Biodegradable polymeric drug delivery systems

The use of biodegradable polymeric materials as drug carriers is a relatively new dimension in polymeric drug delivery systems. A number of biodegradable or bioerodible polymers, such as poly (lactic/glycolic acid) copolymer, poly(α-amino acid), polyanhydride, and poly (ortho ester) are currently being investigated for this purpose. These polymers are useful for matrix and reservoir-type delivery devices. In addition, when chemical functional groups are introduced to the biodegradable polymer backbone, such as poly (N-(2-hydroxypropy) methacrylamide), the therapeutic agent can be covalently bound directly orvia spacer to the backbone polymer. These polymer/drug conjugates represent another new dimension in biodegradable polymeric drug delivery systems. In this paper, major emphasis is placed on clinical applications of biodegradable polymeric delivery systems. In addition, examples of biodegradable polymeric durg delivery systems currently being investigated will be discussed for the purpose of demonstrating the potential importance of this new field.     

Antitumor activity of adriamycin-incorporated polymeric micelles of poly(gamma-benzyl L-glutamate)/poly(ethylene oxide)

The multiblock copolymer composed of poly(gamma-benzyl L-glutamate) (PBLG) and poly(ethylene oxide) (PEO) was synthesized to prepare polymeric micelles as an anticancer drug carrier. Adriamycin (ADR) used as an anticancer drug was incorporated into the polymeric micelles prepared by the multiblock copolymer. The higher the drug feeding ratio, the higher the drug loading contents and the lower the drug loading efficiency. The increased drug feeding ratio resulted in increased particle sizes. At all of the formulations, particle sizes were less than 150 nm. The particles were observed as spherical shapes. ADR release from ADR-loaded polymeric micelles in vitro was decreased with an increased drug loading contents. In in vitro antitumor activity test using CT 26 tumor cells, polymeric micelles showed almost similar cytotoxicity when compared to ADR itself while polymeric micelles themselves did not affect cytotoxicity. In in vivo antitumor activity test using mice tumor xenograft model, the polymeric micelles showed improved survivability of mice with minimized weight changes and excellent tumor growth suppression efficacy. Polymeric micelles of the multiblock copolymer suggested to be a good candidate for anticancer drug delivery carrier.     

Polyelectrolyte complex micelles by self-assembly of polypeptide-based triblock copolymer for doxorubicin delivery

Polyelectrolyte complex micelles were prepared by self-assembly of polypeptide-based triblock copolymer as a new drug carrier for cancer chemotherapy. The triblock copolymer, poly(l-aspartic acid)-b-poly(ethylene glycol)-b-poly(l-aspartic acid) (PLD-b-PEG-b-PLD), spontaneously self-assembled with doxorubicin (DOX) via electrostatic interactions to form spherical micelles with a particle size of 60–80 nm (triblock ionomer complexes micelles, TBIC micelles). These micelles exhibited a high loading capacity of 70% (w/w) at a drug/polymer ratio of 0.5 at pH 7.0. They showed pH-responsive release patterns, with higher release at acidic pH than at physiological pH. Furthermore, DOX-loaded TBIC micelles exerted less cytotoxicity than free DOX in the A-549 human lung cancer cell line. Confocal microscopy in A-549 cells indicated that DOX-loaded TBIC micelles were transported into lysosomes via endocytosis. These micelles possessed favorable pharmacokinetic characteristics and showed sustained DOX release in rats. Overall, these findings indicate that PLD-b-PEG-b-PLD polypeptide micelles are a promising approach for anti-cancer drug delivery.     

Sericin nanomicelles with enhanced cellular uptake and pH-triggered release of doxorubicin reverse cancer drug resistance

Drug resistance is the major challenge facing cancer chemotherapy and nanoscale delivery systems based on natural materials, such as sericin, are a promising means of overcoming drug resistance. Yet, no attempt of introducing synthetic poly(γ-benzyl-L-glutamate) (PBLG) onto sericin polypeptide to fabricate a facile biocompatible and biodegradable micelle has been tried. Here, we prepared a polypeptide-based amphiphilic polymer containing hydrophilic sericin polypeptide backbone and PBLG side chains via ring-opening polymerization (ROP) strategy. The introduction of PBLG side chains remarkably enhances the stability of sericin micelles in water. Meanwhile, the micelles exhibited a high loading capacity and pH-responsive release ability for antitumor drug doxorubicin (DOX), called sericin-PBLG-DOX. Owing to the excellent cell membrane penetration of sericin-PBLG, the cellular uptake of DOX when loaded into micelles was improved. Subsequently, sericin-PBLG-DOX was transferred into perinuclear lysosomes, where the release rate of DOX was accelerated. Compared to the same dose of DOX, sericin-PBLG-DOX could induce a more efficient anti-tumor effect both in vitro and in vivo, and these micelles have promise for future clinical applications in overcoming cancer drug resistance with good biosafety, enhanced cellular uptake, pH-triggered drug release, efficient anti-tumor effects, and minimized systemic toxicity.     

