Formulation considerations

The phenomenon of microemulsification is mainly governed by factors such as (1) nature and concentration of the oil, surfactant, co-surfactant and aqueous phase, (2) oil/surfactant and surfactant/co-surfactant ratio, (3) temperature, (4) pH of the environment and (5) physicochemical properties of the API such as hydrophilicity/lipophilicity, pl Ca and polarity. Hence, all these factors should be considered while formulating microemulsions. From a pharmaceutical perspective, one of the most important factors to be considered is acceptability of the oil, surfactant and co-surfactant for the desired route of administration. This factor is very important while developing micro emulsions for parenteral and ocular delivery as there is only limited number of excipients which are approved for the parenteral and ocular route. In Chapter 3 of this book a more general overview of formulating microemulsions is given and formulation considerations with respect to the components of microemulsions used in pharmaceutical applications are discussed below. 

Selection of an appropriate oil phase is very important as it governs the selection of the other ingredients of microemulsions (mainly in the case of o/w micro emulsions). Usually, 

General class Examples Commercial name Acceptability 

Medium-chain mono- Mono- and di-glycerides of Capmul MCM, Imwitor 742, on 

Long-chain Glyceryl monooleate Peceol, Capmul-GMO on 

Wu-Pong and Byron [15] have contributed a review of the issues associated with pulmonary delivery of ASOs. Since ASOs are freely soluble and highly hygroscopic, it would be reasonable to assume that initial dosage forms will rely upon the aerosolization of simple aqueous solutions. Our data indicate that commercially available nebulization devices will generate suitable aerosolizations of ASO solutions at concentrations up to 180 mg/mL [3]. Ultrasonic and jet nebulizations were found to have essentially no effect on the phosphorothioate stability of the ASO over 40 min, which is longer than typical treatment times. 

Depending on particle size, delivery may be primarily to the upper airways or to the alveoli [15, 16]. Particles with diameters of approximately 5-10 pm will generally deposit in the upper airways, while those in the range of approximately 0.5-5 pm approach the alveoli. Particles smaller than 0.5 pm are often exhaled, while particles larger than 10 pm are generally deposited in the oral capacity and subsequently swallowed. 

Dosea) [mg/kg] Time [h] Oligonucleotide total concentration [g/g tissue] % Intactb) 

The literature reviewed here show that both formulated and unformulated (simple aqueous solution) ASO can be delivered to the lungs, where they subsequently suppress local gene expression, opening a wide variety of diseases to antisense therapy. 

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Baluom, M., Friedman, M., Rubinstein, A., The importance of intestinal residence time of absorption enhancer on drug absorption and implication on formulative considerations, Int. J. Pharmaceut. 1998,... 

Stewart and Tucker assert that hydrolysis is affected by pH, buffer salts, ionic strength, solvent, and other additives such as complexing agents, surfactants, and excipients, and each of these factors is discussed in some detail. Waterman et al. (31) provide a comprehensive treatment of hydrolysis as it relates to pharmaceuticals, with thorough discussions of mechanisms, formulation considerations, pH, ionic strength, buffers, solid-state considerations, hydrolysis of lyophiles, liquid dosage forms, packaging, etc. 

This description of the development of 4 provides a good illustration of the fact that the availability of an active molecule is not the end of the drug development pathway, and that formulation considerations can be critical. In this case NMR played a significant role in understanding tautomeric processes that had a direct bearing on solubility and hence on formulation. 

A suspension of heavy inorganic particles in a liquid will settle the main question is how fast The densities of the liquids and solids are usually set by other formulating considerations, which dictate material choice. Particle size and viscosity of the liquid can be affected by process and formulation. 

Pharmacodynamic profile Onset and duration of action Required clinical effect Formulation considerations Stability Impurity profile... 

The following sections describe the source, physicochemical properties, formulation considerations, stability, incompatibility, storage, and hypersensitivity reactions of some of these bases. 

A concentrated (60% w/v) PFOB/PFDB emulsion (Oxygent AF0144) is currently being produced in a commercial-scale facility. The emulsion is steam-sterilized in a rotary autoclave at or above 121 °C, using a procedure that achieves uniform heat penetration, maintains emulsion integrity, and provides the required probability of less than one non-sterile unit in 10 . As compared to Fluosol, Oxygent is characterized by use of PFCs having some lipophilic character, use of phospholipids as the emulsifier instead of polox-amer, a several-fold increase in PFC concentration, simplification of the overall formulation, considerable increase in stability, and consequently, far superior convenience of use. 

Pfister WR, Hsieh DST. Permeation enhancers compatible with transdermal drug delivery systems. Part I Selection and formulation considerations. Pharm Technol 1990 14(9) 132—140. 

Maa Y-F, Prestrelski SJ. Biophannm cutical powders Particle formation and formulation considerations. Curr Pharm Biotech 2000 1 283-302. 

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