Microneedle particles, vehicle, and substance of interest

Abstract

STAR particles, compositions, and methods of making the same, wherein the STAR particles and / or compositions are effective in preventing and / or reducing unwanted degradation of STAR particles, a substance of interest and / or a component of the STAR particles and / or a composition comprising STAR particles or in stabilizing and / or preserving STAR particles, a substance of interest and / or a component of the STAR particles and / or a composition comprising STAR particles.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 436,984, 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 11,219,816, which is incorporated herein by reference. STAR particles can provide an effective mechanism for improving the delivery of bioactive compounds to biological tissues such as skin and other biological tissues with barrier or barrier-like properties. However, STAR particles and / or such bioactive compounds therein may be prone to undesirable degradation during manufacture, formulation, storage, application to target tissue, and / or after they are applied to the target tissue. Degraded or unstable STAR particles may be less effective for their intended purpose. For example, degraded STAR particles may be less effective in mechanically destroying target tissue and / or delivering the substance of interest to the target tissue. It is desirable to provide a device for reducing or preventing the accidental degradation of STAR particles and / or promoting the overall stability of STAR particles and / or the substance of interest contained therein. Summary of the Invention

[0004] In one aspect, a packaged STAR particle composition is provided, comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue; a medium in which the plurality of STAR particles are dispersed; and a container that holds the medium and the STAR particles. The STAR particles, the medium, and the container are configured to maintain a substantially uniform dispersion of the STAR particles within the medium and within the container. In some embodiments, the STAR particles and the medium have similar average densities. In some embodiments, the medium has a viscosity that is effective to prevent or limit non-uniformity of the STAR particles even if the average densities of the STAR particles and the medium are different from each other. In some embodiments, the medium comprises at least one dispersant. In some embodiments, a container wall in contact with the medium has surface properties that inhibit adhesion of the STAR particles to the wall, optionally, for example, wherein the container wall has a coating that is effective to inhibit adhesion of the STAR particles to the wall. In some embodiments, the STAR particles have electrostatic, steric, and / or magnetic properties that generate repulsive forces between the STAR particles that effectively prevent or limit agglomeration of the STAR particles. In some embodiments, the composition further comprises at least one salt compound suitable for reducing the Debye length of the charge on the STAR particles. In some embodiments, the composition further comprises a surfactant suitable for inhibiting interactions between hydrophobic or hydrophilic surfaces on the STAR particles.

[0005] In another aspect, a composition is provided having a plurality of STAR particles and a vehicle, wherein the plurality of STAR particles are dispersed in the vehicle, wherein the vehicle has a viscosity of at least 100 cP, such that the viscosity of the vehicle is effective to at least partially maintain the dispersion of the STAR particles within the vehicle and / or limit non-uniformity.

[0006] In another aspect, a composition is provided having a plurality of STAR particles having a structure formed at least in part from a first material; and a vehicle in which the plurality of STAR particles are dispersed, wherein the vehicle comprises a solvent for the first material, wherein the composition is configured such that the plurality of STAR particles resist dissolution and / or accidental inactivation within the vehicle. In some embodiments, the STAR particles have a coating thereon that is substantially insoluble in the solvent of the vehicle. In some embodiments, the STAR particles are encapsulated in an encapsulating material that is substantially insoluble in the solvent of the vehicle. In some embodiments, the vehicle is filled with a solute that effectively prevents or limits dissolution of the first material in the solvent of the vehicle. In some embodiments, the structure of the STAR particles is further formed from a second material that is substantially insoluble in the solvent of the vehicle.

[0007] In yet another aspect, a composition is provided having a plurality of STAR particles and a vehicle in which the plurality of STAR particles are dispersed, wherein the STAR particles are adapted to degrade after administration and use (i) by a selected change in pH, osmotic pressure, temperature, or ionic composition of the vehicle, or (ii) in response to an external stimulus. In some embodiments, the external stimulus can be exposure to atmospheric oxygen, light, or water.

[0008] In even further embodiments, a packaged STAR particle composition is provided having: a plurality of STAR particles configured to mechanically disrupt biological tissue; a medium in which the plurality of STAR particles are dispersed; and a container comprising the medium and the STAR particles, wherein the STAR particles and / or the walls of the container contacting the medium are coated with a buffering material that is more deformable than the material forming the STAR particles and / or the walls of the container.

[0009] In another aspect, a composition is provided having a plurality of STAR particles configured to mechanically disrupt biological tissue, wherein the STAR particles have a surface coating composed of a material having a mechanical strength greater than that of an underlying material forming the STAR particles. In some embodiments, the underlying material comprises an organic material and the surface coating material comprises an inorganic material. In some embodiments, the composition comprises a substance of interest (SOI). In some embodiments, the SOI comprises a bioactive agent. In some embodiments, the SOI is located in and / or on the STAR particles. In other embodiments, the SOI is located in the vehicle. In some embodiments, a method of applying a substance of interest (SOI) to the skin of a patient is provided, the method comprising: applying the composition to the surface of the skin; and manipulating the composition to cause the STAR particles to mechanically disrupt the skin surface.

[0010] In an additional aspect, a STAR particle composition is provided, comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue; a plurality of SOI particles separated from the plurality of STAR particles; and a liquid medium in which the plurality of STAR particles and the plurality of SOI particles are dispersed. In some embodiments, the STAR particles and / or the SOI particles have a coating thereon that is effective to substantially prevent dissolution of the STAR particles and / or the SOI particles in the liquid medium.

[0011] In another aspect, a STAR particle composition is provided, comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue; a first liquid phase; and a second liquid phase, wherein the plurality of STAR particles are dispersed in the first liquid phase or the second liquid phase, and a substance of interest (SOI) is provided in the first liquid phase or the second liquid phase. In some embodiments, the first liquid phase is a continuous phase, and the second liquid phase is a discontinuous phase dispersed in the first liquid phase. In some embodiments, the STAR particles are dispersed in only one of the first liquid phase or the second liquid phase, and the SOI is dissolved in the other of the first liquid phase or the second liquid phase. In some embodiments, (i) the STAR particles are dispersed only in the first liquid phase, and the SOI is dissolved in the first liquid phase and the second liquid phase; (ii) the STAR particles are dispersed in the first liquid phase and the second liquid phase, and the SOI is dissolved only in the first liquid phase; (iii) the SOI is dissolved in the first liquid phase and the second liquid phase (or provided in other ways), and the STAR particles are dispersed only in the second liquid phase; (iv) the STAR particles are dispersed in the first liquid phase and the second liquid phase, and the SOI is dissolved only in the second liquid phase; (v) the STAR particles are dispersed only in the first liquid phase, and the SOI is dissolved only in the second liquid phase; (vi) the SOI is dissolved only in the first liquid phase, and the STAR particles are dispersed only in the second liquid phase; or (vii) the STAR particles are dispersed in the first liquid phase and the second liquid phase, and the SOI is dissolved in the first liquid phase and the second liquid phase. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] 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 different elements and / or components than those illustrated in the drawings, and some elements and / or components may not be present in various embodiments. The elements and / or components in the drawings are not necessarily drawn to scale.