In Vitro Evaluation of Sustained Drug Release from Biodegradable Elastomer

Poly(DL-lactic acid) (PLA), poly(-caprolactone) (PCL), and their copolymers (PLA-CL) with various monomer compositions were synthesized, and their properties as matrix for the sustained release of drugs were evaluated. The copolymerization technique produced very soft films which incorporated the drugs without deterioration of the elastic properties. Cisplatin and MD-805 were loaded in the films by casting the polymer solution containing the drugs. Fractions of the drugs released from the PLA-CL films were governed by the initial loading, the film thickness, and the polymer molecular weight. The drug release profiles obeyed the classical Fickian diffusion equation at least in the early stage, but significant hydrolytic degradation of the matrix polymers occurred in the later stage, influencing the kinetics of drug release. The monomer composition of copolymer affected the release profile more strongly than the initial molecular weight of the copolymer.     

Novel pH-sensitive hydrogels for colon-specific drug delivery

The purpose of this study is to develop novel intestinal specific drug delivery systems with pH-sensitive swelling and drug release properties. Acryloyl ester of 5-[4-(hydroxy phenyl) azo] salicylic acid (HPAS) as an azo derivative of 5-amino salicylic acid (5-ASA) was prepared under mild conditions. The HPAS was covalently linked with acryloyl chloride, abbreviated as APAS. Cubane-1,4-dicarboxylic acid (CDA), linked to two 2-hydroxyethyl methacrylate (HEMA) groups, was the cross-linking agent (CA). Methacrylic-type polymeric prodrugs were synthesized by free radical copolymerization of methacrylic acid, poly(ethyleneglycol monomethyl ether methacrylate), and APAS in the presence of cubane cross-linking agent. The effect of copolymer composition on the swelling behavior and hydrolytic degradation were studied in simulated gastric (SGF, pH 1) and intestinal fluids (SIF, pH 7.4). The composition of the cross-linked three-dimensional polymers was determined by FTIR spectroscopy. The hydrolysis of drug–polymer conjugates was carried out in cellophane membrane dialysis bags containing aqueous buffer solutions (pH 1 and pH 7.4) at 37°C. Detection of the hydrolysis product by UV spectroscopy shows that the azo prodrug (HPAS) was released by hydrolysis of the ester bond located between the HPAS and the polymer chain. Drug release studies showed that the increasing content of MAA in the copolymer enhances hydrolysis in SIF. These results suggest that pH-sensitive systems could be useful for preparation of a muccoadhesive system and controlled release of HPAS as an azo derivative of 5-amino salicylic acid (5-ASA).     

Controlled delivery of testosterone from smart polymer solution based systems: in vitro evaluation

The objective of this research is to develop injectable polymers solution based controlled release delivery systems for testosterone (TSN), using phase sensitive and thermosensitive polymers. A combination of poly(lactide) (PLA) and solvents mixture of benzyl benzoate (BB) and benzyl alcohol (BA) was used in the phase sensitive polymer delivery system. The effects of solvents system and drug loading on the in vitro TSN release were evaluated. In the case of thermosensitive polymer delivery systems, a series of low-molecular-weight poly(lactide-co-glycolide)-poly(ethylene glycol)-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers with varying ratio of lactide/glycolide (LA/GA, 2.0-3.5) were studied to control the release of TSN. The effects of varying block length of copolymers 1-4 on the in vitro TSN release were evaluated. Phosphate buffer saline (pH 7.4) containing 0.5% (w/v) Tween-80 was used as in vitro release medium. The amount of the released TSN was determined by an HPLC method. A controlled (zero-order) in vitro release of TSN was observed from both the phase sensitive and thermosensitive polymer delivery systems. Addition of BA (15%, v/v) in solvents system significantly (p<0.05) increased the release rate of TSN (0.33+/-0.01 mg/ml) from phase sensitive delivery system in comparison to solvent without BA (0.27+/-0.00 mg/day). Increasing drug loading also increased release rate. In the case of thermosensitive polymer delivery system, increasing the hydrophobic PLGA block length of copolymers significantly (p<0.05) decreased the release rate of TSN. It is evident from this study that the phase sensitive and thermosensitive polymers are suitable for developing prolong-release injectable implant delivery systems for TSN.     

