Shyam Gupta, Ph.D.11.01.01
Nutraceutical supplements are receiving increasing consumer acceptance, creating demand for new product innovations based on superior delivery systems1. Most current delivery systems for nutraceutical products are based on direct ingestion. These oral delivery systems pose issues relative to their unacceptable odor and taste and degradation of the nutraceutical itself during its transport from the digestive system to the site of desired action. Topical delivery systems circumvent some of these issues due to their application near or at the site of affliction.
Nutraceuticals-based topical delivery systems can be formulated as functional cosmetics (cosmeceuticals) to complement the efficacy of their ingestion-based counterparts. However, the product development of these functional cosmetics faces challenges unique to each nutraceutical ingredient and their targeted performance attributes. For example, the inclusion of a dietary fiber in a functional cosmetic to provide reduced cancer risk benefits of the fiber is not viable due to insignificant absorption of that fiber through a topical delivery system.
The incorporation of nutraceutical supplements in functional cosmetics requires special considerations relative to the aspects of product appearance, dosage level, cosmetic benefits, storage stability, bioavailability, efficacy and cost. Those activities require a combination of cosmetic and pharmaceutical product development technologies2.
The Food & Drug Administration (FDA) regulates the formulation of nutraceuticals in cosmetic products. Specific product claims may determine their status as either drugs or cosmetics. For example, FDA may view a topical product that contains both methylsulfonylmethane (MSM) and Capsicum oleoresin a cosmetic if it does not declare claims relative to the arthritis pain relief function of either ingredient. This same product may be viewed as an OTC drug if pain-relieving action of only Capsicum oleoresin is claimed. However, if arthritis pain relief properties of both MSM and Capsicum oleoresin are claimed, then a New Drug Application (NDA) may be required for that combination product by FDA. In these examples, MSM is considered a cosmetic ingredient and Capsicum oleoresin may fall under two separate classifications: a topical pain relief OTC drug active ingredient and a cosmetic colorant3,4.
It is envisioned that a combination of topical and traditional oral delivery systems of specific nutraceutical supplements may offer advantages that may surpass their delivery by any single method alone. This aspect could open new marketing concepts to provide increased consumer awareness and appreciation for those nutraceutical supplements.
Methylsulfonylmethane (MSM): This ingredient has a long history of use in pain, inflammation and arthritis therapies. The combination of MSM with other muscular and skeletal pain-relieving nutraceuticals (for example, glucosamine, chondroitin and/or boswellin) provide synergistically enhanced pain relief5. In such applications, MSM also acts as a solubilizing and absorption-enhancing agent. MSM is ideally suited for topical delivery systems. Oral ingestion of MSM sometimes results in garlic breath. Topical delivery systems circumvent this consumer concern and also provide expedient delivery at the desired site of action for fast relief.
MSM can be formulated in lotion, cream, gel, spray or other topical form. Combination products containing other pain relief ingredients are also possible. It is important to note that MSM possesses mildly oxidizing properties due to its two oxygen atoms. The inclusion of any ingredients that may have reducing chemical properties (for example, ascorbic acid, hydroquinone, sodium metabisulfite or reducing sugars) and easily oxidized aldehydic fragrances (such as almond and vanilla) should be avoided.
MSM has good solubility in water. Excellent oil-in-water and water-in oil emulsions containing MSM and other complementary nutraceutical ingredients can be formulated to provide lotions and creams with elegant skin feel, rapid absorption and fast action properties. Crystal clear gel delivery systems are also possible.
Glucosamine: Glucosamine and acetyl glucosamine occur widely in the exoskeleton of arthropods and crustaceans as their biopolymer, chitin. Glucosamine is also a basic constituent of cartilage. Glucosamines are of current interest in the nutraceutical management of arthritis pain as it stimulates cartilage cells to synthesize glycosaminoglycans and in animal models has shown a curative effect on inflammation, mechanical arthritis and immune-reactive arthritis. In controlled clinical trials, it has shown efficacy nearly equivalent to ibuprofen in relieving osteoarthritis pain. However, recent publications have mentioned caution against promotional enthusiasm6.
