Hard Capsules as a Flexible Dosage Form

The pharmaceutical industry is at the forefront of innovation, helping people to live better lives. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), there are approximately 7,000 medicines across the drug development pipeline, globally (1). 

Thousands of probable drug candidates are subjected to multiple screening criteria to yield a single chemical entity, which is then developed through three phases of clinical trials to bring that one new drug to patients. The average cost per approved new compound is estimated to be $1.3 billion, and the cost to the point of marketing approval after adjustment for discounted rates is $2.5 billion (2). Although innovations by leading R&D companies, ensure newer and safer medicines, reverse-engineering has made patent-expired drugs available to a larger population. It is crucial for generic pharmaceutical companies to develop drug products that are not only safe and effective, but also easy to use. Oral solid dosage products are preferred by the end-consumers owing to several factors, including ease of swallowing, ease of handling, consumer compliance, and attractive color options.

To confirm the preference for orals solids by the pharma industry, analysis of first-to-fileabbreviated new drug approvals (ANDA) by FDA suggests that almost 60% of them are oral solid dosage products (3). Among oral solids in 2017, compared to 2016, the number of drug approvals for capsule as a dosage delivery form has doubled, indicating the preference towards capsules in first-generic drugs (see Table I). 

Generic drugs that were not first-generics, a study of abbreviated new drug approvals (ANDAs) by FDA indicated that in the past five years, the number of approvals for generic drugs has doubled for capsules. In 2013, some 53 drugs in the capsule form received ANDA approvals; in 2017, the number was 110, which was more than double (3).

Hard capsules allow flexibility in formulation 

There are costs involved in the development of a stable active ingredient, and as its availability is often limited by its quantity, it is appropriate to have a flexible dosage form, such as a capsule, at this stage. A hard capsule represents a flexible dosage form because it is available in various shapes and sizes and limits the need for additional excipients. It also limits the requirement that powders be formed into a compact mass for handling. The capsule allows for limited API to be filled into capsules of sizes between 000 and 5, offering much needed flexibility in the preliminary stages of development. 

The quickest way to first-in-human (FIH) studies

Once the drug candidates have passed through the preclinical stages, they must undergo lengthy clinical trials. Research in humans is performed in three phases: Phase I and early Phase I trials assess the safety profile of the drug at a range of dosages far in excess of its therapeutic dose; Phase II and III trials test and establish the efficacy profile of the drug in a larger number of patients. During early Phase I trials, the dosage form of the drug is often not finalized, which is where capsules may become involved. The quickest option for entering FIH clinical studies (also known as early Phase I or Phase I trials) is filling the API directly into capsules. Because no excipients are needed, three or four months-which would otherwise be used for stability testing and formulation development-are saved (4). It is much easier to formulate an API with a wide dosage range in the capsule form than in the tablet form. Hard capsule shells also offer unique flexibility for modified-release formulations because capsule shells can be coated with appropriate components to modify the release of the drug, thereby limiting the need to add excipients to the formulation while it is still under development. 

An analysis of trials registered at clinicaltrials.gov revealed that there were approximately 500 clinical trials, with 35,000 participants, that used capsules as a dosage form in early Phase I or Phase I trials. Across all Phases (I to III), approximately 1400 clinical trials with more than 300,000 participants globally are using capsules as a dosage form (5). In the early Phase I and Phase I trials, 25% of the trials are focused on patients with cancer, confirming that oncology is a major field for research into therapeutic advancement, alongside alcohol abuse and diabetes. )

Encapsulation is suitable for complex molecules that are difficult to formulate

A paradigm shift is now underway in chemical and pharmaceutical processing, with the major focus now on the specialization of process flows; hence, the production process is often designed as a contained system. Data suggest that more than 50% of all NCEs are potent compounds. Therefore, for smooth production flow, containment is necessary (6). Similarly, in the last few years, there have been advancements in encapsulation technology, allowing the filling of powder, granules, pellets, and liquids; this has made drug candidates easier to test, and reduced manufacturers’ concerns about compressibility and the interaction of ingredients.

Encapsulation with a containment solution ensures the easy formulation of powders, pellets, and granules, enabling the formulation of complex APIs that are potent and difficult to formulate in a dosage form. Drug candidates in therapeutic areas such as oncology are often very potent and difficult to formulate owing to solubility issues and sensitivity to processing technology (7).

Recent advancements: liquid filling hard capsule (LFHC) technology

A sizable percentage of the currently available products and drug candidates in the development pipeline fit the technical definition of “poorly soluble.” The advancements in encapsulation technology with containment have enabled researchers to formulate highly potent or low-dose APIs in capsules using liquid filling hard capsule (LFHC) and capsule-in-capsule technology. There is now a viable alternative for highly potent ingredients, which are difficult to formulate into traditional oral solid dosage forms owing to their hygroscopic and toxic nature. Encapsulation as a liquid in a hard-shell capsule allows the development in an oral solid dosage form (7). Capsule-in-capsule encapsulation technology allows the formulation of a combination of products in one capsule and permits the combination of a prefilled smaller capsule inside a liquid-filled larger capsule for modified-release products.

Conclusion

As many of the NCEs are under development by companies in therapy areas such as oncology, mass production has shifted toward smaller batches that are driving the market for encapsulation machines offering containment solutions. It is now possible for manufacturers to fast-track their manufacturing from laboratory-scale to production-scale by using high-capacity encapsulation machines. There are fully automatic capsule-filling machines under containment available from leading companies. These machines offer the highest safety standards and meet occupational exposure band level 5 (OEB 5). Modern capsule-filling equipment make it possible to fill powders, beads, liquids, granules, small tablets and semisolids, making it a significantly flexible dosage delivery form (8). 

References

1. PhRMA, 2018 Biopharmaceutical Research Industry Profile and Toolkit, www.phrma.org/industryprofile/2018/, accessed Sept. 27, 2018.
2. J. DiMasi, H.G. Grabowski, and R. W. Hansenc, Journal of Health Economics47, 20–33 (2016). 
3. FDA, “2017 First Generic Drug Approvals,” 2017.
4. C. Lorimer,  “Manual and Automated Filling of Powder in Capsules for Clinical Trials,” PharmTech.com, May 18, 2011. 
5. NIH, Clinical Trials Database,  ClinicalTrials.gov.
6. A. Stark, ed., “Containment Calls for Paradigm Change in Solids Production,” Process-Worldwide.com, June 9, 2018.
7. E. Elias, “Overcoming Formulation Challenges with Liquid-fill Capsules,” PharmasAlmanac.com, Mar. 12, 2018. 
8. M.M. De Villiers, “Oral Conventional Solid Dosage Forms,” in Theory and Practice of Contemporary Pharmaceutics(CRC Press, Boca Raton, FL) pp. 279–332, 2004. 

About the authors

Sunil Singh is senior manager corporate marketing and Ilesh Desai is vice president; both are at ACG Capsules.