Nanosphere Delivery Systems
Methods for overcoming bioavailability limitations

By Richard Kaufman, Ph.D.

N utritional formulators are often foiled by the difficulty of getting valuable nutrients into circulation in the body. When a nutraceutical is given orally, its bioavailability and, ultimately, its efficacy depend on the solubility and absorption in the gastrointestinal tract. Many dietary supplements have low bioavailabilities when taken orally due to several interacting reasons.

For example, many supplements are comprised of hydrophobic molecules that are practically insoluble in aqueous solutions. Due to this water-adverse nature they have poor oral absorption due to slow or incomplete dissolution in the lumen of the gastro-intestinal tract. This is especially true of most phytochemicals in plants. Phytochemicals are increasingly accepted as health promoting, maintaining, and repairing agents in cells, tissues, or the whole human body. Over the past two decades, the usage of botanical dietary supplements has steadily increased worldwide. This growing popularity has been especially notable among people in Western countries, where almost 20% of consumers report regular usage of such supplements.1

Bioavailability Means Reaching Circulation

In the human body, bioavailability is determined when substances obtained from ingested materials reach circulatory system for further delivery into designated tissues so that the beneficial compounds are biologically available for exerting healthy functions. The unique properties of many bioactive photochemical phenolics, carotenoids, organic acids, and several miscellaneous bioactive compounds such as saponins and sterols are poorly transported and absorbed into the plasma. Resveratrol, curcumin and quercetin have very low oral bioavailability.2a,2b,3,4

Stomach acids may destroy some enzymes, especially when pH changes are severe. Other enzymes undergo pre-systemic metabolism upon and first pass liver effects oral administration that keeps plasma levels low despite a high intake. Plus the composition, shape, size and morphology of many dietary supplements inhibit their transport across the blood brain barrier, transport into target cells and penetration into cell structures. The dilemma is that many popular supplements produce minimal beneficial effects when ingested.

Gene Alterations Triggered by Nutrients

Postgenomic approaches to dietary supplements open a new paradigm shift in preventive medicine such as dietary cancer prevention. Among these, antioxidants—which are found in many phytochemicals—have received the greatest attention. Many diseases are related to an imbalance between oxidants and antioxidants. Unfortunately, most phyto­chemicals are biologically unstable, poorly soluble in water and poorly distribute to target sites. Because of these shortcomings, therapeutic applications of dietary supplements have run into a wall and not fulfilled their promise.


The dilemma is that many popular
supplements produce minimal
beneficial effects when ingested.


Pharmaceutical Companies Leading the Way

Today, the pharmaceutical giants are exploiting the most advanced chemistry of drug delivery systems to transport the highest levels of therapeutic agents into target cells and tissues for higher efficacy. Pharmaceutical industry experts estimate that approximately 40% of lipophilic (poorly water soluble) drug candidates fail due to solubility and formulation instability.5 This has prompted major research activity in advanced delivery technologies. Sales of pharmaceutical products utilizing advanced drug delivery technologies are approaching 40% of all pharmaceutical sales.6

For Big Pharma, it is the coming age of intelligent nano-sized delivery systems. Pharmaceutical giants continue to develop the most advanced chemistry of nano-sized delivery systems to transport the highest levels of therapeutic agents into target cells and tissues for maximum efficacy. Promising and versatile nano-scale drug-delivery systems include nanoparticles, nanocapsules, nanotubes, nanogels and dendrimers.7

Novel nanostructured biomaterials and formulations are enabling site-specific targeting and controlled release of traditional pharmaceuticals, recombinant proteins, vaccines, nucleic acids and nutraceuticals. Numerous pharmaceuticals for treating cancer, AIDS, fungal infections, high blood pressure, mental illness and skin disease have been formulated with nanoparticle delivery systems.8

Nanoparticle Encapsulation of Nutraceuticals

Researchers worldwide are testing nanoparticle encapsulation of nutraceuticals with poor bioavailability and bioactivity. They have proven significant greater delivery into the circulation system, passage into cells, passage across the blood brain barrier and significant greater therapeutic efficacy not present in regular forms. Unfortunately, in the nutritional supplement industry, there has been lack of basic awareness of the concepts and the technology underlying these new nanoparticle delivery systems … until now.

