Microneedle particles, compositions and methods of particle deactivation

Abstract

STAR particles and compositions thereof, the STAR particles each having a core structure and one or more microneedle protrusions extending from the core structure. The STAR particle composition comprises: a plurality of STAR particles, the plurality of STAR particles being configured for mechanical disruption of biological tissue; and a vehicle in which the plurality of STAR particles are dispersed, where the composition is adapted to contact a surface of a biological tissue in such a manner that the STAR particles mechanically disrupt the biological tissue, and subsequently attenuate the ability of the STAR particles to mechanically disrupt the biological tissue by one or more inactivation mechanisms.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 437,007, filed on January 4, 2023, which is incorporated herein by reference. Background Art

[0003] Some embodiments of microneedle particles (i.e., STAR particles) are described in U.S. Patent 11,291,816, which is incorporated herein by reference. STAR particles can be an effective mechanism for improving the delivery of bioactive compounds to biological tissues such as skin. However, it may not be desirable to use STAR particles on off-target tissues, reuse STAR particles, or use STAR particles in an unexpected manner. Therefore, it is desirable to provide compositions and methods for controlling the time, spatial location, and manner or mechanism at which STAR particles lose their ability to mechanically disrupt tissue sites (e.g., target tissue). It is also desirable to provide various ways to control how STAR particles can interact with skin or other tissue sites. 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 the 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 in a manner that causes the STAR particles to mechanically disrupt the biological tissue, and subsequently (ii) weaken the ability of the STAR particles to mechanically disrupt the biological tissue through one or more inactivation mechanisms. The one or more inactivation mechanisms can include: agglomeration of the STAR particles; immobilization of the STAR particles; addition of a coating substance to the STAR particles; expansion-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.

[0005] In more specific embodiments, the vehicle comprises a liquid comprising water and / or a non-aqueous liquid, the liquid being microencapsulated in a microcapsule, the STAR particles being dispersed in the vehicle and outside the microcapsule, wherein the microcapsule is configured to rupture upon contact with the biological tissue to release the liquid and allow the liquid to contact the STAR particles. In some embodiments, the liquid is water.

[0006] In some embodiments, the STAR particle is configured to dissolve or become porous upon contact with the released liquid. In other embodiments, the STAR particle is configured to absorb the released liquid and swell, undergo a shape change, 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 skin surface from a first state to a second state, wherein the STAR particle is able to penetrate the skin surface in the first state and is unable to penetrate the skin surface in the second state. In some embodiments, the first state is a diseased state and the second state is a healthy state, the first state is a dry state and the second state is a hydrated state, the first state is hyperkeratinized skin and the second state is non-hyperkeratinized skin, or the first state has a first frictional interaction between the skin surface and the STAR particle and the second state has a second frictional interaction between the skin surface and the STAR particle, the second frictional interaction being (i) reduced relative to the first frictional interaction such that the STAR particle easily slides over the skin surface without penetrating, or (ii) increased relative to the first frictional interaction such that the STAR particle is substantially prevented from moving over the skin surface.

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

[0009] In some embodiments, the STAR particle is configured to become inactivated upon contact with interstitial fluid upon penetrating the biological tissue.

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

[0011] In some embodiments, the STAR particles are configured to agglomerate in response to application of an external force that effectively deforms the STAR particles in a manner that promotes agglomeration. In other embodiments, the plurality of STAR particles have magnetic, ionic, or electrostatic affinities that promote agglomeration. In other embodiments, the vehicle comprises a component configured to induce agglomeration of the STAR particles after administration to the biological tissue.

[0012] In some embodiments, the STAR particle has pores that are initially filled with a material that is 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 particle after a period during or after application to the biological tissue.

[0013] In some embodiments, the STAR particle is configured to be inactivated by immobilization of the STAR particle after administration to the biological tissue.In some embodiments, the vehicle is configured to phase transition into an immobilization matrix in which the STAR particle is embedded.

[0014] In some embodiments, the vehicle comprises a microencapsulation agent 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 film containing STAR particles 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 further comprises one or more bioactive agents. In other embodiments, the composition further comprises one or more diagnostic agents, sensors, cosmeceuticals, or nutraceuticals.

[0017] In some embodiments, the biological tissue comprises skin of a patient.

[0018] In another aspect, a composition for administration to tissue is provided, comprising: a plurality of STAR particles configured for mechanical disruption of biological tissue; and a vehicle in which the STAR particles are dispersed. The vehicle may include one or more microencapsulated agents or solvents, wherein microcapsules of the one or more microencapsulated agents or solvents are capable of mechanically disrupting during contact of the composition with the biological tissue to release the one or more microencapsulated agents or solvents and inactivate the ability of the STAR particles to mechanically disrupt the biological tissue.

[0019] In more specific embodiments, the one or more reagents or solvents are configured to cause a phase change in the microneedle of at least the STAR particle. In some embodiments, the one or more reagents or solvents are configured to at least partially dissolve the STAR particle. In other embodiments, the one or more reagents or solvents are configured to promote agglomeration of the STAR particle. In other embodiments, the one or more reagents or solvents are configured to promote fixation of the STAR particle on the biological tissue. In other embodiments, the one or more reagents or solvents are configured to fix the STAR particle in a matrix material. In other embodiments, the one or more reagents or solvents are configured to promote the addition of a coating substance to the STAR particle. In other embodiments, the one or more reagents or solvents are configured to cause the STAR particle to swell or shrink. In other embodiments, the one or more reagents or solvents are configured to induce softening or deformability of the STAR particle. In other embodiments, the one or more reagents or solvents are configured to mechanically weaken the STAR particle.

[0020] In some embodiments, the composition further comprises one or more bioactive agents. In other embodiments, the composition further comprises one or more diagnostic agents, sensors, cosmeceuticals, or nutraceuticals.

[0021] In some embodiments, the biological tissue comprises skin of a patient.

[0022] In another aspect, a method is provided, comprising the steps of: applying a first composition comprising a plurality of STAR particles dispersed in a vehicle to biological tissue; manipulating the composition to mechanically disrupt the biological tissue with the STAR particles; and then inactivating the STAR particles. The STAR particles can be inactivated by allowing or causing one or more of the following: agglomeration of the STAR particles; immobilization of the STAR particles; addition of a coating substance to the STAR particles; expansion-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.

[0023] In more specific embodiments, the inactivation comprises adding a second composition to the first composition, the second composition having a first agent or solvent, and / or the manipulation comprises rupturing a microcapsule comprising a second agent or solvent, the second agent or solvent being effective to initiate or promote the inactivation. In some embodiments, the first agent or solvent and / or the second agent or solvent are configured to dissolve the STAR particle. In other embodiments, the first agent or solvent and / or the second agent or solvent are configured to promote agglomeration of the STAR particle. In other embodiments, the first agent or solvent and / or the second agent or solvent are configured to promote fixation of the STAR particle on the surface of biological tissue. In other embodiments, the first agent or solvent and / or the second agent or solvent are configured to fix the STAR particle in a matrix material. In other embodiments, the first agent or solvent and / or the second agent or solvent are configured to promote the addition of a coating substance to the STAR particle. In other embodiments, the first agent or solvent and / or the second agent or solvent are configured to swell, cause a shape change, or shrink the STAR particle. In other embodiments, the first agent or solvent and / or the second agent or solvent is configured to induce softening or deformability of the microneedles of the STAR particle. In other embodiments, the first agent or solvent and / or the second agent or solvent is configured to mechanically weaken the STAR particle.

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

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

[0026] In some embodiments, the STAR particle has magnetic, ionic, or electrostatic affinity that promotes agglomeration. In other embodiments, the STAR particle is porous and is mechanically weakened during and / or after a period of time after applying the first composition to the biological tissue.

[0027] In some embodiments, the first composition is applied to the biological tissue in liquid or semisolid form and forms a film containing STAR particles, and the method further comprises: removing the film containing STAR particles from the biological tissue.

[0028] In yet another aspect, a method is provided, comprising the steps of applying a first composition comprising a plurality of STAR particles dispersed in a vehicle to biological tissue; manipulating the composition so that the STAR particles 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.

[0029] In more specific embodiments, the composition further comprises one or more bioactive agents. In some other embodiments, the composition further comprises one or more diagnostic agents, sensors, cosmeceuticals, or nutraceuticals.

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

[0031] In an even further aspect, a method is provided comprising the steps of applying a composition comprising a plurality of STAR particles dispersed in a vehicle to the skin of a patient in a first state; and manipulating the composition in the first state so that the STAR particles mechanically disrupt the epidermal stratum corneum of the patient's skin, converting the patient's skin to a second state via contact with one or more components in the vehicle, wherein the STAR particles are unable to mechanically disrupt the epidermal stratum corneum. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Detailed description of the invention is described with reference to the accompanying drawings. The use of the same reference numerals may indicate similar or identical items. Various embodiments may utilize elements and / or components different from those illustrated in the drawings, and some elements and / or components may not be present in various embodiments. Elements and / or components are not necessarily drawn to scale.

[0033] Figure 1Ais a plan view of a planar STAR particle according to one embodiment of the present disclosure.

[0034] Figure 1B yes Figure 1A A perspective view of a flat STAR particle.

[0035] Figure 1C is a plan view of a planar STAR particle according to another embodiment of the present disclosure.

[0036] Figure 1D yes Figure 1C Perspective view of the microneedle particles.

[0037] Figure 1E yes Figure 1C Side view of the microneedle particle.

[0038] Figure 2A is a plan view of a planar STAR particle according to another embodiment of the present disclosure, wherein the tip portions (ie, protrusions) of the microneedles of the particle include additional substances.

[0039] Figure 2B is a plan view of a planar STAR particle according to another embodiment of the present disclosure, wherein the tip portion of the protrusion is undergoing a phase transition from solid to liquid and / or gas.

[0040] Figure 2C is a plan view of a planar STAR particle according to another embodiment of the present disclosure, wherein the protrusions are disintegrating (eg, dissolving).

[0041] Figure 2D Depicted is a disintegrating STAR particle.

[0042] Figure 3A is a plan view of a STAR particle according to another embodiment of the present disclosure, wherein the protrusions have been expanded.

[0043] Figure 3B is a plan view of a STAR particle according to another embodiment of the present disclosure, wherein protrusions have become curved (eg, by becoming elastic or plastically deformed / deformable through softening).

[0044] Figure 3C is a plan view of a STAR particle according to another embodiment of the present disclosure, wherein the protrusions have reduced mechanical strength (eg, become brittle and / or break).

