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Winning formula: Searching for the right formulation for oral solid dose applications

Anil Kane, Ph.D., MBA, e xecutive director, global head of formulation sciences, pharmaceutical development services at Patheon on finding the right formulation for oral solid dose applications

Oral delivery of solid dosage forms continues to be the delivery route of choice, as it is non-invasive, inexpensive, and offers ease of administration. The stability of drugs as chemical entities is far superior in solid forms than in liquids, providing an extended shelf life for the drug product. Oral formulations can be used to deliver the drug to the various parts of the gastrointestinal tract to treat many conditions through systemic absorption. Approximately 60% of new chemical entities in the R&D pipeline, as well as marketed drugs, are in a solid dose format. An additional 30-35% are in sterile injectable form, while the rest use other forms of delivery, such as nasal, ocular, transdermal-subcutaneous, intramuscular or topical, etc.

The most commonly used oral solid dosage forms are capsules and tablets. Capsules continue to be the dosage form of choice for pre-clinical and early clinical studies of toxicity, efficacy and proof-of-concept. Capsules offer the flexibility to dose a wide range of quantities of the drug by using different sizes of capsules. It is easy to fill neat active pharmaceutical ingredient (API) into capsules, and enabling a quick evaluation in the early studies. Tablets offer advantages in formulating large doses of drugs diluted with excipients to be delivered in a compressed form, with ease of swallowing. Tablets are often coated for reasons such as identification or branding. Functional coatings can also enhance stability, with moisture barrier coatings improving the stability of drugs that are sensitive to moisture or for those that can degrade with moisture pick up. Functional polymer coatings or pH sensitive coatings on tablets can help target drug delivery; for example, enteric and controlled-release tablets can be developed to appropriately deliver a drug to treat Crohn’s disease or colon cancers. It is relatively easy to develop placebos as tablets and capsules, enabling a comparison between the efficacy of the test product and placebo in clinical trials.

Tablets: The oral dosage form of choice

Tablets continue to be the oral dosage form of choice moving from early (Phase I-IIa) to late clinical development (Phase IIb-III), offering flexibility of dosing and a favorable cost of goods, as these can be manufactured using high speed equipment. Tablets also offer the option of delivering the drug as a sublingual tablet, oral disintegrating tablet, dispersible tablet or chewable tablet, providing ease of swallowing for pediatric or geriatric patient populations. Based on Patheon’s experience in supporting development of clinical candidates and manufacturing commercial products for more than 400 clients, a change is underway in early clinical development. Due to the fast-track and orphan status of certain drug candidates to address urgent unmet medical needs, there is a move to develop tablets even for early stage Phase I studies. This reduces the time required to bring the drug to late stage clinical trials, avoiding any bridging studies to compare clinical bioequivalence between capsule and tablet.

Capsules offer the advantage of delivering drugs in a powder, granule or liquid semi-solid state. For example, a simple powder blend of drug with excipients can be filled into a capsule. If a drug needs to be formulated as a lipid delivery system, such a system can be filled into a two-piece hard gelatin or hypromellose capsule, or filled into a softgel. This can be advantageous especially when lipid-based delivery is utilised to improve permeability and bioavailability of poorly soluble drugs. Furthermore, these capsules can be coated with polymers to deliver the drug into the stomach, small, large intestine or the colon to target a better absorption or deliver the drug for an optimum site of action. It is also possible to control the release of drugs so as to deliver the drug over an extended period of time, for example, enabling once-daily dosing.  

Benefits of fixed-dose combinations

Fixed-dose combinations have been developed where two or more drug candidates are combined into a single unit dosage form such as tablet or capsule. This enables delivery of the drugs in a way that improves safety, has synergistic clinical efficacy, or improves patient compliance. Several fixed dose combinations have been developed as monolayer, bilayer or trilayer tablets, depending on the chemical stability and compatibility of the chemical entities. Formulators can also combine the drug candidates in a fixed dose combination tablet and have a different release profile for each of the entities. This can improve the safety and efficacy profile, for example, by using a combination of immediate- and controlled-release formulations of the drug candidates. Marketed fixed dose combinations are used to treat a variety of conditions, including diabetes, cardiovascular conditions, and infections.