NanoSphere delivery systems are now in development for dietary supplements and nutraceuticals that are based on the pharmaceutical industry models of nano-sized particles formed from bioactive natural nontoxic phospholipids and their structures in the human body. The emergence of NanoSpheres provides a much needed greater stability, bioavailability, bioactivity and efficacy for many dietary supplements, nutraceuticals and phytonutrients.

NanoSphere delivery systems provide nutraceutical formulations with:

  • Enhancement of biological stability including solubility
  • Improvement of cellular transport
  • Release of the active component inside the cell.
  • Significantly greater bioavailability and bioactivity
  • Site-specific targeting
  • Longer half-life in the body
  • Minimal side effects
  • Enhanced therapeutic value

The Era of Structured-Lipid NanoSphere Carriers

The interdisciplinary field of nanobiotechnology—combining chemistry, biology, engineering, and medicine—is revolutionizing the development of delivery systems for a wide range of biological agents from drugs to nutraceutical factors. Natural, non-toxic biomaterials with nanosize organization are used to create nanoparticle (or NanoSphere) delivery systems.

These systems have an enhanced ability to cross cell membranes, reduce the risk of undesired pre-systemic metabolism, avoid uptake by the reticuloendothelial system of the liver and spleen as foreign substances and prevent premature clearance from the body.9

The Family of Nano-sized Carriers

Solid Lipid Nanoparticle Carriers

Solid lipid NanoSpheres (SLNs) are lipoprotein-like solid lipid nanospheres synthesized from natural lipids that have a solid form and a diameter typically 30–100 nm. They are dynamic structures synthesized from natural lipid surfactants and contain an encapsulated lipid inner core phase surrounded by a phospholipid layer. They provide controlled release, efficient targeting, and stability to its cargo or payload.10

Because of the phospholipids ability to balance between hydrophilic and lipophilic properties, phospholipids such as lecithin form the membrane layer of solid lipid nanosphere particles that surround a lipid core. The lipophilic fatty acids of the phospholipids are arranged in the interior membrane of the nanosphere particles and the hydrophilic head groups of the phospholipid molecules are orientated towards the exterior. A lipophilic inner core consists of simpler lipids. The lipophilic interior of the outer membrane and inner core of the solid lipid nanosphere particles makes it possible to incorporate high levels (up to 90%) of the nutraceutical substance.11

SLNs delivery systems combine the advantages of lipid emulsions and polymeric systems while overcoming the stability issues, and carrier cytotoxicity of other delivery systems. Plus, SLNs permits overall more controlled release.


In the nutritional supplement
industry, there has been a lack of
awareness of the concepts and the
technology underlying nanoparticle
delivery systems … until now.


A variety of nutraceutical, phytochemicals and pharmaceuticals for treating cancer, AIDS, fungal infections, high blood pressure, mental illness and skin disease have been loaded into solid lipid nanopshere particles. They appear to be the ideal carrier structure for DNA, peptides, genes, vaccines, hormones, and phytochemicals

SLNs have emerged as a leading candidate for an advanced drug delivery system. They combine the advantages of lipid emulsions and polymeric nanosphere systems while overcoming the stability issues, and carrier cytotoxicity of these other delivery systems. Plus, SLNs permit more controlled payload release.

Similar to Plasma Lipoproteins

SLNs show a great similarity to endogenous plasma lipoproteins in composition, size, morphology, and surface properties as a carrier system. They are subject to the same uptake cellular uptake process into numerous tissues and organs that occurs by a transport mechanism known as receptor-mediated endocytosis. Because they have a very small particle size, they even can pass easily through a leaky capillary wall. In essence, SLNs are a protein-free analogue of plasma lipoproteins. Advantages of SLNs carriers include:

  • Increased bioavailability
  • Sustained bio-effectiveness and longer-lasting actions
  • Higher-potency responses, allowing reductions in amount and in frequency of administration
  • Increased efficacy of ingredients through site targeting
  • Transport of blocked compounds across the blood-brain barrier
  • Circulation times in vivo extended from hours to days
  • Improved nutritional kinetics and dynamics, such as decreased enzyme degradation, prevention of hepatic metabolism to inactive byproducts and reduced renal clearance
  • 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, 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

