Transdermal delivery system and sustained release dosage form comprising allantoin microcrystalline

Abstract

This specification relates to a transdermal drug delivery composition and active ingredient delivery system comprising a sustained-release dosage form of allantoin microneedle crystals. According to one aspect of the invention, the allantoin microneedle crystals and the composition (regardless of type) containing them penetrate the skin, gradually releasing allantoin, which is continuously absorbed into the stratum corneum and epidermis. It possesses sustained-release characteristics and can be used as an active ingredient delivery system for delivering various ingredients, specifically lipid-soluble or water-soluble active ingredients, into the skin. This allows the allantoin itself or the active ingredient impregnated in the crystals to be released in a sustained-release manner, maintaining a long-term and stable effect. It not only reduces side effects such as skin irritation or allergic reactions but also enables the continuous delivery of active ingredients to specific sites, effectively improving skin condition. Due to the continuous release of small amounts of ingredient, it offers excellent long-term skin care without damaging the skin barrier.

Description

Technical Field

[0001] This specification relates to a transdermal drug delivery composition and active ingredient delivery system comprising a sustained-release dosage form of allantoin microneedle crystals. Background Technology

[0002] Sustained-release formulations are dosage forms designed to slowly release drugs or active ingredients in the body. Sustained-release formulations are widely manufactured and marketed in the pharmaceutical industry.

[0003] Conversely, in the cosmetics industry, it is difficult to produce sustained-release formulations. This is because sustained-release formulations are designed to gradually release active ingredients over time. Due to this characteristic, it is difficult to maintain the stability of the formulation. Moreover, the release rate varies depending on skin absorption characteristics and the skin barrier. Sustained-release formulations are manufactured using special technologies and processes, making the formulation design complex. Furthermore, sustained-release formulations need to maintain structural stability without deformation, but this condition is difficult to meet in the cosmetics industry.

[0004] On the one hand, in recent years, home-use skincare cosmetics employing "microneedling" technology, primarily used in dermatological cosmetic medical devices, have become increasingly popular. These cosmetics leverage the principles of dermatological treatments, which provide a stinging and uncomfortable sensation, to offer the experience of effects achievable through dermatological procedures, thus establishing their selling point. The core ingredients of most home-use skincare cosmetics using microneedling technology correspond to cosmetic ingredients such as Centella Asiatica extract contained in purified silica needles made from animal-derived materials. These microneedles act as a physical delivery system, physically promoting skin penetration without the need for separate devices, thereby stimulating consumer desire. Consumers can directly experience the active ingredients and it also aids in the absorption of other active ingredients.

[0005] However, the main component of these microneedles, bone spicules (hydrolyzed sponges), is made from animal-derived materials, has a sponge-derived skeleton, and is composed of approximately 99% silica. These bone spicules can cause excessive stinging on sensitive skin after application, and the needles can embed themselves in the skin, resulting in persistent pain over time unless rinsed with water.

[0006] To this end, the inventors dedicated themselves to developing a novel material that has the same morphology as microneedles, can penetrate the skin, produce effects similar to dermatological treatments, and can also overcome the shortcomings of bone needles. This material can be used as a sustained-release dosage form that gradually releases effective or active ingredients, and thus the invention was born.

[0007] [Existing Technical Documents]

[0008] [Patent Documents]

[0009] (Patent Document 1) KR 10-2017-0000747 A

[0010] (Patent Document 2) JP 7416309 B1

[0011] (Patent Document 3) KR 10-1999-0063069 A

[0012] (Patent Document 4) KR 10-2024-0060951 A Summary of the Invention

[0013] Problems to be solved

[0014] The inventors are dedicated to developing a novel material that has the same morphology as microneedles, can penetrate the skin, and produce effects similar to dermatological treatments. At the same time, it can overcome the shortcomings of bone needles and can be used as a sustained-release dosage form that gradually releases effective or active ingredients. According to research results, it has been confirmed that precipitating amorphous allantoin into crystals with the same shape as microneedles can achieve the above-mentioned effects.

[0015] Therefore, on the one hand, the object of the present invention is to provide a novel material having the same morphology as microneedles, which provides the user with a dermatological treatment-like sensation when applied to the skin, and is used as a sustained-release dosage form for continuously releasing active ingredients to the skin.

[0016] Problem Solving Methods

[0017] In one aspect, the present invention provides a transdermal drug delivery composition in a sustained-release dosage form comprising allantoin microneedle-like crystals.

[0018] In another aspect, the present invention provides an active ingredient delivery system for delivering an active ingredient into the skin, wherein the system comprises allantoin microneedle crystals having one or more of the following characteristics: an average length of the long axis of 5 to 500 μm; and a thickness greater than 0 and less than or equal to 40 μm.

[0019] Invention Effects

[0020] According to one aspect of the present invention, allantoin microneedle crystals and compositions (regardless of type) containing the same penetrate the skin, gradually releasing allantoin, which is continuously absorbed into the stratum corneum and epidermis. They possess sustained-release properties and can be used as an active ingredient delivery system for delivering various ingredients, specifically lipid-soluble or water-soluble active ingredients, into the skin. This allows the allantoin itself or the active ingredient impregnated in the crystals to be released in a sustained-release manner, maintaining a long-term and stable effect. This not only reduces side effects such as skin irritation or allergic reactions but also enables the continuous delivery of active ingredients to specific sites, effectively improving skin condition. Due to the continuous release of small amounts of ingredient, it offers excellent long-term skin care without damaging the skin barrier. Attached Figure Description

[0021] Figure 1 This is a photograph of allantoin microneedle-like crystals according to an embodiment of the present invention.

[0022] Figure 2a In an in vitro keratinocyte residue assessment experiment according to an embodiment of the present invention, a photograph of the cross-section of the untreated group after staining with Nile red was taken.

[0023] Figure 2b In an in vitro stratum corneum residue assessment experiment according to an embodiment of the present invention, a cross-sectional photograph of allantoin powder, which serves as a control group, was taken 18 hours after being applied to skin biopsy tissue.

[0024] Figure 2c In an in vitro stratum corneum residue assessment experiment according to an embodiment of the present invention, a cross-sectional photograph of allantoin microneedle crystals according to an embodiment of the present invention was taken 18 hours after being applied to skin biopsy tissue.

