Stretching Product Value through Reformulation Strategies

Reformulation of existing drug products is often seen as the cornerstone of lifecycle management strategies in an increasingly cost-constrained environment. While pharma’s R&D productivity appears to be showing signs of recovery (1), developing a new, innovative molecule is not only a lengthy and expensive process, but the risk of failure is also high. On the other hand, new formulations exploiting advanced drug-delivery technologies-whether aimed at reducing dosing frequency, improving patient experience, or using alternative routes of administration-have the potential to deliver quicker returns on investments.

“Pharmaceutical companies are increasingly reformulating existing compounds, often using the FDA’s NDA [new drug application] 505(b)(2) pathway (2), which is generally faster and more cost effective than bringing new compounds to market,” says James Coward, global head of market development, Capsugel Dosage Form Solutions. “The pathway can provide patent extension for existing compounds that secures continued market exclusivities for several additional years. 505(b)2 product development often targets enhanced bioavailability and/or optimized drug delivery profiles-which can result in reduced pill burden-as well as new indications or specialized formulations for pediatrics.”  

There are many different approaches to reformulation, depending on the strategic imperative, observes Jon Sutch, PhD, manager of formulation development at Patheon’s Milton Park facility in the United Kingdom. “If the strategy is marketing-driven, a line extension such as a new presentation, for example, changing a capsule to a tablet or reformulating as a softgel, may be used to differentiate it from the original product,” says Sutch. “There may also be a clinical requirement to improve compliance, in which case, an enteric-release or other controlled-release formulation may be developed, or a fixed-dose combination (FDC) may be used to improve therapy in a particular area. Additionally, extensions to the original indication or patient group might lead to reformulation such as solutions, suspensions, or mini-tablets for pediatric or geriatric use as well.”

According to Sutch, a new presentation must be based on a combination of the target product profile (TPP) and the characteristics of the API. “The TPP, which is driven by the marketing and clinical considerations for the new presentation, must direct the pharmaceutics team in terms of the specifications required-whether it is the dissolution rate for a controlled-release formulation or the dosage levels for FDCs, for example,” he explains. “For more marketing-led line extensions, presentation aspects may also be included to meet the needs of the target population, while the characteristics of the API are important in defining what is practical.”

Sutch cites ibuprofen as a classic example of how reformulation has been used to extend product lines. “Ibuprofen is a non-steroidal anti-inflammatory drug and, therefore, has applications in many areas of medicine. From the original ibuprofen tablet came a controlled-release version for chronic pain and gastric side-effects prevention. Today, however, ibuprofen can be found in many presentations used in different markets or disease areas,” says Sutch. “For example, the softgel presentation of ibuprofen claims to have a faster onset because its active ingredient is dissolved in the softgel matrix--presenting a potential advantage for acute pain. Other ibuprofen presentations include pediatric suspensions, fast-melt tablets, topical gels, and combination products with analgesics or decongestants. Formulations or presentations and packaging that target specific disease areas (such as menstrual pain or headaches) are also available for this drug, each having a marketable advantage for its particular market or disease area.” 

Reducing dosing frequency with extended-release formulations
Extended-release drug products, whether they are oral dosage forms or injectable depots, are often developed as part of a pharmaceutical company’s reformulation strategy to differentiate its brand from generic competition and thereby extend market exclusivity.  Although more challenging to formulate, extended-release drug products provide added value and well-recognized advantages such as improved pharmacokinetic profiles, prolonged duration of therapeutic effect, lower incidence of adverse reactions (due to the maintenance of drug concentration within a desired range without exposing the patient to potentially toxic drug levels), and better patient compliance as a result of reduced dosing frequency, especially in cases of chronic diseases where complex drug regimens are involved (3).

Pfizer, for example, has reformulated its twice-daily, immediate-release 5-mg tablet (tofacitinib citrate, Xeljanz) for rheumatoid arthritis into a once-daily, modified-release formulation. It was announced in July 2015 that FDA has accepted for review Pfizer’s NDA for Xeljanz 11-mg once-daily, modified-release tablet (4).  The NDA was based on data from a clinical pharmacology program that demonstrated pharmacokinetic equivalence in key parameters with Xeljanz 5 mg twice daily.  

The bisphosphonate ibandronate, marketed as Boniva, was initially approved as a once-daily tablet for the treatment and prevention of osteoporosis in postmenopausal women (5). Roche, in collaboration with GlaxoSmithKline, further reformulated the oral bisphosphonate into a once-monthly formulation. FDA’s approval of the improved formulation made Boniva the first-ever oral treatment to be administered on a monthly basis for any chronic disease (6).

Oral bisphosphonates, however, have to be taken according to a strict treatment regime, which involves remaining in the upright position and not eating, drinking (except water), or taking other medications for a period of time before and after administration of the drug. As such, oral bisphosphonates may not be suitable for some women, either due to other medical conditions or because the patient is unable to stay upright for the required length of time. To meet this need, Roche and GlaxoSmithKline developed a quarterly intravenous injection of ibandronate (7). Boniva injection comes in a prefilled syringe, which is administered as a 15- to 30-second injection by a healthcare professional once every three months.

