Technological innovation has become increasingly critical for pharmaceutical companies as they struggle to achieve and maintain a competitive advantage. Industry trends, such as globalization, fast product-cycle times, increased competition, product commoditization, patient-centered approaches, and technology fusions, have added to this importance by creating new avenues of being competitive. Close examination of the pharmaceutical sector shows that, while consistently profitable, it has not been immune to these factors.

Over the past few years, a premium has been placed on managing research and development (R&D) processes in an efficient and effective manner. Some key influences on this focus area are:

1. Fewer drugs introduced and increased R&D expenditures
2. Increased popularity of generic substitutes
3. Increased global competition
4. A higher number of significant drugs coming off patent protection
5. Healthcare reform simultaneously squeezing profit margins and limiting the selection of drugs available to consumers through health plans

These are some of the reasons why many pharmaceutical companies have chosen to outsource some or all of their drug development platforms. The rise in the number and capabilities of contract research organizations (CROs) and contract development and manufacturing organizations (CDMOs) directly correlate with this industry shift in product development channels and after manufacturing.

Incremental innovation in drug therapy can take various forms, including new agents or therapeutic indications for existing drugs and new dosage forms with improved pharmacological profiles. Another incremental innovation, combination therapy, consists of two or more agents with complementary mechanisms of action. In addition, combination therapy is recommended in many cases where there is drug resistance to individual therapeutics and has extended the range of therapeutic options in the treatment of almost every human disease.

In this article, we describe the advantages of using hard capsules in combination therapy, as this dosage form can accommodate two or more drugs.^1,2

Fixed Dose Combinations
The use of free combination therapy, which consists of two or more different drugs, to treat a disease has been trending for many pharmaceutical indications. There are several rationales for using combination therapy rather than increasing the dose of a monotherapy (single drug). If two or more drugs with different mechanisms of action with the same therapeutic endpoint are prescribed to treat a disease, then the overall therapeutic effect will likely be additive, while side effects will likely not be proportional. This is the case for treatments for certain conditions, such as hypertension and type 2 diabetes. Patients with these diseases are rarely able to reach their treatment goals with one therapy alone and so require treatment efficacy that can only be attained through combinatorial approaches.

The disadvantage of free combination therapy is that patients are prescribed multiple drugs. This is associated with several challenges, including increased risk of confusion and making a mistake when taking these medications, resulting in compliance being compromised.

Fixed dose combination (FDC) therapy is necessary to cure patients and prevent the selection of drug-resistant mutants, which may arise during the treatment. The major advantages of using FDCs to treat diseases include simplification of treatment and drug management while reducing the probability of monotherapy will be used. This is a necessary step in curing diseases and preventing further emergence of drug resistance (see Figure 1*).

For these reasons, the use of FDCs containing two or more drugs in a single dosage form is especially attractive. Physicians would prescribe a single medication consisting of two or more drugs to create dosing centered around patient convenience and improve compliance. Another benefit may be lower co-pays as fewer prescriptions need to be filled and the drug supply process is simplified (see Table 1*).

Another possible rationale for developing an FDC is for combinations involving one component being included to prevent side effects incurred by the other component. An example of this strategy is Vimovo (AstraZeneca), which combines esomeprazole and naproxen. Vimovo was approved by the FDA in 2010 and Europe in 2011. This product is indicated for the relief of signs and symptoms of osteoarthritis and decreasing the risk of developing gastric ulcers in these patients.

The therapeutic effect of the FDC must be additive. In other words, each component drug must exert its full effect when used in combination with another drug. If the effect is less than the sum of the parts, regulatory approval is unlikely to be granted. A synergistic effect is preferable over a merely additive effect. This is an additional argument for using FDCs. Furthermore, a synergistic effect can pave the way for a robust patent for a combination of drugs.^3-5

Use of hard capsules in FDCs
Hard capsules are one of the most popular dosage forms in the pharmaceutical industry. Developed in the 19th century, their presence in the market has since continued to increase.
The two main types of hard capsules in the pharmaceutical industry are gelatin and hydroxypropyl methylcellulose (HPMC) capsules.

Gelatin capsules

• Considered the standard legacy capsule;
• Animal origin;
• Most important advantage is its quick dissolution in biological media, where the drug product is released within five minutes;
• Has a high moisture content (13-16% at 35-65% relative humidity), which is not suitable for moisture-sensitive products;
• Water acts as the plasticizer in the capsule and the capsules become brittle in low relative humidity conditions—this is an inconvenience when encapsulating hygroscopic products or when desiccants are used; and
• Crosslinking can occur in certain active and inactive pharmaceutical ingredients, causing dissolution to fall below the specified level.

HPMC capsules

• A new generation of capsules with a plant origin;
• Maintain the advantageous properties of gelatin capsules, while overcoming the major issues associated with gelatin capsules;
• Similar dissolution profile in stomach to gelatin capsules after brief lag time;
• Low moisture content (4-8% at 35-65% relative humidity) and good mechanical properties at low relative humidity;
• Able to encapsulate moisture-sensitive and hygroscopic products while allowing the use of desiccants; and
• Immune to crosslinking.

In the fasted state, stomach volume is approximately 50 mL. With the pyloric sphincter open, small objects are emptied fairly rapidly by normal stomach movements. Conversely, the stomach dilates in volume to about 1.5 L in the fed state. There is a lot of liquid in the stomach during digestion and any capsules and pellets present will float on the surface. During digestion, the stomach muscles contract and mix the contents (liquids and fine materials). If materials are small enough, it is possible they will leak through the sphincter. Larger insoluble particles cannot leave the stomach. Digestion ranges from 30 minutes to 3 hours. After this time, the sphincter opens and a series of muscular contractions push any remaining solids out of the stomach (see Figure 2*).

