Microneedle particles, compositions, and methods for deactivating particles

Abstract

STAR particles and compositions thereof, each having a core structure and one or more microneedle-like projections extending from the core structure. The STAR particle composition comprises a plurality of STAR particles configured for the mechanical disruption of biological tissue and a vehicle in which the plurality of STAR particles are dispersed, the composition adapted to contact a biological tissue surface so as to cause the STAR particles to mechanically disrupt the biological tissue and thereafter reduce the ability of the STAR particles to mechanically disrupt the biological tissue by one or more inactivation mechanisms.

Description

[Technical Field]

[0001] 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 technology]

[0002] Some embodiments of microneedle particles (i.e., STAR particles) are described in U.S. Pat. No. 11,291,816, which is incorporated herein by reference. STAR particles can be an effective mechanism for improving the delivery of bioactive compounds to biological tissues, such as the skin. However, it may be undesirable for the STAR particle to be used in off-target tissues, for the STAR particle to be reused, or for the STAR particle to be used in an unintended manner. Therefore, it would be desirable to provide compositions and methods for controlling the time, spatial location, and manner or mechanism by which a STAR particle loses its ability to mechanically disrupt a tissue site, e.g., a target tissue. It would also be desirable to provide various means for controlling how a STAR particle may interact with the skin or other tissue site. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] U.S. Patent No. 11,291,816 Summary of the Invention

[0004] In one aspect, a composition for application to biological tissue is provided, the composition comprising a plurality of STAR particles configured for mechanical disruption of biological tissue and a vehicle in which the plurality of STAR particles are dispersed. The composition can be adapted to (i) contact the biological tissue to cause the STAR particles to mechanically disrupt the biological tissue, and subsequently (ii) reduce the ability of the STAR particles to mechanically disrupt the biological tissue by one or more deactivation mechanisms. The one or more deactivation mechanisms can include STAR particle aggregation, STAR particle immobilization, addition of a coating substance to the STAR particles, swelling-induced shape change of the STAR particles, contraction of microneedles of the STAR particles, softening or induced deformability of the STAR particles, and mechanical weakening of the STAR particles.

[0005] In more particular embodiments, the vehicle comprises a liquid with water and / or a non-aqueous liquid microencapsulated within microcapsules, the STAR particles are dispersed in the vehicle outside the microcapsules, and the microcapsules are configured to rupture while in contact with biological tissue to release the liquid and allow it to contact the STAR particles. In some embodiments, the liquid is water.

[0006] In some embodiments, the STAR particles are configured to dissolve or become porous upon contact with the released liquid, while in other embodiments, the STAR particles are configured to absorb the released liquid and swell, undergo a change in shape, and / or become soft and flexible.

[0007] In some embodiments the biological tissue is skin and the composition is effective to transform the skin and / or the surface of the skin from a first state to a second state, wherein the STAR particles can penetrate the surface of the skin in the first state and cannot penetrate the surface of the skin 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 surface of the skin and the STAR particles and the second state has a second frictional interaction between the surface of the skin and the STAR particles, and the second frictional interaction is (i) reduced relative to the first frictional interaction so that the STAR particles easily slide over the surface of the skin without penetrating, or (ii) increased relative to the first frictional interaction so that the STAR particles are substantially prevented from moving across the surface of the skin.

[0008] In some embodiments, the vehicle comprises a film-forming composition.

[0009] In some embodiments, the STAR particles are configured to penetrate biological tissue and then be inactivated after contact with interstitial fluid.

[0010] In some embodiments, the vehicle is adapted to dry after the composition is applied to the skin, whereby drying is effective to agglomerate the STAR particles.

[0011] In some embodiments, the STAR particles are configured to aggregate in response to application of an external force effective to deform the STAR particles to promote aggregation. In other embodiments, the plurality of STAR particles have a magnetic, ionic, or electrostatic affinity that promotes aggregation. In other embodiments, the vehicle comprises a component configured to induce aggregation of the STAR particles after application to biological tissue.

[0012] In some embodiments, the STAR particles have pores that are initially filled with a material configured to exit the pores during and / or after application of the composition to biological tissue, thereby opening the pores and mechanically weakening or destroying the STAR particles after a period of or after application to biological tissue.

[0013] In some embodiments, the STAR particles are configured to be inactivated by immobilization of the STAR particles after application to the biological tissue, hi some embodiments, the vehicle is configured to undergo a phase change into an immobilization matrix in which the STAR particles are embedded.

[0014] In some embodiments, the vehicle comprises a microencapsulation reagent configured to encapsulate the STAR particle.

[0015] In some embodiments, the composition is in liquid or semi-solid form and is configured to form a STAR particle-containing film on the tissue and be removable from the tissue. In some embodiments, the liquid is a viscous liquid. In some embodiments, the semi-solid form is a gel.

[0016] In some embodiments, the composition also includes one or more bioactive agents, hi other embodiments, the composition also includes one or more diagnostic agents, sensors, functional cosmetics, or dietary supplements.

[0017] In some embodiments, the biological tissue comprises the patient's skin.

[0018] In another aspect, a composition for application to tissue is provided, the composition comprising a plurality of STAR particles configured for mechanical disruption of biological tissue and a vehicle in which the plurality of STAR particles are dispersed. The vehicle can comprise one or more microencapsulated reagents or solvents, and the microcapsules can be mechanically ruptured upon contacting the composition with biological tissue to release the one or more microencapsulated reagents or solvents, in the process inactivating the ability of the STAR particles to mechanically disrupt biological tissue.

[0019] In more particular embodiments, the one or more reagents or solvents are configured to induce 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 aggregation of the STAR particles. In other embodiments, the one or more reagents or solvents are configured to promote immobilization of the STAR particles on 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.

[0020] In some embodiments, the composition also includes one or more bioactive agents, hi other embodiments, the composition also includes one or more diagnostic agents, sensors, functional cosmetics, or dietary supplements.

[0021] In some embodiments, the biological tissue comprises the patient's skin.

[0022] In a further aspect, a method is provided, the method comprising the steps of applying a first composition comprising a plurality of STAR particles dispersed in a vehicle onto biological tissue, manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue, and then inactivating the STAR particles. The STAR particles can be inactivated by allowing or causing one or more of agglomeration of the STAR particles, immobilization of the STAR particles, addition of a coating substance to the STAR particles, swelling-induced shape change of the STAR particles, contraction of the microneedles of the STAR particles, softening or induced deformability of the STAR particles, and mechanical weakening of the STAR particles.

[0023] In more particular embodiments, the inactivation comprises adding a second composition to the first composition, the second composition having a first reagent or solvent, and / or the operation comprises rupturing microcapsules containing a second reagent or solvent effective to initiate or promote the inactivation. In some embodiments, the first and / or second reagent or solvent is configured to dissolve the STAR particles. In other embodiments, the first and / or second reagent or solvent is configured to promote aggregation 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 cause the STAR particles to swell, change shape, or shrink. In other embodiments, the first and / or second reagent or solvent is configured to induce softening or deformability of the microneedles of the STAR particle, hi other embodiments, the first and / or second reagent or solvent is configured to mechanically weaken the STAR particle.

[0024] In some embodiments, the inactivation comprises application of an external stimulus to the first composition and / or the biological tissue surface, wherein the application of the external stimulus is selected from (a) exposure to visible light, near-infrared light, or ultraviolet light, (b) a change in temperature, (c) a change in pressure, (d) the addition, modification, or removal of a chemical, (e) the application of ultrasound, (f) the application of electromagnetic radiation, (g) the application of a magnetic field, and (h) a combination thereof.

[0025] In some embodiments, the vehicle comprises a film-forming composition, hi other embodiments, the vehicle phase changes into an immobilizing matrix in which the STAR particles are embedded.

[0026] In some embodiments, the STAR particles have magnetic, ionic, or electrostatic affinities that promote aggregation, hi other embodiments, the STAR particles are porous and are mechanically weakened during and / or after a period of time after application of the first composition onto the biological tissue.

[0027] In some embodiments, the first composition is applied to the biological tissue in liquid or semi-solid form to form a STAR particle-containing film, and the method also includes removing the STAR particle-containing film from the biological tissue.

[0028] In yet another aspect, a method is provided, the method comprising the steps of applying a first composition comprising a plurality of STAR particles dispersed in a vehicle onto biological tissue, manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue, and then inactivating the STAR particles by adding a second composition to the first composition, the second composition comprising a solvent that dissolves at least a portion of the STAR particles.

[0029] In more specific embodiments, the composition also comprises one or more bioactive agents. In some other embodiments, the composition further comprises one or more diagnostic agents, sensors, functional cosmetics, or dietary supplements.

[0030] In some embodiments, the biological tissue comprises human skin.

[0031] In yet a further aspect, a method is provided, the method comprising the steps of applying a composition comprising a plurality of STAR particles dispersed in a vehicle onto the skin of a patient in a first state, and manipulating the composition to cause the STAR particles to mechanically disrupt the stratum corneum of the patient's skin in the first state, and transforming the patient's skin, via contact with one or more components of the vehicle, to a second state in which the STAR particles are unable to mechanically disrupt the stratum corneum.

[0032] The detailed description is set forth with reference to the accompanying drawings. The use of the same reference numbers may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those shown 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. [Brief explanation of the drawings]

[0033] [Figure 1A] FIG. 1 is a plan view of a planar STAR particle according to one embodiment of the present disclosure. [Figure 1B] FIG. 1B is a perspective view of the planar STAR particle of FIG. 1A. [Figure 1C] FIG. 2 is a plan view of a planar STAR particle according to another embodiment of the present disclosure. [Figure 1D] FIG. 1D is a perspective view of the microneedle particle of FIG. 1C. [Figure 1E] FIG. 1D is a side view of the microneedle particle of FIG. 1C. [Figure 2A] FIG. 1 is a planar view of a planar STAR particle according to another embodiment of the present disclosure, in which the tips of the particle's microneedles (i.e., protrusions) include an additive. [Figure 2B] FIG. 10 is a planar view of a planar STAR particle according to another embodiment of the present disclosure, in which the tips of the protrusions have undergone a phase change from solid to liquid and / or gas. [Figure 2C]FIG. 10 is a planar view of a planar STAR particle in which the protrusions have collapsed (eg, dissolved) according to another embodiment of the present disclosure. [Figure 2D] A collapsed STAR particle is shown. [Figure 3A] FIG. 10 is a plan view of a STAR particle according to another embodiment of the present disclosure, in which the protrusions are swollen. [Figure 3B] FIG. 10 is a plan view of a STAR particle according to another embodiment of the present disclosure, in which the protrusions are in a folded state (e.g., by softening to be elastically or plastically deformable / transformable). [Figure 3C] FIG. 1B is a plan view of a STAR particle according to another embodiment of the present disclosure, in which the protrusions have reduced mechanical strength (eg, are weakened and / or chipped). [Figure 3D] FIG. 1 is a plan view of a STAR particle according to another embodiment of the present disclosure, in which the protrusions have become mechanically weaker and broken off. [Figure 3E] FIG. 10 is a plan view of a STAR particle in accordance with another embodiment of the present disclosure, in which the protrusions are reduced. [Figure 4] 1 shows aggregated STAR particles according to another embodiment of the present disclosure. [Figure 5A] 1 shows STAR particles immobilized in a matrix according to one embodiment of the present disclosure. [Figure 5B] 1 shows STAR particles immobilized in a matrix according to another embodiment of the present disclosure. [Figure 5C] 1 shows an encapsulated and immobilized STAR particle according to one embodiment of the present disclosure. [Figure 5D] 1 shows a STAR particle immobilized by biological tissue, according to one embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0034] For example, STAR particles configured to be inactivated following or as part of their intended use are disclosed, along with methods for such inactivation. As used herein, the terms "inactivated" and "inactivation" refer to the loss of the ability of the STAR particles to mechanically disrupt biological tissue, particularly the stratum corneum of mammalian skin, especially human skin.

