Microneedle particles, vehicles, and substances of interest

Abstract

STAR particles, compositions, and methods of making them, wherein the STAR particles and / or compositions are effective to prevent and / or reduce undesired degradation or to stabilize and / or preserve the STAR particle, the substance of interest, and / or components of the STAR particle and / or STAR particle-containing composition.

Description

[Background technology]

[0001] Some embodiments of microneedle particles (i.e., STAR particles) are described in U.S. Pat. No. 11,219,816, which is incorporated herein by reference. STAR particles may provide an effective mechanism for improving the delivery of bioactive compounds to biological tissues, such as skin and other biological tissues, that have barrier or barrier-like properties. However, STAR particles and / or such bioactive compounds therein may be susceptible to undesired degradation during manufacture, formulation, storage, and application to the target tissue, and / or after their application 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 at mechanically disrupting the target tissue and / or at delivering the substance of interest to the target tissue. It would be desirable to provide a means for reducing or preventing unintended degradation of STAR particles and / or for promoting the general stabilization of the STAR particles and / or the substance of interest contained therein.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 436,984, filed January 4, 2023, which is incorporated herein by reference. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] U.S. Patent No. 11,219,816 Summary of the Invention

[0004] In one aspect, a packaged STAR particle composition is provided, the 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 holding the vehicle and the STAR particles. The STAR particles, vehicle, and container are configured to maintain a substantially uniform dispersion of the STAR particles within the vehicle and the container. In some embodiments, the STAR particles and the vehicle have similar average densities. In some embodiments, the vehicle has a viscosity effective to prevent or limit dehomogenization of the STAR particles, even when the average densities of the STAR particles and the vehicle are different from each other. In some embodiments, the vehicle comprises at least one dispersing agent. In some embodiments, the wall of the container in contact with the vehicle optionally has surface properties that inhibit STAR particle attachment, for example, if the wall of the container has a coating effective to inhibit STAR particle attachment. In some embodiments, the STAR particles have electrostatic, steric, and / or magnetic properties that generate repulsive forces between the STAR particles effective to prevent or limit STAR particle aggregation. In some embodiments, the composition also comprises at least one salt compound adapted to reduce the Debye length of the charge on the STAR particles. In some embodiments, the composition also comprises a surfactant adapted to inhibit interactions between the hydrophobic or hydrophilic surfaces of the STAR particles.

[0005] In another aspect, a composition is provided, the composition comprising a plurality of STAR particles and a vehicle in which the plurality of STAR particles are dispersed, the vehicle having a viscosity of at least 100 cP, the viscosity of the vehicle being effective to at least partially maintain dispersion of the STAR particles within the vehicle and / or limit dehomogenization.

[0006] In a further aspect, a composition is provided, the composition comprising a plurality of STAR particles having a structure at least partially formed from a first material, and a vehicle in which the plurality of STAR particles are dispersed, the vehicle comprising a solvent for the first material, the composition configured such that the plurality of STAR particles are resistant to dissolution and / or unintentional 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 saturated with a solute effective to prevent or limit 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, the 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 application and use (i) by a selected change in pH, osmolality, temperature or ionic composition of the vehicle, or (ii) by response to an external stimulus. In some embodiments, the external stimulus can be exposure to atmospheric oxygen, light, or water.

[0008] In yet a further embodiment, a packaged STAR particle composition is provided, the 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 containing the vehicle and the STAR particles, wherein the walls of the container in contact with the STAR particles and / or the vehicle are coated with a buffer 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, the composition having a plurality of STAR particles configured to mechanically disrupt biological tissue, the STAR particles having a surface coating made of a material that is mechanically stronger than the underlying material from which the STAR particles are formed. 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 within and / or on the STAR particle. In other embodiments, the SOI is located in a vehicle. In some embodiments, a method of administering a substance of interest (SOI) to the skin of a patient is provided, the method comprising applying a composition to the surface of the skin and manipulating the composition to cause the STAR particles to mechanically disrupt the surface of the skin.

[0010] In a further aspect, a STAR particle composition is provided, the composition having a plurality of STAR particles configured to mechanically disrupt biological tissue, a plurality of SOI particles spaced apart from the plurality of STAR particles, and a liquid vehicle 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 effective to substantially prevent dissolution of the STAR particles and / or the SOI particles in the liquid vehicle.

[0011] In another aspect, a STAR particle composition configured for mechanically disrupting biological tissue is provided having a plurality of STAR particles, a first liquid phase, and a second liquid phase, wherein the plurality of STAR particles are dispersed in the first or second liquid phase, and a substance of interest (SOI) is provided in the first or 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 or second liquid phase, and the SOI is dissolved in the other of the first or second liquid phase. In some embodiments, (i) the STAR particles are dispersed in only the first liquid phase and the SOI is dissolved in the first and second liquid phases, (ii) the STAR particles are dispersed in the first and second liquid phases and the SOI is dissolved in only the first liquid phase, (iii) the SOI is dissolved in the first and second liquid phases and the STAR particles are dispersed in only the second liquid phase, (iv) the STAR particles are dispersed in the first and second liquid phases and the SOI is dissolved in only the second liquid phase, (v) the STAR particles are dispersed in only the first liquid phase and the SOI is dissolved in only the second liquid phase, (vi) the SOI is dissolved in only the first liquid phase and the STAR particles are dispersed in only the second liquid phase, or (vii) the STAR particles are dispersed in the first and second liquid phases.

[0012] The detailed description is set forth with reference to the accompanying drawings. The use of the same reference numbers may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those shown in the drawings, and some elements and / or components may be absent in various embodiments. Elements and / or components in the drawings are not necessarily drawn to scale. [Brief explanation of the drawings]

[0013] [Figure 1A] FIG. 1 is a plan view of a planar STAR particle according to one embodiment of the present disclosure. [Figure 1B] FIG. 1B is a perspective view of the planar STAR particle of FIG. 1A. [Figure 1C]FIG. 2 is a plan view of a planar STAR particle according to another embodiment of the present disclosure. [Figure 1D] FIG. 1D is a perspective view of the microneedle particle of FIG. 1C. [Figure 1E] FIG. 1D is a side view of the microneedle particle of FIG. 1C. [Figure 2] 1 shows aggregated STAR particles according to one embodiment of the present disclosure. [Figure 3A] 10 shows a reduction in the concentration of STAR particles to reduce the likelihood of STAR particle aggregation, according to an embodiment of the present disclosure. [Figure 3B] 10 shows repulsive forces between some embodiments of STAR particles to reduce the likelihood of aggregation of the STAR particles, according to another embodiment of the present disclosure. [Figure 3C] 1 shows STAR particles in a dispersion that reduces the likelihood of STAR particle agglomeration, according to another embodiment of the present disclosure. [Figure 3D] 10 shows weakly agglomerated STAR particles undergoing agglomeration disruption according to another embodiment of the present disclosure. [Figure 4A] 1 is a cross-sectional view of a planar STAR particle according to another embodiment of the present disclosure, in which the STAR particle has a coating. [Figure 4B] 1 shows a storage container containing STAR particles, according to one embodiment of the present disclosure, where the storage container has a coating effective to retard STAR particle-container adhesion. [Figure 5A] 1 shows insoluble STAR particles dispersed in a vehicle in a container, according to one embodiment of the present disclosure. [Figure 5B] 13 shows encapsulated STAR particles dispersed in a vehicle in a container according to another embodiment of the present disclosure. [Figure 6A] Shown are STAR particles that have settled to or near the bottom of the storage container. [Figure 6B] A STAR particle is shown suspended at or near the top of a vehicle within a storage vessel. [Figure 6C] Shows STAR particles attached to the side of a storage container. [Figure 7A]1 shows STAR particles stored in a dispersion according to another embodiment of the present disclosure. [Figure 7B] 13 shows a coated storage container for a STAR particle-containing vehicle according to another embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0014] STAR particles and STAR particle-containing compositions are disclosed, along with methods for preventing and / or reducing undesired degradation or stabilizing and / or preserving the STAR particle, the substance of interest, and / or components of the STAR particle and / or STAR particle-containing composition.