[0025] Figure 3a The first image shows a cross-section of the untreated group (left) after staining with Nile red and without any other treatment, taken during an in vitro stratum corneum residue assessment experiment. The second image shows a cross-section taken 2 hours (middle) and 8 hours (right) after applying an oil-in-water composition containing allantoin microneedle crystals according to an embodiment of the present invention to skin biopsy tissue.

[0026] Figure 3b This is a graph showing the results of measuring the fluorescence intensity detected from an oil-in-water composition containing allantoin microneedle crystals according to an embodiment of the present invention over time.

[0027] Figure 3cThis is a graph showing the results of evaluating skin absorption capacity based on the relative fluorescence intensity over time after applying an oil-in-water composition containing allantoin microneedle crystals according to an embodiment of the present invention to skin biopsy tissue in an in vitro stratum corneum residue assessment experiment.

[0028] Figure 4a The first image shows a cross-section of the untreated group (left) after staining with Nile red and without any other treatment, taken during an in vitro stratum corneum residue assessment experiment. The second image shows a cross-section taken at 2 hours (middle) and 8 hours (right) after a liposomal formulation composition containing allantoin microneedle crystals according to an embodiment of the present invention was applied to skin biopsy tissue.

[0029] Figure 4b This is a graph showing the results of fluorescence intensity measurements over time from a liposomal formulation composition containing allantoin microneedle crystals according to an embodiment of the present invention.

[0030] Figure 5a and Figure 5b The graph shows the results of measuring the skin absorption capacity of an oil-in-water composition and a liposome formulation containing allantoin microneedle crystals according to an embodiment of the present invention.

[0031] Figure 6 These are photographs taken during the manufacturing process of an allantoin microneedle crystal containing retinol-impregnated active ingredient delivery system according to an embodiment of the present invention.

[0032] Figure 7 and Figure 8 The images were taken from allantoin microneedle-shaped crystals containing retinol (According to an embodiment of the present invention). Figure 7 ) and Centella Asiatica extract ( Figure 8 Photograph of allantoin microneedle-like crystals in an active ingredient delivery system. Detailed Implementation

[0033] In this specification, "needle-like" refers to a shape that is long and thin like a needle with a sharp end, "crystal" refers to a crystalline solid that does not contain solvent molecules in a substantially fixed molar ratio within its crystal lattice, i.e., a non-solvent crystalline solid, and "needle-shaped crystal" is a crystal with a pointer shape.

[0034] The present invention will now be described in detail.

[0035] On one hand, the present invention provides a transdermal drug delivery composition in a sustained-release dosage form, comprising allantoin microneedle-like crystals.

[0036] Allantoin (C4H6N4O3, molecular weight 158.116 g / mol, IUPAC name: (2,5-dioxo-4-imidazolidinyl)urea), CAS No. 97-59-6, EC No. 202-592-8) according to one aspect of the present invention is a general pharmaceutical product approved by the US FDA as an effective ingredient for skin protection, and is known to be a poorly soluble component. The allantoin can be represented by the following chemical formula 1:

[0037] [Chemical Formula 1]

[0038]

[0039] According to one aspect of the invention, allantoin crystals have a microneedle-like structure, which can cause slight irritation to the skin when applied, thereby promoting absorption within the skin.

[0040] According to one aspect of the invention, allantoin microneedle crystals may have one or more of the following characteristics: an average length of long axis of 5 to 500 μm; and a thickness greater than 0 μm and less than or equal to 40 μm.

[0041] According to one aspect of the present invention, the average length of the long axis of the allantoin microneedle crystals can be from 5 to 500 μm. Specifically, the average length of the long axis of the allantoin microneedle crystals can be 5 μm or more, 10 μm or more, 20 μm or more, 30 μm or more, 40 μm or more, 50 μm or more, 55 μm or more, 60 μm or more, 65 μm or more, 70 μm or more, 75 μm or more, 80 μm or more, 85 μm or more, 90 μm or more, 92 μm or more, 94 μm or more, 95 μm or more, 96 μm or more, 98 μm or more, 100 μm or more, 110 μm or more, 120 μm or more, 130 μm or more, 140 μm or more, 150 μm or more, 160 μm or more, 170 μm or more, 180 μm or more, 190 μm or more, 200 μm or more, 250 μm or more, or 300 μm. Above, 350μm and above, 400μm and above or above 450μm, can be below 500μm, below 450μm, below 400μm, below 350μm, below 300μm, below 250μm, below 240μm, below 230μm, below 225μm, below 220μm, below 218μm, below 216μm, below 214μm, below 212μm, below 210μm, below 208μm, below 206μm, below 204μm, below 202μm, below 200μm, below 180μm, below 160μm, below 140μm, below 120μm, below 100μm, below 90μm, below 80μm, below 70μm or below 60μm. More specifically, the average length of the long axis of the allantoin microneedle crystals can be 100 to 200 μm, and even more specifically, it can be 150 to 200 μm.

[0042] According to one aspect of the present invention, the thickness of the allantoin microneedle crystals can be greater than 0 μm and less than or equal to 40 μm. Specifically, the thickness of the allantoin microneedle crystals can be greater than 0 μm, greater than 2 μm, greater than 4 μm, greater than 5 μm, greater than 6 μm, greater than 7 μm, greater than 8 μm, greater than 9 μm, greater than 10 μm, greater than 11 μm, greater than 12 μm, greater than 13 μm, greater than 14 μm, greater than 15 μm, greater than 16 μm, greater than 17 μm, greater than 18 μm, greater than 19 μm, greater than 20 μm, greater than 22 μm, greater than 24 μm, greater than 26 μm. The thickness can be greater than 1 μm, greater than 28 μm, greater than 30 μm, or greater than 35 μm, and can be less than 40 μm, less than 38 μm, less than 36 μm, less than 34 μm, less than 32 μm, less than 30 μm, less than 29 μm, less than 28 μm, less than 27 μm, less than 26 μm, less than 25 μm, less than 24 μm, less than 23 μm, less than 22 μm, less than 21 μm, less than 20 μm, less than 15 μm, less than 10 μm, or less than 8 μm. More specifically, the thickness of the allantoin microneedle-like crystals can be 10 to 20 μm. According to one aspect of the invention, the allantoin microneedle-like crystals have a thickness greater than 0 μm and less than or equal to 40 μm, thereby enabling them to slightly penetrate the skin surface and pass through the stratum corneum.

[0043] According to one aspect of the present invention, allantoin microneedle-like crystals can be crystallized by precipitating amorphous allantoin using an antisolvent crystallization method.

