EP4646229A2

EP4646229A2 - Microneedle particles, compositions, and methods of particle deactivation

Info

Publication number: EP4646229A2
Application number: EP24738902.6A
Authority: EP
Inventors: Mark R. Prausnitz; Andrew TADROS
Original assignee: Georgia Tech Research Institute; Georgia Tech Research Corp
Current assignee: Georgia Tech Research Institute; Georgia Tech Research Corp
Priority date: 2023-01-04
Filing date: 2024-01-04
Publication date: 2025-11-12
Also published as: WO2024148146A2; AU2024206237A1; WO2024148146A3; KR20250128990A; CN120529919A; JP2026502835A

Abstract

STAR particles and compositions thereof, the STAR particles each having a core structure and one or more microneedle-like projections extending from the core structure. STAR particle compositions include a plurality of STAR particles configured for mechanical disruption of a biological tissue, and a vehicle in which the plurality of STAR particles are dispersed, wherein the composition is adapted to contact the biological tissue surface in a manner to cause the STAR particles to mechanically disrupt the biological tissue, and subsequently to diminish the STAR particles' ability to mechanically disrupt a biological tissue by one or more deactivating mechanisms.

Description

MICRONEEDLE PARTICLES, COMPOSITIONS, AND METHODS OF PARTICLE DEACTIVATION

Cross-Reference to Related Applications

This application claims priority to U.S. Provisional Application No. 63/437,007, filed January 4, 2023. which is incorporated herein by reference.

Background

Some embodiments of microneedle particles (i.e., STAR particles) are described in U.S. Patent 11,291,816, which is incorporated herein by reference. STAR particles may be effective mechanisms for improving delivery of bioactive compounds to biological tissues, such as the skin. However, it may be undesirable for STAR particles to be used on off-target tissue, for the STAR particles to be reused, or for the STAR particles to be used in an unintended manner. Accordingly, it would be desirable to provide compositions and methods for controlling the time, spatial location, and manner or mechanism for the STAR particles to lose their abi 1 i ty to mechanically disrupt a tissue site, e.g., a target tissue. It would also be desirable to provide various means for controlling how the STAR particles may interact with the skin or other tissue site.

Brief Summary

In one aspect, a composition for application to a biological tissue is provided, the composition having a plurality of STAR particles configured for mechanical disruption of a biological tissue and a vehicle in which the plurality of STAR particles are dispersed. The composition may be adapted to (i) contact the biological tissue in a manner to cause the STAR particles to mechanically disrupt the biological tissue, and subsequently (ii) to diminish the STAR particles ability to mechanically the disrupt a biological tissue by one or more deactivating mechanisms. The one or more deactivating mechanisms may include agglomeration of the STAR particles, immobilization of the STAR particles, addition of a coating substance onto the STAR particles, swelling-induced shape change in the STAR particles, shrinking of microneedles of the STAR particles, softening or induced deformability of the STAR particles, and mechanical weakening of the STAR particles.

In more particular embodiments, the vehicle includes a liquid, which has water and/or a non-aqueous liquid, that is microencapsulated in microcapsules, the STAR particles being dispersed in the vehicle outside of the microcapsules, where the microcapsules are configured to be ruptured while in contact with the biological tissue to release the liquid and permit the liquid to contact the STAR particles. In some embodiments, the liquid is w ater. In some embodiments, the STAR particles are configured to dissolve or become porous in contact with the released liquid. In other embodiments, the STAR particles are configured to absorb the released liquid and swell, undergo a shape change and/or become soft and flexible.

In some embodiments, the biological tissue is skin and the composition is effective to transform the skin and/or the skin surface from a first state to a second state, where the STAR particles are able to penetrate the skin surface in the first state and are unable to penetrate the skin surface in the second state. In some embodiments, the first state is a diseased state and the second state is a healthy state, the first state is a dry state and the second state is a hydrated state, the first state is hyperkeratotic skin and the second state is non-hyperkeratotic skin, or the first state has a first frictional interaction between the skin surface and the STAR particles and the second state has a second frictional interaction between the skin surface and the STAR particles which is (i) reduced relative to the first frictional interaction such that the STAR particles readily slide over the skin surface without penetration, or (ii) increased relative to the first frictional interaction such that the STAR particles are substantially prevented from movement across the skin surface.

In some embodiments, the vehicle includes a film-forming composition.

In some embodiments, the STAR particles are configured to become deactivated following contact with interstitial fluid upon penetrating the biological tissue.

In some embodiments, the vehicle is adapted to dry after the composition is applied to the skin, whereby the dry ing is effective to cause the STAR particles to agglomerate.

In some embodiments, the STAR particles are configured to agglomerate in response to application of an external force effective to deform the STAR particles in a manner that promotes agglomeration. In other embodiments, the plurality of STAR particles have a magnetic, ionic, or electrostatic affinity' that that promotes agglomeration. In other embodiments, the vehicle includes a component configured to induce agglomeration of the STAR particles following application to the biological tissue.

In some embodiments, the STAR particles have pores initially filled with a material that is configured to come out of the pores during and/or following application of the composition to the biological tissue, thereby opening the pores and mechanically weakening or breaking the STAR particles after a period during or following their application to the biological tissue.

In some embodiments, the STAR particles are configured to be deactivated by immobilization of the STAR particles after application to the biological tissue. In some embodiments, the vehicle is configured to phase change into an immobilizing matrix in which the STAR particles are embedded. In some embodiments, the vehicle includes a microencapsulated reagent configured to encapsulate the STAR particles.

In some embodiments, the composition is in a liquid or semi-solid form and configured to form a STAR particle-containing film on and removable from the tissue. In some embodiments, the liquid is a viscous liquid. In some embodiments, the semi-solid form is a gel.

In some embodiments, the composition also includes one or more bioactive agents. In other embodiments, the composition also includes one or more diagnostic agents, sensors, cosmeceuticals, or nutraceuticals.

In some embodiments, the biological tissues includes a patient's skin.

In another aspect, a composition for application to a tissue is provided, the composition including a plurality of STAR particles configured for mechanical disruption of a biological tissue, and a vehicle in which the plurality of STAR particles are dispersed. The vehicle may have one or more microencapsulated reagents or solvents, microcapsules of which can be mechanically ruptured in the process of contacting the composition against the biological tissue to release the one or more microencapsulated reagents or solvents and deactivate the STAR particles' ability to mechanically disrupt the biological tissue.

In more particular embodiments, the one or more reagents or solvents are configured to cause a phase change in at least the microneedles of the STAR particles. In some embodiments, the one or more reagents or solvents are configured to at least partially dissolve the STAR particles. In other embodiments, the one or more reagents or solvents are configured to promote agglomeration of the STAR particles. In other embodiments, the one or more reagents or solvents are configured to promote immobilization of the STAR particles on the biological tissue. In other embodiments, the one or more reagents or solvents are configured to immobilize the STAR particles in a matrix material. In other embodiments, the one or more reagents or solvents are configured to promote addition of a coating substance to the STAR particles. In other embodiments, the one or more reagents or solvents are configured to swell or shrink the STAR particles. In other embodiments, the one or more reagents or solvents are configured to induce softening or deformability of the STAR particles. In other embodiments, the one or more reagents or solvents are configured to mechanically weaken the STAR particles.

In some embodiments, the biological tissue comprises a patient's skin. In a further aspect, a method is provided, the method including the steps of applying a first composition which comprises a plurality’ of STAR particles dispersed in a vehicle, onto a biological tissue, manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue, and then deactivating the STAR particles. The STAR particles may be deactivating by permitting or causing one or more of agglomeration of the STAR particles, immobilization of the STAR particles, addition of a coating substance onto the STAR particles, swelling-induced shape change in the STAR particles, shrinking of microneedles of the STAR particles, softening or induced deformability’ of the STAR particles, and mechanical weakening of the STAR particles.

In more particular embodiments, the deactivating includes addition of a second composition onto the first composition, the second composition having a first reagent or solvent, and/or the manipulation comprises rupturing microcapsules containing a second reagent or solvent effective to initiate or promote the deactivating. In some embodiments, the first and/or second reagent or solvent is configured to cause the STAR particles to be dissolved. In other embodiments, the first and/or second reagent or solvent is configured to promote agglomeration of the STAR particles. In other embodiments, the first and/or second reagent or solvent is configured to promote immobilization of the STAR particles on the biological tissue surface. In other embodiments, the first and/or second reagent or solvent is configured to immobilize the STAR particles in a matrix material. In other embodiments, the first and/or second reagent or solvent is configured to promote addition of a coating substance to the STAR particles. In other embodiments, the first and/or second reagent or solvent is configured to swell, cause a shape change or shrink the STAR particles. In other embodiments, the first and/or second reagent or solvent is configured to induce softening or deformability of microneedles of the STAR particles. In other embodiments, the first and/or second reagent or solvent is configured to mechanically weaken the STAR particles.

In some embodiments, the deactivating includes application of an external stimulus to the first composition and/or the biological tissue surface, the application of the external stimulus being selected from (a) exposure to visible, near-infrared or ultraviolet light, (b) changes in temperature, (c) changes in pressure, (d) addition, modification or removal of chemical entities, (e) application of ultrasound, (f) application of electromagnetic radiation, (g) application of a magnetic field, and (h) combinations thereof.

In some embodiments, the vehicle includes a film-forming composition. In other embodiments, the vehicle undergoes a phase change into an immobilizing matrix in which the STAR particles are embedded. In some embodiments, the STAR particles have a magnetic, ionic, or electrostatic affinity that promotes agglomeration. In other embodiments, the STAR particles are porous and mechanically weakened after a period of time during and/or following the applying of the first composition onto the biological tissue.

In some embodiment, the first composition is applied to the biological tissue in a liquid or semi solid form and forms a STAR particle-containing film, and the method also includes removing the STAR particle-containing film from the biological tissue.

In yet another aspect, a method is provided, the method including the steps of applying a first composition which comprises a plurality of STAR particles dispersed in a vehicle, onto a biological tissue, manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue, and then deactivating the STAR particles by adding a second composition to the first composition wherein the second composition comprises a solvent which dissolves at least a portion of the STAR particles.

In more particular embodiments, the composition also one or more bioactive agents. In some other embodiments, the composition further comprises one or more diagnostic agents, sensors, cosmeceuticals. or nutraceuticals.

In some embodiments, the biological tissue comprises human skin.

In an even further aspect, a method is provided, the method including the steps of applying a composition which comprises a plurality of STAR particles dispersed in a vehicle, onto a patient's skin in a first state, and manipulating the composition to cause the STAR particles to mechanically disrupt the stratum comeum of the patient’s skin in the first state, transforming the patient's skin, via contact with one or more components in the vehicle, into a second state in which the STAR particles are unable to mechanically disrupt the stratum comeum.

Brief Description of the Figures

The detailed description is set forth with reference to the accompanying drawings. The use of the same reference numerals may indicate similar or identical items. Various embodiments may utilize elements and/or components other than those illustrated in the drawings, and some elements and/or components may not be present in various embodiments. Elements and/or components are not necessarily drawn to scale.

FIG. 1 A is a plan view of a planar STAR particle according to one embodiment of the present disclosure.

FIG. IB is a perspective view of the planar STAR particle of FIG. 1 A.

FIG. 1C is a plan view of a planar STAR particle according to another embodiment of the present disclosure. FIG. ID is a perspective view of the microneedle particle of FIG. 1C.

FIG. IE is a side view of the microneedle particle of FIG. 1C.

FIG. 2A is a plan view of a planar STAR particle according to another embodiment of the present disclosure, in which the tip portions of the microneedles (i.e., the projections) of the particles include an additional substance.

FIG. 2B is a plan view of a planar STAR particle according to another embodiment of the present disclosure, in which the tip portions of projections are changing phase from a solid to a liquid and/or gas.

FIG. 2C is a plan view of a planar STAR particle according to another embodiment of the present disclosure, in which the projections are disintegrating (e.g., dissolving).

FIG. 2D depicts a disintegrated STAR particle.