[0015] Stability of the STAR particles and components of STAR particle compositions may be necessary to ensure that the STAR particles can be manufactured, formulated, packaged, transported, stored, and remain suitable for their intended use without undesired degradation or loss of functionality.

[0016] In some cases, the goal is to stabilize the STAR particles during storage, and in other cases, the goal is to stabilize the STAR particles during application to tissue. The methods disclosed herein for stabilization may be the same for both goals, or the methods may 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, as well as between the STAR particles themselves during storage. During application of the STAR particles to tissue, it may be desirable to minimize or prevent interactions between the STAR particles and the applicator, i.e., materials or structures (e.g., mechanical devices, gloved fingers) used to apply force to the STAR particles and cause them to interact with the tissue. Those skilled in the art will be able to adapt the concepts described herein for stabilization in a container to stabilization using an applicator, as needed.

[0017] As used herein, the phrase "packaged STAR particle composition" refers to a STAR particle composition placed in a container suitable for storing and transporting the composition. The container may be essentially any rigid or flexible container known in the art suitable for holding a quantity of STAR particles, alone or in combination with a vehicle. It may be, for example, a vial, jar, pouch, bag or tube, and generally includes a cap, closure, plastic ziplock, or other means for sealing / closing, opening, and optionally reclosing the container.

[0018] It may be important to separate the STAR particle, the drug or other substance of interest (SOI), and other components of the STAR particle formulation (e.g., vehicle). In some embodiments, this may be achieved by having multiple phases present.

[0019] For example, one approach is to have a solid and a liquid phase. The solid phase is the STAR particle, and the liquid phase is the vehicle. The components of the formulation are in / on the vehicle and / or the STAR particle. The SOI may be in / on the vehicle and / or the STAR particle. In some embodiments for separating the solid phase from the liquid phase, the solid phase includes a coating that prevents the STAR particle from interacting with the vehicle (which may dissolve, swell, soften, or otherwise adversely affect STAR particle properties). For example, if the STAR particle is water-soluble and is in an aqueous vehicle, the STAR particle can be coated with a water-insoluble material to prevent the STAR particle from dissolving. Phase separation can also prevent the STAR particle from interacting with the SOI or other components of the formulation.

[0020] In some embodiments, there may be two solid phases. For example, the first solid phase may be SOI separate from the STAR particles (i.e., the second solid phase), such that there is a suspension of STAR particles and SOI particles in the liquid vehicle. Optionally, a coating may be provided 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 have additional formulation components (e.g., excipients) within them.

[0021] In some embodiments, there can be two liquid phases. For example, one phase can be continuous and another phase can be discontinuous (e.g., an emulsion). As another example, both phases can be continuous but mixed before or during application to the tissue (e.g., both phases become discontinuous). One phase can be aqueous and another phase can be non-aqueous. STAR particles can be in one phase and not the other. The SOI can be in the same phase as the STAR particles or a different phase. For example, there can be water-soluble STAR particles in a non-aqueous phase and water-soluble SOI in an 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, as one phase is liquid and the other phase is liquid with solid STAR particles suspended in the liquid.

[0022] The STAR particle-containing compositions and methods disclosed herein can enhance the local delivery of bioactive agents and other substances of interest to improve the desired effect of the compound, to facilitate persistence of the compound in and / or on the target tissue, to facilitate extraction or removal of endogenous substances, compounds and / or analytes from the target tissue, and / or to promote systemic uptake of the compound. The STAR particle-containing compositions and methods disclosed herein can be useful for diagnostic, prognostic, therapeutic, adjuvant, cosmetic and / or preventative purposes.

[0023] The STAR particles can enhance the local administration of another substance or substances by mechanically disrupting the integrity of the outer / upper layer of skin (or other biological tissue) to facilitate local delivery of the substance into / onto a target tissue in a patient, and / or facilitate passage and uptake of the substance through the target tissue in the bloodstream and / or lymphatics for systemic delivery, and / or facilitate passage of the substance through the target tissue and uptake in another tissue or space, including, but not limited to, joint cavities, tendons, ligaments, fascia, nerves, blood vessels, bone, muscle, glands, lymph nodes, subcutaneous tissue, adipose tissue, organs, and / or other tissues and spaces. The patient may be a human or other mammal or other animal or plant. The skin or other biological tissue may be in vivo or ex vivo.

[0024] In some embodiments, the STAR particles are configured to [1] at least partially destroy a first type of biological tissue and [2] prevent or reduce the likelihood that the STAR particles will destroy a second type of off-target biological tissue. As used herein, the term "off-target tissue" refers to any tissue that is not intended to be destroyed by the STAR particles. For example, off-target tissue includes, but is not limited to, the eye or conjunctiva; oral mucosa, gastric mucosa, or vaginal mucosa; and / or, if the target tissue is skin, skin outside the intended area of ​​use. In particular, the second type of biological tissue can include, for example, the skin of a finger, and the first type of biological tissue can include the tissue to be treated, for example, an area of ​​skin or mucosal tissue, that has a relatively thinner stratum corneum than the first type of biological tissue. In this way, for example, the STAR particles may not destroy, or be less likely to destroy, the skin of a finger used to apply or rub the STAR particles onto / into the treatment area of ​​the first biological tissue.

[0025] As used herein, a STAR particle configured to "mechanically disrupt" biological tissue, particularly the stratum corneum of mammalian skin, particularly human skin, refers to a particle having a size and mechanical strength that allows it to create holes or pores in the tissue surface. For example, the mechanical disruption can be making a penetration through the stratum corneum.

[0026] In some embodiments, a STAR particle disclosed herein may be configured to partially or completely lose its mechanical fracture properties after its intended use, such that the STAR particle cannot be reused.

