Implementing a bioavailability enhancing formulation approach can positively impact safety, efficacy, and patient adherence, leading to successful clinical outcomes. This article takes an in-depth look at how lipid-based drug delivery systems (LBDDS) can be used as a bioavailability enhancing technology, as well as the softgel dosage form for their delivery, in order to achieve successful clinical outcomes.
Improving Drug Adherence Rates
In general, following drug approval, only one out of four patients will benefit from a drug, largely due to poor adherence rates, and these rates are much higher for chronically administered drugs. A 2008 study looked at drug adherence during the first 12 months of therapy for 7 major medical conditions (hypertension, hypothyroidism, Type 2 diabetes, epilepsy, hypercholesterolemia, osteoporosis, and gout). The percentage of patients able to achieve 80% or higher adherence rate ranged from 36.8 – 72.3%. Another study examined the persistence rate (time from initiation to discontinuation) at 6 months for 6 drug classes. Six month persistence ranged from 28% for overactive bladder medications to 66% for oral antidiabetic medications.
“If the patient isn’t taking the drug properly and on time, then it doesn’t matter if it’s got a great pharmacologic effect,” according to Professor Kishor Wasan, Dean of the College of Pharmacy and Nutrition at the University of Saskatchewan, Canada.
“It’s an important concept because often patients are taking multiple drugs, and if you give them a complex formulation or a complex dosing regimen, it’s very difficult to get compliance.” And in a clinical trial, that can be disastrous.
One of the reasons that patients go off their medicine or don’t adhere to a clinical trial protocol is because they’re not getting the desired therapeutic effect. As a result, they get discouraged and quit taking their medicine. Another reason that patients quit taking their medications is because they experience serious side effects. If an enabling formulation, such as a LBDDS, can provide optimal drug exposure to reach desired therapeutic performance with mitigated side effects, then the patients are more likely to be motivated to stay on their medication.
Central Dogma of Drug Absorption
The central dogma of drug absorption considers two factors: the drug’s solubility and its permeability. These two factors are the cornerstones of the Biopharmaceutics Classification System (BCS) proposed by Gordon Amidon  and the Developability Classification System (DCS) proposed by James Butler and Jennifer Dressman.
“Solubility and permeability factor into absorption and bioavailability, because if either is poor, it affects the bioavailability of the drug, which in turn leads to pharmacokinetic variability,” says Ronak Savla, Scientific Affairs Manager at Catalent Pharma Solutions and the Catalent Applied Drug Delivery Institute.
The majority of pipeline drug candidates fall within BCS and DCS Class II, which means that they have acceptable permeability but are poorly solubilized in the gastrointestinal tract. BCS and DCS Class II drugs present numerous challenges such as poor bioavailability, significant subject-to-subject variability, absorption leading supra or sub therapeutic levels, and food effects. The challenges associated with these drugs often extend beyond absorption, and even if the drug is absorbed across the gastrointestinal epithelium, many lipophilic molecules undergo extensive first pass metabolism by cytochrome P450 (CYP450) enzymes in hepatocytes.
“The bioavailability needs to be such that the right amount of active ingredient consistently gets into the bloodstream at the site of action to elicit a pharmacological response with low toxicity and a feasible dosing regimen”, says Professor Wasan.
Bioavailability Challenges Associated with Poorly Soluble Molecules
The absorption of certain drugs, including many oral anticancer agents, may be decreased or increased by the presence of food. This is termed a negative or positive food effect, respectively. Poorly soluble drugs often exhibit positive food effects. Safety concerns are amplified for drugs with a narrow therapeutic index. If these drugs experience a positive food effect, wherein food increases absorption, the drug may reach supra-therapeutic, even toxic levels, and can result in very serious side effects which are harmful to the patient.
“This happens because the lipid make-up in the food, especially following ingestion of a high fat meal, actually aid in solubilizing the drug molecule, thereby promoting drug’s absorption, as it travels through the GI system,” explained Dr. Jeff Browne, Director of Science & Technology at Catalent. “Oral anticancer agents are notorious for experiencing significant positive food effects.”
Food effects have important clinical implications: proper patient adherence to instructions on a drug product’s labelling regarding when to take the drug is paramount as lack of adherence can result in potential under- and over-dosing of the medication. For drugs with a positive food effect, patients are often instructed to wait two hours after eating to take the drug because administration with a high-fat meal can significantly increase drug exposure. However, for some classes of drug, a positive food effect can actually be an advantage and patients are instructed to take the medication with food to increase exposure. In this case, the adherence concern is that a patient takes the medication on an empty stomach resulting in lower exposure and therefore a sub-therapeutic amount of drug potentially leading to poor clinical outcome.
