thermosensitive sol–gel reversible hydrogels

Advanced Drug Delivery Reviews 54 (2002) 37–51www.elsevier.com/ locate /drugdeliv

Thermosensitive sol–gel reversible hydrogelsa b b ,*Byeongmoon Jeong , Sung Wan Kim , You Han Bae

a

Pacific Northwest National Laboratory (PNNL), 902 Battelle Blvd. P.O. Box 999, K2-44, Richland, WA 99352, USAbCenter for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake

City, UT 84112, USA

Received 23 July 2001; accepted 10 September 2001

Abstract

Aqueous polymer solutions that are transformed into gels by changes in environmental conditions, such as temperatureand pH, thus resulting in in situ hydrogel formation, have recently attracted the attention of many investigators for scientificinterest and for practical biomedical or pharmaceutical applications. When the hydrogel is formed under physiologicalconditions and maintains its integrity for a desired period of time, the process may provide various advantages overconventional hydrogels. Because of the simplicity of pharmaceutical formulation by solution mixing, biocompatibility withbiological systems, and convenient administration, the pharmaceutical and biomedical uses of the water-based sol–geltransition include solubilization of low-molecular-weight hydrophobic drugs, controlled release, labile biomacromoleculedelivery, such as proteins and genes, cell immobilization, and tissue engineering. When the formed gel is proven to bebiocompatible and biodegradable, producing non-toxic degradation products, it will provide further benefits for in vivoapplications where degradation is desired. It is timely to summarize the polymeric systems that undergo sol–gel transitions,particularly due to temperature, with emphasis on the underlying transition mechanisms and potential delivery aspects. Thisreview stresses the polymeric systems of natural or modified natural polymers, N-isopropylacrylamide copolymers,poly(ethylene oxide) /poly(propylene oxide) block copolymers, and poly(ethylene glycol) /poly(D,L-lactide-co-glycolide)block copolymers. 2002 Elsevier Science B.V. All rights reserved.

Keywords: Aqueous polymer solution; Sol–gel transition; In situ hydrogel formation; Temperature; Drug delivery

Contents

1. Introduction ............................................................................................................................................................................ 382. Natural and modified natural polymers...................................................................................................................................... 383. N-Isopropylacrylamide copolymers .......................................................................................................................................... 404. PEG/PPO block copolymers and related derivatives .................................................................................................................. 415. PEG/PLGA block copolymers ................................................................................................................................................. 436. Summary ................................................................................................................................................................................ 48References .................................................................................................................................................................................. 48

*Corresponding author. Tel.: 11-801-581-6654; fax: 11-801-581-7848.

E-mail address: [email protected] (Y.H. Bae).

0169-409X/02/$ – see front matter 2002 Elsevier Science B.V. All rights reserved.PI I : S0169-409X( 01 )00242-3

38 B. Jeong et al. / Advanced Drug Delivery Reviews 54 (2002) 37 –51

1. Introduction sol–gel transition condition [7]. When a small heavyball resting on top of a solution (gel phase) begins to

Hydrogels preformed by chemical or physical penetrate into the gel under specific conditions, it cancrosslinking are a special class of polymers that be regarded as a gel–sol transition, again beingimbibe a considerable amount of water while main- dependent on the relative ball density compared totaining their shape. The research on hydrogels with the gel strength. When gelation is induced by tem-respect to drug delivery and biomedical devices has perature, the endothermic peak during heating ob-been extensive over the last few decades because of tained from differential scanning calorimetry (DSC)their biocompatible properties and easy control of determines the transition temperature as well as thesolute transport. One of the more recent trends in enthalpy of gelation [8]. Recently, a dynamic me-hydrogel research is in situ hydrogel formation by chanical analysis was used to determine the sol–gelphotopolymerization [1] or by phase transition [2,3]. transition in a more reproducible manner [9]. AnIn situ hydrogel formation makes it more feasible to abrupt change in the storage modulus or viscosityapply hydrogels for macromolecular drug delivery, reflects the sol–gel transition.tissue barriers, and tissue engineering. A particularly In this review, the sol-to-gel transition of aqueousinteresting and important polymeric system is hydro- polymer solutions primarily induced by temperaturegel forming solutions by a simple phase transition will be stressed, covering the natural or seminatural(sol–gel transition) in water without any chemical polymeric systems, N-isopropylacrylamidereaction or external stimulation. This system pro- (NiPAAM) copolymers, poly(ethylene glycol-b-pro-vides simplicity and safety in in vivo situations. pylene glycol-b-ethylene glycol) (Poloxamer) and its

