kywods

Observe normal precautions appropriate to the circumstances and quantity of material handled. No occupational exposure limits have been established. Under conditions of frequent use or heavy exposure, respiratory protection may be required. When heated, lauric acid emits an acrid smoke and irritating fumes; therefore, use in a well-ventilated area is recommended.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Lauric acid is listed as a food additive in the EAFUS list compiled by the FDA. Reported in the EPA TSCA Inventory.

Related Substances

Capric acid; myristic acid; palmitic acid; sodium laurate; stearic acid.

Capric acid

Empirical formula: C10H20O2

Molecular weight: 172.2

CAS number: [334-48-5]

Synonyms: n-capric acid; caprinic acid; caprynic acid; car- boxylic acid C10; decanoic acid; n-decanoic acid; decoic acid; decyclic acid; n-decylic acid; 1-nonanecarboxylic acid.

Appearance: white to pale yellow crystals with an unpleasant odor.

Acid value: 320–330 Boiling point: 2708C Melting point: 31.58C

Refractive index: n40 = 1.4288

Comments: capric acid is used as a flavoring agent in pharmaceutical preparations, providing a citrus-like flavor. It is used in cosmetics as an emulsifying agent. A specification for capric acid is included in the Food Chemicals Codex (FCC). The EINECS number for capric acid is 206-376-4.

Sodium laurate

Empirical formula: C12H23O2Na

Molecular weight: 222.34

CAS number: [629-25-4]

Comments: sodium laurate is used as an emulsifying agent and surfactant in cosmetics. The EINECS number for sodium laurate is 211-082-4.

Comments

Although not included in any pharmacopeias, a specification for lauric acid is contained in the Food Chemicals Codex (FCC);(25) see Table I.

The EINECS number for lauric acid is 205-582-1.

Specific References

Kravchenko IA, Golovenko NY, Larionov VB, et al. Effect of lauric acid on transdermal penetration of phenazepam in vivo. Bull Exp Biol Med 2003; 136(6): 579–581.

Chisty MNA, Bellantone RA, Taft DR, Plakogiannis FM. In vitro evaluation of the release of albuterol sulfate from polymer gels: effect of fatty acids on drug transport across biological membranes. Drug Dev Ind Pharm 2002; 28(10): 1221–1229.

Table I: FCC specification for lauric acid.(24)

Test FCC 1996

Acid value 252–287

Heavy metals 410 mg/kg

Iodine value 43

Residue on ignition 40.1%

Saponification value 253–287

Solidification point 26–448C

Unsaponifiable matter 40.3%

Water 40.2%

Stott PW, Williams AC, Barry BW. Mechanistic study into the enhanced transdermal permeation of a model beta-blocker, propranolol, by fatty acids: A melting point depression effect. Int J Pharm 2001; 219(1–2): 161–176.

Morimoto K, Haruta T, Tojima H, Takeuchi Y. Enhancing mechanisms of saturated fatty acids on the permeations of indomethacin and 6-carboxyfluorescein through rat skins. Drug Dev Ind Pharm 1995; 21(17): 1999–2012.

Ogiso T, Iwak IM, Hirota T, et al. Comparison of the in vitro penetration of propiverine with that of terodiline. Biol Pharm Bull 1995; 18(7): 968–975.

Aungst BJ, Blake JA, Hussain MA. Contributions of drug solubilization, partitioning, barrier disruption, and solvent per- meation to the enhancement of skin permeation of various compounds with fatty acids and amines. Pharm Res 1990; 7(7): 712–718.

Ogiso T, Shintani M. Mechanism for the enhancement effect of fatty acids on the percutaneous absorption of propranolol. J Pharm Sci 1990; 79(12): 1065–1071.

Pfister WR, Hsieh DST. Permeation enhancers compatible with transdermal drug delivery systems. Part I: Selection and formula- tion considerations. Pharm Technol 1990; 14(9): 132–140.

Green PG, Hadgraft J, Wolff M. Physicochemical aspects of the transdermal delivery of bupranolol. Int J Pharm 1989; 55(2–3): 265–269.

