A composition for manufacturing microneedles containing cyclodextrin for retinol stabilization, and microneedles manufactured with such a composition.

Abstract

The present invention relates to retinol-loaded microneedles. The retinol-loaded microneedles according to the present invention contain retinol and a stabilizer, which are the optimal combination for use in microneedles to address the instability of retinol. As a result, the retinol-loaded microneedles according to the present invention achieve high skin delivery efficiency, which is unique to microneedle formulations, and maximize the wrinkle-reducing effects of retinol.

Description

Technical Field

[0001] The present invention relates to a method for stabilizing retinol for application to a micron needle dosage form, and more particularly, to a composition for producing a micron needle containing cyclodextrin for retinol stabilization, and a micron needle produced with such a composition.

Background Art

[0002] Retinol is known to have the efficacy of promoting the differentiation of skin cells, promoting the biosynthesis of collagen and elastin that affect wrinkles, reducing wrinkles, and increasing skin elasticity (see the literature [Reza Kafi, MD; Heh Shin R. Kwak, MD; Wendy E. Schumacher, BS; et al. Arch Dermatol. 2007; 143(5): 606-612]). However, since retinol has a structure with a double bond, it is easily oxidized to form free radicals, or when exposed to ultraviolet rays, it becomes unstable and is converted from the trans form to the cis form (see the literature [Int. J. Environ. Res. Public Health 2005, 2(1), 147-155]). If retinol is oxidized by the influence of the external environment to form free radicals or is converted to an unstable cis form, not only can it not exert the effects such as wrinkle improvement inherent to retinol, but there is also a problem that it may rather have an adverse effect on the skin.

[0003] Thus, although the effects such as wrinkle improvement are certain, retinol is extremely unstable, and it is difficult to develop a technology for stabilizing it, and the number of successful commercializations is still small.

[0004] On the other hand, microneedles are attracting attention as an active ingredient delivery system that combines the efficacy of existing syringes with the convenience of patches, and can directly deliver active ingredients into the skin through the stratum corneum, which is the skin barrier layer. When retinol is incorporated into microneedles, its delivery efficiency can be greatly improved, and if the stability of the incorporated retinol is ensured, it is expected to exhibit even better efficacy than currently available emulsion-type retinol products such as oil-in-water and water-in-oil.

[0005] Therefore, there is a need for a dosage form that can improve the stability of retinol when manufactured in a microneedle form. [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, the present inventors made diligent efforts to develop microneedles and stabilizing formulations that can improve the stability of retinol. As a result, they confirmed that when cyclodextrin is used as a stabilizer, microneedles with greatly improved retinol stability can be obtained, and thus completed the present invention. [Means for solving the problem]

[0007] To achieve the above-mentioned objectives, one aspect of the present invention provides a composition for manufacturing microneedles, comprising retinol or its derivatives, cyclodextrin, and a biodegradable solidifying substance.

[0008] Another aspect of the present invention is to provide soluble microneedles manufactured using the composition.

[0009] Another aspect of the present invention is to provide a patch comprising the microneedles. [Effects of the Invention]

[0010] The retinol-containing microneedle according to the present invention contains retinol and its stabilizer in an optimal combination for use in microneedles, in order to solve the instability of retinol. As a result, the retinol-containing microneedle according to the present invention can achieve high skin delivery efficiency specific to the microneedle dosage form, thereby maximizing the effects of retinol, such as wrinkle improvement. [Brief explanation of the drawing]

[0011] [Figure 1] This graph shows the results of a 4-week accelerated test on candidate retinol raw materials for use in microneedles. [Figure 2] This graph shows the results of a 4-week stability test (accelerated + long-term) on microneedle samples manufactured using tocopherol as a retinol stabilizer. [Figure 3] This graph shows the results of a 4-week stability test (accelerated + long-term) on microneedle samples manufactured using sodium ascorbate as a retinol stabilizer. [Figure 4] This graph shows the results of an 8-week (accelerated) stability test on microneedle samples manufactured using cyclodextrin as a retinol stabilizer. [Figure 5] This is an experimental result evaluating the content stability of different types of cyclodextrin contained in microneedles. [Modes for carrying out the invention]

[0012] The present invention will be described in more detail below.

[0013] One aspect of the present invention provides a composition for manufacturing microneedles, comprising retinol or its derivatives, cyclodextrin, and a biodegradable solidifying substance.

[0014] In this specification, the term "retinol" refers to vitamin A, a fat-soluble vitamin, which is an essential component for the normal differentiation of cells and the growth of bones, teeth, hair, nails, etc. In particular, retinol is known to have excellent antioxidant activity, promote the differentiation of skin cells, and stimulate the biosynthesis of collagen (which affects wrinkles) and elastin (which affects elasticity), thereby reducing wrinkles and increasing skin elasticity.