The sol phase is defined as a flowing fluid, analogs, and poly(ethylene glycol) /poly(D,L-lacticwhereas the gel phase is non-flowing on an ex- acid-co-glycolic acid) block copolymers.perimental time scale, while maintaining its integrity.Above the critical concentration (critical gel con-centration, CGC) of a polymer, the gel phase ap- 2. Natural and modified natural polymerspears. The CGC is most often inversely related to themolecular weight of the polymer employed. The Historically, natural biopolymer gels have beendevelopment of physical junctions in the system is used as food and food processing aids as well as inregarded as one of the prerequisites in determining pharmacy. Thermoreversible gelation has been re-gelation, which must be sufficiently strong with ported for gelatin (a protein prepared from the partialrespect to the entropically driven dissolving forces of hydrolysis of collagen and containing proline,the solvent. The gelation of organic or aqueous glycine, and hydroxy proline as its major aminopolymer solutions occurs by various mechanisms that acids) and polysaccharides such as agarose (extractedhave been reviewed extensively and summarized from red sea weed; alternating copolymer of 1,4-[4,5]. linked 3,6-anhydro-a-L-galactose and 1,3-linked b-D-

The determination of the boundary between the sol galactose), amylose (a 1,4-linked a-D-glucan linearand gel phases depends on the experimental method. polymer), and amylopectin (a-1,6 glucan with a largeA simple test-tube inverting method was employed number of a-1,4-glucan branches), cellulose deriva-to roughly determine the phase boundary [6]. When a tives, carrageenans (extracted from red sea weed;test tube containing a solution is tilted, it is defined alternating copolymers of 1,4-linked a-D-galactoseas a sol phase if the solution deforms by flow, or a and 1,3-linked b-galactose, containing ester sulfate),

gel phase if there is no flow. The flow is a function and Gellan (from bacteria; a polysaccharide con-of time, tilting rate, amount of solution, and the sisting of b-glucose-b-D-glucuronic acid-b-glucose-diameter of the test tube. Considering the time– a-L-rhamnose) [10–14]. All of these biopolymerstemperature superposition principle in polymer de- form gels in water rather than organic solvents.formation, the test parameters should be fixed before Renaturation to the triple helical conformation indetermining the sol–gel boundary. The falling ball gelatin and double helical conformation in polysac-method is another simple way to determine the charides drives the nucleation and growth of crys-

B. Jeong et al. / Advanced Drug Delivery Reviews 54 (2002) 37 –51 39

Fig. 1. Gelation mechanism of polysaccharides in water. Random coils become helices, which subsequently aggregate to form the junctionzones of a gel.

tallites during gel formation [15]. Helix formation An interesting reverse thermogelation of a combi-followed by aggregation of the helices results in a nation of chitosan and glycerol phosphate disodiumjunction point (Fig. 1). At high temperatures, they salt was reported by Chenite et al. [18]. A typicalare assumed to have a random coil conformation. On solution was obtained by mixing a chitosan (91%reducing the temperature, they start to form double deacetylation) solution (200 mg in 9 ml HCl solutionhelices and aggregates that act as knots, i.e. the [0.1 M]) and a glycerophosphate disodium saltphysical junctions of the gels. solution (560 mg in 1 ml distilled water). At neutral

Most natural polymers form a gel phase on pH, the formulation was a homogeneous, clear liquidlowering the temperature. However, aqueous solu- at room temperature and became a gel in the vicinitytions of some cellulose derivatives exhibit reverse of 378C. The gelation temperature increased with athermogelation (gelation at elevated temperatures). decrease in the degree of deacetylation of theCellulose is not soluble in water, but, by introducing polymer, but was not significantly influenced by thehydrophilic moieties, cellulose derivatives become molecular weight of the chitosan. The primarywater soluble. When cellulose derivatives have an gelation force was believed to be a hydrophobicoptimum balance of hydrophilic and hydrophobic interaction of neutral chitosan molecules, which canmoieties, they undergo a sol-to-gel transition in be enhanced by the structuring action of glycerol onwater. The sol–gel transition temperature depends on water at elevated temperatures. The gel was capablethe substitution of cellulose at the hydroxy group of maintaining the bioactivity of loaded bone protein[16]. Water becomes a poorer solvent with increasing (BP, an osteogenic mixture of TGFb family mem-temperature and polymer–polymer interactions be- bers) and released BP. The viability of various cells,come dominant at higher temperatures, resulting in a including chondrocytes, entrapped in the gel wasgel [17]. Methyl cellulose and hydroxypropyl cellu- . 80%. When the chondrocytes in the gel werelose are typical examples. implanted in an animal model, remodeling chon-


drocytes secreting a matrix characteristic of normal above 328C (LCST). Below the LCST, the enthalpycartilage was observed after 3 weeks. term, which is mostly contributed by the hydrogen

bonding between polymer polar groups and watermolecules, leads to dissolution of the polymer.