FIG. 3A is a plan view of a STAR particle according to another embodiment of the present disclosure, in which the projections have become swollen.

FIG. 3B is a plan view of a STAR particle according to another embodiment of the present disclosure, in which the projections have become bent (e.g.. by softening to become elastically or plastically deformed/deformable).

FIG. 3C is a plan view of a STAR particle according to another embodiment of the present disclosure, in which the projections have decreased mechanical strength (e.g., become brittle and/or chipped).

FIG. 3D is a plan view of a STAR particle according to another embodiment of the present disclosure, in which the projections have decreased mechanical strength and broken.

FIG. 3E is a plan view of a STAR particle according to another embodiment of the present disclosure, in which the projections have shrunken.

FIG. 4 depicts agglomerated STAR particles, according to another embodiment of the present disclosure.

FIG. 5A depicts STAR particles immobilized in a matrix, according to one embodiment of the present disclosure.

FIG. 5B depicts STAR particles immobilized in a matrix, according to another embodiment of the present disclosure.

FIG. 5C depicts STAR particles that are encapsulated and immobilized, according to one embodiment of the present disclosure.

FIG. 5D depicts STAR particles immobilized by a biological tissue, according to one embodiment of the present disclosure. Detailed Description

STAR particles that are configured to be deactivated, e.g.. following or as part of their intended use, are disclosed, along with methods for that deactivation. As used herein, the term “deactivated” and “deactivation” refer to the STAR particles’ loss of ability to mechanically disrupt a biologically tissue, particularly the stratum comeum of mammalian skin, particularly, human skin.

As used herein, a STAR particles being configured to “mechanically disrupt” a biologically tissue, particularly the stratum comeum of mammalian skin, particularly, human skin refers to the particle having dimensions and mechanical strength capable of creating holes or pores in the tissue surface. For example, the mechanically disrupting may be forming a penetration through the stratum comeum.

STAR particles may enhance topical administration of another substance, or substances, by mechanically disrupting the integrity of an outer/upper layer of skin (or other biological tissue) to facilitate local deliver}' of the substance(s) into/onto the target tissue of a patient. STAR particles may also promote passage of the substance(s) through a target tissue and uptake in the bloodstream and/or lymphatic system to facilitate systemic delivery, and/or to promote the substance(s) passage through a target tissue for uptake into another tissue or space within the body. For example, it may be desirable to use STAR particles to deliver the substance(s) into a structure beyond the skin (e.g., into the joint space for treating arthritis). The patient may be a human or other mammal. Embodiments of the present disclosure stop, limit, and/or prevent the STAR particles’ interaction with undesired targets.

In some embodiments, the STAR particles are configured to [1] at least partially disrupt a first type of biological tissue, and [2] prevent or decrease the likelihood that the STAR particles can disrupt a second type of off-target biological tissue. As used herein, the term “off-target tissue” refers to any tissue not intended to be disrupted by the STAR particles. Off-target tissues include, but are not limited to, the eye or ocular conjunctiva; oral, gastric, or vaginal mucosal membranes; or skin outside of the area of intended use or skin in the area of intended use, but not at the time of intended use. In particular, the second type of biological tissue, for example, may include the skin of the fingers, while the first type of biological tissue may include a tissue to be treated, for example, an area of the skin having a relatively thinner stratum comeum or a mucosal tissue. In this way, for example, the STAR particles may not disrupt, or may be less likely to disrupt, the skin of the fingers used to apply or rub the STAR particles onto/into the treatment area of the first biological tissue. In some embodiment, the STAR particles advantageously are configured to be selflimiting. For example, if STAR particles do not deactivate, then continued rubbing of them against skin will continue to increase skin permeability, which might be undesirable. However, when the STAR particles are configured to deactivate during rubbing on the skin, then rubbing them for a sufficient duration will produce a desired, selected increase in the amount of skin permeability, but continued rubbing beyond the sufficient duration will not produce a further material increase in permeability because the STAR particles will no longer be active.

The STAR particles disclosed herein may be configured to selectively partially or completely lose the ability to disrupt the target tissue. In some embodiments, the STAR particles may partially or completely lose the ability to disrupt the same tissue, or same tissue type, after passage of a period of time. In some embodiments, the STAR particles may partially or completely lose mechanically disruptive properties so that the STAR particles cannot be reused by the intended user. In other embodiments, the STAR particles lose mechanically disruptive properties so that the STAR particles cannot be subsequently used by a non-intended user. In still other embodiments as mentioned above, the STAR particles lose their mechanically disruptive properties during continued use.

Benefits of limiting the functional ability of STAR particles include, but are not limited to: controlling the efficacy of particle-containing formulations, controlling the number, depth, and/or diameter of micro-punctures, and/or controlling user-perceived sensations associated with applying the STAR particles to the skin, controlling the cosmetic appearance of the STAR particle-containing formulations on the skin, enhancing the safety’ profile of STAR particles and/or STAR particle-containing formulations by preventing, limiting, and/or eliminating mechanical disruption of off-target tissue(s), enhancing the environmental safety profile of STAR particles or STAR particle-containing formulations by preventing, limiting, and/or eliminating transmission between humans and/or other living species (e.g., animals) through either deliberate or inadvertent transmission through the environment, and preventing, limiting, and/or eliminating STAR particle reuse, whether it be intentional or unintentional, by the intended user or subsequent reuse by a non-intended user.

STAR Particles

The STAR particles include a core structure and one or more microneedle-like projections extending from the core structure. The microneedles may be structured to at least partially penetrate or otherw ise mechanically disrupt a biological tissue, such as the stratum comeum of human skin (or other biological tissue). That is. the microneedles are dimensioned and possess the mechanical strength and other properties to enable them to be pressed into and penetrate the biological tissue, forming a microscale hole or channel therein. The microneedles may extend independently in any direction from the core structure.

FIGS. 1A and IB depict a STAR particle 100 according to one embodiment. In this embodiment, the STAR particles 100 each have three microneedles 120 extending from the core structure 110 in the same plane, such that the STAR particle is referred to as a planar particle. The core structure typically is the portion of the microneedle particle that connects the microneedles, especially when there are three or more microneedles. The core structure may be a solid structure, or a hollow structure having one or more internal cavities. In other embodiments, the STAR particles may have two microneedles, four microneedles, five microneedles, six microneedles, seven microneedles, eight microneedles, nine microneedles, or ten microneedles extending from the core structure. In some embodiments, the microneedles extend from the core in different planes. For example, the STAR particle may have three, four, five, or more microneedles extending in different directions and planes, such that the STAR particle is referred to as a non-planar particle.

The microneedles of STAR particles may be tapered. In some embodiments, in the plan view, as shown in FIG. 1 A, the microneedle 120 tapers from the core structure 110 to the tip end, but the height of the microneedles is substantially constant. In some other embodiments, the edges of the microneedle 120 may also be tapered, as the tapered edges are sharp and thereby able to penetrate stratum comeum more easily than untapered edges. For example, in some embodiments, as shown in FIGS. 1C-1E, the microneedles 120 may taper both in width and in height. That is, the height of the microneedle is largest at the core structure and smallest at the tip. In other variations, the core and a base portion of the microneedles may have a uniform height and only the distal tip portion of the microneedles is tapered. In variations, the taper may be from one or both sides of the STAR particle.

Various design features of the STAR particles may be selected to impart the particles with the functionality preventing the entire STAR particle from penetrating a biological tissue. These features may include the core structure itself, the microneedles themselves, or the spatial relationship between/among the microneedles or a subset of those microneedles. A combination of these features may be designed to prevent the entire microneedle particle from penetrating a biological tissue.

For example, the core structure may have a size, shape, and/or a lack of sharp edges that permits one or more of the microneedles extending from the core structure to penetrate a biological tissue, but that inhibits all or substantially all of the core structure from penetrating into the biological tissue. As a further example, the microneedles may have a structural feature, such as tapering, that permits only a portion (i.e., the tip portion distal to the core structure) of the microneedles to penetrate a biological tissue. For example, a microneedle may have a shoulder or plateau that permits only the portion of the microneedle distal to the shoulder or plateau to penetrate the biological tissue. Such a configuration may prevent the core structure from penetrating the biological tissue during a penetration event between the STAR particle and the biological tissue, so that the entire STAR particle cannot become fully embedded within the biological tissue.

Generally, the microneedles of a STAR particle can have the same or different dimensions from one another. In one embodiment, the microneedles of a planar STAR particles have substantially the same dimensions.

The microneedles may have any shape effective to at least partially penetrate a biological tissue. In some embodiments, the microneedles are high-aspect-ratio structures having a length at least two times greater than its width at the base of the microneedle (i.e., at the interface of the microneedle and the core structure). The length of a microneedle is the distance from the interface of the microneedle and the core structure’s edge to the tip of the microneedle. In some embodiments, each of the microneedles independently has a length from 1 pm to 2,000 pm. In some embodiments, each of the microneedles independently has a length from 10 pm to 2,000 pm. In some embodiments, each of the microneedles independently has a length from 50 pm to 2,000 pm. In some embodiments, each of the microneedles independently has a length from 100 pm to 1,000 pm. In some embodiments, each of the microneedles independently has a length from 250 pm to 750 pm. In some embodiments, each of the microneedles independently has a length from 100 pm to 500 pm. In some embodiments, each of the microneedles has a length of about 350 pm.

In a particular embodiment, the STAR particles have three microneedles, wherein each of the microneedles independently has a length of about 1 pm to about 2,000 pm, about 10 pm to about 2,000 pm, about 50 pm to about 2,000 pm, about 100 pm to about 1,000 pm, or about 250 pm to about 750 pm. This STAR particle may be a planar particle.

The microneedles of the STAR particle may have a tip having a radius of curvature of about 0.1 pm to about 50 pm. In some embodiments, the microneedles have a tip having a radius of curvature of about 0. 1 pm to about 50 pm, about 0. 1 pm to about 25 pm, about 0. 1 pm to about 20 pm, about 0. 1 pm to about 15 pm, about 0.1 pm to about 10 pm, about 0. 1 pm to about 5 pm, about 1 pm to about 10 pm, about 1 pm to about 7 pm, about 1 pm to about 5 pm, about 1 pm to about 4 pm, about 1 pm to about 3 pm, about 5 pm to about 50 pm. about 5 pm to about 25 pm, about 5 pm to about 20 pm, about 5 pm to about 15 pm, or about 5 pm to about 10 pm. In some embodiments, each microneedle has a tip having a radius of curvature of about 5 pm to about 30 pm. The “tip” typically is the portion of the microneedles that initially penetrates a biological tissue.

In some embodiments, the STAR particles are shaped and sized to prevent, or reduce the likelihood of, the STAR particle becoming completely or irremovably embedded in the biological tissue. In some embodiments, the greatest dimension of the microneedle particles is about 100 pm to about 5,000 pm. 100 pm to about 10,000 pm. about 250 pm to about 5,000 pm, about 500 pm to about 2,000 pm, or about 500 pm to about 1,000 pm. The “greatest dimension of the microneedle particles” refers to the greatest of the following distances: [1] the distance between the tips of the two microneedles that are the farthest apart (if the microneedle particle includes two or more microneedles), or [2] the farther possible distance between a tip of a microneedle and the side of the core structure that is opposite the side from which the measured microneedle extends. A plurality of microneedle particles may include microneedle particles of one or more sizes.

In some embodiments, the microneedles of a STAR particle are planar microneedles. The phrase “planar microneedles,” as used herein, refers to two or more microneedles, each having either [1] a central axis that extends from the core structure in at least substantially the same plane, or [2] a tip that exists in substantially the same plane. The planar microneedles may include microneedles that extend from the core structure in the same direction, different directions, or a combination thereof. The planar microneedles also may include co-linear planar microneedles, which extend from opposite sides of the core structure in a manner that permits the central axis of each microneedle to at least substantially correspond with a single line. For example, where the STAR particles include two or more pairs of microneedles, the pairs of microneedles, but not necessarily all microneedles, may be co-linear.

