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Pharmaceutical companies are increasingly adopting patient-centric formulation development to ensure that drug products adequately meet the needs of end-users in all target patient populations.
Pharmaceutical companies today face higher hurdles than ever before in getting products to market. The patient, as the end-user, is now a force to be reckoned with as governments, payers, and healthcare providers around the world place increasing emphasis on patient outcomes. With this new emphasis on patient centricity, the pharmaceutical industry has been quick to realize the importance of embracing the patient.
“The industry continues to move toward a system where the value of care determines a drug’s market success, as can be seen with outcomes-based management programs targeting drugs for cancer, obesity, and pulmonary diseases,” observes Elizabeth Hickman, director of sales and marketing, Catalent Pharmatek. “Improving patient outcomes and patient experience is a growing trend,” she says. “And companies are looking at ways to achieve this through better drug design-such as bioavailability enhancement to improve therapeutic effect at lower doses, making drugs last longer with extended-release profiles to reduce dosing frequency, delivering drugs through less invasive methods, simplifying complex regimens with combination drugs, and customized dosage forms for specific patient populations and/or indications.”
Hickman cites a study by MarketWatch, which showed that patient noncompliance costs the pharmaceutical industry approximately $330 billion annually (1). Noncompliance could be due to dose burden, size and quantity of dosage, or patient acceptance, she notes and highlights that aging and pediatric populations often present unique challenges to achieving compliance. “Dosage forms that improve swallowability, palatability, and dosing convenience, as well as reduce the pill burden can lead to better compliance, experiences, and outcomes for aging and pediatric populations,” Hickman explains. “These factors can also support better product differentiation, which can lead to improved product lifecycles and sales.”
Patient-centric drug development considers the end-user from the start of the formulation process through to the selection and design of the dosage form and finished product. The evolving regulatory reforms in Europe and the United States (2–6) reflect the increasing drive toward patient-centric formulation development to ensure that drug products adequately meet the needs of end-users in all target patient populations. Developing a dosage form for geriatrics or pediatrics requires special considerations. In the elderly, factors such as age, morbidity, co-morbidity, multiple drug use, and reduced organ function have an effect on pharmacokinetics. The pediatric population, on the other hand, experience rapid and continual growth, development, and maturation; as a result, there are distinct physiological differences between neonates, infants, children, and adolescents. The most significant compliance challenge in older adults is polypharmacy and the pill burden, whereas for children, taste is often the biggest barrier.
Geriatric. “The pharmaceutical industry acknowledges the special requirements for geriatric patients,” says Ravinder Kodipyaka, senior director and head of formulation R&D, Dr. Reddy’s Custom Pharmaceutical Services. However, he notes that product design and development for the elderly is complex because of the interplay of various factors. Geriatric patients often have concomitant conditions and according to Kodipyaka, pill cocktails for their multiple diseases have very limited clinical data available. “For those with cognitive problems, remembering multiple doses, multiple drugs, and their administration schedules can be a challenge. In addition, the reduced physical strength of the patient affects his/her ability to open packs, break tablets along the break-mark, or swallow tablets,” he adds.
Although there are programs and companies focusing on addressing the needs of older patients, Kodipyaka believes that there is scope to do much more. “We find that most of the drugs for chronic indications and/or that have age-related prescription potential are being developed as single-dose packs, push-pull packaging designs, and fixed-dose combination (FDC) products. Target population is a key factor that needs consideration in a product development program. A holistic approach considering patient age, drug indication, and duration of therapy among others, needs to be adopted for systematic geriatric product development,” he says.
Pediatric. Kodipyaka acknowledges that in terms of work that is done and being done for special populations, the pediatric population is one of the most progressive ones. “The pharmaceutical industry has actually developed and commercialized suitable products for children; for example, orodispersible dosage forms, orally disintegrating tablets, solutions, suspensions, powder for suspension, and drops for anti-retroviral, anti-tuberculosis, and anti-malarial products,” he says. An important driving force, he notes, has been the focus and support of regulatory bodies, non-governmental organizations (NGO), and global agencies such as the World Health Organization (WHO), which have gathered huge data points on what is required for pediatric patients. Despite these efforts, there are still unmet needs, according to Kodipyaka, “particularly with challenges of taste masking; the risk of suboptimal dosing due to spitting/vomiting by children; high dose drugs, where administering large volumes of liquid medications has practical challenges for the child and the drug administrator; and dosing accuracy with liquids.” The measuring cups or spoons routinely used with liquids may have residual volumes and most administrators either add overfills or the dose is administered less, he explains. Kodipyaka sees ample opportunities to develop more patient-centric, innovative drug-delivery systems and packaging systems that could address the specific needs of children.
The shift to personalized medicine and an increasing focus on geriatric and pediatric applications is creating a demand for specialized dosage forms, observes Paul Spencer, head of the Oral Excipients Business at Evonik Health Care. “Controlled-release formulations, including once-daily applications, can improve patient adherence and enhance therapeutic success,” he says. “In an aging society, where there is an increasing number of people with multiple morbidities, who need to administer several drug products every day, controlled-release formulations offer significant advantages. They provide constant plasma levels over a desired timeframe, optimized bioavailability, minimized side effects, and reduced dosing frequency. Such factors help to increase patient quality of life and improve compliance. There are multiple chronic conditions where controlled-release formulations are being used, for example, cardiovascular diseases, diabetes, and diseases of the central nervous system, such as Alzheimer’s.”
