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Drugs and Health Products

MARIGOLD EXTRACT AND ISOLATES (LUTEIN AND ZEAXANTHIN)

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This monograph is intended to serve as a guide to industry for the preparation of Product Licence Applications (PLAs) and labels for natural health product market authorization. It is not intended to be a comprehensive review of the medicinal ingredients.

Notes

  • Text in parentheses is additional optional information which can be included on the PLA and product label at the applicant's discretion.
  • The solidus (/) indicates that the terms and/or statements are synonymous. Either term or statement may be selected by the applicant.
  • A product may include one or more of the ingredients listed in Table 1.

Date

February 25, 2019

Proper name(s), Common name(s), Source material(s)

Table 1. Proper name(s), Common name(s), Source material(s)
Proper name(s) Common name(s) Source material(s)
Proper name(s) Part(s) Common name(s) Preparation

Tagetes erecta

  • Marigold (Tagetes erecta) extract
  • Marigold extract

Tagetes erecta

Flower

N/A

Dried

3R,3´R,6´R)-beta,epsilon-carotene-3,3´-diol

Lutein

Tagetes erecta

Herb flowering oleoresin

N/A

N/A

Lutein Synthetic

  • (3R,3'R)-beta,beta-carotene-3,3'-diol
  • all-trans-beta-Carotene-3,3'-diol

Zeaxanthin

Tagetes erecta

Herb flowering oleoresin

N/A

N/A

Zeaxanthin Synthetic

Lutein esters

Lutein esters

Tagetes erecta

Herb flowering oleoresin

N/A

N/A

Lutein ester Synthetic

Zeaxanthin esters

Zeaxanthin esters

Tagetes erecta

Herb flowering oleoresin

N/A

N/A

Zeaxanthin esters Synthetic

References: Proper names: ChemIDplus 2018, USDA 2018, US FDA 2016, FAO/WHO 2014, USP 34 2011; Common names: ChemIDplus 2018, US FDA 2016, FAO/WHO 2014, USP 34 2011, WHO 2005; Source materials: FAO/WHO 2014, USP 34 2011, WHO 2005.

Route of Administration

Oral

Dosage Form(s)

This monograph excludes foods or food-like dosage forms as indicated in the Compendium of Monographs Guidance Document.

Acceptable dosage forms for the age category listed in this monograph and specified route of administration are indicated in the Compendium of Monographs Guidance Document.

Use(s) or Purpose(s)

  • Source of/Provides antioxidants (for the maintenance of good health) (Miranda et al. 2006; Blakely et al. 2003; Dwyer et al. 2001).
  • Source of/Provides antioxidants for the maintenance of eye health (Miranda et al. 2006; Blakely et al. 2003; Dwyer et al. 2001).
  • Helps to maintain eyesight/support eye health in conditions (associated with sunlight damage), such as cataracts and age-related macular degeneration (Christen et al. 2008; Fletcher et al. 2008; Johnson et al. 2008; Moeller et al. 2008; Alves-Rodrigues and Shao 2004; Richer et al. 2004; Olmedilla et al. 2003; Brown et al. 1999).
  • Helps to reduce the risk of developing cataracts (Christen et al. 2008; Moeller et al. 2008; Brown et al. 1999; Chasan-Taber et al. 1999).
  • Helps to improve macular pigment optical density (Johnson et al. 2008; Richer et al. 2004; Berendschot et al. 2000).

Dose(s)

Subpopulation(s)

Adults 18 years and older

Quantity(ies)

LUTEIN AND ZEAXANTHIN

Method of preparation: Isolate

Antioxidant

Lutein
Not to exceed 20 milligrams of lutein, per day (Christen et al. 2008; Fletcher et al. 2008; Johnson et al. 2008; Moeller et al. 2008).

Zeaxanthin (Optional)
Not to exceed 2.5 milligrams of zeaxanthin, per day (Christen et al. 2008; Fletcher et al. 2008; Johnson et al. 2008; Moeller et al. 2008).

Eyesight

Lutein
6 - 20 milligrams of lutein, per day (Shao and Hathcock 2006; WHO 2005; Alves-Rodrigues and Shao 2004; Richer et al. 2004; Olmedilla et al. 2003; Brown et al. 1999).

