| PATENT NUMBER | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT EXAMPLES |
To prepare PCPM matrices containing cholic acid, a blend of unlabelled and tritiated cholic acids were used. Specifically, unlabelled cholic acid in 15 milligram concentrations was dissolved in 10.0 milliliters (hereinafter "ml") of ethanol. Tritiated cholic acid (2.4-3.0 H) in sufficient quantities was dissolved in 125 microliter (hereinafter "ul") of ethanol to provide a 3.75.times.10.sup.10 DPM/mg concentration. The tritiated solution and the mixture dried in vacuo. The mixture of cholic acids in powder form was added at 10.5 weight percent to the pulverized PCPM prepared as previously described and meltpressed at 121.degree. C. and 22 KPSI as earlier described to yield a disc shaped matrix. This matrix was then sandwiched between two very tin (less than one weight percent) layers of PCPM (150-33 um diameters) and heat compressed to form a single article. The use of PCPM as sandwich layers eliminated the presence of cholic acid particles at the surface of the matrix and provided a PCPM initial exterior surface identical to those matrices containing no cholic acid whatsoever. Each of the PCPM matrices with and without cholic acid were evaluated by in vitro erosion studies. In each instance, the matrices in disc form weighing from 10-50 mg were placed in glass scintillation vials containing 10 ml of 0.2 M phosphate buffer (pH 7.4) at a temperature of 37.degree. C. or 60.degree. C. The buffer was periodically changed by removing the matrix from the vial and placing it in another vial containing fresh buffer. Each of the buffer solutions were then collected and the absorbence at 2434 nanometers (hereinafter "NM") using a Gilford spectrophotometer to detect the presence of the diacid monomer, bis(p-carboxyphenoxy)methane in the liquid. Those buffer solutions containing tritiated cholic acid-containing matrices were analyzed for the presence of tritiated cholic acid using a LS-230 Beckman scintillation counter. The results are graphically illustrated by FIGS. 1-5. FIGS. 1 and 3 demonstrate the erosion curves for PCPM matrices without any cholic acid in phosphate buffer at 37.degree. C. and 60.degree. C. respectively. The weight of the matrices tested at each temperature weighed 23 and 18 milligrams; it is noted that the rate of surface erosion as much slower at 37.degree. C. than when placed at 60.degree. C. FIGS. 3 and 4 illustrate the effect of preeroding PCPM matrices at 60.degree. C. for 50 hours prior to being placed in 37.degree. C. and 60.degree. C. environments for a more extended time. The matrices tested at 37.degree. C. and 60.degree. c. weighed 74 and 25 milligrams respectively. It will be noted that the polymer erosion in each and every instance was 100% of the total mass of the matrix regardless of the time required for such surface erosion to be complete. In all instances as well, each matrix decreased in size and maintained their physical integrity throughout the entire duration of the test demonstrating that only surface erosion of the matrix occurred. It is also appreciated that in all instances the erosion rate is characterized by an induction period which is then followed by a linear loss of mass at a constant rate. All the empirical evidence thus demonstrates that a zero-order erosion reaction is in effect. Similar tests for PCPM matrices containing cholic acid at 10.5 weight percent were conducted in phosphate buffer held at 60.degree. C. The results are illustrated by FIG. 5. The rate of erosion for the PCPM matrix indicated by the circular solid dots follows the rate of cholic acid release indicated by the solid square boxes. Each matrix weighed 25 milligrams initially and eroded completely (100%) within 250 hours duration at 60.degree. C. It is noted that there is also a short induction period followed by a linear loss of mass and release of cholic acid at a constant rate. A comparison of the profiles between FIGS. 1-4 and FIG. 5 reveals a nealy zero-order reaction in all instances and linear loss of mass at constant rates which are very similar. An in vivo erosion study was also performed using three matrices cut from a single melt-pressed PCPM slab, each matrix having a 0.26 square centimeter face surface area, 0.069 centimeters in thickness, and weighing 24 milligrams. Each matrix was essentially square in configuration and each was sterilized using UV light for 30 minutes prior to implantation into the test animal. Sprague-Dawley rate of comparable age and weight were used as the test animals. Each square was implanted subcutaneoulsy in the abdominal region of each rat by surgical procedure and cared for normally thereafter with adequate food and water. Animals were sacrificed at the end of 21, 44 and 153 days after implantation. The matrix was then removed from the site of implantation, dried and weighed. The results showed that in vivo erosion of PCPM rectangular slabs without any biologically active substance demonstrated a half life of about 47 days, a period approximately 5 days less than the life expectancy demonstrated by in vitro erosion at 347.degree. C. Also, after 153 days, it was found that less than 1% of the matrix remained intact. Finally, the matrices at the site of implantation were found to be only slightly encapsulated by the tissues of the animal. |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |