Oral Nano-drug Delivery System 1

With the development of new drug discovery related technologies such as high-throughput screening technology, a large number of drug candidates have been discovered, but their solubility is often low. 40% to 70% of drug candidates are difficult to obtain therapeutic concentrationdue to low solubility and poor oral absorption. In particular, protein and peptide drugs have large molecular weights, are not easy to penetrate biological membranes, are susceptible to the action of enzymes in the organism, and their oral bioavailability is very low. According to the solubility and membrane permeability of the drug, drugs can be divided into 4 categories, namely the Biopharmaceutical Classification System (BCS): Class I is high solubility and high permeability drugs; Class II is low solubility and high permeability drugs ; Class III is a drug with high solubility and low permeability; Class IV is a drug with low solubility and low permeability. A large number of studies have proved that the nano drug delivery system can effectively improve the dissolution and oral bioavailability of class II, class III, and class IV drugs in BCS. Nano drug delivery systems that can be used for oral administration include liposomes, polymer nanospheres/nanocapsules, solid lipid nanoparticles, microemulsions, nanoemulsions, self-emulsifying microemulsions, polymer micelles, dendrimers, and nanodrug crystals, etc.

Liposomes
As a drug carrier, liposomes have a wide range of encapsulation, and water-soluble components, fat-soluble components and amphoteric substances can all be encapsulated. Only the substances that are insoluble in both the water phase and the organic phase, or the substances that are highly soluble in both the water phase and the organic phase, are difficult to be wrapped due to easy leakage. Liposomes have good targeting and slow-release properties, which can protect drugs from the degradation of enzymes in the intestinal tract and improve drug stability. The lipid bilayer structure similar to biomembrane gives liposomes good cell affinity. After oral administration, it is easy to fuse, absorb and exchange lipids with intestinal mucosal cells, promote drugs into human cells, and improve drug biology utilization.
When biological macromolecule drugs such as polypeptides, proteins, and nucleic acids are orally administered, they are easily destroyed by acid and enzymes in the gastrointestinal tract, and their bioavailability is very low. Encapsulating these macromolecular drugs in liposomes can protect and promote absorption. For example, liposomes modified with PEG 2000 are stable in the gastrointestinal pH environment. After coating insulin liposomes with chitosan and sodium alginate, oral administration in mice has a better effect on lowering blood sugar.

One of the biggest obstacles of ordinary liposomes as an oral nano-drug delivery system is that they are extremely unstable under the synergistic effect of intestinal bile salts and intestinal enzymes. Scientists hope to find orally stable liposomes. The tetraether lipid PLFE was extracted from the archaea Sulfolobus acidocaldarius. Compared with ordinary liposomes, the tetraether liposomes prepared by the film dispersion method are very stable in the gastrointestinal environment. Tetraether liposomes can be used as oral vaccine carriers and insulin carriers, and the effect of lowering blood sugar is better. Liposomes of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylethanol will not be catalyzed by phospholipase A and can encapsulate insulin. The liposome modified with N-trimethyl chitosan is used as the carrier of salmon calcitonin. When N-trimethyl chitosan is about 78% quaternized, it has more mucosal adhesion than chitosan . In vivo adhesion experiments show that compared with unmodified liposomes, N-trimethylchitosan modified liposomes stay longer in the body and have better permeability.

Nanoparticles
Nanoparticles can improve drug stability, extend the gastrointestinal retention time of drugs, change the distribution of drugs in the body, have the characteristics of slow release and targeted drug delivery, and have extensive research in improving the bioavailability of oral drugs. Nanoparticles can be divided into: 1, Natural polymer materials, such as albumin, gelatin, and chitosan according to the preparation materials; 2, Synthetic polymer materials, such as polylactic acid glycolic acid (PLGA), polyalkylbutyl cyanoacrylate (PBCA); 3, Solid lipid materials, including natural or synthetic, steroids, and waxes.

• Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLN) is a drug carrier developed in the early 1990s. It uses solid natural or synthetic lipids with low toxicity, good biocompatibility, and biodegradability as materials to encapsulate or embed drugs in In the lipid core, the particle size is usually 10~1000nm. SLN has good stability, less drug leakage, sustained release and targeting properties, and easy sterilization and  mass production.

• Polyester Nanoparticles

Polylactic acid (PLA) and polylactic acid glycolic acid (PLGA) have good tissue compatibility and biodegradability. They have been approved by the US FDA as pharmaceutical excipients and are also the most commonly used polymer materials for preparing nanoparticles. They achieve mucosal adhesion through hydrogen bonding, polymer-mucin adhesion, hydrophobic interaction or other binding mechanisms.

• Chitosan Nanoparticles

Chitosan is a basic and positively charged natural amino polysaccharide with good biocompatibility and biodegradability. The chitosan molecule contains amino and hydroxyl groups, which can form a high-viscosity colloidal solution when dissolved in dilute acid. The aqueous solution is a cationic electrolyte with strong flocculation. The amino groups of chitosan molecules are prone to chemical reactions and can be chemically modified under mild conditions. Chitosan interacts with the negatively charged cell membrane to induce the redistribution of F-actin and ZO1 protein, which are related to the tight junction between cells, increase the permeability of the hydrophilic macromolecule cell bypass, and promote affinity Absorption of water-based macromolecular drugs.