Polyanhydrides release

For many drug delivery applications, the preferred method of delivery of the dosage form is by injection. For controlled release applications, the most frequently used approach to allow this method of administration is to prepare microspheres of the polymer containing the drug to be delivered. Several different techniques have been developed for the preparation of microspheres from polyanhydrides. 

The incorporation and release kinetics from polyanhydride matrices of a number of drugs have been studied. Representative examples of several of these are described below. 

Cortisone acetate has been incorporated into several polyanhydrides (15). The rates of release of cortisone acetate from microcapsules of poly(terephthaUc acid), poly(terephthaUc acid-sebacic acid) 50 50, and poly(carboxyphenoxypropane-sebacic acid) 50 50 are shown in Fig. 8. These microcapsules were produced by an interfacial condensation of a diacyl chloride in methylene chloride with the appropriate dicarboxylic acid in water, with or without the crosslinking agent trimesoyl chloride. This process produces irregular microcapsules with a rough surface. The release rates of cortisone acetate from these microcapsules varied correspondingly with the rate of degradation of the respective polyanhydrides. It can be expected that the duration of release of cortisone acetate from solid microspheres, such as those produced by the hot-melt process, would be considerably longer. 

The controlled release from PTA-SA 50 50 of several drugs known to inhibit the formation of new blood vessels in vivo, cortisone and heparin, is shown in Fig. 9 (15). The inhibitors of angiogenesis delivered in vivo using this polyanhydride were shown to prevent new blood vessel growth for over 3 weeks, following the implantation of the VX2 carcinoma into rabbit cornea (15). 

FIGURE 8 Release of cortisone acetate from 10% loaded microspheres of various polyanhydrides. The microspheres were prepared by an interfacial condensation. Details of the experimental procedure are described in the text. 

Once the blood glucose values in the treated animals had returned to the high, diabetic levels, a second injection of insuUn-containing microspheres again reduced these levels to normal for about 5 more days. It is therefore possible to incorporate labile biological products into the polyanhydrides and to release them in a biologically active form. At the same time, this release can be sustained over a period of time in a controlled fashion. 

Alkaline phosphatase, an enzyme with a molecular weight of approximately 86,000, has been incorporated into a polyanhydride matrix using compression molded PCPP-SA 9 91. Five percent loaded wafers, 50 mg each, were perpared, and measured 1.4 cm in diameter, with a thickness of 0.5 mm. Release experiments were then conducted using techniques similar to those described for carmustine above. As can be seen in Pig. 13, the alkaline phosphatase was released in a well-controlled manner over a prolonged period of time, just over a month, from this polyanhydride. 

As in the alkaline phosphatase example above, p-galactosidase, an enzyme with a molecular weight of approximately 360,000, has also been incorporated into a polyanhydride and released in a well-controlled fashion. As is shown in Fig. 14, the release of 3-galactosidase was quite linear over most of the time examined, and was complete, reaching 100% release in about 800 hr. This experiment utilized 5% loaded, compression-molded wafers of PCPP-SA 9 91, 1.4 cm in diameter and 0.5 mm thick, weighing 50 mg. 

Bovine growth hormone, a difficult protein for which to develop controlled release systems due to its propensity toward self-aggregation and inactivation, has successfully been incorporated into polyanhydride matrices (18). The growth hormone was colyophilized with sucrose, dry-mixed with finely powdered polyanhydride, and then compression molded into 1.4-cm-diaraeter wafers, 1 mm thick. As is shown in Fig. 15, release of bovine growth hormone was well controlled over a prolonged period of time. The assay for bovine... 

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. 

Mathiowitz, E., Leong, K., and Langer, R., Macromolecular drug release from biodegradable polyanhydride microspheres, 12th Int. Symp. Control. Rel. Bioact. Mater., 183-184, 1985. 

L Shieh, J Tamada, Y Tabata, A Domb, R Langer. Drug release from a new family of biodegradable polyanhydrides. J Controlled Release 29 73-82, 1994. 

M Maniar, AJ Domb, A Haffer, J Shah. Controlled-release of a local anesthetic from fatty-acid dimer based polyanhydride. J Controlled Release 30 233-239, 1994. 

The in vitro degradation and drug release of polyanhydride formulations is not necessarily equivalent to the in vivo kinetics. For information on the in vivo kinetics, the interested reader is referred to the recent review by Katti et al. (2002) and the review by Domb et al. (1997). 

Whether in copolymers or blends, inhomogeneous erosion has a nontrivial effect on drug release kinetics as will be shown later. Leong et al. (1985) demonstrated that the pH of the degradation media also has a dramatic effect on the erosion rate, which increases with increasing pH. The acceleration of degradation of polyanhydrides with increase in pH is widely reported and has been used to speed up experiments (Shakesheff et al., 1994). 

Modeling the behavior of bioerodible polyanhydrides is complicated by the many phenomena contributing to release profiles described in the previous section. The degradation kinetics may be coupled to other processes, such as diffusion and dissolution, and the overall erosion kinetics represent the sum of all of these multiple processes (Goepferich, 1996a). 

The encapsulation and release of l,3-bis(2-chloroethyl)nitrosourea (BCNU) in P(CPP-SA) 20 80 wafers was the first implantable controlled release device based on polyanhydrides that was FDA-approved and marketed (Gliadel ) (Chasin et al., 1988). BCNU was encapsulated by two techniques, trituration and co-dissolution, resulting in different release profiles (Chasin et al., 1990, 1991). The triturated samples released faster than those prepared by co-dissolution, presumably due to more homogeneous loading in the samples prepared by co-dissolution. 

The past two decades have produced a revival of interest in the synthesis of polyanhydrides for biomedical applications. These materials offer a unique combination of properties that includes hydrolytically labile backbone, hydrophobic bulk, and very flexible chemistry that can be combined with other functional groups to develop polymers with novel physical and chemical properties. This combination of properties leads to erosion kinetics that is primarily surface eroding and offers the potential to stabilize macromolecular drugs and extend release profiles from days to years. The microstructural characteristics and inhomogeneities of multi-component systems offer an additional dimension of drug release kinetics that can be exploited to tailor drug release profiles. 

The development of new polyanhydrides has sparked researchers to developed new device fabrication and characterization techniques, instrumentation, and experimental and mathematical models that can be extended to the study of other systems. The growing interest in developing new chemistries and drug release systems based on polyanhydrides promises a rich harvest of new applications and drug release technologies, as well as new characterization techniques that can be extended to other materials. Future endeavors will likely focus on multicomponent polyanhydride systems, combining new chemical functionalities to tailor polyanhydrides for specific applications. 

The release characteristics of polyanhydride systems could be used not only to develop clinical treatments, but also to induce chronic disease states as models for studying immune function. Many current models of chronic diseases are based on induction of acute effects, which do not exhibit the same long-term behavior as the disease being modeled. 

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