Parenteral formulations lyophilization

The antimykotie amphotericine is eneapsulated in liposomes and marketed as Am-Bisome" against severe systemic mycosis. The liposomal encapsulation reduces the toxicity of amphotericine while increasing the half-life of the drug and plasma level peaks [31], For stability reasons, the parenteral formulation is a lyophilized powder whieh has to be reeonstituted by adding the solvent just before administration. 

Benzyl alcohol is the most common antimicrobial preservative present in parenteral formulations (Table 5). This observation is consistent with other surveys. ° Parabens are the second most common preservatives. Surprisingly, thimerosal is also common, especially in vaccines, even though some individuals are sensitive to mercuries. Several preservatives can volatilize easily (such as benzyl alcohol, and phenol) and, therefore, should not be used for lyophilized dosage form. Chlorocresol is purported to be a good preservative... 

The amino acid histidine is used as a bulking agent for lyophilization and can additionally serve as a buffer (histidine/histidine hydrochloride) and stabilizer in the formulation (Nema et al., 2002). Histidine is a rather efficient quencher of singlet oxygen and a scavenger of hydroxyl radicals (Halliwell and Gutteridge, 1985). Thus, the presence of histidine in the parenteral formulation can be very important for the photochemical stability of the product. 

Protein-based drugs have been formulated mainly as stable liquids or in cases where liquid stability is limiting as lyophilized dosage forms to be reconstituted with a suitable diluent prior to injection. This is because their delivery has been limited primarily to the parenteral routes of intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration. There are a few drugs that have been developed for pulmonary delivery, such as rhDNase (Pulmozyme ) and an inhalable formulation of insulin (e.g., Exubra ). However, even such drugs have been formulated as either liquid or lyophilized or spray-dried powders. This chapter will focus only on excipients that are applicable to liquid and lyophilized protein formulations. 

Henrar, R.E.C., Kettenes-van den Bosch, J.J., Bult, A., Beijnen, J.H. Pharmaceutical development of a parenteral lyophilized formulation of the novel in-doloquinone antitumor agent E 09. Cancer Chemother. Pharmacol. 34, 416 122,... 

The first set of requirements that closures for lyophilized product containers must meet are those described for stoppers used in containers for parenteral drugs. They must serve as a barrier to microbial contamination, be compatible with the formulated drug product, and not leach out toxic materials. They must be tested in the prescribed manner for seal integrity and product capability. The reader is referred to sections in the United States, European, and Japanese pharmacopoeias for appropriate test methods for evaluating extractables. 

As a stabilizing agent, albumin has been employed in protein formulations at concentrations as low as 0.003%, although concentrations of 1-5% are commonly used. Albumin has also been used as a cosolvend for parenteral drugs, as a cryoprotectant during lyophilization, and to prevent adsorption of other proteins to surfaces. 

Trehalose is used for the lyoprotection of therapeutic proteins, particularly for parenteral administration. Other pharmaceutically relevant applications include use as an excipient for diagnostic assay tablets for stabilization during the freeze-thaw and lyophilization of liposomes and for stabilization of blood cells,cosmetics, and monoclonal antibodies. Trehalose may also be used in formulations for topical application. ... 

Nuijen B, Bouma M, Talsma H, Manada C, Jimeno JM, Lopez-Lazaro L, Bult A, and Beijnen JH. Development of a Lyophilized Parenteral Pharmaceutical Formulation of the Investigational Polypeptide Marine Anticancer Agent Kahalalide F. Drug Dev Ind Pharm 2001 27(8) 767-780. 

Parenteral dosage forms can be categorized as small-volume parenteral (SVP), large-volume parenteral (LVP), and lyophilized products. Three basic types of SVP formulations exist solution, suspension, and emulsion. The following aspects should be addressed to successfully formulate a parenteral dosage form (1) selection of a suitable vehicle (aqueous, co-solvent, or nonaqueous) (2) selection of formulation adjuvants, such as buffering agents. 

Polymeric micropsheres, particularly those prepared from the biodegradable polylactide/ polyglycolide polymers, have been widely investigated as a means to achieve sustained parenteral drug delivery. The advantage of formulating the polymeric matrix as microspheres is the ability to administer them via a conventional needle and syringe as a suspension formulation, rather than as an implant (see below). Lupron depot formulations are available which can provide therapeutic blood levels of leuprolide acetate for up to four months. These products are presented as lyophilized polylactic acid microspheres which are reconstituted to form a suspension prior to administration. 

FDA guidelines are in general directed more towards the required components of a registration dossier and do not offer much in the way of guidance to the formulator. One exception to this is the Guide to Inspection of Lyophilization of Parenterals this provides a useful indication of areas of specific interest to the FDA which the formulator would be well-advised to address during the development programme. 

B Nuijen, M Bouma, REC Henrar, P Floriano, JM Jimeno, H Talsma, JJ Kettenes-van den Bosch, AJR Heck, A Bull, JH Beijnen. Pharmaceutical development of a parenteral lyophilized formulation of the novel antitumor agent aplidine. PDA J Pharm Sci Technol 54(3) 193-208, 2000. 

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