[0027] STAR particles The STAR particle comprises a core structure and one or more microneedle-like protrusions extending from the core structure. The microneedles may be structured to at least partially penetrate or otherwise mechanically disrupt biological tissue, such as the stratum corneum of human skin (or other biological tissue). That is, the microneedles are dimensioned and have mechanical rigidity that allows them to be forced into and penetrate biological tissue, forming microscale holes or channels therein. The microneedles may extend independently from the core structure in any direction.

[0028] 1A and 1B show a STAR particle 100 according to one embodiment. In this embodiment, the STAR particles 100 each have three microneedles 120 extending in the same plane from a core structure 110, and therefore the STAR particles are referred to as planar particles. The core structure is typically the portion of the microneedle particle that connects the microneedles, especially when multiple microneedles are present. The core structure can be a solid structure, a porous structure, or a hollow structure with one or more internal cavities. In other embodiments, the STAR particle can have two, four, five, six, seven, eight, nine, or ten microneedles extending from the core structure. In some embodiments, the microneedles extend from the core in different planes. For example, the STAR particle can have three, four, five, or more microneedles extending in different directions and planes, and therefore the STAR particle is referred to as a non-planar particle.

[0029] The microneedles of the STAR particles may be tapered. In some embodiments, in plan view, as shown in FIG. 1A, the microneedles 120 are tapered from the core structure 110 to the tip, while the height of the microneedles is substantially constant. In some other embodiments, the edges of the microneedles 120 may also be tapered, since tapered edges are sharper and therefore can penetrate the stratum corneum more easily than non-tapered edges. For example, in some embodiments, as shown in FIGS. 1C-1E, the microneedles 120 may be tapered in both width and height. That is, the height of the microneedles is greatest at the core structure and smallest at the tip. In other variations, the core and base portions of the microneedles may have a uniform height, with only the distal tip of the microneedle being tapered. In variations, the taper may be from one or both sides of the STAR particle.

[0030] Various design features of the STAR particle can be selected to impart to the particle the ability to prevent 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 the microneedles or subsets of those microneedles. A combination of these features can be designed to prevent the entire STAR particle from penetrating biological tissue.

[0031] For example, the core structure may be sized, shaped, and / or lack sharp edges that allow one or more microneedles extending from the core structure to penetrate biological tissue, but inhibit all or substantially all of the core structure from penetrating biological tissue. As a further example, the microneedle may have a structural feature, such as a tapered shape, that allows only a portion of the microneedle (i.e., the tip distal to the core structure) to penetrate biological tissue. For example, the microneedle may have a shoulder or plateau that allows only the portion of the microneedle distal to the shoulder or plateau to penetrate biological tissue. Such a configuration can prevent the core structure from contacting biological tissue. In another example, the microneedle particle may have an overall curved shape that reaches a tip and, due to its geometry, allows only the tip portion to penetrate biological tissue.

[0032] In general, the microneedles of a STAR particle can have the same or different dimensions and / or geometric shapes from each other. In one embodiment, the microneedles of a planar STAR particle have substantially the same dimensions and geometric shapes.

[0033] Microneedles may have any shape effective to at least partially penetrate biological tissue. In some embodiments, microneedles are high aspect ratio structures having a length at least twice as long as their width at the base of the microneedle (i.e., the interface between the microneedle and the core structure). The length of a microneedle is the distance from the interface between the microneedle and the edge of the core structure to the tip of the microneedle. In some embodiments, each of the microneedles independently has a length between 1 μm and 2,000 μm. In some embodiments, each of the microneedles independently has a length between 10 μm and 2,000 μm. In some embodiments, each of the microneedles independently has a length between 50 μm and 2,000 μm. In some embodiments, each of the microneedles independently has a length between 100 μm and 1,000 μm. In some embodiments, each of the microneedles independently has a length between 250 μm and 750 μm. In some embodiments, each of the microneedles independently has a length of between 100 μm and 500 μm, hi some embodiments, each of the microneedles has a length of about 350 μm.

[0034] In certain embodiments, the STAR particle has three microneedles, each of which independently has a length of about 1 μm to about 2,000 μm, about 10 μm to about 2,000 μm, about 50 μm to about 2,000 μm, about 100 μm to about 1,000 μm, or about 250 μm to about 750 μm. The STAR particle may be a planar particle.

[0035] The microneedles of the STAR particles may have a tip with a radius of curvature of about 0.1 μm to about 50 μm. In some embodiments, the microneedles have a tip with a radius of curvature of about 0.1 μm to about 50 μm, about 0.1 μm to about 25 μm, about 0.1 μm to about 20 μm, about 0.1 μm to about 15 μm, about 0.1 μm to about 10 μm, about 0.1 μm to about 5 μm, about 1 μm to about 10 μm, about 1 μm to about 7 μm, about 1 μm to about 5 μm, about 1 μm to about 4 μm, 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 typically the portion of the microneedle that first penetrates biological tissue.

[0036] In some embodiments, the STAR particle is shaped and sized to prevent or reduce the likelihood of the STAR particle becoming completely or irremovably embedded in biological tissue. In some embodiments, the maximum dimension of the STAR 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 to about 2,000 μm, or about 500 μm, 1,000 μm. "Maximum dimension of the STAR particle" refers to the greatest of the following distances: [1] the distance between the tips of the two most distant microneedles (if the microneedle particle comprises two or more microneedles), or [2] the furthest possible distance between the tips of the microneedles and the side of the core structure opposite the side from which the measured microneedles extend. A multiple microneedle particle may comprise microneedle particles of one or more sizes.

[0037] In some embodiments, the microneedles of the STAR particle are planar microneedles. As used herein, the phrase "planar microneedles" refers to two or more microneedles, each having either [1] a central axis extending from the core structure in at least substantially the same plane, or [2] a tip residing in substantially the same plane. Planar microneedles may include microneedles extending from the core structure in the same direction, different directions, or a combination thereof. Planar microneedles may also include collinear planar microneedles extending from both sides of the core structure such that the central axis of each microneedle corresponds to at least substantially a line. For example, if a STAR particle includes two or more pairs of microneedles, the pairs of microneedles may be collinear, but not necessarily all of the microneedles.

[0038] 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 microneedle is consistent throughout the length of the microneedle. That is, the height of the microneedle is the same where the microneedle contacts the core structure as it is at the tip. In some embodiments, the height of the microneedle particle decreases along the length of the microneedle. The height of the microneedles may be greatest where the microneedle particles contact the core structure and smallest at the tip.

[0039] In some preferred embodiments of tapered STAR particles, the height of the central core of the STAR particle is between 100 μm and 150 μm, and the radius of curvature of the tip of the microneedle of the STAR particle is between 5 μm and 30 μm.

