New Sports Nutrition Frontier: Transmucosal Delivery System For Muscle-Building Supplements.

One of the most exciting and innovative areas of research in boosting bioavailabilty for certain sports nutrition ingredients is the development and utilization of transmucosal delivery systems... Learn more.

Article Summary:
  • The oral mucosa is permeable and has the ability to absorb some ingredients.
  • Transmucosal delivery is the usage of a substance using a tablet held in the mouth.
  • The newest transmucosal technologies are based on pharmaceutical science.


New Sports Nutrition Frontier:
Transmucosal Delivery System Opens Door For Muscle-Building Supplements

Just as athletes are constantly searching for new products and approaches for increasing their athletic performance and muscle building, sports nutrition companies are researching new ways to increase the bio-effectiveness of their products. In addition to creating new formulas, a major area of focus is making sure that the delivery of the ingredients is maximally effective, in that they are delivered into the body unaltered, at a high rate of absorption.

One of the most exciting and innovative areas of research in boosting bioavailabilty for certain sports nutrition ingredients has been pioneered by the drug industry, and is the development and utilization of transmucosal delivery systems designed for dissolution and absorption of ingredients through the mucosal tissue of the mouth.

Yes, the oral mucosa (lining of the mouth), is permeable to a certain degree and has the ability to absorb some ingredients. Plus, this ability can be greatly enhanced through bioengineering molecules and encasing them in specialized micro-sized delivery systems, such as liposomes.

What Is A Liposome?
Liposome.A liposome is a tiny bubble (vesicle), made out of the same material as a cell membrane. Membranes are usually made of phospholipids, which are molecules that have a head group and a tail group. The head is attracted to water, and the tail, which is made of a long hydrocarbon chain, is repelled by water. Liposomes are used for drug delivery due to their unique properties. A liposome encapsulates a region on aqueous solution inside a hydrophobic membrane; dissolved hydrophilic solutes cannot readily pass through the lipids. Hydrophobic chemicals can be dissolved into the membrane, and in this way liposome can carry both hydrophobic molecules and hydrophilic molecules.


So What Does This Mean For Bodybuilders And Other Athletes?

    It means having the potential to make anabolic compounds 10 to 20 times more potent. It means allowing for the administration of exciting and new anabolic compounds that can only be administered transmucosally - it means more muscle building potential than ever before!

    Transmucosal Delivery: For the purposes of this article transmucosal delivery encompasses the administration of a substance using a tablet that is held in the mouth, usually under the tongue. Tablets for transmucosal delivery in the mouth are specially designed to rapidly dissolve in the mouth and release the ingredients for absorption through the mucosal membrane lining the mouth.

    The primary areas of the mouth where the mucosal membrane has the ability to absorb substances is the area under the tongue (also referred to as sublingual) and the area inside the cheeks (referred to as buccal). The use of the term transmucosal includes delivery of a substance to all of these oral mucosal membranes.

    While the newest transmucosal technologies are indeed based on the cutting edge of pharmaceutical science, it is interesting to note that one of the first "modern medical" uses of transmucosal delivery was reported back in 1897 in a letter published in the medical journal The Lancet, in which Doctor William Murrell described the effects of oral nitroglycerin in relieving the pain of angina pectoris1.

What Is Angina Pectoris?
Angina pectoris, commonly known as angina, is severe chest pain due to ischemia (a lack of blood and hence oxygen supply) of the heart muscle, generally due to obstruction or spasm of the coronary arteries (the heart's blood vessels). Coronary artery disease, the main cause of angina, is due to atherosclerosis of the cardiac arteries. The term derives from the Latin angina ("infection of the throat") from the Greek áγχóνη ankhone ("strangling"), and the Latin pectus ("chest"), and can therefore be translated as "a strangling feeling in the chest".

    Today, this drug is still delivered "fast" via transmucosal administration in the mouth. Our understanding of how some substances have the ability to be absorbed through the oral mucosa, and the permeability of the oral mucosa itself, has led to a plethora of research and development of specialized ingredients and products to utilize this avenue of bioactive administration.

