KR20170046043A - Soluble microneedle patch for delivery of anti-leukoplakia drug - Google Patents

Soluble microneedle patch for delivery of anti-leukoplakia drug Download PDF

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Publication number
KR20170046043A
KR20170046043A KR1020150166661A KR20150166661A KR20170046043A KR 20170046043 A KR20170046043 A KR 20170046043A KR 1020150166661 A KR1020150166661 A KR 1020150166661A KR 20150166661 A KR20150166661 A KR 20150166661A KR 20170046043 A KR20170046043 A KR 20170046043A
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KR
South Korea
Prior art keywords
skin
vitiligo
microneedles
treatment
microneedle
Prior art date
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KR1020150166661A
Other languages
Korean (ko)
Inventor
이선화
심우선
황영민
강내규
Original Assignee
주식회사 엘지생활건강
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Publication of KR20170046043A publication Critical patent/KR20170046043A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • 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

Abstract

The present invention relates to a skin administration system of a therapeutic agent for leukoplakia, which can show an excellent effect by stably impregnating a therapeutic agent for leukoplakia and effectively transferring the same into skin and, more specifically, to a microneedle comprising a therapeutic agent for leukoplakia.

Description

Soluble microneedle patch for delivery of anti-leukocyte treatment for anti-leukoplakia drug

The present invention relates to a microneedle and a microneedle patch.

In general, microneedle is used for delivery of an active substance such as a drug in vivo, detection of an analyte in the body, and biopsy. The delivery of the pharmacologically or cosmetically active ingredient using microneedles is intended for the delivery of the active substance through the skin, not the vascular system such as blood vessels or lymphatic vessels.

Examples of the method using the microneedle include a method of forming a predetermined number of holes or more on the skin using a microneedle device such as a roller with a microneedle attached thereto, (Active ingredient) is coated on the skin to allow the active ingredient to be administered simultaneously with the perforation of the skin.

On the other hand, leukoplakia (vitiligo) is a kind of pigment deficiency skin disease and has a prevalence rate of 0.5 ~ 2% of the world population. Vitiligo occurs in one or two parts of the body, or in a wide range of areas, with white spots where the skin appears white due to a decrease in melanin pigment, and the range varies from patient to patient. The melanin cells that synthesize the melanin pigment are destroyed and are caused, and the exact cause of it is unknown.

Photochemotherapy, which is mainly used for the treatment of vitiligo, is a method of eating ultraviolet rays by applying oral methoxsalen, or applying methosalone ointment. Methoxalenes are not well soluble in water and are difficult to penetrate into general cosmetics or ointment formulations and are difficult to penetrate through the skin, making it difficult to absorb methoxsalen components and to see their effects.

Thus, there is a need for a new method that can be used to overcome the limitations of efficacious substance delivery due to skin barrier and improve skin permeation efficiency, in the application of a treatment for vitiligo, especially for treatment of vitiligo such as methoxsalen with low solubility.

Korean Patent Publication No. 10-2014-0125364

A problem to be solved by the present invention is to provide a system for stably immersing a therapeutic agent for vitiligo in a soluble micro-needle and delivering a therapeutic agent for vitiligo effectively into the skin, and a method for producing such a system.

Accordingly, the present invention provides a soluble micro-needle comprising a treatment for alleviating vitiligo.

The present invention also provides a microneedle patch comprising the microneedles.

In addition, the present invention provides a method for producing a microneedle comprising a therapeutic agent for leukoplakia.

In order to solve the above problems, the present invention provides a dissolvable micro-needle including a treatment for vitiligo, and more preferably, the material forming the micro-needle is dissolved in the skin, and when the skin of the micro- The collagen is released into the skin.

The inventors of the present invention have found that, in addition to the fact that the treatment of vitiligo can be effectively delivered into the skin by impregnating a therapeutic agent for vitiligo in a soluble micro-needle after a long period of research, it is not easy to control the dosage in the case of conventional ointment or cream formulations, And thus it is difficult to incorporate them into general cosmetics and / or ointment formulations. Thus, the present invention has been completed.