[0044] According to one aspect of the present invention, the allantoin microneedle crystals can be soluble. The allantoin microneedle crystals can be water-soluble or lipid-soluble. The allantoin microneedle crystals exhibit excellent solvent solubility, thus possessing soluble properties and effectively solving the problem of poor solubility inherent in general allantoin powders.

[0045] According to one aspect of the present invention, allantoin microneedle-shaped crystals can penetrate into the skin when applied to the skin. Furthermore, according to one aspect of the present invention, allantoin microneedle-shaped crystals can remain within the stratum corneum of the skin 2 to 36 hours after application. Specifically, the allantoin microneedle-shaped crystals can remain within the stratum corneum of the skin after 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 30 hours, or 36 hours after application. According to one embodiment of the present invention, by having a microneedle-like morphology similar to a needle, it remains within the stratum corneum even after a long period of time after application, thus allowing it to penetrate into the skin and be absorbed simply by applying it to the skin (see Experimental Example 1 and...). Figure 2c ).

[0046] According to one aspect of the invention, allantoin microneedle crystals can dissolve and be absorbed into the skin after application. The process is as follows: First, when allantoin microneedle crystals are applied to the skin, the crystals themselves adhere to the skin surface directly. Then, the applied allantoin microneedle crystals have a thickness greater than 0 μm and less than or equal to 40 μm, specifically 5 to 40 μm, allowing for slight penetration into the skin surface and through the stratum corneum. At this point, the allantoin component can be immediately delivered into the skin, and absorption is further promoted due to the slight stimulation of the skin by the microneedle structure. Subsequently, rolling or rubbing the skin surface with the hand or fingers approximately 10 times maximizes the contact between the allantoin microneedles and the skin surface, thereby facilitating successful penetration. The rolling or rubbing action promotes the dissolution and absorption of the allantoin microneedle crystals in the skin, and the microstimulation is also expected to improve microcirculation. Furthermore, allantoin microneedle-like crystals that penetrate the skin or stratum corneum gradually dissolve upon contact with moisture within the skin, releasing allantoin. This process can occur within 2 to 36 hours after application. Specifically, absorption occurs initially within the stratum corneum (keratin layer), where it reacts with subcutaneous moisture and gradually dissolves. Some components then reach the epidermis and are reabsorbed. Typically, most of the allantoin microneedle-like crystals dissolve and are absorbed within the stratum corneum.

[0047] According to one aspect of the invention, allantoin microneedle crystals can be dissolved and absorbed in the skin after being repeatedly rolled 10 times at a weight of 0.5 to 1.0 kg / cm². The allantoin microneedle crystals can be dissolved and absorbed in the skin after 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 27 hours, 30 hours, 33 hours, or 36 hours after application, but can be further dissolved and absorbed by rolling with the hands or fingers. Specifically, allantoin microneedle crystals can be dissolved in the skin and absorbed by the stratum corneum after being applied to the skin and repeatedly rolled 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times at weights of 0.5 kg / cm² or more, 0.6 kg / cm² or more, 0.7 kg / cm² or more, 0.8 kg / cm² or less, 0.7 kg / cm² or less, 0.7 kg / cm² or less. The rolling or rubbing motion can promote the dissolution of allantoin microneedle crystals and their absorption by the skin, and the microstimulation is also expected to improve microcirculation.

[0048] The composition according to one aspect of the present invention can be a sustained-release dosage form. The sustained-release dosage form, as a dosage form that utilizes a sustained-release agent to uniformly and continuously release the active ingredient or even the active ingredient contained in the composition, enables the active ingredient or active ingredient to be continuously absorbed in the body, thereby maintaining the effect over time.

[0049] The composition according to one aspect of the present invention can be used for transdermal drug delivery.

[0050] According to one aspect of the present invention, the allantoin microneedle crystals, based on the total weight of the allantoin microneedle crystals, may contain 3 to 16% by weight of allantoin. Specifically, the allantoin microneedle crystals, based on the total weight of the allantoin microneedle crystals, may contain 3% or more, 3.5% or more, 4% or more, 4.2% or more, 4.4% or more, 4.6% or more, 4.8% or more, 5% or more, 5.2% or more, 5.4% or more, 5.6% or more, 5.8% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, and 11% or more by weight of allantoin. The allantoin may be present in concentrations of 12% or more, or 14% or more, but may also contain less than 16% by weight, less than 15% by weight, less than 14% by weight, less than 13% by weight, less than 12% by weight, less than 11% by weight, less than 10% by weight, less than 9% by weight, less than 8.8% by weight, less than 8.6% by weight, less than 8.4% by weight, less than 8.2% by weight, less than 8% by weight, less than 7.8% by weight, less than 7.6% by weight, less than 7.4% by weight, less than 7.2% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, or less than 4% by weight. More specifically, the allantoin microneedle crystals may contain 4 to 9% by weight of allantoin, based on the total weight of the allantoin microneedle crystals.

[0051] According to one aspect of the invention, the allantoin microneedle crystals may further contain betaine. When the allantoin microneedle crystals contain betaine, allantoin can be crystallized into a microneedle form with higher purity and yield.

[0052] According to one aspect of the present invention, the allantoin microneedle crystals, based on the total weight of the allantoin microneedle crystals, may contain 9 to 72% by weight of betaine. Specifically, the allantoin microneedle crystals, based on the total weight of the allantoin microneedle crystals, may contain 9% or more, 10% or more, 12% or more, 14% or more, 16% or more, 18% or more, 20% or more, 22% or more, 24% or more, 26% or more, 28% or more, 30% or more, 35% or more, 36% or more, 40% or more, 50% or more, or 60% by weight of betaine. The above-mentioned amounts may contain less than 72% by weight, less than 70% by weight, less than 60% by weight, less than 50% by weight, less than 40% by weight, less than 38% by weight, less than 36% by weight, less than 34% by weight, less than 32% by weight, less than 30% by weight, less than 28% by weight, less than 26% by weight, less than 24% by weight, less than 22% by weight, less than 20% by weight, less than 19% by weight, less than 18% by weight, less than 16% by weight, less than 14% by weight, less than 12% by weight, or less than 10% by weight. More specifically, the allantoin microneedle crystals may contain 12 to 36% by weight of betaine based on the total weight of the allantoin microneedle crystals.

