Advances in Biodegradable Polymers for Drug Delivery Systems

Korea Polymer Journal, Vol. 8, No. 5, pp 199-208 (2000) Korea Polymer Journal Volume 8, Number 5 October 31, 2000 @ Copyright 2000 by The Polymer Society of Korea Advances in Biodegradable Polymers for Drug Delivery Systems Yong Kiel Sung* Department of Chemistry, Dongguk University, Seoul 100«7I5, Korea Sung Wan Kim Ceriterfor Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112, U. S. A. Received September 20, 2.000 Abstract : The recent development of biodegradable polymers for drug delivery system (DDS) has been investigated. The biodegradable polymers for DDS are mainly discussed in two categories: one cat- egory is natural biodegradable polymers such as polysaccharides, modified celluloses, polybe-amino acid)s, modified proteins, and microbial biodegradable polymers; the other is synthetic biodegradable polymers such as poly(ester)s, poly(ortho ester)s, poly(phosphazene)s, po1y(anhydride}s, poly(alkyl cyanoacrylate)s, and muitiblock copolymers. The bioconjugate poiymeric drug delivery systems have been also proposed for the design of biocompatible polymeric controlled drug delivery. Introduction The controlled drug delivery utilizes some of proper polymeric systems to provide the desired drug release profiles. Biodegradable polymers have been recently used to develop the advanced drug delivery systems.” The drug delivery sys- tems have been extensively examined to over- * e-mail: yksung@dgu.edu come the disadvantages of conventional drug therapy. In order to improve the conventional methods, the drug delivery systems have been introduced in the following wayss: One is the release system of drugs in a sustained method, keeping the plasma drug concentration between minimum effective level and minimum toxic level for the desired duration of time. The others are the controlled drug delivery systems, providing for the drug release at a controlled rate over the spec- Korea Polymer Journal, Vol. 8, No. 5, pp 199- 208 (2000) Y.-K. Sung and S.-W. Kim ified period of time. A variety of advanced drug delivery systems have been recently made in several ways, using transdermal systems, self-regulating systems, drug targeting systems, stimuli-responsive modulating systems, and so forth.“ Those have been led to investigate the new polymeric sys- tems for the drug delivery. There has been simul- taneously a growing interest in biodegradable polymers for medical and pharmaceutical appli- cations.9’13 A number of biodegradable polymers have been developed for the purpose of drug delivery systems. Those important biodegradable polymers are natural and synthetic nortoxic polymers, including polysaccharides, celluloses, proteins, po|y{oc-amino acid)s, polylesterls, poly (ortho esterls, poly(phosphazene)s, poly(anhy- dride)s, polylalkyl cyanoacrylatels, and so on. The useful biodegradable polymers can be biode- graded into nontoxic intermediate monomers in the living body. The rate of biodegradation is one of the most important criteria for the useful applications of the biodegradable polymers. The degradation process of the biodegradable poly mers should be examined either in vivo or in uitro tests. The in viva biodegradation tests are usually carried out by introducing the biodegra- dable polymers into the particular site of the ani- mals such as subdermal muscle peritoneal cavity, subcutaneous tissue, and blood stream.” The in vitro biodegradation tests were carried out in pseudo extra cellular fluid, plasma solution, enzymes and buffer solutions.” The researches on the polymeric drug delivery systems were also developed by using the water-insoluble polymers such as poly(glycolic acid) or polyllactic acid) for the controlled delivery of a Ll-IR}-I analogue from biodegradable injectable microspheresfm Poly- mer—based drug delivery to the brain has been recently examined using biodegradable polymers of chemotherapy for recurrent gliomas.