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Enhancing Skin Delivery.

Skin is a dynamic delivery system for nutrients, nutraceuticals and drugs. Tetrahydropiperine is a natural compound with the potential to enhance bioavailability of drugs and nutrients through the skin.

SELECTIVE NUTRIENT absorption is an important physiologic property of the skin. This selective process starts with the outermost layer of the skin, the stratum corneum, which provides an outstanding barrier against the external environment.[1] The function of this barrier is related to the unique composition of the lipid moiety in the epidermis.[2-5] These keratinocyte manufactured lipids are released to the intercellular spaces where they undergo enzymatic processing to produce a lipid mixture consisting of ceramides, cholesterol and fatty acids. The intercellular lipids become organized into a complex structure that fills most of the intercellular space of the stratum corneum, sealing it. The intercellular lipids mediate transdermal delivery of both lipophilic and hydrophilic molecules.[6]

Fatty acids play a central role among the epidermal lipids in regulating nutrient bioavailability because they are important components of cell membranes and form the hydro-lipid skin surface filmy Topical application of certain fatty acids can lead to changes in the bioavailability of nutrients through the skin. On the one hand, fatty acids may restore a damaged stratum corneum barrier. On the other hand, fatty acids are able to enhance nutrient and drug transport through the skin by increasing cell membrane fluidity. The fluidity of cell membranes in the epidermis translates to better accommodation of the absorbed molecule.

Hyaluronic acid (HA), a high molecular weight glycosaminoglycan of the extracellular skin matrix involved in growth, inflammation and wound healing, also contributes to the hydration and elastic properties of the skin.

Research shows that regulating the composition of intracellular lipids in the skin can increase or decrease the bioavailability of nutrients. For example, skin's sealant can initially be diminished (the skin barrier becomes more porous and more permeable) by a diet deficient in essential fatty acids, topical organic solvents, or prolonged topical application of agents interfering with lipid synthesis, e.g. lovastatin, fluvastatin or cholesterol sulfate.[4] This decrease, however, would lead to an overcompensation mechanism, increasing the synthesis of lipids, DNA and the number of epidermal cells. These are defensive mechanisms which are the means to restore the integrity of the skin barrier and its function.

Interestingly, the artificial barrier repair, e.g. applying topical sealant in the form of latex, prevents the above mentioned skin-repair mechanisms, probably by exerting an epidermal sealing effect.[4] Besides the modification of skin lipid composition there are several strategies to improve topical nutrient bioavailability.[8] Improvement can be accomplished by supersaturation of the delivered ingredient. The delivery formulation may also contain ingredients which decrease the diffusional (electrostatic) resistance of the lipid bi-layer to the passing molecule. Topical liposome preparations are effective penetration enhancers for the delivery of certain coapplied drugs and biological compounds (e.g. interferon), probably due to their role in increasing cell membrane fluidity.[9,10] In addition, an increase in blood supply to the skin can enhance absorption of delivered nutrients.[8] All of these methods can be combined for a synergistic effect.

A Natural Delivery Enhancer

Sabinsa has developed a novel method of enhancing nutrient absorption through the skin with a natural compound derived from black pepper fruits. There are two goals to consider when optimizing skin delivery of nutrients:

* to keep skin healthy and selectively receptive to various forms of nutrients and

* to actively and safely enhance absorption of nutrients through the skin.

Certain nutrients, such as UV light, can best be provided through well-maintained, healthy skin. The skin benefits from UV action while also being able to phase out the excess of the pro-oxidant (free-radical forming) action of sun rays. However, the delivery of more conventional nutrients should be based on the principle of enhancing physiological events leading to nutrient delivery, or ways which least interfere in human physiology. For example, the use of organic solvents or inhibitors of lipid synthesis for increased skin permeability may in fact be counterproductive. By decreasing the lipid barrier to increase absorption of a particular nutrient, other aspects of nutrient delivery and overall skin health may be compromised.