[0015] As used in this specification, the term "retinol derivative" refers to a compound obtained by modifying retinol in order to improve the functionality and stability of retinol. Examples of retinol derivatives include, but are not limited to, retinol esters (e.g., retinyl palmitate, retinyl acetate, and retinyl propionate), retinoic acid, retinol aldehyde, and retinal.

[0016] In one embodiment of the present invention, commercially available retinol raw materials were utilized. As described below, a total of four commercially available retinol raw materials (hereinafter referred to as A to D) were selected as candidate retinol raw materials. Of these, one retinol raw material with relatively high stability, for example A, was selected and subjected to retinol stabilization experiments. However, it should not be understood that the retinol stabilization method or retinol stabilization formulation unique to the present invention is effective only for a specific retinol raw material. Anyone skilled in the art can easily attempt to stabilize any number of commercially available retinol raw materials using the method described in the specification of the present invention and obtain the same effect. Therefore, regardless of which retinol raw material is used, it falls within the scope of the retinol stabilization method or formulation of the present invention.

[0017] The biodegradable solid substance can form microneedles and maintain its form, and can be used without limitation as long as it can be dissolved in the body after permeating the skin. Specifically, the biodegradable solid substance may be a hydrophilic substance. The biodegradable solid substance may be, for example, hyaluronic acid (HA), or a cosmetically acceptable salt thereof, carboxymethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polylactic acid-glycolic acid, gelatin, collagen, chitosan, or a mixture thereof, but is not limited thereto.

[0018] As an embodiment of the present invention, the biodegradable solid substance may be hyaluronic acid, or a cosmetically acceptable salt thereof. The average molecular weight of the hyaluronic acid may be 10 to 5000 kDa, preferably 40 kDa to 150 kDa.

[0019] Hyaluronic acid is a biogenic polymer substance in which N-acetyl-D-glucosamine and D-glucuronic acid are alternately linked in a chain. It is abundant in animal tissues such as skin and umbilical cords, is suitable as a biomaterial, and has the advantage of being easy to adjust physical properties.

[0020] Another aspect of the present invention provides soluble microneedles manufactured using the composition.

[0021] The term "microneedle" used in this specification means a needle-shaped structure having a length in micrometers (μm), with a tip shaped like a needle and capable of permeating the skin. The microneedle forms pores in the stratum corneum, which is the outermost layer of the skin, and transmits drugs through the pores thus formed. Also, the microneedle has an extremely short length and does not affect nerve cells, so it hardly causes pain.

[0022] As used in this specification, the term "dissolvable microneedle" refers to a microneedle that releases the loaded drug by dissolving in the body when applied to the skin. In the case of a hydrogel-type microneedle that is not dissolvable, when applied to the skin, it swells, which may cause pressure on the skin and irritation, and pain may occur during the removal process. However, in the case of the dissolvable microneedle, it disappears after application to the skin, so there is less irritation to the skin and there is no need for removal.

[0023] In one embodiment of the present invention, the microneedle may be manufactured by a blowing and stretching (DEN, Droplet Extension) method.

[0024] The DEN method is a technique for simultaneously producing two microneedle patches by dropping droplets composed of an active ingredient onto one patch, contacting the other patch, stretching (Extension) to form microneedles, and then solidifying by blowing air and separating. This is a unique technique that is simpler in manufacturing process and has excellent mass productivity compared to the molding method, which is an existing method for manufacturing microneedles, and is suitable for loading biopharmaceuticals.

[0025] Regarding the microneedles manufactured by the DEN method, reference can be made to Korean Registered Patents Nos. 1254240, 1285085, 1636069, 1816922, 2103194, and 2127123, and all the contents of these patents are included in this application as references.

[0026] In one embodiment of the present invention, the microneedle may be used for wrinkle improvement or increasing skin elasticity.

[0027] Another aspect of the present invention provides a patch including the microneedle.

[0028] As used in this specification, the term "patch" refers to a dosage form that is applied to the skin to deliver a drug into the body.

[0029] The present invention will be described in more detail below using the following examples. However, the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited to these examples.

[0030] Example 1. Selection of retinol raw materials for microneedles To select a retinol raw material with superior stability when formulated into microneedles, four commercially available retinol raw materials (A, B, C, and D) were tested for stability.

[0031] For the constituent components of the four retinol raw material candidates mentioned above, please refer to Table 1 below.

[0032] [Table 1]

[0033] The four retinol raw materials described above were each sealed in aluminum pouches used for packaging microneedle formulations, and then exposed to accelerated conditions (40±2°C, relative humidity 75±5%) for 4 weeks to conduct accelerated stability testing. The retinol content stability was evaluated at 1 week, 2 weeks, and 4 weeks. As a result, it was confirmed that candidate retinol raw material A showed relatively high stability (Figure 1). Therefore, retinol raw material A was selected as the retinol raw material for microneedle formulation.