3. N-Isopropylacrylamide copolymers Above the LCST, the entropy term (hydrophobicinteractions) dominates, resulting in precipitation of

Polymer precipitation in solution on raising the the polymer in water. The shift of C–H stretchingtemperature often occurs in aqueous systems and band can be observed on the nano scale by an atomicresults from the balance of intermolecular forces force microscope (AFM) [25]. This is caused by thebetween the polymer and the solvent as well as dehydration of the hydrophobic isopropyl groupsbetween polymers. Table 1 shows some examples of during the coil-to-globule transition. However, afterpolymers showing a low critical solution temperature precipitation, most (83%) of the carbonyl groups of(LCST) in water. NiPAAM still form hydrogen bonds with water

N-Isopropylacrylamide homopolymer (poly- molecules [26]. The LCST of NiPAAM polymers(NiPAAM); Fig. 2) and its copolymers are most can be controlled by copolymerizing with otheroften investigated for the structure–property relation- monomers with different hydrophobicity [27]. Theship [19,20], drug delivery [21], tissue engineering more hydrophobic the comonomer, the lower the[22], and enzyme or protein modification [23,24]. resulting LCST. By controlling the polymer topolo-

An aqueous poly(NiPAAM) solution precipitates gy, the kinetics of the coil-to-globule transition canalso be controlled. NiPAAM copolymers grafted witholigoNiPAAM [28] or PEG [29] show a fast response

Table 1 to temperature changes. The grafted short chain ofPolymers showing a LCST in water

oligoNiPAAM in the former case contributes to rapidPolymer LCST (8C) dehydration while PEG provides the water channelPoly(N-isopropylacrylamide), PNIPAM |32 for fast rehydration.Poly(vinyl methyl ether), PVME |40 It was found that an aqueous solution of high-Poly(ethylene glycol), PEG |120 molecular-weight NiPAAM/acrylic acid (2–5 mol%)Poly(propylene glycol), PPG |50

copolymer synthesized in benzene showed reversiblePoly(methacrylic acid), PMAA |75gelation above a critical concentration ( | 4 wt%),Poly(vinyl alcohol), PVA |125

Poly(vinyl methyl oxazolidone), PVMO |65 without noticeable hysteresis around 328C, ratherPoly(vinyl pyrrolidone), PVP |160 than polymer precipitation [30]. The polymers werePoly(silamine) |37 characterized as having a distribution of polymerMethylcellulose, MC |80

composition. Gelation was attributed to polymerHydroxypropylcellulose, HPC |55chain entanglements and the weak physical associa-Polyphosphazene derivatives 33–100

Poly(N-vinylcaprolactam) |30 tion of polymer precipitates with fewer ionizablePoly(siloxyethylene glycol) 10–60 groups at lower temperatures while maintaining

hydration by more charged and expanded polymerstrands. This resulted in an opaque, loose gel thatwas deformable under shear stress. It was proposedthat such properties could be used for the design of arefillable macrocapsule-type biohybrid artificial pan-creas. Isolated islets of Langerhans suspended in thepolymer solution were effectively entrapped in thegel when the solution temperature was raised from258C to body temperature, and the gel showed nocytotoxicity. Another advantage of the gel was thesignificantly higher permeability of insulin secreted

Fig. 2. The chemical structure of poly(N-isopropylacrylamide). from entrapped islets, because of the gel’s heteroge-


neous character, rather than a traditional cell-entrap- Pluronic (BASF) or Poloxamer (ICI)) series withping matrix of alginate [31]. various molecular weights and PEG/PPO block

Chondrocytes immobilized in a thermoreversible ratios was used as a non-ionic surfactant, and theNiPAAM/acrylic acid copolymer gel demonstrated aqueous solutions of some Poloxamers exhibitedbetter phenotype expression with a round shape than phase transitions from sol to gel (low temperaturethat cultured in a two-dimensional matrix (culture sol–gel boundary) and from gel to sol (high tem-dish) [32]. perature gel–sol boundary) as the temperature in-

Poly(NiPAAM)/poly(ethylene glycol) copolymers creased monotonically when the polymer concen-with various architectures have been investigated, tration was above a critical value. The physico-such as poly(ethylene glycol)-b-poly(NiPAAM)-b- chemical characteristics and applications of Polox-poly(ethylene glycol) triblock copolymers and poly- amers were reviewed extensively by Alexandridis(NiPAAM)-g-PEG copolymers, which form ther- and Hatton [35]. Continuously heating the gel phasemoreversible micelles [33]. More recently, diblock above the high temperature boundary produces anand star-shaped block copolymers AB, A(B) , opaque solution. The polymer exists in the gel form2

