# US 11,013,670 B2 · Hyaluronic acid microstructure having excellent solubility characteristics

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- Number: US 11,013,670 B2
- Document ID: US11013670B2
- Status: Granted
- Kind: B2
- Application number: 16/310,488
- Filed: 2017-06-16
- Published: 2019-11-07
- Granted: 2021-05-25
- Earliest claimed: 2016-06-16
- Assignees: Endoderma Co., Ltd.
- Applicants: Endoderma Co., Ltd.
- Inventors: Jae Soo Kim; Soon Chang Kwon; Sang Jin Park
- Web page: https://patentgrep.com/patent/US11013670B2

## CPC

- A61K 8/0216: {Solid or semisolid forms}
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K 8/735: {Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof}
- A61K 9/0021: {Intradermal administration, e.g. through microneedle arrays or needleless injectors}
- A61K 47/38: Cellulose; Derivatives thereof
- A61M 37/00: Other apparatus for introducing media into the body (for reproduction or fertilisation A61B17/425; apparatus for iontophoresis or cataphoresis A61N1/30); Percutany, i.e. introducing medicines into the body by diffusion through the skin (salt baths A61H33/04)
- A61M 37/0015: {by using microneedles}
- A61Q 19/00: Preparations for care of the skin
- A61Q 19/08: Anti-ageing preparations
- A61K 2800/91: Injection
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS

## Abstract

The present invention relates to a hyaluronic acid microstructure having excellent solubility characteristics. More specifically, the present invention relates to a biodegradable microstructure comprising crosslinked hyaluronic acid and having excellent solubility characteristics during skin penetration. When the microstructure of the present invention is penetrated into the skin, the solubility characteristics in the skin are excellent, the dissolution rate in the skin can be easily controlled according to the content ratio of the crosslinked hyaluronic acid, and, while effective ingredients provided on the microstructure can be stably delivered into the skin, the release rate of the provided effective ingredients can be easily controlled, and thus the present invention can be used as a transdermal delivery system for pharmacologically active materials or skin improvement materials.

## Claims

### Claim 1

A skin penetrating microneedle comprising, as a main ingredient, i) crosslinked hyaluronic acid or ii) a mixture of crosslinked hyaluronic acid and non-crosslinked hyaluronic acid, wherein, relative to the weight of the overall hyaluronic acid, the content of the crosslinked hyaluronic acid is 5-100% (w/w) and the content of the non-crosslinked hyaluronic acid is 0-95% (w/w),
wherein the skin penetrating microneedle has a length of 80-1500 μm,
wherein a tip of the skin penetrating microneedle is in a cone shape, and configured to penetrate the skin,
wherein when the microneedle is allowed to penetrate the skin by a force of 3 kgf, the microneedle shows a dissolution rate at which, on the basis of the length of the microneedle, 60% or less dissolves 10 minutes after skin penetration, 75% or less dissolves 30 minutes after skin penetration, and 85% or less dissolves 60 minutes after skin penetration.

### Claim 2 (depends on 1)

The skin penetrating microneedle of claim 1, wherein the crosslinked hyaluronic acid is 15-30% on the basis of the weight of the overall hyaluronic acid when the microneedle is allowed to penetrate the skin by a force of 3 kgf, the microneedle shows a dissolution rate at which, on the basis of the length of the microneedle, 50-60% dissolves 10 minutes after skin penetration, 65-75% dissolves 30 minutes after skin penetration, and 70-85% dissolves 60 minutes after skin penetration.

### Claim 3 (depends on 1)

The skin penetrating microneedle of claim 1, wherein the crosslinked hyaluronic acid is 30-35% on the basis of the weight of the overall hyaluronic acid when the microneedle is allowed to penetrate the skin by a force of 3 kgf, the microneedle shows a dissolution rate at which, on the basis of the length of the microneedle, 45-55% dissolves 10 minutes after skin penetration, 56-68% dissolves 30 minutes after skin penetration, and 65-75% dissolves 60 minutes after skin penetration.

### Claim 4 (depends on 1)

The skin penetrating microneedle of claim 1, wherein the crosslinked hyaluronic acid is 35-50% on the basis of the weight of the overall hyaluronic acid when the microneedle is allowed to penetrate the skin by a force of 3 kgf, the microneedle shows a dissolution rate at which, on the basis of the length of the microneedle, 40-55% dissolves 10 minutes after skin penetration, 51-61% dissolves 30 minutes after skin penetration, and 55-65% dissolves 60 minutes after skin penetration.

### Claim 5 (depends on 1)

The skin penetrating microneedle of claim 1, wherein the crosslinked hyaluronic acid is 50-70% on the basis of the weight of the overall hyaluronic acid when the microneedle is allowed to penetrate the skin by a force of 3 kgf, the microneedle shows a dissolution rate at which, on the basis of the length of the microneedle, 35-45% dissolves 10 minutes after skin penetration, 44-54% dissolves 30 minutes after skin penetration, and 48-58% dissolves 60 minutes after skin penetration.

### Claim 6 (depends on 1)

The skin penetrating microneedle of claim 1, wherein the crosslinked hyaluronic acid is 70-90% on the basis of the weight of the overall hyaluronic acid when the microneedle is allowed to penetrate the skin by a force of 3 kgf, the microneedle shows a dissolution rate at which, on the basis of the length of the microneedle, 35-45% dissolves 10 minutes after skin penetration, 41-51% dissolves 30 minutes after skin penetration, and 45-56% dissolves 60 minutes after skin penetration.

### Claim 7 (depends on 1)

The skin penetrating microneedle of claim 1, wherein the concentration of the hyaluronic acid is 1-10% (w/v) relative to water or an aqueous solvent constituting i) the crosslinked hyaluronic acid or ii) the hyaluronic acid mixture.

### Claim 8 (depends on 1)

The skin penetrating microneedle of claim 1, wherein the molecular weight of the crosslinked and the non-crosslinked hyaluronic acid is 100-5000 kDa.

### Claim 9 (depends on 1)

The skin penetrating microneedle of claim 1, wherein the crosslinked hyaluronic acid has a degree of crosslinking of 1-50%.

### Claim 10 (depends on 1)

The skin penetrating microneedle of claim 1, wherein the microneedle has a Young's modulus of 0.4-0.7 N/100 μm.

### Claim 11 (depends on 1)

The skin penetrating microneedle of claim 1, wherein 80% of the microneedle penetrates the skin.

### Claim 12 (depends on 1)

The skin penetrating microneedle of claim 1, wherein the microneedle further comprises a biocompatible polymer or an adhesive.

### Claim 13 (depends on 12)

The skin penetrating microneedle of claim 12, wherein the biocompatible polymer is at least one polymer selected from the group consisting of carboxymethyl cellulose (CMC), alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polylactide, polyglycolide (PGA), polylactide-glycolide copolymer (PLGA), pullulan polyanhydride, polyorthoester, polyetherester, polycaprolactones, polyesteramide, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefin, polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), hydroxypropyl cellulose (HPC), cyclodextrin, copolymers of monomers forming these polymers, and cellulose.

### Claim 14 (depends on 12)

The skin penetrating microneedle of claim 12, wherein the adhesive is at least one adhesive selected from the group consisting of silicone, polyurethane, a physical adhesive (Gecko), polyacryl, ethyl cellulose, hydroxy methyl cellulose, ethylene vinyl acetate, and polyisobutylene.

### Claim 15 (depends on 1)

The skin penetrating microneedle of claim 1, wherein the microneedle further comprises a pharmacologically active ingredient or a cosmetical ingredient.