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COPOLYMERS IN THE PREPARATION OF PARENTERAL DRUG DELIVERY SYSTEMS

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Copolymers in the Preparation of Parenteral Drug Delivery Sysyems Rossella Dorati, Claudia Colonna, Ida Genta, Tiziana Modena and Bice Conti (Authors) 2010. 978-1-61668-892-9

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COPOLYMERS IN THE PREPARATION OF PARENTERAL DRUG DELIVERY SYSTEMS

ROSSELLA DORATI, CLAUDIA COLONNA, IDA GENTA, TIZIANA MODENA AND BICE CONTI

Nova Science Publishers, Inc. New York

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CONTENTS Preface

ix 

Abbreviations

1 

Introduction

3 

Chapter 1

Definition and Classification of Block Copolymers

Chapter 2

Synthesis of Block Copolymers from PEO and Lactones

11 

Mechanism of Copolymerization from PEO and Lactone

15 

Physico-Chemical Properties of Block Copolymers from PEO and Lactones

21 

Degradation of ABA Triblock Copolymers Based on PEO and Polyesters

25 

Parenteral Drug Delivery Systems Based on ABA Polymers

31 

Overview on Sterilization Techniques for Block Copolymers

51 

Conclusion

63 

Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8

7 

References

65 

Index

81 

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PREFACE Poly orthoesters have been the most intensively studied polymers for biomedical applications for their low immunogenicity, good biocompatibility and excellent mechanical properties. In the last decade, the synthesis of polyester-polyether block copolymers has attracted increasing attention, because they may be used in several pharmaceutical and medical applications such as sutures, implants for bone fixation, carriers in drug delivery and temporary matrix or scaffolds in tissue engineering. Multiblock copolymers of PEO and PLA/PLGA were originally developed to offer versatility in the polymer choice, to get the control of the polymer degradation, to facilitate the loading of pharmaceutical molecules, to modulate the encapsulated (bio)active agents release and to preserve their activity during drug delivery systems preparation. A wide range of performance characteristics can be obtained by manipulation of different monomers, such as PEO, PLA and PLGA. The polymer composition, molecular weight and number of arms are the main parameters which affect the block copolymers physical properties including thermal behaviour, solubility and swelling. Architectural modifications of polymers lead to change in chain length, crystalline state and morphology and they significantly affect formulation process, degradation behaviour and in vivo fate of the prepared delivery systems. In the last two decades, block copolymers containing PEO, hydrophilic B-blocks, and PLA or PLGA, hydrophobic A-blocks, have been widely utilized to formulate parenteral drug delivery systems for peptides and proteins, such as micro and nanoparticles, implants, micelles, hydrogels and scaffolds.

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ABBREVIATIONS LA GA PLA PGA PEG PEO PCL PET PLGA PLA-PEG-PLA PDLLA LLA/EO PLLGA mPEG-PLA DDS Mw Mn Tm Tg EPR SDS-PAGE

lactic acid glycolic acid polylactide polyglycolide polyethylenglycol poly(ethylen oxide) poly(ε-caprolactone) poly(ehtylen terephatalate) polylactide-co-glycolide polylactide-polyethylenglycol-polylactide poly D,L-lactide L-lactic acid/ethylene oxide poly-L-lactide-co-lycolide methoxy polyethylenglycol- poly-L-lactide drug delivery systems average molecular weight number average molecular weight melting temperature glass transition temperature Electron Paramagnetic Resonance Sodium Dodecyl Sulphate – PolyAcrylamide Gel Electrophoresis

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INTRODUCTION Biodegradable polymers as PLA, PGA and related copolymer constitute the biodegradable polymers family most commonly used in the pharmaceutical, medical and biomedical engineering field. Among all these polymers, PLA has been widely investigated, as surgical material, as carriers in drug delivery and as scaffolds in tissue engineering, due to its biodegradability, biocompatibility, high mechanical properties and excellent shaping and molding features [1, 2, 3]. The main difficulty, associated with PLA applications in pharmaceutical and medical biomedical engineering fields, was the inadequate interaction between the polymer and cells due to the hydrophobic features of poly lactides which can lead to in vivo foreign body reaction: inflammation, infection, local tissue necrosis and thrombosis. Moreover, the poly orthoesters functional groups lack reduce the possibility to modify easily polymer compounds with biological active agent [4]. To extend the potential application area of aliphatic polyester polymers, multiblock copolymers with a more complex structure such as star, brushes, cyclic and cross-linked organization have been extensively synthesized and investigate [5]. Many authors have tried to modify aliphatic polyester polymers with the intention to improve their phisico-chemical properties and to introduce functional groups in the polymer main chain which can may be used for ligand coupling [1-6]. A common approach to overcome aliphatic polyesters limits has been to combine hydrophilic segments, such as PEO, into polymer chains [2]. PEO has been often incorporated in PLA, PGA, PLGA, PCL and PET hydrophobic chains for its several favorable biological and chemical properties such as high hydrophilicity, biocompatibility, atoxicity and non-immugenicity [1].

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Moreover, PEO is an uncharged, highly flexible polymer that is known to reduce protein adsorption and cell interaction when presented on the surface. It has been shown that PEO with a molecular weight lower than 6 · 103 g/mol is passively excreted by the kidneys [7]. The most important aspect that have made amphiphilic copolymers attractive for pharmaceutical and biomedical applications is represented by the chance to vary the chemical composition, the molecular weight (Mw) and the block length ratio of block copolymers depending on the final applications [8]. Varying the chemical composition, Mw and hydrophobic/hydrophilic chains ratio is expected to control the degradation rate of block copolymers and, in the pharmaceutical field, to modulate the release of the encapsulated active agent according to the specific purpose. A wide range of pharmaceutical parenteral DDS, such as micelles, micro and nanoparticles, and hydrogels have been developed using multyblock copolymers [3]. Multiblock copolymers of PEO and PLA and PLGA polyester polymer have been extensively used to prepare protein and peptide delivery systems [6, 9-11]. Micro and nanoparticulate systems made by multiblock copolymers as PLA-PEG-PLA and PLGA-PEG-PLGA have shown clear advantage over PLA and PLGA systems as protein delivery systems considering drug loading, the protein release rate control, degradation behaviour and stabilization of active agent either during the encapsulation process or release conditions [12]. In recent years, amphiphilic multiblock copolymers have also gained much attention for their unique phase behaviour in aqueous media [13]. The large solubility difference between hydrophilic segment and the hydrophobic blocks enhances the tendency of amphiphilic block copolymers to selfassemble into micelles in aqueous environments. Indeed, the amphiphilic block copolymers are able to form micelles with core-shell structure in aqueous solution, providing a loading space to accommodate mainly hydrophobic active molecules. Moreover, the hydrophilic dense PEO shell may guarantee the biocompatibility of micelles providing a system with stealth characteristic in the blood compartment and a longer blood circulation time [14]. Block copolymers have been investigated for in situ hydrogel formation because they are able to form physical crosslinking in an aqueous environment through hydrophobic interactions, crystalline microdomains or chains entanglement [15]. Physical associations of hydrophobic domains maintain swollen soft portions together and keep the polymer network stable in water. These biodegradable, physical hydrogels may offer an alternative material of

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Introduction

5

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choice in designing DDS as well as other biomedical applications. Indeed, aqueous solutions of low Mw PEO-polyester-PEO block copolymers are well known to have thermo-reversible sol-gel transition, forming in situ hydrogels without harmful organic solvents or any chemical reactions [16-18]. Moreover, multiblock copolymers have been studied in various tissue engineering applications, including bone regeneration because they have great design flexibility and their composition and structure can be easily adapted to the specific needs [19]. Biodegradability is generally required for a scaffold material intended for tissue engineering, and the degradation rate also needs to match the neo tissue formation rate [20]. For example, linear aliphatic PLA, PGA and their copolymers PLGA are frequently used as polymers in the preparation of scaffolds for hard tissue because of their wide range of biodegradability, their well accepted biocompatibility and good mechanical properties [21, 22]. On the contrary, multiblock copolymers, such as PLAPEG-PLA, do not present the required biodegradability, but they are biocompatible hydrogel materials that have similar mechanical characteristics to certain soft tissues such as cartilage [23].

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Chappter 1

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1.1. DEFINITIO E ON AND CLASSIIFICATIO ON O BLOCK COP OF POLYME ERS B Block copolym mers are defiined as a speccial class of polymer p in w which each moleccule consists of two or more m different monomer unnits joined in a defined arrangement. In general, g polyymers can bbe classified as homopolyymer and copollymer; in thee case of hom mopolymers each molecuule is compossed of the same type of moonomers, whhile for copoolymers each molecule consists in differrent monomeers organizedd into distincct segments (random, ( alteernate and graft copolymers) or blocks (bllock copolym mers) (figure 1). 1

Figuree 1. Different type t of copolym mers: random,, alternate, blocck and graft coopolymer .

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Block copolymers can be classified by the number of blocks contained in each molecule, and by the way they are arranged: block copolymers containing two, three or more blocks are called diblock, triblock and multiblock copolymers, respectively. Referring to the way of blocks arrangement, the polymer can be define linear or star block copolymer (figure 2).

Figure 2. Types of block copolymer: diblock, triblock, multyblock and starblock copolymer.

The simplest block copolymer is AB-type block, a linear diblock copolymer composed of two monomer types: one unit of homopolymer A and another one of homopolymer B are end-to-end connected. ABA-type block copolymer is a triblock copolymer containing two monomer types: both terminals of homopolymer B unit copolymerize with two homopolymer A units. ABC-type block copolymer is a triblock copolymer composed of three monomer types: terminals of homopolymer B unit are connected with the end

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Definition and Classification of Block Copolymers

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of the units of homopolymers A and C. The multiblock copolymer is composed of homopolymers A and B segments attached many times. The star block copolymer is the most complex block copolymer containing one unit of homopolymer A which presents multiarm functionalities copolymerized with segments of homopolymer B to achieve a star-like shape [24]. The arms number of star block copolymers is equivalent to the number of the functional groups in the unit of homopolymer A. The retrospective analysis of data reported in literature becomes difficult and sometimes impossible because of the lack of a commonly and accepted block copolymers nomenclature. Two systems have been suggested: the first block copolymer nomenclature was proposed in 1987 by Younes et al [25] and included the Mw of hydrophilic block and the average degree of polymerization of the hydrophobic block (e.g. PEG-PLA 6000/2770). In 1996 Li et al presented a second approach adding the average degree of polymerization as subscript to the designated blocks (e.g. PLA109/PEG41/PLA109) [26]. In this chapter the discussion is limited to polyester/polyether block copolymers of AB and ABA structures, where A designates an hydrophobic biodegradable polyester block and B consists of PEO segments.

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Chapter 2

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1.2. SYNTHESIS OF BLOCK COPOLYMERS FROM PEO AND LACTONES In the last three decades, the synthesis of ABA triblock copolymers composed of PEO B-blocks and PLA or PLGA A-blocks (figure 3) has been widely investigated [5]. Homo and copolymers of lactic acid and glycolic acid are usually synthesized by Ring-Opening Polymerization (ROP) of cyclic monomers (e.g. lactide and glycolide).The polymerization of lactones is generally carried out in bulk or in solution (THF, dioxane, toluene etc), emulsion or dispersion. The temperature applied in the bulk polymerization was generally ranges from 100 to 150 °C, whereas in the solution polymerization reaction, lower temperatures are used (0 - 25 °C) to minimize second side reactions (inter- and intramolecular transesterification reactions) [27].

Figure 3. Molecular structure of PEO-PLA-PEO and PEO-PLGA-PEO block copolymers.

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The physical properties and the bidegradability of multiblock copolymers prepared by ROP of lactones and lactides can be easily controlled playing whit the structure and the composition of the repeated unit, the chain flexibility, the presence of polar groups, the molecular mass, the crystallinity, and the chain orientation [5]. Since the copolymerization reaction permits to modify hydrophilic/hydrophobic properties and the PEO/PLA ratio of multiblock copolymers, it represents the most attractive way to modulate the main properties of comopolymers [27]. The most widely used technique is the living polymerization, in which the Mw of the individual blocks, the volume ratio (variation of monomer/monomer ratio) and the block arrangement (AB, ABA, BAB and ABC) can be taylored as function of the final application. The most common techniques to synthesize block copolymers are: i) carbocationic polymerization, ii) anionic polymerization and iii) coordination-insert polymerization. Among these techniques, the anionic and coordination-insert ring-opening polymerization are the most utilized techniques to obtain high Mw multiblock copolymers. The synthetic route selected for the preparation of multiblock copolymers intended for pharmaceutical and biomedical purposes should satisfy the following requirements: i) the Mw of backbone chain/arm of block copolymer and also of the single block unit should be modifiable; ii) the type, number and arrangement of block and star copolymers have to be known; iii) the chemical structure should be analyzed exactly and it as uniform as possible; iv) the polymers should not contain impurities such as starting compounds having low molecular weight (catalysts or initiators), solvent residuals, homopolymers, by-products or degradation products. The fulfillment of these requirements potentially leads to a final product with an elucidated chemical structure and a highly narrow Mw distribution [24]. In the multiblock copolymers synthesis, terminal hydroxyl groups present in PEO chains can initiate successfully the polymerization of lactones in the presence of catalyst molecules [28]. Many organometallic compounds, such as oxides, carboxilates and alkoxides are effective initiators for controlled synthesis of multiblock copolymers using ROP of lactones. Different compounds have been used as co-initiators or catalysts for the polymerization of lactides in presence of PEO, such as metal oxides (SnO, SnO2, Sb2O3, PbO and GeO2) and salts (SnCl2, KtBuO, etc) or hydride (NaH) to yield high Mw diblock and triblock copolymers. Furthermore, high Mw multiblock copolymers can be synthesized using stannous octanoate as catalyst, even if it

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Synthesis of Block Copolymers from PEO and Lactones

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was identified as cytotoxic compound [27]. However, among all the catalyst compounds cited above, stannous octanoate is the catalyst more frequently used because it leads to block coplymers with high Mw and with the best polymerization reaction yields. In order to avoid any non-biocompatible and toxic impurities in the final product multyblock copolymers were also synthesized from PEO segments and PLA blocks without catalyst compounds. The negative aspect of the noncatalyzed polymerization technique was identified to be the reaction time, since it runs too slowly. In addition, catalyst-free polymerization of lactides in presence of PEO yielded block copolymers composed of low Mw PLA blocks attached to PEO central block.

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Chapter 3

1.3. MECHANISM OF COPOLYMERIZATION FROM PEO AND LACTONE

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1.3.1. ANIONIC POLYMERIZATION The most important catalysts used in the anionic polymerization of lactones are alkali metals and alkali metal oxide [29]. The reaction may proceed either by a living or non-living mechanism since the polymerization process depends mainly on reaction conditions such as the type of initiators and the nature of monomers. In general, β-lactones polymerization is initiated by the nucleophilic attack of a negatively charged initiators on the carbon of the carbonyl group (1) or on the alkyl-oxygen (2) resulting in a linear polyester (figure 4). The initiator can be a weak or strong base: in presence of a weak base, the polymerization reaction proceeds via alkyl-oxygen scission and carboxylate ions behave as propagating species, whereas for strong bases as alkali metal alkoxides, the polymerization reaction may follows two manners: i) the acyl-oxygen scission takes place and the alcoholate ion is the propagating species; ii) the propagation advances due to both alcoholate and carboxylate anions formed by alkyl-oxygen and acyl-oxygen scission [5]. The multiblock copolymers polymerization is a nucleophilic reaction in which the initiator molecules directly attack the carbonyl group of PLA (figure 5), thereby the formed alkoxide ions act as propagating species [5, 28]. In 1987 Cohn et al firstly described the synthesis of ABA triblock copolymer using Sb2O3 as catalyst. The block copolymers were obtained

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through the polycondensation of lactic acid in presence of PEO segment under nitrogen flow. The composition of synthesized ABA block copolymers varied between 20-80 mol% of PLA and the PEO Mw ranged from 600 to 6000 Dalton. The method showed several drawbacks, mainly the high reaction temperature (about 200°C) and the long reaction time (> 35h) [30, 31].

