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Few scientific developments in recent years have captured the popular imagination like the subject of'biodegradable' plastics. The reasons for this are complex.
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Few scientific developments in recent years have captured the popular imagination like the subject of'biodegradable' plastics. The reasons for this are complex and lie deep in the human subconscious. Discarded plastics are an intrusion on the sea shore and in the countryside.

The fact that nature's litter abounds in the sea and on land is acceptable because it is biodegradable - even though it may take many years to be bioassimilated into the ecosystem.

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Plastics litter is not seen to be biodegradable and is aesthetically unacceptable because it does not blend into the natural environment. To the environmentally aware but often scientifically naive, biodegradation is seen to be the ecologically acceptable solution to the problem of plastic packaging waste and litter and some packaging manufacturers have exploited the 'green' consumer with exaggerated claims to 'environmentally friendly' biodegradable packaging materials. The principles underlying environmental degradation are not understood even by some manufacturers of 'biodegradable' materials and the claims made for them have been categorized as 'deceptive' by USA legislative authorities.

This has set back the acceptance of plastics with controlled biodegradability as part of the overall waste and litter control strategy. This negative campaign has concentrated on the supposed incompatibility of degradable plastics with aspects of waste management strategy, notably materials recycling. It is a major contribution to the literature on polymer technology and will undoubtedly be widely read. JavaScript is currently disabled, this site works much better if you enable JavaScript in your browser.

Free Preview. Buy eBook. Buy Hardcover. Buy Softcover. FAQ Policy. About this book Few scientific developments in recent years have captured the popular imagination like the subject of'biodegradable' plastics. Show all. Table of contents 13 chapters Table of contents 13 chapters Introduction to the abiotic degradation of carbon chain polymers Pages Scott, Gerald. In the development of three-dimensional structures, vinyl-terminated polydimethylsiloxanes are crosslinked by branched polydimethylsiloxanes with reactive SiH- groups under the catalysis of platinum [ 38 ].

Due to the hydrophobic nature of crosslinked PDMS Figure 3 , hydrophobic drugs are commonly loaded in PDMS-based delivery devices to achieve prolonged release profiles. As shown in Table 1 , drug release from PDMS-based delivery devices can be sustained to over a month. Similar to polyurethanes, PDMS can also be fabricated into reservoir- and matrix-type devices Figure 2.

As for crosslinked PDMS network, the network density is described by the average molecular weight Mn number average of the crosslinked units [ 38 ]. In addition to crosslink density, water uptake is another important impact factor which may affect the degree of swelling and solute transport within the PDMS network. Thus, there seems to be a correlation between water uptake and release kinetics for the matrix-type PDMS devices.

In addition, zero-order release pattern can be achieved by fabricating PDMS into reservoir-type devices. For instance, Maeda et al designed a covered-rod formulation with a silicone inner matrix containing active ingredient and a silicone outer layer functioning as the rate-controlling membrane. In contrast to the typical first-order release profile with matrix-type devices, near zero-order release of ivermectin IVM from a PDMS reservoir-type device was observed.

With the addition of poly ethylene glycol PEG in the matrix, a four-fold increase in IVM release velocity was observed while the zero-order profile has been maintained [ 22 ], which was mainly due to the effect of PEG as a solubility enhancing agent. Studies on PDMS based intravaginal rings reservoir-type, IVR for the delivery of a hydrophobic drug TMC also displayed a near zero-order release profile with a short initial burst phase [ 23 , 24 ].

The initial burst was attributed to the enhanced dissolution of the active drugs within the core of the ring, and the incorporation of hydrophilic lactose greatly decreased the burst effect while increasing the release rate in a concentration-dependent manner [ 23 ]. In biomedical engineering, PEVA has been used in the development of medical and controlled drug delivery devices by employing casting and freeze drying methods. PEVA based devices are designed to slowly release drug compounds over a relatively long period of time [ 40 ].

Subcutaneous implantation of ethylene-vinyl acetate copolymer films in Sprague-Dawley rats confirmed that the base polymer provoked no inflammatory responses and the polymer had good tissue compatibility [ 41 ]. The permeability of these copolymer films changes substantially with varying VA content and thus it is possible to tailor the release rate to a desired value by slightly changing the membrane compositions [ 42 ]. An increase in crystallinity would also reduce the diffusivity of polymer [ 43 ].

Similarly, PEVA is also a diffusion-controlled polymer, and it has been formulated into either microporous films to achieve zero-order release or matrix-type devices to sustain drug release over time Table 1.

