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Release date:2022/6/2 17:17:52
The oral route of administration is one of the main drug delivery techniques and it is one of the most popular dosage forms among patients. Despite the high patient compliance, the deliveries of anti-cancerous drugs, vaccines, proteins, etc. via the oral route are limited and have recorded a very low bioavailability. Oral administration must overcome physiological barriers such as low solubility, permeability, and early degradation in order to achieve effective and sustained delivery.

We focus on the physiological barriers to oral drug delivery and some technical means to overcome them through this article, such as nanoparticles, microemulsions, hydrogels, prodrugs, 3D printing and other technical means. And through these technical means, oral drugs have gradually achieved the span from conventional to ultra-long-lasting drug delivery.

Figure 1. Challenges of oral drug delivery and technical design to overcome these challenges

Challenges in oral drug delivery

1. Buccal cavity, oesophagus and stomach

  • ▶ The buccal cavity (salivary glands) are the first obstacle encountered with oral formulations, and the presence of some enzymes in the oral cavity, such as salivary amylase, may lead to drug degradation. However, because of the short retention time of the drug in the oral cavity, barriers in the oral cavity generally have less impact on drug absorption.
  • ​ The oesophagus is not involved in digestion or drug absorption, but rather helps in the translocation of the drug, which it pushes through the stomach by peristalsis.
  • ​ The presence of fat-digesting enzymes in the stomach, such as lipase, can also lead to hydrolysis of the drug.

Enzymatic degradation hinders the dissolution of the drug and if the solubility is reduced, the effective drug concentration will change, thus affecting the absorption of the drug. Precipitation or supersaturation may also occur in the stomach if the drug has different solubility at different pH values. Once the drug crosses these biochemical barriers (pH and enzymes), the intestinal permeability of the drug further determines its fate.

2. Small intestine and colon

Orally administered drugs reach the small intestine after undergoing physiological barriers in the stomach. At the entrance to the small intestine (duodenum), pancreatic enzymes trigger several enzymatic transformations that may also lead to first-pass metabolism, resulting in reduced drug bioavailability. Therefore, orally administered drugs must overcome these physiological barriers.

The small intestinal mucosa has villi, and the villi in the intestinal epithelium play a crucial role in drug absorption, as they increase the surface area by up to 300 m2, thus facilitating drug absorption. Drugs administered orally can be absorbed via trans- or paracellular pathways. Due to the presence of lipid cell membranes, hydrophobic drugs prefer the transcellular pathway, while hydrophilic molecules are transported via the paracellular pathway.

In addition, the biological membrane of the gastrointestinal tract has a hydrophilic head and a lipophilic tail. The lipid bilayer hinders the free movement of drug molecules through the cell membrane. Usually, the higher the molecular weight, the lower the chance of being absorbed. The charge on the drug molecule also determines its chance of absorption. Since mucins are negatively charged, positively charged molecules may adhere due to electrostatic interactions.

The final absorption of a drug in the colon is limited by its solubility and non-specific interactions. Non-specific interactions here refer to the adherence of the drug to feces, mucus or other secretions in the colon. Since the colon absorbs water, hydrophilic drugs are more readily absorbed compared to hydrophobic drugs. Therefore, the main challenge in the oral route of administration is the formulation of insoluble macromolecules, as they are susceptible to enzymatic degradation and are difficult to absorb.

Physiological-barriers-to-oral-drug-delivery

Figure 2. Physiological barriers to oral drug delivery

Strategies to enhance drug bioavailability

In order to overcome the above mentioned physiological barriers, there are several technologies used to overcome the physiological barriers to oral drug delivery and thus improve the absorption and bioavailability of drugs, such as nano-formulations and technical means such as hydrogels.

1. Nanoparticles

The high surface area to volume ratio of nanoparticles improves the solubility and stability of the drug. The particle size of nanoparticles generally ranges from 100 to 1000 nm. Drugs can be encapsulated in nanoparticles to obtain sustained release, which in turn protects the drug from drastic pH changes and the harsh enzymatic environment of the gastrointestinal tract. The size, shape, and surface charge of the nanoparticles affect the pharmacokinetics of the drug.

nanoparticles

Figure 3. Nanoparticles

The pH-dependent carboxylate nanoparticles are a boon to oral drug delivery systems, where carboxylate ions do not ionize at acidic pH, thus protecting the drug from harsh environments and providing targeted release when in the intestinal environment. Eudragits are commonly used copolymers for this technology and are widely used to enhance the bioavailability of lipophilic drugs.

The poly(ethylene glycol) (PEG), a passive mucopenetrating system, has been widely used in surface modification of nanoparticles due to the property of reducing interactions with both luminal components and mucus in the gut. Biopharma PEG can provide high purity PEG derivatives in GMP and non-GMP grades for your research of nanoparticles for oral drug delivery.  

2. Hydrogels

Hydrogels are three-dimensional polymer networks formed by physical or chemical cross-linking methods. A certain amount of space is left between the network, and due to the presence of this mesh, the structure of the hydrogel is rich in porosity. The polymer networks can trap large amounts of water and prevent its transport to the external environment, thus mimicking the physical properties of biological tissues. This ability to retain water allows the hydrogel to provide a platform for good biocompatibility and encapsulation of drug molecules. The network can limit the penetration of different enzymes, thus protecting the encapsulated drug from degradation by various enzymes.

Hydrogels

Figure 4. Hydrogels

Long-acting oral drug delivery

1. The prodrug approach

Prodrugs are inactive or less active bioreversible derivatives of active drug molecules that undergo enzymatic or biotransformation prior to producing pharmacological effects. The predrug strategies enhance the performance of many molecules and it helps in enhancing the drug absorption as well as stability after oral administration. The prodrug approach has also been implemented in injectables and has shown similar success, the following are some of the FDA approved long-acting prodrugs.

/FDA-approved-prodrugs
Table 1. FDA approved long-acting prodrugs

However, there are also some challenges to overcome with prodrug technology. It involves complex chemical reactions, as controlling the site of transformation can be cumbersome, and the release of the active drug in the pre-drug may also involve the release of by-products, each of which is critically important for toxicity assessment.

prodrug

Figure 5. The prodrug approach

2. 3D printing

3D printing technology has evolved because it does not require granulation, compaction, and coating, and it allows for flexible control of drug dosage and release. 3D printing technologies include selective laser sintering (SLS), Stereolithography (SLA), fused deposition modeling(FDM), semi-solid extrusion (SSE), and inkjet printing (IJP). 3D printed drugs are currently represented by the FDA-approved Spritam.

3d-printing
Figure 6. 3D printing

Conclusion

With the development of nanotechnology and 3D printing, oral formulations have made great progress. The development of long-acting as well as ultra-long-acting oral drugs is a major focus of research by researchers and scientists. Pharmacokinetic studies have shown that ultra-long-acting release has the potential to reduce side effects and improve patient compliance.

Two-ultra-long-acting-drug-delivery-designs
​Figure 7. Two ultra-long acting drug delivery designs

References:
​1. Utkarsh Bhutani, Tithi Basu, Saptarshi Majumdar, Oral Drug Delivery: Conventional to Long Acting New-Age Designs, European Journal of Pharmaceutics and Biopharmaceutics, Volume 162, 2021, Pages 23-42, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2021.02.008.

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