The increasing costs in new drug development as well as the number of fast track development programs are considered major challenges for the sustainability of the pharmaceutical industry.
While in the early stages, drug safety and efficacy are the main focus, mitigating the risk for the drug formulation and dosage form after the clinical proof of concept is becoming highly relevant. Challenging physicochemical characteristics of the drug, tight time lines, and the phase 3 clinical supplies have to be tackled within a rational, scientific yet pragmatic approach.
The target product profile (TPP) is the starting point for the drug product development, defining the required and desired drug product attributes for the final marketed product1.
While the TPP sets the goals, there are various ways to achieve these goals through different excipients and processing options. The evaluation of the different options and the selection of the final dosage form have to be thought through carefully to mitigate the risk throughout the life-cycle, starting from early development stages to the market phase.
The physicochemical and the pharmacokinetic-dynamic properties of the drug substance determine if functional excipients and applied technology are required to achieve the desired drug concentration at the site of action. The selection of the approaches is based on a fundamental understanding of the solubility characteristics of a specific drug substance. Drugs with poor aqueous solubility require solubilizing and bio-enhancing approaches2.
Particle size reduction is the simplest way to increase drug dissolution, eventually in combination with a crystallization inhibitor, followed by hot melt extrusion or spray drying to maintain the drug in an amorphous state. For example, drugs with high lattice energy and weak bases that are in their protonated form in the gastric juice, but crystallize at the higher pH of the intestinal environment, are suitable candidates for the formation of supersaturated solutions with hydroxypropyl methylcellulose (HPMC) as a crystallization inhibitor.
The bioavailability of drugs might also depend on presystemic degradation or metabolism that can be circumvented by delivering the molecules to the intestinal site of absorption. Bypassing the stomach with an enteric dosage form is traditionally used to release the drug in the small intestine and achieve the desired absorption profile.
Excipients are pharmacologic inert components in regard to pharmacological activity, but contribute to the performance of the drug product by providing a desired functionality. During the past few decades, excipient suppliers focused on material science to optimize or develop excipients with specific targeted functionality.
One of the best examples of a pharmaceutical excipient that has undergone significant enhancements that led to the expansion of its functionalities is the hard capsule.
From Gelatin to Additional Pharma Polymers
Hard capsules made of gelatin have been used over a century to provide immediate release properties for orally administered dry (e.g. powder, granules, pellets) and semi-solid or liquid formulations.
Another major, relatively new application of hard gelatin capsules is in dry powder inhalation (DPI) formulation, used to release a metered monodose after activation in a device. Hard gelatin capsules are manufactured using a dip molding process, whereby the shell is formed after retraction of the dipping pins from a hot liquid solution by a slight temperature drop.
The dip molding process requires polymers set by forming a stable gel due to the temperature drop. In the last step, the formed gels are dried to a desired moisture level to form the hard capsules. The transformation from the liquid to a gel state of a polymer is the basic principle of the dip molding process for capsule manufacturing.
In the 1990s, gelling systems were introduced that allowed the use of HPMC and pullulan as suitable polymers for capsule manufacturing by a dip molding process similar to the gelatin manufacturing process.
The gelling polymers are either carrageenan or gellan gum, which in combination with cations, even at very low concentration (normally below 1 percent), lead to gelification of the hot polymers solution when retracted by the cold dipping pins.
The HPMC-based and pullulan-based capsules differ from gelatin capsules due to a variety of characteristics that allow the use and application of capsule to drug molecules and delivery systems with special functional requirements. For example, water activity or head space humidity is a critical parameter for inhalation products as well as biotherapeutics like probiotics.
HPMC capsules can be adjusted to a defined and narrow water activity window by targeting a specific shell water content without compromising on other desired characteristics. This is especially required for inhalation products that are either an interactive powder blend with a carrier or engineered particles with the amorphous drug.
The impact of the gelling system (gellan gum) on the dissolution at low pH has been used to develop a capsule providing delayed in vitro and in vivo dissolution. Even though the capsule does not fulfill the requirements to be considered enteric, it is applied to many dietary supplement products to prevent regurgitation and aftertaste caused by product release in the upper part of the stomach.
Innovation in Capsule Manufacturing
The oral drug delivery limitations of the HPMC capsules containing gelling agent are related to the pH and ionic strength dependent dissolution characteristics of the capsules that lead to higher variability in the in vitro dissolution testing as well as in vivo disintegration.
A new capsule manufacturing process was developed that takes advantage of the ability of HPMC to undergo sol-gel transition within a specific temperature range. This was achieved by controlled heating of the dipping pins to reach the sol-gel transformation from the cold HPMC solution on the dipping pins.