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Biodegradable polymers are widely used in the development of controlled delivery systems that can dramatically improve patient compliance and reduce side effects through extended dosing and targeting [ 44 ]. Several pharmaceutical products based on biodegradable delivery systems have been approved by the FDA, including hormones, antitumour drugs and antibiotics [ 45 ].

In general, biodegradable polymers contain labile bonds such as ester-, amide-, and anhydride-bonds that are prone to hydrolysis or enzymatic degradation Figure 4. Surface degradation and bulk degradations are two typical modes of degradation. In a surface-degrading polymer, degradation is confined to the outer surface of the device [ 46 , 47 ].

In a bulk-degrading polymer, however, degradation occurs homogeneously throughout the material [ 48 ]. Water is an important factor during hydrolysis and thus water intrusion into the device is of significant importance for the study of degradation kinetics as well as release kinetics. The degradation of semicrystalline polymers occurs in two stages: i.

The first stage consists of water infusion into the amorphous regions with random hydrolytic scission of labile bonds, such as ester bonds; ii. The second stage starts when most of the amorphous regions are degraded [ 49 ]. As degradation results in the scission of polymer chain, the change in the average molecular weight of the polymer could be used to quantify the degradation process over time.

Using gel permeation chromatography GPC , the degradation process is usually characterized by plotting the average molecular weight of the degraded material versus time.

Characterization of Novel Degradable Polymers for Drug Delivery Applications

The following two equations are widely used to describe the degradation kinetics:. Representative functional groups of biodegradable polymers Adapted from [ 52 ]. Polymer degradation has been defined by Siepmann and Gopferich as the chain scission process by which polymer chains are cleaved into oligmers and monomers, while bioerosion refers to the loss of material from bulk or surface in contact with a biological system [ 52 ].

By virtue of these definitions, the two concepts are not mutually exclusive but are interrelated. PLGA is one of the most commonly used biodegradable polymers in developing particulate drug delivery systems [ 53 ]. PLGA is synthesized by ring-opening copolymerization of two different monomer, the cyclic dimmers 1,4-dioxane-2,5-diones of glycolic acid and lactic acid [ 54 ]. PLGA degrades via hydrolysis of its ester linkages in the presence of water.

The typical release profile for PLGA particulate delivery systems is the initial burst phase followed by a near-zero order phase [ 57 ]. Various intramuscular or subcutaneous controlled delivery systems in the form of implants or microparticles have been developed using biodegradable polyesters such as PLA and PLGA [ 58 ]. In vitro release study of diltiazem hydrochloride and buserelin acetate from in situ forming delivery systems ISM, PLA or PLGA solution dispersed in an external oil phase displayed a triphasic release pattern Table 2 [ 59 ].

The initial burst was most likely due to the rapid release of surface associated drug molecules, the second phase was probably due to material degradation via chain scission, and the third phase was mainly the result of polymer erosion which led to the loss of bulk materials [ 60 ]. Though PLA and PLGA are bulk-erosion type biodegradable materials, studies showed that release kinetics of selected solutes from such biodegradable polymeric matrices are not simply driven by degradation [ 61 , 62 ].

In the early stage, the concentration gradient and the shape of the device seem to have a more profound impact on the release rate. While in the later stage, degradation becomes the dominant driving force and thus the release profile corresponded to the degradation kinetics of the material [ 62 ].

In addition to the property and the structure of the material, the physicochemical properties of the drug compounds also influence the release behavior. For example, the in vitro release of a hydrophobic drug, estradiol, from PLGA nanoparticles displayed zero-order release for 31 — 54 days, and the linear release pattern was observed with all formulation groups, which has been found to occur through diffusion-cum-degradation mediated process Table 2 [ 56 ].

Summary of release kinetics and transport mechanisms of degradable polymer based delivery devices. Polyanhydrides are a group of surface-erosion dominated biodegradable materials. Therefore, the hydrophilic and hydrophobic nature of the drugs may potentially affect release rate and cumulative release percentage from the surface-erosion type devices. In the case of taxol, the degradation of polyanhydride might be the main driving force for taxol release, while for cefazolin sodium, the concentration gradient between the devices and the release medium would be dominant for solute transport [ 64 ].

