Biodegradable block copolymers for delivery of proteins and water-insoluble drugs

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Abstract

Release of several drugs from new ABA-type biodegradable thermal gels, ReGel®, including proteins and conventional molecules, are presented. These are biodegradable, biocompatible polymers that demonstrate reverse thermal gelation properties. Organic solvents are not used in the synthesis, purification, or formulation of these polymers. The unique characteristics of ReGel® hinge on the following two key properties: (1) ReGel® is a water soluble, biodegradable polymer at temperatures below the gel transition temperature; (2) ReGel® forms a water-insoluble gel once injected. This is consistent with a hydrophobically bonded gel state where all interactions are physical, with no covalent crosslinking. An increase in viscosity of approximately 4 orders of magnitude accompanies the sol–gel transition. The gel forms a controlled release drug depot with delivery times ranging from 1 to 6 weeks. ReGel®’s inherent ability to solubilize (400 to >2000-fold) and stabilize poorly soluble and sensitive drugs, including proteins is a substantial benefit. The gel provided excellent control of the release of paclitaxel for approximately 50 days. Direct intratumoral injection of ReGel®/paclitaxel (OncoGel™) results in a slow clearance of paclitaxel from the injection site with minimal distribution into any organ. Efficacies equivalent to maximum tolerated systemic dosing were observed at OncoGel™ doses that were 10-fold lower. Data on protein release (pGH, G-CSF, insulin, rHbsAg) and polymer biocompatibility are discussed.

Introduction

The need for controlled release injectable dosage forms for the delivery of protein and poorly soluble conventional drug molecules over a 1–6-week period is established. Usable systems will show properties consistent with high level compatibility with sensitive drugs, and facile manufacture and administration. Clearance of the dosage form from the injection site, obviating the need to surgically retrieve the exhausted depot, requires the use of biodegradable polymers. Reverse thermal gelation of biodegradable polymers has been reported [1], [2], [3], [4], [5]. These polymers were triblock copolymers consisting of A-blocks and B-blocks arranged as BAB or ABA, where A is poly(lactide-co-glycolide) (PLGA) and B is poly(ethylene glycol). The polymers are soluble in water, forming a free-flowing solution that spontaneously gels at body temperature (37°C) to create a water-insoluble gel [5], [6]. These thermal gels remain at the injection site for approximately 1 month [5], [7] in contrast to non-biodegradable thermal gels, poloxamers, that are water soluble and dissolve from the injection site within a few days [5]. These biodegradable, thermally reversible drug delivery systems are based on custom designed polymers/processes that control drug release and offer substantial advantages in administration and manufacture. They hold particular promise to provide solutions to the parenteral delivery problems of protein drugs and poorly soluble drugs. Thus, the biodegradable thermal gels hold high potential as injectable, long-term drug delivery systems.

A variety of poloxamer gels, and poloxamer gels modified with additives such as methylcellulose, hydroxypropyl methylcellulose, and polycaprolactone have been reported as delivery vehicles for drugs such as IL-2, urease, mitomycin C, and bovine serum albumin [8], [9], [10], [11], [12]. Low-molecular weight polyorthoester [13], and vegetable oil-based gels [14], have shown controlled release properties for tetracycline and levonorgestrel, respectively, for periods of 2–3 weeks. Injectable forms of poly(dl-lactide-co-glycolide) dissolved in N-methyl pyrrolidone that precipitate upon contact with aqueous biological fluids have been reported for delivery of naltrexone [15]. Drug release from biodegradable gels follow the typical profile of an initial diffusion-controlled mechanism that transitions into a combined mechanism of diffusion/degradation as the polymer properties deteriorate upon hydrolysis of the PLGA blocks [16], [17], [18], [19].

The need for acceptable vaccine adjuvants for humans is accentuated by the fact that several new vaccines, and particularly those prepared by modern molecular biology approaches, are weakly immunogenic. These expensive recombinant proteins and peptides often require multiple immunizations to induce a protective response. Although the mechanisms for the adjuvant effects of individual substances are poorly understood, empirical experience suggests that factors such as slow and sustained release of antigens, enhanced antigen presentation, or release of cytokines that promote humoral and/or cell-mediated immune responses may be responsible for their effects.

In this paper the drug release profiles of several drugs from new ABA-type biodegradable thermal gels, ReGel®, including proteins and conventional molecules, are presented. These are biodegradable polymers that demonstrate reverse thermal gelation properties where a free-flowing aqueous solution of the polymer spontaneously gels at physiological temperatures. Organic solvents are not used in the synthesis, purification, or formulation of these polymers. Data on drug solubility, stability, in vivo efficacy and biocompatibility of these new biodegradable thermal gels is discussed.

Section snippets

Chemicals

Polyethylene glycols (PEG1000 and PEG1450) were purchased from Union Carbide (US). dl-Lactide and glycolide were purchased from PURAC (The Netherlands) and used without further purification. Stannous 2-ethylhexanoate and insulin were obtained from Sigma (US) and were used as received. Paclitaxel (Genexol®; Samyang Genex) was >99% pure and used as received. Radiolabelled paclitaxel (paclitaxel-[2-benzoyl ring-UL-14C]; 60 mCi per mmol; ethyl acetate removed prior to use) was purchased from Sigma.

ReGel® characterization

Gelation was defined as the physical state where the polymer solution did not readily flow upon inverting a vial of polymer solution. A typical phase diagram (Fig. 1) of the polymer as a function of temperature was generated. The novel, reverse thermal gelation behavior was clearly apparent, and occurred as the triblock copolymer solutions were heated. The gelation at physiologically relevant temperatures (e.g., 37°C) was particularly prevalent and formed the basis for the utility of the

Conclusions

ReGel® has been developed as a biodegradable drug delivery system that is injected as a liquid, thereafter forming a gel in response to body temperature. The gel forms a controlled release drug depot with delivery times ranging from 1 to 6 weeks. These properties make ReGel® well suited for either local or systemic drug delivery applications. ReGel®’s inherent ability to solubilize and stabilize poorly soluble and sensitive drugs, including proteins is a substantial benefit. The exclusive use

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All procedures involving animals were performed according to a protocol approved by the Institutional Animal Care and Use Committee.

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