Recent Advancement in Capsule: Emerging Novel Technologies and Alternative Shell Materials for Wide Range of Therapeutic Needs

Pratik Singh^{1,2 *, 2}Denish Gandhi, ²Ajay Khopade, ¹Mukesh Sharma, ¹Kushagra Nagori, ¹Kalyani Sakure, ¹Ajazuddin

¹Rungta College of pharmaceutical science and research Bhilai, Chhattisgarh

²Sun Pharmaceutical Industries Limited (R&D), Vadodara Gujarat

ABSTRACT

Advancements in capsule technology are revolutionizing drug delivery by enhancing therapeutic efficacy, patient compliance, and precision medicine. This review examines innovative capsule systems, including the Novel Floating Ring Capsule for extended gastric retention, Telemetric Capsules for real-time health monitoring, and CODAS for circadian rhythm-based drug release. Technologies such as Innercap's capsule-in-capsule design, SODAS® and DUOCAP® for controlled and sustained release, and hydrogel-based and hydrophilic sandwich capsules for targeted delivery are discussed. These cutting-edge capsules offer improved stability, targeted release, and multi-phase delivery, paving the way for personalized and more effective therapeutic options.

Keywords: Capsule technology, Drug delivery, Floating ring capsule, Telemetric capsule, CODAS, Innercap, SODAS®, DUOCAP®, Hydrogel capsules, Targeted release.

 

INTRODUCTION

Capsules represent exquisite pharmaceutical preparations that encapsulate drugs or excipients within a soluble shell, encompassing both soft and hard variants. These shells, crafted from gelatin or other polymers, possess the remarkable ability to offer a tasteless, odourless, and effortlessly ingestible dosage form, obviating the need for supplementary coating. Classifications of capsules extend to the soft variety, characterized by a pliable gelatin film, as well as the hard variation, comprising distinct cap and body components (1). Within these capsules lie a myriad of possibilities, accommodating dry powders, semisolids, liquids, beads, mini-tablets, and beyond, all intended for oral administration. Furthermore, the realm of capsules extends to specialized applications such as inhaler loading, diagnostic kit reagents, and the soft-shell variety, employed for rectal or vaginal insertion. In recent years, the landscape of capsules has witnessed remarkable progress, introducing non-gelatin alternatives such as HPMC, PVA, and starch capsules. This comprehensive review encompasses the vast realm of capsule types, formulation intricacies, filling techniques, locking mechanisms, sealing methods, stringent quality control measures, and the art of packaging (3). Advancements in capsule technology have brought about a revolution in the field of drug delivery, effectively addressing specific challenges in order to enhance therapeutic outcomes. These advancements encompass the creation of the Novel Floating Ring Capsule, an ingenious invention that possesses buoyancy, enabling it to remain in the stomach for extended periods of time and to administer medication in a regulated manner. Moreover, the design of Capsules with Asymmetric Membranes allows for customized drug release, considering the membrane's permeability. Additionally, the introduction of Telemetric Capsules has enabled real-time monitoring for personalized treatment, while CODAS capsules have been created to optimize drug delivery by controlling the onset and delaying the action. Innercap technology allows for the sequential release of multiple drugs, while Port Capsules offer the flexibility of on-demand release or the incorporation of additional components. Chew Capsules provide an alternative mode of administration that is particularly beneficial for specific populations. Fast Disintegrating Capsules have been developed to improve compliance, and Duocaps have been designed to streamline dosing. Furthermore, the integration of Capsule Drug Devices with targeted therapy systems highlights the immense potential of these advancements in advancing drug delivery.

1. NOVEL TECHNOLOGIES FOR CAPSULE SYSTEM

"Novel Technologies for Capsule Systems" signify a breakthrough in drug delivery, offering improved efficacy, patient compliance, and regulatory adherence. These innovations leverage advanced materials and manufacturing processes to address challenges like stability, compatibility, and controlled release, ultimately revolutionizing pharmaceutical formulation for enhanced therapeutic outcomes.

1.1 NOVEL FLOATING RING CAPSULE

The primary aim of this advancement is to enhance drug release dynamics and stability. Formulating buoyant annular capsules targets stomach-specific delivery, extending medication presence for improved therapeutic efficacy. Figure 1 Novel floating ring capsule This innovative approach involves creating capsules that float gracefully in the gastric environment, enabling controlled release and absorption. Comprehensive studies are evaluating their effectiveness in delivering various medications, including levofloxacin (4,5). The Floating Ring Capsule is an innovative medication format designed for precise drug delivery to the stomach, integrating soluble and insoluble elements effective in the gastric environment. Developed using various polymers, the combination of Hydroxypropyl Methylcellulose (HPMC) and Sodium Carboxymethylcellulose (Sodium CMC) demonstrated enhanced floating properties due to entrapped air and lower densities. In vitro studies showed faster drug release with low Carbopol concentration and extended release times with higher HPMC concentrations. Fourier Transform Infrared (FT-IR) spectroscopy confirmed negligible chemical interactions between the drug and polymers. Overall, the capsule shows promise for targeted stomach-specific drug delivery, with the HPMC and Sodium CMC formulation offering superior floating properties and controlled release(6). Drug release rates in capsules can be adjusted by polymer concentrations, offering flexibility. However, complex formulation may raise production costs. Balancing swift and prolonged release poses challenges, and stomach-specific design limits applicability. Despite advanced techniques like FT-IR spectroscopy, unexpected drug-polymer interactions persist. The Novel Floating Ring Capsule holds promise for targeted drug delivery, requiring thorough evaluation(7).

Despite the significant progress that has been achieved in the field of drug delivery, when considering factors such as expenses and patient adherence, the oral route of administration continues to be the most favoured method for administering therapeutic agents. The composition of the gastrointestinal tract experiences notable variations as it progresses from the stomach to the large intestine(8). This particular variation holds the potential to act as a highly promising platform for the targeted transportation of Therapeutic drugs to specific sites within the body. The existence of a specific form of medication in the upper region of the gastrointestinal system holds significant importance, particularly for drugs that undergo degradation or metabolism within the intestine, as well as for drugs that possess localized activity within the stomach.(9,10). Likewise Singh and Kim (11) suggested that floating drug delivery is of particular interest for drugs which have local action in the stomach are primarily absorbed in the stomach have poor solubility at an alkaline pH, have a narrow window of absorption, and are unstable in the intestinal or colonic environment. Gastrointestinal retention depends on many factors such as density and size of the dosage form, the fasting or fed condition of the patient, and the nature of the meal as well as posture (12,13).

Figure 1 Novel floating ring capsule

Several gastroretentive formulation approaches such as high density. (14) swelling (14), bioadhesive(15), magnetic(16), and floating(17) systems have been developed for enhanced gastroretention. Local intervention within the gastric region is frequently employed in the treatment of gastric infection, as well as to enhance the bioavailability of pharmaceutical agents, thus exemplifying the solubility characteristics that are reliant on pH levels. Ofloxacin, a well-known example, exhibits pH-dependent solubility; it demonstrates heightened solubility in an acidic environment, while displaying only slight solubility under neutral or alkaline pH conditions (18).  The novel design possesses the potential to extend the release of medication, thereby enhancing therapeutic efficacy and prolonging the duration of residence through its floating behaviour. The optimization of this floating phenomenon in porous filled capsules can be accomplished by impeding the ingress of water into the formulation or by enhancing the swelling characteristics of the dosage form. Furthermore, it was observed that these formulations exhibited no instances of chemical interaction. The findings from the in vitro experimental investigation demonstrated the successful application of this innovative concept for targeted drug delivery in the gastrointestinal tract. Despite the introduction of this pioneering concept, there will persist challenges due to the possibility of further refinement. The study introduces an innovative capsule-type dosage form designed to float in the stomach for targeted drug delivery. It aims to develop and assess floating ring capsules containing both soluble and insoluble components for effective medication delivery. Various polymer compositions were explored, with HPMC and sodium CMC showing exceptional buoyancy. In vitro release studies revealed the impact of polymer concentration on drug release, with formulations containing higher HPMC concentrations exhibiting more favourable release profiles. FT-IR spectroscopy confirmed no chemical interactions, indicating the suitability of the developed capsules for targeted drug delivery to the stomach(19).