Manoharan et al investigated poly 1,3-bis- p-carboxyphenoxy propane-co-sebacic acid p CPP:SA microspheres for controlled delivery of basal insulin. Insulin was released within 3 days from SA-only microspheres, while a significant amount of insulin was not released from CPP-only microspheres over a month due to the slow degradation in CPP polymers. Environmentally sensitive polymeric delivery systems are designed to achieve targeted delivery and controlled release in vivo upon specific stimuli, such as pH, ionic strength, enzyme-substrate, magnetic, thermal, electrical, ultrasound, etc [ 66 ].

Drug release from pH- and enzyme-sensitive polymeric delivery systems is mainly attributed to stimuli-triggered degradation. Aimetti and coworkers developed a poly ethylene glycol hydrogel platform with human neutrophil elastase sensitive peptide crosslinks. The crosslinked hydrogel was formed using thiol-ene photopolymerization, rendering the gel degradable at sites of inflammation. A zero-order release of bovine serum albumin in the presence of human neutrophil elastase has been observed, and the release was arrested in the absence of human neutrophil elastase, indicating enzyme-triggered degradation was the driving force for BSA release from this gel matrix Table 2 [ 67 ].

Another example is poly ortho ester amides copolymer, the degradation of which is triggered by acids.

Both the mass loss kinetics of poly ortho ester amides in physiological aqueous buffers and the release of fluorescently labeled dextran followed the near zero-order pattern, suggesting the release was predominantly driven by surface restricted polymer erosion Table 2. Moreover, the rates of polymer erosion and drug release were much faster at pH 5.

Dissolution of polymers in solvents, an important phenomenon in polymer science, has been extensively applied in areas such as microlithography, controlled drug release, membrane science, etc [ 69 ]. In general, polymer dissolution involves two transport processes, i. Though polymer dissolution does not result in the scission of polymer chains, it does lead to the loss of bulk material. One example is polysaccharides, a class of hydrophilic macromolecules that are widely used in pharmaceutical industry owing to low toxicity, biocompatibility, availability and abundance.

Polysaccharides such as hydroxypropyl methylcellulose HPMC , cyclodextrin, dextran, gellan gum, remain stable under physiological pH and temperature, but will undergo hydrolysis at extreme pH and temperatures. More importantly, polysaccharides undergo dissolution in the aqueous medium due to solvent penetration effect, swelling, and polymer chain disentanglement and relaxation [ 71 ]. For example, the fractional release of adinazolam mesylate from tablets consisting of HPMC matrices corresponded well with the fractional release of HPMC, indicating drug release is primarily driven by dissolution Table 2 [ 72 ].

Mathematical modeling of drug release kinetics provides a basis for the study of mass transport mechanisms that are involved in the control of drug release [ 73 ]. There have been several nicely written reviews on mathematical modeling for bioerodible polymeric delivery systems [ 52 ], dissolution controlled drug delivery systems [ 69 ], microsphere delivery systems [ 2 ] and hydrogel networks [ 74 ]. In general, diffusion, erosion, and degradation are the most important mechanisms for solute transport from polymeric matrices.

Mathematical models based on each aforementioned mechanism are summarized here. In addition, models for materials with more complex compositions and structures are also discussed. Several commonly used power law equations for modeling release kinetics are summarized Table 3. These models are easy to use and the established empirical rules may help explain transport mechanism s. However, these models do not provide additional insights into a more complex transport mechanism.

Furthermore, these models might fail whenever there is a need for taking into account specific physicochemical processes [ 52 ]. The study also revealed that polymer erosion, swelling and dissolution were all involved in the release process and the authors suggested that the conclusion of a non-Fickian drug release mechanism, simply based on the diffusional exponent, n , of the Peppas models Eq 4 , can be misleading [ 80 ]. The late-time approximation, which holds for the final portion of the drug release, i. The assumption for the application of the above equations is the dimension and physical properties of the material matrices do not change during the release process, i.

To predict the release profile, the diffusion coefficient of the solute within the polymer matrix D should be available, which could be measured by nuclear magnetic resonance and fluorescence correlation spectroscopy [ 83 ]. Furthermore, Eq. The models achieved good correlations with experimental data in both studies, indicating the transport mechanism was primarily Fickian diffusion.

Degradable Polymers - Principles and applications | G. Scott | Springer

Polymer dissolution refers to the process that polymer begins to release its contents to the surrounding fluid when in the presence of a thermodynamically compatible solvent [ 69 ]. Narasimhan and Peppas developed a model for polymer dissolution based on the molecular mechanism.