[0040] STAR particles can be made of one or more biocompatible materials, such as metals, polymers, biopolymers, ceramics, bioactive agents, sugars, sugar alcohols, or combinations thereof. Bioactive agents can generally include one or more drugs, one or more sensors, one or more functional cosmetics, or a combination thereof. Thus, STAR particles can be composed of a combination of bioactive components (drugs, small molecule excipients (e.g., trehalose), sensors, functional cosmetics, or a combination thereof) and inert components (metals, polymers, ceramics, sugars, etc.). If a portion of the STAR particles remains in and / or on the biological tissue after removal of the STAR particles, the portion of the STAR particles remaining in and / or on the biological tissue can include at least one bioactive component, at least one inert component, or a combination thereof.

[0041] In some embodiments, the STAR particle is made of a water-insoluble material. In some embodiments, the STAR particle is made of or comprises at least one water-soluble and / or erodible material. If the STAR particle is made of a water-soluble and / or erodible material, the STAR particle, or portions thereof, can safely degrade if left in living tissue or after disposal. In one example, the STAR particle has a matrix structure that may consist of or comprise a water-soluble or bioerodible material. As used herein, the term "bioerodible" means that the structure / material degrades in vivo or ex vivo by dissolution, enzymatic degradation, hydrolysis, erosion, resorption, chemical reaction, or a combination thereof. "Ex vivo" in this case will be understood to refer to STAR particles on a tissue surface or otherwise present in the environment, but not necessarily in contact with living tissue. Other methods of degradation of water-soluble and / or water-insoluble STAR particles include, but are not limited to, dissolution, hydrolysis, degradation upon contact with sunlight (i.e., ultraviolet light), or degradation resulting from reaction with environmental factors (e.g., oxygen).

[0042] In some embodiments, the STAR particle is a metal microneedle particle. A metal microneedle particle is one in which all or substantially all of the structure of the microneedle particle is composed of a metal or metal alloy (e.g., stainless steel). In some other embodiments, the majority of the STAR particle is made of such a metal or metal alloy material.

[0043] In some embodiments, the STAR particle is a polymeric microneedle particle, where all or substantially all of the structure of the microneedle particle is made from one or more polymeric materials (e.g., biodegradable materials such as poly(lactic-co-glycolic acid) (PLGA) or polycaprolactone (PCL) and / or water-soluble materials such as carboxymethylcellulose or polyvinyl alcohol). In some other embodiments, the majority of the STAR particle is made from one or more such polymeric materials.

[0044] In some embodiments, the STAR particle is a ceramic microneedle particle, where all or substantially all of the structure of the microneedle particle is made from one or more ceramic materials (e.g., aluminum oxide, titanium dioxide, zinc oxide, iron oxide). In some other embodiments, the majority of the STAR particle is made from one or more such ceramic materials.

[0045] In some embodiments, all or substantially all of the structure of the microneedle particle is made of a bioactive agent and / or another substance of interest, hi some embodiments, the majority of the STAR particle is made of one or more drugs.

[0046] In some embodiments, the STAR particle is an excipient microneedle particle, wherein all or substantially all of the structure of the microneedle particle is made from one or more pharmaceutically acceptable excipient materials known in the art (e.g., sugars, salts, starches, etc.).

[0047] In some embodiments, the STAR particles have a structure formed from a combination of (i) at least one metal (or metal alloy), (ii) at least one polymeric material, (iii) at least one ceramic material, and / or (iv) at least one bioactive component.

[0048] The STAR particles provided herein can be made by any suitable method capable of forming the desired geometric shape of the STAR particle. Non-limiting examples of such methods include molding, mechanical or chemical etching, laser cutting, 3D printing, or other microfabrication techniques known in the art. For example, the STAR particle can be formed by laser etching a sheet of material. As a further example, the STAR particle can be made using a molding process that can include placing a build material into a mold having a cavity corresponding to the desired geometric shape of the resulting STAR particle. The build material can be a polymer or its precursor, which can be loaded into the mold in powder or liquid form (e.g., molten polymer and / or polymer dissolved or dispersed in a vehicle) and then solidified into a monolithic solid form in the mold. In another example, an array of discrete particles is formed from a sheet of solid material by a process that includes at least one of etching, punching, or cutting, such as laser cutting. The STAR particle can also be sintered, densified, and / or mechanically hardened via heating, cooling, chemical modification, exposure to light, drying, compression, and / or other processes.

[0049] Composition containing STAR particles In various embodiments, the STAR particles are provided as a composition that facilitates application of the STAR particles to a target tissue site, e.g., a biological tissue surface such as the skin of a mammal. For example, the composition may comprise or consist of STAR particles dispersed in a suitable medium that can flow. The medium may be a liquid, solution, lotion, cream, ointment, gel, paste, emulsion, aerosol foam or spray, powder, or semi-solid. A suitable medium is referred to herein as a "vehicle."

[0050] Essentially any suitable biocompatible vehicle can be used in the STAR particle-containing composition. The vehicle can be an aqueous medium and / or a non-aqueous medium. The vehicle can contain water, stabilizers, pH adjusters, thickeners, or other pharmaceutically acceptable excipients known in the art for use in topical therapeutic applications, including materials listed as Generally Recognized as Safe (GRAS) by the U.S. Food and Drug Administration.

[0051] The STAR particle-containing composition may comprise one or more bioactive agents (e.g., therapeutic or prophylactic agents) and / or other substances of interest (e.g., diagnostic agents, sensors, cosmetics / functional cosmetics). The bioactive agents and / or other substances of interest may be disposed in or on the STAR particle, in the vehicle, or in or on both the STAR particle and the vehicle. In some embodiments, the bioactive agent is dissolved in the vehicle. In some embodiments, the bioactive agent is dispersed, i.e., dispersed in the vehicle as a particle suspension.

[0052] A STAR particle-containing composition generally has a viscosity suitable for its intended storage, packaging, and use (e.g., application to a target tissue). In some embodiments, the STAR particle-containing composition is a viscous composition, e.g., the vehicle of the composition has a viscosity of at least 100 cP. In some embodiments, the composition or 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 STAR particle-containing composition is a non-viscous composition having a viscosity of less than 100 cP, e.g., 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 STAR particle-containing composition has a viscosity of about 1 cP.

[0053] The concentration of STAR particles in the vehicle can be selected based on the particular application, but is generally selected to achieve the intended function of the STAR particles at a particular tissue site. For example, the concentration of STAR particles can be selected to be sufficient to create sufficient pores in the stratum corneum to deliver a therapeutically effective amount of a bioactive agent to the skin at the site of application of the STAR particle-containing composition.