[0045] Figure 3D is a plan view of a STAR particle according to another embodiment of the present disclosure, wherein the protrusions have reduced mechanical strength and are broken.

[0046] Figure 3Eis a plan view of a STAR particle according to another embodiment of the present disclosure, in which the protrusions have been retracted.

[0047] Figure 4 Agglomerated STAR particles according to another embodiment of the present disclosure are depicted.

[0048] Figure 5A Depicted are STAR particles immobilized in a matrix according to one embodiment of the present disclosure.

[0049] Figure 5B Depicted are STAR particles immobilized in a matrix according to another embodiment of the present disclosure.

[0050] Figure 5C Depicted are encapsulated and immobilized STAR particles according to one embodiment of the present disclosure.

[0051] Figure 5D Depicted are STAR particles immobilized by biological tissue according to one embodiment of the present disclosure. DETAILED DESCRIPTION

[0052] Disclosed are STAR particles configured to be inactivated, for example, after or as part of their intended use, and methods for such inactivation. As used herein, the term "inactivation" refers to the loss of the STAR particle's ability to mechanically disrupt biological tissue, particularly the stratum corneum of mammalian skin, and especially human skin.

[0053] As used herein, STAR particles configured to "mechanically disrupt" biological tissue, particularly the stratum corneum of mammalian skin (particularly human skin), refer to particles having a size and mechanical strength capable of creating holes or pores in the tissue surface. For example, mechanical disruption can penetrate the stratum corneum.

[0054] STAR particles can facilitate local delivery of a substance into / onto a target tissue of a patient by mechanically disrupting the integrity of the outer / upper layer of the skin (or other biological tissue), thereby enhancing the local administration of another substance or substances. STAR particles can also facilitate the passage of a substance through a target tissue and uptake into the bloodstream and / or lymphatic system to facilitate systemic delivery, and / or facilitate the passage of a substance through a 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 to a structure other than the skin (e.g., into a joint space for the treatment of arthritis). The patient can be human or other mammal. Embodiments of the present disclosure stop, limit and / or prevent the interaction of STAR particles with undesirable targets.

[0055] In some embodiments, the STAR particles are configured to [1] at least partially disrupt a first type of biological tissue and [2] prevent or reduce the likelihood that the STAR particles may disrupt 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 disrupted by the STAR particles. Off-target tissue includes, but is not limited to, the eye or conjunctiva; oral, gastric, or vaginal mucosa; or skin outside the area of ​​intended use or skin within the area of ​​intended use, but not at the time of intended use. In particular, for example, the second type of biological tissue may include the skin of a finger, while the first type of biological tissue may include tissue to be treated, such as an area of ​​skin having a relatively thin epidermal stratum corneum or mucosal tissue. In this manner, for example, the STAR particles may not disrupt or be less likely to disrupt the skin of a finger used to apply or rub the STAR particles onto / in the treatment area of ​​the first biological tissue.

[0056] In some embodiments, STAR particles are advantageously configured to be self-limiting. For example, if the STAR particles were not inactivated, continued rubbing of the particles against the skin would continue to increase skin permeability, which may be undesirable. However, when the STAR particles are configured to be inactivated during rubbing against the skin, rubbing them for a sufficiently long time will result in a desired, selected increase in skin permeability, but continued rubbing beyond a sufficient time will not result in a further substantial increase in permeability because the STAR particles will no longer be active.

[0057] The STAR particles disclosed herein can be configured to selectively partially or completely lose the ability to fragment target tissue. In some embodiments, after a period of time, the STAR particles may partially or completely lose the ability to fragment the same tissue or the same tissue type. In some embodiments, the STAR particles may partially or completely lose their mechanical fragmentation properties, making the STAR particles incapable of repeated use by the intended user. In other embodiments, the STAR particles lose their mechanical fragmentation properties, making the STAR particles incapable of subsequent use by unintended users. In still other embodiments as described above, the STAR particles lose their mechanical fragmentation properties during continuous use.

[0058] Benefits of limiting the functional capabilities of STAR particles include, but are not limited to, controlling the efficacy of a particle-containing formulation, controlling the number, depth, and / or diameter of micropunctures, and / or controlling the user-perceived sensation associated with applying STAR particles to the skin, controlling the cosmetic appearance of a STAR particle-containing formulation on the skin, enhancing the safety characteristics of STAR particles and / or STAR particle-containing formulations by preventing, limiting, and / or eliminating mechanical fragmentation of off-target tissue, enhancing the environmental safety of STAR particles or STAR particle-containing formulations by preventing, limiting, and / or eliminating intentional or unintentional transmission between humans and / or other biological species (e.g., animals) through the environment, and enhancing the environmental safety of STAR particles or STAR particle-containing formulations by preventing, limiting, and / or eliminating intentional or unintentional reuse of STAR particles by an intentional user or subsequent reuse by an unintentional user.

[0059] STAR particles

[0060] The STAR particle comprises a core structure and one or more microneedle-like protrusions extending from the core structure. The microneedles can be configured to at least partially penetrate or otherwise mechanically disrupt biological tissue, such as the epidermal stratum corneum of human skin (or other biological tissue). That is, the size, mechanical strength, and other properties of the microneedles enable them to be pressed into and penetrate biological tissue, forming tiny pores or channels therein. The microneedles can independently extend from the core structure in any direction.

[0061] Figure 1A and Figure 1B A STAR particle 100 according to one embodiment is depicted. In this embodiment, each STAR particle 100 has three microneedles 120 extending from a core structure 110 in the same plane, thereby referring to the STAR particle as a planar particle. The core structure is typically the portion of the microneedle particle that connects the microneedles, especially when there are three or more microneedles. The core structure can be a solid structure, or a hollow structure with one or more internal cavities. In other embodiments, the STAR particle can have two microneedles, four microneedles, five microneedles, six microneedles, seven microneedles, eight microneedles, nine microneedles, or ten microneedles extending from the core structure. In some embodiments, the microneedles extend from the core in different planes. For example, a STAR particle can have three, four, five, or more microneedles in different directions and different planes, thereby referring to the STAR particle as a non-planar particle.

[0062] The microneedles of the STAR particles can be tapered. In some embodiments, in plan view, as shown Figure 1AAs shown, the microneedle 120 tapers from the core structure 110 to the tip, but the height of the microneedle is substantially constant. In some other embodiments, the edge of the microneedle 120 may also be tapered, because the tapered edge is sharp and can penetrate the epidermal stratum corneum more easily than a non-tapered edge. For example, in some embodiments, as Figures 1C to 1E As shown, the microneedle 120 can taper in both width and height. That is, the height of the microneedle is greatest at the core structure and smallest at the tip. In other variations, the core and base of the microneedle can have a uniform height, and only the distal tip portion of the microneedle can be tapered. In these variations, the taper can be on one or both sides of the STAR particle.

[0063] Various design features of STAR particles 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 / among the microneedles or subsets of those microneedles. Combinations of these features can be designed to prevent the entire microneedle particle from penetrating biological tissue.

[0064] For example, the core structure may have a size, shape and / or lack of sharp edges that allow one or more microneedles in the microneedle to extend from the core structure to penetrate biological tissue but prevent all or substantially all of the core structure from penetrating into the biological tissue. As another example, the microneedle may have structural features, such as a cone, that only allow a portion of the microneedle (i.e., the tip portion away from the core structure) to penetrate biological tissue. For example, the microneedle may have a shoulder or plateau that only allows the portion of the microneedle away from the shoulder or plateau to penetrate biological tissue. This configuration prevents the core structure from penetrating the biological tissue during a penetration event between the STAR particle and the biological tissue, such that the entire STAR particle cannot be completely embedded within the biological tissue.

[0065] In general, the microneedles of a STAR particle can have the same or different sizes as each other. In one embodiment, the microneedles of a planar STAR particle have substantially the same size.

[0066] The microneedle may have any shape that effectively penetrates biological tissue at least partially. In some embodiments, the microneedle is a high aspect ratio structure whose length is at least twice its width at the microneedle base (i.e., at the interface of the microneedle and the core structure). The length of the microneedle is the distance from the interface of the microneedle and the edge of the core structure to the tip of the microneedle. In some embodiments, each microneedle in the microneedle independently has a length of 1 μm to 2,000 μm. In some embodiments, each microneedle in the microneedle independently has a length of 10 μm to 2,000 μm. In some embodiments, each microneedle in the microneedle independently has a length of 50 μm to 2,000 μm. In some embodiments, each microneedle in the microneedle independently has a length of 100 μm to 1,000 μm. In some embodiments, each microneedle in the microneedle independently has a length of 250 μm to 750 μm. In some embodiments, each microneedle in the microneedle independently has a length of 100 μm to 500 μm. In some embodiments, each of the microneedles has a length of about 350 μm.

[0067] In certain embodiments, the STAR particle has three microneedles, wherein each of the microneedles 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 can be a planar particle.

[0068] The microneedles of the STAR particles can 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 generally the portion of the microneedle that initially penetrates biological tissue.

[0069] In some embodiments, the shape and size of the STAR particles are designed to prevent or reduce the likelihood of the STAR particles 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 a microneedle particle" refers to the maximum of the following distances: [1] the distance between the tips of the two microneedles that are farthest apart (if the microneedle particle includes two or more microneedles), or [2] the further possible distance between the microneedle tip and the side of the core structure opposite to the side from which the measured microneedle extends. A plurality of microneedle particles may include microneedle particles of one or more sizes.

[0070] 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 microneedle having [1] a central axis extending from a core structure in at least substantially the same plane, or [2] a tip residing in substantially the same plane. Planar microneedles can include microneedles extending from the core structure in the same direction, in different directions, or a combination thereof. Planar microneedles can also include colinear planar microneedles extending from opposite sides of the core structure in a manner that allows the central axis of each microneedle to at least substantially correspond to a single straight line. For example, when a STAR particle includes two or more pairs of microneedles, the microneedle pairs (but not necessarily all of the microneedles) can be colinear.

[0071] When the microneedle is a planar microneedle, 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 over the entire length of the microneedle. That is, the height of the microneedle is the same as the height at the tip when the microneedle contacts the core structure. In some embodiments, the height of the microneedle particles decreases along the length of the microneedle. The height of the microneedle may be the largest when the microneedle particles contact the core structure and the smallest at the tip.

[0072] In some preferred embodiments of the tapered STAR particle, the core height at the center of the STAR particle is 100 μm to 150 μm, and the radius of curvature at the microneedle tip is 5 μm to 30 μm.