When the microneedles are planar microneedles, the microneedle particles may have a substantially planar, i.e., flat, structure. The substantially planar, i.e., flat, microneedle particles may have a thickness of about 1 pm to about 1,000 pm, about 5 pm to about 500 pm, about 10 pm to about 250 pm. 50 pm to about 250 pm, about 50 pm to about 200 pm, about 50 pm to about 150 pm, about 75 pm to about 200 pm, about 75 pm to about 150 pm, about 75 pm to about 125 pm, or about 80 pm to about 120 pm. In some embodiments, the height (thickness) of the microneedles is consistent throughout the length of the microneedle. That is, the height of the microneedle is the same where the microneedle contacts the core structure as at the tip. In some embodiments, the height of the microneedle particles decreases along the length of the microneedle. The height of the microneedle may be largest where the microneedle particle contacts the core structure and smallest at the tip.

In some preferred embodiments of tapered STAR particles, the height of the core in the center of the STAR particles is from 100 pm to 150 pm, and the radius of curvature at the tip of the microneedles is from 5 pm to 30 pm.

In some preferred embodiments of ceramic or polymeric STAR particles, the height of the core in the center of the STAR particles is from 50 pm to 150 pm. In some embodiments of stainless steel STAR particles, the height of the core in the center of the STAR particles may be as small as 12.5 pm, and up to 150 pm. These ceramic, polymeric, or stainless steel STAR particles may include tapered microneedles, for example, having a radius of curv ature at the tip of the microneedles from 5 pm to 30 pm.

The STAR particles may be made of one or more biocompatible materials, such as metals, polymers, biopolymers, ceramics, bioactive agents, sugars, sugar alcohols, or a combination thereof. The bioactive agents generally may include one or more drugs, one or more sensors, one or more cosmeceuticals, one or more nutraceuticals, or a combination thereof. Therefore, the microneedle particles may be made of a combination of bioactive components (drugs, small molecule excipients (e g., trehalose), sensors, cosmeceuticals, nutraceuticals or a combination thereof) and inactive components (metals, polymers, ceramics, sugars, etc.). If a portion of the STAR particle remains in and/or on a biological tissue after removal of the STAR particle, then the portion of the STAR particle remaining in and/or on the biological tissue may include at least one bioactive component, at least one inactive component, or a combination thereof.

In some embodiments, the STAR particles are made of water-insoluble material(s). In some embodiments, the STAR particles are made of, or include, at least one water-soluble and/or erodible material. When the STAR particles are made of water-soluble and/or erodible material(s), the STAR particles or a portion thereof may safely degrade if left in and/or on a biological tissue, or after disposal. In one example, the STAR particle has a matrix structure, which may consist of or include a water-soluble or bioerodible material. As used herein, the term “bioerodible” means that the structure/material degrades in vivo or ex vivo by dissolution, enzymatic hydrolysis, erosion, resorption, or a combination thereof. This degradation of the STAR particles may occur on the tissue surface or in the environment but not necessarily in contact with a biological tissue. Other methods of degradation of water-soluble and/or waterinsoluble STAR particles include, but are not limited to, dissolution, hydrolysis, degradation upon contact with sunlight (i.e., UV rays), degradation resulting from a reaction with another chemical entity, degradation resulting from physical or mechanical erosion, and/or degradation resulting from a reaction with environmental factors (e.g., oxygen).

In some embodiments, the STAR particle is a metal microneedle particle. A metal microneedle particle is one in which all or substantially all of the entire structure of the microneedle particle is made of a metal or metal alloy (e.g., a stainless steel). In some other embodiments, a majority of the STAR particle is made of such metal or metal alloy materials.

In some embodiments, the STAR particle is a polymeric microneedle particle. A polymeric microneedle particle is one in which all or substantially all of the structure of the microneedle particle is made of one or more polymeric materials (e.g., biodegradable materials like poly (lactic-co-gly colic acid) (PLGA) or poly caprolactone (PCL) and/or water-soluble materials like carboxymethylcellulose or polyvinyl alcohol). In some other embodiments, a majority of the STAR particle is made of such one or more polymeric materials.

In some embodiments, the STAR particle is a ceramic microneedle particle. A ceramic microneedle particle is one in which the all or substantially all of the structure of the microneedle particle is made of one or more ceramic materials (e.g., aluminum oxide, titanium dioxide, zinc oxide, iron oxides). In some other embodiments, a majority of the STAR particle is made of such one or more ceramic materials.

In some embodiments, all or substantially all of the structure of the microneedle particle is made of a bioactive agent and/or another other substance of interest. In some embodiments, a majority of the STAR particle is made of one or more drugs.

In some embodiments, the STAR particle is an excipient microneedle particle. An excipient microneedle particle is one in which the entire structure of the microneedle particle is made of one or more pharmaceutically acceptable excipient materials known in the art (e.g., sugar, salt, starch, etc.).

In some embodiments, the STAR particle has a structure that is formed of a combination of (i) at least one metal (or metal alloy), (ii) at least one polymeric material, (iii) at least one ceramic material, (iv) at least one excipient material, and/or (v) at least one bioactive component.

The STAR particles provided herein may be made by any suitable method capable of forming a desired geometric shape of the STAR particles. Non-limiting examples of such methods include molding, mechanical or chemical etching, laser cutting, 3D printing, or other microfabrication techniques know n in the art. For example, the STAR particles may be formed by laser etching a sheet of a material. As a further example, the STAR particles may be made using a molding process that may include placing a material of construction in a mold having cavities that correspond to the desired geometry of the resulting microneedle particles. The material of construction may be a polymer or precursor thereof, and may be loaded into the mold in a powder or liquid form (e.g., molten polymer and/or polymer dissolved or dispersed in a liquid medium), and then solidified into solid monolithic form in the mold. In another example, an array of discrete particles is formed from a solid sheet of the material by a process that includes at least one of etching, punching, or cutting, such as laser cutting. The STAR particles also may be sintered, densified, and/or mechanically hardened via heating, cooling, chemical modification, light exposure, drying, compressing, and/or other processes.

STAR Particle-Containing Compositions

In various embodiments, the STAR particles are provided as a composition that facilitates application of the STAR particles to a target tissue site, e.g., a biological tissue surface, such as mammalian skin. For example, the composition may include or consist of STAR particles dispersed in a suitable medium that can flow. The medium may be a liquid, solution, lotion, cream, ointment gel, paste, emulsion, aerosol foam or spray, powder, or semi-solid. The suitable medium is referred to herein as a “vehicle”.

Essentially any suitable biocompatible vehicle may be used in the STAR particlecontaining composition. The vehicle may be an aqueous medium and/or a non-aqueous medium. The vehicle may include water, stabilizers, pH modifiers, thickening agents, or other pharmaceutically acceptable excipients known in the art for use in topical therapeutic applications, including materials that listed as Generally Recognized as Safe (GRAS) by the U.S. Food and Drug Administration.

The STAR particle-containing composition may include one or more bioactive agents (e.g., a therapeutic, adjuvant or prophylactic agent) and/or other substances of interest (e.g., diagnostic agents, sensors, cosmeceuticals). The bioactive agent, and/or the other substance of interest, may be disposed in and/or on the STAR particles, in the vehicle, or in and/or on both the STAR particles and the vehicle. In some embodiments, the bioactive agent is dissolved in the vehicle. In some embodiments, the bioactive agent is dispersed, e.g., as a particulate suspension, and/or as an emulsion, in the vehicle.

The STAR particle-containing composition generally has a viscosity suitable for its intended storage, packaging, and use (e.g.. application to a target tissue). In some embodiments, the STAR particle-containing composition is a viscous composition, having a viscosity of at least 1,000 cP. In some embodiments, the composition has a viscosity of about 1,000 cP to about 200,000 cP, about 1,000 cP to about 150,000 cP, about 1,000 cP to about 100,000 cP, about 1,000 cP to about 75.000 cP, or about 1,000 cP to about 50,000 cP. In some embodiments, the STAR particle-containing composition is a non- viscous composition, having a viscosity of less than 1,000 cP, for example, about 5 cP to about 500 cP, about 5 cP to about 250 cP, or about 5 cP to about 100 cP. In some embodiments, the STAR particle-containing composition has a viscosity of about 1 cP.

The concentration of STAR particles in the vehicle may be selected based on the particular application, but generally would be selected to achieve the intended function of the STAR particles at a particular tissue site. For example, the STAR particle concentration may be selected to be sufficient to create enough pores in the stratum comeum to deliver a desired dose (e.g.. a therapeutically effective amount) of a bioactive agent into the skin at the site of application of the STAR particle-containing composition.

In some embodiments, the concentration of STAR particles in the vehicle ranges from about 100 to about 100,000 particles per cm³ of the vehicle. In some embodiments, the concentration of STAR particles in the vehicle ranges from about 500 to about 50,000 particles per cm³ of the vehicle. In some embodiments, the concentration of STAR particles in the vehicle ranges from about 1,000 to about 25,000 particles per cm³ of the vehicle. In some embodiments, the concentration of STAR particles in the vehicle is greater than 10,000 particles per cm³ of the vehicle. In some embodiments, the concentration of STAR particles in the vehicle is less than 10,000 particles per cm³ of the vehicle.

In some embodiments, the concentration of STAR particles in the vehicle ranges from about 0.1 wt% to about 30 wt% of the vehicle. In some embodiments, the concentration of STAR particles in the vehicle ranges from about 1 wt% to about 20 wt% of the vehicle. In some embodiments, the concentration of STAR particles in the vehicle ranges from about 5 wt% to about 15 wt% of the vehicle. In some embodiments, the concentration of STAR particles in the vehicle ranges from about 8 wt% to about 12 wt% of the vehicle. In some preferred embodiments, the concentration of STAR particles in the vehicle is about 5 wt% to about 10 wt% of the vehicle.

STAR particle compositions may also include at least one substance of interest. As used herein, “substance of interest” refers to a molecule or collection of matter that has a prophylactic, therapeutic, diagnostic, or cosmetic purpose. Substances of interest may include, but are not limited to, active pharmaceutical ingredients, vaccines, allergens, vitamins, cosmetic agents, cosmeceuticals, diagnostic agents, sensors, markers (e.g., colored dyes or radiological dyes or markers), other bioactive agents, and other materials that are desirable to introduce into or onto a biological tissue. A list of substances of interest is included in U.S. Patent No. 11,291.816, which is incorporated herein by reference. Tthe substance of interest may be a small molecule, polymer, peptide, or biologic agent. In some embodiments, the substance of interest is a biological agent or a living organism. In further embodiments, the substance of interest has electronic properties. For example, the substance of interest may be responsive to radio-frequency identification (RFID).

Compositions and Methods of Deactivating STAR Particles

The STAR particles disclosed herein may be deactivated while on the skin, while in the skin, and/or after the STAR particles leave the skin. The STAR particles may also be transiently capable of mechanically disrupting tissue due to the inherent properties or synthesis of the STAR particles. For example, the STAR particles may have an inherent propensity towards addition, loss, or alteration of material, molecular or chemical instability, or instability toward changes in ambient temperature, pressure, light, and/or air composition. The STAR particles may also interact with the vehicle, target tissue, non-target tissue, and/or the environment in a manner that may also cause deactivation.

In some embodiments, a composition is provided for application to a biological tissue, wherein the composition includes (A) a plurality of STAR particles configured for mechanical disruption of a biological tissue; and (B) a vehicle in which the plurality of STAR particles are dispersed, wherein the composition is adapted (i) to contact the biological tissue surface in a manner to cause the STAR particles to mechanically disrupt the biological tissue, and subsequently (ii) to diminish the STAR particles’ ability to mechanically disrupt a biological tissue by one or more of the following deactivating mechanisms: agglomeration of the STAR particles, immobilization of the STAR particles, addition of a coating substance onto the STAR particles, swelling-induced shape change in the STAR particles, shrinking of microneedles of the STAR particles, softening or induced deformability of the STAR particles, and mechanical weakening of the STAR particles.

