Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1994-03-28
2004-01-13
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S486000, C424S487000
Reexamination Certificate
active
06677362
ABSTRACT:
BACKGROUND OF THE INVENTION
The bioavailabilities of many poorly water soluble drug entities are limited by their dissolution rates which in turn are governed by the particle size and hence the specific surface area and/or the polymorphic state of the active ingredient. At times, these problems are overcome by particle size reduction. There are cases, however, where the dissolution rates of the drug are not favorable enough to improve its bioavailability. Therefore, techniques such as lyophilization, solvent deposition, solvate formation and solid dispersion have been employed to improve the absorption of drugs.
A solid dispersion is a pharmaceutical formulation which may be defined as “a dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by melting the two (fusion), dissolving them in a solvent, or a combination of approaches, i.e., a quasi melting-solvent method”. The solvent-based process uses organic solvents to dissolve and intimately disperse the drug and carrier molecules. The process is relatively difficult. Identification of a common solvent for both drug and carrier is a tedious exercise, and complete solvent removal from the product is, if at all possible, a lengthy process. In addition, the volume of solvents required is excessive, and the cost of solvent recovery systems is prohibitive. The drug and carrier are dissolved in a solvent such as methylene chloride, acetone, ethanol and mixtures thereof and the solvent is later removed by evaporation or the like while the drug/carrier solid dispersion is collected as a powdered mass. Not only is the process lengthy and expensive, but the use of organic solvents renders it hazardous and toxic as well.
The second process for the manufacture of pharmaceutical dispersions involves fusion of the two components where the drug and the carrier are allowed to melt at temperatures at or above the melting point of the drug. In the fusion process, the drug and carrier are first blended and melted in a suitable mixer. The molten mixture is then cooled rapidly to provide a congealed mass which is subsequently milled to produce a powder. The fusion process is technically simple provided that the drug and carrier are miscible in the molten state but this is not always the case and furthermore, the process is limited in that it tends to lead to drug decomposition due to the high temperatures required to melt the two components.
A third method that is used to produce a solid dispersion when there is difficulty with thermal instability and immiscibility between the drug and the carrier is the hybrid fusion-solvent method. The drug is first dissolved in a small quantity of organic solvent and added to the molten carrier. The solvent is then evaporated to generate a product that is subsequently milled to produce a powder. The pharmacokinetics, dissolution rates and processes for formulation of many different solid pharmaceutical dispersions is discussed at length in an article by Ford, J., in Pharm. Acta. Helv. 61, 3; 69-88 (1986).
It is an object of the present invention to describe a novel manufacturing process for a solid pharmaceutical dispersion which obviates the need for organic solvents, elevated melting temperatures or the use of both. In particular, it is an object of the present invention to produce a solid pharmaceutical dispersion by incorporating in the formulation a solubilizer/plasticizer which acts as a vehicle to reduce the transition temperature by partially solubilizing the drug and/or plasticizing the polymer. This is particularly useful in the formulation of solid pharmaceutical dispersions for drugs that decompose at or near their melting temperatures.
U.S. Pat. No. 4,803,081 to Falk et al. discloses an extended release preparation of an active compound with very low solubility wherein the compound is dispersed in a liquid or semi-solid non-ionic solubilizer such as esters and ethers of polyethylene glycols. The solubilized drug is then combined with a hydrophilic gel system which controls the release of the drug and solubilizer at a constant even rate.
U.S. Pat. No. 4,689,235 to Barnes et al. discloses an extrudable encapsulation matrix which improves the loading capacity for oils, flavors, pharmaceuticals and the like. The matrix is comprised of maltodextrin and hydrogen octenylbutanedioate amylodextrin or its equivalent. The formulation improves the extrusion processability of the drug and enables high levels of active agent to be incorporated into the dosage form.
U.S. Pat. No. 4,678,516 to Alderman et al. teaches the formation of sustained release dosage forms utilizing a gel matrix comprised of hydroxypropyl methyl cellulose (HPMC) and a major amount of a plasticizer in which the active pharmaceutical is dispersed. Suitable plasticizers include low molecular weight polyols such as ethylene glycol, propylene glycol, polyethylene glycol and the like. The plasticizer is employed to render the matrix thermoformable and comprises a major amount thereof, i.e., at least 30%. The active agent must be heat stable however, so that it is capable of being heated to a temperature sufficient to prepare a gel matrix from the HPMC and the plasticizer without being rendered inactive.
PCT Appln. No. WO 83/00091 teaches the formulation of a polymeric diffusion matrix for the sustained release of water insoluble cardiovascular drugs such as 5-[(3,4-dimeth-oxyphenyl ethyl)methylamino]-2-(3,4 dimethoxyphenyl)-2-isopropyl valeronitirile. The matrix is comprised of a polar plasticizer, polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) in ratios of about 2:1:1 respectively. The cardiovascular pharmaceutical matrix is particularly useful in transdermal formulations wherein the drug is delivered at a constant sustained rate across the skin.
The present invention does away with the need for elaborate chemical matrices and increases the bioavailability of water insoluble drugs through the formation of a solid pharmaceutical dispersion. The dispersion is formulated without the need of using organic solvents or melting temperatures of drugs (fusion) which would otherwise decompose many drugs which do so at or near their melting temperature.
SUMMARY OF THE INVENTION
The present invention is a novel pharmaceutical solid dispersion and the process for its preparation whereby generally water insoluble drugs are combined with a carrier polymer such as polyvinyl pyrrolidone (PVP) without the need for organic solvents and/or high fusion temperatures. The process utilizes a vehicle such as polyethylene glycol which reduces the transition temperature and facilitates the molecular interaction between the drug and a polymer such as, polyvinyl pyrrolidone (PVP) by partially solubilizing the drug and/or plasticizing the polymer. This allows for a continuous and well controlled processing mode of manufacture.
DETAILED DESCRIPTION OF THE INVENTION
The solid pharmaceutical dispersions of the present invention increase the bioavailability of various water insoluble drugs by increasing their dissolution rates which in turn produce increases in both the rates and extent of the drugs absorption. Hence, the dosage of many solid dispersed drugs can be decreased and it is also believed that due to the increased dissolution and associated rapid absorption may reduce the proportion of the drug that is metabolized presystematically.
Nearly any water-insoluble drug may be formulated in the practice of the present invention so as to increase its solubility and hence its bioavailability. Drugs that are particularly useful in the practice of the present invention are those that decompose at or near their melting temperature since these certainly cannot be formulated into solid pharmaceutical dispersions using the fusion method. Suitable pharmaceuticals include, but are not limited to acetohexamide, ajamaline, amylobarbitone, bendrofluozide, benzbromarone, benzonatate, benzylbenzoate, betamethasone, chloramphenicol, chlorpropamide, chlorthalidone, clofibrate, corticesteroids, diazepam, dicumerol, digitoxin, d
Fawzi Mahdi B.
Ghebre-Sellassie Isaac
Nesbitt Russell U.
Parikh Riten
Reisch, Jr. Robert
Ashbrook Charles W.
Russo Matthew J.
Travers Russell
Warner-Lambert & Company
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