med 10

Table VI: LD50 values of selected polyoxyethylene castor oil derivatives.(24,25)

Gizurarson S, Aggerback H, Gudmundsson M, Heron I. Intranasal vaccination: pharmaceutical evaluation of the vaccine delivery system and immunokinetic characteristics of the immune response.

Name Animal and

route

LD50 (g/kg body-weight)

Pharm Dev Technol 1998; 3: 385–394.

Nerurkar MM, Burton PS, Borchardt RT. The use of surfactants to enhance the permeability of peptides through Caco-2 cells by

Polyoxyl 35 castor oil (Cremophor EL) Cat (oral) >10

inhibition of an apically polarized efflux system. Pharm Res 1996;

13: 528–534.

Miura M, Micca PL, Fisher CD, et al. Synthesis of a nickel tetracarbonylphenylporphyrin for boron neutron-capture therapy: biodistribution and toxicity in tumor-bearing mice. Int J Cancer 1996; 68: 114–119.

Polyoxyl 40 hydrogenated castor oil

Vergote GJ, Vervaet C, Van Driessche I, et al. An oral controlled release matrix pellet formulation containing nanocrystalline ketoprofen. Int J Pharm 2001; 219: 81–87.

Hua L, Weisan P, Jiayu L, Hongfei L. Preparation and evaluation

Polyoxyl 60 hydrogenated castor oil Mouse (IP) >12.5

Rat (oral) >16.0

Handling Precautions

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

Regulatory Status

Included in the FDA Inactive Ingredients Guide (IV injections and ophthalmic solutions). Included in parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Polyoxyethylene alkyl ethers; polyoxyethylene stearates.

Comments

Note that the trade name Cremophor (BASF Corp.) is also used for other polyoxyethylene derivatives, e.g., the Cremophor A series are polyoxyethylene alkyl ethers of cetostearyl alcohol.

Specific References

Macek TJ. Preparation of parenteral dispersions. J Pharm Sci

1963; 52: 694–699.

Webb NE. Method for solubilization of selected drug substances.

Bull Parenter Drug Assoc 1976; 30: 180–186.

Ran Y, Zhao L, Xu Q, Yalkowsky SH. Solubilization of cyclosporin A. AAPS Pharm Sci Tech 2001; 2(1): Article 2.

Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL: the drawbacks and advances of vehicle selection for drug formulation. Eur J Cancer 2001; 37: 1590–1598.

Gelderblom H, Loos WJ, Verweij J, et al. Modulation of cisplatin pharmacodynamics by Cremophor EL: experimental and clinical studies. Eur J Cancer 2002; 38: 205–213.

Holm R, Porter CJ, Edwards GA, et al. Examination of oral absorption and lymphatic transport of halofantrine in a triple- cannulated canine model after administration in self-microemulsi- fying drug delivery systems (SMEDDS) containing structured triglycerides. Eur J Pharm Sci 2003; 20: 91–97.

Kang BK, Lee JS, Chon SK, et al. Development of self- microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. Int J Pharm 2004; 274: 65–73.

Carmignani C, Rossi S, Saettone MF, Burgalassi S. Ophthalmic vehicles containing polymer-solubilized tropicamide: in vitro–in vivo evaluation. Drug Dev Ind Pharm 2002; 28: 101–105.

of microemulsion of vinpocetin for transdermal delivery. Pharma- zie 2004; 59: 274–278.

Ueda K, Yamazaki Y, Noto H, et al. Effect of oxyethylene moieties in hydrogenated castor oil on the pharmacokinetics of menate- trenone incorporated in O/W lipid emulsions prepared with hydrogenated castor oil and soybean oil in rats. J Drug Target 2003; 11: 37–43.

Itoh K, Matsui S, Tozuka Y, et al. Improvement of physicochemical properties of N-4472. Part II: characterization of N-4472 microemulsion and the enhanced oral absorption. Int J Pharm 2002; 246: 75–83.

Sakeada T, Hirano K. Effect of composition on biological fate of oil particles after intravenous injection of O/W lipid emulsions. J Drug Target 1998; 6: 273–284.

Kato Y, Hosokawa T, Okubo Y, et al. Modification of liposomes by addition of HCO60. II. Encapsulation of doxorubicin into liposomes containing HCO60. Biol Pharm Bull 1993; 16: 965–

969.

Kato Y, Watanabe K, Hosokawa T, et al. Modification of liposomes by addition of HCO60. I. Targeting of liposomes to liver by addition of HCO60 to liposomes. Biol Pharm Bull 1993; 16: 960–964.