[0053] According to one aspect of the invention, the composition may contain 3 to 12 by weight of the allantoin microneedle crystals, based on the total weight of the composition. Specifically, the composition, based on the total weight of the composition, may contain more than 3% by weight, more than 3.5% by weight, more than 4% by weight, more than 4.2% by weight, more than 4.4% by weight, more than 4.6% by weight, more than 4.8% by weight, more than 5% by weight, more than 5.2% by weight, more than 5.4% by weight, more than 5.6% by weight, more than 5.8% by weight, more than 6% by weight, more than 7% by weight, more than 8% by weight, more than 9% by weight, or more than 10% by weight, or may contain less than 12% by weight, less than 11% by weight, less than 10% by weight, less than 9% by weight, less than 8.8% by weight, less than 8.6% by weight, less than 8.4% by weight, less than 8.2% by weight, less than 8% by weight, less than 7.8% by weight, less than 7.6% by weight, less than 7.4% by weight, less than 7.2% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, or less than 4% by weight. More specifically, the composition may contain 4 to 9 by weight of the allantoin microneedle crystals, based on the total weight of the composition.

[0054] The composition according to one aspect of the present invention can be a topical skin composition.

[0055] The composition according to one aspect of the present invention can be a transdermal drug delivery composition.

[0056] The composition according to one aspect of the present invention can be a cosmetic composition or a pharmaceutical composition.

[0057] The cosmetic composition according to one aspect of the invention can be used for exfoliation, for skin moisturizing, for skin wound healing, for promoting skin regeneration, or for protecting the skin from irritation.

[0058] The compositions according to one aspect of the invention can be in the form of cosmetic compositions containing a media or matrix acceptable to cosmetics or dermatology. They are available in all dosage forms suitable for topical application, for example, as solutions, gels, solids, anhydrous pastes, emulsions obtained by dispersing an oil phase in an aqueous phase, suspensions, microemulsions, microcapsules, microspheres, or ionic (liposomes) and nonionic cysteine ​​dispersions, or as creams, lotions, emulsions, powders, ointments, sprays, or concealer sticks. These compositions can be prepared according to conventional methods in the art. Furthermore, the compositions according to this disclosure can also be used in the form of foams or, further, as aerosol compositions containing compressed propellants.

[0059] According to one aspect of the invention, the dosage form of the cosmetic composition is not particularly limited, and for example, it can be formulated as a gentle lotion, astringent lotion, nourishing lotion, nourishing cream, massage cream, serum, eye cream, eye essence, cleansing cream, cleansing foam, makeup remover, cleansing wipes containing the cosmetic composition, face mask, powder, body lotion, moisturizing cream, moisturizing oil, and moisturizing essence, etc.

[0060] When the dosage form of the cosmetic composition is a paste, cream, or gel, the composition according to one aspect of the present invention may utilize animal oils, vegetable oils, waxes, paraffin wax, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide as carrier components.

[0061] When the cosmetic composition is in the form of a powder or a spray, the composition according to one aspect of the invention may utilize lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder as a carrier component, especially in the case of a spray, and may further include a propellant such as chlorofluorohydrocarbon, propane / butane or dimethyl ether.

[0062] When the dosage form of the cosmetic composition is a solution or emulsion, the composition according to one aspect of the present invention utilizes a solvent, solvator or emulsifier as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylethylene glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid esters of sorbitol.

[0063] When the dosage form of the cosmetic composition is a suspension, the composition according to one aspect of the present invention may utilize liquid diluents such as water, ethanol or propylene glycol; suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitan ester and polyoxyethylene sorbitan anhydride ester; microcrystalline cellulose; aluminum hydroxide; bentonite, agar or astragalus gum, etc., as carrier components.

[0064] The composition according to one aspect of the invention may further comprise functional additives and ingredients commonly found in conventional cosmetic compositions. As said functional additives, they may include ingredients selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, high molecular weight peptides, high molecular weight polysaccharides, squalane, sphingolipids, and seaweed concentrate.

[0065] Furthermore, in addition to the aforementioned functional additives, the compositions according to one aspect of the present invention may, if necessary, include ingredients typically found in cosmetic compositions. Examples of such additional formulation ingredients include oils, moisturizers, lubricants, emulsifiers, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, bactericides, antioxidants, plant extracts, pH adjusters, alcohols, pigments, fragrances, blood circulation promoters, cooling agents, antiperspirants, purified water, etc.

[0066] The pharmaceutical composition according to one aspect of the present invention can be a pharmaceutical composition for skin wound healing.

[0067] The pharmaceutical composition according to one aspect of the invention can be provided in any dosage form suitable for topical application. For example, it can be administered orally, transdermally, intravenously, intramuscularly, or subcutaneously, particularly via transdermal administration. The pharmaceutical composition can be, but is not limited to, a topical solution, suspension, emulsion, gel, patch, or spray. The dosage form can be readily prepared according to conventional methods in the art, and surfactants, excipients, wettable powders, emulsifiers, suspending agents, salts or buffers for adjusting osmotic pressure, colorants, spices, stabilizers, preservatives, or other commonly used adjuvants may be appropriately used.

[0068] The active ingredient of a pharmaceutical composition according to one aspect of the invention can vary depending on the subject's age, sex, weight, pathological condition and its severity, route of administration, or the prescribing physician's judgment. Determining the dosage based on these factors is within the scope of expertise of those skilled in the art, and the daily dosage can range from, for example, 0.1 mg / kg / day to 5000 mg / kg / day, more specifically from 50 mg / kg / day to 500 mg / kg / day, but is not limited thereto.

[0069] The composition according to one aspect of the invention can be an oil-dispersible, water-dispersible, water-in-oil, oil-in-water, or multi-emulsion composition. According to one embodiment of the invention, the composition comprising allantoin microneedle crystals according to one aspect of the invention, regardless of its type (e.g., liposome formulation) or oil-in-water, penetrates into the stratum corneum after being applied to the skin, and then allantoin, as the active ingredient, is gradually released and continuously absorbed into the stratum corneum and epidermis over a long period of time, thereby exhibiting sustained-release properties (refer to Experimental Example 2 and Figures 3 to 5).

[0070] On the other hand, the present invention provides an active ingredient delivery system comprising allantoin microneedle-like crystals for delivering an active ingredient into the skin. The description of the allantoin microneedle-like crystals also applies to the active ingredient delivery system in transdermal drug delivery compositions comprising sustained-release dosage forms of the allantoin microneedle-like crystals.