““9 The biodegradable polymeric system of paclitaxel such as a novel antimicrotubule agent has been recently demonstrated that its significant activity shows in the clinical trials for a wide variety of tumors, including breast, non-small cell lung can- cer, and AIDS-related Kaposis sacoma.Z° Biode- gradable polyrner-based cytokine gene delivery has been also recently developed for cancer treatment.21 200 Biodegradable Polymers for Drug Deli- very Systems The biodegradable polymers for drug delivery systems are mainly classified into the following two categories: one category is the natural and modified biodegradable polymers, and the other ' is the synthetic biodegradable polymers. The nat- ural and modified biodegradable polymers will be discussed first in this section. Natural and Modified Biodegradable Poly- mers. There are many useful natural biodegrad- able polymers such as polysaccharides, modified celluloses, polyloc-amino acidls and modified pro- teins. However, the natural products are not able to apply directly themselves without purification or modification into drug delivery systems. Some examples developed for drug delivery systems will be described briefly in the followings: Polysaccharides: The polysaccharides are naturally consisted of long chains having many monosaccharides. The monosaccharide consists of a single polyhydroxyketone or polyhydroxyal- dehyde units. Oligosaccharides consist of several short chains of monosaccharide units joined by glycosidic linkage together. The polysaccharides can be divided into several groups based on their sources: microbial, algae, seaweeds, bacteria, fungi, plants, and animals.” The grafting of natu- ral polysaccharide has been of considerable inter- est in drug delivery. The enzymes hydrolyze either O-glycosyl, N-glycosyl or S—glycosyl bonds in the drug delivery systems. The enzymes hydrolyzing polysaccharides are mainly glycosidases in a polysaccharide chains.” Modified starch systems have been widely used as drug delivery systems“, Using glycidylacrylate, starch has been usually derivatized to introduce acrylol groups that are necessary for polymerization into microspheres. If the contents of derivatization are low, the modi- fied starch microspheres are readily biodegrad- able in biological fluids.25'26 The potentiality of injectable modified starch microsphere has been investigated for drug targeting to the reticulo- endotherial systems.m° Chemically modified polysaccharides for enzymatically controlled oral drug delivery had been examined for the release of low and high molecular weight drugs from the Korea Polym. J., Vol. 8, No. 5, 2000 Advances in Biodegradable Polymers for Drug Delivery Systems calcium crosslinked starch matrix in stimulated gastric and intestinal solutions containing oc-amy- lose.“ The modified dextrans have been also widely used as drug carrier or as prodrug. The deriva- tized dextrans are mainly investigated for their biodegradation by dextranases, which exist in the colon, intestinal mucosa, kidney, liver, and spleen.32'35 The natural chitin and chitosan often exist a coplymer of glycosamine and acetylated glycosamines. The degrees of actylation and deacetylation are those of the most important structural parameters in chitin and chitosan. The application of partially deacetylated chitin had been made in self-regulated drug delivery sys- tems.35 It has been obtained that the release of high concentration cis-platinum under an implan- tation to mouse muscle during more than eight weeks. The additional studies were aimed at the development of drug delivery systems using chitin and chitosan derivatives.37‘3E N—Acetylation in chi- tosan and the rate of its enzymatic hydrolysis by lysozyme and chitinase were mainly investi- gated.” Modified Celluloses: Modified celluloses have been widely used in a variety of formulations including microcapsulation and drug delivery matrix systems.“ The oxidations of celluloses pro- duce several kind of absorbable biomaterials. The oxidized cellulose materials can be used in medi- cal applications such as absorbable hemostatic agents and absorbable adhesion barriers. Cellu- lose is rendered bioaborbable using an oxidizing process. The oxidized celluloses can be also used as a vehicle for drug delivery system.“ Due to the bioavailability of many carboxyl groups, the oxi- dized celluloses have a low pH condition in aque- ous solution. The oxidized regenerated celluloses produce antibacterial activities against a broad range of pathogens.42‘” The partially substitLited oxidized celluloses by sodium salts are less acidic. They show their biocompatibility with acid sensi- tive biologics such as thrombin. Considering the drug delivery system, it has been focused on the chemical moiety that can be easily bound to the oxidized celluloses. The chemical moieties have been studied for the applications of adhesion pre- vention by heparin“ and tissue plasminogen acti- Korea Polym. J., Vol. 8, No. 5, 2000 vator.4'3 The binding with