[0073] In some preferred embodiments of ceramic or polymeric STAR particles, the core height at the center of the STAR particle is 50 μm to 150 μm. In some preferred embodiments of stainless steel STAR particles, the core height at the center of the STAR particle can be as small as 12.5 μm and as large as 150 μm. These ceramic, polymer, or stainless steel STAR particles can include tapered microneedles, for example, with a radius of curvature at the microneedle tip of 5 μm to 30 μm.

[0074] 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 typically include one or more drugs, one or more sensors, one or more cosmeceuticals, one or more nutraceuticals, or combinations thereof. Thus, microneedle particles can be made of a combination of bioactive components (drugs, small molecule excipients (e.g., trehalose), sensors, cosmeceuticals, nutraceuticals, or combinations thereof) and inactive components (metals, polymers, ceramics, sugars, etc.). If, after removal of the STAR particles, a portion of the STAR particles remains in and / or on the biological tissue, the portion of the STAR particles that remains in and / or on the biological tissue can comprise at least one bioactive component, at least one inactive component, or a combination thereof.

[0075] In some embodiments, the STAR particles are made of a water-insoluble material. In some embodiments, the STAR particles are made of or comprise at least one water-soluble and / or erodible material. When the STAR particles are made of a water-soluble and / or erodible material, the STAR particles or portions thereof can safely degrade if left in and / or on biological tissue, or after being discarded. In one example, the STAR particles have a matrix structure that can be composed of or comprise a water-soluble or bioerodible material. As used herein, the term "bioerodible" means that the structure / material degrades in vivo or in vitro by dissolution, enzymatic hydrolysis, erosion, resorption, or a combination thereof. Such degradation of the STAR particles can occur on a tissue surface or in the environment, but not necessarily in contact with biological tissue. Other degradation methods for water-soluble and / or water-insoluble STAR particles include, but are not limited to, dissolution, hydrolysis, degradation upon exposure to sunlight (i.e., UV light), degradation due to reaction with another chemical entity, degradation due to physical or mechanical erosion, and / or degradation due to reaction with environmental factors (e.g., oxygen).

[0076] In some embodiments, the STAR particles are metal microneedle particles. Metal microneedle particles are particles in which the entire structure of the microneedle particle is made entirely or substantially entirely of a metal or metal alloy (e.g., stainless steel). In some other embodiments, a majority of the STAR particles are made of such a metal or metal alloy material.

[0077] In some embodiments, the STAR particles are polymeric microneedle particles. A polymeric microneedle particle is a particle in which the entire structure of the microneedle particle is made entirely or substantially entirely of one or more polymeric materials (e.g., a biodegradable material such as poly(lactic-co-glycolic acid) (PLGA) or polycaprolactone (PCL) and / or a water-soluble material such as carboxymethyl cellulose or polyvinyl alcohol). In some other embodiments, a majority of the STAR particles are made of such one or more polymeric materials.

[0078] In some embodiments, the STAR particles are ceramic microneedle particles. Ceramic microneedle particles are particles in which all or substantially all of the structure of the microneedle particle is made of one or more ceramic materials (e.g., aluminum oxide, titanium dioxide, zinc oxide, iron oxide). In some other embodiments, a majority of the STAR particles are made of such one or more ceramic materials.

[0079] 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. In some embodiments, a majority of the STAR particle is made of one or more drugs.

[0080] In some embodiments, the STAR particles are excipient microneedle particles. Excipient microneedle particles are particles in which the entire structure of the microneedle particle is made of one or more pharmaceutically acceptable excipient materials known in the art (eg, sugars, salts, starches, etc.).

[0081] In some embodiments, a STAR particle has 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 material, and / or (v) at least one biologically active component.

[0082] The STAR particles provided herein can be made by any suitable method capable of forming the desired geometry of the STAR particles. 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, STAR particles can be formed by laser etching a sheet of material. As another example, STAR particles can be manufactured using a molding process that can include placing a construction material in a mold having a cavity corresponding to the desired geometry of the resulting microneedle particles. The construction material can be a polymer or a precursor thereof and can be loaded into the mold in powder or liquid form (e.g., a molten polymer and / or a polymer dissolved or dispersed in a liquid medium) and then solidified into a solid monolithic form in the mold. In another example, an array of discrete particles is formed from a solid sheet of material by a process comprising at least one of etching, stamping, or cutting (such as laser cutting). STAR particles can also be sintered, densified, and / or mechanically hardened via heating, cooling, chemical modification, exposure, drying, compression, and / or other processes.

[0083] Compositions containing STAR particles

[0084] In various embodiments, STAR particles are provided as compositions that facilitate administration of the STAR particles to a target tissue site, e.g., a biological tissue surface, such as mammalian skin. For example, a composition can comprise or consist of STAR particles dispersed in a suitable medium that can flow. The medium can be a liquid, solution, lotion, cream, ointment gel, paste, emulsion, aerosol foam or spray, powder, or semisolid. A suitable medium is referred to herein as a "vehicle."

[0085] Essentially any suitable biocompatible vehicle can be used in a composition containing STAR particles. The vehicle can be an aqueous medium and / or a non-aqueous medium. The vehicle can include water, a stabilizer, a pH adjuster, a thickener, or other pharmaceutically acceptable excipients known in the art for topical therapeutic administration, including materials generally recognized as safe (GRAS) by the U.S. Food and Drug Administration.

[0086] Compositions containing STAR particles can include one or more bioactive agents (e.g., therapeutic agents, adjuvants, or prophylactic agents) and / or other substances of interest (e.g., diagnostic agents, sensors, cosmeceuticals). The bioactive agents and / or other substances of interest can 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 microparticle suspension and / or as an emulsion.

[0087] The composition containing STAR particles generally has a viscosity suitable for its intended storage, packaging and use (e.g., application to a target tissue). In some embodiments, the composition containing STAR particles 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 composition containing STAR particles is a non-viscous composition having a viscosity of less than 1,000 cP, for example, about 5 cP to about 500 cP, about 5 cP to about 250 cP, or about 5 cP to about 100 cP. In some embodiments, the composition containing STAR particles has a viscosity of about 1 cP.

[0088] The concentration of the STAR particles in the vehicle can be selected based on the specific application, but will generally be selected to achieve the intended function of the STAR particles at a specific tissue site. For example, the concentration of the STAR particles can be selected to be sufficient to create sufficient pores in the stratum corneum of the epidermis to deliver a desired dose (e.g., a therapeutically effective amount) of the bioactive agent to the skin at the site of application of the STAR particle-containing composition.

[0089] In some embodiments, the concentration of STAR particles in the vehicle ranges from 100 to 200 nm. 3 In some embodiments, the concentration of STAR particles in the vehicle ranges from about 100 to about 100,000 particles per cm 3 In some embodiments, the concentration of STAR particles in the vehicle ranges from about 500 to about 50,000 particles per cm 3 The vehicle contains from about 1,000 to about 25,000 particles. In some embodiments, the concentration of STAR particles in the vehicle is greater than 100 particles per cm 3 In some embodiments, the concentration of STAR particles in the vehicle is less than 10,000 particles per cm 3Vehicle 10,000 particles.

[0090] In some embodiments, the concentration of STAR particles in the vehicle ranges from about 0.1 wt % to about 30 wt % of the vehicle. In some embodiments, the concentration of STAR particles in the vehicle ranges from about 1 wt % to about 20 wt % of the vehicle. In some embodiments, the concentration of STAR particles in the vehicle ranges from about 5 wt % to about 15 wt % of the vehicle. In some embodiments, the concentration of STAR particles in the vehicle ranges from about 8 wt % to about 12 wt % of the vehicle. In some preferred embodiments, the concentration of STAR particles in the vehicle ranges from about 5 wt % to about 10 wt % of the vehicle.

[0091] The STAR particle composition may also include at least one substance of interest. As used herein, "substance of interest" refers to a molecule or collection of substances that has a prophylactic, therapeutic, diagnostic, or cosmetic purpose. Substances of interest may include, but are not limited to, active pharmaceutical ingredients, vaccines, allergens, vitamins, cosmetics, cosmeceuticals, diagnostic agents, sensors, markers (e.g., colored or radioactive dyes or labels), other bioactive agents, and other materials that are desired to be introduced into or onto biological tissue. A list of substances of interest is included in U.S. Patent No. 11,291,816, which is incorporated herein by reference.

[0092] The substance of interest can be a small molecule, a polymer, a peptide, or a biological agent. In some embodiments, the substance of interest is a biological agent or a living organism. In other embodiments, the substance of interest has electronic properties. For example, the substance of interest can respond to radio frequency identification (RFID).

[0093] Compositions and methods for inactivating STAR particles

[0094] The STAR particles disclosed herein can be inactivated while on the skin, while in the skin, and / or after the STAR particles leave the skin. STAR particles may also be temporarily capable of mechanically disrupting tissue due to the inherent properties or synthesis of the STAR particles. For example, STAR particles may have inherent tendencies to the addition, loss, or alteration of material, molecular or chemical instability, or instability to changes in ambient temperature, pressure, light, and / or air composition. STAR particles may also interact with the vehicle, target tissue, off-target tissue, and / or the environment in a manner that may also result in inactivation.

[0095] In some embodiments, a composition for application to biological tissue is provided, wherein the composition comprises: (A) a plurality of STAR particles configured for mechanical disruption of biological tissue; and (B) a vehicle in which the plurality of STAR particles are dispersed, wherein the composition is adapted to (i) contact a surface of biological tissue in a manner that causes the STAR particles to mechanically disrupt the biological tissue, and subsequently (ii) weaken the ability of the STAR particles to mechanically disrupt the biological tissue by one or more of the following inactivation mechanisms: agglomeration of the STAR particles; immobilization of the STAR particles; addition of a coating material to the STAR particles; expansion-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.

[0096] In some embodiments, the STAR particles can be inactivated during and / or after their intended use by including a microneedle configured to reduce or eliminate the ability of the microneedle to partially re-penetrate biological tissue. In some embodiments, after penetrating biological tissue at least once, the microneedle of the STAR particle is configured to mechanically fail, thereby preventing the microneedle from re-penetrating the biological tissue. In some embodiments, after penetrating biological tissue at least once, the microneedle of the STAR particle is configured to chemically fail, thereby preventing the microneedle from re-penetrating the biological tissue. In some embodiments, after penetrating biological tissue at least once, the microneedle of the STAR particle is configured to mechanically and chemically fail, thereby preventing the microneedle from re-penetrating the biological tissue. Mechanical failure and / or chemical failure may occur after the microneedle penetrates biological tissue once, twice, three times, or more. Non-limiting examples of mechanical failure include disintegrating, dissolving, softening, or breaking the microneedle so that it no longer has a sharp tip and / or sufficient rigidity and length to penetrate biological tissue. Non-limiting examples of chemical failure include at least partially dissolving or degrading through a chemical reaction so that it no longer has a sharp tip and / or sufficient rigidity and length to penetrate biological tissue.