Takada K, Furuya Y, Yoshikawa H, Muranishi S. Biological and pharmaceutical factors affecting the absorption and lymphatic delivery of cyclosporin A from gastrointestinal tract. J Pharmaco- biodyn 1988; 11: 80–87.

Takada K, Shibata N, Yoshimura H, et al. Promotion of the selective lymphatic delivery of cyclosporin A by lipid-surfactant mixed micelles. J Pharmacobiodyn 1985; 8: 320–323.

Berko S, Regdon GJr, Eros I. Solutol and cremophor products as new additives in suppository formulation. Drug Dev Ind Pharm 2002; 28: 203–206.

Berko S, Regdon GJr, Ducza E, et al. In vitro and in vivo study in rats of rectal suppositories containing furosemide. Eur J Pharm Biopharm 2002; 53: 311–315.

Tayrouz Y, Ding R, Burhenne J, et al. Pharmacokinetic and pharmaceutic interaction between digoxin and cremophor RH40. Clin Pharm Ther 2003; 73: 397–405.

BASF Corporation. Technical literature: Cremophor EL, 2004.

BASF Corporation. Technical literature: Cremophor RH grades, 2004.

Final report on the safety assessment of PEG-30, 33, 35, 36, and 40 castor oil and PEG-30 and 40 hydrogenated castor oil. Int J Toxicol 1997; 16(3): 269–306.

Forrest ARW, Watrasiewicz K, Moore CJ. Long-term althesin infusion and hyperlipidaemia. Br Med J 1977; 2: 1357–1358.

Dye D, Watkins J. Suspected anaphylactic reaction to cremophor EL. Br Med J 1980; 280: 1353.

Knell AJ, Turner P, Chalmers EPD. Potential hazard of steroid anaesthesia for prolonged sedation [letter]. Lancet 1983; i: 526.

Lawler PGP, McHutchon A, Bamber PA. Potential hazards of prolonged steroid anaesthesia [letter]. Lancet 1983; i: 1270–1271.

Moneret-Vautrin DA, Laxenaire MC, Viry-Babel F. Anaphylaxis caused by anti-cremophor EL IgG STS antibodies in a case of reaction to althesin. Br J Anaesth 1983; 55: 469–471.

Chapuis B, Helg C, Jeannet M, et al. Anaphylactic reaction to intravenous cyclosporine. N Engl J Med 1985; 312: 1259.

Polyoxyethylene Castor Oil Derivatives 579

Howrie DL, Ptachcinski RJ, Griffith BP, et al. Anaphylactoid reactions associated with parenteral cyclosporine use: possible role of cremophor EL. Drug Intell Clin Pharm 1985; 19: 425–427.

van Hooff JP, Bessems P, Beuman GH, Leunissen KML. Absence of allergic reaction to cyclosporin capsules in patient allergic to standard oral and intravenous solution of cyclosporin [letter]. Lancet 1987; ii: 1456.

Siddall SJ, Martin J, Nunn AJ. Anaphylactic reactions to tenipo- side. Lancet 1989; i: 394.

McCormick PA, Hughes JE, Burroughs AK, McIntyre N. Reformulation of injectable vitamin A: potential problems. Br Med J 1990; 301: 924.

Fja¨ llskog M-L, Frii L, Bergh J. Is cremophor EL, solvent for paclitaxel, cytotoxic? Lancet 1993; 342: 873.

Liebmann J, Cook JA, Mitchell JB. Cremophor EL, solvent for paclitaxel, and toxicity. Lancet 1993; 342: 1428.

Badary OA, Al-Shabanah OA, Al-Gharably NM, Elmazar MM. Effect of Cremophor EL on the pharmacokinetics, antitumor activity and toxicity of doxorubicin in mice. Anticancer Drugs 1998; 9: 809–815.

Sanchez H, Bigard X, Veksler V, et al. Immunosuppressive treatment affects cardiac and skeletal muscle mitochondria by the toxic effect of vehicle. J Mol Cell Cardiol 2000; 32: 323–331.

Bowers VD, Locker S, Ames S, et al. The hemodynamic effects of Cremophor-EL. Transplantation 1991; 51: 847–850.

Verani R. Cyclosporin nephrotoxicity in the Fischer rat. Clin Nephrol 1986; 25( Suppl 1): S9–13.

Thiel G, Hermle M, Brunner FP. Acutely impaired renal function during the intravenous administration of cyclosporin A: a cremophore side-effect. Clin Nephrol 1986; 25( Suppl 1): S40–42.

Windebank AJ, Blexrud MD, de Groen PC. Potential neurotoxicity of the solvent vehicle for cyclosporin. J Pharmacol Exp Ther 1994; 268: 1051–1056.

