluronic acid, sodium carboxymethyl cellulose, vinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, saccharide or these A mixture of may be used. As the sugar, xylose, sucrose, maltose, lactose, trehalose, or a mixture thereof may be used.

Among these microneedle-forming materials, considering comprehensively the skin penetration intensity of the microneedle, the dissolution rate in the skin, and in particular, the stability of the liquid crystal according to the present invention and the compatibility with the liquid crystal according to the present invention, etc., a mixture of hyaluronic acid, sodium carboxymethyl cellulose, and sugar is preferable, and in this mixture, the sugar is even more preferably trehalose.

In the present invention, the active ingredient may be included in an amount of 0.01 to 10% by weight, preferably 0.05 to 8% by weight, and more preferably 0.1 to 5% by weight, based on the total weight of the microneedle. When included in less than 0.01% by weight, an effective effect may not be exhibited, and when included in more than 10% by weight, physical properties and durability of the microneedle may be affected, which is undesirable.

Preferably, the microneedle according to the present invention may further include a plasticizer, a surfactant, a preservative, an anti-inflammatory agent, and the like, in addition to the above-mentioned material for forming the structure of the microneedle.

As such a plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin may be used alone or in combination. In particular, as a result of various evaluations in terms of stability of the liquid crystal according to the present invention and compatibility with the liquid crystal used in the present invention, glycerin was more preferable.

The liquid crystal according to the present invention preferably contains a lipid component, and more preferably is prepared using ceramide, cholesterol, surfactant, higher alcohol, oil and polyol.

As the lipid component for preparing the liquid crystal according to the present invention, ceramide, cholesterol, sphingosine, cholesterol ester, higher fatty acid, or a mixture thereof may be used, and ceramide is particularly preferred for the purpose of the present invention.

As the surfactant for preparing the liquid crystal according to the present invention, a nonionic surfactant is preferable, and is not particularly limited as long as it can be used in a conventional cosmetic composition. For example, alkyl glucosides; sorbitan fatty acid esters (sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, penta-2-ethylhexyl acid diglycerol sorbitan, tetra-2-ethylhexy acid diglycerol sorbitan, etc.); glycerol polyglycerin fatty acids (mono-cottonseed oil fatty acid glycerin, monoerucate glycerin, sesquioleate glycerin, monostearate glycerin, α,α'-oleate pyroglutamic acid glycerin, monostearate glycerin malic acid, etc.); POE-sorbitan fatty acid esters (POE-sorbitan monooleate, POE-sorbitan monostearate, POE-sorbitan tetraoleate, etc.); POE-sorbitic fatty acid esters (POE-sorbit monolaurate, POE-sorbit monooleate, POE-sorbit pentaoleate, POE-sorbit monostearate, etc.); POE-glycerin fatty acid esters (POE-glycerin monostearate, POE-glycerin monoisostearate, POE-glycerin triisostearate, etc.); POE-fatty acid esters (POE distearate, POE-monodioleate, ethylene glycol distearate, etc.); POE-alkyl ethers (POE-lauryl ether, POE-oleyl ether, POE-stearyl ether, POE-behenyl ether, POE-2-octyldodecyl ether, POE-cholestanol ether, etc.) may be used alone or in combination, and in particular, alkyl glucosides are more preferable for the purpose of the present invention.

As the higher alcohol for preparing the liquid crystal according to the present invention, an alcohol having 12 to 22 carbon atoms or a mixture thereof may be used, and in particular, a higher alcohol having 16 to 20 carbon atoms is more preferable for the purpose of the present invention.

The type of the oil for preparing the liquid crystal according to the present invention is not particularly limited, and conventional oil used in cosmetic compositions may be used. Specifically, hydrocarbon-based oils such as squalane and mineral oil; Caprylic/Capric Triglyceride, Neopentyl Glycol Dicaprate, 2-Octyldodecyl Myristate, Isopropyl Myristate, Iso-Cetylethylhexanoate, Pentaerythrityl Tetraethylhexanoate, Butylene Glycol Dicaprylate Caprate, Hexylaurate, Distearyl Maleate, Cetyl 2-Ethylhexanoate, Octyldodecanol, Glyceryl Triglyceride ester oils such as ethyl hexanoate; vegetable oils such as olive oil, avocado oil, jojoba oil, and macadamia oil; animal oils such as lanolin; Silicone oils such as dimethylpolysiloxane, methylphenylpolysiloxane, decamethylcyclopentasiloxane, methyl trimethicone, phenyl trimethicone, cyclomethicone, and dimethicone may be used alone or in combination.

