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Nanoclusters for delivery of therapeutics

Nanoclusters for delivery of therapeutics description/claims

This application claims the benefit of U.S. Provisional Application No. 60/751,172, filed Dec. 16, 2005, the contents of which are incorporated by reference.

A. Field of the Invention The present invention relates generally to delivery vehicles that can be used to transport active ingredients to a subject. In certain aspects, the delivery vehicles can be nano-clusters that can be used in preventative or therapeutic applications.

B. Background of the Invention

Millions of people worldwide suffer from a wide variety of diseases or conditions that would benefit from the effective delivery of therapeutic and or preventative agents. Examples of these diseases or conditions include pulmonary diseases, circulatory diseases, muscular diseases, bone diseases, cancers, etc.

The use of nano-particles as drug delivery vehicles has been employed for a variety of indications (John 2003). Nano-particles, for example, have been shown to improve the dissolution of poorly water-soluble drugs and enhance the transport of drugs both intra- and paracellularly. In addition, literature indicates that plasmid DNA can be effectively delivered by polycantionic polymers that form nano-particles when mixed with DNA resulting in enhanced gene expression (Kumar 2003). Research efforts on nano-particle-mediated gene therapy also address treating genetic disorders such as Cystic Fibrosis (Griesenbach 2004).

Most nano-particle formulations are designed for action at the cellular level. This assumes the efficient delivery of the nano-particle to the appropriate cellular target. However, current nano-particle treatment options are limited in the ability to access the cellular target. For example, two research groups are currently investigating microencapsulated nano-particles as a mode of nano-particle delivery to the pulmonary epithelium (Sham 2004, Grenha 2005). These efforts are hindered by the common inability to control microparticle size, distribution, and difficulty in delivering a large payload of therapeutic nano-particles.

The present invention overcomes the deficiencies in the art by providing effective drug delivery systems that can: (1) formulate nano-particles as a nano-cluster to facilitate handling, administering, or targeting, for example; and (2) maintain the cluster or disperse the nano-particles at the targeted site.

In one aspect of the present invention, there is disclosed a nano-cluster comprising a plurality of nano-particles. In certain non-limiting aspects, the nano-cluster is maintained at the targeted site (e.g., the nano-cluster does not disperse into separate nano-particles). In other aspects, the nano-particles disperse in response to an environmental cue. The nano-cluster, in certain non-limiting embodiments, can have a size of about 1 to about 200 microns. In certain aspects, the nano-cluster size is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 microns. In other aspects, the size of the nano-cluster can be greater than 200 microns (e.g., 210, 220, 230, 240, 250, 300, 350, 400, 450, 500, 600, 700, or more microns in size.) The nano-cluster of the present invention can also have a variety of shapes (e.g, spherical and non-spherical shapes). In certain embodiments, the nano-cluster can be solid or hollow. A person of ordinary skill in the art will recognize that a solid nano-cluster can be completely solid throughout or can have spaces, such as pores or a hollow core, that are created by the packing of the nano-particles within the nano-cluster. The size of these packing spaces can be from about 1 nm to about 1000 nm, in non-limiting aspects. In certain aspects, the size of the packing spaces can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 or more nanometers, in non-limiting aspects. Hollow nano-clusters can have an empty space or cavity. The size of the cavity can vary, for example, from about 50 m to about 20 μm, in non limiting aspects. The size of the cavity, for example, can be 50, 100, 150, 200, 250, 300, 3500, 400, 450, 500, 550, 600, 650, 700, 750, 800 . . . 20 μm, and any range derivable therein.

The nano-particles that are included in the nano-cluster, in some embodiments, are not held (e.g., adhered or chemically bound (e.g., covalent bond, non-covalent bond, van der waals forces)) together by a functional group on the nano-particles. The nano-particles can be in direct contact with one another in some aspects. In other aspects, the nano-particles are not in direct contact with one another. In certain embodiments of the present invention, the nano-particles are not encapsulated. In other embodiments, the nano-particles do not include a functional group. In other aspects, however, the nano-particles can include a functional group such as, for example, a carboxyl, sulhydryl, hydroxyl, or amino group. All types of functional groups that can be used to bind other nano-particles together, active ingredients to the surface of nano-particles, or other compounds are contemplated as being useful with the present invention.