The model describes solute transport in one-dimensional system, such as a film, slab, disk or tablet. In Eq 10 , S-R is defined as the gel layer thickness and the variation of the gel-layer thickness S-R with time was established [ 84 ]. In Eq. To investigate the effect of various parameters on the drug release behavior, the normalized drug released as a function of time was simulated using drugs of different molecular sizes. An increase of drug release was observed with a higher drug diffusion coefficient.

The model successfully captures Fickian and Case II type behavior and the transition state in between. Both release patterns have been well characterized using this model, e. The model was demonstrated to be valid due to the good agreement between experimental data and the equation. The equation is valid for spheres, cylinders and slabs:.

Following the analysis, Katzhendler et al developed a general mathematical model for drug release from an erodible matrix. The model takes into account radial and axial erosion. Rothstein et al developed a unified model for both surface- and bulk-eroding materials. Integrating the total normalized concentration of agent in the matrix over all space yields the cumulative fraction of agent remaining in the matrix at each point in time Eq.

The cumulative fraction of drug release R t , is simply Eq. The time- and space- dependant matrix porosity follows a cumulative normal distribution function based on a molecular weight or degradation rate distribution of the given polymer Eq The molecular weight of the polymer matrix during release M w,r has been previously correlated to the molecular weight of the agent for common biodegradable systems [ 90 ].

The model has been successfully applied to dye release data from POE disks Figure 5. Predictions of release from A bulk eroding and B surface eroding poly orthoester matrices. Copyright , with permission from Elsevier. The model development has been conducted through the modeling of release kinetics of each material component respectively. PCL is the type of slowly degrading polymer which takes over two years to be completely degraded under physiological conditions. It is also important to note that no degradation term in Eq. The model developed for PLGA took into consideration all three steps i.

Though not discussed in detail, drug release profile is related to the forms of delivery devices, for example sphere, disk, film, cylinder, etc. The aforementioned mathematical models are applicable to a certain type of devices. Table 4 summarizes the applicability and common assumptions for the previously discussed mathematical models. To sum up, no universally applicable mathematical models are available for release kinetics from non-degradable or degradable polymer systems due to the multiple factors involved during the process of solute transport.

The established models seem to be material specific, drug specific, and formulation specific. Therefore, the applicability of a specific model should be carefully reviewed before it is applied to experimental data, such as the structural characteristics of materials, physicochemical properties of model drugs, dimension and geometry of the delivery devices, and any assumptions or limiting cases related to the model.

Degradable polymers : principles and applications

In the design and development of a therapeutic agent, in vitro release study has been considered as one of the key standards to evaluate and optimize the formulation. The in vitro release results reveal the structure-function relationship of the material matrices, contribute to the tailoring of material for optimal controlled release and also provide insights into the performance of the formulation in vivo. However, a major concern with in vitro release study is the lack of direct correlation between in vitro and in vivo release profiles.

Currently, attentions have been focused on the in vivo release studies and the correlation between in vitro and in vivo release data [ 92 , 93 ]. The physiological conditions are much more complex than buffer solutions that are commonly employed for in vitro evaluations. The release profile of a drug may be affected by various proteins, cells, and enzymes in vivo. For example, simulated release medium including intestinal fluid, gastric fluid, saliva, lachrymal fluid, and blood serum can be employed to enhance the accuracy of evaluation.

Alternatively, in vivo release models can be developed but they are often time laborious and costly. Additionally, the complex compositions of tissue fluids also present great challenges on the sensitivity and reliability of a single conventional analytical method. Nevertheless, the rapid development in advanced analytical techniques, such as liquid chromatography coupled with mass spectrometry, fluorescent probes, and mass imaging techniques provide potential means to conquer these difficulties.

In case studies of release kinetics, burst release is a phenomenon commonly observed in delivery devices of different forms and compositions. The burst effect may be favorable for certain indications or applications such as wound treatment, encapsulated flavors, targeted delivery and pulsatile release. Burst release is often associated with device geometry, surface characteristics of host material, heterogeneous distribution of drugs within the polymer matrix, intrinsic dissolution rate of drug, heterogeneity of matrices pore density , etc.

However, few studies have been conducted to develop mechanism based mathematical models for burst release. To better predict the burst release, it would be worthwhile developing models to elucidate the mechanisms of burst release. In addition, it would be of great significance to develop models that take into account physiological conditions, including such variables as pH, osmotic pressure, cellular tissue reactions, enzyme concentration, and etc [ 52 ]. This would benefit the mathematical prediction for the stimuli-triggered delivery systems as well as material systems employed under patho physically relevant conditions.

