December 6, 2018 PAO-M12-18-CL-002
Delivery of drugs and dietary supplements formulated with sensitive compounds can be challenging, particularly if the actives must be released into the body at targeted locations. Protecting tablets with enteric coatings is one approach to ensure deliberate delivery. In general, hard-shell capsules designed to degrade under specific conditions are a better option for many sensitive compounds, including probiotics.
Many active pharmaceutical ingredients (APIs) and key components of dietary supplements are sensitive to pH or other conditions. They may degrade improperly if exposed to saliva but perform appropriately in the acidic conditions of the stomach. Alternatively, they may be rendered ineffective if exposed to acidic conditions and thus must be delivered to the intestine before being released into the body.
Capsule coatings have traditionally been used to overcome these challenges. These coatings are formulated with polymers designed to disintegrate under specific conditions, such as low or high pH. They act as a barrier, protecting the active ingredient until the appropriate conditions are reached. At that time, the active must be released within 15 minutes.
Controlled release of actives can also be achieved by incorporating different types of polymer matrix systems, enzyme-activated systems, or systems that respond to changes in physical conditions within the formulation.1 These systems function via a variety of mechanisms, including dissolution, diffusion, osmotic pressure, maintaining a hydrologic or hydrodynamic balance and ion exchange. Newer approaches are based on nanotechnology, buoyant systems and mucoadhesive systems.
In the past, natural materials, such as fatty acids and waxes, were employed. Today, modified cellulosic polymers, including ethyl cellulose and hydroxypropyl methylcellulose (HPMC) and synthetic methacrylate polymers, are widely used.2 Other materials include ethyl vinyl acetates (EVAs), silicone elastomers and thermoplastic polyurethanes (TPUs).
For delayed-release formulations that allow for release of the active at a target location within the body, such as the intestines, the most commonly used excipients are acrylic polymers and cellulose derivatives that dissolve at specific pH levels.2
While enteric coatings for tablets can be highly effective, their effectiveness is dramatically reduced if they are breached in any way. They only function properly if the tablet remains whole and intact without any damage to the coating.
Often, patients break tablets in half or crush them to make them easier to swallow. Unbanded capsules can also be broken in half. Doing so eliminates the controlled-release features of the medications, resulting in reduced efficacy. Crushing tablets that were not designed to be taken in this manner can also potentially lead to unanticipated side effects.3
One way to avoid this problem is to formulate acid-sensitive APIs and nutraceutical actives in banded hard-shell capsules formulated for controlled release in a targeted location within the body. Polymer formulations for the production of hard-shell capsules, combined with control of the capsule shape, enable the design of capsules that will dissolved in targeted areas for optimal therapeutic effect, such as the upper intestinal tract.
When banded, these capsules, including acid-sensitive formulations, are tamper resistant. During the banding process, the material used for banding is customized to work with the composition of the hard shell used to produce the two parts of the capsule. The band material seeps into the seams of the capsule and dries and hardens at the same time, allowing complete fusion. For liquid products, including most probiotic supplement formulations, banding provides an airtight seal that prevents product from leaking out of the capsule until the desired pH is reached. In addition, they cannot be easily broken apart like traditionally sealed capsules or crushed like tablets. Furthermore, there is no potential for damage of the controlled release features during shipping.
As an added benefit, banding allows for greater brand recognition through customization of the capsules. The variety of capsule sizes and capsule and band colors, finishes and printing options enable significant differentiation while providing assurance of quality and effective delivery.
Probiotics are an example of actives that are highly sensitive to acidic conditions. They are also sensitive to thermal stress during long-term storage and manufacturing processes, oxidative stress and osmotic shock during drying.4 If exposed to the acidic gastric juices in the stomach, the live cultures contained in probiotic formulations are degraded. For probiotics, therefore, delivery to the to the intestines5 is essential to realizing their maximum benefits.
Demand for this class of dietary supplements is growing rapidly. The value of the global market (including functional foods and beverages, dietary supplements and animal feeds) is projected to expand at a compound annual growth rate of 7.35% from $40.1 billion in 2017 to $65.9 billion by the end of 2024.6 The active ingredients in probiotics are bacteria (the largest segment) or yeast. The growth of the probiotic market is driven by an increasing awareness among consumers of their potential to improve digestive health.
Because the acidic environment in the stomach can damage the bacteria and yeast that are the active ingredients in probiotics, it is essential that probiotic dietary supplements be delivered to the upper intestinal tract before being released into the body.
One option for delivery is freeze-drying (lyophilization). This approach is most often used when probiotics are intended for as additives in foods and beverages. It typically requires the use of various cryoprotectants or microencapsulation to protect the microbes from damage during the freezing process.5
Use of gastro-resistant polymers in enteric coatings for tablets or in hard-shell capsule formulations that resist the acidic gastric conditions in the stomach but dissolve in the alkaline environment in the intestine allows for site-specific delivery of probiotics to the intestinal system.5 Encapsulation can also protect probiotic actives from osmotic pressure.4 These polymers must be noncytotoxic and nonantimicrobial.7 Synthetic polymers, such as hydroxypropyl methylcellulose phthalate and carboxymethyl high amylose starch, as well as natural polymers including alginates, xanthum and other gums and natural proteins such as casein are examples of polymers with demonstrated or potential use in this application.4,5,7
In fact, research has suggested that, for many food applications, better delivery is achieved when probiotics are encapsulated before incorporation into foods.5
Banded hard-shell capsules can be designed to achieve targeted delivery of probiotics to the intestine while also providing protection against damage during product shipment and prevention of tampering –– and loss of their controlled-release properties –– by patients.
Successful development of effective hard-shell capsule probiotic products requires an understanding of the probiotic formulation properties, potential capsule formulations and the capsule filling and banding processes in order to select the optimal polymeric formulation.
As a capsule manufacturer with experience not only producing off-the-shelf and customized capsules, but also with the manufacture of pharmaceutical products, CapsCanada brings a unique combination of capabilities to the development of unique capsule solutions for each probiotic formulation.
Our proprietary capsule formulations have been developed through internal R&D efforts to find effective solutions for our own range of sensitive APIs. We also have extensive experience developing customized polymeric formulations for a variety of customers developing their own dietary supplements and pharmaceutical products.
As a result of this knowledge, we are able to make recommendations regarding the appropriate capsule polymer for each probiotic formulation based on its properties and the delivery and other goals for the product. That includes vegetarian capsule options for probiotic dietary supplement manufacturers looking to produce vegan products.
All of our capsules are manufactured according to Good Manufacturing Practice guidelines. We conduct extensive microbial testing to ensure that all capsules that leave our facility are free of any opportunistic bacteria or other contaminants.
Eli started at CapsCanada in 2015 and plays an essential role in daily operations. In his position as Director of Business Development, he is responsible for client acquisition, client happiness, strategic partnerships and intercompany relations. Eli acts as a liaison between CapsCanada’s global factories, unifying the global market presence. Eli frequently speaks across North America on proper encapsulation methods and the future of formulation and dosage control. Eli is an engineer by trade, having graduated from Yeshiva University.