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Drugs and Health Products

Hydrolyzed Collagen

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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 ingredient.

Notes
  • For the purpose of this monograph, hydrolyzed collagen has no jelling power and is soluble in cold water (Schrieber and Gareis 2007; Moskowitz 2000).The average molecular weight of hydrolyzed collagen is approximately 2-6 kDa (Moskowitz 2000; Oesser et al. 1999).
  • 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 are synonyms or that the statements are synonymous. Either term or statement may be selected by the applicant.

Date

June 12, 2013

Proper name(s)

Hydrolyzed collagen (ChemID 2012; ICIDH 2008)

Common name(s)

  • Hydrolyzed collagen (ChemID 2012; ICIDH 2008)
  • Collagen hydrosylate (ChemID 2012; ICIDH 2008; Moskowitz 2000)

Source material(s)

  • Porcine skin (FCC 7; Baziwane and He 2003)
  • Porcine bones (FCC 7; Baziwane and He 2003)
  • Fish skin (FCC 7; Baziwane and He 2003)
  • Fish bones (FCC 7; Baziwane and He 2003)
  • Bovine skin/hide split (FCC 7; Schrieber and Gareis 2007; Baziwane and He 2003)
  • Gallus gallus (chicken) cartilage (Schauss et al 2012)

Route(s) of administration

Oral

Dosage form(s)

  • The acceptable pharmaceutical dosage forms include, but are not limited to capsules, chewables (e.g. gummies, tablets), liquids, powders, strips or tablets.
  • This monograph is not intended to include foods or food-like dosage forms such as bars, chewing gums or beverages.

Use(s) or Purpose(s)

Statement(s) to the effect of

  • Source of the essential amino acids histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, valine for the maintenance of good health and involved in protein synthesis (CNF 2010; Eastoe 1955).
  • Source of the non-essential amino acids alanine, arginine, aspartic acid, glutamic acid, glycine, proline, serine, tyrosine involved in protein synthesis (CNF 2010; Eastoe 1955).
  • Source of the essential amino acid lysine to help in collagen formation (derMarderosian and Beutler 2011; Baziwane and He 2003; Garrison and Somer 1995; Jansen 1962)
  • Helps to reduce joint pain associated with osteoarthritis (Bruyère et al. 2012; Benito-Ruiz et al. 2009; Clark et al. 2008).

Dose(s)

Quantity(ies)

Source of the essential amino acids histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, valine:
Minimum 5%Quantity footnote1 of each specific amino acid Recommended Dietary AllowanceQuantity footnote2 to a maximum of 10 g hydrolyzed collagen, per day (JC 2012; Benito-Ruiz et al. 2009; IOM 2005; Moskowitz 2000).

Source of the non-essential amino acid(s) (alanine, arginine, aspartic acid, glutamic acid, glycine, proline, serine, tyrosine):
Minimum 5%Footnote1 of each specific amino acid Mean IntakeQuantity footnote3 to a maximum of 10 g hydrolyzed collagen, per day (JC 2012; Benito-Ruiz et al. 2009; IOM 2005; Moskowitz 2000).

Source of lysine:
Minimum 5%Quantity footnote 1 of the Recommended Dietary AllowanceFootnote 2 to a maximum of 10 g hydrolyzed collagen, per day (derMarderosian and Beutler 2011; IOM 2005; Flodin 1997).

Joint pain:
1.2 – 10 g hydrolyzed collagen, per day (Bruyère et al. 2012; Benito-Ruiz et al. 2009; Clark et al. 2008).

Quantity Footnotes

Quantity footnote 1

The rationale used to support a minimum dose of 5% of the RDA or MI is based on the Food and Drug Regulations for making a health claim on food containing vitamins and minerals (JC 2012).

Return to Quality footnote 1 referrer

Quantity footnote 2

See Appendix 1 for the Recommended Dietary Allowance (RDA).

Return to Quality footnote 2 referrer

Quantity footnote 3

See Appendix 1 for the Mean Intake (MI).

Return to Quality footnote 3 referrer

Refer to Appendix 2 for examples of dosage preparations. The purpose of Appendix 2 is to provide guidance to industry.

Duration(s) of use

Joint pain:
Use for a minimum of 5 months to see beneficial effects (Bruyère et al. 2012; Benito-Ruiz et al. 2009; Clark et al. 2008).

