Anita Solanki, Milind Biyani and Jnanadeva Bhat, PhD , ACG Capsules03.01.21
Pharmaceutical dosage form encompasses various administration routes like oral, injectables, topical, rectal, and pulmonary. The demand for solid orals as a dosage form is unparalleled. When we consider any pharmaceutical dosage form, the preferred choice is oral dosage form such as tablets and capsules. It is self-administered and non-invasive, unlike injectables, where dependencies are unavoidable. In fact, the demand for empty hard capsules is currently at approximately 700 billion units, and it seems like a trend that will continue to rise. Much of this demand is owed to this delivery system's versatility.
In the cluttered pharma market, to gain a competitive advantage or enhance existing formulations, there is an increased focus on developing 505(b)(2) improvements. These upgrades include enhancing bioavailability, changing dosage forms, new therapeutic indications, changing the route of administration, substitutions in combination products, new dosing regimens, and so on. Solid oral dosages provide an ideally suited and cost-effective platform for all such efforts due to the large variety of available options, sizes, and sophisticated manufacturing processes. There is also a push to transform newer therapeutic forms like peptides and biologics into easily consumable oral forms. The nutraceutical market is no different from pharmaceuticals and follows similar trends. The nutraceutical dosage form primarily includes only oral dosage forms.
This vast demand for solid oral dosages has also led to a broad array of customization, as well as the introduction of innovative technologies and materials to suit the specific needs of consumer segments, new actives, and varied formulations. Let us look at some of these trends and recent advancements in this space.
Trends in Pharmaceuticals
Patient-centric care
Patient-centricity continues to be the most significant trend in medicine and reflects all aspects of therapy, including solid oral drug formulations. Making solid orals easy to swallow and masking unpleasant taste and odor are core tenets of making drugs more patient-friendly. Formulation of sprinkle capsules, mini or micro-tablets also can make medicines easier to swallow, especially for pediatric and geriatric populations. Fast-dissolving, fast-dispersing, or fast-melting formulations are more acceptable to these special populations. Other ways of devising patient-friendly dosages that can increase compliance include segmented easy-to-score tablets, gel-forming easy-to-swallow oral films, multiple scored tablets, and solid dosage pen devices.
Inhaled drugs: the new frontier
Among the fastest expanding markets are inhalers. Various drugs are being formulated for use in inhalers, including interferons used in anti-cancer and anti-viral therapies; one such inhaled drug is being tested for Covid-19. Capsules are convenient to use in dry powder inhalers, meaning they may even play a role in improving patient adherence to therapy over reservoir or blister-based systems that can be complicated to use. Gelatin or HPMC (Hydroxy Propyl Methyl Cellulose) capsules can be suitable for hygroscopic molecules popularly used in inhalers. Such re-formulations are another trend amid the increased focus on patient-centric care.
Compartmentalizing combined APIs
Combination products are another trend, with many gaining approval in the U.S. and the world over. Combination products are designed with multiple active ingredients and technologies to avoid several challenges associated with formulations. Combination fill offers a wide array of development options like immediate release with sustained release or delayed-release. Capsule inside a capsule provides a unique advantage to avoid drug-drug interaction and incompatibilities. Multiple pellets filling in capsules offer a great degree of uniformity by preventing the segregation of pellets. Mini- and micro-tablets can provide accuracy in weight variation and dose apart from different release options. The use of various therapies and doses can be incorporated together into a single capsule for combination therapy. Hard capsules enable filling powders, pellets, mini or micro tablets, or even another capsule in the same pill for offering fixed-dose combinations, once-daily combination, multi-drug resistance therapies, and avoiding missing doses (see Figure 1).
Figure 1. Combination fill.
Complex oral delivery systems for novel therapeutics
For the delivery of insoluble drugs, biologics, peptides, and other novel forms of therapeutics, complex dosage forms are evolving.