    Among nutritional products, one of the classic uses of transmucosal delivery of conventional nutrients has been utilized for delivery of vitamin B-12. This became popularized based on the belief that some people may have problems absorbing vitamin B-12 through regular ingestion.

    Another group of nutrients using transmucosal delivery that became popularized by the 1980's best selling health book, Life Extension, include some amino acids, such as GABA (gamma amino butyric acid), which efficiently delivers the GABA into the bloodstream very close to the primary target tissues of the brain.

    However, some of these Next Generation Nutrient Delivery Systems go well beyond the simple vitamin B12 and GABA transmucosal administration, and employ super sophisticated liposomal technology that was developed in the pharmaceutical industry. While transmucosal delivery is a viable delivery system when matched with compatible substances, note that for most of the nutrients, conventional ingestion is adequately effective.

    Most recently these transmucosal delivery systems are catching on and now being used by sports nutrition companies. The transmucosal oral delivery approach offers distinct absorption and function advantages when used with compatible ingredients.

Conventional Peroral Nutrient Administration Transmucosal Nutrient Administration
Ingested Bioactive Nutrient / Substance Subject To:
  • Digestive system enzyme breakdown.
  • Competition for intestinal absorption.
  • Combining with other molecules.
  • Alteration from passing through the liver.
  • Low delivery of bioactive into bloodstream for delivery to target tissues
Bioactive Nutrients / Substances designed for maximal uptake and bioeffectiveness:
  • Liposomal delivery enhances potency.
  • Avoids potential destruction from digestive system and from first pass through the liver after intestinal absorption.
  • Designed for higher rate of absorption directly into the bloodstream through oral mucosal tissue.


Overview Of Peroral And Transmucosal

    Sports nutrition and other dietary supplement products are usually designed for traditional oral (peroral) route delivery, such as conventional tablets, capsules, liquid gel caps, softgels, and other solid dosage forms.

    You swallow a tablet, which enters into the digestive system, it gets absorbed (or maybe not) into the body via the bloodstream or lymph system, passes through the liver where alterations may occur, then whatever amount of the bioactive that survived metabolic destruction goes on to the body via the bloodstream to perform its function.

    This conventional peroral dosing can sometimes have disadvantages for certain compounds that are subject to a high level of degradation in the gastrointestinal tract and once absorbed into the bloodstream can be subjected to further degradation from first pass metabolism in the liver.

    Another factor that can reduce delivery of ingredients into the body is poor intestinal absorption. This poor absorption of ingredients causes them to simply pass through the intestinal tract, ending up being excreted from the body. Collectively these obstructive processes may reduce the ultimate bioactivity of certain ingredients.

This Poor Absorption Of Ingredients Causes Them To Simply Pass Through The Intestinal Tract, Ending Up Being Excreted From The Body.

    We like to believe that theoretically the bioactive constituents of a nutrition product starts out with 100% bioavailability potential, meaning that if it was 100% absorbed into the bloodstream, and was not subject to any degradation along the way to its destination within the body tissues, there could be 100% bioactivity inside the body.

    However, 100% bioactivity for all substances is rarely achievable through the peroral dosage delivery route of administration, and for certain compounds the actual effective bioactivity score can be reduced to only 10% or lower. This may mean that 100 milligrams of actives in the tablet may only deliver 10 milligrams of usable ingredients into the body.

    With ingredients that are subject to high rates of degradation and/or low intestinal absorption, transmucosal routes of delivery may offer major advantages over peroral route delivery.

    For these sensitive compounds, the transmucosal route of delivery avoids gastrointestinal tract and first pass liver metabolism alteration and destruction of the bioactive substance(s). Destruction that can take place includes molecular cleavage, functional group alterations, and even compounding with other molecules.

100% Bioactivity Is Rarely Achievable Through The Peroral Dosage Delivery Route Of Administration.
+ Click To Enlarge.
100% Bioactivity Is Rarely Achievable Through The
Peroral Dosage Delivery Route Of Administration.


