ABSTRACT

Biodegradable polymers have been used and developed extensively for the application in drug delivery system. Continuous studies and improvement has been made in order to optimize the therapeutic value of active agents. This includes the designation of the characteristic and properties of the biodegradable polymers, as well as their in vitro and in vivo degradability to meet the needs of bioactivity and biocompatibility in the human body system. Modern approaches of drug delivery system introduced the development of nanoparticles drug-polymer combination, enhancing the efficiency of the therapeutic agent. These nanoparticles polymeric drug delivery offers a better prospect in the dreadful diseases treatment such as cancer, diabetes and malaria.INTRODUCTIONBiodegradable polymeric biomaterials include both synthetic polymers and natural polymers. It involves cleavage of hydrolytically in the polymer leading to polymer erosion. Biodegradable polymeric materials are being investigated in three-dimensional porous structures, developing therapeutic devices, and for pharmacological applications, such as drug delivery that are both localized and targeting systems [32]. There have been constant efforts of drug delivery scientists to enhance the drug delivery system by developing and integrating the biodegradable polymer in the application. The upsurge of the research has been evolve since 1970s and the potential biodegradable polymers that being used in drug delivery systems those early days are poly(lactic acid), poly(caprolactone), polyamides, poly(glutamic acid), and poly(alkyl 2-cyanoacrylates) [47]. Though there is an enormous amount of work done to improve the properties of the biodegradable polymers, the advantages of using polymers and the conducted study still weighed against following concerns: (1) the toxicity of polymers and their degradation products in the body i.e. biocompatibility (2) the overall cost of polymeric drug delivery systems (3) problem associated with release, i.e. dose dumping or release failure, and (4) the discomfort caused by the delivery system [29].In order to optimize the therapeutic value of active agents, drug delivery technologies have changing methods of drug administration from simple tablets, injectable and liquids to complex systems employing polymers and bioengineered products. Many of the new products use polymer-based drug delivery systems including environmentally-sensitive systems, microspheres, nanoparticles, and solvent precipitating depots. Some drug delivery systems provide both physical targeting to the target body site and controlled release of the drug [11].In this review, the important features that being highlighted, particularly, the characteristic and properties of the polymers, the in vitro and in vivo degradation of the polymers, the studies of nanotechnology recent developments of the polymers, and their role in several dreadful disease conditions. CHARACTERISTIC AND PROPERTIESThere has been a need to develop more rational approaches for creating biomaterials for drug delivery, especially biodegradable polymers. Polyanhydrides are believed to predominantly undergo surface erosion due to (i) the high water lability of the anhydride bonds on the surface and (ii) hydrophobicity , which restricts water penetration into the bulk. A decrease in the device thickness throughout the erosion process, maintenance of the structural integrity and the nearly zero-order degradation kinetics suggest the dominancy of heterogenous surface erosion [42]. High hydrolytic reactivity of the anhydride linkage provides an intrinsic advantage in versatility and control of degradation rates. By varying the type of monomers and their ratios, surface-eroding polymers with degradation of 1 week to several years can be designed and synthesized. The hydrolytic degradation rates can be obtaines varying several thousand folds by simple changes in the polymer backbone and by altering the hydrophobic and hydrophilic balance of the polymer [9,10]. Most of the polyphosphazenes synthesized consists more than 700 different polymers are hydrolytically stable and also are very unique in terms of the properties they exhibit, include optical properties[2], thermal properties[41], electrolytic properties[1] and electroactivity[31]. The rate of erosion as well as the physio-chemical properties of these polymers can be tuned by incorporating appropriate ratios of different pendant group [38]. Poly(lactic-co-glycolic acid) (PLGA) is the most widely used polymer in drug delivery[9], is a copolymers of Poly(lactic acid) and glycolide, has a versatile degradation kinetics, established safety, and biocompatibility, have made them ideal materials for drug delivery applications [49]. Some polymer such as copolymers of poly(lactic acid) and poly(ethylene glycol) (PLA-PEG) exhibit low molecular weight properties. The polymer with low molecular weight or low crystallinity degrades faster than polymers with high molecular weight or high crystallization. The polymer of lactic acid and glycolic acid degradable matrices (PLA-PEG) were used for the sustained release of bioactive substances. It is a new tool for controlled release formulations and delivery platforms. It is recently used for the delivery of anti-cancer drugs. There is free space between the linear core forming PLA chains of the micellar type PLA/PEG 30:70, 50:50 and 70:30 [15]. Thus, drug molecules can be incorporated into these regions of the solid core without influencing the particle size of the assembly. However, there is less free space amongst entangled chains of the PLA/PEG 90:10 and the core has expanded to allow incorporation of drug to occur [15].

