Bioadhesive nanoparticulate compositions having cationic surface stabilizers
View Patent ↗Bioadhesive nanoparticulate compositions, comprising active agent particles and one or more cationic surface stabilizers, are described. The cationic surface stabilizers prevent aggregation of the nanoparticles and increase bioadhesion of the nanoparticles to biological substrates, such as an insect, teeth, bone, nails, chitin, feathers, scales, mucous, skin, hair, plant tissue, etc. The particles may consist of pharmacologically active compounds (e.g., drug compounds for human or veterinary use), agricultural chemicals (pesticides, herbicides, fertilizers, and the like), cosmetic agents, consumer products (coloring agents, flavors, or fragrances), or other materials which function by interacting with biological substrates. In addition, the invention relates to methods of preparing and using such bioadhesive nanoparticulate compositions.
1. A method of preparing a stable bioadhesive nanoparticulate composition comprising:
(a) combining active agent droplets, wherein the active agent is in a liquid state at or near room temperature, with an emulsifying agent and a liquid non-solvent;
(b) emulsifying the resultant mixture to produce an emulsion of active agent droplets dispersed in the liquid non-solvent; and
(c) adding at least one cationic surface stabilizer for a time and under conditions sufficient for the cationic surface stabilizer to adsorb to the surface of the active agent liquid droplets to form a stable nanoparticulate composition, wherein the cationic surface stabilizer is in an amount effective to cause nanoparticles of the stable bioadhesive nanoparticulate composition to adhere to a biological surface,
wherein: (i) the active agent droplets are insoluble within said non-solvent; (ii) the active agent droplets have an effective average particle size of less than about 4000 nm; and (iii) the nanoparticulate composition adsorbs to a biological surface, and (iv) the composition does not comprise a phospholipid.
2. The method of claim 1 , wherein said emulsification of the active agent droplets is accomplished by using a device selected from the group consisting of a homogenizer, a high-shear mixer, a rotor-stator type device, and a high shear fluid processor.
3. The method of claim 1 , wherein said at least one cationic surface stabilizer is added to the mixture of active agent droplets, emulsifying agent, and liquid non-solvent prior to emulsification.
4. The method of claim 1 , wherein said at least one cationic surface stabilizer is added to the mixture of active agent droplets, emulsifying agent, and liquid non-solvent during emulsification.
5. A method of preparing a stable bioadhesive nanoparticulate composition comprising:
(a) dissolving or dispersing active agent in a liquid and combining with an emulsifying agent and a liquid non-solvent, wherein the active agent is in a liquid state at or near room temperature;
(b) emulsifying the resultant mixture to produce an emulsion of liquid droplets; and
(c) adding at least one cationic surface stabilizer for a time and under conditions sufficient for the cationic surface stabilizer to adsorb to the surface of the active agent emulsion droplets to form a stable nanoparticulate composition, wherein the cationic surface stabilizer is in an amount effective to cause nanoparticles of the stable bioadhesive nanoparticulate composition to adhere to a biological surface,
wherein: (i) the active agent is dissolved or dispersed in the liquid droplets of the emulsion; (ii) the liquid droplets comprising said active agent have an effective average particle size of less than about 4000 nm; and (iii) the nanoparticulate composition adsorbs to a biological surface, and (iv) the composition does not comprise a phospholipid.
6. The method of claim 5 , wherein said emulsification of the agent is accomplished by using a device selected from the group consisting of a homogenizer, a high-shear mixer, a rotor-stator type device, and a high shear fluid processor.
7. The method of claim 5 , wherein said at least one cationic surface stabilizer is added to the mixture of active agent, emulsifying agent, and liquid non-solvent prior to emulsification.
8. The method of claim 5 , wherein said at least one cationic surface stabilizer is added to the mixture of active agent, emulsifying agent, and liquid non-solvent during emulsification.
9. A method of preparing a stable bioadhesive nanoparticulate composition comprising:
(a) combining active agent droplets , wherein the active agent is in a liquid state at or near room temperature, with an emulsifying agent and a liquid non-solvent;
(b) emulsifying the resultant mixture to produce an emulsion of active agent droplets dispersed in the liquid non-solvent; and
(c) adding at least one cationic surface stabilizer for a time and under conditions sufficient for the cationic surface stabilizer to adsorb to the surface of the active agent liquid droplets to form a stable nanoparticulate composition, wherein the cationic surface stabilizer is in an amount effective to cause nanoparticles of the stable bioadhesive nanoparticulate composition to adhere to a biological surface,
wherein: (i) the active agent droplets are insoluble within said non-solvent; (ii) the active agent droplets have an effective average particle size of less than about 4000 nm; (iii) the nanoparticulate composition adsorbs to a biological surface; (iv) the surface stabilizer does not comprise a phospholipid; (v) the active agent is selected from the group consisting of: proteins, peptides, nutriceuticals, anti-obesity agents, corticosteroids, elastase inhibitors, analgesics, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, penicillins, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (antiparkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, steroids, anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators and xanthines; and (vi) the emulsifier is selected from the group consisting of: ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters of sorbitan, or mixtures thereof.