For many nutritional supplements and nutraceuticals …

Intraoral Delivery is
a Better Route

Intraoral delivery of dietary supplements and nutraceuticals through the mucosal
linings of the oral cavity offers distinct advantages over
peroral delivery through the GI tract

By Richard Clark Kaufman, Ph.D.

W ithin the oral cavity (the mouth), the delivery of nutritional supplements and nutraceuticals may be categorized three ways: 1) Intraoral sublingual, which is systemic delivery through the mucosal membranes lining the floor of the mouth under the tongue, 2) Intraoral buccal, which is administration through the mucosal membranes lining the cheeks (buccal mucosa), and 3) Peroral, which is passage through the mouth into the gastrointestinal tract.

Problems of swallowing nutritional supplements and nutraceuticals

Figure 1. Factors that decrease oral bioavailability and bio-effectiveness of supplements.
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Among the routes for delivering nutritional supplements and nutraceuticals, the peroral route is most commonly employed. However, oral delivery of nutritional supplements from the GI tract into systemic circulation has numerous disadvantages. These include the acid-induced hydrolysis in the stomach, enzymatic degradation throughout the gastrointestinal tract, bacterial fermentation in the colon and pre-systemic metabolism. Together, these impediments significantly lower bioavailability.* Plus the insolubility, hydrophobic nature, or molecular structure of certain compounds may reduce their absorption from the GI tract. Fig. 1 shows the primary factors that decrease the bioavailability and the bio-effectiveness of the supplements that you swallow.


* Bioavailability is subcategory of absorption and is the fraction of a nutrient that is absorbed and detected in system circulation after its administration. It does not refer to the bio-effectiveness of a substance.


Advantages of intraoral delivery through the oral mucosa

Intraoral delivery of dietary supplements and nutraceuticals through the mucosal linings of the oral cavity offers distinct advantages over peroral delivery through the GI tract. However, while mucosal delivery gives rapid absorption and good bioavailability for some small permeants, additional assistance is required for larger molecules and such help can be found with the use of advanced microencapsulation.

The oral mucosae are extremely rich in blood vessels and lymphatic vessels that, unlike the GI tract, do not drain into the portal hepatic vein. Supplements taken up by the oral mucosae directly enter the systemic circulation from the jugular vein, thus avoiding passage through the liver where they may undergo undesirable metabolism (1st pass liver effects). Other tangible benefits include increased absorption, faster onset of actions and greater bioavailability. Furthermore, intraoral delivery does not require swallowing and does not produce gastrointestinal irritation.

Advantages of intraoral delivery

  • Increased bioavailability
  • Higher plasma levels
  • Rapid absorption and onset of actions
  • Avoids pre-systemic elimination in the GI tract
  • Avoids first-pass effect of the liver
  • Avoids exposure to a hostile GI environment
  • Ability to swallow is not required
  • From the mouth directly to the jugular vein

    No one has claimed that the pathway of delivering dietary supplements from the mouth to the jugular vein for systemic distribution is free of challenges. With sublingual or buccal administration, biological agents encounter the multilayered squamous epithelium barrier of the oral mucosa. The cells of the oral mucosae are bound together by small structures called desmosomes with a tight junction space of approximately 20 nm space between adjacent cells.

    The barrier membrane is permeable to lipophilic molecules

    A continuous phospholipid membrane assembled into the upper third of epithelial cells and within the extracellular space forms a protective barrier of the oral mucosa. Luckily, the phospholipid membrane is permeable to lipophilic molecules and certain delivery system carriers. As a result, dietary supplements can readily diffuse through the phospholipid membrane of the oral mucosa into the systemic circulation.

    In most cases, supplements and nutraceuticals cross cell membranes of the oral mucosa by passive diffusion down a concentration gradient due to random molecular movements produced by thermal energy. The rate of transfer is directly proportional to the difference in concentration, and to the solubility of materials carried into the epithelial membranes. Active transport and pinocytosis through aqueous cellular pores plays a minimal role in transporting biological agents across the oral mucosa into the circulatory system.


    † Pinocytosis is the ingestion of liquid into a cell by the budding of small vesicles from the cell membrane.


    The ability of molecules to permeate through the oral mucosa is related to molecular size and ionization, but to a lesser degree than the concentration gradient and lipid solubility. Small molecules of less than 250 Daltons appear to cross the mucosae rapidly. As molecular size increases, the permeability decreases rapidly. Maximum absorption occurs when molecules are un-ionized or neutral in electrical charges. Highly polar molecules are insoluble in membrane lipids and unable to penetrate cellular membranes.