Figure 1: Copolymer of PLA and PEGJoost et al. has developed designated poly(polyol sebacate) (PPS) polymers, a family of synthetic biodegradable polymers that are composed of structural units endogenous to the human metabolism. PPS polymers exhibited comparable biocompatibility to materials approved for human use, such as PLGA. Chemical, physical, and mechanical properties as well as degradation rates of these polymers can be turned by altering the polyol and stoichiometry of the reacting sebacid acid [23]. The characteristics and properties of polymers for drug delivery purpose are important features of consideration in order to optimize the therapeutic value. BIODEGRADABILITY TESTINGIn many cases, a hydrolysis reaction is involved and frequently it is desirable to perform accelerated tests using extreme pH conditions, elevated temperature or enzymes.

In vitro degradation

In vitro experiments can be used in preliminary screening tests and also provide more detailed information about the mechanism of degradation. Homogenous degradation studies have been reported for the poly(alkyl 2-cyanoacrylate) series, in which the polymer was dissolved in acetonitrile, the presence of water being required for degradation to occur. The heterogeneous degradation was followed in boiling water systems. Both in vitro methods showed a similar trend, in which the methyl ester degraded fastest, and as the size of the alkyl substituent increased, the rate of degradation decreased [30]. Vezin and Florence (1980) found that the degradation rate was dependent on the surface area of the sample and suggested that degradation at the ends of the polymer chains was much faster than in the main chain [43]. Polymers such as polyanhydrides are made of sparingly water diacid monomers connected to each other by anhydrides bonds, which are hydrolytically very labile and split readily into two carboxylic acids in the presence of water molecules. Hydrolysis of the anhydride bond is base catalyzed and therefore the rate of degradation of the polymer and the diffusion of oligomers and monomers formed by polymer degradation depends on the pH of the surrounding medium and solubilities of these compounds in the medium. Since polyanhydrides degrade into carboxylic acids, solubility of these degradation products is more at a higher pH [40]. At low pH, these degradation products are in their unionized form, difficult to solubilize in surrounding biological media at implantation site and thus polyanhydrides in general degrade rapidly in basic media than acidic media [14]. The use of enzymes to assess whether a polymer is susceptible to enzymic degradation and to what extent a particular enzyme accelerates the degradation has been reported in several early studies. Several different enzymes have been used to accelerate the degradation of several different types of polymers [22]. Besides, the chymotryptic degradation of a low molecular weight poly(ester-urea) containing phenylalanine also has been studied using weight loss measurements and it was found out that it is necessary to correct the results for hydrolysis due to the buffer salts present. A similar polymer derived from glycine was found to resist chymocryptic cleavage [21]. Other biological in vitro techniques involving organ cultures produced useful information about the degradability of poly(lactic acid) and several of the poly(alkyl 2-cyanoacrylates) in less than 24 hours[18]. There was a biological in vitro degradation study using chick embryo liver homogenates and found, in accordance with expectation, that the degradation of poly(D,L-lactic acid) was faster than that of poly(L-lactic acid) [26]. In vivo degradation

In vivo studies are required at an early stage in any development programme to confirm the in vitro results and to begin assessment of the ultimate fate of the polymer and its metabolites. Simple methods such as weighing the residual polymer and microscopy can reveal important morphological changes and Vezin and Florence (1980) used this technique to demonstrate surface erosion of poly(alkyl 2-cyanoacrylates) when degraded in vitro. This scanning electron microscopy were also being used to present a visual proof of the erosion process for the study of morphological changes of Gliadel wafers during in vivo degradation in rat brain as well as during in vitro degradation in phosphate buffered saline [8]. The decrease in molecular weight of poly(L-lactic/glycolic acid) copolymer (90 : 10) in the form of implanted beads in the monkey was done by Wise et al. (1978) who found a decrease from 37,000 to 18,000 after 28 days [46]. Certain studies exhibited that the in vivo degradation of poly(caprolactone) (PCL) is significantly accelerated compared to the in vitro experiments. The enzymatic degradation of PCL polymers has been investigated, especially in the presence of lipase-type enzymes [45] .Wu et al. (2000) claimed that the presence of the microbial Pseudomonas lipase enhanced the degradation of PCL nanoparticles by a factor of 1000 compared with their purely hydrolytic degradation [48]. The use of radiolabelled polymer allows a convenient assessment of degradation and can be measured as per cent remaining after a given period of implantation or can be followed continuously as the label excreted. The use of radiolabelled material also provides assessment of whether the degradation products, either molecules of low molecular weight derived from the monomer or oligomeric material which has diffused from the implantation site, concentrate in particular organs in the body. Brady et al. (1973) implanted blocks of [14C]-labelled poly(D,L-lactic acid in the rat and found 36.8% of the radioactivity had been lost from the implant after 168 days. However, only 4.6% was recovered in the urine 2.8% in the faces and less than 0.3% was found in tissues, and therefore it was suggested that the elimination of the radioactivity was mainly via respiration [4]. Domb et al. studied the metabolic disposition and elimination process of [P(CPP-SA) 20 : 80 copolymer is extensively hydrolyzed 7 days post-implantation and revealed that the anhydride bonds in the copolymer are gradually degraded into sebacic acid monomers which are extensively metabolized in the body and excreted mostly as carbon dioxide. The approach of in vitro and in vivo methods during the development of a controlled release device a basic understanding of the polymer provides a background for detailed and extensive study of the drug-polymer in its final dosage form.