Poor water solubility is a considerable challenge in approximately 90% of drugs in the development and approval pipeline. Methods being employed to improve solubility are micronization or nano-milling, which reduces the size of API particles. Creating solid dispersions in a carrier polymer like HPMC is another technique that can increase solubility by avoiding the creation of insoluble API crystals. Lipid or polymer-based systems are also employed to encapsulate these insoluble drugs. Polymeric (PLGA) particles, solid-lipid particles, liposomes, and reverse cubic phase particles are popular technologies toward this goal.
Biologics and peptides are commonly found as injectables, but there is a need to evolve them into oral and nasal forms to enhance patient compliance. Absorption enhancers, conjugation with other entities, and gastro-retentive delivery systems are increasingly being used to achieve these drugs' oral administration.
Robotic pills
A robotic pill is a capsule that dissolves in the gut's acidic environment, which in turn prompts a valve with a chemical compartment of acids to release carbon dioxide. The carbon dioxide gas inflates a balloon-like structure that releases microneedles of sugar-coated with the peptide drug into the body.
Harnessing 3D printing for customized dosing
3D printing is revolutionizing every manufacturing industry. For pharmaceuticals, 3D printing brings the versatility needed to develop novel dosage forms rapidly and at a low cost. Through this technology, it is now possible to create complex drugs and house multiple actives in one single dosage form. These can also be designed to have customized release profiles and even individualized designs adapted per patient needs. One fascinating aspect is production flexibility, as the 3D printing of these drugs can often occur at a pharmacist's lab or even a patient's own home. 3D printing will soon clear the proof-of-concept stage and emerge into a widely accepted manufacturing tool with a bevy of potential benefits. However, this has already become a reality in the dietary supplement segment.
Tackling counterfeiting with micro tags and DNA tagging
WHO reports that at least 1 in 10 medical products in developing countries is falsified or sub-standard. Complex supply chains and online sales often make it difficult to track products and their distribution, creating opportunities for counterfeiters. Counterfeiting is not only a significant hazard for health and safety but can also cause loss of trust and revenue for brand owners, and estimated monetary losses approach up to $200 billion annually. The conventional methods of using packaging codes to counterfeit may no longer be enough.
A novel way of fighting these fake medicines is creating micro tags made of inert materials like silicon dioxide, invisible printing, and DNA printing with multiple security codes printed on their surface. The size of an average micro tag is 50–110 µm—the size of a dust speck. These tags can be printed either inside or outside the capsule surface without changing existing manufacturing processes. Similarly, for tablets, these taggants can be included in coating or printing.
Trends in Nutraceuticals Immunity boosters
The Covid-19 pandemic has demanded near-total attention in the past year and continues to do so. Due to the lack of a cure, boosting the body's immunity has become the reliant method for fighting this disease. Most immune-boosting formulations are plant-based, Ayurvedic products, micronutrient supplements, or probiotics that are easily formulated and delivered in solid oral formats. Not only in Covid-19, but immunity boosters are also essential for the body in general to prevent the occurrence of any diseases.
Moving toward vegetarian sources
Replacing animal-origin gelatin with materials of vegetarian sources such as cellulose, starch, carrageenan, and pullulan (polysaccharide) has gained momentum, with the trend toward vegan and vegetarian lifestyles. There is an increase in demand for HPMC (Hydroxy Propyl Methyl Cellulose) capsules mainly driven by nutraceuticals, herbals, and dietary supplements such as vitamins and minerals.
Time-dependent DR (Delayed-Release) HPMC capsules help protect probiotics, enzymes, and other acid-sensitive ingredients from degrading in the stomach. These capsules' delayed-release mechanism helps deliver ingredients that can irritate the gastric mucosa and acid reflux—for example, garlic oil, fish oil, mint, or krill oil. They can also mask unpleasant odors and diminish bad aftertaste for a more patient-friendly experience.
For formulations where moisture significantly affects the product's activity, HPMC capsules offer a suitable alternative to gelatin-based capsules, owing to HPMC capsule comparably low inherent moisture content of 3-8%.
Demand for HPMC capsules without gelling agents is also increasing. HPMC capsules are also useful for actives incompatible with gelatin capsules, are resistant to cross-linking, and offer superior stability for hygroscopic products.
Liquid-solid combinations
Commonly, liquid filling in hard capsules is more advantageous than with soft gelatin capsules and allows effortless, more efficient manufacturing of small-scale batches during development trials.