[0013] Figure 1A is a plan view of a planar STAR particle according to one embodiment of the present disclosure.

[0014] Figure 1B yes Figure 1A A perspective view of a flat STAR particle.

[0015] Figure 1C is a plan view of a planar STAR particle according to another embodiment of the present disclosure.

[0016] Figure 1D yes Figure 1C Perspective view of the microneedle particles.

[0017] Figure 1E yes Figure 1C Side view of the microneedle particle.

[0018] Figure 2 Agglomerated STAR particles according to one embodiment of the present disclosure are depicted.

[0019] Figure 3A Reducing the concentration of STAR particles to reduce the likelihood of STAR particle agglomeration according to embodiments of the present disclosure is depicted.

[0020] Figure 3B Repulsive forces between some embodiments of STAR particles according to another embodiment of the present disclosure are depicted to reduce the likelihood of STAR particle agglomeration.

[0021] Figure 3C Depicted are STAR particles between dispersants to reduce the likelihood of STAR particle agglomeration according to another embodiment of the present disclosure.

[0022] Figure 3D Depicted are weakly agglomerated STAR particles undergoing disruption of agglomeration according to another embodiment of the present disclosure.

[0023] Figure 4A is a cross-sectional view of a planar STAR particle according to another embodiment of the present disclosure, wherein the planar STAR particle has a coating.

[0024] Figure 4B Depicted is a storage container containing STAR particles according to one embodiment of the present disclosure, wherein the storage container has a coating effective to prevent STAR particle-container adhesion.

[0025] Figure 5A Depicted are insoluble STAR particles dispersed in a vehicle in a container according to one embodiment of the present disclosure.

[0026] Figure 5B Depicted are encapsulated STAR particles dispersed in a vehicle in a container according to another embodiment of the present disclosure.

[0027] Figure 6A Depicted are STAR particles that have settled at or near the bottom of a storage vessel.

[0028] Figure 6B Depicted are STAR particles floating on or near the top of a medium within a storage container.

[0029] Figure 6C Depicted are STAR particles adhered to the side of a storage container.

[0030] Figure 7ADepicted are STAR particles stored in a dispersant according to another embodiment of the present disclosure.

[0031] Figure 7B Depicted is a coated storage container for a STAR particle-containing vehicle according to another embodiment of the present disclosure. DETAILED DESCRIPTION

[0032] Disclosed are STAR particles and compositions containing STAR particles, as well as methods for preventing and / or reducing unwanted degradation of STAR particles, substances of interest and / or components of the STAR particles and / or compositions containing STAR particles, or for stabilizing and / or preserving STAR particles, substances of interest and / or components of the STAR particles and / or compositions containing STAR particles.

[0033] Stability of STAR particles and components of STAR particle compositions may be necessary to ensure that STAR particles can be produced, formulated, packaged, shipped, stored, and remain suitable for their intended use without undesirable degradation or loss of function.

[0034] In some cases, the goal is to stabilize the STAR particles during storage, while in other cases, the goal is to stabilize the STAR particles during administration of the STAR particles to tissue. The stabilization methods disclosed herein can be the same for both goals, or the aspect can be different for each goal. For example, it may be desirable to minimize or prevent interactions between the STAR particles and the walls of the storage container and between the STAR particles during storage. During administration of the STAR particles to tissue, it may be desirable to minimize or prevent interactions between the STAR particles and an applicator (i.e., a material or structure (e.g., a mechanical device, a glove finger) used to apply force to the STAR particles so that they interact with the tissue). One skilled in the art can adapt the concepts described herein for stabilization in a container to stabilization with an applicator, where appropriate.

[0035] As used herein, the phrase "packaged STAR particle composition" refers to a STAR particle composition that is disposed in a container suitable for storage and transport of the composition. The container can be essentially any rigid or flexible container known in the art that is suitable for holding a quantity of STAR particles, either alone or in combination with a vehicle. For example, the container can be a vial, jar, pouch, bag, or tube, and will typically include a cap, closure, plastic zip lock, or other means for sealing / closing, opening, and optionally reclosing the container.

[0036] It may be important to separate the STAR particle, drug or other substance of interest (SOI), and other components of the STAR particle formulation (eg, vehicle). In some embodiments, this can be achieved by the presence of multiple phases.

[0037] For example, one approach is to have a solid phase and a liquid phase. The solid phase is the STAR particles, and the liquid phase is the vehicle. The formulation components are in the vehicle and / or in / on the STAR particles. The SOI can be in the vehicle and / or in / on the STAR particles. In some embodiments where the solid phase is separated from the liquid phase, the solid phase includes a coating that prevents the STAR particles from interacting with the vehicle (which may dissolve or swell or soften or otherwise adversely affect the properties of the STAR particles). For example, if the STAR particles are water-soluble and are in an aqueous vehicle, the STAR particles can be coated with a water-insoluble material to prevent the STAR particles from dissolving. Phase separation can also prevent the STAR particles from interacting with the SOI or other formulation components.

[0038] In some embodiments, two solid phases may be present. For example, the first solid phase may be SOI, which is separated from the STAR particles (i.e., the second solid phase) such that a suspension of STAR particles and SOI particles exists in a liquid vehicle. Optionally, a coating may be present around the SOI solid particles and / or STAR particles to prevent the STAR particles and SOI particles from dissolving in the liquid vehicle. The SOI particles may contain additional formulation components (e.g., excipients).

[0039] In some embodiments, there may be two liquid phases. For example, one phase may be continuous and the other phase may be discontinuous (e.g., an emulsion). As another example, both phases may be continuous but may mix before or during application to tissue (e.g., both phases become discontinuous). One phase may be aqueous and the other phase may be non-aqueous. STAR particles may be in one phase and not in the other. SOI and STAR particles may be in the same phase or in different phases. For example, water-soluble STAR particles may be present in the non-aqueous phase and water-soluble SOI may be present in the aqueous phase. In this way, water-soluble STAR particles (undissolved) and water-soluble SOI (dissolved) can be in the same formulation. This is actually a three-phase system because one phase is liquid and the other phase is liquid with solid STAR particles suspended in the liquid.

