Softgel capsules have been instrumental in the success of many drugs that use lipid-based formulation technology. Such capsules are typically made using gelatin as the primary shell, but alternative non-animal and plant-based shell materials such as carrageenan, a high molecular weight polysaccharide extracted from red seaweeds, and starch can also be used. This versatility in composition enables the creation of gelatin-based and non-gelatin softgel capsules to encapsulate a wide range of active pharmaceutical ingredients (APIs).
The drug compound enclosed within a softgel can exist in a solution, suspension or semi-solid form within the capsule- fill matrix. The characteristics of the fill formulation can vary, with some fills having hydrophilic properties and containing materials such as polyethylene glycols, propylene glycol, glycerin, surfactants and water or a mixture of these. In contrast, others may have a lipophilic nature and may be composed of triglycerides or vegetable oils.
The versatility of the softgel capsule format has made them increasingly popular, as they can cater to various formulation requirements and offer the possibility of administration through multiple routes — including oral, ophthalmic, nasal, topical, optical, vaginal and anal — for targeted applications.
Advantages of Oral Softgel Capsules
Oral softgel technology has garnered substantial attention and made remarkable advancements in the past few decades. Figure 1 illustrates the key milestones in the evolution of softgel technologies, highlighting how the technology evolved from simple immediate-release softgels to more complex systems like delayed-release, multiphase, and plant-based softgels. The evolution of the technology reflects a growing trend towards diversifying softgels in drug delivery methods to meet patients’ various needs. By addressing these diverse patient needs and preferences, softgels exemplify a patient- centric approach in pharmaceutical development.
For example, the ease of swallowing softgel capsules addresses patient preferences, especially for those who struggle with swallowing conventional tablets. Furthermore, softgel capsules offer several advantages over hard gelatin capsules, including the potential to mask unpleasant tastes and odors and improve dose content uniformity, absorption, and bioavailability of poorly water-soluble drugs. Softgels can also be designed to provide a delayed or controlled release of the drug over time. With recent advancements in formulation and manufacturing techniques, innovative oral softgels can now be developed by modulating the shell and fill formulation to achieve desired release properties for diverse applications.
Softgel encapsulation technology also allows for the secure handling and delivery of potent drugs and hormonal products, minimizing the risk of exposure during the manufacturing process. The encapsulation ensures that APIs are contained within the softgel, reducing the potential for occupational hazards associated with handling potent compounds. Softgel capsules can deliver low dose API in a uniform, homogenous mix, ensuring precise dosage levels. This is particularly crucial for hormonal and highly potent drugs, where dosage accuracy is paramount to efficacy and safety. The sealed nature of softgels also protects sensitive APIs from oxidation and degradation when exposed to environmental factors, thereby extending the product’s shelf life.
Customization Options in Softgel Design
The softgel dosage form provides a versatile platform that offers numerous customization options to enhance the functionality of pharmaceutical formulations and improve patient compliance and appeal. Its dose form design can be tailored by adjusting multiple parameters, such as the route of administration, size, shape, shell, fill formulation, and release profile of the medication. Each of these options plays a crucial role in determining the efficacy of the medication and the overall patient experience. For instance, the size and shape of the capsule can influence its ease of swallowing, while the type of shell can affect the release profile and the stability of the medication. The fill formulation can be customized to improve the solubility of the active ingredient and its bioavailability.
In the subsequent section, we will explore the various customization options available for softgel design and demonstrate how they meet the diverse needs of the pharma industry, ultimately leading to better patient outcomes.
The ‘Conventional’ Softgel Capsule
Instant-release or immediate-release softgel capsules (Figure 2) are formulated for the immediate delivery of drugs upon oral administration and are designed to disintegrate rapidly in the gastrointestinal tract. This format allows for the drug to dissolve quickly and be absorbed into the patient’s bloodstream, making instant-release softgel capsules advantageous for drugs requiring an immediate onset of action.
Chewable Softgels
Chewable softgels (Figure 3) offer patients swift relief through their unique mechanism for immediate release upon chewing. They combine ease-of-use with improved organoleptic properties that make them easier to take without water. The format couples taste-masked fills encapsulated within advanced formulation chewable shells, simplifying medication administration and enabling ‘on the go’ administration.
