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Triolein 757 and tablets). Included in the Canadian List of Acceptable Non- 3 Steurnagel CR. Latex emulsions for controlled drug delivery. McGinity medicinal Ingredients. JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms. New York: Marcel Dekker, 1989; 1–61. 4 Gutierrez-Rocca JC, McGinity JW. Influence of aging on the physical– 17 Related Substances mechanical properties of acrylic resin films cast from aqueous Acetyltributyl citrate; acetyltriethyl citrate; tributyl citrate. dispersions and organic solutions. Drug Dev Ind Pharm 1993; 19(3): 315–332. 5 Liu J, Williams R. Properties of heat-humidity cured cellulose acetate 18 Comments phthalate free films. Eur J Pharm Sci 2002; 17(1–2): 31–41. 6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th A specification for triethyl citrate is contained in the Food (7) edn. New York: Wiley, 2004; 3546. Chemicals Codex (FCC). 7 Food Chemicals Codex, 6th edn. Bethesda, MD: United States The EINECS number for triethyl citrate is 201-070-7. The Pharmacopeia, 2008; 988. PubChem Compound ID (CID) for triethyl citrate is 6506. 20 General References 19 Specific References Vertellus Specialties Inc. Technical data sheet: Citroflex 2, 2007. 1 Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and insoluble plasticizers on the physical and mechanical properties of 21 Author acrylic resin copolymers. Int J Pharm 1994; 103: 293–301. J Teckoe. 2 Lehmann K. Chemistry and application properties of polymethacrylate coating systems. McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms. New York: Marcel Dekker, 1989; 153– 22 Date of Revision 245. 24 February 2009. Triolein 1 Nonproprietary Names 6 Functional Category None adopted. Emollient; penetration enhancer; solubilizing agent; solvent. 2 Synonyms 7 Applications in Pharmaceutical Formulation or Captex GTO; glycerol trielaidate; glyceryl trioleate; 9-octadecenoic Technology acid-1,2,3-propanetriyl ester; olein; 1,2,3-propanetriyl tris((E)-9- Triolein is used as a solubilizer and solvent in injectable prepara- octadecenoate); trielaidin; trielaidoylglycerol; 1,2,3-tri(cis-9-octa- tions. It has been used in marketed preparations of sustained-release decenoyl)glycerol. injections of cytarabine and multivesicular liposomal injections of morphine sulfate. It has also been used in enteric coatings for oral preparations in combination with other enteric coating excipients to 3 Chemical Name and CAS Registry Number protect against degradation by pancreatic lipase.(1) 2,3-bis[[(Z)-octadec-9-enoyl]oxy]propyl (Z)-octadec-9-eno- Triolen is used in personal care products as a skin-conditioning T ate [122-32-7] and viscosity-controlling agent. 4 Empirical Formula and Molecular Weight 8 Description C57H104O6 885.43 Triolein occurs as a clear, colorless to yellowish oily liquid, and is tasteless and odorless. 5 Structural Formula 9 Pharmacopeial Specifications — 10 Typical Properties Boiling point 235–2408C Density 0.915 g/cm3 Flash point 3308C Free fatty acids 40.1% Iodine value 80–100 Melting point À5toÀ48C Peroxide value 42 Refractive index 20 nD = 1.4676; 60 nD = 1.4561. 758 Triolein Solubility Soluble in chloroform, ether, carbon tetrachloride; 17 Related Substances slightly soluble in ethanol (95%); practically insoluble in water. — Specific gravity 0.9 at 258C (water = 1) Vapor density >1 (air = 1) 18 Comments Vapor pressure <133.3 Pa (<1 mmHg) at 258C Viscosity (kinematic) 74 mm2/s (74 cSt) at 258C Triolein enhances the transfection efficiency of polycation nano- structured lipid carrier.(4) Transferrin-conjugated solid lipid nano- 11 Stability and Storage Conditions particles containing triolein were found to enhance the delivery of quinine dihydrochloride to the brain for the treatment of cerebral Triolein is classified as a stable compound but is sensitive to air and malaria.(5) light. It should be stored in tightly sealed containers in a dry area at A nanoemulsion lipoprotein delivery system, comprising triolein 8 2–8 C. Thermal decomposition of triolein may lead to release of in its oily phase, has been found to show lower cytotoxicity than irritating gases and vapors such as carbon oxides. Exposure to air conventional systems in in vitro gene transfection in human glioma and moisture over prolonged periods should be avoided. cells.(6) Gadolinium-containing lipid nanoemulsions have also been prepared using triolein.