A(B) , and A(B) , where A is the central hydro- only between two critical transition temperatures,4 8

philic star-shaped PEG block (molecular weight that vary with polymer composition and concen-(MW) per arm 2000–2460) and B is the tem- tration.perature-responsive NiPAAM oligomer block (MW The gelation mechanism of Poloxamer aqueous1900–2400), have been synthesized. These were solutions remains a controversial issue. In the earlyreported to form a somewhat viscoelastic gel upon 1980s, an intrinsic change in the micellar properties,heating (gelation temperature 26–338C) when the such as aggregation number and micellar symmetry,typical polymer concentration was . 20 wt%, and was thought to cause aqueous Poloxamer solutions tothe resulting gels showed no syneresis [34]. This form a gel. This was based on the observation of aprocess was reversible without hysteresis. Based on decrease in the critical micelle concentration withdifferential scanning calorimetry (DSC) and dynamic increasing temperature [36]. A little later, the dehy-mechanical analysis, the gelation mechanism was dration of poly(propylene oxide) (PPO) was pro-observed to be micellar aggregation for the AB posed as a cause of the gelation of aqueous Polox-

13diblock copolymer. It was found to be a strong amer solutions based on a C-NMR study [37]. Theassociative network formation for the other polymer change in the chemical shift and peak broadening ofarchitectures via hydrophobic interaction of col- the PPO methyl group at the transition temperaturelapsed NiPAAM oligomer blocks. The polymer was interpreted as the dehydration of PPO from thearchitecture influenced the resulting gel strengths and existing micelles. This resulted in increasing frictionA(B) showed the highest gel strength of 860 Pa between the polymer chains followed by viscosity of4

yield stress. the solution, resulting in the gel phase. Vadnere et al.claimed that the entropy change caused by locallyordered water around the core PPO drove the sol-to-

4. PEG/PPO block copolymers and related gel transition [38]. This is a traditional view ofderivatives hydrophobic interactions. They suggested a two-state

model for (O–C–C–O) groups, assuming polarThe commercial poly(ethylene oxide-b-propylene (gauche) and nonpolar (anti) states. With increasing

oxide-b-ethylene oxide) (PEO–PPO–PEO, Fig. 3; temperature, the population of the nonpolar antiformincreases, driving gel formation. Zhou and Chuobserved the dehydration of poly(ethylene oxide)(PEO) with increasing temperature. This dehydrationwas thought to drive the gelation of aqueous Polox-amer solutions [39]. Attwood et al. observed that theFig. 3. The chemical structure of poly(ethylene oxide-co-pro-hydrodynamic radii of Poloxamer micelles werepylene oxide-co-polyethylene oxide) (PEO–PPO–PEO) (Polox-constant, while the aggregation number and volumeamer or Pluronic).


fraction of the micelles increased with increasing (acrylic acid)-g-Poloxamer by coupling monoamine-temperature [40]. Recently, mechanistic studies on terminated Poloxamer to poly(acrylic acid) (PAA)the phase transition and characterization of the using dicyclohexyl carbodiimide [53]. This polymersolution and gel states of Poloxamers were reported showed bioadhesive as well as thermosensitive gel-using various instrumental techniques, such as ultra- ling properties. Bromberg developed Poloxamer-g-sound velocity, dynamic and static light scattering, PAA via a C–C bond [54–59]. Simple radicalsmall angle neutron scattering (SANS), rheometry, polymerization of acrylic acid in the presence ofdielectric constant measurement, and mi- Poloxamer gave the graft copolymer by chain trans-crocalorimetry [41–44]. fer reactions. The transition temperature of the

Taken together, triblock copolymers form micelles resulting Poloxamer-g-PAA (M | 400,000) aqueousn

which equilibrate with Poloxamer unimers at low solution (1% w/v) was 358C when the Poloxamertemperature above the critical micelle concentration F127/PAA weight ratio was 0.55:1.00. The transition(CMC), about 1 mg/ml [45]. As the temperature temperature was controlled between 10 and 308Cincreases, the equilibrium shifts from unimers to over the concentration range 0.2–2.5 wt%. Com-spherical micelles, reducing the number of unas- pared with Poloxamer (CGC . 20 wt%), this graftsociated unimers in solution, leading to an increase copolymer showed a gel phase at much lowerin the micelle volume fraction (f ). When f . concentrations. This trend implies that the high-m m

0.53, the system becomes a gel by micelle packing molecular-weight Poloxamer-g-PAA easily forms(hard-sphere crystallization) [46,47]. The hard-sphere physical crosslinking junctions in water; however,interaction radius increases steadily with tempera- the sol–gel transition temperature and onset ofture, while the micelle volume fraction increases micellization were observed at similar temperatures,abruptly in a certain temperature range, which is indicating a similar mechanism of gelation with andependent upon the concentration. When the volume aqueous Poloxamers solution (Fig. 4). The Polox-fraction of the micelles is . 0.53, the system amer-g-PAA system contains pH-sensitive functionalbecomes a gel. groups. When compared with PAA, the carboxylic