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Figure 4. Initiation of ring-opening polymerization of lactones by anionic initiators: 1. acyl-oxygen scission and 2. alkyl-oxygen scission.

Figure 5. Schematic diagram of anionic polymerization mechanism for multiblock polyesters.

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Mechanism of Copolymerization from PEO and Lactone

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A limitation of ABA block copolymers over multiblock copolymers is that they must be prepared at high temperatures (100-200°C) under inert conditions to obtain the complete conversion of all starting monomers and a polymer with an appropriate Mw. Furthermore, process trans-esterification and other sidereaction can arise across the ABA block copolymer synthesis, resulting in a randomized monomer sequence. Metal compounds such as metal oxides have been widely investigated as catalysts for block copolymer synthesis: GeO2 and SnO2 led to a low conversion of lactide, whereas Sb2O3 caused partial racemization of L-lactide. The only catalyst compound that gave satisfactory results was SnO [32]. The synthesis of block copolymers from PEO and PLA through anionic polymerization was made a fast running reaction in presence of sodium PEO alkoxide, in THF at 25°C; indeed, the homopolymer was almost consumed in the first 5 minutes of reaction. The obtained block copolymer showed a higher Mw compared to the original homopolymer and a unimodal Mw distribution by the GPC, with a low racemization degree [5, 33]. Kincheldorf et al synthesized AB diblock and ABA triblock copolymers by anionic polymerization using KOt-Bu as catalyst, in mild conditions (50 – 80°C). 1H-NMR and GPC analysis confirmed the quantitative reaction of PEO segments with PLA homopolymer. The 1H-NMR study demonstrated the presence of more hydroxyl terminal groups than ester groups. Moreover, a racemization reaction indicative of a chain transfer reaction with the monomer via deprotonation was observed [34]. PLA/PEO/PLA triblock copolymers with short poly(lactic acid) chains were synthesized using CaH2 or Zn2+ as co-initiators. CaH2 was frequently selected as catalyst in the polymerization of triblock copolymers with short poly(lactic acid) chains since it is known as PLA initiator and no toxic impurities are developed during the synthetic process. Zinc is widely utilized as a life-friendly standard initiator for the preparation PLA block copolymers. Zn2+ ions are atoxic at trace doses and the residual zinc particles can be easily removed from the final product by filtration at the end of the polymerization reaction. Slight racemization and formation of PLA homopolymer were detected; moreover, triblock copolymer with PLA block length shorter than 100 units was not detectable. Adding CaCl2 as catalyst, the reaction was completed after 14h at 140 - 145°C and PLA hopolymer formation was not observed. The Mw distribution of the obtained multiblock copolymers was monomodal and rather narrow; an increase in block copolymer Mw was highlighted and the polydispersity index of the block copolymers remained very narrow (Mw/Mn ≤ 1.08) [27].

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CaH2 and Zn2+ were also used as co-initiators in the preparation of PLA/PEO/PLA triblock copolymers with long poly(lactic acid) chains. Block copolymers sinthetized in this way exhibited PLA/PEO molar ratio very close to the corresponding theoretical PLA/PEO ratio. These findings suggested that all monomer molecules were engaged in polymer chains. The 1H-NMR analysis highlighted that PEG hydroxyl end groups were fully esterified and neither PEO residuals nor PLA/PEO diblock copolymers were present in the final product at the end of polymerization reaction. Therefore, it was concluded that the polymer recovered from the polymerization of poly(lactic acid) in presence of PEO and Zn2+ or CaH2 could be considered composed exclusively of OH-terminated PLA/PEO/PLA triblock copolymers. The presence of OH-ended lactic units in the triblock copolymer indicated that the polymerization reaction proceeded via acyl-oxygen bond cleavage (figure 5). CaH2 co-initiator led to some racemization whereas Zn2+ appeared as configuration-respecting as in the case of lactide homopolymer [26].

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1.3.2. COORDINATION-INSERTION POLYMERIZATION The coordination-insertion polymerization has been extensively used for the preparation of multiblock copolymers. Various initiators such as aluminium and tin alkoxides and carboxilates, are used in the preparation of multiblock copolymers by coordination-insertion polymerization reaction. The carboxilates are weaker nucleophilies compared with alkoxides compounds and they act more like a catalyst than an initiator. Therefore, carboxilates are used in combination with an active hydrogen compound (e.g. alcohol) to behave as co-initiators. As remarked by Du et al, in presence of both stannous alkoxide and tin salt of carboxylic acid, the ROP reaction is started by the stannous alkoxide initiator since the alkoxide initiator is more active than the tin salt [35]. The covalent metal alkoxides or carboxilates with vacant ‘d’ orbitals react as coordination initiators and not as anionic initiators. In presence of PEO molecules, the coordination-insertion polymerization involves a transfer of metal alkoxide to metal PEOate [35, 36]. The ring opening polymerization is initiated by this metal alkoxide macro-initiator following a coordinationinsertion mechanism similar to the low Mw metal alkoxide catalyst: lactide inserts into ‘Al-O’ bond of the macro-initiator molecule followed by the selective acyl-oxigen cleavage of the monomer (figure 6) [28, 36].

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Mechanism of Copolymerization from PEO and Lactone

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Figure 6. Schematic diagram of coordination-insertion polymerization mechanism for multiblock polyesters.

Many investigations demonstrated that hydroxyl groups are the terminal groups of the product obtained by ring-opening polymerization of lactones initiated by stannous octoate, indicating that hydroxyl groups, e.g., residual water or other impurities, participate in the initiation as co-catalysts. Tin catalysts have been frequently used in the ring opening polymerization of lactones. Stannous chloride (SnCl2) has been frequently used to synthesize ABA triblock copolymers of PEO and PLA. The polymerization was carried out at high temperature ranging from 170 to 200°C, getting copolymers with unimodal Mw distribution and narrow polydispersity (1.39) and a good polymerization yield of about 84% [4, 5, 37, 28]. Zhu et al improved the multiblock copolymer synthesis yield (96%) using stannous octanoate at 180°C. The multiblock copolymer showed a low Mn and a polydispersity index between 2.0-3.0 [38]. Deng et al synthesized triblock PLA-PEO-PLA copolymers using Al(Bu)3-H3PO4-H2O complex system as catalyst. The polymerization reaction was carried out at 140-160°C with a conversion percentage higher than 90%. The Mw distribution of obtained block copolymers was narrow and the polydispersity index (Mw/Mn) ranged from 1.29 to 1.83. The triblock copolymers were also prepared with lanthanum acetate which is a more stable

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catalyst and the preparation technique resulted to be simpler. The copolymerization reaction was carried out in bulk and the conversion was about 60-87% [39]. Block copolymers with PEO percentages between 0.51 and 9% were produced using a variety of PEO in presence of tetrapheniltin as initiator. The copolymers resulted to be in the solid state both at room temperature and at body temperature (37°C) [40]. The monomer sequence length of the copolymer is mainly determined by the choice of building components and at lower extent by the reaction time and temperature

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1.3.3. COUPLING REACTION The coupling approach allows to modify polymer properties for a specific application using well-defined pre-polymers in an alternate arrangement. Figure 7 shows the schematic diagram of coupling polymerization reaction: multiblock copolymers are synthesized by polycondensation reaction of PEO segment and PLA blocks in presence of dicyclohexyl carbodiimide (DCC) and N-dimethylaminopyridine (D-MAP). D-MAP is added to the solution as a catalyst compound while DCC is used as a coupling agent. To obtain linear multiblock copolymer, the starting polymer has to present reactive end groups for the consecutive coupling reaction. Using this method, Huh et al synthesized multiblock copolymers with high Mw, narrow Mw distribution, polydispersity index of 0.94, achieving reaction yield of 85-95% [41].

Figure 7. Schematic diagram of coupling polymerization reaction for multiblock polyesters.

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Chapter 4

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1.4. PHYSICO-CHEMICAL PROPERTIES OF BLOCK COPOLYMERS FROM PEO AND LACTONES A multiblock copolymer is composed of pre-selected blocks having specific properties, e.g. thermal, physico-chemical, and degradation properties. A proper combination of pre-polymers leads to define copolymer properties. The introduction of hydrophilic PEO segments into hydrophobic polylactones produces a new family of biomaterials which may possess specific properties of the invidual pre-polymers, as well as additional properties obtained by the combination of segments. Indeed, physico-chemical properties and biological behaviour of starting homopolymers affect the biodegradability and the biocompatibility of obtained block copolymers [28]. Polymer composition, Mw and structure (number of arms) are the three main parameters expected to affect the block copolymers physico-chemical properties, namely thermal behaviour, hydrophilicity, swelling and sol-gel transition.

1.4.1. MICROPHASE SEPARATION AND CRYSTALLINITY The different water affinity of hydrophilic PEO segments and hydrophobic blocks leads to a microphase separation in block copolymers depending on their final composition. The microphase separation phenomena can be recognize by DSC. The existence of two distinct melting endotherms

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corresponding to two components included in the multiblock copolymer is indicative of microphase separation into block copolymer. Huh et al observed that the melting peak of PEG bound to PLA blocks in multiblock copolymer shifted to lower temperature compared to the sharp and strong melting peak of the PEO homopolymer. These findings were ascribed to the presence of PLA blocks which partly varied the crystallization of PEG segments resulting in a decrease of PEG melting point. In the second DSC run, the PEG Tm peak disappeared while the PLA Tm peak remained: these results demonstrated that PLA blocks actually recrystallized, while PEG segments were not recrystallized. This behaviour was associated to the higher melting temperature of PLA blocks and not to the greater tendency of PLA polymer to crystallize. When the copolymer cools after melting, PLA blocks are solidified at higher temperature with respect to PEG segments inhibiting the mobility of PEO segments and consequently hindering PEO segments crystallization. No melting point was detected in block copolymers containing short PEO segments. This could be due to the increase of phase compatibility of short PEO segments with long PLA chains and limited phase separation [42]. PLA/PEO/PLA multiblock copolymer with slightly short PEO segments leads to an increased disposition of PLA blocks to crystallize keeping their steroregularity and chain structure. When the total length of PLA blocks is closed to PEO segment neither PLA blocks nor PEO segments can spontaneously crystallize, whereas with PLA blocks longer than PEO segments, PLA crystallizes and Tm point increases proportionally with the PLA chain length [26, 36]. Kubies et al observed that block copolymers showed modified thermal behaviour compared with semicrystalline PEO and PLA homopolymers. A decrease in melting points was related to their incorporation into a block copolymer structure and it was a consequence of a partial phase compatibility. The presence of PEO endotherm was indicative of the presence of a separated PEO phase with a certain degree of crystallinity [42]. As reported in literature, blends of two immiscible polymers exhibit two Tgs of the each single component, while only one Tg can be detected in the case of blends of two miscible polymers, whose value is in between the Tgs characteristic of each component. DSC analysis of multiblock copolymers highlighted the presence of two Tgs due to a microphase separation of multiblock copolymer [43]. On the contrary, only one Tg resulted from DSC analysis of m-PEO-PLA coplymers, indicating the enhanced miscibility of PEO and PLA and the limited phase separation into the copolymer [42]. The

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high phase miscibility between PEO and PLA blocks was explained by the shift of PEO Tg, the absence of a Tg peak related to PLA blocks and the decrease in the crystalline melting point of block copolymer [41].

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1.4.2. Hydrophilicity and Swelling Behaviour Hydrophilic PEO segments modify the physico-chemical properties of hydrophobic blocks and, in particular, their hydrophilic features and swelling behaviour. Block copolymers of PEO segments and PLA blocks are expected to show an increased tendency to interact with water. When a polymeric matrix is dipped into water, the amount of water into the polymer network increases rapidly and an initial equilibrium can be reached after few hours. The rapid diffusion of water inside the matrix derives from the introduction of hydrophilic segments in the multiblock backbone and the diffusion rate can be regulate by varying the content of PEO in the block copolymer. Generally, block copolymers show a biphasic water uptake profile with a rapid water uptake followed by a slow increase of water content inside the matrix concomitant with the polymer erosion. This biphasic behaviour is due the contribution of two processes: i) the rapid diffusion of water into the initially miscible PEO and PLA blocks and ii) the hydration rate reduction related to the phase separation characteristic of multiblock copolymers and the cleavage of PLA blocks [28, 36]. The ability of the polymer to absorb and retain water results from the physical crosslinking formed between PEO and PLA domains in the block copolymer. Several complex factors can promote physical crosslinking such as hydrophobic interactions among polymer chains, crystalline microdomains and chains entanglement. The diffusion of water inside the block copolymer organized in PEO and PLA domains can be responsible of the matrix swelling. The swelling ratio of multiblock copolymer results to be dependent to the Mw of PEO and PLA homopolymers: the swelling ratio decrease with the increases of PLA block length. [41].

1.4.3. SOL-GEL TRANSITION Block copolymers composed of PEO and PLGA blocks show a temperature-dependent gel-sol transition in water which is dependent to the

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concentration and composition of block copolymers. These polymers have amphiphilic nature and they form micelles with core shell structure in contact with water. They are defined amphiphilic because water is a poor solvent for the hydrophobic blocks while it is a good solvent for hydrophilic segments: in contact with water, hydrophobic polyester blocks tend to aggregate reducing the surface area exposed to the surrounded aqueous environment and allowing a decrement of the system entropy [44]. Micelle formation and micelles behaviour are dependent to the polymer molecular structure and its hydrophobic-hydrophilic balance in water. The increase in polymer concentration can cause higher micelles concentration: the gelation is induced by the clustering of aggregated micelles and the faster increase in the aggregate micelles number can induced sol-gel transition at lower temperature. The phase diagrams of block copolymers in water shows a critical gel concentration (CGC), a lower transition temperature curve from sol to gel and an upper transition temperature curve from gel to sol. The gelation of block copolymers in aqueous solution takes place at a proper temperature value which is correlated to the length of the homopolymers sequence. The transition temperature (CGT) can be modified changing the block length of block copolymers: the CGC and CGT decrease increasing the polyester length, whereas an increment of PEO length shifts the CGT to a higher value [45]. Since longer PLGA chains in the block copolymer can favor stronger hydrophobic interactions and increase the association affinity, they can interact with more micelles initiating the formation of links among different micelles. Micelles connections lead to: i) CGC reduction, ii) decrease of sol-gel transition temperature and iii) increment of gel-sol transition temperature [4548].

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Chapter 5

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1.5. DEGRADATION OF ABA TRIBLOCK COPOLYMERS BASED ON PEO AND POLYESTERS Polymer degradation is the chain scission process that breaks down polymer chains into oligomers and, finally, into monomers. The degradation process leads to the erosion of the polymeric DDS, which is the process of material elimination from the injection site by means of the polymer mass loss. Two different degradation processes can be distinguished with respect to the relative water diffusion rate, the polymer degradation and matrix erosion: i) surface (or heterogenous) degradation and ii) bulk (or homogenous) degradation. When the polymer degradation is faster than the water diffusion into the polymer matrix, the degradation and erosion process become a surface phenomena, whereas when the water diffusion is faster than polymer degradation, the whole matrix undergoes bulk degradation [49]. Degradation of aliphatic polyesters such as PLA and PGA in an aqueous environment occurs through simple hydrolysis of ester bonds auto-catalyzed by carboxylic groups accumulated in the matrix during the polymer degradation. The degradation proceeds in three main stages: i) the water permeation into the amorphous regions which are less organized allowing to water molecules to diffuse more easily than through the highly structured crystalline regions; ii) the ester-bonds hydrolysis in the polymer amorphous regions, resulting in water soluble degradation products; and iii) the polymer mass loss through the transport of cleavage products into the surrounding buffer [50].