Reducing the pill burden with fixed-dose combinations
Reformulating and combining drugs that have been proven to be safe and effective into FDCs is another popular lifecycle-management strategy for pharmaceutical companies seeking to maximize the value of their products. FDCs can be used either to combine different actives into one, single-dosage form, or to achieve a precise release profile of a specific active (e.g., combining an immediate-release with an extended-release formulation).

One of the advantages of FDCs is the enhanced efficacy through the synergistic effect of potentially lower doses (8, 9). “In addition to delivering increased therapeutic benefit, FDCs reduce the pill burden and can thereby increase overall patient compliance,” says Coward.

Examples of successful FDCs include:

• antihypertensive combinations to provide better blood pressure control-Prestalia (ACE inhibitor perindopril + calcium channel blocker amlodipine); Avelide (angiotensin II receptor antagonists irbesartan + diuretic hydrochlorthiazide)

• antidiabetic combinations for more effective glycemic control-Glucovance (glibenclamide + metformin); Actoplus Met (pioglitazone + metformin)

• antiretroviral combinations for the treatment of HIV/AIDS-Prezcobix (darunavir + cobicistat); Atripla (efavirenz + emtricitabine + tenofovir disoproxil fumarate)

• antitubercular combinations-Voractiv (rifampicin + isoniazid + pyrazinamide + ethambutol)

• antimalarial combinations-Coartem (artemether and lumefantrine) 

• topical combination therapy for acne-Onexton gel (clindamycin + benzoyl peroxide).

Improving patient experience with user-friendly dosage forms
The increasing focus on patient-centricity is driving the shift towards the development of more user-friendly dosage forms. Martin Koeberle, PhD, senior manager of Analytical Development at Hermes Pharma, defines such formulations as dosage forms that provide a more positive experience compared to traditional tablets and capsules. “User-friendly dosage forms also overcome the widespread problems associated with swallowing traditional solid oral dosage forms,” he highlights. 

Findings from a 2014 survey revealed that more than 55% of people from all age groups and genders experience swallowing difficulties when taking their pills (10). Various reasons were cited by survey respondents, but the most frequent ones were related to the tablets or capsules being too large, getting stuck in the throat, or having an unpleasant taste or odor.

Swallowing difficulties are known to have a negative impact on patient compliance. “By offering an active ingredient solely as a tablet or capsule, pharmaceutical and life-sciences companies ignore the needs of more than 50% of their target audience,” said Thomas Hein, PhD, senior vice-president, Commercial and Regulatory Affairs, Hermes Pharma, in a press release (10). “Given the weaknesses exhibited by conventional tablets and capsules, there is a significant opportunity to capture market share by formulating user-friendly dosage forms.”

Reformulating large tablets, such as paracetamol into effervescent tablets or aspirin into orally disintegrating granules (ODGs), avoids swallowing difficulties and provides a faster onset of action due to the dissolved API, according to Koeberle. “There is also the option to include additional APIs (e.g., caffeine or phenylephrine) due to the removal of tablet-size restrictions,” he adds.

Lately, there has been a lot of interest in orally disintegrating tablets (ODTs) and ODGs as a solution to the widespread problem of swallowing difficulties. With ODGs, patients pour the granules into their mouths, where they dissolve without the need for water, says Koeberle.

“ODTs are primarily defined by their performance characteristic of rapid oral disintegration in saliva with no need for chewing or drinking water,” explains Robert Smith, Zydis global R&D director at Catalent. Catalent’s Zydis ODT fast-dissolve formulation is a freeze-dried product that disperses almost instantly in the mouth, usually in about three seconds, according to Smith, and no water is required. Another key feature of the Zydis technology is the ability to formulate peptides, allergens, and vaccines into fast-dissolve ODTs. “Benefits include low-temperature processing, which minimizes manufacturing losses of labile drugs; solution or suspension dosing, which achieves good content uniformity for low-dose actives; the solid dosage form and low water activity, which aid long-term stability; liquid processing, which facilitates containment of potent drugs in production; and the potential for sublingual or buccal absorption,” Smith adds.

Capsugel has designed its Coni-Snap Sprinkle capsules to address swallowing difficulties, particularly prevalent in pediatric and geriatric patients. “Our sprinkle capsules feature an innovative closure that makes it easier and safer for patients and/or their caregivers to open the capsule and administer the medication by sprinkling the contents-typically powders, pellets, or granules-onto soft food for oral consumption,” explains Coward.

“We tested sprinkle capsules with older consumers and caregivers of young children to gauge usability, ease of opening, and user accuracy when sprinkling capsule contents,” he says. “Eighty-one percent of participants described the new design as ‘easy’ or ‘very easy’ to open. The convenience of sprinkle capsules may encourage those with swallowing difficulties to more easily comply with taking their medicine as prescribed. It’s also an easier alternative to using reconstitutable powders administered via sachet/stick-packs or bottles.”  

