ORALLY DISINTEGRATING TABLETS - Designed With Patients in Mind: The Art of Patient-Centric Drug Formulation

INTRODUCTION

Patient-centric formulations and dosage forms can benefit a range of target patient populations. They may also improve the market value of a pharmaceutical product, especially when drug formulation technologies are considered throughout the drug development process. Drug delivery technologies can be used to meet the needs of certain patient populations, such as pediatric, geriatric, and dysphagic patients; adolescents; and patients with neurological disorders, thereby encouraging adherence while supporting optimal disease management and improved outcomes.

Certain patient populations, including geriatric and pediatric patients, and patients who suffer from neurological disorders, often have difficulties swallowing tablet or capsule dosage forms. Dysphagia is seen in elderly populations with up to 22% prevalence in those aged over 50 years in the community setting—with even higher prevalence in assisted living facilities and nursing homes.¹ With pediatric patients, there is often a fear of choking when swallowing a solid oral dosage form, whereas the practice of “cheeking” (hiding medications in one’s cheeks to avoid swallowing) often occurs in institutionalized psychiatric patients.

Patient-centric dosage forms, such as orally disintegrating tablets (ODTs), offer easier administration for patients who experience nausea or vomiting, and those with difficulty swallowing, including elderly and pediatric patients, people who have had a stroke, and patients who are bedridden. ODTs combine the advantages of an easy-to-swallow dosage form, such as a liquid, with the administration convenience of a tablet for increased adherence, particularly for pediatric and geriatric patients, and can address cheeking issues among psychiatric patients.

ODTs demonstrate a strong trend in the pharmaceutical industry, and the demand for ODTs is projected to reach $3.6 billion by 2020.² Preferred by patients over traditional dosage forms, ODTs are designed to disintegrate rapidly on the tongue. Disintegration should result in an easy-to-swallow, smooth suspension and, ideally, contain taste-masked drug microparticles to eliminate bitter drug aftertaste. According to the US FDA Guidance for Industry Orally Disintegrating Tablets, ODTs should disintegrate within approximately 30 seconds or less with no need for chewing or drinking liquids, meaning ODTs should be able to be administered by the patient with or without water.³

Geriatric patients face additional administration burdens because of the need to take multiple drugs, multiple times throughout the day. Dosage form design has helped address needs of elderly patients through variations of size, color, and shape, whereas long-acting formulations or combination products can assist in reducing pill burden.

By making drugs more palatable, taste-masking can improve compliance and extend product reach to patients who are more taste sensitive, such as pediatric patients. In the pediatric market (which is forecasted to be the fastest growing global drug market over the next 10 years) drug adherence can be challenging due to bitter-tasting medication.⁴

Patient nonadherence to medication results in an annual revenue loss of approximately $564 billion for the global pharmaceutical industry—in fact, this is a conservative estimate.⁵ Factors such as unpleasant taste, inconvenience, and difficulty in administration, coupled with determinants of taste preference, such as genes, gender, and cultural and regional differences, are driving pharmaceutical companies to seek partnerships with drug delivery companies that have a proven track record in meeting patients’ unmet medical needs.

Table 1 demonstrates how patient needs can be addressed by specific dosage forms. By addressing specific unmet patient needs, a unique formulation with a novel technology can add market value and differentiate the product, especially if it competes in a crowded therapeutic area. Market exclusivity can be protected by technology and product patents, potentially minimizing generic intrusion. An expert drug development partner with a broad range of proprietary technologies and experience in developing complex drug formulations, can optimize R&D returns by reformulating existing products or creating entirely new products.

COMMERCIAL SUCCESS OF PATIENT-CENTRIC FORMULATIONS

The World Health Organization (WHO) estimates that there are approximately 3.2 million children worldwide living with HIV.⁶ VIREAD^® (tenofovir disoproxil fumarate) was originally approved by the FDA in 2001 as a once-daily 300 mg tablet for individuals aged 18 years and above for the treatment of HIV-1 infection in combination with other antiretroviral agents. In March 2010, the 300 mg dose was approved for use in the United States for adolescents aged 12 to 17 years, and in January 2012, three lower-strength, once-daily tablets of VIREAD in doses of 150 mg, 200 mg, and 250 mg were approved for children aged 6 to 12 years.7 In order to provide a pediatric-optimized dosage form, the drug needed to be reformulated. Gilead Sciences, Inc., partnered with Adare to develop a pediatric oral powder formulation of VIREAD.⁸

By using Microcaps^® Taste Masking Technology, Adare delivered VIREAD oral powder. Microcaps technology provides complete and uniform polymeric membranes of adjustable thickness, thereby effectively taste-masking drug particles.