[0071] It is possible that the active ingredient delivery system according to one aspect of the invention comprises allantoin microneedle crystals having one or more of the following characteristics: an average length of the long axis of 5 to 500 μm; and a thickness greater than 0 μm and less than or equal to 40 μm.

[0072] According to one aspect of the present invention, the active ingredient delivery system may further include an active ingredient within the allantoin microneedle crystals. Specifically, the active ingredient may be a water-soluble or fat-soluble active ingredient. More specifically, the active ingredient may be selected from retinol, ascorbic acid, niacinamide, coenzyme Q10, resveratrol, glutathione, ceramide, azelaic acid, astaxanthin, epigallocatechin gallate (EGCG), phytosterols, Centella asiatica extract (CENTELLA ASIATICA TRITERPENE (ASIATICOSIDE) triterpenoids (CENTELLA ASIATICA TRITERPENE (ASIATICOSIDE)) MADECASSIC ACID One or more of the following groups are included: ASIATIC ACID, salicylic acid, oleanolic acid, nicotinamide mononucleotide, hyaluronic acid, L-carnitine, vitamin B complex, amino acids, acetyl hexapeptide-8, panthenol (vitamin B5), ubiquinone, hydrolyzed ginseng saponins, ginseng root extract, ginseng seed oil, ginseng berry extract, peony root extract, purslane rhizome extract, lotus extract, lily bulb extract, and mixtures thereof.

[0073] According to one embodiment of the present invention, retinol, a typical fat-soluble component, and Centella asiatica extract, a typical water-soluble component soluble in polyols, are respectively impregnated in allantoin microneedle crystals. Therefore, the allantoin microneedle crystals according to one aspect of the present invention, by converting poorly soluble allantoin into a soluble form and crystallizing it, can be used as an active ingredient delivery system for delivering various components, specifically fat-soluble or water-soluble active ingredients, into the skin (see Experimental Example 3 and...). Figure 6 and Figure 8 ).

[0074] On the other hand, the present invention may relate to a method for exfoliation, skin moisturization, skin wound healing, promoting skin regeneration, or protecting the skin from irritation, the method comprising the step of transdermal administration of a composition comprising a sustained-release dosage form of allantoin microneedle crystals to an individual who requires exfoliation, skin moisturization, skin wound healing, promotion of skin regeneration, or protection of the skin from irritation.

[0075] In another aspect, the present invention may relate to the use of allantoin microneedle crystals in the preparation of pharmaceutical compositions for exfoliation, skin moisturizing, skin wound healing, promoting skin regeneration, or protecting the skin from irritation.

[0076] In another aspect, the present invention may relate to the use of allantoin microneedle crystals in the preparation of cosmetic compositions for exfoliation, skin moisturizing, skin wound healing, promoting skin regeneration, or protecting the skin from irritation.

[0077] In another aspect, the present invention may relate to the use of allantoin microneedle crystals in the preparation of food compositions for exfoliation, skin moisturizing, skin wound healing, promoting skin regeneration, or protecting the skin from irritation.

[0078] In another aspect, the present invention may relate to the use of allantoin microneedle crystals for exfoliation, skin moisturizing, skin wound healing, promoting skin regeneration, or protecting the skin from irritation.

[0079] The present disclosure is further described by the following implementation examples, which do not limit the scope of the claims.

[0080] Example 1. A sustained-release transdermal drug delivery composition comprising allantoin microneedle-like crystals.

[0081] Implementation Example 2. A composition according to Implementation Example 1, wherein the allantoin microneedle-like crystals have one or more of the following characteristics: an average length of the long axis of 5 to 500 μm; and a thickness greater than 0 and less than or equal to 40 μm.

[0082] Example 3. A composition according to Example 1 or 2, wherein the allantoin microneedle crystals are soluble.

[0083] Implementation Example 4. A composition according to any one of Implementation Examples 1 to 3, wherein the allantoin microneedle-like crystals penetrate into the skin when applied to the skin.

[0084] Example 5. A composition according to any one of Examples 1 to 4, wherein the allantoin microneedle crystals remain within the stratum corneum of the skin for 2 to 36 hours after application.

[0085] Example 6. A composition according to any one of Examples 1 to 5, wherein the allantoin microneedle crystals, after being applied to the skin, are dissolved and absorbed within the skin when repeatedly rolled 10 times at a weight of 0.5 to 1.0 kg / cm².

[0086] Example 7. A composition according to any one of Examples 1 to 6, wherein the allantoin microneedle crystals further comprise betaine.

[0087] Example 8. A composition according to any one of Examples 1 to 7, wherein the composition is a cosmetic composition for exfoliation, for skin moisturizing, for skin wound healing, for promoting skin regeneration, or for protecting the skin from irritation.

[0088] Example 9. A composition according to any one of Examples 1 to 8, wherein the composition is a pharmaceutical composition for healing skin wounds.

[0089] Example 10. A composition according to any one of Examples 1 to 9, wherein the composition is an oil dispersion, a water dispersion, a water-in-oil emulsion, an oil-in-water emulsion, or a multi-emulsion composition.

[0090] Example 11. An active ingredient delivery system for delivering an active ingredient into the skin, wherein the system comprises allantoin microneedle crystals having one or more of the following characteristics: an average length of the long axis of 5 to 500 μm; and a thickness greater than 0 μm and less than or equal to 40 μm.

[0091] Implementation Example 12. An effective ingredient delivery system, according to Implementation Example 11, wherein the system further comprises an effective ingredient within the allantoin microneedle-like crystals.

[0092] Implementation Example 13. An effective ingredient delivery system, according to Implementation Example 10 or Implementation Example 11, wherein the effective ingredient is water-soluble or fat-soluble.

[0093] The following examples and experimental cases will provide a more detailed description of the structure and effects of the present invention. However, these examples and experimental cases are for illustrative purposes only to aid in understanding the present invention and are not intended to limit the scope or range of the invention.

[0094] [Experimental Example] Confirmation of the skin penetration and long-term absorption capacity of allantoin microneedle crystals

[0095] Allantoin powder (C4H6N4O3, molecular weight 158.116 g / mol, IUPAC name: (2,5-dioxo-4-imidazolidinyl)urea, CAS No. 97-59-6, EC No. 202-592-8) (Clariant Produkte (Deutschland) GmbH, ALANTOIN Premium) 90 g was dissolved in 600 g of glycerin along with 30 g of urea and 270 g of betaine. After adding water, precipitation was achieved, thus preparing the allantoin microneedle crystals of Example 1. Figure 1 The allantoin microneedle crystals have a needle-like morphology with an average length of 150 to 200 μm for the long axis and a thickness of 5 to 40 μm.

