Dennis Stephens

Polyanhydride implant for antibiotic delivery--from the bench to the clinic.

A polyanhydride implant (Septacin) containing gentamicin sulfate was developed for sustained local delivery of the drug to the site of infection in the treatment of osteomyelitis. Laboratory-scale injection molding equipment was utilized to fabricate the implant for in vitro characterization. Molding conditions were optimized to produce implants with a skin-core structure which was found to be critical in preventing the initial cracking of the implant during in vitro drug release test in water. A manufacturing process consisting of twin-screw extrusion, pelletizing, and injection molding was developed. Polymer-drug pellets were characterized with respect to copolymer molecular weight and drug content uniformity. The implants were terminally sterilized by gamma-radiation which was found to cause increase in copolymer molecular weight as a result of polymer chain extension. The stability of Septacin was evaluated as a function of storage temperature and time. A marked decline in copolymer molecular weight occurred in samples stored above freezing temperatures and significantly slower drug-release profiles were also exhibited by these samples. In vivo drug release from Septacin in rats showed that the gentamicin plasma levels were extremely low, indicating the low systemic exposure to gentamicin. Furthermore, Septacin samples have demonstrated efficacy in the rat skin-abscess and horse-joint infection models. Results from a human in vivo study also showed high local drug concentrations at implantation sites while systemic exposure to the drug was minimal.

Investigation of the in vitro release of gentamicin from a polyanhydride matrix.

Septacin¿trade mark omitted¿ is a sustained release formulation consisting of gentamicin sulfate dispersed in a biodegradable polyanhydride matrix. The polyanhydride matrix is a copolymer of erucic acid dimer (EAD) and sebacic acid in a 1:1 weight ratio. In vitro drug release was performed in both water and pH 7.4 phosphate buffer. The drug release in water was faster than that in the buffer, which was the opposite of what would be expected based upon a faster polymer hydrolysis rate in the buffer. Theoretical treatment of the data using the Peppas model revealed that release in water was anomalous, while the release in pH 7.4 phosphate buffer was diffusion-controlled. Profound bead morphology differences were observed between beads in these two in vitro release media. Cracking was observed in beads in water and swelling with no apparent cracking was seen in beads in buffer. Concurrent monitoring of drug and sebacic acid release indicated that drug release is not via surface erosion. Osmotic effects were found to play little role in the in vitro drug release. There was no spectroscopic evidence of amide formation between the drug and copolymer. Sulfate release was monitored along with drug release and the results indicate that there is ion-exchange occurring during the pH 7.4 in vitro release. It was subsequently demonstrated that gentamicin can form an insoluble salt with EAD. This salt formation explains the slower drug release in pH 7.4 phosphate buffer.

The Effect of Storage Temperatures on the In Vitro Properties of a Polyanhydride Implant Containing Gentamicin

ABSTRACT 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.

A statistical experimental approach to cosolvent formulation of a water-insoluble drug.

19-Nor-1 alpha, 25-dihydroxyvitamin D2, an analog of vitamin D2, is a nonpolar compound with limited solubility in water. An injectable solution was formulated using a cosolvent system consisting of water, ethanol, and propylene glycol. A statistical response surface approach was used to evaluate the effect of these three solvents on the solubility of the drug (25 degrees C) in the ternary cosolvent system. The data generated from five selected formulations were used to develop a multiple linear regression model that quantitatively defines the solubility of the drug as a function of the cosolvent composition. Close agreement was found between the experimental data and data calculated using the model. The capability of this model to predict drug solubility in cosolvent systems with various combinations of the three solvents was also verified.

Effect of γ-radiation on a polyanhydride implant containing gentamicin sulfate

Septacin™, a polyanhydride implant containing gentamicin sulfate, was sterilized by γ-radiation. Its copolymer molecular weight (Mw by GPC) was increased after this radiation. No cross-linking was shown in the radiated samples as no gel content was found by the filtration method. The chemical structure as detected by 1H NMR for non-radiated and radiated samples was comparable. For samples radiated at higher dose levels (70–100 kGy), the IR spectra showed that the intensity of absorbance attributable to the CH stretching vibration (at 2852 and 2927 cm−1) was attenuated, indicating free-radical formation or loss of hydrogen atoms from CH bonds. However, the mass spectra for the γ-radiated and the non-radiated controls after they were completely depolymerized in methylene chloride were virtually identical. Therefore, it could be concluded that the increase in copolymer molecular weight for radiated Septacin was a result of chain extension in the copolymer backbone during radiation. In addition, wide-angle X-ray diffraction and polarizing light microscopy (PLM) revealed a change in the physical structure of the radiated copolymer. There was an increase in crystallinity of the copolymer with increasing radiation doses; the greatest increase in crystallinity occurred at the dose range of 70–80 kGy, which was also shown to result in the greatest molecular-weight increase. The crystalline morphology of the samples as detected by PLM was not altered by γ-radiation, regardless of the dose levels.