(7) A w/o/w insulin emulsion system 12 Incompatibilities containing triolein in its oily phase has demonstrated strong (8) Triolein is incompatible with strong oxidizing agents and sponta- hypoglycemic effects. The use of multivescicular liposomes of neously flammable products. Being a triglyceride ester, triolein can breviscapine from a triolein/tricaprylin system as an intramuscular (9) be hydrolyzed by strong acids, and particularly by strong bases. It is injection for sustained delivery has been reported. possible for primary amines to form an adduct across the olefinic A paclitaxel prodrug has been incorporated into a lipid double bonds (analogous to a Michael addition). nanoparticle formulation comprising triolein in a mixture of lipids and has shown promising results in the treatment of folate receptor tumors.(10) Improved drug distribution to the tumor has been 13 Method of Manufacture reported with parenteral administration of a submicrometer lipid Triolein is manufactured by the esterification of fractionated fatty emulsion of paclitaxel with triolein as the oily core.(11) Folate acids, mainly oleic acid and glycerin. receptor-targeted solid lipid nanoparticles of hematoporphyrin containing triolein have also shown specific receptor binding and 14 Safety potential as a targeted drug delivery system.(12) Triolein is used in injectable preparations, in enteric coatings for The EINECS number for triolein is 204-534-7. The PubChem oral preparations, and in personal care products. Chronic exposure Compound ID (CID) for triolein is 5497163. may cause nausea and vomiting, and higher exposures may cause unconsciousness. 19 Specific References The Cosmetic Ingredient Review (CIR) Expert Panel found that 1 Yoshitomi H et al. Evaluation of enteric coated tablet sensitive to dermal application of triolein was not associated with significant pancreatic lipase. II. In vivo evaluation. Biol Pharm Bull 1993; 16: irritation, and no evidence of sensitization or photosensitization 1260–1263. was observed.(2) Ocular exposures were found to be only mildly 2 Johnson W Jr. Cosmetic Ingredient Review Expert Panel. Final report irritating to eyes. Triolein has not been found to be genotoxic in a on the safety assessment of trilaurin, triarachidin, tribehenin, tricaprin, tricaprylin, trierucin, triheptanoin, triheptylundecanoin, triisonanoin, number of in vitro and in vitro assay systems. Subcutaneous triisopalmitin, triisostearin, trilinolein, trimyristin, trioctanoin, triolein, injections of triolein in rats showed no tumors at the injection site. tripalmitin, tripalmitolein, triricinolein, tristearin, triundecanoin, gly- The CIR Expert Panel also noted that metabolism data indicated ceryl triacetyl hydroxystearate, glyceryl triacetyl ricinoleate, and that glyceryl triesters (including triolein) followed the same glyceryl state diacetate. Int J Toxicol 2001; 20(Suppl. 4): 61–94. metabolic pathways as fats in food. They were split into 3 Souza LC, Campa A. Pharmacological parameters of intravenously monoglycerides, free fatty acids, and glycerol, all of which were administered amphotericin B in rats: comparison of the conventional absorbed into the intestinal mucosa and metabolized further. formulation with amphotericin B associated with a triglyceride-rich Therefore, oral exposure to these compounds was not found to be emulsion. J Antimicrob Chemother 1999; 44: 77–84. T (2) 4 Zhang Z et al. Polycation nanostructured lipid carrier, a novel nonviral a concern. vector constructed with triolein for efficient gene delivery. Biochem A triolein-based amphotericin emulsion showed better safety Biophys Res Commun 2008; 370: 478–482. with a higher LD50 in rats as compared with the conventional 5 Gupta Y et al. Transferrin-conjugated solid lipid nanoparticles for amphotericin deoxycholate.(3) enhanced delivery of quinine dihydrochloride to the brain. J Pharm Pharmacol 2007; 59: 935–940. 15 Handling Precautions 6 Pan G et al. In vitro gene transfection in human glioma cells using a novel and less cytotoxic artificial lipoprotein delivery system. Pharm Observe normal precautions appropriate to the circumstances and Res 2003; 20: 738–744. quantity of the material handled. Use of a mask and/or respirator is 7 Ichikawa H et al. Formulation considerations of gadolinium lipid recommended in case aerosol/dust is formed. Ventilation is nanoemulsion for intravenous delivery to tumors in neutron-capture recommended to control dust or fumes from the material. For eye therapy. Curr Drug Deliv 2007; 4: 131–140. protection, safety glasses with side shields are recommended. For 8 Morishita M et al. Improving insulin enteral absorption using water-in- hand protection, PVC or other plastic material gloves are oil-in-water emulsion. Int J Pharm 1998; 172(1–2): 189–198. 9 Zhong H et al. Multivesicular liposome formulation for the sustained recommended. delivery of breviscapine. Int J Pharm 2005; 301: 15–24. 10 Stevens PJ et al. A folate receptor-targeted lipid nanoparticle formula- 16 Regulatory Status tion for a lipophilic paclitaxel prodrug. Pharm Res 2004; 21: 2153– Included in the FDA Inactive Ingredients