[0040] The compositions and methods comprising STAR particles disclosed herein can enhance the local delivery of bioactive agents and other substances of interest to improve the desired effect of the compound, promote retention of the compound in and / or on the target tissue, promote extraction or removal of endogenous substances, compounds, and / or samples from the target tissue, and / or promote systemic uptake of the compound. The compositions and methods comprising STAR particles disclosed herein can be used for diagnostic, prognostic, therapeutic, adjuvant, cosmetic, and / or preventive purposes.

[0041] STAR particles can enhance the local administration of another substance or multiple substances by mechanically disrupting the integrity of the outer / upper layer of the skin (or other biological tissue) to promote local delivery of the substance into / on the target tissue of the patient, and / or promote the passage of the substance through the target tissue and uptake into the bloodstream for systemic delivery and / or lymphatic vessels for systemic delivery, and / or promote the passage of the substance through the target tissue and uptake into another tissue or space, which includes but is not limited to joint spaces, tendons, ligaments, fascia, nerves, blood vessels, bones, muscles, glands, lymph nodes, subcutaneous tissue, adipose tissue, organs and / or other tissues and spaces. The patient can be human or other mammals or other animals or plants. The skin or other biological tissue can be in vivo or ex vivo.

[0042] 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. For example, off-target tissue includes, but is not limited to, the eye or conjunctiva; oral, gastric, or vaginal mucosa; and / or skin outside the intended area of use when the target tissue is skin. 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 thinner epidermal stratum corneum than the first type of biological tissue 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.

[0043] 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.

[0044] In some embodiments, a STAR particle disclosed herein can be configured to partially or completely lose its mechanical fragmentation properties after its intended use, such that the STAR particle cannot be reused.

[0045] STAR particles

[0046] The STAR particle comprises a core structure and one or more microneedle-like projections 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 and mechanical strength 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.

[0047] 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 multiple microneedles are present. The core structure can be a solid structure, a porous structure, or a hollow structure having 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.

[0048] The microneedles of the STAR particles can be tapered. In some embodiments, in plan view, as shown Figure 1A As 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.

[0049] Various design features of STAR particles can be selected to impart functionality to the particle that prevents the entire STAR particle from penetrating (i.e., mechanically disrupting) 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 STAR particle from penetrating biological tissue.

[0050] For example, the core structure may have a size, shape, and / or lack 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 contacting biological tissue. In another example, the microneedle particle may have a generally curved shape close to the tip, and due to the geometry, the microneedle particle only allows the tip portion to penetrate biological tissue.

[0051] In general, the microneedles of a STAR particle can have the same or different sizes and / or geometries as one another. In one embodiment, the microneedles of a planar STAR particle have substantially the same size and geometry.

[0052] 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.

[0053] 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.

[0054] 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, or 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 first penetrates biological tissue.

[0055] In some embodiments, the shape and size of the STAR particle are designed to prevent or reduce the likelihood that the STAR particle will become completely or irremovably embedded in biological tissue. In some embodiments, the maximum dimension of the STAR particle is from about 100 μm to about 5,000 μm, from 100 μm to about 10,000 μm, from about 250 μm to about 5,000 μm, from about 500 μm to about 2,000 μm, or from about 500 μm to 1,000 μm. "The maximum dimension of a STAR particle" refers to the maximum of the following distances: [1] the distance between the tips of the two microneedles that are furthest 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.

[0056] 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.

[0057] When the microneedles are planar microneedles, the STAR particles may have a substantially planar (i.e., flat) structure. Substantially planar (i.e., flat) STAR particles may have a height (thickness) of about 1 μm to about 1,000 μm, about 5 μm to about 500 μm, about 10 μm to about 250 μm, about 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 of the microneedles is consistent over the entire length of the microneedles. That is, the height of the microneedles is the same as the height at the tip when the microneedles contact the core structure. In some embodiments, the height of the microneedles particles decreases along the length of the microneedles. The height of the microneedles may be the largest when the microneedle particles contact the core structure and the smallest at the tip.

[0058] In some preferred embodiments of the tapered STAR particle, the height of the core in the center of the STAR particle is 100 μm to 150 μm, and the radius of curvature at the microneedle tip of the STAR particle is 5 μm to 30 μm.

[0059] 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, or combinations thereof. Thus, STAR particles can be made of a combination of bioactive components (drugs, small molecule excipients (e.g., trehalose), sensors, cosmeceuticals, or combinations thereof) and inactive components (metals, polymers, ceramics, sugars, etc.). If, after removal of the STAR particle, a portion of the STAR particle remains in and / or on the biological tissue, the portion of the STAR particle 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.

[0060] In some embodiments, STAR particles are made of water-insoluble materials. In some embodiments, STAR particles are made of or comprise at least one water-soluble and / or erodible material. When STAR particles are made of water-soluble and / or erodible materials, the STAR particles or portions thereof can safely degrade if left in 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 ex vivo by dissolution, enzymatic degradation, hydrolysis, erosion, resorption, chemical reaction, or a combination thereof. It should be understood that "ex vivo" in this case refers to STAR particles on a tissue surface, or STAR particles that are otherwise present 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 rays), or degradation caused by reaction with environmental factors (e.g., oxygen).

[0061] In some embodiments, the STAR particles are metal microneedle particles. Metal microneedle particles are particles in which all or substantially all of the structure of the microneedle particle is made 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] In some embodiments, the STAR particles are excipient microneedle particles. Excipient microneedle particles are particles in which the entire or substantially the entire structure of the microneedle particle is made of one or more pharmaceutically acceptable excipient materials known in the art (e.g., sugars, salts, starches, etc.).

[0066] 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, and / or (iv) at least one biologically active component.

[0067] 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 STAR 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 vehicle) 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.

[0068] Compositions containing STAR particles

[0069] 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."

[0070] 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.

[0071] Compositions containing STAR particles can include one or more bioactive agents (e.g., therapeutic or prophylactic agents) and / or other substances of interest (e.g., diagnostic agents, sensors, cosmetics / 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 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 as a microparticle suspension.

[0072] The composition containing STAR particles generally has a viscosity suitable for its expected storage, packaging and use (e.g., application to target tissue). In some embodiments, the composition containing STAR particles is a viscous composition, such as wherein the vehicle of the composition has a viscosity of at least 100 cP. In some embodiments, the composition or the vehicle 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, which has a viscosity of less than 100 cP, for example, about 5 cP to about 75 cP, about 5 cP to about 50 cP, or about 5 cP to about 25 cP. In some embodiments, the composition comprising STAR particles has a viscosity of about 1 cP.