As used herein, the term "treatment for treating vitiligo" includes all substances and / or products used for treatment of vitiligo, and is not limited to any substance and / or product exhibiting a treatment for treating vitiligo. Therefore, it can be used for oral administration, skin application, etc., and is not limited to any substance used for drugs and / or photochemotherapy, and preferably a substance or product used for photochemotherapy can be used.

Examples of the treatment of vitiligo which can be used in the present invention include methoxsalen, protopic / alldel, clobetasol, betamethasone, fluocinonide, Dovonex ), V-tar, and caustic catalase.

Particularly, methoxsalen is used in the present invention, and methoxsalene can be preferably used because it has a remarkable effect.

The present inventors have studied various administration systems and do not resemble the method in which any system is impregnated with the soluble micro-needle of the above-mentioned treatment of vitiligo. The inventors of the present invention have surprisingly invented that, after various efforts, the present inventors impregnated a micro-needle with a therapeutic agent for alleviating sebum, solved the skin permeability problem of a low-solubility antiglaucoma treatment agent and confirmed a remarkable effect without side effects. In addition, the use of the microneedles according to the present invention enables non-skilled individuals to easily apply the therapeutic agent for vitiligo without side effects in a non-invasive manner, and can deliver all the therapeutic agents for vitiligo to the transdermal system. Therefore, Excellent effect can be exhibited.

As used herein, the term "impregnation" may refer to a form in which a treatment for vitiligo can be contained in a microneedle, preferably i) a solution containing a therapeutic agent for vitiligo together with a solubilizing substance which forms a microneedle Or ii) a micro-needle may be punctured to contain a treatment for vitiligo in the pore. When the microneedles are prepared in the form of i) and ii), the treatment of vitiligo can effectively penetrate into the skin, and in particular, when microneedles are produced in the form of i), the low solubility and / or transdermal permeability The problem can be solved at its source.

Therefore, it is most preferable that the material forming the microneedles is dissolved in the living body so that the treatment for treating vitiligo contained in the microneedles is effectively released into the skin.

In a preferred embodiment of the present invention, the material forming the microneedles dissolves in the skin, and when the microneedles are applied to the skin, the microneedles are dissolved or collapsed to effectively penetrate the skin treatment agent contained in the microneedles into the skin Since the microneedles contain a soluble polymer, it is possible to reduce the number of applications and to maximize the effect of the treatment of vitiligo because the effect of the treatment of the vitiligo can be sustained for a long time by releasing a small amount of the treatment for vitiligo in the skin. In particular, the microneedles may contain a sustained-release polymer in order to release a small amount of the antileukemic agent in the skin. The sustained-release polymer may include, but is not limited to, poly (lactide), poly (glycolide), poly (lactide-co-glycolide), polyanhydride, polyorthoester, polyetherester , Biodegradable polymers such as polycaprolactone, polyester amide, poly (butyric acid), poly (valeric acid), polyurethane and copolymers thereof. Particularly, the release behavior can be controlled by changing the decomposition rate of the polymer according to the control of the fraction or the molecular weight of the copolymer material during the copolymerization.

In the present invention, the microneedles are preferably soluble in the skin. For example, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), or the like may be used to form a soluble microneedle. , Water-soluble polymers such as vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, and polyvinyl pyrrolidone; Sugars such as Xylose, Sucrose, Maltose, Lactose and Trehalose; Or a mixture thereof may be used. Considering the skin penetration strength of the micro-needle and the dissolution rate in the skin in general, it is preferable to use hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), and saccharide (Trehalose) is preferable, and it is more preferable to mix glycerin.

Preferably, the microneedles of the present invention may further include plasticizers, surfactants, preservatives, anti-inflammatory agents, etc. in addition to the above-mentioned components for forming microneedles.