[0035] As used herein, a STAR particle configured to "mechanically disrupt" biological tissue, particularly the stratum corneum of mammalian skin, particularly human skin, refers to a particle having a size and mechanical strength that allows it to create holes or pores in the tissue surface. For example, the mechanical disruption can be making a penetration through the stratum corneum.

[0036] STAR particles can enhance the local administration of another substance or substances by mechanically disrupting the integrity of the outer / upper layer of the skin (or other biological tissue) to facilitate local delivery of the substance into / onto the target tissue of the patient. STAR particles can also facilitate passage of the substance to the target tissue and uptake in the bloodstream and / or lymphatic system to facilitate systemic delivery and / or facilitate passage of the substance to the target tissue for uptake into another tissue or space in the body. For example, it may be desirable to use STAR particles to deliver a substance into a structure beyond the skin (e.g., into a joint cavity to treat arthritis). The patient may be a human or other mammal. Embodiments of the present disclosure stop, limit, and / or prevent the interaction of STAR particles with undesired targets.

[0037] In some embodiments, the STAR particles are configured to [1] at least partially destroy a first type of biological tissue and [2] prevent or reduce the likelihood that the STAR particles will destroy a second type of off-target biological tissue. As used herein, the term "off-target tissue" refers to any tissue that is not intended to be destroyed by the STAR particles. Off-target tissue includes, but is not limited to, the eye or conjunctiva; oral mucosa, gastric mucosa, or vaginal mucosa; or skin outside the intended area of ​​use, or skin in the intended area of ​​use but not at the time of intended use. In particular, the second type of biological tissue can include, for example, finger skin, and the first type of biological tissue can include the tissue to be treated, for example, an area of ​​skin with a relatively thin stratum corneum or mucosal tissue. In this way, for example, the STAR particles may not destroy, or be less likely to destroy, the skin of a finger used to apply or rub the STAR particles onto / into the treatment area of ​​the first biological tissue.

[0038] In some embodiments, the STAR particles are advantageously configured to be self-limiting. For example, if the STAR particles are not deactivated, continued rubbing of them against the skin will continue to increase the permeability of the skin, which may be undesirable. However, if the STAR particles are configured to deactivate while rubbing against the skin, rubbing them for a sufficient period of time will result in a desired, selected increase in the amount of permeation of the skin, but continued rubbing beyond a sufficient period of time will not result in a substantial further increase in permeability, because the STAR particles are no longer active.

[0039] The STAR particles disclosed herein can be configured to selectively lose, partially or completely, their ability to destroy target tissue. In some embodiments, the STAR particle may lose, partially or completely, its ability to destroy the same tissue or the same tissue type after a certain period of time. In some embodiments, the STAR particle may lose, partially or completely, its mechanical destruction properties, such that the intended user cannot reuse the STAR particle. In other embodiments, the STAR particle loses its mechanical destruction properties, such that the STAR particle cannot be subsequently used by an unintended user. In yet other embodiments as described above, the STAR particle loses its mechanical destruction properties during continued use.

[0040] Advantages of limiting the functional capacity of a STAR particle include, but are not limited to, controlling the effectiveness of the particle-containing formulation, controlling the number, depth, and / or diameter of micropunctures and / or controlling the sensations perceived by the user associated with applying the STAR particle to the skin, controlling the cosmetic manifestations of the STAR particle-containing formulation on the skin, improving the safety profile of the STAR particle and / or STAR particle-containing formulation by preventing, limiting, and / or eliminating mechanical destruction of off-target tissues, preventing, limiting, and / or eliminating transmission between humans and / or other species (such as animals) through intentional or accidental transmission through the environment, and improving the environmental safety profile of the STAR particle or STAR particle-containing formulation by preventing, limiting, and / or eliminating reuse of the STAR particle, whether intentional or unintentional, by the intended user or subsequent reuse by an unintended user.

[0041] STAR particles The STAR particle comprises a core structure and one or more microneedle-like protrusions extending from the core structure. The microneedles may be structured to at least partially penetrate or otherwise mechanically disrupt biological tissue, such as the stratum corneum of human skin (or other biological tissue). That is, the microneedles are dimensioned and have mechanical strength and other properties that allow them to be forced into and penetrate biological tissue, forming microscale holes or channels therein. The microneedles may extend independently from the core structure in any direction.

[0042] 1A and 1B show a STAR particle 100 according to one embodiment. In this embodiment, the STAR particles 100 each have three microneedles 120 extending in the same plane from a core structure 110, and therefore the STAR particles are referred to as planar particles. The core structure is typically the portion of the microneedle particle that connects the microneedles, especially when more than two microneedles are present. The core structure may be a solid structure or a hollow structure with one or more internal cavities. In other embodiments, the STAR particle may have two, four, five, six, seven, eight, nine, 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, and therefore the STAR particle is referred to as a non-planar particle.

[0043] The microneedles of the STAR particles may be tapered. In some embodiments, in plan view, as shown in FIG. 1A, the microneedles 120 are tapered from the core structure 110 to the tip, while the height of the microneedles is substantially constant. In some other embodiments, the edges of the microneedles 120 may also be tapered, since tapered edges are sharper and therefore can penetrate the stratum corneum more easily than non-tapered edges. For example, in some embodiments, as shown in FIGS. 1C-1E, the microneedles 120 may be tapered in both width and height. That is, the height of the microneedles is greatest at the core structure and smallest at the tip. In other variations, the core and base portions of the microneedles may have a uniform height, with only the distal tip of the microneedle being tapered. In variations, the taper may be from one or both sides of the STAR particle.

[0044] Various design features of the STAR particle can be selected to impart functionality to the particle that prevents the entire STAR particle from penetrating biological tissue. These features can include the core structure itself, the microneedles themselves, or the spatial relationships between the microneedles or subsets of those microneedles. A combination of these features can be designed to prevent the entire microneedle particle from penetrating biological tissue.

[0045] For example, the core structure may be sized, shaped, and / or lack sharp edges that allow one or more of the microneedles extending from the core structure to penetrate biological tissue, but inhibit all or substantially all of the core structure from penetrating biological tissue. As a further example, the microneedles may have structural features, such as a taper, that allow only a portion of the microneedle (i.e., the tip distal to the core structure) to penetrate biological tissue. For example, the microneedle may have a shoulder or plateau that allows only a portion of the microneedle distal to the shoulder or plateau to penetrate biological tissue. Such a configuration may prevent the core structure from penetrating biological tissue during a penetration event between the STAR particle and biological tissue, resulting in the inability of the entire STAR particle to be fully embedded within the biological tissue.

[0046] In general, the microneedles of a STAR particle can have the same or different dimensions from each other, hi one embodiment, the microneedles of a planar STAR particle have substantially the same dimensions.

[0047] Microneedles may have any shape effective to at least partially penetrate biological tissue. In some embodiments, the microneedles are high aspect ratio structures having a length at least two times longer than the width at the base of the microneedle (i.e., the interface between the microneedle and the core structure). The length of a microneedle is the distance from the interface between the microneedle and the edge of the core structure to the tip of the microneedle. In some embodiments, each of the microneedles independently has a length between 1 μm and 2,000 μm. In some embodiments, each of the microneedles independently has a length between 10 μm and 2,000 μm. In some embodiments, each of the microneedles independently has a length between 50 μm and 2,000 μm. In some embodiments, each of the microneedles independently has a length between 100 μm and 1,000 μm. In some embodiments, each of the microneedles independently has a length between 250 μm and 750 μm. In some embodiments, each of the microneedles independently has a length of between 100 μm and 500 μm, hi some embodiments, each of the microneedles has a length of about 350 μm.

[0048] In certain embodiments, the STAR particle has three microneedles, each of which independently has a length of about 1 μm to about 2,000 μm, about 10 μm to about 2,000 μm, about 50 μm to about 2,000 μm, about 100 μm to about 1,000 μm, or about 250 μm to about 750 μm. The STAR particle may be a planar particle.

[0049] The microneedles of the STAR particles may have a tip with a radius of curvature of about 0.1 μm to about 50 μm. In some embodiments, the microneedles have a tip with a radius of curvature of about 0.1 μm to about 50 μm, about 0.1 μm to about 25 μm, about 0.1 μm to about 20 μm, about 0.1 μm to about 15 μm, about 0.1 μm to about 10 μm, about 0.1 μm to about 5 μm, about 1 μm to about 10 μm, about 1 μm to about 7 μm, about 1 μm to about 5 μm, about 1 μm to about 4 μm, about 1 μm to about 3 μm, about 5 μm to about 50 μm, about 5 μm to about 25 μm, about 5 μm to about 20 μm, about 5 μm to about 15 μm, or about 5 μm to about 10 μm. In some embodiments, each microneedle has a tip with a radius of curvature of about 5 μm to about 30 μm. The "tip" is typically the portion of the microneedle that first penetrates biological tissue.

[0050] In some embodiments, the STAR particle is shaped and sized to prevent or reduce the likelihood of the STAR particle becoming completely or irremovably embedded in biological tissue. In some embodiments, the maximum dimension of the microneedle particle is about 100 μm to about 5,000 μm, 100 μm to about 10,000 μm, about 250 μm to about 5,000 μm, about 500 μm to about 2,000 μm, or about 500 μm to about 1,000 μm. The "maximum dimension of the microneedle particle" refers to the largest of the following distances: [1] the distance between the tips of the two most distant microneedles (if the microneedle particle comprises two or more microneedles), or [2] the furthest possible distance between the tips of the microneedles and the side of the core structure opposite the side from which the measured microneedles extend. A plurality of microneedle particles may comprise microneedle particles of one or more sizes.

