1. Field of the Invention
This invention relates to a pharmaceutical suspension. More particularly, the instant invention is concerned with a suspension of titanium dioxide for use in admixing with gelatin solutions from which opaque empty gelatin capsules can be manufactured which are suitable as containers for unit doses of pharmaceutically active agents.
2. Prior Art
Almost all of the billions of empty gelatin capsules used each year in the world are manufactured by dipping highly polished, but lubricated, forming pins into a warm viscous gelatin solution. The forming pin is slowly withdrawn from the solution with a thin film of gelatin adhering thereto. The gelatin film is dried on the forming pin until the moisture content of the film is somewhere in the neighborhood of 13-16 percent, preferably about 14-15 percent. A special stripping tool is used to remove the gelatin film from the forming pin and the edges of the open end of the gelatin are trimmed to provide one of the two pieces of an empty gelatin capsule. Separate forming pins of different diameters are used to form each of the two pieces of an empty capsule so that, when properly trimmed, the two pieces will telescope together to make a package which can be filled with various physiologically active agents to provide a pharmaceutical unit dosage form.
Gelatin is a material which has been used since the late nineteenth century for making capsules for use in holding unit dosage forms of various active agents.
A simple solution (actually a colloidal solution) of gelatin can be used to make capsules in the manner described briefly above. It is preferred, however, to include preservatives in the gelatin solution because in such solution gelatin is a highly desirable substrate for microbial growth. And when the organisms are gas formers, little bubbles appear in the solution which are not easy to remove.
Early capsules were made without coloring and, if the gelatin was of good quality, such capsules would be essentially transparent. Later on various approved soluble dyes were added to the gelatin solution to make capsules of various colors. Even so, such capsules, colored or plain, came to be known as clear capsules.
As the demand for empty gelatin capsules increased, a need arose for a wider range of colors and hues for use in identifying different medicaments. A group of opaque capsules were developed to meet this need, and titanium dioxide was adopted as the opaquing agent because of its lack of toxicity and high opaquing properties.
Opaquing grade titanium dioxide must be finely divided particles, preferably in the micron range. Generally, particles this small are difficult to wet, and titanium dioxide is no exception. It was soon found that it was impractical to mix finely-divided titanium dioxide powder directly into a viscous gelatin solution. Consequently, paste formulations of titanium dioxide were developed which could be mixed into the viscous gelatin solution with only moderate difficulty. However, these titanium pastes had to be prepared very nearly simultaneously with the preparation of the gelatin solution as the pastes tended to coalesce and harden within a short time.
Then it was discovered that the addition of glycerin to the paste formulation would substantially retard the hardening and make it possible to prepare such a paste many days ahead of its use.
Sometime later a suspension of titanium dioxide was developed which was suitable for admixing with a solution of gelatin for the manufacture of opaque gelatin capsules. And, for many years this suspension proved satisfactory for its purpose. It consisted essentially of titanium dioxide powder, glycerin, water, and the preservatives methylparaben, propylparaben. Later chloroform and alcohol S.D.A. No. 20 were added.
Then a few months ago it became impossible to obtain adequate amounts of the grade of titanium dioxide which had been used for years in preparing the suspension. A new supplier of titanium dioxide was found and a different grade of titanium dioxide was substituted for that which had been used in the past. With the new grade of titanium dioxide it was no longer possible to prepare a suitable suspension having a viscosity within the range required for effective additions to gelatin solutions. And, when a mixture of the titanium dioxide and the gelatin solution was accomplished, the capsules produced therefrom were grainy and reflected light unevenly. It was learned that, even though an analysis of the particle size of the two grades indicated a similar range of sizes, an average of about 1 micron, one grade, the longused quality, was specified as an oil dispersible material, whereas the newer material was categorized as a water dispersible grade. This classification was supported by the fact that a 25 percent aqueous suspension of the so-called oil dispersible grade had a viscosity of between 1,400 and 2,200 centipoises at 25.degree. C., and a similarly prepared aqueous suspension of the water dispersible grade had a viscosity of about 3 centipoises at 25.degree. C. It was also found that the water dispersible grade of titanium dioxide had a zeta potential of about -35 millivolts whereas the oil dispersible material had exhibited a zeta potential of -17 to -27 millivolts.
Accordingly, it is an object of this invention to provide a pharmaceutical suspension of titanium dioxide of either oil or water dispersible grades that can be admixed with gelatin solutions for manufacturing empty opaque capsules of consistent quality.
Another object of this invention is to provide a process for preparing a pharmaceutical suspension of titanium dioxide utilizing either oil or water dispersible titanium dioxide, said suspension being for use in admixing with gelatin solutions for manufacturing empty opaque capsules of consistent quality.
Still another object of this invention is to provide a pharmaceutical suspension of titanium dioxide of whatever source or grade that resists caking and settling of the dispersed phase and which, after dead storage for a year or more, can be readily re-suspended by simple shaking or stirring.