Relating emulsion stability to interfacial properties for pharmaceutical emulsions stabilized by Pluronic F68 surfactant.

We explore mechanisms of emulsion stability for several systems using Pluronic F68 and a range of oils commonly used in pharmaceutics and cosmetics. We report measurements of dynamic emulsion drop size, zeta potential, and creaming time, as well as dynamic interfacial tension and interfacial viscoelasticity. Experiments show that with 1wt% Pluronic F68, soybean oil emulsions were the most stable with no creaming over six months, followed by isopropyl myristate, octanoic acid, and then ethyl butyrate. The eventual destabilization occurred due to the rising of large drops which formed through Ostwald ripening and coalescence. While Ostwald ripening is important, it is not the dominant destabilization mechanism for the time scale of interest in pharmaceutical emulsions. The more significant destabilization mechanism, coalescence, is reduced through surfactant adsorption, which decreases surface tension, increases surface elasticity, and adds a stearic hindrance to collisions. Though the measured values of elasticity obtained using a standard oscillatory pendant drop method did not correlate to emulsion stability, this is because the frequencies for the measurements were orders of magnitude below those relevant to coalescence in emulsions. However, we show that the high frequency elasticity obtained by fitting the surface tension data to a Langmuir isotherm has very good correlation with the emulsion stability, indicating that the elasticity of the interface plays a key role in stabilizing these pharmaceutical formulations. Further, this study highlights how these important high frequency elasticity values can be easily estimated from surface isotherms.

Propofol emulsion-free drug concentration is similar between batches and stable over time.

Despite their widespread use for anesthesia and sedation, propofol emulsions have several unresolved issues, including pain on injection, stability concerns, and propensity to support bacterial growth. Pain accompanying a propofol injection has been attributed to the amount of free as opposed to emulsified propofol in the blood, which can differ with the formulation. Emulsions are inherently unstable and subject to several types of destabilization, but the actual mechanism may vary between formulations or batches. Free drug concentration and emulsion stability have not been widely studied between batches of propofol emulsions. Verifying whether batch-to-batch variability is a contributing factor to pain on injection or emulsion destabilization will help us better assess the causes and guide the design of future propofol formulations. METHODS: Several samples of generic 1% propofol emulsion from various batches were compared. Free drug concentration was measured using an equilibrium dialysis method. Emulsion stability was evaluated by visible observation and by measuring droplet size distribution and polydispersity during shelf storage for up to 21 months. RESULTS: Small differences in free drug concentration were observed between samples (10.6-16.7 µg/mL), but these differences were not statistically significant (p > 0.05). Emulsion droplet size (235.4-221.1 nm) and polydispersity (0.115-0.095) did not differ statistically over 21 months of storage. All batches were resistant to creaming and other destabilization mechanisms. CONCLUSIONS: Batch-to-batch variability does not significantly alter the free drug concentration or stability of propofol formulations. If pain on injection of propofol is in fact related to the free propofol drug concentration, then it is unlikely that batch-to-batch variability causes any changes in pain on propofol injection.

"Micro to macro (M2M)"--A novel approach for intravenous delivery of propofol.

PURPOSE: Propofol emulsions have limited shelf life and safety concerns for injection. Microemulsions of propofol are thermodynamically stable and simpler to manufacture, but cause additional pain on injection. We propose a novel micro to macro (M2M) approach of destabilizing a microemulsion immediately prior to injection. METHODS: Microemulsions of propofol were prepared at two to three times the drug loadings of commercial formulations. We determined suitable microemulsion compositions which destabilize into macroemulsions after two or three fold dilutions with water. Droplet growth after dilution was measured with dynamic light scattering. Increasing solution turbidity after dilution was also measured optically with millisecond resolution. Experimental data was analyzed in the context of a coalescence model. RESULTS: Microemulsions rapidly coalesce into larger droplet size macroemulsions after dilution according to the phase diagram shift. The resulting macroemulsions are metastable retaining their droplet size for several hours. Droplet growth occurs on the order of seconds and a metastable size of about 1 micron is reached in minutes. Rates of droplet growth and metastable droplet sizes depend on the surfactant composition. The coalescence model predicts droplet growth with good agreement but only after accounting for the finite probability of coalescence from each collision. CONCLUSIONS: The M2M concept has been demonstrated for the anesthetic drug propofol which may improve stability and manufacturability in addition to reducing pain on injection. This approach could be adapted to other hydrophobic vesicant drugs as well.

Parenteral emulsions and liposomes to treat drug overdose.