Kiorpes AL, Keith IM, Dubielzig RR. Pulmonary changes in rats following the administration of 3-methylindole in Cremophor EL. Histol Histopathol 1988; 3: 125–132.

General References

Rischin D, Webster LK, Millward MJ, et al. Cremophor pharmaco- kinetics in patients receiving 3, 6, and 24 hour infusions of paclitaxel. J Natl Cancer Inst 1996; 88: 1297–1301.

Polyoxyethylene Sorbitan Fatty Acid Esters

Nonproprietary Names

BP: Polysorbate 20, Polysorbate 40, Polysorbate 60,

and Polysorbate 80

JP: Polysorbate 80

Table II: Chemical names and CAS Registry Numbers of selected polysorbates.

Polysorbate Chemical name CAS number

PhEur: Polysorbatum 20, Polysorbatum 40, Polysorbatum

60, and Polysorbatum 80

USPNF: Polysorbate 20, Polysorbate 40, Polysorbate 60,

and Polysorbate 80

Synonyms

For synonyms of selected polysorbates, see Table I; see also

Section 3.

Chemical Names and CAS Registry Numbers

See Table II.

Empirical Formula and Molecular Weight

Approximate molecular weights for selected polysorbates are shown in Table III.

Polysorbate 20 Polyoxyethylene 20 sorbitan

monolaurate Polysorbate 21 Polyoxyethylene (4) sorbitan

monolaurate

Polysorbate 40 Polyoxyethylene 20 sorbitan

monopalmitate Polysorbate 60 Polyoxyethylene 20 sorbitan

monostearate Polysorbate 61 Polyoxyethylene (4) sorbitan

monostearate Polysorbate 65 Polyoxyethylene 20 sorbitan

tristearate

Polysorbate 80 Polyoxyethylene 20 sorbitan

monooleate

Polysorbate 81 Polyoxyethylene (5) sorbitan

monooleate

Polysorbate 85 Polyoxyethylene 20 sorbitan

trioleate

Polysorbate 120 Polyoxyethylene 20 sorbitan

Table I: Synonyms of selected polysorbates.

Polysorbate Synonym

Polysorbate 20 Armotan PML 20; Capmul POE-L; Campul POE-L Low PV; Crillet 1; Drewmulse; E432; Durfax 20; E432; Eumulgin SML; Glycosperse L-20; Hodag PSML-20; Lamesorb SML-20; Liposorb L-20; Liposorb L-20K; Montanox 20; Nissan Nonion LT-221; Norfox Sorbo T-20; POE-SML; Ritabate 20; Sorbax PML-20; sorbitan monododecanoate; Sorgen TW-20; T-Maz 20; T-Maz 20K; poly(oxy-1,2-ethanediyl) derivatives; polyoxyethylene 20 laurate; Protasorb L-20; Tego SML 20; Tween 20.

Polysorbate 21 Crillet 11; Hodag PSML-4; Protasorb L-5; Tween 21.

Polysorbate 40 Crillet 2; E434; Eumulgin SMP; Glycosperse S-20; Hodag PSMP-20; Lamesorb SMP-20; Liposorb P-20; Lonzest SMP-20; Montanox 40; poly(oxy-1,2-ethanediyl) derivatives; Protasorb P-20; Ritabate 40; sorbitan monohexadecanoate; Sorbax PMP- 20; Tween 40.

Polysorbate 60 Atlas 70K; Atlas Armotan PMS 20; Capmul POE-S; Cremophor PS 60; Crillet 3; Drewpone 60K; Durfax 60; Durfax 60K; E435; Emrite 6125; Eumulgin SMS; Glycosperse S-20; Glycosperse S-20FG; Glycosperse S-20FKG; Hodag PSMS-20; Hodag SVS- 18; Lamsorb SMS-20; Liposorb S-20; Liposorb S-20K; Lonzest SMS-20; Nikkol TS-10; Norfox SorboT-60 Montanox 60; Polycon T 60 K; polyoxyethylene 20 stearate; Ritabate 60; Protasorb S-20; Sorbax PMS-20; sorbitan monooctadecanoate poly(oxy-1,2-ethanediyl) derivatives; T-Maz 60; T-Max 60KHS; Tween 60; Tween 60K; Tween 60 VS.

Polysorbate 61 Crillet 31; Hodag PSMS-4; Liposorb S-4; Protasorb S-4; Tween 61.