[0051] In some embodiments, the microneedles of the STAR particle are planar microneedles. As used herein, the phrase "planar microneedles" refers to two or more microneedles, each having either [1] a central axis extending from the core structure in at least substantially the same plane, or [2] a tip residing in substantially the same plane. Planar microneedles may include microneedles extending from the core structure in the same direction, different directions, or a combination thereof. Planar microneedles may also include collinear planar microneedles extending from both sides of the core structure such that the central axis of each microneedle corresponds to at least substantially a line. For example, if a STAR particle includes two or more pairs of microneedles, the pairs of microneedles may be collinear, but not necessarily all of the microneedles.

[0052] When the microneedles are planar microneedles, the microneedle particles may have a substantially planar, i.e., flat, structure. Substantially planar, i.e., flat, microneedle particles may have a thickness of about 1 μm to about 1,000 μm, about 5 μm to about 500 μm, about 10 μm to about 250 μm, 50 μm to about 250 μm, about 50 μm to about 200 μm, about 50 μm to about 150 μm, about 75 μm to about 200 μm, about 75 μm to about 150 μm, about 75 μm to about 125 μm, or about 80 μm to about 120 μm. In some embodiments, the height (thickness) of the microneedle 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 it is at the tip. In some embodiments, the height of the microneedle particle decreases along the length of the microneedle. The height of the microneedles may be greatest where the microneedle particles contact the core structure and smallest at the tip.

[0053] In some preferred embodiments of tapered STAR particles, the height of the central core of the STAR particle is between 100 μm and 150 μm, and the radius of curvature of the tip of the microneedle is between 5 μm and 30 μm.

[0054] In some preferred embodiments of ceramic or polymer STAR particles, the height of the core at the center of the STAR particle is between 50 μm and 150 μm. In some embodiments of stainless steel STAR particles, the height of the core at the center of the STAR particle can be as low as 12.5 μm and up to 150 μm. These ceramic, polymer, or stainless steel STAR particles can include, for example, tapered microneedles with a radius of curvature at the tip of the microneedle of between 5 μm and 30 μm.

[0055] STAR particles can be made of one or more biocompatible materials, such as metals, polymers, biopolymers, ceramics, bioactive agents, sugars, sugar alcohols, or combinations thereof. Bioactive agents can generally include one or more drugs, one or more sensors, one or more functional cosmetics, one or more dietary supplements, or a combination thereof. Thus, microneedle particles can be composed of a combination of bioactive components (drugs, small molecule excipients (e.g., trehalose), sensors, functional cosmetics, dietary supplements, or a combination thereof) and inert components (metals, polymers, ceramics, sugars, etc.). If a portion of the STAR particles remains in and / or on the biological tissue after removal of the STAR particles, the portion of the STAR particles remaining in and / or on the biological tissue can include at least one bioactive component, at least one inert component, or a combination thereof.

[0056] In some embodiments, the STAR particle is made of a water-insoluble material. In some embodiments, the STAR particle is made of or comprises at least one water-soluble and / or erodible material. If the STAR particle is made of a water-soluble and / or erodible material, the STAR particle, or parts thereof, can be safely degraded if left in and / or on living tissue, or after disposal. In one example, the STAR particle has a matrix structure that can consist of or comprise 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 particle can occur at the surface or in the environment of the tissue, but not necessarily in contact with living tissue. Other methods of degradation of water-soluble and / or water-insoluble STAR particles include, but are not limited to, dissolution, hydrolysis, degradation upon contact with sunlight (i.e., ultraviolet light), degradation resulting from reaction with another chemical entity, degradation resulting from physical or mechanical erosion, and / or degradation resulting from reaction with environmental factors (e.g., oxygen).

[0057] In some embodiments, the STAR particle is a metal microneedle particle. A metal microneedle particle is one in which the entire structure of the microneedle particle is entirely or substantially entirely composed of a metal or metal alloy (e.g., stainless steel). In some other embodiments, the majority of the STAR particle is made of such a metal or metal alloy material.

[0058] In some embodiments, the STAR particle is a polymeric microneedle particle, where all or substantially all of the structure of the microneedle particle is made from one or more polymeric materials (e.g., biodegradable materials such as poly(lactic-co-glycolic acid) (PLGA) or polycaprolactone (PCL) and / or water-soluble materials such as carboxymethylcellulose or polyvinyl alcohol). In some other embodiments, the majority of the STAR particle is made from one or more such polymeric materials.

[0059] In some embodiments, the STAR particle is a ceramic microneedle particle, where all or substantially all of the structure of the microneedle particle is made from one or more ceramic materials (e.g., aluminum oxide, titanium dioxide, zinc oxide, iron oxide). In some other embodiments, the majority of the STAR particle is made from one or more such ceramic materials.

[0060] In some embodiments, all or substantially all of the structure of the microneedle particle is made of a bioactive agent and / or another substance of interest, hi some embodiments, the majority of the STAR particle is made of one or more drugs.

[0061] In some embodiments, the STAR particle is an excipient microneedle particle, where the entire structure of the microneedle particle is made from one or more pharmaceutically acceptable excipient materials known in the art (e.g., sugars, salts, starches, etc.).

[0062] In some embodiments, the STAR particles have a structure formed from 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, and / or (v) at least one bioactive ingredient.

[0063] The STAR particles provided herein can be fabricated by any suitable method capable of forming the desired geometric shape of the STAR particle. Non-limiting examples of such methods include molding, mechanical or chemical etching, laser cutting, 3D printing, or other microfabrication techniques known in the art. For example, the STAR particle can be formed by laser etching a sheet of material. As a further example, the STAR particle can be fabricated using a molding process that can include placing a build material into a mold having a cavity corresponding to the desired geometric shape of the resulting microneedle particle. The build material can be a polymer or its precursor, which can be loaded into the mold in powder or liquid form (e.g., molten polymer and / or polymer dissolved or dispersed in a liquid medium) and then solidified into a monolithic solid form in the mold. In another example, an array of discrete particles is formed from a sheet of solid material by a process that includes at least one of etching, punching, or cutting, such as laser cutting. The STAR particle can also be sintered, densified, and / or mechanically hardened via heating, cooling, chemical modification, exposure to light, drying, compression, and / or other processes.

[0064] Composition containing STAR particles 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 comprise 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. A suitable medium is referred to herein as a "vehicle."

[0065] Essentially any suitable biocompatible vehicle can be used in the STAR particle-containing composition. The vehicle can be an aqueous medium and / or a non-aqueous medium. The vehicle can contain water, stabilizers, pH adjusters, thickeners, or other pharmaceutically acceptable excipients known in the art for use in topical therapeutic applications, including materials listed as Generally Recognized as Safe (GRAS) by the U.S. Food and Drug Administration.

[0066] The STAR particle-containing composition may comprise one or more bioactive agents (e.g., therapeutic, adjuvant, or prophylactic agents) and / or other substances of interest (e.g., diagnostic agents, sensors, functional cosmetics). The bioactive agents and / or other substances 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 in the vehicle, for example as a particle suspension and / or as an emulsion.

[0067] A 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, e.g., 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.

[0068] The concentration of STAR particles in the vehicle can be selected based on the particular application, but is generally selected to achieve the intended function of the STAR particles at a particular tissue site. For example, the concentration of STAR particles can be selected to be sufficient to create sufficient pores in the stratum corneum to deliver a desired dose (e.g., a therapeutically effective amount) of bioactive agent to the skin at the site of application of the STAR particle-containing composition.

[0069] In some embodiments, the concentration of STAR particles in the vehicle is 1 cm per vehicle. 3 In some embodiments, the concentration of STAR particles in the vehicle ranges from about 100 to about 100,000 particles per cm of vehicle. 3 In some embodiments, the concentration of STAR particles in the vehicle ranges from about 500 to about 50,000 particles per cm of vehicle. 3 In some embodiments, the concentration of STAR particles in a vehicle ranges from about 1,000 to about 25,000 particles per cm of vehicle. 3 In some embodiments, the concentration of STAR particles in the vehicle is greater than 10,000 particles per cm of the vehicle. 3 Lower than 10,000 particles per

[0070] In some embodiments, the concentration of the STAR particles in the vehicle ranges from about 0.1% to about 30% by weight of the vehicle. In some embodiments, the concentration of the STAR particles in the vehicle ranges from about 1% to about 20% by weight of the vehicle. In some embodiments, the concentration of the STAR particles in the vehicle ranges from about 5% to about 15% by weight of the vehicle. In some embodiments, the concentration of the STAR particles in the vehicle ranges from about 8% to about 12% by weight of the vehicle. In some preferred embodiments, the concentration of the STAR particles in the vehicle is from about 5% to about 10% by weight of the vehicle.

[0071] The STAR particle composition may also contain at least one substance of interest. As used herein, "substance of interest" refers to a collection of molecules or substances with preventive, therapeutic, diagnostic, or cosmetic purposes. Substances of interest may include, but are not limited to, active pharmaceutical ingredients, vaccines, allergens, vitamins, cosmetic agents, functional cosmetics, diagnostic agents, sensors, markers (e.g., color dyes or radioactive dyes or markers), other bioactive agents, and other materials that are desirable to introduce into or onto biological tissue. A list of substances of interest is included in U.S. Pat. No. 11,291,816, which is incorporated herein by reference.

[0072] The substance of interest may be a small molecule, polymer, peptide, or biological agent. In some embodiments, the substance of interest is a biological agent or organism. In further embodiments, the substance of interest has electronic properties. For example, the substance of interest may respond to radio frequency identification (RFID).

[0073] Compositions and methods for deactivating STAR particles The STAR particles disclosed herein can be inactivated while on the skin, while in the skin, and / or after the STAR particles have left the skin. The STAR particles may also be temporarily capable of mechanically disrupting tissue due to the inherent properties or composition of the STAR particles. For example, the STAR particles may have an inherent tendency to material addition, loss, or change, molecular or chemical instability, or instability to 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 environment in a manner that can also cause inactivation.

[0074] In some embodiments, a composition for application to biological tissue is provided, the composition comprising: (A) a plurality of STAR particles configured to mechanically disrupt biological tissue; and (B) a vehicle in which the plurality of STAR particles are dispersed, the composition adapted to (i) contact the biological tissue surface in a manner that causes the STAR particles to mechanically disrupt the biological tissue, and subsequently (ii) reduce the ability of the STAR particles to mechanically disrupt the biological tissue by one or more of the following inactivation mechanisms: aggregation of the STAR particles, immobilization of the STAR particles, addition of a coating substance to the STAR particles, swelling-induced shape change of the STAR particles, contraction of the microneedles of the STAR particles, softening or induced deformability of the STAR particles, and mechanical weakening of the STAR particles.