With polypharmacy and compliance being a huge problem, especially in the geriatric patient population, Anil Kane, global head of Technical and Scientific Affairs at Patheon, part of Thermo Fisher Scientific, points out that FDCs offer the possibility of combining several drug candidates into a single pill. “FDCs could benefit patients from the potential increase in efficacy, synergistic effect, and a potentially lower dose, leading to higher convenience in administration and compliance,” he says.
Kane explains that several drugs in the same category of therapeutic effectiveness have been combined for synergistic effects. “Specific examples include elvitegravir, emtricitabine, tenofovir disoproxil fumarate, cobicistat (Stribild, Gilead) for the treatment of HIV/AIDS; metformin combinations with glipizide, glimepiride, pioglitazone, rosiglitazone, and many other gliptins for diabetes; and amlodipine, valsartan, and hydrochlorothiazide (Exforge HCT, Novartis) for hypertension,” he says. Citing an article (7) that listed the top 10 drugs that registered the maximum growth in global sales over 2015, Kane observes that interestingly, three of the 10 drugs are FDCs as highlighted in the following:
From a development and manufacturing perspective, Kane says that various types of drugs have been successfully combined into a single unit of a solid oral dosage form, including low- and high-potency drugs; low- and high-dose drugs, and immediate- and controlled-release profiles for individual drugs based on the site of absorption and efficacy. “Based on the chemical and physical stability of each active drug in the FDC, the dosage form can be developed as a simple monolithic tablet or a blend of actives with some excipients in a capsule,” he explains. “With molecules having stability challenges, we could develop dosage forms such as bilayer, tri-layer, tablet-in-tablet, or multi-particulates of each active in a bead/pellet form and filled into capsules. The techniques and technology have developed enough to achieve a good shelf life for a combination pill in one of these dosage form options.”
Palatability and taste are crucial parameters for oral dosage forms because they have a significant impact on patient compliance, especially for the pediatric population. Several approaches have been used to mask the taste of bitter APIs, such as the addition of flavors and sweeteners, modification of the API to minimize its solubility in the oral cavity, complexation with cyclodextrins, or the application of a coating to form a barrier between the drug and palate.
User-friendly dosage forms are increasingly popular with patients and consumers and are becoming more widely available on the market. “User-friendly dosage forms are orally administered formulations that are designed to make taking medication as convenient and trouble-free as possible for end-users,” explains Martin Koeberle, head of Analytical Development and Stability Testing at Hermes Pharma. “These formulations, which include instant drinks, effervescent tablets, orally disintegrating tablets/granules (ODTs/ODGs), chewable tablets, and lozenges, overcome many of the difficulties commonly experienced with conventional tablets and capsules. As well as being easy to swallow, they can be formulated to offer a more pleasant taste and mouthfeel than traditional solid oral dosage forms. Some forms can be taken without any liquid, enabling consumers to conveniently integrate them into their daily routines.”
Koeberle notes that traditional oral dosage forms such as tablets and capsules pose a significant challenge for large number of people. A consumer survey, conducted in the US and Germany by Hermes Pharma and the Spiegel Institut Mannheim, found that more than half of the respondents from all age groups and genders experienced difficulties swallowing tablets and capsules (8). Various reasons were cited, but the most frequent were related to the pill being too large to swallow, becoming stuck in the throat, or having an unpleasant taste or odor. “As a result of these swallowing issues, some individuals reported not taking their medicine as intended (such as by crushing tablets or dissolving them in water), or worse still, not taking them at all,” Koeberle says. “For patients with chronic diseases or the elderly, who may need to take multiple medicines daily, this poses a significant problem.” He adds that because user-friendly dosage forms simplify administration and are more convenient to take, they can significantly improve patient compliance and treatment efficacy, as well as improve quality of life.
According to Koeberle, Hermes Pharma has developed a range of user-friendly combined calcium and vitamin D3 products for several international pharmaceutical companies. “These products are designed for osteoporosis patients, with doses ranging from 500 mg to 1200 mg calcium and 200 IU to 2000 IU vitamin D3. Our own versions are sold under the Calcimed brand, and include effervescent and chewable tablets as well as ODGs,” he says. “Many aspirin products are available on the market as effervescent and chewable tablets, instant drinks, and ODG formulations. With these user-friendly formulations, aspirin is often combined with other active ingredients such as phenylephrine, caffeine, and paracetamol.” Koeberle also highlights that in Germany, the most widely used formulation for mucolytic cough remedies containing acetylcysteine are effervescent tablets. “This user-friendly dosage form is more popular than other formulations, including syrups and conventional film-coated tablets,” he says.
Kodipyaka sees a growing focus on patient-centric product developments. “In addition to safety and efficacy, patient compliance, convenience, and cost effectiveness are recognized as important elements for the commercial success of a drug product,” he says. Previous misconceptions that a business model focused on putting the patient first will not generate sufficient profits to satisfy shareholders are now being reconsidered; most pharmaceutical executives are beginning to see that patient centricity holds the key to sustainable profitability.
Vol. 41, No. 11
When referring to this article, please cite it as A. Siew, “Patient Centricity Takes Center Stage,” Pharmaceutical Technology 41 (11) 16–23 (2017).