Description. Cremophor A 6 is a whitish waxy substance. Cremophor A 25 is supplied in the form of free-flowing, non-dusting microbeads. Identity. Cremophor A. August Supersedes issue dated May MEMC e/Page 1 of 8. Cremophor® A Grades. ® = Registered trademark of BASF Aktiengesellschaft. INCI: Ceteareth-6 (and) Stearyl AlcoholThe Cremophor A grades are Combinations of Cremophor A6 and Cremophor A25 can emulsify oils with a.
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Baker, Mohamed Naguib; Propofol: The Challenges of Formulation. We have emailed you at with instructions on how to set up a new password. If you do not receive an email in the next 24 hours, or if you misplace your new password, please contact:. To get started with Anesthesiology, we’ll need to send you an email.
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Anesthesiology 10Vol. You will receive an email whenever this article is corrected, updated, or cited in the literature. You can manage this and all other alerts in My Account.
You must be logged in to access this feature. This is primarily because of its rapid onset, short duration of action, and minimal side effects. High incidences of anaphylaxis with the Cremophor EL formulation prompted its withdrawal from development.
The ability to formulate propofol in a biocompatible vehicle having minimal side effects and appropriate pharmacodynamic profiles is critical cremophorr the use of propofol as an intravenous agent. This is a particular challenge cremophpr propofol because of its high lipophilicity.
Despite the market success of propofol emulsions, there continue to be drawbacks associated with the current formulations. The objective of this review is to provide a background on propofol formulations, highlight clinical implications of each, and discuss newer efforts to reformulate propofol. Propofol is a unique compound compared to the other intravenous anesthetics. It is a simple phenol substituted with two isopropyl groups in each of the positions adjacent to the hydroxyl group, the ortho positions fig.
Although most intravenous anesthetics can be administered as aqueous salts, propofol cannot be. Its lone ionizable functional group, the hydroxyl, has a pK a of 11, which renders it unsuitable for forming salts in solution. Because vehicles for clinical delivery of anesthetics should be devoid of sedative and anesthetic properties, as well as toxic cremopho effects, nearly all small-molecular-weight organic solvents into which propofol cremophkr freely miscible are not useful.
Chemical structure of propofol, 2,6-diisopropylphenol. The purpose of a vehicle for an intravenous drug is to evenly disperse the active ingredient in a suitable volume that allows the clinician to administer the drug in a convenient dose size while not inducing side effects that are too great. A requirement for maintaining highly lipophilic substances dispersed in an aqueous solution is for the formulation to contain additional substances, emulsifiers or surfactants, that facilitate dispersion of the drug molecule within the aqueous phase.
Discovery of the anesthetic effects of crmophor in the ICI labs of James Glen involved the screening and synthesis of a large array of related alkyl-substituted phenol compounds. Clinically, propofol injection in Cremophor EL was found to cause significant pain upon injection. Consequently, initial development of propofol continued with the Cremophor EL—based vehicle. Its synthesis is accomplished by the treatment of castor oil with ethylene oxide, a cremopnor that yields a family of polyethoxylated compounds.
Consequently, the major component of Cremophor EL is polyoxyethyleneglyceroltriricinoleate. Chemical structure of the major component of Cremophor EL, polyoxyethyleneglyceroltriricinoleate, represented in free form.
Cremophor EL has a critical micellar concentration of approximately 0. Studies of paclitaxel, another lipophilic drug formulated in Cremophor, have shown that after injection, the micelles in part function to slow the release of free drug.
For example, intravenous infusion of 0. Other formulations were also considered for propofol during its initial development around These included lipid-based emulsions, Tween and Mulgofen surfactants, and some ccremophor written personal communication, John B.
The first lipid emulsions examined were not satisfactory because the onset of anesthesia was delayed, potency was lost, and duration of anesthesia was prolonged compared with propofol formulated in Cremophor EL. Tween and Mulgofens generally produced histamine release crfmophor dogs and pigs and were not pursued.
The poloxamers studied exhibited toxicologic problems and were not given to humans. In the early s, emulsion technology had improved to the point that propofol emulsions could be made that were stable and had the droplet sizes that maintained the anesthetic properties of propofol.
This reformulation represented a significant improvement in intravenous propofol formulation and is the current mainstay of propofol delivery.
CREMOPHOR (R) A6 CAS#:
Although injection pain remained a problem, propofol in a lipid emulsion formulation was found not to cause anaphylactic reactions, and it resulted in good pharmacodynamic characteristics. Emulsions with differing oils, e. Soybean oil holds the bulk of the propofol in a medium that can be stabilized and dispersed; lecithin serves as an emulsifier to stabilize the small propofol—soybean oil droplets in aqueous dispersion, and glycerol maintains the formulation isotonic with blood.
In such a formulation, propofol is highly concentrated in the emulsified oil droplets defined as the discontinuous phasewith only small quantities in the aqueous phase i. Upon administration of a propofol-containing emulsion, propofol diffuses across the droplet interface and passes into the bloodstream. Major factors that govern this process for propofol or any lipophilic drug are the drug concentration gradient, the partition coefficient, the drug diffusivity in both phases, and the interfacial area of the drug-containing oil droplets.