Examples of the plasticizer include polyols such as ethylene glycol, propylene glycol, dipropylene glycols, butylene glycol, and glycerin. Or may be used in combination.

The length of the microneedles according to the present invention is not limited to a specific size.

In the present invention, the treatment for treating vitiligo can be 0.001 to 10% by weight, preferably 0.01 to 5% by weight, more preferably 0.1 to 3% by weight based on the total weight of the micro needle. If it is contained in an amount of less than 0.001% by weight, it may not exhibit an effective effect, and if it is contained in an amount exceeding 10% by weight, the physical properties and durability of the fine needle may be affected.

When the microneedles according to the present invention are applied to the skin, the skin permeation amount can be remarkably improved as compared with the conventional skin administration systems.

The present invention also provides a microneedle patch comprising the microneedles, that is, a microneedle patch for administration (or delivery) of a treatment with a lyophilized drug to which the microneedle is attached.

In the present invention, the patch may mean a sheet prepared by attaching one or more micro-needles impregnated with the anti-vitals treatment agent of the present invention and attaching the micro-needle-attached surface to the skin. The size of the sheet is not limited to a specific size, but can be appropriately adjusted depending on the amount or the attachment site of the treatment for treating vitiligo to be absorbed into the skin. In addition, one or more, preferably a plurality of micro-needles may be attached to the surface of the sheet which can be attached to the skin.

In addition, it is also possible to add a therapeutic agent for vitiligo to the surface of the patch which can be attached to the skin, so that the therapeutic agent for vitiligo can penetrate into the hole formed by the micro-needle. In order to achieve a superior skin administration effect, .

The present invention also relates to a method for preparing a microcapsule, comprising the steps of: S1) filling a mold with a substance for forming micro-needles including a treatment for vitiligo and a solubility material in a skin; And S2) heating the mold, drying and then separating the mold, and a method for producing a microneedle comprising the treatment for alleviating leukoplakia.

The above method can be prepared by impregnating a micro-needle with a therapeutic agent for vitiligo, and the impregnation preferably includes, but is not limited to, i) a treatment for vitiligo together with a skin-soluble substance forming a micro needle, ii) A hole in the needle to contain a treatment for leprosy in the hole, and the like.

In the present invention, in order to impregnate a treatment agent for vitiligo with a micro-needle, a substance for forming a micro-needle and a treatment for vitiligo are mixed together and filled into a mold for microneedle formation, Needles can be made.

In the present invention, the in-skin solubility material may include, for example, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol vinyl alcohol, and polyvinyl pyrrolidone; Sugars such as Xylose, Sucrose, Maltose, Lactose and Trehalose; Or a mixture thereof may be used.

The present invention provides a method of manufacturing a system for treating vitiligo which can exhibit excellent effects through effective skin delivery of a treatment for vitiligo.

BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate exemplary embodiments of the invention and, together with the description of the invention, Should not be construed as limited.
FIG. 1 is a view showing one example of various methods for manufacturing a microneedle according to the present invention.
FIG. 2 shows a Franz diffusion cell for evaluating the drug release behavior of the microneedles according to the present invention.
FIG. 3 is a graph showing the skin permeation amount of a treatment for the treatment of vitiligo (methoxsalen) in Example 1 and Comparative Example 1. FIG.

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

≪ Preparation of soluble fine needle >

Soluble microneedles are prepared by solution casting method, and they are prepared by casting solution into mold, filling solution into micro mold by vacuum or centrifugation and drying.

Conventional synthetic and natural water-soluble polymers were used for the materials forming the microneedle structure.