Bioactive Breakdown Concerns

    During the digestive system process, molecular cleavage can involve the breaking apart of a molecule that primarily occurs from the action of destructive type of enzymes. Many of these destructive enzymes occupy the gastrointestinal system and liver to play a vital role to breakdown food for use in the body. However, these same enzymes also destroy certain bioactives used in products, rendering them ineffective.

    Functional group alteration involves modification of the active part(s) of a molecule's structure that are responsible for its bioactivity in the body. During digestion or in the liver when the alteration of the bioactive's function group occurs, this can deactivate the molecule, preventing it to perform its' function.

    The other major way a bioactive molecule's functioning in the body can be prevented occurs when a bioactive complexes with other molecules to form an entirely new compound. As you can imagine there are many other molecules and molecule fragments present in the gastrointestinal system and bloodstream. Based on the molecular architecture of a bioactive, it may react with these other substances to form a new compound that does not function as originally intended.

The Digestive System.
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The Digestive System.


Transmucosal Works For Anabolic Bioactives

    A good example of comparing peroral versus transmucosal delivery system routes is reported in research examining anabolic substances such as testosterone and androstendiol.

    When using the transmucosal delivery route substantially lower amounts of testosterone and androstendiol were needed to produce the same effects as much higher dosages of perorally administered dosage forms. Transmucosal delivery indeed yielded results similar to injected dosage administration.

    Dr. Wang and co-researchers 2 reported that transmucosal administration in the mouth of 5 mg of testosterone led to marked increases in serum total and free testosterone within 30 minutes. Increases in strength, lean body mass and sexual function were reported from this study using sublingual testosterone during a 6 month period.

    The results of this research confirmed the results of an earlier study using transmucosal administration, which was conducted by Dr. Salehian and co-researchers3. This earlier study examined the efficacy of testosterone cyclodextrin (transmucosal administration in the mouth) versus testosterone enanthate injections. In this study the researchers were interested in the effects of using the different routes of testosterone administration on sexual performance of hypogonadal men.

    Both therapies resulted in causing subjects to experience significant improvements in sexual motivation and performance, with no significant difference between the injectable and trans-mucosal administration.

Transmucosal Administration In The Mouth Of 5 Mg Of Testosterone Led To Marked Increases In Serum Total And Free Testosterone Within 30 Minutes.

    To further demonstrate the effectiveness of transmucosal delivery in the mouth, in another research project, Dr. Brown and co-researchers 4 examined the effectiveness of transmucosal administration of androstenediol.

    These researchers pointed out that using the conventional orally ingested androstenediol was determined to have very low absorption, very low bioavailability, and very low effectiveness in raising blood serum levels of testosterone and androstenediol.

    In comparison, their research study found that when eight strength trained young men (average age 22.9 years) were administered just 20 mg of transmucosal administered androstenediol tablets that dissolved in the mouth, their serum levels of androstenediol and testosterone were increased within 30 to 60 minutes.

    The researchers noted that because 200 mg of androstenediol taken orally does not change serum free or total testosterone levels in young men (as reported in another study), trans-mucosal dosing in the mouth is superior for the delivery of androstenediol to the peripheral tissues and conversion to testosterone; over 10 times more effective.

There are effective products containing steroidal anti-aromatase and thyroid hormone potentiating substances, reports improved efficacy using the transmucosal delivery system.

In addition to being effective for improving the delivery and effectiveness of steroidal type molecules transmucosal delivery also offers advantages for other categories of molecules, such as large peptides.

For example, when researching for substances that could dramatically boost the levels of IGF-1, it was determined that the hexapeptide (6 chain peptide) molecule called GHRP-2 Hexapeptide Acetate, was very effective via intravenous injection. Regarding conventional ingestion, the gastrointestinal system is only capable of absorbing free amino acids, di-peptides, and tri-peptides, therefore peroral administration would be ineffective.