N-Acetylglucosamine and its polymers have also been shown to accelerate wound healing by activation of macrophases, stimulation of fibroblast production and enhancement of collagen deposition7. The wound healing property of glucosamine is additionally ascribed to accelerated production of hyaluronic acid in the early stages of wound healing8. ATP and enzyme lysyl oxidase are known to further enhance the wound healing property of glucosamines9. A decrease in glycosaminoglycans content of skin is responsible for impaired wound healing of diabetics, as revealed in a rat model study10.
The development of topical delivery systems requires different strategies for the salts (sulfate or hydrochloride) and N-acetyl (N-acetyl-D-glucosamine) derivatives of glucosamine.
Glucosamine contains a free amino group that is naturally reactive toward any other additive, fragrance or preservative that may contain a free aldehyde, ketone or lactone moiety. The ester functionality, ubiquitously present in popular emollient esters, can also react with glucosamine under elevated temperature conditions of formula production and product storage. Aldehydic fragrances (almond, vanilla) and sweet fragrances that contain oil of wintergreen (methyl salicylate, an ester) will thus react with glucosamine and cause product discoloration and loss of the nutraceutical's efficacy, especially under neutral to alkaline pH conditions. Additionally, the inclusion of ascorbic acid with glucosamine may cause both rapid discoloration of the product and potency loss of both ingredients.
Glucosamine salts pose challenges for topical delivery systems. The use of carbomer, a common ingredient for rheology management, necessitates the neutralization of its carboxyl function with an alkali. This neutralization also affects sulfate and hydrochloride moiety of the corresponding glucosamines, resulting in the formation of emulsion destabilizing electrolytes. The use of electrolyte insensitive emulsifiers provides limited help in such cases.
The use of acetyl glucosamine circumvents these issues. This ingredient does not contain any free amino or salt-forming moieties. Therefore, acetyl glucosamine is the ingredient of choice for functional cosmetic delivery systems.
Chondroitin: Chondroitin is also a glycosaminoglycan, chemically similar to glucosamine. It is reported to maintain viscosity in skeletal joints, stimulate cartilage repair and inhibit cartilage reactive enzymes11. In a clinical trial, chondroitin sulfate was shown to be an effective, slow acting drug for the treatment of knee osteoarthritis with modulation of bone and joint metabolism12.
The management of osteoarthritis frequently utilizes a combination of glucosamines, chondroitin and MSM13. Topical preparations containing a combination of those three ingredients are of current marketing interest, although it is difficult to formulate them in a stable product that also delivers their maximum bioavailability.
The absorption of chondroitin through skin is generally poor in topical applications due to its large molecular weight. The application of low molecular weight chondroitin sulfate in the treatment of degenerative joint disease via both topical and oral administration has recently been reported14.
Chondroitin is most commonly available as its sulfate or hydrochloride derivative. The hydrochloride provides more chondroitin on a molar basis than the corresponding sulfate derivative.
The formulation of a topical product with these derivatives offers challenges. The use of a rheology modifier or emulsifier that requires an alkali for its activation causes the concomitant formation of corresponding alkali sulfate or hydrochloride; the latter may cause the loss of viscosity or destabilization of emulsion system due to its ionic activity or salting-out effect. For these reasons. it is advantageous to formulate such topical preparations in an acidic pH range of 4.5 to 5.5.
Carnitine: Carnitine is a popular nutritional supplement known for its energy generation action via metabolism of fat. Carnitine has found applications in sports performance and exercise enhancement; weight, vascular and triglyceride management; and diabetes control15.
Carnitine is reported to find applications in topical management of muscle and body tone due to its ability to metabolize triglycerides, especially in combination with coenzyme Q1016.
Only L-carnitine provides these benefits; D-form is inactive and DL-form provides only 50% activity. Carnitine is available as carnitine base or as derivatives that include carnitine hydrochloride, carnitine magnesium citrate, carnitine tartrate, carnitine fumarate, acetyl-L-carnitine and propionyl-L-carnitine.
L-Carnitine base, acetyl-L-carnitine and propionyl-L-carnitine are best suited for topical formulations. It is advisable to formulate topical products in a pH range of 6.5 to 7.5 due to the zwitterionic nature of carnitine and its acyl esters.