In some embodiments, the STAR particles may be deactivated, during and/or following its intended use, by including microneedles configured to reduce or eliminate the microneedles’ ability to partially re-penetrate a biological tissue. In some embodiments, upon penetrating a biological tissue at least once, the microneedles of the STAR particle are configured to fail mechanically, thereby preventing the microneedles from re-penetrating the biological tissue. In some embodiments, upon penetrating a biological tissue at least once, the microneedles of the STAR particle are configured to fail chemically, thereby preventing the microneedles from repenetrating the biological tissue. In some embodiments, upon penetrating a biological tissue at least once, the microneedles of the STAR particle are configured to fail mechanically and chemically, thereby preventing the microneedles from re-penetrating the biological tissue. The mechanical and/or chemical failures may occur after the microneedles penetrate a biological tissue once, twice, three times, or more. Non-limiting examples of mechanical failures include disintegrating, dissolving, softening, or fracturing the microneedles, such that there is no longer a sharp tip and/or sufficient rigidity and length to penetrate the biological tissue. Non-limiting examples of chemical failures include at least partially dissolving, or degrading by a chemical reaction, such that there is no longer a sharp tip and/or sufficient rigidity and length to penetrate the biological tissue.

Addition of Material to STAR Particles

In some embodiments, the STAR particles may be deactivated, during and/or following its intended use, by the addition of material to at least a portion of the microneedle and/or core structure, which may change the shape and/or size of the STAR particles, which may decrease or negate the STAR particles’ ability to effectively penetrate a biological tissue. FIG. 2A depicts a STAR particle 200 with added material 250 covering the tips of the microneedles 220. The added material covers sharp pointed tips of the microneedles of the STAR particles as a rounded or bulbous mass such that STAR particles lack sharp tips for penetrating tissue, and are thereby rendered nonfunctional, or deactivated. In some embodiments, the added material covers the base or core of the STAR particles to decrease or negate the STAR particles’ ability to interact with the biological tissue effectively, thereby disrupting the ability' of the STAR particles to mechanically disrupt the tissue. Sources of the (deactivating) additional material include, but are not limited to, components in the delivery’ vehicle, the STAR particles themselves, the skin, other parts of the biological tissue (e.g., components of interstitial fluid), and/or the environment. For example, the delivery’ vehicle may deposit a film onto the STAR particles such that the film prevents the STAR particles from mechanically disrupting the target tissue.

Material can associate with or adsorb to STAR particles by various mechanisms, including hydrophobic interactions, ionic bonding, hydrogen bonding, polarized bonding, covalent bonding, metallic bonding, van der Waals forces, and clathrate formation. There can also be physical entanglement at the molecular level and at longer length scales.

In some embodiments, skin debris (e.g., hair, skin cells, ISF, blood, makeup or other exogeneous material present on the skin) may associate with and accumulate on STAR particles’ as they are rubbed on the skin and thereby’ at least partly limit STAR particles’ ability to disrupt the skin. In other embodiments, STAR particles are at least partly composed of a hydrophobic polymer(s) (e.g., acry lics, epoxies. polyethylene, polysty rene, polyvinylchloride, polytetrafluorethylene, poly dimethylsiloxane, polyesters, and polyurethanes) and the formulation is at least partly composed of a hydrophobic polymer(s) where over time the formulation component(s) are added and/or adsorbed onto the STAR particles.

Removal of Material from STAR Particles

In some embodiments, the STAR particles may be deactivated, during and/or following their intended use, by the removal of solid material from at least a portion of the microneedle and/or core structure, which may decrease or negate the STAR particles’ ability’ to effectively penetrate a biological tissue. FIGS. 2B-2D depict STAR particles with loss of matter, according to several embodiments. FIG. 2B depicts a STAR particle 200 with the tip portions of the microneedles 220 undergoing a phase change from a solid to a liquid and/or a gas. Only the microneedles or the entire STAR particle may change phases. The phase change may result from exposure to the target tissue, non-target tissue, delivery vehicle, and/or the ambient environment during and/or after application of the STAR particles to a tissue site. Examples of triggers of the removal of solid material from the microneedles include changes in temperature, pH, and/or application of and/or exposure to radiant energy. In one example, the STAR particle is formed at least in part of sodium bicarbonate, which could form gaseous carbon dioxide either spontaneously or through a chemical reaction in the presence of an acid. In another example, the STAR particle is formed, at least in part, of a material with a melting point below physiologic or ambient temperature, such that the STAR particle undergoes a phase change when interacting with target biological tissue and/or the environment.

FIGS. 2C-2D depict disintegration of a STAR particle. As used herein, ‘"disintegration” refers to dissolution, breaking into pieces, chemical dissociation, biodegradation, or other similar processes. FIG. 2C depicts a STAR particle 200 where only the microneedles 220 are disintegrating. In some embodiments, the core structure may disintegrate or dissolve, while the microneedles remain intact. FIG. 2D depicts a STAR particle, where the entire particle is disintegrating. The disintegration may be or include dissolution of all or a part of the material(s) of construction forming the STAR particle.

In some embodiments, the vehicle of the STAR particle-containing composition may include a microencapsulated solvent for the material(s) of construction of the STAR particle and/or may include another material configured to cause disintegration/deactivation of the STAR particles (the other material being referred to herein as a “functional additive”). The microcapsules of the solvent (e.g., water, or a non-aqueous solvent) or material may be configured to mechanically rupture when the STAR particle-containing composition is rubbed/pressed onto the skin during an application process, to thereby release the solvent or material and permit the solvent to contact the STAR particles and disintegrate/deactivate them. The functional additive may, directly or indirectly, interact with the STAR particles in a manner effective to disintegrate/deactivate them. For example, the functional additive may be an acid (e.g., citric acid) that facilitates reaction of sodium bicarbonate in the STAR particles. The functional additive may also be an acid or base that changes the pH of the STAR particles, thereby changing the charge state of material(s) in the STAR particles and causing deactivation by dissolution. That is, changes to the pH of the STAR particles may alter the solubility and mechanically weaken the STAR particles, causing them to break from the resulting loss of ionic bonds. The functional additive may also be an enzyme or other catalyst that promotes a chemical reaction that causes the STAR particles to disintegrate/deactivate.

In some embodiments, a solvent for the material(s) of construction of the STAR particle may be added to the STAR particle-containing composition before, during, and/or following an application process. The solvent may be effective to gradually or immediately dissolve the STAR particles. The solvent may be applied alone, or in combination with a second formulation, after the STAR particle-containing composition has been applied.

The solvent or different material may also be contained within the STAR particles themselves. For example, the solvent or different material may be microencapsulated or otherwise temporarily isolated from the bulk of the materials forming the STAR particle. The solvent or different material may be configured to be released when the STAR particle-containing composition is rubbed/pressed into the skin during an application process, to thereby permit the solvent or different material to contact the bulk of the materials forming the STAR particle.

Particle Phase Change Inducement

In yet another embodiment, the STAR particles may dissolve when undergoing a phase change. For example, the phase change may change the solubility or miscibility properties of the STAR particles so that the STAR particles may be more easily dissolved in the formulation. Exposure to the ambient environment, and/or changes in temperature and/or pressure, may also be effective to dissolve the STAR particles due to, for example, change of solubility of material(s) comprising the STAR particles.

In some embodiments, the STAR particle is configured to be deactivated, following its intended use. by undergoing a change in shape, dimensions, and/or rigidity effective to reduce or negate its ability to penetrate a biological tissue. For example, the STAR particle may undergo a swelling and/or softening, causing the microneedle tips to become dull and rounded, and/or causing the microneedles to become bent or easily deformed, such that the tip portions of the microneedles are substantially incapable of penetrating the stratum comeum. Similarly, the core structure of the STAR particle may swell and/or soften, causing mechanical instability of the STAR particle and rendering it at least partially ineffective in penetrating the stratum comeum. FIG. 3A depicts a STAR particle 300 wherein the microneedles 320 have become swollen. In some embodiments, STAR particles may be configured to absorb water or another liquid (e.g., interstitial fluid), causing the STAR particles to swell. In some embodiments, the STAR particlecontaining composition may include microencapsulated water or non-aqueous liquid. When the microcapsules are ruptured, the liquid is released and absorbed by the STAR particles. The STAR particles may also absorb the vehicle of STAR particle-containing composition, or a part thereof.

In embodiments, STAR particles may be made of ice and stored below the water freezing temperature before use. Upon removal from frozen storage, the STAR particles undergo a phase change to liquid water and become deactivated. In another embodiment, STAR particles may comprise a wax, such as those used to make suppositories (e.g.. Witepsol fatty bases that melt between 30 and 44 °C). The STAR particles are stored below the melting temperature of the wax and then experience a temperature above the melting temperature of the wax during or after use, which deactivates the STAR particles.

In embodiments, STAR particles may be composed, at least in part, of a material such as a polymer that is stored below its glass transition temperature and when the STAR particle for ulation comes into contact with the target tissue or after it comes into contact with the target tissue, the formulation is heated above the glass transition temperature of the STAR particle. In such an embodiment, when the STAR particle is heated above its glass transition temperature it has a decreased mechanical stiffness or rigidity and loses its functionality at least in part. In some embodiments, the STAR particle glass transition temperature is about 25 °C to about 50 °C, about 30 °C to about 40 °C, or about 37 °C.

Particle Swelling and/or Softening

The STAR particles may be configured to absorb the formulation, compounds, or solvents gradually, such that the STAR particles will be ineffective after a period of time. The for ulation, compounds, and/or solvents may also react with the ambient environment and/or biological tissue during and/or after application, such that the STAR particles may absorb the reacted formulation, rendering the STAR particles at least partially ineffective. The swollen STAR particles, and in particular the swollen microneedles, may have a decreased abil i ty to mechanically disrupt the target tissue. For example, the swollen microneedles may flex against the target tissue, or may lack the sharpness required to mechanically disrupt the target tissue.

FIG. 3B depicts a STAR particle 300 that has lost its rigi di ty, or has a decreased flexural modulus, such that the STAR particle is bent or easily elastically or plastically deformed. In embodiments, the microneedles 320 and the core structure 310 of the STAR particle 300 has decreased rigidity. In other embodiments, only the microneedle particles 320 have decreased rigidity. In some embodiments, the flexibility of the STAR particles is impacted by material deposits on the microneedles, as described with respect to the embodiments illustrated in FIG. 2A. In other embodiments, the STAR particles absorb liquid in a manner that modulates the flexibility, flexural modulus or other mechanical properties of the microneedles. The rigidity, flexural modulus or flexibility, of the microneedles impact the ability of the microneedle particles to mechanically disrupt the skin. For example, a low flexural modulus or flexible microneedle will bend when contacting the target tissue, whereas a high flexural modulus or rigid microneedle will overcome elastic deformation of the tissue and mechanically disrupt the target tissue.

In some embodiments, the STAR particle-containing composition includes a vehicle which comprises a liquid, which comprises water and/or a non-aqueous liquid, that is microencapsulated in microcapsules, the STAR particles being dispersed in the vehicle outside of the microcapsules, wherein the microcapsules are configured to be ruptured while in contact with the biological tissue to release the liquid and permit the liquid to contact the STAR particles, wherein the STAR particles are configured to absorb the released liquid and swell, undergo a shape change and/or become soft and flexible.

In embodiments, STAR particle may be made of a material that swells in the presence of water, such as a crosslinked polymer, such as crosslinked carboxy-methyl-cellulose. The degree of crosslinking, among other factors, determines the rate at which water is taken up into the polymer material and thereby the rate and extent to which the material swells. In this way, a STAR particle comprising a material like crosslinked carboxy-methyl-cellulose can take up water, swell and thereby become deactivated with controlled kinetics. In another embodiment, STAR particles contain a porous microstructure whereby the pores contained within STAR particles create a capillary force to enable fluid uptake and thereby swell the STAR particle. The porous structure in this embodiment may be modified to enable stronger or weaker capillary driving forces.