In other similar products technical overview researchers reported developing a way to deliver GHRP-2 into the body by bioengineering a transmucosal liposomal based formula for delivering this hexapeptide directly into the bloodstream through the oral mucosal membrane.

Transmucosal Delivery Also Offers Advantages For Other Categories Of Molecules, Such As Large Peptides.
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Transmucosal Delivery Also Offers Advantages
For Other Categories Of Molecules, Such As Large Peptides.


Transmucosal Tablet Technology

    Recently, transmucosal delivery system tablet designs have become more sophisticated than merely dissolving a conventional solid dosage form in the mouth. Advanced developmental steps when designing a transmucosal tablet product can include:

    • Evaluation of the bioactive molecular structure for transmucosal compatibility.
    • Modifications to bioactive molecule for enhancing absorption, bioavailability, and effectiveness.
    • Synergistic effects when combined with other ingredients.
    • Liposomal carrier optimization.

    The oral mucosa of the mouth is composed of distinct layers of cells. The outer most cell layer is called the epithelium, moving in the next layer of cells is called lamina propria, and this is followed by the innermost layer called the submucosa.

    The target of a transmucosal delivery system is this submucosa layer of cells. This submucosal cell layer is highly vascularized and has a rich supply of blood.

    When designing products to take advantage of the transmucosal route of delivery, researchers need to ensure that the tablets will dissolve properly, and the bioactive ingredients encased in liposomes will adhere to the mucosal membrane and optimal delivery the bioactives through the mucosal membrane into the bloodstream will occur.

    Within the oral cavity, the mucosal tissues lining the mouth are highly vascularized with a rich supply of blood. The buccal mucosal membrane is also selectively permeable and can uptake certain substances for delivery directly into the bloodstream.

    But, while the transmucosal bioactive delivery route seems very attractive, there are characteristics that make using this route of administration challenging. These challenges include:

    1. Adhesion of the bioactives to the mucosal membrane
    2. Penetration of the bioactives through the mucosal membrane
    3. Transport through the mucosal tissue layers to the bloodstream

The Mucosal Tissues Lining The Mouth Are Highly Vascularized With A Rich Supply Of Blood.
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The Mucosal Tissues Lining The Mouth Are Highly
Vascularized With A Rich Supply Of Blood.


Liposomal Technology Optimizes Transmucosal Delivery

    The creation of the liposome was a major breakthrough that has enabled taking transmucosal delivery to the next level compared to the early days of merely dissolving a conventional tablet and ingredient in the mouth. With the advent of liposomes, transmucosal delivery technology has evolved to a new level of sophistication and effectiveness.

    Liposomes are complex microspheres that emulate the bilipid structure of cell membranes. By utilizing liposomes this provides a special bioengineered vehicle to encase the bioactive ingredients. Since the development of liposomes several decades ago this technology has made significant advancements.

    Recently scientists have advanced the liposomal bioengineering process to develop highly customized liposomes based on the specific bioactive to achieve liposomal optimization, which translates into greatly enhancing the delivery and effectiveness of the bioactives.

    Transmucosal tablets can now be custom designed to take advantage of all the transmucosal pathways for the most rapid and complete delivery and absorption into the bloodstream. They are designed for rapid tablet disintegration and dissolution of the bioactive in the mouth.

    In general, liposomes are designed to be stable in salvia, rapidly disperse, quickly saturate the mucosal tissue lining of the mouth, and release the bioactives to permeate into this highly vascularized tissue.

    In this way the bioactives are delivered directly into the bloodstream, completely intact, with near 100% delivery. This avoids the unwanted destruction that can take place passing through the GI and Liver.

    To ensure stability and bioactivity, bioactives may also need to be modified to have improved stability in the bloodstream to maintain bioactivity for longer periods of time, which can greatly enhancing the effectiveness of the product formula.

    • Liposomes can carry a wide variety of bioactives, both water soluble and lipid soluble.
    • Liposomes can protect the bioactives from degradation by environmental and metabolic processes.
    • Liposomes can enhance solubility.
    • Liposomes can increase the rate of bioactive absorption.
    • Liposomes can improve bioavailability of bioactives.