[0097] Adding Materials to STAR Particles

[0098] In some embodiments, the STAR particles can be inactivated during and / or after their intended use by adding materials to at least a portion of the microneedle and / or core structure, which can change the shape and / or size of the STAR particles, thereby reducing or eliminating the ability of the STAR particles to effectively penetrate biological tissue. Figure 2AA STAR particle 200 is depicted having an added material 250 covering the tip of a microneedle 220. The added material covers the sharp tip of the STAR particle's microneedle in the form of a rounded or spherical substance, causing the STAR particle to lack a sharp tip for penetrating tissue and thus become non-functional or inactivated. In some embodiments, the added material covers the base or core of the STAR particle to reduce or eliminate the ability of the STAR particle to effectively interact with biological tissue, thereby destroying the ability of the STAR particle to mechanically disrupt tissue. The sources of the additional material (to inactivate it) include, but are not limited to, components in the delivery vehicle, the STAR particle itself, the skin, other parts of the biological tissue (e.g., components of the interstitial fluid), and / or the environment. For example, the delivery vehicle may deposit a film on the STAR particle such that the film prevents the STAR particle from mechanically disrupting the target tissue.

[0099] Materials can associate with or adsorb onto STAR particles through a variety of mechanisms, including hydrophobic interactions, ionic bonding, hydrogen bonding, polar bonding, covalent bonding, metallic bonding, van der Waals forces, and inclusion complex formation. Physical entanglement may also exist at the molecular level and on longer scales.

[0100] In some embodiments, skin debris (e.g., hair, skin cells, ISF, blood, makeup, or other foreign matter 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 composed at least in part of a hydrophobic polymer (e.g., acrylics, epoxies, polyethylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polydimethylsiloxane, polyester, and polyurethane), and the formulation is composed at least in part of a hydrophobic polymer, wherein formulation components are added to and / or adsorbed onto the STAR particles over time.

[0101] Removing material from STAR particles

[0102] In some embodiments, the STAR particles can be inactivated during and / or after their 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 particles to effectively penetrate biological tissue. Figures 2B to 2D Depicted are STAR particles with mass loss according to several embodiments. Figure 2BA STAR particle 200 is depicted in which the tip portion of the microneedle 220 undergoes a phase change from a solid to a liquid and / or a gas. Only the microneedle or the entire STAR particle can undergo a phase change. The phase change may be caused by exposure to target tissue, off-target tissue, delivery vehicle and / or the surrounding environment during and / or after administration of the STAR particle to the tissue site. Examples of triggers for removal of solid material from the microneedle include changes in temperature, pH and / or application of radiation energy and / or exposure to radiation energy. In one example, the STAR particle is formed at least in part from sodium bicarbonate, which can form gaseous carbon dioxide spontaneously or in the presence of an acid through a chemical reaction. In another example, the STAR particle is formed at least in part from a material having a melting point below physiological or ambient temperature, such that the STAR particle undergoes a phase change upon interaction with the target biological tissue and / or the environment.

[0103] Figures 2C to 2D Depicts the disintegration of a STAR particle. As used herein, "disintegration" refers to dissolution, breaking into pieces, chemical decomposition, biodegradation, or other similar processes. Figure 2C A STAR particle 200 is depicted with only the microneedles 220 disintegrating. In some embodiments, the core structure can disintegrate or dissolve while the microneedles remain intact. Figure 2D A STAR particle is depicted wherein the entire particle is disintegrating. Disintegration can be or include the dissolution of all or part of the construction materials forming the STAR particle.

[0104] In some embodiments, the vehicle of the STAR particle-containing composition can include a microencapsulated solvent for the material of construction of the STAR particles, and / or can include another material configured to cause disintegration / inactivation of the STAR particles (the other material is referred to herein as a "functional additive"). The solvent (e.g., water or a non-aqueous solvent) or microcapsules of the material can be configured to mechanically rupture when the STAR particle-containing composition is rubbed / pressed onto the skin during the application process, thereby releasing the solvent or material and allowing the solvent to contact the STAR particles and disintegrate / inactivate the particles.

[0105] The functional additive can interact with the STAR particles directly or indirectly in a manner that effectively causes the STAR particles to disintegrate / inactivate. For example, the functional additive can be an acid (e.g., citric acid) that promotes the reaction of sodium bicarbonate in the STAR particles. The functional additive can also be an acid or base that changes the pH of the STAR particles, thereby changing the charge state of the material in the STAR particles and causing inactivation by dissolution. That is, changing the pH of the STAR particles may change the solubility and mechanically weaken the STAR particles, causing them to break due to loss of ionic bonds. The functional additive can also be an enzyme or other catalyst that promotes a chemical reaction that causes the disintegration / inactivation of the STAR particles.

[0106] In some embodiments, a solvent for the material of construction of the STAR particles can be added to the composition containing the STAR particles before, during, and / or after the application process. The solvent can be effective to dissolve the STAR particles gradually or immediately. After the composition containing the STAR particles has been applied, the solvent can be applied alone or in combination with a second agent.

[0107] The solvent or dissimilar material may also be included in the STAR particle itself. For example, the solvent or dissimilar material may be microencapsulated within the bulk material forming the STAR particle or otherwise temporarily isolated from the bulk material. The solvent or dissimilar material may be configured to be released during the application process when the STAR particle-containing composition is rubbed / pressed onto the skin, thereby allowing the solvent or dissimilar material to contact the bulk material forming the STAR particle.

[0108] Particle phase transition induction

[0109] In yet another embodiment, the STAR particles can dissolve when undergoing a phase transition. For example, the phase transition can change the solubility or miscibility of the STAR particles, allowing the STAR particles to dissolve more easily in the formulation. Exposure to changes in the ambient environment and / or temperature and / or pressure can also effectively dissolve the STAR particles due to, for example, changes in the solubility of the material containing the STAR particles.

[0110] In some embodiments, the STAR particles are configured to be inactivated after their intended use by undergoing a change in shape, size, and / or rigidity that effectively reduces or eliminates their ability to penetrate biological tissue. For example, the STAR particles may undergo swelling and / or softening, causing the microneedle tips to become blunt and rounded, and / or causing the microneedles to bend or easily deform, rendering the tip portions of the microneedles substantially incapable of penetrating the stratum corneum. Similarly, the core structure of the STAR particles may swell and / or soften, resulting in mechanical instability of the STAR particles and rendering them at least partially ineffective at penetrating the stratum corneum. Figure 3A A STAR particle 300 is depicted with microneedles 320 having expanded. In some embodiments, the STAR particle can be configured to absorb water or another liquid (e.g., interstitial fluid), causing the STAR particle to expand. In some embodiments, a composition containing a STAR particle can include microencapsulated water or a non-aqueous liquid. When the microcapsule ruptures, the liquid is released and absorbed by the STAR particle. The STAR particle can also absorb a vehicle or a portion thereof in the composition containing the STAR particle.

[0111] In an embodiment, the STAR particles can be made of ice and stored below the freezing temperature of water prior to use. Upon removal from frozen storage, the STAR particles undergo a phase transition to liquid water and become inactivated. In another embodiment, the STAR particles can comprise a wax, such as a wax used to prepare suppositories (e.g., a Witepsol fat base that melts between 30°C and 44°C). The STAR particles are stored below the melting temperature of the wax and then subjected to temperatures above the melting temperature of the wax during or after use, thereby inactivating the STAR particles.

[0112] In embodiments, the STAR particles may be composed at least in part of a material, such as a polymer, that is stored below its glass transition temperature, and when the STAR particle formulation is in contact with the target tissue or after contact with the target tissue, the formulation is heated to a temperature above the glass transition temperature of the STAR particles. In such embodiments, when the STAR particles are heated above their glass transition temperature, the STAR particles have reduced mechanical hardness or rigidity and at least partially lose their functionality. In some embodiments, the STAR particle glass transition temperature is about 25°C to about 50°C, about 30°C to about 40°C, or about 37°C.

[0113] Particle expansion and / or softening

[0114] The STAR particles can be configured to gradually absorb the formulation, compound, or solvent, such that the STAR particles will lose effectiveness after a period of time. The formulation, compound, and / or solvent can also react with the surrounding environment and / or biological tissue during and / or after administration, such that the STAR particles can absorb the reacted formulation, rendering the STAR particles at least partially ineffective. The ability of expanded STAR particles (particularly expanded microneedles) to mechanically disrupt target tissue can be reduced. For example, the expanded microneedles may bend against the target tissue or may lack the sharpness required to mechanically disrupt the target tissue.

[0115] Figure 3B A STAR particle 300 is depicted that has lost its rigidity or has a reduced flexural modulus such that the STAR particle bends or is easily deformed elastically or plastically. In embodiments, the microneedles 320 and the core structure 310 of the STAR particle 300 have reduced rigidity. In other embodiments, only the microneedle particle 320 has reduced rigidity. In some embodiments, the flexibility of the STAR particle is affected by the deposition of material on the microneedles, such as with respect to Figure 2AIn other embodiments, the STAR particles absorb liquid in a manner that modulates the flexibility, flexural modulus, or other mechanical properties of the microneedles. The rigidity, flexural modulus, or flexibility of the microneedles influences the ability of the microneedle particles to mechanically disrupt the skin. For example, a low flexural modulus or flexible microneedle will bend upon contact with the target tissue, while a high flexural modulus or rigid microneedle will overcome the elastic deformation of the tissue and mechanically disrupt the target tissue.

[0116] In some embodiments, a composition comprising STAR particles comprises a vehicle comprising a liquid including water and / or a non-aqueous liquid, the liquid being microencapsulated in a microcapsule, the STAR particles being dispersed in the vehicle and outside the microcapsule, wherein the microcapsule is configured to rupture upon contact with the biological tissue to release the liquid and allow the liquid to contact the STAR particles, wherein the STAR particles are configured to absorb the released liquid and swell, undergo a shape change, and / or become soft and flexible.

[0117] In an embodiment, STAR particles can be made of a material that swells in the presence of water, such as a cross-linked polymer, such as cross-linked carboxymethyl cellulose. Among other factors, the degree of cross-linking determines the rate at which the polymer material absorbs water, thereby determining the rate and degree of expansion of the material. In this way, STAR particles comprising a material such as cross-linked carboxymethyl cellulose can absorb water, swell, and thereby inactivate with controlled kinetics. In another embodiment, the STAR particles comprise a porous microstructure, whereby the pores contained in the STAR particles generate capillary forces, enabling the ingestion of fluids, thereby causing the STAR particles to swell. The porous structure in this embodiment can be modified to achieve a stronger or weaker capillary driving force.