The chewable softgel production process involves making the softgels flexible with plasticizers like glycerin and sorbitol, while using anti-adhesion agents like starch to prevent them from sticking together. These softgels are designed to overcome manufacturing and storage hurdles and can be customized with colorants and adjustable shell water content to meet specific needs. A starch-based dusting can also be applied to the exterior to reduce tackiness, making the softgels more palatable and easier to swallow. The format is versatile and acceptable for a variety of vitamins, minerals and supplements, making them suitable for a wide range of consumers, including children, adolescents and older people.
Plant-Based Capsules
Softgel capsules made from plant-based materials have been developed as a sustainable alternative to gelatin- based capsules. Plant-based materials are mainly made from carrageenan, a polysaccharide extracted from certain seaweeds. These capsules are suitable for both nutraceutical and pharmaceutical applications (Figure 4).
The main difference between manufacturing plant- and gelatin-based softgels is the temperature at which the shells are formed. Plant-based softgels require higher temperatures to form a stable gel. This makes them capable of encapsulating semi-solid and highly viscous liquids that can be heated and hot-filled into capsules. This enables the controlled release delivery of APIs through semi-solid matrices that can now be encapsulated in soft capsules. This shell is also capable of handling fill material with high pH.
Tablet-in-Capsule
Innovative tablet-in-capsule technology (Figure 5) has been developed to encapsulate pre-formed tablets in a liquid- filled softgel. This multiphase approach has made it possible to combine multiple APIs with varying release kinetics, or combine chemically incompatible ingredients in a single dose, effectively reducing pill burden and thus enhancing patient compliance with multi-drug regimens. Stable formulations of Omega-3 capsules combined with various statins and aspirin tablets have been successfully manufactured, demonstrating significant stability and efficacy even under accelerated storage conditions. This promising technology represents a breakthrough in drug delivery and offers a way to develop advanced pharmaceutical formulations.
Softgels for Oral Delivery of Macromolecules
By employing lipid-based formulations with surfactants, permeation enhancers and complexing agents, the oral delivery of macromolecules like peptides, oligosaccharides and certain proteins is possible. Macromolecules are often poorly absorbed orally, and undergo enzymatic degradation in the gastrointestinal tract (GIT). The lipid-based formulation design combined with delayed-release technology or enteric coating of the softgel capsule can address the bioavailability and stability challenges in the GIT. The efficacy of the formulation is influenced by the molecular structure of the API, including factors like molecular weight, charge and resistance to enzymatic degradation. A rigorous screening process is therefore employed to identify APIs that are suitable for this technology.
Mini Softgel Technology
At around 30% smaller than the smallest traditional softgels currently available and with a fill weight of 50- 60 mg, reduced-size softgels are designed to be easier to swallow, making them particularly suitable for patients with swallowing difficulties, such as pediatric and geriatric populations. To reduce the size of the softgel, the amount of API and lipidic excipients/solvent needs to be optimized to achieve a highly concentrated solution in the fill composition. A high drug dose may be achieved with a more concentrated fill composition without compromising the size of the softgel and its ease-of-use.
Micro Softgel Technology
Micro technology (Figure 6) produces seamless micro softgels, aptly named for their significantly smaller diameter compared to traditional softgels, typically ranging from 1-7 mm with 10 mg liquid fill. These softgels are particularly designed to facilitate easier swallowing, benefiting the elderly populations and children who may struggle with larger capsules.
Unlike the conventional softgel manufacturing process that joins together two-halves of the shell, the softgels are formed using a specialized manufacturing process that employs droplets and a streamlined flow to produce spherical-shaped capsules that are filled and sealed in a single, continuous operation without a visible seam. The key advantage of seamless softgels over mini softgels is their ability to tailor the dose to meet the needs of individual patients. The required dose size may be achieved by packing the appropriate number of capsules into a stick pack or sachet, which has the added benefit of making them easy to administer. Capsules can be coated for delayed or controlled release purposes — similar to pellets — to achieve modulated drug release. Good dose uniformity ensures an equal dose of the therapeutic agent in each micro shell, and multiple dosing levels can also be packaged from the same production lot.