Bioactives May Also Need To Be Modified To Have Improved Stability In The Bloodstream To Maintain Bioactivity For Longer Periods Of Time.

    Some of the steps that are involved in creating Bio-Compatible Liposomes include achieving three critical bioengineering design goals:

    • Preparation of the bioactive molecule(s) for stabilization, optimum liposomal compatibility and maximum bio-effectiveness.
    • Development of the precisely bioengineered custom liposome.
    • Design of the transmucosal tablet matrix for liposomal optimization.

    The first goal is to ensure that the bioactive ingredients are designed for stability in the tablet and in the body. Bioengineered stability of the bioactives provides for maximum potency and prolonged bioactivity in the body, such as extended plasma half-life.

    This includes choosing the ingredients with the optimal molecular structure or slightly modifying the molecular structure for maximum results. Some of the chemical modifications of bioactives can include oligomerization, amino acid substitution, bromination, or esterification.

    Once the molecular customization is finalized, the specific bioactive solution determination and preparation is undertaken to guarantee compatibility with the liposomalization process.

    The second goal typically employs proprietary technology required to create the most highly effective customized lipophilized micro-particulates (liposomes) for housing the bioactives. For each product ingredient the liposomes are custom designed to possess optimal functioning once the tablet is dissolved in the mouth.

    Liposomes primarily function to stabilize and preserve potency of the bioactives, promote bio-adherence to the mucosal membrane once dissolved in the mouth they facilitate immediate penetration and transmucosal uptake and ensure the fastest migration of bioactives to the highly vascularized submucosal tissue layer for delivery directly into the bloodstream.

    The third goal ensures that the tablet matrix to dissolve quickly and disperse the liposomes over a maximal area of the mucosal membrane. Other design goals that are achieved include using mucosal absorption and permeation enhancers that are designed to facilitate the penetration and uptake process.

    The liposomal and tablet matrix design therefore both stabilized the bioactives and allowed for rapid and high levels of absorption directly into the bloodstream primarily through transmucosal absorption.

    As you can imagine, from just going through these bioengineering ingredient and product design steps, extreme care is taken to insure that the highest quality, potent ingredients are utilized.

    As the sports supplement industry takes notice of the advantages of transmucosal delivery, it will be vital that companies also have the knowledge, training, skills, and technical expertise to properly prepare and or modify the compounds and then develop the appropriate liposomes and tablet matrix for maximum efficacy.

Some Of The Dynamic Features Of Liposomal Design And Function.
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Some Of The Dynamic Features Of
Liposomal Design And Function.


Getting More With Less?

    Among the variety of benefits that can be provided using tablets designed for transmucosal delivery, it typically takes much less of an amount of bioactive to achieve bioeffectiveness, versus traditional ingestion. This is due to the near 100% bioavailability that can be achieved using properly designed transmucosal tablets.

    Contrast this to certain bioactives that experience poor intestinal absorption, and a high amount of destruction during the digestion process and first pass through the liver metabolism. To compensate for the low bioavailability of some bioactives using conventional dosage forms will contain much higher amounts when compared to the transmucosal tablet type products.

It Typically Takes Much Less Of An Amount Of Bioactive To Achieve Bioeffectiveness, Versus Traditional Ingestion.
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It Typically Takes Much Less Of An Amount Of Bioactive
To Achieve Bioeffectiveness, Versus Traditional Ingestion.


When Transmucosal Is The Only Effective Delivery

    Scientists have discovered various peptides, which have been shown to exert tremendous anabolic properties and other performance benefits, such as the previously mentioned GHRP-2 Hexapeptide Acetate. However, these peptides are not suited for peroral administration.

    Peptides, which are molecules consisting of a chain of amino acids linked together, which are larger than tripeptides (3 amino acids long) are not well absorbed by the intestinal tract. Peptides, also larger amino acid chain molecules, proteins, are efficiently broken down in the gut during digestion.

