Among all pharmaceuticals, oral dosages are preferred, when pharmacokinetics permit them. And among oral dosages, oral solids—pills—are the most common form. But there have been, and will continue to be, a significant number of drugs that are administered as oral liquids; additional forms of liquid products include topical ointments, droplets, or sprayed or inhaled aerosols.
Oral liquids have some disadvantages in commercial distribution, according to industry sources. They generally need airtight packaging and have a shorter shelf life. Manufacturing is more challenging, and care must be taken to keep the formulation components in suspension. (It is for some of these same reasons that certain injectable drugs are freeze-dried [lyophilized] into powders and then reconstituted as a liquid prior to injection.)
Meanwhile, a certain number of products available as oral solids get reformulated as liquids to meet specialized patient needs. A case in point is Access Pharmaceuticals (Dallas), which last month announced entering into a pre-licensing feasibility agreement with a biopharmaceutical company to develop an oral formulation of an undisclosed prostate cancer compound utilizing its proprietary vitamin B-12-based CobOral Drug Delivery Technology. Access’ CobOral product development program initially focused on the oral delivery of insulin and human growth hormone, two peptides which currently can only be given by injection. Since presenting promising results at a major conference in mid-2008, Access says it has made substantial improvements to the formulation technology.
An improved CobOral insulin-containing nanoparticle formulation delivered orally provided a pharmacological response (lowering of blood glucose levels in an animal model of diabetes) equivalent to greater than 80% of that achieved by insulin delivered subcutaneously. This represents a substantial oral bioavailability, indicating this formulation has potential for clinical development and, ultimately, commercialization. “Having recently rebranded our vitamin B-12 oral-delivery technology as CobOral has helped raise our visibility with pharmaceutical and biotechnology companies in search for a novel broad-based oral drug-delivery technology,” states Phillip Wise, VP for business development. “We anticipate moving forward on various applications of our platform.”
A major reason why oral drugs have evolved is patient convenience, which leads to improved compliance, industry members say. During the past few years, the appearance, taste and formulation of oral drug-delivery methods have evolved to meet patient requirements. “There are many people for whom swallowing pills is difficult and the oral solution, which can be substituted milligram for milligram to the oral tablet, will be helpful to adults with swallowing difficulties,” states Ilo E. Leppik, MD, director, Epilepsy Research and Education Program, University of Minnesota, in commenting on a June announcement from UCB (Brussels) regarding the development of an oral solution for Vimpat (lacosamide) C-V.
This antiepileptic drug (AED) is an add-on treatment of partial-onset seizures in people with epilepsy age 17 years and older. Bringing Vimpat to market in a third formulation spotlights UCB’s commitment to providing a wide range of treatment options to people living with epilepsy, says James Zackheim, PhD, CNS medical director. “Long-term efficacy and safety data, and more than 50,000 global patient exposures, further strengthens Vimpat’s role as an add-on therapy for the treatment of partial-onset seizures in adults.” Vimpat is a clear, colorless to yellow or yellow-brown, strawberry-flavored liquid supplied in 465-mL PET bottles and does not require refrigeration.
Serving patient populations
Developing an oral liquid fulfills an unmet medical need by expanding the patient population to those unable to swallow solid dosage forms. “This patient group includes young children, geriatric patients, and specific patient populations that have challenges swallowing solid dosage forms due to their disease,” observes Debra Pereira, RPh, director, pharmaceutical development at Pfizer (New York). “In addition, oral liquid formulations provide dosing flexibility, which is particularly suited to oral drugs that are dosed by patient weight or body surface area.”
When it comes to manufacturing, tablets are usually faster and less costly to produce while oral liquids are more fragile and chemistry is more challenging to negotiate through the development phase. Because active materials have a better chance of breaking down in liquid form, stability and contamination are bigger concerns. Stability is also impacted by suspending agents, flavors, colorants, and sweetening agents.
