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Cetalkonium chloride

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Cetalkonium chloride
Names
IUPAC name
Benzylhexadecyldimethylazanium chloride
Other names
Benzyldimethylhexadecylammonium chloride; Benzyldimethyl-n-hexadecylammonium chloride; Cetyldimethylbenzylammonium chloride
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.004.116 Edit this at Wikidata
  • InChI=1S/C25H46N.ClH/c1-4-5-6-7-8-9-10-11-12-13-14-15-16-20-23-26(2,3)24-25-21-18-17-19-22-25;/h17-19,21-22H,4-16,20,23-24H2,1-3H3;1H/q+1;/p-1
    Key: SXPWTBGAZSPLHA-UHFFFAOYSA-M
  • InChI=1/C25H46N.ClH/c1-4-5-6-7-8-9-10-11-12-13-14-15-16-20-23-26(2,3)24-25-21-18-17-19-22-25;/h17-19,21-22H,4-16,20,23-24H2,1-3H3;1H/q+1;/p-1
    Key: SXPWTBGAZSPLHA-REWHXWOFAX
  • CCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1.[Cl-]
Properties
C25H46ClN
Molar mass 396.10 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Cetalkonium chloride (CKC) is a quaternary ammonium compound of the alkyl-benzyldimethylammonium chlorides family, the alkyl group having a chain length of C16 (16 carbons). It is used in pharmaceutical products either as an excipient (Cationorm®, Retaine MGD®) or as an active ingredient (Bonjela®, Pansoral®). It may be found in very small amount in the excipient benzalkonium chloride mixture (typically less than 5% of the total mixture).

Properties

At 20 °C, cetalkonium chloride is soluble in alcohols, acetone, ethyl acetate, propylene glycol, sorbitol solutions, glycerol, ether, slightly in water (2 mg/ml at 25 °C) and readily soluble in oils (triglycerides and mineral oils).

Availability

Cetalkonium chloride is purchased as a raw material in dry form as a white powder.

Applications

Cetalkonium chloride can be used in different applications depending on its concentration.

Anti-infective agent

It can be used as an active ingredient to relieve the pain of mouth ulcers and denture sores in buccal solutions or gels such as Pansoral® (Pierre Fabre laboratories) or in Bonjela® (Reckitt Benckiser Healthcare). The usual concentration in these products is 0.01% (w/w). However, it is not known as a very potent bactericidal compound, mainly because of its low solubility in water. For example, US and European pharmacopeias enforce suppliers of benzalkonium chloride (BAK) to limit the amount of cetalkonium chloride in the mixture to less than 5% w/w. Indeed the bactericical and bacteriostatic properties of BAK are due to the C12 dodecyl and C14 myristyl alkyl derivatives.

Cationic surface-active agent

Cetalkonium chloride can also be used as a pharmaceutical excipient due to its amphiphilic property and cationic charge. For example, it has recently been included in a contact lens to bind an anionic active drug to serve as reservoir and extend the release rate of the molecule.[1] Most frequently, it is used as an emulsifier and cationic agent in ophthalmic nanoemulsions (Cationorm® from Santen and Retaine MGD® from Ocusoft). Due to its high lipophilicity, cetalkonnium chloride is strongly associated to oil nanodroplets at the oil/water interface in oil-in-water emulsions, hence providing a positive charge at the surface of the oil nanodroplets. This polarization of the nanodroplets stabilizes the emulsion by creating an electrostatic repulsion between the nanodroplets and is the driving force behind the biological adhesion of the nanodroplets to negatively charged cell epithelium in vivo.[2] In life science the cationic charge of cetalkonium is used to separate biological extracts according to their charge,.[3][4]

Biological activity

Biological activity of cetalkonium chloride as excipient has been widely described in the scientific literature[5] and books.[6] Cetalkonium chloride acts by creating a positive charge that provides bioadhesive properties of the cationic nanoemulsions on the negatively charged ocular surface. Hence, increasing the penetration of active ingredients formulated in cationic nanoemulsions into ocular tissues.[7] Even more, cetalkonium chloride cationic emulsions seem to improve healing of corneal lesions.[8]

Toxicology

The product as raw material is classified:[9] 67/548/EEC: Xn;R21/22 C;R34 N;R50

GHS/CLP: Acute Tox. 4;H302 - Acute Toxicity. 4;H312 - Skin Corr. 1B;H314 - Aquatic Acute 1;H400

Human health: the raw material is harmful in contact with skin and if swallowed, may cause severe skin burns and eye damage. If in repeated or prolonged contact with skin it may cause allergic reactions in sensitive individuals.