Using alternative routes of administration
Reformulation strategies can also include using alternative routes of administration. AstraZeneca’s nasal spray formulation of zolmitriptan (Zomig) for the acute treatment of migraine is one example. It was developed in addition to zolmitriptan tablets and ODTs as a lifecycle management strategy to expand AstraZeneca’s Zomig product line. The nasal spray provides rapid onset of action for migraine sufferers and is a convenient, alternative, non-oral formulation for patients who experience nausea or vomiting in conjunction with their migraine attacks (11). 

Another alternative to the oral route is transdermal drug delivery, which offers a number of advantages such as the avoidance of first metabolism and gastrointestinal toxicity. It allows the administration of drugs with narrow therapeutic windows, can prolong the activity of drugs with short half-lives, and eliminates the need for hypodermic injections (12).

“Patient preference is becoming increasingly important,” Simmon Schaefer, director of business development, 3M Drug Delivery Systems, told Pharmaceutical Technology, “and transdermal patches are a great alternative for those who struggle with swallowing pills and want a more comfortable alternative to injections.” Another advantage is that, in the event of adverse reactions or other problems, patients can terminate the therapy rapidly at any point, simply by removing the patch (12).

The pharmaceutical landscape is becoming more competitive, driving the demand for new drug delivery devices, observes Mark Tomai, head of TLR and MTS Business Development, 3M Drug Delivery Systems. “In general, patient-friendly delivery systems, such as microneedles or passive transdermal patches, are attractive options when considering reformulation as a lifecycle management strategy,” he says. “For instance, reformulating an oral drug into a transdermal patch may be ideally suited for caregiver-intensive conditions. Elderly patients often have difficulty swallowing (dysphagia) or remembering to take their medications. That’s where reformulation into a transdermal system may help, providing a potential to increase compliance, and ultimately treatment outcome.”

According to Tomai, the 3M Hollow Microstructured Transdermal System offers a number of unique benefits that could be advantageous for lifecycle management strategy, including reproducible intradermal delivery, a proven ability to deliver formulations up to 2 mL with various viscosities, and API-dependent pharmacokinetic profile benefits. “Its patient-friendly features and the ability for patients to self-administer opens new opportunities to move treatments out of the clinic and into the patient’s own home,” he adds.

The process of developing a transdermal patch is not straightforward, “which is why companies turn to experts in drug delivery for help with selecting the right technology for their drug product, and then developing and manufacturing the final product,” says Tomai. “Product lifecycle management, technological performance, and opportunity to capture additional market share are just a few of the many factors that should be considered when considering a reformulation strategy, such as converting from an oral dosage form to a transdermal patch or from injectable into microneedle administration. It is essential to involve your contract manufacturing organization early on, so they can help avoid unnecessary pitfalls, such as delays in project timelines and/or additional steps during formulation processing.’’

Summary
Reformulation strategies include both technical and commercial objectives, according to Coward. “The first step involves defining the goals of reformulation, whether it is to improve ease-of-swallowing, enhance taste, or offer convenience. The approach can also address specific marketing objectives, helping to strengthen a brand or identifying new target groups and effectively meeting their expectations,” says Koeberle. “Then comes the evaluation of the current product and its requirements: the characteristics and strength of the API, the particular dosage form, and the kind of packaging (e.g., child resistant versus senior-friendly packaging). These are important factors that give users a more positive experience when taking their medication, and will benefit companies and patients alike by improving compliance.” 

References
1. KPMG, “Pharma R&D Innovation Showing Signs of Resurgence After A Decade of Decline".
2. FDA, Guidance for Industry, Applications Covered by Section 505(b)(2) (Rockville, MD, October 1999).
3. A. Siew, Pharm Technol. 39 (4) 2015. 
4. Pfizer, “Pfizer Announces FDA Acceptance for Review of New Drug Application for A Once-Daily Formulation of XELJANZ (tofacitinib citrate) Modified Release Tablets,” Press Release July 2, 2015. 
5. Roche, “FDA approves new drug application for osteoporosis drug Boniva (ibandronate sodium),” Press Release, May 19, 2003. 
6. Roche, “FDA approves once-monthly Boniva for osteoporosis,” Press Release, March 29, 2005. 
7. Roche, “FDA approves first quarterly I.V. injection for postmenopausal osteoporosis in US,” Press Release 9 January 2006. 
8. A. Siew, Pharm Technol. 38 (4) 2014. 
9. N. Udupa, A. Gupta, and D. Sreedhar, Pharm Technol. Eur. 24 (1) 2012. 
10. Hermes Pharma, “Conventional Tablets May No Longer be the Go-To-Solution,” Press Release, Sept. 2, 2014. 
11. AstraZeneca, “FDA Approves New ZOMIG (Zolmitriptan) Nasal Spray Formulation,” Press Release, Oct. 1, 2003. 
12. A. Siew, Pharm Technol. 39 (5) 2015.

Article DetailsPharmaceutical Technology
Vol. 39, No. 10
Pages: 24–30

Citation: When referring to this article, please cite it as A. Siew, “Stretching Product Value 
through Reformulation Strategies,” Pharmaceutical Technology39 (10) 2015.