 

1.1 CLINICAL IMPACT:The development of novel floating ring capsules presents several potential clinical impacts

1. Enhanced Gastric Retention: Floating ring capsules utilize buoyancy to remain in the stomach for an extended period, prolonging drug release and improving drug absorption

2. Tailored Drug Delivery: By incorporating different polymers and coatings, these capsules can be customized to release drugs at specific rates and locations within the gastrointestinal tract, optimizing therapeutic outcomes(19).

 

Figure 2 Telemetric capsule

Telemetric capsules Figure 2 Telemetric capsule have surfaced as a pioneering technological advancement in the realm of gastrointestinal health monitoring. These capsules, which can be ingested, are outfitted with sensors and offer the noteworthy capability of providing immediate and up-to-date perspectives on both the upper and lower regions of the gastrointestinal tract. These ingestible capsules, enhanced with sensors, furnish invaluable information for the purpose of diagnosing a variety of conditions, such as gastrointestinal haemorrhage, melena, and large bowel bleeding, which may be caused by angioectasias (20,21) The Telemetric capsule is furnished with a location detector, a transmitter, a lithium battery, and an interchangeable drug reservoir tip. Consequently, it holds the distinction of being the largest among the devices, with a length of 39 mm and a weight of 3.5 g. When the tracking cogwheel is exposed, the capsule widens to a width of 20 mm, which is presumably the cause for the reported instances of prolonged stomach retention. Unfortunately, the activation mechanism consumes a substantial amount of current, thereby limiting the device to a mere 8 hours of operation. Nevertheless, advancements in battery technology have the potential to prolong this duration. Activation is initiated through the use of an external magnet, which engages a magnetic switch within the capsule to establish a connection between the battery and a microfurnace. Consequently, a plastic strip is disrupted, subsequently releasing a previously compressed spring that clears the aspiration orifice. The drug reservoir is upheld within a vacuum, resulting in the prompt expulsion of the capsule contents, which are in the form of a solution. Likewise, the limited release opening poses difficulties in delivering particulates using this specific apparatus (22).  Telemetric capsules, like the HemoPill® acute, are pill-shaped devices administered orally for real-time blood detection in the upper gastrointestinal tract (23). Table 1 Various Formulation Component of Telemetric Capsule These capsules utilize advanced sensor technology, allowing clinicians to remotely monitor patients' conditions. A feasibility study on the novel telemetric sensor capsule demonstrated its safety and feasibility in a clinical setting, paving the way for future investigations(24,25).

1.2.1 FORMULATION COMPONENT

 Table 1 Various Formulation Component of Telemetric Capsule

Component	Function	Examples	Reference
Capsule shell	Encloses and protects components	HPMC, gelatin	(26)
Sensor	Detects and measures specific parameters	pH sensor,temperature sensor,blood sensor	(27)(20)
Transmitter	Sends sensor data wirelessly	Radio transmitter	(27)
Battery	Powers the capsule's components	Lithium battery	(28)
Excipients	Aid in capsule formation and component function	Buffers, lubricants, disintegrants	(20)

 

1.2.2 CLINICAL IMPACT

The utilization of telemetric capsules has brought about a revolutionary transformation in the process of triaging endoscopy urgency, thereby furnishing indispensable information for expeditious and precise diagnoses. These capsules present an uninterrupted 24-hour evaluation of the fundamental body temperature, thereby demonstrating their adaptability in overseeing a wide range of physiological parameters.(29). A telemetric capsule represents an innovative apparatus intended for the investigation and surveillance of the gastrointestinal tract. By employing cutting-edge sensor technology, Table 2 Overview of Telemetric Capsule these capsules offer instantaneous observations into diverse facets of gastrointestinal well-being.

Table 2 Overview of Telemetric Capsule

Capsule Formulation	Target Area	Advantages	Examples	References
Hydrogen-sensing capsule	Gastrointestinal tract	Non-invasive gas measurement aids in diagnosing malabsorption syndromes like lactose intolerance and SIBO, sensitive to low hydrogen, pain-free.	IBS-Smart™ (BreathTracker), Gastrointestinal Hydrogen Monitor (GM Instruments)	(30)
pH-sensing capsule	Esophagus and stomach	Continuous esophageal pH monitoring aids in diagnosing acid reflux and Barrett's esophagus, offering comfort and convenience for patients.	Bravo pH Monitoring System (Medtronic), Digitrapper pH-Z Monitoring System (Medtronic), Ohmega pH-Z Monitoring System (Medtronic)	(31)
Pressure-sensing capsule	Gastrointestinal tract	assesses gut motility, detects obstructions, differentiates bowel movements, providing objective gut function measures, surpassing subjective patient diaries.	SmartPill (Given Imaging), Motilis (Crospon)	(32)
Temperature-sensing capsule	Gastrointestinal tract	Non-invasive method detects digestive system inflammation or infection via localized temperature changes, aiding in diagnosing Crohn's disease or ulcerative colitis safely.	CorTemp (HQInc), e-Celsius (BodyCap)	(33)
Imaging capsule	Small intestine	Non-invasive imaging for the small intestine aids in diagnosing tumors, Crohn's disease, and other conditions, avoiding colonoscopy risks.	PillCam SB3 (Given Imaging), CapsoCam Plus (CapsoVision), MiroCam (IntroMedic)	(32)
Drug-delivery capsule	Gastrointestinal tract	Directs medication to stomach/intestines, enhancing absorption and efficacy, especially for local treatments, while minimizing systemic side effects.	PillCam Colon 2 (Given Imaging) for targeted imaging and drug delivery, Abilify MyCite (Otsuka Pharmaceutical) for tracking medication adherence	(14)

 

1.3 CODAS TECHNOLOGY

CODAS technology, an acronym for Chronotherapeutic Oral Drug Absorption System, (Fig.4) represents a ground-breaking approach to drug delivery. Specifically, CODAS-Verapamil, a novel system designed for bedtime dosing, ensures controlled onset and extended-release of the drug. Figure 3 CODAS technology This optimized release aligns with circadian rhythms, enhancing therapeutic efficacy while minimizing side effects (34).  In specific instances, an immediate release of a drug may not be ideal, and there may be a need to introduce a delay in the drug's action for various reasons.

Figure 3 CODAS technology

Chronotherapy is a prime example wherein the intentional timing of drug release is scheduled to occur after a prolonged interval following administration. In order to address this requirement, Elan Drug Technology has developed CODAS® technology, which is a sophisticated system designed to achieve and regulate this extended timeframe. The CODAS® technology boasts numerous advantages, including its alignment with circadian patterns, its capability of ensuring a controlled onset, its utilization of an extended release delivery system, and its ability to maintain a release rate that remains essentially unaffected by factors such as pH, posture, and food intake. Additionally, it offers the convenience of "sprinkle" dosing by allowing the opening of the capsule and dispersing the contents over food, thereby reducing the effective daily dose and overall drug exposure. Furthermore, CODAS® facilitates the targeting of the gastrointestinal tract for localized effects and minimizes systemic exposure in order to achieve a specific therapeutic profile. Verelan® PM, which utilizes the proprietary CODAS^TM technology, serves as an exemplification of this approach with a design specifically tailored for bedtime dosing, featuring a deliberate 4- to 5-hour delay in drug delivery. This controlled-onset system ensures the attainment of a peak plasma concentration (Cmax) of verapamil during the morning hours. The concept of CODAS focuses on achieving a delay in drug action, providing a strategic advantage in drug delivery systems (35).  It has been utilized in cardiovascular pharmacology, with studies emphasizing once-daily bedtime dosing to optimize blood pressure control. (36)Trials assessing racial/ethnic differences underscore its safety and efficacy across diverse populations (34). Developed by Elan and FDA-approved in 1998, CODAS technology extends its impact beyond a single drug formulation. It is a key player in the broader landscape of Chronopharmaceutic Drug Delivery Systems (ChDDs), contributing to the development of extended-release tablets (34,37). The human body is a symphony of rhythms, a dance of hormones and physiological processes that ebb and flow with the rising and setting sun. Our susceptibility to disease, however, often doesn't follow a uniform beat. Conditions like hypertension, asthma, and migraine often peak during specific times of day, leaving conventional medication schedules lagging behind. This is where CODAS technology, the Chronotherapeutic Oral Drug Absorption System, steps in, offering a revolutionary approach to drug delivery.