[0075] In some embodiments, the STAR particles can be deactivated during and / or after intended use by including microneedles configured to reduce or eliminate the ability of the microneedles to partially re-penetrate the biological tissue. In some embodiments, the microneedles of the STAR particles are configured to mechanically break upon penetrating the biological tissue at least once, thereby preventing the microneedles from re-penetrating the biological tissue. In some embodiments, the microneedles of the STAR particles are configured to chemically break upon penetrating the biological tissue at least once, thereby preventing the microneedles from re-penetrating the biological tissue. In some embodiments, the microneedles of the STAR particles are configured to mechanically and chemically break upon penetrating the biological tissue at least once, thereby preventing the microneedles from re-penetrating the biological tissue. The mechanical and / or chemical breakdown can occur after the microneedles have penetrated the biological tissue one, two, three or more times. Non-limiting examples of mechanical breakdown include the collapse, dissolution, softening or shattering of the microneedles, such that they no longer have a sharp tip and / or sufficient rigidity and length to penetrate the biological tissue. Non-limiting examples of chemical destruction include at least partially dissolving or decomposing by a chemical reaction such that it no longer has a sharp tip and / or sufficient stiffness and length to penetrate biological tissue.

[0076] Adding materials ~ STAR particles In some embodiments, a STAR particle can be deactivated during and / or after its intended use by adding a material to at least a portion of the microneedle and / or core structure, which can change the shape and / or size of the STAR particle, thereby reducing or eliminating the ability of the STAR particle to effectively penetrate biological tissue. Figure 2A shows a STAR particle 200 to which a material 250 has been added that covers the tip of the microneedle 220. The added material covers the sharp tip of the STAR particle's microneedle as a rounded or bulbous mass so that the STAR particle lacks a sharp tip for penetrating tissue, thereby rendering it non-functional or deactivated. In some embodiments, the added material covers the base or core of the STAR particle, reducing or eliminating the ability of the STAR particle to effectively interact with biological tissue, thereby destroying the STAR particle's ability to mechanically disrupt tissue. Sources of additional (inactivating) material include, but are not limited to, components in the delivery vehicle, the STAR particles themselves, the skin, other parts of the body 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.

[0077] Materials can associate or adsorb with STAR particles through a variety of mechanisms, including hydrophobic interactions, ionic bonds, hydrogen bonds, polar bonds, covalent bonds, metallic bonds, van der Waals forces, and clathrate formation. Physical entanglements at the molecular level and on longer length scales can also exist.

[0078] In some embodiments, skin debris (e.g., hair, skin cells, ISF, blood, cosmetics, or other exogenous materials present on the skin) may associate with and accumulate on the STAR particles when rubbed against the skin, thereby at least partially limiting the ability of the STAR particles to disrupt the skin. In other embodiments, the STAR particles are at least partially composed of hydrophobic polymers (e.g., acrylic, epoxy, polyethylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polydimethylsiloxane, polyester, and polyurethane), the formulation is at least partially composed of hydrophobic polymers, and formulation components are loaded and / or adsorbed onto the STAR particles over time.

[0079] Removal of material from STAR particles In some embodiments, STAR particles can be deactivated during and / or after intended use by removing solid material from at least a portion of the microneedle and / or core structure, thereby reducing or eliminating the ability of the STAR particle to effectively penetrate biological tissue. Figures 2B-2D show a STAR particle with loss of material, according to some embodiments. Figure 2B shows a STAR particle 200 in which the tip portion of the microneedle 220 undergoes a phase change from solid to liquid and / or gas. Only the microneedle or the entire STAR particle can change phase. The phase change can result from exposure to target tissue, non-target tissue, delivery vehicle, and / or the surrounding environment during and / or after application of the STAR particle to a tissue site. Examples of triggers for removal of solid material from the microneedle include a change in temperature, pH, and / or the application and / or exposure to radiant energy. In one example, the STAR particle is formed at least in part from sodium bicarbonate, which can form gaseous carbon dioxide spontaneously or via a chemical reaction in the presence of an acid. In another example, the STAR particle is formed, at least in part, of a material that has a melting point below physiological or ambient temperature, such that the STAR particle undergoes a phase change when interacting with the target biological tissue and / or environment.

[0080] Figures 2C-2D show the disintegration of a STAR particle. As used herein, "disintegration" refers to dissolution, breaking down into small pieces, chemical dissociation, biodegradation, or other similar processes. Figure 2C shows a STAR particle 200 in which only the microneedles 220 have disintegrated. In some embodiments, the core structure may disintegrate or dissolve, while the microneedles remain intact. Figure 2D shows a STAR particle in which the entire particle has disintegrated. Disintegration may be or include dissolution of all or part of the constituent materials that form the STAR particle.

[0081] In some embodiments, the vehicle of the STAR particle-containing composition may comprise a microencapsulated solvent for the constituent material of the STAR particles and / or may comprise another material configured to cause disintegration / inactivation of the STAR particles (the other material is referred to herein as a "functional additive"). The microcapsules of 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 against the skin during the application process, thereby releasing the solvent or material and allowing the solvent to come into contact with the STAR particles and disintegrate / inactivate them.

[0082] The functional additive may directly or indirectly interact with the STAR particles in a manner effective to disrupt / passivate the STAR particles. For example, the functional additive may be an acid (e.g., citric acid) that promotes the 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 the materials in the STAR particles and causing inactivation by dissolution. That is, a change in the pH of the STAR particles may change the solubility and mechanically weaken the STAR particles, causing them to break down from the resulting loss of ionic bonds. The functional additive may also be an enzyme or other catalyst that promotes a chemical reaction that disrupts / passivates the STAR particles.

[0083] In some embodiments, a solvent for the constituent materials of the STAR particles can be added to the STAR particle-containing composition before, during, and / or after the application process. The solvent can be effective to gradually or immediately dissolve the STAR particles. The solvent can be applied alone or in combination with a second formulation after the STAR particle-containing composition has been applied.

[0084] The solvent or different material may also be contained within the STAR particle itself. For example, the solvent or different material may be microencapsulated or otherwise temporarily isolated from the bulk of the material 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 the application process, thereby allowing the solvent or different material to come into contact with the bulk of the material forming the STAR particle.

[0085] Inducing phase changes in particles In yet another embodiment, the STAR particles may dissolve when they undergo a phase change. For example, the phase change may change the solubility or miscibility of the STAR particles so that they can be more easily dissolved in the formulation. Exposure to the ambient environment and / or changes in temperature and / or pressure may also be effective in dissolving the STAR particles, for example due to a change in the solubility of the material that contains the STAR particles.

[0086] In some embodiments, the STAR particle is configured to be inactivated following its intended use by undergoing a change in shape, size, and / or stiffness effective to reduce or negate its ability to penetrate biological tissue. For example, the STAR particle may undergo swelling and / or softening, causing the microneedle tip to become blunt and rounded and / or the microneedle to bend and easily deform, thereby rendering the tip portion of the microneedle substantially unable to penetrate the stratum corneum. Similarly, the core structure of the STAR particle may swell and / or soften, causing mechanical instability of the STAR particle, which at least partially disables it from penetrating the stratum corneum. Figure 3A shows a STAR particle 300 with a swollen microneedle 320. In some embodiments, the STAR particle is configured to absorb water or another liquid (e.g., interstitial fluid), allowing the STAR particle to swell. In some embodiments, the STAR particle-containing composition may comprise microencapsulated water or a non-aqueous liquid. When the microcapsules rupture, the liquid is released and absorbed by the STAR particle. The STAR particles may also absorb the vehicle or part of the STAR particle-containing composition.

[0087] In some embodiments, STAR particles may be made from ice and stored below the freezing temperature of water before use. Upon removal from frozen storage, the STAR particles undergo a phase change to liquid water and become inactive. In another embodiment, the STAR particles may comprise a wax such as that used to make suppositories (e.g., Witepsol fatty base, which melts between 30 and 44°C). The STAR particles are stored below the melting temperature of the wax and then, during or after use, undergo temperatures above the melting temperature of the wax, which inactivates the STAR particles.

[0088] In embodiments, the STAR particle may be at least partially composed of a material such as a polymer that is stored below its glass transition temperature, and when or after the STAR particle formulation comes into contact with the target tissue, the formulation is heated to a temperature above the glass transition temperature of the STAR particle. In such embodiments, when the STAR particle is heated above its glass transition temperature, it loses mechanical stiffness or rigidity and at least partially loses its functionality. In some embodiments, the glass transition temperature of the STAR particle is about 25°C to about 50°C, about 30°C to about 40°C, or about 37°C.

[0089] Particle swelling and / or softening The STAR particle may be configured to gradually absorb the compound, compound, or solvent, such that the STAR particle becomes ineffective after a certain period of time. The compound, compound, and / or solvent may also react with the surrounding environment and / or biological tissue during and / or after application, resulting in the STAR particle absorbing the reacted compound and at least partially inactivating the STAR particle. Swollen STAR particles, particularly swollen microneedles, may have a reduced ability to mechanically disrupt target tissue. For example, swollen microneedles may bend relative to the target tissue or may lack the sharpness required to mechanically disrupt the target tissue.

[0090] 3B shows a STAR particle 300 that has lost its rigidity or has a reduced bending modulus, so that the STAR particle bends or easily deforms elastically or plastically. In an embodiment, the microneedle 320 and core structure 310 of the STAR particle 300 have reduced rigidity. In another embodiment, only the microneedle particle 320 has reduced rigidity. In some embodiments, the flexibility of the STAR particle is influenced by the material deposits on the microneedle, as described with respect to the embodiment shown in FIG. 2A. In another embodiment, the STAR particle absorbs liquid to adjust the flexibility, bending modulus or other mechanical properties of the microneedle. The rigidity, bending modulus or flexibility of the microneedle influences the ability of the microneedle particle to mechanically disrupt skin. For example, a microneedle with a low bending modulus or flexibility will bend when in contact with the target tissue, whereas a microneedle with a high bending modulus or rigidity will overcome the elastic deformation of the tissue and mechanically disrupt the target tissue.

[0091] In some embodiments, the STAR particle-containing composition comprises a liquid-containing vehicle comprising water and / or a non-aqueous liquid microencapsulated in microcapsules, the STAR particles being dispersed in the vehicle outside the microcapsules, the microcapsules being configured to rupture while in contact with biological tissue to release the liquid and allow the liquid to contact the STAR particles, and the STAR particles being configured to absorb the released liquid and swell, undergo a shape change, and / or become soft and flexible.

