Propofol formulation

Glycerin is used occasionally in injectable formulations. Glycerin comprises of 2.5% of the idarubicin formulation, Idamycin PFS (preservative-free solution) and is administered undiluted by IV infusion. Glycerin comprises of 2.2%i of the propofol formulation, Diprivan 1%, and is administered undiluted by IV bolus or infusion. The dose of Diprivan 1% is up to 30 ml, which is 6.75 ml of glycerin per dose, representing the estimated maximum amount administered intravenously. 

Schaub E, Kern C, Landau R. Pain on injection a double-blind comparison of propofol with lidocaine pretreatment versus propofol formulated with long- and medium-chain triglycerides. Anaesth Analg 2004 99 1699—1702. 

Figure 11.10. Pharmacodynamic activity (sleep time, mean s.d., n = 4) of propofol formulations after tail vein dosing to male MFl mice. Mice were dosed with 0.2 mg propofol in a 100 volume administered as either propofol emulsion (10 mg mL , Fresenius, Germany) diluted to 2 mg mL with phosphate buffered saline (PBS, pH = 7.4) or a filtered chitosan amphiphile formulation (quaternary ammonium palmitoyl glycol chitosan - 5 mg mL , propofol 1.9 mg mL in PBS - pH = 7.4). No sleep times were recorded in animals receiving the polymer alone. + = statistically significantly different (p < 0.05).

Prick testing with propofol is said to be unreliable and intradermal testing is recommended. Prick testing is performed with the undiluted propofol formulation (10 mg/ml). For intfadermal testing, the maximum concentration is a 1 in 10 dilution, that is, propofol 1 mg/ml. Testing should start at 1 in 1,000 and proceed up to the 1 in 10 dilution. 

In Asia allergies to soy are well known and an association of soybean allergy with propofol-induced anaphylaxis has been suggested. In a recent convincing case, anaphylaxis with severe oropharyngeal edema and bronchospasm occurred in a 74-year-old woman with a history of soy allergy a few minutes after receiving propofol. Skin prick tests revealed positive reactions to propofol and 20 % Intralipid which, like the propofol formulation, contains soybean oil. It was concluded that the anaphylactic reaction was caused by the soybean oil present in the administered propofol. 

The caloric contribution from propofol infusions can require adjustment of a patient s nutrition regimen. The caloric contribution from amphotericin liposomal and lipid complex formulations is not clinically relevant. 

Drugs formulated with Cremophor EL (Althesin, propanidid, propofol EL)... 

Propofol is properly named 2,6-diisoproplylphenol. Because there are 12 carbon atoms, this compound is not very soluble in water, and it is much more soluble in hydrophobic solvents. Therefore propofol is formulated as an emulsion2 of the 2,6-diisoproplylphenol suspended in a mixture of soybean oil and water. An egg-based phospholipid (e.g., lecithin) is added to stabilize the emulsion. By the way, you can buy flavored water-soybean oil-lecithin mixtures, but you call it mayonnaise. 

Chen, H. Zhang, Z. Ahnarsson, O. Marier, J-F. Berkovitz, D. Gardner, C.R. A novel, hpid-free nanodispersion formulation of propofol and its characteristics. Pharmaceutical Research 2005, 22 (3), 356-361. 

Five adults with head injuries inexplicably had fatal cardiac arrests in a neurosurgical intensive care unit after the introduction of a sedation formulation containing an increased concentration of propofol (72). There were striking similarities with the previously reported syndrome of myocardial failure, metabolic acidosis, and rhabdomyolysis in children who received high-dose propofol infusions for more than 48 hours. 

Soon after the introduction of propofol in 1989, clusters of infections related to its use were reported, and there have since been several reports (77,78). The complications include hypotension, tachycardia, septic shock, convulsions, and death. Ethylenediaminetetra-acetic acid (EDTA) was added to the formulation to retard microbial growth. However, there have been concerns over the effects of this additive on trace element homeostasis, particularly when it is used in intensive care units for long-term sedation. Five randomized controlled trials have been reviewed, and minimal or no effects have been found on zinc, magnesium, or calcium homeostasis. However, there is no evidence to suggest that cluster infection has been or will be reduced with this formulation and there is still a need for care with sterility when using this product. 

