Capsule Dosage Forms: A Comprehensive Review of Manufacturing Technologies and Methods

Abstract

Oral drug delivery is widely used route of drug administration by wide range of populations. Various types of oral dosage forms available are tablets, capsules, solutions, strips etc. Among all these dosage forms, capsules offer various advantages and are widely accepted. Capsules are defined as solid unit oral dosage form which contains medicaments which are encapsulated into various shell materials. Major types of capsules are Hard gelatin and Soft gelatin capsules. Other types of capsules shell material used are HPMC, Starch, Pullulan which offers increased benefits when compared to gelatin material. Emerging capsules technologies are ruling the capsule world by offering numerous advantages which helps in large scale production of capsules. Various types of capsules include control release capsules, Nano capsules, Micro capsules, Enteric coated capsules, 3D printed capsules and sustained release capsules. Newer technology in capsule formation includes capsules in capsule form, which contain different types of medicaments which are incorporated into single capsules which helps in increasing patient compliance. AI in use of capsule formulation has been developed in a few areas of manufacturing. Telemetric capsules are the capsules which are used for real time monitoring of the body’s various physiological parameters. Recently 10 capsule forms have been approved by FDA in 2022. Improvement in manufacturing technology has led to increase in usage of capsules.

Keywords

Introduction

Oral Drug Delivery:

Oral drug delivery is the widely used route of drug administration due to various advantages such as non-destructive, patient compliance, cost effective, ease of administration and easy manufacturing procedures. Factors which affect oral drug absorption are solubility, permeability and stability along the entire length of GI tract. Orally administered drugs are targeted to various parts of GIT for achieving targeted drug effect. It is used for both systemic and local treatment of gastro intestinal disorders. Despite these advantages, it possess several challenges such as different physiochemical properties of various drug substance, limited drug solubility, permeability. Some drugs can even cause nausea and local irritation. Pharmacodynamics of drug is a key factor to be considered for designing drugs for oral absorption. Orally administered drugs are absorbed through duodenum and jejunum. Drug absorption of stomach is less as compared to intestine because of its smaller surface area. The formulations that can be delivered through oral route are tablets, capsules, solutions, syrups, suspensions, emulsion, pills etc.

One of such important solid unit oral dosage forms are Capsules-

Capsules are defined as a solid unit oral unit dosage form which contains measured amount of active ingredients along with required quantity of additives that are enclosed within a shell. They were invented in 1833. They are usually used to deliver drugs and supplements to body. The outer shell is usually made up of gelatin. The word Capsule is usually derived from Latin word Capsula, which means small box. Capsules may be hard and soft depending upon composition of gelatin. The contents present inside capsules are dry powder, liquids or semi solid materials. Capsules exists in various sizes, shapes and capacities. Capsules work by breaking the outer shell and releasing the medicaments in required amounts to produce necessary actions. Capsules are the most utilized dosage forms which has higher patient compliance. Capsules are taken orally or also used as suppositories.

ADVANTAGES:

• Capsules can easily be broken down compared to tablets, hence provides faster action.
• They are highly palatable, thus an increase in rate of consumption.
• They are manufactured so that they can’t easily be broken down or crushed like tablets. Hence, they are termed as tamper resistant.
• When compared to tablets, capsules have higher bioavailability.
• They can be formulated into various size and shapes.
• They can be customized according to patients’ requirements.
• Capsules provide consistent amount of medications.
• They are designed to reduce gastric irritation.
• They can easily be swallowed, hence provide better patient compliance.
• They require less additives for manufacturing, making them easier to manufacture.
• They are available in wide variety of colors making them visually attractive.
• Drugs which are partially soluble in aqueous or non-aqueous vehicles can be delivered through capsule.
• Oily solutions can be formulated as capsules.