    Therefore in order to administer a large bioactive peptide molecule, it must be protected from digestive system destruction and designed to take advantage of effective uptake routes, such as transmucosal delivery.

Peptides, Also Larger Amino Acid Chain Molecules, Proteins, Are Efficiently Broken Down In The Gut During Digestion.

    Similarly, other molecules with potent biological activity that have poor absorption profiles can benefit from transmucosal delivery.

    As discussed earlier in this article, the once popular supplement ingredient androstenediol is poorly absorbed through the intestines and modified during first pass through the liver, rendering it minimally effective through peroral administration. But, the same androstenediol molecule is very effective using transmucosal delivery.

    A host of other ingredients like complex glycoside photochemicals and amines that are deactivated during digestion or first pass through the liver may also be suitable for transmucosal delivery.

Glycoside:
Glycosides are molecules in which a sugar is bound to a non-carbohydrate moiety, usually a small organic molecule. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme hydrolysis, which causes the sugar part to be broken off, making the chemical available for use.


The Future Of Transmucosal Delivery

    With specialized companies taking the lead on utilizing transmucosal delivery technology, others are sure to try to follow. It will be interesting to see what comes next in the sports nutrition category of transmucosal products.

    One thing is certain though; it takes a tremendous effort of trained experts to create an effective transmucosal tablet with the highest quality control measures in place. Consumers and companies need to be mindful of this high level of product development and manufacturing requirement to make sure to offer a well made transmucosal product.

    Simply dissolving a tablet under the tongue doesn't ensure transmucosal absorption. Maximally effective transmucosal delivery requires the proper compounding of bioactives and bio-compatible liposomes.

    In addition to transmucosal delivery, there is also the application of using liposomes to improve stability, intestinal uptake, and bioavailability of certain bioactives that are either subject to massive gastrointestinal destruction or are poorly absorbed.

    Furthermore, the most advanced liposomes being designed in the pharmaceutical industry, possess the ability to enter into the blood stream intact, and delivery their bioactives to specific target tissues inside the body; truly remarkable.

Simply Dissolving A Tablet Under The Tongue Doesn't Ensure Transmucosal Absorption.
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Simply Dissolving A Tablet Under The Tongue
Doesn't Ensure Transmucosal Absorption.

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Conclusion
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There is certainly opportunity for utilizing transmucosal delivery with existing ingredients having sports nutrition applications, like Coenzyme Q10, glutathione, Vitamin B12, antioxidants, phytonutrients, and NADH. But the real excitement for bodybuilders and other athletes lies in the potential for new novel anabolic compounds to be administered through transmucosal delivery. This new frontier will take muscle building and sports performance supplementation to the new level.

Recommended Articles:

References:

  1. Squier, C.A., The Permeability of Oral Mucosa.,Critical Reviews in Oral Biology and Medicine, 2(1): 13-32, 1991.
  2. Wang, C., et al., Sublingual Testosterone Replacement Improves Muscle Mass and Strength, Decreases Bone Resorption, and Increases Bone Formation Markers in Hypogonadal Men - A Clinical Research Center Study., J Clin Endocrinol Metab 81:3654-3662, 1996.
  3. Salehian, B., et al., Pharmacokinetics , Bioefficacy, and Safety of Sublingual Testosterone Cyclodextrin in Hypogonadal Men: Comparison to Testosterone Enanthate - A Clinical Research Center Study. J Clin Endocrinolo Metab 80: 3567-3575, 1995.
  4. Brown, G.A., et al., Acute hormonal response to sublingual androstenediol intake in young men., J Appl Physiol 92:142-146, 2002.

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Notice And Disclaimer:

This article is not intended for use as a substitute for consultation with a qualified medical / health practitioner to determine your individual requirements and special needs. If you have symptoms of any illness or injury, it is essential that you see your doctor immediately for proper treatment. The author does not recommend and or endorse any specific tests, products, treatments, procedures, or other content presented in the publication. This information is for education and or entertainment purposes only. Reliance on any information provided by the author is solely at your own risk.