Combination filling is a distinctive concept where hard capsules encapsulate incompatible ingredients to offer multidose and multiphasic delivery in single capsules. Combinations like capsule inside a capsule, tablet in liquid-filled capsule, and pellets in liquid-filled capsule are possible in liquid encapsulation (see Figure 2).
Figure 2. Liquid-solid combination capsules.
Capsule in a capsule: Two incompatible active ingredients can be incorporated into one capsule to avoid stability or incompatibility concerns. One compound can be dissolved or dispersed in a liquid, while the other can be encapsulated in a smaller capsule to segregate two actives effectively.
Tablet in a capsule: Different nutraceutical active ingredients can be incorporated into one dosage form to obtain customized release profiles. The ingredient in solution form can deliver an immediate release, while the tablet can give delayed-release.
Pellets in a capsule: Pellets can be incorporated into a capsule to obtain sustained release profiles, with one active ingredient dissolved in a liquid for immediate absorption.
Eco, Green, Clean
These labels symbolize the brand's commitment to environmental issues. The rise of the green consumer who actively avoids non-sustainable goods has made many brands find ways to reduce their ecological footprint. Many fast-moving consumer goods (FMCG) and cosmetics companies have stated their commitment to achieving 100% sustainable manufacturing and packaging products. Ecofriendly labels have become a valuable opportunity to increase brand equity for the consumer.
ACG has received a certification of compliance from the U.S.-based Clean Label Project for its H+ capsules—the first capsules to receive such a designation. The Clean Label distinction requires materials to be free of over 400 industrial and environmental contaminants, in addition to meeting consumable safety requirements laid out by the U.S. FDA.
References
In the cluttered pharma market, to gain a competitive advantage or enhance existing formulations, there is an increased focus on developing 505(b)(2) improvements. These upgrades include enhancing bioavailability, changing dosage forms, new therapeutic indications, changing the route of administration, substitutions in combination products, new dosing regimens, and so on. Solid oral dosages provide an ideally suited and cost-effective platform for all such efforts due to the large variety of available options, sizes, and sophisticated manufacturing processes. There is also a push to transform newer therapeutic forms like peptides and biologics into easily consumable oral forms. The nutraceutical market is no different from pharmaceuticals and follows similar trends. The nutraceutical dosage form primarily includes only oral dosage forms.
This vast demand for solid oral dosages has also led to a broad array of customization, as well as the introduction of innovative technologies and materials to suit the specific needs of consumer segments, new actives, and varied formulations. Let us look at some of these trends and recent advancements in this space.
Trends in Pharmaceuticals
Patient-centric care
Patient-centricity continues to be the most significant trend in medicine and reflects all aspects of therapy, including solid oral drug formulations. Making solid orals easy to swallow and masking unpleasant taste and odor are core tenets of making drugs more patient-friendly. Formulation of sprinkle capsules, mini or micro-tablets also can make medicines easier to swallow, especially for pediatric and geriatric populations. Fast-dissolving, fast-dispersing, or fast-melting formulations are more acceptable to these special populations. Other ways of devising patient-friendly dosages that can increase compliance include segmented easy-to-score tablets, gel-forming easy-to-swallow oral films, multiple scored tablets, and solid dosage pen devices.
Inhaled drugs: the new frontier
Among the fastest expanding markets are inhalers. Various drugs are being formulated for use in inhalers, including interferons used in anti-cancer and anti-viral therapies; one such inhaled drug is being tested for Covid-19. Capsules are convenient to use in dry powder inhalers, meaning they may even play a role in improving patient adherence to therapy over reservoir or blister-based systems that can be complicated to use. Gelatin or HPMC (Hydroxy Propyl Methyl Cellulose) capsules can be suitable for hygroscopic molecules popularly used in inhalers. Such re-formulations are another trend amid the increased focus on patient-centric care.