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In the hydrolysis of biodegradable polymers such as PLA and PLGA, it was observed the increase of polymer crystallinity subsequent to both the degradation of the amorphous regions and the reorganization of loose chain ends [51]. The remaining undamaged polymer chains acquire more space and mobility, leading to polymer chains reorganization and, therefore, to the increment of polymer crystallinity. These phenomena could be optically highlighted by the whitening of samples caused by the molecular reorganization and the simultaneous decrease of the mechanical strength and the molar mass [51]. The second stage begins when most or all of amorphous regions have been removed and the water slowly penetrates the crystalline regions. If the hydrolysis continues, the crystallinity decreases while crystalline domains undergo hydrolysis leading to the increase of mass loss rate and finally to the complete polymer resorption [51]. The hydrolytic degradation of PLA homo- and co-polymers is defined as a homogenous process since any mass losses were detected until the molecular average molecular weight was significantly decrease. Several studies have dealt with in vitro degradation of aliphatic polyesters. However, the results reported in the literature are often in disagreement because the degradation studies were performed on polymeric DDS which vary in size and shape. Indeed, it has been reported that the degradation rate increases with increasing sample thickness [52]. Li et al observed that the degradation of PLA in aqueous medium proceeds more rapidly inside the polymer matrix, because of the auto-catalytic effect caused by the accumulation of compounds containing carboxylic end groups. These low Mw chains were not able to permeate to the outer shell, whereas the degradation products in the surface layer were continuously dissolved in the surrounding buffer solution [53]. The hydrolytic PLLA degradation is the most documented one and the time for the complete polymer resorption was defined in the range from some months for low Mw film to 50-60 years for oriented fiber. The different stability of PLLA polymers can be ascribed to the raw polymers purity, the Mw and Mw distribution, the crystallinity degree and chain orientation. For example, the type of catalyst/initiator used to synthesize the polymer was found to significantly affect the water uptake, the degradation and the erosion rate. The incorporation of hydrophilic PEO soft segments (B blocks) into a degradable PLA, PLGA chains (A blocks) may improve the degradation pattern of aliphatic polyesters (PLA and PLGA). The A and B-blocks ratio and average A- and B-block chain lengths may affect the phisico-chemical

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properties of block copolymers such as swelling, hydrophilicity and crystallinity, all parameters that play an important role in the degradation mechanisms. Pitt et al investigated the degradation behaviour of relatively short PLA– PEO–PLA copolymers and they found that the chain scission rate was independent to ABA block copolymers composition and that PLA homopolymers showed a comparable chain scission rate. These findings suggested that the shorter induction period prior to the erosion onset were not due to a probably higher chain scission rate but it was associated to the greater solubility of the PEO–PLA oligomers and to higher diffusion rate of oligomers in the hydrated multiblock copolymer samples [38]. In this terms, the swelling properties of the ABA triblock copolymers were identified as the main critical factor for their degradation behaviour [54]. The incorporation of hydrophilic PEO segments into hydrophobic A blocks leads to the reduction of the induction period which precedes the erosion onset, resulting in the increment of the multiblock copolymers erosion rate [55-58]. Crystalline regions are known to be a physical barrier for water uptake into polymer matrix, whereas amorphous domains are able to improve the water uptake. Indeed, highly crystalline PLLA–PEO–PLLA absorbs small amounts of water, whereas slightly crystalline PLLA–PEO–PLLA, with a relatively higher PEO content, is able to absorb and retain higher amount of water (60%) [26]. The capacity of multiblock copolymer to absorb water has been found to be dependent on the content of PEO, which enhances the polymer hydrophilicity improving the water diffusion and consequently the polymer erosion [59]. The acceleration of the initial degradation phase and the slightly increase of the terminal degradation rate have been detected increasing the PEO content in the copolymer composition [55]. The rapid water uptake was due to the microphase separation, resulting in the preferential scission of block copolymer at the PLLA/PEO interface. As a consequence of the microphase separation, three microphases in different physical states at different composition have been hypothesized: i) phase A, which consists in the semycrystalline, glassy PLLA with lowest water content; ii) phase B, which contains the swollen PEO phase with the highest water content; and finally iii) phase C, in which both PLLA and PEO blocks co-exist in a rubbery state with water content much higher than phase A [55]. The degradation of PLLA can occurs both in A and C phases, but it has been demonstrated that, after the rapid swelling, the cleavage of the ABA block copolymer proceeds

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preferentially in phase C because the degradation of PLLA occurs preferentially in the amorphous regions. pH determination inside ABA rods using electron paramagnetic resonance (EPR) spectroscopy demonstrated that acidic degradation products were not accumulate inside the ABA rods, and they were easily released in the surrounding buffer [60]. This rapid transport of degradation products from the formation site into the surrounding medium was attributed to the polymer swelling. Cohn et al and Younes et al investigated the influence of different pH values, namely pH 5, 7.5 and 9, on the in vitro degradation of PEG3400-PLA126 and PEG1500-PLA45 copolymers. They found out that block copolymer matrices degraded faster in alkaline buffer than in physiological or acidic media suggesting a base-sensitive ester bond-cleavage [28]. It was also demonstrated that the mass loss and Mw decay were accelerated both in alkaline and in acidic pH [61], whereas the degradation behaviour in different buffer (300 and 600 mOsm) were not significantly different, suggesting that the ionic strength of the surrounding medium did not influence the degradation of block copolymers [61]. Regarding the influence of temperature, the degradation kinetics were found to be faster at higher temperature, as expected [28]. Will et al investigated the degradation behaviour of four different parenteral delivery systems (PDS) such as rods, tablets, films and microspheres examining the effect of the PDS shape on the polymer system erosion with respect to Mw, PDS weight, polymer composition and microstructure. It was found out that: i) PLGA PDS degraded faster than ABA PDS, ii) PLGA degradation rates were irrespective to the geometry of the PDS and iii) the geometry of polymeric DDS had strong influence on the bulk erosion profile. Micrographs of eroding films and microspheres suggested that a complex pore diffusion mechanism controlled the erosion of PLLGA devices. On the contrary, PDS based on PLLGA–PEO–PLLGA ABA triblock copolymers showed a swelling followed by parallel Mw decay and polymer erosion, independent of their geometry. Micrographs of eroding ABA devices confirmed the swollen structure of polymer matrix during the entire incubation time. All the tested PDS prepared from ABA copolymers showed comparable degradation and erosion profiles, demonstrating that the device geometry was not a rate limiting factor for the continuous erosion process. These findings suggested that with the incorporation of hydrophilic PEO segments, the erosion was controlled by the degradation on ABA copolymers, while the bulk

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erosion rate of PLGA systems was regulated by a complex pore diffusion mechanism of degradation products [54]. PLLGA Vert et al. studied the degradation of PLLA43 –PEO41 –PLLA43 and PLLA49 –PEO101 – PLLA49 and they found evidence for a hydrolytic degradation by random chain scission. PEO blocks linked to very short PLLA blocks were released in particular at the latest stages of degradation, resulting in an increasing LLA/EO ratio in the residual material [56, 57]. A preferential cleavage of PLLA–PEO–PLLA triblock copolymers at the PLLA/PEO interface was postulated by 1H-NMR analysis. In the initial degradation phase a rapidly decrease of PEO content was found, suggesting that at first ester– ether bonds were cleaved facilitating the release of PEO segments [55]. A biphasic degradation profile has been observed for PLLA–PEO–PLLA copolymer films characterized by a rapid initial decrease in Mn which was followed by a slower Mn decay [55, 66]. In both stages Mw decay was concomitant to the polymer mass loss. The results obtained for PLLGA–PEO–PLLGA copolymers demonstrated a significantly accelerated Mn decay and a less pronounced biphasic behaviour if compared to PLLA-PEO-PLLA block copolymer. The Mw decay was shown to be concomitant to polymer mass loss, as well. Comparing the mass loss rates of PLLA–PEO–PLLA and PLLGA–PEO–PLLGA copolymers, it was found that the copolymer of PEO and PLGA blocks eroded substantially faster. After 40 days, the PLLA–PEO–PLLA copolymer lost 27% of weight, while the PLLGA–PEO–PLLGA copolymer lost 40% of weight. As demonstrate by Li et al, the degradation was not dominated by the loss of PEO segments but by the elimination of A and B blocks. These results were justified considering the random structure of PLGA blocks in the block copolymer which improved the phase compatibility of PLLGA blocks with PEO segments and the different physical state of compared to PLLA homopolymer. Indeed, the swollen PLLGA–PEO–PLLGA matrix with the PLLGA phase can be considered completely in an amorphous rubbery state whereas the PLLA phase of the swollen PLLA–PEO–PLLA copolymers may consist of a partially crystalline core surrounded by an amorphous, rubbery shell [7]. As frequently reported for hydrolytically degrading PLA and PLGA, GPC analysis of PLLA-PEO-PLLA block copolymers highlights bimodal Mw distributions [32, 57, 58, 62-65]. In order to justify the generation of bimodal molecular mass distribution in ABA polymer degradation three theories have been formulated: i) the degradation rate of the polymer is estimated faster inside the matrix than at the surface, causing bimodal GPC profiles due to the

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heterogeneous degradation mechanism [62, 63], [58, 63, 64], ii) the degradation of amorphous domains is responsible of a polymer crystallinity degree increment resulting in narrow polydispersity and an additional peak which is associated to low molecular fragments, iii) the initially degradation of amorphous domains at the crystalline zone edges was followed by the degradation of crystalline domains leading to a bimodal or even multimodal GPC profiles [58]. The last theory seems to be the most appropriate for the degradation profile of a copolymer composed of longer PLLA blocks. Indeed, polyester blocks are initially long enough to generate well-defined crystalline structures which lead to a preferential degradation of the amorphous domains, resulting in a bimodal Mw distribution [57].

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.

Chapter 6

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1.6. PARENTERAL DRUG DELIVERY SYSTEMS BASED ON ABA POLYMERS Biodegradable polymers are the materials of choice in drug delivery technology (DDT) because they are very versatile and they offer the opportunity to modulate drug release rate and to achieve drug targeting. The use of biodegradable polymers as carriers in controlled DDS has been investigated. These materials offer several advantages: i) protection of sensitive therapeutically active molecules against in vivo degradation, ii) reduction of toxic side effects that can occur when highly active drugs are administered, and iii) increase in patient compliance by the reduction of repeated drug administrations [67]. Peptide and protein drugs have gained an increasing attention during last years. Their therapeutic use is limited by their poor bioavailability for oral administration and their short half life in biological tissues. Due to these characteristics, multiply daily injections are often required. To overcome compliance problems, biodegradable polymer as PLA and PLGA have been widely investigated to obtain polymer DDS with continuous and controlled release from day to months. Poly orhoesters such as PLA and PLGA, are the biodegradable polymers that have been most successfully employied in the formulation of micro, nanoparticulate DDS and implants for parenteral drug administration [68]. Their success is proved by the presence on the market of several pharmaceutical products based on these polymers, and loaded with hormons, antitumoral drugs and antibiotics. In general, DDS act as carrier which release the active agent at welldefined rate, degrading into atoxic compounds which are excreted by the body.

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It has been demonstrated that the polymer can reduce the activity of the encapsulated molecules, in particular proteins and peptides, prior their release. Irreversible aggregation phenomena of proteins due to chemical interactions between the hydrophobic polymer and hydrophilic proteins are the main factors which lead to loss of protein activity. In addition, an acidic microenvironment can develop with time inside the polymer matrix due to the accumulation of acidic degradation products generating with the hydrolysis of the polymer chains. It has been found that the pH inside degrading PLGA implants can drop in vivo to pH 2 and, under these conditions protein aggregation phenomena may take place. A strategy has been developed to minimize these interactions introducing hydrophilic block such as PEO inside the hydrophobic polyester backbone [69, 70]. The presence of PEG hydrophilic portions makes ABA block copolymer good candidates for the formulation of micro-and nanoparticulates loaded with polypeptide and protein drugs. Indeed, PEG is a hydrophilic, biodegradable and biocompatible polymer which has been widely used in the pharmaceutical and biomedical areas to improve the biocompatibility of the blood contacting materials. Huang et al observed that the PEG outer layer in the corona-core microspheres increased the hydrophilicity of the surface, so that the aspecific interaction with liver Kupffer cells was limited [71]. Alternatively, it has been found that PEG may sterically prevent binding of serum opsonins to the particle surface, reducing the affinity for Reticular Endotelial System (RES) [72]. It has been also demonstrated that the incorporation of PEG into polylactic acid homopolymers increased the hydrophilicity of the polymer carriers, thus enhancing their degradation rate and preventing pH changes inside the matrix [40]. Indeed, the swollen polymer structure improves exchanges of the polymer degradation products with the surrounding medium, minimizing the risk of acid-induced degradation [73]. It is known from the literature that the release mechanism of drugs from polymeric devices made of poly orthoesters and their derivatives involve the diffusion and/or dissolution of the drug through the polymeric matrix, and the polymer degradation [74]. This last mechanism depends mainly on polymer characteristics and should be an important point of polymer characterization. Polymer degradation is achieved by random hydrolysis of the backbone chain. The rate of hydrolysis depends on several factors such as polymer composition and Mw, hydrophilicity, crystallinity or amorphous state. Moreover, when the polymer is formulated in a DDS, some other factors related for example to

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Parenteral Drug Delivery Systems Based on ABA Polymers

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system morphology and structure, can also affect the degradation as observed in section 1.5. In general, the release profile of protein from PLA or PLGA microspheres has a tri-phasic pattern: an initial burst due to release of the protein adsorbed on the microparticle surface, followed by a slow release which is caused by the low diffusivity of protein and the slow erosion rate of polymers [75]. Hydrophilic PEG segments in the PLA homopolymers may enhance the diffusivity of water inside the polymeric matrix and consequentially the diffusivity of the drug molecules in the surrounding medium. This should contribute to get more linear protein release from microsphere and to reduce the burst effect. PEG-PDLLA copolymers have shown a good potential to minimize the aggregation and the denaturation of proteins [76]. Compared to PLA homopolymers, they offer an advantage due to their swelling in the medium, generating a more stabilizing environment for proteins. The swollen structure causes a rapid ion exchange, which leads to a neutral pH inside the matrix, preventing aggregation and denaturation of sensitive proteins. As a novel polymer matrix for DDS, block copolymers of PEO and PLA or PLGA have shown some advantages over PLA and PLGA, especially for hydrophilic drugs, peptides, proteins and antigens.

