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Meeting formulation and delivery challenges for macromolecular drugs: how lipid-based drug delivery systems can meet complex formulation, solubility and bloavailabillty challenges, including specific issues in improving the delivery of peptide and biologic therapeutics.

The biotech market reached revenues of $172 billion in 2014, which accounts for 23 percent of global pharmaceutical drug revenues, and it is expected to grow to 27 percent by 2020 (1). In a recent drug delivery landscape survey (2), oral delivery of macromolecules was voted as the top trend set to influence drug development over the next five years.

Lipid-based drug delivery systems (LBDDS) incorporated into softgel technologies are frequently used to improve the bioavailability of poorly soluble compounds, and have been used successfully to bring more than 50 poorly soluble molecules to market. Softgel technology enables improved delivery of low-solubility BCS Class II and IV drugs and also provides benefits in modulating membrane permeability for drugs where solubility is not the only biopharmaceutical hurdle to overcome. By modulation of the membrane's permeability, this technology can be applied to enable the delivery of macromolecular BCS Class III drugs.


The basic principles of LBDDS technology, which has proven to be one of the most successful advanced drug delivery methods applied to BCS Class II drugs, ensure that drug substances are delivered in a solution form that is maintained within biological fluids before the API reaches the intestinal membrane. In addition to the solubility issue, some poorly soluble drug candidates pose further challenges to attain the desired target product profile. LBDDSs have the versatility to offer a broad range of formulation possibilities.

For example, some poorly soluble drugs display excessive inter/intra individual variability which may not be compatible with the desired therapeutic effect. There are several strategies specifically designed to reduce such variability, including the self-micro emulsifying drug delivery system (SMEDDS), a lipid-based 'pre-concentrate' of solubilized drug, composed of lipid excipients, surfactants and co-surfactants, and co-solvents. Dilution of these formulations with gastrointestinal fluids results in the formation of a stable microemulsion, whereby the drug stays in solution and precipitation does not occur. Several new drugs formulated in this way have been commercialized.

Other strategies that have been applied to optimize formulations beyond solubility enhancement include the limitation of serum peak concentrations, thus reducing the Cmax/Cmin ratio. To achieve this, semi-solid formulations combining solubility enhancement properties with a modulated release rate have been developed. The technology upon which this formulation is based enables the encapsulation of various LBDDSs at higher temperatures.


Currently there are 200+ therapeutic macromolecules in the market and several have entered clinical trials (3). The best known, and most widely administered, is insulin, which accounts for a $25 Billion market worldwide (4), followed by monoclonal antibodies. The traditional approach to deliver these macromolecules has been through subcutaneous or intravenous injection, due to absorption, distribution, metabolism, and elimination (ADME) challenges associated with them. However, these dosage forms suffer from short plasma half-lives, necessitating frequent administration and ultimately, the risk of poor patient compliance in chronic conditions.

Oral drug delivery has always been the ultimate goal for any new therapy, not only because oral forms are so much more convenient and less invasive for patients, but also because clinical development of an orally delivered form is usually more straightforward, and clinical development costs are less than for an injectable formulation. Therefore, development of targeted and efficient oral formulations of macromolecules represents an unmet need.

To cater to this need, Catalent initiated research into the application of LBDDS technology for the non-invasive delivery of biologic drugs back in 2007. This has resulted in the development of OptiGel[TM] Bio technology, a lipid-based formulation that incorporates enteric coating and targeted permeation enhancement to increase the bioavailability of macromolecules, therefore enabling oral delivery of macromolecules.

The OptiGelBio technology combines various mechanisms in an effort to counter the challenges faced by macromolecules such as poor stability in the harsh conditions of GI tract, and poor permeability through the intestine cell wall, and therefore, poor bioavailability. When macromolecular peptide or protein drugs are delivered to the stomach, the molecule degrades or denatures when exposed to the acidic environment (pH 1-3) and proteolytic enzymes.

The enteric coating applied to OptiGel Bio softgel formulations is intended to enable macromolecules to pass through the stomach and deliver active APIs to the intestine, thus potentially allowing for targeted delivery. In the small intestine, the macromolecules cannot permeate through tight junctions of the intestinal cell wall because of multiple factors, including molecular size and steric hindrance effects, and are vulnerable to further enzymatic and hydrolytic degradation.

OptiGel Bio technology dissolves the macromolecule in a Generally Recognized as Safe (GRAS) lipid-based formulation within a softgel. Overcoming the mucus layer, the coated softgel capsule dissolves only after reaching the intestine wall and the lipid formulation evolves under normal biological conditions to release locally high concentrations of permeation enhancers along with the macromolecular API. The permeation enhancers open up the tight junctions, allowing the macromolecules to pass through into the bloodstream. After a short period the tight junctions close again, preventing absorption of any toxic molecules.

Furthermore, Catalent has created standard pre-formulation and formulation screening models in order to quickly evaluate whether OptiGel Bio technology can assist in the delivery of candidate macromolecules, including peptides. These models enable the determination of potential structural changes to the peptides that could maximize the ability to cross the enterocyte along with the permeation-enhancing system when formulated.

Biologies hold great promise with their low immunogenicity and targeted mechanism of action while offering their marketers better brand differentiation. A delivery technology that can enable a convenient administration method, such as the oral route, for these macromolecules could potentially change the landscape of the biopharmaceutical industry.

OptiGel Bio technology combines a GRAS lipid-based formulation and enteric coating to offer targeted permeation enhancement and macromolecule protection. The technology offers the potential to increase the bioavailability of macromolecules without absorbing unwanted toxic molecules, and may therefore enable oral delivery of macromolecules. It also has unique design features to reduce intra/inter individual dose variability. These characteristics set it apart from alternative technologies.

OptiGel Bio technology is applicable to various classes of macromolecules, including oligosaccharides as well as peptides and proteins. Catalent is conducting further research.


(1.) Evaluate Pharma, June 2014

(2.) The 3rd annual drug delivery landscape survey was sponsored by Catalent Applied Drug Delivery Institute. For more information, visit

(3.) Advanced Drug Delivery Review, July 2013, Ezan E, Pharmacokinetic studies of protein drugs: past, present and future

(4.) IMS data, 2013


An early-stage biotechnology company had developed a novel macromolecular-intravenous (IV) therapy for a thrombolytic post-surgical indication, and approached Catalent to enable conversion of the dose form to oral delivery. The aim was to enable this drug unique safety/efficacy profile to be applied to longer-term indications.

The macromolecule was soluble, but it had a high molecular weight (>2500 Da), a strong negative charge and a rigid, inflexible geometry which challenged the desired delivery across the walls of the small intestine into the blood.

Catalent's formulation expertize and OptiGel Bio technology achieved an optimized oral therapy which combined both the permeability enhancement and targeted delivery desired.

A stepwise screening approach utilizing both in-vitro and in-vivo models was adopted to evaluate formulation candidates and so to overcome the permeability challenge of the macromolecule. These studies demonstrated that lipid formulations, made of GRAS ingredients, releasing under normal biological permeation enhancers showed superior performance to formulations evolving into nanoparticulate systems. Those formulations have proven a superior permeability enhancement.

Despite the improvements in bioavailability, the pharmacokinetic (PK) variability highlighted the need for dose form optimization. The final dose form design was optimized.

By Julien Meissonnier, Catalent Pharma Solutions
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Author:Meissonnier, Julien
Publication:Pharmaceutical Processing
Date:Jul 1, 2015
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