The sulfate, hydrochloride, tartrate or fumarate derivatives of carnitine pose formulation problems as described for glucosamine salts and chondroitin sulfate and hydrochloride
Coenzyme Q 10 (CoQ10): CoQ10 is a potent antioxidant that is essential for energy production for body functions via its participation in NADH cytochrome C reductase enzyme catalyzed intracellular electron transport mechanisms17.
CoQ10 is commonly utilized in combination with other nutraceutical ingredients due to its synergistic action2,17. In combination products CoQ10 has a quinone molecular structure that is especially reactive toward primary and secondary amine and sulfhydryl (thiol) groups. The combination of CoQ10 and glucosamine (a primary amine), for example, may result in the loss of activity of both ingredients due to their chemical reaction with each other. The use of reduced glutathione (a thiol) with CoQ10 may result in a similar reaction with each other.
The topical formulation of CoQ10 offers significant challenges from a bioavailability point of view. CoQ10 is insoluble in water. It also has poor solubility in many fatty emollients commonly used in topical preparations. The topical formulations that contain CoQ10 in a solid state (powder, micronized powder) usually provide poor absorption and inadequate bioavailability. It is an expensive ingredient with bright yellow to orange color. The use of a large amount of this ingredient in a topical preparation may lead to staining of skin and yellowing of fabrics. The development of topical formulations to provide both enhanced absorption and bioavailability, therefore, is of current commercial interest17,18.
CoQ10 formulations that incorporate solubilized forms of this ingredient usually provide better absorption and bioavailability19. A number of recently introduced organic solubilizing emollients are an excellent choice for this function. These solutions of CoQ10 can be formulated in various lotion, cream, clear gel and spray delivery systems to provide a dual performance: enhanced absorption and bioavailability of CoQ10 and improved skin feel and skin protection action delivered by those emollients. NW
Acknowledgement:
Special thanks to Gary Grason, Jesus San Miguel and Lori Murphy, who provided expert laboratory assistance.
About the author:
Shyam Gupta is director of R&D at Arizona Natural Resources, Twin Lakes, WI, a contract manufacturing company specializing in nutraceuticals and phytopharmaceuticals-based cosmetics. He is also a consultant in topical delivery systems based on nutraceutical and phytopharmaceutical ingredients. He can be reached at 602-569-6900; Fax: 602-569-9697; E-mail: shyam@aznat.com or theformulator@home.com.
References
1. P. Leighton, "Up-And-Coming Delivery Systems," Nutraceuticals World, 40, (October 2000); M.V. Patel et al., U.S.Patent 6,248,363 (June 19,2001); Newsfront, "Demand for Cosmeceutical Chemicals to Increase," HAPPI, 16 (July 2001).
2. S. Gupta, "Antioxidants: Formulation of Cosmetic Delivery Systems," HAPPI, 56, (July 2001).
3. T. Harrison, "Revisiting DSHEA," Nutraceuticals World, 26, (April 2001); J. Gruenwald, "Regulating Botanicals As Traditional Medicinal Products," Ibid, 30, (April 2001).
4. Federal Register, CFR Title 21, various sections; www.fda.gov; J.B. Atwater, "Botanical Drug Product Development," Nutraceuticals World Supplement, S-4, (March 2001).
5. S.W. Jacob, R.M. Lawrence, and M. Zucker, The Miracle of MSM: The Natural Solution for Pain, G.P. Putnam, NY, (1999); J.R. Cronin, Methylsulfonylmethane, Alternative & Complementary Therapies, 386, (December 1999); MSM In Cosmetics, Cardinal Nutrition, Vancouver, WA, USA.
