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).

A bioresorbable, polylactide reservoir for diffusional and osmotically controlled drug delivery.

The purpose of this study was to design and characterize a zero-order bioresorbable reservoir delivery system (BRDS) for diffusional or osmotically controlled delivery of model drugs including macromolecules. The BRDS was manufactured by casting hollow cylindrical poly (lactic acid) (PLA): polyethylene glycol (PEG) membranes (10 x 1.6 mm) on a stainless steel mold. Physical properties of the PLA:PEG membranes were characterized by solid-state thermal analysis. After filling with drug (5 fluorouracil [5FU] or fluorescein isothiocyanate [FITC]-dextran:mannitol, 5:95 wt/wt mixture) and sealing with viscous PLA solution, cumulative in vitro dissolution studies were performed and drug release monitored by ultraviolet (UV) or florescence spectroscopy. Statistical analysis was performed using Minitab (Version 12). Differential scanning calorimetry thermograms of PLA:PEG membranes dried at 25 degrees C lacked the crystallization exotherms, dual endothermal melting peaks, and endothermal glass transition observed in PLA membranes dried at -25 degrees C. In vitro release studies demonstrated zero-order release of 5FU for up to 6 weeks from BRDS manufactured with 50% wt/wt PEG (drying temperature, 25 degrees C). The release of FITC dextrans of molecular weights 4400, 42 000, 148 000, and 464 000 followed zero-order kinetics that were independent of the dextran molecular weight. When monitored under different concentrations of urea in the dissolution medium, the release rate of FITC dextran 42 000 showed a linear correlation with the calculated osmotic gradient(DeltaPi). This study concludes that PEG inclusion at 25 degrees C enables manufacture of uniform, cylindrical PLA membranes of controlled permeability. The absence of molecular weight effects and a linear dependence of FITC-dextran release rate on DeltaPi confirm that the BRDS can be modified to release model macromolecules by an osmotically controlled mechanism.

Controlled release captopril microcapsules: effect of non-ionic surfactants on release from ethyl cellulose microcapsules.

Captopril microcapsules were prepared with different viscosity grades of ethyl cellulose by temperature induced coacervation from cyclohexane. Both non-ionic surfactants or their combinations and 2 per cent absolute alcohol as cosolvent were added to the coacervation system to ensure complete solvation of the ethyl cellulose and efficient microencapsulation of the drug. The in vitro dissolution was studied in 0.1 N hydrochloric acid. Microcapsules prepared using 2 per cent Tween 80 with ethyl cellulose of 41 c.p. viscosity grade exhibited the most prolonged release with a t70 per cent of 55 min in comparison to 7.75 min for control microcapsules prepared without surfactant. Different kinetic models have been used to explain the release. The best fit with the highest correlation coefficients was the first-order kinetics plot with two straight lines having two different slopes. The initial slope presents the faster release rate than the terminal slope. This fast release would be useful for the initial dose of the prolonged release formulation.

Controlled release captopril microcapsules: effect of ethyl cellulose viscosity grade on the in vitro dissolution from microcapsules and tableted microcapsules.

Captopril microcapsules were prepared using four different viscosity grades of ethyl cellulose (core: wall ratios 1:1, 1:2 and 1:3) by temperature induced coacervation from cyclohexane. In vitro dissolution studies in 0.1 M hydrochloric acid showed that the drug release was dependent on the core to wall ratio, the viscosity grade of the ethyl cellulose and thus the total viscosity of the coacervation system. Viscosity grade of greater than 100 c.p. was unsuitable for microencapsulation by coacervation method at the concentration used. The surface characteristics of a 1:2 core to wall ratio were studied by scanning electron microscopy. The surface of the microcapsules prepared with 10 c.p. viscosity grade was comparatively more porous with larger size pores than 50 c.p. viscosity grade of ethyl cellulose. However, 300 c.p. viscosity grade showed incomplete wall formation. The microcapsules did not fragment during dissolution, alter in shape or size, or show evidence of enlargement of the surface pores. The tensile strength of tablets prepared at constant pressure from each batch of microcapsules (mean diameter 675 microns) increased as both the core to wall ratios and the viscosity of ethyl cellulose increased. The dissolution rate of the drug from tableted microcapsules was significantly delayed. The in vitro release gave best correlation with first order release kinetics when compared to zero-order and square-root-of-time equations.