 

1.3.1 CLNICAL IMPACT

 CODAS (Chronotherapeutic Oral Drug Absorption System) is an advanced drug delivery method that enhances treatment effectiveness by timing drug release to match the body's circadian rhythms. This approach is particularly beneficial for conditions like hypertension, asthma, and arthritis, where symptoms worsen at specific times. CODAS use a unique system that delays drug release by 4 to 5 hours, allowing for medication to be taken at night with effects peaking in the early morning when symptoms are more severe. This method improves patient compliance, treatment efficacy, and safety by avoiding high drug concentrations at inappropriate times. CODAS has been effectively applied in antihypertensive drugs like Verelan® PM, showing better blood pressure control and reduced cardiovascular risks. The technology's potential extends to various therapeutic areas, with growing applications as the understanding of circadian biology advances.

 

1.4 INNERCAP TECHNOLOGY

Innercap technology Figure 4 Innercap technology provides a sophisticated and patent-pending delivery system that is characterized by its multi-phased and multi-compartmentalized nature. The utilization of this system holds the potential to augment the value and benefits of pharmaceutical and biopharmaceutical products. By employing two-piece hard-shell capsules, the industry can discover remedies to the issues that afflict pharmaceutical companies, patients, and healthcare providers. Innercap possesses the capacity to fill a company's portfolio with a diverse range of combination drug therapies. The licensing of the capsular based drug delivery system, which is multi-phased and multi-compartmentalized, will further amplify the excellence of pharmaceutical and biopharmaceutical products. This system demonstrates itself to be an extraordinarily effective approach to delivering multiple active chemical compounds in various physical phases, all while sustaining controlled release profiles. This ground-breaking delivery system offers advantageous resolutions to the extensively debated requirement of the pharmaceutical and biopharmaceutical industries to repackage and reformulate existing patented blockbuster drugs with expiring patents in the imminent five years. Forward-thinking enterprises will embrace this exhilarating solution to address concerns such as life cycle management, compliance, bioavailability, stability, challenging combination drug therapies, expansion of their product portfolio, reduction of generic competition, utilization of more promising compounds, and amplification of the difficulty of counterfeiting high-value products.( Fig.5 ) provides a depiction of the features of Innercap technology(38). INNERCAP Technologies, Inc., a pharmaceutical delivery enterprise, presents an innovative patented multi-phase, multi-compartment delivery system that is based on capsules. This system can be employed to amplify the worth and advantages of pharmaceutical, biopharmaceutical, medical food, nutraceutical and nutritional, dietary supplement, and herbal products. By utilizing two-piece capsules, this technology provides solutions to problems that affect pharmaceutical companies, patients, and healthcare providers. INNERCAP has the capability to enrich a company's product portfolio with a plethora of combination therapies. The capsule-based combination product delivery system, which encompasses multiple phases and compartments, will be authorized to enhance various pharmaceutical, biopharmaceutical, and nutraceutical offerings.

Figure 4 Innercap technology

This method proves to be highly effective in delivering numerous active chemical compounds in distinct physical phases while maintaining controlled release profiles. The delivery system brings forth an exciting resolution that forward-thinking companies can employ to address challenges such as life-cycle management, compliance, bioavailability, stability, complex combination drug therapies, and other combination products. INNERCAP collaborates with prominent enterprises in the pursuit of developing and manufacturing unique combination products utilizing INNERCAP's exclusive delivery system for advanced offerings that cater to unmet demands in the market. Secure the products that can enrich your company's product portfolio and augment shareholder value in the future. Get in touch with INNERCAP Technologies, Inc.(39) Innercap technology presents numerous opportunities for both the pharmaceutical and biopharmaceutical industries. It addresses a range of challenges that cannot be met by other innovative drug delivery systems. One of its key advantages is its ability to enhance patient compliance through its visually appealing and elegant pharmaceutical product. Additionally, Innercap technology offers the advantage of reduced generic competition and the opportunity to implement new sales and marketing strategies. The capsular-based system of Innercap dosage forms makes them easier for patients to swallow, making them a preferred choice. Furthermore, Innercap technology enriches a company's product pipeline with a wide array of combination drug therapies. By utilizing Innercap technology, it becomes possible to achieve multiple release profiles for incompatible drugs simultaneously. This technology also contributes to increased bioavailability and stability of drugs. Consequently, Innercap technology, also referred to as a technology for multi-phase and multi-compartment delivery systems, provides various industrial solutions to the challenges faced by pharmaceutical companies, patients, and healthcare providers. It represents a new era in the field of novel drug delivery systems (40).

1.4.1 CLINICAL IMPACT

INNERCAP technology offers a suite of advantages for pharmaceuticals, leveraging its multi-phase, multi-compartment capsules to enhance branding and marketing strategies. The visually appealing and elegant design of these capsules, coupled with unique color banding and combinations, facilitates product differentiation and reduces the risk of counterfeiting. The technology significantly improves patient compliance by simplifying dosing regimens, providing a user-friendly experience, and contributing to better treatment outcomes. For pharmaceutical companies, INNERCAP extends product life cycles through distinctive features, making it challenging for generics to replicate and reducing competition. This strategic advantage not only safeguards intellectual property but also minimizes the threat of generic competition and counterfeiting, ultimately benefiting both patients and pharmaceutical companies alike (38).

 

1.5 SODAS®

SODAS® (Spheroidal Oral Drug Absorption System) Figure 5 SODAS®Technology is an innovative multiparticulate drug delivery system developed by Elan Drug Technologies. This technology is designed to optimize drug release, enhancing bioavailability and therapeutic efficacy. The system involves the production of controlled-release capsules using spheroidal beads with a multi-layered structure. These beads are created through drug layering techniques, often utilizing novel calcium phosphate-based starting pellets. SODAS® has garnered attention for its versatility, making it suitable for various drug formulations, including controlled release and delayed-release capsules.

Its impact extends to sprinkle formulations, offering a precise and patient-centric dosing approach. The technology's success lies in its ability to achieve modified-release drug delivery formulations with engineering precision. The controlled release achieved by SODAS® is particularly beneficial for drugs with specific absorption requirements. This technology has been integrated into commercial products, contributing to advancements in drug absorption and delivery (41,42).  It employs a spherical bead with a multi-layered structure for controlled release of drugs. The system employs innovative technology for controlled drug release, featuring a unique multi-layered spherical bead structure. This controlled release mechanism ensures gradual drug absorption over time. Known as the System of Drug Absorption (SODAS), it functions as a multiparticulate drug delivery system, providing flexibility in formulation and precise control over therapeutic effects. SODAS have applications in sprinkle formulations and commercial products, contributing significantly to patient-centric dosing strategies and pharmaceutical advancements. Its attributes, including controlled release and multiparticulate nature, make SODAS a valuable tool for optimizing drug delivery and improving overall patient outcomes (41,43).