GERALD YAKATAN, IRISYS
“The big issues are dose, solubility, and taste,” points out Gerald Yakatan, PhD, chairman of Irisys (San Diego), an organization offering pharmaceutical R&D, cGMP manufacturing, and regulatory strategic planning services. “This dosage form also lacks patient acceptability as a final marketed form because it may be bulky to carry if multiple doses during the day are required, may require the use of a measuring cup or spoon, and does not make for a discreet form of dosing.”
One area which presents numerous formulation problems for oral liquids is maintaining stability throughout their expiry period, according to FDA. For example, there have been several recalls of vitamins with fluoride oral liquid products because of vitamin degradation. Drugs in the phenothiazine class, such as perphenazine, chlorpromazine and promethazine, have shown evidence of instability. Good practice for this class of drug products would include quantitation of both the active and primary degradant, FDA says.
Generally speaking, formulation scientists face challenging decisions relative to the selection of excipients, solubility and stability assessments, just to name a few. “I think we can handle some of the solubility issues if the doses are reasonable, because we can apply physical-chemical principles to develop solvent mixtures to improve solubility,” Yakatan says. “Taste masking can still be a problem until we develop better ways to coat powders and use suspensions for liquid dosage forms. Nanotechnology may also help with solubility for liquid dosage forms.”
Such deficiencies do not make oral liquids a candidate for patent extension, except in the case of pediatric dosage forms developed to obtain six-month patent extensions, Yakatan says. “It should not be difficult to develop a generic liquid dosage form and overcome a patent.”
Many types of formulations, both aqueous and non-aqueous, are included among those which can be classified as oral liquids. When an oral liquid formulation is desired, there are several options available. The more common are oral solutions, suspensions and concentrates, and powder for constitution (POS) formulations. “The option selected is based on many considerations, and is designed to ensure quality, safety, and efficacy,” Pfizer’s Pereira says. “Formulation considerations include ensuring appropriate chemical and physical stability, dose delivery, and microbial control.”
Oral liquids usually require the development of specific analytical methods due to the nature of the excipients used in the formulation to improve palatability. Formulation excipients and their usage levels must be within acceptable limits, experts say, or a strategy must be put in place to obtain regulatory acceptance. “In addition, the patient population and target markets are considered to ensure the product will meet what is required,” Pereira says. “For example, if potable water is not freely accessible in a target market, a POS formulation would not be a good option for that market.”
IriSys reports one other aspect of a type of oral liquid found useful in early drug development: liquid-filled hard gelatin capsule. While the liquids must be non-aqueous, Yakatan says, developing a product in the most bioavailable oral form and overcomes the taste issue of an oral liquid is a big plus. “We often recommend this type of formulation for Phase I or II products where poor aqueous solubility and, therefore, potentially poor oral bioavailability may be a problem. This provides the client with a good shot at good bioavailability without a tremendous amount of expenditure for development of a poorly water-soluble compound.”
It would be more difficult to manufacture such a product on a commercial scale, Yakatan says, but using this type of technology allows the client to determine whether they have a viable drug product in the early development stages. “If the product looks good, other formulation techniques that require more time and money can be employed to develop a bioavailable formulation prior to Phase III studies and commercialization.”
Clearly, there are strong incentives for pharma companies to pursue oral liquids. For example, certain medications can only be delivered by liquid because of a very high dosage level, or particular characteristic of the active ingredient, experts say. Liquids are mandatory for certain target markets, like infants.
Geriatric care is another growing target market for oral liquid formulations. By 2050, there will be an estimated 2 billion people aged 60 years and older worldwide, a demographic outnumbering children aged 14 and under for the first time ever.
Indeed, many other patient populations would benefit from having greater access to oral liquid meds, experts say. While oral liquids may always be a smaller niche than solid dosage forms, increased patient demand are making this drug type more viable to pursue. Pharma companies who respond to market demands for new medicines and appropriate delivery systems such as oral liquids stand to reap the economic benefits. PC