    Permeation differences between the sublingual and buccal mucosa

    Anatomical and permeability differences between the sublingual and buccal mucosa necessitate different delivery system designs. Because of its high permeability and rich blood supply, the sublingual mucosa route gives fast absorption, a rapid onset of action and overall high bioavailability. The sublingual mucosa is best suited for a delivery system of small particles providing a high concentration of compounds in short delivery period time. Nano-sized (between 20 and 200 billionths of a meter) solid lipid and droplet lipid nanospheres have an ideal composition and molecular structure for a sublingual delivery system.

    The buccal mucosa is considerably less permeable than the sublingual area, and does not provide the rapid absorption and superior bioavailability of sublingual administration. In several comparative studies, sublingual delivery was more effective than buccal delivery.

    Nanospheres … the delivery system of choice

    The solution for delivering nutritional supplements and nutraceuticals through the oral mucosa lies in encapsulating biological compounds into highly permeable lipid nanospheres. These are easy to administer to the mouth’s sublingual oral mucosa via an eyedropper for rapid uptake into the circulatory system.

    Phospholipids: The basis of nanospheres

    Nanospheres are formed from essential phospholipids, fatty acids, and surfactants that are entirely safe and non-toxic. A highly purified phosphatidylcholine fraction, exceeding 60% purity, creates dynamically-structured nanosphere reservoirs protecting the encapsulating and protecting biological agents from destruction. Nano­spheres are made of the same phospholipids that comprise the major components of biological membranes and lipoproteins. They are highly permeable to the cell membrane and capable of encapsulating a high concentration of different biological agents for unimpeded rapid delivery through the oral mucosa.

    Submicron Stealth Spheres

    Nanosphere size is extremely important. Nanospheres with diameters ranging from 20 nm to 200 nm demonstrate the most prolonged circulation times. Smaller nanospheres are stealth delivery systems, meaning that their solid lipid structures mimic plasma lipoproteins and provide a cloaked carrier system. Appearing like lipoproteins avoids detection and destruction by the body’s immune system as a foreign substance. Because of their nanosize, they can easily navigate across protective cell and membrane barriers. Also, they can readily cross the blood-brain barrier into specific neurological sites.

    Some of the beneficial effects from a nanosphere delivery system are rapid absorption into the circulatory system, increased bioavailability, a fast onset of action, high plasma levels for a sustained period, and improved bio-effectiveness.

    Nanospheres have proven advantages that include:

    • Increased bioavailability through transmucosal absorption and direct oral-cavity delivery
    • Sustained blood levels with greater bio-effectiveness and longer-lasting beneficial actions
    • Higher-potency responses, allowing reductions in amount and in frequency of administration
    • Transport of blocked compounds across the blood-brain barrier and into brain structures
    • Improved user convenience (less frequent use and easier compliance)
    • Increased circulatory half-life (studies with pharmaceutical delivery loads have demonstrated up to 100-fold increases, resulting in dramatic rises in potency—up to 500-fold)
    • Glutathione is the Most Powerful
      Antioxidant Produced by Cells

      Glutathione (also known as GSH for glutathione sulfhydryl) is a tripeptide composed of the amino acids glutamic acid, cysteine, and glycine. Glutathione is found in all cells in the body, in the epithelial lining fluid of the lungs, and—at much smaller concentrations—in the blood. Glutathione is the main intracellular defense against oxidative stress. It regulates cellular redox potential, maintains the immune system, and is critical for the well-being of cells.

      Glutathione participates directly in the neutralization of free radicals and reactive oxygen species that are generated intracellularly and at sites of inflammation. Glutathione plays a major role in the detoxification of toxic xenobiotics (substances that are alien to the body) and carcinogens, cellular immune functions, neuro­protection, and maintaining exogenous antioxidants such as vitamins C and E in their active reduced forms. Glutathione also protects the tissues of the arteries, brain, heart, kidneys, lens of the eyes, liver, lungs, and skin from free radicals. In fact, Glutathione is considered the most important antioxidant because it is the only antioxidant capable of collaborating with enzymes. One enzyme, glutathione peroxidase, works with glutathione to prevent membranes from being oxidized.

      The failure of orally administered glutathione

      Although orally administered glutathione is efficiently absorbed in rats, the same is not true for glutathione supplements in humans. For example, a single oral dose of 3000 mg of glutathione did not significantly raise blood glutathione levels in human subjects. The authors concluded “… the systemic availability of glutathione is negligible in humans.” In a recent study, oral glutathione supplementation (500 mg twice daily) was given to the forty volunteers for 4 weeks. No significant changes were observed in biomarkers of oxidative stress, and glutathione status including total reduced glutathione (GSH), oxidized glutathione (GSSG), and their ratio (GSH:GSSG). The oral absorption of glutathione is better in rats because the human gastrointestinal tract contains high amounts of the enzyme glutamyltranspeptidase that breaks down GSH.