6. M. Majeed and L. Prakash, N-Acetylglucosamine, Sabinsa Corporation, NJ, USA; J.J. Kaysor, S.S. Currey, and L.F. Callahan, "Behavioral Aspects of Arthritis and Rheumatic Disease Self-Management," Disease Management and Health Outcomes, 9, 89 (2001); C. Basleer et al., Int. J. Tissue React, 14, 231 (1992); M.F. McCarty, "The Neglect of Glucosamines as a Treatment for Osteoarthritis: A Personal Perspective," Med. Hypotheses, 42, 542 (1994); I. Setnikar et al., "Antiarthritic Effects of Glucosamine Sulfate Studied in Animal Models," Arzneimittelforschung, 41, 542 (1991); W. Noack et al., Osteoarthritis Cartilage, 2, 51 (1994); H. Muller-Fassbender et al., "Glucosamine Sulfate Compared to Ibuprofen in Osteoarthritis of the Knee," Osteoarthritis Cartilage, 2, 61 (1994); T.E. McAlindon et al., "Glucosamine and Chondroitin for Treatment of Osteoarthritis: A Systematic Quality Assessment and Meta-analysis," JAMA, 283, 1469 (2000); E. Tanveer and T.P. Anastassiades, "Glucosamine and Chondroitin for Treating Symptoms of Osteoarthritis," JAMA, 283, 1483 (2000).
7. D.J. Cole et al., "A Pilot Study Evaluating the Efficacy of a Fully Acetylated Poly-N-Acetyl Glucosamine Membrane formulation as a Topical Hemostatic Agent," Surgery, 126, 510 (1999); M. Majeed and L. Prakash, N-Acetylglucosamine, Sabinsa, NJ, USA; M.W. Chan et al., "Comparison of Poly-N-Acetyl Glucosamine with Absorbable Collagen and Fibrin Sealant for Achieving Hemostasis in a Swine Model of Splenic Hemorrhage," J. Trauma, 48, 454 (2000).
8. M.F. McCarty, "Glucosamines for Wound Healing," Med. Hypotheses, 47, 273 (1996); J. Lezdey, U.S.Patent 6,262,020 (July 17,2001).
9. C.P. Dietrich et al., Semin. Thromb. Hemost., 17, 65 (1991); H. Kuivaniemi et al., "Secretion of Lysyl Oxidase by Cultures Human Skin Fibroblasts and Effect of Monensin, Nigericin, Tunicamycin, and Colchicine," Biochem. Biophys. Acta, 883, 326 (1986).
10. M. Cechowska-Pasko, J. Palka, and E. Bankowski, Exp. Toxicol. Pathol., 51, 239 (1999).
11. V.R. Pipitone, "Chondroprotection with Chondroitin Sulfate," Drugs Exp. Clin. Research, 17, 3 (1991).
12. D. Uebelhart et al., "Effects of Oral Chondroitin Sulfate on the Progression of Knee Osteoarthritis: A Pilot Study," Osteoarthritis Cartilage, 6 Suppl. A, 39 (1998).
13. G.S. Kelly, "The Role of Glucosamine Sulfate and Chondroitin Sulfates in the Treatment of Degenerative Joint Disease," Altern. Med. Rev., 3, 27 (1998); R.W. Henderson et al., U.S.Patent 6,255,295 (July 3, 2001); L.R. Bucchi, "Supplements for Joint Health," HAPPI, 72 (July 2001).
14. Xenos Biosource, Inc., CA, USA; H. Scipioni et al., "Efficacy of the Topical Use of Low Molecular Weight Chondroitin Sulfate Triethanolamine Salt in Induced Arthritis in Horses," in press; D.I. Videla, "Use of Low Molecular Weight Chondroitin Sulfate in the Treatment of Induced Aseptic Arthritis," in press.
15. B.E. Leibovitz, L-Carnitine: The Energy Nutrient, Keats Publishing, Los Angeles, 1998; Lonza, L-Carnitine, NJ, USA; Lonza, L-Carnitine Research & Review, NJ, USA; Sigma Tau Health Science, L-Carnitine Its Salts and Derivatives, NY, USA; S.L. DeFelice, The Carnitine Defense, Rodale Press, USA, 1999; C. Cavazza, U.S.Patent 6,217,898 (April 17,2001).
16. S.T. Sinatra, L-Carnitine and the Heart, Keats Publishing, IL, USA, (1999); J.R. Howard, U.S.Patent 5,973,004 (October 26,1999).