The transition from gel to sol at high temperatures groups of Poloxamer-g-PAA are less ionized at pHis relatively poorly understood and could be related 3–12. The ionization of PAA causes expansion of theto the shrinkage of the PEO corona of the micelles polymer and increases the gel modulus over the pHdue to temperature effects on PEO solubility and the range 5.4–12.0. The sol-to-gel transition temperatureinteraction of PEO chains with the PPO hard core decreases with ionization in this range of pH. The[48]. A recent SANS study proposed the transition of addition of NaCl affects the gel modulus. Increasingthe micelle structure from spherical to cylindrical, NaCl from 0 to 10% w/v decreased the gel modulusthus releasing micelle-packing constraints, as the decreased significantly (DG9 | 80 Pa), while the sol-cause of the high temperature gel–sol transition to-gel transition temperature remained almost un-[43,49]. changed (DT , 58C). As polymer ionization in-

The phase transition behavior was studied with creases with pH, the environment of the PPO seg-altered triblock structures, where poly(butylene ments become more polar, driving the PPO tooxide) (PBO) was used in place of PPO in the aggregate at lower temperatures.middle block or with PEO–PBO diblock copolymers This unique sol-to-gel transition has made the[50,51]. During synthesis via anionic living poly- system attractive as an injectable drug deliverymerization, ethylene oxide–butylene oxide block matrix in an in situ gel-forming drug depot. Mostcopolymers avoided chain transfer reactions, which applications are based on Poloxamer PF-127 andare inherent in propylene oxide polymerization [52]. include delivery of protein /peptide drugs, such asThe polymer solutions showed only a gel-to-sol insulin, urease, interleukin-2, epidermal growth fac-transition with increasing temperature (high tempera- tor (EGF), bone morphogenic protein (BMP), fi-ture gel–sol boundary). broblastic growth factor (FGF), and endothelial cell

Polymers coupled with Poloxamers also exhibit growth factor (ECGF). Most release profiles showgelation in water. Hoffman et al. developed poly- sustained release kinetics over several hours. Polox-


Fig. 4. Gelation mechanism of PAA-g-Poloxamer.

amer hydrogels show a zero-order release profile for LD for subcutaneous injection for a mouse is 5.550

interleukin-2 and urease over 8 h [60,61]. Tride- g /kg [84,85].capeptide melanotan-I (MT-I) and mitomycin C Because of the dissociation of packed micelles inwere released from Poloxamer 407 hydrogel over 4 an excess of water, the gel integrity of Poloxamersto 6 h [62,63]. The weight percent of gel dissolved does not persist for more than a few days. In vitrowas well correlated with the MT-I release profile. experiments showed that 25 wt% of Poloxamer 407The higher the polymer concentration, the slower the gel was completely dissolved in the release mediumrelease rate observed. The release rate was manipu- in 4 h. For 35 wt% Poloxamer 407, the gel was 50%lated by mixing excipients. dissolved in 4 h [67]. Therefore, Poloxamer formula-

Poloxamers have been suggested for use as an tions are only useful for a short period after adminis-ocular drug delivery carrier of pilocarpine, but an tration.animal study of PF-127 showed marked destructionof the retina [64]. The addition of poly(ethyleneglycol) (PEG) or poly(vinyl pyrrolidone) (PVP) 5. PEG/PLGA block copolymersaccelerated pilocarpine release, while the addition ofmethylcellulose slowed the release rate [65]. Table 2 A novel concept, which combines thermogelation,further summarizes the recent applications of Polox- biodegradability, and no toxicity, has been proposedamers for drug delivery [66–83]. for an injectable gel system with better safety and

Some low-molecular-weight Poloxamers are longer gel duration [86]. Poly(ethylene glycol-b-L-classified as inactive ingredients for currently mar- lactic acid-b-ethylene glycol) (PEG–PLLA–PEG)keted drug products [84,85]. For example, Polox- was synthesized by ring-opening polymerization ofamer 188, PEO–PPO–PEO (3500–1570–3500), is L-lactide onto monomethoxy poly(ethylene glycol)used as an intravenous injection formulation and an (MW 5000), which produced PEG–PLLA diblockoral formulation, and Poloxamer 407, PEO–PPO– copolymers, followed by coupling of the resultingPEO (4300–3770–4300), as an ophthalmic solution. diblock copolymers with hexamethylene diisocyanateHowever, an animal toxicity study of Poloxamers to produce triblock copolymers with a PLLA centralshowed that rats receiving 7.5 wt% of Poloxamer in block (MW 2000–5000). The copolymers onlytheir diet exhibited a decrease in growth rate. Acute exhibited a single sol-to-gel transition with decreas-animal toxicity data for Poloxamer 188 show that the ing temperature in water, like a gelatin solution. As


Table 2Applications of Poloxamers for drug delivery

Drug Comments Ref.