Influence of amphiphilic block copolymer induced changes in membrane ion conductance on the reversal of multidrug resistance

Block copolymers are able to reverse multidrug resistance (MDR) of tumor cells by a yet unknown mechanism. The drug efflux system's direct and indirect inhibition mediated by polymer P-glycoprotein (Pgp) interactions or adenosine triphosphate (ATP) depletion, respectively, may be involved in MDR reversal as well as damage to the membrane barrier caused by polymer insertion into the membrane. To test the latter hypothesis, cellular drug accumulation was monitored in the presence of both overexpressed fluorescently labeled Pgp and different block copolymers. Therefore, a new triblock copolymer (poly(ethylene oxide)- block-poly(hexafluoropropylene oxide)- block-poly(ethylene oxide)) was designed and synthesized by combined polymerization and polymer analogous reaction. Its administration induced drug uptake, whereas control cells with high Pgp expression levels showed no drug accumulation. Drug uptake was even more pronounced in the presence of another triblock copolymer: (poly(perfluorohexylethyl methacrylate)- block-poly(ethylene oxide)- block-poly(perfluorohexylethyl methacrylate). The latter polymer's lack of ionophoric activity suggests that ion transport facilitation by polymers is not a determinative factor for MDR reversal.     

Macromolecular composition and drug-loading effect on the delivery of paclitaxel and folic acid from acrylic matrices

Drug delivery systems based on synthetic polymers are widely employed in the treatment of several pathologies. In particular, the use of implantable devices able to release one or more active principles in a topic site with a controlled delivery kinetic represents an important improvement in this field. However, the release kinetic, that could be affected by different parameters, like polymer composition or chemical nature and initial drug loading, represents one of the problems related to the implantation of delivery systems. In this study, acrylic membranes with different macromolecular composition were prepared and studied analyzing delivery kinetic properties. Drug delivery systems were prepared using as matrix the copolymer poly(methylmethacrylate-co-butylmethacrylate) in three different compositions and folic acid (less hydrophobic) or Paclitaxel (more hydrophobic) as drugs, to evaluate the effect of macromolecular composition and hydrophilicity degree on the release properties. In addition, the effect of the initial drug loading was considered, loading drug delivery systems with four different initial drug percentages. Results showed a direct dependence of kinetics from macromolecular composition, hydrophilicity degree of solutes, and initial drug loading, allowing one to conclude that it is possible to design and to develop drug delivery systems starting from poly(methylmethacrylate-co-butylmethacrylate) matrices with specific properties by varying these three parameters.     

Injectable biodegradable temperature-responsive PLGA-PEG-PLGA copolymers: synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels

Injectable biodegradable temperature-responsive poly(DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers with DL-lactide/glycolide molar ratio ranging from 6/1 to 15/l were synthesized from monomers of DL-lactide, glycolide and polyethylene glycol and characterized by 1H NMR. The resulting copolymers are soluble in water to form free flowing fluid at room temperature but become hydrogels at body temperature. The hydrophobicity of the copolymer increased with the increasing of DL-lactide/glycolide molar ratio. In vitro dissolution studies with two different hydrophobic drugs (5-fluorouracil and indomethacin) were performed to study the effect of DL-lactide/glycolide molar ratio on drug release and to elucidate drug release mechanism. The release mechanism for hydrophilic 5-fluorouracil was diffusion-controlled, while hydrophobic indomethacin showed an biphasic profile comprising of an initial diffusion-controlled stage followed by the hydrogel erosion-dominated stage. The effect of DL-lactide/glycolide molar ratio on drug release seemed to be dependent on the drug release mechanism. It has less effect on the drug release during the diffusion-controlled stage, but significantly affected drug release during the hydrogel erosion-controlled stage. Compared with ReGel system, the synthesized copolymers showed a higher gelation temperature and longer period of drug release. The copolymers can solubilize the hydrophobic indomethacin and the solubility (13.7 mg/ml) was increased 3425-fold compared to that in water (4 microg/ml, 25 degrees C). Two methods of physical mixing method and solvent evaporation method were used for drug solubilization and the latter method showed higher solubilization efficiency.     