Risk information

Statement(s) to the effect of

Caution(s) and warning(s)

Doses above 2.8 g hydrolyzed collagen, per day:
  • If you are pregnant or breastfeeding, consult a health care practitioner prior to use.
  • If you have liver or kidney disease or if you have been instructed to follow a low protein diet, consult a health care practitioner prior to use (Shils et al. 2006; Goldman and Ausiello 2004).

Known adverse reaction(s)

May cause mild gastrointestinal disturbances (Moskowitz 2000).

Non-medicinal ingredients

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

Storage conditions

Protect from heat and moisture (Ph.Eur. 2012).

Specifications

  • The finished product specifications must be established in accordance with the requirements described in the NNHPD Quality of Natural Health Products Guide.
  • The medicinal ingredient must comply with the requirements outlined in the Natural Health Products Ingredients Database (NHPID). In addition the medicinal ingredient may comply with the specifications outlined in the Gelatin Monograph published in the British, European, or United States Pharmacopoeias.

References cited

  • Asghar A, Henrickson RL. Chemical, biochemical, functional, and nutritional characteristics of collagen in food systems. Advances in Food Research 1982;28:231-372.
  • Baziwane D, He Q. Gelatin: The paramount food additive. Food Reviews International 2003;19(4):423-435.
  • Benito-Ruiz P, Camacho-Zambrano MM, Carrillo-Arcentales JN, Mestanza-Peralta MA, Vallejo-Flores CA, Vargas-López SV, Villacís-Tamayo RA, Zurita-Gavilanes LA. A randomized controlled trial on the efficacy and safety of a food ingredient, collagen hydrolysate, for improving joint comfort. International Journal of Food Sciences and Nutrition 2009;60 Suppl 2:99-113.
  • BP 2012: British Pharmacopoeia 2012. Volume I. London (GB): The Stationary Office on behalf of the Medicines and Healthcare products Regulatory Agency (MHRA); 2012.
  • Bruyère O, Zegels B, Leonori L. Rabenda V, Janssen A, Bourges C, Reginster JY. Effect of collagen hydrolysate in articular pain: A 6-month randomized, double-blind, placebo controlled study. Complementary Therapies in Medicine 2012;20:124-130.
  • Clark KL, Sebastianelli W, Flechsenhar KR, Aukermann DF, Meza F, Millard RL, Deitch JR, Sherbondy PS, Albert A. 24-Week study on the use of collagen hydrolysate as a dietary supplement in athletes with activity-related joint pain. Current Medical Research and Opinions 2008;24(5):1485-1496.
  • CNF 2010:Next link will take you to another Web site Canadian Nutrient File. Health Canada. [Last modified: 2010 October 21]. [Accessed 2013 May 21].
  • derMarderosian A, Beutler JA, editors. The Review of Natural Products. ?Lysine: Issue date February 2011? St Louis (MO): Facts and Comparisons, Wolters Kluwer Health; Printed in 2008 and Updated to June 2011.
  • Eastoe JE. The amino acid composition of mammalian collagen and gelatin. Biochemical Journal 1955;61(4):589-600.
  • FCC 7: Food Chemical Codex, Seventh Edition. Rockville (MD): The United States Pharmacopeial Convention, 2010.
  • Flodin NW. The Metabolic Roles, Pharmacology, and Toxicology of Lysine. Review Article. Journal of the American College of Nutrition 1997;16(1):7-21.
  • Garrison RH, Somer E. Nutrition Desk Reference, 3rd edition. New Canaan (CT): Keats Publishing, 1995.
  • Goldman L, Ausiello D, editors. Cecil Textbook of Medicine, Volume 1, 22nd edition. Philadelphia (PA): Saunders; 2004.
  • ICIDH 2008: International Cosmetic Ingredient Dictionary and Handbook, Twelfth Edition, Volume 1. Gottschalck TE, Bailey JE, editors. Washington (DC): The Cosmetic, Toiletry, and Fragrance Association, 2008.
  • IOM 2005: Institute of Medicine of the National Academies.Next link will take you to another Web site Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Food and Nutrition Board, [Accessed 2012 May 15].
  • Jansen GR. Lysine in Human Nutrition. The Journal of Nutrition 1962;76:1-35.
  • JC 2012.Next link will take you to another Web site Justice Canada. Food and Drug Regulations (C.R.C., c.870). [Regulations are current to 2013 April 29; Last amended 2013 March 21; Accessed 2013 May 21].
  • Moskowitz RW. Role of collagen hydrolysate in bone and joint disease. Seminars in Arthritis and Rheumatism 2000;30(2):87-99.
  • NAS 2005: Next link will take you to another Web site National Academy of Sciences, Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients), Food and Nutrition Board, [Accessed 2012 May 15].
  • Oesser S, Adam M, Babel W, Seifert J. Oral administration of 14C labeled gelatin hydrolysate leads to an accumulation of radioactivity in cartilage of mice (C57/BL). Journal of Nutrition 129(10):1891-5, 1999.
  • Ph.Eur. 2012: European Pharmacopoeia. 7th edition. Strasbourg (FR): Directorate for the Quality of Medicines and HealthCare of the Council of Europe (EDQM); 2012.
  • Schauss AG, Stenehjem J, Park J, Endres JR, Clewell A. Effect of the novel low molecular weight hydrolyzed chicken sternal cartilage extract, BioCell Collagen, on improving osteoarthritis-related symptoms: a randomized, double-blind, placebo-controlled trial. J Agric Food Chem. 2012 Apr 25;60(16):4096-101
  • Schrieber R, Gareis H. Gelatine Handbook: Theory and Industrial Practice. Weinheim: Wiley-VCH. 2007
  • Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. Modern Nutrition in Health and Disease, 10th edition. Philadelphia (PA): Lippincott Williams and Wilkins, 2006.
  • USDA 2002. National Organic Standards Board Technical Advisory Panel Review for the USDA National Organic Program. Next link will take you to another Web site Gelatin processing. Compiled by Organic Materials Review Institute [Dated: 2002 March 1; Consulted: 2012 May 23].
  • USP 35: United States Pharmacopeia and the National Formulary (USP 35 - NF 30). Rockville (MD): The United States Pharmacopeial Convention; 2012.