Hard capsules are an interesting option as a delivery system in FDC formulations for the following reasons:

• They are inert and do not react with the product contained within.
• They are available in many sizes Standard hard capsules typically range as big as size 000 to as tiny as size 5 and can accommodate various fill volumes. To encapsulate additional fill volumes outside traditional sizes, some intermediate sizes are available which are termed “elongated sizes.” These typically have an extra 10% of fill volume over the standard sizes to handle density variations.
• Customized sizes can be developed if a formulation or delivery technology calls for such engineering.
• The proper capsule can be filled with moisture-sensitive and hygroscopic products. Furthermore, the capsule moisture content can be reduced by drying the capsule (storing at a low relative humidity) after filling if desired for certain formulations.
• Versatile delivery system capable of accommodating partial filling, such as for inhalation formulations or liquids up to 70°C.
• Great development of encapsulation equipment filling technology. In addition to powders, it is possible to fill these capsules with pellets, liquids, micro-tablets, another capsule, or combinations of these (see Figure 3*).

Examples
There are many successful FDC products that use hard capsules as a drug container. Here are some examples:

Combodart/Jalyn
Combodart (see Figure 4*) was the first FDC created for the treatment of moderate-to-severe benign prostatic hyperplasia (BPH) and reducing the risk of acute urinary retention in BPH-related surgery. The product consists of an alpha reductase inhibitor dutasteride and the alpha blocker tamsulosin hydrochloride.

Dutasteride delays progression of BPH by inhibiting the production of the male prostate growth-stimulating hormone dihydrotestosterone, while tamsulosin provides rapid symptom relief by reducing smooth muscle tone in the prostate and bladder neck.

The product structure within the delivery system is sophisticated and consists of:

1. A softgel capsule filled with a liquid additive.
2. The above softgel capsule introduced into a hard size-00 HPMC capsule.
3. Pellets from the other additive filling the HPMC capsule to accompany the softgel in the final dosage form.⁶

Cardiovascular polypill
The Fuster CNIC-Ferrer CV polypill (see Figure 5*) consists of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 mg) in a capsule. Studies have demonstrated treatment of patients with established cardiovascular disease with polypills decreases mortality.

This combination of different active ingredients in a simple capsule successfully avoids physico-chemical incompatibilities and conserves the biopharmaceutical and pharmacokinetic properties of each component.⁸

Inhalation combinations
Hard capsules can be used for inhalation delivery of drugs, where the capsule is punctured and the patient inhales to facilitate the powder reaching the lungs.

In capsuled-based dry powder inhalation technology, the use of a combination therapy usually yields better results that using a single ingredient. A good example is the mixture formoterol-budesonide. The single capsule combination of formoterol-budesonide appears to be more efficacious and safer than budesonide alone for the treatment of asthma.⁹

With increasing interest in the development of channels for inhalation worldwide, FDCs could be an option for capsule-based products. As new therapeutic classes, such as pulmonary hypertension, oncology, and biologics, are considered for treatment using inhalants in addition to classical chronic obstructive pulmonary disease and asthma, combinations could provide therapeutic advantages in this simple delivery system (see Figure 6*).

Variation in encapsulation equipment for FDCs
With increased interest in FDCs, encapsulation equipment has been adapted to commercialize formulator molecules using added technology. Standard powder- and liquid-filling encapsulation machines are capable of handling FDCs upon the addition of attachments to equipment already utilized by the market. Camera inspection systems and their sensitivities have also evolved to ensure precise dosing. Production can continue to operate equipment at cost-effective speeds to encapsulate these combination drugs without negatively affecting product quality.
A few examples of equipment technology include:

1. Weight control for individual encapsulation stations and static eliminators can be added to the equipment for pellet filling.
2. Vision system cameras able to monitor the number of tablets added to a capsule.
3. Cameras placed in a special enclosure to monitor micro-tablet additions.
4. Delayed-release pellets placed into the same capsules as an immediate-release liquid using an attachment to the standard liquid-filling equipment.¹⁰

Conclusions
Currently, FDCs are useful tools for R&D formulators to increase the therapeutic effects of drugs, reduce their side effects, and extend their patent life. With most simple products already being developed in the pharmaceutical community, many developments have shifted to niche products. Protecting the patent life of these products is very important as they are typically considered high-value in a company pipeline. The development of proper FDCs will help pharmaceutical companies enhance management of their product life cycle and evergreen patents.

Capsules are the most suitable dosage form for FDCs. They are inert in nature and available in multiple sizes. Capsules can accommodate pellets, minitablets, micro-tablets, and any combination of solid/solid and solid/liquid. Advances in encapsulation technology make this type of a combination filling a reality. 

*Note: All Figures appear in the image slider at the top of the article.
 
References

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2. T. Ellery et al. Pharmaceutical Life cycle management. Wyley. 2012
3. A. Wertheimer. Combination drugs. Innovation in Pharmacotherapy. P&T. 2001
4. B. Jones et al. Pharmaceutical capsules. PhP. 2014
5. M.E. Aulton. Pharmaceutics the science of dosage form design. Churchill Livingstone. 2002
6. M. Lebwohl et al. Treatment of skin disease comprehensive therapeutic strategy. Elsevier Health Sciences p 327-337. 2013
7. Combodart. FDA. www.drugs.com
8. J. Tamargo et al. The Fuster – CNIC – Ferrer Cardiovascular polypill. Int. J. Cardiol. 2015
9. R. Stirbulov et al. Evaluation of the efficacy and safety of a fixed dose single capsule budesonide-formoterol combination in uncontrolled asthma.
10. D. D’Penha – Special Purpose Encapsulation Case Studies: Customized Oral Dosage Encapsulation. ACG TechnoVersity Seminar – 4th September 2015, Mumbai.