Cross-linked amino acid-containing polyanhydrides for controlled drug release applications

Cross-linked amino acid-containing polyanhydrides based on N-trimellitylimido-β-alanine (TMA-ala) or N-trimellitylimido-glycine (TMA-gly) and sebacic acid (SA) were synthesized by copolycondensation using 1,3,5-benzenetricarboxylic acid (BTC) prepolymer as a cross-linking agent. Differential scanning calorimetric (DSC) studies of the insoluble copolymers revealed only one sharp melting transition, indicating their cross-linked and/or randomly copolymeric structure. These cross-linked polymers can degrade completely into water-soluble molecules such as amino acids and natural fatty acid, which can be further metabolized by the body. This is an improvement over the photo-cross-linked polyanhydrides reported in the literature, whose cross-links hydrolyze to poly(methacrylic acid), a non-degradable and non-metabolizable macromolecule with limited biocompatibility. The cross-linked polymers were mixed with p-nitroaniline (PNA) and compressed into discs. In vitro degradation and solute release into physiological media were quantified for up to 70 h. Results showed that, relative to their linear counterparts, cross-linking has little effect on the degradation and solute release of these specific polymers.     

Sustained-Release Butorphanol Microparticles

Various butorphanol-loaded microparticles have been prepared with a biodegradable copolymer P(FAD-SA) of erucic acid dimer (FAD) and sebacic acid (SA) and a copolymer P(CPP-SA) of carboxyphenoxypropane (CPP) and SA using a melt compounding and milling method. Drug release was measured in vitro following incubation of drug-loaded microparticles in water for injection at 37°C. It was found that butorphanol was released in a sustained manner, yielding a cumulative drug release of about 100% over a period of 48 hr. Also, drug release was affected by drug loading and the size of the microparticles; however, it was not significantly influenced by the copolymer composition. Scanning electron microscopic (SEM) results showed that most of the particles were irregular in shape with uneven surfaces. The molecular weights of the copolymers were not changed after this fabrication process. In addition, 20% butorphanol-encapsulated microspheres were prepared with copolymer P(FAD-SA) by spray-drying. The SEM micrograph shows that the particle sizes of the microspheres ranged from 2 to 10 μm, and the external surfaces appear smooth. Moreover, rapid drug release was observed for these microspheres, with more than 92% of the encapsulated drug released within the first 2 hr.     

The effect of storage temperatures on the in vitro properties of a polyanhydride implant containing gentamicin

Septacin® is a biodegradable sustained-release implant containing 20% (w/w) gentamicin sulfate. The matrix of the implant is a polyanhydride copolymer composed of erucic acid dimer (EAD) and sebacic acid (SA) in a one-to-one weight ratio. The effect of storage temperatures (-15°C and 25°C) on the stability of Septacin® was evaluated with respect to gentamicin potency, copolymer molecular weight, and in vitro drug release. The drug in polymer matrix was stable for at least 12 months when stored at 25°C, but the molecular weight of the copolymer declined rapidly at this temperature. At -15°C, there was no change in the molecular weight of the copolymer. However, the placebo (copolymer without gentamicin) exhibited a significant drop in copolymer molecular weight at both temperatures. The drug release profiles showed no change for samples stored at -15°C for the duration of this study, while the release of drug slowed down significantly for samples stored at 25°C for longer than one month. A pronounced difference in the morphology of the -15°C samples and the 25°C samples was observed during the in vitro dissolution test; cracking of the -15°C samples was evident, but the 25°C samples remained intact.     

New polyanhydrides derived from C12,C13,C14,C15 dibasic acid: synthesis and characterization

Poly(dodecanedioic acid-tetradecandioic acid) (P(DDDA-TA)) copolymers and poly(brassylic acid-pentadecandioic acid) (P(BA-PA)) copolymers have been prepared by melt polycondensation of the corresponding mixed anhydride prepolymers derived from dodecanedioic acid, brassylic acid, tetradecandioic acid and pentadecandioic acid. The copolymers were characterized by FT-IR, gel permeation chromatography (GPC), differential scanning calorimetry (DSC), wide angle X-ray powder-diffraction, and thermal gravimetric analysis (TGA). In vitro studies showed that all the copolymers are degradable in phosphate buffer at 37 °C. The release profiles of hydrophilic model drug, ciprofloxcin hydrochloride, from the copolymers, follows first order release kinetics. All the preliminary results suggested that the copolymer might be potentially used as drug delivery devices.     

Sustained-release butorphanol microparticles

Various butorphanol-loaded microparticles have been prepared with a biodegradable copolymer P(FAD-SA) of erucic acid dimer (FAD) and sebacic acid (SA) and a copolymer P(CPP-SA) of carboxyphenoxypropane (CPP) and SA using a melt compounding and milling method. Drug release was measured in vitro following incubation of drug-loaded microparticles in water for injection at 37°C. It was found that butorphanol was released in a sustained manner, yielding a cumulative drug release of about 100% over a period of 48 hr. Also, drug release was affected by drug loading and the size of the microparticles; however, it was not significantly influenced by the copolymer composition. Scanning electron microscopic (SEM) results showed that most of the particles were irregular in shape with uneven surfaces. The molecular weights of the copolymers were not changed after this fabrication process. In addition, 20% butorphanol-encapsulated microspheres were prepared with copolymer P(FAD-SA) by spray-drying. The SEM micrograph shows that the particle sizes of the microspheres ranged from 2 to 10 μm, and the external surfaces appear smooth. Moreover, rapid drug release was observed for these microspheres, with more than 92% of the encapsulated drug released within the first 2 hr.     

Emerging Perspectives in the Synthesis of Novel Degradable Biomedical Copolymers

Biodegradable polymer is playing an increasingly significant role in the development of biomedical materials due to its good biocompatibility and biodegradability, and is undoubtedly the focus in the biomedical fields, such as controlled drug delivery, tissue engineering, and regenerative medicine. In this review, some new degradable biomedical copolymers reported over the past 5 years are introduced and discussed in combination with some our research results. The molecular design, chemical structures and related properties of these novel biodegradable copolymers are reported. In summarizing the review, the development, potential applications and future directions of the degradable biomedical copolymers are discussed.