Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2001-06-21
2004-01-27
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C264S004100, C264S004300, C264S004600
Reexamination Certificate
active
06682758
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a drug delivery system for water-insoluble drugs, in particular, 17-allylaminogeldanamycin and carboxyamidotriazole, to a method of delivering a drug to a host, and to a pharmaceutical composition comprising such a drug delivery system.
BACKGROUND OF THE INVENTION
Difficulties exist in developing safe and sterile intravenous formulations of sparingly water-soluble (i.e., water-insoluble) compounds. One such compound is 17-allylaminogeldanamycin (17-AAG) which is under development for clinical use as an anticancer agent because of its unique mechanism of action as a modulator of HSP-90. This compound was selected for clinical studies based on its in vitro activity against chemorefractory tumor and novel biological actions. Its effect on the depletion of the erB-2 gene product p185 has been reported (Miller et al.,
Cancer Res.,
54, 2724-30 (1994)). Another such compound is carboxyamidotriazole (CAI) which is currently under development for clinical use as an antitumor agent based on its antiangiogenic and antimetastatic effects.
Delivery systems for water-insoluble compounds have been developed using lipid vesicles and oil-in-water type emulsions (Ogawa et al., U.S. Pat. No. 5,004,756; Tabibi et al., U.S. Pat. No. 5,039,527, Cotter, U.S. Pat. No. 5,461,037; Lundquist, U.S. Pat. No. 5,660,837, Tabibi et al., U.S. Pat. No. 5,672,358, Sanofi et al., French Patent Application No. 2,609,631, Waranis et al., European Publication No. 0,648,494). However, these formulations require complicated processing steps, and the presence of non-aqueous solvents such as dimethylsulfoxide (DMSO) causes physical instability in the formulation. For example, the complete removal of organic solvent in the processing of the liposomes has been reported to be very important to the stability of the vesicles of some systems (Vemuri et al.,
Acta Helvetica
, 70(2), 95-111 (1995); see also Love, European Publication No. 0,720,853). Other methods are said to require high-speed homogenization of the phospholipids with the active ingredient followed by complete evaporation of the organic solvent with vigorous stirring to achieve optimal entrapment of the active ingredient (Xu et al.,
Pharm. Research
, 7(5), 553-57 (1990)). Likewise, it has been demonstrated that the addition of organic solvents to oil-in-water type emulsions causes the oil droplets to coalesce, resulting in instability (Li et al.,
Pharmaceutical Research
, 10(4), 535-41 (1993); see also Rosenburg et al., German Publication No. 4,125,255, requiring the immediate delivery of a liposomal formulation upon addition of the active agent).
Thus, there is a need for a more satisfactory delivery system for water-insoluble drugs. The present invention provides such a drug delivery system that incorporates an organic solvent, desirably without adversely affecting the physical stability of the surfactant within the aqueous medium. The present invention also provides methods of preparing and using such a drug delivery system. These and other benefits and advantages of the present invention will be apparent from the description of the present invention herein.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a drug delivery system comprising a water-insoluble drug, a water-miscible organic solvent for the water-insoluble drug, a surfactant, and water, wherein the water-insoluble drug is dissolved in the water-miscible organic solvent that forms a continuous phase with the water that contains the surfactant. The present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the drug delivery system of the present invention. In addition, the present invention provides a method of delivering a drug to a host by administering the drug delivery system of the present invention to the host.
The present invention also provides a process for the preparation of a drug delivery system comprising (a) providing a drug solution comprising a water-insoluble drug and a water-miscible organic solvent for the water-insoluble drug, (b) providing a surfactant solution comprising a surfactant and water, and (c) combining the drug solution and the surfactant solution to provide a drug delivery system.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a drug delivery system for water-insoluble compounds, in particular, a drug delivery system for 17-AAG and CAI, and methods of preparing and using such a drug delivery system.
For the purposes of describing the present invention, the term “drug” means any compound which is biologically active, e.g., exhibits a therapeutic or prophylactic effect in vivo, or a biological effect in vitro. The term “water-insoluble” as used in conjunction with the present invention encompasses the terms sparingly water-soluble, slightly or very slightly water-soluble, and practically or totally water-insoluble compounds (
Remington: the Science and Practice of Pharmacy
, vol. I, 194-195 (Gennaro, ed., 1995)). A compound is water-insoluble for the purposes of this invention if it requires at least 30 parts solvent to dissolve one part solute (Id.). The term “water-miscible” as used in conjunction with the present invention means susceptible of being mixed with, and forming a continuous phase with, water. The term “isotonizing agent” is used to refer to any compound or composition capable of changing the osmotic pressure of a solution. Concentrations expressed as “percent weight in volume” (% w/v) refer to the number of grams of solute in 100 ml of solution. The term “particle size” is used in the context of the present invention to refer to the average diameter of particles, e.g., lipid vesicles, in a suspension.
Drug Delivery System
The drug delivery system of the present invention is comprised of a water-insoluble drug, a water-miscible organic solvent for the water-insoluble drug, a surfactant, and water. The water-insoluble drug is dissolved in the water-miscible organic solvent. The water-insoluble organic solvent forms a continuous phase with the water, which water contains the surfactant. The drug delivery system provided by the present invention is physically and chemically stable. Thus, the components of the system will not micro-crystallize or precipitate when stored at approximately 20° to 30° Celsius for up to 24 hours.
Any water-insoluble drug, or combination of drugs including at least one water-insoluble drug, can be used in conjunction with the present invention. Suitable drugs include antihypertension drugs, antibiotic drugs, and anticancer or antitumor drugs. The present invention is particularly useful with the water-insoluble drugs geldanamycin, especially 17-AAG, and CAI.
Any suitable water-miscible organic solvent can be used in conjunction with the present invention. Selection of a suitable organic solvent will depend in part upon the solubility of the particular drug in the solvent, the degree to which the solvent is miscible in water, and the toxicity of the solvent. The solvent desirably is physiologically acceptable. Examples of solvents that may be used in conjunction with the present invention include, but are not limited to, dimethylsulfoxide (DMSO), dimethylacetamide (DMA), dimethylformamide, various alcohols such as ethanol, glycols, glycerin, propylene glycol, and various polyethylene glycols. It is preferred that the solvent be DMSO or DMA.
Any suitable surface active agent (surfactant) can be used in the context of the present invention. The surfactant desirably is physiologically acceptable. Physiologically acceptable surfactants are generally known in the art and include various detergents and phospholipids. It is preferred that the surfactant is a phospholipid such as, but not limited to, an egg phospholipid, a vegetable oil phospholipid such as a soybean phospholipid, or phosphatidylcholine. Most preferably, the surfactant is an egg phospholipid.
The surfactant is typically present in a concentration of about 0.5-25% w/v based on the amount of the water and/or othe
Ezennia Emmanuel I.
Gupta Shanker
Tabibi S. Esmail
Vishnuvajjala B. Rao
Kishore Gollamudi S.
Leydig , Voit & Mayer, Ltd.
The United States of America as represented by the Department of
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