In certain embodiments, the nano-cluster can include an active ingredient. Non-limiting examples of active ingredients that are contemplated as being useful in the context of the present invention include those known to a person of ordinary skill and those described throughout this specification. By way of example only, active ingredients can include medical pharmaceuticals and specialties such as preventive agents, for example vaccines, diagnostic agents, for example tracers of various types and imaging enhancers, therapeutic agents, for example small molecules (e.g., nucleic acids, proteins, peptides, polypeptides, etc.), drugs, peptides, and radiation, immuno-modulators, vaccine and virus vectors, and combinations of these classes. The nano-particles can include particular embodiments, respirable non-medical specialties such as physiochemical agents, for example gas antidotes, biophysical modulators, for example paramagnetics, emitters, for example electromagnetic wave emitters, and imaging enhancers. The active ingredients, in certain embodiments, can be associated with the nano-particles. For example, the active ingredients can be entangled, embedded, incorporated, encapsulated, bound to the surface (e.g., covalently or non-covalently bonded), or otherwise associated with the nano-particle. In certain preferred aspects, the active ingredient is the nano-particle. In other aspects, the nano-particles can include a polymer material (including, for example, biodegradable and non-biodegradable polymers). Non-limiting examples of polymer materials that can be used include those known to a person of ordinary skill and those described throughout this specification. In certain embodiments, the nano-particles can include a mixture of a polymer and an active ingredient.

In other non-limiting embodiments, the nano-cluster or nano-particles, or both, can include at least one, two, three, four, five, six, seven, or more different active ingredients. In a preferred embodiment, the nano-cluster or nano-particles include a first drug on its surface, and a second active ingredient encapsulated within the nano-cluster or nano-particles or other incorporated into the nano-cluster or nano-particle material. It is contemplated that a nano-cluster can release the active ingredients in a given environment, or after a given period of time in a controlled manner. For example, a nano-cluster having at least one active ingredient can be released in response to an environmental cue or after a pre-determined amount of time. Also by way of example only, a nano-cluster having at least two different active ingredients can be released in response to different environmental cues or after pre-determined periods of time. For example, active ingredient 1 can be released first and then active ingredient 2 can be released second. In certain non-limiting aspects, the release of the first active ingredient can improve the performance of the second active ingredient.

In other particular aspects, the nano-clusters of the present invention can include a dispersing material that holds the plurality of nano-particles together and/or disperses the nano-particles in response to an environmental cue. The dispersing materials that can be used with the present invention include those materials that are known to a person of skill in the art and those that are disclosed throughout this specification. Non-limiting examples of dispersing material include liquid sensitive materials (e.g., water-soluble materials (e.g., polymers)), biodegradable polymers, polyelectrolytes, metals, surfactants, polymeric cross-linkers, small molecule cross-linkers, pH sensitive materials, pressure sensitive materials, enzymatic sensitive materials, and temperature sensitive materials. Non-limiting examples of environmental cues that can be used with the present invention include liquid (e.g., water, blood, mucous, solvent, etc.), a selected pH range, a selected temperature range, an electric current, a selected ionic strength, pressure, the presence of a selected enzyme, protein, chemical, electromagnetic wavelength range (e.g., visible light, UV light, infrared, ultraviolet light, microwaves, X-rays, and gamma-rays), or the presence of an external force (e.g., vibration, shearing, shaking, etc.). In certain aspects, the dispersing material can be coated onto the surface of the nano-particles before or after nano-cluster formation. In certain embodiments, the dispersing material can be between the nano-particles or link the nano-particles together (e.g., covalently or non-covalently couple a first nano-particle to a second nano-particle). The dispersing material can be adhered to or covalently or non-covalently coupled to the nano-particles.

In particular embodiments of the present invention, the nano-cluster can include from about 1% to about 99% by weight or volume of the nano-particles or dispersing materials. The nano-cluster can also be completely made up of nano-particles (i.e., 100%). In preferred embodiments, the nano-cluster includes from about 10% to about 90%, 15% to about 80%, 20% to about 70%, 30% to about 60%, and about 40% to about 50% of nano-particles or dispersing materials. In certain embodiments, the nano-cluster includes at least 50% of the nano-particles or dispersing material.