Capsules also offer benefits in being able to deliver immediate or controlled-release active ingredients as well as fixed-dose combinations. Formulators can develop multiple types of drugs in pellet form, and fill these pellets in a capsule, thereby offering various release profiles. One of the limitations of capsules is their fixed volume. Drug candidates can be formulated and packed into a capsule, with size 00 being the largest capsule size that can be swallowed. In such cases, tablets offer an advantage, since drugs can be compressed or compacted into a caplet or capsule shaped tablet form for ease of administration. 

Tablets and capsules can be packaged into unit-dose or multi-dose configurations that offer ease of transportation, as well as ease of dosing for in-home or outpatient settings. These dosage forms have a much higher degree of patient compliance than other delivery formats.

Small molecule drug candidates are typically developed as a solid oral dosage form; however large molecules such as proteins and peptides must be formulated as injectables, since they cannot be delivered orally due to degradation by the acidic pH of the stomach, which renders them inactive. Significant efforts are underway to overcome this issue and develop oral formulations of large molecules using innovative drug delivery techniques.

Types of oral formulations include:

Conventional

Immediate-release tablets

Powder-filled capsules

Powders, granules and coated beads

Specialised

Liquid-filled capsules

Controlled-release tablets

Multilayer tablets

Fast-dispersible tablets

Softgels

Softgel Capsules

Twist-Off Softgels

EnteriCare Softgels

LiquiSoft Softgels

Versatrol Softgels

Solvatrol Softgels

Soflet Gelcaps

Chewels Chewable Gels

Softgels offer another format for oral dosage, developed to deliver the drug with improved bioavailability due to increased permeation and absorption. Lipid-based simple, binary or tertiary systems can be developed to formulate a softgel to deliver the drug to the stomach (conventional softgel) or to the small intestine (enteric softgel - Entericare), or to release over different regions of the gastro-intestinal tract (Versatrol softgels). Twist-Off softgels are a special delivery format that is not swallowed whole; instead, the lipidic contents can be squeezed out and administered to a neonate or a child. This is especially beneficial as neonates require delivery of drugs using a small volume of vehicle. Chewels are delivered as pediatric dosage forms for delivering drug substances that have an unpleasant taste and need to be taste-masked to improve patient compliance. Softlet is a format of softgel where a tablet in enrobed into a gelatin coat for a variety of reasons. These may include ease of swallowing, taste masking, identification or branding, or for blinding the comparator and test product for clinical studies. In blinding, softlets are an improved option over the conventional technique of over-encapsulation.

Softgels are easily scaled to match changing commercial supply demands, since small and large batches are made with the same process and on the same equipment. Considerations to maximise the technical advantages of softgels include:

Powder for reconstitution is another oral solid-dose format that offers the benefit of multi-dosing. This is especially popular for anti-infectives, including antibiotics that need to be taste-masked and dosed over a few days or a week. This format is also very popular as a pediatric dosage form.

Conclusion

There is scope for pharma companies to expand their options with innovative combinations of solid dosage forms and a variety of controlled-release technologies. Formulation choice may depend on whether companies are establishing a clinical supply or commercial supply for a new product, transferring an existing product, have a life cycle management project for an established drug, or seek opportunities and resources in the over-the-counter market.

Looking ahead, solid dosage forms will remain important for oral delivery of novel drug candidates, reformulation of existing products, fixed-dose combinations, controlled release or pediatric formulations, and other life cycle management strategies. A favorable cost of goods and high levels of patient compliance will continue to be key advantages. Further evolution in manufacturing technologies for solid dosage forms is expected, with important drivers including functional improvements, safety, and development and commercial manufacturing costs.

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