DEVELOPMENT OF NANOPARTICLES DRUG-POLYMER COMBINATION FOR DRUG DELIVERY

Nanoparticles are submicron-sized polymeric colloidal particles with a therapeutic agent of interest encapsulated within their polymeric matrix or adsorbed or conjugated onto the surface [28]. Due to their sub-cellular and sub-micron size, nanoparticles can penetrate deep into tissues through fine capillaries, cross the fenestration present in the epithelial lining, for example, liver, and are generally taken up efficiently by the cells [44]. Several disease related drugs/bioactive molecules are successfully encapsulated to improve bioavailability, bioactivity and control delivery. Nanomedicines of the dreadful diseases like cancer, AIDS , diabetes , malaria , prion disease and tuberculosis are in different trial phase for the testing and some of them are commercialized [27]. Polymeric nanoparticles have been synthesized using various methods [5] according to needs of its application and type of drugs to be encapsulated. These nanoparticles are extensively used for the nanoencapsulation of various useful bioactive molecules and medicinal drugs to develop nanomedicine. Biodegradable polymeric nanoparticles are highly preferred because they show promise in drug delivery system. Such nanoparticles provide controlled or sustained release property, subcellular size and biocompatibility with tissue and cells [36]. Apart from this, these nanomedicines are stable in blood, non-toxic, nonthrombogenic, nonimmunogenic, noninflammatory, do not activate neutrophills, biodegradable, avoid reticuloendothelial system and applicable to various molecules such as drugs, proteins, peptides, or nucleic acids [37]. The general synthesis and encapsulation of biodegradable nanomedicines are represented in Figure 1. The drug molecules either bound to surface as nanosphere or encapsulated inside as nanocapsules.

Figure 2: Type of biodegradable nanoparticles drug-polymerFor the past two decades, countless work has been conducted to develop most effective nanomedicines from biocompatible and biodegradable nanopolymers [25]. The role of nanosystems for drug delivery through oral, nasal, ocular administration is reviewed by Alonso [3]. The various methods of synthesis and encapsulation of different bioactive molecules on nanoparticles has been reviewed by Pinto Reis et al. [5]. Most of the reported methods are frequently used for the synthesis of biodegradable nanomedicines. Some medicinal drugs on different nanosystems are different in their administration, activity and therapeutic importance, for example taxol (anticancer drug) nanomedicine have 100% and 20% encapsulation efficiency on PLGA [33] and PCL [24] nanodevices respectively. However, the therapeutic activity and stability of PCL nanomedicines are reasonably higher than PLGA nanomedicine [24]. BIODEGRADABLE POLYMERS IN DRUG DELIVERY FOR SEVERAL DREADFUL DISEASES CONDITIONSCancerCancer or neoplasm can be defined as an abnormal mass of tissue, the growth of which exceeds and is uncoordinated as compared to that of normal tissues and persist in the same excessive manner after the cessation of stimuli, which evoked the changes. Malignant tumors grow rapidly, sometimes at an erratic pace. It is accompanied by progressive infiltration, invasion and destruction o surrounding tissue and metastasis, which unequivocally marks a tumor malignant [13]. For the case of brain tumor, although neurosurgery and neuroradiation have been improved, because of limitations like the risk of removal of functional brain tissue and an increased radiation dose or size of the irradiated field which can cause acute and chronic adverse effect [39], some other novel approaches to treat the condition are needed. Various polyanhydride and drug combinations have been used to obtain the optimum release profile and treat brain tumor or glioma, for example, Gliadel wafer is one of the most successful commercially available delivery systems using polyanhydrides [16]. Using biodegradable polymers, which release the loaded drug as they degrade and preclude the need for removal of the delivery system after exhaustion is an important advantage in case of drug delivery to brain.

