Formulation of immunopotentiators

Abstract

Immunopotentiators can be adsorbed to insoluble metal salts, such as aluminium salts, to modify their pharmacokinetics, pharmacodynamics, intramuscular retention time, and / or immunostimulatory effect. Immunopotentiators are modified to introduce a moiety, such as a phosphonate group, which can mediate adsorption. These modified compounds can retain or improve their in vivo immunological activity even when delivered in an adsorbed form.

Description

[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 379,126 (filed Sep. 1, 2010), U.S. Provisional Application No. 61 / 448,394 (filed Mar. 2, 2011) and U.S. Provisional Application No. 61 / 466,887 (filed Mar. 23, 2011), the complete contents of all of which are hereby incorporated herein by reference for all purposes.TECHNICAL FIELD[0002]The invention is in the field of formulating immunopotentiating compounds for in vivo use. More particularly, the invention relates to the design of immunopotentiating agents for formulation by association with insoluble metal salts e.g. by adsorption.BACKGROUND ART[0003]Early detection of specific classes of pathogens is accomplished by the innate immune system with help of pattern recognition receptors (PRRs). The detected pathogens include viruses, bacteria, protozoa and fungi, and each constitutively expresses a set of class-specific, mutation-resistant molecules called pathogen-associated molecular patterns (PAMPs).[0...

AI Technical Summary

Benefits of technology

[0009]The inventors have surprisingly found that the PK / PD of immunopotentiators (and in particular TLR agonists), and their retention at sites of injection, can be modified by adsorbing them to insoluble metal salts, such as aluminium salts. Stable adsorption of the compounds ideally takes place by ligand exchange, but known SMIPs typically lack suitable functional groups. Thus SMIPs can be modified to introduce an adsorptive moiety, such as a phosphonate group, which can then mediate adsorption. The inventors have found that these modified SMIPs (in particular, TLR7 agonists) can retain their in vivo immunological activity even when delivered in an adsorbed form, and so the improved PK / PD properties are not at the expense of immunostimulating activity. Indeed, adsorption of TLR7 agonists is shown herein to improve their immunostimulatory activity. Furthermore, adsorption of the compounds can reduce peak serum concentrations and increase residence times at sites of intramuscular injection, which can contribute to modifying and controlling the level of systemic exposure. High systemic exposure can elicit the production of high levels of proinflammatory cytokines in the blood, so higher residence time at an injection site can help to minimise the production of proinflammatory cytokines in the blood, thus improving safety and / or tolerability of the compounds. Cellular uptake of the compounds can also be enhanced by adsorption.

Problems solved by technology

Stable adsorption of the compounds ideally takes place by ligand exchange, but known SMIPs typically lack suitable functional groups.

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