[0073] 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 therapeutically effective amount of the bioactive agent to the skin at the site of application of the STAR particle-containing composition.

[0074] 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 cm3 In some embodiments, the concentration of STAR particles in the vehicle ranges from about 500 to about 50,000 particles per cm 3 In some embodiments, the concentration of STAR particles in the vehicle is greater than 10,000 particles per cm 3 of vehicle. In some embodiments, the concentration of STAR particles in the vehicle is less than 10,000 particles per cm 3 of vehicle.

[0075] 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.

[0076] 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.

[0077] 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).

[0078] Methods for stabilizing STAR particles and compositions containing STAR particles

[0079] STAR particles and compositions containing STAR particles may be susceptible to degradation during manufacture, formulation, packaging, transport, storage, during use, and / or after use. As used herein, "degradation" refers to the change of a STAR particle, vehicle, substance of interest, or any combination thereof from a functional and safe state to (i) a less functional or nonfunctional state and / or (ii) a less safe or unsafe state. Here, a functional state refers to a state in which a STAR particle can perform a particular intended function. A less functional or nonfunctional state refers to a loss of the ability to perform the intended function, but does not mean that the STAR particle cannot perform any other function.

[0080] In some embodiments, due to external stimuli, STAR particles, vehicles and / or substances of interest may degrade and / or lose function. As used herein, "external stimulus" refers to any condition applied to a STAR particle, vehicle and / or substance of interest that causes a change in the function, usability and / or safety of the STAR particle, vehicle and / or substance of interest. 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, (h) exposure to atmospheric conditions (e.g., oxygen), (i) application of mechanical forces (e.g., compression, tension, shearing), (j) exposure to target tissue, and the like.

[0081] In other embodiments, the STAR particle, vehicle, and / or substance of interest may degrade due to a chemical reaction of one or more components of these materials.As used herein, "chemical reaction" refers to the formation and / or breaking of non-covalent and / or covalent bonds.

[0082] The STAR particles may be adapted to degrade after their administration and use. In this context, the term "degrade" means losing their ability to mechanically disrupt biological tissue. This loss of function may be due to one or more of the constituent materials of the STAR particle undergoing a phase transition and / or cleavage such that the STAR particle no longer has the mechanical strength or structural dimensions required to mechanically disrupt biological tissue, for example, to form pores in the stratum corneum of the epidermis. Such degradation may be caused (i) by selected changes in the pH, osmotic pressure, temperature, or ionic composition of the vehicle, and / or (ii) in response to an external stimulus.

[0083] As described herein, the STAR particles, vehicles, and / or substances of interest can be stabilized to reduce the likelihood of degradation and / or significantly delay degradation. As used herein, "stabilize" refers to the complete or partial inhibition of degradation to maintain the functionality of the STAR particles, vehicles, and / or substances of interest. Stabilization can be achieved by the addition of stabilizing compounds, the presence of certain inherent or external conditions, and / or the application of external stimuli to the STAR particles, vehicles, and / or substances of interest.

[0084] Degradation of STAR particles may result in premature loss of function, i.e., accidental inactivation. As used herein, the phrase "accidental inactivation" with respect to STAR particles means that the STAR particles lose the ability to mechanically disrupt or penetrate the epidermal stratum corneum (or other tissue) prior to their intended use.

[0085] In some embodiments, due to physical and / or chemical changes, only the vehicle and / or the substance of interest may be prone to degradation. An exhaustive list of physical and chemical changes that may cause instability can be found in "Drug stability for pharmaceutical scientists" (Thorsteinn Loftsson, Academic Press 2014). In one embodiment, molecular instability may make the vehicle and / or the substance of interest unstable. Molecular instability is described in "Overview of pharmaceutical excipients used in tablets and capsules" (RHDave, Drug Topics 2008). In another embodiment, the instability that causes degradation occurs at the non-molecular level, an example of which is described in "Drug Suspensions - From Vehicle Development to Manufacturing" (AK Kulshreshtha et al., Springer 2010).

[0086] Thus, the vehicle and / or composition of interest can be formulated to contain antioxidants, buffers, emulsifiers, sugars, carbohydrates, and / or other agents known in the art that are effective to physically and / or chemically stabilize the drug ingredient, which may be contained in the STAR particles or in the vehicle of the composition containing the STAR particles. For example, lists of stabilizers and stabilization methods can be found in "Pharmaceutical Dosage Forms and Drug Delivery Systems" (LV Allen, Wolters Kluwer Health, 10th ed.), "Drug Stability for Pharmaceutical Scientists" (T. Loftsson, Academic Press, 1st ed.), and "The development of microgels / nanogels for drug delivery applications" (JK Oh, Progress in Polymer Science (2008) 33(4) pp. 448-477), which are incorporated herein by reference.

[0087] In some embodiments, the composition containing STAR particles, the vehicle, and the substance of interest may be unstable. For example, the substance of interest may diffuse out of the STAR particles and into the vehicle prematurely. In another example, the substance of interest may degrade within the STAR particles and / or the formulation. In yet another example, a substance of interest designed to be dispersed in a vehicle may be undesirably absorbed by the STAR particles and / or storage container, resulting in instability of the STAR particles and loss of efficacy of the formulation and / or the substance of interest. In yet another example, a substance of interest designed to be coated onto and / or into a STAR particle may dissolve and / or leach out of the STAR particle prematurely prior to its intended use.

[0088] In some embodiments, STAR particles may be unstable during storage. For example, STAR particles may agglomerate, weaken, break, deform, become chemically unstable, expand, change size, shape, hardness, porosity, and / or become non-homogeneous within the medium. This instability can be controlled as described below.

[0089] In some embodiments, the vehicle or STAR particles may be inherently prone to agglomeration. Figure 2Depicted are multiple agglomerated STAR particles 200. The medium containing STAR particles may dry out, increasing the concentration of STAR particles in the medium. This increased concentration causes the STAR particles in the medium to be closer in space, thereby potentially increasing the likelihood of interaction and agglomeration between the STAR particles. STAR particles may also have magnetic dipoles and / or electrostatic charges, wherein the presence of these dipoles and / or charges increases the likelihood of interaction between the STAR particles. The ion concentration in the medium may also cause changes in the surface charge of the STAR particles, increasing the likelihood of agglomeration. STAR particles may also have their surfaces chemically modified to give them adhesion properties, which can further agglomerate the STAR particles when they are very close to each other.