[0092] In embodiments, STAR particles can be made of materials that swell in the presence of water, such as cross-linked polymers such as cross-linked carboxymethyl cellulose. The degree of cross-linking determines, among other factors, the rate at which water is taken up by the polymeric material, thereby determining the rate and extent to which the material swells. In this way, STAR particles containing materials such as cross-linked carboxymethyl cellulose can take up water, swell, and thereby inactivate at a controlled kinetic rate. In another embodiment, the STAR particles comprise a porous microstructure, whereby pores contained within the STAR particles generate capillary forces to allow fluid uptake, thereby swelling the STAR particles. The porous structure in this embodiment can be modified to enable stronger or weaker capillary driving forces.

[0093] Mechanical weakening of STAR particles In some embodiments, the STAR particle is configured to be at least partially deactivated after its intended use by undergoing a reduction in its mechanical strength by an amount effective to cause at least a tip portion of the microneedle to break instead of penetrating biological tissue. FIG. 3C shows a STAR particle 300 with reduced mechanical strength, resulting in cracks and chips in the STAR particle 300. In embodiments, the microneedle 320 is cracked and chipped. In embodiments, both the microneedle 320 and the core structure 310 are cracked and chipped. In some embodiments, the STAR particle absorbs a fluid according to the method described with respect to FIG. 3A, which may be effective to weaken the microneedle. For example, the fluid may be effective to dissolve a portion of the STAR particle, thereby forming cracks and / or chips in the STAR particle. Weakened microneedles may be made more fragile, for example, so as to be more susceptible to cracking / breakage during application. That is, they are manufactured with predetermined defects (e.g., cracks / chips) that allow the STAR particle to mechanically fail in a predetermined, desired manner, consistent with their intended use. They are effective when in use, but become ineffective during / after use. For example, ceramic STAR particles may be incompletely sintered, which can cause microcracks and / or porosity that can weaken the STAR particles, thereby promoting subsequent loss of function.

[0094] STAR particles 300 can also be weakened to be susceptible to breaking, as shown in Figure 3D. A weakened STAR particle can break upon contact with target tissue instead of mechanically disrupting the tissue as intended. For example, the STAR particle can be made of a composite material that includes a water-soluble component that dissolves or leaches out during the first use / application of the STAR particle, resulting in the STAR particle being mechanically weakened shortly thereafter and, at least in part, unable to be reused to mechanically disrupt tissue. A weakened STAR particle can break at the tip and / or at other locations within the STAR particle, such as in and / or near the core region.

[0095] In some embodiments, the STAR particle-containing composition comprises STAR particles having pores that are initially filled with a material configured to exit the pores during and / or after application of the composition to biological tissue, thereby opening the pores and mechanically weakening or destroying the STAR particles after a period of or after application to biological tissue. For example, the filling substance may be water-soluble and dissolve on contact with interstitial fluid.

[0096] In some embodiments, the STAR particle-containing composition comprises a liquid-containing vehicle comprising water and / or a non-aqueous liquid microencapsulated in microcapsules, the STAR particles being dispersed in the vehicle outside the microcapsules, the microcapsules being configured to rupture while in contact with biological tissue to release the liquid, allowing the liquid to contact and mechanically weaken the STAR particles, and the STAR particles may be configured to dissolve or become porous upon contact with the released liquid.

[0097] Particle shrinkage In some embodiments, the STAR particle is configured to be inactivated during and / or after intended use by causing the microneedles, core structure, and / or the entire STAR particle to shrink or shorten to such an extent that the microneedles, core structure, and / or the entire STAR particle, or any remaining portions thereof, are at least partially unable to penetrate biological tissue. Figure 3E shows a shrunken STAR particle 300. In embodiments in which the STAR particle 300 shrinks, the shrunken microneedles 320 may be too short to mechanically disrupt the target tissue. The shrunken microneedles may also lack the sharpness required 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 compared to the other components. For example, one or more microneedles may shrink more than the other microneedles and / or core structures.

[0098] In some embodiments, the STAR particle may comprise a hydrogel swollen with water. Upon loss of water, the hydrogel material collapses, thereby reducing the size of the STAR particle. For example, the STAR particle may comprise a material that shrinks when heated, such as polyvinyl chloride or polyolefin (e.g., shrink wrap).

[0099] Particle agglomeration In some embodiments, STAR particles are configured to be inactivated during and / or after intended use by undergoing agglomeration to the extent that the aggregated STAR particles are substantially or at least partially unable to mechanically disrupt the stratum corneum or other target tissue site. This may occur because some or many of the microneedles of the STAR particles in the aggregate are shielded from contact with biological tissue. Figure 4 shows an aggregation of STAR particles 400. As used herein, "aggregate" or "aggregate" refers to an entangled or otherwise physically associated mass of at least two STAR particles. In some embodiments, based on experimental evidence, an aggregate of STAR particles comprises 2-10,000 STAR particles, 2-5,000 STAR particles, 2-1,000 STAR particles, 2-500 STAR particles, or 2-100 STAR particles.

[0100] In some embodiments, a STAR particle-containing composition is provided that is configured to inactivate the STAR particles by agglomeration of the STAR particles. In some embodiments, the vehicle is adapted to dry after the composition is applied to the skin, whereby drying is effective to agglomerate the STAR particles. In some embodiments, the STAR particles are configured to aggregate in response to application of an external force effective to deform the STAR particles to promote aggregation. In some embodiments, the plurality of STAR particles have a magnetic, ionic, or electrostatic affinity that promotes aggregation. In some embodiments, the vehicle comprises a component configured to induce aggregation of the STAR particles after application to biological tissue.

[0101] The aggregation of STAR particles can be caused by forces that hold the STAR particles in close proximity to one another. In some embodiments, mechanical forces can promote physical interactions between the STAR particles that keep them grouped together. These mechanical forces can include geometric features of the STAR particles, such as the geometry of the surface of the STAR particles. These geometric features can be present on the STAR particles before application. For example, hook-shaped structures, possibly combined with ring-shaped structures, can be incorporated into the STAR particles, including on the surface of the STAR particles, or as part of the microneedle structure. Alternatively, the geometry of the STAR particles can be created during and / or after use of the STAR particles. In some embodiments, chemical forces, such as the creation of covalent or non-covalent bonds (e.g., hydrogen bonds, electrostatic interactions (i.e., ionic bonds), van der Waals interactions, hydrophobic bonds), can promote aggregation. In some embodiments, the STAR particles can have a surface charge that is positive, negative, or zwitterionic. Positively charged regions of a particle are attracted to negatively charged regions of other STAR particles, causing aggregation. In some embodiments, STAR particles with at least partially hydrophobic surfaces are attracted and aggregated in hydrophilic (e.g., aqueous) vehicles, and in some embodiments, STAR particles with at least partially hydrophilic surfaces are attracted and aggregated in hydrophobic (e.g., non-aqueous) vehicles.

[0102] In embodiments, the force causing aggregation can be an electromagnetic force from the material properties of the STAR particles or the vehicle. In some embodiments, the STAR particles can be made from or contain a magnetic material that attracts each other and becomes agglomerated during and / or after application to the target tissue. In some embodiments, an external electromagnetic force can be applied to induce aggregation of the STAR particles within the vehicle and / or the aggregated STAR particles can be collected after intended use for safe disposal.

[0103] STAR particle-containing compositions can directly or indirectly cause aggregation. The vehicle of the composition can evaporate and / or be absorbed by the target tissue during or shortly after application of the composition to the target tissue, thereby increasing the STAR particle concentration of the composition. Increasing the STAR particle concentration can increase the likelihood of particle-particle interactions, leading to aggregation. The vehicle can also have a viscosity that promotes particle-particle interactions, thereby increasing the likelihood of aggregation.

[0104] The vehicle may also contain a microencapsulated reagent capable of promoting aggregation. The microencapsulated reagent may be released upon contact with the skin or the surrounding environment, or upon application. The reagent may directly cause aggregation. For example, the reagent may increase the thickness of the composition or increase friction within the composition, causing the STAR particles to adhere. The reagent may also be an adhesive that adheres the STAR particles to each other. The reagent may also react with one or more components of the vehicle and / or the STAR particles to cause aggregation. Alternatively, the formulation may contain at least one non-encapsulated reagent that causes aggregation upon a chemical reaction. The vehicle itself—without any reagent—may also undergo a chemical reaction that causes aggregation. As used herein, "chemical reaction" refers to the formation and / or cleavage of covalent or non-covalent bonds.

[0105] External stimuli can also be used to induce aggregation of STAR particles. As used herein, the term "external stimulus" refers to any condition applied to the STAR particles, the STAR particle-containing composition, and / or the target tissue. These may include, but are not limited to, (a) exposure to visible light, (b) a change in temperature, (c) a change in pressure, (d) the addition, modification, or removal of chemicals, (e) the application of ultrasound, (f) the application of electromagnetic radiation (e.g., ultraviolet, visible, infrared), (g) the application of electric and / or magnetic fields, etc. For example, the STAR particles can interact with the physical, chemical, or biological properties of the target tissue to induce aggregation. The force of application can induce aggregation. The force of application can induce interactions between the STAR particles or deform the STAR particles, increasing the likelihood of aggregation. Rubbing the STAR particle-containing composition onto the skin or other target tissue can result in mechanical interaction of the STAR particles with each other and / or with other components of the composition, and / or with the skin, and / or with the applicator used to apply the STAR particle-containing composition to the skin. Rubbing may also result in deformation of the STAR particles (e.g., creating "hooks" at the tips of the STAR particle microneedles), encouraging the STAR particles to become physically interconnected. To induce aggregation, reagents or formulations can be applied to the target tissue before or after applying the STAR particles.

[0106] STAR particles may also have an affinity for aggregation. For example, STAR particles may have magnetic dipoles that attract each other. STAR particles may also have ionic affinities, whereby changes in ion concentration within a STAR particle-containing composition may affect the surface charge of the STAR particles. These affinities increase the likelihood of particle-particle interactions, thereby increasing the likelihood of aggregation.

[0107] fixed In some embodiments, STAR particles are configured to be inactivated after their intended use by immobilizing them on or within a material, thereby preventing their subsequent use and rendering them non-functional. That is, STAR particles can be encapsulated, embedded, or coated in a matrix that causes a loss of tissue disruption function. The encapsulating agent can immobilize the STAR particles in a macroscale matrix or coat individual STAR particles to reduce, limit, and / or prevent function. After encapsulation, the encapsulation matrix containing the STAR particles can be removed from the skin, thereby removing multiple STAR particles together in a single encapsulation matrix. For example, a sheet-like encapsulation matrix or strip of matrix containing STAR particles can be formed on the tissue surface, and the sheet or strip can be peeled off and, optionally, discarded.