[0096] To confirm the skin absorption capacity of the allantoin microneedle crystals of Example 1, an in vitro (exvivo) stratum corneum residue assessment experiment was performed. The allantoin microneedle crystals stained with Nile-red (Sigma Aldrich, 72485-100mg) in Example 1 were applied to the epidermis of an in vitro skin biopsy tissue (Genoskin, NativeSkin™ #NSA20) taken from the abdomen of a 54-year-old woman, with a diameter of 20 mm. A cross-sectional image of the skin biopsy tissue was then taken after 18 hours. The image is shown below. Figure 2c As shown. As the untreated group, cross-sections of skin biopsy tissues that underwent only fluorescent staining without any treatment of allantoin microneedle crystals or allantoin powder were captured. Figure 2a As shown. In addition, as a control group, allantoin powder (Clariant Produkte (Deutschland) GmbH, ALLANTOIN Premium) was applied to skin biopsy tissue using the same method, and its cross-section was photographed; the image is shown below. Figure 2b As shown. The specific experimental procedure is as follows.

[0097] Fluorescent staining

[0098] Fluorescent staining is performed by dissolving the Nile Red fluorescent dye reagent in DMSO solution to a concentration of 1 mg / mL. To stain allantoin microneedle crystals or allantoin powder separately, Nile Red and raw material powder are mixed separately at a volume ratio of 5:1000 and stained at room temperature for 1 hour. Then, the allantoin microneedle crystals or allantoin powder are dissolved in deionized water (DI water) to a final concentration of 5%, thus preparing the sample.

[0099] Sample processing

[0100] On the day the skin biopsy tissue arrived, 2 mL of tissue culture medium was added, and the tissue was stabilized and cultured for 1 day at 37°C in a 5% CO2 incubator. The next day, 20 μL of allantoin microneedle crystals or powder solution stained with Nile Red was dropped onto the epidermis and then rubbed with silicone rubber. After air-drying at 37°C for 1 hour using a thermomixer in a laminar flow hood, the tissue was further cultured for 17 hours at 37°C in a 5% CO2 incubator. 18 hours after application, the epidermis was rinsed with deionized water and fixed with formalin solution. Frozen sections of the fixed skin tissue were prepared and observed using a confocal laser scanning microscopy (Carl Zeiss, model: LSM980).

[0101] Microscope measurement conditions

[0102] To observe cross-sections of skin tissue, a 40X objective lens was used with an excitation wavelength of 561 nm and an emission wavelength of 600 to 700 nm. Three images of Nile red fluorescence and brightfield signals were acquired for each group.

[0103] like Figure 2a and Figure 2c As shown, Nile Red is a lipid-soluble fluorescent substance that disperses in water and cannot penetrate the stratum corneum. Figure 2a Conversely, the allantoin powder used as a control group remained on the outermost layer of the stratum corneum and could not penetrate the skin even after a long time following application. Figure 2bHowever, in Example 1, the allantoin microneedle crystals migrate from the surface of the stratum corneum inwards. As the microneedle crystals inside the stratum corneum become fixed and dissolve, allantoin, as the active ingredient, is gradually released, thus continuously acting within the stratum corneum and epidermis. Figure 2c In particular, it was confirmed that the sustained-release components of the crystals in Example 1 remained in the stratum corneum for an extended period, even 18 hours after application, thus exerting the effects of allantoin. It was also confirmed that the allantoin crystals, with their needle-like morphology, easily penetrated the skin and were absorbed.

[0104] Therefore, it can be understood that the microneedle-shaped allantoin crystals of one aspect of the present invention, having the same microneedle-shaped morphology as needles, can penetrate into the skin simply by being applied to the skin, where they are fixed and dissolved in the stratum corneum, thereby gradually releasing the active ingredient allantoin, which is continuously absorbed into the stratum corneum and epidermis to exert its effect.

[0105] [Experimental Example 2] Confirmation of the sustained-release properties of a composition containing allantoin microneedle crystals

[0106] Since allantoin microneedle crystals have been demonstrated in Experiment 1 to penetrate the skin and be absorbed over a long period of time, a time-based in vitro (ex vivo) stratum corneum absorption capacity experiment was conducted to confirm whether the composition containing allantoin microneedle crystals has sustained-release properties. The in vitro skin was an in vitro skin biopsy tissue (Genoskin, NativeSkin™ #NSA20, Lot No. 20250210.02, skin type (Fitzpatrick classification) 3) taken from the abdomen of a 40-year-old woman.

[0107] [Experimental Example 2-1] Confirmation of the sustained-release properties of an oil-in-water composition containing allantoin microneedle crystals

[0108] First, Nile Red (Sigma Aldrich, 72485-100mg) fluorescent dye reagent was dissolved in DMSO solution to a concentration of 1 mg / mL, and then mixed into the allantoin microneedle crystals of Example 1 to a concentration of 2% (v / w) (Nile Red concentration: 20 μg / mL). Subsequently, as an oil-in-water composition containing the allantoin microneedle crystals, an essence formulation (specifically, purified water, butylene glycol, dipropylene glycol, glycerin, propylene glycol, 1,2-hexanediol, caprylic / capric triglyceride, ammonium acryloyl dimethyl taurate / VP copolymer, polyglycerol-6 caprylate, polyglycerol-4 caprate, hydrogenated lecithin, cholesterol, sodium methylstearoyl taurate, ethylhexylglycerin, tocopherol) was mixed at a volume ratio of 50:950 to prepare an essence formulation composition (Example 2) (Nile Red concentration: 1 μg / mL). The serum-form cosmetic composition was prepared by mixing according to methods commonly used in the cosmetics industry. Subsequently, it was left to stand at room temperature for 1 hour and stained, and the allantoin microneedle crystals were dissolved in deionized water (DI water) to achieve a final concentration of 5%, thereby preparing the sample.