Mechanical Weakening of STAR Particles

In some embodiments, the STAR particle is configured to be at least partially deactivated, following its intended use. by undergoing a reduction in its mechanical strength in an amount effective to cause at least the tip portions of the microneedles to fracture instead of penetrating a biological tissue. FIG. 3C depicts a STAR particle 300 having decreased mechanical strength, such that the STAR particle 300 is cracked and chipped. In embodiments, the microneedles 320 are cracked and chipped. In embodiments, both the microneedles 320 and the core structure 310 are cracked and chipped. In some embodiments, the STAR particles absorb fluid according to the methods described with respect to FIG. 3A, which may be effective to weaken the microneedles. For example, the fluid may be effective to dissolve portions of the STAR particles, thereby- forming cracks and/or chips in the STAR particles. The weakened microneedles may be more fragile, such that they are susceptible to cracking/fracture during application, for example. That is, they are manufactured with predetermined defects (e.g., cracks/chips) that enable the STAR particles to mechanically fail in a predetermined and desired manner, consistent with their intended use. They are effective at the time of use, but become ineffective during/ after use. For example, ceramic STAR particles may be incompletely sintered, which may cause microscopic cracks and/or porosities effective to weaken the STAR particles and may thereby facilitate their subsequent loss of function.

The STAR particles 300 may also be weakened such that they are susceptible to breaking, as shown in FIG. 3D. The weakened STAR particles may break when contacting the target tissue, instead of mechanically disrupting the tissue as intended. For example, the STAR particle may be made of a composite material that includes a water-soluble component, which dissolves or leaches out during the initial use/application of the STAR particles, such that shortly thereafter the STAR particles are rendered mechanically weakened and at least partly unable to be reused to mechanically disrupt a tissue. The weakened STAR particles may break at the tips and/or may break elsewhere within the STAR particle, such as at and/or near in the core region.

In some embodiments, the STAR particle-containing composition includes STAR particles that have pores initially filled with a material that is configured come out of the pores during and/or following application of the composition to the biological tissue, thereby opening the pores and mechanically w eakening or breaking the STAR particles after a period during or following their application to the biological tissue. For example, the filling substance may be water soluble and dissolve in contact with interstitial fluid.

In some embodiments, the STAR particle-containing composition includes a vehicle which comprises a liquid, which comprises water and/or a non-aqueous liquid, that is microencapsulated in microcapsules, the STAR particles being dispersed in the vehicle outside of the microcapsules, wherein the microcapsules are configured to be ruptured while in contact with the biological tissue to release the liquid and permit the liquid to contact and mechanically weaken the STAR particles. The STAR particles may be configured to dissolve or become porous in contact with the released liquid.

Particle Shrinking

In some embodiments, the STAR particle is configured to be deactivated, during and/or following its intended use, by having the microneedles, core structure, and/or the entire STAR particle shrink or shorten to a degree that the microneedles, core structure, and/or the entire STAR particle, or what remains of them, are at least partly unable to penetrate a biological tissue. FIG. 3E depicts a shrunken STAR particle 300. In embodiments where the STAR particles 300 shrink, the shrunken microneedles 320 may be too short to mechanically disrupt the target tissue. The shrunken microneedles may also lack the sharpness necessary' to mechanically disrupt the target tissue. In some embodiments, the microneedles, core structure, and/or the entire STAR particle may shrink or shorten relatively symmetrically. In other embodiments, the microneedles, core structure, and or the entire STAR particle may shrink or shorten asymmetrically as compared to the other components. For example, one or more of the microneedles may shrink more than the other microneedles and/or the core structure.

In embodiments, a STAR particle may comprise a hydrogel swollen with water. Upon loss of the water, the hydrogel material collapses, thereby causing the STAR particle to become smaller. For example, a STAR particle could comprise a material that shrinks upon heating like polyvinyl chloride or polyolefin (e.g., shrink wrap).

Particle Agglomeration

In some embodiments, the STAR particles are configured to be deactivated, during and/or following their intended use, by undergoing agglomeration to a degree that the agglomerated STAR particles are substantially or at least partly unable to mechanically disrupt the stratum comeum or other target tissue site. This may occur because some or many of the microneedles of the STAR particles in the agglomerate are shielded from contact with the biological tissue. FIG. 4 depicts an agglomeration of STAR particles 400. As used herein, “agglomerate” or “agglomeration” refers to an entangled or otherwise physically associated mass of at least two STAR particles. In some embodiments based on experimental evidence, an agglomerate of STAR particles includes from 2 to 10,000 STAR particles, from 2 to 5,000 STAR particles, from 2 to 1,000 STAR particles, from 2 to 500 STAR particles, or from 2 to 100 STAR particles.

In some embodiments, a STAR particle containing composition is provided, which is configured to have the STAR particles deactivated by agglomeration of the STAR particles. In some embodiments, the vehicle is adapted to dry’ after the composition is applied to the skin, whereby the drying is effective to cause the STAR particles to agglomerate. In some embodiments, the STAR particles are configured to agglomerate in response to application of an external force effective to deform the STAR particles in a manner that promotes agglomeration. In some embodiments, the plurality of STAR particles have a magnetic, ionic, or electrostatic affinity that promotes agglomeration. In some embodiments, the vehicle comprises a component configured to induce agglomeration of the STAR particles following application to the biological tissue.

Agglomeration of STAR particles may be caused by forces that hold STAR particles in proximity to each other. In some embodiments, mechanical forces may promote physical interactions between the STAR particles that keep the STAR particles grouped together. These mechanical forces may include the geometric features of the STAR particles, such as the geometry of the surfaces of the STAR particles. These geometric features could be present in the STAR particles before application. For example, hook-like structures, possibly in combination with ring-like structures, could be incorporated into the STAR particle, including on the surface of the STAR particles or as part of the microneedle structure. Alternatively, the geometry of the STAR particles could be created during and/or after use of the STAR particles. In some embodiments, chemical forces due to the creation of covalent or non-covalent (e.g., hydrogen bonding, electrostatic interactions (i.e., ionic bonding), van der Waals interactions, hydrophobic bonding) bonds may promote agglomeration. In some embodiments, STAR particles could carry' a surface charge that is positive, negative, or zwitterionic. Positively charged regions of particles will be attracted to negatively charged regions of other STAR particles, causing agglomeration. In some embodiments, STAR particles with an at least partially hydrophobic surface in a hydrophilic (e.g., aqueous) vehicle will be attracted and agglomerate. In some embodiments, STAR particles with an at least partially hydrophilic surface in a hydrophobic (e.g., non-aqueous) vehicle will be attracted and agglomerate.

In embodiments, the forces causing agglomeration could be electromagnetic forces from the material properties of the STAR particles or the vehicle. In some embodiments, STAR particles could be fabricated from or contain magnetic materials that become attracted to and agglomerate with each other during and/or after application to the target tissue. In some embodiments, an external electromagnetic force could be applied to induce agglomeration of STAR particles within the vehicle and/or collect the agglomerated STAR particles following their intended use for safe disposal.

The STAR particle-containing composition may cause agglomeration, either directly or indirectly. The vehicle of the composition may evaporate and/or be absorbed by the target tissue, as or shortly following application of the composition to the target tissue, thereby increasing the STAR particle concentration in the composition. The increased STAR particle concentration increases the likelihood of particle-to-particle interactions, which can lead to agglomeration. The vehicle may also have a viscosity that facilitates particle-to-particle interactions, thereby increasing the likelihood of agglomeration. The vehicle may also include a microencapsulated reagent that can promote agglomeration. The microencapsulated reagent may be released when it contacts the skin or ambient environment, or with the force of application. The reagent may directly cause agglomeration. For example, the reagent may increase the thickness of the composition, or may increase friction within the composition, causing the STAR particles to stick together. The reagent may be an adhesive that causes the STAR particle to stick to each other. The reagent may also react with the one or more components of the vehicle and/or with the STAR particles to cause agglomeration. Alternatively, the formulation may include at least one non-encapsulated reagent that causes agglomeration upon a chemical reaction. The vehicle itself — absent any reagents — may also undergo a chemical reaction that causes agglomeration. As used herein, "chemical reaction” refers to the formation and/or breaking of covalent or noncovalent bonds.

An external stimulus may also be used to cause the STAR particle agglomeration. As used herein, the term “external stimulus” refers to any condition applied to the STAR particles, STAR particle containing compositions, and/or the target tissue. These may include, but are not limited to, (a) exposure to visible light, (b) changes in temperature, (c) changes in pressure, (d) addition, modification or removal of chemical entities, (e) application of ultrasound, (1) application of electromagnetic radiation (e.g., ultraviolet, visible, infrared radiation), (g) application of electrical and/or magnetic fields, and others. For example, the STAR particles may interact with the physical, chemical, or biological properties of the target tissue in a manner that causes agglomeration. The force of application may cause agglomeration. The force of application may induce interactions between the STAR particles, or deform the STAR particles, increasing the likelihood of agglomeration. Rubbing of the STAR particle-containing composition on the skin or other target tissue may lead to mechanical interactions of STAR particles with each other and/or with other components of the composition and/or with the skin and/or with an applicator used to apply the STAR particle-containing composition to the skin. Rubbing may also result in STAR particle deformation (e.g., creating “hooks” on the tips of microneedles of the STAR particles) to promote STAR particles becoming physically interconnected. A reagent or formulation may be applied to the target tissue, before or after the STAR particles are applied, to induce agglomeration.

The STAR particles may also have an affinity for agglomeration. For example, the STAR particles may have magnetic dipoles that attract one another. The STAR particles may also have an ionic affinity', where a change in the ionic concentration within the STAR particle-containing composition may affect the surface charges of the STAR particles. These affinities increase the likelihood of particle-to-particle interactions, thereby increasing the likelihood of agglomeration. Immobilization

In some embodiments, the STAR particles are configured to be deactivated, following their intended use, by immobilizing them on or within a material, thereby preventing their subsequent use, rendering them non-functional. That is, the STAR particles may be encapsulated, embedded or coated in matrix that causes their loss of tissue-disrupting functionality. The encapsulating agents can either immobilize the STAR particles in a macroscale matrix, or coat individual STAR particles to reduce, limit and/or prevent function. After encapsulation, the encapsulating matrix containing STAR particles can be removed from the skin, thereby removing multiple STAR particles together in a single encapsulating matrix. For example, a sheet or strip of encapsulating matrix containing STAR particles may be formed on the tissue surface, and the sheet or strip can be peeled off and possibly discarded.

In some embodiments, a composition is provided which is configured to have the STAR particles deactivated by immobilization of the STAR particles after application to the biological tissue. In some embodiments, the vehicle is configured to phase change into an immobilizing matrix in which the STAR particles are embedded. In some embodiments, the vehicle comprises a microencapsulated reagent configured to encapsulate the STAR particles. In some embodiments, the composition is in a liquid or semi-solid form and configured to form a STAR particle-containing film on and removable from the tissue. The liquid may be a viscous liquid. The semi-solid may be a gel.

FIGS. 5A-5B depict STAR particles immobilized in a matrix that prevents the STAR particles from contacting the target tissue. In FIG. 5 A, the STAR particles 500 are fixed within an immobilizing matrix 550. The immobilizing matrix may be formed at least in part by components in the vehicle of the STAR particle-containing composition, following its application/use on a target tissue. For example, the vehicle may undergo a phase change that creates the immobilizing matrix. For example, the formulation may be applied as a liquid, but becomes viscous, semisolid, gelatinous, and/or solid over time or upon the application of external stimulus. For example, a volatile liquid in the vehicle may evaporate or be absorbed by the target tissue, causing other components in the vehicle to thicken, gel, precipitate, and/or agglomerate to form the immobilizing matrix. In FIG. 5B. the STAR particles 500 are fixed within an immobilizing matrix 550 and an additional overlying material 570. For example, the vehicle of the STAR particle-containing composition may react with the overlying material 570. This additional compound or material may be applied with or subsequent to the STAR particle-containing composition. FIG. 5C depicts STAR particles 500 encapsulated and immobilized in a matrix 590. The STAR particle-containing formulation may include at least one encapsulating agent 580 that encapsulates the STAR particles 500 upon application of external stimulus or addition of another substance. The encapsulating agent may also coat the STAR particles to reduce their effectiveness, without fully encapsulating the STAR particles. The encapsulating matrix may be the target tissue itself. The encapsulating matrix may be hair or molecular components of hair (i.e., keratin).

