Issue link: https://www.e-digitaleditions.com/i/1163217
32 September 2019 Tablets & Capsules 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 prod- uct, so HPMC capsules are typically a better option for products targeted for use in low-RH climates, such as the Middle East or Africa. was approved by the FDA in 2010 and by the European Medicines Agency (EMA) in 2011. The product is indi- cated for the relief of osteoarthritis, while decreasing the risk of developing gastric ulcers. If the naproxen portion is delivered alone for osteoarthritis, patients may experi- ence gastric ulcers as a side effect of the medication. The combination approach allows for treatment of the symp- toms with a single formulation while reducing the risk of this side effect [5]. 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 formula- tions are, for the most part, harder for generic companies to copy after the patent expires. Ideas discussed between brand development scientists and contract research orga- nizations 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 com- pared to separately administered products [6]. 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 recom- mended to fill capsules to a maximum of 90 percent of the capsule's body volume [7]. 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 develop- ers should be aware of different raw material options. The two most common choices are gelatin and hydroxypro- pyl methylcellulose (HPMC). A comparison of the prop- erties 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 devel- oping 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 sol- vent 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. Simi- larly, 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 sensitiv- ity of the APIs. In gelatin capsules, water acts as the plas- ticizer. If interaction with the capsule's contents removes Component drugs Therapeutic area Aspirin/Dipyridamole Cardiovascular diseases Atorvastatin/Amlodipine Cardiovascular diseases Captopril/ Hydrochlorothiazide Cardiovascular diseases Fluticasone/Salmeterol Respiratory diseases Ipratropium bromide/ Albuterol Respiratory diseases Ritonavir/lopinavir Infectious diseases Amoxicillin/Clavulanate Infectious diseases Rifampicin/Isoniazid Tuberculosis Isoniazid/Ethambutol Tuberculosis Artesunate/Amodiaquine Malaria Artesunate/Mefloquine Malaria Lamivudine/Nevirapine/ Stavudine Human immunodeficiency virus infection Esomeprazole/Naproxen Osteoarthritis Table 1 Examples of commercial combination products in different therapeutic areas Source: A Wertheimer & A. Morrison. Combination Drugs: Innovation in Pharmacotherapy. P&T. January 2002, 27:1. Table 2 Properties of gelatin and HPMC capsules Gelatin HPMC Origin Animal Vegetable Structure Protein Cellulose Moisture content 13-16% 3-8% Brittleness Brittle at low relative humidity Very low Crosslinking Yes No Source: ACG.