[0108] In some embodiments, a composition is provided that is configured to inactivate STAR particles by immobilizing them after application to biological tissue. In some embodiments, the vehicle is configured to undergo a phase change to an immobilization matrix in which the STAR particles are embedded. In some embodiments, the vehicle comprises a microencapsulation reagent configured to encapsulate the STAR particles. In some embodiments, the composition is in liquid or semi-solid form and is configured to form a STAR particle-containing film on the tissue and be removable from the tissue. The liquid may be a viscous liquid. The semi-solid may be a gel.

[0109] 5A-5B show STAR particles immobilized in a matrix that prevents the STAR particles from contacting the target tissue. In FIG. 5A, STAR particle 500 is immobilized within immobilization matrix 550. The immobilization matrix may be formed, at least in part, by components in the vehicle of the STAR particle-containing composition after its application / use to the target tissue. For example, the vehicle may undergo a phase change that generates the immobilization matrix. For example, the formulation may be applied as a liquid, but over time or upon application of an external stimulus, become viscous, semi-solid, gelatinous, and / or solid. For example, volatile liquid in the vehicle may evaporate or be absorbed into the target tissue, causing other components in the vehicle to thicken, gel, precipitate, and / or aggregate to form the immobilization matrix. In FIG. 5B, STAR particle 500 is immobilized within immobilization matrix 550 and additional overlayer material 570. For example, the vehicle of the STAR particle-containing composition may react with overlayer material 570. This additional compound or material may be applied together with or subsequent to the STAR particle-containing composition.

[0110] Figure 5C shows STAR particles 500 encapsulated and immobilized in a matrix 590. The STAR particle-containing formulation may include at least one encapsulating agent 580, which encapsulates the STAR particles 500 upon application of an external stimulus or addition of another substance. The encapsulating agent may also coat the STAR particles to reduce their effectiveness without completely encapsulating them. The encapsulating matrix may be the target tissue itself. The encapsulating matrix may be hair or a molecular component of hair (i.e., keratin).

[0111] Figure 5D shows a STAR particle 500 immobilized by a tissue surface 525 and / or hair thereon 527. For example, if the target tissue is skin, the skin and / or hair thereon can encapsulate or immobilize the STAR particle.

[0112] Target tissue and tissue surface changes In some embodiments, changes to the target tissue and / or tissue surface can reduce the effectiveness of the STAR particles. In embodiments where the skin is the target tissue, the STAR particle-containing composition or at least its vehicle can affect the properties of the skin or the skin's surface to render the STAR particles ineffective. These changes to the skin can include, but are not limited to, changes in skin hydration, skin morphology, skin mechanics, including changes in skin deformability and / or elasticity, skin topography, e.g., skin roughness or smoothness, and / or the density of hair follicles and / or hair shafts in / on the target skin. The composition can also be formulated to change the physiological state of the skin to render the STAR particles ineffective. This change can occur immediately or gradually over time with consistent application of the formulation and STAR particles. Physiological changes can include changes to the stratum corneum, viable epidermis, dermis, or subcutaneous tissue. Changes can also include changes to nerves, sweat glands, sebaceous glands, sebum, collagen, elastin, cell populations in the skin, cytokine or biomolecule profiles in the skin, hair follicles, or hair shafts present in and / or on the skin. For example, STAR particles can be designed with shorter microneedles to function effectively in hyperkeratotic (e.g., psoriasis, skin warts, chronic atopic dermatitis) skin due to the abnormal biomechanical properties of diseased skin (e.g., thickened, hardened, roughened). As skin is treated with a STAR-containing formulation and becomes less hyperkeratotic and therefore more elastic, the shorter microneedles on the STAR particles become less effective because the skin deforms and does not allow for effective STAR puncture.

[0113] In some embodiments, a topical composition is provided, the composition being effective to transform a patient's skin from a first state to a second state, wherein the STAR particles are able to penetrate the surface of the skin in the first state and are unable to penetrate the surface of the skin 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.

[0114] In some embodiments, in a first state, the surface of the skin has a frictional interaction with the STAR particles such that the STAR particles can penetrate the skin, and in a second state, the surface of the skin has a reduced frictional interaction with the STAR particles such that the STAR particles slide over the surface of the skin without penetrating (e.g. the surface of the skin is very slippery). This change in the state of the skin surface can be induced by depositing a material from the topical composition onto the surface of the skin to reduce friction.

[0115] In some embodiments, in a first state, the surface of the skin has a frictional interaction with the STAR particles such that the STAR particles penetrate the skin, and in a second state, the surface of the skin has an increased frictional interaction with the STAR particles such that the STAR particles slide very slowly over the surface of the skin without penetrating (i.e., the surface of the skin is very viscous). This change in the state of the skin surface can be induced by depositing material from the topical composition onto the surface of the skin to increase friction, or the change can be induced because liquid in the topical composition evaporates, is absorbed into the skin, or is otherwise lost, resulting in excipients and other materials in the topical composition concentrating as a thin film on the surface of the skin and becoming very viscous.

[0116] Changes in particle surface properties In further embodiments, the surface properties of the STAR particles may be altered, reducing their functionality. A change in the physical and / or chemical properties of the particle's surface may alter the functional interaction between the STAR particle and the formulation, or between the STAR particle and the target tissue. For example, the STAR particle may become adhesive or sticky, which may immobilize or inhibit the function of the STAR particle. The STAR particle may also become slippery or lubricated, which may prevent the STAR particle from effectively interacting with and penetrating the target tissue. The STAR particle may also become rough, which may create resistance during application due to increased friction and therefore reduced mobility across the target tissue.

[0117] Removal of particles from tissue In a further embodiment, the STAR particles can be removed and recovered from the target tissue after use. Removal and recovery of the STAR particles is effective in preventing the STAR particles from further damaging the target tissue. The STAR particles can simply fall out of the target tissue or can be recovered from the target tissue. The STAR particles can be recovered and returned to their original packaging or container. The STAR particles can be removed with a flexible material such as cloth or other woven or nonwoven fabric. Alternatively, the particles can be removed with a rigid, semi-rigid, or flexible object such as one made of glass, metal, sugar, biopolymer, polymer, or any combination thereof. Removal of the STAR particles can be facilitated by attractive forces between the material and / or object used to collect the STAR particles. For example, the removing material and / or object can have an adhesive, an electrostatic charge opposite to that of the STAR particles, and / or an attractive magnetic dipole that facilitates interaction between the material and / or object and the STAR particles. The STAR particles can also be "removed" by dissolving, and the dissolved STAR particles are absorbed into the target tissue.

[0118] In some embodiments, a trigger may initiate the removal of STAR particles. An external stimulus may be effective to cause the removal of STAR particles from the target tissue. Forms of external stimulus may include, but are not limited to, the application of a magnetic, electric, or electromagnetic field, the application of a liquid to the target tissue that can partially or completely dissolve the STAR particles or carry them away from the target tissue, the application of soap or a solubilizing dispersant or surfactant to the target tissue, the application of any ultrasonic, audible, or quasi-audible vibration, the application of negative pressure such as suction to the target tissue, and the application of positive pressure such as wiping to the target tissue. In other embodiments, the target tissue is skin, the process of epidermal renewal and regeneration may trigger the removal of STAR particles.

[0119] Use of Microencapsulated Materials in Compositions In some embodiments, a composition for application to tissue is provided, the composition comprising (i) a plurality of STAR particles configured to mechanically disrupt biological tissue, and (ii) a vehicle in which the plurality of STAR particles are dispersed, the vehicle comprising one or more microencapsulated reagents or solvents, and the microcapsules can be mechanically ruptured upon contacting the composition with biological tissue to release the one or more microencapsulated reagents or solvents, in the process inactivating the ability of the STAR particles to mechanically disrupt biological tissue. Alternatively, the microcapsules can release their contents due to changes in temperature, pH, light (e.g., wavelength, intensity) or other environmental conditions, or due to biodegradation or dissolution of the materials comprising the microcapsules.

[0120] In embodiments, microcapsules are comprised of a core region surrounded by a shell region. Capsules can range in size from about 1 μm to about 10 mm. Microcapsules can also be about 10 nm to 1000 nm in size, in which case they can alternatively be referred to as nanocapsules. The core material can be solid, liquid, and / or gas. The shell material can be solid or liquid and can be permeable, semi-permeable, or impermeable to the substance within the core. Microcapsules can have one or more cores.

[0121] Microcapsules can be made by chemical and / or physical methods including solvent evaporation / extraction, spray drying, melt congealing, sol-gel encapsulation, sonication, coprecipitation, desolvation, emulsification, gelation, thin film hydration, homogenization, liposomal encapsulation, coacervation, emulsion solvent diffusion and other methods.

[0122] Shell materials can include a wide variety of natural and synthetic polymers, including polysaccharides (gums, starches, cellulose, cyclodextrins, chitosan), proteins (gelatin, casein, soy protein), lipids (waxes, paraffins, oils), and synthetic polymers (acrylic polymers, poly(vinyl alcohol), poly(vinylpyrrolidone)). Inorganic materials such as silicates, clays, and polyphosphates can also be used. Biopolymers (natural polymers) and biodegradable polymers can be used, such as chitosan and aliphatic polyesters such as poly(lactic acid) (PLA) and copolymers of lactic acid and glycolic acid (e.g., PLGA-poly(lactic-co-glycolic acid)).

[0123] In some embodiments, the one or more reagents or solvents are configured to induce a phase change at least in the microneedles of the STAR particles, in 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 aggregation of the STAR particles, as described above.

[0124] In some embodiments, the one or more reagents or solvents are configured to facilitate immobilization of the STAR particle on biological tissue, as described above. In some embodiments, the one or more reagents or solvents are configured to immobilize the STAR particle in a matrix material, as described above. In some embodiments, the one or more reagents or solvents are configured to facilitate addition of a coating substance to the STAR particle, as described above. In some embodiments, the one or more reagents or solvents are configured to swell or shrink the STAR particle, as described above. In some embodiments, the one or more reagents or solvents are configured to induce softening or deformability of the STAR particle, as described above. In some embodiments, the one or more reagents or solvents are configured to mechanically weaken the STAR particle, as described above.

[0125] In some embodiments, the microcapsules contain water, and the STAR particles are water-soluble or swellable, or can soften in water. Because the formulation in which the microcapsules and STAR particles reside does not contain water or does not contain enough water to dissolve, swell, or soften the STAR particles, the STAR particles are not inactivated unless the microcapsules release water. Once water is released from the microcapsules, the STAR particles become inactivated by at least partial dissolution, swelling, or softening due to the presence of water. Similar techniques can be used with solvents other than water, such as ethanol.