 

1.6 DUOCAP^® CAPSULE

The Duo capsule, referred to as a capsule in capsule formulation, comprises two capsules: a larger one housing a smaller capsule inside. These capsules can take different forms, including liquids, solids, powders, tablets, pellets, etc (44). The field of innovative drug delivery systems aims to overcome limitations of conventional dosage forms by introducing capsule systems. These capsules, including the advanced Capsule in capsule technology (Duo caps), enable controlled drug delivery, sustained release, and targeted release profiles. They offer advantages over traditional forms and have led to various formulations like tablets within capsules, pellets within capsules, and liquid-filled capsules. The Duo caps technology involves inserting one capsule into another, allowing for modified drug release patterns, combination of incompatible drugs, incorporation of drugs in different phases, and targeted delivery to specific gastrointestinal regions. Capsules, typically solid and containing gelatin shells, have evolved significantly, driven by the demand for innovation (44,45). Duo capsules represent an innovative drug delivery technology consisting of a capsule within another capsule, offering both immediate and sustained release patterns. This dual-action feature reduces the need for frequent dosing, enhancing medication efficacy. The technology precisely directs drugs to their intended site, resulting in lower dosage requirements and consistent delivery. Particularly beneficial for drugs with specific characteristics, DUO CAP utilizes a two-phase formulation for enhanced patient adherence and reduced dosing frequency. It has demonstrated utility in treating conditions like gastrointestinal cancers, Crohn's disease, and acid reflux, facilitating efficient studies in preclinical and clinical settings (46,47).

1.6.1 CLINICAL IMPACT DUO CAPSULES

1.Offering A Mix of Release Profiles or Multiple Profiles for Releasing: Solubilized prebiotics are encapsulated within the external capsule, whereas probiotics are encased within the internal capsule. The prebiotic component is expeditiously liberated, subsequently succeeded by the gradual liberation of probiotics, thereby amalgamating both constituents within a solitary pharmaceutical formulation aiming to amplify patient compliance (44).

2. In Diabetes Therapy: Capsule-in-capsule tech allows creating a diabetes medication with a combined release effect. A slow-release Glimepiride tablet is put in a bigger capsule. This bigger capsule is then filled with a liquid dose of Glimepiride. This is useful for conditions needing both immediate and long-lasting effects, like diabetes. This unique system offers many possibilities for designing oral medications (44).

3. Safeguarding Nutraceutical Formulation: During digestion, nutrients like flavonoids and vitamins degrade, affecting efficacy. Proteins and peptides are vulnerable to enzyme degradation. Coating tablets and encapsulating bioactives help counter acid sensitivity. Capsules, especially those made from cellulose or acrylic derivatives, are favored for efficient delivery. Advanced technologies like DUOCAP® offer targeted release at lower costs. Magnetic localization in tumors shows promise for reducing side effects during dosing (44,48).

4.Treatment of H. Pylori Infection: H. pylori bacteria cause damage to the stomach lining, leading to ulcers. Various therapies, including the FDA-approved PPI-based triple therapy, exist for H. pylori treatment. However, the current therapies may have drawbacks, such as inconvenience and toxicity due to high-dose dosage forms. To address these issues, an effort was made to develop a combination dosage form (Amoxicillin + Clarithromycin + Lansoprazole) using a capsule-in-capsule approach for improved patient compliance and convenience (45)(44).

5.Stability Enhancement: DUOCAP technology may contribute to the stability of certain formulations, preserving the integrity of sensitive ingredients during storage and transportation (49).

6. Combined treatment: Rifampicin and isoniazid, primary drugs for tuberculosis treatment, interact in the stomach's acidic environment, forming an inactive compound and contributing to drug-resistant tuberculosis and treatment failure. A capsule-in-capsule formulation is employed to address this issue, with rifampicin in the outer capsule for stomach release and isoniazid in the inner capsule for targeted release in the small intestine, aiming to prevent the interaction and enhance treatment effectiveness (50)(44).

 

1.7 HYDROGEL-BASED CAPSULES

Hydrogel-based capsules represent a cutting-edge technology in drug delivery systems, showcasing remarkable versatility and innovation. hydrogel-based capsules signify a remarkable stride in drug delivery technology, offering a tailored and responsive approach to enhance therapeutic outcomes. These capsules are designed with intelligent hydrogels that respond to specific environmental cues, such as pH or temperature changes, enabling targeted and controlled drug release at desired sites within the body (51). One key advantage lies in their sustained-release capability, offering a prolonged therapeutic effect and reducing the frequency of dosing (52). Placing hydrogels within the body bypasses epithelial barriers, concentrating drug release precisely at the target site (52). These capsules are made from biocompatible and nontoxic materials, ensuring their safety as drug carriers (53). Innovations such as 4D printing have contributed to the development of smart hydrogel capsules. These capsules can autonomously control drug release behaviours based on ambient conditions, as demonstrated in in vitro drug release tests (54). Hydrogel-based capsules represent a sophisticated frontier in pharmaceutical drug delivery, leveraging intelligent hydrogels to achieve precise and controlled release mechanisms. These capsules respond dynamically to environmental stimuli, such as changes in pH or temperature, facilitating targeted drug delivery with unprecedented precision and efficacy within the body (51). The pharmaceutical application of hydrogel-based capsules is profound. Their sustained-release capability ensures a prolonged therapeutic effect, offering a significant advantage in chronic disease management and improving patient compliance (55). By bypassing epithelial barriers, these capsules concentrate drug release directly at the target site, optimizing drug bioavailability and minimizing systemic side effects (56). The biocompatibility and non-toxic nature of the materials used in hydrogel-based capsules underscore their safety profile as drug carriers, addressing critical considerations in pharmaceutical formulations (53).

1.8 HYDROPHILIC SANDWICH CAPSULE

A Hydrophilic Sandwich Capsule, also known as the HS capsule, Figure 6 Hydrophilic Sandwich Capsule is a cutting-edge technology in the field of drug delivery systems.

 

 

 

 

 

 

It involves a unique design where a drug formulation is encapsulated within an inner capsule, surrounded by a hydrophilic material. This innovative approach allows for controlled and delayed drug release, offering a pulsatile drug delivery system. The hydrophilic sandwich design, often utilizing materials like Hypromellose, creates a barrier gel layer that plays a crucial role in regulating the release of the drug (57,58). This capsule design offers advantages such as targeted drug release and reduced side effects, makin

VARIOUS PATENT NOVEL CAPSULE SYSTEM

Table 3 Various Patent capsule system

Capsule System	Description	Potential Patents
Telemetric Capsule	Capsule designed for internal monitoring and data transmission, includes sensors and communication systems.	US Patent 6,306,098: Ingestible event marker system US Patent 7,421,553: Telemetric temperature measurement capsule
CODAS Technology	Chronotherapeutic Oral Drug Absorption System, provides delayed release to align with circadian rhythms.	US Patent 5,837,284: Chronotherapeutic oral drug absorption system
INNERCAP TECHNOLOGY	Capsule-in-capsule design for multiple release profiles; inner and outer capsules may have different substances.	US Patent 6,352,722: Oral dosage form for timed release US Patent 7,018,660: Multi-layered capsule for delivering active compounds
SODAS® (Spheroidal Oral Drug Absorption System)	Controlled release using spheroidal particles, allows for consistent drug release.	US Patent 5,508,040: Multiparticulate modified release composition US Patent 5,837,284: Also relevant for modified release systems
DUOCAP® CAPSULE	Capsule-in-capsule design for dual release, combines immediate and delayed release.	US Patent 8,318,230: Capsule-in-capsule dosage form
Hydrogel-based Capsules	Capsules using hydrogel for controlled release, hydrogel can swell and release active ingredients over time.	US Patent 6,531,154: Controlled-release pharmaceutical compositions using hydrogel US Patent 7,674,470: Hydrogel capsules for oral delivery of active agents

                     

2. EVOLUTION OF CAPSULE SHELL MATERIAL

The evolution of capsule shell materials has been extensively documented in recent review articles and research studies. These sources provide valuable insights into the development and advancement of capsule shell materials over time. From traditional gelatin-based capsules to innovative alternatives like hydroxypropyl methylcellulose (HPMC) and goatskin gelatin, the capsule industry has witnessed a significant shift towards more versatile, stable, and ethical materials (3). The physicochemical, pharmaceutical, and biopharmaceutical properties of these materials have been thoroughly investigated, contributing to their widespread adoption in pharmaceutical formulations (60). Moreover, ethical considerations have driven the development of vegetarian capsule options, addressing concerns regarding animal-derived gelatin capsules (61).Through meticulous evaluation and characterization studies, researchers have enhanced our understanding of capsule shell performance, paving the way for improved drug delivery systems (62,63).