Polysorbate 65 Alkamuls PSTS-20; Crillet 35; E436; Glycosperse TS-20; Glycosperse TS-20 FG; Glycosperse TS-20 KFG; Hodag PSTS-20; Lamesorb STS-20; Lanzet STS-20; Liposorb TS-20; Liposorb TS-20A; Liposorb TS-20K; Montanox 65; Protasorb STS-20; Sorbax PTS-20; sorbitan trioctadecanoate poly(oxy-1,2-ethanediyl) derivatives; T-Maz 65K; Tween 65; Tween 65K; Tween 65V.

Polysorbate 80 Atlas E; Armotan PMO 20; Capmul POE-O; Cremophor PS 80; Crillet 4; Crillet 50; Drewmulse POE-SMO; Drewpone 80K; Durfax 80; Durfax 80K; E433; Emrite 6120; Eumulgin SMO; Glycosperse O-20; Hodag PSMO-20; Liposorb O-20; Liposorb O-20K; Montanox 80; polyoxyethylene 20 oleate; Protasorb O-20; Ritabate 80; (Z)-sorbitan mono-9-octadecenoate poly(oxy1,2- ethanediyl) derivatives; Tego SMO 80; Tego SMO 80V; Tween 80.

Polysorbate 81 Crillet 41; Hetsorb O-5; Hodag PSMO-5; Protasorb O-5; Sorbax PMO-5; sorbitan mono-9-octadecenoate poly(oxy-1,2- ethanediyl) derivatives; T-Maz 81; Tego SMO 81; Tween 81.

Polysorbate 85 Alkamuls PSTO-20; Crillet 45; Glycosperse TO-20; Hodag PSTO-20; Lonzest STO-20; Liposorb TO-20; Montanox 85; Protasorb TO-20; Sorbax PTO-20; sorbitan tri-9-octadecenoate poly(oxy1,2-ethanediyl) derivatives; Tego STO 85; Tween 85.

Polysorbate 120 Crillet 6.

Polyoxyethylene Sorbitan Fatty Acid Esters 581

Table III: Empirical formula and molecular weight of selected polysorbates.

The resulting product is therefore a mixture of molecules of varying sizes rather than a single uniform compound.

Polysorbates containing 20 units of oxyethylene are hydro- philic nonionic surfactants that are used widely as emulsifying agents in the preparation of stable oil-in-water pharmaceutical

Structural Formula

114 26

emulsions. They may also be used as solubilizing agents for a variety of substances including essential oils and oil-soluble vitamins, and as wetting agents in the formulation of oral and parenteral suspensions. They have been found to be useful in improving the oral bioavailability of drug molecules that are substrates for p-glycoprotein.(1)

Polysorbates are also widely used in cosmetics and food products. See Table IV.

Table IV: Uses of polysorbates.

Use Concentration (%)

Emulsifying agent

Used alone in oil-in-water emulsions 1–15

Used in combination with hydrophilic emulsifiers in oil-in-water emulsions Used to increase the water-holding properties of ointments

Solubilizing agent

For poorly soluble active constituents in lipophilic bases

Wetting agent

For insoluble active constituents in lipophilic bases

1–10

0.1–3

8 Description

Polysorbates have a characteristic odor and a warm, somewhat bitter taste. Their colors and physical forms at 258C are shown in Table V, although it should be noted that the absolute color intensity of the products may vary from batch to batch and from manufacturer to manufacturer.

w + x + y + z = 20 (Polysorbates 20, 40, 60, 65, 80, and 85)

w + x + y + z = 5 (Polysorbates 81)

w + x + y + z = 4 (Polysorbates 21 and 61) R = fatty acid

Functional Category

Emulsifying agent; nonionic surfactant; solubilizing agent; wetting, dispersing/suspending agent.

Applications in Pharmaceutical Formulation or Technology

Polyoxyethylene sorbitan fatty acid esters (polysorbates) are a series of partial fatty acid esters of sorbitol and its anhydrides copolymerized with approximately 20, 5, or 4 moles of ethylene oxide for each mole of sorbitol and its anhydrides.

Table V: Colors and physical forms of selected polysorbates at 258C.

Polysorbate Color and form at 258C

Polysorbate 20 Yellow oily liquid

Polysorbate 21 Yellow oily liquid

Polysorbate 40 Yellow oily liquid

Polysorbate 60 Yellow oily liquid

Polysorbate 61 Tan solid

Polysorbate 65 Tan solid

Polysorbate 80 Yellow oily liquid

Polysorbate 81 Amber liquid

Polysorbate 85 Amber liquid

Polysorbate 120 Yellow liquid

Pharmacopeial Specifications

See Table VI.

582 Polyoxyethylene Sorbitan Fatty Acid Esters

med 10

728x90

468x60

mob

Wednesday, November 6, 2024

No comments:

Post a Comment

اتصل بنا