Some preliminary studies have been well documented in the review paper by Lin and Metters [ 74 ]. However, mathematical models that can represent the real physiological conditions have yet to be developed. Furthermore, the goal for mathematical modeling of release kinetics is to elucidate the potential transport mechanisms, especially the structure-function relationship of the material system. In return, understanding of the fundamentals will provide guidance for future material design and device development. A current trend in the controlled drug delivery field is the development of multi-component material systems, i.

For instance, semi-interpenetrating networks composed of crosslinked, stable PEG matrices and biodegradable labile gelatin macromolecules have shown to be effective drug delivery matrices and tissue scaffold for wound healing [ 95 , 96 ]. As a result, the release kinetics is driven by multiple factors and cannot be described by a single mathematical model mentioned previously [ 97 ]. The authors state no conflict of interest and have received no payment in preparation of this manuscript. Europe PMC requires Javascript to function effectively.

Recent Activity. The advancement in material design and engineering has led to the rapid development of new materials with increasing complexity and functions. The structure and function information of selected non-degradable and degradable polymers have been collected and summarized from literature published after the s. The release kinetics of selected drug compounds from various material systems is discussed in case studies.

Recent progress in the mathematical models based on different transport mechanisms is highlighted. The snippet could not be located in the article text. This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Expert Opin Drug Deliv. Author manuscript; available in PMC Apr 1. PMID: Copyright notice. The publisher's final edited version of this article is available at Expert Opin Drug Deliv. See other articles in PMC that cite the published article. Abstract Importance of the field The advancement in material design and engineering has led to the rapid development of novel materials with increasing complexity and functions.

Areas covered in this review The structure and function information of selected non-degradable and degradable polymers have been collected and summarized from literatures published after s. What the reader will gain This article aims to provide an overview of structure-function relationships of selected non-degradable and degradable polymers as drug delivery matrices.

Take home message Understanding the structure-function relationship of the material system is key to the successful design of a delivery system for a particular application. Keywords: degradable polymer, non-degradable polymer, mathematical model, release kinetics. Introduction Drug release has been an important topic in the field of drug delivery for decades. Open in a separate window. Figure 1. Release kinetics from non-degradable polymeric matrices Non-degradable polymers have been widely applied in the fabrication of peroral dosage forms, transdermal films, and implant devices [ 4 ].

Figure 2.

Degradable Polymers: Principles and applications

Figure 3. Structures of representative non-degradable pharmaceutically related polymer. Table 1 Summary of release kinetics and transport mechanisms of nondegradable polymer based delivery devices. Biodegradable polymeric matrices 3. Figure 4. Table 2 Summary of release kinetics and transport mechanisms of degradable polymer based delivery devices.

Mathematical models for drug release kinetics from polymeric systems Mathematical modeling of drug release kinetics provides a basis for the study of mass transport mechanisms that are involved in the control of drug release [ 73 ]. Table 3 Empirical mathematical models for drug release kinetics.

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Model Expression Eq. Application Ref. Figure 5. Table 4 Summary of the mathematical models. Mechanism of Transport Eq. Form of Devices Assumptions Diffusion 8 , 9 slab, disk i Diffusion takes place only in one dimension ii Constant drug diffusion coefficient iii No matrix swelling or degradation Dissolution 10 , 11 , 12 , 13 slab, disk, film i Two moving boundaries: R, the glassy-rubbery interface; S, the rubbery-solvent interface ii Constant drug and solvent diffusion coefficient Erosion 14 sphere, cylinder, slab i Zero-order surface detachment of drug ii Constant material erosion rate 15 slab, cylinder i Zero-order surface detachment of drug ii Constant material erosion rate iii Two dimensional erosion, i.

Expert opinion In the design and development of a therapeutic agent, in vitro release study has been considered as one of the key standards to evaluate and optimize the formulation. Footnotes Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript. Langer R. New methods of drug delivery. Mathematical modeling and simulation of drug release from microspheres: implication to drug delivery systems.

Adv Drug Deliv Rev. Grassi M, Grassi G. Mathematical modeling and controlled drug delivery: matrix systems. Curr Drug Deliv. Pillai O, Panchagnula R. Polymers in drug delivery. Curr Opin Chem Biol. Encyclopedia of biomaterials and biomedical engineering. New York: Marcel Dekker; Orthopedic biomaterials. Polymeric implants for cancer chemotherapy.