[0118] Mechanical weakening of STAR particles

[0119] In some embodiments, the STAR particle is configured to be at least partially inactivated after its intended use by undergoing a reduction in its mechanical strength by an amount effective to break at least the tip portion of the microneedle rather than penetrate biological tissue. Figure 3C A STAR particle 300 is depicted having reduced mechanical strength such that the STAR particle 300 breaks and fragments. In an embodiment, the microneedles 320 break and fragment. In an embodiment, both the microneedles 320 and the core structure 310 break and fragment. In some embodiments, the STAR particle is formed according to reference Figure 3AThe described methods absorb fluid, which can effectively weaken the microneedles. For example, the fluid can effectively dissolve portions of the STAR particles, thereby forming cracks and / or fragments in the STAR particles. The weakened microneedles can be more fragile, for example making them susceptible to cracking / breaking during administration. That is, these microneedles are manufactured with predetermined defects (e.g., cracks / fragments) that enable the STAR particles to mechanically fail in a predetermined and desired manner, consistent with their intended use. These microneedles are effective when in use, but become ineffective during / after use. For example, ceramic STAR particles may not be completely sintered, which can result in microcracks and / or pores that effectively weaken the STAR particles, thereby potentially contributing to their subsequent loss of function.

[0120] like Figure 3D As shown, STAR particles 300 can also be weakened so that they are susceptible to rupture. Weakened STAR particles can rupture upon contact with target tissue, rather than mechanically disrupting the tissue as intended. For example, STAR particles can be made of a composite material comprising a water-soluble component that dissolves or leaches out during initial use / application of the STAR particles, such that the STAR particles are mechanically weakened shortly thereafter and cannot, at least partially, be reused for mechanically disrupting tissue. Weakened STAR particles can break at the tip and / or can break elsewhere within the STAR particle, such as at and / or near the core region.

[0121] In some embodiments, a STAR particle-containing composition comprises a STAR particle having a pore initially filled with a material that is configured to exit the pore during and / or after administration of the composition to the biological tissue, thereby opening the pore and mechanically weakening or destroying the STAR particle after a period of time during or after administration to the biological tissue. For example, the filler material can be water-soluble and dissolve upon contact with interstitial fluid.

[0122] In some embodiments, a composition comprising a STAR particle comprises a vehicle comprising a liquid, including water and / or a non-aqueous liquid, the liquid being microencapsulated in a microcapsule, the STAR particles being dispersed in the vehicle and outside the microcapsule, wherein the microcapsule is configured to rupture upon contact with the biological tissue to release the liquid and allow the liquid to contact the STAR particle and mechanically weaken the STAR particle. The STAR particle can be configured to dissolve or become porous upon contact with the released liquid.

[0123] Particle shrinkage

[0124] In some embodiments, the STAR particle is configured to be inactivated during and / or after its intended use by causing the microneedle, core structure and / or entire STAR particle to shrink or shorten to an extent that the microneedle, core structure and / or entire STAR particle or remnants thereof are at least partially unable to penetrate biological tissue. Figure 3E A contracted STAR particle 300 is depicted. In embodiments where the STAR particle 300 is contracted, the contracted microneedles 320 may be too short to mechanically disrupt the target tissue. The contracted 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 contract or shorten relatively symmetrically. In other embodiments, the microneedles, core structure, and / or the entire STAR particle may contract or shorten asymmetrically compared to other components. For example, one or more of the microneedles may contract more than the other microneedles and / or core structure.

[0125] In embodiments, STAR particles may comprise a hydrogel that swells with water. Upon loss of water, the hydrogel material collapses, causing the STAR particle to become smaller. For example, STAR particles may comprise a material that shrinks when heated, such as polyvinyl chloride or a polyolefin (e.g., shrink wrap).

[0126] Particle agglomeration

[0127] In some embodiments, the STAR particles are configured to be inactivated during and / or after their intended use by undergoing agglomeration to the extent that the agglomerated STAR particles are substantially unable or at least partially unable to mechanically disrupt the stratum corneum of the epidermis or other target tissue sites. This may be because some or many of the microneedles of the STAR particles in the agglomerate are shielded from contact with biological tissue. Figure 4 An agglomeration of STAR particles 400 is depicted. As used herein, "agglomerate" or "agglomeration" refers to an entangled or otherwise physically associated mass of at least two STAR particles. In some embodiments based on experimental evidence, an agglomerate of STAR particles includes 2 to 10,000 STAR particles, 2 to 5,000 STAR particles, 2 to 1,000 STAR particles, 2 to 500 STAR particles, or 2 to 100 STAR particles.

[0128] In some embodiments, a composition containing STAR particles is provided, wherein the composition containing STAR particles is configured to inactivate the STAR particles by agglomeration of the STAR particles. In some embodiments, the vehicle is suitable for drying after the composition is applied to the skin, whereby drying effectively agglomerates the STAR particles. In some embodiments, the STAR particles are configured to agglomerate in response to application of an external force that effectively deforms the STAR particles in a manner that promotes agglomeration. In some embodiments, a plurality of STAR particles have magnetic, ionic, or electrostatic affinities that promote agglomeration. In some embodiments, the vehicle comprises components configured to induce agglomeration of the STAR particles after application to biological tissue.

[0129] Agglomeration of STAR particles may be caused by forces that bring STAR particles closer to each other. In some embodiments, mechanical forces may promote physical interactions between STAR particles, thereby keeping the STAR particles aggregated together. These mechanical forces may include geometric features of STAR particles, such as the geometry of the STAR particle surface. These geometric features may be present in the STAR particles before administration. For example, a hook structure (possibly in combination with a ring structure) may be incorporated into the STAR particles, including incorporation onto the surface of the STAR particles or as part of a microneedle structure. Alternatively, the geometry of the STAR particles may be generated during and / or after the use of the STAR particles. In some embodiments, chemical forces generated due to the generation of covalent or non-covalent bonds (e.g., hydrogen bonding, electrostatic interactions (i.e., ionic bonding), van der Waals interactions, hydrophobic bonding) may promote agglomeration. In some embodiments, STAR particles may carry a positive charge, a negative charge, or a zwitterionic surface charge. The positively charged regions of the particles will be attracted by the negatively charged regions of other STAR particles, resulting in agglomeration. In some embodiments, STAR particles having at least partially hydrophobic surfaces in a hydrophilic (e.g., aqueous) medium will be attracted and agglomerated. In some embodiments, STAR particles having at least partially hydrophilic surfaces in a hydrophobic (e.g., non-aqueous) medium will be attracted and agglomerated.

[0130] In embodiments, the force causing agglomeration 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 of or include a magnetic material that becomes attracted to each other and agglomerates during and / or after administration to the target tissue. In some embodiments, an external electromagnetic force can be applied to induce agglomeration of the STAR particles within the vehicle and / or to collect the agglomerated STAR particles after their intended safe disposal.

[0131] Compositions containing STAR particles can directly or indirectly cause agglomeration. When the composition is applied to the target tissue or soon thereafter, the vehicle of the composition can evaporate and / or be absorbed by the target tissue, thereby increasing the concentration of STAR particles in the composition. The increased STAR particle concentration increases the possibility of interparticle interaction, thereby potentially leading to agglomeration. The vehicle can also have a viscosity that promotes interparticle interaction, thereby increasing the possibility of agglomeration.

[0132] The vehicle may also contain a microencapsulated agent that can promote agglomeration. The microencapsulated agent can be released when the microencapsulated agent contacts the skin or the surrounding environment, or when force is applied. The agent may directly cause agglomeration. For example, the agent may increase the thickness of the composition or increase the friction within the composition, causing the STAR particles to stick together. The agent can be a binder that causes the STAR particles to adhere to each other. The agent can also react with one or more components of the vehicle and / or with the STAR particles, causing agglomeration. Alternatively, the formulation can contain at least one non-encapsulated agent that causes agglomeration upon chemical reaction. The vehicle itself—without any agent—can also undergo a chemical reaction that causes agglomeration. As used herein, "chemical reaction" refers to the formation and / or breaking of covalent or non-covalent bonds.

[0133] External stimuli can also be used to cause STAR particles to agglomerate. As used herein, the term "external stimulus" refers to any condition applied to the STAR particles, the composition containing the STAR particles, and / or the target tissue. These may include, but are not limited to: (a) exposure to visible light, (b) changes in temperature, (c) changes in pressure, (d) addition, modification, or removal of chemical entities, (e) application of ultrasound, (f) application of electromagnetic radiation (e.g., ultraviolet, visible, infrared radiation), (g) application of electric and / or magnetic fields, and the like. For example, the STAR particles may interact with the physical, chemical, or biological properties of the target tissue in a manner that causes agglomeration. The applied force may cause agglomeration. The applied force may induce interaction between the STAR particles or deform the STAR particles, thereby increasing the likelihood of agglomeration. Friction of the composition containing the STAR particles on the skin or other target tissue may result in mechanical interaction between the STAR particles and / or with other components of the composition and / or with the skin and / or with the applicator used to apply the composition containing the STAR particles to the skin. Friction may also cause deformation of the STAR particles (eg, creating "hooks" on the microneedle tips of the STAR particles) to promote the STAR particles to become physically interconnected. Before or after application of the STAR particles, an agent or formulation may be applied to the target tissue to induce agglomeration.

[0134] STAR particles may also have an affinity for agglomeration. For example, STAR particles may possess magnetic dipoles that attract each other. STAR particles may also have ionic affinities, where changes in ion concentration within a composition containing STAR particles can affect the surface charge of the STAR particles. These affinities increase the likelihood of interparticle interactions, thereby increasing the likelihood of agglomeration.

[0135] fixed

[0136] In some embodiments, STAR particles are configured to be inactivated after their intended use by affixing them to or within a material, thereby preventing their subsequent use and rendering them inoperative. That is, STAR particles can be encapsulated, embedded, or coated in a matrix, resulting in the loss of their tissue-destroying function. The encapsulant can affix the STAR particles in a macroscopic matrix, or coat individual STAR particles to reduce, limit, and / or prevent function. After encapsulation, the encapsulating matrix containing the STAR particles can be removed from the skin, thereby removing multiple STAR particles together in a single encapsulating matrix. For example, a sheet or strip of an encapsulating matrix containing STAR particles can be formed on a tissue surface, and the sheet or strip can be peeled off and potentially discarded.

