Poly surface erosion

Convincing evidence for a surface erosion process is shown in Fig. 8, which shows the concomitant release of the incorporated marker, methylene blue, release of the anhydride excipient hydrolysis product, succinic acid, and total weight loss of the device. According to these data, the release of an incorporated drug from an anhydride-catalyzed erosion of poly (ortho esters) can be unambiguously described by a polymer surface erosion mechanism. 

In the early 1970s, the ALZA Corporation began its search for polymers suitable for erodible drug delivery systems. The ideal polymer was identified as one undergoing surface erosion in vivo and degrading to non-toxic, low molecular weight products at a rate that could be manipulated over a broad time span. To meet these criteria, a novel family of hydrolyzable polymers was developed, the poly(orthoesters), POEs [285]. The general structure is schematically shown in... 

One candidate polymer system is the poly(ortho esters), which are pH-sensitive and undergo enhanced hydrolysis rates with decreasing external pH values (6). Furthermore, this system has demonstrated surface erosion characteristics and can be prepared in both linear and crosslinked forms (7., 8). The crosslinked form is particularly interesting because sensitive macromolecules can be incorporated into the polymer under very mild conditions and without denaturation. These mild conditions are important because both insulin and glucose oxidase are proteins. 

Polyanhydrides have been modified by incorporating amino acids into im-ide bonds. The imide with the terminal carboxylic acids is activated with acetic anhydride and copolymerized with sebacic acid or CCP. Poly(anhydride-imides) increase the mechanical properties of the polyanhydrides. Degradation of poly(anhydride-imide)s is similar to that of polyanhydrides (i.e., surface erosion). Two different cleavable bonds (anhydride and ester) in the polymer chains have been included in polyanhydrides. Carboxylic acid-terminated e-caprolactone oligomers or carboxylic acid-terminated monomers (e.g., salicylic acid) have been polymerized with activated monomers (e.g., SA). 

Poly(ortho esters) offer the advantage of controlling the rate of hydrolysis of acid-labile linkages in the backbone by means of acidic or basic excipients physically incorporated in the matrix. This results in polymer degradation proceeding purely by surface erosion, which results in zero-order drag release from disk-shaped devices. 

Degradation of poly(FAD-SA) has also been reported to be nearly zero-order based on the rate of SA release from the polymer. ° However, evidence suggests that devices prepared from these polymers do not necessarily degrade by a purely surface-erosion mechanism. Cumulative release profiles of individual... 

A much more desirable erosion mechanism is surface erosion, where hydrolysis is confined to a narrow zone at the periphery of the device. Then, if the drug is weU-immobihzed in the matrix so that drug release due to diffusion is minimal, the release rate is completely controlled by polymer erosion, and an ability to control erosion rate would translate into an ability to control dmg delivery rate. For a polymer matrix that is very hydrophobic so that water penetration is limited to the surface (thus Hmiting bulk erosion), and at the same time, allowing polymer hydrolysis to proceed rapidly, it should be possible to achieve a drug release rate that is controlled by the rate of surface erosion. Two classes of biodegradable polymers successfully developed based on this rationale are the polyanhydrides [31] and poly (ortho esters) [32], the latter of which is the subject of this chapter. 

After investigating a number of linear poly (ortho esters) a material prepared from 3,9-(bis ethylidene 2,4,8,10-tetraoxaspiro [5,5] undecane) and 1,6-hexa-nediol was selected as the best material [42]. Figure 23 shows results of a study where both 5FU release and weight loss were determined. The data show that with this particular system, concomitant drug release and polymer erosion has been achieved. Further, because the molecular weight of the residual polymer remains unchanged, the hydrolysis process is confined to the outer surface of the device and surface erosion has been achieved. 

In the initial approach, and before the action of acidic excipients was clearly understood, the slightly acidic and relatively water insoluble salt, calcium lactate, was used with the hopes of catalyzing long term surface erosion of linear poly (ortho esters). In this work, rod-shaped devices were prepared by incorporating 30 wt% levonorgestrei and 2 wt% calcium lactate into a polymer prepared from 3,9-bis (ethylidene-2,4,8,10-tetraoxaspiro [5,5] undecane) and a 60/40 mol mixture of trans-cyclohexane dimethanol and 1,6-hexanediol and the devices were implanted into rabbits. The devices were then explanted at various time intervals and examined by scanning electron microscopy. A device ex-planted after 10 weeks is shown in Fig. 27 [25]. 

Poly(ortho esters) (XVII) contain acid-labile linkages in the polymer backbone. As with the polyanhydrides discussed above, poly(ortho esters) are a class of polymers that can degrade heterogeneously by surface erosion. These polymers lose material from the surface only, while retaining their original geometry. As such, their primary use is in drug delivery. 

Poly(ortho esters) were first developed by the ALZA corporation (Alzamer) in 1970 in order to seek new synthetic polymer for drug delivery applications. These polymers degrade by surface erosion and degradation rates may be controlled by incorporation of acidic or basic excipients. The polymer is hydrophobic enough such that its erosion in aqueous environments is very slow. The unique features of poly(ortho esters), in addition to their surface erosion mechanism, is the rate of degradation for these polymers, pH sensitivity, and glass transition temperatures, which... 

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