[0090] In some embodiments, agglomeration can be triggered by a chemical reaction. In some embodiments, the chemical reaction is a reaction of at least one reagent contained in the vehicle. Alternatively, the reagent is not contained in the vehicle, but is added by the user when administering the STAR particle. In some embodiments, the chemical reaction is a reaction of at least one encapsulated reagent contained in the vehicle. The encapsulated reagent can react with an encapsulated reagent or a non-encapsulated reagent.

[0091] An external stimulus can be applied intentionally or unintentionally to the composition containing STAR particles, wherein the external stimulus causes agglomeration. In some embodiments, the force of applying the composition containing STAR particles to the tissue surface can cause the STAR particles to agglomerate or can deform the STAR particles in a manner that increases their likelihood of agglomeration (e.g., wherein the tips bend and form hook-like structures that can mechanically connect to other STAR particles). In some embodiments, the STAR particles 300 can interact with the physical and / or chemical properties of the target tissue, thereby increasing the likelihood of agglomeration or causing agglomeration.

[0092] Figures 3A to 3D Methods for preventing and / or disrupting agglomeration are depicted. Generally, agglomeration can be prevented by minimizing the opportunity and / or intensity of STAR particles 300 interacting with other STAR particles 300, with the container in which the STAR particles 300 are stored, and / or with materials or compositions within the medium in which the STAR particles 300 are dispersed.

[0093] In some embodiments, as Figures 3A to 3C As shown, reducing the likelihood of interaction between STAR particles 300 can effectively reduce and / or prevent agglomeration. Figure 3A As illustrated, reducing the concentration of STAR particles 300 within the vehicle (ie, increasing the average spacing between particles) can effectively reduce the likelihood of interaction between STAR particles 300. When STAR particles 300 are less likely to contact each other, agglomeration is less likely to occur.

[0094] Figure 3B Depicted are embodiments in which a repulsive force 370 between STAR particles 300 is effective to maintain a relatively uniform distribution of the STAR particles within the medium. In some embodiments, the repulsive force 370 is an electrostatic force. In some embodiments, the repulsive force is a magnetic force. In some embodiments, the repulsive force is a result of steric hindrance. In some embodiments, the STAR particles may be at least partially or completely encapsulated in a material that limits the ability of the STAR particles to agglomerate and / or interact through macroscopic, microscopic and / or atomic steric hindrance. The material used to encapsulate the STAR particles may be composed of metals, polymers, biopolymers, ceramics, bioactive agents, sugars, sugar alcohols, other materials insoluble in the medium, or combinations thereof. If agglomeration of the STAR particles is desired, the material used to encapsulate the STAR particles may subsequently undergo degradation.

[0095] In some embodiments, the STAR particles can also be lubricated to prevent interactions between the STAR particles that could cause agglomeration. In some embodiments, at least one compound in the vehicle lubricates the STAR particles. In some embodiments, the STAR particles are coated with a lubricant and / or encapsulated in a lubricant. In some embodiments, the surface energy of the STAR particles can act as a lubricant, thereby preventing interactions between the STAR particles.

[0096] The medium in which the STAR particles are dispersed is effective to prevent agglomeration. In some embodiments, the viscosity of the medium is effective to prevent agglomeration of the STAR particles. That is, the viscosity of the medium is sufficiently high that the movement of the STAR particles within the medium is restricted. In some embodiments, such as Figure 3C As shown, the vehicle includes a dispersant 360 that can reduce the interaction between the STAR particles 300 and prevent agglomeration. As used herein, a "dispersant" is a substance, typically a surfactant, that is added to a suspension of solid or liquid particles in a liquid (such as a colloid or emulsion) to improve the separation of the particles and prevent them from settling or agglomerating. Various suitable dispersants known in the art can be used together with STAR particles, and pharmaceutically acceptable dispersants known in the art include but are not limited to gum arabic, gum tragacanth, bentonite, carbomer, cellulose, dextrin, maltodextrin, gelatin, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, hyaluronic acid, pectin and / or starch. Other agents well known in the art can be found in the official monographs of the USP. In some embodiments, minimizing turbulence in the vehicle and / or maintaining laminar flow can reduce the possibility of STAR particle movement. In the case where STAR particles are unlikely to move, agglomeration can be reduced or eliminated.

[0097] In some embodiments, as Figure 3DAs illustrated, the agglomeration of STAR particles 300 can be weakened (shown to the left of the arrow). Upon application of an external stimulus 380 (shown to the right of the arrow), the STAR particles 300 whose agglomeration has been weakened can be broken up. For example, the storage container and medium containing the STAR particles can be shaken manually or with the aid of suitable mixing or vibration equipment known in the art to break up any agglomerates that have formed.

[0098] Some STAR particles may be inherently mechanically fragile or may weaken over time, for example, due to exposure to another material, such as a vehicle, a substance of interest, or any other component present in the vehicle or storage container. Such STAR particles may rupture upon collision with other STAR particles and / or the walls of a storage container in which a composition containing STAR particles is disposed. In some embodiments, fluid flow within the vehicle may also cause STAR particles to rupture. In some embodiments, contact with other STAR particles or fluid flow in a storage container or vehicle may cause unweakened STAR particles to rupture.

[0099] In some embodiments, as Figure 4A As shown, the STAR particle 400 may have a coating 430 that prevents the microneedles 420 from weakening and / or breaking, or otherwise improves the mechanical strength of the STAR particle 400. For example, when the STAR particle is easily weakened by aqueous solutions, the coating can be hydrophobic, and vice versa. The coating can also act as a barrier to prevent fluids from contacting the STAR particle. The coating can also be composed of a mechanically strong but fragile sacrificial material that breaks, decomposes, and / or breaks when it comes into contact with another material (such as another STAR particle) or the wall of a storage container, thereby acting as a protective layer for the STAR particle. As used herein, the phrase "mechanically stronger" used to compare the material coating the STAR particle to the underlying material forming the STAR particle means that the coating material can withstand an applied load better than the underlying structural material without failing or undergoing plastic deformation. For example, the coating material can have greater compressive strength than the underlying structural material.

[0100] In some embodiments, a storage container for STAR particles can be configured to delay or prevent breakage due to contact with the walls of the storage container. Figure 4BIn one embodiment shown, the walls of the storage container are coated with a coating 430 to prevent contact and / or adhesion between the container and the STAR particles 400. For example, the coating can be a lubricant, can have an electrical charge that repels the STAR particles, or can be a material that is relatively softer than the container and / or STAR particle construction material. The repulsive property can be inherent or can be enhanced by the presence of the coating. Exemplary coatings can include, but are not limited to, polymers (e.g., polyvinyl alcohol, poly(ethyleneimine), poly(methyl methacrylate)), biopolymers (e.g., deoxynucleic acids, ribonucleic acids, polyamino acids such as poly(l-lysine), chitosan), proteins, ceramics (metal oxides), metals, sugars, and / or other excipients known in the art.