1.6.1. CLASSIFICATION OF PARENTERAL DRUG DELIVERY SYSTEMS Parenteral DDS are devices which release the encapsulated bioactive agent over several days up to months at a constant rate. After subcutaneous or intramuscular administration, drugs are able to reach directly the target tissue or the general circulation maintaining the drug concentration ideally in an infusion-like manner over a prolonged time period [28]. Various types of drug formulations, such as nano- and microparticles, hydrogels, micelles and implants have been developed using block copolymer of PEO and PLA or PLGA to deliver hydrophobic drug as well as hydrophilic peptide and protein [77, 24]. Implants are cylindrical devices (rods) of 1 mm diameter and 10-20 mm length which are deposited into subcutaneous tissue using a hollow needle. Implants with other sizes and shapes have been experimentally realized, such as tablets and films, according to the final application. One of the main

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advantages of polymeric implants is the chance to stop the therapy, by a small surgical operation, when side-effects such as inflammation, infection, local tissue necrosis, appear [28]. Micro and nanoparticles are by definition spherical devices with diameter in the range of 1-100 μm for microsystems and 100-200 nm for nanosystems; they are usually administered by subcutaneous or intramuscular injection as suspension using conventional syringes. Micro and nanospheres are monolithic devices in which the drug is either dissolved or dispersed in the polymeric matrix, whereas micro e nanocapsules consist of a drug core coated with rate-controlling polymeric shell. Hydrogels are three dimensional, hydrophilic, polymeric networks able to absorb large amounts of water or biological fluid [17]. The network is composed of homopolymer or block copolymers, which are insoluble due to the presence of chemical crosslinks (tie-points, junctions), or physical crosslinks, such as entanglements or crystalline domains [17, 24, 28]. Block copolymer consisting of hydrophobic and hydrophilic blocks are able to form physical crosslinking in an aqueous environment through hydrophobic interaction, crystalline microdomains or chain entanglement. Physical associations of hydrophobic domains maintain swollen soft blocks together and keep the polymer network stable. Hydrogels are like natural living tissue more than any other class of synthetic biomaterials due to their high water contents and soft consistency which is comparable to natural tissue consistency [24]. The chemical structures of the polymer affect the swelling ratio of the hydrogels. Hydrogels containing hydrophilic group swell more than those ones containing hydrophobic groups because hydrophobic groups collapse in presence of water, minimizing their area exposed to water molecules. Infinitesimal changes in temperature, pH, electronic field or chemical surroundings of hydrogels can be responsible of important volumetric phase transition. Thermoreversible gels have been widely investigated because they can undergo gel-sol transition upon heating or cooling [24] Block copolymer micelles are water-soluble, biocompatible nanosystems in the range of 10-100 nm and they can be defined as aggregated copolymers in dynamic equilibrium with monomers. Amphiphilic block copolymer such as PLGA-PEG-PLGA form micelles composed of a hydrophobic PLGA core and hydrophilic PEG shell when in contact with water. PLGA chains are segregated from the aqueous environment to form an inner core surrounded by a corona of hydrophilic segments. The block copolymer micelles can be used to encapsulate high concentration of hydrophobic drugs increasing the drug

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Parenteral Drug Delivery Systems Based on ABA Polymers

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stability in aqueous medium above the drug solubility limit. Moreover, the ability of polymeric micelles to target certain cells such as cancer cells could lower the required therapeutic dosage. The size and morphology of block copolymer micelles can be easily controlled by adjusting the chemical composition, the Mw, PEO/PLGA chain ratio. Long circulation times result from the steric hindrance due to the presence of the hydrophilic shell and from the small polymeric micelles scale (10–100 nm). Indeed, micelles are sufficiently large to avoid renal excretion (>50 kDa), yet small enough ( 4 in table 1 illustrates always the dominance of chain scission over cross-linking reactions in irradiated polymer samples irradiated at 5, 15, 25 and 50 kGy total dose. The authors observed that the Mw decrease trend changed for samples irradiated below and above 25 kGy. This difference was justified considering two different radiation-induced chain scission mechanisms: the initial decay in Mw was supposed to be due to the backbone main chains scission, where long polymeric backbone chains break into shorter chains. The energy from gamma-rays exceeds the attractive forces between atoms [154]. This can occur because the excited states dissipate part of the excess energy by bond scission, within both the amorphous and crystalline domains. At higher radiation doses (50 kGy), hydrogen abstractions become the main radiation induced scission mechanism due to higher oxygen diffusivity in the amorphous regions. The alkyl free radicals in the amorphous domains react with oxygen to form

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Overview on Sterilization Techniques for Block Copolymers

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peroxyl free radicals. The peroxyl radicals cause chain scissions, within the amorphous region and the crystal domain surface, through hydrogen abstraction [156]. The GPC analysis of PEG-PLGA and PEG-PDLLA block copolymers after gamma-irradiation did not show bimodal Mw distributions as frequently reported for hydrolytically degrading PLA and PLGA copolymers. Table 1. Chain scission yield G(s) and cross linking yield G(x) of polymer samples irradiated at 5, 15, 25 and 50 kGy Polymer PEGd,lPLA

PLA

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PEG-PLGA

PLGA

Doses (kGy) 5 15 25 50 5 15 25 50 5 15 25 50 5 15 25 50

G(s)

G(x)

G(s)/G(x)

2.963 1.857 0.606 0.412 1.802 1.406 0.691 0.683 10.216 5.200 2.743 1.487 6.291 3.016 2.021 0.863

0.585 0.309 0.080 0.051 0.236 0.168 0.066 0.096 0.621 0.322 0.213 0.129 0.671 0.280 0.213 0.073

5.064 6.009 7.575 8.078 7.635 8.369 10.469 7.114 16.450 16.149 12.877 11.527 9.375 10.77 9.488 11.82

To examine the stability of the polymer samples after irradiation each polymer (PEG-PDLLA and PEG-PLGA) was subsequently stored for 4 months (120 days) under controlled temperature (+4°C) and relative environmental humidity (40% RH). The changes in molecular weight (ΔMw %), as a function of storage time, were detected by GPC on irradiated samples: the Mw decay entity after irradiation did not seem to be dependent on initial irradiation dose. Indeed, polymer samples irradiated at lower irradiation dose (5 kGy) after 30 days of storage presented Mw reduction % higher than the samples at time zero. A further increase of Mw reduction was detected only for PEG-PLGA multiblock copolymer, while for PEG-PDLLA, PLA and PLGA polymer samples the percentage values observed at 30th day were kept in the range of 15 and 40% up to day 120th. PEG-PDLLA, PEG-PLGA and PLGA polymer samples irradiated at 50 kGy showed a gradual reduction of Mw during the storage time: PEG-PDLLA

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presented a Mw reduction of about 70% at 120th day, against 50% of Mw reduction for PEG-PLGA and PLGA. PLA homopolymer sample did not show a detectable variation of Mw during the storage time: a Mw reduction of 50% was observed up to 120th day. These findings were due to the free radicals number formed during irradiation treatment, which are linearly correlated to the absorbed dose and to the oxidation reactions. The oxidation reaction kinetic depended to the diffusion of the oxygen among free radicals in the polymeric matrix [68]. Since oxygen molecules can continuously permeate into depleted areas of the material, the effect of ionizing energy continues over a much longer period of time after gamma irradiation treatment, resulting in a greater degree of chain scission. The alkyl free radicals generated by irradiation process in the polymer matrix may react with oxygen to form peroxyl free radicals [157]. The slow decrease observed in the stability study could be due to the time needed for permeation and diffusion of oxygen through polymer chains.

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1.7.2. EFFECT OF PROCESS CONDITIONS ON BLOCK COPOLYMERS Standard conditions for sterilization of polymeric drug delivery systems using ionizing radiation is still matter of debate and they should be defined considering the physical-chemical properties of the polymer submitted to gamma-radiation treatment and how the raw polymer responds to the irradiation process [142, 158, 159]. The extent of degradation reactions induced by gamma irradiation is affected by the environmental conditions under which the radiation treatment was carried out, and the post-radiation storage environment [68,160-163]. The environmental conditions under which radiation process is conducted can significantly affect the impact of radiations on the polymer material. The presence of oxygen or air during irradiation produces free radicals that are often rapidly converted to peroxidic radicals. The fate of these radicals depends on the nature of the irradiated polymer, the presence of additives, and other parameters such as temperature, total dose, dose rate, and sample size [158, 164]. In most cases, the polymer radicals generated by gamma irradiation transform into oxidized moieties if oxygen is present in proximity of formed radicals, or remain trapped in the polymer matrix for a certain period of time after irradiation. These trapped radicals may further undergo

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some reactions during storage time after irradiation, resulting insignificant alteration of the physical properties of the irradiated polymer. It is highly probable that post-irradiation effects appear during storage time and they can deeply influence the in vivo polymer performance. Understanding the effects of sterilization method and shelf aging, on the oxidation of polymers is crucial in developing polymeric systems with longer outcomes [165-167]. Even if a number of studies have been performed on the effects of gammasterilization on biodegradable polymers for pharmaceutical uses, only a limited number of works investigated the influence of the environmental conditions under which the irradiation process is conducted on the degradation reactions induced by gamma irradiation. (A sentence was canceled) Dorati et al evaluated how the presence of oxygen in the samples during irradiation process and during post irradiation storage time can affect irradiation-induced degradation reactions of PEG-PDLLA and PEG-PLGA multiblock copolymers submitted to gamma irradiation at 25 kGy. A set of samples was irradiated at 25 kGy in presence of air and a second set under vacuum. The behaviour of the multiblock copolymers to irradiation was compared to that of PLA and PLGA polymers. The stability of the polymers irradiated in different environmental conditions was evaluated by GPC and DSC immediately after ionizing treatment and during storage in refrigerator (+4°C, 40% RH) for 120 days. The evacuation of the PEG-PLGA samples reduces oxygen diffusion in the polymer matrix and leads to a lower extent of Mw and Mn reduction: PEGPLGA Mw and Mn reduction (%) was 15.5 and 19.5% after irradiation under vacuum, against the 21.8 and 42.1% detected on samples submitted to gammairradiation in presence of air. The great sensitivity of this multiblock copolymer to oxidative degradation may be due to the high percentage of PEG in its structure. PEG as plasticizer was expected to induce important intrinsic modification in the polymer such as: (i) significant changes in local structure/microstructure; (ii) enhancement in fraction of amorphous phase; (iii) increasing free volume and the flexibility of the polymer chains [168, 151, 152]. Irradiated PEG-PLGA polymer segments in the amorphous region present high mobility due to the low glass transition temperature (< 33ºC). It is also possible that the radicals trapped in the crystalline regions of the polymer can migrate along the polymer main chain and finally appear in the amorphous region (table 2).

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Table 2. DSC results of PEG-PDLLA, PEG-PLGA multyblock copolymers and PLA, PLGA polymers non-irradiated and irradiated at 25 kGy in presence of air and under vacuum Polymer

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PEG-PDLLA PLA PEG-PLGA PLGA

Non-irradiated Tg (ºC)

43.23±0.5 47.3±0.5 35.24±0.5 42.4±0.5

Irradiated at 25 kGy Tg (ºC) In presence of oxygen 35.86±0.5 43.3±0.5 32.61±0.5 39.9±0.5

Under vacuum 37.85±0.5 46.2±0.5 32.51±0.5 42.0±0.5

When oxygen molecules enter into the amorphous region of polymer they react with free hydrogen atoms (free radicals), increasing amorphous state domains and creating creeks which could lead to a reduction of Mw and Mn. PEG-PDLLA did not respond in the same manner, the Mw and Mn reductions evaluated after irradiation under vacuum did not present significant differences compared to the variations observed on polymer samples irradiated in air. This could be due either the low percentage of hydrophilic polymer (5% mol) in the multiblock polymer with respect to PEG-PLGA (60% mol) or the high molecular weight (105 kDa) of PEG-PDLLA polymer. PLA and PLGA polymer samples presents hydrophobic features and the chains have a lower mobility compared to PEG-PLGA, consequently the oxygen molecules meet more difficulties to permeate through the polymer chains. The irradiation of polymers resulted in a reduction of Tg value due to radiation-induced chain scission reactions which led to a remarkable increase of free volume and chains mobility. The absence of oxygen during the irradiation of PEG-PDLLA, PLA and PLGA led up to a lower reduction of Tg compared to polymers irradiated in air. A different behaviour was recorded for PEG-PLGA multiblock copolymer since the Tg value of samples irradiated under vacuum (32.51 ºC) was pretty the same as that of sample treated by gamma-rays in presence of air (32.61 ºC) . This feature can be explained by admitting the formation of intermolecular hydrogen bonding interactions between end terminal groups (-COOH, -OH) of polymer chains, as a consequence of chain scission reactions which take place during the sterilization process. The presence of oxygen molecules likely promotes the formation of the hydrogen bonding interactions, which lead to an alteration of the polymer chains mobility. The reduction of the chain mobility involves an increase of the transition temperature with respect to what expected.

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1.7.3. RADIOLYTIC MECHANISM INVESTIGATION BY ELECTRON PARAMAGNETIC RESONANCE (EPR) Electron paramagnetic resonance (EPR) is an useful technique used to evaluate the nature and the concentration of free radicals formed upon exposure of multiblock copolymers. In general, EPR spectra were first recorded at 77K, in order to identify the primary species, and subsequently after stepwise increases of the temperature above 77K up to room temperature. This procedure was aimed to obtain suitable conditions for the reactions of the primary species and for the identification of the secondary radicals [157, 160, 162, 163, 169]. The presence of PEG units in the PEG-PDLLA copolymer chains and in the PLGA-PEG copolymer chains had two major consequences: i) a decrease of the radiolytic yield of radicals -C(=O)O-C•(CH3)-O- at 77 K (Figure 11 and 12). This species was practically absent in the low temperature spectrum of PLGA-PEG (60 % of PEO) but it showed up with increasing intensity on warming toward 290 K as a consequence of the activation of H abstraction reactions (figure 12). The same effect by PEG was observed when dealing with the PEG-PDLLA copolymer. In this case however, due to the lower concentration of PEG, the obliteration of the C(=O)O-C•(CH3)-O- signal at 77 K it was not complete but it appeared with a lower intensity as compared to neat PLA or PLGA (figure 11), ii) the increase of the segmental chain mobility in the polymer matrix resulting in a decrease of the radical trapping efficiency and ultimately in faster radical decay rates at 290 K. Indeed, 20 minutes storage time at 290 K was sufficient to cause a 98 % decrease of the overall initial radical concentration whilst in PLA and PLGA the residual radical concentration after the same storage time at 290 K was ca 28 %. This effect is consistent with the observed Tg decrease and the enhanced radiolytic effects on Mn and Mw in presence of air. On the basis of the mechanism proposed for the generation of the – • CH (CH3)- radicals in the radiolysis of PLGA and PLA, the effect of PEG can be rationalized by assuming that it interferes with the intermolecular H abstraction reaction by the ester cation-radicals and that the intramolecular H abstraction mechanism is of minor importance. The cation-radicals will therefore be driven toward alternative reaction paths, like the C-O scission, thus affording an additional contribution to the formation of the tertiary chain scission radicals –C•(CH3)-. The H abstraction at the tertiary C-H sites leading

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to –CH•(CH3)- radicals was not inhibited above the Tg because of the great enhancement of segmental mobility in the mixed PLGA-PEG matrix.

Figure 11. EPR spectra of PEG-PDLLA (5% mol of PEG) recorded as function of temperature after irradiation at 77K [ 169].

The EPR spectral sequence recorded from the PLGA-PEG copolymer (60 % of PEO) during storage at 290 K, beside showing a faster decay rate, presented the appearance of a novel signal with a peak to peak splitting of about 12 (figure 12). This spectrum, which account for less that 2 % of the initial radical concentration, was tentatively suggested to arise from the superimposition of the quartet signal due to the PLGA radical –C•(CH3)- with

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the doublet shifted toward low field of the aldehyde –CH•C(=O)H radical from PEG radiolysis. In this temperature range the radical decay process involved almost exclusively the radical -C•(CH3)- as observed by the difference spectrum C.

Figure 12. EPR spectra of PEG PLGA 60 (5% mol of PEG) recorded as function of temperature after irradiation at 77 K [from 169].

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Chapter 8

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CONCLUSION ABA block copolymers of hydrophobic PLGA and PLA (A blocks) and hydrophilic PEO (B blocks) have proven useful and versatile biodegradable polymers in the preparation of DDS for several therapeutic agents. They provide prolonged systemic circulation, passive targeting and enhance the hydrophobic drugs encapsulation. The efficiency of DDS prepared by ABA block copolymers has been demonstrated to be dependent on the composition, molecular geometry and relative block lengths of the constitutive copolymers. Systematic experimentation has shown that restrained changes in these variables can lead suitable variations in the physico-chemical properties and morphologies of the resulting DDS. In any case, even if a wide investigation about these polymers has been already developed, a huge potential in terms of their chemical modification and final application has still to be discovered.

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REFERENCES [1]

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

[2]

[3]

[4]

[5]

[6]

[7]

Deng C, Chen X, Yu H, Sun J, Lu T, Jing X. A biodegradable triblock copolymer poly(ethylene glycol)-b-poly(L-lactide)-b-poly(L-lysine): Synthesis, self-assembly, and RGD peptide modification. Polymer (2007) 48 139--149. Wang F, Bronich T K, Alexander, Kabanov V, Rauh R D, Roovers J. Synthesis and Characterization of Star Poly(ε-caprolactone)-bPoly(ethyleneglycol) and Poly(L-lactide)-b-Poly(ethylene glycol) Copolymers: Evaluation as Drug Delivery Carriers. Bioconjugate Chem. (2008) 19 1423--1429. Dong Y, Fenga S-S. Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs Biomaterials (2004) 25 2843--2849. Mohammadi-Rovshandeh J, Farina SMF, Sarbolouki MN. Synthesis and Thermal Behaviour of Triblock Copolymers from L-Lactide and Ethylene Glycol with Long Center PEG Block J. Appl. Pol. Science. (1998) 68, 1949--1954. Albertsson A-C, Varma IK. Recent Developments in Ring Opening polymerization of Lactones for Biomedical Applications Biomacromolecules (2003) 4 (6) 1466--1486. Ben-Shabat S, Kumar N, Domb AJ. PEG-PLA Block Copolymer as Potential Drug Carrier: Preparation and Characterization Macromol. Biosci. (2006) 6 1019--1025. Zweers MLT, Engbers GHM, Grijpma DW, Feijen J. In vitro degradation of nanoparticles prepared from polymers based on dllactide, glycolide and poly(ethylene oxide) J. Control. Rel. (2004) 100 347--356.