FIG. 5D depicts STAR particles 500 immobilized by the tissue surface 525 and/or hairs 527 thereon. For example, where the target tissue is the skin, the skin and/or hair on the skin may encapsulate or immobilize the STAR particles.

Target Tissue and Tissue Surface Alteration

In some embodiments, changes to the target tissue and/or tissue surface may decrease the efficacy of the STAR particles. In embodiments where the skin is the target tissue, the STAR- particle containing composition, or at least the vehicle thereof, may affect the properties of the skin or the skin surface in a manner that renders the STAR particles ineffective. These changes to the skin may include, but are not limited to skin hydration, skin morphology, skin mechanics including changes in deformability and/or elasticity of the skin, skin topography, for example, the roughness or smoothness of the skin, and/or the density⁷ of the hair follicles and/or shafts in/on the target skin. The composition may also be formulated to change the physiological state of the skin to render the STAR particles ineffective. This change may occur immediately or gradually⁷ over time with consistent application of the formulation and STAR particles. Physiological changes may include changes to the stratum comeum, viable epidermis, dermis, or hypodermis. Changes may also include changes to the nerves, sweat glands, sebaceous glands, sebum, collagen, elastin, cell populations within the skin, cytokine or biomolecule profiles within the skin, hair follicles, or hair shafts present within and/or on the skin. For example, STAR particles may be designed with shorter microneedles to function effectively in skin with hyperkeratosis (e.g., psoriasis, cutaneous warts, chronic atopic dermatitis) due to the abnormal biomechanical properties of the diseased skin (e.g., thickened, hardened, roughened). As the skin is treated with STAR containing formulations and becomes less hyperkeratotic, and thereby more elastic, the shorter microneedles on the STAR particles become less effective since the skin deforms and does not allow for effective STAR puncture.

In some embodiments, a topical composition is provided wherein the composition is effective to transform a patient's skin from a first state to a second state, wherein the STAR particles are able to penetrate the skin surface in the first state and are unable to penetrate the skin surface in the second state, or vice versa. In some embodiments, the first state is a dry state and the second state is a hydrated state. In some embodiments, the first state is hyperkeratotic skin and the second state is non-hyperkeratotic skin.

In some embodiments, in the first state, the skin surface has frictional interaction with STAR particles such that the STAR particles are able to penetrate the skin, and in the second state, the skin surface has reduced frictional interaction with STAR particles such that the STAR particles slide over the skin surface without penetration (e.g., the skin surface is very slippery). This change of state of the skin surface may be induced by deposition of a material from atopical composition onto the skin surface to decrease friction.

In some embodiments, in the first state, the skin surface has frictional interaction with STAR particles such that STAR particles penetrate the skin, and in the second state, the skin surface has increased frictional interaction with STAR particles such that the STAR particles slide very slowly over the skin surface without penetration (i.e., the skin surface is very viscous). This change of state of the skin surface may be induced by deposition of a material from the topical composition onto the skin surface to increase friction, or the change could be induced because a liquid in the topical composition evaporates, is absorbed into the skin or otherwise disappears, such that the excipients and other materials in the topical composition become so concentrated as a thin film on the skin surface that the viscosity becomes very’ high.

Particle Surface Property Alteration

In additional embodiments, the surface properties of the STAR particle may change, decreasing their functionality. Changes to the physical and/or chemical properties of the surface of the particles may alter the functional interactions between the STAR particles and the formulation, or the STAR particles and the target tissue. For example, the STAR particles may become adhesive or sticky, which may immobilize or abrogate the STAR particles’ function. The STAR particles may also become slippery or lubricated, which may prevent the STAR particles from effectively interacting with and penetrating the target tissue. The STAR particles may also become rough, which may generate resistance during application due to increased friction and thereby decreased mobility across the target tissue.

Particle Removal from Tissue

In further embodiments, STAR particles may be removed and collected from the target tissue after use. The removal and collection of the STAR particles is effective to prevent the STAR particles from further disrupting the target tissue. The STAR particles may simply fall off the target tissue, or they may be collected from the target tissue. The STAR particles may be collected and returned to the original packaging or container. The STAR particles may be removed with a flexible material, such as a cloth or other woven or non-woven fabric. Alternatively, the particles may be removed with a rigid, semi-rigid, or pliable object, such as one made of glass, metal, sugar, biopolymer, a polymer, or any combination thereof. Removal of STAR particles may be facilitated by attractive force between the material and/or object used to collect the STAR particles. For example, the removal material and/or object may have an adhesive, electrostatic charge that is opposite the charge on the STAR particles, and/or attractive magnetic dipoles that promote interactions between the material and/or object and the STAR particles. The STAR particles may also be ‘'removed” by dissolving, where the dissolved STAR particles are absorbed into the target tissue.

In some embodiments, a trigger may initiate removal of the STAR particles. External stimulus may be effective to trigger removal of STAR particles from the target tissue. Forms of external stimulus may include, but are not limited to, application of magnetic, electric, or electromagnetic fields, application of a liquid to the target tissue that could partially or completely dissolve the STAR particles or carry the STAR particles away from the target tissue, application of soap or a solubilized dispersant or surfactant to the target tissue, application of any ultrasonic, audible, or sub-audible vibration, application of negative pressure, such as suction, to the target tissue, and application of positive pressure, such as wiping, to the target tissue. In other embodiments, where the target tissue is the skin, the process of epidermal renewal and regeneration may trigger STAR particle removal.

Use of Microencapulated Substances in the Compositions

In some embodiments, a composition for application to a tissue is provided, wherein the composition includes (i) a plurality of STAR particles configured for mechanical disruption of a biological tissue; and (ii) a vehicle in which the plurality of STAR particles are dispersed, wherein the vehicle comprises one or more microencapsulated reagents or solvents, microcapsules of which can be mechanically ruptured in the process of contacting the composition against the biological tissue to release the one or more microencapsulated reagents or solvents and deactivate the STAR particles’ ability to mechanically disrupt a biological tissue. Alternatively, the microcapsule could release its contents due to change of temperature. pH, light (e.g., wavelength, intensity) or other environmental conditions or due to biodegradation or dissolution of materials comprising the microcapsule.

In embodiments, microcapsules are comprised of a core region surrounded by a shell region. The capsules can range in size from about 1 pm to about 10 mm. Microcapsules may also be from about 10 nm to 1000 nm in size, in which case they can alternatively be called nanocapsules. The core material may be solid, liquid and/or gas. The shell material may be solid or liquid and could be permeable, semi-permeable or impermeable to substances in the core. A microcapsule may have one or more cores.

Microcapsules may be made by chemical and/or physical methods, including solvent evaporation/extraction, spray drying, melt solidification, sol-gel encapsulation, sonication, coprecipitation, desolvation, emulsification, gelation, thin film hydration, homogenization, liposome entrapment, coacervation, emulsion solvent diffusion, and other methods.

Shell materials can include a wide variety of natural and synthetic polymers, including polysaccharides (gums, starches, celluloses, cyclodextrins, chitosan), proteins (gelatin, casein, soy proteins), lipids (waxes, paraffin, oils) and synthetic polymers (acry lic polymers, poly(vinyl alcohol), poly(vinylpyrrolidone)). Inorganic materials, such as silicates, clays and polyphosphates, can also be used. Biopolymers (natural polymers) and biodegradable polymers, such as chitosan and aliphatic polyesters like poly(lactic acid) (PLA) and copolymers of lactic and glycolic acids (e.g. PLGA - poly(lactic co-glycolic acid) can be used.

In some embodiments, the one or more reagents or solvents are configured to cause a phase change in at least the microneedles of the STAR particles, the core region of the STAR particles, or a combination of both as described above. In some embodiments, the one or more reagents or solvents are configured to at least partially dissolve the STAR particles, as described above. In some embodiments, the one or more reagents or solvents are configured to promote agglomeration of the STAR particles, as described above.

In some embodiments, the one or more reagents or solvents are configured to promote immobilization of the STAR particles on the biological tissue, as described above. In some embodiments, the one or more reagents or solvents are configured to immobilize the STAR particles in a matrix material, as described above. In some embodiments, the one or more reagents or solvents are configured to promote addition of a coating substance to the STAR particles, as described above. In some embodiments, the one or more reagents or solvents are configured to swell or shrink the STAR particles, as described above. In some embodiments, the one or more reagents or solvents are configured to induce softening or deformability of the STAR particles, as described above. In some embodiments, the one or more reagents or solvents are configured to mechanically weaken the STAR particles, as described above.

In some embodiments, the microcapsules contain water and the STAR particles are soluble or swellable or able to be softened in water. Because the formulation in which the microcapsules and STAR particles reside contains no water, or insufficient water to dissolve or sw ell or soften the STAR particles, the STAR particle are not deactivated as long as the microcapsules do not release w ater. Upon release of w ater from the microcapsules, the STAR particles become deactivated by at least partial dissolution or swelling or softening due to the presence of water. A similar approach can be used for solvents other than water, such as ethanol.

In another embodiment, the microcapsules contain a material to cause gelation or crosslinking of polymers or other materials contained in the formulation in which the microcapsules and STAR particles reside. For example, microcapsules could contain calcium ions and the surrounding formulation contain pectic acid and/or sodium pectate. or the microcapsules could contain pectic acid and/or sodium pectate and the surrounding formulation contain calcium ions, or the microcapsules could contain calcium ions and the STAR particles could be comprised of pectic acid and/or sodium pectate.

Methods of Deactivating

In some embodiments, methods are provided that include (i) applying a first composition which comprises a plurality of STAR particles dispersed in a vehicle, onto a biological tissue; (ii) manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue; and then (iii) deactivating the STAR particles by permitting or causing one or more of: agglomeration of the STAR particles, immobilization of the STAR particles, addition of a coating substance onto the STAR particles, swelling-induced shape change in the STAR particles, shrinking of microneedles of the STAR particles, softening or induced deformability of the STAR particles, and mechanical weakening of the STAR particles. In some embodiments of the method (i) the deactivating comprises addition of a second composition onto the first composition, the second composition comprising a first reagent or solvent, and/or (ii) the manipulation comprises rupturing microcapsules containing a second reagent or solvent effective to initiate or promote the deactivating.

In some embodiments, the first and/or second reagent or solvent is configured to cause the STAR particles to be dissolved. In some embodiments, the first and/or second reagent or solvent is configured to promote agglomeration of the STAR particles. In some embodiments, the first and/or second reagent or solvent is configured to promote immobilization of the STAR particles on the biological tissue surface. In some embodiments, the first and/or second reagent or solvent is configured to immobilize the STAR particles in a matrix material. In some embodiments, the first and/or second reagent or solvent is configured to promote addition of a coating substance to the STAR particles. In some embodiments, first and/or second reagent or solvent is configured to swell, cause a shape change or shrink the STAR particles. In some embodiments, the first and/or second reagent or solvent is configured to induce softening or deformability of microneedles of the STAR particles. In some embodiments, the first and/or second reagent or solvent is configured to mechanically weaken the STAR particles. In some embodiments, the deactivating comprises application of an external stimulus to the first composition and/or the biological tissue surface, the application of the external stimulus being selected from (a) exposure to visible, near-infrared or ultraviolet light, (b) changes in temperature, (c) changes in pressure, (d) addition, modification or removal of chemical entities, (e) application of ultrasound, (f) application of electromagnetic radiation, (g) application of a magnetic field, and (h) combinations thereof.

In some embodiments, the deactivation comprises encapsulating the STAR particles with an encapsulation material. In some embodiments, the deactivation comprises immobilization of the STAR particles. For example, the vehicle may undergo a phase change into an immobilizing matrix in which the STAR particles are embedded.

In some embodiments, the STAR particles are or become porous and mechanically weaken after a period of time during and/or following the applying of the first composition onto the biological tissue.