Green PG, Guy RH, Hadgraft J. In vitro and in vivo enhancement of skin permeation with oleic and lauric acids. Int J Pharm 1988; 48(1–3): 103–111.

Green PG, Hadgraft J. Facilitated transfer of cationic drugs across a lipoidal membrane by oleic acid and lauric acid. Int J Pharm 1987; 37(3): 251–255.

Ogiso T, Iwaki M, Kashitani Y, Yamashita K. Enhancement effect of lauric acid on the rectal absorption of propranolol from suppository in rats. Chem Pharm Bull 1991; 39(10): 2657–2661.

Muranishi S. Characteristics of drug absorption via the rectal route. Methods Find Exp Clin Pharmacol 1984; 12: 763–772.

Shojaei AH, Chang RK, Guo X, et al. Systemic drug delivery via the buccal mucosal route. Pharm Technol 2001; 25(6): 70–81.

Constantinides PP, Welzel G, Ellens H, et al. Water-in-oil microemulsions containing medium-chain fatty acids/salts: for- mulation and intestinal absorption enhancement evaluation. Pharm Res 1996; 13(2): 210–215.

Yamada K, Murakami M, Yamamoto A, et al. Improvement of intestinal absorption of thyrotropin-releasing hormone by chemi- cal modification with lauric acid. J Pharm Pharmacol 1992; 44(9): 717–721.

Buszello K, Harnisch S, Muller RH, Muller BW. The influence of alkali fatty acids on the properties and the stability of parenteral O/W emulsions modified with Solutol HS 15. Eur J Pharm Biopharm 2000; 49(2): 143–149.

Gupta PK, Hickey AJ. Contemporary approaches in aerosolized drug delivery to the lung. J Control Release 1991; 17(2): 129–147.

Health Evaluation Report on Lauric Acid Exposure during Flaking and Bagging Operations at Emery Industries, Los Angeles, CA. National Institute for Occupational Safety and Health, HHE 80- 160-897, NTIS Doc. No. PB 82-25694-2, 1981.

408 Lauric Acid

Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, and stearic acid. J Am Coll Toxicol 1987; 6(3): 321–401.

Verschueren K, ed. Handbook of Environmental Data of Organic Chemicals, 2nd edn. New York: Van Nostrand Reinhold, 1983: 793.

Swern D, Wieder R, McDonough M, et al. Investigation of fatty acids and derivatives for carcinogenic activity. Cancer Res 1970; 30: 1037.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2204.

Oro R, Wretlind A. Pharmacological effects of fatty acids, triolein, and cottonseed oil. Acta Pharmacol Toxicol 1961; 18: 141.

Food Chemicals Codex, 4th edn. Washington, DC: National Academy Press, 1996: 218.

Empirical Formula and Molecular Weight

The USPNF 23 describes lecithin as a complex mixture of acetone-insoluble phosphatides that consists chiefly of phos- phatidylcholine, phosphatidylethanolamine, phosphatidylser- ine, and phosphatidylinositol, combined with various amounts of other substances such as triglycerides, fatty acids, and carbohydrates as separated from a crude vegetable oil source. The composition of lecithin (and hence also its physical properties) varies enormously depending upon the source of the lecithin and the degree of purification. Egg lecithin, for example, contains 69% phosphatidylcholine and 24% phos- phatidylethanolamine, while soybean lecithin contains 21% phosphatidylcholine, 22% phosphatidylethanolamine, and

19% phosphatidylinositol, along with other components.(1)

Structural Formula

a-Phosphatidylcholine

R1 and R2 are fatty acids, which may be different or identical.

Lecithin is a complex mixture of materials; see Section 4. The structure above shows phosphatidylcholine, the principal component of egg lecithin, in its a-form. In the b-form, the phosphorus-containing group and the R2 group exchange positions.

Functional Category

Emollient; emulsifying agent; solubilizing agent.

