Compositions and methods for enhancing receptor-mediated cellular internalization

• US 6,387,390 B1
• Filed: 10/05/1999
• Issued: 05/14/2002
• Est. Priority Date: 10/05/1998
• Status: Expired

• Current Assignee: Penn State Research Foundation
• Original Assignee: Penn State Research Foundation
• Inventors: Deaver, Daniel R., Edwards, David A.
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US09/412,821
• Time in Patent Office: 952 Days
• Field of Search: 424/423, 424/451, 424/464, 424/430, 424/434, 424/435
• US Class Current: 424/423
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 48/0008 characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
• CPC Class Codes: A61K 48/0083 characterised by an aspect of the administration regime
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0046 Ear
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: Y10S 977/906 Drug delivery

Abstract

Compositions and methods for improving cellular internalization of one or more compounds are disclosed. The compositions include a compound to be delivered and a biocompatible viscous material, such as a hydrogel, lipogel, or highly viscous sol. The composition also include, or are administered in conjunction with, an enhancer in an amount effective to maximize expression of or binding to receptors and enhance RME of the compound into the cells. This leads to high transport rates of compounds to be delivered across cell membranes, facilitating more efficient delivery of drugs and diagnostic agents. Compositions are applied topically orally, nasally, vaginally, rectally, and ocularly. The enhancer is administered with the composition or separately, either systemically or preferably locally. The compound to be delivered can also be the enhancer.

Claims

1. A method for delivering an agent to cells at a site where uptake is desired comprising administering to the cells at the site where uptake is desired a composition comprising

(a) a viscous material having an apparent viscosity between 10 and 2000 Poise and approximately the same apparent viscosity, at a shear stress of between approximately 1 and 200 Pascal at a strain rate approximately that of endocytosis, as the cytosolic fluid of the cell to which the agent is to be delivered,

(b) a compound to be delivered, and

(c) an enhancer in an amount effective to enhance expression of or binding to receptors eliciting receptor-mediated endocytosis on the cells at the site where uptake is desired.

2. The method of claim 1 wherein the enhancer is a steroid.

3. The method of claim 1 wherein the cells to which the compound is to be delivered are in the nose, rectum, mouth, ear, eye, or lungs.

4. The method of claim 1 wherein the composition is administered topically.

5. The method of claim 1 wherein the enhancer is administered systemically.

6. The method of claim 1 wherein the composition is administered to the vaginal mucosa.

7. The method of claim 1 wherein the compound to be delivered is selected from the group consisting of proteins, peptides, carbohydrates, nuceilc acid molecules, and chemotherapeutic agents.

8. The method of claim 7 wherein the enhancer is selected from the group consisting of hormones, glucocorticoids, and other molecules specifically binding to a receptor on a cell surface to induce endocytosis.

9. The method of claim 8 wherein the enhancer is a reproductive hormone.

10. The method of claim 1 wherein the enhancer is a glucocorticoid.

11. The method of claim 9 wherein the reproductive hormone is selected from the group consisting of progesterone, estradiol, and combinations thereof.

12. The method of claim 1 wherein the viscous material is selected from the group consisting of hydrogels, lipogels and sols.

13. The method of claim 12 wherein the hydrogel is selected from the group consisting of celluloses, polyalkyleneoxide, polyvinylpyrrolidone, dextrans, alginates, agaroses, gelatin, hyaluronic acid, trehalose, polyvinyl alcohol, and copolymers and blends thereof.

14. A composition for delivering an agent to cells at a site where uptake is desired comprising:

(a) a viscous fluid having an apparent viscosity between 10 and 2000 Poise and approximately the same apparent viscosity, at a shear stress of between approximately 1 and 200 Pascal at a strain rate approximately that of endocytosis, as the cytosolic fluid of the cell to which the agent is to be delivered,

(b) a compound to be delivered, and

(c) an enhancer in an amount effective to enhance expression of or binding to receptors eliciting receptor-mediated endocytosis on the cells at the site where uptake is desired.

15. The composition of claim 14 in a formulation suitable for administration to mucosa of tissue selected from group consisting of the nose, the rectum, the mouth, the ear, the eye, and the lungs.

16. The composition of claim 14 wherein the compound to be delivered is selected from the group consisting of proteins, peptides, carbohydrates, nucleic acid molecules, and chemotherapeutic agents.

17. The composition of claim 14 wherein the enhancer is selected from the group consisting of hormones and glucocorticoids.

18. The composition of claim 14 wherein the hormone is a reproductive hormone.

19. The composition of claim 14 wherein the viscous material is selected from the group consisting of hydrogels, lipogels and sols.

20. The composition of claim 19 wherein the hydrogel is selected from the group consisting of celluloses, polyalkyleneoxide, polyvinylpyrrolidone, dextrans, alginates, agaroses, gelatin, hyaluronic acid, trehalose, polyvinyl alcohol, and copolymers and blends thereof.

21. A kit for delivering a compound to cells comprising:

a first composition comprising a viscous fluid and the compound to be delivered, wherein the viscous fluid has an apparent viscosity between 10 and 2000 Poise and approximately the same apparent viscosity, at a shear stress of between approximately 1 and 200 Pascal at a strain rate approximately that of endocytosis, as the cytosolic fluid of the cell to which the agent is to be delivered, and

a second composition comprising an enhancer in an amount effective to enhance expression of receptors eliciting receptor-mediated endocytosis on the cells, thereby to enhance receptor mediated endocytosis of the agent into the cells.

22. The kit of claim 21 wherein the second composition is in a formulation suitable for topical or systemic administration.