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Last Updated: January 26, 2022

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Claims for Patent: 7,264,933

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Summary for Patent: 7,264,933
Title:Methods to identify biologically active agents and synergistic combinations
Abstract: Methods are described using a particular type of assay system, the Multi-Pathway High Throughput Assay, in conjunction with a novel experimental strategy, whereby repeated cycles of experiments result in the identification of the most effective synergistic combinations of potential active agents from a library of materials. The novel experimental strategy not only requires far fewer total experiments than would be required using conventional discovery strategies but also maximizes the probability of finding highly synergistic combinations through the principle of multiple-pathway intervention.
Inventor(s): Scott; Ian R. (Mahwah, NJ)
Assignee: Synergy Biosystems Ltd (Stratford Upon Avon, GB)
Application Number:10/807,811
Patent Claims:1. A method for identifying highly synergistic combinations of biologically active agents comprising: i. selecting a library of ingredients to be tested as potentially biologically active agents in which synergy is sought, said ingredients being designated as components of the library; ii. identifying a subset of components S(1) from the library which display significant activity by testing each component of the library for activity in a Multi-Pathway High Throughput Assay said assay targeting a biological end effect for which synergy is sought; iii. carrying out a Single-Component Scaling Protocol on one or more of the S(1) components identified in Step (ii), wherein the one or more S(1) component is repeatedly diluted and retested in the Multi-Pathway High Throughput Assay, and determining a concentration at which its activity in said assay is .lamda. C.sub.Max,1, where .lamda. is a scaling factor in the range from about 0.01 to 0.5, and C.sub.Max,1 is the maximum activity measurable in said assay; iv. identifying a subset of binary mixtures designated S(2) that display synergy, by testing in the Multi-Pathway High Throughput Assay all or a portion of S(1) components in binary mixtures with substantially each component of the library, including components that exhibited marginal or no activity in step ii), wherein the concentration of each S(1) component in the binary mixture is the concentration found in step iii to have an activity .lamda. C.sub.max,1; v. carrying out a Multi-Component Scaling Protocol on one or more of the S(2) binary mixtures identified in Step (iv), wherein the concentration of each component of the one or more S(2) binary mixture is independently varied and the activity of the mixture is measured in the Multi-Pathway High Throughput Assay and determining concentrations for each of the components of the one or more S(2) mixtures at which the activity of said mixture in said assay is .lamda. C.sub.Max,1; vi identifying a subset of ternary synergistic mixtures, S(3) by testing in the Multi-Pathway High Throughput Assay all or a portion of the synergistic binary mixtures S(2) in combination with substantially each component of the library, including components that exhibited marginal or no activity in step ii), wherein the concentrations of each of the S(2) components used in the ternary mixture is the value found in step v that provides the S(2) mixture with an activity in said assay of .lamda. C.sub.Max,1; vii. carrying out a Multi-Component Scaling Protocol on one or more of the S(3) mixtures identified in Step (vi), wherein the concentration of each component of the one or more S(3) mixture is independently varied and the activity of the mixture is measured in the Multi-Pathway High Throughput Assay and determining concentrations for each of the components of the one or more S(3) mixtures at which the activity of said S(3) mixture in said assay is .lamda. C.sub.Max,1 and determining whether any component of each ternary S(3) mixture may be eliminated in further testing cycles because it has become marginally effective in the ternary mixture; viii. optionally identifying a further subset of synergistic mixtures S(4) by testing one or more of the S(3) mixtures in combination with substantially each component of the library including components that exhibited marginal or no activity in step ii), wherein the concentrations of each of the S(3) components used in the S(4) mixture is the value found in step vii that provides an activity in said assay of .lamda. C.sub.Max,1, with the proviso that some components of the S(3) mixture may be eliminated from this testing step if they are deemed marginally effective in the S(3) ternary mixture when tested in step vii; ix optionally carrying out a Multi-Component Scaling Protocol on further one or more S(N-1) mixtures that display significant activity in the assay, said mixtures being identified in an analogous fashion to step viii, wherein the concentration of each component of the one or more S(N-1) mixtures is independently varied and the activity of the mixture is measured in the Multi-Pathway High Throughput Assay and determining concentrations for each of the components of the one or more S(N-1) mixtures at which the activity of said S(N-1) mixture in said assay is .lamda. C.sub.Max,1 and determining whether any component of each S(N-1) mixture may be eliminated in further testing cycles because its has become marginally effective in the S(N-1) mixture, wherein N is an integer greater than 4; x) optionally identifying a further subset of synergistic mixture S(N) by testing one or more of the S(N-1) mixtures in combination with substantially each component of the library including components that exhibited marginal or no activity in step ii), wherein the concentrations of each of the S(N-1) components used in the S(N) mixture is the value found in step ix that provides an activity in said assay of .lamda. C.sub.Max,1, with the proviso that some components of the S(N-1) mixture may be eliminated from this testing step if they are deemed marginally effective in the S(N-1) mixture when tested in step ix.

2. The method according to claim 1 wherein the subsets of S(1) through S(N) tested in combinations with members of the library contain only one or a small number of the components.

3. The method according to claim 1 or 2 wherein the library of potential actives comprises actives selected from the European EINECS list.

4. The method according to claim 1 wherein the library of potential active ingredients comprises ingredients selected from the Cosmetics, Toiletries and Fragrance Association Dictionary of Compounds.