References reviewed

  • American College of Toxicology. Final Report on the Safety Assessment of Hydrolyzed Collagen. International Journal of Toxicology 1985;4:199-221.
  • Balian G, Bowes JH. The structure and properties of collagen. In: Ward AG, Courts A, editors. The science and technology of gelatin. London (GB): Academic Press, 1977.
  • Barnett ML, Kremer JM, St Clair EW, Clegg DO, Furst D, Weisman M, Fletcher MJ, Chasan-Taber S, Finger E, Morales A, Le CH, Trentham DE. Treatment of rheumatoid arthritis with oral type II collagen. Results of a multicenter, double-blind, placebo-controlled trial. Arthritis and Rheumatism 1998;41(2):290-7.
  • Bello AE, Oesser S. Collagen hydrolysate for the treatment of osteoarthritis and other joint disorders: a review of the literature. Current Medical Research and Opinion 2006;22(11):2221-2232.
  • Bornstein P, Sage H. Structurally Distinct Collagen Types. Annual Review of Biochemistry 1980;49:957-1003.
  • BP 2008: British Pharmacopoeia Commission. 2007. British Pharmacopoeia 2008. Volume I. London (GB): The Stationary Office on behalf of the Medicines and Healthcare products Regulatory Agency (MHRA).
  • ChemID 2012: Next link will take you to another Web site ChemIDplus advanced. Bethesda (MD): United States National Library of Medicine; 2012. [Hydrolyzed collagen: CAS # 92113-31-0; Accessed 2012 May 22].
  • Clark KL, Sebastianelli W, Flechsenhar KR, Aukermann DF, Meza F, Millard RL, Deitch JR, Sherbondy PS, Albert A. 24-Week study on the use of collagen hydrolysate as a dietary supplement in athletes with activity-related joint pain. Current Medical Research and Opinions 2008;24(5):1485-1496.
  • Deparle LA, Gupta RC, Canerdy TD, Goad JT, D'Altilio M, Bagchi M, Bagchi D. Efficacy and safety of glycosylated undenatured type-II collagen (UC-II) in therapy of arthritic dogs. Journal of Veterinary Pharmacology and Therapeutics 2005;28(4):385-90.
  • Djagny KB, Wang Z, Xu S. Gelatin: A Valuable Protein for Food and Pharmaceutical Industries: Review. Critical Reviews in Food Science and Nutrition 2001;41(6):481-492.
  • European Food Safety Authority (EFSA). Opinion of the Scientific Panel on Biological Hazards of the European Food Safety Authority on the "Quantitative assessment of the human and animal BSE risk posed by gelatine with respect to residual BSE risk". Question No EFSA-Q-2003-099. Adopted on 18 January 2006. The EFSA Journal 2006:312:1-29.
  • FDA 1975: U.S. Food and Drug Administration.Next link will take you to another Web site Database of Select Committee on GRAS Substances (SCOGS) Reviews. Gelatin. [Last Updated: 2006 October 31; Accessed 2012 May 15].
  • Fini M, Torricelli P, Giavaresi G, Carpi A, Nicolini A, Giardino R. Effect of L-lysine and L-arginine on primary osteoblast cultures from normal and osteopenic rats. Biomedical Pharmacotherapy 2011;55:213-220.
  • Fragakis AS, Thomson C. The Health Professional's Guide to Popular Dietary Supplements, 3rd edition. Chicago (IL): American Dietetic Association.
  • Fujita T, Ohue M, Fujii Y, Miyauchi A, Takagi Y. The effect of active absorbable algal calcium (AAA Ca) with collagen and other matrix components on back and joint pain and skin impedance. Journal of Bone and Mineral Metabolism 2002;20:298-302.
  • Goldman L, Ausiello D, editors. Cecil Textbook of Medicine, Volume 1, 22nd edition. Philadelphia (PA): Saunders; 2004.
  • Groff J, Gropper S. Advanced Nutrition and Human Metabolism. 3rd edition. Belmont (CA): Wadsworth/Thomson Learning; 2000.
  • Hays NP, Kim H, Wells AM, Kajkenova O, Evans WJ. Effects of whey and fortified collagen hydrolysate protein supplements on nitrogen balance and body composition in older women. Journal of the American Dietetic Association 2009;109(6):1082-7.
  • Iwai K, Hasegawa T, Taguchi Y, Morimatsu F, Sato K, Nakamura Y, Higashi A, Kido Y, Nakabo Y, Ohtsuki K, Identification of Food-Derived Collagen Peptides in Human Blood after Oral Ingestion of Gelatin Hydrolysates. Journal of Agricultural and Food Chemistry 2005;53:6531-6536.
