Injectable formulations

Injected formulation of leuptoleine and triptoreline [57773-63 ] ate used to treat metastasized cancer of the prostrate, whereas an encapsulated formulation of bromocryptin [25614-03-3] is used to inhibit milk production in women after pregnancy. The performance of encapsulated hormonal polypeptides is weU documented (47). Injectable biodegradable mictocapsules loaded with fertUity control agents have been under development for a number of years and have been carried to various stages of clinical development (48) (see Contraceptives). 

The currendy (ca 1992) marketed injectable and implantable contraceptives are designed to be effective for maximum periods of three months and five years, respectively. There is Htde evidence from programmatic or health reasons that an injectable formulation with a longer effective life span, eg, six months, would not be equally effective. The acceptabiUty and effectiveness of long-acting contraceptives may be determined by the means by which a community deUvers contraceptive products to the pubHc the active life of a product may be determined by economic rather than programmatic or health related factors. 

The first inactivated poliovirus vaccine was introduced in the 1950s in an injectable formulation, and replaced in the 1960s by a live oral poliovirus vaccine. The oral poliovirus vaccine not only elicits systemic immunogenicity but also a localized immune response in the intestinal tract. Unfortunately, the oral poliovirus vaccine has the risk of vaccine-associated paralytic poliomyelitis occurring in approximately 1 case of every 2.4 million doses distributed. The risk with the first dose of oral poliovirus vaccine is 1 case in 750,000 doses.11... 

More subtle effects of preservatives on injectable formulations are possible. Formulation of insulin is an illustrative case study. Insulin is usually formulated as a multiple-dose vial, since individual dosage varies among patients. Preservation of zinc insulin with phenol causes physical instability of the suspension, whereas methyl-paraben does not. However, the presence of phenol is required for obtaining protamine insulin crystals [9]. 

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. 

Loomis, E.C. and R.C. Schock. 1978. Comparison of famphur (Warbex) pour-on and intramuscular injectable formulations for cattle grub control, California, 1975-1976. Jour. Med. Entomol. 14 649-651. 

Another proposed in vitro assay for muscle irritancy for injectable formulations is the red blood cell hemolysis assay (Brown et al., 1989). Water-soluble formulations in a 1 2 ratio with freshly collected human blood are gently mixed for 5 min. The percentage of red blood cell survival is then determined by measuring differential absorbance at 540 nm this value is then compared to values for known irritants and nonirritants. Against a very small group of compounds (four), this assay reportedly accurately predicts muscle irritation. 

Strickley RG. Solubilizing excipients in oral and injectable formulations. Pharm Res 2004 21 201. 

Aminomethyl- cyclines Amino- methyl- cycline MK-2764 (PTK-0796 BAY 73-7388) (153) Antibacterial (broad spectrum antibiotic against MRS A, MDR Streptococcus pneumoniae and vancomycin-resistant enterococci) Inhibits bacterial protein synthesis Phase III (treatment of hospital infections in both oral and i.v. injectable formulations) Paratek/Novartis 810... 

In another example, the stability of a solution of a peptide drug shown in Figure 6.17, being developed as an injectable formulation development, was... 

Sumatriptan was specifically developed as an anti-migraine drug. Injectable sumatriptan has been shown to be more effective than injectable DHE at two hours but the rate of recurrence (30 0%) is higher than with DHE. Efficacy is better and delay to action is shorter with the injectable formulation. Both the nasal spray and the injectable formulation... 

Cortisone acetate injectable formulations have been reported to be incompatible with various drugs, but the compatibility depends on several factors (such as drug concentrations, resulting pH, temperature, etc.). Specialized references should be consulted for specific incompatibility information [61]. 

Contraindications Hypersensitivity to methocarbamol or any component of the formulation, renal impairment (injection formulation)... 

This section includes the most important container materials glass, plastic, and elastomers and addresses the contamination issues for injectable formulations. 

Excipients used in injectable formulations have to meet several stringent requirements. A positive identification test uniquely applicable to the excipients is required (e.g., infrared spectrophotometry and chromatography). It is important that manufacturers identify and set appropriate limits for impurities. These limits should be based upon appropriate toxicological data, or the limits described in national compendial requirements. Manufacturing processes should be adequately controlled so that the impurities do not exceed such established specifications. Solvents or catalysts used in the excipient production process should be removed to appropriate levels. If naturally derived, excipients should meet endotoxin levels and may require further testing for bovine spongiform encephalopathy (BSE) /... 

Biocompatibility of injectable formulations with tissues can be tested by observing microscopic histology of the tissues so exposed, or by using erythrocyte hemolysis as a surrogate for these other tissues. Alternatively, one can measure the level of the cytosolic enzyme creatine phosphokinase that is released from damaged tissues (18). 

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