the moieties may be occurred through adsorption, absorption, ionic bond, and intermolecular interactions. Modified cellulose derivatives used in drug delivery systems are hydroxyethylmethylcellulose(I-IEMC), hydroxy- propylmethylcellulose(HPMC), ethylhydroxyethyl— cellulose(EHEC), hydroxyethylcellulose(HEC), hydroxypropylcellulose(HPC), and methylcellu— lose(MC). Their physical properties of modified cellulose derivatives are depended upon the amounts of the substituent groups on the cellu- lose.'”’48 The influences of surfactants on drug release from the hydroxylpropyl methylcellulose (HPMC) matrices were also mainly investigated.” Poly(w-amino acid)s: Poly(0c—amino acid) has been used as a model compound to study the physicochemical properties of natural high mole- cular—weight polymer such as protein. The poly (05-amino acid) is composed of a—amino acids as natural molecules which exist in the living organ- ism. Poly(0c—amino acid) linked by peptide bonds had been synthesized by a ring—opening polymer- ization of N—carboxy—a:x—amino acid anhydrides ini- tiated with a base.5° The characterized poly(or— amino acid) has been recently used as a drug car- rier.6 The water soluble poly(0c—amino acid) has been applied as a carrier for drug delivery system. This idea has been extended to the drug delivery systems such as norethindrone, naltrexone, and antihypertensive drugs coupled to the poly(0r— amino acid) backbones.51'56 Several series of the polymers have been syn- thesized and investigated: poly(N—acyl hydroxy- proline ester)s, pOly(L-lysine ester)s, poly(gluta— mylalanine anhydride)s, and poly(iminocarbo— nate)s with tyrosine dipeptides.576°'The copolymers of or-amino acids and rx—hydroxy carboxylic acids have been prepared to produce the polydep— sipeptides. The copolymers contain both ester and amide linkages on the backbones.61'63 The degradation of polydepsipeptide has been inves- tigated in viva as well as in uitro.“ The biodegra- dation of polydepsipeptide was also revealved that both proteases and resterases were responsible to degrade the polymers.65 Modified Proteins: Protein biopolymers are sequential polypeptides with complex structural repeat units. Gelatin is also a protein obtained by 201 Y.-K. Sung and S.-W. Kim partial hydrolysis of collagen. The collagen is a main component of skin, bones, hides, and con- nective tissues. Collagen proteins have been identified at least nineteen different molecular f0rrns.6M8 The biopolymers can be also produced using gene template directed synthesis. The development of new protein biopolyrner involves the polymerization of a gene template that encodes the amino acid sequence of the desired protein.69 Albumin microspheres have been widely used as carriers for studying active as well as pas- sive drug targeting systems.7°72 The influencing factors on the release of drugs from the micro- spheres have been investigated precisely.-"3"-'5 Gel- atin has been known to be a natural, nontoxic, biodegradable polymer with low antigenecity. The modified gelatin microspheres have been usually prepared with a crosslinker such as glutaralde— hyde or formaldehyde?” The preparation and evaluation of modified gelatin microspheres and beadlets for drug delivery systems have been deeply investigated for controlled sustained release, anti—angiogenic agent TNP—470, strepto- mycin sulphate, mitoxantrone, targeting interferon, sulfonamides, phenytoin sodium microspheresffll Collagenous proteins form the structural frame- work of all mammalian extracellular matrices. Collagen has been applied as a biodegradable polymeric system for release of drugs such as 5- fluorouracil, antibiotics, insulin, hormone, dexam— ethasone, cyclosporine, and bone morphogenetic protein.82'87 Microbial Biodegradable Polymers: The site- specific drug delivery to colon can be achieved by exploiting the microbial enzymes predominantly present in the colon. The oral drug deliveries are unstable in the upper gastrointestinal tract due to the activities of proteolytic enzymes. That might be delivered to produce the local therapeutic effects in the colon. Among these drug delivery systems, the low and high molecular weights drug bioconjugates containing bonds susceptible to biodegradation by glycosidase or others have been recently examinedfm” Insulin and vaso- pressin deliveries to the colon had been examined by using pellets coated with poly(hydroxyethyl methacrylate-co-styrene) containing azoaromatic crosslinl