  • Lee SK, Posthauer ME, Dorner B, Redovian V, Maloney MJ. Pressure ulcer healing with a concentrated, fortified, collagen protein hydrolysate supplement: a randomized controlled trial. Advances in Skin and Wound Care 2006;19(2):92-6.
  • Li F, Jia Dongying, Yao K. Amino acid composition and functional properties of collagen polypeptide from Yak (Bos grunniens) bone. Food Science and Technology 2009;42:945-949.
  • Martin-Bautista E. Marint-Matillas M, Maring-Lagos JA, Miranda-Leon MT, Muñoz-Torres M, ruiz-Requena E, Rivero M, Quer J, Puigdueta I, Campoy C. A nutritional intervention study with hydrolyzed collagen in pre-pubertal Spanish children: influence on bone modeling biomarkers. Journal of Pediatric Endocrinology and Metabolism 2011;24(3-4):147-53Oesser S, Adam M, Babel W, Seifert J. Oral administration of 14C labeled gelatin hydrolysate leads to an accumulation of radioactivity in cartilage of mice (C57/BL). Journal of Nutrition 1999;129(10):1891-5.
  • Oesser S, Seifert J. Stimulation of type II collagen biosynthesis and secretion in bovine chondrocytes cultured with degraded collagen. Cell and Tissue Research`2003;311(3):393-9.
  • Merck 2012: Next link will take you to another Web site The Merck Index Version 14.1. Whitehouse Station (NJ): Merck & Co., Inc. Copyright © 2006, 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. [Accessed 2012 May 15.]
  • Popenoe EA, Aronson RB, Van Slyke DD. Hydroxylysine formation from lysine during collagen biosynthesis. Biochemistry 1966;55:393-397.
  • Rowe RC, Sheskey PJ and Owen SC. Handbook of Pharmaceutical Excipients 5th edition. American Pharmacists Association, 2006.
  • Schauss AG, Merkel DJ, Glaza SM, Sorenson SR. Acute and subchronic oral toxicity studies in rats of a hydrolyzed chicken sternal cartilage preparation. Food and Chemical Toxicology 2007;45(2):315-21.
  • Schrieber R and Gareis H. Gelatine Handbook: Theory and Industrial Practice. Weinheim (DE): Wiley-VCH, 2007.
  • Shils ME, Olson JA, Shike M, Ross AC, editors. Modern Nutrition in Health and Disease, 10th edition. Philadelphia (PA): Lippincott Williams and Wilkins, 2006.
  • Sieper J, Kary S, Sörensen H, Alten R, Eggens U, Hüge W, Hiepe F, Kühne A, Listing J, Ulbrich N, Braun J, Zink A, Mitchison NA. Oral type II collagen treatment in early rheumatoid arthritis. A double-blind, placebo-controlled, randomized trial. Arthritis and Rheumatism 1996;39(1):41-51.
  • Sundell MB, Cavanaugh KL, Pingsheng W, Shintani A, Hakim RM, Ikizler TA. Oral Protein Supplementation Alone Improves Anabolism in a Dose-Dependent Manner in Chronic Hemodialysis Patients. Journal of Renal Nutrition 2009;19(5):412-421.
  • Trentham DE, Dynesius-Trentham RA, Orav EJ, Combitchi D, Lorenzo C, Sewell KL, Hafler DA, Weiner HL. Effects of oral administration of type II collagen on rheumatoid arthritis. Science 1993;261(5129):1727-1730.
  • Veis A, The macromolecular chemistry of gelatine. New York (NY): Academic Press, 1964.
  • Ward AG and Courts A. The Science and Technology of Gelatin. London (GB): Academic Press, 1977.
  • Wei W, Zhang LL, Xu JH, Xiao F, Bao CD, Ni LQ, Li XF, Wu YQ, Sun LY, Zhang RH, Sun BL, Xu SQ, Liu S, Zhang W, Shen J, Liu HX, Wang RC. A multicenter, double-blind, randomized, controlled phase III clinical trial of chicken type II collagen in rheumatoid arthritis. Arthritis Res Ther. 2009;11(6):R180.
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  • Zhao W, Tong T, Wang L, Li PP, Chang Y, Zhang LL, Wei W. Chicken type II collagen induced immune tolerance of mesenteric lymph node lymphocytes by enhancing beta2-adrenergic receptor desensitization in rats with collagen-induced arthritis. International Immunopharmacology 2011;11(1):12-8.
  • Zuckley L, Angelopoulou KM, Carpenter MR, McCarthy S, Meredith BA, Kline G, Rowinski M, Smith D, Angelopoulos TJ, Rippe JM. Collagen Hydrolysate Improves Joint Function in Adults with Mild Symptoms of Osteoarthritis of the Knee. Medicine and Science in Sports and Exercise 2004;36(5):S153-S154.

