“Smart” polymers, which reversibly change their physical properties in response to small and controllable stimuli (e.g., changes in pH, termpature, and light), reversibly cycle between an extended and hydrophilic random coil and a collapsed hydrophobic state that is reduced in size.
Inverse (or negative) temperature-dependence:
Reversible Gels:
Most polymers increase their water solubility as the temperature increases. Polymers with LCST, however, decrease their water solubility as the temperature increases. The LCST can be changed by adjusting the ratio of hydrophilic and hydrophobic segment of the polymer. Polymers that show this type of behavior are block copolymers of poly ethyleneoxide (PEO) and poly (propyleneoxide) (PPO) commercially available as Pluronic poloxamers (BASF, Ludwigshafen, German) and generically known as poloxamers (US 4,188,373, 4,478,822 and 4,474,751). Adjusting the temperature of the polymer gives the desired liquid-gel transition. However, concentrations of the poloxamer polymer of at least 18-20% concentrations of the poloxamer polymer of at least 18-20% by weight are needed to produce a composition which exhibits such a transition at commercially or physiologically useful temperatures. Also, solutions containg 18-20% by weight of responsive polymer are typically very viscous even in the “liquid” phase, so that these solutions can not function under conditions wehre low viscosity, free flowing is required prior to transition.
Another known system which is liquid at room temerpature, but forms a semi-solid when warmed to about body temperature is formed from tetrafunctional block polymers of polyoxyethylene and polyoxypropylene condensed with ethylenediamine, commercially available as Tetronic poloxamers. These compositions are formed from about 10-50 by weight of the poloxamer in an aqueous medium (US 5,252,318).
Although Pluronic and Tetronic based block copolymers exhibit reversible viscosificaiton, they do not offer any bioadhesion properties.
Elastin-like Polypeptide (ELP)
ELP is a thermally responsive polypeptide which forms aggregates in solution above a specific temperature. When injected into the body, ELP is cleared from circulation except at sites where local heat is applied and ELP accumulates. This property of ELP can be exploited for drug delivery by fusing a therapeutic molecule to ELP (Bidwell, “Development of elastin-like polyppeptides for thermally targeted delivery of inhibitory peptides and small molecule drugs” Dissertation Abstracts International, 2007, 68(5B), p. 2754).
The fusion of a drug to elastin-like polypeptides (ELPs) promotes the formation of aggregating particles that form a “drug depot” at physiologic tmerpatures, a phenomenon intended to prolong the presence of the dug (Shamji, Arthritis and Rheumatism, 56(11), 3650-3661, 2007).
(Floss, J. Biomedicine and Biotechnology, 2010, article ID 27434) discloses a fusion between elastin-like peptide (ELP) and Ag85B and ESAT-6 which are produced in plants. Mice and piglets immunized with the TBAg-ELP fusion exhibited exhibited a mycobacterial specific immune response with no side effects. The ain reactivity of the TBAg-ELP induced antibodies against Ag85B.
Furgeson (US8,367,626) discloses elastin-like polymer (ELP) delivery compositions which may be used to delivery therpauetic nucleic acids, polypeptides and small molecules.
pH-sensitive gelling polymer and temperature sensitive gelling polymer:
combine a physical blend of a pH sensitive gelling polymer (such as a cross linked poly(acrylic acid) and a temerpature sensitive gelling polymer (such as methyl cellulose or block copolymers of poly(ethyleneoxide) and poly(propyleneoxide) (US 5252318).
US 6,486,213 describes clock and graft copolymers for use in the topical delivery of drugs. The copolymer is physically mixed with one or more drugs to form a coppolymer-drug mixture. These copolymers contain a pH-sensitive polymer component, which swells and adheres to the treatment area upon uptake of water and a temperature sensitive polymer component, which facilitates controlled release of the drug.
US 6,165509 describes PEGylated drugs complexed wtih bioadhesive polymers (e.g., polyacrylic, polymethacrylic, polyethylacrylic acids and chitosan). Upon uptake of water at the treatment site, the bioadhesive polymer becomes sticky and neutral pH exposure facilitates the dissociation of the PEGylated drug form the bioadhesive polymer. Sustained drug release is thereby achieved va topical administration.
Applications
Inner ear delivery: Biopolymer of the triblock poloxamer class are particularly attractive for delivery of drugs to the inner ear because of their thermoreversible gelling and mucoadhesive properties and safety profile in humans. Piu has explored the potential of poloxamer 407 hydrogels as drug carrriers for local delivery of dexamethasone to the inner ear (Otology & Neurotology, 2010). Poloxamer (Pluronic) 407 is one of the classical thermsensitive polymers, the aqueous solution of which can interchange between solution and gel phase when the termpature is elevated (Lee, J Control Release, 2004, 96: 107).