Copolymers in the Preparation of Parenteral Drug Delivery Systems, Nova Science Publishers, Incorporated, 2010. ProQuest

66 [8]

[9]

[10]

[11]

[12]

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

[13]

[14]

[15] [16]

[17]

[18]

[19] [20]

Rossella Dorati, Claudia Colonna, Ida Genta et al. Rösler A, Vandermeulen GWM, Klok H-A. Advanced drug delivery devices via self-assembly of amphiphilic block copolymers Adv. Drug Del. Rev. (2001) 53 95--108. Van Dijkhuizen-Radersma R, Roosma JR, Kaim P, Métairie S, Péters FLAMA, de Wijn J, Zijlstra PG, de Groot K, Bezemer JM. Biodegradable poly(ether-ester) multiblock copolymers for controlled release applications. J. Biomed. Mater Res. A (2003) 67(4) 1294--1304. Van Dijkhuizen-Radersma R, Métairie S, Roosma JR, de Groot K, Bezemer JM. Controlled release of proteins from degradable poly(etherester) multiblock copolymers J. Control Rel. (2005) 101 175--186. Li Y-P, Pei Y-Y, Zhang X-Y, Gu Z-H, Zhou ZH, Yuan W-F, Zhou J-J, Zhu J-H, Gao X-J. PEGylated PLGA nanoparticles as protein carriers: synthesis, preparation and biodistribution in rats J. Control Rel. 71 (2001) 203–211. Yang Y, J Wenxiang, Q Xin, Yang C, Liu L, Zhang Z, Ma J, Zhou S, Li X. Novel Biodegradable Polymers as Gene Carriers Macromol. Biosci. (2004) 4 1113--1117. Zhang Y, Zhuo R-x. Synthesis and in vitro drug release behaviour of amphiphilic triblock copolymer nanoparticles based on poly (ethylene glycol) and polycaprolactone Biomaterials (2005) 26 6736--6742. Otsukaa H, Nagasaki Y, K Kazunori. PEGylated nanoparticles for biological and pharmaceutical applications Adv. Drug Del. Rev. (2003) 55 403--419. Hoffman AS. Hydrogels for Biomedical Applications Adv. Drug Deliv. Rev. (2002) 43 3--12. Jiang Z, Hao J, You YJ, Liu Y Wang Z, Deng X. Biodegradable and thermoreversible hydrogels of poly(ethylene glycol)-poly(ecaprolactone-co-glycolide)-poly(ethylene glycol) aqueous solutions J. Biomed. Mat. Res. A (2007) 87(1) 45--51. Jeong B, Bae YH, Kim SW. Drug release from biodegradable injectable thermosensitive hydrogel of PEG–PLGA–PEG triblock copolymers J. Control. Rel. 63 (2000) 155--163. Jeong B, Choi YK, Bae YH, Zentner G, Kim SW. New biodegradable polymers for injectable drug delivery Systems J. Control. Rel. (1999) 62 109--114. Ma PX. Biomimetic materials for tissue engineering Adv. Drug Del. Rev. (2008) 60184--198. Olah L, Borbas L. Properties of calcium carbonate-containing composite scaffolds Acta Bioeng. and Biomech. (2008) 10(1) 61-66.

Copolymers in the Preparation of Parenteral Drug Delivery Systems, Nova Science Publishers, Incorporated, 2010. ProQuest

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

References

67

[21] Rezwan K, Chen QZ, Blaker JJ, Boccaccini AR. Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering Biomaterials. (2006) 27 3413--3431. [22] Stevens B, Yang Y, M Arunesh, Stucker B, Nguyen KT. A Review of Materials, Fabrication Methods, and Strategies Used to Enhance Bone Regeneration in Engineered Bone Tissues J. Biomed. Mat. Res. B 85(2) (2007) 573--582. [23] Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables and applications Biomaterials. (2003) 24 4337--4351. [24] Kumar N, Ravikumar MNV, Domb AJ. Biodegradable block copolymers Adv. Drug Del. Rev. (2001) 53 23--44. [25] Younes H, Cohn D. Morphological study of biodegradable PEO/PLA block copolymers J. Biomed. Mater Res. (1987) 21 1301--1316. [26] Li SM, Rashkov I, Espartero JL, Manolova N, Vert M. Synthesis, characterization and hydrolytic degradation of PLA/PEO/PLA copolymers with long poly(L-lactic acid) chains Macromolecules (1996) 29(1) 57–62. [27] Rashkov I, Manolova N, Li SM, Espartero J L, Vert M. Synthesis, Characterization, and Hydrolytic Degradation of PLA/PEO/PLA Triblock Copolymers with Short Poly(l-lactic acid) Chains Macromolecules (1996) 29(1) 50--56. [28] Kissel T, Lib Y, Unger F. ABA-triblock copolymers from biodegradable polyester A-blocks and hydrophilic poly(ethylene oxide) B-blocks as a candidate for in situ forming hydrogel delivery systems for proteins Adv. Drug Del. Rev. (2002) 54 99--134. [29] Lemmouchi Y, Perry MC, Amass AJ, Chakraborty K, Schue F. Novel Synthesis of Biodegradable Poly(lactide-co-ethylene glycol) Block Copolymers J. Pol. Sci. A: Pol. Chem. (2007) 45(11) 2235--2245. [30] Kissel T, Li YX, Unger F. ABA-triblock copolymers from biodegradable polyester A-blocks and hydrophilic poly-(ethylene oxide) B-blocks as a candidate for in situ forming hydrogel delivery systems for proteins Adv. Drug Deliv. Rev. (2002) 54 99--134. [31] Cohn D, Marom G, Younes H. Design and synthesis of biodegradable poly(ether-esters). In: Pizzoferrato A, Marchetti PG, Ravaglioli A, Lee AJC (Eds.), Biomaterials and Clinical Applications Elsevier, Amsterdam, (1987) 503--510. [32] Hu DS-G, Liu H-J. Structural analysis and degradation behaviour in polyethylene glycol/poly(l-lactide) copolymers. J. Appl. Polym. Sci. (1994) 51 473--482.

Copolymers in the Preparation of Parenteral Drug Delivery Systems, Nova Science Publishers, Incorporated, 2010. ProQuest

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

68

Rossella Dorati, Claudia Colonna, Ida Genta et al.

[33] Jedlinski Z, Kurcok P, Walach W, Janeczek H, Radecka I. Polymerization of lactones, 17. Synthesis of ethylene glycol-L-lactide block copolymers Makromol. Chem. (1993) 194 1681--1689. [34] Kricheldorf HR, Boettcher C. Polylactones. Anionic polymerization of L-lactide. Variation of end groups and synthesis of block copolymers with poly (ethylene oxide) Makromol. Chem, Macromol. Symp. (1993) 27 47--64. [35] Du YJ, Lemstra PJ, Nijenhuis AJ, Van Aert HAM, Bastiaansen C. ABA type copolymers of lactide with poly-(ethylene glycol). Kinetic, mechanistic, and model studies. Macromolecules (1995) 28 2124--2132. [36] Li Y, Kissel T. Synthesis and properties of biodegradable ABA triblock copolymers consisting of poly(L-lactic acid) or poly(L-lactic-co-glycolic acid) A-blocks attached to central poly(oxyethylene) B-blocks J. Control Rel. (1993) 27 247-257. [37] Deng XM, Xiong CD, Cheng LM, Xu RP. Synthesis an characterization of block copolymers from D,L-lactide and poly(ethylene glycol) with stannous chloride J. Polym. Sci, Polym. Lett. Ed (1990) 28 411–416. [38] Zhu KJ, Xiangzhou L, Shilin Y. Preparation, Characterization, and Properties of Polylactide (PLA)-Poly(ethylene Glycol) (PEG) Copolymers: A Potential Drug Carrier J. App. Pol. Sci. (1990) 39 1--9. [39] Deng XM, Li XH, Yuan ML,. Xiong CD, Huang ZT,. Jia WX, Zhang YH. Optimization of preparative conditions for poly-DLlactidepolyethylene glycol microspheres with entrapped Vibrio Cholera antigens J. Control Rel. (1999) 58 123--131. [40] Quesnel R, Hildgen P. Synthesis of PLA-b-PEH Multiblock Copolymers for Stealth Drug Carrier Preparation Molecules. (2005) 10 98--104. [41] Huh KM, Bae YH. Synthesis and characterization of poly(ethylene glycol)/poly(l-lactic acid) alternating multiblock copolymers Polymer. (1999) 40 6147--6155. [42] Kubies D, F Rypáĕk, J Kovářová, F. Lenický Microdomain structure in polylactide-block-poly(ethylene oxide) copolymer films Biomaterials. (2000) 21 529--536. [43] Zhu Z, Xiong C, Zhang L, Yuan M, Deng X. Preparation of biodegradable polylactide-co-poly(ethyleneglycol) copolymer by lactide reacted poly(ethylene glycol) Eur. Pol. J. (1999) 35 1821--1828. [44] Letchford K, Burt H. A review of the formation and classification of amphiphilic block copolymer nanoparticulate structures: micelles, nanospheres, nanocapsules and polymersomes Eur. J. Pharm. Biopharm. (2007) 65 259--269.

Copolymers in the Preparation of Parenteral Drug Delivery Systems, Nova Science Publishers, Incorporated, 2010. ProQuest

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

References

69

[45] Jiang Z, Hao J, You YJ, Liu Y, Wang Z, Deng X. Biodegradable and thermoreversible hydrogels of poly(ethylene glycol)-poly(ecaprolactone-co-glycolide)-poly(ethylene glycol) aqueous solutions J. Biom. Mat. Res. A (2007) 87(1) 45--51. [46] Chen S, Pieper R, Webster D C, Singh J. Triblock copolymers: synthesis, characterization, and delivery of a model protein Int. J. Pharm. (2005) 288 207--218. [47] Cohn D, Hotovely Salomon A. Designing biodegradable multiblock PCL/PLA thermoplastic Elastomers Biomaterials (2005) 26 2297--2305. [48] Jeong B, Choi YK, Bae YH, Zentner G, Kim SW. New biodegradable polymers for injectable drug delivery Systems J. Control Rel. (1999) 62 109--114. [49] Göpferich A. Polymer Degradation and Erosion: Mechanisms and Apllications Eur. J. Pharm. Biopharm. (1996) 42(1) 1-11. [50] Mathiowitz E, Jacob J, Pekarek K, Chickering D. III Morphological characterization of bioerodible polymers. 3. Characterization of the erosion and intact zones in polyanhydrides using scanning electron microscopy Macromolecules (1993) 26 6756--6765. [51] Södergård A, Stolt M. Properties of lactic acid based polymers and their correlation with composition Prog. Polym. Sci. (2002) 27 1123--1163. [52] Li S. Hydrolytic degradation characteristics of aliphatic polyesters derived from lactic and glycolic acids J. Biomed. Mater Res. (1999) 48 342– 353. [53] Li SM, Garreau H. Structure-property relationshipin the case of the degradation of massive aliphatic poly-(α-hydroxy acids) in aqueous media Part 1 Poly(D,L-lactic acid) J. Mater Sci. Mater Med. (1990) 1 123--130. [54] Witt C, Kissel T. Morphological characterization of microspheres, films and implants prepared from poly(lactide-co-glycolide) and ABA triblock copolymers: is the erosion controlled by degradation, swelling or diffusion? European J. Pharm. Biopharm. (2001) 51 171--181. [55] Li Y, Volland C, Kissel T. In-vitro degradation and bovine serum albumine release of the ABA triblock copolymers consisting of poly(L(+)lactic acid), or poly(L(+)lactic acid-co-glycolic acid) A-blocks attached to central polyoxy ethylene B-blocks J. Control Rel. (1994) 32 121–128. [56] Shah SS, Zhu KJ, Pitt CG. Poly-DL-lactic acid: poly-ethylene glycol block copolymers. The influence of polyethylene glycol on the

Copolymers in the Preparation of Parenteral Drug Delivery Systems, Nova Science Publishers, Incorporated, 2010. ProQuest

70

[57]

[58]

[59]

[60]

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

[61]

[62]

[63]

[64] [65]

[66]

Rossella Dorati, Claudia Colonna, Ida Genta et al. degradation of poly-DL-lactic acid J. Biomater. Sci, Polym. Ed. 5, (1994) 421--431. Li S, Anjard S, Rashkov I, Vert M. Hydrolytic degradation of PLA/PEO/PLA triblock copolymers prepared in the presence of Zn metal or CaH2 Polymer. (1998) 39 5421--5430. Li SM, Garreau H, Vert M. Structure–property relation-ships in the case of the degradation of massive poly(α-rhydroxy acids) in aqueous media. Part III: Influence of the morphology of poly(L-lactic acid), PLA 100 J. Mater Sci. Mater Med. (1990) 1 198—206. Cerrai P, Tricoli M, Lelli L, Guerra GD, Sbarbati DelGuerra R, Cascone MG, Giusti P. Block copolymers of L-lactide and poly(ethylene glycol) for biomedical applications J. Mater Sci. Mater Med. 5 (1994) 308--313. Witt C, Mader K, Kissel T. The degradation, swelling and erosion properties of biodegradable implants prepared by extrusion or compression moulding of poly(lactide-co-gly-colide) and ABA triblock copolymers Biomaterials (2000) 21 931--938. Bittner B, Witt C, Mader K, Kissel T. Degradation and protein release properties of microspheres prepared from biodegradable poly(lactide-coglycolide) and ABA triblock copolymers: influence of buffer media on polymer erosion and bovine serum albumin release J. Control Rel. (1999) 60 297--309. Li SM, Garreau H, Vert M. Structure–property relation-ships in the case of the degradation of solid aliphatic poly(α-hydroxy acids) in aqueous media I: Poly(D,L-lactic acid) or PLA 50 J. Mater Sci. Mater Med. (1990) 1 123—130. Li SM, Garreau H, Vert M. Structure–property relation-ships in the case of the degradation of massive poly(α- hydroxy acids) in aqueous media. II: Degradation of lactide /glycolide copolymers: PLA37.5GA25 and PLA75GA25 J. Mater Sci. Mater Med. (1990) 1 131—139. Vert M, Li SM, Garreau H. More about the degradation of LA/GAderived matrices in aqueous media J. Control Rel. (1991) 16 15--26. Hu DSG, Liu HJ. Effect of soft segment on degradation kinetics in polyethylene glycol / poly(L-lactide) block copoly-mers Polym. Bull. (1993) 30 669--676. Dorati R, Genta I, Colonna C, Modena T, Pavanetto F, Perugini P, Conti B. Investigation of the degradation behaviour of poly(ethylene glycolco-d,l-lactide) copolymer Polymer Degradation and Stability (2007) 92 1660--1668.

