Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-01-03
2003-09-09
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C424S752000, C424S755000, C424S757000, C424S764000, C514S023000, C514S060000, C514S561000, C514S563000, C514S613000, C514S634000, C514S665000, C514S709000, C514S711000, C514S770000, C514S777000, C514S778000, C514S783000, C514S944000, C514S969000
Reexamination Certificate
active
06617356
ABSTRACT:
The present invention relates to a new drug delivery system, a method for suspending both water insoluble and water intolerant materials in edible oils and products based thereon which are stable over prolonged periods of time and are well suited as for oral and topical administration. The method of the invention has particular advantage when the material involved undergoes changes disadvantageous to its intended application on direct exposure to water. Such materials include creatine, various Lactobacillus species, herbal products, vitamins, etc. It is therefore desirable to have a product which can be delivered in its active state without the use of water in its preparation, which is stable, readily taken up by the body and provided in practical concentrations.
The drug delivery system of the invention comprises an edible oil to which a gelling agent, such as silicon dioxide is added. This system allows for uniform suspensions of the active agent, facilitating drug delivery as well as in some instances regulating the rate of drug delivery. The active agent is incorporated into the oil-gelling agent preparation providing formulations for therapeutic use.
The method of the invention comprises a series of steps whose sequence can be varied. In accordance with one embodiment of the invention, the active material is introduced into the vegetable oil under conditions for forming a uniform dispersion, emulsion or suspension and then a silica product, namely silicon dioxide is introduced to form a pourable gel again under conditions whereby a stable uniform thickened suspension of the active material in the gel will result. Alternatively the silica dioxide can be added to the oil, and the active material then introduced into the thickened mixture to form the suspension of the active material in the carrier gel.
The edible vegetable oils suitable for use herein include soybean, corn, orange and citrus oils, cottonseed, olive oil, peanut oil, sunflower oil, safflower oil, coconut oil, canola oil, palm kernel oil, palm oil. Mineral oils of varied molecular weights can also be used for some preparations. Mineral oil is a standard ingredient in commercially available creams, ointment-type bases, as for example available from Schering and is frequently used in topical drug delivery systems. Mineral oil can also be used for oral ingestion. It has the advantage of being non-caloric and is without toxicity unless taken in large doses. The vegetable oils mentioned are known food, nutritional supplement and drug components and are especially suitable for use in the invention. Natural gums such as acacia or tragacanth can be added to the combination of oil, active ingredient and silica product primarily to aid in suspension of the insoluble pharmacologically active or nutritional supplement substance in the oil. Substances such as synthetic mucilagenous materials including polyvinyl alcohol, methyl cellulose and carboxymethyl-cellulose can be used in a similar manner to the natural gums. The synthetic gums have the advantage of not being glycogenetic. The colloidal character and viscosity of the gums contribute further towards preventing sedimentation of the suspended agents.
The dispersions or suspensions of the invention can be prepared by dispersing the silicon dioxide product in the oil. As a rule, the dispersal step, e.g., treatment with a high angular speed agitator, and the active ingredient then dissolved or dispersed in the gel formed after the initial dispersal step. The second dispersal step can be carried out using the same stirrer, or other conventional type homogenizing or emulsifying equipment. A suspension of the active agent in the pourable gelled oil is thus formed. This suspension has a suitably long shelf life and can be used directly for its application. When administered perorally, this suspension is used in a manner consistent with the type of effective substance present, the amount of effective substance present and the therapeutic dose which is commonplace for such administration. It is also possible to reverse the sequence by forming first the dispersion of active ingredient in the oil, followed by a second dispersal step in which the silicon dioxide is introduced and distributed forming the gelled product.
In accordance with one embodiment of the invention the silica product can be added in increments so that a first amount is added to the oil suspension and then a second amount of silica product, preferably silicon dioxide, introduced again under conditions for ensuring the formation of a stable thickened suspension of the active material in the gel.
A thixotropic gel is formed through the mechanism of hydrogen bonding between the silica and active materials added. The gel suspends the ingredients that would normally precipitate or settle out. The resultant stable suspensions contain the active material in discrete amounts in unaltered form. The gel suspensions are suitable for oral and topical administration and can be use per se or with the addition of the conventional adjuvants, colorants, flavorants etc.
Silicon dioxide or fumed silica the preferred gelling agent is characterized by extremely small particle size, its enormous surface, high purity and its chain forming tendencies. Silicon dioxide is produced by the vapor phase hydrolysis of silicon tetrachloride in a hydrogen-oxygen flame. The combustion process creates silicon dioxide molecules which condense to form particles. The particles collide, attach and sinter together resulting in a three-dimensional branched chain aggregate. Once the aggregates cool further collisions result in mechanical entanglement of the chains, termed agglomeration. The resulting white powder is of agglomerate size of less than 325 US mesh (44 microns).
The surface chemistry of silicon dioxide is extremely important especially in relation to its ability to thicken non-polar and semi-polar liquid systems. During the preparation of silicon dioxide, hydroxyl groups become attached to some of the silicon atoms of the particle surface making it hydrophilic and capable of bonding with suitable molecules of material in vapor, liquid or solid form. The surface OH groups are capable of forming H bonds between silicon dioxide aggregates. This network increases the viscosity of the system and produces thixotropic behavior. Thixotropic behavior is the time dependent recovery of viscosity after shearing (shearing forces due to mixing). The viscosity decreases in proportion to the length of time of mixing or the intensity of the mixing. Once the shearing force has been removed, the bonds rebuild over time and the viscosity approaches its original value. The presence of these OH groups is the key to the mechanism through which silicon dioxide is able to perform many of its functions. The most important and widespread use of silicon dioxide in liquid systems is for the control and increase of viscosity and thixotropy. A major determinant of the effect of silicon dioxide will produce in any system is the nature of the solvent or suspending material used. Network formation is determined to a large degree by the capability of the solvent or suspending agent to participate in the formation of hydrogen bonds. Heretofore this capacity of silicon dioxide has not been applied to the thickening of oils or for the purpose of producing stable suspensions of water-soluble, water insoluble and water intolerant drugs and supplements suitable for oral and topical administration.
In accordance with the invention, the suspending medium can be grouped into three classifications. It is in the non-hydrogen-bonding systems (class 111) that silicon dioxide displays its greatest efficiency, the silica particle has no choice but to hydrogen bond with other silica particles and the greatest degree of network formation is achieved at the lowest concentration of silicon. Concentrations of 3% to 6% silicon dioxide by weight are usually sufficient to provide fairly thick gel formations, smaller concentrations will provide any viscosity required up to the stage of gelation. E
Bizub Dennis
Goodman Louis P.
Choi Frank
Hartley Michael G.
Sommer Evelyn M.
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