Parenteral formulations poorly soluble drugs

Technological advances in both biotechnology and molecular biology have yielded a surge in the number of new chemical entities that are produced to treat specific diseases or ailments. However, a growing portion of these new chemical entities display poor aqueous solubility, leading to poor oral bioavailability and an inability to form intravenous formulations. Nanoparticle formation has been proposed and utilized as a method to improve oral bioavailability of poorly soluble drugs and as a method for delivery of particles via parenteral, pulmonary, and topical administration. 

Dimethylacetamide is used as a solvent in oral and injectable pharmaceutical formulations. It has been used as a cosolvent to solubilize poorly soluble drugs. The use of dimethylacetamide has also been investigated as a vehicle for the parenteral delivery of relatively small peptides. ... 

One of the main problems associated with developing a parenteral or any other solution formulation of a compound is its aqueous solubility. For poorly soluble drug candidates, there are several strategies for enhancing their solubility. These include pH manipulation, cosolvents, surfactants, emulsion formation and complexing agents. More sophisticated delivery systems, e.g., liposomes, can also be used in this way. 

The biological interest of acronycine was revealed in 1966 by Svoboda at the Eli-Lilly Laboratories (27, 28). Acronycine was found to be active against a broad spectrum of solid tumors including sarcoma, myeloma, carcinoma and melanoma. In contrast, it only exhibited poor activity against leukemias. The activity against X-5563 myeloma was of particular interest, since this plasma cell tumor has several properties that relate to those of multiple myeloma in human patients. This is the reason why Scarffe in 1983 (29) performed phase I-II clinical evaluation of acronycine in patients with refractory multiple myeloma. Oral acronycine capsules produced one clear response in sixteen patients. The remission was maintained 72 weeks, using daily dose of 300 mg/m. The limited success of that trial is probably related to the moderate potency of acronycine and to its very low water-solubility (cfl. 2-3 mg per liter of water) which do not permit an efficient parenteral formulation of the drug. 

Though povidone is used in a variety of pharmaceutical formulations, it is primarily used in solid-dosage forms. In tableting, povidone solutions are used as binders in wet-granulation processes. Povidone is also added to powder blends in the dry form and granulated in situ by the addition of water, alcohol, or hydroalcoholic solutions. Povidone is used as a solubilizer in oral and parenteral formulations, and has been shown to enhance dissolution of poorly soluble drugs from solid-dosage forms. 

Benzoic acids substituted with a basic side chain also are also of interest as pro-moieties whose physicochemical properties and rates of enzymatic hydrolysis can readily be modulated. A number of drugs have been converted to prodrugs with this type of pro-moiety, e.g., hydrocortisone, prednisolone, acyclovir, chloramphenicol, and paracetamol [148] [149], These prodrugs appear well suited as parenteral formulations, being water-soluble, stable in slightly acidic solution, and readily hydrolyzed enzymatically. As examples, we consider here the hydrolysis in human plasma of a number of (aminomethyl)ben-zoates of metronidazole (8.109-8.115, Sect. 8.5.5.1, Table 8.9) [138], These prodrugs are very rapidly activated, which may be beneficial for parenteral administration. However, this type of pro-moiety may be cleaved too rapidly after oral administration to be of interest for poorly absorbed drugs. 

ME systems intended for parenteral application have to be formulated using nontoxic and biocompatible ingredients. The o/w ME systems would be suitable to improve the solubility of poorly water soluble drug molecules whereas w/o ME systems would be best suited for optimizing the delivery of hydrophilic drug molecules that are susceptible to the harsh GI conditions. Moreover, w/o systems can serve to prolong the release and mask any potential tissue irritation and site toxicity that are caused by intramuscular (i.m.) administration of hydrophilic drug molecules. 

The aqueous solubility of a drug in the 2-8 pH range has a direct influence on its oral and parenteral formulations. A drug with poor solubility (i.e., less than O.lmg/ml) in acidic media may show poor and erratic oral bioavailability due to the dependency of absorption processes in GI fluids. Intravenous dosing requires that the drug be administered in a soluble form. The adjustment of pH, the addition of a cosolvent or a ligand for complexation, or the formation of an emulsion may permit solubilization, but each of these techniques has limitations. Rapid intravenous... 

In pharmaceutical preparations, soybean oil emulsions are primarily used as a fat source in total parenteral nutrition (TPN) regimens. Although other oils, such as peanut oil, have been used for this purpose, soybean oil is now preferred because it is associated with fewer adverse reactions. Emulsions containing soybean oil have also been used as vehicles for the oral and intravenous administration of drugs drug substances that have been incorporated into such emulsions include amphotericin, " diazepam, retinoids, vitamins, poorly water-soluble steroids, fluorocarbons, and insulin. In addition, soybean oil has been used in the formulation of many drug delivery systems such as liposomes, microspheres, dry emulsions, self-emulsifying systems, and nanoemulsions and nanocapsules. ... 

Apart from the already established formulations, researchers are trying to develop novel oil-based formulations to combat the poor solubility and bioavailablity of NCE. Shevachman et al. developed novel U-type microemulsions to improve the percutaneous permeability of diclofenac. Shah et al.2 2 used microwave heating for the preparation of solid lipid nanoparticles by microemulsion techniques, which resulted in improved particle characteristics. Ki et al. reported sustained-release liquid crystal of injectable leuprolide using sorbitan monooleate. Recently, various novel oil-based drug delivery technologies are reported, which includes tocol emulsions, solid lipid nanopar-ticles, nanosuspensions, Upid microbubbles, sterically stabilized phospholipid micelles, and environmentally responsive drug delivery systems for parenteral administration.25 259... 

Vries et al. [3.59] described the development of a stable parenteral dosage form of the cytotoxic drug E 09. E 09 dissolves poorly in water and its solution is unstable. With the addition of 200 mg of lactose per vial containing 8 mg of E 09, an optimum formulation was developed with respect to solubility, dosage of E 09 and length of the freeze drying cycle. DSC studies have been used to select the most effective parameters. The freeze dried product remains stable for 1 year when stored at 4 °C in a dark environment. 

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