Applications in Pharmaceutical Formulation or Technology

Lecithins are used in a wide variety of pharmaceutical applications; see Table I. They are also used in cosmetics(2) and food products.

Lecithins are mainly used in pharmaceutical products as dispersing, emulsifying, and stabilizing agents and are included in intramuscular and intravenous injections, parenteral nutri- tion formulations, and topical products such as creams and ointments.

Lecithins are also used in suppository bases,(3) to reduce the brittleness of suppositories, and have been investigated for their absorption-enhancing properties in an intranasal insulin formulation.(4) Lecithins are also commonly used as a component of enteral and parenteral nutrition formulations.

There is evidence that phosphatidylcholine (a major component of lecithin) is important as a nutritional supplement to fetal and infant development. Furthermore, choline is a required component of FDA-approved infant formulas.(5) Other studies have indicated that lecithin can protect against alcohol cirrhosis of the liver, lower serum cholesterol levels, and improve mental and physical performance.(6)

Liposomes in which lecithin is included as a component of the bilayer have been used to encapsulate drug substances; their potential as novel delivery systems has been investigated.(7) This application generally requires purified lecithins combined in specific proportions.

Therapeutically, lecithin and derivatives have been used as a pulmonary surfactant in the treatment of neonatal respiratory distress syndrome.

Table I: Uses of lecithin.

Use Concentration (%)

Aerosol inhalation 0.1

IM injection 0.3–2.3

Oral suspensions 0.25–10.0

Description

Lecithins vary greatly in their physical form, from viscous semiliquids to powders, depending upon the free fatty acid content. They may also vary in color from brown to light yellow, depending upon whether they are bleached or

410 Lecithin

unbleached or on the degree of purity. When they are exposed to air, rapid oxidation occurs, also resulting in a dark yellow or brown color.

Lecithins have practically no odor. Those derived from vegetable sources have a bland or nutlike taste, similar to that of soybean oil.

9 Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for lecithin.

Test USPNF 23

Water 41.5%

Lead 40.001%

Heavy metals 420 mg/g

Acid value +

Hexane-insoluble matter 40.3%

Acetone-insoluble matter —

Organic volatile impurities +

10 Typical Properties

Density:

0.97 g/cm3 for liquid lecithin;

0.5 g/cm3 for powdered lecithin.

Iodine number:

95–100 for liquid lecithin; 82–88 for powdered lecithin.

Isoelectric point: ≈3.5

Saponification value: 196

Solubility: lecithins are soluble in aliphatic and aromatic hydrocarbons, halogenated hydrocarbons, mineral oil, and fatty acids. They are practically insoluble in cold vegetable and animal oils, polar solvents, and water. When mixed with water, however, lecithins hydrate to form emulsions.

Stability and Storage Conditions

Lecithins decompose at extreme pH. They are also hygroscopic and subject to microbial degradation. When heated, lecithins oxidize, darken, and decompose. Temperatures of 160–1808C will cause degradation within 24 hours.

Fluid or waxy lecithin grades should be stored at room temperature or above; temperatures below 108C may cause separation.

All lecithin grades should be stored in well-closed containers protected from light and oxidation. Purified solid lecithins should be stored in tightly closed containers at subfreezing temperatures.

Incompatibilities

Incompatible with esterases owing to hydrolysis.

Method of Manufacture

Lecithins are essential components of cell membranes and, in principle, may be obtained from a wide variety of living matter. In practice, however, lecithins are usually obtained from vegetable products such as soybean, peanut, cottonseed, sunflower, rapeseed, corn, or groundnut oils. Soybean lecithin is the most commercially important vegetable lecithin. Lecithin

obtained from eggs is also commercially important and was the first lecithin to be discovered.

Vegetable lecithins are obtained as a by-product in the vegetable oil refining process. Polar lipids are extracted with hexane and, after removal of the solvent, a crude vegetable oil is obtained. Lecithin is then removed from the crude oil by water extraction. Following drying, the lecithin may be further purified.(1)

With egg lecithin, a different manufacturing process must be used since the lecithin in egg yolks is more tightly bound to proteins than in vegetable sources. Egg lecithin is thus ob- tained by solvent extraction from liquid egg yolks using ac- etone or from freeze-dried egg yolks using ethanol (95%).(1)

Synthetic lecithins may also be produced.