[0126] In another embodiment, the microcapsules contain a material that causes gelling or cross-linking of polymers or other materials contained in the formulation that the microcapsules and STAR particles are in. For example, the microcapsules may contain calcium ions and the surrounding formulation may contain pectinic acid and / or sodium pectate, or the microcapsules may contain pectinic acid and / or sodium pectate and the surrounding formulation may contain calcium ions, or the microcapsules may contain calcium ions and the STAR particles may be comprised of pectinic acid and / or sodium pectate.

[0127] Inactivation Methods In some embodiments, a method is provided, the method comprising: (i) applying a first composition comprising a plurality of STAR particles dispersed in a vehicle onto biological tissue; (ii) manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue; and then (iii) inactivating the STAR particles by allowing or causing one or more of: aggregation of the STAR particles, immobilization of the STAR particles, addition of a coating substance onto the STAR particles, swelling-induced shape change of the STAR particles, contraction of the 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 inactivation comprises addition of a second composition to 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 inactivation.

[0128] In some embodiments, the first and / or second reagent or solvent is configured to dissolve the STAR particles. In some embodiments, the first and / or second reagent or solvent is configured to promote aggregation 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 a 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, the first and / or second reagent or solvent is configured to swell, change shape or shrink the STAR particles. In some embodiments, the first and / or second reagent or solvent is configured to induce softening or deformability of the microneedles of the STAR particles. In some embodiments, the first and / or second reagent or solvent is configured to mechanically weaken the STAR particles.

[0129] In some embodiments, the inactivation comprises application of an external stimulus to the first composition and / or the biological tissue surface, wherein the application of the external stimulus is selected from (a) exposure to visible light, near-infrared light, or ultraviolet light, (b) a change in temperature, (c) a change in pressure, (d) the addition, modification, or removal of a chemical, (e) the application of ultrasound, (f) the application of electromagnetic radiation, (g) the application of a magnetic field, and (h) a combination thereof.

[0130] In some embodiments, deactivation comprises encapsulating the STAR particle with an encapsulating material. In some embodiments, deactivation comprises immobilizing the STAR particle. For example, the vehicle may undergo a phase change to an immobilizing matrix in which the STAR particle is embedded.

[0131] In some embodiments, the STAR particles are or become porous and are mechanically weakened during and / or after a period of time after application of the first composition onto the biological tissue.

[0132] In some embodiments, the first composition is applied to the biological tissue in liquid or semi-solid form to form a STAR particle-containing film, and the method further comprises removing the STAR particle-containing film from the biological tissue.

[0133] In some embodiments, a method is provided that includes: (i) applying a first composition onto biological tissue, the first composition comprising a plurality of STAR particles dispersed in a vehicle; (ii) manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue; and then (iii) inactivating the STAR particles by adding a second composition to the first composition, the second composition comprising a solvent that dissolves at least a portion of the STAR particles.

[0134] In some embodiments, as described above, a method is provided, comprising: (i) applying a composition comprising 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 corneum of the patient's skin in the first state; and (iii) transforming the patient's skin, via contact with one or more components of the vehicle, to a second state in which the STAR particles are unable to mechanically disrupt the stratum corneum.

[0135] Embodiment Some embodiments of the present disclosure can be described in consideration of one or more of the following. Embodiment 1: A composition for application to biological tissue comprising a plurality of STAR particles configured for mechanical disruption of biological tissue and a vehicle in which the plurality of STAR particles are dispersed, wherein the composition is adapted to (i) contact the biological tissue surface in a manner that causes the STAR particles to mechanically disrupt the biological tissue, and subsequently (ii) reduce the ability of the STAR particles to mechanically disrupt the biological tissue by one or more of the following inactivation mechanisms: aggregation of the STAR particles, immobilization of the STAR particles, addition of a coating substance to the STAR particles, swelling-induced shape change of the STAR particles, contraction of the microneedles of the STAR particles, softening or induced deformability of the STAR particles, and mechanical weakening of the STAR particles.

[0136] Embodiment 2. The composition of embodiment 1, wherein the vehicle comprises water and / or a non-aqueous liquid, the liquid being microencapsulated in microcapsules, the STAR particles being dispersed in the vehicle outside the microcapsules, and the microcapsules are configured to rupture while in contact with biological tissue to release the liquid and allow it to contact the STAR particles.

[0137] Embodiment 3. The composition of embodiment 1 or 2, wherein the liquid is water.

[0138] Embodiment 4. The composition of any one of embodiments 1 to 3, wherein the STAR particles are configured to dissolve or become porous upon contact with the emitted liquid.

[0139] Embodiment 5. A composition according to any one of embodiments 1 to 4, wherein the STAR particles are configured to absorb released liquid and swell, undergo a shape change, and / or become soft and flexible.

[0140] Embodiment 6. The composition of any one of embodiments 1 to 5, wherein the biological tissue is skin, and wherein the composition is effective to transform the skin and / or the surface of the skin from a first state to a second state, and wherein the STAR particles are capable of penetrating the surface of the skin in the first state and are unable to penetrate the surface of the skin in the second state.

[0141] Embodiment 7. The composition of any one of embodiments 1 to 6, wherein the first state is a diseased state and the second state is a healthy state; wherein the first state is a dry state and the second state is a hydrated state; wherein the first state is hyperkeratotic skin and the second state is non-hyperkeratotic skin; or wherein the first state has a first frictional interaction between the surface of the skin and the STAR particles and the second state has a second frictional interaction between the surface of the skin and the STAR particles, and wherein the second frictional interaction is (i) reduced relative to the first frictional interaction such that the STAR particles slide easily over the surface of the skin without penetrating, or (ii) increased relative to the first frictional interaction such that the STAR particles are substantially prevented from moving across the surface of the skin.

[0142] Embodiment 8. The composition of any one of embodiments 1 to 7, wherein the vehicle comprises a film-forming composition.

[0143] Embodiment 9. A composition according to any one of embodiments 1 to 8, wherein the STAR particles are configured to be inactivated after contact with interstitial fluid upon penetration into biological tissue.

[0144] Embodiment 10. A composition according to any one of embodiments 1 to 9, configured to inactivate STAR particles by agglomeration of the STAR particles.

[0145] Embodiment 11. A composition according to any one of embodiments 1 to 10, wherein the vehicle is adapted to dry after the composition is applied to the skin, whereby drying is effective to agglomerate the STAR particles.

[0146] Embodiment 12. The composition of any one of embodiments 1 to 11, wherein the STAR particles are configured to aggregate in response to the application of an external force effective to deform the STAR particles so as to promote aggregation.

[0147] Embodiment 13. The composition of any one of embodiments 1 to 12, wherein the plurality of STAR particles have a magnetic, ionic, or electrostatic affinity that promotes aggregation.

[0148] Embodiment 14. A composition according to any one of embodiments 1 to 13, wherein the vehicle comprises a component configured to induce aggregation of STAR particles after application to biological tissue.

[0149] Embodiment 15. A composition according to any one of embodiments 1 to 14, wherein the STAR particles have pores that are initially filled with a material configured to exit the pores during and / or after application of the composition to biological tissue, thereby opening the pores and mechanically weakening or destroying the STAR particles during or after a period of time after application to biological tissue.

[0150] Embodiment 16. A composition according to any one of embodiments 1 to 15, configured to inactivate STAR particles by immobilization of the STAR particles after application to biological tissue.

[0151] Embodiment 17. A composition according to any one of embodiments 1 to 16, wherein the vehicle is configured to undergo a phase change into an immobilization matrix in which the STAR particles are embedded.

[0152] Embodiment 18. A composition according to any one of embodiments 1 to 17, wherein the vehicle comprises a microencapsulation reagent configured to encapsulate the STAR particle.

[0153] Embodiment 19. A composition according to any one of embodiments 1 to 18, which is in liquid or semi-solid form and is configured to form a STAR particle-containing film on the tissue and be removable from the tissue.

[0154] Embodiment 20. The composition of any one of embodiments 1 to 19, wherein the liquid is a viscous liquid.

[0155] Embodiment 21. The composition of any one of embodiments 1 to 20, wherein the semi-solid form is a gel.

[0156] Embodiment 22. The composition of any one of embodiments 1 to 21, further comprising one or more bioactive agents.

[0157] Embodiment 23. The composition of any one of embodiments 1 to 22, further comprising one or more diagnostic agents, sensors, functional cosmetics, or dietary supplements.

[0158] Embodiment 24. The composition of any one of embodiments 1 to 23, wherein the biological tissue comprises the patient's skin.

[0159] Embodiment 25. A composition for application to tissue, comprising a plurality of STAR particles configured to mechanically disrupt 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, and wherein the microcapsules can be mechanically ruptured upon contacting the composition with biological tissue to release the one or more microencapsulated reagents or solvents, in the process inactivating the ability of the STAR particles to mechanically disrupt biological tissue.

[0160] Embodiment 26. The composition of embodiment 25, wherein the one or more reagents or solvents are configured to induce a phase change in at least the microneedles of the STAR particle.

[0161] Embodiment 27. The composition of either embodiment 25 or 26, wherein the one or more reagents or solvents are configured to at least partially dissolve the STAR particles.

[0162] Embodiment 28. The composition of any one of embodiments 25 to 27, wherein one or more reagents or solvents are configured to promote aggregation of the STAR particles.

[0163] Embodiment 29. The composition of any one of embodiments 25 to 28, wherein one or more reagents or solvents are configured to promote immobilization of the STAR particles to biological tissue.

[0164] Embodiment 30. The composition of any one of embodiments 25 to 29, wherein the one or more reagents or solvents are configured to immobilize the STAR particles in the matrix material.

[0165] Embodiment 31. A composition according to any one of embodiments 25 to 30, wherein one or more reagents or solvents are configured to facilitate addition of the coating substance to the STAR particles.

[0166] Embodiment 32. The composition of any one of embodiments 25 to 31, wherein the one or more reagents or solvents are configured to swell or shrink the STAR particles.

[0167] Embodiment 33. The composition of any one of embodiments 25 to 32, wherein one or more reagents or solvents are configured to induce softening or deformability of the STAR particles.

[0168] Embodiment 34. The composition of any one of embodiments 25 to 33, wherein one or more reagents or solvents are configured to mechanically weaken the STAR particles.

[0169] Embodiment 35. The composition of any one of embodiments 25 to 34, further comprising one or more bioactive agents.

[0170] Embodiment 36. The composition of any one of embodiments 25 to 35, further comprising one or more diagnostic agents, sensors, functional cosmetics, or dietary supplements.