Overview of Gelatin Capsule:

Capsules offer advantages over tablets for delivering therapeutic compounds orally, as they can administer solids, non-aqueous liquids, and semisolids in one dose. Their formulation depends on the shell material, which can be rigid or flexible and made of substances like gelatin or non-gelatin polymers. Capsule shell design can be tailored to control content release in the gastrointestinal tract. The discussion focuses on the use of polymeric film-forming materials and manufacturing technologies in crafting capsule shells (64).

Composition of Gelatin Capsule Shells:

Gelatin capsule shells typically consist of gelatin, a natural biopolymer primarily composed of water-soluble proteins, mineral salts, and water. Gelatin can be derived from various sources, including animal collagen through processes like acid, alkaline, enzymatic, or thermal hydrolysis. The formulation of gelatin capsules may also include plasticizers like sorbitol-sorbitan and glycerin to improve flexibility and stability [6]. Additionally, other materials such as starch may be incorporated into the capsule composition to enhance specific properties (64).

Advantage and Limitation of Gelatin:

Gelatin capsules have long been favoured in pharmaceutical formulations due to their biocompatibility and ease of processing, sourced from animal collagen. They dissolve smoothly in the gastrointestinal tract, facilitating effective drug release. However, they are prone to cross-linking and brittleness, affecting drug stability and raising concerns for certain dietary restrictions and ethical considerations. Researchers are exploring alternatives like Hypromellose (HPMC) to address these limitations, reflecting a commitment to meeting diverse consumer preferences and advancing drug delivery systems (65,66).

GELATIN VERSUS NON GELATIN CAPSULES- SCIENTIFIC PERSPECTIVES

Capsules, a variety of medicinal format, are widespread in the domain of our routine well-being upkeep. Capsules consist of gelatin (either firm or soft) and non-gelatin casings, generally acquired through the breakdown of collagen (via acidic, alkaline, enzymatic, or thermal procedures) derived from creatures or cellulose-based substances. However, presently, there is a growing concern surrounding the distinction between vegetarian and non-vegetarian capsules. In order to address this matter, the Central Drugs Standard Control Organization (CDSCO) has solicited feedback from various stakeholders. In order to tackle this issue, it is imperative to acknowledge the variations in needs and dietary preferences among individuals and regions. Nevertheless, should we categorize drugs based on their origin for the purpose of health management, considering the potentially grave consequences on one's well-being and life? Hence, in this present discourse, we shall delve into the origins and characteristics of capsules within the scientific domain (61). Both gelatin hard capsule shells and soft capsule shells can be prepared using gelatin. The presence of moisture ranging from 12% to 16% is crucial for maintaining the integrity of the gelatin hard capsule shell. In the manufacturing process of soft shells, plasticizers, particularly non-volatile plasticizers, are utilized. These plasticizers serve to diminish the interaction between protein molecules, thereby allowing gelatin to retain moisture. While glycerol and sorbitol are commonly used, it is worth noting that sorbitol is prone to blooming or crystallization when stored at low humidity levels. Consequently, a blend of glycerol and sorbitol is employed. Alternatively, polyethylene glycols (PEGs) can also be employed (67)(68). Gelatin capsules pose technical challenges such as susceptibility to cross-linking and brittleness during storage, affecting capsule integrity. Ethical concerns arise due to their animal-derived nature, conflicting with vegetarian or vegan preferences. Additionally, there is a potential risk of infectious agent transmission. Alternative materials like Hypromellose address these issues, aligning with dietary and ethical considerations in pharmaceutical formulations. “The real issue: Transmissible spongiform encephalopathy” The initial regulatory notification was issued by the US-Food and Drug Administration (FDA) in November 1992, wherein the FDA apprised manufacturers of dietary supplements about the apprehension surrounding transmissible spongiform encephalopathies (TSEs). These manufacturers were instructed to collect relevant data pertaining to any bovine or ovine substances and to ensure that said materials did not originate from countries that have a prevalence of bovine spongiform encephalopathy (BSE). On December 17, 1993, the US-FDA advised manufacturers against utilizing bovine-derived substances obtained from cattle residing in or originating from BSE-endemic nations. Additionally, the FDA provided guidance on the identification of the origin of bovine-derived substances and mandated the maintenance of a traceable record for each batch of said materials, specifying the country from which they originated (61).  Moisture content and stability problem Water (13%w/w to 16%w/w) in the gelatin film acts as a plasticiser and enables the formation of a tough but flexible film. Change in relative humidity of the environment may either lead to brittle or soggy shells with sometimes a negative impact on the fill material. Sensitivity of gelatin to extremes of humidity is the major area of concern for use of capsules in too humid/dry climates(60).

2. NOVEL MATERIALS FOR CAPSULE SHELL

The pharmaceutical sector is currently undergoing a significant transformation in the field of capsule formulation, as it explores various options to replace the conventional use of gelatin. This shift is propelled by multiple factors, such as the pursuit of cost-effectiveness, environmental considerations, and the desire for enhanced characteristics. Some noteworthy alternatives being considered encompass (68).

2.1 HYDROXYPROPYL METHYLCELLULOSE

Hydroxypropyl Methylcellulose (HPMC) emerges as a versatile substitute for capsule shells, derived from plant cellulose with a partially synthetic composition. It resolves cross-linking issues, dissolves readily in cold water, and offers stability in fluctuating conditions. HPMC capsules, exemplified by Quali-V® from Shionogi Qualicaps, show stability in low humidity, making them suitable for moisture-sensitive products. They resist breakage, have high compatibility with excipients and APIs, and require no TSE certification, reducing regulatory filing time. HPMC's adhesive property facilitates uniform coating for modified-release drugs. They meet pharmaceutical standards, are recognized for human consumption, and certified Kosher, Halal, and vegetarian-friendly. Non-GMO, preservative-free, and allergen-free, HPMC capsules are eligible for organic labeling and suitable for organic ingredients. They offer various printing options and anti-counterfeit measures, with dissolution performance similar to gelatin capsules, providing a sustainable alternative in pharmaceutical and nutraceutical applications (60). Hydroxypropyl Methylcellulose (HPMC) stands out as an ideal material for capsule shells, owing to its myriad benefits. Derived from plant cellulose, HPMC accommodates individuals adhering to various dietary restrictions, including vegetarian, vegan, and religious practices. Notably, HPMC exhibits superior stability in the presence of moisture, reducing the risk of cracking or shrinking in high humidity, a marked improvement over gelatin capsules. Its compatibility with a diverse range of fill materials, even those sensitive to moisture, underscores its versatility without compromising stability. HPMC boasts taste masking and acid resistance properties, effectively concealing unpleasant tastes and protecting sensitive ingredients from stomach acid. Additionally, its controlled drug release capabilities permit adjustment of dissolution rates across different digestive tract segments. The biodegradable nature of HPMC sets it apart environmentally, in contrast to gelatin capsules, and its hypoallergenic qualities make it a safe choice for individuals with sensitivities to animal-derived materials. However, despite its many advantages, HPMC does have certain drawbacks. One of these is its higher cost compared to gelatin capsules, which must be taken into consideration in cost-sensitive applications (68). Additionally, the slower disintegration of HPMC capsules may have an impact on the absorption of drugs, and their thicker walls result in a slightly reduced capacity for active ingredients compared to gelatin capsules of the same size. Another concern is the brittleness of HPMC in very dry environments, as it may lead to breakage. Moreover, there is a possibility of interactions between HPMC and certain active pharmaceutical ingredients (APIs), which could affect their stability or release. Therefore, careful evaluation is necessary during the formulation process. Furthermore, the adoption of HPMC for pharmaceutical applications is complicated by regulatory considerations, which entail additional testing and documentation (60,69).

