Diazepam formulation

Levy, M.Y., Langerman, L., Gottschalk-Sabag, S., and Benita, S. (1989) Side effect evaluation of a new diazepam formulation venous sequalae reduction following i.v. injection of diazepam emulsion in rabbits.Pharm. Res., 6 510-516. 

Shah AK, Simons KJ, Briggs CJ. Physical, chemical, and bioavailability studies of parenteral diazepam formulations containing propylene glycol and polyethylene glycol 400. Drug Dev Ind Pharm 1991 17 1635-1654. 

T. Kronevi and S. Ljungbcrg, Sequale following intra-arterially injected diazepam formulations. Acta Pharm. Suecica. 20 389-396, 198,3. 

Drug formulation Pharmacokinetics and bioavailability of parental diazepam were compared with two novel intranasal diazepam formulations (intranasal solution and intranasal suspension) in a randomised, open-label, pilot study in 24 healthy volxmteers [9 ]. Participants received two intranasal and one intravenous dose of diazepam with 2 weeks washout period between doses. Both intranasal formulations were well tolerated. Diazepam concentration... 

Local reactions of Cremophor-containing formulations are discussed. A significant decrease in the frequency of local vascular side effects from i.v. diazepam formulations can be achieved by replacing the propylene-alcohol solvent with Cremophor-water [139,140]. The surfactant will modify the nature of the precipitation reaction as the solvent is diluted in vivo. 

Midazolam (Versed), diazepam (Valium), and lo-razepam (Ativan) are benzodiazepine derivatives that are useful in anesthesia. Midazolam is the most popular of these agents for the induction of anesthesia. Its popularity is related to its aqueous solubility and to its short duration of action, which permits a prompt return of psychomotor competence. Unlike midazolam, lor-azepam and diazepam are not water soluble and must be formulated in propylene glycol the latter is irritating to the vasculature on parenteral administration. 

During the early twentieth century the barbiturates were used in children and adolescents for their sedative and hypnotic effects however, their safety profile and propensity to cause physical dependence led scientists in search of safer anxiolytics. The development of animal models of behavioral disorders facilitated the formulation of drugs with more specific central nervous system (CNS) effects. In 1959, chlordiazepoxide (Librium) was the first benzodiazepine (BZ) to receive a patent. It entered the market in 1960, followed by diazepam (Valium) in 1963. Today, over 35 BZs have been formulated and over 10 are available in the United States (Ballenger, 1995 Hobbs et ah, 1996). 

Diazepam, lorazepam, and midazolam are used in anesthetic procedures. The primary indication is for premedication because of their sedative and amnestic properties. (The basic pharmacology of benzodiazepines is discussed in Chapter 22 Sedative-Hypnotic Drugs.) Diazepam and lorazepam are not water-soluble, and their intravenous use necessitates nonaqueous vehicles, which may cause local irritation. Midazolam formulations are water-soluble and thus produce less irritation, but the drug becomes lipid-soluble at physiologic pH and readily crosses the blood-brain barrier. 

I. I. Hewala, GLC and HPLC determination of diazepam and its degradation products in pharmaceutical formulations, Anal. Lett., 25 1877(1992). 

A sensitive reverse-phase HPLC method has been developed for the analysis of etodolac in tablet formulation [22]. The chromatographic separation was achieved using a reverse-phase Cu column, having dimensions of 3.3 cm x 0.46 cm i.d. (3 pm particles) and which was maintained at 30°C. The mobile phase consisted of pH 6.0 phosphate buffer / methanol (60 40 v/v), and was eluted at 1 mL/min. Analyte detection was effected on the basis of UV detection at 230 nm. Diazepam was used as an internal standard. The sample preparation entailed grinding the etodolac tablets, followed by extraction with methanol (using sonication). A retention time of 1.46 min was obtained for etodolac under these conditions, and the method was found to be linear, precise, and accurate over the concentration range of 0.01 to 0.1 mg/mL. 

Fatouros, D. G, and Antimisiaris, S. G. (2002), Effect of amphiphilic drugs on the stability and zeta-potential of their liposome formulations A study with prednisolone, diazepam and griseofulvin, J. Coll. Interf. Sci., 251, 271-277. 

Diazepam As mentioned earlier, because of shortcomings of rectal administration, the nasal delivery of diazepam has gained interest. The nasal bioavailability of diazepam in sheep was estimated and further compared with results obtained earlier in humans and rabbits [106] in this study, human and rabbit nasal bioavailability for the first 30min was reported to be 37 and 54%, respectively [113]. Diazepam solubilized in PEG 300 was used for nasal administration via a modified nasal device, a Pfeiffer unit dose (Princeton, NJ). The sheep received the nasal formulations in a fixed standing position such that the head was slightly tilted back. It was found that the serum concentration after administration of a 7-mg solution of diazepam was... 

Gangrene has been previously reported with intra-arterial injection of diazepam and is also well known with other classes of drugs, such as barbiturates and phenothiazines. It appears to be caused by the drug rather than the solvent used in the intravenous formulations. 

Pellock JM. Safety of Diastat, a rectal gel formulation of diazepam for acute seizure treatment. Drug Saf... 

Rectal absorption is efficient with an appropriate formulation and has been used for diazepam and theophyllines this route may be preferred with an uncooperative infant. 

When a child has febrile convulsions the decision to embark on continuous prophylaxis is serious for the child, and depends on an assessment of risk factors, e.g. age, nature and duration of the fits. Most children who have febrile convulsions do not develop epilepsy. Prolonged drug therapy, e.g. with phenytoin or phenobarbitone, has been shown to interfere with cognitive development, the effect persisting for months after the drug is withdrawn. Parents may be supplied with a specially formulated solution of diazepam for rectal administration (absorption from a suppository is too slow) for easy and early administration, and advised on managing fever, e.g. use paracetamol at the first hint of fever, and tepid sponging. 

Alternatively, Rubino and Yalkowsky found that a was a linear function of cosolvent polarity for a given solute. This is illustrated in Fig. 3 for the three lipophilic compounds phenytoin, diazepam, and benzocaine. Thus, knowledge of the solubility of a given drug in water and at least two cosolvents would permit cr to be estimated for other cosolvents by interpolation using an index of the desired cosolvent polarity. These studies permit the use of Eq. (4) as a means to rationally choose or eliminate solvents for formulation studies based on limited experimental solubility data and commonly obtained indexes of solute and solvent polarity. 

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