[0171] Embodiment 37. The composition of any one of embodiments 25 to 36, wherein the biological tissue comprises the patient's skin.

[0172] Embodiment 38. A method comprising applying a first composition comprising a plurality of STAR particles dispersed in a vehicle onto biological tissue, manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue, and then inactivating the STAR particles by allowing 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 changes of the STAR particles, contraction of the microneedles of the STAR particles, softening or induced deformability of the STAR particles, and mechanical weakening of the STAR particles.

[0173] Embodiment 39. The method of embodiment 38, wherein (i) the inactivating comprises adding a second composition to the first composition, the second composition comprising a first reagent or solvent, and / or (ii) the act comprises rupturing microcapsules comprising a second reagent or solvent effective to initiate or promote the inactivation.

[0174] Embodiment 40 The method of any of embodiments 38 or 39, wherein the first and / or second reagent or solvent is configured to dissolve the STAR particles.

[0175] Embodiment 41 The method of any one of embodiments 38 to 40, wherein the first and / or second reagent or solvent is configured to promote aggregation of the STAR particles.

[0176] Embodiment 42. The method of any one of embodiments 38 to 41, wherein the first and / or second reagent or solvent is configured to promote immobilization of the STAR particles on the biological tissue surface.

[0177] Embodiment 43. The method of any one of embodiments 39 to 42, wherein the first and / or second reagent or solvent is configured to immobilize the STAR particles in a matrix material.

[0178] Embodiment 44. The method of any one of embodiments 38 to 43, wherein the first and / or second reagent or solvent is configured to facilitate addition of the coating substance to the STAR particles.

[0179] Embodiment 45. The method of any one of embodiments 38 to 44, wherein the first and / or second reagent or solvent is configured to swell, cause a shape change, or shrink the STAR particle.

[0180] Embodiment 46. The method of any one of embodiments 38 to 45, wherein the first and / or second reagent or solvent is configured to induce softening or deformability of the microneedles of the STAR particles.

[0181] Embodiment 47. The method of any one of embodiments 38 to 46, wherein the first and / or second reagent or solvent is configured to mechanically weaken the STAR particles.

[0182] Embodiment 48. The method of any one of embodiments 38 to 47, wherein the inactivating comprises application of an external stimulus to the first composition and / or the biological tissue surface, wherein the application of the external stimulus is selected from one or more of: (a) exposure to visible light, near-infrared light, or ultraviolet light; (b) a change in temperature; (c) a change in pressure; (d) the addition, modification, or removal of a chemical; (e) the application of ultrasound; (f) the application of electromagnetic radiation; (g) the application of a magnetic field; and (h) combinations thereof.

[0183] Embodiment 49. The method of any one of embodiments 38 to 48, wherein the vehicle comprises a film-forming composition.

[0184] Embodiment 50. The method of any one of embodiments 38 to 50, wherein inactivating comprises contacting the STAR particles with interstitial fluid.

[0185] Embodiment 51 The method of any one of embodiments 38 to 51, wherein the inactivating comprises agglomerating STAR particles.

[0186] Embodiment 52. The method of any one of embodiments 38 to 51, wherein the STAR particles have a magnetic, ionic, or electrostatic affinity that promotes aggregation.

[0187] Embodiment 53. The method of any one of embodiments 38 to 52, wherein the STAR particles are porous and are mechanically weakened during and / or after a period of time after application of the first composition onto the biological tissue.

[0188] Embodiment 54 The method of any one of embodiments 38 to 53, wherein the inactivation comprises immobilization of the STAR particles.

[0189] Embodiment 55 The method of any one of embodiments 38 to 54, wherein the vehicle undergoes a phase change into an immobilization matrix in which the STAR particles are embedded.

[0190] Embodiment 56 The method of any one of embodiments 38 to 55, wherein the inactivation comprises encapsulating the STAR particles with an encapsulating material.

[0191] Embodiment 57. The method of any one of embodiments 38 to 56, wherein the first composition is applied to the biological tissue in liquid or semi-solid form to form a STAR particle-containing film, and the method further comprises removing the STAR particle-containing film from the biological tissue.

[0192] Embodiment 58. A method comprising applying a first composition comprising a plurality of STAR particles dispersed in a vehicle onto biological tissue, manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue, and then inactivating the STAR particles by adding a second composition to the first composition, wherein the second composition comprises a solvent that dissolves at least a portion of the STAR particles.

[0193] Embodiment 59. The method of any one of embodiments 38 to 58, wherein the composition further comprises one or more bioactive agents.

[0194] Embodiment 60. The method of any one of embodiments 38 to 59, wherein the composition further comprises one or more diagnostic agents, sensors, functional cosmetics, or dietary supplements.

[0195] Embodiment 61. The method of any one of embodiments 38 to 60, wherein the biological tissue comprises human skin.

[0196] Embodiment 62. A method comprising applying a composition comprising 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 corneum of the patient's skin in the first state, and transforming the patient's skin, via contact with one or more components of the vehicle, to a second state in which the STAR particles are unable to mechanically disrupt the stratum corneum.

[0197] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. As used herein, the term "about" indicates that a given quantity value can include an amount within a range of within 10% of the stated value, or optionally within 5% of the value, or in some embodiments within 1% of the value.

[0198] While the present disclosure has been described with reference to several exemplary embodiments, it will be understood by those skilled in the art that the present 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 present disclosure.

Claims

1. A composition for application to biological tissue, comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue; and a vehicle in which the plurality of STAR particles are dispersed; The composition (i) contacts the surface of the biological tissue in a manner that causes the STAR particles to mechanically disrupt the biological tissue, followed by (ii) the following inactivation mechanism: agglomeration of the STAR particles; Immobilization of the STAR particles; adding a coating material to the STAR particles; Swelling-induced shape change of the STAR particles; Contraction of the microneedles of the STAR particles; the softening or induced deformability of the STAR particles; or a) mechanical weakening of said STAR particles; b) mechanical weakening of said STAR particles; c) mechanical weakening of said STAR particles; d) mechanical weakening of said STAR particles;

2. 2. The composition of claim 1, wherein the vehicle comprises water and / or a non-aqueous liquid, the liquid being microencapsulated in microcapsules, the STAR particles being dispersed in the vehicle outside the microcapsules, and the microcapsules are configured to rupture while in contact with the biological tissue to release the liquid and allow the liquid to come into contact with the STAR particles.

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

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

5. 3. 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. 2. The composition of claim 1, wherein the biological tissue is skin, the composition is effective to transform the skin and / or the surface of the skin from a first state to a second state, and the STAR particles are capable of penetrating the surface of the skin in the first state and are unable to penetrate the surface of the skin in the second state.

7. the first condition is a diseased condition and the second condition is a healthy condition; the first state being a dry state and the second state being a hydrated state; the first condition is hyperkeratotic skin and the second condition is non-hyperkeratotic skin; or 7. The composition of claim 6, wherein the first state has a first frictional interaction between the surface of the skin and the STAR particles, and the second state has a second frictional interaction between the surface of the skin and the STAR particles, the second frictional interaction being either (i) reduced relative to the first frictional interaction such that the STAR particles easily slide across the surface of the skin without penetrating, or (ii) increased relative to the first frictional interaction such that the STAR particles are substantially prevented from moving across the surface of the skin.

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

9. 10. The composition of claim 1, wherein the STAR particles are configured to be inactivated upon contact with interstitial fluid upon penetration into the biological tissue.

10. 10. The composition of claim 1, configured to inactivate the STAR particles by agglomeration of the STAR particles.

11. 11. 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 agglomerate the STAR particles.

12. 11. The composition of claim 10, wherein the STAR particles are configured to aggregate in response to application of an external force effective to deform the STAR particles so as to promote aggregation.

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

14. The composition of claim 10 , wherein the vehicle comprises a component configured to induce aggregation of the STAR particles after application to the biological tissue.

15. 2. The composition of claim 1, wherein the STAR particles have their pores initially filled with a material configured to exit the pores during and / or after application of the composition to the biological tissue, thereby opening the pores and mechanically weakening or destroying the STAR particles during or after a period of time after application to the biological tissue.

16. 10. The composition of claim 1, configured to inactivate the STAR particles by immobilization of the STAR particles after application to the biological tissue.

17. 17. The composition of claim 16, wherein the vehicle is configured to undergo a phase change into an immobilization matrix in which the STAR particles are embedded.

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

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

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

21. 20. 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. 10. The composition of claim 1, further comprising one or more diagnostic agents, sensors, functional cosmetics, or dietary supplements.

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

25. 1. A composition for application to tissue, comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue; and a vehicle in which the plurality of STAR particles are dispersed; A composition wherein the vehicle contains one or more microencapsulated reagents or solvents, and the microcapsules can be mechanically ruptured by contacting the composition with the biological tissue to release the one or more microencapsulated reagents or solvents, in the process inactivating the ability of the STAR particles to mechanically disrupt biological tissue.

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

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

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

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

30. 26. 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. 26. The composition of claim 25, wherein the one or more reagents or solvents are configured to facilitate application of a coating substance to the STAR particles.

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

33. 26. 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. 26. The composition of claim 25, wherein the one or more reagents or solvents are configured to mechanically weaken the STAR particles.

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

36. 26. The composition of claim 25, further comprising one or more diagnostic agents, sensors, functional cosmetics, or dietary supplements.

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

38. 1. A method comprising: applying a first composition comprising a plurality of STAR particles dispersed in a vehicle onto biological tissue; manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue; and The STAR particles are agglomeration of the STAR particles; Immobilization of the STAR particles; adding a coating material onto the STAR particles; Swelling-induced shape change of the STAR particles; Contraction of the microneedles of the STAR particles; the softening or induced deformability of the STAR particles; or mechanical weakening of said STAR particles.

39. 39. The method of claim 38, wherein (i) the inactivating comprises adding a second composition to the first composition, the second composition comprising a first reagent or solvent, and / or (ii) the act comprises rupturing microcapsules comprising a second reagent or solvent effective to initiate or facilitate the inactivation.

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

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

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

43. 40. 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. 40. The method of claim 39, wherein the first and / or second reagent or solvent is configured to facilitate application of a coating substance to the STAR particles.

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

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

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

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

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

50. 39. The method of claim 38, wherein said inactivating comprises contacting said STAR particles with interstitial fluid.

51. 39. The method of claim 38, wherein said inactivating comprises agglomerating said STAR particles.

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

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

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

55. 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. 39. The method of claim 38, wherein said inactivating comprises encapsulating said STAR particles with an encapsulating material.

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

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

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

60. 39. The method of claim 38, wherein the composition further comprises one or more diagnostic agents, sensors, functional cosmetics, or dietary supplements.

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

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

Images