Study results have shown that VIREAD oral powder achieved clinical bioequivalence compared with the original VIREAD tablet formulation.⁸

To help encourage accurate dosing, VIREAD oral powder features a multidose bottle with a calibrated measuring scoop. The use of Microcaps technology provided effective taste-masking of the active pharmaceutical ingredient (API).⁸ VIREAD oral powder has been approved by the FDA and the European Commission.^8-10,*

Another example of patient-centric formulation success was the development of an ODT formulation of a central nervous system (CNS) drug, which was co-developed by Adare with a private partner. Estimates are that this CNS condition affects 0.6% to 1% of the US population, with the highest incidences in young children and the elderly.¹¹ The condition has a nonadherence rate of 30% to 50%. These patients may also have low self-management skills, require caregiver support, and have a high prevalence of depression as a comorbidity.¹²

Another significant CNS condition has been shown to affect approximately 5.7 million adults in the US in a given year.¹³ Furthermore, the National Center for Health Statistics reported that within a 10-year period, the diagnosis of this CNS disorder among adults had almost doubled. In the same time period, the number of diagnoses of this CNS disorder increased by 40 times in children and adolescents.¹⁴ As in many chronic disease states with intermittent symptoms, medication nonadherence is a common occurrence and is associated with poorer outcomes.¹⁵

Adare was approached by its partner to consider patient-centric needs for the brand. The solution would be the development of a taste-masked ODT. In just 18 months, Adare developed an ODT form of the drug—from formulation, to successful pharmacokinetic (PK) testing, and completion of a new drug application filing with the FDA.

This dosage form was bioequivalent to the existing doses, and met the following criteria:

• An immediate release (IR) ODT with dose-proportional formulations to enable clinicians to titrate the medication

•  Disintegration within 30 seconds, with rapid and complete release in the stomach

•  Delivery of a taste-masked ODT with excellent organoleptic properties for patient acceptance, including taste, mouth feel, and swallowability

Using Microcaps technology, the API crystals were microencapsulated. The taste-masking process was combined with AdvaTab^® Orally Disintegrating Tablets—providing the added benefit of rapid disintegration in the mouth without the need to administer with water.

ODT PATIENT SATISFACTION STUDY

Patient convenience and satisfaction with the AdvaTab ODT formulation was measured in a study of 97 patients who had been taking the IR formulation.⁸

Patients found the AdvaTab ODT to be significantly more convenient than the IR reference product (P<0.001) (see Figure 1), with convenience being defined as ease of use, ease of planning when to use, and convenient to take as instructed. Significantly more patients reported that they were more adherent with the AdvaTab ODT than the IR reference product. Overall, both patients and caregivers significantly preferred the AdvaTab ODT over the IR product.⁸

TECHNOLOGY OVERVIEW

Taste may be the most important organoleptic property for the acceptance of oral drugs, and many drugs require taste-masking. As such, many methods have been developed, with varying levels of success. Methods for taste-masking include sugar or flavoring additions and more sophisticated methods involving wax coatings, heat treatments, chemical modifications, and sensory blocking, such as with Microcaps technology.

Microcaps technology achieves a uniform and efficient drug particle (crystal, granulate, or liquid) coating and may enhance overall patient adherence by improving the product’s acceptability. Microencapsulation technology employs versatile and precise coating techniques to encapsulate individual drug particles. This process uses coacervation (ie, phase separation) and can also incorporate a spray-coating process, creating polymeric membranes of varying degrees of porosity and thickness to completely encapsulate drug particles. The membrane improves taste by forming a barrier between the drug and taste buds in the mouth.