Safety

Lecithin is a component of cell membranes and is therefore consumed as a normal part of the diet. Although excessive consumption may be harmful, it is highly biocompatible and oral doses of up to 80 g daily have been used therapeutically in the treatment of tardive dyskinesia.(8) When used in topical formulations, lecithin is generally regarded as a nonirritant and nonsensitizing material.(2) The Cosmetic Ingredients Review Expert Panel (CIR) has reviewed lecithin and issued a tentative report revising the safe concentration of the material from 1.95% to 15.0% in rinse-off and leave-in products. They note, however, that there are insufficient data to rule on products that are likely to be inhaled.(9)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Lecithins may be irritant to the eyes; eye protection and gloves are recommended.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (inhalations; IM and IV injections; otic preparations; oral capsules, suspensions and tablets; rectal, topical, and vaginal prepara- tions). Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

—

Comments

Poloxamer lecithin organogels have been used in topical formulations for the delivery of non-steroidal anti-inflamma- tory drugs.(10)

Lecithins contain a variety of unspecified materials; care should therefore be exercised in the use of unpurified lecithin in injectable or topical dosage forms, as interactions with the active substance or other excipients may occur. Unpurified lecithins may also have a greater potential for irritancy in formulations.

Supplier’s literature should be consulted for information on the different grades of lecithin available and their applications in formulations.

Lecithin 411

A specification for lecithin is contained in the Food Chemicals Codex (FCC). The EINECS number for lecithin is 232-307-2.

Specific References

Schneider M. Achieving purer lecithin. Drug Cosmet Ind 1992;

150(2): 54, 56, 62, 64, 66, 101–103.

Anonymous. Lecithin: its composition, properties and use in cosmetic formulations. Cosmet Perfum 1974; 89(7): 31–35.

Novak E, Osborne DW, Matheson LE, et al. Evaluation of cefmetazole rectal suppository formulation. Drug Dev Ind Pharm 1991; 17(3): 373–389.

Anonymous. Intranasal insulin formulation reported to be promising. Pharm J 1991; 247: 17.

US Congress. Infant Formula Act of 1980. Public Law 96-359, 1980.

Canty D, Zeisel S, Jolitz A. Lecithin and Choline Research Update on Health and Nutrition. Fort Wayne, IN: Central Soya Company, Inc, 1996.

Grit M, Zuidam NJ, Underberg WJM, Crommelin DJA. Hydro- lysis of partially saturated egg phosphatidylcholine in aqueous liposome dispersions and the effect of cholesterol incorporation on hydrolysis kinetics. J Pharm Pharmacol 1993; 45: 490–495.

Growdon JH, Gelenberg AJ, Doller J, et al. Lecithin can suppress tardive dyskinesia [letter]. N Engl J Med 1978; 298: 1029–1030.

Anonymous. ‘The Rose Sheet’ FDC Reports 1997; 18(39): 8.

Franckum J, Ramsey D, Das NG, Das SK. Pluronic lecithin organogel for local delivery of anti-inflammatory drugs. Int J Pharm Compound 2004; 8(2): 101–105.

General References

Arias C, Rueda C. Comparative study of lipid systems from various sources by rotational viscometry and potentiometry. Drug Dev Ind Pharm 1992; 18: 1773–1786.

Hanin I, Pepeu G, eds. Phospholipids: Biochemical, Pharmaceutical and Analytical Considerations. New York: Plenum Press, 1990.

JP: L-Leucine PhEur: Leucinum USP: Leucine

Synonyms

a-Aminoisocaproic acid; L-a-aminoisocaproic acid; 2-amino-4- methylpentanoic acid; 2-amino-4-methylvaleric acid; a-amino- g-methylvaleric acid; 1,2-amino-4-methylvaleric acid; DL-leu- cine; L-leucine; leu; 4-methylnorvaline.