Figure 3: Gladiel wafer implantation at tumor resection site. Around 7-8 afwers are placed for localized delivery of BCNU via P(CPP:SA) polymer Diabetes

Diabetes is a disease that has received a great deal of attention because of the potential for therapies using controlled drug delivery. Since the parenteral administration is the only rout of insulin delivery, alternative routes of administration, for example oral, nasal, rectal, pulmonary and ocular have been extensively investigated [35]. Thereof, insulin nanopasrticles are prepared with well accepted polymers: a biodegradable polymer, poly(-caprolactone) used for the manufacturing of resorbable threads and second, a polyacrylic polymer, Eudragit RS, widely used for the formulation of conventional solid dosage forms [19]. Besides, work with biodegradable polymer has also yielded polyorthoesters that are pH sensitive and that will degrade more quickly in acidic environments [20].Malaria

Malaria is a mosquito-borne disease caused by a parasite. People with malaria often experience fever, chills, and flu-like illness. Left untreated, they may develop severe complications and die. Several studies involving the efficacy of nanoparticles drug delivery has been conducted and showed promising therapeutic results. Very recently, there was a study of the efficacy of chitosan nanoparticles complexed with phosphorothioate anti-sense oligodeoxynucleotides, against malarial topoisomerase II gene. The polymeric nanoparticles were shown to be effective in inhibiting the growth of Plasmodium falciparum K1 strain in vitro [12]. Mosqueira et al. [32], fabricated halofantrine loaded PEG-coated Polylactic acid (PLA) nanocapsules for the treatment of malaria. The efficacy and pharmacokinetics of halofantrine nanocapsules on intravenous administration wre compared to that of halofantrine solution. The result is that no toxic effects were observed with halofantrine in the form of nanocapsules after intraveneous administration for doses up to 100mg/kg, whereas the solubilized form in polyethylene glycol-dimethylacetamide was toxic at this dose. MiscellaneousBiodegradable polymers also have been used for many other delivery applications. Delivery of macromolecules especially proteins and peptides via polymer is an important issue. Polyanhydrides matrices can be used for controlled delivery of proteins or polymer-drug conjugates. Fluorescent-labeled, sized fraction dextran release can be controlled from a polyanhydride matrix by adjusting the size of particles dispersed in the matrix [7]. According to the work of Hanes et al., poly(anhydride-co-imides) have a erosion mechanism which leads to predictable drug release. They have used bovine serum albumin as a model compound and suggested that the polymer may be appropriate for delivery of many therapeutic proteins, including vaccine antigents [17].CONCLUSION

Biodegradable polymers are credited as the most prolific and widely used in the drug delivery applications. Their excellent biocompatibility combined with their ability to exhibit biological erosion makes them attractive materials for drug delivery applications. Their success in both the in vitro and in vivo environments for drug delivery applications makes them potentially ideal candidates for the delivery of bioactive molecules. FUTURE RESEARCH

The using of biodegradable polymers in pharmaceuticals and biomedical devices has increased radically over the past decade especially in the areas of controlled drug delivery systems. The most important criteria for selecting a polymer to use it as degradable polymer is to match the mechanical properties and the degradation rate to the needs of application. The development of novel materials in controlled drug delivery is more focusing on the preparation and use of these responsive polymers with specifically designed structural and chemical features. Considerable effort has been devoted to develop novel micro and nano fibrication techniques for biodegradable polymers in the current years. One of the micro and nano fabrication techniques that would be developed for biodegradable polymers is Replication Techniques. The mechanisms behind these processes are direct and straightforward. It is also familiar in macroworld. The advantage from these mechanisms is about it cost because the initial fabrication of the main structure will be replicate many times into polymer substrate. Besides, the main structure could be fabricated with a large number of different microfabrication technologies so that variety of geometries could be realize. The application techniques include Microimprinting Lithography and Soft Lithography. Another micro and nano fabrication techniques for biodegradable polymers is Rapid Prototyping techniques. To manufacture components with complex geometries beyond the reach of conventional precise machining, the rapid prototyping techniques could be applied. These techniques would apply the computer aid design of a definite component. The methods that include in these techniques are direct deposition, 3D printing, stereolithography and selective laser sintering. Successfully developing all sorts of novel formulations then will obviously require assimilation of a great deal of emerging information about the chemical nature and physical structure of these new materials. With manufacturing costs and biocompatibility in mind the newly fabrication techniques would be developed and will lead to new technologies in the fabrication of novel drug delivery system.REFERENCES1) Allcock H.R., Kellam III E. C., Morford R.V.(2001). Gel electrolytes from co-substituted oligoethyleneoxy / trifluoroethoxy linear polyphosphazenes. Solid State Ionics 142, 297-308.

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