[0034] Example 2. Evaluation of retinol stabilizers in microneedle dosage form. Four stabilizers, as presented in Table 2 below, were selected as candidate stabilizers. The main physicochemical functions of the candidate stabilizers are as shown in Table 2.

[0035] [Table 2]

[0036] Of the aforementioned stabilizer candidates, BHT, which is unsuitable for sensitive skin, was excluded, and stability tests were conducted on the remaining three candidates. First, to test the stability when incorporated into microneedles manufactured by the Droplet Extension (DEN) method using hyaluronic acid (HA), hyaluronic acid was used as a solidifying agent, and retinol raw material A, stabilizer candidate substances (tocopherol, sodium ascorbate, or cyclodextrin), and 100 mM NaOH were added. In a total of three compositions, namely Composition 1 to Composition 3 (tocopherol, sodium ascorbate, or cyclodextrin), the remaining components (hyaluronic acid, retinol raw material A, NaOH) and their composition ratios were the same, excluding the type of stabilizer candidate. The hyaluronic acid content was adjusted to a level that would allow for the manufacture of microneedles using the DEN method, and the stabilizer content was adjusted to within the range of general excipient content percentages. After adjusting the weight of the compound sample produced by the above-described process to a constant level, it was applied to the DEN process, which was commercially available at the time of filing the present invention and whose details are disclosed in the above-mentioned registered patent of the applicant, and solidified by applying appropriate air blowing conditions.

[0037] Copies of solidified microneedles were placed in aluminum pouches, sealed, and exposed to accelerated conditions (40±2°C, 75±5% relative humidity) for 4 weeks for accelerated stability testing. Retinol stability was evaluated at 1, 2, and 4 weeks. For cyclodextrin-containing samples that showed excellent stability up to 4 weeks, the accelerated stability test was continued up to 8 weeks to evaluate retinol stability. Retinol stability was evaluated using the same method as in Example 1.

[0038] As a result, in the case of microneedle formulations using hyaluronic acid as a solidifying agent, the stability effect on retinol was confirmed to be highest in the order of cyclodextrin > sodium ascorbate > tocopherol (see Figures 2 to 4).

[0039] Figure 5 shows the experimental results evaluating the content stability of different types of cyclodextrin contained in microneedles. As a result, it was confirmed that all alpha, beta, and gamma cyclodextrins achieved extremely excellent retinol stabilization.

[0040] The stabilizing effect of cyclodextrin in microneedle formulations, as described above, is thought to be due to the effect of the stabilizer changing depending on the retinol-containing formulation.

[0041] The achievement of this invention lies in opening up a new way to effectively preserve retinol components, particularly when incorporated into biodegradable microneedles, as retinol is prone to losing its inherent skin-improving efficacy due to oxidation-induced free radical formation or transformation from trans to cis form. Prior to this invention, numerous attempts had been made to stabilize retinol components, but none of these attempts yielded an effective method of stabilizing retinol in biodegradable microneedle formulations like the one presented in this invention. The environment in which retinol is placed within a microneedle formulation is clearly different from the environment within an oil-in-water (w / o), oil-in-water (o / w), or oil-in-water (o / w / o) emulsion (the hyaluronic acid microneedles used in this embodiment are a water-based formulation; see reference [Katsunori Yoshida, et al., 1999, Stability of vitamin A in oil-in-water-in-oil-type multiple emulsions, Journal of the American Oil Chemists' Society, volume 76, pages 1-6]), therefore, retinol stabilization methods used in other environments cannot be applied to biodegradable microneedle formulations.

[0042] In summary, it was found that when retinol is incorporated into hyaluronic acid microneedles, cyclodextrin achieves the best retinol stabilization. Furthermore, stability tests using cyclodextrin showed an astonishing 99.32% of the initial content not only at 4 weeks under accelerated conditions, but also at 8 weeks under accelerated conditions.

Claims

1. A composition for manufacturing microneedles, comprising retinol or its derivatives, cyclodextrin, and a biodegradable solidifying substance, The biodegradable solidified substance is hydrophilic, and when the composition is applied to the skin, the composition dissolves in the body, releasing the contained drug. The cyclodextrin mentioned above consists of beta-cyclodextrin. Composition for manufacturing microneedles.

2. The composition for manufacturing microneedles according to claim 1, wherein the biodegradable solidifying substance is hyaluronic acid or a cosmetically acceptable salt thereof.

3. A soluble microneedle manufactured using the composition described in claim 1 or 2.

4. The soluble microneedle according to claim 3, wherein the microneedle is used for wrinkle improvement or increased skin elasticity.

5. A patch comprising the microneedles described in claim 3.

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