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Solutions to improve solubility

Increasing the bioavailability of pharmaceutical active substances
Solutions to improve solubility

No matter how good an active substance may be, it cannot be efficacious if it does not reach the bloodstream after oral intake. This problem occurs as a rule when a substance is not readily soluble in water. The technologies described below allow poorly soluble substances to be made available to the body. This permits many new active substances to be tested in clinical studies and allows existing drugs to be improved for patients.

It is estimated that about 40 % of the active substances newly developed today are poorly soluble in water. This proportion will increase due to the use of high-throughput technologies for identifying active substances. Abbott’s Soliqs business unit is working successfully on improving the bioavailability of active substances with low solubility and developing formulations allowing controlled release in the human body. In principle, the processes are based on converting large crystals of active substances that are poorly soluble in water into many small particles or on dissolving them directly in a polymer matrix. These tiny particles have a relatively large surface area, so they can be dissolved more readily. As the chemical and physical properties of different active substances may vary considerably, Soliqs is currently offering four patented technologies to meet these different needs.

Melt extrusion technology (Meltrex) is based on a thermoplastic process that has already been in use for about 80 years and is still used today, mainly to manufacture plastic and rubber parts. However, the process is still relatively new in the production of drugs, where it is used to develop and manufacture formulations of soluble and poorly soluble active substances with tailor-made dissolution profiles and improved bioavailability. Initially, the main challenge was to find polymers that combined several properties. In the production process they should become thermoformable rapidly and at not too high a temperature, so that the added active substances are not destroyed by the heat. However, for storage purposes the formulation has to be so physically stable that the active substance does not crystallise, even at room temperature.
Active substances and excipients are mixed with a polymer in a continuous process. Then this mixture is fed continuously into an extruder and conveyed slowly through a screw. This mixes the components even more thoroughly and heats them slightly so that the polymer becomes thermoformable and the active substance particles are dispersed in the polymer matrix.
Dissolved in a polymer matrix
This dispersion is so fine that the active substance is present in a dissolved state in the solidifying polymer. Ideally, the matrix releases the active substance in the form of colloidally dispersed nanoparticles. The cooled product can then be compressed, for example, into tablets.
At present, there are only a few products that are manufactured using this process. One of these is Abbott’s anti-HIV drug Lopinavir/Ritonavir, the first protease inhibitor with a combination of active substances that does not have to be stored in a refrigerator and does not have to be taken at mealtimes – two decisive advantages for the supply of anti-HIV drugs, especially in developing countries. Furthermore, the tablet formulation offers the advantage of simpler dosage due to the smaller number of tablets (the total daily dose consists of four tablets instead of six soft gelatin capsules).
Xellex technology is used in the development and production of polymer coatings and films for targeted delivery of active substances in the body or for multi-purpose coatings of dosage forms. It is similar to the Meltrex process but instead of tablets it produces thin, water-soluble polymer films that contain the active substances or other components. For example, this process can be used to add colorants or flavors, or even an additional active substance. The polymer films are suitable for direct administration in the oral cavity as well as for coating tablets. The Meltrex and Xellex processes can be combined directly. Depending on the thickness of the film, it is possible to control the dissolution of the active substance from a tablet so that the onset of action is more rapid or delayed.
In the NanoMorph process, active substances in crystalline form are converted into amorphous nanoparticles by means of precipitation. In contrast to crystals, amorphous nanoparticles are tiny particles without a strictly ordered molecular structure. Compared with large crystals, the tiny amorphous nanoparticles have a relatively large surface area. This enhances their solubility. SmartCrystal technology is also suitable for the formulation of poorly soluble active substances. In contrast to NanoMorph technology, it produces crystalline nanoparticles by means of suitable processes such as high-pressure homogenisation.
Abbott GmbH & Co KG

cpp: In October 2008 Abbott inaugurated a new research and development facility and pilot plant in Ludwigshafen. This expansion forms part of Soliqs, Abbott’s drug delivery unit that is active worldwide. Dr. Breitenbach, what part does Soliqs play in the Abbott Group?
Dr. Breitenbach: As Abbott’s global drug delivery unit, Soliqs specialises in the research and development of new pharmaceutical formulation technologies. Soliqs currently employs about 100 people, mainly in R&D, thereby providing a good example of our commitment to developing innovative treatment options for patients in the future and to continually improve them. Investments totaling 15 million euros were made in the Soliqs R&D facilities in the last business year.
cpp: What was the intended objective of these investments in the R&D facilities?
Dr. Breitenbach: We will use the new research and development facilities to consolidate and expand our leading position throughout the world in the area of melt extrusion. This technology allows better processing of active substances and delivery to the body. Improvement of the bioavailability of poorly soluble drugs is an important issue in pharmaceutical R&D. Nowadays, thanks to newly developed technologies, increasingly complex active substances are being discovered but the body has a hard time absorbing them. The new facilities will allow us to refine our technologies in this field and bring them to market.
cpp: Will there be further investments of this kind in Germany or Europe?
Dr. Breitenbach: As there is a very great demand for solutions to improve the bioavailability and targeted release of active substances in the human body, we assume that the demand for innovative technologies will continue to grow and that the Soliqs business will expand accordingly. So in our view, further investments will be required.
cav: Which technologies is Soliqs concentrating on?
Dr. Breitenbach: Soliqs has developed patented technologies that are primarily intended to make poorly soluble active substances bioavailable for the body. Naturally, these substances have different chemical and physical properties, which is why we provide various technologies for different requirements; Meltrex, our melt extrusion technology that is already mentioned, is certainly the most prominent. It forms the basis for the successful reformulation of our anti-HIV drug. In addition, Xellex technology is suitable for the production of film packed with active substance. Furthermore, this technology allows us to apply a multi-purpose coating to dosage forms. NanoMorph technology uses precipitation to convert crystalline active substances into amorphous nanoparticles. SmartCrystal technology produces crystalline nanoparticles by means of high-pressure homogenisation.
cav: Which direction will the Soliqs R&D programme take in future?
Dr. Breitenbach: We are naturally always on the lookout for new pioneering technologies. As our new facilities are equipped to the highest safety standards for the protection of our employees, we will in future be able to work routinely with highly potent substances. We regard nanotechnology as one of the key technologies of the 21st century. Soliqs has valuable core competence in this area, which is still full of potential. With the new research facilities we are able to explore new technologies as well as to test technologies on a larger scale.
cav: Will these new facilities be made available to other companies?
Dr. Breitenbach: There is a global demand for our research, so we are cooperating with science and industry all over the world. We also offer our services to third-party customers in the pharmaceutical industry but our facilities are not available for use by other companies.
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