Compartmentalizing combined APIs
Combination products are another trend, with many gaining approval in the U.S. and the world over. Combination products are designed with multiple active ingredients and technologies to avoid several challenges associated with formulations. Combination fill offers a wide array of development options like immediate release with sustained release or delayed-release. Capsule inside a capsule provides a unique advantage to avoid drug-drug interaction and incompatibilities. Multiple pellets filling in capsules offer a great degree of uniformity by preventing the segregation of pellets. Mini- and micro-tablets can provide accuracy in weight variation and dose apart from different release options. The use of various therapies and doses can be incorporated together into a single capsule for combination therapy. Hard capsules enable filling powders, pellets, mini or micro tablets, or even another capsule in the same pill for offering fixed-dose combinations, once-daily combination, multi-drug resistance therapies, and avoiding missing doses (see Figure 1).
Figure 1. Combination fill.
Complex oral delivery systems for novel therapeutics
For the delivery of insoluble drugs, biologics, peptides, and other novel forms of therapeutics, complex dosage forms are evolving.
Poor water solubility is a considerable challenge in approximately 90% of drugs in the development and approval pipeline. Methods being employed to improve solubility are micronization or nano-milling, which reduces the size of API particles. Creating solid dispersions in a carrier polymer like HPMC is another technique that can increase solubility by avoiding the creation of insoluble API crystals. Lipid or polymer-based systems are also employed to encapsulate these insoluble drugs. Polymeric (PLGA) particles, solid-lipid particles, liposomes, and reverse cubic phase particles are popular technologies toward this goal.
Biologics and peptides are commonly found as injectables, but there is a need to evolve them into oral and nasal forms to enhance patient compliance. Absorption enhancers, conjugation with other entities, and gastro-retentive delivery systems are increasingly being used to achieve these drugs' oral administration.
Robotic pills
A robotic pill is a capsule that dissolves in the gut's acidic environment, which in turn prompts a valve with a chemical compartment of acids to release carbon dioxide. The carbon dioxide gas inflates a balloon-like structure that releases microneedles of sugar-coated with the peptide drug into the body.
Harnessing 3D printing for customized dosing
3D printing is revolutionizing every manufacturing industry. For pharmaceuticals, 3D printing brings the versatility needed to develop novel dosage forms rapidly and at a low cost. Through this technology, it is now possible to create complex drugs and house multiple actives in one single dosage form. These can also be designed to have customized release profiles and even individualized designs adapted per patient needs. One fascinating aspect is production flexibility, as the 3D printing of these drugs can often occur at a pharmacist's lab or even a patient's own home. 3D printing will soon clear the proof-of-concept stage and emerge into a widely accepted manufacturing tool with a bevy of potential benefits. However, this has already become a reality in the dietary supplement segment.
Tackling counterfeiting with micro tags and DNA tagging
WHO reports that at least 1 in 10 medical products in developing countries is falsified or sub-standard. Complex supply chains and online sales often make it difficult to track products and their distribution, creating opportunities for counterfeiters. Counterfeiting is not only a significant hazard for health and safety but can also cause loss of trust and revenue for brand owners, and estimated monetary losses approach up to $200 billion annually. The conventional methods of using packaging codes to counterfeit may no longer be enough.
A novel way of fighting these fake medicines is creating micro tags made of inert materials like silicon dioxide, invisible printing, and DNA printing with multiple security codes printed on their surface. The size of an average micro tag is 50–110 µm—the size of a dust speck. These tags can be printed either inside or outside the capsule surface without changing existing manufacturing processes. Similarly, for tablets, these taggants can be included in coating or printing.
Trends in Nutraceuticals Immunity boosters
The Covid-19 pandemic has demanded near-total attention in the past year and continues to do so. Due to the lack of a cure, boosting the body's immunity has become the reliant method for fighting this disease. Most immune-boosting formulations are plant-based, Ayurvedic products, micronutrient supplements, or probiotics that are easily formulated and delivered in solid oral formats. Not only in Covid-19, but immunity boosters are also essential for the body in general to prevent the occurrence of any diseases.
Moving toward vegetarian sources
Replacing animal-origin gelatin with materials of vegetarian sources such as cellulose, starch, carrageenan, and pullulan (polysaccharide) has gained momentum, with the trend toward vegan and vegetarian lifestyles. There is an increase in demand for HPMC (Hydroxy Propyl Methyl Cellulose) capsules mainly driven by nutraceuticals, herbals, and dietary supplements such as vitamins and minerals.
