Poly(anhydride) administration in high doses <i>in vivo</i>: Studies of biocompatibility and toxicology

Laurencin, Cato T.; Domb, Abraham J.; Morris, C J; Brown, V. K. H.; Chasin, Mark; McConnell, R.G.; Lange, Nicholas; Langer, Robert

doi:10.1002/jbm.820241105

Cited by 87 publications

(45 citation statements)

References 9 publications

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“…Molecular (18). The polyanhydrides after purification (12) were frozen in liquid nitrogen, micronized in a Technilab micromill (Baxter Scientific Products, McGaw, IL), and sieved to 130-150 ,um.…”

Section: Methodsmentioning

confidence: 99%

“…However, the polymers used for such delivery are limited to those that are inert toward the incorporated proteins-i.e., those polymers that neither bind to irreversibly nor promote decomposition of the proteinaceous therapeutic agent. Polyanhydrides have been investigated in our and other laboratories as biodegradable implants (10)(11)(12). Furthermore, polyanhydrides are one of the few synthetic biodegradable polymers being studied clinically as injectable or as implantable matrices.…”

mentioning

confidence: 99%

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Controlled release of polypeptides from polyanhydrides.

Ron

Turek

Mathiowitz

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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The effects of both polymer hydrophobicity and addition of stabilizers on the release and integrity of polymer-encapsulated proteins were studied. By using very hydrophobic poly [l,3-bis(p-carboxyhydroxy)hexane anhydride] with sucrose as an excipient, both recombinant bovine somatotropin and zinc insulin were released intact over 3 weeks. The released proteins appeared to maintain their integrity as judged by acidic reverse-phase HPLC, size-exclusion HPLC, radioimmunoassay, and conformation-sensitive immunoassays. Our results also suggest how polymer hydrophobicity can be used to enhance protein stability. more important is the chemical instability of rb-STH in aqueous environments leading to deamidated, chain-cleaved, and covalently bonded oligomeric products (16). This instability presents an intriguing problem to attempt to overcome; solving it will demonstrate the potential of using hydrophobic polymers to reduce aggregation and to control the release of unstable proteins. Insulin was used to study the extent to which in vitro release and activity would compare with in vivo activity. The diabetic rat model is well documented in the literature and the successful use of our final formulation for delivery of intact protein would be a good affirmation.Most peptidic and proteinic drugs are susceptible to degradation at the site of administration, whether administered by subcutaneous, intramuscular, intestinal, buccal, rectal, nasal, or vaginal routes (1, 2). In addition, some proteins have very short in vivo half-lives and, as a consequence, multiple injections are required to achieve desirable therapy. One way to increase the therapeutic efficacy of these proteins is to incorporate them in a controlled release system that releases the proteins continuously. Several controlled release systems have been tested for their ability to sustain the release of peptidic drugs such as insulin (3), epidermal growth factor (4), interferon (5), and luteinizing hormone-releasing hormone and its analogs (6-9). It is also possible that, in addition to providing sustained release, polymers may help to protect the polypeptides from denaturing conditions, water, and proteolytic enzymes. Furthermore, the use of bioerodible polymers does not require posttreatment removal of the device. However, the polymers used for such delivery are limited to those that are inert toward the incorporated proteins-i.e., those polymers that neither bind to irreversibly nor promote decomposition of the proteinaceous therapeutic agent. Polyanhydrides have been investigated in our and other laboratories as biodegradable implants (10-12). Furthermore, polyanhydrides are one of the few synthetic biodegradable polymers being studied clinically as injectable or as implantable matrices. We used several polyanhydrides with different hydrophobicities to explore the effect of hydrophobicity and excipients on the release and activity of two proteins. We also studied the implications of possible interactions between the polymer, its degradation products, a...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Controlled release of polypeptides from polyanhydrides.

Ron

Turek

Mathiowitz

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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“…Tissue reactions and toxicological studies showed that polyanhydrides were biocompatible. 13,14 For example, they are currently used in clinics to deliver BCNU (carmustine, 1,3-bis [2-chloroethyl]-1-nitro-sourea) locally within the brain to treat patients with brain tumors. 15 However, it is difficult, if not impossible, to keep the surface area of a bulk polyanhydride sample constant during the erosion except for a very thin film.…”

Section: Introductionmentioning

confidence: 99%

Laser light scattering study of the degradation of poly(sebacic anhydride) nanoparticles

2001

J. Polym. Sci. B Polym. Phys.

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“…Polyanhydrides are biocompatible and degrade in vivo into nontoxic dicarboxylic acids in predictable rates and patterns counterparts that are eliminated from the body as metabolites. Recent studies on polyanhydrides as drug carriers show that the anhydrides degrade in a controlled fashion and are biocompatible with the human body tissues including the brain [1,2] .…”

Section: Introductionmentioning

confidence: 99%

Preparation and Properties of Copolyanhydrides Based on 2-Hexadecylsuccinic Acid and Sebacic Acid

Hamdan¹,

Xiangmei²,

Huang³

et al. 2007

American J. of Applied Sciences

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Poly(2-hexadecylsuccinic acid-sebacic acid) (P(HSA-SA)) copolymers have been prepared by melt polycondensation. The copolymers were characterized by FT-IR, 1 HNMR, gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). In vitro studies showed that all our prepared copolymers are degradable in phosphate buffer at 37 °C. The release profiles of hydrophilic model drug, ciprofloxcin hydrochloride, from the copolymers, follow first order release kinetics. All the preliminary results suggested that the copolymer might be potentially used as drug delivery devices.

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Poly(anhydride) administration in high doses in vivo: Studies of biocompatibility and toxicology

Cited by 87 publications

References 9 publications

Controlled release of polypeptides from polyanhydrides.

Controlled release of polypeptides from polyanhydrides.

Laser light scattering study of the degradation of poly(sebacic anhydride) nanoparticles

Preparation and Properties of Copolyanhydrides Based on 2-Hexadecylsuccinic Acid and Sebacic Acid

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