17. G.D. Birkmayer, U.S. Patent 6,248,855 (June 19,2001); B. Alberts, et al., "Energy Conversion: Mitochondria and Chloroplasts," in Molecular Biology of the Cell, 3rd Ed., Garland Publishing Inc., pp. 653-720 (1994); L. Packer et al., "Antioxidant Activity of Coenzyme Q and Ubiquinols: Reactions with Tocopheroxyl and Nitric Oxide Radicals," Proceedings of the First Conference of the International Coenzyme Q10 Association, Boston, 22 (1998); V.E. Kagan, "Why Do Coenzyme Q and Vitamin E Need Each Other as Antioxidants," Ibid., 25 (1998).
18. R.R. Chopra, et al., "Relative Bioavailability of Coenzyme Q10 Formulations in Human Subjects," International Journal for Vitamin and Nutrition Research, 68, 109 (1998); S. Neigut, U.S. Patent 6,048,886 (April 11, 2000); T. Mae et al., U.S.Patent 6,148,255 (February 6, 2001); A. Ribier et al., U.S.Patent 6,051,250 (April 18, 2000).
19. M.J. Sole et al., U.S.Patent 6,232,346 (May 15, 2001); H. Borowy-Borowski et al., U.S.Patent 6,191,172 (February 20, 2001); U.S. Patent 6,045,826 (April 4, 2001); S. Amselem, U.S.Patent 5,989,583 (November 23, 1999); U. Hoppe et al., U.S.Patent 6,261,575 (July 17, 2001); A. Bertelli, U.S.Patent 4,654,373 (March 31,1987).
Nutraceuticals-based topical delivery systems can be formulated as functional cosmetics (cosmeceuticals) to complement the efficacy of their ingestion-based counterparts. However, the product development of these functional cosmetics faces challenges unique to each nutraceutical ingredient and their targeted performance attributes. For example, the inclusion of a dietary fiber in a functional cosmetic to provide reduced cancer risk benefits of the fiber is not viable due to insignificant absorption of that fiber through a topical delivery system.
The incorporation of nutraceutical supplements in functional cosmetics requires special considerations relative to the aspects of product appearance, dosage level, cosmetic benefits, storage stability, bioavailability, efficacy and cost. Those activities require a combination of cosmetic and pharmaceutical product development technologies2.
The Food & Drug Administration (FDA) regulates the formulation of nutraceuticals in cosmetic products. Specific product claims may determine their status as either drugs or cosmetics. For example, FDA may view a topical product that contains both methylsulfonylmethane (MSM) and Capsicum oleoresin a cosmetic if it does not declare claims relative to the arthritis pain relief function of either ingredient. This same product may be viewed as an OTC drug if pain-relieving action of only Capsicum oleoresin is claimed. However, if arthritis pain relief properties of both MSM and Capsicum oleoresin are claimed, then a New Drug Application (NDA) may be required for that combination product by FDA. In these examples, MSM is considered a cosmetic ingredient and Capsicum oleoresin may fall under two separate classifications: a topical pain relief OTC drug active ingredient and a cosmetic colorant3,4.
It is envisioned that a combination of topical and traditional oral delivery systems of specific nutraceutical supplements may offer advantages that may surpass their delivery by any single method alone. This aspect could open new marketing concepts to provide increased consumer awareness and appreciation for those nutraceutical supplements.
Methylsulfonylmethane (MSM): This ingredient has a long history of use in pain, inflammation and arthritis therapies. The combination of MSM with other muscular and skeletal pain-relieving nutraceuticals (for example, glucosamine, chondroitin and/or boswellin) provide synergistically enhanced pain relief5. In such applications, MSM also acts as a solubilizing and absorption-enhancing agent. MSM is ideally suited for topical delivery systems. Oral ingestion of MSM sometimes results in garlic breath. Topical delivery systems circumvent this consumer concern and also provide expedient delivery at the desired site of action for fast relief.
MSM can be formulated in lotion, cream, gel, spray or other topical form. Combination products containing other pain relief ingredients are also possible. It is important to note that MSM possesses mildly oxidizing properties due to its two oxygen atoms. The inclusion of any ingredients that may have reducing chemical properties (for example, ascorbic acid, hydroquinone, sodium metabisulfite or reducing sugars) and easily oxidized aldehydic fragrances (such as almond and vanilla) should be avoided.