<Preparation of Methoxsalen-containing Soluble Fine Needles (Example 1)>

ingredient Example 1
(Unit: wt%) oligo-HA 6 Na-CMC 6 Trehalose 10 Glycerin 4 Dipropylene glycol 2.7 PEG-40 Hydrogenated Chain Oil One Methoxsalen 0.3 water To 100

Oligo-HA TM (Hyaluronic acid) , Na-CMC (Sodium carboxymethyl cellulose) and then the dissolved in purified water trehalose (Trehalose), glycerin (Glycerin), PEG-40 dihydro jeneyi suited Kester five days (HCO-40 TM) and Methoxsalen solution (Methoxsalen 10%, dipropylene glycol 90%) was added to prepare a microneedle solution in which Methoxsalen was dispersed. The prepared Methoxsalen dispersion solution was cast in a silicon microneedle mold and then centrifuged at 3000 rpm for 10 minutes to fill the micro mold with the solution. After the solution was filled, it was dried in a drying oven (70 ° C) for 3 hours, and the fine needle was separated from the silicone mold using an adhesive film (Example 1).

&Lt; Preparation of methoxsalen-containing cream (Comparative Example 1) >

ingredient Comparative Example 1
(Unit: wt%) C14-22 alcohol, C12-20 alkyl glucoside
(Mixture C14-22 alcohol: C12-20 alkyl glucoside = 80:20 weight ratio) 1.5 Glyceryl stearate, phage-100 stearate
(Mixture 50:50 weight ratio) 1.2 Glyceryl stearate 0.9 Cetearyl alcohol 1.5 Polyglyceryl-3 methyl glucoside distearate 1.5 Hydrogenated polydecene 4.5 Cyclohexasiloxane 3.5 Carbomer 0.2 Tromethamine 0.2 glycerin 3 Dipropylene glycol 5 1,2-hexanediol 2 Methoxsalen One Purified water To 100

In order to compare the effect of the active ingredient applied to the active ingredient impregnated with the microneedle and the cream of the underwater emulsifier type, a cream containing methoxsalen was prepared with the composition shown in Table 2 (Comparative Example 1).

<Experimental Example 1>

Drug release behavior

The present inventors measured the methoxsalen content of the pig skin tissue and the acceptor solution with Franz diffusion cell using time-lapse chromatography (Liquid Chromatography). Example 1 was applied to pig skin and Comparative Example 1 was applied to penetrate into pig skin and dissolve, followed by removal of fine needle and cream.

Pig skin absorbed with Methoxsalen by Example 1 and Comparative Example 1 was placed in a franz diffusion cell (Fig. 2), and skin permeation amount of methoxsalen was compared with time.

As a result, as shown in FIG. 3, the amount of permeation through the skin of Comparative Example 1 was as low as about 1.4 μg, but methoxsalen impregnated with the fine needle was directly penetrated to the skin by the needle, The amount of permeation was about 21 μg or more, which was about 15 times higher than that of cream.

Claims (9)

Soluble microneedles containing a treatment for vitiligo. The method according to claim 1,
Wherein the material forming the microneedle is dissolved in the skin. 3. The method of claim 2,
The microneedle forming material may be selected from the group consisting of hyaluronic acid, sodium-carboxymethylcellulose, sodium carboxymethyl cellulose (Na-CMC), vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol Poly vinyl alcohol, polyvinyl pyrrolidone, saccharides, or a mixture of two or more thereof. The method of claim 3,
Wherein the microneedles further comprise a plasticizer in addition to the material forming the microneedles. The method according to claim 1,
Wherein the leukocyte therapeutic agent is methoxsalen. The method according to claim 1,
Wherein the leukodystrophy agent is contained in an amount of 0.001 to 10% by weight based on the total weight of the microneedles. The method according to claim 1,
Wherein the microneedles improve the skin permeation amount of a treatment for treating vitiligo. A microneedle patch comprising a microneedle according to any one of claims 1 to 7. S1) filling a mold with a substance for forming fine needle including a treatment for vitiligo and an intracutaneous solubility material; And
S2) warming the mold, drying and then separating the mold.
KR1020150166661A 2015-10-20 2015-11-26 Soluble microneedle patch for delivery of anti-leukoplakia drug KR20170046043A (en)

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KR1020150146103 2015-10-20
KR20150146103 2015-10-20

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