Chemical Name and CAS Registry Number

L-Leucine [61-90-5]

Empirical Formula and Molecular Weight

C6H13NO2 131.20

Structural Formula

Functional Category

Antiadherent; flavoring agent; lubricant.

Applications in Pharmaceutical Formulation or Technology

Leucine is used in pharmaceutical formulations as a flavoring agent.(1) It has been used experimentally as an antiadherent to improve the deagglomeration of disodium cromoglycate microparticles in inhalation preparations;(2) and as a tablet lubricant.(3) Leucine copolymers have been shown to success- fully produce stable drug nanocrystals in water.(4)

Description

Leucine occurs as a white or almost off-white crystalline powder or shiny flakes.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for leucine.

Test JP 2001 PhEur 2005 USP 28

Chloride 40.021% 4200 ppm 40.05%

Sulfate 40.028% 4300 ppm 40.03%

Ammonium 40.02% 4200 ppm —

Ninhydrin-positive — + —

substances

Iron — 410 ppm 40.003%

Heavy metals 420 ppm 410 ppm 40.0015%

Arsenic 42 ppm — —

Other amino acids + — —

Loss on drying 40.30% 40.5% 40.2%

Residue on ignition 40.10% 40.1% 40.4%

Organic volatile — — +

impurities

Assay 598.5% 98.5—101.5% 98.5—101.5%

Typical Properties

Density: 1.293 g/cm3

Dissociation constant: pKa = 2.35 at 138C.

Isoelectric point: 6.04

Melting point: 2938C

Solubility: soluble in acetic acid, ethanol (99%) and water.

Practically insoluble in ether.

Stability and Storage Conditions

Leucine is sensitive to light and moisture and should be stored in an airtight container in a cool, dark, dry place.

Incompatibilities

Leucine is incompatible with strong oxidizing agents.

Method of Manufacture

Leucine is produced microbially by incubating an amino-acid- producing microorganism including but not exclusive to Pseudomonas, Escherichia, Bacillus, or Staphylococcus in the presence of oxygen and a hydrocarbon. The nutrient medium should contain an inhibitory amount of a growth inhibitor that is a chemically similar derivative of leucine, e.g: methylallyl- glycine, a-hydrozinoisocaproic acid, or b-cyclopentanealanine, so as to inhibit the growth of the organism except for at least one mutant that is resistant to the inhibitory effect. The resistant mutant is then isolated and grown in the presence of oxygen and the hydrocarbon in the absence of the inhibitor. The mutant cells are then harvested and a nutrient medium is

Leucine 413

formed that includes a hydrocarbon as the sole source of carbon. Finally, the harvested cells are incubated in the medium in the presence of oxygen.(5)

Safety

Leucine is an essential amino acid and is consumed as part of a normal diet. It is generally regarded as a nontoxic and nonirritant material. It is moderately toxic by the subcutaneous route.

LD50 (rat, IP): 5.379 g/kg(6)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of the material handled.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (IV infusion; oral tablets). Included in nonparenteral medicines licensed in the UK.

Related Substances

DL-Leucine

Empirical formula: C6H13NO2 Molecular weight: 131.20 Appearance: white leaflets.

Dissociation constant:

pKa1 = 2.36;

pKa2 = 9.60.

Solubility: soluble in ethanol (90%) and water. Practically insoluble in ether.

Comments

A specification for leucine is included in the Food Chemicals Codex (FCC). The EINECS number for leucine is 200-522-0.

Specific References

Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd edn. Endicott, NY: Synapse Information Resources, 2002: 542.

Abdolhossien RN, Kambiz G, Mohahhadali B, Morteza R. The effect of vehicle on physical properties and aerosolisation behaviour of disodium cromoglycate microparticles spray dried alone or with L-leucine. Int J Pharm 2004; 285: 97–108.

Gusman S, Gregoriades D. Effervescent potassium chloride tablet. United States Patent No. 3,903,255; 1975.