MSM has good solubility in water. Excellent oil-in-water and water-in oil emulsions containing MSM and other complementary nutraceutical ingredients can be formulated to provide lotions and creams with elegant skin feel, rapid absorption and fast action properties. Crystal clear gel delivery systems are also possible.
Glucosamine: Glucosamine and acetyl glucosamine occur widely in the exoskeleton of arthropods and crustaceans as their biopolymer, chitin. Glucosamine is also a basic constituent of cartilage. Glucosamines are of current interest in the nutraceutical management of arthritis pain as it stimulates cartilage cells to synthesize glycosaminoglycans and in animal models has shown a curative effect on inflammation, mechanical arthritis and immune-reactive arthritis. In controlled clinical trials, it has shown efficacy nearly equivalent to ibuprofen in relieving osteoarthritis pain. However, recent publications have mentioned caution against promotional enthusiasm6.
N-Acetylglucosamine and its polymers have also been shown to accelerate wound healing by activation of macrophases, stimulation of fibroblast production and enhancement of collagen deposition7. The wound healing property of glucosamine is additionally ascribed to accelerated production of hyaluronic acid in the early stages of wound healing8. ATP and enzyme lysyl oxidase are known to further enhance the wound healing property of glucosamines9. A decrease in glycosaminoglycans content of skin is responsible for impaired wound healing of diabetics, as revealed in a rat model study10.
The development of topical delivery systems requires different strategies for the salts (sulfate or hydrochloride) and N-acetyl (N-acetyl-D-glucosamine) derivatives of glucosamine.
Glucosamine contains a free amino group that is naturally reactive toward any other additive, fragrance or preservative that may contain a free aldehyde, ketone or lactone moiety. The ester functionality, ubiquitously present in popular emollient esters, can also react with glucosamine under elevated temperature conditions of formula production and product storage. Aldehydic fragrances (almond, vanilla) and sweet fragrances that contain oil of wintergreen (methyl salicylate, an ester) will thus react with glucosamine and cause product discoloration and loss of the nutraceutical's efficacy, especially under neutral to alkaline pH conditions. Additionally, the inclusion of ascorbic acid with glucosamine may cause both rapid discoloration of the product and potency loss of both ingredients.
Glucosamine salts pose challenges for topical delivery systems. The use of carbomer, a common ingredient for rheology management, necessitates the neutralization of its carboxyl function with an alkali. This neutralization also affects sulfate and hydrochloride moiety of the corresponding glucosamines, resulting in the formation of emulsion destabilizing electrolytes. The use of electrolyte insensitive emulsifiers provides limited help in such cases.
The use of acetyl glucosamine circumvents these issues. This ingredient does not contain any free amino or salt-forming moieties. Therefore, acetyl glucosamine is the ingredient of choice for functional cosmetic delivery systems.
Chondroitin: Chondroitin is also a glycosaminoglycan, chemically similar to glucosamine. It is reported to maintain viscosity in skeletal joints, stimulate cartilage repair and inhibit cartilage reactive enzymes11. In a clinical trial, chondroitin sulfate was shown to be an effective, slow acting drug for the treatment of knee osteoarthritis with modulation of bone and joint metabolism12.
The management of osteoarthritis frequently utilizes a combination of glucosamines, chondroitin and MSM13. Topical preparations containing a combination of those three ingredients are of current marketing interest, although it is difficult to formulate them in a stable product that also delivers their maximum bioavailability.
The absorption of chondroitin through skin is generally poor in topical applications due to its large molecular weight. The application of low molecular weight chondroitin sulfate in the treatment of degenerative joint disease via both topical and oral administration has recently been reported14.
Chondroitin is most commonly available as its sulfate or hydrochloride derivative. The hydrochloride provides more chondroitin on a molar basis than the corresponding sulfate derivative.
The formulation of a topical product with these derivatives offers challenges. The use of a rheology modifier or emulsifier that requires an alkali for its activation causes the concomitant formation of corresponding alkali sulfate or hydrochloride; the latter may cause the loss of viscosity or destabilization of emulsion system due to its ionic activity or salting-out effect. For these reasons. it is advantageous to formulate such topical preparations in an acidic pH range of 4.5 to 5.5.