The total interfacial surface area is a highly important factor in the rate of drug release from a drug-containing droplet. This in turn is dependent on the size and number of oil droplets resulting from the injection. If it were to contain uniform droplets monodisperse of 1. However, if the particle size were reduced to 0. Studies of propofol anesthesia in rats demonstrated that propofol emulsion formulations have distinct clinical advantages. Propofol emulsion administration resulted in a smaller propofol volume of distribution and shorter times to peak electroencephalographic activity at onset, loss of righting reflex, and maximal electroencephalographic effects as compared with propofol administered in the lipid-free vehicle.
Coadministration of propofol in this lipid-free vehicle with a lipid emulsion containing no propofol provided evidence that propofol needed to be incorporated into the emulsion soybean oil droplets for the better pharmacodynamic profile.
The cremophir that lung concentrations of propofol were significantly higher after the administration of the propofol in the lipid-free formulation compared with the emulsion formulation led the authors to hypothesize that the emulsion formulation protected propofol from a high first-pass sequestration by the lung, possibly by maintaining more propofol in the central vascular space.
Emulsions are not composed of stable uniform molecular structures but of emulsified oil droplets whose integrity is dependent on a number of interactive forces.
Furthermore, emulsions need to have a great enough physical stability to withstand heat sterilization and maintain their integrity for their prescribed shelf life. Propofol emulsion and other emulsions for intravenous delivery are manufactured so that the oil droplets average 0.
In general, emulsions with droplets of 0. Macroemulsions require vigorous mixing to manufacture. The visible appearance of propofol and other emulsions as white milky solutions results from the property of small particles, but those that are large relative to the wavelength of white light, to reflect crmeophor refract light in a regular manner when dispersed. At that size, a single droplet appears as a very small oil globule. Consequently, extensive droplet enlargement in emulsions can occur and not be detected by visual inspection.
Suspended particles less than one fourth the average wavelength crejophor visible light 0. These include laser light scattering, Coulter counter, ultrasonic spectroscopy, and microscopy.
Relation of particle size to visual appearance of particle-containing dispersions. Obtaining long-term droplet stability is a major challenge in developing commercial emulsions for intravenous administration. Micelle-containing formulations, such as propofol in Cremophor EL, are thermodynamically stable and remain intact for indefinite periods. Oil-in-water macroemulsions, however, are thermodynamically unstable.
The lowest energy state of a mixture of emulsion components is represented by two completely separated phases, an upper layer of oil and a lower layer of water. The critical emulsion component cremmophor allows for small oil droplets to be dispersed in the water phase with relatively good stability is the emulsifier.
The emulsifier reduces the interfacial tension between an oil and water and allows s6 oil to form stable dispersed droplets discontinuous phase within the water phase continuous phase. The major emulsifier components in egg yolk lecithin, phosphatidylcholine and phosphatidylethanolamine, consist of lipophilic side chains esterified fatty acids bound to z6 heads at one end fig.
These molecules bridge the interface between the dispersed oil droplets and water. The oil-miscible side chains interact with the soybean oil, and the polar head interacts with the aqueous phase. The phosphates and nitrogen-containing moieties are charged negative for phosphate and positive for the choline nitrogen and confer a polar character to the head group, allowing aqueous interactions that form a mechanical barrier.
Schematic of a soybean oil droplet emulsified with lecithin components. The negative electrostatic repulsive forces are derived from small quantities of free fatty acids and phosphatidic acids in egg yolk lecithin. In early studies, it was found that pure phosphatidylcholine was a poor emulsifier compared with mixtures of phosphospholipids that occur naturally. These free long-chain acids cause the emulsified oil droplets to possess a net negative electrostatic charge on their outer surfaces.
The effective charge on emulsion oil droplets, thus a measure of emulsion stability, is characterized by its zeta potential. Therefore, autoclaving can confer a greater stability to the emulsion.
However, accompanying fatty acid release is a cremophir in pH that acts to destabilize the emulsion. Emulsion degradation has been studied by many investigators. Upon some collisions, attractive forces van der Waal interactions develop between droplets due to droplet surface imperfections. S6 attractive forces overcome the repulsive forces, droplets adhere to each other, a state called flocculation.
In the flocculated state, the thin aqueous film between two adhered droplets can rupture causing the oil of the two droplets to combine, thus creating a larger but still emulsified droplet, a process termed coalescence.
Continuing coalescence yields droplets of increasingly larger size, which have a greater tendency to rise toward the emulsion surface creamingwhich in turn causes an increase in frequency of droplet collision. Last, droplets become sufficiently large so that free oil is formed on the surface of the emulsion, a process called cracking. Flocculation and creaming are the only reversible processes crdmophor emulsion degradation. After droplets coalesce and increase in size, they cannot be reduced in size except by rehomogenization.
Because of the possibility of a small degree of creaming in commercial propofol emulsions, even in those within their shelf life, it is recommended that they be shaken by hand before use. Schematic of the process of emulsion degradation. The clinical significance of emulsion degradation is severalfold. It may cause variations of propofol concentrations within a volume of emulsion due to creaming.