Temperature-responsive gels and thermogelling polymer matrices for protein and peptide delivery

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Abstract

The explosive development of protein and peptide drugs has ushered in a great need for effective delivery systems for such drugs. Two decades of studies of protein delivery from polymeric systems has revealed the great potential of gels that respond to environmental stimuli, such as temperature, pH, etc. Protein and peptide release can be engineered to occur in a pulsatile mode. The mechanism of this release is greatly affected by polymer design. `Intelligent' amphiphilic copolymers emerge as a novel trend in the application of thermodynamically stable self-assembling lyophilic colloids to protein and peptide delivery.

Introduction

Rapid progress in recombinant DNA technology has resulted in the ready availability of a wide variety of protein- and peptide-based drugs targeting poorly controlled diseases 1, 2. Several hundred protein drugs are currently undergoing clinical trials 2, 3. It has been understood for more than 20 years [4]that large proteins could be delivered slowly and continuously from polymeric systems, and since that time an explosive growth in the number of publications in the field of controlled delivery of proteins and peptides has occurred. Parenteral and, to a certain extent, oral routes of administration of proteins and peptides were dominated by micro- and nano-particulate systems where the drug is encapsulated in a solid polymer 5, 6, 7, 8. The first Food and Drug Administration (FDA) approved system was an analog of lutenizing hormone-releasing hormone (LHRH), leuprolide acetate, encapsulated into microspheres composed of lactic acid–glycolic acid copolymer (Lupron Depot) [9]. It is quite significant that this progress has not been matched by comparable advances in development and formulation of non-parenteral peptide and protein drug delivery systems. It appears that the bioavailability of peptides and proteins from non-oral mucosal routes is in general poor when compared with the parenteral route. This is due to several basic barriers, including highly selective epithelia that exclude macromolecules, the presence of proteolytically destructive multistage enzyme systems, as well as non-enzymatic clearance mechanisms [10]. On the other hand, unlike other drug formulations, protein formulations are susceptible to loss of both native structure (through cleavage of peptide bonds and destruction of amino acid residues, e.g. proteolysis, oxidation, deamidation, and β-elimination) and conformation (from the disruption of noncovalent interactions, e.g. aggregation, precipitation, and adsorption) 11, 12, 13. Mechanisms leading to protein destabilization in drug delivery formulations have been recently reviewed [14]. Among other strategies used to circumvent the poor bioavailability of proteins and peptides, numerous penetration enhancers were studied as a means to affect and, to a certain extent, alter the mechanism with which proteins cross mucosal membranes 15, 16. Depending on the type of epithelia that a drug should ultimately cross in order to reach its intended site of action, penetration enhancers may target transcellular or paracellular routes [17]. In some cases, like in the case of poly(ethylene oxide)-modified proteins [18], not only is penetration enhanced, but also the stability of the protein formulations [19]. Optimization of the delivery system with respect to retention at the absorption site appears to be an alternative to traditional penetration enhancers [10]. Various dosage forms have been studied in this regard, including aqueous solutions [20], powders [21], microspheres 14, 22, and gels 23, 24, 25, 26, 27, 28. In the present review, the authors focus on the gel systems only, as they can be designed to combine several potential ways to improve protein and peptide availability: (i) protect the drug from the hostile environment, including proteolytic enzymes and low pH (as in the stomach); (ii) control reaction of the body to the drug formulation; and, most importantly, (iii) control the release of the drug on demand by triggering changes in the gel structure by environmental stimuli. The latter possibility can be realized if a gel constituent is capable of responding to a stimulus (i.e. change in temperature, pH, solvent composition, etc.). In general, a temperature or other stimulus can be found that triggers volume phase transition in any gel 29, 30. However, the main subject of our study was safe `intelligent' gel systems that can be safely applied in the human body. Herein, we concentrate on protein and peptide release using temperature-sensitive permanently crosslinked gels as well as polymer solutions that gel at body temperatures. The definition of the term `gel' thus far has some ambiguity [31]. We will define a gel according to its phenomenological characteristics as a soft, solid-like material that consists of several components, one of which is a liquid, present in substantial quantity. In drug delivery, the term `hydrogel' is typically reserved for polymeric materials that can absorb a substantial amount of water while maintaining a distinct three-dimensional structure [32].

Section snippets

Hydrophobic effect and critical solution temperatures

Covalently crosslinked temperature-sensitive gels are perhaps the most extensively studied class of environmentally-sensitive polymer systems in drug delivery 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45. At least one component of the polymer system should possess temperature-dependent solubility in a solvent (i.e. water, with a few exceptions 46, 47). In order to obtain a hydrogel that dramatically changes its swelling degree in water, the gel constituents must be insoluble above or

Thermally reversible gels (TRG)

The limitations to the use of permanently crosslinked gels in temperature-controlled drug delivery as discussed above have indicated the need for a change in the `gel paradigm,' in order to broaden the gel applicability. Namely, if a polymer solution can be found that is a free-flowing liquid at ambient temperature and gels at body temperature, such a system would be easy to administer into a desired body cavity. Moreover, the loading of such a system with a drug could be achieved by simple

Concluding remarks

The majority of current drug formulations represent lyophobic colloids, such as suspensions, emulsions, powders, crosslinked gels, etc. These colloids are thermodynamically unstable, i.e. they require additional energy to be applied for their dispersion. Recently, however, a new trend toward application of lyophilic colloids in drug delivery has emerged [246]. Lyophilic colloids spontaneously assemble from macroscopic phases and are thermodynamically stable. It has been stated [246]that this is

Acknowledgements

The authors are grateful to Dr. E.C. Lupton, Jr., Dr. Michal Orkisz and Thomas H.E. Mendum for practical help. The in vivo study of the oesophageal retention of Smart Hydrogel™ performed by Drs. C.G. Wilson, P. Gilchrist and A.M. Potts (University of Strathclyde) and Drs. N. Washington and S. Jackson (Queen's Medical Centre, Nottingham) is gratefully acknowledged. We are indebted to Prof. Toyoichi Tanaka (Massachusetts Institute of Technology), Prof. Allan S. Hoffman (University of Washington),

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