Carnitine: Carnitine is a popular nutritional supplement known for its energy generation action via metabolism of fat. Carnitine has found applications in sports performance and exercise enhancement; weight, vascular and triglyceride management; and diabetes control15.
Carnitine is reported to find applications in topical management of muscle and body tone due to its ability to metabolize triglycerides, especially in combination with coenzyme Q1016.
Only L-carnitine provides these benefits; D-form is inactive and DL-form provides only 50% activity. Carnitine is available as carnitine base or as derivatives that include carnitine hydrochloride, carnitine magnesium citrate, carnitine tartrate, carnitine fumarate, acetyl-L-carnitine and propionyl-L-carnitine.
L-Carnitine base, acetyl-L-carnitine and propionyl-L-carnitine are best suited for topical formulations. It is advisable to formulate topical products in a pH range of 6.5 to 7.5 due to the zwitterionic nature of carnitine and its acyl esters.
The sulfate, hydrochloride, tartrate or fumarate derivatives of carnitine pose formulation problems as described for glucosamine salts and chondroitin sulfate and hydrochloride
Coenzyme Q 10 (CoQ10): CoQ10 is a potent antioxidant that is essential for energy production for body functions via its participation in NADH cytochrome C reductase enzyme catalyzed intracellular electron transport mechanisms17.
CoQ10 is commonly utilized in combination with other nutraceutical ingredients due to its synergistic action2,17. In combination products CoQ10 has a quinone molecular structure that is especially reactive toward primary and secondary amine and sulfhydryl (thiol) groups. The combination of CoQ10 and glucosamine (a primary amine), for example, may result in the loss of activity of both ingredients due to their chemical reaction with each other. The use of reduced glutathione (a thiol) with CoQ10 may result in a similar reaction with each other.
The topical formulation of CoQ10 offers significant challenges from a bioavailability point of view. CoQ10 is insoluble in water. It also has poor solubility in many fatty emollients commonly used in topical preparations. The topical formulations that contain CoQ10 in a solid state (powder, micronized powder) usually provide poor absorption and inadequate bioavailability. It is an expensive ingredient with bright yellow to orange color. The use of a large amount of this ingredient in a topical preparation may lead to staining of skin and yellowing of fabrics. The development of topical formulations to provide both enhanced absorption and bioavailability, therefore, is of current commercial interest17,18.
CoQ10 formulations that incorporate solubilized forms of this ingredient usually provide better absorption and bioavailability19. A number of recently introduced organic solubilizing emollients are an excellent choice for this function. These solutions of CoQ10 can be formulated in various lotion, cream, clear gel and spray delivery systems to provide a dual performance: enhanced absorption and bioavailability of CoQ10 and improved skin feel and skin protection action delivered by those emollients. NW
Acknowledgement:
Special thanks to Gary Grason, Jesus San Miguel and Lori Murphy, who provided expert laboratory assistance.
About the author:
Shyam Gupta is director of R&D at Arizona Natural Resources, Twin Lakes, WI, a contract manufacturing company specializing in nutraceuticals and phytopharmaceuticals-based cosmetics. He is also a consultant in topical delivery systems based on nutraceutical and phytopharmaceutical ingredients. He can be reached at 602-569-6900; Fax: 602-569-9697; E-mail: shyam@aznat.com or theformulator@home.com.
References
1. P. Leighton, "Up-And-Coming Delivery Systems," Nutraceuticals World, 40, (October 2000); M.V. Patel et al., U.S.Patent 6,248,363 (June 19,2001); Newsfront, "Demand for Cosmeceutical Chemicals to Increase," HAPPI, 16 (July 2001).
2. S. Gupta, "Antioxidants: Formulation of Cosmetic Delivery Systems," HAPPI, 56, (July 2001).
3. T. Harrison, "Revisiting DSHEA," Nutraceuticals World, 26, (April 2001); J. Gruenwald, "Regulating Botanicals As Traditional Medicinal Products," Ibid, 30, (April 2001).
4. Federal Register, CFR Title 21, various sections; www.fda.gov; J.B. Atwater, "Botanical Drug Product Development," Nutraceuticals World Supplement, S-4, (March 2001).