2.2 STARCH CAPSULE SHELL

Recently, there has been an upsurge in the utilization of starch capsules in a variety of controlled release formulations. This rise in usage can be attributed to the growing demand for products that are not derived from animals. It should be noted that the gelatin shells have the potential to dissolve or soften when exposed to a coating material during the spraying process, and they can also become brittle upon drying. On the other hand, starch capsules offer a more convenient option for coating compared to gelatin capsules. This becomes especially beneficial when utilizing materials sensitive to redox or pH for precise delivery to the small intestine. Furthermore, these capsules may undergo an additional coating that breaks down through specific enzymes or bacteria in the colon, enhancing a targeted delivery strategy. Additionally, the use of starch capsules contributes to a more consistent coating due to their higher bulk density. The preparation of these capsules involves the injection moulding process, ensuring accurate dimensions and effective sealing. The filling and sealing processes take place simultaneously, yielding a finished product that is well-sealed, secure, and resistant to tampering. Furthermore, starch capsules exhibit greater resistance to heat and humidity compared to gelatin capsules. Additionally, their non-static properties make the filling process considerably easier. It is worth noting that the dissolution of starch capsules is not influenced by pH and they are ready for filling immediately after manufacturing (44,70). Starch capsules, as a substitution for conventional gelatin-based capsules, present distinctive characteristics for pharmaceutical transportation mechanisms. Soft-shell capsules derived from plant-based substances, such as starch, have been investigated for their physical and mechanical attributes (71). European pharmacopoeias commonly reference gelatin as an ingredient for capsule shells; however, there is a growing presence of starch-based shells as viable vegetarian alternatives (61,72). Different sources of starch, including pea starch and sago starch, have been examined to determine their appropriateness as materials for soft capsules (73). The techniques used for preparation consist of the extrusion of starch materials followed by the application of a gel coating, which demonstrates the wide range of applications of starch-based soft capsules (74). Notably, hydroxypropyl pea starch, such as LYCAGEL® VS 720 PREMIX, is studied as a vegetal soft capsule shell material, emphasizing the potential of starch in pharmaceutical applications (73).

2.3 PVA COPOLYMER CAPSULE SHELL

Hard capsules have conventionally been employed for the administration of powdered or granulated formulations, and they have also been modified to accommodate oily liquids, tablets, and inhalable powders. Certain compounds possessing potential medicinal attributes exhibit extremely limited solubility owing to their strong affinity for receptors, consequently heightening their lipophilic nature. In order to augment their solubility, these insoluble pharmaceuticals are amalgamated with macrogol 400. Nevertheless, conventional capsules face difficulties in effectively encapsulating macrogol 400 due to its significant magnitude. As a remedy, capsules that possess the capability to encapsulate macrogol 400 have been synthesized. These capsules are fabricated through the copolymerization of acrylic acid (AA) and methyl methacrylate (MMA) on polyvinyl alcohol (PVA), which serves as a structural framework. The resultant PVA copolymer is subsequently utilized as the shell for these capsules. These shells are water-soluble and exhibit lesser hygroscopicity when compared to gelatin capsules. Moreover, they possess a distinctive characteristic of displaying minimal oxygen permeability whilst retaining the capacity to encapsulate macrogol 400 (44,70). The distinct physicochemical properties of PVA copolymer capsules confer upon them a notable advantage, rendering them suitable for drug delivery systems. Historically, gelatin capsules have been widely employed in the pharmaceutical industry; however, certain limitations associated with gelatin, such as susceptibility to moisture and specific storage requirements, are effectively addressed by PVA copolymer capsules. Researchers have invested considerable effort in investigating the application of PVA copolymers in capsule technology, with the aim of enhancing the stability and versatility of capsule formulations. Pharmaceutical research has devoted attention to a specially developed PVA copolymer, examining its properties and suitability as a material for capsule shells. This research delves into the intricacies of PVA copolymer capsules, scrutinizing their physical and chemical characteristics to ensure optimal performance in drug delivery applications. The objective is to provide pharmaceutical companies with a viable and efficient alternative to traditional capsules, thereby broadening the range of options for drug encapsulation. Moreover, PVA copolymer capsules offer distinct advantages in encapsulating hydrophilic solvents, presenting an opportunity for improved drug delivery systems. This particular feature assumes great significance in the pharmaceutical field, where the efficient encapsulation and controlled release of active pharmaceutical ingredients are pivotal to the success of medications. PVA copolymer capsules exhibit promise in overcoming challenges associated with certain solvents, thereby enhancing compatibility with a wider spectrum of pharmaceutical compounds. Additionally, a patent sheds light on the versatility of PVA in capsule shell technology. The patent explores the utilization of polyvinyl alcohol (PVA) in the creation of hollow capsules for medical accessories, thereby indicating the adaptability of PVA copolymer capsules beyond traditional drug delivery systems. This versatility opens up avenues for the development of specialized capsules tailored to meet specific medical and industrial requirements. To conclude, PVA copolymer capsule shells embody a significant advancement in capsule technology. Their unique properties, such as low water content, low electrification, and compatibility with hydrophilic solvents, position them as valuable alternatives to gelatin capsules. As ongoing research continues to unveil the full potential of PVA copolymer capsules, their applications are poised to expand, offering enhanced solutions in the pharmaceutical and various other industries (75).

2.4 PULLULAN

Pullulan, a naturally occurring water-soluble polysaccharide, has gained attention as an eco-friendly and sustainable alternative for capsule shell formulation. Derived from the fermentation process involving Aureobasidium pullulans, Pullulan offers distinct advantages in pharmaceutical applications. One key feature is its biocompatibility, ensuring safety in medical use. The production of Pullulan involves minimal environmental impact, aligning with the growing demand for sustainable practices in the pharmaceutical industry. As a capsule shell material, Pullulan provides biodegradability, addressing concerns related to the environmental impact of traditional capsule materials. This aligns with the broader industry trend towards green and sustainable solutions. Moreover, Pullulan exhibits excellent film-forming properties, contributing to its suitability as a capsule shell material. It can be easily processed into films with desirable mechanical properties, ensuring the integrity of the capsule. This characteristic makes Pullulan a versatile choice for encapsulating pharmaceutical compounds. Capsules utilizing Pullulan as the shell material cater to a diverse range of dietary preferences, including vegetarian and vegan choices. Its plant-derived origin makes it an attractive option for those seeking alternatives to animal-based capsule materials like gelatin. As dietary restrictions and cultural considerations play an increasingly significant role, Pullulan provides a solution that aligns with these evolving consumer needs. In conclusion, Pullulan stands out as a promising and sustainable alternative for capsule shell formulation. Its biocompatibility, biodegradability, and ease of processing make it a versatile choice that not only meets pharmaceutical standards but also addresses the industry's growing emphasis on environmental responsibility and consumer preferences.(69,76).