Zeaxanthin (Optional)
0.7 - 2.5 milligrams of zeaxanthin, per day (Shao and Hathcock 2006; WHO 2005; Alves-Rodrigues and Shao 2004; Richer et al. 2004; Olmedilla et al. 2003; Brown et al. 1999).

LUTEIN AND ZEAXANTHIN ESTERS

Method of preparation: Isolate

Antioxidant

Lutein esters
Not to exceed 40 milligrams of lutein esters, per day (Christen et al. 2008; Fletcher et al. 2008; Johnson et al. 2008; Moeller et al. 2008).

Zeaxanthin esters (Optional)
Not to exceed 5 milligrams of zeaxanthin esters, per day (FAO/WHO 2014; USP 34 2011; Christen et al. 2008; Fletcher et al. 2008; Johnson et al. 2008; Moeller et al. 2008).

Eyesight

Lutein esters
12 - 40 milligrams of lutein esters, per day (Bone and Landrum 2010; Shao and Hathcock 2006; WHO 2005; Alves-Rodrigues and Shao 2004; Richer et al. 2004; Olmedilla et al. 2003; Brown et al. 1999).

Zeaxanthin esters (Optional)
1.5 - 5 milligrams of zeaxanthin esters, per day (FAO/WHO 2014; USP 34 2011; Christen et al. 2008; Fletcher et al. 2008; Johnson et al. 2008; Moeller et al. 2008).

MARIGOLD EXTRACT

Methods of preparation: Standardized extracts

Antioxidant

Extract containing 60% or less lutein esters and providing 40 milligrams or less of lutein esters, per day (Bone and Landrum 2010; Christen et al. 2008; Fletcher et al. 2008; Johnson et al. 2008; Moeller et al. 2008).

Optional potency
Not to exceed 5 milligrams of zeaxanthin esters, per day (FAO/WHO 2014; USP 34 2011; Christen et al. 2008; Fletcher et al. 2008; Johnson et al. 2008; Moeller et al. 2008).

Eyesight

Extract containing 60% or less lutein esters and providing 12-40 milligrams of lutein esters, per day (Bone and Landrum 2010; Shao and Hathcock 2006; WHO 2005; Alves-Rodrigues and Shao 2004; Richer et al. 2004; Olmedilla et al. 2003; Brown et al. 1999).

Optional potency
1.5 - 5 milligrams of zeaxanthin esters, per day (FAO/WHO 2014; USP 34 2011; Christen et al. 2008; Fletcher et al. 2008; Johnson et al. 2008; Moeller et al. 2008).

Notes

  • The quantity of the marigold extract must be indicated on the PLA form and label.
  • Lutein and zeaxanthin esters are potencies of marigold extract and must be indicated as such on the PLA form and label. The amounts of the esters must be expressed as the quantity (mg) and/or percent (%) of the total quantity of the marigold extract.
  • The maximum daily amount indicated for lutein and zeaxanthin esters should not be exceeded when lutein esters and/or zeaxanthin esters are combined with marigold extract.
  • Disclosing the amount of zeaxanthin ester in a product is optional.

Direction(s) for use

Lutein and zeaxanthin esters, and marigold extract

Take with a meal containing oil/fat (Chung et al. 2004; Roodenburg et al. 2000).

Duration(s) of Use

No statement required.

Risk Information

Caution(s) and warning(s)

No statement required.

Contraindication(s)

No statement required.

Known adverse reaction(s)

No statement required.

Non-medicinal ingredients

Must be chosen from the current Natural Health Products Ingredients Database (NHPID) and must meet the limitations outlined in the database.

Storage conditions

Store in tightly sealed, light- and oxygen-resistant container in a cool, dry place (USP 34 2011).