Lee J, Lee SJ, Choi JY, et al. Amphiphilic amino acid copolymers as stabilizers for the preparation of nanocrystal dispersion. Eur J Pharm Sci 2005; 24: 441–449.

Mobil Oil Corp. Synthesis of amino acids. UK Patent No. 1 071 935; 1967.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2224.

Emersol 310; Emersol 315; leinoleic acid; 9-cis,12-cis-linoleic acid; 9,12-linoleic acid; linolic acid; cis,cis-9,12-octadecadi- enoic acid; Pamolyn; Polylin No. 515; telfairic acid.

Chemical Name and CAS Registry Number

(Z,Z)-9,12-Octadecadienoic acid [60-33-3]

Empirical Formula and Molecular Weight

C18H32O2 280.45

Structural Formula

Functional Category

Dietary supplement; emulsifying agent; skin penetrant.

Applications in Pharmaceutical Formulation or Technology

Linoleic acid is used in topical transdermal formulations,(1–14) in oral formulations as an absorption enhancer,(15,16) and in topical cosmetic formulations as an emulsifying agent.(17) It is also administered in parenteral emulsions as a dietary sup- plement.

Description

Linoleic acid occurs as a colorless to light-yellow-colored oil.

Pharmacopeial Specifications

See Section 18.

Typical Properties

Boiling point: 2308C at 16 mmHg

Density: 0.9007 g/cm3

Iodine value: 181.1

Melting point: –58C

Refractive index: n20 = 1.4699

Solubility: freely soluble in ether; soluble in ethanol (95%); miscible with dimethylformamide, fat solvents, and oils.

Stability and Storage Conditions

Linoleic acid is sensitive to air, light, moisture, and heat. It should be stored in a tightly sealed container under an inert atmosphere and refrigerated.

Incompatibilities

Linoleic acid is incompatible with bases, strong oxidizing agents, and reducing agents.

Method of Manufacture

Linoleic acid is obtained by extraction from various vegetable oils such as safflower oil.

Safety

Linoleic acid is widely used in cosmetics and topical pharma- ceutical formulations and is generally regarded as a nontoxic material. On exposure to the eyes, skin, and mucous membranes, linoleic acid can cause mild irritation.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Gloves and eye protection are recommended.

Regulatory Status

GRAS listed. Approved for use in foods in Europe and the USA.

Related Substances

Ethyl linoleate; methyl linoleate.

Ethyl linoleate

Empirical formula: C20H36O2

CAS number: [544-35-4]

Synonyms: linoleic acid ethyl ester; 9,12-octadecadienoic acid ethyl ester; vitamin F.

Comments: ethyl linoleate is used in pharmaceutical formula- tions as an emollient and humactent. It is also used as a solvent for fats. The EINECS number for ethyl linoleate is 208-868-4.

Methyl linoleate

Empirical formula: C19H34O2

CAS number: [112-63-0]

Synonyms: 9,12-octadecadienoic acid, methyl ester.

Comments: methyl linoleate is used in cosmetics as an emollient. The EINECS number for methyl linoleate is 203-993-0.

Comments

Studies have shown that conjugated linoleic acid increases paracellular permeability across human intestinal-like Caco-2

Linoleic Acid 415

cell monolayers, and consequently may also, as a dietary supplement, increase calcium absorption in vivo.(16)

Linoleic acid has been shown to reduce skin irritation following acute perturbations, exhibiting clinical effects that are comparable to glucocorticoids.(17)

A pre-emulsified linoleic acid system has been used to investigate the protective actions of phenolic compounds against lipid peroxidation.(18)

Although not included in any pharmacopeias, a specifica- tion for linoleic acid is contained in the Food Chemicals Codex (FCC); see Table I.

The EINECS number for linoleic acid is 200-470-9.

Table I: FCC Specification for linoleic acid.(19)

Tanojo H, Junginger HE. Skin permeation enhancement by fatty acids. J Dispers Sci Technol 1999; 20(1–2): 127–138.