 2.5 CARRAGEENAN

Carrageenan, which is derived from red seaweed, has garnered attention as a substitute material for capsule shells, presenting distinctive benefits over conventional gelatin. One noteworthy advantage resides in its compatibility with vegetarian and vegan formulations, thus meeting the growing demand for plant-based alternatives. The capability of carrageenan to form a stable, transparent, and flexible capsule shell renders it an appealing choice for the encapsulation of pharmaceutical and nutraceutical products. Furthermore, carrageenan demonstrates superior stability under various environmental conditions, including resistance to elevated temperatures and humidity. This robust stability contributes to the prolonged shelf life of capsules, ensuring the effectiveness of encapsulated substances over an extended period. Additionally, carrageenan capsules have exhibited promising outcomes in controlled-release formulations, offering a versatile platform for applications in drug delivery. However, it is imperative to consider the limitations of carrageenan as a material for capsule shells. Certain formulations may encounter challenges related to fragility and the potential for the shell to crack under specific circumstances. Moreover, the extraction and processing of carrageenan raise concerns regarding sustainability and the environmental impact, prompting ongoing research efforts to address these aspects and enhance the overall feasibility of carrageenan capsules.In conclusion, carrageenan emerges as a promising substitute for gelatin in capsule shell formulations, providing advantages in terms of its plant-based origin, stability, and controlled release. While the resolution of issues associated with fragility and environmental concerns is crucial, continuous research and development endeavors may further establish carrageenan as a valuable option within the diverse landscape of capsule materials (77,78).

 2.6 EUDRAGIT

Alginate, which is a type of polysaccharide derived from seaweed, has garnered considerable attention as a versatile substance for the production of capsule shells. The process of alginate gelation involves the reaction between sodium alginate and divalent cations, typically calcium ions, resulting in the creation of a stable gel. This gelation process is exploited in the manufacturing of alginate core-shell capsules, thereby showcasing its utility in a variety of industries. The characteristics of alginate capsules render them suitable for a wide range of applications. These capsules possess properties that are both biocompatible and biodegradable, making them highly favourable for use in the pharmaceutical, cosmetic, textile, and food industries. The compatibility of alginate with diverse materials allows for the creation of core-shell structures, thereby enhancing its versatility (79). Extensive research has been conducted to optimize the properties of alginate capsules, with studies exploring various factors such as the concentration of calcium chloride and the feed rate of alginate-to-oil. The physicochemical properties of gelatin-alginate capsule shells have been thoroughly investigated, thus highlighting the potential of alginate in producing robust capsule shells with desirable attributes (80). In pharmaceutical applications, hard alginate capsules have exhibited promising characteristics as enteric capsules, demonstrating resistance to gastric conditions both in vitro and in vivo, while also possessing favourable disintegration properties. Furthermore, alginate core-shell capsules find application in 3D cultivation systems, where the outer alginate barrier aids in the diffusion of nutrients and waste (81). Although alginate presents itself as a promising alternative to conventional capsule shell materials, ongoing research endeavours continue to refine its properties, addressing challenges such as brittleness and optimizing formulations tailored to specific applications. The natural origin, biocompatibility, and adaptability of alginate make it an intriguing candidate for future advancements in capsule technology (82,83).

2.7 SHELLAC

Shellac, an organic substance obtained from the lac insect, has achieved considerable recognition in diverse sectors such as pharmaceuticals, wherein it is employed as a versatile substance for the fabrication of capsule shells. The exceptional physical attributes of shellac render it a perfect option for this particular utilization. The intricate composition of shellac, as explicated in scientific investigations (84). Shellac, a resin obtained from the lac insect, has become widely recognized in diverse sectors, such as pharmaceuticals, due to its multifaceted utility in the form of capsule shells. The exceptional characteristics of shellac render it a perfect candidate for this specific purpose. Its intricate composition, as elucidated in various studies (85). the utilization of thin-walled, liquid-filled composite capsules is emphasized, thus providing a demonstration of the mechanical properties possessed by the material. The significance of this durability lies in its ability to uphold the structural integrity of the capsule shell, thereby safeguarding the contents enclosed within from external environmental factors and ensuring the dependability of drug administration. Furthermore, the stability of shellac is elevated by means of the creation of composite films, as thoroughly examined in various research studies (86). By combining shellac with materials like gelatin, polymerization can be reduced, contributing to the longevity and effectiveness of the capsule as a drug delivery system. In the pharmaceutical industry, shellac serves as a pharmaceutical excipient, particularly as a coating material for tablets and capsules (87). Its natural resinous composition makes it a preferred choice for encapsulating drugs, providing a protective layer that aids in controlled release and drug stability. The physico-chemical properties of shellac are further exemplified in research (88). where its incorporation significantly influences the properties of capsules. The feasibility of integrating shellac into pharmaceutical formulations is closely tied to its impact on capsule characteristics, showcasing its adaptability to different drug delivery systems. Shellac's role extends beyond mere encapsulation; it actively contributes to modifying drug release rates, as evidenced in studies. he combination of shellac gum with carrageenan alginate creates core-shell structures, showcasing its ability to tailor drug delivery profiles. This versatility positions shellac as a valuable tool for pharmaceutical formulation scientists seeking precise control over drug release kinetics. In conclusion, shellac stands out as an excellent material for capsule shells in the pharmaceutical industry. Its natural origin, coupled with desirable physical and chemical properties, makes it a preferred choice for encapsulating drugs. The ongoing research in this field continues to explore and harness the full potential of shellac, emphasizing its significance in the development of advanced and efficient drug delivery systems (87).

2.8 POLYETHYLENE GLYCOL

Polyethylene Glycol (PEG) is a versatile polymer that has found applications in various pharmaceutical formulations, including as a material for capsule shells. With physicochemical properties ranging from liquid to waxy solid, PEG offers flexibility in formulation design and drug delivery systems (89). The choice of PEG as a capsule shell material is attributed to its tunable properties and well-established safety profile, meeting prime requisites for pharmaceutical applications (90). Its use has been studied in soft capsules, with researchers highlighting its versatility in formulating pharmaceutical products. Moreover, PEG has a high affinity for both the gelatin capsule material and plasticizers used in the capsule shell, contributing to its compatibility and ease of formulation (91). PEG's advantages extend beyond its physical properties; it is a USFDA-approved polymer, adding an extra layer of credibility to its use in pharmaceuticals. Additionally, PEG's ability to absorb moisture from gelatin in the capsule shell may cause hardening, offering unique characteristics that can be harnessed for specific drug formulations (92). In conclusion, Polyethylene Glycol (PEG) stands out as a promising material for capsule shells due to its tunable properties, safety profile, and compatibility with other capsule materials, making it a valuable component in the development of pharmaceutical formulations.

 

2.9 CELLULOSE ACETATE

Cellulose Acetate has surfaced as a propitious substance for encasement envelopes, presenting distinctive attributes that render it an advantageous selection in the realm of pharmaceuticals and encapsulation endeavours. Stemming from cellulose, an inherent polymer present in the cell walls of plants, cellulose acetate showcases the capacity for biodegradation and the potential for reuse, thus establishing itself as an ecologically sound alternative for capsule compositions (93). The versatility of fabrication processes is a notable characteristic of cellulose acetate. Researchers have investigated modified configurations to produce mono-component devices, thus enhancing the efficiency and adaptability of cellulose acetate micro-vectors in drug delivery systems. These advancements in fabrication contribute to the material's appropriateness for various pharmaceutical formulations. The biocompatibility of cellulose acetate further establishes it as an appealing option for capsule shells. It enables the secure administration of pharmaceuticals, ensuring minimal adverse reactions upon interaction with biological systems. This aspect is crucial for upholding patient safety and guaranteeing the efficacy of the enclosed medications. Cellulose acetate has also undergone examination for its potential in the elimination of contaminants. Capsules derived from cellulose acetate have been utilized for the extraction of phenol from water and synthetic textile wastewater, thereby demonstrating its potential beyond the conventional application of drug delivery (94,95). This versatility expands the scope of cellulose acetate in various industries, aligning with the growing emphasis on sustainable and eco-friendly materials. Moreover, cellulose acetate has been investigated in combination with other substances, such as Cyanex 923, to create microcapsules for specific applications. This further demonstrates the material's adaptability and potential for customization to meet the requirements of different drug formulations and encapsulation needs the realm of patents, novel cellulose ether acetate phthalates have been introduced, indicating ongoing research and development to enhance the properties of cellulose acetate for capsule shells. These innovations can potentially address specific challenges or requirements in pharmaceutical formulations (95).

