Formulation development topical formulations

Regardless of the cause, the mainstay of treatment for dry eye is artificial tears. Artificial tears augment the tear film topically and provide relief. If a patient uses artificial tears more than four times daily, recommend a preservative-free formulation. Preservative-free formulations are also appropriate if the patient develops an allergy to ophthalmic preservatives. Artificial tears are available in gel, ointment, and emulsion forms that provide a longer duration of relief and may allow for less frequent instillation. Ointment use is appropriate at bedtime.30... 

Rifaximin is broad-spectrum antibiotic, which covers many skin pathogens, whose lack of transcutaneous absorption has been well documented by both animal [8] and human [9] studies. On these grounds, a topical formulation (i.e. cream) containing 5% of the active compound was developed and tested in the treatment of pyogenic skin infections. Some open trials [20, 21] showed the efficacy and safety of the formulation and pointed out the lack of selection of resistant strains after topical application of rifaximin. In any event, drug delivery from the topical formulation is orders of magnitude higher than the... 

Composition (E), (Figure 1, R=Ci2H25) had many of the sought-after attributes however, border line saline compatibility in topical formulations was viewed as a weak point. By contrast, composition (F) had the same desirable features with the added advantage of saline compatibility in formulated products. Therefore, composition (F) became a leading candidate for topical contraceptive development. 

Penciclovir is approved as a topical formulation for the treatment of herpes labialis. In immunocompetent individuals, penciclovir shortens the duration of lesion presence and pain by approximately half a day when it is initiated within an hour of lesion development and applied every 2 hours during waking hours for 4 days. 

The objective of this chapter is to show how the concepts of chemical kinetics can be applied to the passage of molecules across the skin. The barrier function of the skin is still not totally understood but application of kinetic principles has allowed us to gain a better understanding of the barrier and how penetration enhancers may modulate it. The application of kinetics has allowed a mechanistic interpretation and therefore the development of predictive models. These can assist in the identification and design of novel transdermal drugs, and in the optimal design of topical formulations. 

There are many high-molecular-weight, polypeptide, elastase inhibitors which have been isolated from animal or plant sources. Most of these, the non-human proteins, would probably induce an immunogenic response and are not suitable for clinical development. However, a subset of these inhibitors, predominantly human in origin, is being explored as a source for clinically-useful elastase inhibitors. Each of the human compounds is found in a specific location, which probably is its primary site for inhibitory action. The physical properties of many of these natural inhibitors have been reported (see Table 2.i)[45-51]. Due to their size and other physical properties, only intravenous or topical formulations of the proteinaceous inhibitors have been considered for clinical use. The pharmacological studies have included natural inhibitors, recombinant variants (i.e. peptides with identical sequences to the natural inhibitors but not necessarily the same glycosylation) and recombinant mutants (peptides with unnatural sequences) [52],... 

Although not strictly developed for pharmaceutical formulation, this system has been included since it is the only one known for formulating topicals. It was developed to assist formulators in the formulation of sun care products—a highly skilled occupation requiring 3-4 years of experience to attain a reasonable level of experience. 

Tetracaine is a highly lipid-soluble, potent aminoester. It is primarily used as a constituent of many different topical formulations and for spinal anesthesia. It is four times as potent as lidocaine, and unless great caution is taken in dosage, serious systemic adverse effects can develop. 

For instance, fluticasone propionate is dosed topically to the lung via metered dose inhalers or dry-powder inhalers, and its high lipophilicity and low aqueous solubility are important for the drug s pharmacokinetic and pharmacodynamic profile [8, 9]. Models predicting solubility in specific formulations, or models predicting dissolution rate, may be useful in formulation development and drug delivery. 

Many oral solutions are intended for pediatric administration, of which oral solution formulations are a subset of a larger choice of formulation type such as suspension, syrup, powder or microcapsules for constitution to a suspension, powder for reconstitution to a solution or suspension, solid particles (powder, coated particles, extended release, enteric-coated granules, beads) in packets or capsules to be sprinkled on food, oral powders, and chewable tablets. The broader topic of pediatric formulation development is beyond the scope of this chapter, but this chapter will cover selected oral solutions for pediatric administration. 

Due to experimental and ethical concerns, development of topical formulations tends to utilise skin ex vivo in vitro) which inherently reduces some of the above noted complexity—regeneration stops, immune responses cease and metabolic activity is usually greatly reduced or lost in these studies. However, it should always be borne in mind that data obtained from excised skin may not translate directly to the in vivo situation. In particular, applying exogenous chemicals, such as solvents in a formulation, can induce immunological, histological and metabolic changes that may not be evident from in vitro studies. 

A choice of salts can also expand the formulation options for a material. The antimalarial agent a-(2-piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrene-methanol hydrochloride (Fig. 9) exhibited poor solubility, was delivered as an oral formulation, and required a single dosing of 750 mg (13). Seven salts and the free base were evaluated. The lactate salt was found to be 200 times as soluble as the hydrochloride salt (Table 3). This enhanced solubility would make it possible to reduce the oral dose to achieve the same therapeutic response as well as develop a parenteral formulation for the treatment of malaria. However, the case of lidocaine hydrochloride (Fig. 14) demonstrates that a compound limited to parenteral and topical formulations can be expanded to oral administration by changing to a salt form with acceptable physical properties (16). The hydrochloride salt was hygroscopic, difficult to prepare, and hard to handle. Six salts were evaluated for salt formation, solubility, and hygroscopicity. Other salts, such as phosphate, exhibited properties acceptable for dry pharmaceutical dosage forms. 

Based on these facts, in 1989, Fujisawa began to develop a topical formulation of tacrolimus to allow for the local treatment of immune-mediated dermatologic... 

Recently, Novartis has begun development of a new macrolide immunosuppressant, an ascomycin derivative (pimecrolimus ASM 981 Fig. 7), in a topical formulation of a 1% cream. Preliminary data presented at several international conferences suggest that it may have benefit in mild atopic dermatitis with a good safety profile, but definitive studies have not yet been published. 

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