Specific interactions between diphenhydramine and alpha-helical poly(glutamic acid) - A new ion-pairing complex for taste masking and pH-controlled diphenhydramine release.

Formation of drug/excipient complex through ionic interactions has proven to be very effective for both controlled release and taste masking. Unfortunately, the ionic interactions between drugs and small molecule excipients are usually weak, and the stability of the formed complexes can be greatly influenced by solution ionic strength. In this study, we explored to formulate diphenhydramine (DPH), a very bitter tasting drug, using small molecular weight and carboxyl group containing polymers. Studies showed that DPH interacted with alpha-helical poly(glutamic acid) specifically to produce DPH/poly(glutamic acid) complexes, mostly spherical in shape with a diameter of around 1.0mum. Other drugs with similar chemical structures as DPH, such as phenylephrine and pseudoephedrine, could not form complexes with poly(glutamic acid) or other polymers under the same conditions. Although DPH in DPH/poly(glutamic acid) complexes existed amorphously, it showed increased stability.In vitro studies using electronic tongue demonstrated that poly(glutamic acid) might be as effective as sucralose for DPH bitter taste blocking. In addition, DPH/poly(glutamic acid) complexes were not stable in neutral or weak acidic (pH>5) environments and dissolved rapidly and completely. Therefore, DPH/poly(glutamic acid) complex may serve as a new formulation for taste masking and controlled DPH release in gastrointestinal tract. This is the first report that small molecule drugs can interact with peptides of specific secondary structures to form stable complexes. In addition to greatly expanded ion-pairing excipient pool, application of peptides in drug formulation may also solve the selectivity and stability problems faced by current small molecule excipients.     

The release behavior of doxorubicin hydrochloride from medicated fibers prepared by emulsion-electrospinning.

The release behavior of a water-soluble small molecule drug from the drug-loaded nanofibers prepared by emulsion-electrospinning was investigated. Doxorubicin hydrochloride (Dox), a water-soluble anticancer agent, was used as the model drug. The laser scanning confocal microscopic images indicated that the drug was well incorporated into amphiphilic poly(ethylene glycol)-poly(l-lactic acid) (PEG-PLA) diblock copolymer nanofibers, forming "core-sheath" structured drug-loaded nanofibers. The drug release behavior of this drug-loaded system showed a three-stage diffusion-controlled mechanism, in which the release rate of the first stage was slower than that of the second stage, but both obeyed Fick's second law. Based on these results, it is concluded that the Dox-loaded fibers prepared by emulsion-electrospinning represent a reservoir-type delivery system in which the Dox release rate decreases with the increasing Dox content in the fibers.     

Visual Evidence of Acidic Environment Within Degrading Poly(lactic-co-glycolic acid) (PLGA) Microspheres

Purpose. In the past decade, biodegradable polymers have becomethe materials of choice for a variety of biomaterials applications. Inparticular, poly(lactic-co-glycolic acid) (PLGA) microspheres havebeen extensively studied for controlled-release drug delivery. However,degradation of the polymer generates acidic monomers, andacidification of the inner polymer environment is a central issue in thedevelopment of these devices for drug delivery. Methods. To quantitatively determine the intrapolymer acidity, weentrapped pH-sensitive fluorescent dyes (conjugated to 10,000 Dadextrans) within the microspheres and imaged them with confocalfluorescence microscopy. The technique allows visualization of thespatial and temporal distribution of pH within the degradingmicrospheres (1). Results. Our experiments show the formation of a very acidicenvironment within the particles with the minimum pH as low as 1.5. Conclusions. The images show a pH gradient, with the most acidicenvironment at the center of the spheres and higher pH near the edges,which is characteristic of diffusion-controlled release of the acidicdegradation products.     