Copolymers in the Preparation of Parenteral Drug Delivery Systems, Nova Science Publishers, Incorporated, 2010. ProQuest

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References

71

[67] Kaparisside C, Alexandridou S, Kotti Katerina, Chaitidou S. Recent Advance in Novel Drug Delivery Systems J. Nanotech. Online. (2006) 2 1--11. [68] Dorati R, Genta I, Montanari L, Cilurzo F, Buttafava A, Faucitano A, Conti B. The effect of γ-irradiation on PLGA/PEG microspheres containing ovalbumin J. Control Rel. 107 (2005) 78—90. [69] Sinha VR, Trehan A. Biodegradable microspheres for protein delivery J. Control Rel. (2003) 90 281--290. [70] Lewis DH. Controlled release of bioactive agents from lactide/glycolide polymers In Chasin M, Langer R editors. Biodegradable polymers as drug delivery systems New York: Marcel Dekker; (1990) 1--41 [chapter I]. [71] Huang YY, Chung TW, Tzeng TW. A method using biodegradable polylactides/polyethylene glycol for drug release with reduced initial burst Int. J. Pharm. (1999) 182 93--100. [72] Bazile D, Prud’Homme C, Bassoullet MT, Marlard M, Spenlehauer G. Stealth PEG-PLA nanoparticles avoid uptake by the mononuclear phagocytes system J. Pharm. Sci. (1995) 84 493--498. [73] Jiang W, Schwendeman SP. Stabilization and controlled release of bovine serum albumin encapsulated in poly(D,L-lactide) and poly(ethylene glycol) microsphere blends Pharm. Res. (2001) 18 878-885. [74] Younes H, Nataf PR, Cohn D, Appelbaum YJ, Pizov G, Uretzky G. Biodegradable PELA block copolymers: in vitro degradation and tissue reaction Biomater Artif. Cells Artif. Organs. (1988) 16 705--719. [75] Kim JH, Bae YH. Albumin loaded microsphere of amphiphilic poly(ethylene glycol)/poly(alpha-ester) multiblock copolymer Eur. J. Pharm. Sci. (2004) 23 245--251. [76] Deng XM, Li XH, Yuan ML, Xiong CD, Huang ZT, Jia WX, Zhang YH. Optimization of preparative conditions for poly-DL-lactidepolyethylene glycol microspheres with entrapped Vibrio Cholera antigens J. Control Rel. (1999) 58 123--131. [77] Huh KM, Cho YW, Park K. PLGA-PEG Block Copolymers for Drug Formulations Drug Del. Tech. (2003) 3(5). [78] Gaucher G, Dufresne M-H, Sant V Pa Kang N, Maysinger D, Leroux JC. Block copolymer micelles: preparation, characterization and application in drug delivery J. Control Rel. (2005) 109 169–188

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

72

Rossella Dorati, Claudia Colonna, Ida Genta et al.

[79] Wang C-H, Wang C-H, Hsiue G-H. Polymeric micelles with a pHresponsive structure as intracellular drug carriers J. Control Rel. (2005) 108 140--149. [80] Lee J, Cho EC, Cho K. Incorporation and release behaviour of hydrophobic drug in functionalized poly(D,L-lactide)-block– poly(ethylene oxide) micelles J. Control Rel. (2004) 94 323--335. [81] Zhang X, Jackson JK, Wong W, Min W, Cruz T, Hunter WL, Burt HM. Development of biodegradable polymeric paste formulations for taxol: an in vitro and in vivo study J. Pharm. (1996) 137199--208. [82] Saito N, Okada T, Horiuchi H, Murakami N, Takahashi J, Nawata M, Ota H, Nozaki K, Takaoka K A Biodegradable polymer as a cytokine delivery system for inducing bone formation Nature Biotec. (2001) 19 332--335. [83] Huang YY, Chung TW, Tzeng TW. A method using biodegradable polylactides/polyethylene glycol for drug release with reduced initial burst Int. J. Pharm. (1999)182 93--100. [84] Mäder K, Bittner B, Li Y, Wohlauf W, Kissel T. Monitoring Microviscosity and Microacidity of the Albumin Microenvironment Inside Degrading Microparticles from Poly(lactide-co-glycolide) (PLG) or ABA-triblock Polymers Containing Hydrophobic Poly(lactide-coglycolide) A Blocks and Hydrophilic Poly(ethyleneoxide) B Blocks Pharm. Res. (1998) 15(6) 787--793. [85] Morlock M, Kissel T, Li YX, Koll H, Winter G. Erythropoietin loaded microspheres prepared from biodegradable LPLG–PEO–LPLG triblock copolymers: protein stabilization and in-vitro release properties J. Control. Rel. (1998) 56 105--115. [86] Mundargi RC, Babu VR. Rangaswamy V, Patel P, Aminabhavi T M. Nano/micro technologies for delivering macromolecular therapeutics using poly(D,L-lactide-co-glycolide) and its derivatives J. Control. Rel. (2008) 125 193--209. [87] Stolnik S, Dunn SE, Garnett MC, Davies MC, Coombes AGA, Taylor DC, Irving MP, Purkiss SC, Tadros TF, Davis SS, Illum L. Surface modification of poly(L-lactide-co-glycolide) nanospheres by biodegradable poly(L-lactide)-poly(ethyleneglycol) copolymers Pharm. Res. (1994) 11 1800–1808. [88] Matsumoto J, Nakada Y, Sakurai K, Nakamura T, Takahashi Y. Preparation of nanoparticles consisted of poly(L-lactide)–poly(ethylene glycol)–poly(L-lactide) and their evaluation in vitro International J. Pharm. (1999) 185 93--101.

Copolymers in the Preparation of Parenteral Drug Delivery Systems, Nova Science Publishers, Incorporated, 2010. ProQuest

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

References

73

[89] Gref R, Minamitake Y, Peracchia MT, Trubetskoy V,Torchilin V, Langer R. Biodegradable long-circulating polymeric nanospheres Science. (1994) 263 1600–1603. [90] Bazile D, Prudhomme C, Bassoullet M, Marlard M, Spenlehauer G, Veillard M. Stealth MePEG-PLA nanoparticles avoid uptake by the mononuclear phagocytes system J. Pharm. Sci. (1995) 84 493–498. [91] Verrecchia T, Spenhauer G, Bazile DV, Murry-Brelier A, Archimbaud Y, Veillard M. Non-stealth (poly(lactic acid:albumin)) and stealth (poly(lactic acid-polyethylene glycol)) nanoparticles as injectable drug carriers J. Control Rel. (1995) 36 49--61. [92] Nakada Y, Sakurai K, Horiushi M, Tudomi R, Nakamura T, Takahashi Y. Long-circulating nanoparticles using biodegradable ABA triblock copolymers containing of poly(L-lactic acid) A-blocks attached to central poly(oxyethylene) B-blocks Pharm. Sci. (1997) 3 1--4. [93] Tobío M, Gref R, Sànchez A, Langer R, Alonso MJ. Stealth PEG-PLA nanoparticles as protein carriers for nasal administration Pharm. Res. (1998)15 (2) 270--275. [94] Tobío M, Sanchez A, Vila A, Soriano I, Evora C, Vila-Jato JL, Alonso MJ. The role of PEG on the stability in digestive fluids and in vivo fate of PEG-PLA nanoparticles following oral administration Colloids Surf B Biointerfaces (2000) 18 315– 323. [95] Vila, A. Sànchez, C. Evora, I. Soriano, O. McCallion, M.J. Alonso. PLA-PEG particles as nasal vaccine carriers: influence of the particle size Int. J. Pharm. (2005) 292 43--52. [96] Vila, A. Sánchez, A. Pérez C, . Alonso MJ, PLA-PEG nanospheres: new carriers for transmucosal delivery of proteins and plasmid DNA Polym. Adv. Technol. 13 (2002) 1--8. [97] Vila A, Gill H, McCallion O, Alonso MJ. Transport of PLA-PEG particles across the nasal mucosa: effect of particle size and PEG coating density J. Control Rel. (2004) 98 231--244. [98] Choi S-W, Kim J-H. Design of surface-modified poly(D,L-lactide-coglycolide) nanoparticles for targeted drug delivery to bone J. Control Rel. (2007) 122 24--30. [99] Heald CR, Stolnik S, Kujawinski KS, De Matteis C, Garnett MC, Illum L, Davis SS, Purkiss SC, Barlow RJ, Gellert PR. Poly(lactic acid)poly(ethylene oxide) (PLA-PEG) nanoparticles: NMR studies of the central solid like PLA core and the liquid PEG corona Langmuir (2002) 18 3669--3675.

Copolymers in the Preparation of Parenteral Drug Delivery Systems, Nova Science Publishers, Incorporated, 2010. ProQuest

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

74

Rossella Dorati, Claudia Colonna, Ida Genta et al.

[100] Riley T, Stolnik S, Heald CR,. Xiong CD, Garnett MC, Illum L, Davis SS, Purkiss SC, Barlow RJ, Gellert PR. Physicochemical evaluation of nanoparticles assembled from poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) block copolymers as drug delivery vehicles Langmuir (2001) 17 3168--3174. [101] Wang D, Miller S, Sima M, Kopečková P, Kopeček J. Synthesis and evaluation of water-soluble polymeric bone-targeted drug delivery systems Bioconjugate Chem. 14 (2003) 853–859. [102] Wang D, Miller SC, Kopečková P, Kopeček J. Bone-targeting macromolecular therapeutics Adv. Drug Deliv. Rev. 57 (2005) 1049-1076. [103] He C, Kim SW, Lee DS. In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery J. Control Rel. (2008) 127189-207. [104] Choi SW, Choi SY, Jeong B, Kim SW, Lee DS. Thermoreversible gelation of poly(ethylene oxide) biodegradable polyester block copolymers II J. Pol. Sci. A (1999) 37 2207--2218. [105] Molina I, Li S, Martinez, MB, Vert M. Protein release from physically crosslinked hydrogels of the PLA/PEO/PLA triblock copolymer-type Biomaterials (2001) 22 363--369. [106] Jeong JH, Kim SW, Park TG. Biodegradable triblock copolymer of PLGA–PEG–PLGA enhances gene transfection efficiency Pharm. Res. (2004) 21 50--54. [107] Packhaeuser CB, Schnieders J, Oster CG, Kissel T In situ forming parenteral drug delivery systems: an overview Eur. J. Pharm. Biopharm. (2004) 58 445--455. [108] Jeong B, Bae YH, Lee DS, Kim SW. Biodegradable block copolymers as injectable drug-delivery systems Nature (1997) 388 860--862. [109] Li Z, Ning W, Wang J, Choi A, Lee PY, Tyagi P, Huang L. Controlled gene delivery system based on thermosensitive biodegradable hydrogel Pharm. Res. (2003) 20 884--888. [110] Lee PY, Li Z, Huang L. Thermosensitive hydrogel as a Tgf-b1 gene delivery vehicle enhances diabetic wound healing Pharm. Res. (2003) 20 1995--2000. [111] Zentner GM, Rathi R, Shih C, Mcrea JC, Seo MH, Oh H, Rhee BG, Mestecky J, Moldoveanu Z, Morgan M, Weitman S. Biodegradable block copolymers for delivery of proteins and water insoluble drugs J. Control Rel. (2001) 72 203--215.

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

References

75

[112] Kim YJ, Choi S, Koh JJ, Lee M, Ko KS, Kim S.W. Controlled release of insulin from injectable biodegradable triblock copolymer Pharm. Res. (2001) 18 548--550. [113] Shim MS, Lee HT, Shim WS, Park I, Lee H, Chang T, Kim SW, Lee DS. Poly(D,L-lactic acid-co-glycolic acid)-b-poly(ethylene glycol)-bpoly (D,L-lactic acid-co-glycolic acid) triblock copolymer and thermoreversible phase transition in water J. Biom. Mat. Res. (2002) 61 188--196. [114] Choi S, Kim SW. Controlled release of insulin from injectable biodegradable triblock copolymer depot in ZDF rats Pharm. Res. (2003) 20 2008--2010. [115] Choi S, Baudys M, Kim SW. Control of blood glucose by novel GLP-1 delivery using biodegradable triblock copolymer of PLGA–PEG–PLGA in type-2 diabetic rats Pharm. Res. (2004) 21 827--831. [116] Chen S, Singh J. Controlled delivery of testosterone from smart polymer solution based systems: in vitro evaluation Int. J. Pharm. (2005) 295 183--190. [117] Chen S, Singh J. In vitro release of levonorgestrel from phase sensitive and thermosensitive smart polymer delivery systems Pharm. Dev. Tech. (2005) 10 319--325. [118] Samlowski WE, McGregor JR, Jurek M, Baudys M, Zentner GMFowers KD. ReGel® polymer-based delivery of interleukin-2 as a cancer treatment J. Immun. (2006) 29 524--535. [119] Lin H, Tian HY, Sun JR, Zhuang XL, Chen XS, Li YS, Jing XB. Synthesis, characterization and drug release of temperature-sensitive PLGA–PEG–PLGA hydrogel Chem. J. Chinese Uni. 27 (2006) 1385-1388. [120] Kwon GS, Kataoka K. Block copolymer micelles as long circulating drug vehicles Adv. Drug Deliv. Rev. (1995) 16 295--309. [121] Kreuter J, Nanoparticles, in: J. Kreuter (Ed.), Colloidal Drug Delivery Systems, Marcel Dekker, New York (1994) 219--342. [122] Kwon GS, Okano T. Polymeric micelles as new drug carriers Adv. Drug Deliv. Rev. (1996) 21 107--116. [123] Kataoka K, Kwon GS, Yokoyama M, Okano T, Sakurai Y. Block copolymer micelles as vehicles for drug delivery J. Control Rel. (1993) 24 119--132. [124] Bronich TK, Kabanov AV, Kabanov VA, Yu K, Eisenberg A. Soluble complexes from poly(ethylene oxide)b- lock-polymethacrylate anions and N-alkylpyridinium cations Macromolcules (1997) 30 3519--3525.

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76

Rossella Dorati, Claudia Colonna, Ida Genta et al.

[125] Harada A, Kataoka K. Chain length recognition: core-shell supramolecular assembly from oppositely charged block copolymers Science (1999) 283 65--67. [126] Nishiyama N, Yokoyama M, Aoyagi T, Okano T, Sakurai Y, Kataoka K. Preparation and characterization of self-assembled polymer–metal complex micelle from cis-dichlorodiamineplatinum (IT) and poly(ethylene glycol-)poly(α, β-aspartic acid) block copolymer in an aqueous medium Langmuir (1999) 15 377—383. [127] Yasugi K, Nagasaki Y, Kato M, Kalsoka K. Preparation and characterization of polymer micelles from poly-(ethylene glycol)poly(D,L-lactide) block copolymer as potential drug carrier J. Control Rel. (1999) 62 89--100. [128] Zhang X, Jackson JK, Burt HM. Development of amphiphilic diblock copolymers as micellar carriers of taxol Int. J. Pharm. (1996) 132 195-206. [129] Kwon GS, Naito M, Yokoyama M, Okano T, Sakurai Y, Kataoka K. Micelles based on AB block copolymers of poly(ethylene oxide) and poly(β-benzyl L-aspartatic) Langmuir (1993) 9 945—949. [130] Kataoka K, Ishihara A, Harada A, Miyazaki H. Effect of secondary structure of poly(L-lysine) segments on the micellization in aqueous milieu of poly(ethylene glycol)-poly(L-lysine) block copolymer partially substituted with hydrocinnamoyl-group at the N-position Macromolecules (1998) 31 6071--6076. [131] Lee J, Cho E C, Kilwon C. Incorporation and release behaviour of hydrophobic drug in functionalized poly(D,L-lactide)-block– poly(ethylene oxide) micelles J. Control Rel. (2004) 94 323--335. [132] Yokoyama M, Okano T, Sakurai Y, Kataoka K. Improved synthesis of adriamycin-conjugated poly(ethylene oxide)–poly(aspartic acid) block copolymer and formation of unimodal micellar structure with controlled amount of physically entrapped adriamycin J. Control Rel. (1994) 32 269--277. [133] Yamamoto Y, Nagasaki Y, Kato M, Kataoka K. Surface charge modulation of poly(ethyleneglycol)-poly(D,L-lactide) block copolymer micelles: Conjugation of charged peptides Colloid Surf. B Biointerfaces (1999) 16 135--146. [134] Yasugi K, Nakamura T, Nagasaki Y, Kato M, Kataoka K. Sugarinstalled polymer micelles: Synthesis and micellization of poly(ethylene glycol)-poly(D,L-lactide) block copolymers having sugar groups at the PEG chain end Macromolecules (1999) 32 8024--8032.