Pilocarpine Poloxamer (PF-127) /PEG, PVP, PVA, MC, HPMC [65]Insulin Poloxamer (PF-127) / fatty acid; potential application [66]

for buccal deliveryPilocarpine Carbopol /poloxamer; ophthalmic drug delivery [67]Insulin Poloxamer PF-127; subcutaneous injection [68]S-Nitroso-N-acetyl Poloxamer; local delivery of NO donor to preventpenicillamine initial hyperplasia [69]

C-myb antisense Poloxamer (PF-127); prevents initial hyperplasia [70]oligonucleotide

Tyrphostin-47 Poloxamer (PF-127); inhibits smooth muscle cell proliferation [71]Urease Poloxamer (PF-127); intraperitoneal injection in the rat [72]Interleukin-2 Poloxamer (PF-127); intraperitoneal injection in mice [73]EGF Poloxamer (PF-127) [74]Gene delivery Poloxamer (PF-127) / fusogenic peptide /haemagglutinin / [75]

chloroquineIbuprofen Poloxamer (PF-127) / liposomal gel [76]BMP Poloxamer (PF-127) [77]Vancomycin Poloxamer (PF-127); antibiotic delivery [78]Lidocaine / Poloxamer (PF-127); epidural injection for prolonged [79]ibuprofen systemic absorption

Sulfadiazine Poloxamer 188; antibacterial agent for wound healing [80]BFGF, ECGF Poloxmer (PF-127) [81]Lidocaine Poloxamer (PF-127); rat experiments for local anesthetics [82]Methotrexate Poloxamer (PF-127); topical administration [83]

EGF, epidermal growth factor; BMP, bone morphogenic protein; BFGF, basic fibroblast growth factor; ECGF, endothelial cell growthfactor.

shown in the gelation phase diagram of the triblock by the length of the middle block when the terminalcopolymer (Fig. 5), the gelation concentration (10– PEG block was kept constant. When FITC-labelled30 wt%) and temperature (20–608C) were influenced dextran (MW 20,000) was mixed with an aqueous

solution of the 5000–2040–5000 triblock copolymerabove the critical gelation temperature at a givenpolymer concentration, and the mixture was gelledby cooling to body temperature. Dextran was thenreleased at a constant release rate over 10 days withor without a burst effect depending on the polymerconcentration, as shown in Fig. 6.

Changing the polymer composition further, par-ticularly the middle block composition, the blocklength, and the block ratio, produced the nextgeneration of poly(ethylene glycol-b-L-lactic acid-co-glycolide-b-ethylene glycol) (PEG–PLGA–PEG) tri-block copolymers (Fig. 7). The aqueous polymersolution is a free-flowing sol at room temperatureand becomes a gel at body temperature [3]. Thephase diagram of a PEG–PLGA–PEG triblock co-Fig. 5. Gel–sol transition curves of PEG–PLLA–PEG triblockpolymer aqueous solution, which is shown in Fig. 8,copolymers: (d) 5000–2040–5000; (m) 5000–3000–5000; (j)

5000–5000–5000. Reproduced from Ref. [86], with permission. resembles that of Poloxamer F127.


Fig. 6. In vitro release profile of FITC-labelled dextran (MW20,000) from PEG–PLLA–PEG (MW 5000–2040–5000) triblockcopolymer. FITC-labelled dextran (5.4 mg) was mixed with 0.5ml of aqueous polymer solution [(j) 23 wt%; (d) 35 wt% Fig. 8. Phase diagram of a PEG–PLGA–PEG (550–2810–550)polymer]. Reproduced from Ref. [86], with permission. triblock copolymer aqueous solution. Circles indicate sol–gel

transitions and squares are the temperatures where the gelbecomes turbid. Reproduced from Ref. [3], with permission.