Thiomers

In recent years, thiolated polymers (thiomers) have been introduced as a promising new tool in the field of mucoadhesive drug delivery. Generated by the immobilization of sulfhydryl-bearing compounds on the backbone of well established mucoadhesive polymeric excipients, such as chitosan and poly(acrylates), thiomers display significantly increased mucoadhesive properties as a result of a covalent attachment to mucus glycoproteins. Strong cohesive properties obtained by the formation of inter- and intramolecular disulfide bonds result in comparatively higher stability, leading to prolonged disintegration times and sustained drug release from tablets, microparticles, and gels. The transport rate of peptide and protein drugs as well as hydrophilic model compounds across various animal mucosal tissues, studied in Ussing-type diffusion chambers, can be highly improved by the use of thiomers. Furthermore, thiomers exhibit an increased inhibitory effect towards membrane-bound and luminally secreted peptidases, respectively. The efficacy of thiomer-based drug delivery systems has been confirmed in various in vivo studies. Oral application of salmon calcitonin, insulin, and low-molecular weight heparin as well as intranasal application of human growth hormone embedded in a thiolated carrier matrix to conscious rats resulted in significantly increased bioavailability compared with use of unmodified basis polymers. Moreover, a study performed in human volunteers revealed that ocular inserts based on thiolated poly(acrylic acid) provide a detectable fluorescein concentration on the cornea for >8 hours, whereas the fluorescein concentration rapidly decreased after application of eye drops or inserts based on unmodified polymer. In light of these promising results, thiomers seem to be a valuable tool for the noninvasive delivery of mainly peptide and protein drugs.     

In situ Hydrogels Prepared by Photo-initiated Crosslinking of Acrylated Polymers for Local Delivery of Antitumor Drugs

A triblock copolymer was synthesized by ring opening polymerization of ε‐caprolactone in the presence of poly(ethylene glycol) (PEG). The resulted PCL-PEG-PCL triblock copolymer, PEG and monomethoxy (MPEG) were functionalized by end group acrylation. NMR and FT-IR analyses evidenced the successful synthesis and functionalization of polymers. A series of photo-crosslinked hydrogels composed of acrylated PEG-PCL-Acr and MPEG-Acr or PEG-Acr were prepared by exposure to visible light using lithium phenyl-2,4,6-trimethylbenzoylphosphinate as initiator. The hydrogels present a porous and interconnected structure as shown by SEM. The swelling performance of hydrogels is closely related to the crosslinking density and hydrophilic content. Addition of MPEG or PEG results in increase in water absorption capacity of hydrogels. In vitro degradation of hydrogels was realized in the presence of a lipase from porcine pancreas. Various degradation rates were obtained which mainly depend on the hydrogel composition. MTT assay confirmed the good biocompatibility of hydrogels. Importantly, in situ gelation was achieved by irradiation of a precursor solution injected in the abdomen of mice. Doxorubicin (DOX) was selected as a model antitumor drug to evaluate the potential of hydrogels in cancer therapy. Drug-loaded hydrogels were prepared by in situ encapsulation. In vitro drug release studies showed a sustained release during 28 days with small burst release. DOX-loaded hydrogels exhibit antitumor activity against A529 lung cancer cells comparable to free drug, suggesting that injectable in situ hydrogel with tunable properties could be most promising for local drug delivery in cancer therapy.     

Preparation,characterization, and drug release behaviors of drug nimodipine-loaded poly(epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) amphiphilic triblock copolymer micelles

Amphiphilic triblock copolymers, poly(epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) (PCL-PEO-PCL), were synthesized by ring opening polymerization of epsilon-caprolactone initiated with the hydroxyl functional groups of poly(ethylene glycol) at both ends of the chain. The micelles composed of this type of copolymer had such a structure that both ends of the PEO chain were anchored to the micelle. The critical micelle concentration of the block copolymer in distilled water was determined by a fluorescence probe technique using pyrene. As the hydrophobic components of the block copolymer increased, the critical micelle concentration value decreased. To estimate the feasibility as novel drug carriers, the block copolymer micelles were prepared by precipitation of polymer from acetone solution into water. From the observation of transmission electron microscopy, the micelles exhibited a spherical shape. Nimodipine was incorporated into the hydrophobic inner core of micelles as a lipophilic model drug to investigate the drug release behavior. The PEO/PCL ratio of copolymer was a main factor in controlling micelle size, drug-loading content, and drug release behavior. As PCL weight ratio increased, the micelle size and drug-loading content increased, and the drug release rate decreased.     