Copolymers in the Preparation of Parenteral Drug Delivery Systems, Nova Science Publishers, Incorporated, 2010. ProQuest

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References

77

[135] Liggins RT, Burt HM. Polyether-polyester diblock copolymers for the preparation of paclitaxel loaded polymeric micelle formulations Adv. Drug Deliv. Rev. (2002) 54 191--202. [136] Yoo HS, Park TG. Biodegradable polymeric micelles composed of doxorubicin conjugate PLGA-PEG block copolymer J. Control Rel. (2001) 70 63--70. [137] Sinha VR, Trehan A. Biodegradable microspheres for protein delivery J. Control Rel. (2003) 90 281--290. [138] Hausberger AG, Kenley RA, DeLuca PP. Gamma irradiation effects on molecular weight and in vitro degradation of Poly(D,L-lactide-coglycolide) microparticles Pharm. Res. (1995) 12(6) 851--856. [139] USP 31, 〈1211〉 Sterilization and sterility assurance of compendial articles (2008) 670--675. [140] Eur Pharm 6.0, 5.1.1. Methods of preparation of sterile products (2008) 525--527. [141] Hemmerich KJ. Radiation sterilization: Polymer materials selection for radiation-sterilized products. Medical Device MDDI Feb 2000 p 78. [142] Hausberger AG, Kenley RA, DeLuca PP. Gamma irradiation effects on molecular weight and in vitro degradation of Poly(D,L-lactide-coglycolide) microparticles Pharm. Res. (1995) 12(6) 851--856. [143] Yoshioka S, Aso Y, Otsuka T, Koima S. The effect of γ-irradiation on drug release from poly(lactide) microspheres Radiat. Phys. Chem. (1995) 46(2) 281--285. [144] Bittner B, Mader K, Kroll C, Borchert HH, Kissel T. Tetracycline-HClloaded poly(DL-lactide-co-glycolide) microspheres prepared by a spray drying technique: influence of γ-irradiation on radical formation and polymer degradation J. Control Rel. (1999) 59: 23--32. [145] Mohr D, Wolff M, Kissel T. Gamma irradiation for terminal sterilization of 17β-estradiol loaded poly-(D,L-lactide-co-glycolide) microparticles J. Control Rel. (1999) 61 203--217. [146] Shameem M, Lee H, Burton K, Thanoo BC, DeLuca P.P. Effect of gamma irradiation on peptide-containing hydrophilic poly(D,L-lactideco-glycolide) microspheres J. Pharm. Sci. Technol. (1999) 53(6) 309-313. [147] Herrero-Vanrell R, Ramirez L, Fernandez-Carballido A, Refojo MF. Biodegradable PLGA microspheres loaded with Ganciclovir for intraocular administration. Encapsulation technique, in vitro release profiles, and sterilization process Pharm. Res. (2000) 17 1323--1328.

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78

Rossella Dorati, Claudia Colonna, Ida Genta et al.

[148] Gèze A, Venier-Julienn MC, Cottin J, Faisant N, Benoit JP. PLGA microsphere bioburden evaluation for radiosterilization dose selection J. Microencapsul. (2001) 18(5) 627--636. [149] Montanari L., Cilurzo F., Valvo L., Faucitano A., Buttafava A., Groppo A., Genta I., Conti B. Gamma irradiation effects on stability of poly(lactide-co-glycolide) microspheres containing clonazepam. J. Control Rel. (2001) 75 317--330. [150] Dorati R, Colonna C, Serra M, Genta I, Modena T, Pavanetto F, Perugini P, Conti B. γ-Irradiation of PEGd,lPLA and PEG-PLGA multiblock copolymers: I. Effect of irradiation doses AAPS Pharm. Sci. Tech. (2008) 9(2) 718--725. [151] Nakane K, Hata Y, Morita K, Ogihara T, Ogata N. Porous poly(L-lactic acid)/poly(ethylene glycol) blend films. J. Appl. Polym. Sci. (2004) 94(3) 965--970. [152] Cleek RL, Ting KC, Eskin SG, Mikos AG. Microparticles of poly(d,llactic-co-glycolic acid)/poly(ethyleneglycol) blends for controlled drug delivery J. Control Rel. (1997) 48 259--268. [153] Moad CL, Winzor DJ. Quantitative characterization of radiation degradation in polymers by evaluation of scission and cross-linking yields Prog. Polym. Sci. (1998) 23 759--813. [154] Devasahayam S, Hill DJT, Whittaker AK. G values for scission and crosslinking on γ-radiolysis of ultem at 303K High Perform. Polym. (2003)15 259--263. [155] Nugroho P, Mitomo H, Yoshii F, Kume T. Degradation of poly(L-lactic acid) by γ-irradiation Polym. Degrade Stab. (2001) 72 337--343. [156] Sintzel MB, Merkli A, Tabatabay C, Gurny R. Influence of irradiation sterilization on polymers used as a drug carriers-A review Drug Dev. Ind. Pharm. (1997) 23(9) 857--879. [157] Montanari L, Cilurzo F, Valvo L, Faucitano A, Buttafava A, Groppo A, Genta I, Conti B. Gamma irradiation effects on stability of poly(lactideco-glycolide) microspheres containing clonazepam J. Control Rel. (2001) 75 317--330. [158] Haugen HJ, Brunner M, Pellkofer F, Aigner J, Will J, Wintermantel E. Effect of different γ-irradiation doses on cytotoxicity and material properties of porous polyether-urethane polymer J. Biomed. Mater Res. B Appl. Biomat. (2006) 415-423. [159] Fayolle B, Audolin L, Verdu J. Radiation induced embrittlement of PTFE Polymer. (2003) 44 2773--2789.

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References

79

[160] Montanari L, Cilurzo F, Selmin F, Conti B, Genta I, Poletti G, Orsini F, Valvo L. Poly(lactide-co-glycolide) microspheres containing bupivacaine: comparison between gamma and beta irradiation effects. J. Control Rel. (2003) 90(3) 281--290. [161] Bushel JA, Claybourn M, Williams HE, Murphy DM. An EPR and ENDOR study of γ and β-radiation sterilization in poly(lactide-coglycolide) polymers and microspheres J. Control Rel. (2005)110 49--57. [162] Faucitano A, Buttafava A, Montanari L, Cilurzo F, Conti B, Genta I, Valvo L. Radiation induced free radical reactions in polymer/drug systems for controlled release: an EPR investigation Radiat. Phys. Chem. (2003) 67 61--72. [163] Montanari L, Costantini M, Signoretti EC, Valvo L, Santucci M, Bortolomei M, Fattibene P, Onori S, Faucitano A, Conti B, Genta I. Gamma-irradiations effects on poly(d,l-lactie-co-glycolide) microspheres J. Control Rel. (1998) 56(2) 219--229. [164] Claybourn M, Gray H, Murphy DM, Purnell IJ, Rowlands CC. Electron magnetic resonance study of gamma-irradiated poly(lactide-coglycolide) microspheres J. Control Rel. (2003) 91 431--438. [165] The use of ionizing radiation in the manufacture of medicinal products European Guidelines 3AQ4a. [166] Gèze A, Venier-Julienne MC, Cottin J, Faisant N, Benoit JP. PLGA microsphere bioburden evaluation for radiosterilization dose selection Eur. J. Pharm. Sci. (2003) 56(2) 271--279. [167] Huang YY, Chung TW. Microencapsulation of gentamicin in biodegradable PLA and/or PLA/PEG copolymer J. Microencapsul. (2001) 18(4) 457—465. [168] Fayolle B, Audolin L, Verdu J. Mechanism of degradation induced embrittlement in polyethylene. Polymer degradation and stability (2007) 92 231--238. [169] Dorati R, Colonna C, Tomasi C, Genta I, Genta I, Modena T, Faucitano A, Buttafava A, Conti B. γ-Irradiation of PEGd,lPLA and PEG-PLGA multiblock copolymers; II. Effect of oxygen and EPR investigation AAPS Pharm. Sci. Tech. (2008) 9 (4) 1110-1118.

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INDEX

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A acceleration, 27 acetate, 19 acid, 1, 11, 16, 17, 18, 32, 47, 48, 67, 68, 69, 70, 73, 74, 75, 76, 78 acidic, 28, 32, 36 activation, 59 additives, 56 administration, 31, 33, 40, 42, 43, 51, 73, 77 adriamycin, 76 adsorption, 4, 40, 43 agent, 3, 4, 20, 31, 33, 35, 38 agents, ix, 63, 71 aggregates, 38 aggregation, 32, 33, 38, 41, 44, 47 aging, 57 air, 53, 56, 57, 58, 59 albumin, 37, 73 alcohol, 18 alkali, 15 alkaline, 28 alpha, 71 alternative, 4, 59 aluminium, 18 amino, 48 amino acid, 48

amorphous, 25, 26, 27, 28, 29, 30, 32, 54, 57, 58 amphiphiles, 48 Amsterdam, 67 antibiotic, 35 antibiotics, 31 antibody, 41 anticancer, 42, 65 anticancer drug, 42, 65 aqueous solution, 4, 5, 24, 40, 44, 45, 46, 66, 69 aqueous solutions, 5, 46, 66, 69 arginine, 38 aseptic, 51 atoms, 54, 58 autocatalysis, 41

B barrier, 27, 37 beam radiation, 52 behaviours, 46, 47 binding, 32, 43 bioavailability, 31 biocompatibility, ix, 3, 4, 5, 21, 32 biocompatible, 5, 13, 32, 34, 46 biodegradability, 3, 5, 21 biodegradable, 3, 4, 9, 26, 31, 32, 39, 46, 51, 57, 63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 79

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Index

82 biomaterials, 21, 34 biomedical applications, ix, 4, 5, 70 biomolecules, 44 blend films, 78 blends, 22, 71, 78 blocks, ix, 4, 7, 8, 9, 11, 12, 13, 20, 21, 22, 23, 26, 27, 29, 30, 34, 36, 37, 44, 49, 63, 67, 68, 69, 73 blood, 4, 32, 39, 41, 46, 47, 75 blood glucose, 46, 47, 75 blood stream, 41 body temperature, 20 bonding, 37, 47, 48, 58 bonds, 25, 29, 53 bone morphogenetic proteins, 36 bovine, 69, 70, 71 buffer, 25, 26, 28, 37, 70 bulk polymerization, 11 bypass, 35 by-products, 12

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C calcium, 66 calcium carbonate, 66 cancer, 35, 75 cancer cells, 35 cancer treatment, 75 candidates, 32, 47 capillary, 39 caprolactone, 1, 65, 66, 69 carbon, 15 carboxylic, 18, 25, 26, 47, 48 carboxylic groups, 25 carrier, 31, 36, 42, 76 cartilage, 5 catalyst, 12, 13, 15, 17, 18, 19, 20, 26 catalytic effect, 26 cation, 59 cell, 4, 35 cell growth, 35 CGC, 24, 44 CGT, 24 chain mobility, 58, 59

chain scission, 25, 27, 29, 52, 53, 54, 56, 58, 59 chain transfer, 17, 52 channels, 37 chemical interaction, 32 chemical properties, 3, 21, 23, 27, 44, 56, 63 chemical reactions, 5 chemical structures, 34 chloride, 19, 68 Cholera, 68, 71 chromatography, 48 circulation, 4, 33, 35, 38, 40, 47, 63 cis, 76 classification, 68 cleavage, 18, 23, 25, 27, 28, 29, 53 CLSM, 42 clustering, 24 CMC, 48, 49 compatibility, 22, 29, 44 compliance, 31 components, 20, 22 composition, ix, 4, 5, 12, 16, 21, 24, 27, 28, 32, 35, 36, 38, 40, 41, 52, 63, 69 compounds, 3, 12, 13, 17, 18, 26, 31 concentration, 24, 33, 34, 40, 42, 44, 45, 46, 47, 49, 59, 60 configuration, 18 Congress, vi conjugation, 49 constant rate, 33, 46 control, ix, 4, 43, 47 control group, 47 conversion, 17, 19 cooling, 34 copolymer, 3, 7, 8, 9, 12, 15, 17, 18, 19, 20, 21, 22, 23, 24, 27, 28, 29, 30, 32, 33, 34, 35, 36, 37, 38, 40, 41, 42, 43, 44, 45, 48, 49, 53, 55, 57, 58, 59, 60, 65, 66, 68, 70, 71, 74, 75, 76, 77, 79 copolymer micelles, 34, 71, 75, 76 copolymerization, 12, 20 copolymerization reaction, 12, 20 copolymers, ix, 3, 4, 5, 7, 8, 9, 11, 12, 13, 15, 17, 18, 19, 20, 21, 22, 23, 24,

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Index 27, 28, 29, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 52, 53, 55, 57, 58, 59, 63, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79 core-shell, 4, 44, 76 corona, 32, 34, 37, 48, 73 correlation, 69 costs, 51 coupling, 3, 20 covalent, 18 critical temperature, 43 crosslinking, 4, 23, 34, 78 cross-linking, 53, 54, 78 cross-linking reaction, 53, 54 crystalline, ix, 4, 23, 25, 26, 27, 29, 30, 34, 54, 57 crystallinity, 12, 26, 27, 30, 32 crystallization, 22, 44 cytokine, 72 cytotoxic, 13, 35 cytotoxicity, 78

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D decay, 28, 29, 53, 54, 55, 59, 60 definition, 34 degradation, ix, 4, 5, 12, 21, 25, 26, 27, 28, 29, 31, 32, 35, 36, 37, 38, 40, 45, 46, 51, 53, 56, 57, 65, 67, 69, 70, 71, 77, 78, 79 degradation mechanism, 27, 30 degradation process, 25 degradation rate, 4, 5, 26, 27, 28, 29, 32, 40 degrading, 29, 31, 55 degree of crystallinity, 22 delivery, ix, 1, 3, 4, 28, 31, 35, 36, 39, 42, 43, 46, 47, 48, 51, 56, 65, 66, 67, 69, 71, 72, 73, 74, 75, 77, 78 denaturation, 33 density, 41, 42, 73 derivatives, 32, 72 diabetes, 46 dialysis, 48

83 diffusion, 23, 25, 27, 28, 32, 35, 37, 40, 45, 56, 57, 69 diffusivity, 33, 54 dispersion, 11 disposition, 22 distribution, 12, 17, 19, 20, 26, 29, 36, 39, 40, 47 DNA, 41, 46, 73 domain structure, 44, 46 dominance, 42, 54 dosage, 35 drug carriers, 39, 41, 48, 72, 73, 75, 78 drug delivery, ix, 1, 3, 31, 39, 42, 43, 44, 47, 51, 56, 66, 69, 71, 73, 74, 75, 78 drug delivery systems, ix, 1, 51, 56, 71, 74 drug release, 31, 39, 40, 45, 46, 66, 71, 72, 75, 77 drugs, 31, 32, 33, 34, 36, 44, 46, 49, 63, 74 drying, 77 DSC, 21, 22, 57, 58

E ECM, 47 electron, 28, 38, 51, 52, 54, 69 electron microscopy, 38, 69 Electron Paramagnetic Resonance, 1, 28, 59 electrophoresis, 37 emulsification, 37 encapsulated, ix, 4, 32, 33, 37, 38, 42, 71 encapsulation, 4, 36, 42, 63 ENDOR, 79 endotherms, 21 end-to-end, 8 energy, 44, 52, 54, 56 entanglement, 4, 23, 34, 36 entanglements, 34 entrapment, 49 entropy, 24 environment, 4, 24, 25, 33, 34, 37, 44, 51, 56 environmental conditions, 56, 57