In vitro properties of an in situ forming gel for the parenteral delivery of macromolecular drugs.

The purpose of this research was to (i) formulate a solution of a water-insoluble interpolymeric complex (IPC) containing poly(methacrylic acid) (PMA), 15 kDa, and poly(ethylene glycol) (PEG), 20 kDa, in a biocompatible cosolvent system; (ii) demonstrate that the IPC solution can transform into a gel, in situ, at physiological pH; and (iii) determine the ability of the gel to entrap, protect, and control the release of macromolecular drugs such as proteins and oligonucleotides. Ternary phase diagrams were prepared to identify cosolvent composition containing N-methylpyrrolidone (NMP), ethanol, and water that dissolve the IPC. IPC solutions (40, 50, or 60% w/v) each containing 1 mg of either model proteins, fluorescein isothiocyanate (FITC)-insulin and FITC-albumin, or 24-mer phosphorothioate oligonucleotides, were placed in containers that were immersed in buffer, pH 7.4. Aliquots of the buffer were sampled periodically and analyzed for the macromolecular content. In addition, in vitro bioactivity of another model protein, alpha-amylase, contained in the IPC solution was also determined. The studies demonstrated that a cosolvent containing 1:1:2 ratio of NMP/ethanol/water was most suitable for dissolving the IPC. Concentrations > 30% w/v IPC were required to form the gel, however, those mixtures containing > 60% w/v IPC could not be easily injected via 18-22 gauge needle. The gel can entrap and control the release of the model macromolecules for up to 6 days, in vitro. In addition, the gel can maintain the bioactivity of the protein, alpha-amylase, for 6 days. Therefore, an IPC gel can entrap, protect, and control the release of macromolecular drugs over a period of 6 days, in vitro, and therefore can be considered for in vivo investigation.

A slow release calcium delivery system for the study of reparative dentine formation.

Several liquid, semi-solid and solid delivery systems were formulated and tested to devise a method of reproducibly administering accurate micro-doses of calcium into a 700 microns diameter cavity in a rat maxillary incisor tooth, in the absence of hydroxyl ions. Development of this delivery system was necessary to facilitate studies of the mechanisms of pulpal repair and odontoblast differentiation. The principal requirements for the delivery system were that it should be easily administered into a small pulp exposure in the rat incisor and that a greater than 1000-fold range in calcium ion concentrations could be incorporated and delivered for a period of 2-3 days, preferably in an acidic environment to minimize the effect of non-specific nucleation under alkaline conditions. Poly- (ethylene) glycol microspheres were found to be an ideal vehicle. Under the in vitro dissolution conditions used, complete release of all calcium salts occurred within 12-15 hours, except for the very water-insoluble calcium stearate. It was anticipated that the release of calcium ions would be significantly more prolonged in vivo because of the physical constraints of the prepared cavity as well as the restricted access to fluid flow.

In vitro characterization of poly(ethylene) glycol calcium citrate microspheres as a delivery system for the study of reparative dentinogenesis.

The characterization of poly(ethylene) glycol calcium citrate microspheres is described. The calcium content and content uniformity of microspheres, prepared at five concentrations ranging from 46.56 micrograms/g to 81.49 mg/g, were determined by spectroscopy. Under sink conditions first-order in vitro dissolution kinetics were observed. Granules containing approximately 80 mg Ca++/g PEG gave an in vitro calcium release over a 3-day period similar to that of a calcium hydroxide product, Pulpdent.