      Administered intraoral administered glutathione works

      A study found glutathione formulated into lipid nanospheres of less than 20 nm increased GSH levels of blood in human subjects up to 34% in less than 45 minutes. Healthy subjects were given an intraoral (oral) dose of 1 g of glutathione by administering 100 mg increments of glutathione between their gums and cheeks over a period of 5 minutes. Venous blood samples were drawn from the antecubital vein. Total glutathione (tGSH) and GSSG were measured and the content of glutathione calculated as the difference between tGSH and GSSG. Test data suggests an optimal dosage administration of every 3 hours, which corresponds with the consensus of glutathione half-life studies.


      Glutathione is considered
      the most important antioxidant
      because it is the only antioxidant
      capable of collaborating with
      enzymes.


      Administering glutathione formulated into lipid nanospheres via intraoral delivery through the mucosal membranes, lining the cheeks or the floor of the mouth, helps sustain GSH blood levels, achieves higher-potency responses, increases the circulatory half-life, and enhances site-specific bioactivity. Furthermore, such a delivery system has the ability to replenish intracellular GSH by transporting GSH across the blood-brain barrier and providing neuroprotection. The ability of an encapsulated GSH compared with non-encapsulated GSH for replenishment of intracellular levels was 100-fold more potent as a source for intracellular GSH repletion.


    • Improved nutritional kinetics and dynamics, such as decreased enzyme degradation, prevention of hepatic metabolism to inactive byproducts, reduced renal clearance, and fewer adverse reactions
    • Site-specific actions that minimize loss of biological activity and expand therapeutic potential
    • Unique molecular “stealth technology,” cloaking from the Mononuclear Phagocytic System and enzymatic destruction, thus prolonging and increasing the beneficial effects
    • Reduced adverse effects — decreased allergic reactions, side effects, and potential liver toxicity
    • Improved cost-effectiveness on a per-unit amount
    • Precision metering in small, incremental amounts

    The need for intraoral and advanced delivery systems


    LEM1301graph2_200.gif
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    The intraoral route of administration is been investigated clinically for numerous types of biological agents. For example, intraoral delivery systems for insulin and heparin have been developed. Intraoral delivery systems have demonstrated increased bioavailability compared to peroral delivery for various nutraceuticals and drugs. Figure 2 shows a significant increased bioavailable isosorbide (a nitrate drug) from a sublingual dose in comparison to a peroral dose.


    References

    1. Allen J, Bradley RD. Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. J Altern Complement Med 2011 Sep;17(9):827-33.
    2. Shojaei AH, Chang RK, Guo X, Burnside BA, Couch RA. Systemic drug delivery via the buccal mucosal route. Pharm Tech 2001;70-81.
    3. Favilli F, Marraccini P, Lantomasis T, Vincenzini MT. Effect of orally administered glutathione on glutathione levels in some organs of rats: role of specific transporters. Br J Nutr 1997; 78:293-300.
    4. Hagen TM, Wierzbicka TG, Sillau AH, et al. Fate of dietary glutathione: disposition in the gastrointestinal tract. Am J Physiol 1990;259:G524-G9.
    5. Harris D, Robinson JR. Drug delivery via the mucous membranes of the oral cavity. J Pharm Sci 1992 Jan;81(1):1-10.
    6. Hunjan MK, Evered DF. Absorption of glutathione from the gastrointestinal tract. Biochim Biophys Acta 1985; 815:184-18.
    7. Lomaestro BM, Malone M. Glutathione in health and disease: pharmacotherapeutic issues. Ann Pharmacother 1995;29:1263-73.
    8. Jones D. The health dividend of glutathione. Nat Med J Feb 2011; http://www.naturalmedicinejournal.com/article_content.asp?article=18 .
    9. Wilson C, Washington N, Washington C. Physiological Pharmaceutics: Barriers to Drug Absorption. 2nd ed, Boca Raton, FL:CRC Press;2001.
    10. Patel VF, Liu F, Brown MB. Advances in oral transmucosal drug delivery. J Control Release 2011 Jul 30;153(2):106-16.
    11. Shojaei AH. Buccal mucosa as a route for systemic drug delivery: a review. J Pharm Pharm Sci 1998 Jan-Apr;1(1):15-30.
    12. Valencia E, Marin A, Hardy G. Glutathione-nutritional and pharmacologic viewpoints: Part IV. Nutrition 2001;17:783-4.
    13. Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic availability of oral glutathione. Eur J Clin Pharmacol 1992;43(6):667-9.


    Dr. Richard Clark Kaufman is the author of the Age Reduction System, a book on reducing biological age. He was the co-director of one of America's first Life-Extension Medical Clinics in Beverly Hills, California, along with Life Extension pioneer Dr. Ward Dean.

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