Parenteral formulations emulsions

Parenteral emulsion formulations for improvement in solubility, stability, local irritation or toxicity, and/or compatibility issues... 

Iron-deficiency anemia in chronic PN patients may be due to underlying clinical conditions and the lack of iron supplementation in PN. Parenteral iron therapy becomes necessary in iron-deficient patients who cannot absorb or tolerate oral iron. Parenteral iron should be used with caution owing to infusion-related adverse effects. A test dose of 25 mg of iron dextran should be administered first, and the patient should be monitored for adverse effects for at least 60 minutes. Intravenous iron dextran then may be added to lipid-free PN at a daily dose of 100 mg until the total iron dose is given. Iron dextran is not compatible with intravenous lipid emulsions at therapeutic doses and can cause oiling out of the emulsion. Other parenteral iron formulations (e.g., iron sucrose and ferric gluconate) have not been evaluated for compounding in PN and should not be added to PN formulations. 

During the past 30 years, there have been significant developments of parenteral disperse formulations. The use of parenteral emulsions can overcome the problems of low aqueous solubility and water hydrolysis of many drugs [184, 185]. Such formulations can avoid the use of conventional co-solvent systems and the undesirable effects caused by precipitation of drugs at the injection site. Recent developments of parenteral disperse formulations have the potential to provide sustained release and targeting of drugs [186-189],... 

Emulsifiers. Natural lecithin is one of the most widely used emulsifiers because it is metabolized in the body. However, type I allergic reaction to soybean lecithin emulsified in lipid solutions has been observed [195], Among the synthetic emulsifying agents, block copolymers of polyoxyethylene-polyoxypropylene (poloxamer) have attracted increasing interest for parenteral emulsions. Other examples of emulsifiers commonly found in parenteral formulations are given in Table 9 [190]. 

For parenteral emulsions, the formulation scientist must be particularly aware of changes in particle size distribution of the oil phase. Droplet coalescence results in increased droplet size. As a general rule, average droplet size should be less than 1 pm. Droplet sizes of more than 6 pm can cause blockage of capillaries (capillary emboli). 

Oner, F., Yalin, M, and Hincal, A.A. Stability and hemolytic effect of parenteral lorazepam emulsion formulations,FABAD J. Pharm. Sci, 20, 61-66, 1995. 

Atypical parenteral o/w emulsion is composed of lipid droplets (10-20%), emulsiLer, and osmotic agent it is administered by either intravenous (IV) bolus or IV infusion. In addition, when an emulsion formulation is packed in a multidose container, antimicrobial agents should be included in the formulation to prevent the growth of microorganisms. 

Conformance to one or more of the above criteria generally qualiLes development of an emulsion formulation for drugs that otherwise cannot be successfully administered parenterally as a solution. Hence, emulsions have been explored for improved drug efLcacy after oral, topical and parenteral administration, and for improved patient compliance (e.g., reduced pain or irritation after parenteral administration, and improved palatability after oral delivery). 

Flurbiprofen Park and Kim (1999) Solubilization in emulsion formulation reduces volume required for parenteral delivery... 

Linoleic acid is used in topical transdermal formulations, in oral formulations as an absorption enhancer, and in topical cosmetic formulations as an emulsifying agent. It is also administered in parenteral emulsions as a dietary supplement. 

Parenteral emulsions were first introduced to provide an IV source of essential fatty acids and calories. This has developed into the extensive and routine use of products such as Intraplipid, Lipofundin and Liposyn in total parenteral nutrition. There are relatively few commercially available emulsions containing active compounds the only example on the U.S. market is Diprivan Injectable Emulsion, the formulation of which is shown in Table 9.4. Diazepam is also available as an injectable emulsion on the UK market (Diazemuls ). For a more detailed discussion of the issues involved in developing parenteral emulsions, the reader is referred to Collins-Gold et al. (1990). 

All parenteral emulsions are oil-in-water formulations, with the oil as the internal phase dispersed as fine droplets in an aqueous continuous phase. An emulsifier, usually egg or soy lecithin, is needed to lower the interfacial tension and prevent flocculation and coalescence of the dispersed oil phase. Mechanical energy, usually in the form of homogenization, is required to disperse the oil phase into droplets of a suitable size. For IV administration, the droplet size should be below 1 p.m to avoid the potential for emboli formation. 

Clearly, physical stability is of critical importance for emulsion formulations, and care must be taken to ensure not only that the product itself is physically stable but that any infusion solutions which may be prepared by dilution of the emulsion are also physically stable over the required period of time. In addition, parenteral emulsions should be able to withstand the stresses associated with moist heat sterilization. Alternatively, if this cannot be achieved, it may be possible to prepare an emulsion aseptically from sterile components, provided the process can be suitably validated. For a good introduction to the formulation and preparation of IV emulsions, the reader is referred to Hansrani et al. (1983). 

Perrilla ketone Drug formulated in propylene glycol, ethanol, and water to be diluted in a parenteral emulsion before IV administration. IV administration in 5% dextrose led to loss of 20-60% drug by adsorption to the polyvinylchloride (PVC) of the infusion tubing. This problem was overcome in IV emulsion formulation... 

The ever-increasing demands on the performance of pharmaceutical formulations with respect to, e.g., storage stability, increased dosage levels, greater bioavailability, fewer side effects, controlled release, and biological response (e.g., tissue distribution) constitute the main motivation for drug delivery research. In the last few decades, this research has resulted in the development of, e.g., parenteral emulsions, liposomes with improved circulation in the bloodstream, cyclodextrins, and lipoprotein mimics for cancer therapeutics. 

Parenteral 0/W emulsion formulations have also been adapted to the delivery of hydrophilic or poorly lipophilic drugs by synthesizing lipophilic prodrugs or drug derivatives that can be located in the oil phase of the emulsion, as for instance ... 

The use of parenteral emulsions may be apparently useful in overcoming solubility and/or stability problems of selected drug substances for which intravenous formulations are desired and difficult to develop (8). Interest in this concept has increased significantly with the greater understanding of the processes involved in drug delivery both at the cellular and subcellular level. 

A wide variety of surface-active agents can be used to prepare emulsion formulations. This variety is tremendously narrowed in the case of parenteral formulations. One of the major obstacles is the hemolytic effect of the majority of emulsifiers, which excludes their use for intravenous application (49) as seen in Fig. 9. The emulsion droplet surface can be charged negatively or positively by the incorporation of charged emulsifiers or enriched with reactive groups to which ligands can be covalently linked. 

Administration of emulsions has been carried out by every conceivable enteral and parenteral route. The oral route is problematic since many emulsion formulations are rapidly destabilized in the gut following interactions with bile salts. 

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