Another embodiment to the present invention is a composition comprising a nano-cluster of the present invention. The composition in certain non-limiting aspects can have a plurality (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, or more nano-clusters. The composition can further include an active ingredient. As discussed throughout this specification, the composition can be formulated into a dry powder, an aerosol, a spray, a tablet, or a liquid. The compositions of the present invention can include at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nano-clusters of the present invention. In certain aspects, the compositions of the present invention can include a plurality of identical or similar nano-clusters. In other aspects, the compositions of the present invention can include at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more nano-clusters that have different characteristics (e.g., different active ingredients attached, different shapes, hollow or solid, etc.). The compositions of the present invention can be formulated into a pharmaceutically acceptable carrier.

In another embodiment, there is disclosed a method of preventing or treating a disease or condition in a subject comprising administering a therapeutically effective amount of a composition comprising a nano-cluster of the present invention to a subject (e.g., human, pigs, horses, cows, dogs, cats, mouse, rat, rabbit, or any other mammal and non-mammals) in need of the composition. The method can further include a method for determining whether a subject is in need of the prevention or treatment. The disease or condition can include all types of diseases conditions known to a person of skill in the art and discussed throughout this specification. In certain preferred aspects, the disease or condition can be a pulmonary associated disease or condition (e.g., common cold, flu, cystic fibrosis, emphysema, asthma, tuberculosis, severe acute respiratory syndrome, pneumonia, lung cancer, etc.), a circulatory disease or condition, a muscular disease or condition, a bone disease or condition, an infection, a cancer, etc. In certain embodiments, the method can include the administration of a second therapy used to treat or prevent the disease (e.g., combination therapy). In preferred embodiments, the compositions of the present invention are administered nasally. Other modes of administration known to those of skill in the art or discussed in this specification are also contemplated. In particular aspects, the nano-clusters within the composition are delivered to the deep lung (e.g., bronchiole or alveolar regions of the lung).

In certain preferred aspects of the present invention, the nano-clusters of the present invention can be used to deliver vaccines or components of vaccines. For instance, cells of the immune system, especially macrophages and dendrocytes, are targets for immunization. These “professional” antigen-presenting cells (APCs) can elicit a desired T-cell response to vaccine components. APCs are typically capable of phagocytosis of particles in the range of 1 to 10 μm. By generating in this size range nano-clusters or nano-particles containing vaccine components, one can passively target delivery of the vaccine to APCs. U.S. Pat. No. 6,669,961, for example, provides a non-limiting explanation of this process.

The nano-clusters of the present invention can also have a particular mass density. In certain preferred embodiments, for example, the mass density can be greater than, equal to, or less than 0.1 g/cm3. In particular embodiments, the mass density of the nano-clusters of the present invention can be about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 g/cm3, or greater.

Also disclosed is a method of preparing a nano-cluster comprising: (i) obtaining a plurality of nano-particles; (ii) obtaining a dispersion material (when desired); and (iii) admixing (i) and (ii), wherein the admixture is formulated into a nano-cluster. In certain aspects, obtaining a plurality of nano-particles comprises: (i) obtaining an aqueous suspension of nano-particles; (ii) emulsifying the suspension into a non-aqueous phase; (iii) allowing water in the aqueous suspension to absorb into the non-aqueous phase; (iv) allowing the nano-particles to aggregate together; and (v) retrieving the aggregated nano-particles. In other non-limiting embodiments, obtaining a plurality of nano-particles includes: (i) obtaining a non-aqueous suspension of nano-particles; (ii) emulsifying the suspension into an aqueous phase; (iii) allowing liquid in the non-aqueous suspension to absorb into the aqueous phase; (iv) allowing the nano-particles to aggregate together; and (v) retrieving the aggregated nano particles. The disclosed method represents a non-limiting method with other methods being evident by one skilled in the art (e.g. emulsion/solvent evaporation, extraction, spray-drying, spray freeze-drying, self-assembly in solution, etc.). In certain aspects, it is contemplated that the nano-clusters can be prepared in a solution without using spray and/or freeze dry techniques. It is also contemplated that the nano-clusters can be recovered from the solution by using freeze dry or spray dry techniques that are known to those of skill in the art. As noted throughout this specification, the nano-cluster can be included within a composition. The composition can be formulated into a liquid, a spray, an aerosol, or a dry powder in non-limiting embodiments.

• Provisional Patent
• Utility Patent

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