Maximizing Medicinal Potential Through Bioavailability Enhancement Technologies

Over the last couple of decades, the concept of bioavailability has garnered significant attention in the pharmaceutical industry. It is considered to be one of the most important pharmacokinetic properties of a drug. Bioavailability refers to the proportion of a drug that reaches systemic circulation unaltered, post dose administration. It is a direct consequence of the absorption potential of an active pharmaceutical ingredient (API). The bioavailability of a drug is dependent on several factors, such as solubility, route of administration and metabolism of the drug post administration.

Given the rapid increase in the number of new chemical entities (NCEs) with low solubility and considering that this trend persists in the future as well, there is likely to be a surge in the demand for technologies that facilitate bioavailability enhancement. There are a number of technologies which are already available for improving drug bioavailability. Broadly, these technologies can be distributed across three main categories, namely physical, chemical and biological approaches. However, as pharmacological interventions gradually become more complex and novel drug classes are introduced, further innovation may be required to enable the development of better bioavailability enhancement techniques / methods. Bioavailability enhancement technologies and services market is anticipated to grow at a CAGR of around 11%, till 2035, according to Roots Analysis.

Assessment of Drug Bioavailability

The pharmacological response elicited by a drug depends upon the availability of the drug in relevant concentrations at the site of action (in the patient’s blood). The true dose of a drug that an individual is exposed to is not what is administered during the dosing process; rather it is the amount of active drug substance that is available at the appropriate biological site (after dissolution, absorption and metabolism). The bioavailability of a drug has been demonstrated to be impacted by several factors, such as dosage form used, dissolution rate, hindrances posed by biological membranes and metabolic degradation, during the absorption process. The bioavailable fraction factor (F) is a term which refers to the fraction of the administered dose that actually enters into systemic circulation. Mathematically, this factor is represented as follows:

Studies in Healthy Subjects and Patients

Ideally, a drug should be tested only in patients who have been diagnosed with a particular disease for which it is being developed. However, evaluating bioavailability by conducting studies in patients suffering with the relevant disease can also produce false results, as such subjects may often be on other medications, which can have an impact on the bioavailability of the drug under evaluation. Therefore, it is necessary for bioavailability assessment studies to be conducted in young, healthy volunteers, in a controlled environment.

Different Bioavailability Assessment methods

In order to assess / evaluate bioavailability, several direct and indirect methods are presently available. The rate and extent of drug absorption are used to describe the in vivo bioavailability of a drug molecule. The aforementioned determinants can be based on various quantifiable parameters, such as concentration of active therapeutic ingredient in blood, cumulative urinary excretion rates, or other pharmacological effects. The following figure presents an illustrated representation of the different approaches used in order to evaluate the bioavailability of drugs.

Need for Bioavailability Enhancement

A study conducted on terminated drug development projects revealed that majority of the drug candidates fail in early drug development phases, due to the problems associated with their pharmacokinetic profiles, ADME (distribution, metabolism, absorption and excretion) properties and toxicity-related issues. Moreover, it is a well-established fact that the systemic / local absorption and distribution of a therapeutic intervention is directly proportional to its bioavailability. Further, it was reported that more than 90% of new chemical entities (NCEs) developed by pharmaceutical companies and nearly 40% of the top-ranking oral drugs marketed in North America and Europe are insoluble in water and hence, their low solubility can lead to deficient drug concentration, which further leads to in vivo failure. As a result, a large number of companies are now considering adopting various types of bioavailability enhancement approaches in order to ensure that their proprietary pharmacological product candidates are made bioavailable at optimal quantities at the desired site of action.

As per the USFDA’s guidelines, a drug substance is considered to be highly soluble only when its highest dose strength is soluble in less than 250 ml of water, over a pH range of 1 to 6.8 at 37℃. Similarly, a drug molecule is said to be highly permeable when the extent of its absorption in humans is determined to be more than 90% of the administered dose, based on either mass-balance, or in comparison to an intravenous reference dose.

Bioavailability Enhancement Technologies

Given the rapid increase in the number of NCEs with low solubility and considering that this trend persists in the future as well, there is likely to be a surge in the demand for technologies that facilitate bioavailability enhancement. There are a number of technologies which are already available for improving drug bioavailability. Broadly, these technologies can be distributed across three key categories, namely physical, chemical and biological approaches. However, as pharmacological interventions gradually become more complex and novel drug classes are introduced, further innovation may be required to enable the development of better bioavailability enhancement techniques / methods.

Biological Formulations for Bioavailability Enhancement

In recent years, researchers are also using biological technologies / methods for bioavailability enhancement. The following points highlight the various biological approaches that are being employed for the enhancement of drug bioavailability.

• Cyclodextrin: Cyclodextrins are starch derivatives, having lipophilic inner cavities and hydrophilic outer surface. These are used widely for solubility and stability enhancement of drugs. Cyclodextrins have been shown to be capable of interacting with a variety of molecules to form non-covalent inclusion complexes, resulting in decreased side effects and increased bioavailability.
• Phytosome: Phytosome is a patented technology developed by Indena to incorporate standardized plant extract or water soluble phytoconstituents into phospholipids. This results in production of molecular complexes, which enhance absorption and bioavailability.
• Niosomes: Niosomes are the vesicular systems comprising of non-ionic surfactants, with or without the presence of cholesterol, and mimic the biological membrane. They are more stable as compared to liposomes due to oxidative degradation and hydroxylation of unsaturated fatty acids and ester bindings of phospholipids. The thin film technique can be employed for the formulation of niosomes.
• Bilosomes: Bilosomes are an advanced form of niosomes, which are prepared by incorporation of niosomes with the bile salts to enhance their penetration properties and confer better membrane stability against the detrimental effects of bile acids. These bile salt stabilized carriers are known as blossoms and have been demonstrated to possess good biocompatibility and increased bioavailability.

Concluding Remarks

In recent years, the focus of drug developers has shifted towards the development of lipophilic drug compounds due to the increasing issues with aqueous solubility / bioavailability of these drugs. As mentioned earlier, around 90% of NCEs belong to BCS class II and IV, which are known to be associated with low solubility / permeability. Given that a large number of drugs fail to reach the market due to poor bioavailability, the industry is looking for various tools / methods to mitigate this challenge. Moreover, as many companies seek to re-formulate existing product candidates that exhibit poor bioavailability (via the 505(b)(2) pathway), the demand for novel bioavailability enhancement methods has grown significantly. It is worth mentioning that since 2000, more than 55 players offering bioavailability enhancement technologies and services have been established. Amidst growing competition, the availability of cutting-edge tools and technologies has emerged as a differentiating factor. This has led many service / technology providers to actively expand their portfolios, either through strategic acquisitions / mergers or entering into service alliances with other bioavailability enhancement companies. Moreover, as drug developers continue to evaluate novel drug targets and classes, the bioavailability enhancement domain is expected to grow at a steady pace over the next decade.