[0054] In some embodiments, the concentration of STAR particles in the vehicle is 1 cm per vehicle. 3 In some embodiments, the concentration of STAR particles in the vehicle ranges from about 100 to about 100,000 particles per cm of vehicle. 3 In some embodiments, the concentration of STAR particles in the vehicle ranges from about 500 to about 50,000 particles per cm of vehicle. 3 In some embodiments, the concentration of STAR particles in a vehicle ranges from about 1,000 to about 25,000 particles per cm of vehicle. 3 In some embodiments, the concentration of STAR particles in the vehicle is greater than 10,000 particles per cm of the vehicle. 3 Lower than 10,000 particles per

[0055] In some embodiments, the concentration of the STAR particles in the vehicle ranges from about 0.1% to about 30% by weight of the vehicle. In some embodiments, the concentration of the STAR particles in the vehicle ranges from about 1% to about 20% by weight of the vehicle. In some embodiments, the concentration of the STAR particles in the vehicle ranges from about 5% to about 15% by weight of the vehicle. In some embodiments, the concentration of the STAR particles in the vehicle ranges from about 8% to about 12% by weight of the vehicle. In some preferred embodiments, the concentration of the STAR particles in the vehicle is from about 5% to about 10% by weight of the vehicle.

[0056] The STAR particle composition may also contain at least one substance of interest. As used herein, "substance of interest" refers to a collection of molecules or substances with preventive, therapeutic, diagnostic, or cosmetic purposes. Substances of interest may include, but are not limited to, active pharmaceutical ingredients, vaccines, allergens, vitamins, cosmetic agents, functional cosmetics, diagnostic agents, sensors, markers (e.g., color dyes or radioactive dyes or markers), other bioactive agents, and other materials that are desirable to introduce into or onto biological tissue. A list of substances of interest is included in U.S. Pat. No. 11,291,816, which is incorporated herein by reference.

[0057] The substance of interest can be a small molecule, polymer, peptide, or biological agent. In some embodiments, the substance of interest is a biological agent or organism. In further embodiments, the substance of interest has electronic properties. For example, the substance of interest can respond to radio frequency identification (RFID).

[0058] Methods for stabilizing STAR particles and STAR particle-containing compositions STAR particles and STAR particle-containing compositions may be susceptible to degradation during manufacturing, 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 functional or non-functional state and / or (ii) a less safe or unsafe state. Here, a functional state refers to a state in which the STAR particle is able to perform some intended function. A less functional or non-functional state refers to the loss of the ability to perform its intended function, but does not imply that the STAR particle is unable to perform any other function.

[0059] In some embodiments, the STAR particle, vehicle, and / or substance of interest may degrade and / or lose functionality as a result of an external stimulus. As used herein, "external stimulus" refers to any condition applied to the STAR particle, vehicle, and / or substance of interest that results in a change in the functionality, usefulness, 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) a change in temperature, (c) a change in pressure, (d) the addition, modification, or removal of chemicals, (e) the application of ultrasound, (f) the application of electromagnetic radiation (e.g., ultraviolet, visible light, infrared), (g) the application of electric and / or magnetic fields, (h) exposure to atmospheric conditions (e.g., oxygen), (i) the application of mechanical forces (e.g., compression, tension, shear), (j) exposure to target tissue, etc.

[0060] In other embodiments, the STAR particle, vehicle, and / or substance of interest may decompose as a result of 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.

[0061] The STAR particles can be adapted to degrade after their application and use. The term "degrade" in this context refers to the loss of the ability to mechanically disrupt biological tissue. Such functional loss can be caused by one or more of the building blocks of the STAR particles undergoing a phase change and / or degradation, such that the STAR particles no longer have the mechanical strength or structural dimensions necessary to mechanically disrupt biological tissue, for example, to form pores in the stratum corneum. Such degradation can be caused (i) by a selected change in the pH, osmolality, temperature, or ionic composition of the vehicle, and / or (ii) in response to an external stimulus.

[0062] As described herein, STAR particles, vehicles, and / or substances of interest can be stabilized to reduce and / or substantially delay their likelihood of degradation. As used herein, "stabilization" refers to the complete or partial inhibition of degradation processes to maintain the functionality of the STAR particle, vehicle, and / or substance of interest. Stabilization can be achieved by the addition of a stabilizing compound, the presence of certain inherent or external conditions, and / or the application of an external stimulus to the STAR particle, vehicle, and / or substance of interest.

[0063] Degradation of STAR particles can result in premature loss of functionality, i.e., unintentional inactivation. As used herein, the phrase "unintentional inactivation" with respect to a STAR particle refers to the loss of the ability of the STAR particle to mechanically disrupt or pierce the stratum corneum (or other tissue) prior to intended use.

[0064] In some embodiments, only the vehicle and / or the substance of interest may be susceptible to degradation as a result of physical and / or chemical changes. A comprehensive list of physical and chemical changes that can cause destabilization can be found in "Drug stability for pharmaceutical scientists" (Thorsteinn Loftsson, Academic Press 2014). In one embodiment, instability at the molecular level can destabilize the vehicle and / or the substance of interest. Molecular instability is described in "Overview of pharmaceutical excipients used in tablets and capsules" (RH Dave, Drug Topics 2008). In another embodiment, instability that causes degradation occurs at a non-molecular level, examples of which are described in "Pharmaceutical Suspensions—From Vehicle Development to Manufacturing" (AK Kulshreshtha et al., Springer 2010).

[0065] Thus, the subject vehicle and / or composition of matter may be formulated to include antioxidants, buffers, emulsifiers, sugars, carbohydrates, and / or other agents known in the art to be effective in physically and / or chemically stabilizing pharmaceutical ingredients that may be included in the STAR particle or STAR particle-containing composition vehicle. For example, a list of stabilizers and stabilization methods can be found in "Pharmaceutical Dosage Forms and Drug Delivery Systems" (LV Allen, Wolters Kluwer Health 10 th Ed.), “Drug Stability for Pharmaceutical Scientists” (T. Loftsson, Academic Press, 1 stEd), and “The development of microgels / nanogels for drug delivery applications” by JK Oh, Progress in Polymer Science (2008) 33(4) pp. 448-477, which are incorporated herein by reference.

[0066] In some embodiments, the STAR particle-containing composition, vehicle, and substance of interest may become destabilized. For example, the substance of interest may prematurely diffuse from the STAR particle into the vehicle. In another example, the substance of interest may degrade within the STAR particle and / or within the formulation. In yet another example, a substance of interest designed to disperse within the vehicle may be undesirably absorbed by the STAR particle and / or storage container, resulting in destabilization of the STAR particle, loss of efficacy of the formulation, and / or loss of the substance of interest. In yet another example, a substance of interest designed to be coated on and / or in the STAR particle may prematurely dissolve and / or leach from the STAR particle prior to intended use.

[0067] In some embodiments, STAR particles may become destabilized during storage. For example, STAR particles may aggregate, weaken, break, deform, chemically destabilize, swell, change size, change shape, change hardness, change porosity, and / or dehomogenize within the vehicle. Such destabilization can be controlled as described below.