Specifications

  • The finished product specifications must be established in accordance with the requirements describes in the Natural and Non-prescription Health Products Directorate (NNHPD) Quality of Natural Health Products Guide.
  • The medicinal ingredient must comply with the requirements outlined in the NHPID.
  • Some commercial lutein preparations are sold as "5% or 10% lutein". These preparations are actually purified lutein (esterified or free) typically added at 5-15% to an inert stabilizing medium (e.g. USP 34 2011: Lutein Preparation).
  • When using these preparations, the applicant must specify whether lutein is esterified or free and use the appropriate dose information. For these preparations, the stabilizing medium must be listed as a non- medicinal ingredient in the PLA and label and identified as "stabilizing agent" in the PLA.
  • In all cases where lutein and zeaxanthin (free or esterified) are listed on the PLA form, potency testing at the finished product stage is required to verify the quantity as different preparations may provide different amounts of lutein and zeaxanthin
    OR
    The manufacturer of the finished product should ensure that there are sufficient controls on the raw materials so that the quantity of lutein and zeaxanthin (esterified or free) is the actual amount of lutein and zeaxanthin and not the amount of the lutein and zeaxanthin with the stabilizing excipient.

LUTEIN AND ZEAXANTHIN

The medicinal ingredient must comply with the specifications outlined in either of the following references:

  • FAO/WHO 2014: LUTEIN from TAGETES ERECTA: Lutein
  • USP 34 2011: Lutein, Lutein preparation

Lutein and zeaxanthin are preparations from the oleoresin of marigold (Tagetes erecta) petals obtained by hexane extraction and purified by saponification and crystallisation.

LUTEIN AND ZEAXANTHIN ESTERS

Lutein and zeaxanthin esters are preparations of oleoresin of marigold (Tagetes erecta) petals obtained by hexane extraction and then purified and concentrated.

MARIGOLD EXTRACT

  • Marigold extract is a hexane extraction of the oleoresin of marigold (Tagetes erecta) petals which provides less than 60% lutein.
  • The medicinal ingredient may comply with the specifications outlined in the FAO/WHO 2014: LUTEIN from TAGETES ERECTA.