[0101] The materials forming the STAR particle, or at least the outer portion thereof, and the vehicle can be selected or formulated to prevent degradation of the STAR particle in the vehicle. Figure 5A As shown, the STAR particles 500 are insoluble in the vehicle 540. For example, in some cases, the STAR particles are formed from one or more materials that are substantially insoluble in water, and the vehicle is an aqueous vehicle. For example, in some other cases, the STAR particles are formed from one or more water-soluble materials, and the vehicle is a non-aqueous vehicle. In some other cases, the STAR particles can be formed from a material (such as a water-soluble material) that is then coated with a coating material that is insoluble in water, and the vehicle is an aqueous vehicle, wherein the coating material acts as a barrier to prevent the water-soluble material of the STAR particles dispersed in the aqueous vehicle from dissolving. In similar variations, such as Figure 5B As shown, STAR particle 500 is encapsulated in an encapsulating material 545 that is insoluble in vehicle 540 .

[0102] In some preferred embodiments, the STAR particles are made of one or more water-soluble materials but have a substantially water-insoluble coating thereon so that the STAR particles do not dissolve upon storage or during use, wherein the coating is configured to dissolve later, thereby inactivating the (used) STAR particles. For example, the coating can be made of a material that is insoluble in water at low pH but soluble in water at neutral pH. Such materials are known in the art, for example, Eudragit TM polymer.

[0103] In some embodiments, the vehicle is a non-solvent for the constructed STAR particle material. In some other embodiments, the vehicle is a solvent for the STAR particle material, but the vehicle is full or overfull of dissolved material (solute) such that no additional material (i.e., no material from the STAR particle) can dissolve into the vehicle.

[0104] Figures 6A to 6CDepicts a STAR particle that has been inhomogenized within a medium. Figure 6A In FIG, STAR particles 600 have settled out of the medium at or near the bottom of storage container 640. Figure 6B In FIG, STAR particles 600 float at or near the top of storage container 640. Figure 6C In the embodiment of the present invention, the STAR particles 600 adhere to the wall of the storage container 640. When the average density of the STAR particles is greater than the average density of the medium expelled by the STAR particles, or when the force exerted by the STAR particles on the medium exceeds the force exerted by the medium on the STAR particles (i.e., the net buoyancy), the STAR particles can settle to the bottom of the storage container. When the average density of the STAR particles is less than the average density of the medium expelled by the STAR particles, the STAR particles can float on the top of the storage container. For example, the net buoyancy can be changed by increasing the average density of the medium. Alternatively or additionally, the average density of the STAR particles can be reduced.

[0105] As used herein, the term "density" refers to mass per unit volume, and "average density" refers to the average value of density.

[0106] STAR particles can be porous. In a preferred embodiment, STAR particles are composed of ceramic materials (e.g., aluminum oxide, titanium dioxide, zinc oxide, magnesium oxide), which form a microporous ceramic structure in their sintered state. Similarly, polymeric STAR particles can be produced to form a microporous structure. The average density of STAR particles can be changed by increasing the porosity of the STAR particles, so that air or air pockets remain trapped inside the STAR particles. The porosity of STAR particles can be changed by changing the ceramic or polymer particle size, sintering or heating temperature, processing conditions and / or ceramic or polymer formulation. The average density of STAR particles can also be changed by changing the material used to make STAR particles. The net buoyancy of STAR particles can also be changed by changing the geometry or size of the STAR particles. For example, larger STAR particles will discharge more medium volume, while smaller STAR particles will discharge less medium volume, thereby changing the net buoyancy.

[0107] STAR particles that adhere to the walls of a storage container may be more likely to agglomerate. A concentration or uneven distribution of STAR particles in a particular space within a storage container may generally be undesirable. Instead, it is generally preferred that the STAR particles be substantially evenly dispersed in the medium.

[0108] Various techniques can be used to slow down the non-homogenization of STAR particles to help maintain a uniform dispersion of STAR particles in a vehicle (e.g., in a storage container). In some embodiments, the vehicle composition is adjusted to match the density of the STAR particles, and / or a suitable dispersant or other additive is included in the vehicle to reduce or prevent the STAR particles from settling or floating or adhering to the container walls. Figure 7A In the embodiment, additive 735 is included in the vehicle so that the STAR particles 700 remain uniformly dispersed in the vehicle. Figure 7B , the wall of the storage container 740 is coated with material 730 to prevent STAR particles from adhering to the inner wall of the storage container 740.

[0109] The STAR particle composition dispersed in the fluid vehicle preferably maintains a substantially uniform dispersion, even if the average densities of the STAR particles and the vehicle differ from one another. In this context, the term "maintain" means a duration long enough to allow for use after manufacture, including transportation and storage prior to use by the end user. For example, the duration can range from a few weeks to one or more years, e.g., 2 weeks to 48 weeks.

[0110] Implementation Plan

[0111] Some embodiments of the present disclosure may be described in terms of one or more of the following:

[0112] Embodiment 1. A packaged STAR particle composition, comprising: a plurality of STAR particles, the plurality of STAR particles being configured to mechanically disrupt biological tissue; a medium in which the plurality of STAR particles are dispersed; and a container comprising the medium and the STAR particles, wherein the STAR particles, the medium, and the container are configured to maintain a substantially uniform dispersion of the STAR particles within the medium and within the container.

[0113] Embodiment 2. The packaged STAR particle composition of Embodiment 1, wherein the STAR particle and the vehicle have similar average densities.

[0114] Embodiment 3. The packaged STAR particle composition according to embodiment 1 or 2, wherein the vehicle has a viscosity effective to prevent or limit non-homogenization of the STAR particles even if the average densities of the STAR particles and the vehicle are different from each other.

[0115] Embodiment 4. The packaged STAR particle composition of any one of Embodiments 1 to 3, wherein the vehicle comprises at least one dispersant.

[0116] Embodiment 5. A packaged STAR particle composition according to any one of Embodiments 1 to 4, wherein the container wall in contact with the vehicle has surface properties that inhibit the STAR particles from adhering to the wall, optionally, for example, wherein the container wall has a coating that effectively inhibits the STAR particles from adhering to the wall.

[0117] Embodiment 6. A packaged STAR particle composition according to any one of Embodiments 1 to 5, wherein the STAR particles have electrostatic, steric and / or magnetic properties that generate repulsive forces between the STAR particles that effectively prevent or limit agglomeration of the STAR particles.

