Lyophilized dosage forms

Ikeda, M. Development of a multilayer lyophilization technique for parenteral dosage forms. PDA Asian Symposium, p. 261-266, Tokyo, 1994... 

Drug development, proteins in, 20 839 Drug discovery, yeasts in, 26 488 Drug dosage forms, 15 702-718 aerosols, IS 717 biotechnology and, IS 717-718 capsules, 15 708 granules, 15 702-705 liquid, 15 712-713 lyophilization, 15 716 ophthalmic, 15 716 parenteral, IS 713-716 prolonged action/controlled release solid, 15 708-712... 

Dosage form Leukine is formulated as a sterile, preserved, injectable solution (500pg/l) in a 1ml vial. Lyophilized Leukine is a sterile, preservative-free powder (250 pg) that requires reconstitution with sterile water for injection or bacteriostatic water for injection. 

Dosage form Neumega is available for injection in single-use vials containing 5 mg of oprelvekin as a sterile lyophilized powder. It is reconstituted by the addition of sterile water for injection. 

Dosage form BeneFix is formulated as a sterile nonpyrogenic, lyophilized preparation, intended for injection after reconstitution with sterile water for injection. It is available in single-use vials containing the labeled amount of factor IX activity, expressed in international units (lU). Each vial contains nominally 250,500, or 1000 lU of Coagulation Factor IX (Recombinant). 

Dosage form NovoSeven is supplied as a sterile lyophilized powder of coagulation... 

Dosage form Angiomax is available as a sterile lyophilized powder for injection after reconstitution with sterile water for injection. Each single-use vial contains bivalirudin 250 mg. 

Dosage form Proleukin is supplied as a sterile, lyophilized cake in single-use vials intended for injection on reconstitution with sterile water for injection. When reconstituted, each ml contains aldesleukin 18 million lU (1.1 mg). 

Dosage form Protropin is supplied as a sterile, lyophilized powder for reconstitution with bacteriostatic water for injection. Each vial contains somatrem 5 mg or 10 mg. 

Dosage form Ceredase is a sterile solution for injection, supplied in 5ml bottles containing alglucerase 80 units/ml. Cerezyme is supplied as a sterile lyophilized product for injection. Each vial contains imiglucerase 212 or 424 units. Amost all patients with Gaucher s disease use Cerezyme for enzyme replacement therapy. Ceredase is only available in limited supplies for the treatment of patients who do not tolerate Cerezyme. 

Dosage form Simulect is a sterile lyophilized powder, packaged in glass vials. Each vial contains basiliximab 20 mg, to be reconstituted in sterile water for injection. 

Dosage form Mylotarg is a sterile, preservative-free lyophilized powder containing 5 mg of drug conjugate in a 20ml vial. The contents of the vial are reconstituted with sterile water for injection. 

Dosage form Synagis is supplied in single-use vials as lyophilized powder to deliver either 50 or 100 mg when reconstituted with sterile water for injection. 

The sterile solutions are filled in different sizes of vials and ampoules. One dosage form is lyophilized injection and filled in A-ml vials. To ensure the sterility during the aseptic processing, it was decided to revalidate the A-ml vials sterilization/depyrogenation cycle once in a year by one heat penetration study and endotoxin challenge test. 

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. 

As part of the preformulation activities, investigations include physiochemical character, purity, solubility, stability, and optimal pH studies. In preparation for clinical studies, potential product formulations considering route of administration and solution stability are also studied. Unique to dosage form development studies for lyophilized products, thermal analysis of the drug substance and product formulations are also necessary. Data generated during this phase of product development is useful for future development activities, along with validation. 

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. 

Crystalline cellulose, hydroxypropyl cellulose, and Carbopol 934 have been studied in combination with lyophilized insulin as bioadhesive powder dosage forms for nasal delivery. Each formulation tested resulted in an decrease in plasma glucose level after nasal administration in dog and rabbit models. The most effective formulation, crystalline cellulose blended with insulin, decreased the plasma glucose level to 49% of the control value. In ternary systems the lyophilized Carbopol 934 and insulin blend with crystalline cellulose powder has been the most effective, leading to a hypoglycemia on the order of one-third of the effect obtained after intravenous injection of the same dose of insulin. The plasma glucose levels obtained in the volunteers after administration of the insulin-Carbopol-crystalline cellulose powder formulation were quite variable [38],... 

The lyophilized drug nanosuspensions can be transferred to a hnal dry oral dosage form such as tablets or reconstituted prior to administration. Drug nanosuspensions can be directly used as parenteral products. A shelf life of up to three years was shown for selected nanosuspensions. Sterilization can be achieved by aseptic processing of previously sterilized components, membrane filtration for particles sufficiently small or for drugs that can withstand it, steam sterilization, or y-irradiation. 

Lyophilization technology, adapted from existing practices in formulating chemically synthesized drugs, was at first applied directly to proteins. However, research into refining the process for proteins was undertaken, and problems associated with protein stabilization and dosage form and lyophilization cycle devel-... 

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