JP-7856246-B2 - Tip-loaded microneedle array for percutaneous insertion

Inventors

• ルイス ディー． ファロ ジュニア
• ゲーザ エルドス
• オー． ブラック オズドガンラー

Assignees

• ユニバーシティ オブ ピッツバーグ － オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション
• カーネギーメロン ユニバーシティ

Dates

Publication Date

20260511

Application Date

20210913

Priority Date

20120501

Claims (6)

1. A microneedle array for treating skin cancer in a target skin region, It's cargo, A soluble biocompatible material containing a dehydrated carboxymethylcellulose hydrogel layer , and The dehydrated carboxymethylcellulose hydrogel layer contains a therapeutically effective amount of one or more bioactive components, the one or more bioactive components comprising 100 μg of doxorubicin and at least one viral vector per microneedle array , cargo, The invention comprises a base and a plurality of microneedles extending from the base, The plurality of microneedles include an upper half, a lower half, and an intermediate portion located between the upper half and the lower half. The aforementioned plurality of microneedles taper from the middle portion to a certain point in the upper half, The aforementioned point has a vertex angle greater than 30 degrees, The cargo is positioned within the upper half of the plurality of microneedles, and the base does not contain any bioactive components. The microneedle array is configured to be inserted into the target skin region of the subject, and the microneedle array is configured to penetrate the stratum corneum and deliver one or more of the bioactive components to the epidermis and/or dermis by dissolving the microneedles, thereby providing the subject with a therapeutically effective amount of one or more of the bioactive components through local skin delivery without systemic exposure. Microneedle array.
2. The microneedle array according to claim 1, wherein the one or more bioactive components of the microneedle array include at least two different chemotherapeutic agents.
3. The microneedle array according to claim 2, wherein the at least two chemotherapeutic agents include a cytotoxic agent and an immunostimulant.
4. The microneedle array according to claim 3, wherein the immunostimulator comprises at least one adjuvant.
5. The microneedle array according to claim 1, wherein the one or more bioactive components are selected from the group consisting of chemotherapeutic agents, adjuvants, and chemoattractants for cancer chemoimmunotherapy.
6. The microneedle array according to claim 1, wherein the at least one viral vector comprises an adenovector.

Description

Related Application: This application claims the benefit of U.S. Provisional Patent Application No. 61/641,209, filed on 1 May 2012, which is incorporated herein by reference in its entirety. Field This disclosure relates to systems and methods for transdermal drug delivery, and more particularly to systems and methods for preparing and using soluble microneedle arrays. Government-Supported Approval: This invention was made with government support under authorization numbers EB012776, AI076060, and CA121973, granted by the National Institutes of Health. The government has certain rights in this invention. Background: The skin's prominent physical barrier function presents significant challenges for transdermal drug delivery. To address these challenges, various microneedle array-based drug delivery devices have been developed. For example, one conventional method uses solid or hollow microneedle arrays that contain no active ingredients. Such microneedle arrays can pre-treat the skin by perforating the stratum corneum and upper layers of the epidermis to enhance transdermal drug penetration before topical application of biopharmaceutical carriers or traditional patches. While this method has been shown to significantly increase skin permeability, it offers only limited ability to control the dosage and amount of the drug or vaccine being delivered. Another conventional method uses solid microneedles coated with the drug. While this method offers somewhat better dose control, it severely limits the amount of drug delivered. This drawback restricts the widespread application of this technique, for example, hindering the simultaneous delivery of optimal amounts of antigen and/or adjuvants in vaccine administration. Another conventional method involves using hollow microneedles attached to a reservoir of the biopharmaceutical. The syringe-needle-like characteristics of these arrays can significantly increase the speed and accuracy of delivery, as well as the volume of cargo delivered. However, complex fabrication procedures and specific application settings limit the applicability of such reservoir-based microneedle arrays. Another conventional method involves using biodegradable and soluble solid microneedle arrays. Current fabrication techniques for soluble polymer-based microneedles generally utilize a microcasting process. However, such conventional processes are wasteful because they are limited to the active ingredients that can be embedded in the array and require the active ingredients to be homogeneously embedded in the microneedles and their supporting structures. Figure 1 shows exemplary microneedles and their dimensions.Figure 2 shows an exemplary microneedle array and its dimensions.Figures 3A and 3B show exemplary microneedles with the active ingredient loaded at their tips.Figures 4A and 4B show exemplary microneedles with the active ingredient loaded at their tips.Figures 5A and 5B show exemplary microneedles with the active ingredient loaded at their tips.Figures 6A and 6B show exemplary microneedles with the active ingredient loaded at their tips.Figure 7 shows a miniature precision micromilling system used to manufacture microneedle master molds.Figure 8 is an SEM image of a micromilled master mold with a pyramidal needle.Figure 9 is an SEM image of a pyramid production mold.Figure 10 is an SEM image of a magnified segment of a manufacturing mold, showing a pyramidal needle molding well in the center of the image.Figures 11A to 11D show exemplary CMC solids and embedded active ingredients.Figures 12A and 12B show exemplary CMC solids and embedded active ingredients.Figure 13 is a schematic diagram of an exemplary vertical multilayered structure and a method for fabricating it.Figure 14 is a schematic diagram of an exemplary microneedle array fabricated using stratification and spatial distribution techniques for embedded active ingredients.Figure 15 is a schematic diagram of an exemplary microneedle array fabricated in a spatially controlled manner.Figure 16A shows SEM images of multiple pyramidal molded microneedles.Figure 16B is an SEM image of a single pyramidal molded microneedle.Figure 17 is an SEM image of a columnar molded microneedle.Figure 18 is a micrograph of a pyramidal-shaped molded microneedle.Figure 19 is a micrograph of a columnar molded microneedle.Figure 20 shows various microneedle geometries that can be formed using a micro-milled master mold or by directly micro-milling a block of material.Figure 21 shows a test apparatus for conducting destructive and piercing tests.Figure 22 shows the force-displacement curves for a columnar microneedle (left) and a pyramidal microneedle (right).Figure 23 shows finite element models of the deflection of columnar microneedles (left) and pyramidal microneedles (right).Figure 24 shows various stereomicrographs of pyramidal (A, C, E) and columnar (B, D, F) microneedle penetrations in skin explants.Figures 25A, 25B, and 25C illustrate the ef