The Future of Dosage Forms

The pharmaceutical industry as a whole is undergoing certain transformations, such as the move to specialty drugs targeted to specific patient groups and in the longer term, the move to personalized medicines. Although this emphasis is typically oriented toward tailoring an active ingredient to more specific patient groups, personalized/targeted dosing regimes will play an important role in realizing the paradigm of more specialized/personalized medicines.

“Mass-customization offers individualized products for everyone to address individual health issues with tailored medication,” observes François Scheffler, vice-president of global marketing at BASF’s Pharma Ingredients & Services business unit. “Today’s medication is mostly bound to the indication, not to the individual patient or consumer and his specific needs. A prerequisite for a customized medication approach is probably a genetic and phenotypic assessment at affordable costs, basically looking into the human body and predicting the likelihood of possible health problems throughout life.”

In its recent report, Paving the Way for Personalized Medicine, FDA’s Role in a New Era of Medical Product Development, FDA notes that the term “personalized medicine” is often described as providing “the right patient with the right drug at the right dose at the right time” (1), but more broadly, “personalized medicine may be thought of as the tailoring of medical treatment to the individual characteristics, needs, and preferences of a patient during all stages of care, including prevention, diagnosis, treatment, and follow-up” (1). Personalized medicine generally involves the use of two medical products--a diagnostic device and a therapeutic product--to improve patient outcomes. “While considerable attention in personalized medicine is currently being paid to the use of genetic tests to guide therapeutic decisions, a vast variety of medical devices can be used in a personalized approach to improve patient outcomes” (1). Many medical-device therapies can be tailored to specific patient characteristics, such as patient anatomy (e.g., size), physiology (e.g., nervous and cardiovascular systems, metabolism, and reproduction) and environment (e.g., intensive care unit, home use). Also, physiological sensors may predict treatment responses for individual patients, such as three-dimensional (3D) printing, to create personalized medical devices based on imaging of a patient’s anatomy (1).

The confluence of traditional therapeutics with devices provides the foundation for the pharmaceutical of the future. Customization is taking root through emerging technologies, such as bioelectronic medicines and 3D printing of pharmaceuticals, through select investment by pharmaceutical companies, venture-capitalists, and academic researchers.

Making investments
In August 2013, GlaxoSmithKline (GSK) launched the Action Potential Venture Capital (APVC) Limited, a new $50-million strategic venture-capital fund that will invest in companies developing bioelectronic medicines and technologies (2). The fund’s first investment is in SetPoint Medical, a Valencia, California-based company, which has developed proprietary implantable neuromodulation devices that stimulate the body’s vagus nerve to treat inflammatory diseases, such as Crohn’s disease and rheumatoid arthritis (2, 3). In August 2013, SetPoint secured $27 million in financing from investors, which included GSK’s Action Potential Venture, Covidien Ventures, and Boston Scientific, to fund ongoing clinical development of the SetPoint bioelectronics therapy approach in rheumatoid arthritis and Crohn’s disease and advance development of its neuromodulation platform (2).

APVC complements the work of GSK’s Bioelectronics R&D unit, which was established in 2012. The name of the fund comes from electrical signals called action potentials that pass along the nerves in the body. Irregular or altered patterns of these impulses may occur in association with a broad range of diseases (2). GSK believes that miniaturized devices, or bioelectronic medicines, can be designed to read these patterns. The devices could be designed to interface between the peripheral nervous system and specific organs to read, change, or generate electronic impulses that help treat disorders, such as inflammatory bowel disease, rheumatoid arthritis, and respiratory and metabolic diseases (2). In addition to working with the new venture fund, GSK’s Bioelectronics R&D will offer up to 20 new exploratory research grants and create a network of investigators. Work is focusing on the relationship between the nerves in the body and a range of diseases, the particular pattern of impulses along these nerves, and technologies that can interface with individual nerve fibers (2). In December 2013, GSK announced a $1-million dollar prize in bioelectronics research for creating a miniaturized, fully implantable device to read, write, and block the body’s electrical signals to treat disease.

Action Potential Venture Capital intends to build a portfolio of five to seven companies over the next five years. The fund will focus investments in three areas: new start-up companies that seek to pursue the vision of bioelectronic medicines; existing companies with technologies that are interacting with the peripheral nervous system through first-generation devices that can stimulate or block electrical impulses; and companies advancing technology platforms that will underpin these treatment modalities (2).

