Melt extrusion technology can add value to the formulation of new molecular entities and established products. SOLIQS’ Meltrex technology has been developed by combining expertise in the fields of pharmaceuticals, polymer chemistry and analytical techniques.
Meltrex technology is a simple way of combining the possibility of achieving amorphous or crystalline embedding of a drug while adjusting the release profile from extended release up to zero-order kinetics. However, little has been publicised about the stability benefits of amorphous solid dispersions manufactured by melt extrusion.
Solid dispersions are polymer-based solids in which the drug is molecularly dispersed in the amorphous state and must remain so throughout the shelf-life of the final drug product in order to maintain bio-availability. The extrusion process yields a viscous thermoplastic solution of the drug substance in a polymer matrix. This viscous material is subsequently shaped and cooled into final solid dosage forms or extrudate intermediates. By this concept, the drug is transformed into a non-crystalline form, which has a bioavailability in most cases that is comparable with, or even superior to, that achieved using more conventional oral dosage forms such as soft gelatin capsules (SGC).
Physical stability
To maintain bioavailability throughout the shelf-life of a Meltrex-based product, the drug must be prevented both from crystallising within the polymer matrix and from degrading chemically. Crystallisation prevention is referred to as ‘physical stability’. SOLIQS meets stringent physical stability requirements by developing formulations that immobilise the drug at the molecular level within the polymer matrix. Immobilisation is achieved by taking advantage of a physical state of polymers known as the ‘vitreous’ or ‘glassy’ state. This is critical in supersaturated formulations.
The very low molecular mobility that is necessary to achieve physical stability in special cases is also beneficial when achieving good chemical stability, as the kinetics of potential degradation reactions is sharply reduced by the vitreous state of the polymer matrix. This vitreous state inhibits the diffusion of reactants that may be involved in the degradation mechanisms of the drug substance. Although diffusion is never completely eliminated, it is slowed down by orders of magnitude, resulting in excellent chemical stability.
Dosage forms
This chemical stability provides a distinct advantage over conventional dosage forms such as SGCs. In an SGC, a liquid or semi-solid vehicle (lipid or co-solvent formulations) holding the drug in solution is encapsulated by an outer shell. Such dosage forms are more prone to chemical stability issues because of the largely unrestricted molecular mobility of the vehicle, drug and capsule shell materials.
In this case, chemical instability mitigation requires slowing down molecular mobility by refrigeration throughout the storage and distribution chain. By contrast, Meltrex tablets do not require refrigeration, a distinct advantage for distribution, especially
in locations where cold storage and transportation are not available.
SOLIQS has developed physical stability tests designed to enable a more rapid assessment of potential drug recrystallisation, compared with standard ICH stability testing. These tests are designed to push suboptimal formulations to failure and to provide a relative assessment for formulation screening.
Formulators also benefit from scientific knowledge on the physics of the glassy state. This includes advanced modeling of the thermodynamic and kinetics of glassy materials, as well as experimental methods to characterise the segmental mobility of vitreous polymers and their solutes. Formulators use this array of tools to guide formulation strategy and to verify the robustness of final products.
Added value
In conclusion, Meltrex technology is more than a bioavailability enabler or enhancer for poorly soluble compounds or another controlled release approach. It also offers significant stability advantages compared with conventional dosage forms. This is achieved by taking advantage of the unique properties of the glassy state and by drawing on a variety of scientific methods, both theoretical and empirical.
Company profile
Based in Ludwigshafen, Germany, SOLIQS is the global drug delivery business of Abbott Laboratories. SOLIQS and Meltrex are trademarks of the Abbott group of companies in various jurisdictions.
Visit: www.soliqs.com
Smart solution to challenging compounds
More drug makers are turning to melt extrusion technology as a low risk way of formulating drug molecules with challenging profiles. A unique alternative has been developed that will add value to the formulation of both new molecular entities and established products.
A critical first step for success in drug development is choosing the right drug-delivery technology, whether the drug compound is a new molecular entity (NME) or reformulation of a mature product. Drug manufacturers must ensure that the delivery vehicle they select for their active pharmaceutical ingredient (API) will carry them to market safely, from development and regulatory, and patient acceptance standpoints.
Drug makers have increasingly turned to melt-extrusion technology as an innovative, low-risk means of formulating drug molecules with challenging profiles (such as poor solubility) or specifically tailored release profiles. Meltrex, an adaptation of conventional melt extrusion for pharmaceutical use and the proprietary technology of SOLIQS, enhances the bioavailability and release kinetics of formulations through a solvent-free, polymer-based process. It also provides a unique solution for poorly soluble molecules, and is a safe choice for formulating and developing from bench-to-batch scale.
Success story
The reformulation of the HIV protease inhibitor Kaletra is a notable success of SOLIQS Meltrex technology. The two poorly soluble, BCS class IV active ingredients, lopinavir and ritonavir, were originally formulated as a soft-gel capsule. The Kaletra capsule had a high pill burden (six per day), had to be ingested with food, and required refrigeration to enable stabilisation. Reformulated by Meltrex as a tablet, Kaletra now boasts reduced inter-patient variability, a reduced pill count (four per day), room temperature stability, and can be taken with or without food.
The new Kaletra tablet formulated via SOLIQS Meltrex was a major improvement for patients using the drug. It was granted fast-track approval by the FDA, and now has over 350 manufacturing batches released and approved without one failure.
Manufacturing via Meltrex
SOLIQS Meltrex is a proven solid dispersion technology in which APIs are mixed with or dissolved in a patented polymer/surfactant combination to form a consistent drug-polymer matrix. This technology has the advantage of being a solvent- and dust-free process, which allows for a clean processing environment with a reduction in environmental pollution, explosion proofing and residual organic solvents. MeltrextherapeuticMeltrextherapeutic therapeutic advantages include improved dissolution kinetics, enhanced bioavailability – and efficacy – improved safety and the ability to customise release.
By selecting the optimal polymer composition, a hard and ‘plastic’-like tablet can be manufactured with low brittleness. These tablets cannot be crushed into a fine powder, which reduces the potential for physical tampering.
Bioavailability
With Meltrex, the drug substance is stabilised by the molecular interactions between the drug and polymeric carrier. Enhanced bioavailability is achieved by the solid dispersion, in which the dissolved drug substance remains as a molecular dispersion in the hardened polymer. Formulations with embedded crystalline particles have been developed primarily to achieve customised controlled-release pharmacokinetic profiles. By varying the type of polymer used, manufacturers can achieve in vivo profiles ranging from those that reach peak blood levels within minutes to once-a-day formulations. Drug loads of 80% to 90% have been obtained with embedded crystalline formulations.
- Meltrex technology may also allow manufacturers to:
- Safeguard the feature profile, avoiding risk in regulatory and commercial process
- Gain improved tolerability and fewer side-effects
- Minimise interactions with food and alcohol, thereby limiting dose dumping
- Adopt a robust and elegant manufacturing process using standard, proven production equipment
- Formulate unique and directly shaped tablets
The SOLIQS team represents a partner with expertise in feasibility studies, formulation technology, research and analysis, scale-up, regulatory matters, and commercialisation. In choosing SOLIQS Meltrex, drug makers put themselves on the right path to commercialisation.
Company profile
SOLIQS is the drug delivery business unit of Abbott GmbH & C and was formed from a collaboration between Knoll and BASF to adapt extrusion technology for use in the formulation of pharmaceuticals. For more information, visit: www.soliqs.com