Drug overdoses from both pharmaceutical and recreational drugs are a major public health concern. Although some overdoses may be treated with specific antidotes, the most common treatment involves providing supportive care to allow the body to metabolize and excrete the toxicant. In many cases, supportive care is limiting, ineffective, and expensive. There is a clear medical need to improve the effectiveness of detoxification, in particular by developing more specific therapies or antidotes for these overdoses. Intravenous lipid emulsions (ILEs) have been investigated as a potential treatment for overdoses of local anesthetics and other hydrophobic drugs. While ILE therapy has been successful in several cases, its use beyond local anesthetic systemic toxicity is controversial and its mechanism of detoxification remains a subject of debate. ILEs were not originally developed to treat overdose, but clarifying the mechanisms of detoxification observed with ILE may allow us to design more effective future treatments. Liposomes are highly biocompatible and versatile formulations, thus it was a natural step to explore their use for drug overdose therapy as well. Several researchers have designed liposomes using a variety of approaches including surface charge, pH gradients, and inclusion of enzymes in the liposome core to optimize the formulations for detoxification of a specific drug or toxicant. The in vitro results for drug sequestration by liposomes are very promising and animal trials have in some cases shown comparable performance to ILE at reduced lipid dosing. This narrative review summarizes the current status and advances in the use of emulsions and liposomes for detoxification and also suggests several areas in which studies are needed for developing future therapies.

Kinetically stable propofol emulsions with reduced free drug concentration for intravenous delivery.

PURPOSE: Intravenous injections of propofol emulsions are accompanied by pain likely due to the interaction of the dissolved drug with endothelial cells of the vasculature. It is commonly hypothesized that reducing the aqueous phase concentration of propofol could reduce pain. METHODS: To minimize the propofol concentration in the aqueous phase, we developed stable oil-in-water emulsions with excipient oil mixtures that have an increased partition coefficient for propofol. We then explored the emulsion stability by measuring size distributions after extended durations of shelf storage and also after freeze-thaw cycling. The effects of oil type, surfactant and salt concentration on emulsion stability were also explored. RESULTS: Small chain oils like ethyl butyrate exhibit high drug partitioning but poor stability, while larger molecules such as soybean oil exhibit lower partitioning but excellent emulsion stability. Emulsions with mixtures of soybean oil and ethyl butyrate are stable for longer than a year, resistant to freeze-thaw cycling, and reduce aqueous drug concentrations of propofol twofold compared to pure soybean oil emulsions. CONCLUSIONS: Oil-in-water emulsions of propofol formulated with mixtures of ethyl butyrate and soybean oil are kinetically stable and significantly reduce the aqueous phase drug concentration making them promising candidates for future propofol therapies.

Rapid dissolution of propofol emulsions under sink conditions.

PURPOSE: Pain accompanying intravenous injections of propofol is a major problem in anesthesia. Pain is ascribed to the interaction of propofol with the local vasculature and could be impacted by rapid dissolution of the emulsion formulation to release the drug. In this paper, we measure the dissolution of propofol emulsions including the commercial formulation Diprivan(®). METHODS: We image the turbidity of blood protein sink solutions after emulsions are injected. The images are digitized, and the drug release times are estimated from the pixel intensity data for a range of starting emulsion droplet size. Drug release times are compared to a mechanistic model. RESULTS: After injection, pixel intensity or turbidity decreases due to reductions in emulsion droplet size. Drug release times can still be measured even if the emulsion does not completely dissolve such as with Diprivan(®). Both pure propofol emulsions and Diprivan(®) release drug very rapidly (under five seconds). Reducing emulsion droplet size significantly increases the drug release rate. Drug release times observed are slightly longer than the model prediction likely due to imperfect mixing. CONCLUSIONS: Drug release from emulsions occurs very rapidly after injection. This could be a contributing factor to pain on injection of propofol emulsions.

Comparison of intravenous lipid emulsion, bicarbonate, and tailored liposomes in rabbit clomipramine toxicity.

OBJECTIVES: Liposome (LIP)-like lipid dispersions have emerged as useful detoxification vehicles in vitro. The authors compare resuscitation with tailored LIPs, 20% intravenous lipid emulsion (ILE), and sodium bicarbonate (BIC), in a rabbit model of clomipramine toxicity. METHODS: Sedated, instrumented New Zealand white rabbits underwent clomipramine infusion at 3.2 mg/kg/min to 50% baseline mean arterial pressure (MAP) and then at 1.6 mg/kg/min for 30 minutes. BIC (3 mL/kg 8.4%), ILE (3 mL/kg 20%), or LIP (24 mg/kg) were infused as rescue treatments at toxicity and were repeated at 10 minutes (n = 5 in each group). RESULTS: Thirty-minute MAP was greatest in ILE-treated animals: 61 mm Hg ILE (interquartile range [IQR] = 49 to 64 mm Hg), 43 mm Hg LIP (IQR = 36.5 to 49 mm Hg), and 10 mm Hg BIC (IQR = 10 to 44 mm Hg; all p = 0.02). Two of the five BIC-treated animals survived to 30 minutes, compared with all five of the ILE-treated animals and all five of the LIP-treated animals (p = 0.044). CONCLUSIONS: Both ILE and LIPs improved hemodynamic recovery compared with bicarbonate in clomipramine-induced cardiotoxicity in rabbits. Greater 30-minute MAP was observed in the ILE group.