Appendix 1 Minimum doses for Amino Acids present in Hydrolyzed Collagen

Table 1: Recommended Daily Allowance (RDA) and minimum dosesTable 1 footnote1 for essential amino acids present in hydrolyzed collagen
Essential Amino Acids RDATable 1 footnote2
(mg/kg/d)
Minimum doses
(mg/d)

Table 1 Footnotes

Table 1 Footnote 1

Minimum doses have been calculated as 5% of the RDA with a reference weight of 70kg.

Return to Table 1 footnote 1 referrer

Table 1 Footnote 2

IOM 2005

Return to Table 1 footnote 2 referrer

Histidine 14 49
Isoleucine 19 66.5
Leucine 42 147
Lysine 38 133
Methionine 19 66.5
Phenylalanine 33 115.5
Threonine 20 70
Valine 24 84


Table 2: Mean Intake and minimum dosesTable 1 footnote1 for non-essential amino acids present in hydrolyzed collagen
Non-Essential Amino Acids Mean IntakeTable 2 footnote2
(g/d)
Minimum doses
(mg/d)

Table 2 Footnotes

Table 2 Footnote 1

Minimum doses have been calculated as 5% of the Mean Intake.

Return to Table 2 footnote 1 referrer

Table 2 Footnote 2

IOM 2005

Return to Table 2 footnote 2 referrer

Alanine 3.63 181.5
Arginine 4.17 208.5
Aspartic acid 6.52 325
Glutamic acid 15.22 750
Glycine 3.2 160
Proline 5.19 259.5
Serine 3.51 175.5
Tyrosine 2.78 139

Appendix 2 Examples of dosage preparations and duration of use for Hydrolyzed Collagen

  • 10 g hydrolyzed collagen, per day, for two months (Adam 1991)
  • 10 g collagen hydrolysate, per day, for 24 weeks (Moskowitz 2000)
  • 10 g hydrolyzed collagen, per day, for 6 months (Benito-Ruiz et al. 2009)