[0068] In some embodiments, the vehicle or STAR particles may be inherently prone to aggregation. Figure 2 shows a plurality of aggregated STAR particles 200. A vehicle containing STAR particles may dry, increasing the concentration of STAR particles within the vehicle. This increase in concentration may result in closer spatial proximity of the STAR particles within the vehicle, thereby increasing the likelihood of STAR particle-to-STAR particle interactions and aggregation. STAR particles may also have magnetic dipoles and / or electrostatic charges, and the presence of these dipoles and / or charges increases the likelihood of STAR particle-to-STAR particle interactions. Ion concentrations within the vehicle may also cause changes in the surface charge of the STAR particles, increasing the likelihood of aggregation. STAR particles may also have chemical modifications on their surfaces that give them adhesive properties that may further cause them to aggregate when they are in close proximity to one another.

[0069] In some embodiments, the agglutination can be caused by a chemical reaction. In some embodiments, the chemical reaction is a reaction of at least one reagent contained within the vehicle. Alternatively, the reagent is not contained within the vehicle, but rather is added by the user when applying the STAR particles. In some embodiments, the chemical reaction is a reaction of at least one encapsulated reagent contained within the vehicle. The encapsulated reagent can react with either an encapsulated or a non-encapsulated reagent.

[0070] An external stimulus may be applied, intentionally or inadvertently, to the STAR particle-containing composition, which external stimulus causes aggregation. In some embodiments, the force of applying the STAR particle-containing composition to a tissue surface may cause aggregation or may deform the STAR particles in a way that increases their likelihood of aggregation (e.g., when their tips bend and form hook-like structures that can mechanically bind with other STAR particles). In some embodiments, STAR particles 300 can interact with the physical and / or chemical properties of the target tissue, increasing the likelihood of aggregation or causing aggregation.

[0071] 3A-3D show methods of preventing and / or breaking up agglomeration. In general, agglomeration can be prevented by minimizing the likelihood and / or strength with which STAR particles 300 interact with other STAR particles 300, the container in which the STAR particles 300 are stored, and / or materials or compositions within the vehicle in which the STAR particles 300 are dispersed.

[0072] In some embodiments, reducing the likelihood of interaction between STAR particles 300 can be effective in reducing and / or preventing aggregation, as shown in Figures 3A-3C. For example, as shown in Figure 3A, reducing the concentration of STAR particles 300 in the vehicle (i.e., increasing the average spacing between particles) can be effective in reducing the likelihood of interaction between STAR particles 300. If STAR particles 300 are less likely to come into contact with each other, aggregation is less likely to occur.

[0073] 3B shows an embodiment in which repulsive forces 370 between STAR particles 300 are effective to maintain a relatively uniform distribution of the STAR particles within the vehicle. In some embodiments, the repulsive forces 370 are electrostatic forces. In some embodiments, the repulsive forces are magnetic forces. In some embodiments, the repulsive forces are the result of steric hindrance. In some embodiments, the STAR particles may be at least partially or fully encapsulated in a material that limits the ability of the STAR particles to aggregate and / or interact via 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 that are not soluble in the vehicle, or combinations thereof. The material used to encapsulate the STAR particles may subsequently undergo degradation if aggregation of the STAR particles is desired.

[0074] In some embodiments, the STAR particles may also be lubricated to prevent interactions between the STAR particles that could lead to agglomeration. In some embodiments, at least one compound in the vehicle lubricates the STAR particles. In some embodiments, the STAR particles are coated with and / or encapsulated in a lubricant. In some embodiments, the surface energy of the STAR particles acts as a lubricant and prevents interactions between the STAR particles.

[0075] The vehicle in which the STAR particles are dispersed can be effective in preventing aggregation. In some embodiments, the viscosity of the vehicle is effective in preventing the STAR particles from aggregating. That is, the viscosity of the vehicle is high enough to restrict the movement of the STAR particles within the vehicle. In some embodiments, as shown in FIG. 3C, the vehicle includes a dispersant 360, which can reduce interactions between STAR particles 300 and prevent aggregation. As used herein, a "dispersant" or "dispersing agent" is a substance, typically a surfactant, added to a suspension of solid or liquid particles in a liquid (such as a colloid or emulsion) to improve particle separation and prevent their settling or aggregation. Various suitable dispersants known in the art can be used with STAR particles; pharmaceutically acceptable dispersants include, but are not limited to, acacia, tragacanth, bentonite, carbomer, cellulose, dextrin, maltodextrin, gelatin, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, hyaluronic acid, pectin, and / or starch. Other agents commonly known in the art can be found in official USP monographs. In some embodiments, minimizing turbulence and / or maintaining laminar flow within the vehicle can reduce the likelihood of STAR particle migration. If the STAR particles are less likely to migrate, aggregation can be reduced or eliminated.

[0076] In some embodiments, as shown in Figure 3D, STAR particles 300 may be weakly aggregated (shown to the left of the arrow). Weakly aggregated STAR particles 300 may be disrupted after application of an external stimulus 380 (shown to the right of the arrow). For example, the storage container containing the STAR particles and vehicles may be shaken manually or with a suitable mixing or vibrating device known in the art to break up any aggregates that occur.

[0077] Some STAR particles may be inherently mechanically fragile or may weaken over time, for example as a result of exposure to other materials, such as the vehicle, the substance of interest, or any other components present in the vehicle or storage container. Such STAR particles may be destroyed upon collision with other STAR particles and / or the walls of a storage container in which the STAR particle-containing composition is located. In some embodiments, fluid flow within the vehicle may also cause STAR particles to break down. In some embodiments, contact with other STAR particles or the storage container, or fluid flow of the vehicle, may cause unweakened STAR particles to break down.

[0078] In some embodiments, as shown in FIG. 4A, the STAR particle 400 may have a coating 430 that prevents weakening and / or breakage of the microneedles 420 or otherwise improves the mechanical strength of the STAR particle 400. For example, if the STAR particle is susceptible to weakening by aqueous solutions, the coating may be hydrophobic, or vice versa. The coating may also function as a barrier to prevent fluids from contacting the STAR particle. The coating may also be composed of a mechanically strong but brittle sacrificial material that breaks, disintegrates, and / or cracks upon contact with another substance, 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 strong," used to compare a material coating a STAR particle with the underlying material forming the STAR particle, means that the coating material is better able to withstand an applied load without breaking or plastic deformation than the underlying structural material. For example, the coating material may have a higher compressive strength than the underlying structural material.

[0079] 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. For example, in one embodiment shown in FIG. 4B, the walls of the storage container are coated with a coating 430 to delay contact and / or adhesion between the container and STAR particles 400. For example, the coating may be a lubricant, may have an electrical charge that repels the STAR particles, or may be a material that is relatively softer than the construction material of the container and / or STAR particles. The repulsive properties may be inherent or may be enhanced by the presence of a coating. Exemplary coatings may include, but are not limited to, polymers (e.g., polyvinyl alcohol, poly(ethyleneimine), poly(methyl methacrylate)), biopolymers (e.g., deoxynucleic acid, ribonucleic acid, polyamino acids such as poly(L-lysine), chitosan), proteins, ceramics (metal oxides), metals, sugars, and / or other excipients commonly known in the art.