Glycerin, methylgluceth-20, butylene glycol, propylene glycol, dipropylene glycol, pentylene glycol, hexylene glycol, polyethylene glycol, sorbitol, or mixtures thereof may be used as the polyol for preparing the liquid crystal according to the present invention, and in particular, glycerin and methylgluceth-20 are more preferred for the purpose of the present invention.

In the liquid crystal containing the active ingredient according to the present invention, the liquid crystal preferably contains 0.01 to 30% by weight of the active ingredient and 0.01 to 15% by weight of the lipid component, based on the total weight of the liquid crystal. More preferably, it contains 0% by weight and the balance of polyol.

The present invention provides not only the microneedle itself containing the liquid crystal containing the active ingredient, but also the microneedle patch to which a plurality of such microneedles are attached. The size of the patch is not limited to a specific size, and may be appropriately adjusted according to the amount of the active ingredient to be absorbed into the skin or the attachment site.

The present invention also provides a method for administering an active ingredient, characterized in that the microneedle containing the active ingredient according to the present invention is applied to the skin. For example, as a method of applying or using such a microneedle, a microneedle device such as a roller to which the microneedle is attached according to the present invention is used to form a certain number of holes in the skin while dissolving microneedles in the skin. It can be used as a method of remaining in the skin.

When the microneedle technology according to the present invention is used, the stability of the active ingredient can be improved and the speed of transdermal administration of the active ingredient can be improved at the same time.

In addition, when the microneedle technology of the present invention is used, even in the case of active ingredients that are difficult to absorb percutaneously, the active ingredients that are not easily absorbed can be delivered to the body through the skin by containing these active ingredients in liquid crystal and passing them through the skin.

The following drawings attached to this specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention together with the contents of the above-described invention, so that the present invention is limited to those described in the drawings. It should not be construed.
1 is a view showing one example of several methods for manufacturing a microneedle according to the present invention. The soluble microneedle may be manufactured by a solution casting method, and may be manufactured by casting a solution in which the microneedle forming material is dissolved in a mold, filling the mold with the liquid by vacuum and/or centrifugation, and then drying. As the material forming the microneedle structure, various materials well known to those skilled in the art may be used, and general biocompatible synthetic polymers, natural water-soluble polymers, and the like may be used.
2 shows a Franz diffusion cell for evaluating the vitamin C release behavior of the microneedle according to the present invention.
3 is an experimental result showing the degree of skin penetration with time in Comparative Examples 2 and 3 for comparing the degree of skin penetration of the microneedle according to Example 1 according to the present invention and the present invention.

Hereinafter, examples and the like will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

<Production of liquid crystal gel base>

They were mixed according to the raw materials and compositions shown in Table 1 below, dissolved by heating at 85 to 90 °C, and then cooled. This was stirred at 70 to 75 ° C. with a homomixer at 5000 rpm, and then cooled to room temperature to prepare a liquid crystal gel base.

raw material name Content (unit: % by weight) C14-22 alcohol 10 C12-20 Alkylglucoside 2 squalane 10 Caprylic/Capric Triglyceride 5 Ceramide 3 5 cholesterol 2 glycerin TO 100 vitamin C 20

<Manufacture of soluble microneedle>

Soluble microneedles were prepared by a solution casting method (see FIG. 1). A preparation solution for making microneedles was cast into a mold, filled with a solution in a micro-mold by vacuum and/or centrifugal separation, and then dried. As a material for forming the microneedle structure, synthetic and/or natural water-soluble polymers commonly known in the field to which the present invention pertains were used.

<Manufacture of microneedle impregnated with vitamin C>

Example 1: Preparation of soluble microneedle impregnated with liquid crystal gel containing vitamin C

According to Table 2 below, microneedles in which vitamin C was included in the liquid crystal gel and the liquid crystal gel was dispersed in the soluble microneedles were prepared. After dissolving oligo-HA (hyaluronic acid), Na-CMC (sodium carboxymethyl cellulose), and trehalose in purified water, glycerin and liquid crystal gel were added to prepare an emulsion solution. After casting the prepared emulsion solution in a silicon microneedle mold, centrifugation was performed at 3000 rpm for 10 minutes to fill the micro-mold with the liquid. After filling the solution, it was dried in a drying oven (70° C.) for 3 hours, and the microneedle was separated from the silicon mold using an adhesive film.