[0109] Then, on the day the skin biopsy tissue arrived, 2 mL of tissue culture medium was added, and the tissue was stabilized and cultured for 1 day in a 37°C, 5% CO2 incubator. The next day, 20 μL of the oil-in-water composition of Example 2 stained with Nile Red was dropped onto the epidermis and then rubbed with silicone rubber (Nile Red concentration: 1 μg / mL). After air-drying at 37°C for 1 hour using a thermomixer in a laminar flow hood, the tissue was further cultured for 1 hour and 7 hours in a 37°C, 5% CO2 incubator, respectively. After 1 hour or 7 hours following application, the epidermis was rinsed with deionized water (DI water) and fixed with formalin solution. Frozen sections of the fixed skin tissue were prepared and observed using a confocal laser scanning microscopy (Carl Zeiss, model: LSM980).

[0110] To observe cross-sections of skin tissue, a 40X objective lens was used with an excitation wavelength of 561 nm and an emission wavelength of 600 to 700 nm. Three images of Nile red fluorescence and brightfield signals were acquired for each group.

[0111] Finally, cross-sections of skin biopsy tissues were photographed 2 hours and 8 hours after application of the oil-in-water composition containing allantoin microneedle crystals from Example 2. Figure 3a And the skin absorption capacity is assessed by measuring the relative fluorescence intensity (au) through the fluorescent staining. Figure 3b As the untreated group, cross-sections of skin biopsy tissues that were not treated with allantoin microneedle crystals and allantoin powder but only fluorescently stained were photographed, and the relative fluorescence intensity was measured.

[0112] like Figure 3a and Figure 3b As shown, the oil-in-water composition of Example 2 was rapidly absorbed by the skin after 2 hours of application, exhibiting a fluorescence intensity of 7.17 au. Even after 8 hours of application, the fluorescence intensity remained at 4.25 au. This confirms that the composition of Example 2 remained in the stratum corneum of the skin for an extended period.

[0113] Furthermore, based on the above results, skin absorption capacity was assessed by considering the relative fluorescence intensity over time, based on the skin depth (z-depth) from the outermost layer of the stratum corneum to the interior. Figure 3c It was confirmed that, after 2 to 8 hours of application, allantoin microneedle-like crystals were still present inside the stratum corneum of the oil-in-water composition of Example 2. Moreover, as time went on, the median value of z-depth shifted to the right, which suggests that the allantoin microneedle-like crystals moved inward into the skin. For a full 8 hours after application, allantoin continued to be released from inside the stratum corneum, thus the oil-in-water composition of Example 2 has sustained-release properties.

[0114] [Experimental Example 2-2] Confirmation of the sustained-release properties of an oil-in-water composition containing allantoin microneedle crystals

[0115] Since the sustained-release properties of the water-in-oil composition containing allantoin microneedle crystals have been demonstrated by Experiment 2-1, the same experiment as in Experiment 2-1 was conducted to confirm whether the oil-in-water composition also has sustained-release properties.

[0116] However, in this Experimental Example 2-2, an oil-in-water composition (Example 3) was used instead of the water-in-oil composition of Example 2. Specifically, the oil-in-water composition, as a liposome dosage form, was prepared according to methods commonly used in the cosmetics industry, and the result is as follows: Figure 4a and Figure 4b As shown.

[0117] like Figure 4a and Figure 4b As shown, the liposome formulation composition of Example 3 exhibited similar fluorescence intensities of 4.26 au and 4.34 au after 2 hours and 8 hours of application, respectively, thus confirming that the composition of Example 3 remained in the stratum corneum of the skin for a long time and was continuously absorbed by the skin.

[0118] [Experimental Examples 2-3] Confirmation of the sustained-release properties of oil-in-water and liposomal formulations containing allantoin needle crystals

[0119] Based on the results of Experiments 2-1 and 2-2 above, the skin absorption capacity of the oil-in-water and liposomal formulations containing allantoin needle crystals from Example 1 was compared. Figure 5a and Figure 5b ).

[0120] like Figure 5a As shown, the oil-in-water composition of Example 2 was confirmed to have a faster skin absorption rate and better skin penetration compared to the liposome formulation composition of Example 3. Furthermore, as... Figure 5b As shown, the oil-in-water composition of Example 2 and the water-in-oil composition of Example 3 both exhibited high fluorescence intensity in the stratum corneum of the skin after 2 hours and 8 hours of application. This indicates that the allantoin microneedle crystals within the compositions continuously release allantoin after penetrating the stratum corneum, thus the compositions of Examples 2 and 3 possess sustained-release properties. In particular, the liposome formulation composition of Example 3 exhibited similar fluorescence intensity values ​​after 2 hours and 8 hours of application, confirming that it remains within the stratum corneum at a certain rate, thereby possessing a sustained-release mechanism.

[0121] Therefore, it can be understood that compositions containing allantoin microneedle crystals according to one aspect of the present invention, regardless of their type, penetrate into the stratum corneum of the skin after being applied to the skin, and then slowly release the active ingredient allantoin over a long period of time, allowing it to be continuously absorbed by the stratum corneum and the epidermis, thereby having a sustained-release characteristic.

[0122] [Experimental Example 3] Confirmation of the effectiveness of allantoin microneedle crystals as an active ingredient delivery system

[0123] As shown in the results of Experiments 1 and 2 above, the allantoin microneedle crystals according to one aspect of the present invention can penetrate into the skin to continuously release allantoin in a sustained-release manner. Therefore, it is speculated that the allantoin microneedle crystals can be used as an active ingredient delivery system, and experiments were conducted to confirm this effect.

[0124]

Experimental Example 3-1

[0125] The allantoin powder from Experimental Example 1 was completely dissolved in glycerol, and then water was added to precipitate the allantoin using the same method as in Experimental Example 1. The precipitate was then filtered and dried under reduced pressure to prepare allantoin microneedle-like crystals. Subsequently, retinol (Soybean oil and glycerol 10s) were added... RETINOL))) (BASF CompanyLtd.,Retinol 10 SU TM The retinol-impregnated microneedle crystals were then added to the dried crystals for impregnation. After dispersion and mixing, the mixture was dried again to obtain retinol-impregnated microneedle crystals (Example 4). The components and contents in the above preparation process are shown in Table 1 below.

[0126]

Experimental Example 3-2

[0127] The allantoin powder from Experiment 1 and Centella asiatica selec. extract (asiaticoside, hydroxyasiatic acid, and asiatic acid) were used. MADECASSIC ACID ASIATIC ACID)) (Givaudan Fragrances Shanghai LTD, CENTELLA ASIATICA TRITERP. / C TM The extract was dissolved together with glycerol, then precipitated by adding water using the same method as in Example 1, followed by filtration and vacuum drying. Through this process, microneedle-shaped crystals containing Centella asiatica extract were obtained (Example 5). The components and their contents in the above preparation process are shown in Table 1 below.