One new topical bioavailability enhancer is tetrahydropiperine or THP, a derivative of pungent alkaloid piperine extracted from the fruits of the black pepper plant. THP has recently been developed and introduced to the cosmetic industry under the trade name Cosmoperine. Based on initial research, Cosmoperine enhances the skin's natural abilities to absorb nutrients for local and systemic utilization.

A Non-irritating Material

Of course, safety is paramount for any skin delivery system. Although Cosmoperine is based on a pungent material, it is non-irritating and interacts with the skin quantitatively and qualitatively in a different way than a pungent principle such as capsaicin from cayenne pepper. Capsaicin is recognized by the U.S. Food and Drug Administration (FDA) an OTC topical pain reliever in a dose of 0.025%. However, besides the pain relieving action this dose provides, it often causes skin reddening due to vascular engorgement as well as a slight skin tingling sensation. This reaction to capsaicin can occur within minutes or a few hours after topical application and usually lasts from half an hour to several hours from the moment it occurs. Interestingly, this reaction tends to subside with regular, sustained use of topical capsaicin in a pain relieving dose.

Recently a study was conducted to determine whether Cosmoperine, at a level of 0.01-0.1%, which is considered an effective dose range for the compound, produced symptoms of topical irritation. A skin patch test using Cosmoperine in a petrolatum vehicle was conducted on 50 healthy volunteers for 48 hours. Readings were taken after 48 and 72 hours.

Neither dose caused skin irritation at the time of clinical evaluation of the study subjects. The 0 irritation score was reported by the supervising physician, a practicing dermatologist. This study was conducted by the U.S. FDA accredited BioScreen Testing, Inc. laboratory. These results indicate that Cosmoperine does not act as a skin irritant at a dose range considered effective for topical nutrient delivery.

The bioenhancing potential of Cosmoperine was also evaluated in experiments with the steroidal antiinflammatory drug betamethasone dipropionate, or BMDP, and a topical antioxidant compound derived from turmeric root (Curcuma longa, Fam. Zingiberaceae), tetrahydrocurcuminoids or THC.

In the experiment involving BMDP, the skin preparation was mounted in a Franz diffusion cell which resulted in two compartments: "donor" and "receptor." The drug (100 ug/ml) was applied with 0.1% (active sample) or without (control sample) of Cosmoperine in the donor compartment.

Subsequently the absorbances of the fluid in the receptor compartment for the presence of BMDP and THP were measured in time intervals of 5-, 10-, 15-, 20-, 30-, 45- and 60 minutes. The active sample resulted in 100% diffusion of the BMDP within the first 10 minutes. The control sample resulted in 29% diffusion of BMDP after 45 minutes and only 54% diffusion after 60 minutes.

In another experiment, the bioenhancing potential of Cosmoperine on the free-radical scavenging properties of topically applied THC was evaluated. In this in vitro DPPH radical scavenging method, the ability of an antioxidant to bind and inactivate the 1,1 diphenyl-2-picrylhydrazyl radical, or DPPH, was measured. DPPH is considered an example of a very stable free radical. The control sample contained 0.01% of THC while active samples contained 0.01% of THC with Cosmoperine concentrations ranging from 0.0001-0.1%. Additionally, controls containing various concentrations of Cosmoperine alone were tested for DPPH binding.

Cosmoperine did not show any significant antioxidant properties, but when combined with THC it was shown to enhance the antioxidant properties of THC by as much as 30% as compared to when THC was used alone. Even in its highest dilution of 0.0001%, Cosmoperine still displayed some beneficial THC bioenhancing activity.

More experimental data is needed to postulate the bioenhancing mechanism of Cosmoperine. However, in vitro and in vivo experiments conducted with the parent compound piperine, indicate that Cosmoperine may operate by increasing membrane fluidity and creating affinity of nutrient/drug to the cell membrane.[11] It should be also noted that Cosmoperine, which is a lipophylic compound, may increase solubilization of the intracellular lipid moiety in the skin, making it more permeable to the applied nutrient/ drug.