Lipid Emulsion Nanosphere Carriers

Lipid emulsion NanoSphere (LEN) carriers are dynamic structured, dispersed particle droplets created from natural lipids that possess an outer phospholipid layer and an encapsulated inner lipid core.12a,12b

An emulsion is a liquid system in which one liquid is dispersed in a second, immiscible liquid (with or without emulsifiers), usually in droplets. LEN consists of a water phase with droplets composed of a fatty acid core stabilized with a phospholipid monolayer. The phospholipid monolayer stabilizes the emulsion by long-range repulsive electrostatic forces and short-range repulsive hydration forces.


The emergence of NanoSpheres
provides a much needed greater
stability, bioavailability, bioactivity
and efficacy for many dietary
supplements, nutraceuticals and
phytonutrients.


LEN carriers can be formed with a composition with a droplet size of 75–140 nm and distribution that are much like those of chylomicrons, the endogenous aggregates that distribute lipids in the bloodstream. In both systems, phospholipids are the emulsifier. Advantages of LENs include:

  • Sustained bio-effectiveness and longer-lasting actions
  • Protection of agents from the hostile environment and degradation in the gut.
  • Increased efficacy of ingredients through site targeting.
  • Much higher surface area and free energy than macroemulsions that make them an effective transport system.
  • Increased tissue penetration over micron-sized regular emulsions
  • Increased effectiveness resulting in reduced dose and frequency of administrations
  • Reduced adverse effects
  • Improved cost-effectiveness on a per-unit amount

Essential Phospholipids: The Preferred Material of NanoSphere Delivery System

Many of NanoSphere delivery systems are composed of the same GRAS phospholipids that comprise the major components of biological membranes and lipoproteins. The most abundant phospholipid is phosphatidylcholine, aka lecithin.

Lipid NanoSpheres are build from the Essential Phospholipids (EPLs)—1,2 Dilinolenylphosphatidylcholine. Imported from Europe, EPLs are lipid-protein complexes that bind together to form a membrane similar to that which surrounds all living cells in the body, protecting their contents. Polyenylphosphatidylcholine provides an essential nutrient comprising approximately (65%) of every cell membrane in your body.


The lipophilic interior of the outer
membrane and inner core of the
solid lipid nanosphere particles
makes it possible to incorporate
high levels (up to 90%) of the
nutraceutical substance.


EPLs are recognized as a superior way to maintain cellular membrane structure and function. Pure polyenylphosphatidylcholine provides an essential nutrient comprising approximately (65%) of every cell membrane in your body.

Once ingested and digested, the EPLs are distributed throughout the body where its effects vary with location. Research proven benefits include: maintaining cell membrane structure and function; supplying choline for the crucial neurotransmitter acetylcholine; supporting hepatocyte protection, function and regeneration; sustaining healthy lipid levels; gastric mucosa protection; protecting insulin-producing pancreatic cells; emulsification of fat and bile, detoxification of xenobiotics; energy storage and production; aid in blood clotting; and antioxidant protection.13a,13b

In addition to, EPLs in NanoSpheres maintain proper cardiovascular, male sexual, gastrointestinal, and neurological functions. EPLs are able to take up more cholesterol from low-density lipoprotein (LDL; “bad cholesterol”) and transport it back to the liver, a function known as reverse cholesterol transport. Other types of lipid-lowering agents (e.g., the statins drugs) either reduce cholesterol absorption in the body or cholesterol synthesis in the liver and its distribution around the body. The ability to enhance reverse cholesterol transport is unique to EPLs.

