Capsules: Developing Combination Drug Products Using Liquid-Filled Hard-Shell Capsules

In today’s pharmaceutical landscape there’s a dearth of true blockbuster drugs on the horizon, driving many companies to place more emphasis on developing combination and niche products. Drug product development personnel have begun to shift away from legacy powder- and bead-filling of hard-shell capsules toward more complex drug delivery systems, including hard-shell capsules filled with liquids or a fixed combination of liquids and other materials such as pellets, beads, microtablets, or capsules. Solubilizing active pharmaceutical ingredients (APIs) in an appropriate vehicle and adding one or more different dosage types into hard capsules is an attractive strategy for producing drug products that are able to achieve vital medicinal effects. 

Benefits of liquid-filled capsules 

Liquid filling of hard-shell capsules was developed in the late 1800s1. In its early development, the process experienced challenges with overall acceptance and leakage issues. With advancements in capsule filling and new technology yielding improved repeatability, liquid-filled capsules have become easier to manufacture and more palatable to consumers. Several APIs currently under development show poor solubility and low bioavailability. Further, these APIs have complex structures when compared to previously developed drugs, as shown in Figure 1. This is partly because easier compounds have generally already been developed and commercialized, and only the more difficult compounds remain. 

Solubilizing a complex API into a liquid fill for hardshell capsules is an effective drug delivery tool that increases the API’s bioavailability and may counteract its inherent limitations. As shown in Figure 2, only around 5 percent of new chemical entities under development are classified as having high bioavailability (Class I), under the Biopharmaceutics Classification System (BCS)2. Approximately 70 percent of APIs under development are classified as BCS Class II, indicating low bioavailability. These poorly bioavailable APIs will require bioavailability enhancements during development. Solubilization and liquid filling can increase this important parameter3. 

Benefits of combination capsule products 

Combination capsule products have naturally evolved from the advancements and innovations in capsule-filling technology, including easily integrated niche filling stations and stricter quality controls. Formulation scientists can achieve combination liquid-filled capsule products in a number of ways, including by mixing beads and pellets with a liquid or by inserting small liquid-filled capsules into larger capsules that are also filled with liquid. Technology and increased understanding of the self-emulsifying drug delivery system (SEDDS), coupled with the advances in commercial filling equipment, have reduced formulation difficulties. As a result, developing and commercializing liquid-nonliquid combination products is easier than ever and can benefit both consumer health and brand owners’ commercial success. 

When combining APIs that demonstrate different mechanisms of action, the therapeutic effects may be additive and side effects may be decreased compared to delivering the APIs separately, which can exacerbate or increase the number of side effects4. A successful product that illustrates this benefit is Vimovo (AstraZeneca), which combines esomeprazole and naproxen. Vimovo was approved by the FDA in 2010 and by the European Medicines Agency (EMA) in 2011. The product is indicated for the relief of osteoarthritis, while decreasing the risk of developing gastric ulcers. If the naproxen portion is delivered alone for osteoarthritis, patients may experience gastric ulcers as a side effect of the medication. The combination approach allows for treatment of the symptoms with a single formulation while reducing the risk of this side effect5. Table 1 lists a number of commercial combination products in different therapeutic areas, including esomeprazole/naproxen. 

For pharmaceutical brand owners, another advantage of developing capsules that combine liquids and other fill materials is strictly strategic: these complicated formulations are, for the most part, harder for generic companies to copy after the patent expires. Ideas discussed between brand development scientists and contract research organizations often include the development of novel and more complex products for this reason. Strengthening intellectual property and associated patents adds immense value to a product. 

Patient adherence may also improve through the use of combination drug products. Combining two or more products into a single dose can drastically reduce the chances of patients taking the wrong medication or an improper dose at the wrong time of day. Studies have shown that fixed-dose combination products can reduce the risk of patient non-adherence by 26 percent compared to separately administered products6. 

When filling capsules with liquids or a combination of other dosage formulations, it’s important to not overfill the capsule, which could lead to leakage. It’s recommended to fill capsules to a maximum of 90 percent of the capsule’s body volume7. Formulation scientists should be cautious and be sure to consider the volume displacement of the solid materials in a combination fill. 

Choosing the right capsules 

When working with hard-shell capsules, drug developers should be aware of different raw material options. The two most common choices are gelatin and hydroxypropyl methylcellulose (HPMC). A comparison of the properties of both capsule-shell types is shown in Table 2. 

When selecting a capsule for a liquid-filled product, developers should have the same mindset as when developing a powder-filled capsule product. The first priority is to ensure that the APIs and excipients are compatible with the capsule shell. Propylene glycol (PG) is a common solvent used to ensure adequate dissolution of APIs and excipients. PG dissolves both gelatin and HPMC capsule shells, so it cannot be used with either capsule type. Similarly, APIs that contain an aldehyde group may crosslink with the gelatin in gelatin capsules and negatively impact the product’s dissolution. If this occurs, the capsule will essentially implode on itself, preventing proper fill release. 

Developers should also consider the moisture sensitivity of the APIs. In gelatin capsules, water acts as the plasticizer. If interaction with the capsule’s contents removes water from the capsule shell, the capsules may become brittle. For this reason, moisture-sensitive materials are generally encapsulated in HPMC capsules, which have a lower water content than gelatin capsules. 