[0137] In some embodiments, a composition is provided that is configured to inactivate the STAR particle by immobilization of the STAR particle after administration to the biological tissue. In some embodiments, the vehicle is configured to phase-transition into a fixation matrix in which the STAR particle is embedded. In some embodiments, the vehicle comprises a microencapsulation agent configured to encapsulate the STAR particle. In some embodiments, the composition is in the form of a liquid or semisolid and is configured to form a film containing STAR particles on the tissue and capable of being removed from the tissue. The liquid can be a viscous liquid. The semisolid can be a gel.

[0138] Figures 5A to 5B Depicts a STAR particle immobilized in a matrix that prevents the STAR particle from contacting the target tissue. Figure 5A In the embodiment of the present invention, STAR particles 500 are fixed in an immobilization matrix 550. After the STAR particle-containing composition is applied / used on the target tissue, the immobilization matrix can be formed at least in part by components in the vehicle of the STAR particle-containing composition. For example, the vehicle can undergo a phase change that produces an immobilization matrix. For example, the formulation can be applied as a liquid, but become viscous, semi-solid, gel-like and / or solid over time or when an external stimulus is applied. For example, a volatile liquid in the vehicle may evaporate or be absorbed by the target tissue, causing other components in the vehicle to thicken, gel, precipitate and / or agglomerate to form an immobilization matrix. In the embodiment of the present invention, STAR particles 500 are fixed in an immobilization matrix 550. After the STAR particle-containing composition is applied / used on the target tissue, the immobilization matrix can be formed at least in part by components in the vehicle of the STAR particle-containing composition. For example, the vehicle can undergo a phase change that produces an immobilization matrix. Figure 5BIn the embodiment of the present invention, STAR particles 500 are immobilized within an immobilization matrix 550 and an additional covering material 570. For example, a vehicle of the STAR particle-containing composition can react with the covering material 570. Such additional compounds or materials can be administered with or after the STAR particle-containing composition.

[0139] Figure 5C Depicted are STAR particles 500 encapsulated and immobilized in a matrix 590. A formulation containing STAR particles can include at least one encapsulating agent 580 that encapsulates the STAR particles 500 upon application of an external stimulus or addition of another substance. The encapsulating agent can also coat the STAR particles to reduce their effectiveness, rather than completely encapsulating them. The encapsulating matrix can be the target tissue itself. The encapsulating matrix can be hair or a molecular component of hair (i.e., keratin).

[0140] Figure 5D A STAR particle 500 is depicted being immobilized by a tissue surface 525 and / or hair 527 thereon. For example, where the target tissue is skin, the skin and / or hair thereon can encapsulate or immobilize the STAR particle.

[0141] Target tissue and tissue surface changes

[0142] In some embodiments, changes in the target tissue and / or tissue surface may reduce the efficacy of the STAR particles. In embodiments where skin is the target tissue, the composition containing the STAR particles, or at least its vehicle, may affect the properties of the skin or skin surface in a manner that renders the STAR particles ineffective. These changes in the skin may include, but are not limited to, skin hydration, skin morphology, skin mechanics (including changes in skin deformability and / or elasticity), skin topography (e.g., roughness or smoothness of the skin), and / or the density of hair follicles and / or hair shafts in / on the target skin. The composition may also be formulated to alter the physiological state of the skin to render the STAR particles ineffective. Such changes may occur immediately or gradually over time with the consistent application of the formulation and STAR particles. Physiological changes may include changes in the stratum corneum, the viable epidermis, the dermis, or the subcutaneous tissue. Changes may also include changes in nerves, sweat glands, sebaceous glands, sebum, collagen, elastin, cell populations within the skin, cytokines or biomolecule properties within the skin, or changes in the hair follicles or hair shafts present in and / or on the skin. For example, STAR particles can be designed with shorter microneedles to effectively work in skin with hyperkeratosis (e.g., psoriasis, skin warts, chronic atopic dermatitis) due to the abnormal biomechanical properties of diseased skin (e.g., thickening, hardening, roughening). When the skin is treated with a STAR-containing formulation and becomes less hyperkeratotic and thus more elastic, the shorter microneedles on the STAR particles become less effective because the skin deforms and does not allow effective STAR penetration.

[0143] In some embodiments, a topical composition is provided, wherein the composition is effective to transform a patient's skin from a first state to a second state, wherein the STAR particles are able to penetrate the skin surface in the first state and are unable to penetrate the skin surface in the second state, or vice versa. In some embodiments, the first state is a dry state and the second state is a hydrated state. In some embodiments, the first state is hyperkeratotic skin and the second state is non-hyperkeratotic skin.

[0144] In some embodiments, in a first state, the skin surface has a frictional interaction with the STAR particles such that the STAR particles can penetrate the skin, and in a second state, the skin surface has a reduced frictional interaction with the STAR particles such that the STAR particles slide over the skin surface without penetrating (e.g., the skin surface is very smooth). This change in skin surface state can be induced by depositing a material from a topical composition onto the skin surface to reduce friction.

[0145] In some embodiments, in a first state, the skin surface has a frictional interaction with the STAR particles such that the STAR particles penetrate the skin, and in a second state, the skin surface has an increased frictional interaction with the STAR particles such that the STAR particles slide very slowly over the skin surface without penetrating (i.e., the skin surface is very sticky). This change in skin surface state can be induced by depositing material from a topical composition onto the skin surface to reduce friction, or can be induced by liquid in the topical composition evaporating, being absorbed by the skin, or otherwise disappearing, such that the excipients and other materials in the topical composition concentrate into a thin film on the skin surface such that the viscosity becomes very high.

[0146] Changes in particle surface properties

[0147] In additional embodiments, the surface properties of the STAR particles may change, reducing their functionality. Changes in the physical and / or chemical properties of the particle surface may alter the functional interactions between the STAR particles and the formulation or between the STAR particles and the target tissue. For example, the STAR particles may become sticky or tacky, which may immobilize or eliminate the functionality of the STAR particles. The STAR particles may also become smooth or lubricated, which may prevent the STAR particles from effectively interacting with and penetrating the target tissue. The STAR particles may also become rough, which may create drag during administration due to increased friction, thereby reducing mobility across the target tissue.

[0148] Removal of particles from tissue

[0149] In another embodiment, the STAR particles can be removed and collected from the target tissue after use. The removal and collection of the STAR particles can effectively prevent the STAR particles from further fragmenting the target tissue. The STAR particles can simply fall off the target tissue or be collected from the target tissue. The STAR particles can be collected and returned to the original packaging or container. The STAR particles can be removed with a flexible material, such as cloth or other woven or non-woven fabric. Alternatively, the particles can be removed with a rigid, semi-rigid or flexible object (such as an object made of glass, metal, sugar, biopolymer, polymer or any combination thereof). The attraction between the material and / or object used to collect the STAR particles can promote the removal of the STAR particles. For example, the removal material and / or object can have a binder, an electrostatic charge opposite to the charge on the STAR particles, and / or an attractive magnetic dipole that promotes interaction between the material and / or object and the STAR particles. The STAR particles can also be "removed" by dissolution, wherein the dissolved STAR particles are absorbed into the target tissue.

[0150] In some embodiments, a trigger can initiate the removal of STAR particles. An external stimulus can effectively trigger the removal of STAR particles from the target tissue. The form of the external stimulus can include, but is not limited to, applying a magnetic field, an electric field, or an electromagnetic field, applying a liquid to the target tissue that can partially or completely dissolve the STAR particles or carry the STAR particles away from the target tissue, applying soap or a dissolved dispersant or surfactant to the target tissue, applying any ultrasonic, auditory, or sub-auditory vibration, applying negative pressure to the target tissue, such as suction, and applying positive pressure to the target tissue, such as wiping. In other embodiments, where the target tissue is skin, the process of epidermal renewal and regeneration can trigger the removal of STAR particles.

[0151] Use of microencapsulated substances in compositions

[0152] In some embodiments, a composition for administration to a tissue is provided, wherein the composition comprises: (i) a plurality of STAR particles configured for mechanical disruption of biological tissue; and (ii) a vehicle in which the plurality of STAR particles are dispersed, wherein the vehicle comprises one or more microencapsulated agents or solvents, wherein the microcapsules of the one or more microencapsulated agents or solvents are capable of mechanically disrupting during contact of the composition with the biological tissue to release the one or more microencapsulated agents or solvents and inactivate the ability of the STAR particles to mechanically disrupt the 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 material comprising the microcapsules.

[0153] In an embodiment, the microcapsule consists of a core region surrounded by a shell region. The size of the capsule can range from about 1 μm to about 10 mm. The size of the microcapsule can also be from about 10 nm to 1000 nm, in which case these microcapsules 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 in the core. The microcapsule can have one or more cores.

[0154] Microcapsules can be prepared by chemical and / or physical methods including solvent evaporation / extraction, spray drying, melt solidification, sol-gel encapsulation, sonication, coprecipitation, desolvation, emulsification, gelation, thin film hydration, homogenization, liposome entrapment, coacervation, emulsion solvent diffusion, and other methods.

[0155] The shell material can comprise a variety of natural and synthetic polymers, including polysaccharides (gums, starches, celluloses, cyclodextrins, chitosans), proteins (gelatin, casein, soy protein), lipids (waxes, paraffins, oils), and synthetic polymers (acrylic polymers, poly(vinyl alcohol), poly(vinyl pyrrolidone)). Inorganic materials such as silicates, clays, and polyphosphates can also be used. Biopolymers (natural polymers) and biodegradable polymers such as chitosans 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)) can be used.

[0156] In some embodiments, the one or more agents or solvents are configured to cause a phase transition at least in the microneedles of the STAR particles, the core region of the STAR particles, or a combination thereof, as described above. In some embodiments, the one or more agents or solvents are configured to at least partially dissolve the STAR particles, as described above. In some embodiments, the one or more agents or solvents are configured to promote agglomeration of the STAR particles, as described above.

[0157] In some embodiments, the one or more reagents or solvents are configured to facilitate fixation of the STAR particle on the biological tissue, as described above. In some embodiments, the one or more reagents or solvents are configured to fix 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 cause the STAR particle to swell or shrink, 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.

[0158] In some embodiments, the microcapsule contains water, and the STAR particle is soluble, swellable, or capable of softening in water. Because the formulation in which the microcapsule and STAR particle are contained does not contain water, or does not contain enough water to dissolve, swell, or soften the STAR particle, the STAR particle will not be inactivated as long as the microcapsule does not release water. When water is released from the microcapsule, the STAR particle is inactivated due to at least partial dissolution, swelling, or softening due to the presence of water. Similar methods can be used for solvents other than water, such as ethanol.