[0128] [Experimental Example 3-3] Solubility and somatosensory evaluation of allantoin microneedle crystals containing the active ingredient.

[0129] The solubility, crystal morphology, and skin sensation of the allantoin microneedle crystals of Examples 4 and 5 in polyols, specifically glycerol, were evaluated and are shown in Table 1 below. Solubility is indicated by X for insoluble, △ for slightly soluble, and ○ for readily soluble. Skin sensation is an assessment of whether applying Examples 4 and 5 to the face resulted in a sensation similar to that experienced in dermatological treatment.

[0130] Table 1

[0131] Unit: weight %

[0132]

[0133] [Experimental Examples 3-4] Confirmation of the effectiveness of allantoin microneedle crystals as an active ingredient delivery system

[0134] To confirm whether the allantoin microneedle crystals of Examples 4 and 5 could function as an active ingredient delivery system, the amount of active ingredient added in each of Examples 3-1 and 3-2, the content in the final prepared crystals, and the content ratio in the crystals relative to the amount added were measured. The results are shown in Table 2 below.

[0135] Table 2

[0136]

[0137] This result confirms retinol as a representative fat-soluble component. Figure 6 The retinol is completely impregnated in the allantoin microneedle crystals, thereby turning the white retinol into yellow, and is absorbed and loaded into the crystals while maintaining the retinol content. Figure 7 This is a photograph of allantoin microneedle-like crystals containing retinol dissolved in deionized water. Furthermore, water solubility was confirmed, specifically the solubility in polyols, as seen in Centella asiatica extract (a representative component). Figure 8 Approximately 60% to 67% of the allantoin co-crystallizes to form the allantoin microneedle-like crystals, while the remaining approximately 33% to 40% dissolves in water and is dispersed. The homogeneity of both components is % RSD < 2%.

[0138] Thus, according to one aspect of the invention, allantoin microneedle crystals convert poorly soluble allantoin into soluble and crystallize it, thereby making the crystals usable as an active ingredient delivery system for delivering various ingredients, specifically lipid-soluble or water-soluble active ingredients, into the skin.

[0139] Therefore, it can be confirmed that the allantoin microneedle crystals and compositions (regardless of type) containing the allantoin according to one aspect of the present invention penetrate into the skin, gradually releasing allantoin, which is continuously absorbed into the stratum corneum and epidermis, exhibiting sustained-release properties. Furthermore, they can be used as an active ingredient delivery system to deliver various ingredients, specifically lipid-soluble or water-soluble active ingredients, into the skin, thereby releasing the allantoin itself or the active ingredient impregnated in the crystals in a sustained-release manner, maintaining a long-term and stable effect. This not only reduces side effects such as skin irritation or allergic reactions but also enables the continuous delivery of active ingredients to specific sites, effectively improving skin condition. Due to the continuous release of small amounts of ingredient, it has excellent effects in facilitating long-term skin care without damaging the skin barrier.

[0140] Examples of dosage forms of compositions according to the present invention will be described below, but these are not intended to limit the invention, but only to illustrate the invention in detail.

[0141] [Dosage Form Example 1] Nourishing Toner

[0142] Nourishing toners can be prepared using conventional methods according to the components listed in Table 3 below.

[0143] Table 3

[0144]

[0145] [Dosage Form Example 2] Nutritional Emulsion

[0146] Nutritional emulsions can be prepared using conventional methods according to the components listed in Table 4 below.

[0147] Table 4

[0148]

[0149] [Dosage Form Example 3] Nourishing Cream

[0150] The nourishing cream can be prepared using conventional methods according to the components listed in Table 5 below.

[0151] Table 5

[0152]

[0153] [Dosage Form Example 4] Ointment

[0154] The ointment can be prepared using conventional methods according to the components listed in Table 6 below.

[0155] Table 6

[0156]

[0157] While specific aspects of the invention have been described above in detail, those skilled in the art should understand that these specific descriptions are merely preferred embodiments and are not intended to limit the scope of the invention. Therefore, the essential scope of the invention will be defined by the appended claims and their equivalents.

Claims

1. A sustained-release dosage form of transdermal drug delivery composition comprising allantoin microneedle-like crystals.

2. The composition according to claim 1, wherein, The allantoin microneedle-like crystals have one or more of the following characteristics: an average length of long axis of 5 to 500 μm; and a thickness greater than 0 and less than or equal to 40 μm.

3. The composition according to claim 1, wherein, The allantoin microneedle-shaped crystals are soluble.

4. The composition according to claim 1, wherein, The allantoin microneedle-shaped crystals penetrate the skin when applied.

5. The composition according to claim 1, wherein, The allantoin microneedle-like crystals remain within the stratum corneum of the skin after 2 to 36 hours following application.

6. The composition according to claim 1, wherein, The allantoin microneedle crystals, after being applied to the skin, dissolve and are absorbed when rolled repeatedly 10 times at a weight of 0.5 to 1.0 kg / cm².

7. The composition according to claim 1, wherein, The allantoin microneedle-like crystals also contain betaine.

8. The composition according to claim 1, wherein, The composition is an oil-dispersible, water-dispersible, water-in-oil, oil-in-water, or multi-emulsion composition.

9. Use of allantoin microneedle crystals in the preparation of transdermal drug delivery cosmetic compositions for use in sustained-release formulations for exfoliation, skin moisturizing, skin wound healing, promoting skin regeneration, or protecting the skin from irritation.

10. Use of allantoin microneedle crystals in the preparation of transdermal drug delivery pharmaceutical compositions for sustained-release dosage forms used to heal skin wounds.

11. An active ingredient delivery system, serving as an active ingredient delivery system for delivering an active ingredient into the skin, wherein, The system contains allantoin microneedle-shaped crystals. The allantoin microneedle-like crystals have one or more of the following characteristics: an average length of long axis of 5 to 500 μm; and a thickness greater than 0 and less than or equal to 40 μm.

12. The active ingredient delivery system according to claim 11, wherein, The system also contains an active ingredient within the allantoin microneedle-shaped crystals.

13. The active ingredient delivery system according to claim 12, wherein, The active ingredient is water-soluble or fat-soluble.

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