Selective Absorbtion

Interestingly, Cosmoperine may be a skin nutrient theoretically able to improve skin health by enhancing its ability to receive and selectively absorb various nutrients. This hypothesis is based on the experimental data with its parent compound piperine, which was shown to be involved in the regulation of several neuropeptides.[12] Neuropeptides include proteins functioning as neurotransmitters, neuromodulators and neurohormones which participate in nutrient delivery through the skin to the body.

Based on clinical experimentation with its parent compound piperine, Cosmoperine holds real promise as a versatile ajuvant in nutrient delivery through the skin. Piperine has been previously evaluated in oral dosages for its potential to enhance the gastrointestinal absorption of drugs and nutrients in animals and humans. Compounds successfully studied include drugs such as vasicine, pyrazinamide, rifampicin, isoniazid, propranolol, theophylline and phenytoin, and nutrients such as fat soluble beta carotene, water soluble vitamin B6, vitamin C, coenzyme Q10 and the mineral selenium in the form of L selenomethionine.[13]

The common phrase that beauty is only skin deep is being re-written. As our understanding deepens, we are becoming increasingly aware that skin is the gatekeeper to the treasury of body organs. One of the simplest ways to maintain this organ and keep it in top shape is to secure its nourishment so it can, in turn, nourish the rest of the body. Botanical compounds such as Cosmoperine may offer a safe and simple solution for nutrient delivery through the skin, and to the skin, particularly in the course of skin aging.


[1.] Marjukka Suhonen T, Bouwstra JA, Urtti A. Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations. J Control Release 1999 May 20; 59(2):149-161.

[2.] Prokosch F, Prokosch E. Regulation of the epidermal permeability barrier by lipids and hyperproliferation. Hautarzt 1992 June; 43(6):331-338.

[3.] Wertz PW. Lipids and barrier function of the skin. Acta Derm Venereol Suppl (Stockh) 2000; 208: 7-11.

[4.] Proksch E, Holleran WM, Menon GK, Elias PM, Feingold KR. Barrier function regulates epidermal lipid and DNA synthesis. Br J Dermatol 1993 May; 128(5):473-482.

[5.] Prokosch E. The epidermis as metabolically active tissue: regulation of lipid synthesis by the barrier function. Z Hautkr 1990 March; 65(3):296-300.

[6.] Tsai JC, Guy RH, Thornfeldt CR, Gao WN, Feingold KR, Elias PM Metabolic approaches to enhance transdermal drug delivery. 1. Effect of lipid synthesis inhibitors. J Pharm Sci 1996 Jun; 85(6): 643-648.

[7.] Schneider IM, Wohlrab W, Neubert R. Fatty acids and the epidermis. Hautarzt 1997 May;48(5): 303-310.

[8.] Hadgraft J. Passive enhancement strategies in topical and transdermal drug delivery. Int J Pharm 1999 Jul 5;184(1): 1-6.

[9.] Golden GM, McKie JE, Potts RO. Role of stratum corneum lipid fluidity in transdermal drug flux. J Pharm Sci 1987 Jan; 76(1): 25-28.

[10.] Short SM, Rubas W, Paasch BD, Mrsny RJ. Transport of biologically active interferon-gamma across human skin in vitro. Pharm Res 1995 Aug; 12(8): 1140-1145.

[11.] Majeed M, Badmaev V, Prakash S. Bioperine: nature's own thermonutrient and Natural bioavailability enhancer. NutriScience Publishers, Inc. 1999. pp. 82.

[12.] Ibid

[13.] Ibid
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Author:Badmaev, Vladimir; Majeed, Muhammed
Publication:Household & Personal Products Industry
Date:Mar 1, 2001
Previous Article:Skin Care Delivery Systems.
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