Response to intracrevicular controlled delivery of 25% tetracycline from poly(lactide/glycolide) film strips in SPT patients.

Controlled local delivery of antibiotics has been shown to reduce periodontopathic micro-organisms with minimal side-effects. Clinical studies in our laboratory have shown that 25% tetracycline HCl delivered from poly(D,L-lactide/glycolide) film strips (25 TTC-PLGA) released therapeutic concentrations of tetracycline for 10 days. The present pilot study compared the intracrevicular delivery of 25% tetracycline HCl incorporated in these biodegradable film strips to scaling and root planing (SRP) in 10 adult periodontitis patients, who in spite of therapy and regular supportive periodontal treatment (SPT), continued to possess 5 bleeding periodontal pockets at least 5 mm deep. Sites were randomly selected to receive the following treatments: (1) 25 TTC-PLGA, (2) control strips without TTC (PLGA), (3) SRP, and (4) untreated control. Film-strip retention was augmented with a suture/cement technique, followed by strip removal after 2 weeks. Clinical parameters and subgingival bacterial morphotypes (darkfield analysis) were evaluated over time (0, 2.4, 8, 12, 26 weeks). Results indicated that, compared to baseline, 25 TTC-PLGA film strips caused significant (p < or = 0.01): (1) probing depth reduction for 26 weeks, (2) a clinical attachment level gain for 12 weeks, (3) lower %s of spirochetes for 4 weeks and motile rods for 8 weeks (p < or = 0.05), and (4) an accompanying increase in cocci for 4 weeks. In the scaled and root planed sites, probing depth was the only finding that demonstrated a significant change from baseline (p < or = 0.01). Controls and PLGA showed isolated reductions in probing depth and % of motile organisms. From these findings, applications of intracrevicular 25 TTC-PLGA, when compared to scaling and root planing, appears to have an enhanced antibacterial effect and a similar clinical effect in SPT patients. The results of this study indicate further investigation of 25 TTC-PLGA film strips should be undertaken using more subjects and sophisticated microbiological and clinical measurements.

Effects of locally-delivered human macrophage products and estrogen on murine inflammatory bone resorption.

The objective of this study was to use an in vivo model of periodontitis (mouse calvaria) to quantify the effects of local release of secreted human macrophage products, 17beta-estradiol (E2), and proinflammatory lipopolysaccharide (LPS) on histologic bone resorption. Human THP-1 monocytes (106) were converted to macrophage phenotype by 500 ng/ml phorbol 12-myristate- 13-acetate (PMA) and treated as follows: no stimulation or Escherichia coli LPS (10 microg/ml) alone or in combination with a physiologic dose of E2 (100 pg/ml) for 24 h in RPMI/10% FBS, washed extensively, then incubated for 24 h in serum-free media. Supernatant products were concentrated and incorporated into a 4% (w/v) methylcellulose gel. Separate gels were incorporated with the following: LPS (500 microg/animal) alone, high dose of E2 (10 ng/animal) alone, a combination of LPS + E2, or gel only (controls). Loaded or control gels were placed into a polylactic acid occlusive dome, inserted subcutaneously over the calvaria of mature ovariectomized ICR Swiss mice (8 mice x 7 groups x 2 times [5/14 days] = 112 animals), then calvaria were evaluated histologically. Macrophage stimulation with LPS alone, but not LPS in combination with E2, produced supernatants which upregulated osteoclast numbers in the suture area compared to gel controls at 5 days (p = 0.009). The addition of LPS directly to the local delivery gels significantly upregulated osteoclasts in endosteal surfaces compared to gel controls at 5 days (p = 0.024) and at 14 days (p = 0.025). The addition of E2 to LPS down-regulated resorption to a level not different from gel controls at 14 days. This in vivo model appears effective in studying inflammatory bone resorption, which may be inhibited by E2 directly or through its influence on secreted macrophage products.