The Relationship Between Structures and In Vitro Properties of a Polyanhydride Implant Containing Gentamicin Sulfate

Laboratory scale injection-molding equipment was utilized to fabricate an implant consisting of poly(FAD:SA 1:1) and 20% (w/w) gentamicin sulfate. Characterizations were performed to determine the molecular weight and glass transition temperature of poly(FAD:SA 1:1). A study was carried out to investigate the relationships between the in vitro performance, morphology, and micro-structures of the molded implants. It was found that implants produced with different structures exhibited different physical integrities in water, i.e., cracking or non-cracking. For the non-cracking implants, a skin–core structure formed by an oriented skin layer was observed under a polarized light microscope. The same morphology was not seen in the cracking implants. The crystal orientation in the skin layer of the non-cracking implants was further identified using a wide-angle x-ray diffraction method (WAXD). No crystal orientation could be found in the cracking implants by WAXD. Furthermore, studies were carried out to evaluate the in vitro drug release for implants showing different degrees of integrity in water. The in vitro drug release of the cracking implants was markedly faster than that of the non-cracking implants due to the pronounced initial drug-burst effect as a result of crack formation in the implants.

Identification of a Yellow Impurity in Aged Samples of Aqueous Butamben Suspension: Evidence for the Oxidative Degradation of Poly(ethylene glycol)

Butamben (butyl p-aminobenzoate) has been formulated to provide long-acting treatment for chronic pain. The suspension, which contains poly(ethylene glycol) and polysorbate 80, was found to yellow under ambient conditions if not adequately protected from oxygen. The impurity responsible for the color was isolated and identified on the basis of nuclear magnetic resonance spectroscopy and mass spectrometry. The compound is an oxalamidine, which is formally the condensation product of oxalic acid with four equivalents of butamben, and may be formed by the reaction of butamben with an oxidation product of poly(ethylene glycol).

Development of a topical suspension containing three active ingredients.

ABSTRACT The objective of this study was to develop a topical suspension that contains sarafloxacin hydrochloride (1 mg/mL), triamcinolone acetonide (1 mg/mL), and clotrimazole (10 mg/mL), and is stable at room temperature (15–28°C) for clinical usage. Due to the difference in the physicochemical properties and chemical stability profiles of these three active ingredients, it is a challenge to develop a stable suspension formulation containing these three drugs. In this study, the stability of these drugs in different buffer solutions was determined under different accelerated isothermal conditions. The Arrhenius equation was subsequently utilized to predict the room-temperature stability of these three drugs in these buffer solutions. By knowing the room-temperature solubility of the drugs in the buffer solution, the stability of the drugs in suspension was predicted. As a result, a 0.02 M phosphate buffer (pH 7.0) containing 0.02% (w/v)polysorbate 20, 1% (w/v) NaCl, and 0.1% (w/v) EDTA was determined to be an acceptable medium. In addition, 0.35% (w/v) high-viscosity carboxymethylcellulose (HV-CMC) was first selected as the suspending agent to enhance the redispersibility of the suspension. Stability data further supported that all three drugs were stable in the suspension containing HV-CMC with less than 5% potency loss for at least 6 months at 40°C and 12 months at 25°C. However, the viscosity drop of this HV-CMC formulation at 25°C and 40°C became a product stability concern. To improve the viscosity stability of the suspension, the medium-viscosity carboxymethylcellulose (MV-CMC) was selected to replace the HV-CMC as the suspending agent. The optimal combination of MV-CMC and sodium chloride in achieving the most desirable dispersion properties for the formulation was determined through the use of a 32 factorial design. The optimal formulation containing 1% MV-CMC and 1% sodium chloride has shown improved viscosity stability during storage and has been used for clinical studies.

Particle Size Determination of a Flocculated Suspension Using a Light-Scattering Particle Size Analyzer

Microscopy is a useful and direct method for measuring the particle size of a suspension because, in addition to the particle size and size distribution, it provides visual detection of the shape and state of aggregation of the particles in the suspension. However, this method suffers from the shortcomings of being tedious and time consuming. In this study, a light-scattering particle size analyzer was used to determine the particle size and size distribution of a flocculated suspension. The sonication of the sample prior to and during measurement was found to be critical in ensuring that data are representative of the size distribution of the primary particles of the suspension. The light-scattering results were further confirmed by data generated using a polarized light microscope equipped with an image analyzer.

Effect of postmolding heat treatment on in vitro properties of a polyanhydride implant containing gentamicin sulfate

A polyanhydride implant containing gentamicin sulfate was fabricated using a laboratory‐scale injection‐molding machine. After injection molding, the implants were subject to heat treatment at 60°C for various time periods with or without nitrogen protection. The impact of this heat treatment on the in vitro properties of the implants including copolymer molecular weights, mechanical properties, and in vitro drug‐release profiles was investigated. This heat treatment caused a drastic drop in the molecular weight of the copolymer. Heating without nitrogen protection resulted in the hardening of the implant, but heating in the presence of nitrogen rendered the implant less rigid. It was also found that a faster in vitro drug release profile was shown by implants heated without nitrogen protection and a pronounced slowing down in drug release was exhibited by implants heated with nitrogen protection.