As mentioned previously, many oral anticancer agents experience a positive food effect. However these drugs are typically labelled to be taken on an empty stomach. If a patient took their medication with a meal, the primary concern would be the higher toxicity associated with plasma levels that are above the maximum therapeutic dose. For example, nilotinib is an oral kinase inhibitor known to have a significant positive food effect. Supra-therapeutic levels of this drug may cause life threatening arrhythmias.
There are studies investigating the ability of LBDDS to mimic food effect. Because the lipid content in a LBDDS is considerably less than that in a high fat meal, while a LBDDS
does have an effect on a drug’s pharmacokinetics, it is normally a lower magnitude of effect compared with a high fat meal.
“We looked at oral drugs formulated in LBDDS. Twenty-one FDA approved oral drugs contained language about food effect in their product labels. Eight drugs were labelled to be taken with a meal. With one exception, these drugs capitalized on a positive food effect. Drugs labelled to be taken without regard to food experience either no change in their pharmacokinetic parameter or the magnitude of the change (increase of decrease) is not clinically significant to affect the safety and efficacy of the drug,” explained Dr. Savla.
Another bioavailability challenge for poorly soluble drugs is they typically have greater intra- and inter-patient variability, expressed using the measure of coefficient of variability (CV%). In regards to intra-patient variability (pharmacokinetic variability within a single patient), it is possible that the plasma level may fall within the therapeutic window one day and be sub-therapeutic or supra-therapeutic the following day. It becomes difficult to find a consistent dose for the patient and dose titration is often required.
“The immunosuppressant cyclosporine is an example of drug with a narrow therapeutic index. This drug is available as two approved softgel products, each using a different lipid formulation. One product, Sandimmune®*, was initially introduced to the market as a corn oil-based formulation with surfactant. The other, Neoral®*, was subsequently introduced, as a newer glyceride microemulsion formulation. The intra-patient variability (CV%) of the older Sandimmune® product is reported to be between 19-26%. The newer Neoral® product, formulated as a microemulsion, has a lower CV% of 9-21%. The Neoral® product therefore allowed clinicians to better titrate the correct dose for a patient to maintain a safe and effective plasma level,” said Dr. Browne.
Again referring to the Neoral® product, Professor Wasan indicated the lower pharmacokinetic variability between patients (inter-patient variability) is important because physicians could better predict pharmacologic response from patient-to-patient.
Design Principles of Lipid Based Drug Delivery Systems for Poorly Soluble Drugs
There’s not a one-size-fits-all approach, or off-the-shelf LBDDS that can be used for drug molecules. Every drug compound is unique and formulators must first understand the molecule’s physical-chemical properties, and importantly what is the likely reason for poor bioavailability (poor solubility, poor permeability, or both). Only then, can a LBDDS be rationally designed to take into account the specific drug molecule’s properties.
“For compounds exhibiting poor solubility, we design lipid formulations to keep the drug in solution and prevent it from precipitating out as it travels through the GI tract. By doing so we maximize our chances of increasing exposure knowing the solubilized form of the drug is needed to cross the GI membrane,” said Dr. Browne. “One of the big benefits of LBDDS is the wide range of different excipients that the formulator can choose from in order to design a lipid formulation that is able to solubilize the required dose of drug prior to its administration to the patient.”
“Once we solubilize the drug in the formulation, then we often try to design a lipid system so that it readily disperses. By incorporating dispersion and digestion properties into the design of our lipid systems, we're often able to keep the drug in solution in the body,” says Vincent Plassat, Scientific Affairs manager at Catalent.
Bioavailability Challenges Associated with Poorly Permeable Macromolecules
Oral delivery of macromolecules such as peptides continues to receive a lot of attention in the pharmaceutical industry. However, achieving acceptable bioavailability to provide exposure levels for successful clinical outcomes is challenging to say the least. While possessing reasonable aqueous solubility, the permeability of these molecules is often limited with oral bioavailability of 1-2% or less. Factors that can contribute to poor permeability include size , charge, hydrophilicity, and molecular flexibility. Poorly permeable compounds, as is the case with poorly soluble compounds, not only can result in low bioavailability, but also significant variability.