References Cited

  • Alves-Rodrigues A, Shao A. The science behind lutein. Toxicology Letters 2004;150(1):57-83.
  • Berendschot TT, Goldbohm RA, Klöpping WA, van de Kraats J, van Norel J, van Norren D. Influence of lutein supplementation on macular pigment, assessed with two objective techniques. Investigative Ophthalmology & Visual Science 2000;41(11):3322-3326.
  • Blakely S, Herbert A, Collins M, Jenkins M, Mitchell G, Grundel E, O'Neill KR, Khachik F. Lutein interacts with ascorbic acid more frequently than with alpha-tocopherol to alter biomarkers of oxidative stress in female zucker obese rats. The Journal of Nutrition 2003;133(9):2838-2844.
  • Bone RA, Landrum JT. Dose-dependent response of serum lutein and macular pigment optical density to supplementation with lutein esters. Archives of Biochemistry and Biophysics 2010;504(1):50-55.
  • Brown L, Rimm EB, Seddon JM, Giovannucci EL, Chasan-Taber L, Spiegelman D, Willett WC, Hankinson SE. A prospective study of carotenoid intake and risk of cataract extraction in US men. The American Journal of Clinical Nutrition 1999;70(4):517-524.
  • Chasan-Taber L, Willett WC, Seddon JM, Stampfer MJ, Rosner B, Colditz GA, Speizer FE, Hankinson SE. A prospective study of carotenoid and vitamin A intakes and risk of cataract extraction in US women. The American Journal of Clinical Nutrition 1999;70(4):509-516.
  • ChemID 2018: ChemIDplus advanced [Internet]. Bethesda (MD): United States National Library of Medicine; 2018. [Lutein, Lutein esters: CAS 127-40-2; Accessed 2018 December 20]. Available from: https://chem.nlm.nih.gov/chemidplus/rn/startswith/127-40-2
  • Christen WG, Liu S, Glynn RJ, Gaziano JM, Buring JE. Dietary carotenoids, vitamins C and E, and risk of cataract in women: a prospective study. Archives of Ophthalmology 2008;126(1):102-109.
  • Dwyer JH, Navab M, Dwyer KM, Hassan K, Sun P, Shircore A, Hama-Levy S, Hough G, Wang X, Drake T, Merz CN, Fogelman AM. Oxygenated carotenoid lutein and progression of early atherosclerosis: the Los Angeles atherosclerosis study. Circulation 2001;103(24):2922-2927.
  • FAO/WHO 2014: Food and Agriculture Organization of the United Nations and the World Health Organization. Joint FAO/WHO Expert Committee on Food Additives. 2014. LUTEIN from TAGETES ERECTA. In: Combined Compendium of Food Additive Specifications [Internet]. Rome (IT): Food and Agriculture Organization of the United Nations. [Accessed 2018 December 20]. Available from: http://www.fao.org/tempref/codex/Meetings/CCFA/ccfa47/fa47_04e.pdf
  • Fletcher AE, Bentham GC, Agnew M, Young IS, Augood C, Chakravarthy U, de Jong PT, Rahu M, Seland J, Soubrane G, Tomazzoli L, Topouzis F, Vingerling JR, Vioque J. Sunlight exposure, antioxidants, and age-related macular degeneration. Archives of Ophthalmology 2008;(10):1396- 1403.
  • Johnson EJ, Chung HY, Caldarella SM, Snodderly DM. The influence of supplemental lutein and docosahexaenoic acid on serum, lipoproteins, and macular pigmentation. The American Journal of Clinical Nutrition 2008;87(5):1521-1529.
  • Miranda M, Muriach M, Roma J, Bosch-Morell F, Genovés JM, Barcia J, Araiz J, Díaz-Llospis M, Romero FJ. Estrés oxidativo en un modelo de retinopatía diabética experimental ii: utilidad de agentes secuestrantes de peroxinitritos. Archivos de la Sociedad Española de Oftalmología 2006;81(1):27-32. Spanish. [Oxidative stress in a model of experimental diabetic retinopathy: the utility of peroxynitrite scavengers.]
  • Moeller SM, Voland R, Tinker L, Blodi BA, Klein ML, Gehrs KM, Johnson EJ, Snodderly DM, Wallace RB, Chappell RJ, Parekh N, Ritenbaugh C, Mares JA; CAREDS Study Group; Women's Health Initiative. Associations between age-related nuclear cataract and lutein and zeaxanthin in the diet and serum in the carotenoids in the Age-Related Eye Disease Study, an Ancillary Study of the Women's Health Initiative. Archives of Ophthalmology 2008;126(3):354- 364.
  • Olmedilla B, Granado F, Blanco I, Vaquero M. Lutein, but not alpha-tocopherol, supplementation improves visual function in patients with age-related cataracts: a 2-y double- blind, placebo-controlled pilot study. Nutrition 2003;19(1):21-24.
  • Richer S, Stiles W, Statkute L, Pulido J, Frankowski J, Rudy D, Pei K, Tsipursky M, Nyland J. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry 2004;75(4):216-230.
  • Shao A, Hathcock JN. Risk assessment for the carotenoids lutein and lycopene. Regulatory Toxicology and Pharmacology 2006;45(3):289-298.
  • USDA 2018: United States Department of Agriculture, Agricultural Research Service, National Genetic Resources Program. Germplasm Resources Information Network (GRIN) [Internet]. Beltsville (MD): National Germplasm Resources Laboratory. [Tagetes erecta L. Asteraceae: Last updated 24-Mar-2012; Accessed 2018 December 20]. Available from: https://npgsweb.ars-grin.gov/gringlobal/taxonomydetail.aspx?id=36197
  • US FDA 2016: United States Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Food Additive Safety: March 10, 2016. GRAS Notification for Xangold® lutein esters. Response to Cognis Corporation submission. [Accessed 2018 December 20]. Available from: https://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/UCM514709.pdf
  • USP 34 2011: United States Pharmacopeia and the National Formulary (USP 34 - NF 29). Rockville (MD): The United States Pharmacopeial Convention; 2011.
  • WHO 2005: World Health Organization. Evaluation of certain food additives: sixty-third report of the Joint FAO/WHO Expert Committee on Food Additives. (WHO Technical Report Series 928) [Internet]. Geneva (CH): World Health Organization; 2005. [Accessed 2018 December 20]. Available from: http://whqlibdoc.who.int/trs/WHO_TRS_928.pdf