Self-Emulsifying Nanoparticle Delivery System

A recent development is a self-emulsifying NanoSphere delivery system (SENDS), designed to improve the oral absorption of many nutraceuticals that have a low aqueous solubility.14 SENDS consists of mixtures of natural phospholipids, surfactants and solvents which emulsify spontaneously to produce fine oil-in-water nano-emulsions when introduced into aqueous phase in the gastrointestinal tract with mild agitation provided by gastric mobility. Advantages of SENDS include:

  • Enhanced oral bioavailability enabling reduction in dose
  • More consistent temporal profiles of ingredient absorption
  • Targeting toward specific absorption window in the gastrointestinal tract
  • Protection of agents from the hostile environment in the gut

Three Forms of Oral Delivery

Within the mouth, the delivery of nutraceutical factors and drugs is classified into three categories: a) Intraoral sublingual delivery, which is systemic delivery through the mucosal membranes lining the floor of the mouth, b) Intraoral buccal delivery, which is administration through the mucosal membranes lining the cheeks (buccal mucosa), and c) Peroral delivery, which is passage through the mouth into the gastrointestinal tract.

Peroral Delivery

Among the routes for delivering nutraceuticals, peroral delivery is most commonly used. However, the oral delivery of nutraceutical factors from the GI tract into the systemic circulation has numerous disadvantages. They include the acid-induced hydrolysis in the stomach, enzymatic degradation throughout the gastrointestinal tract, bacterial fermentation in the colon and presystemic metabolism significantly lower bioavailability. Plus the insolubility, hydrophobic nature, or molecular structure of certain compounds prevents their absorption from the GI tract.

Intraoral Delivery

Intraoral delivery of nutraceutical supplements through the mucosal linings of the oral cavity offers distinct advantages over peroral delivery through the GI tract. The oral mucosa is extremely rich in blood vessels and lymphatics that unlike the GI tract do not drain into the portal hepatic vein. Factors from the oral mucosa directly enter the systemic circulation from the jugular vein, thus avoiding passage through the liver where they may undergo undesirable metabolism (1st pass liver effect). Other tangible benefits include increased absorption, faster onset of actions, and greater bioavailability. Furthermore, intraoral delivery does not require swallowing and does not produce GI irritation.

Permeation Varies between Sublingual and Buccal Mucosa

Anatomical and permeability differences between the sublingual and buccal mucosa necessitate different delivery system designs. The sublingual mucosa route gives fast absorption, a rapid onset of action and overall high bioavailability. This route is best suited for a delivery system of small particles providing a high concentration of compounds in short delivery period time. Nano-sized solid lipid and droplet lipid nanospheres have a superior composition and molecular structure for a sublingual delivery system.

NanoSphere Delivery Across the Oral Mucosa

The solution for delivering supplements nutraceutical factors and nutraceuticals through the oral mucosa are encapsulating them into highly permeable lipid NanoSpheres. They can be administered to the mouth’s oral mucosa via controlled dropper device of actuator pump for rapid deliver across the oral mucosa and uptake into the circulatory system.

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

NanoSphere Delivery Across the Blood-Brain Barrier

The brain needs a barrier that separates it from the blood, to permit the rigorous control of the brain microenvironment that is necessary for complex neural signaling. The blood brain barrier (BBB) is an endothelial barrier present in the capillaries that course through the brain. It closely oversees what enters the brain from the rest of the body.

The BBB allows only required elements, such as nutrients and proteins used by the brain, to enter the brain’s capillaries, turning myriad other blood borne molecules away. In its task of protecting the chemistry of the brain, the BBB barricades many beneficial compounds. According to an article in Nature Reviews Drug Discovery,15 the BBB prevents the brain uptake of >98% of all potential neurotherapeutics. These problems have led researchers to develop new delivery technologies to pass the BBB well-guarded gates of the central nervous system.

The capillary endothelial cells that make up the BBB form very tight, high-resistance junctions that line the blood vessels that run through the brain. They act as a continuous lipid blockade, preventing the free diffusion through extracellular pathways that occurs regularly at most other organs.

For a molecule to diffuse through the BBB, it must have a sufficient amount of lipid solubility. In addition, the larger it is, the more difficult diffusion will be. Small polar molecules, such as glucose and amino acids, and larger proteins, like insulin are also vital to the workings of the brain.

Normally the tight junctions of the BBB permit the diffusion of only very small amounts of water-soluble compounds (paracellular aqueous pathway), while the large surface area of the lipid membranes of the endothelium offers an effective diffusive route for lipid-soluble agents (trans­cellular lipophilic pathway).