Hollow poly(MPC-g-PEG-b-PLA) graft copolymer microcapsule as a potential drug carrier

In this article, an amphiphilic graft copolymer composed of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) as the hydrophilic backbone, poly(L-lactic acid) (PLA) as the hydrophobic side-chains and polyethylene glycol (PEG) as the spacer was synthesized. Transmission electron microscopy revealed that the graft copolymer could self-assemble into hollow microcapsules when dialyzed in aqueous solution and particle sizes ranged from 200 to 300 nm, while the graft copolymer formed core-shell microspheres with the absence of PEG spacer. X-ray photoelectron microscope showed that MPC polymers were located at the surface of the microcapsules. The amounts of adsorbed bovine serum albumin and Fg on the microcapsules were significantly decreased than that on the conventional PLA particles (74% and 60%, respectively), well indicating the anti-adhesive property of the microcapsules. Paclitaxel was chosen as a prototype anticancer drug for the encapsulation and release studies, the results showed that the drug encapsulation efficiency was 89.3?±?1.2% and the microcapsules exhibited controlled release behaviour.     

Development and in vitro evaluation of a mucoadhesive vaginal delivery system for nystatin

The purpose of the present study was to design and evaluate a novel vaginal delivery system for nystatin based on mucoadhesive polymers. L-Cysteine and cysteamine, respectively, were covalently attached to poly(acrylic acid), and the two different thiolated polymers were evaluated in vitro regarding their swelling behavior, mucoadhesive properties and release behavior. Tablets comprising these thiolated polymers and nystatin demonstrated a high stability in vaginal fluid simulant pH 4.2 and an increase in weight by swelling whereas control tablets comprising unmodified poly(acrylic acid) disintegrated and dissolved. The mucoadhesion time of tablets on freshly excised bovine vaginal mucosa on a rotating cylinder and the total work of adhesion of gels and tablets increased significantly due to the formation of disulfide bonds between the thiolated polymer and cysteine rich subdomaines of the mucus layer. The drug nystatin was released more slowly out of thiomer tablets and gels than out of PAA control tablets and gels. Therefore these thiolated polymers are promising delivery systems for nystatin providing a prolonged residence time and a sustained drug release in vitro under physiological relevant conditions.     

罗替戈汀原位形成植入剂的制备及体内药动学考察

目的:制备抗帕金森病药物罗替戈汀原位形成植入剂(R-ISFI),并对其体内长效释药行为进行考察。方法:以N-甲基-二吡咯烷酮(NMP)为溶剂、聚乳酸-羟基乙酸共聚物(PLGA)为载体材料,制备R-ISFI。采用摇床法进行体外释放度的考察,采用大鼠体内药动学实验考察罗替戈汀的体内释药特性。大鼠皮下注射R-ISFI,HPLC法测定不同时间血浆中药物浓度。结果:高分子材料的类型、高分子材料与溶剂比、药物与高分子材料的用量比及ISFI的形状均对药物体外释放有显著的影响。R-ISFI体外释药平缓,30 d可累积释放85%,体内药动学结果表明,R-ISFI在体内缓释效果良好,突释小,可持续释放30 d。结论:制备的R-ISFI可持续平稳释放达一个月,是一种很有开发应用前景的长效缓释制剂。     

Controlled release of growth hormone from thermosensitive triblock copolymer systems: In vitro and in vivo evaluation

The purpose of this study was to design injectable controlled release polymer formulations for growth hormone using triblock copolymer PLGA-PEG-PLGA (MW 1400-1000-1400). Porcine growth hormone (pGH) formulations were prepared by adding pGH into 30% (w/v) aqueous solution of triblock copolymer. pGH concentrations in the released samples were determined using a standard MicroBCA method. In vitro release studies demonstrated that there were no initial burst of pGH from both formulations containing a low dose (0.12%, w/v) and a high dose (0.42%, w/v) of pGH. In vivo absorption study of pGH in rabbits showed that constant serum levels of exogenous pGH (3-7 ng/mL from high dose and 2-4 ng/mL from low dose) were detected for nearly 4 weeks from delivery systems upon single subcutaneous injection. The absolute bioavailability of pGH enhanced from the thermosensitive polymer-based systems, which was approximately 5-15-fold those of subcutaneous aqueous solution. MTT assay and light microscopy were used to investigate the in vitro and in vivo biocompatibility of thermosensitive polymer delivery systems, respectively. Both in vitro and in vivo results support the biocompatible nature of these polymer delivery systems. Thus, the triblock copolymer used in this study was able to control the release of incorporated pGH in vitro and in vivo for longer duration and the delivery system was biocompatible.