[0159] In another embodiment, the microcapsule comprises a material that causes gelation or cross-linking of polymers or other materials contained in the formulation in which the microcapsule and STAR particle are located. For example, the microcapsule may comprise calcium ions and the surrounding formulation may comprise pectin acid and / or sodium pectate, or the microcapsule may comprise pectin acid and / or sodium pectate and the surrounding formulation may comprise calcium ions, or the microcapsule may comprise calcium ions and the STAR particle may comprise pectin acid and / or sodium pectate.

[0160] Deactivation method

[0161] In some embodiments, a method is provided, comprising: (i) applying a first composition comprising a plurality of STAR particles dispersed in a vehicle to a biological tissue; (ii) manipulating the composition to mechanically disrupt the biological tissue with the STAR particles; and then (iii) 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 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. In some embodiments of the method, (i) the inactivation comprises adding a second composition to the first composition, the second composition comprising a first agent or solvent, and / or (ii) the manipulation comprises rupturing a microcapsule comprising a second agent or solvent, the second agent or solvent effective to initiate or promote the inactivation.

[0162] In some embodiments, the first agent or solvent and / or the second agent or solvent are configured to dissolve the STAR particle. In some embodiments, the first agent or solvent and / or the second agent or solvent are configured to promote agglomeration of the STAR particle. In some embodiments, the first agent or solvent and / or the second agent or solvent are configured to promote fixation of the STAR particle on the surface of biological tissue. In some embodiments, the first agent or solvent and / or the second agent or solvent are configured to fix the STAR particle in a matrix material. In some embodiments, the first agent or solvent and / or the second agent or solvent are configured to facilitate the addition of a coating material to the STAR particle. In some embodiments, the first agent or solvent and / or the second agent or solvent are configured to cause the STAR particle to swell, cause a shape change, or shrink. In some embodiments, the first agent or solvent and / or the second agent or solvent are configured to induce softening or deformability of the microneedle of the STAR particle. In some embodiments, the first agent or solvent and / or the second agent or solvent are configured to mechanically weaken the STAR particle.

[0163] In some embodiments, the inactivation comprises applying an external stimulus to the first composition and / or the biological tissue surface, wherein the application of the external stimulus is selected from the group consisting of: (a) exposure to visible light, near infrared light or ultraviolet light, (b) changes in temperature, (c) changes in pressure, (d) addition, modification or removal of chemical entities, (e) application of ultrasound, (f) application of electromagnetic radiation, (f) application of a magnetic field, and (h) combinations thereof.

[0164] In some embodiments, the inactivation comprises encapsulating the STAR particle with an encapsulating material. In some embodiments, the inactivation comprises immobilization of the STAR particle. For example, the vehicle can undergo a phase transition into an immobilization matrix in which the STAR particle is embedded.

[0165] In some embodiments, the STAR particle is porous or becomes porous and is mechanically weakened after a period of time during and / or after application of the first composition to the biological tissue.

[0166] In some embodiments, the first composition is applied to the biological tissue in liquid or semisolid form and forms a film containing STAR particles, and wherein the method further comprises: removing the film containing STAR particles from the biological tissue.

[0167] In some embodiments, a method is provided, comprising: (i) applying a first composition comprising a plurality of STAR particles dispersed in a vehicle to biological tissue; (ii) manipulating the composition so that the STAR particles mechanically disrupt the biological tissue; and then (iii) 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.

[0168] In some embodiments, a method is provided, comprising: (i) applying a composition comprising a plurality of STAR particles dispersed in a vehicle to the skin of a patient in a first state; (ii) manipulating the composition in the first state so that the STAR particles mechanically disrupt the epidermal stratum corneum of the patient's skin; and (iii) converting the patient's skin to a second state via contact with one or more components in the vehicle, in which second state the STAR particles are unable to mechanically disrupt the epidermal stratum corneum.

[0169] Implementation Plan

[0170] Some embodiments of the present disclosure may be described in terms of one or more of the following:

[0171] Embodiment 1. A composition for application to biological tissue, the composition comprising: a plurality of STAR particles, the plurality of STAR particles being configured for mechanical disruption of the biological tissue; and a medium in which the plurality of STAR particles are dispersed, wherein the composition is suitable for (i) contacting the surface of the biological tissue in a manner that causes the STAR particles to mechanically disrupt the biological tissue, and subsequently (ii) weakening the ability of the STAR particles to mechanically disrupt the biological tissue by one or more of the following inactivation mechanisms: agglomeration of the STAR particles; fixation of the STAR particles; addition of a coating material to the STAR particles; expansion-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.

[0172] Embodiment 2. A composition according to embodiment 1, wherein the vehicle comprises a liquid comprising water and / or a non-aqueous liquid, the liquid is encapsulated in a microcapsule, the STAR particles are dispersed in the vehicle and outside the microcapsule, wherein the microcapsule is configured to rupture upon contact with the biological tissue to release the liquid and allow the liquid to contact the STAR particles.

[0173] Embodiment 3. The composition of embodiment 1 or 2, wherein the liquid is water.

[0174] Embodiment 4. The composition of any one of Embodiments 1 to 3, wherein the STAR particle is configured to dissolve or become porous upon contact with the released liquid.

[0175] Embodiment 5. The composition of any one of Embodiments 1 to 4, wherein the STAR particle is configured to absorb released liquid and swell, undergo a shape change, and / or become soft and flexible.

[0176] Embodiment 6. A composition according to any one of embodiments 1 to 5, wherein the biological tissue is skin and the composition effectively transforms the skin and / or skin surface from a first state to a second state, wherein the STAR particles are able to penetrate the skin surface in the first state and are unable to penetrate the skin surface in the second state.

[0177] Embodiment 7. The composition of any one of Embodiments 1 to 6, wherein the first state is a disease 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 hyperkeratinized skin and the second state is non-hyperkeratinized skin, or the first state has a first frictional interaction between the skin surface and the STAR particle and the second state has a second frictional interaction between the skin surface and the STAR particle, the second frictional interaction being (i) reduced relative to the first frictional interaction such that the STAR particle easily slides over the skin surface without penetrating, or (ii) increased relative to the first frictional interaction such that the STAR particle is substantially prevented from moving over the skin surface.

[0178] Embodiment 8. The composition of any one of embodiments 1 to 7, wherein the vehicle comprises a film-forming composition.

[0179] Embodiment 9. The composition of any one of Embodiments 1 to 8, wherein the STAR particle is configured to become inactivated upon contact with interstitial fluid upon penetrating the biological tissue.

[0180] Embodiment 10. The composition of any one of Embodiments 1 to 9, configured to inactivate the STAR particles by agglomeration of the STAR particles.

[0181] Embodiment 11. The composition of any one of embodiments 1 to 10, wherein the vehicle is adapted to dry after application of the composition to the skin, whereby drying is effective to agglomerate the STAR particles.

[0182] Embodiment 12. The composition of any one of Embodiments 1 to 11, wherein the STAR particles are configured to agglomerate in response to application of an external force effective to deform the STAR particles in a manner that promotes agglomeration.

[0183] Embodiment 13. The composition of any one of Embodiments 1 to 12, wherein the plurality of STAR particles have magnetic, ionic, or electrostatic affinities that promote agglomeration.

[0184] Embodiment 14. The composition of any one of Embodiments 1 to 13, wherein the vehicle comprises components configured to induce agglomeration of the STAR particles upon administration to the biological tissue.

[0185] Embodiment 15. A composition according to any one of Embodiments 1 to 14, wherein the STAR particle has pores initially filled with a material that is configured to emerge from 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 particle after a period during or after application to the biological tissue.

[0186] Embodiment 16. The composition of any one of Embodiments 1 to 15, configured to inactivate the STAR particle by immobilization of the STAR particle after administration to the biological tissue.

[0187] Embodiment 17. The composition of any one of Embodiments 1 to 16, wherein the vehicle is configured to phase change into an immobilization matrix in which the STAR particle is embedded.

[0188] Embodiment 18. The composition of any one of Embodiments 1 to 17, wherein the vehicle comprises a microencapsulation agent configured to encapsulate the STAR particle.

[0189] Embodiment 19. The composition of any one of Embodiments 1 to 18, which is in liquid or semisolid form and is configured to form a film comprising STAR particles on the tissue and is capable of being removed from the tissue.

[0190] Embodiment 20. The composition of any one of embodiments 1 to 19, wherein the liquid is a viscous liquid.

[0191] Embodiment 21. The composition according to any one of embodiments 1 to 20, wherein the semi-solid form is a gel.

[0192] Embodiment 22. The composition of any one of embodiments 1 to 21, further comprising one or more bioactive agents.

[0193] Embodiment 23. The composition of any one of embodiments 1 to 22, further comprising one or more diagnostic agents, sensors, cosmeceuticals, or nutraceuticals.

[0194] Embodiment 24. The composition of any one of embodiments 1 to 23, wherein the biological tissue comprises the patient's skin.

[0195] Embodiment 25. A composition for application to tissue, 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, wherein the vehicle comprises one or more microencapsulated agents or solvents, the microcapsules of the one or more microencapsulated agents or solvents being capable of mechanically disrupting during contact of the composition with the biological tissue to release the one or more microencapsulated agents or solvents and inactivate the ability of the STAR particles to mechanically disrupt the biological tissue.

[0196] Embodiment 26. The composition of embodiment 25, wherein the one or more reagents or solvents are configured to cause a phase change in at least the microneedles of the STAR particle.

[0197] Embodiment 27. The composition of Embodiment 25 or 26, wherein the one or more reagents or solvents are configured to at least partially dissolve the STAR particle.

[0198] Embodiment 28. The composition of any one of Embodiments 25 to 27, wherein the one or more agents or solvents are configured to promote agglomeration of the STAR particles.

[0199] Embodiment 29. The composition of any one of Embodiments 25 to 28, wherein the one or more reagents or solvents are configured to promote fixation of the STAR particle on the biological tissue.

[0200] 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 particle in a matrix material.

[0201] Embodiment 31. The composition of any one of Embodiments 25 to 30, wherein the one or more agents or solvents are configured to facilitate the addition of a coating substance to the STAR particle.

[0202] Embodiment 32. The composition of any one of Embodiments 25 to 31, wherein the one or more reagents or solvents are configured to expand or contract the STAR particle.

[0203] Embodiment 33. The composition of any one of Embodiments 25 to 32, wherein the one or more agents or solvents are configured to induce softening or deformability of the STAR particle.