Bhatia KS, Singh J. Synergistic effect of iontophoresis and a series of fatty acids on LHRH permeability through porcine skin. J Pharm Sci 1998; 87: 462–469.

Santoyo S, Arellano A, Ygartua P, Martin C. Penetration enhancer effects on the in vitro percutaneous absorption of piroxicam through rat skin. Int J Pharm 1995; 117(18): 219–224.

Carelli V, Di Colo G, Nannipieri E, Serafini MF. Enhancement effects in the permeation of alprazolam through hairless mouse skin. Int J Pharm 1992; 88(8): 89–97.

Ibrahim SA, Hafez E, El-Shanawany SM, et al. Formulation and evaluation of some topical antimycotics. Part 3. Effect of promotors on the in vitro and in vivo efficacy of clotrimazole ointment. Bull Pharm Sci Assiut Univ 1991; 14(1–2): 82–94.

12 Swafford SK, Bergmann WR, Migliorese KG, et al. Characteriza-

Test FCC 1996

Identification +

Acid value 196–202

Heavy metals 410 mg/kg

Iodine value 145–160

Residue on ignition 40.01%

Saponification value 194–202

Unsaponifiable matter 42.0%

Water 40.5%

Assay 560%

Specific References

Gwak HS, Chun IK. Effect of vehicles and penetration enhancers on the in vitro percutaneous absorption of tenoxicam through hairless mouse skin. Int J Pharm 2002; 236(1–2): 57–64.

Bhattachrya A, Ghosal SK. Effect of hydrophobic permeation enhancers on the release and skin permeation kinetics from matrix type transdermal drug delivery system of ketotifen fumarate. Acta Pol Pharm 2001; 58(2): 101–105.

Gwack HS, Chun IK. Effect of vehicles and enhancers on the in vitro skin permeation of aspalatone and its enzymatic degradation across rat skins. Arch Pharm Res 2001; 24(6): 572–577.

Shin SC, Shin EY, Chow CW. Enhancing effects of fatty acids on piroxicam permeation through rat skins. Drug Dev Ind Pharm 2000; 26(5): 563–566.

Meaney CM, O’Driscoll CM. Comparison of the permeation enhancement potential of simple bile salt and mixed bile salt: fatty acid micellar systems using the Caco-2 cell culture model. Int J Pharm 2000; 207(10): 21–30.

Effect of hydrophobic permeation enhancers on the release and skin permeation kinetics from matrix type transdermal drug delivery system of ketotifen fumarate. Eastern Pharmacist 2000; 43: 109–112.

tion of swollen micelles containing linoleic acid in a microemulsion system. J Soc Cosmet Chem 1991; 42: 235–247.

Mahjour M, Mauser BE, Fawzi MB. Skin permeation enhance- ment effects of linoleic acid and Azone on narcotic analgesics. Int J Pharm 1989; 56(1): 1–11.

Gwak HS, Oh IS, Chun IK. Transdermal delivery of ondansetron hydrochloride: effects of vehicles and penetration enhancers. Drug Dev Ind Pharm 2004; 30(2): 187–194.

Muranushi N, Nakajima Y, Kinugawa M, et al. Mechanism for the inducement of the intestinal absorption of poorly absorbed drugs by mixed micelles. Part 2. Effect of the incorporation of various lipids on the permeability of liposomal membranes. Int J Pharm 1980; 4: 281–290.

Jewell C, Cashmen KD. The effect of conjugated linoleic acid and medium-chain fatty acids on transepithelial calcium transport in human intestine-like Caco-2 cells. Br J Nutr 2003; 89(5): 639–647.

Schurer NY. Implementation of fatty acid carriers to skin irritation and the epidermal barrier. Contact Dermatitis 2002; 47(4): 199–

205.

Cheng Z, Ren J, Li Y, et al. Establishment of a quantitative structure–activity relationship model for evaluating and predicting the protective potentials of phenolic antioxidants on lipid peroxidation. J Pharm Sci 2003; 92(3): 475–484.

Food Chemicals Codex, 4th edn. Washington, DC: National Academy Press, 1996: 227.

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