Time-dependent DR (Delayed-Release) HPMC capsules help protect probiotics, enzymes, and other acid-sensitive ingredients from degrading in the stomach. These capsules' delayed-release mechanism helps deliver ingredients that can irritate the gastric mucosa and acid reflux—for example, garlic oil, fish oil, mint, or krill oil. They can also mask unpleasant odors and diminish bad aftertaste for a more patient-friendly experience.
For formulations where moisture significantly affects the product's activity, HPMC capsules offer a suitable alternative to gelatin-based capsules, owing to HPMC capsule comparably low inherent moisture content of 3-8%.
Demand for HPMC capsules without gelling agents is also increasing. HPMC capsules are also useful for actives incompatible with gelatin capsules, are resistant to cross-linking, and offer superior stability for hygroscopic products.
Liquid-solid combinations
Commonly, liquid filling in hard capsules is more advantageous than with soft gelatin capsules and allows effortless, more efficient manufacturing of small-scale batches during development trials.
Combination filling is a distinctive concept where hard capsules encapsulate incompatible ingredients to offer multidose and multiphasic delivery in single capsules. Combinations like capsule inside a capsule, tablet in liquid-filled capsule, and pellets in liquid-filled capsule are possible in liquid encapsulation (see Figure 2).
Figure 2. Liquid-solid combination capsules.
Capsule in a capsule: Two incompatible active ingredients can be incorporated into one capsule to avoid stability or incompatibility concerns. One compound can be dissolved or dispersed in a liquid, while the other can be encapsulated in a smaller capsule to segregate two actives effectively.
Tablet in a capsule: Different nutraceutical active ingredients can be incorporated into one dosage form to obtain customized release profiles. The ingredient in solution form can deliver an immediate release, while the tablet can give delayed-release.
Pellets in a capsule: Pellets can be incorporated into a capsule to obtain sustained release profiles, with one active ingredient dissolved in a liquid for immediate absorption.
Eco, Green, Clean
These labels symbolize the brand's commitment to environmental issues. The rise of the green consumer who actively avoids non-sustainable goods has made many brands find ways to reduce their ecological footprint. Many fast-moving consumer goods (FMCG) and cosmetics companies have stated their commitment to achieving 100% sustainable manufacturing and packaging products. Ecofriendly labels have become a valuable opportunity to increase brand equity for the consumer.
ACG has received a certification of compliance from the U.S.-based Clean Label Project for its H+ capsules—the first capsules to receive such a designation. The Clean Label distinction requires materials to be free of over 400 industrial and environmental contaminants, in addition to meeting consumable safety requirements laid out by the U.S. FDA.
References
- Radhakrishnan A, Kuppusamy G, Ponnusankar S, Shanmukhan NK. Pharmacogenomic phase transition from personalized medicine to patient-centric customized delivery. The pharmacogenomics journal. 2020;20(1):1-8.
- J.Sanjiv Mervyn et al. Int.J. PharmTech Res.2014-2015;7(3):432-437
- Samiei N. Recent trends on applications of 3D printing technology on the design and manufacture of pharmaceutical oral formulation: a mini review. Beni-Suef University Journal of Basic and Applied Sciences. 2020;9:1-2.
- Liang, W et al. Pulmonary Delivery of Biological Drugs. Pharmaceutics 2020:12(1025); doi:10.3390/pharmaceutics12111025
- Hassani, L, Lewis, A, Richard J. Oral Peptide Delivery: Technology Landscape & Current Status. Fredrick Furness Publishing 2015.
- https://pharma-trends.com/2020/03/30/the-reign-of-oral-solid-dosage-forms-in-the-era-of-biopharmaceuticals/
- https://www.statnews.com/2019/05/07/stopping-murder-counterfeit-medicine/
- https://www.pharmtech.com/view/authenticating-drugs-edible-microtags
- https://cen.acs.org/articles/93/i8/Fighting-Fake-Drugs.html