Ecotoxicity: Very toxic to aquatic life.

Degradability: The product is easily biodegradable; approx. 70% (FeF Chemicals A/S, 1993).

LD (oral, rat) > 500 mg/kg; moderately toxic by ingestion.

Safety

Even though cetalkonium chloride is belongs to the family of benzalkonium chloride, the ophthalmic use of cetalkonium chloride cationic nanoemulsions has been shown to be very safe in animal model [10] and human.[11] These observations are explained by the fact that cetalkonium chloride present in oil-in-water emulsions is bound to the oil nanodroplets therefore sequestered from the water phase and not available to cause damages to ocular tissues.[12] Pansoral® has been on the market since 1981 and Cationorm® since 2008. Both products being well accepted by patients.

Conversely, a 2015 study showed a "considerable" corneal toxicity in Cationorm.[13]

Regulatory

Cetalkonium is listed on the FDA OTC ingredient list updated April 2010.[14] The MHRA has published in 2012 the “Consolidated list of substances which are present in authorized medicines for general sale” in which CKC is cited. The highest authorized concentration is 0.1% when administered topically and in the mouth.[15]

References

  1. ^ Bengani LC, Chauhan A. Extended delivery of an anionic drug by contact lens loaded with a cationic surfactant. Biomaterials. 2013 Apr;34(11):2814-21
  2. ^ Lallemand F, Daull P, Benita S, Buggage R, Garrigue JS. Successfully improving ocular drug delivery using the cationic nanoemulsion, Novasorb. J Drug Deliv. 2012
  3. ^ Philipp S, Jakoby T, Tholey A, Janssen O, Leippe M, Gelhaus C. Cationic detergents enable the separation of membrane proteins of Plasmodium falciparum-infected erythrocytes by 2D gel electrophoresis. Electrophoresis. 2012 Apr;33(7):1120-8
  4. ^ Nothwang HG, Schindler J. Two-dimensional separation of membrane proteins by 16-BAC-SDS-PAGE. Methods Mol Biol. 2009;528:269-77
  5. ^ Lallemand F, Daull P, Benita S, Buggage R, Garrigue JS. Successfully improving ocular drug delivery using the cationic nanoemulsion, Novasorb. J Drug Deliv. 2012
  6. ^ Lallemand F, Daull P, Garrigue JS, Development of a cationic nanoemulsion platform (Novasorb) for ocular delivery; J das Neves, B Sarmento Editors, Mucosal delivery of biopharmaceuticals, Springer Science New York 2014
  7. ^ Daull P, Lallemand F, Philips B, Lambert G, Buggage R, Garrigue JS. Distribution of cyclosporine A in ocular tissues after topical administration of cyclosporine A cationic emulsions to pigmented rabbits. Cornea. 2013 Mar;32(3):345-54
  8. ^ Liang H, Baudouin C, Daull P, Garrigue JS, Buggage R, Brignole-Baudouin F. In vitro and in vivo evaluation of a preservative-free cationic emulsion of latanoprost in corneal wound healing models. Cornea. 2012 Nov;31(11):1319-29
  9. ^ http://www.fefchemicals.com/media/63520/cetalkonium_chloride__ckc__gb_10.0.pdf
  10. ^ Liang, H., F. Brignole-Baudouin, et al. (2008). "Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions: an in vivo study in rabbits." Mol Vis 14: 204-16
  11. ^ Amrane M, Creuzot-Garcher C, Robert PY, Ismail D, Garrigue JS, Pisella PJ, Baudouin C. Ocular tolerability and efficacy of a cationic emulsion in patients with mild to moderate dry eye disease - A randomised comparative study. J Fr Ophtalmol. 2014 Oct;37(8):589-98
  12. ^ Daull P, Lallemand F, Garrigue JS. Benefits of cetalkonium chloride cationic oil-in-water nanoemulsions for topical ophthalmic drug delivery. J Pharm Pharmacol. 2014 Apr;66(4):531-41
  13. ^ Pinheiro, Ralph; Panfil, Claudia; Schrage, Norbert; Dutescu, Ralf Michael (2015-10-01). "Comparison of the lubricant eyedrops Optive®, Vismed Multi®, and Cationorm® on the corneal healing process in an ex vivo model". European Journal of Ophthalmology. 25 (5): 379–384. doi:10.5301/ejo.5000593. ISSN 1724-6016. PMID 25790809.
  14. ^ http://www.fda.gov/downloads/aboutfda/centersoffices/cder/ucm135688.pdf
  15. ^ http://www.mhra.gov.uk/home/groups/pl-a/documents/websiteresources/con009485.pdf

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