Capsules manufactured by the thermogelation process dissolve consistently in aqueous media with different pH or ionic strength as well as form a favorable microenvironment to act as a crystallization inhibitor to form in vitro and in vivo metastable supersaturated solutions of drugs with limited aqueous solubility3.
It has been shown that such effects enhance the oral bioavailability of drugs and simplify the formulation, the drug micronization, and the filling. All this identifies HPMC capsules as a functional excipient and not a simple container.
The introduction of the thermogelling process enabled the use of other cellulose derivatives for manufacturing two-piece capsules with new intended functionalities. Combining HPMC with HPMC-AS resulted in a capsule that is in accordance with the pharmaceutical requirements for enteric release.
The capsule does not dissolve or release content within two hours at pH 1.2, but rapidly dissolves when changing to a pH 6.8 buffer. Such capsules have demonstrated equivalence in in vitro dissolution profiles to marketed products like budesonide or bisacodyl.
Additional cellulose-based polymers are under investigation for capsule manufacturing that protects even high-moisture or acid-sensitive products from being exposed to moisture during the two hours in acidic aqueous media.
In addition to the functionalities provided by the polymer or polymer blend, other functionalities can further be built into a capsule by different design elements like the body-cap locking mechanism or targeted specification ranges like head space humidity.
This increasing functionality of hard capsules in product performance allows a rational selection of the capsule based on the physicochemical characteristics of the drug substance and the defined TPP. The selection process starts from the application and/or dosage form of the product in development and spans through to the targeted markets and economic environment.
For example, inhalation products for the treatment of chronic obstructive pulmonary disease (COPD) generally require large volume manufacturing capacities, and face a significant and increasing demand from emerging markets.
The most efficient way, in terms of cost and flexibility, to address these challenges is to use standard manufacturing operations and excipients as well as simple inhalation device technology. In contrast to this, oncology drugs benefit most from flexible and lean manufacturing due to the hazardous nature of the drugs and the relatively low annual volume to be manufactured.
Choosing the Right Capsule
Dabrafenib is a good example of how the right capsule selection can impact the drug application. Dabrafenib is an oral drug for the treatment of melanoma with a recommended dose of initially 150 mg twice daily and subsequent reduction to 100 mg, 75 mg, and 50 mg twice daily.
To adequately address this dosing requirement, two dose strengths, 75 mg and 50 mg, have been developed4. Dabrafenib has an aqueous solubility of 81 µg/ml at pH 1.2 and < 5 µg/ml from pH 2.0 onwards.
It was found that in the presence of the HPMC from the capsules, which is about 20 percent of the formulation, a supersaturated solution was formed through its crystallization inhibiting effect translating in a two-fold increase of the oral bioavailability5.
The product is marketed using a simple formulation composed of a diluent (microcystalline cellulose/MCC) and a lubricant/glidant system (Mg-stearate, silicon dioxide), and a two-step manufacturing process (blending, capsule filling).
Modern pharmaceutical drug development and manufacturing increasingly demand excipients with functional characteristics to enhance the product performance and increase the manufacturing efficiency. Capsules have evolved from the orally administered gelatin capsule to a portfolio of capsules with different physicochemical characteristics and application designs.
Using polymer science and innovative manufacturing technologies, a variety of performance characteristics can be adapted to achieve the desired performance of the finished drug.
1 ICH, (2009, August), ICH Harmonised Tripartite Guideline Pharmaceutical Development Q8 (R2). Retrieved from https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf
2 Stegemann, S., et al (2007, May 21), When poor solubility becomes an issue: from early stage to proof of concept, Eur J Pharm Sci, 31, 249 – 261.
3 Xu, S., Dai, W.G., (2013, May 2013), Drug precipitation inhibitors in supersaturable formulations Drug precipitation inhibitors in supersaturable formulations, Int J Pharm, 453 (1), 36-43.
4 Food and Drug Administration (2014, January), TAFINLAR (dabrafenib) capsules label. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202806s002lbl.pdf
5 Ouellet, D., et al (2013, April 22), Effects of particle size, food, and capsule shell composition on the oral bioavailability of dabrafenib, a BRAF inhibitor, in patients with BRAF mutation‐positive tumors. Int J Pharm Sci 102(9):3100-3109.
About the Authors
At Lonza Pharma & Biotech, Sven Stegemann, Ph.D. is Director of Pharmaceutical Business Development; Ljiljana Palangetic, Ph.D. and Tom Huysmans serve as Managers of R&D Projects; and Stef Vanquickenborne is Senior Director of R&D Engineering.
This story can also be found in the September/October 2018 issue of Pharmaceutical Processing.