A practical route through which a substance may cross the endothelium is by the transcellular lipophilic pathway. There is a good correlation between BBB penetration in vivo and the lipid solubility of compound or molecular structure. Molecules that are small enough and lipid-soluble enough can slip through the BBB in pharmacologically significant amounts

Lipid NanoSpheres represents a practical carrier system for delivering compounds to brain via the transcellular lipophilic pathway. Lipid nanoparticle carriers can not only circumvent the BBB limiting characteristics of the carried molecule, but can also protect it from chemical/enzymatic degradation, and additionally provide the opportunity for sustained release characteristics. A wide range of agents been formulated into lipid-structured nanoparticle carriers and proven to pass the blood brain barrier in high dosage percentages.

References

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2a. Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. 2004 Dec;32(12):1377-82.
2b. Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res. 2005 May;49(5):472-81.
3. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007 Nov-Dec;4(6):807-18.
4. Cai X, Fang Z, Dou J, Yu A, Zhai G. Bioavailability of quercetin: problems and promises. Curr Med Chem. 2013 Jul 1;20(20):2572-82.
5. Prajapati BG, Patel MM. Conventional and alternative pharmaceutical methods to improve oral bioavailability of lipophilic drugs. Asian J Pharm. 2007;1:1-8.
6. Singh AK, Chaurasiya A et al. Oral Bioavailability Enhancement of Exemestane from Self-Microemulsifying Drug Delivery System (SMEDDS). AAPS PharmSciTech. 2009 September; 10(3): 906-16.
7. Goldberg M, Langer R, Jia X. Nanostructured materials for applications in drug delivery and tissue engineering. J Biomater Sci Polym Ed. 2007;18(3):241-68.
8. Shah CV, Shah V, Upadhyay U. Solid Lipid Nanoparticles: A Review. Curr Pharma Res. 1(4), 2011, 351-68.
9. Basu, B, Garala K, Bhalodia R, Joshi B, Mehta K. Solid lipid nanoparticles: A promising tool for drug delivery system. J Pharm Res. 2010;3(1):84-92.
10. Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. Eur J Pharm Biopharm. 2000 Jul;50(1):161-77.
11. Sinha VR, Srivastava S, Goel H. Solid Lipid Nanoparticles (SLN’S) – Trends and Implications in Drug Targeting Solid Lipid Nanoparticles. Int J Adv Pharma Sci. 2010; 1(3):212-38.
12a. Iqbal MA, Md S, Sahni JK, Baboota S, Dang S, Ali J. Nanostructured lipid carriers system: recent advances in drug delivery. J Drug Target. 2012 Dec;20(10):813-30.
12b. Radtke M, Souto EB, Müller RH. Nanostructured Lipid Carriers: A Novel Generation of Solid Lipid Drug Carriers. Pharm Tech Eur. Apr 2005;17(4):45-50.
13a. Fricker G, Kromp T, et al. Phospholipids and lipid-based formulations in oral drug delivery. Pharm Res. 2010 Aug;27(8):1469-86.
13b. Gundermann KJ. The “essential” phospholipids as a membrane therapeutic. Szczecin, Poland: Polish Section of European Society of Biochemical Pharmacology, Institute of Pharmacology and Toxicology, Medical Academy, Szczecin; 1993.
14. Kohli K, Chopra S, Dhar D, Arora S, Khar RK. Self-emulsifying drug delivery systems: an approach to enhance oral bioavailability. Drug Discov Today. 2010 Nov;15(21-22):958-65.
15. Pardridge WJ. Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discovery. 2002;1:131–9.

General Reference

Indah Epriliati and Irine R. Ginjom (2012). Bioavailability of Phytochemicals, Phytochemicals — A Global Perspective of Their Role in Nutrition and Health, Dr Venketeshwer Rao (Ed.), ISBN: 978-953-51-0296-0, InTech, DOI: 10.5772/26702. Available from: http://www.intechopen.com/books/phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health/bioavailability-of-phytochemicals


Richard Kaufman, Ph.D.is the author of the Age Reduction System.

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