5. The method of claim 4 wherein the library of potential active ingredients is a subset of the Cosmetics, Toiletries and Fragrance Association Dictionary of Compounds selected on the basis of being reported in that volume as having biological activity.

6. The method according to claim 1 wherein the library of potential active ingredients comprises ingredients selected from at least two of the classes selected from the group consisting of retinol and its esters, retinol boosters, short peptides with or without hydrophobic modification or complexation with copper, minoxidil, natural products providing hypertensive activity, natural products containing antiandrogens, and chemicals capable of binding to the vitamin D receptor.

7. The method according to claims 1 wherein the Multi-Pathway High Throughput Assay targets the biological end effect of hair growth.

8. The method according to claim 7 wherein the Multi-Pathway High Throughput Assay is the Isolated Hair Follicle Assay said assay comprising a multiplicity of cultures of individual hair follicles contained in a suitable growth medium wherein said follicles are removed from sectioned dermis in a viable state through the action of collagenase, and wherein hair growth is measured by a high throughput hair growth measurement technique which is not affected by the presence of contaminating tissues in the culture.

9. The method according to claim 8 wherein the high throughput hair growth measurement technique comprises the visualization of an incorporated fluorescent agent in the growing hair.

10. The method according to claim 7 wherein the Multi-Pathway High Throughput Assay is the Low Temperature Whole Skin Organ Culture Assay, said assay comprising a multiplicity of miniaturized cultures of skin maintained in a serum free growth medium at a temperature below about 30, wherein said skin contains intact viable hair follicles below the sebaceous gland, and wherein hair growth is measured by a high-throughput measurement technique.

11. The method according to claim 10 wherein the high throughput hair growth measurement technique comprises the visualization of an incorporated fluorescent agent in the growing hair.

12. The method according to claim 1 wherein the Multi-Pathway High Throughput Assay targets the biological effect of skin anti-aging.

13. The method according to claim 12 wherein the Multi-Pathway High Throughput Assay is the High Throughput Histology Organ Culture Assay said assay comprising the steps of simultaneously treating with test agents viable cultures of pieces of epidermis having at least a portion of their associated dermis intact, said pieces of epidermis contained in a multiple well assembly, wherein said treatment is followed by the embedding of large numbers of cultured skin pieces in a single block and histological sectioning of the entire assembly and the automated histology, histochemistry or immunohistochemisty of histological sections carried out in a high throughput manner.

14. The method according to claim 12 wherein the Multi-Pathway High Throughput Assay is the Topical Application High Throughput Histology Organ Culture Assay said assay comprising a culture of a sheet of viable epidermis and associated dermis, partitioned by the application of a surface barrier film into a pattern of isolated regions to which different test samples can be topically applied, followed after said treatment by the embedding of large numbers of cultured skin pieces in a single block and histological sectioning of the entire assembly and the automated histology, histochemistry or immunohistochemisty of histological sections carried out in a high throughput manner.

15. The method according to claim 1 Wherein the Multi-Pathway High Throughput Assay identifies one or more compounds that ameliorate of acne.

16. The method of claim 15 where the Multi-Pathway High Throughput Assay is the Simulated Follicle P. Acnes Assay said assay comprising a culture of P. Acnes dispersed in a synthetic analogue of human sebum and held in an assembly comprising pieces of tubing of dimensions similar to the sebaceous duct, said assembly being exposed to antibacterial agents under realistic conditions and wherein growth of the surviving P. Acnes is measured by a high throughput measurement technique.

17. The method of claim 15 where the Multi-Pathway High Throughput Assay is the Inhibition of IL1-Induced Hypercornification Assay said assay comprising: i) forming a viable culture of pieces of epidermis with at least a portion of associated dermis using a culture medium containing a level of IL1 sufficient to cause hypercornification; ii) topically applying to the epidermis the ingredient or ingredients to be tested; iii) embedding the cultured pieces of epidermis in a single block; iv) sectioning the single block into histological sections; v) carrying out automated high throughput assays of histology, histochemistry or immunohistochemisty of the histological sections; and vi) determining the extent of reduction of IL1 induced hypercornification by the topically applied ingredient or ingredients.

18. The method according to claim 1 wherein the Multi-Pathway High Throughput Assay targets the biological end effect of dental plaque control.

19. The method according to claim 18 wherein the Multi-Pathway High Throughput Assay is the Plaque Biofilm Regrowth Assay said assay comprising the growth of a plaque biofilm in multiwell plates under conditions of medium replenishment approximately simulating chemostat conditions, followed by the partial removal of the biofilm using mechanical abrasion in the presence of the test agents and detection of the rate of regrowth of the biofilm, optionally using a disclosing agent, via automated image detection.

20. The method according to claim 1 wherein the Multi-Pathway High Throughput Assay targets the biological end effect of microbial growth inhibition or control.

21. The method according to claims 1 wherein the Multi-Pathway High Throughput Assay targets the biological end effect of skin pigmentation control.

22. The method according to claims 1 wherein the Multi-Pathway High Throughput Assay targets the biological end effect of sebum control.

23. The method according to claim 1 wherein the Multi-Pathway High Throughput Assay targets the biological end effect of dandruff control.

24. The method according to claim 1 wherein .lamda. is less than or equal to 0.2.

25. The method according to claim 1 wherein .lamda. is less than or equal to 0.1.

26. The method according to claim 1 wherein N is an integer between 5 and 10.

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