Emulsions - liquid dispersions usually of an oil phase and an aqueous phase - are a traditional pharmaceutical dosage form. Oil-inwater systems have enjoyed a renaissance as vehicles for the delivery of lipid-soluble dmgs (e.g. propofol). Their use as a dosage form necessitates an understanding of the factors governing the formulation and stability of oil-in-water (o/w) and water-in-oil (w/o) emulsions, multiple emulsions (w/o/w or o/w/o) and microemulsions, which occupy a position between swollen micelles and emulsions with very small globule sizes. Photomicrographs of o/w, w/o systems and multiple emulsions are shown in Fig. 7.10. It is also possible to formulate nonaqueous or anhydrous emulsions, that is oil-in-oil systems and even multiple oil-in-oil-in-oil systems. 

The commercially available veterinary preparations are emulsions of propofol in soybean oil, glycerol and egg lecithin. These formulations do not contain preservatives and provide a suitable substrate for bacterial growth, so aseptic technique is recommended when drawing the drug from the vial into a syringe and opened vials should be discarded within 24 h. 

After cyclodextrins and co-solvents, other approaches can be applied including the use of surfactants and micelle forming agents. Surfactants can be classified as amphoteric (lecithin), non-ionic (Tween 80 or Cremophor EF) or ionic (sodium lauryl sulfate or sodium palmitate). Cremophor is a polyoxyethylenated castor oil derivative which is a common solubilizing excipient in a number of formulations including those for paclitaxel, propofol, teniposide and clanfenur... 

Sodium metabisulflte and EDTA have been used individually as microbiological preservatives in different approved formulations of propofol injectable emulsion. The choice of antioxidant must be made with care as some are restricted by use and/or concentration in different countries. BHA is widely used in fixed oils and fats at concentrations up to 0.02% but is permitted up to 0.1% in some essential oils. Its close relative, BHT, is recommended as an alternative to tocopherol at concentrations up to 10 ppm for the stabilization of liquid paraffin. Other antioxidants widely used in emulsion formulations include the propyl, octyl and dodecyl esters of galhc acid at concentrations up to 0.001% (fixed oils and fats) and up to 0.1% (essential oils). ... 

Propofol (diprnan Figure 13—1) is the most commonly used parenteral anesthetic in the U.S. The drug is insoluble in aqueous solutions and is formulated only for IV administration as a 1% (10 mg/mL) emulsion in 10% soybean oil, 2.25% glycerol, and 1.2% purified egg phosphatide. Significant bacterial contamination of open containers has been associated with serious patient infection propofol should be either administered or discarded shortly after removal from sterile packaging. 

This dmg, also known as Diprivan, is chemically unlike any of the previously described iv agents and was developed following the discovery of the anesthetic activity of the 2,6-diethyl analogue (111). Propofol itself is insoluble in water and is usually formulated in a soya bean oil emulsion. Propofol induction, with or without an opioid, is smooth and similar to that of other agents, although pain at the injection site and apnea have been reported (112,113). Recovery after induction and maintenance is faster, with fewer side effects, than with thiopentone (114), although sexual disinhibition has been anecdotally reported (115). Propofol is rapidly distributed, metabolized, and eliininated (116). 

A. Parenteral. Propofol (Diprivan) 1% (10 mg/mL) emulsion in 10% soybean oil with 2.25% glycerol and 1.25% purified egg phospholipid in 20-, 50-, or 100-mL vials and a 50-mL prefilled syringe. Contains disodium EDTA or sodium metabisulfite in the US formulation as preservatives. A 2% (20 mg/mL) emulsion has been formulated to provide the same amount of drug with less lipid concentration, but is not yet approved in the United States. Note Propofol is provided as a ready-to-use preparation, but if dilution is necessary, only use D5W and don t dilute to conoentrations less than 2 mg/mL. 

The original formulation of propofol in Cremophor was found to increase the blockade due to vecuronium, but the more recent formulation in soybean oil and egg phosphatide has been found in an extensive study not to interact with vecuronium." Propofol also appears not to interact with mivacurium. ... 

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