Parenteral formulations sterility

As pharmaceutical scientists gain experience and tackle the primary challenges of developing stable parenteral formulations of proteins, the horizons continue to expand and novel delivery systems and alternative routes of administration are being sought. The interest in protein drug delivery is reflected by the wealth of literature that covers this topic [150-154]. Typically, protein therapeutics are prepared as sterile products for parenteral administration, but in the past several years, there has been increased interest in pulmonary, oral, transdermal, and controlled-release injectable formulations and many advances have been made. Some of the more promising recent developments are summarized in this section. 

Preservatives are necessary when developing multidose parenteral formulations that involve more than one extraction from the same container. Their primary function is to inhibit microbial growth and ensure product sterility throughout the shelf life or duration of use of the drug product. Commonly used preservatives include benzyl alcohol, phenol, and m-cresol. Although preservatives have a long history of use with small-molecule parenterals, the development of protein formulations that include... 

Aseptic Lltration is necessary for parenteral formulations. Because both lipids and the structure of liposomes are unstable at high temperatures, conventional terminal steam sterilization is not suitable for liposome formulations. Thus, the membrane aseptic Lltration is the most reliable method for sterilizing liposome formulations. Since the possibility exists for the membrane being defective, it is advisable to test the integrity of the assembled unit by carrying out a bubble-point test. This test... 

Routine parenteral administration by injection serves to deliver drugs to specific body tissues. The most important routes of injection of these sterile products are intramuscular (im), intravenous (iv) and subcutaneous (sc). Basic parenteral formulation involves the selection of appropriate bases (e.g. aqueous, oily and emulsions) to achieve the desired bioavailability following injection. The detailed description of... 

Liquid formulations for parenteral use require preparation methods and composition that make the formulation stable and sterile. Other requirements for parenteral formulations are given by the European Pharmacopoeia such as tonicity, efficacy of the antimicrobial... 

This chapter gives an overview of parenteral dosage forms and the rational for their use. Parenterals are sterile preparations that are injected intravascularly, administered into body tissues or into visceral cavities. The parenteral route of administration is often chosen for active substances that are poorly absorbed via the oral route or when rapid systemic availability and effects are required, or both. An introduction to the formulation and preparation of parenteral dosage forms is provided. Parenteral medicines can be formulated as solutions, emulsions or suspensions. Products, such as implants and microspheres are only briefly discussed. Knowledge about these types of products is a prerogative for the sound education of patients and caregivers in using the products. 

As SLN are of particular interest for parenteral administration, sterility of the formulations is an important issue. The common method for the sterilization of aqueous systems is autoclaving. Sterilization is also possible by filtration of the formulation through a 0.2 f/m membrane filter. However, this method is less safe and can only be applied for solutions or colloidal dispersions with appropriately small particles. ... 

Sterility. Sterility is largely a concern to be answered in the process of preparing a final clinical formulation, and it is not addressed in detail in this chapter. However, it should be clear that it is essential that no viable microorganisms are present in any material to be parenterally administered (except for vaccines). 

The drug is commercially available as the acetate ester, being esterified at the hydroxy methyl group (at C21). It is formulated as oral tablets (dosage strengths of 5 mg, 10 mg, and 25 mg), or as a parenteral sterile suspension (50 mg/mL) for intra-muscular administration. 

Some of the dosage formulations available for protein pharmaceuticals are listed in Table 5.7. An examination of Table 5.7 reveals that no protein drug up until this time has been formulated for oral administration. Most protein drugs are administered by means of injection (parenteral administration). Parenteral administration includes intravenous, intra-arterial, intracardiac, intraspinal or intrathecal, intramuscular, intrasynovial, intracuta-neous or intradermal, subcutaneous injections, and injection directly into a dermal lesion (e.g., a wart). The parenteral route of administration requires a much higher standard of purity and sterility than oral administration. It also may require trained... 

As discussed in Chapter 5, most biotechnology products (i.e., proteins and peptides) are formulated in sterile solution or suspensions designed for injection. A survey of the biotechnology products available in the United States reveals that over 90% of protein and peptide drugs are designed for parenteral administra-... 

SpeciLc problems exist with parenteral manufacture the most obvious being the need to ensure sterility. It is necessary to assess the effect that a heat sterilization process will have on a drug (e.g., pKg shift on heating) and on the formulation. Certain solubilization systems such as emulsions may not be suitable for autoclaving. 

Preservatives In addition to those processing controls mentioned above (Section 3.1.4.3), the sterility of a product may be maintained through the addition of antimicrobial preservatives. Preservation against microbial growth is an important aspect of multidose parenteral preparations as well as other formulations that require preservatives to minimize the risk of patient infection upon administration, such as infusion products [52], Aqueous liquid products are prone to microbial contamination because water in combination with excipients derived from natural sources (e.g., polypeptides, carbohydrates) and proteinaceous active ingredients may serve as excellent media for the growth [57], The major criteria for the selection of an appropriate preservative include efficiency against a wide spectrum of micro-... 

To get a better idea of how to formulate the nanosized emulsion delivery systems suitable for parenteral, ocular, percutaneous, and nasal uses, the reader is referred to more detailed descriptions of methods of nanosized emulsion preparation [6, 116], A hot-stage high-pressure homogenization technique or combined emulsification technique (de novo production) is frequently employed in order to prepare nanosized emulsions with desired stability even after subjection to autoclave sterilization. Therefore, the steps involved in this technique in making blank anionic and cationic emulsions were arranged in the following order ... 

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