[0118] Embodiment 7. The packaged STAR particle composition of any one of Embodiments 1 to 6, further comprising at least one salt compound suitable for reducing the Debye length of the charge on the STAR particle.

[0119] Embodiment 8. The packaged STAR particle composition of any one of Embodiments 1 to 7, further comprising a surfactant suitable for inhibiting interactions between hydrophobic or hydrophilic surfaces on the STAR particles.

[0120] Embodiment 9. A composition comprising: a plurality of STAR particles; and a vehicle in which the plurality of STAR particles are dispersed, wherein the vehicle has a viscosity of at least 100 cP or greater than 100 cP, such that the viscosity of the vehicle is effective to at least partially maintain the dispersion of the STAR particles within the vehicle and / or limit non-uniformity.

[0121] Embodiment 10. A composition comprising: a plurality of STAR particles having a structure formed at least in part from a first material; and a vehicle in which the plurality of STAR particles are dispersed, wherein the vehicle comprises a solvent for the first material, wherein the composition is configured such that the plurality of STAR particles resist dissolution and / or accidental inactivation within the vehicle.

[0122] Embodiment 11. The composition of embodiment 9 or 10, wherein the STAR particle has a coating thereon that is substantially insoluble in the solvent of the vehicle.

[0123] Embodiment 12. The composition of any one of Embodiments 9 to 11, wherein the STAR particle is encapsulated in an encapsulating material that is substantially insoluble in the solvent of the vehicle.

[0124] Embodiment 13. The composition of any one of embodiments 9 to 12, wherein the vehicle is impregnated with a solute effective to prevent or limit dissolution of the first material in the solvent of the vehicle.

[0125] Embodiment 14. The composition of any one of Embodiments 9 to 13, wherein the structure of the STAR particle is further formed of a second material that is substantially insoluble in the solvent of the vehicle.

[0126] Embodiment 15. A composition comprising: a plurality of STAR particles; and a vehicle in which the plurality of STAR particles are dispersed, wherein the STAR particles are adapted to degrade after administration and use (i) by a selected change in pH, osmotic pressure, temperature, or ionic composition of the vehicle or (ii) in response to an external stimulus.

[0127] Embodiment 16. The composition of embodiment 15, wherein the external stimulus comprises exposure to atmospheric oxygen, light, or water.

[0128] Embodiment 17. A packaged STAR particle composition, comprising: a plurality of STAR particles, the plurality of STAR particles being configured to mechanically disrupt biological tissue; a medium in which the plurality of STAR particles are dispersed; and a container comprising the medium and the STAR particles, wherein the walls of the STAR particles and / or the container contacting the medium are coated with a buffer material that is more deformable than the material forming the walls of the STAR particles and / or the container.

[0129] Embodiment 18. A composition comprising a plurality of STAR particles configured to mechanically disrupt biological tissue, wherein the STAR particles have a surface coating composed of a material that is mechanically stronger than an underlying material forming the STAR particles.

[0130] Embodiment 19. The composition of embodiment 18, wherein the basecoat material comprises an organic material and the surface coating material comprises an inorganic material.

[0131] Embodiment 20. The composition of any one of Embodiments 1 to 19, wherein the composition comprises a substance of interest (SOI).

[0132] Embodiment 21. The composition of any one of Embodiments 1 to 20, wherein the SOI comprises a bioactive agent.

[0133] Embodiment 22. The composition of any one of Embodiments 1 to 21, wherein the SOI is located in and / or on the STAR particle.

[0134] Embodiment 23. The composition of any one of Embodiments 1 to 22, wherein the SOI is located in the vehicle.

[0135] Embodiment 24. A method of administering a substance of interest (SOI) to the skin of a patient, the method comprising: applying a composition according to any one of embodiments 20 to 23 to the skin surface; and manipulating the composition to cause the STAR particles to mechanically disrupt the skin surface.

[0136] Embodiment 25. A STAR particle composition, comprising: a plurality of STAR particles, wherein the plurality of STAR particles are configured to mechanically disrupt biological tissue; a plurality of SOI particles, wherein the plurality of SOI particles are separated from the plurality of STAR particles; and a liquid medium, wherein the plurality of STAR particles and the plurality of SOI particles are dispersed in the liquid medium.

[0137] Embodiment 26. The composition of Embodiment 25, wherein the STAR particle and / or the SOI particle has a coating thereon effective to substantially prevent dissolution of the STAR particle and / or the SOI particle in the liquid vehicle.

[0138] Embodiment 27. A STAR particle composition, comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue; a first liquid phase; and a second liquid phase, wherein the plurality of STAR particles are dispersed in the first liquid phase or the second liquid phase, and a substance of interest (SOI) is provided in the first liquid phase or the second liquid phase.

[0139] Embodiment 28. The composition of embodiment 27, wherein the first liquid phase is a continuous phase and the second liquid phase is a discontinuous phase dispersed in the first liquid phase.

[0140] Embodiment 29. A composition according to Embodiment 27 or 28, wherein the STAR particles are dispersed in only one of the first liquid phase or the second liquid phase, and the SOI is dissolved in the other of the first liquid phase or the second liquid phase.

[0141] Embodiment 30. The composition of any one of Embodiments 27 to 29, wherein (i) the STAR particles are dispersed only in the first liquid phase, and the SOI is dissolved in the first liquid phase and the second liquid phase (or is otherwise provided); (ii) the STAR particles are dispersed in the first liquid phase and the second liquid phase, and the SOI is dissolved only in the first liquid phase (or is otherwise provided); (iii) the SOI is dissolved in the first liquid phase and the second liquid phase (or is otherwise provided), and the STAR particles are dispersed only in the second liquid phase; (iv) the STAR particles (v) the STAR particles are dispersed in the first liquid phase and the second liquid phase, and the SOI is dissolved only in the second liquid phase (or provided in another way); (vi) the SOI is dissolved only in the first liquid phase (or provided in another way), and the STAR particles are dispersed only in the second liquid phase; or (vii) the STAR particles are dispersed in the first liquid phase and the second liquid phase, and the SOI is dissolved in the first liquid phase and the second liquid phase (or provided in another way).

[0142] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. The term "about" as used herein 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.

[0143] Modifications and variations of the methods and systems described herein will be apparent to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to fall within the scope of the appended claims.

Claims

1. A packaged STAR particle composition, comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue; a vehicle in which the plurality of STAR particles are dispersed; and a container comprising the vehicle and the STAR particle, Wherein the STAR particles, the vehicle, and the container are configured to maintain a substantially uniform dispersion of the STAR particles within the vehicle and within the container.