Similarly, in low-RH environments, gelatin capsules may become brittle by the time consumers use the product, so HPMC capsules are typically a better option for products targeted for use in low-RH climates, such as the Middle East or Africa.

Scientists developing new drug products may also encounter several issues that must be tackled in the early stages. For example, during formulation studies, researchers may identify a suitable solvent for improving bioavailability but then experience multiple problems once this liquid is placed into a gelatin or HPMC capsule for feasibility testing. Gelatin capsules may crack and HPMC capsules may dissolve. If this occurs, the problem is most likely attributable to the use of a moisture-sensitive API and a solvent that is incompatible with HPMC capsules. The only option may be to reformulate, which will likely increase costs, delay the drug development sequence, and potentially derail long-term project plans. 

Familiarity with the solvents used in drug development plays a vital role in this process, as the solvent must be compatible with the capsule that works best for a specific API. The same is true for ingredients used to produce banding solutions. Once the capsule is filled, a banding solution is applied to the joint between the capsule body and cap to prevent the capsules from leaking. A typical solution for banding gelatin capsules contains gelatin, polysorbate 80, colorants, and purified water. A banding solution for HPMC capsules may contain a mixture of HPMC colorants, purified water, isopropyl alcohol, and ethyl alcohol. In either case, the filled capsules may degrade if appropriate processes are not applied7.

Another benefit of hard-shell liquid-filled capsules is that they can be used with hot-melt extrusions. Both gelatin and HPMC capsules can withstand temperatures greater than 70°C, making them suitable for use with high-viscosity materials where the API requires heating to lower its viscosity for accurate filling. 

Many pharmaceutical and nutraceutical companies are adding liquid-filling capabilities and combination products to their current portfolios. Changes often involve differentiation from commonly available products and implementing innovative ideas to attract new consumers. The increase in the development of cannabis products in the past three years has partly been promoted by increasing familiarity with filling hard-shell capsules with oils. This may form part of a strategy to portray such products in a clinical light, as opposed to being merely recreational products. 

Like pharmaceutical APIs, certain nutraceutical ingredients show increased bioavailability when solubilized. A study investigating vitamin E and coenzyme Q10 used NanoSolve technology to solubilize both ingredients. The results indicated ten- and five-fold bioavailability increases for vitamin E and coenzyme Q10, respectively, compared to that of their pure forms [8]. With both applications, manufacturers should assess whether consumers would benefit from combining these two common ingredients in liquid form with other nutritional ingredients. Familiarity has also increased with regard to the self-emulsifying nutraceutical delivery system (SENDS), which uses the same type of equipment as that used by the pharmaceutical industry, as shown in Figure 3. 

Pharmaceutical companies design combination products containing liquids to add value to their current products. This can be as simple as combining an immediate- release liquid with a delayed-release bead, or in the nutraceutical niche, combining a prebiotic and a probiotic. Within these applications, formulators can modify dissolution release profiles to benefit patients. Placing a delayed-release capsule inside a larger immediate-release liquid-filled capsule is also possible. 

Table 3 lists various active ingredient candidates for filling combination products. These include liquids with pellets, liquids with tablets, and liquids with capsules, all contained within a capsule. The most important development for these applications would be working toward a release profile that is beneficial for both the product and consumers. With the available technology and acceptance of novel products in the pharmaceutical and nutraceutical markets, the only obstacles limiting new product development lie in the minds of formulation scientists. 

References 

1. Tschanter (Pharm. Zeit.). Pharmaceutical Journal. April 18, 1896, page 307. 

2. L. Z. Benet. “Predicting Drug Disposition by Application of BDDCS.” AAPS 2018. 

3. Jnanadeva Bhat, Fernando Diez, and Justin Kalafat. “Liquid-Filled Hard Capsules Help Meet Today’s Formulation Challenges.” Tablets & Capsules. September 2017, pages 39-43. 

4. US Food & Drug Administration. “Finding and Learning about Side Effects (adverse reactions).” July 19, 2018. https://www.fda.gov/drugs/drug-informationconsumers/ finding-and-learning-about-side-effectsadverse- reactions. 

5. Fernando Diez, Justin Kalafat, and Jnanadeva Bhat. “Fixed Dose Combinations in Capsules.” Contract Pharma. March 2019, pages 56-59.

6. Ulrich Laufs, Volker Rettig-Ewen, and Michael Böhm. “Strategies to improve drug adherence.” European Heart Journal. Vol. 32, No. 3, pages 264-268. 

7. Justin Kalafat and Fernando Diez. “Hard Shell Capsules: An Appropriate Choice for Liquid Formulations.” AAPS 2018. 

8. Rudi Wajda, Jürgen Zirkel, and Tanja Schaffer. “Increase of Bioavailability of Coenzyme Q10 and Vitamin E.” Journal of Medicinal Food. Vol. 10, No. 4, pages 731-734. 

Justin Kalafat is scientific business development manager for ACG (www.acg-world.com). The company offers end-to-end capsule and tablet manufacturing solutions for the pharmaceutical industry.

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