The taste-masking membrane may comprise at least one gastrosoluble organic, inorganic, or polymeric poreformer. The gastrosoluble pore-former of the taste-masking membrane, being insoluble at saliva pH, provides effective taste-masking when placed in the oral cavity; however, the pore-former rapidly dissolves upon entry into the stomach for rapid release of the drug from coated/taste-masked drug particles, thereby enhancing the probability of success in achieving bioequivalence to an IR reference listed drug (RLD).

In addition to taste-masking, Microcaps technology can be combined with customized release profiles and used for encapsulation of liquids for oral powder delivery. Microcaps technology can also be used to separate incompatible APIs in fixed dose combination products. Figure 2 shows examples of various microencapsulated drug particles.

This versatile multifunctional technology has been used alone and in combination with other technologies to create innovative patient-centric dosage forms. AdvaTab tablets incorporate coated drug particles that are uniformly dispersed in a low-moisture, rapidly disintegrating matrix. Each ODT is formulated to achieve an acceptable taste, a disintegration time of approximately 30 seconds or less, and desired release profile. Additionally, AdvaTab tablets enable rapid disintegration in the mouth without water. AdvaTab tablets have been formulated to be bioequivalent to IR RLDs.

The technology features robust tablets that are suitable for multiple packaging configurations, including push-through blister packs (Figure 3) and high drug-loading capability—up to 500 mg.

SUMMARY

Patient-centric drug delivery enables the development of customized products across multiple patient populations, enhancing disease management through improved patient adherence. By partnering with an expert in drug delivery technology, whose portfolio features a broad range of proprietary technologies, pharmaceutical companies have the potential to add further value to their products and extend market exclusivity.

This article is intended to promote the proprietary technologies of Adare Pharmaceuticals. It is not intended to promote any product.

DISCLAIMER

VIREAD^® is marketed by Gilead Sciences, Inc. Please see full Prescribing Information, including Boxed Warning, available at www.gilead.com.

REFERENCES

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3. US Food and Drug Administration. Guidance for Industry: Orally Disintegrating Tablets. Silver Spring, MD: Center for Drug Evaluation and Research (CDER), US Dept of Health and Human Services. 2008.
4. Mulberg AE, Murphy D, Dunne J, Mathis LL, eds. Pediatric Drug Development: Concepts and Applications. 2nd ed. Wiley Blackwell. August 2013.
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6. World Health Organization. Global Health Observatory (GHO) data: antiretroviral therapy (ART) coverage among all age groups. http://www.who.int/gho/hiv/epidemic_response/ART_text/en/. Accessed December 11, 2015.
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8. Data on file. Adare Pharmaceuticals, Inc.
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11. Centers for Disease Control and Prevention. Epilepsy: one of the nation’s most common neurological conditions at a glance 2016. http://www.cdc.gov/chronicdisease/resources/publications/aag/epilepsy.htm. Updated April 27, 2016. Accessed June 13, 2016.
12. Ferrari CMM, de Sousa RMC, Castro LHM. Factors associated with treatment nonadherence in patients with epilepsy in Brazil [published online March 9, 2013]. Seizure. 2013;22(5):384-389. doi:10.1016/j.seizure.2013.02.006.
13. National Institute of Mental Health. The numbers count: mental disorders in America. http://www.lb7.uscourts.gov/documents/12-cv-1072url2.pdf. Accessed December 14, 2015.
14. Moreno C, Laje G, Blanco C, Jiang H, Schmidt AB, Olfson M. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007;64(9):1032-1039. doi:10.1001/archpsyc.64.9.1032.
15. Bates JA, Whitehead R, Bolge SC, Kim E. Correlates of medication adherence among patients with bipolar disorder: results of the Bipolar Evaluation of Satisfaction and Tolerability (BEST) study: a nationwide cross-sectional survey. Prim Care Companion J Clin Psychiatry. 2010;12(5): PCC.09m00883. doi:10.4088/PCC.09m00883yel.

Anthony Recupero, PhD, is Senior Director Business Development at Adare Pharmaceuticals, where he is responsible for global business development and licensing. Over the past 20 years, he has held several other business development and marketing positions in the biotechnology, bioinformatics, and biochemical industries. He earned his PhD in Cell and Molecular Biology from the University of Cincinnati and completed his postdoctoral research in Molecular Oncology at the Cleveland Clinic. Dr. Recupero can be contacted by email at Anthony.Recupero@adarepharma.com.