Comparative Example 1: Preparation of soluble microneedle impregnated with vitamin C

According to Table 2 below, microneedles in which vitamin C itself was dispersed in soluble microneedles were prepared. Oligo-HA (hyaluronic acid), Na-CMC (sodium carboxymethyl cellulose), and Trehalos were dissolved in purified water, and then glycerin, HCO-40, and ascorbic acid were added to prepare a solution. After casting the prepared solution in a silicon microneedle mold, centrifugation was performed at 3000 rpm for 10 minutes to fill the micro-mold with the liquid. After filling the solution, it was dried in a drying oven (70° C.) for 3 hours, and the microneedle was separated from the silicon mold using an adhesive film.

Unit: % by weight Example 1 Comparative Example 1 oligo-HA 6 6 Na-CMC 6 6 Trehalose 10 10 Glycerin 5 8 HCO-40 - 0.2 liquid crystal gel base 5 - vitamin C One water To 100 To 100

<Manufacture of liquid crystal gel-containing cream>

Comparative Example 2: Preparation of cream containing vitamin C

A conventional cream formulation containing a liquid crystal gel as shown in Table 3 was prepared by a method well known to those skilled in the art and used as Comparative Example 2 of the present invention. That is, in order to compare the skin permeation amount of the vitamin C-containing liquid crystal gel impregnated into the microneedle, the liquid crystal gel was applied to a general oil-in-water cream and compared.

As shown in Table 3 below, raw materials 1 to 5 and raw materials 6 to 12 of Table 3 were heated and dissolved at 70 to 75 ° C., stirred at 5500 rpm with a homomixer, cooled, and then added with raw material 13 at a temperature of 55 ° C. After stirring with a homomixer at 5500 rpm, it was cooled to room temperature to prepare a liquid crystal gel-containing cream formulation.

Raw material name (unit: % by weight) Comparative Example 2 One C14-22 alcohol 5.0 2 C12-20 Alkylglucoside 0.8 3 Glyceryl Stearate One 4 squalane 5 5 Cyclohexasiloxane 3 6 Purified water To 100 7 glycerin 10 8 Methylgluses-20 5 9 1,2-hexanediol 2 10 carbomer Appropriate amount 11 xanthan gum 0.2 12 tromethamine Appropriate amount 13 liquid crystal gel 15

Experimental Example 1: Drug release behavior (FIG. 3)

Using a Franz diffusion cell, the vitamin C content of porcine skin tissue and acceptor solution over time was measured using an ELISA kit. Example 1 or Comparative Example 1 was attached to pig skin, or Comparative Example 2 was applied to compare the skin permeation amount of vitamin C over time.

Comparative Example 2 (vitamin C-containing cream) had an insignificant amount of about 1.5 μg or less permeating through the skin, but Example 1 and Comparative Example 1 impregnated with microneedles had about 18 μg permeation, which was about 10 times higher than that of cream. In particular, in the case of Example 1 impregnated with the liquid crystal gel, the amount of active ingredient permeation over time was improved compared to Comparative Example 1 containing the active ingredient as it was. From these results, it was confirmed that the skin penetration rate of the active ingredient can also be improved using the technique according to the present invention.

Experimental Example 2: Measurement of stability over time

Example 1 and Comparative Examples 1 and 2 were stored at 0 ° C, room temperature, and 40 ° C constant temperature conditions for 4 weeks to confirm the vitamin C content of the sample. The results are shown in Table 4.

As can be seen from the results of Table 4 below, Example 1 in which the liquid crystal gel was impregnated with the active ingredient showed better results in terms of stability than Comparative Examples 1 and 2.

division Content after 30 days room temperature 40℃ 0℃ Example 1 100% 95% 100% Comparative Example 1 95% 70% 96% Comparative Example 2 70% 50% 90%

Claims (5)

In the soluble microneedle in the skin containing an active ingredient,
The active ingredient is a microneedle for transdermal administration of an active ingredient, characterized in that contained in a liquid crystal (liquid crystal) containing ceramide as a lipid component and contained in the microneedle. The active ingredient according to claim 1, wherein the active ingredient is vitamin C, magnesium ascorbyl phosphate, ascorbyl glucoside, sodium ascorbyl phosphate, aminopropyl ascorbyl phosphate, 3-o-ethoxy-ascorbic acid, niacinnamide, retinol, retinyl acetate, retinyl palmitate, arbutin, adenosine, kojic acid, caffeine, white extract oil, diosmetin, mayslignan , Asiaticoside, polydatin, ginsenoside, prangenidine, hydroxyproline, or a microneedle, characterized in that a mixture thereof. delete The microneedle according to claim 1, wherein the liquid crystal is made of a mixture of ceramide, surfactant, higher alcohol, cholesterol, oil and polyol. A patch containing the microneedle of any one of claims 1, 2, and 4.