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Index

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84 epithelium, 41 EPR, 1, 28, 36, 37, 59, 60, 61, 79 EPR-spectroscopy, 37 equilibrium, 23, 34 erosion, 23, 25, 26, 27, 28, 33, 36, 40, 42, 69, 70 erythropoietin, 38 ester, 17, 25, 28, 29, 41, 49, 59, 66 ester bonds, 25 esterification, 17 esters, 67 estradiol, 77 estrogen, 43 ethylene, 1, 51, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78 ethylene glycol, 65, 66, 67, 68, 69, 70, 71, 72, 74, 75, 76, 78 ethylene oxide, 1, 51, 65, 67, 68, 72, 73, 74, 75, 76 ethyleneglycol, 65, 68, 72, 76, 78 evacuation, 57 evaporation, 37 excretion, 35 exposure, 35, 37, 52, 54, 59 expulsion, 46 extravasation, 43 extrusion, 36, 70

G Gamma, 51, 77, 78, 79 gamma radiation, 52 gamma-ray, 54, 58 Ganciclovir, 77 gas, 51 gauge, 45 gel, 5, 21, 23, 24, 34, 43, 44, 45, 46 gel formation, 44 gelation, 24, 44, 74 gels, 34, 43 gene, 46, 74 generation, 29, 59 gentamicin, 79 glass, 1, 57 glass transition, 1, 57 glass transition temperature, 1, 57 GLP-1, 46, 75 glucose, 46, 47, 75 glycerine, 37 glycol, 48, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78 Good Manufacturing Practice, 51 GPC, 17, 29, 55, 57 groups, 3, 9, 12, 17, 18, 19, 20, 25, 26, 34, 47, 48, 58, 68, 76 growth, 35

F family, 3, 21 fiber, 26 film, 26 films, 28, 29, 33, 68, 69, 78 filtration, 17, 35, 39 fixation, ix flexibility, 5, 12, 57 flow, 16, 37 fluid, 34, 41 free energy, 46 free radical, 54, 56, 58, 59, 79 free radicals, 54, 56, 58, 59 free volume, 37, 57, 58 fulfillment, 12

H half-life, 40 heat, 51 heating, 34 hematopoietic, 36 heterogeneous, 30, 41 high temperature, 17, 19, 44, 51 histidine, 38 homogenous, 25, 26 homopolymers, 7, 9, 12, 21, 22, 23, 24, 27, 32, 33 hormone, 46 human, 38 humidity, 55

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Index hydration, 23, 43, 44 hydride, 12 hydro, ix, 3, 4, 9, 12, 21, 23, 24, 26, 27, 28, 32, 33, 34, 36, 37, 40, 41, 42, 44, 45, 47, 58, 63, 67, 77 hydrodynamic, 42, 43 hydrogels, ix, 4, 33, 34, 43, 45, 46, 47, 66, 69, 74 hydrogen, 18, 37, 47, 48, 54, 58 hydrogen abstraction, 54 hydrogen atoms, 58 hydrolysis, 25, 26, 32, 51 hydrophilic, ix, 3, 4, 9, 12, 21, 23, 24, 26, 27, 28, 32, 33, 34, 36, 37, 40, 41, 42, 44, 45, 47, 58, 63, 67, 72, 77 hydrophilicity, 3, 21, 27, 32, 39 hydrophobic, ix, 3, 4, 9, 12, 21, 23, 24, 27, 32, 33, 34, 36, 37, 41, 42, 44, 45, 47, 58, 63, 72, 76 hydrophobic groups, 34 hydrophobic interactions, 4, 23, 24 hydrophobic properties, 12 hydrophobicity, 44 hydroxyapatite, 43 hydroxyl, 12, 17, 18, 19 hydroxyl groups, 12, 19

I identification, 59 IgG, 41 immune response, 41 immunogenicity, ix implants, ix, 31, 32, 33, 34, 35, 36, 45, 51, 69, 70 impurities, 12, 13, 17, 19 in situ, 4, 43, 67 in vitro, 26, 28, 35, 37, 40, 43, 46, 66, 71, 72, 75, 77 in vivo, ix, 3, 31, 32, 39, 43, 46, 57, 72, 73 incubation, 28, 36, 46 incubation time, 28, 36 induction, 27 induction period, 27

85 inert, 17 infection, 3, 34 inflammation, 3, 34 inhibitor, 35 initiation, 19 injection, 25, 34, 39, 40, 46, 47 injections, 31 injury, vi inorganic, 67 insertion, 18, 19 instability, 38 insulin, 46, 47, 75 integrity, 52 interaction, 3, 4, 32, 34, 41, 42, 47, 48 interactions, 4, 23, 24, 32, 47, 58 interface, 27, 29, 37 interleukin, 47, 75 interleukin-2, 47, 75 intermolecular, 47, 58, 59 intramuscular, 33, 34, 39 intramuscular injection, 34 intraocular, 77 intravenous, 39 intrinsic, 57 invasive, 47 Investigations, 52 ionic, 28 ionizing radiation, 51, 54, 56, 79 ions, 15, 17, 38 irradiation, 51, 52, 54, 55, 56, 57, 58, 60, 61, 71, 77, 78, 79 irradiations, 52, 79

K kidneys, 4 kinetics, 28, 70

L lactic acid, 1, 11, 16, 17, 18, 67, 68, 69, 70, 73, 74, 75, 78 lactones, 11, 12, 15, 16, 19, 68 Langmuir, 73, 74, 76

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Index

86 lanthanum, 19 ligand, 3 limitation, 17 linear, 5, 8, 15, 20, 33, 46 links, 24 liposomes, 39 liquids, 35 liver, 32, 40 L-lactide, 1, 17, 65, 68, 70, 71, 72, 73, 76, 77 loading, ix, 4, 35, 39, 40, 42, 47, 48 localization, 43 losses, 26 low molecular weight, 12 lysine, 65, 76 lysozyme, 45

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M magnetic, vi, 79 magnetic resonance, 79 manipulation, ix manners, 15, 53 market, 31 marrow, 36, 43 mass loss, 25, 26, 28, 29 matrix, ix, 23, 25, 26, 27, 28, 29, 32, 33, 34, 37, 40, 41, 42, 53, 56, 57, 59, 60 mechanical properties, ix, 3, 5, 36 media, 4, 28, 37, 40, 69, 70 medical products, 52 melting, 1, 21, 22, 23, 35 melting temperature, 1, 22, 35 metal oxide, 12, 15, 17 metal oxides, 12, 17 metals, 15 mice, 36, 41 micelles, ix, 4, 24, 33, 34, 44, 47, 48, 49, 68, 72, 75, 76, 77 microencapsulation, 36, 39 microenvironment, 32, 72 microparticles, 33, 37, 38, 77 microscopy, 38 microspheres, 28, 32, 33, 36, 37, 38, 39, 68, 69, 70, 71, 72, 77, 78, 79

microstructure, 28, 57 microtubule, 35 mixing, 35, 44 MLT, 65 mobility, 22, 26, 37, 43, 48, 53, 57, 58, 59, 60 modulation, 76 moieties, 45, 48, 56 molar ratio, 18 molecular mass, 12, 29 molecular mobility, 43 molecular structure, 24 molecular weight, ix, 1, 4, 12, 26, 53, 54, 55, 58, 77 molecules, ix, 4, 12, 15, 18, 25, 31, 32, 33, 34, 35, 36, 37, 43, 45, 47, 48, 53, 56, 58 monomer, 7, 8, 12, 17, 18, 20 monomer molecules, 18 monomers, ix, 7, 11, 15, 17, 25, 34, 49 morphological, 36 morphology, ix, 33, 35, 70 moulding, 36, 70 mouse, 35 mouse model, 35 MPS, 39 mucosa, 42, 73

N nanocapsules, 34, 68 nanoparticles, ix, 4, 34, 39, 65, 66, 71, 72, 73, 74 nanoparticulate, 4, 31, 68 nanosystems, 34 natural, 34 necrosis, 3, 34 network, 4, 23, 34 New York, v, vi, 71, 75 nitrogen, 16 NMR, 17, 18, 29, 36, 41, 44, 48, 73 normal, 46

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Index

O oligomers, 25, 27 oral, 31, 73 organ, 12 organic, 5, 37, 42 organic solvent, 5, 37 organic solvents, 5 organometallic, 12 orientation, 12, 26, 37, 41 oxidation, 56, 57 oxidative, 57 oxide, 1, 51, 65, 67, 68, 72, 73, 74, 75, 76 oxides, 12, 17 oxygen, 15, 16, 18, 54, 56, 57, 58, 79

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P paclitaxel, 35, 42, 49, 77 paramagnetic, 28, 59 parenteral, ix, 4, 28, 31, 38, 51, 74 particles, 17, 37, 39, 41, 42, 43, 51, 73 partition, 45 passive, 63 peptide, 4, 31, 33, 46, 65, 77 peptides, ix, 32, 33, 36, 76 permeability, 40 permeation, 25, 37, 40, 42, 45, 56 permit, 43 PET, 1, 3 PGA, 1, 3, 5, 25, 44 pH values, 28 phagocyte, 39 pharmaceutical, ix, 3, 4, 12, 31, 32, 52, 57, 66 pharmacopoeia, 51 phase diagram, 24, 45 physical properties, ix, 12, 57 physico-chemical properties, 21, 23, 44, 63 physiological, 28 plasma, 47 plasmid, 46, 73

87 plasticizer, 57 play, 27 PLGA, ix, 1, 3, 4, 5, 11, 23, 24, 26, 28, 29, 31, 32, 33, 34, 36, 37, 38, 40, 42, 43, 44, 45, 46, 47, 49, 52, 53, 54, 55, 57, 58, 59, 60, 61, 63, 66, 71, 74, 75, 77, 78, 79 PLLA, 26, 27, 29, 44, 46 polar groups, 12 poly(L-lactide), 70, 72 polycondensation, 16, 20 polydispersity, 17, 19, 20, 30 polyester, ix, 3, 4, 5, 9, 15, 24, 30, 32, 44, 67, 74, 77 polyesters, 3, 16, 19, 20, 25, 26, 69 polyether, 9, 78 polyethylene, 67, 69, 70, 71, 72, 73, 79 polylactones, 21 polymer, ix, 3, 4, 7, 8, 17, 18, 20, 22, 23, 24, 25, 26, 27, 28, 29, 31, 32, 33, 34, 36, 37, 38, 40, 41, 42, 43, 45, 47, 49, 51, 52, 53, 54, 55, 56, 57, 58, 59, 67, 70, 72, 75, 76, 77, 78, 79 polymer chains, 3, 18, 23, 25, 26, 32, 36, 47, 53, 56, 57, 58 polymer matrix, 25, 26, 27, 28, 32, 33, 40, 42, 56, 57, 59 polymer molecule, 53 polymer properties, 20 polymer structure, 32 polymer swelling, 28 polymer-based, 51, 75 polymerization, 9, 11, 12, 13, 15, 16, 17, 18, 19, 20, 65, 68 polymerization mechanism, 16, 19 polymerization process, 15 polymers, ix, 3, 5, 7, 12, 20, 21, 22, 24, 26, 31, 33, 35, 39, 44, 47, 51, 52, 53, 57, 58, 63, 65, 66, 69, 71, 78, 79 polypeptide, 32 Polysaccharides, iii Polysorbate 80, 40 poor, 24, 31, 39 pore, 28 pores, 43

Copolymers in the Preparation of Parenteral Drug Delivery Systems, Nova Science Publishers, Incorporated, 2010. ProQuest

Index

88 porous, 67, 78 precipitation, 41 product performance, 52 production, 51 progesterone, 40 propagation, 15 protection, 31 protein, 4, 31, 32, 33, 37, 38, 40, 41, 45, 48, 66, 69, 70, 71, 72, 73, 77 protein aggregation, 32 proteins, ix, 32, 33, 36, 46, 66, 67, 73, 74 Proteins, 36 PTFE, 78

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R racemization, 17, 18 radiation, 51, 52, 53, 54, 56, 58, 77, 78, 79 radical formation, 77 radical reactions, 79 radius, 42 random, 7, 29, 32, 37, 53 range, ix, 4, 5, 26, 34, 55, 61 rat, 42 rats, 41, 46, 47, 66, 75 reaction temperature, 16 reaction time, 13, 16, 20 receptors, 48 recognition, 47, 76 recombination, 52 recrystallized, 22 regeneration, 5 renal, 35 reparation, ix, 66, 71 resection, 35 residuals, 12, 18 residues, 48 risk, 32 rods, 28, 33 room temperature, 20, 45, 59 ROP, 11, 12, 18 rubbery state, 27, 29

S safety, 51 salt, 18 salts, 12 sample, 26, 56, 58 saturation, 49 scaffold, 5, 47, 67 scaffolds, ix, 3, 5, 51, 66, 67 Scanning electron, 38 scanning electron microscopy, 69 scattering, 44 SDS, 1, 37 selectivity, 48 self-assembly, 65, 66 sensitivity, 52, 53, 54, 57 separation, 21, 22, 23, 27 series, 46 serum, 32, 38, 69, 70, 71 serum albumin, 38, 69, 70, 71 services, vi shape, 9, 26, 28, 36, 37, 39, 42, 45 shaping, 3 side effects, 31 sites, 59 sodium, 17 sol-gel, 5, 21, 24, 44 solid state, 20 solubility, ix, 4, 27, 35, 49 solvent, 12, 24, 37 solvents, 5 spatial, 37 species, 15, 59 spectroscopy, 28 spectrum, 37, 59, 60 speed, 40 spleen, 35, 40 stability, 26, 35, 39, 47, 48, 55, 56, 57, 73, 78, 79 stabilization, 4, 52, 72 stages, 25, 29 steric, 35 sterile, 52, 77 sterilization, 51, 52, 53, 56, 57, 58, 77, 78, 79

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Index

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stiffness, 44 Stimuli, 43 storage, 55, 56, 57, 59, 60 strength, 26, 28 structural changes, 52 subcutaneous injection, 39, 46, 47 subcutaneous tissue, 33 substances, 35 sugar, 48, 76 sugars, 48 Sun, 65, 75 superimposition, 60 supramolecular, 76 surface area, 24 surface layer, 26 surface structure, 37 surfactant, 40 surgical, 3, 34, 35, 45 swelling, ix, 21, 23, 27, 28, 33, 34, 36, 37, 69, 70 synthesis, ix, 11, 12, 15, 17, 19, 66, 67, 68, 69, 76 systemic circulation, 63

T temperature, 11, 19, 20, 22, 23, 24, 28, 34, 35, 36, 43, 44, 45, 46, 51, 55, 56, 58, 59, 60, 61, 75 terminals, 8 testosterone, 47, 75 Tetanus, 41 therapeutic agents, 63 therapeutics, 72, 74 therapy, 34 thermoplastic, 69 three-dimensional, 53 thrombosis, 3 tin, 18 tissue, ix, 3, 5, 33, 34, 66, 67, 71 toluene, 11 toxic, 13, 17, 31 toxic side effect, 31 toxicity, 3, 43 trans, 17, 41

89 transesterification, 11 transesterification reaction, 11 transfection, 74 transfer, 17, 18, 52 transition, 1, 5, 21, 23, 24, 34, 43, 44, 46, 57, 58, 75 transition temperature, 1, 24, 44, 57, 58 transport, 25, 28, 41, 42 tumor, 35 tumor cells, 35 tumor growth, 35 type 2 diabetes, 46

U uniform, 12, 37 urethane, 78

V vaccination, 41 vaccine, 39, 41, 73 vacuum, 57, 58 validation, 52 values, 28, 36, 54, 55, 78 variables, 63, 67 variation, 12, 56 vasculature, 43 vehicles, 74, 75 versatility, ix viscosity, 37, 42

W water, 4, 19, 21, 23, 24, 25, 26, 27, 33, 34, 35, 37, 40, 42, 48, 49, 74, 75 water diffusion, 25, 27 water permeability, 40 water-soluble, 34, 48, 74 wettability, 40 wound healing, 74

Copolymers in the Preparation of Parenteral Drug Delivery Systems, Nova Science Publishers, Incorporated, 2010. ProQuest

Index

90

X

Z

XPS, 42

zinc, 17, 46

Y

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yield, 12, 19, 20, 54, 55, 59

Copolymers in the Preparation of Parenteral Drug Delivery Systems, Nova Science Publishers, Incorporated, 2010. ProQuest