Design Principles of Lipid Based Drug Delivery Systems for Poorly Permeable Drugs
To meet the challenges posed by macromolecules, Catalent’s OptiGel™ Bio technology, a LBDDS delivered via softgel dose form, has been developed in recent years based on numerous experiments to increase permeability and stability of macromolecules.
“Catalent’s OptiGel™ Bio technology is based on our knowledge around lipid-based formulations. This technology has already been shown to hold great promise for BCS Class III compounds, or water soluble macromolecules with poor permeability,” said Plassat.
One approach encompassed by this technology uses enteric coated capsules, which are engineered to bypass the detrimental effects encountered in the stomach. As a result, the formulation and molecule contained within, will be protected from the acidic conditions of the stomach and subsequently released in the intestine or the colon.
General speaking, molecules can pass through the gut wall either through the cell (transcellular route) or between the cells of the intestine (paracellular route). Some lipid formulations can be designed to improve permeability of the molecule through the addition of permeation enhancers that increase the transcellular route of absorption. Other lipid formulations include permeation enhancers that primarily affect paracellular transport by opening up the tight junctions that exist between cells. The characteristics of macromolecules (size, charge, hydrophilicity, and molecular flexibility) do not lend them to be absorbed via the transcellular route. Another approach encompassed by OptiGel™ Bio technology increases the permeability of macromolecules by transiently opening up the tight junctions between enterocytes enough for macromolecules to pass through. This is accomplished by using GRAS (generally regarded as safe) excipients which simplifies the later regulatory approval pathway.
“These tight junctions are an evolutionary mechanism to prevent any toxins or xenobiotics from entering the body. With these permeation enhancers, we can control their activity so they open for a certain period of time and quickly close to avoid any long-term toxicity,” Savla said.
Avoid the First Pass Metabolism
Designing a lipid system that avoids the first pass metabolism in the liver would add yet another clinical benefit for patients. CYP450 enzymes in the liver are known to have high levels of genetic variation and make it difficult to apply a uniform dose across a diverse patient population. The end result is that these drugs don't provide sufficient exposure to the patient and can lead to significant variation either within a given patient or from patient to patient. This also leads to potential drug-drug interactions in patients taking multiple medications. Patients may have to stagger their medication to avoid these interactions. Improving the formulation of these drugs through the use of LBDDS may help mitigate metabolism.
An emerging area of research interest as a way of mitigating first pass metabolism is the design of drugs and formulation to promote lymphatic uptake. The mechanisms of lymphatic uptake and transport are still unclear. However, what is clear, studies have demonstrated that through proper selection of drug compounds and design of LBDDS, lymphatic uptake of drugs can be facilitated to avoid1st pass effect in the liver.
Dosage Form Considerations for Oral Lipid-based Drug Delivery Systems
“Our analysis revealed that soft gelatin capsules or softgels were the most common dosage form for orally administered LBDDS,” said Dr. Savla. Softgels are compatible with a wide range of lipid excipients and well suited for LBDDS.
Patients prefer softgels because they can easily swallow softgel capsules. Softgels can mask the strong taste or odors of certain medications. These characteristics of the softgel dosage form lead to a positive patient experience which is paramount to achieving good adherence to any medication.
Therapeutically, softgels for immediate release of drugs quickly dissolve in the gut and release the liquid contents. The softgel shell provides an excellent barrier to oxygen and the fill is hermetically sealed without headspace to ensure the contents are protected from the environment and the formulation quality and performance characteristics are maintained. More recently, the enteric coating of softgels has been employed to target where in the GI the softgels will dissolve and release the lipid-based contents.
LBDDS help overcome many of the challenges posed by molecules in today’s pharma development pipelines including poor solubility, poor permeability, and GI metabolism. These challenges often lead to poor bioavailability as evidenced by inadequate exposure, pharmacokinetic variability, and food effects. LBDDS can be applied to a wide variety of molecules, including macromolecules, given the versatility they offer. Softgels are the most common dosage form for oral administration of LBDDS. In addition to being compatible with LBDDS, softgels can be used for both immediate and controlled or targeted release applications. Finally, softgels are preferred by patients and lead to a positive patient experience which in turn assures a successful clinical outcome.
*Sandimmune® is a registered trademark of Novartis AG Corporation
*Neoral® is a registered trademark of Novartis AG Corporation