# US 12,005,221 B2 · Cryo formulation-based microneedle device for transdermal delivery of bioactive therapeutic agents and cancer immunotherapy using a cryo-microneedle patch

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- Number: US 12,005,221 B2
- Document ID: US12005221B2
- Status: Granted
- Kind: B2
- Application number: 17/443,507
- Filed: 2021-07-27
- Published: 2022-03-03
- Granted: 2024-06-11
- Earliest claimed: 2020-08-28
- Assignees: City University of Hong Kong
- Applicants: City University of Hong Kong
- Inventors: Peng Chen; Chenjie Xu; Hao Chang
- Web page: https://patentgrep.com/patent/US12005221B2

## CPC

- A61M 37/0015: {by using microneedles}
- A61K 35/15: Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells (presenting a specific antigen A61K39/00; therapeutic combinations of antibodies, or fragments thereof, and blood-derived cells A61K39/00)
- B29C 39/003: {characterised by the choice of material}
- B29C 39/026: {characterised by the shape of the surface}
- B29C 39/26: Moulds or cores
- B29C 39/38: Heating or cooling
- A61M 2037/0023: {Drug applicators using microneedles}
- A61M 2037/0046: {Solid microneedles}
- A61M 2037/0053: {Methods for producing microneedles}
- A61M 2037/0061: {Methods for using microneedles}
- B29K 2105/0035: {Medical or pharmaceutical agents}
- B29K 2105/0073: {Solution}
- B29K 2883/00: Use of polymers having silicon, with or without sulfur, nitrogen, oxygen, or carbon only, in the main chain, as mould material
- B29K 2905/00: Use of metals, their alloys or their compounds, as mould material
- B29L 2031/7544: {Injection needles, syringes}
- B29L 2031/756: {Microarticles, nanoarticles}
- 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)}
- 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)
- B29C: SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING (making preforms B29B11/00; making laminated products by combining previously unconnected layers which become one product whose layers will remain together B32B37/00 - B32B41/00)
- B29K: INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR {MOULDS, } REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
- B29L: INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES

## Abstract

A cryo formulation-based microneedle device for transdermal delivery of bioactive therapeutic agents. The microneedle device includes: one or more microneedle patches each including an array of miniaturized needles, wherein each miniaturized needle defining a base end and a tip; and a substrate to which the base end of the array of miniaturized needles is attached or integrated thereto; wherein the microneedle patch is in a cryo status; wherein each of the one or more microneedle patch is adapted to be applied on a skin surface, in which the miniaturized needles penetrates into skin; and wherein the miniaturized needles is further arranged to melt so as to release one or more bioactive therapeutic agents into the skin to achieve a targeted therapeutic effect.

## Claims

### Claim 1

A cryo formulation-based microneedle device for transdermal delivery of bioactive therapeutic agents, comprising:
one or more microneedle patches each including an array of miniaturized needles, each miniaturized needle defining a base end and a tip; and
a substrate to which the base end of the array of miniaturized needles is attached or integrated thereto;
wherein the microneedle patches are in a cryo status;
wherein each of the one or more microneedle patches are adapted to be applied on a skin surface, in which the miniaturized needles penetrate into skin;
wherein the one or more microneedle patches consist of a matrix solution and a plurality of biological cells as the one or more bioactive therapeutic agent;
wherein the miniaturized needles are further arranged to melt so as to release one or more bioactive therapeutic agents into the skin to achieve a targeted therapeutic effect; and
wherein the matrix solution consists of water and a cryoprotectant, the cryoprotectant comprises 2.5% wt of dimethyl sulfoxide (DMSO) and 100 to 200 mM sucrose.

### Claim 2 (depends on 1)

The microneedle device according to claim 1, wherein the plurality of biological cells including at least one of cancer cells, fibroblasts, endothelial cells, smooth muscle cells, stem cells, melanocytes, dendritic cells, neutrophils, and T-cells.

### Claim 3 (depends on 1)

The microneedle device according to claim 1, wherein the therapeutic agents plurality of biological cells comprise antigen-presenting cells and at least one substance arranged to boost the therapeutic effect of the antigen-presenting cells.

### Claim 4 (depends on 3)

The microneedle device according to claim 3, wherein the at least one substance includes an immune checkpoint inhibitor.

### Claim 5 (depends on 4)

The microneedle device accordance to claim 4, wherein the immune checkpoint inhibitor includes antibodies against programmed cell death protein 1 (anti-PD-1), programmed death-ligand 1 (anti-PD-L1) or cytotoxic T-lymphocyte-associated protein (anti-CTLA-4).

### Claim 6 (depends on 3)

The microneedle device according to claim 3, wherein the antigen-presenting cells include dendritic cells.

### Claim 7 (depends on 6)

The microneedle device according to claim 6, wherein the antigen-presenting cells include antigen-pulsed dendritic cells.

### Claim 8 (depends on 3)

The microneedle device according to claim 3, wherein the therapeutic effect includes activation of T-cells to enhance an antitumor immunity of the activated T-cells.

### Claim 9 (depends on 1)

A method of fabricating a microneedle device in accordance with claim 1, comprising the steps of:
casting the matrix solution containing the bioactive therapeutic agents into a mold defined with an array of microneedle structures;
freezing the solution to define the array of microneedle structures on one of the one or more microneedle patches; and
detaching the one or more microneedle patches from the mold.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the mold includes a PDMS mold or a metal mold.

### Claim 11 (depends on 9)

The method according to claim 9, further comprising the step of urging the matrix solution into the array of microneedle structures defined on the mold.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the matrix solution is urged into the mold using centrifugation.

### Claim 13 (depends on 1)

A method of using the microneedle device in accordance with claim 1, comprising the step of:
removing the microneedle device from a storage place; and
applying the microneedle device within a predetermined period of time after removal from the storage place.

### Claim 14 (depends on 13)

The method of claim 13, wherein the predetermined period of time is 1-30 seconds.

### Claim 15 (depends on 13)

The method of claim 13, wherein the one or more microneedle patches are arranged to facilitate a predetermined penetration depth of the one or more bioactive therapeutic agents into the skin.

### Claim 16 (depends on 15)

The method of claim 15, wherein the predetermined penetration depth is 50-1000 μm.

### Claim 17 (depends on 13)

The method of claim 13, further comprising the step of temporally attaching the microneedle device to a handle, thereby allowing an operator to apply the microneedle device by holding the handle.