In May 2013, Proteus Digital Health, a Redwood City, California-based company developing digital medicines, raised
$62.5 million, which included a new corporate investor Oracle, as well as investment from earlier investors Otsuka, Novartis, and Sino Portfolio. Proteus’ focus is on digital medicines based on ingestible sensing (4). In July 2012, Proteus received FDA clearance for its ingestible sensor for marketing as a medical device (5). The Proteus ingestible sensor (i.e., the ingestible event marker) is a prescription device used to record time-stamped patient-logged events. The ingestible component links wirelessly through intrabody communication to an external recorder that records the date and time of ingestion. The company’s personal monitor (i.e., patch) is a body-worn sensor that collects physiological and behavioral metrics, including heart rate, body angle, and time-stamped, user-logged events generated when a user marks an event by swallowing an ingestion event marker or by manually pressing an event marker button on the patch, which stores and wirelessly sends the ingestion event marker data to a general computing device. The ingestion event marker is attached to an excipient/tablet for ease of handling and swallowability. Software pairs the patch with a mobile computing device that organizes and displays ingestion events (6). Proteus received a CE Mark approval for its ingestible sensor personal physiologic monitor system in the European Union in 2010 (7). In their deal, Oracle and Proteus will work together to provide clinical investigators the ability to measure information about medication ingestion, dose timing, and associated physiologic response. The two companies will integrate Proteus’ ingestible sensor with Oracle’s clinical-trial products (8).

In October 2012, Qualcomm, a provider of wireless technology and services, granted $3.75 million to the Scripps Translational Science Institute to advance clinical trials of wireless biosensor systems, rapid pharmacogenomic diagnostic tests, apps, and embedded sensors for tracking and predicting disease. The money will support additional staffing and other resources for a three-year program, called Scripps Digital Medicine, designed to advance promising medical apps and devices for clinical development. Some start-up companies involved are: AirStrip Technologies (San Antonio, Texas), a provider of mobile healthcare software, and DNA Electronics (London), a spin-out from the Center of Bio-Inspired Technology in the Institute of Biomedical Engineering at Imperial College London and a provider of a handheld genotyping device (i.e., Genalysis) that can be used to better tailor prescriptions to individual patients. Other projects involve  a blood-borne biosensor system and a mobile apps for embedded sensors (9).

“Digital health feedback systems are a logical consequence of the trend toward preventive medication and healthier living,” notes Scheffler. “The influence on the formulation of the drugs and, therefore, the usage of excipients and ingredients and their interactions will be significant. For example, it would not just mean measuring certain body reactions but addressing them as quickly, as precisely, and as early as possible. An increase in life quality and significant cost savings will be the main benefits of this technology.” As a case in point, Metanomics Health, a company of BASF, is specialized in translating phenological indicators into potential dysfunctions of the body that can then be addressed early with changes of behaviors or medicine.

A literature review shows some recent work using digital tablets. In one study, a digital health feedback system used a digital tablet, which consisted of an ingestion sensor that was embedded in a tablet containing nonpharmacologic excipients, in which subjects (12 adults with bipolar disorder and 16 adults with schizophrenia) coingested with their regularly prescribed medication (9). The formulation of this digital tablet allowed ingestion sensor separation and activation by stomach fluids after ingestion, followed by communication of a unique identifying signal from the ingestion sensor to an adhesive sensor worn on the torso, which automatically logged the date and time of each digital tablet ingestion. The wearable sensor also collected physiologic measures, including activity and heart rate (10).

MicroCHIPs has developed an alternative to daily injections: a programmable, wirelessly controlled microchip with an implantable device that allows drugs to be released inside the body without percutaneous connections in or on the patient. An implantable microchip device also offers the potential for real-time dose schedule-tracking and for physicians to remotely adjust treatment schedules. The technologies use microreservoir arrays to hermetically store and protect pharmaceuticals or sensors for extended periods of time. The microchip is controlled by microprocessors, wireless communications, or sensor feedback loops for dynamic control of drug delivery or sensing. MicroCHIPs licensed the technology from the Massachusetts Institute of Technology, which reported in 2012, a successful human clinical trial for a wirelessly controlled drug-delivery chip. In the trial, human teriparatide, a parathyroid hormone fragment [hPTH(1-34)] and anabolic osteoporosis treatment, was delivered from the device in vivo. The microchip-based devices contained discrete doses of lyophilized hPTH(1-34) and were implanted in eight osteoporotic postmenopausal women for four months and wirelessly programed to release doses from the device once daily for up to 20 days. A computer-based programmer established a bidirectional wireless communication link with the implant to program the dosing schedule and receive implant confirmation status (11-13).

3D printing of  pharmaceuticals
3D printing of pharmaceuticals is another vision. “3D printing is probably the most innovative idea in the pharmaceutical industry since decades,” says Scheffler. “It will change our lives and will play a major role, in fact, in literally all industries. New formulations with existing and approved excipients and ingredients will benefit from these creative new ways because we can customize medicine to each individual patient. The effect is less waste, less costs, and less complexity for patients.”  