[0080] The materials forming the STAR particle, or at least an outer portion thereof, and the vehicle can be selected or formulated to prevent degradation of the STAR particle in the vehicle. For example, as shown in FIG. 5A, the STAR particle 500 is insoluble in the vehicle 540. In some cases, for example, the STAR particle is formed from one or more materials that are substantially insoluble in water, and the vehicle is an aqueous vehicle. In some other cases, for example, the STAR particle is formed from one or more water-soluble materials, and the vehicle is not an aqueous vehicle. In some other cases, the STAR particle can be formed from a material (such as a water-soluble material) that is subsequently coated with a water-insoluble coating material, and the vehicle is an aqueous vehicle, where the coating material acts as a barrier to prevent dissolution of the water-soluble material of the STAR particle dispersed in the aqueous vehicle. In a similar variation, as shown in FIG. 5B, the STAR particle 500 is encapsulated in an encapsulating material 545 that is insoluble in the vehicle 540.

[0081] In some preferred embodiments, the STAR particles are made of one or more water-soluble materials but have a coating thereon that is substantially water-insoluble, so that the STAR particles do not dissolve during storage or use, and the coating is configured to later dissolve, thereby inactivating the STAR particles (as used). For example, the coating can be made of a material that is water-insoluble at low pH but water-soluble at neutral pH. Such materials, such as Eudragit™ polymers, are known in the art.

[0082] In some embodiments, the vehicle is not a solvent for the constituent materials of the STAR particle, in some other embodiments, the vehicle is a solvent for the STAR particle material, but the vehicle is saturated or supersaturated with dissolved material (solute), so that no additional material (i.e., material from any STAR particle) can be dissolved in the vehicle.

[0083] 6A-6C show STAR particles dehomogenized within a vehicle. In FIG. 6A, the STAR particles 600 settle from the vehicle at or near the bottom of the storage container 640. In FIG. 6B, the STAR particles 600 float at or near the top of the storage container 640. In FIG. 6C, the STAR particles 600 adhere to the wall of the storage container 640. If the average density of the STAR particles is greater than the average density of the vehicle being moved by the STAR particles, or if the force exerted by the STAR particles on the vehicle exceeds the force exerted by the vehicle on the STAR particles (i.e., net buoyancy), the STAR particles may settle to the bottom of the storage container. If the average density of the STAR particles is less than the average density of the vehicle being moved by the STAR particles, the STAR particles may float to the top of the storage container. For example, the net buoyancy can be altered by increasing the average density of the vehicle. Alternatively or additionally, the average density of the STAR particles may be decreased.

[0084] As used herein, the term "density" refers to mass per volume, and "average density" refers to the average value of density.

[0085] STAR particles can be porous. In a preferred embodiment, the STAR particles are composed of ceramic materials (e.g., alumina, titania, zinc oxide, magnesium oxide) that form a microscopically porous ceramic structure in the sintered state. Similarly, polymeric STAR particles can be fabricated that form a microscopically porous structure. The average density of the STAR particles can be modified by increasing the porosity of the STAR particles so that air or gas pockets remain trapped inside the STAR particles. Modifying the porosity of the STAR particles can be achieved by changing the ceramic or polymer particle size, sintering or heating temperature, processing conditions, and / or ceramic or polymer formulation. The average density of the STAR particles can also be modified by modifying the materials used to fabricate the STAR particles. The net buoyancy of the STAR particles can also be modified by changing the geometry or size of the STAR particles. For example, larger STAR particles displace more vehicle volume, while smaller STAR particles displace less vehicle volume, thereby changing the net buoyancy.

[0086] STAR particles that adhere to the walls of the storage vessel may be more prone to agglomeration. A non-uniform distribution of STAR particles within a particular spatial concentration or storage vessel can often be undesirable. Rather, it is generally preferable for the STAR particles to be approximately uniformly dispersed within the vehicle.

[0087] To help maintain a uniform dispersion of the STAR particles within a vehicle, e.g., a storage container, various techniques can be used to slow dehomogenization of the STAR particles. In some embodiments, the vehicle composition is adjusted to match the density of the STAR particle density, and / or a suitable dispersant or other additive is included in the vehicle to mitigate or prevent the STAR particles from settling or floating or adhering to the walls of the container. In Figure 7A, additive 735 is included in the vehicle so that STAR particles 700 remain uniformly dispersed within the vehicle. In Figure 7B, the walls of storage container 740 are coated with material 730 to prevent the STAR particles from adhering to the interior walls of storage container 740.

[0088] Preferably, a composition of STAR particles dispersed in a fluid vehicle maintains a substantially uniform dispersion even when the average densities of the STAR particles and vehicle differ from one another. In this context, the term "maintain" refers to a period of time long enough to be useful after manufacture, including shipping and storage prior to use by an end user. For example, the period can range from a few weeks to a year or more, e.g., 2 weeks to 48 weeks.

[0089] Embodiment Some embodiments of the present disclosure can be described in consideration of one or more of the following. Embodiment 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 containing the vehicle and the STAR particles, wherein the STAR particles, vehicle, and container are configured to maintain a substantially uniform dispersion of the STAR particles within the vehicle and within the container.

[0090] Embodiment 2. A packaged STAR particle composition according to embodiment 1, wherein the STAR particle and the vehicle have similar average densities.

[0091] Embodiment 3. A packaged STAR particle composition according to any one of embodiments 1 or 2, wherein the vehicle has a viscosity effective to prevent or limit dehomogenization of the STAR particles, even when the average densities of the STAR particles and the vehicle differ from each other.

[0092] Embodiment 4. A packaged STAR particle composition according to any one of embodiments 1 to 3, wherein the vehicle comprises at least one dispersant.

[0093] Embodiment 5. A packaged STAR particle composition according to any one of embodiments 1 to 4, wherein the walls of the container in contact with the vehicle have surface properties that inhibit adhesion of the STAR particles, optionally, for example, the walls of the container have a coating that is effective to inhibit adhesion of the STAR particles.

[0094] 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 effective to prevent or limit aggregation of the STAR particles.

[0095] Embodiment 7. A packaged STAR particle composition according to any one of embodiments 1 to 6, further comprising at least one salt compound adapted to reduce the Debye length of the charge of the STAR particle.

[0096] Embodiment 8. A packaged STAR particle composition according to any one of embodiments 1 to 7, further comprising a surfactant adapted to inhibit interactions between hydrophobic or hydrophilic surfaces on the STAR particles.

[0097] 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 dispersion of the STAR particles within the vehicle and / or limit dehomogenization.

[0098] 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, the vehicle comprising a solvent for the first material, the composition being configured such that the plurality of STAR particles are resistant to dissolution and / or unintentional inactivation within the vehicle.

[0099] Embodiment 11. The composition of either embodiment 9 or 10, wherein the STAR particle has a coating thereon that is substantially insoluble in the solvent of the vehicle.