The mechanism of the sol-to-gel transition (lowertransition) of an aqueous solution of a PEG–PLGA–PEG triblock copolymer is believed to be a micellar Aqueous Poloxamer solutions are known to under-expansion accompanying an increase in aggregation go the sol-to-gel transition by a shift in equilibriumnumber driven by hydrophobic forces [94,95]. From from unimer to micelle, whereas the PEG–PLGA–SLS and DLS studies on PEG–PLGA–PEG triblock PEG triblock copolymer in water seems to undergocopolymer aqueous solutions, two important facts the sol-to-gel transition by micellar growth. Thewere noted [87]. First, water becomes less favorable upper gel-to-sol transition is driven by a change infor the PEG–PLGA–PEG triblock copolymers, as the three-dimensional micellar structures, which arereflected in the second viral coefficients, and such a broken in PEG–PLGA–PEG triblock copolymers.trend is rather abrupt at about 308C, which is the The structure–property relationship in the sol–gelsol-to-gel transition temperature at high concentra- transition showed that the sol–gel transition tempera-tion. A decrease in the second viral coefficient ture and critical gel concentration decreased withindicates that the polymer–polymer attraction in- increasing hydrophobicity of the triblock copolymerscreases relative to polymer–solvent interactions. [88]. The precise control of the sol–gel transitionSecond, the micelles grow by an increase in aggrega- temperature is of importance in designing a drugtion number as well as the diameter of the micelle. delivery system. The transition temperature deter-The growth of the micelles also occurred abruptly mines the applicability of the system, formulationaround 308C. Therefore, micellar growth and an temperature, and injectability. The sol–gel transitionincrease in polymer–polymer attraction may drive temperature can be controlled by changing thethe sol-to-gel transition at high concentrations (above molecular parameters of PEG–PLGA–PEG triblockCGC) with increasing temperature. copolymers, such as the PLGA length, the PEG

Fig. 7. The chemical structure of a PEG–PLGA–PEG triblock copolymer. For the sake of simplicity, the coupling part of the PLGA middleblock via hexamethylene diisocyanate is omitted.


length, and the ratio of DLLA to GA in the middle A transparent gel was formed and the shape of theblock. The hydrophobic block (PLGA) length of a gel maintained its three-dimensional form due to thePEG-PLGA-PEG triblock copolymer was increased rapid sol-to-gel transition. The integrity of the gelfrom 2320 to 2840 at a fixed PEG length of 550. persisted for more than 1 month in the rat. SuchThen, the sol-to-gel transition temperature (DT | 2 characteristics make it possible for PEG–PLGA–108C) and the critical gel concentration (CGC), PEG triblock copolymers to formulate a drug su-above which the gel phase appears (DCGC|211 perior to the other injectable drug delivery systemswt%), decreased, indicating that this transition is available thus far. The gel was degraded to form andriven by hydrophobic forces. The gel-to-sol transi- opaque gel at a later stage of degradation because oftion temperature also increased (DT | 108C) with a preferential mass loss of the PEG part.increasing hydrophobic block length. Once the gel is Ketoprofen and spironolactone release kineticsformed, an opposing force, such as kinetic energy, is were studied from a PEG–PLGA–PEG triblockneeded to overcome this interaction. The longer the copolymer hydrogel [91]. The release profile washydrophobic block length, the stronger the shear strongly affected by the hydrophobicity of the drug.stress required to make the gel system flow. There- The more hydrophilic ketoprofen was released con-fore, the gel region, the width between the lower and tinuously over 2 weeks, and the release rate wasupper transition temperatures, was controlled by controlled by the initial polymer concentration. Thevarying the PLGA length. On increasing the PEG more hydrophobic spironolactone was released overlength of a PEG–PLGA–PEG triblock copolymer 2 months, and the release pattern showed a biphasicfrom 550 to 780 at a fixed PLGA length of 2300, the mechanism, an initial diffusion followed by a combi-phase diagrams were shifted to higher temperatures nation of degradation and diffusion at a later stage.(DT | 188C). The gel region remained almost con- This primarily results from the difference in parti-stant. This indicates that the gel strength is mainly tioning between ketoprofen and spironolactone in adetermined by the hydrophobic block. The DL-lactic hydrogel with domain morphology. The more hydro-acid moiety is more hydrophobic than glycolic acid phobic drug partitioned more into the hydrophobicin PLGA. A similar interpretation can be drawn core. Smaller amounts of the drug were initiallyregarding the effect of the PLGA length on the released from the PEG shell region followed by asol–gel transition. The hydrophobicity was increased stagnant phase. And finally release from the hydro-by increasing the ratio of DL-lactic acid to glycolic phobic PLGA core domain during degradation of theacid from 78:22 to 72:28 of a PEG–PLGA–PEG system. The release profiles of spironolactone fitted(550–2900–550) triblock then, the sol-to-gel transi- well to theoretical curves by assuming a domaintion temperature (DT | 2 58C) and CGC (DCGC|2 structure of the gel. The release of spironolactone5 wt%) decreased, and the gel stability region could be controlled by the initial polymer concen-increased. Furthermore, the gelation temperature was tration, loading of drug, and the structure of thecontrolled by additives. The addition of a salting-out polymer (Fig. 9).salt (1 wt%), such as NaCl, decreased the sol–gel Interestingly, a series of low-molecular-weighttransition temperature by 58C, whereas a salting-in PLGA–PEG (MW 1000 or 1450)–PLGA (BAB-salt, NaSCN, increased the sol-to-gel transition tem- type) block copolymers with varying LA/GA (1.5–perature by 58C. Interestingly, a 1 wt% addition of 4.0) and PEG/PLGA (0.34–0.5) ratios also showedPEG 2000 decreased the sol-to-gel transition by similar thermo-reversible sol–gel transitions to1.58C, indicating that PEG may play a role in the ABA-type block copolymers [92,93]. The synthesisphysical junction to make a gel. In the case of the of the copolymers required no coupling agent, thusPoloxamer system, the addition of PEG homopoly- they were prepared using a simpler procedure andmers increased the sol-to-gel transition temperature resulted in more favorable degradation products[89]. when applied in vivo than ABA-type block co-

