Bioerodable

Poly(orthoesters) represent the first class of bioerodible polymers designed specifically for dmg deUvery appHcations (52). In vivo degradation of the polyorthoester shown, known as the Al amer degradation, yields 1,4-cydohexanedimethanol and 4-hydroxybutyric acid as hydrolysis products (53). 

Poly(anhydrides). Poly(anhydrides) are another class of synthetic polymers used for bioerodible matrix, dmg dehvery implant experiments. 

Chemically Controlled. These systems are classified together because of the hydrolysis or enzymatic cleavage of a chemical bond that allows dehvery of the dmg. There are two main types of systems, ie, pendent chain systems and bioerodible systems. 

Hie ester linkage of aliphatic and aliphatic-aromatic copolyesters can easily be cleaved by hydrolysis under alkaline, acid, or enzymatic catalysis. This feature makes polyesters very attractive for two related, but quite different, applications (i) bioresorbable, bioabsorbable, or bioerodible polymers and (ii) environmentally degradable and recyclable polymers. 

Among other uses, these polymers have been employed in a variety of biomedical applications. Poly(phosphazenes) containing organic side chains, derived from the anaesthetics procaine and benzocaine, have been used to prolong the anaesthetic effect of their precursor drugs. They have also been used as the bioerodable matrix for the controlled delivery of drugs. 

Laurencin CT, Koh HJ, Neenan TX, Allcock HR, and Longer R. Controlled release using a new bioerodible polyphosphazene matrix system. J Biomed Mater Res, 1987, 21, 1231. 

Phosphazene polymers can act as biomaterials in several different ways [401, 402,407]. What is important in the consideration of skeletal properties is that the -P=N- backbone can be considered as an extremely stable substrate when fluorinated alcohols [399,457] or phenoxy [172] substituents are used in the substitution process of the chlorine atoms of (NPCl2)n> but it becomes highly hydrolytically unstable when simple amino acid [464] or imidazole [405-407] derivatives are attached to the phosphorus. In this case, an extraordinary demolition reaction of the polymer chain takes place under mild hydrolytic conditions transforming skeletal nitrogen and phosphorus into ammonium salts and phosphates, respectively [405-407,464]. This opens wide perspectives in biomedical sciences for the utilization of these materials, for instance, as drug delivery systems [213,401,405,406,464] and bioerodible substrates [403,404]. 

Polyphosphazenes can be considered as biomaterials in several different ways, depending on the type of utilization one can predict for these substrates. In this regard, we will consider three different topics concerning water-soluble POPs and their hydrogels, bioerodible POPs for drug delivery systems and for tissue engineering, and the surface implications of POP films. 

Skeletal Biocompatibility. Two Substituent Groups Attached to the Same Phosphazene Skeleton. Hydrolytical Instability 0 II — NH- CH2— C- OC2H5 Glycine or Lower Alkyl Aminoacid Esters Hydrolytically Unstable Polymers. Bioerodible Materials. Drug Delivery Systems. Tissue Engineering... 

Skeletal Biocompatibility. Hydrolytical Instability Glycolic Esters or Lactic Esters Hydrolytically Unstable Polymers. Bioerodible Materials... 

Several investigators have utilized the 85 15 DL-lactide/glycolide copolymer for 90-day delivery of bioactive agents. This polymer is essentially bioeroded by about 150 days, thus making the 85 15 a useful matrix for 90-day systems. 

Deong, K. W., Brott, B. C., and Danger, R., Bioerodible polyanhydrides as drug-carrier matrices. I. Characterization, degradation and release characteristics, J. Biomed. Mater. Res., 19, 941-955, 1985. 

Grossman, S. A., Reinhard, C., Colvin, O. M., Chasin, M., Brundrett, R., Tamargo, R., and Brem, H., The intracerebral distribution of BCNU delivered by surgically implanted bioerodable polymers. Submitted. 

Brem, H., Kader, A., Epstein, J. I., Tamargo, R., Domb, A., Danger, R., and Leong, K., Biocompatibility of bioerodible controlled release polymers in the rabbit brain. Selective Caacer Therapeutics. 5, 55-65, 1989. 

FIGURE 6 Schematic representation of water intrusion and erosion for one side of a bioerodible device. (From Ref. 18.)... 

The development of a bioerodible implant capable of releasing controlled amounts of a contraceptive steriod from a subcutaneous implant for periods of time ranging from three months to about a year has been in progress for many years. The three principal bioerodible polymers currently in use are copolymers of lactic and glycolic acid (25), poly(e-caprolactone) (26), and poly (ortho esters) (14). The desire to develop such a contraceptive system was the principal motivation for the initial development of the poly(ortho ester) polymer system. 

Capozza, R. C., Sendelbeck, L., and Balkenhol, W. J., Preparation and evaluation of a bioerodible naltrexone delivery system, in Polymeric Delivery Systems (R. J. Kostelnik, ed.), Gordon and Breach, New York, 1978, pp. 59-73. 

The first bioerodible polyphosphazenes synthesized possessed amino acid ester side groups (25). The structure and preparation of one example is shown in Scheme V. The ethyl glycinato derivative shown... 

A substantial number of bioactive molecules, such as polypeptides, N-acetyl-DL-penicillamine, p-(dipropylsulfamoyl)benzoic acid, and nicotinic acid, contain a carboxylic acid function, and this provides a site for linkage to a polyphosphazene chain. A number of prototype polymers have been synthesized in which pendent amino groups provide coupling sites for the carboxylic acid (34). The amide linkages so formed are potentially bioerodible, but the use of a hydrolytic sensitizing cosubstituent would be expected to accelerate the process. 

A recent development has been the synthesis of bioerodible poly-phosphazenes that bear glyceryl side groups (35). The synthesis of these polymers requires a protection-deprotection sequence to reduce the functionality of the glycerol and prevent crosslinking. 

It has been demonstrated that a variety of different polyphosphazenes can be developed as biomaterials, membranes or hydrogels, bioactive polymers, and bioerodible polymers. As with most new areas of polymer chemistry and biomaterials science, molecular design forms the basis of most new advances, but the rate-controlling step is the testing and evaluation of the materials in both in vitro and in vivo environments. This is particularly true for polyphosphazenes where the availability of research quantities only has limited the... 

Kohn, J., and Langer, R., A new approach to the development of bioerodible polymers for controlled release applications employing naturally occurring amino acids, in Proceeding of the ACS Division of Polymeric Materials. Science and Engineering. American Chemical Society, 1984, Vol. 51, pp. 119-121. 

However, in the foregoing systems, the predominant mechanism allows easy mathematical description. In practice, the dominant mechanism for release will overshadow other processes enough to allow classification as either dissolution rate-limited or diffusion-controlled. Bioerodible devices, however, constitute a group of systems for which mathematical descriptions of release characteristics can be quite complex. Characteristics of this type of system are listed in Table 7. A typical system is shown in Fig. 8. The mechanism of release from simple erodible slabs, cylinders, and spheres has been described [36], A simple expression describing release from all three of these erodible devices is... 

Another method for the preparation of bioerodible systems is to attach the drug directly to the polymer by... 

Fig. 8 Representation of a bioerodible matrix system. Drug is dispersed in the matrix before release at time = 0. At time = t, partial release by drug diffusion or matrix erosion has occurred.

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