5. S.W. Jacob, R.M. Lawrence, and M. Zucker, The Miracle of MSM: The Natural Solution for Pain, G.P. Putnam, NY, (1999); J.R. Cronin, Methylsulfonylmethane, Alternative & Complementary Therapies, 386, (December 1999); MSM In Cosmetics, Cardinal Nutrition, Vancouver, WA, USA.
6. M. Majeed and L. Prakash, N-Acetylglucosamine, Sabinsa Corporation, NJ, USA; J.J. Kaysor, S.S. Currey, and L.F. Callahan, "Behavioral Aspects of Arthritis and Rheumatic Disease Self-Management," Disease Management and Health Outcomes, 9, 89 (2001); C. Basleer et al., Int. J. Tissue React, 14, 231 (1992); M.F. McCarty, "The Neglect of Glucosamines as a Treatment for Osteoarthritis: A Personal Perspective," Med. Hypotheses, 42, 542 (1994); I. Setnikar et al., "Antiarthritic Effects of Glucosamine Sulfate Studied in Animal Models," Arzneimittelforschung, 41, 542 (1991); W. Noack et al., Osteoarthritis Cartilage, 2, 51 (1994); H. Muller-Fassbender et al., "Glucosamine Sulfate Compared to Ibuprofen in Osteoarthritis of the Knee," Osteoarthritis Cartilage, 2, 61 (1994); T.E. McAlindon et al., "Glucosamine and Chondroitin for Treatment of Osteoarthritis: A Systematic Quality Assessment and Meta-analysis," JAMA, 283, 1469 (2000); E. Tanveer and T.P. Anastassiades, "Glucosamine and Chondroitin for Treating Symptoms of Osteoarthritis," JAMA, 283, 1483 (2000).
7. D.J. Cole et al., "A Pilot Study Evaluating the Efficacy of a Fully Acetylated Poly-N-Acetyl Glucosamine Membrane formulation as a Topical Hemostatic Agent," Surgery, 126, 510 (1999); M. Majeed and L. Prakash, N-Acetylglucosamine, Sabinsa, NJ, USA; M.W. Chan et al., "Comparison of Poly-N-Acetyl Glucosamine with Absorbable Collagen and Fibrin Sealant for Achieving Hemostasis in a Swine Model of Splenic Hemorrhage," J. Trauma, 48, 454 (2000).
8. M.F. McCarty, "Glucosamines for Wound Healing," Med. Hypotheses, 47, 273 (1996); J. Lezdey, U.S.Patent 6,262,020 (July 17,2001).
9. C.P. Dietrich et al., Semin. Thromb. Hemost., 17, 65 (1991); H. Kuivaniemi et al., "Secretion of Lysyl Oxidase by Cultures Human Skin Fibroblasts and Effect of Monensin, Nigericin, Tunicamycin, and Colchicine," Biochem. Biophys. Acta, 883, 326 (1986).
10. M. Cechowska-Pasko, J. Palka, and E. Bankowski, Exp. Toxicol. Pathol., 51, 239 (1999).
11. V.R. Pipitone, "Chondroprotection with Chondroitin Sulfate," Drugs Exp. Clin. Research, 17, 3 (1991).
12. D. Uebelhart et al., "Effects of Oral Chondroitin Sulfate on the Progression of Knee Osteoarthritis: A Pilot Study," Osteoarthritis Cartilage, 6 Suppl. A, 39 (1998).
13. G.S. Kelly, "The Role of Glucosamine Sulfate and Chondroitin Sulfates in the Treatment of Degenerative Joint Disease," Altern. Med. Rev., 3, 27 (1998); R.W. Henderson et al., U.S.Patent 6,255,295 (July 3, 2001); L.R. Bucchi, "Supplements for Joint Health," HAPPI, 72 (July 2001).
14. Xenos Biosource, Inc., CA, USA; H. Scipioni et al., "Efficacy of the Topical Use of Low Molecular Weight Chondroitin Sulfate Triethanolamine Salt in Induced Arthritis in Horses," in press; D.I. Videla, "Use of Low Molecular Weight Chondroitin Sulfate in the Treatment of Induced Aseptic Arthritis," in press.
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