[0100] Embodiment 12. The composition of any one of embodiments 9 to 11, wherein the STAR particles are encapsulated in an encapsulating material that is substantially insoluble in the solvent of the vehicle.

[0101] Embodiment 13. The composition of any one of embodiments 9 to 12, wherein the vehicle is saturated with a solute effective to prevent or limit dissolution of the first material in the solvent of the vehicle.

[0102] Embodiment 14. The composition of any one of embodiments 9 to 13, wherein the structure of the STAR particle is further formed from a second material that is substantially insoluble in the solvent of the vehicle.

[0103] 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 application and use (i) by a selected change in pH, osmolality, temperature or ionic composition of the vehicle, or (ii) by response to an external stimulus.

[0104] Embodiment 16. The composition of embodiment 15, wherein the external stimulus comprises exposure to atmospheric oxygen, light, or water.

[0105] Embodiment 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 containing the vehicle and the STAR particles, wherein the walls of the container in contact with the STAR particles and / or the vehicle are coated with a buffer material that is more deformable than the material forming the STAR particles and / or the walls of the container.

[0106] Embodiment 18. A composition comprising a plurality of STAR particles configured to mechanically disrupt biological tissue, the STAR particles having a surface coating composed of a material that is mechanically stronger than the underlying material forming the STAR particles.

[0107] Embodiment 19. The composition of embodiment 18, wherein the underlying material comprises an organic material and the surface coating material comprises an inorganic material.

[0108] Embodiment 20. The composition of any one of embodiments 1 to 19, wherein the composition comprises a substance of interest (SOI).

[0109] Embodiment 21. A composition described in any one of embodiments 1 to 20, wherein the SOI comprises a bioactive agent.

[0110] Embodiment 22. A composition according to any one of embodiments 1 to 21, wherein the SOI is located in and / or on the STAR particle.

[0111] Embodiment 23. A composition according to any one of embodiments 1 to 22, wherein the SOI is located within a vehicle.

[0112] 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 surface of the skin, and manipulating the composition to cause the STAR particles to mechanically disrupt the surface of the skin.

[0113] Embodiment 25. A STAR particle composition comprising a plurality of STAR particles configured to mechanically disrupt biological tissue, a plurality of SOI particles spaced apart from the plurality of STAR particles, and a liquid vehicle in which the plurality of STAR particles and the plurality of SOI particles are dispersed.

[0114] Embodiment 26. The composition of embodiment 25, wherein the STAR particles and / or SOI particles have a coating thereon that is effective to substantially prevent dissolution of the STAR particles and / or SOI particles in the liquid vehicle.

[0115] 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 or second liquid phase, and a substance of interest (SOI) is provided in the first or second liquid phase.

[0116] 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.

[0117] Embodiment 29. A composition according to either embodiment 27 or 28, wherein the STAR particles are dispersed in only one of the first or second liquid phases, and the SOI is dissolved in the other of the first or second liquid phases.

[0118] Embodiment 30. (i) the STAR particles are dispersed in only the first liquid phase, and the SOI is dissolved (or otherwise provided) in the first and second liquid phases; (ii) the STAR particles are dispersed in the first and second liquid phases, and the SOI is dissolved (or otherwise provided) in only the first liquid phase; (iii) the SOI is dissolved (or otherwise provided) in the first and second liquid phases, and the STAR particles are dispersed in only the second liquid phase; (iv) the STAR particles are dispersed in the first and second liquid phases, and the SOI is dissolved (or otherwise provided) in the second liquid phase. 30. The composition of any one of embodiments 27-29, wherein (i) the STAR particles are dispersed in the first and second liquid phases and the SOI is dissolved (or otherwise provided) only in the first liquid phase; (ii) the STAR particles are dispersed in the second liquid phase; (iii) the STAR particles are dispersed in the first and second liquid phases and the SOI is dissolved (or otherwise provided) in the first and second liquid phases.

[0119] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the content clearly dictates otherwise. As used herein, the term "about" indicates that a given quantity value can include an amount within a range of within 10% of the stated value, or optionally within 5% of the value, or in some embodiments, within 1% of the value.

[0120] 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. 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 containing the vehicle and STAR particles; A composition 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. 10. The packaged STAR particle composition of claim 1, wherein the STAR particles and the vehicle have similar average densities.

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

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

5. 2. 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, and optionally, for example, the container wall has a coating that is effective in inhibiting adhesion of the STAR particles.

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

7. 7. The packaged STAR particle composition of claim 6, further comprising at least one salt compound adapted to reduce the Debye length of the charge of the STAR particles.

8. 7. The packaged STAR particle composition of claim 6, further comprising a surfactant adapted to inhibit interactions between hydrophobic or hydrophilic surfaces on the STAR particles.

9. 1. A composition comprising: a plurality of STAR particles, and a vehicle in which the plurality of STAR particles are dispersed; A composition 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 dehomogenization.

10. 1. 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, the vehicle comprising a solvent for the first material; The composition is configured such that the plurality of STAR particles are resistant to dissolution and / or unintentional inactivation within the vehicle.

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

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

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

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

15. 1. A composition comprising: a plurality of STAR particles, and a vehicle in which the plurality of STAR particles are dispersed; A composition wherein the STAR particles are adapted to degrade after application and use (i) by a selected change in the pH, osmolality, temperature or ionic composition of the vehicle, or (ii) by responding to an external stimulus.

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

17. 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 containing the vehicle and STAR particles; A composition wherein the walls of the container in contact with the STAR particles and / or the vehicle are coated with a buffer material that is more deformable than the material forming the STAR particles and / or the walls of the container.

18. 1. A composition comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue; A composition wherein the STAR particles have a surface coating composed of a material that is mechanically stronger than the underlying material forming the STAR particles.

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

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

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

22. 21. 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 within the vehicle.

24. 1. A method of administering a substance of interest (SOI) to the skin of a patient, said method comprising: applying the composition of claim 20 to the surface of the skin; and manipulating said composition to cause said STAR particles to mechanically disrupt the surface of said skin.

25. 1. A STAR particle composition comprising: a plurality of STAR particles configured to mechanically disrupt biological tissue; a plurality of SOI particles spaced apart from the plurality of STAR particles; and a liquid vehicle in which the plurality of STAR particles and the plurality of SOI particles are dispersed.

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

27. 1. 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; the plurality of STAR particles are dispersed in the first or second liquid phase; A composition wherein a material of interest (SOI) is provided in said first or second liquid phase.

28. 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. 28. 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. (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) the SOI is provided 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) the SOI is provided only in the first liquid phase, and the STAR particles are dispersed only in the second liquid phase; or (vii) The composition of claim 27, wherein the STAR particles are dispersed in the first liquid phase and the second liquid phase, and the SOI is disposed in the first liquid phase and the second liquid phase.

31. (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) the SOI is provided 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 composition of claim 30, wherein the SOI is provided solely in the first liquid phase and the STAR particles are dispersed solely in the second liquid phase.

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