A three-dimensional osteochondral composite scaffold for articular cartilage repair.

There is a recognized and urgent need for improved treatment of articular cartilage defects. Tissue engineering of cartilage using a cell-scaffold approach has demonstrated potential to offer an alternative and effective method for treating articular defects. We have developed a unique, heterogeneous, osteochondral scaffold using the TheriForm three-dimensional printing process. The material composition, porosity, macroarchitecture, and mechanical properties varied throughout the scaffold structure. The upper, cartilage region was 90% porous and composed of D,L-PLGA/L-PLA, with macroscopic staggered channels to facilitate homogenous cell seeding. The lower, cloverleaf-shaped bone portion was 55% porous and consisted of a L-PLGA/TCP composite, designed to maximize bone ingrowth while maintaining critical mechanical properties. The transition region between these two sections contained a gradient of materials and porosity to prevent delamination. Chondrocytes preferentially attached to the cartilage portion of the device, and biochemical and histological analyses showed that cartilage formed during a 6-week in vitro culture period. The tensile strength of the bone region was similar in magnitude to fresh cancellous human bone, suggesting that these scaffolds have desirable mechanical properties for in vivo applications, including full joint replacement.

Preformulation studies to meet the challenges in the manufacture of betaine solid dosage form.

The objectives were (1). to perform solid-state characterization of anhydrous betaine (A) and betaine monohydrate (M), (2). to develop a pressure differential scanning calorimetric (DSC) technique for the quantification of M when present as a minor component in a mixture with A and, (3). to study the effect of annealing of A on the kinetics of A --> M transition. X-ray powder diffractometer (XRD), DSC, thermogravimetric analyzer (TGA), and an automated moisture sorption apparatus were used to characterize the phases. DSC at an elevated pressure of 200 psi enabled quantification of M in mixtures of A and M. Humidity-controlled TGA allowed study of the kinetics of A --> M transition. Automated moisture studies showed that A has a strong tendency to sorb water (at RH >or= 20%, 25 degrees C) and convert to M. When M was subjected to DSC at ambient pressure, the endotherms due to dehydration and vaporization of water overlapped. Pressure DSC enabled separation of these two thermal events. In mixtures of A and M, the enthalpy of dehydration (deltaH(d)) of M could be used for its quantification. A linear relationship was obtained when deltaH(d) was plotted as a function of the weight fraction of M in the mixture. The limits of detection and quantification of M in A were 0.15% and 1.5% w/w, respectively. The kinetics of water uptake by the annealed as well as the unannealed A, could be best described by the Avrami-Erofeev model (three-dimensional nucleation and growth). The calculated rate constant (k) of unannealed A (0.075 +/- 0.002 min(-1)) was significantly higher than that of annealed A (0.052 +/- 0.004 min(-1)). DSC at elevated pressure was a sensitive technique for quantification of M when present as a mixture with A. Annealing of A decelerated the A --> M phase transition reaction, possibly by increasing the degree of crystallinity of A.

Development of near zero-order release dosage forms using three-dimensional printing (3-DP) technology.

Three near zero-order controlled-release pseudoephedrine hydrochloride (PEH) formulations demonstrating proportional release rates were developed using 3-Dimensional Printing (3-DP) technology. Mixtures of Kollidon SR and hydroxypropylmethyl cellulose (HPMC) were used as drug carriers. The release rates were adjusted by varying the Kollidon SR-HPMC ratio while keeping fabrication parameters constant. The dosage forms were composed of an immediate release core and a release rate regulating shell, fabricated with an aqueous PEH and an ethanolic triethyl citrate (TEC) binder, respectively. The dosage form design called for the drug to be released via diffusional pathways formed by HPMC in the shell matrix. The release rate was shown to increase correspondingly with the fraction of HPMC contained in the polymer blend. The designed formulations resulted in dosage forms that were insensitive to changes in pH of the dissolution medium, paddle stirring rate, and the presence/absence of a sinker. The near zero-order release properties were unchanged regardless of the dissolution test being performed on either single cubes or on a group of eight cubes encased within a gelatin capsule shell. The chemical and dissolution properties of the three formulations remained unchanged following 1 month's exposure to 25 degrees C/60% RH or 40 degrees C/75% RH environment under open container condition. The in vivo performance of the three formulations was evaluated using a single-dose, randomized, open-label, four-way crossover clinical study composed of 10 fasted healthy volunteers. The pharmacokinetic parameters were analyzed using a noncompartmental model. Qualitative rank order linear correlations between in vivo absorption profiles and in vitro dissolution parameters (with slope and intercept close to unity and origin, respectively) were obtained for all three formulations, indicating good support for a Level A in vivo/in vitro correlation.

Evaluation of critical formulation factors in the development of a rapidly dispersing captopril oral dosage form.

New methods of manufacture have enabled the creation of novel dosage forms with unique rapid-dispersion properties. This study combines one such technique with a statistical experimental design to develop dosage forms from captopril, an angiotensin-converting enzyme inhibitor used to treat cases of hypertensive emergency. The TheriForm process, a novel microfabrication technique, was used to build the dosage forms in a layer-by-layer fashion. Three key formulation factors were chosen for the design of experiments. A modified central composite design (Box-Behnken design) was used to maximize the efficiency of the experiments. A total of 13 distinct formulations were fabricated and tested, using mannitol as the bulk excipient. In addition, three replicates of the center point were tested to assess variability and experimental error. These formulations were tested for speed of dispersion (flash time), active content, hardness, friability, and moisture absorption. Regression analysis was performed to fit data responses to quadratic equations. Excellent dose accuracy (95% to 102% of target) and content uniformity (between 1.03% to 2.84%) were observed from all experimental formulation batches. As expected, the choice of powder additive (maltitol, maltodextrin, polyvinyl pyrrolidone), level of additive (2.5% to 7.5%), and saturation level of the binder liquid (45% to 65%) were all found to be significant factors for the TheriForm process. The regression analysis suggested that a rapidly dispersing dosage form of optimal physical properties would be obtained when a powder mixture of mannitol (97.5%) and maltitol (2.5%) is used at a saturation level of 45%. In conclusion, rapidly dispersing captopril oral dosage forms were successfully fabricated and tested. A wide range of physical properties, flash time, and hardness, were determined experimentally, and the effects of key formulation factors were identified.