[0204] Embodiment 34. The composition of any one of Embodiments 25 to 33, wherein the one or more agents or solvents are configured to mechanically weaken the STAR particle.

[0205] Embodiment 35. The composition of any one of embodiments 25 to 34, further comprising one or more bioactive agents.

[0206] Embodiment 36. The composition of any one of embodiments 25 to 35, further comprising one or more diagnostic agents, sensors, cosmeceuticals, or nutraceuticals.

[0207] Embodiment 37. The composition of any one of Embodiments 25 to 36, wherein the biological tissue comprises the patient's skin.

[0208] Embodiment 38. A method comprising: applying a first composition comprising a plurality of STAR particles dispersed in a vehicle to biological tissue; manipulating the composition so that the STAR particles mechanically disrupt the biological tissue; and then inactivating the STAR particles by allowing or causing one or more of the following: agglomeration of the STAR particles; immobilization of the STAR particles; adding a coating material to the STAR particles; expansion-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.

[0209] Embodiment 39. A method according to embodiment 38, wherein (i) the inactivation comprises adding a second composition to the first composition, the second composition comprising a first agent or solvent, and / or (ii) the manipulation comprises rupturing a microcapsule comprising a second agent or solvent, the second agent or solvent being effective to initiate or promote the inactivation.

[0210] Embodiment 40. The method of embodiment 38 or 39, wherein the first reagent or solvent and / or the second reagent or solvent is configured to dissolve the STAR particle.

[0211] Embodiment 41. The method of any one of Embodiments 38 to 40, wherein the first agent or solvent and / or the second agent or solvent is configured to promote agglomeration of the STAR particles.

[0212] Embodiment 42. The method of any one of Embodiments 38 to 41, wherein the first reagent or solvent and / or the second reagent or solvent is configured to promote immobilization of the STAR particle on the surface of biological tissue.

[0213] Embodiment 43. The method of any one of Embodiments 39 to 42, wherein the first reagent or solvent and / or the second reagent or solvent is configured to immobilize the STAR particle in a matrix material.

[0214] Embodiment 44. The method of any one of Embodiments 38 to 43, wherein the first reagent or solvent and / or the second reagent or solvent is configured to facilitate the addition of a coating substance to the STAR particle.

[0215] Embodiment 45. The method of any one of Embodiments 38 to 44, wherein the first reagent or solvent and / or the second reagent or solvent is configured to cause the STAR particle to swell, cause a shape change, or shrink.

[0216] Embodiment 46. The method of any one of Embodiments 38 to 45, wherein the first agent or solvent and / or the second agent or solvent is configured to induce softening or deformability of the microneedles of the STAR particle.

[0217] Embodiment 47. The method of any one of Embodiments 38 to 46, wherein the first agent or solvent and / or the second agent or solvent is configured to mechanically weaken the STAR particle.

[0218] Embodiment 48. A method according to any one of embodiments 38 to 47, wherein the inactivation comprises applying 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) addition, modification or removal of a chemical entity, (e) application of ultrasound, (f) application of electromagnetic radiation, (h) application of a magnetic field, and (h) a combination thereof.

[0219] Embodiment 49. The method of any one of embodiments 38 to 48, wherein the vehicle comprises a film-forming composition.

[0220] Embodiment 50. The method of any one of Embodiments 38 to 50, wherein the inactivation comprises contacting the STAR particle with interstitial fluid.

[0221] Embodiment 51. The method of any one of Embodiments 38 to 51, wherein the inactivation comprises agglomeration of the STAR particles.

[0222] Embodiment 52. The method of any one of Embodiments 38 to 51, wherein the STAR particles have magnetic, ionic, or electrostatic affinity that promotes agglomeration.

[0223] Embodiment 53. The method of any one of Embodiments 38 to 52, wherein the STAR particle is porous and is mechanically weakened during and / or after a period of time after applying the first composition to the biological tissue.

[0224] Embodiment 54. The method of any one of Embodiments 38 to 53, wherein the inactivation comprises immobilization of the STAR particle.

[0225] Embodiment 55. The method of any one of Embodiments 38 to 54, wherein the vehicle undergoes a phase transition into an immobilization matrix in which the STAR particle is embedded.

[0226] Embodiment 56. The method of any one of Embodiments 38 to 55, wherein the inactivation comprises encapsulating the STAR particle with an encapsulating material.

[0227] Embodiment 57. A method according to any one of Embodiments 38 to 56, wherein the first composition is applied to the biological tissue in liquid or semisolid form and forms a film containing STAR particles, and wherein the method further comprises: removing the film containing STAR particles from the biological tissue.

[0228] Embodiment 58. A method comprising: applying a first composition comprising a plurality of STAR particles dispersed in a vehicle to biological tissue; manipulating the composition so that the STAR particles 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.

[0229] Embodiment 59. The method of any one of embodiments 38 to 58, wherein the composition further comprises one or more biologically active agents.

[0230] Embodiment 60. The method of any one of embodiments 38 to 59, wherein the composition further comprises one or more diagnostic agents, sensors, cosmeceuticals, or nutraceuticals.

[0231] Embodiment 61. The method of any one of Embodiments 38 to 60, wherein the biological tissue comprises human skin.

[0232] Embodiment 62. A method comprising: applying a composition comprising a plurality of STAR particles dispersed in a vehicle to the skin of a patient in a first state; and manipulating the composition in the first state so that the STAR particles mechanically disrupt the epidermal stratum corneum of the patient's skin, converting the patient's skin to a second state via contact with one or more components in the vehicle, wherein the STAR particles are unable to mechanically disrupt the epidermal stratum corneum.

[0233] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. As used herein, the term "about" indicates that a value of a given amount may include an amount within 10% of the stated value, or, optionally, within 5% of the value, or in some embodiments, within 1% of the value.

[0234] Although 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 embodiments of the present disclosure may be modified to incorporate any number of variations, alterations, substitutions, or equivalent arrangements not described herein but 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 for mechanical disruption of biological tissue; and a medium in which the plurality of STAR particles are dispersed, wherein the composition is adapted to (i) contact a biological tissue surface in a manner that causes the STAR particles to mechanically disrupt the biological tissue, and subsequently (ii) impair the ability of the STAR particles to mechanically disrupt the biological tissue by at least one of the following inactivation mechanisms: The agglomeration of the STAR particles, The immobilization of the STAR particles, Adding a coating material to the STAR particles, The expansion-induced shape change of the STAR particle, The contraction of the STAR particle microneedles, The softening or induced deformability of the STAR particles, or Mechanical weakening of the STAR particle.

2. The composition of claim 1 , wherein the vehicle comprises a liquid comprising water and / or a non-aqueous liquid, the liquid being encapsulated in a microcapsule, the STAR particles being dispersed in the vehicle and outside the microcapsule, wherein the microcapsule is configured to rupture upon contact with the biological tissue to release the liquid and allow the liquid to contact the STAR particles.

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

4. The composition of claim 2, wherein the STAR particle is configured to dissolve or become porous upon contact with the released liquid.

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

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

7. The composition according to claim 6, wherein: the first state is a disease state, and the second state is a healthy state, the first state being a dry state, and the second state being a hydrated state, The first state is hyperkeratotic skin and the second state is non-hyperkeratotic skin, or The first state has a first frictional interaction between the skin surface and the STAR particle, and the second state has a second frictional interaction between the skin surface and the STAR particle, which second frictional interaction (i) is reduced relative to the first frictional interaction, so that the STAR particle easily slides on the skin surface without penetrating, or (ii) is increased relative to the first frictional interaction, so that the STAR particle is substantially prevented from moving on the skin surface.

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

9. The composition of claim 1, wherein the STAR particle is configured to become inactivated upon contact with interstitial fluid upon penetrating the biological tissue.

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

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

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

13. The composition of claim 10, wherein the plurality of STAR particles have magnetic, ionic, or electrostatic affinities that promote agglomeration.

14. The composition of claim 10, wherein the vehicle comprises components configured to induce agglomeration of the STAR particles upon administration to the biological tissue.

15. The composition of claim 1, wherein the STAR particle has pores initially filled with a material that is 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 particle after a period during or after application to the biological tissue.

16. The composition of claim 1, configured to inactivate the STAR particle by immobilization of the STAR particle after administration to the biological tissue.

17. The composition of claim 16, wherein the vehicle is configured to phase transition into an immobilization matrix in which the STAR particle is embedded.

18. The composition of claim 16, wherein the vehicle comprises a microencapsulation agent configured to encapsulate the STAR particle.

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

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

21. The composition of claim 19, wherein the semisolid form is a gel.

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

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

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

25. A composition for application to tissue, the composition comprising: a plurality of STAR particles configured for mechanical disruption of biological tissue; and a medium in which the plurality of STAR particles are dispersed, wherein the vehicle comprises one or more microencapsulated agents or solvents, the microcapsules of which are capable of mechanically disrupting during contact of the composition with the biological tissue to release the one or more microencapsulated agents or solvents and inactivate the ability of the STAR particles to mechanically disrupt the biological tissue.

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

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

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

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

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

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

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

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

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

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

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

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

38. A method comprising: applying a first composition comprising a plurality of STAR particles dispersed in a vehicle to a biological tissue; manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue; and then The STAR particle is deactivated by allowing or causing at least one of the following: The agglomeration of the STAR particles, The immobilization of the STAR particles, Adding a coating material to the STAR particles, The expansion-induced shape change of the STAR particle, The contraction of the STAR particle microneedles, softening or induced deformability of the STAR particle, or Mechanical weakening of the STAR particle.

39. The method of claim 38, wherein (i) the inactivation comprises adding a second composition to the first composition, the second composition comprising a first agent or solvent, and / or (ii) the manipulation comprises rupturing a microcapsule comprising a second agent or solvent effective to initiate or promote the inactivation.

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

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

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

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

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

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

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

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

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

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

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

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

52. The method of claim 51, wherein the STAR particles have magnetic, ionic, or electrostatic affinities that promote agglomeration.

53. The method of claim 38, wherein the STAR particle is porous and is mechanically weakened after a period of time during and / or after applying the first composition to the biological tissue.

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

55. The method of claim 54, wherein the vehicle undergoes a phase transition into an immobilization matrix in which the STAR particle is embedded.

56. The method of claim 38, wherein the inactivation comprises: The STAR particles are encapsulated with an encapsulating material.

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

58. A method comprising: applying a first composition comprising a plurality of STAR particles dispersed in a vehicle to a biological tissue; manipulating the composition to cause the STAR particles to mechanically disrupt the biological tissue; and then The STAR particle is inactivated 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 particle.

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

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

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

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

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