In situ gel formation in vivo was also confirmed polymers. Gelation may occur by a mechanismby subcutaneous injection of PEG–PLGA–PEG distinguishable from that of ABA block copolymerstriblock copolymer aqueous solutions into rats [90]. because of the PLGA end blocks. The polymer forms


Fig. 9. Spironolactone release from a PEG–PLGA–PEG (550–2810–550) triblock copolymer hydrogel. The legend indicates theinitial concentration of polymer in the PBS buffer. The drug loadwas fixed at 0.25 wt%. The lines are theoretical curves derivedfrom a mathematical model. Reproduced from Ref. [3], withpermission.

micelles with the core of the PLGA block and thebent PEG shell below the CGC, but may also formbridging micelles with increasing concentration and Fig. 10. (a) In vitro release of pGH and Zn-pGH from ReGel

temperature. Only a brief study by dynamic light (23% w/w, in water). (b) Efficacy of single dose ReGel /pGHscattering was made for this particular polymer versus 14 daily conventional pGH injections. Reproduced from

Ref. [93], with permission.gelation. It described the micelle size and sizedistribution as a function of temperature, togetherwith a hypothetical mechanism. Further characteriza- for pGH. In a separate study, insulin crystals formedtion and examination will elucidate a more detailed in the presence of zinc were mixed with a BAB

mechanism. block copolymer (MW 1500–1000–1500, ReGel )Block copolymers have been investigated inten- solution and the mixture was injected subcutaneously

sively for the solubilization and stabilization of into rats. A fasting plasma insulin level in the rangewater-insoluble drugs, such as cyclosporin A and 20–35 mIU/ml was maintained for at least 2 weekspaclitaxel, and various protein pharmaceuticals, in- (Fig. 11) [94].cluding Zn-insulin, porcine growth hormone (pGH), A more recent study on low-molecular-weightand glycosylated granulocyte colony stimulating (|10,000) PEG-g-PLGA and PLGA-g-PEG poly-factor (G-CSF) [93]. Aqueous formulations in- mers (25 wt% in water) showed reverse thermogela-creased the solubilities of paclitaxel and cyclosporin tion as for ABA- or BAB-type block copolymersA by 400- and .2000-fold, respectively, and the [95,96]. PEG-g-PLGA was synthesized by ring-resulting gels released the incorporated drugs over 50 opening polymerization of lactide and glycolide indays in a controlled fashion. The controlled release the presence of PEG pendant hydroxy groups, andof protein drugs was also obtained over 2 weeks. All PLGA-g-PEG by one-step ring-opening polymeri-of these behaviors are in sharp contrast to the results zation of epoxy-terminated PEG, lactide, and gly-from Poloxamer formulations, which allowed short- colide. The gelation temperature was around 308C,term controlled release. The in vitro / in vivo relation- and it dissolved below 208C (hysteresis).ship (in vivo efficacy) of the gel formulation was The thermogelation of multiblock copolymers ofwell demonstrated, for example as shown in Fig. 10 PEG and poly(´-caprolactone), coupled by hexa-


Fig. 11. Fasting plasma insulin level of male Sprague–Dawley rats (n55). Polymer / insulin /zinc (0.6 ml; 23 wt% triblock copolymer, 10IU insulin /ml) solution was injected subcutaneously. Reproduced from Ref. [94], with permission.

methylene diisocyanate, in water has been reported solution, particularly for labile biomacromolecules.[97]. This was accomplished by reducing the tem- The transition will also be useful for cell immobiliza-perature. All these results suggest that gelation is not tion in an extracellular matrix and for providing alimited to a specific polymer composition and topol- scaffold for tissue regeneration. Micelle-formingogy, but rather that the desired gel property can be polymers may solubilize water-insoluble drugs andtailored by designing polymers to meet degradation, subsequently release the entrapped drugs in a con-gel strength, and gel duration targets. trolled fashion after gelation.

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