Dual Controlled Release
Dual controlled release technology, an extension of the conventional softgel capabilities offered by CDMOs such as Catalent, combines a modified, delayed-release shell with a controlled release fill matrix. Modulated drug release is achieved by altering the polymer-to-gelatin ratio or modifying the fill matrix. The dual controlled release softgels offer benefits like protecting pH-sensitive actives from gastric degradation, prolonging drug release up to 24 hours, and enabling lower intestine or colonic delivery of drugs.
Topical Application Capsules
Dual-chamber capsules offer a solution for topical applications using a novel dual-chamber plant-based softgel that encapsulates two otherwise incompatible active ingredients in separate chambers (Figure 7). The design ensures stability of each component, allows the mixing of different products at the point of use, and creates a versatile, all-in-one consumer product. Additionally, the plant-based material ensures the long-term stability of formulations with high ethanol.
Enteric-Coated Softgels
A significant advancement in softgel technology is the development of an enteric/delayed-release capsule that enables the enteric or delayed release of drugs. This facilitates targeted drug delivery and a longer-lasting therapeutic effect. The enteric coating, applied to the softgel, utilizes polymers that dissolve at specific pH levels. This pH-dependent solubility ensures that the capsule contents are released in the intestinal area rather than the stomach, optimizing the absorption and effectiveness of the medication. The selection of an appropriate coating polymer is crucial as it determines the coating’s solubility profile, thereby ensuring the desired release location in the GIT based on pH levels.
pH-Sensitive Capsules
Softgels can also be developed with pH-sensitive shell formulations by including specific excipients, such as pectin, a biopolymer obtained from plant sources, that interact with gelatin to form reversible cross-links when the pH goes over pH 4, eliminating the need for a coating process. Such capsules represent offer a one-step manufacturing process and allow for the encapsulation of a broader range of APIs, including thermolabile substances.
In order to ensure the effectiveness of delayed- release softgels, they must meet enteric performance
standards outlined in the European and the United States Pharmacopeias. These standards require softgels to withstand low pH in the stomach before releasing the API in the intestines. Comprehensive testing in various biorelevant media is also conducted to rigorously assess performance under diverse physiological conditions. Compared to traditional enteric-coated softgel capsules, these capsules exhibit a shiny, clear and smooth appearance and are a cost-effective option because of the simplified one-step manufacturing process.
Cost-Benefit Analysis
Contrary to the common perception that softgels are costly, a comparative analysis of bioavailability-enhancing technologies shows that lipid-based softgels offer a cost-effective and scalable solution (Table 1). Softgels are a versatile dosage form, well-suited for a wide range of drugs across all classes of the Developability Classification System (DCS) classes I-IV, and are particularly effective for lipophilic and low-dose APIs. The standard development of softgels requires 1.5-2.0 kg of API, while an abbreviated approach may need only 0.1-0.5 kg. This makes the softgel format an advantageous option for early development through to commercial production.
Comparatively, spray-dried dispersions and hot melt extrusion are also effective for DCS IIb compounds and require similar API quantities. However, spray-dried dispersion is more complex and incurs higher costs, while hot melt extrusion offers a middle-ground in cost and complexity. Micronization is the most cost-effective option for DCS I and IIa compounds and requires slightly less API. It is also less complex to scale and maintains high commercial capacity.
Overall, while each technology has its own niche, lipid-based formulations and softgel technologies provide a balanced, economically viable option suitable for a broad spectrum of pharmaceutical applications. They offer a cost-effective, scalable and commercially viable solution that can provide long-term financial benefits compared to other bioavailability- enhancing technologies.
With a rich history, softgel technology is preferred by consumers and patients, and yet innovation is driving the application of this flexible dose form to meet many of the challenges presented by modern drugs and patient groups.
About the Author
Karunakar (Karu) Sukuru, R.Ph., Ph.D. is the Global VP of Rx Product Development at Catalent Pharma Solutions, with over 29 years of experience. He specializes in drug delivery systems, working with 300+ clients and holding two patents with 20+ pending applications. Karu earned his Ph.D. from IIT-BHU in 1995 and worked for several pharmaceutical companies for around 20 years before joining Catalent in 2016 as VP of Product Development.
Publication Details
This article appeared in Tablets and Capsules Magazine:
Vol. 22, No. 5
November/December 2024
Pages: 18-23