 2.10 POLYVINYLPYRROLIDONE

Polyvinylpyrrolidone (PVP) is a polymer with hydrophilic characteristics that has garnered extensive recognition and practicality in various sectors, particularly within the pharmaceutical and biomedical domains. Famed for its exceptional qualities, PVP functions as a versatile and invaluable substance, frequently employed as a carrier within drug delivery systems and other realms. One of the primary attributes of PVP resides in its remarkable solubility in water and a diverse array of organic solvents, rendering it an optimal selection for pharmaceutical applications where controlled discharge and dissolution are of utmost importance (96). The efficient dispersion and dissolution of drugs is essential in order to achieve the desired therapeutic effects, and this is made possible by the water-solubility of PVP. Furthermore, the compatibility of PVP with different solvents greatly contributes to its flexibility in the design of formulations. The utility of PVP extends beyond its solubility, as it possesses outstanding characteristics in terms of film formation, adhesion, and chemical stability. These properties enhance its effectiveness as a material for capsule shells. In this regard, PVP serves as an effective encapsulating agent, providing a stable and protective environment for pharmaceutical compounds. The ability of PVP to form films is particularly advantageous, as it allows for the creation of uniform and strong capsule shells. PVP is highly regarded for its binding, dispersing, and stabilizing capabilities, which make it a popular choice in pharmaceutical formulations. It is available in various grades, such as K17, K30, and K90, each catering to specific application requirements (97,98). The flexibility provided by these grades allows pharmaceutical scientists to customize formulations based on the specific requirements of different medications, resulting in optimal performance. Recent progress in research has investigated the utilization of polyvinylpyrrolidone (PVP) in the creation of microcapsule shells. As a commonly used material for microcapsule shells, PVP demonstrates exceptional abilities in forming films, being hydrophilic, and possessing antibacterial properties. This highlights the versatility of PVP beyond conventional encapsulation, suggesting its potential role in innovative systems for delivering drugs. In summary, Polyvinylpyrrolidone (PVP) emerges as a multifaceted substance with a wide array of applications, particularly as a material for capsule shells in the pharmaceutical industry. Its solubility, film-forming capability, and compatibility with various solvents make it an essential component in drug delivery systems, contributing to the advancement of effective and efficient pharmaceutical formulations (99).

2.11 HYPROMELLOSE

Hypromellose, also known as hydroxypropyl methylcellulose (HPMC), is a versatile polymer widely used in the pharmaceutical industry as a capsule shell material. This compound is a methyl and hydroxypropyl mixed ether of cellulose, available in different grades such as E series and K series, each with specific characteristics and applications (60). The utilization of HPMC capsules offers several advantages, making them a preferred choice for drug delivery systems. Hypromellose exhibits excellent physicochemical properties that contribute to its suitability as a capsule shell material. Research indicates that the material can reduce the solubility of gelatin capsules, providing an alternative for specific formulations (90). Moreover, HPMC's compatibility with other substances, such as carrageenan and potassium chloride, has been proven effective in gelation, enhancing the stability and performance of the capsule. The pharmaceutical and biopharmaceutical properties of HPMC capsules make them ideal for various drug formulations. The material’s-controlled release characteristics have been studied extensively, with comparisons made between HPMC capsules and traditional gelatin capsules. These studies reveal differences in shell dissolution properties, emphasizing the potential benefits of HPMC in specific drug delivery applications (99). One of the key advantages of HPMC capsules lies in their applications in drug delivery. These capsules can be used for the administration of a wide range of drugs, allowing for precise control over the release of active pharmaceutical ingredients. The versatility of HPMC capsules extends to their use in targeted drug delivery systems, offering a customizable platform for pharmaceutical formulations (98).

Table 4 Various Capsule Formulation Having Novel Shell Material

No.	Drug Composition	Capsule Shell Material	Brand Name
1	Lansoprazole.	Cellulose acetate phthalate	Prevacid® 24HR
2	Calcium Citrate, Vitamin D3	Cellulose acetate phthalate	Citracal® Maximum D
3	Lipase, Protease, Amylase	Hypromellose	Schiff® Digestive Enzymes
4	Vitamin C	Pullulan	Garden of Life® Vitamin C
5	Omega-3 Fatty Acids	Hydroxypropyl methylcellulose (HPMC)	Vcaps Plus
6	Curcumin	Pullulan	Vegetarian Caps
7	Ashwagandha Extract	Pullulan	NatVcaps
8	Fish Oil	Modified starch and carrageenan	Caplique
9	Coenzyme Q10	Modified starch	VEGE-Caps
10	Vitamin D3	Starch	Quali-V Caps

 

FUTURE PROSPECT

The future of capsule technology holds immense promise, with innovations aimed at addressing diverse therapeutic needs and enhancing patient care. Emerging technologies such as the Novel Floating Ring Capsule, Telemetric Capsules, and CODAS represent significant advancements in drug delivery, providing more precise control over drug release and targeted delivery to specific sites within the body. These advancements not only improve therapeutic efficacy but also enhance patient compliance by optimizing the timing and location of drug release. The integration of smart technologies, such as sensors embedded within Telemetric Capsules, will enable real-time monitoring and personalized treatment, potentially transforming the management of various diseases. Additionally, the development of non-gelatin capsule materials like hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA) addresses dietary restrictions and expands the versatility of capsules across different patient populations. However, these advancements come with several challenges that must be addressed to fully realize the potential of these technologies. The cost and complexity associated with the production of sophisticated capsules, especially those incorporating smart technology or novel materials, pose significant barriers. Simplifying manufacturing processes and reducing production costs will be essential to make these advanced capsule technologies more affordable and widely accessible. Regulatory hurdles also present a challenge, as new materials and technologies must comply with stringent safety and efficacy standards before they can be brought to market. Ensuring that these innovations meet regulatory requirements without compromising their effectiveness will be critical. Another challenge lies in managing drug-polymer interactions, which can impact the stability and release profile of medications encapsulated in new materials. Understanding and optimizing these interactions will be crucial for developing reliable and consistent drug delivery systems. Furthermore, while advancements such as fast-disintegrating capsules aim to improve patient compliance, ensuring that patients understand and accept these new technologies is vital. Educating patients on the benefits and proper use of these advanced capsules will play a key role in enhancing adherence to treatment regimens.

CONCLUSION

The exploration of recent advancements in capsule innovation, focusing on emerging novel technologies and alternative capsule shell materials, has revealed a dynamic landscape of progress within the pharmaceutical field. The comprehensive review has highlighted a diverse array of cutting-edge technologies such as floating ring capsules, telemetric capsules, CODAS technology, Innercap technology, Sodas®, Duo Cap® capsules, hydrogel-based capsules, and hydrophilic sandwich capsules. Additionally, a meticulous examination of the evolutionary path of capsule shell materials, including insights into the composition, advantages, and limitations of gelatin capsules, provides a foundation for understanding the changing landscape of capsule formulations. The incorporation of novel materials for capsule shells underscores the industry's commitment to advancing drug delivery systems. This exploration not only contributes to a deeper understanding of emerging technologies in pharmaceutical sciences but also serves as a catalyst for further research and development in the realm of capsule-based drug delivery. As the field continues to evolve, the pursuit of innovative technologies and alternative materials remains pivotal, ensuring a constant drive towards enhanced efficacy, patient adherence, and overall pharmaceutical excellence.

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