2. The packaged STAR particle composition of claim 1, wherein the STAR particle and the vehicle have similar average densities.

3. The packaged STAR particle composition of claim 1, wherein the vehicle has a viscosity effective to prevent or limit non-homogenization of the STAR particles even if the average densities of the STAR particles and the vehicle are different from each other.

4. The packaged STAR particle composition of claim 1, wherein the vehicle comprises at least one dispersant.

5. The packaged STAR particle composition of claim 1, wherein the container wall in contact with the vehicle has surface properties that inhibit adhesion of the STAR particles to the wall, optionally, for example, wherein the container wall has a coating effective to inhibit adhesion of the STAR particles to the wall.

6. The packaged STAR particle composition of claim 1, wherein the STAR particles have electrostatic, steric, and / or magnetic properties that create repulsive forces between the STAR particles that are effective to prevent or limit agglomeration of the STAR particles.

7. The packaged STAR particle composition of claim 6, further comprising at least one salt compound suitable for reducing the Debye length of the charge on the STAR particle.

8. The packaged STAR particle composition of claim 6, further comprising a surfactant suitable for inhibiting interactions between hydrophobic or hydrophilic surfaces on the STAR particles.

9. A composition comprising: multiple STAR particles; and a medium in which the plurality of STAR particles are dispersed, Wherein the vehicle has a viscosity of at least 100 cP, such that the viscosity of the vehicle is effective to at least partially maintain dispersion of the STAR particles within the vehicle and / or limit non-homogenization.

10. A composition comprising: a plurality of STAR particles having a structure formed at least in part from a first material; and a vehicle in which the plurality of STAR particles are dispersed, wherein the vehicle comprises a solvent for the first material, wherein the composition is configured such that the plurality of STAR particles resist dissolution and / or inadvertent inactivation within the vehicle.

11. The composition of claim 10, wherein the STAR particle has a coating thereon that is substantially insoluble in the solvent of the vehicle.

12. The composition of claim 10, wherein the STAR particle is encapsulated in an encapsulating material that is substantially insoluble in the solvent of the vehicle.

13. The composition of claim 10, wherein the vehicle is impregnated with a solute effective to prevent or limit dissolution of the first material in the solvent of the vehicle.

14. The composition of claim 10, wherein the structure of the STAR particle is further formed of a second material that is substantially insoluble in the solvent of the vehicle.

15. A composition comprising: multiple STAR particles; and a medium in which the plurality of STAR particles are dispersed, Wherein the STAR particle is adapted to degrade after administration and use (i) by a selected change in pH, osmotic pressure, temperature, or ionic composition of the vehicle or (ii) in response to an external stimulus.

16. The composition of claim 15, wherein the external stimulus comprises exposure to atmospheric oxygen, light or water.

17. A packaged STAR particle composition, comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue; a vehicle in which the plurality of STAR particles are dispersed; and a container comprising the vehicle and the STAR particle, Wherein the STAR particle and / or the wall of the container contacts the vehicle is coated with a cushioning material that is more deformable than the material forming the STAR particle and / or the wall of the container.

18. A composition comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue, The STAR particle has a surface coating, and the surface coating is composed of a material with a mechanical strength greater than that of an underlying material forming the STAR particle.

19. The composition of claim 18, wherein the basecoat material comprises an organic material and the surface coating material comprises an inorganic material.

20. The composition of any one of claims 1 to 19, wherein the composition comprises a substance of interest (SOI).

21. The composition of claim 20, wherein the SOI comprises a bioactive agent.

22. The composition of claim 20, wherein the SOI is located in and / or on the STAR particle.

23. The composition of claim 20, wherein the SOI is located in the vehicle.

24. A method of administering a substance of interest (SOI) to the skin of a patient, the method comprising: applying the composition according to claim 20 to the surface of the skin; as well as The composition is manipulated to cause the STAR particles to mechanically disrupt the skin surface.

25. A STAR particle composition comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue; a plurality of SOI particles, the plurality of SOI particles being separated from the plurality of STAR particles; and A liquid medium in which the plurality of STAR particles and the plurality of SOI particles are dispersed.

26. The composition of claim 25, wherein the STAR particle and / or the SOI particle has a coating thereon effective to substantially prevent dissolution of the STAR particle and / or the SOI particle in the liquid vehicle.

27. A STAR particle composition comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue; a first liquid phase; and The second liquid phase, in: The plurality of STAR particles are dispersed in the first liquid phase or the second liquid phase, and A substance of interest (SOI) is provided in the first liquid phase or the second liquid phase.

28. The composition of claim 27, wherein the first liquid phase is a continuous phase and the second liquid phase is a discontinuous phase dispersed in the first liquid phase.

29. The composition of claim 27, wherein the STAR particles are dispersed in only one of the first liquid phase or the second liquid phase, and the SOI is dissolved in the other of the first liquid phase or the second liquid phase.

30. The composition of claim 27, wherein: (i) the STAR particles are dispersed only in the first liquid phase, and the SOI is provided in the first liquid phase and the second liquid phase; (ii) the STAR particles are dispersed in the first liquid phase and the second liquid phase, and the SOI is provided only in the first liquid phase; (iii) providing the SOI in the first liquid phase and the second liquid phase, and the STAR particles are dispersed only in the second liquid phase; (iv) the STAR particles are dispersed in the first liquid phase and the second liquid phase, and the SOI is provided only in the second liquid phase; (v) the STAR particles are dispersed only in the first liquid phase, and the SOI is provided only in the second liquid phase; (vi) providing the SOI only in the first liquid phase, and the STAR particles only dispersed in the second liquid phase; or (vii) The STAR particles are dispersed in the first liquid phase and the second liquid phase, and the SOI is provided in the first liquid phase and the second liquid phase.

31. The composition of claim 30, wherein: (i) the STAR particles are dispersed only in the first liquid phase, and the SOI is provided in the first liquid phase and the second liquid phase; (ii) the STAR particles are dispersed in the first liquid phase and the second liquid phase, and the SOI is provided only in the first liquid phase; (iii) providing the SOI in the first liquid phase and the second liquid phase, and the STAR particles are dispersed only in the second liquid phase; (iv) the STAR particles are dispersed in the first liquid phase and the second liquid phase, and the SOI is provided only in the second liquid phase; (v) the STAR particles are dispersed only in the first liquid phase, and the SOI is provided only in the second liquid phase; or (vi) The SOI is provided only in the first liquid phase, and the STAR particles are dispersed only in the second liquid phase.

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