In some embodiments, the first composition is applied to the biological tissue in a liquid or semi solid form and forms a STAR particle-containing film, and wherein the method further comprises removing the STAR particle-containing film from the biological tissue.

In some embodiments, a method is provided that includes (i) applying a first composition which comprises a plurality of STAR particles dispersed in a vehicle, onto a biological tissue; (ii) manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue; and then (iii) deactivating the STAR particles by adding a second composition to the first composition wherein the second composition comprises a solvent which dissolves at least a portion of the STAR particles.

In some embodiments, a method is provided that includes (i) applying a composition which comprises a plurality of STAR particles dispersed in a vehicle, onto a patient’s skin in a first state; (ii) manipulating the composition to cause the STAR particles to mechanically disrupt the stratum comeum of the patient’s skin in the first state, and (iii) transforming the patient’s skin, via contact with one or more components in the vehicle, into a second state in which the STAR particles are unable to mechanically disrupt the stratum comeum, as described above. EMBODIMENTS

Some embodiments of the present disclosure can be described in view of one or more of the following:

Embodiment 1. A composition for application to a biological tissue comprising a plurality of STAR particles configured for mechanical disruption of a biological tissue, and a vehicle in which the plurality of STAR particles are dispersed, wherein the composition is adapted (i) to contact the biological tissue surface in a manner to cause the STAR particles to mechanically disrupt the biological tissue, and subsequently (ii) to diminish the STAR particles’ ability to mechanically disrupt a biological tissue by one or more of the following deactivating mechanisms: agglomeration of the STAR particles, immobilization of the STAR particles, addition of a coating substance onto the STAR particles, swelling-induced shape change in the STAR particles, shrinking of microneedles of the STAR particles, softening or induced deformability of the STAR particles, and mechanical weakening of the STAR particles.

Embodiment 2. The composition of Embodiment 1, wherein the vehicle comprises a liquid, which comprises water and/or a non-aqueous liquid, that is microencapsulated in microcapsules, the STAR particles being dispersed in the vehicle outside of the microcapsules, wherein the microcapsules are configured to be ruptured while in contact with the biological tissue to release the liquid and permit the liquid to contact the STAR particles.

Embodiment 3. The composition of either of Embodiments 1 or 2, wherein the liquid is water.

Embodiment 4. The composition of any one of Embodiments 1 through 3, wherein the STAR particles are configured to dissolve or become porous in contact with the released liquid.

Embodiment 5. The composition of any one of Embodiments 1 through 4, wherein the STAR particles are configured to absorb the released liquid and swell, undergo a shape change and/or become soft and flexible.

Embodiment 6. The composition of any one of Embodiments 1 through 5, wherein the biological tissue is skin and the composition is effective to transform the skin and/or the skin surface from a first state to a second state, wherein the STAR particles are able to penetrate the skin surface in the first state and are unable to penetrate the skin surface in the second state.

Embodiment 7. The composition of any one of Embodiments 1 through 6, wherein the first state is a diseased state and the second state is a healthy state, the first state is a dry state and the second state is a hydrated state, the first state is hyperkeratotic skin and the second state is non-hyperkeratotic skin, or the first state has a first frictional interaction between the skin surface and the STAR particles and the second state has a second frictional interaction between the skin surface and the STAR particles which is (i) reduced relative to the first frictional interaction such that the STAR particles readily slide over the skin surface without penetration, or (ii) increased relative to the first frictional interaction such that the STAR particles are substantially prevented from movement across the skin surface.

Embodiment 8. The composition of any one of Embodiments 1 through 7, wherein the vehicle comprises a film-forming composition. Embodiment 9. The composition of any one of Embodiments 1 through 8, wherein the STAR particles are configured to become deactivated following contact with interstitial fluid upon penetrating the biological tissue.

Embodiment 10. The composition of any one of Embodiments 1 through 9, which is configured to have the STAR particles deactivated by agglomeration of the STAR particles.

Embodiment 11. The composition of any one of Embodiments 1 through 10, wherein the vehicle is adapted to dry after the composition is applied to the skin, whereby the drying is effective to cause the STAR particles to agglomerate.

Embodiment 12. The composition of any one of Embodiments 1 through 11, wherein the STAR particles are configured to agglomerate in response to application of an external force effective to deform the STAR particles in a manner that promotes agglomeration.

Embodiment 13. The composition of any one of Embodiments 1 through 12, wherein the plurality of STAR particles have a magnetic, ionic, or electrostatic affinity that that promotes agglomeration.

Embodiment 14. The composition of any one of Embodiments 1 through 13, wherein the vehicle comprises a component configured to induce agglomeration of the STAR particles following application to the biological tissue.

Embodiment 15. The composition of any one of Embodiments 1 through 14, wherein the STAR particles have pores initially filled with a material that is configured to come out of the pores during and/or following application of the composition to the biological tissue, thereby opening the pores and mechanically weakening or breaking the STAR particles after a period during or following their application to the biological tissue.

Embodiment 16. The composition of any one of Embodiments 1 through 15, which is configured to have the STAR particles deactivated by immobilization of the STAR particles after application to the biological tissue.

Embodiment 17. The composition of any one of Embodiments 1 through 16, wherein the vehicle is configured to phase change into an immobilizing matrix in which the STAR particles are embedded.

Embodiment 18. The composition of any one of Embodiments 1 through 17, wherein the vehicle comprises a microencapsulated reagent configured to encapsulate the STAR particles.

Embodiment 19. The composition of any one of Embodiments 1 through 18, which is in a liquid or semi-solid form and configured to form a STAR particle-containing film on and removable from the tissue. Embodiment 20. The composition of any one of Embodiments 1 through 19, wherein the liquid is a viscous liquid.

Embodiment 21. The composition of any one of Embodiments 1 through 20, wherein the semi-solid form is a gel.

Embodiment 22. The composition of any one of Embodiments 1 through 21, further comprising one or more bioactive agents.

Embodiment 23. The composition of any one of Embodiments 1 through 22, further comprising one or more diagnostic agents, sensors, cosmeceuticals, or nutraceuticals.

Embodiment 24. The composition of any one of Embodiments 1 through 23, wherein the biological tissue comprises a patient’s skin.

Embodiment 25. A composition for application to a tissue comprising a plurality of STAR particles configured for mechanical disruption of a biological tissue, and a vehicle in which the plurality of STAR particles are dispersed, wherein the vehicle comprises one or more microencapsulated reagents or solvents, microcapsules of which can be mechanically ruptured in the process of contacting the composition against the biological tissue to release the one or more microencapsulated reagents or solvents and deactivate the STAR particles’ ability to mechanically disrupt a biological tissue.

Embodiment 26. The composition of Embodiment 25, wherein the one or more reagents or solvents are configured to cause a phase change in at least the microneedles of the STAR particles.

Embodiment 27. The composition of either of Embodiments 25 or 26, wherein the one or more reagents or solvents are configured to at least partially dissolve the STAR particles.

Embodiment 28. The composition of any one of Embodiments 25 through 27, wherein the one or more reagents or solvents are configured to promote agglomeration of the STAR particles.

Embodiment 29. The composition of any one of Embodiments 25 through 28, wherein the one or more reagents or solvents are configured to promote immobilization of the STAR particles on the biological tissue.

Embodiment 30. The composition of any one of Embodiments 25 through 29, wherein the one or more reagents or solvents are configured to immobilize the STAR particles in a matrix material.

Embodiment 31. The composition of any one of Embodiments 25 through 30, wherein the one or more reagents or solvents are configured to promote addition of a coating substance to the STAR particles. Embodiment 32. The composition of any one of Embodiments 25 through 31, wherein the one or more reagents or solvents are configured to swell or shrink the STAR particles.

Embodiment 33. The composition of any one of Embodiments 25 through 32, wherein the one or more reagents or solvents are configured to induce softening or deformability of the STAR particles.

Embodiment 34. The composition of any one of Embodiments 25 through 33, wherein the one or more reagents or solvents are configured to mechanically weaken the STAR particles.

Embodiment 35. The composition of any one of Embodiments 25 through 34, further comprising one or more bioactive agents.

Embodiment 36. The composition of any one of Embodiments 25 through 35, further comprising one or more diagnostic agents, sensors, cosmeceuticals. or nutraceuticals.

Embodiment 37. The composition of any one of Embodiments 25 through 36, wherein the biological tissue comprises a patient’s skin.

Embodiment 38. A method comprising applying a first composition which comprises a plurality of STAR particles dispersed in a vehicle, onto a biological tissue; manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue; and then deactivating the STAR particles by permitting or causing one or more of: agglomeration of the STAR particles, immobilization of the STAR particles, addition of a coating substance onto the STAR particles, swelling-induced shape change in the STAR particles, shrinking of microneedles of the STAR particles, softening or induced deformability of the STAR particles, and mechanical weakening of the STAR particles.

Embodiment 39. The method of Embodiment 38, wherein (i) the deactivating comprises addition of a second composition onto the first composition, the second composition comprising a first reagent or solvent, and/or (ii) the manipulation comprises rupturing microcapsules containing a second reagent or solvent effective to initiate or promote the deactivating.

Embodiment 40. The method of either of Embodiments 38 or 39, wherein the first and/or second reagent or solvent is configured to cause the STAR particles to be dissolved.

Embodiment 41. The method of any one of Embodiments 38 through 40, wherein the first and/or second reagent or solvent is configured to promote agglomeration of the STAR particles.

Embodiment 42. The method of any one of Embodiments 38 through 41, wherein the first and/or second reagent or solvent is configured to promote immobilization of the STAR particles on the biological tissue surface. Embodiment 43. The method of any one of Embodiments 39 through 42, wherein the first and/or second reagent or solvent is configured to immobilize the STAR particles in a matrix material.

Embodiment 44. The method of any one of Embodiments 38 through 43, wherein the first and/or second reagent or solvent is configured to promote addition of a coating substance to the STAR particles.

Embodiment 45. The method of any one of Embodiments 38 through 44. wherein the first and/or second reagent or solvent is configured to swell, cause a shape change or shrink the STAR particles.

Embodiment 46. The method of any one of Embodiments 38 through 45, wherein the first and/or second reagent or solvent is configured to induce softening or deformability of microneedles of the STAR particles.

Embodiment 47. The method of any one of Embodiments 38 through 46, wherein the first and/or second reagent or solvent is configured to mechanically weaken the STAR particles.

Embodiment 48. The method of any one of Embodiments 38 through 47, wherein the deactivating comprises application of an external stimulus to the first composition and/or the biological tissue surface, the application of the external stimulus being selected from (a) exposure to visible, near-infrared or ultraviolet light, (b) changes in temperature, (c) changes in pressure, (d) addition, modification or removal of chemical entities, (e) application of ultrasound, (f) application of electromagnetic radiation, (g) application of a magnetic field, and (h) combinations thereof.

Embodiment 49. The method of any one of Embodiments 38 through 48, wherein the vehicle comprises a film-forming composition.

Embodiment 50. The method of any one of Embodiments 38 through 50, wherein the deactivating comprises contacting the STAR particles with interstitial fluid.

Embodiment 51. The method of any one of Embodiments 38 through 51, wherein the deactivating comprises agglomeration of the STAR particles.

Embodiment 52. The method of any one of Embodiments 38 through 51, wherein the STAR particles have a magnetic, ionic, or electrostatic affinity that promotes agglomeration.

Embodiment 53. The method of any one of Embodiments 38 through 52, wherein the STAR particles are porous and mechanically weakened after a period of time during and/or following the applying of the first composition onto the biological tissue.

Embodiment 54. The method of any one of Embodiments 38 through 53, wherein the deactivation comprises immobilization of the STAR particles. Embodiment 55. The method of any one of Embodiments 38 through 54, wherein the vehicle undergoes a phase change into an immobilizing matrix in which the STAR particles are embedded.

Embodiment 56. The method of any one of Embodiments 38 through 55, wherein the deactivation comprises encapsulating the STAR particles with an encapsulation material.