A recent review article in the Journal of the American Pharmacists Association summarized the published literature on existing 3D printing technologies for pharmaceutical manufacturing and outlined the limitations and potential of these technologies (14). A structured search of PubMed and Embase identifed articles published between Jan. 1, 1990 and Aug. 31, 2012. Search terms included drug printing, drug 3D printing, and drug three-dimensional printing. Twenty-one of 511 identified references were included in the review. Inkjet and powder-based printing were the primary printing technologies used for drug development and fabrication. Eleven articles described a powder-delivery system, and 10 identified inkjet printing. These printing technologies allow for certain advantages, such as precise control of droplet size, high reproducibility, complex drug-release profiles, and personalized medication therapy (14). The article specified that printable dosage forms on paper may be easier to deliver than powder-based printed forms. Medications with narrow therapeutic indices or with a higher likelihood to be influenced by genetic polymorphisms may be the first to be printed via this technology (14).

A research team led by Simon Gaisford, reader in pharmaceutics at the University College London’s School of Pharmacy, has applied thermal inkjet printing technology to make personalized-dose oral films of salbutamol sulfate by replacing the paper in the printer with a sheet of polymer film that allowed the drug to be jetted onto the surface (15-17). A printer cartridge was modified so that aqueous drug solutions replaced the ink (15-17). Film strips were cut. Varying the concentration of drug solution, area printed, or number of print passes allowed the dose to be controlled (15-17). The print-solution viscosity and surface tension were used to determine the performance of the printer. A calibration curve for salbutamol sulfate was prepared, which showed that drug deposition onto an acetate film varied linearly with concentration. The printer was used to deposit salbutamol sulfate onto an oral film made of potato starch. The researchers found that when doses were deposited in a single pass under the print head, the measured dose was in good agreement with the theoretical dose. With multiple passes, the measured dose was always significantly less than the theoretical dose (15-17) The researchers surmised that the losses result from the printed layer eroding by shear forces during paper handling.

References
1. FDA, Paving the Way for Personalised Medicine: FDA’s Role in a New Era of Medical Product Development (Rockville, MD, Oct. 2013).
2. GlaxoSmithKline, “GSK Launches $50 Million Venture Capital Fund to Invest in Pioneering Bioelectronic Medicines and Technologies,” Press Release, Aug. 8, 2013.
3. SetPoint Medical, “SetPoint Medical Secures $27 Million Financing, Adding Action Potential Venture Capital/GSK, Boston Scientific and Covidien Ventures as New Investors,” Press Release, Aug. 8,  2013.
4. Proteus Digital Health, “Proteus Digital Health Completes $62.5 Million Financing,” Press Release, May 1, 2013.
5. Proteus Digital Health, “Proteus Digital Health Announces FDA Clearance of Ingestible Sensor, Press Release, July 30, 2013.
6. FDA, “Evaluation of Automatic Class II Designation (De Novo) for Proteus Personal Monitor Including Ingestion Marker,” Decision Summary (Rockville, MD, May 14, 2012), accessed 17 Dec. 2012.
7. Proteus Proteus Digital Health, “Proteus Biomedical Announces European CE Mark Approval of Ingestible Sensor and Monitor System,” Press Release, Aug. 13,  2010.
8. Proteus Digital Health, “Oracle Invests in Proteus Digital Health and Its FDA-Approved Ingestible Sensor Platform,” Press Release, May 1, 2013.
9. Scripps Translational Science Institute, “Scripps Creates Digital Medicine Program with Qualcomm,” Press Release, Oct. 13. 2013.
10. J.M. Kane, Clin. Pyschiatry 74 (6), 533-540 (2013).
11. R. Farra et al., Sci. Transl. Med. online, DOI: 10.1126/scitranslmed.3003276, Feb. 16, 2012.
12. A. Trafton, “Successful Human Tests for First Wirelessly Controlled Drug-Delivery Chip,” Press Release, May 16, 2013.
13. J. Santini, M. Cima, and R. Langer, Nature 397 (6717), 335-338 (1999).
14. I.D. Ursan, L. Chiu,and A. Pierce, J. Am. Pharm. Assoc. 53, 136-144 (2013).
15. P. Van Arnum, Pharm. Technol. 37 (5) 58 (2013).  
16. UCL, “Profile (S. Gaisford): Research Summary,” accessed 17 Dec. 2013.
17. S. Gaisford et al., Pharm Res. 28 (10) 2386-92 (2011).