Embodiment 57. The method of any one of Embodiments 38 through 56, wherein the first composition is applied to the biological tissue in a liquid or semi solid form and forms a STAR particle-containing film, and wherein the method further comprises removing the STAR particlecontaining film from the biological tissue.

Embodiment 58. A method comprising applying a first composition which comprises a plurality of STAR particles dispersed in a vehicle, onto a biological tissue; manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue; and then deactivating the STAR particles by adding a second composition to the first composition wherein the second composition comprises a solvent which dissolves at least a portion of the STAR particles.

Embodiment 59. The method of any one of Embodiments 38 through 58. wherein the composition further comprises one or more bioactive agents.

Embodiment 60. The method of any one of Embodiments 38 through 59, wherein the composition further comprises one or more diagnostic agents, sensors, cosmeceuticals, or nutraceuticals.

Embodiment 61 . The method of any one of Embodiments 38 through 60, wherein the biological tissue comprises human skin.

Embodiment 62. A method comprising applying a composition which comprises a plurality of STAR particles dispersed in a vehicle, onto a patient’s skin in a first state, and manipulating the composition to cause the STAR particles to mechanically disrupt the stratum comeum of the patient’s skin in the first state, transforming the patient’s skin, via contact with one or more components in the vehicle, into a second state in which the STAR particles are unable to mechanically disrupt the stratum comeum.

As used in this specification and the appended claims, the singular forms "a.” “an,” and “the” include plural referents unless the context clearly dictates otherwise. The term “about,” as used herein, indicates the value of a given quantity⁷ can include quantities ranging within 10% of the stated value, or optionally, within 5% of the value, or in some embodiments, within 1% of the value. While the disclosure has been described with reference to a number of exemplary embodiments, it would be understood by those skilled in the art that the disclosure is not limited to such disclosed embodiments. Rather, the disclosed embodiments can be modified to incorporate any number of variations, alterations, substitutions, or equivalent arrangements not described herein, but which are commensurate with the spirit and scope of the disclosure.

Claims

CLAIMS That which is claimed is:

1. A composition for application to a biological tissue comprising: a plurality of STAR particles configured for mechanical disruption of a biological tissue; and a vehicle in which the plurality of STAR particles are dispersed, wherein the composition is adapted (i) to contact the biological tissue surface in a manner to cause the STAR particles to mechanically disrupt the biological tissue, and subsequently (ii) to diminish the STAR particles’ ability to mechanically disrupt a biological tissue by at least one of the following deactivating mechanisms: agglomeration of the STAR particles, immobilization of the STAR particles, addition of a coating substance onto the STAR particles, swelling-induced shape change in the STAR particles, shrinking of microneedles of the STAR particles, softening or induced deformability of the STAR particles, or mechanical weakening of the STAR particles.

2. The composition of claim 1, wherein the vehicle comprises a liquid, which comprises water and/or a non-aqueous liquid, that is microencapsulated in microcapsules, the STAR particles being dispersed in the vehicle outside of the microcapsules, wherein the microcapsules are configured to be ruptured while in contact with the biological tissue to release the liquid and permit the liquid to contact the STAR particles.

3. The composition of claim 2, wherein the liquid is water.

4. The composition of claim 2, wherein the STAR particles are configured to dissolve or become porous in contact with the released liquid.

5. The composition of claim 2, wherein the STAR particles are configured to absorb the released liquid and swell, undergo a shape change and/or become soft and flexible.

6. The composition of claim 1, wherein the biological tissue is skin and the composition is effective to transform the skin and/or the skin surface from a first state to a second state, wherein the STAR particles are able to penetrate the skin surface in the first state and are unable to penetrate the skin surface in the second state.

7. The composition of claim 6, wherein: the first state is a diseased state and the second state is a healthy state, the first state is a dry state and the second state is a hydrated state. the first state is hyperkeratotic skin and the second state is non-hyperkeratotic skin, or the first state has a first frictional interaction between the skin surface and the STAR particles and the second state has a second frictional interaction between the skin surface and the STAR particles which is (i) reduced relative to the first frictional interaction such that the STAR particles readily slide over the skin surface without penetration, or (ii) increased relative to the first frictional interaction such that the STAR particles are substantially prevented from movement across the skin surface.

8. The composition of claim 1, wherein the vehicle comprises a film-forming composition.

9. The composition of claim 1, wherein the STAR particles are configured to become deactivated following contact with interstitial fluid upon penetrating the biological tissue.

10. The composition of claim 1 , which is configured to have the STAR particles deactivated by agglomeration of the STAR particles.

1 1. The composition of claim 10, wherein the vehicle is adapted to dry after the composition is applied to the skin, whereby the drying is effective to cause the STAR particles to agglomerate.

12. The composition of claim 10, wherein the STAR particles are configured to agglomerate in response to application of an external force effective to deform the STAR particles in a manner that promotes agglomeration.

13. The composition of claim 10, wherein the plurality' of STAR particles have a magnetic, ionic, or electrostatic affinity that that promotes agglomeration.

14. The composition of claim 10, yvherein the vehicle comprises a component configured to induce agglomeration of the STAR particles following application to the biological tissue.

15. The composition of claim 1, wherein the STAR particles have pores initially filled with a material that is configured to come out of the pores during and/or following application of the composition to the biological tissue, thereby opening the pores and mechanically weakening or breaking the STAR particles after a period during or following their application to the biological tissue.

16. The composition of claim 1, which is configured to have the STAR particles deactivated by immobilization of the STAR particles after application to the biological tissue.

17. The composition of claim 1 , wherein the vehicle is configured to phase change into an immobilizing matrix in which the STAR particles are embedded.

18. The composition of claim 16, wherein the vehicle comprises a microencapsulated reagent configured to encapsulate the STAR particles.

19. The composition of claim 16, which is in a liquid or semi-solid form and configured to form a STAR particle-containing film on and removable from the tissue.

20. The composition of claim 19, wherein the liquid is a viscous liquid.

21. The composition of claim 19, wherein the semi-solid form is a gel.

22. The composition of claim 1, further comprising one or more bioactive agents.

23. The composition of claim 1, further comprising one or more diagnostic agents, sensors, cosmeceuticals, or nutraceuticals.

24. The composition of claim 1, wherein the biological tissue comprises a patient’s skin.

25. A composition for application to a tissue comprising: a plurality of STAR particles configured for mechanical disruption of a biological tissue; and a vehicle in which the plurality of STAR particles are dispersed, wherein the vehicle comprises one or more microencapsulated reagents or solvents, microcapsules of which can be mechanically ruptured in the process of contacting the composition against the biological tissue to release the one or more microencapsulated reagents or solvents and deactivate the STAR particles’ ability to mechanically disrupt a biological tissue.

26. The composition of claim 25, wherein the one or more reagents or solvents are configured to cause a phase change in at least the microneedles of the STAR particles.

27. The composition of claim 25, wherein the one or more reagents or solvents are configured to at least partially dissolve the STAR particles.

28. The composition of claim 25, wherein the one or more reagents or solvents are configured to promote agglomeration of the STAR particles.

29. The composition of claim 25, wherein the one or more reagents or solvents are configured to promote immobilization of the STAR particles on the biological tissue.

30. The composition of claim 25, wherein the one or more reagents or solvents are configured to immobilize the STAR particles in a matrix material.

31. The composition of claim 25, wherein the one or more reagents or solvents are configured to promote addition of a coating substance to the STAR particles.

32. The composition of claim 25, wherein the one or more reagents or solvents are configured to swell or shrink the STAR particles.

33. The composition of claim 25, wherein the one or more reagents or solvents are configured to induce softening or deformability of the STAR particles.

34. The composition of claim 25, wherein the one or more reagents or solvents are configured to mechanically weaken the STAR particles.

35. The composition of claim 25, further comprising one or more bioactive agents.

36. The composition of claim 25, further comprising one or more diagnostic agents, sensors, cosmeceuticals, or nutraceuticals.

37. The composition of claim 25, wherein the biological tissue comprises a patient’s skin.

38. A method comprising: applying a first composition which comprises a pl ural ity of STAR particles dispersed in a vehicle, onto a biological tissue; manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue; and then deactivating the STAR particles by permitting or causing at least one of: agglomeration of the STAR particles, immobilization of the STAR particles, addition of a coating substance onto the STAR particles, swelling-induced shape change in the STAR particles, shrinking of microneedles of the STAR particles, softening or induced deformability of the STAR particles, or mechanical weakening of the STAR particles.

39. The method of claim 38, wherein (i) the deactivating comprises addition of a second composition onto the first composition, the second composition comprising a first reagent or solvent, and/or (ii) the manipulation comprises rupturing microcapsules containing a second reagent or solvent effective to initiate or promote the deactivating.

40. The method of claim 39, wherein the first and/or second reagent or solvent is configured to cause the STAR particles to be dissolved.

41. The method of claim 39, wherein the first and/or second reagent or solvent is configured to promote agglomeration of the STAR particles.

42. The method of claim 39, wherein the first and/or second reagent or solvent is configured to promote immobilization of the STAR particles on the biological tissue surface.

43. The method of claim 39, wherein the first and/or second reagent or solvent is configured to immobilize the STAR particles in a matrix material.

44. The method of claim 39, wherein the first and/or second reagent or solvent is configured to promote addition of a coating substance to the STAR particles.

45. The method of claim 39, wherein the first and/or second reagent or solvent is configured to swell, cause a shape change or shrink the STAR particles.

46. The method of claim 39, wherein the first and/or second reagent or solvent is configured to induce softening or deformability of microneedles of the STAR particles.

47. The method of claim 39, wherein the first and/or second reagent or solvent is configured to mechanically weaken the STAR particles.

48. The method of claim 38, wherein the deactivating comprises application of an external stimulus to the first composition and/or the biological tissue surface, the application of the external stimulus being selected from at least one of (a) exposure to visible, near-infrared or ultraviolet light, (b) changes in temperature, (c) changes in pressure, (d) addition, modification or removal of chemical entities, (e) application of ultrasound, (f) application of electromagnetic radiation, (g) application of a magnetic field, or (h) combinations thereof.

49. The method of claim 38, wherein the vehicle comprises a film-forming composition.

50. The method of claim 38, wherein the deactivating comprises contacting the STAR particles with interstitial fluid.

51. The method of claim 38, wherein the deactivating comprises agglomeration of the STAR particles.

52. The method of claim 51, wherein the STAR particles have a magnetic, ionic, or electrostatic affinity that promotes agglomeration.

53. The method of claim 38, wherein the STAR particles are porous and mechanically weakened after a period of time during and/or following the applying of the first composition onto the biological tissue.

54. The method of claim 38, wherein the deactivation comprises immobilization of the STAR particles.

55. The method of claim 54, wherein the vehicle undergoes a phase change into an immobilizing matrix in which the STAR particles are embedded.

56. The method of claim 38, wherein the deactivation comprises encapsulating the STAR particles with an encapsulation material.

57. The method of claim 38, wherein the first composition is applied to the biological tissue in a liquid or semi solid form and forms a STAR particle-containing film, and wherein the method further comprises removing the STAR particle-containing film from the biological tissue.

58. A method comprising: applying a first composition which comprises a plurality of STAR particles dispersed in a vehicle, onto a biological tissue; manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue; and then deactivating the STAR particles by adding a second composition to the first composition wherein the second composition comprises a solvent which dissolves at least a portion of the STAR particles.

59. The method of claim 38, wherein the composition further comprises one or more bioactive agents.

60. The method of claims 38, wherein the composition further comprises one or more diagnostic agents, sensors, cosmeceuticals, or nutraceuticals.

61. The method of claim 38, wherein the biological tissue comprises human skin.

62. A method comprising: applying a composition which comprises a plurality of STAR particles dispersed in a vehicle, onto a patient’s skin in a first state; and manipulating the composition to cause the STAR particles to mechanically disrupt the stratum comeum of the patient’s skin in the first state, transforming the patient’s skin, via contact with one or more components in the vehicle, into a second state in which the STAR particles are unable to mechanically disrupt the stratum comeum.