DISADVANTAGES:

• Capsules are less durable in the sense they are highly susceptible to environmental changes.
• Due to high sensitive to moisture and humidity, they have less shelf life.
• They usually contain animal products which are allergic to majority of individuals who are vegetarian and vegan friendly.
• It is difficult to encapsulate larger doses of drugs into capsules.
• Pediatrics finds difficulty in swallowing the capsule dosage form.
• Low melting point ingredients can’t be dispensed into capsules.
• Capsules are more expensive to manufacture compared to other solid oral dosage forms.

Advanced Technology Used in Manufacturing of Capsules:

Recent advancements in technology has been developed in capsule formulation for improving efficiency of capsule filling and to make improvements in capsule formulation by utilizing different raw materials. Each steps involved in capsule manufacturing has been optimized for efficiency, stability and compliance with tightening regulations. Traditional encapsulation techniques such as manual filling and sealing have been replaced by automatic machinery and robotics. These systems have increased production speed and decreased manual labor which in turn saves money and time. This enables manufacturing companies to meet the on-growing demand and improve product quality and safety.

Newer technologies used in capsule manufacturing are:

• Nano capsules
• Microcapsules
• Enteric coated capsules
• 3D printing
• AI in capsule manufacturing

Nanocapsules:

Nano capsules contain shells and a core into which desired medications are placed. These nano capsules are covered with certain receptors which binds to various cells and tissues to release specific medicaments. They can also be designed into various shapes and sizes by using different polymers. Their size ranges from 5nm to 1000nm, but most of them are in between 100nm to 500nm. The active ingredients are encapsulated into shell material in various forms such as solid, liquid and solid dispersion. They can be used for delivering both hydrophilic and lipophilic drugs. They can also be used for both control release and target release of required drug substances. They are used for site specific delivery of drugs that has degradation problems.

FIG:1 Nano capsules containing solid drug substances which are entrapped inside shell material.

Types of nanocapsules:¹

• Polymeric Nano capsules - They are formed using various biodegradable polymers, which provide wide range of biocompatibility and stability.
• Lipid Nano capsules - They are prepared by using various types of lipids such as triglycerides, fatty acids or waxes.
• Inorganic Nano capsules – They are composed of inorganic ingredients such as silica, gold.

Nano capsules consist of oily or aqueous core surrounded by polymeric membrane. They are developed using wide range of technologies such as-

• Interfacial polymerization.
• Emulsion based polymerization.
• Micro fluidics method.
• Nanoprecipitation.
• Super critical fluid technology.

They are used for oral drug delivery of proteins and peptides. They are majorly used in the treatment of breast cancer. Recent advances in Nano capsules are utilizing it in nano capsular bandages for treatment of certain infection. They are used to deliver vitamins and antioxidants. They are also used in cosmetics.

Microcapsules:

They are defined as small spherical shaped capsules which contain internal core material which is coated by a polymeric membrane. It’s size ranges from 1µ -7mm. Solid, liquid and gaseous substances can be encapsulated into it. This offers increased stability and controlled release of drug substances. The core material contains active drug substance along with suitable excipients. Coating substance may be of either natural origin or synthetic one. Bioactive compounds such as such as omega-6 and omega-3 fatty acids, phenolic compounds, vitamins and carotenoids can be delivered through microcapsules.

Different Types of microcapsules:     

• Mononuclear.
• Polynuclear.
• Matrix type.

FIG:2 Detailed microscopic structure of micro capsules.

Method of preparation of microcapsules depends on properties of core material, coating material and morphological properties of capsules.²

Techniques used in preparation of microcapsules are-

• Coacervation process
• Centrifugal extrusion process
• Spray drying and congealing method
• Solvent evaporation method
• Interfacial polymerization

Microencapsulation offers numerous applications by encapsulating various drug substances to protect it against heat, moisture and light. Microcapsules used to deliver vaccine. They are used to encapsulate various vitamins such as Vitamin A and vitamin K. They are used in Gene therapy. Recent advances in microcapsules have come into existence by utilizing biocompatible and biodegradable proteins as coating material. They are divided into three categories based on their composition such as single protein microcapsules, composite protein microcapsules and modified protein microcapsules. Protein structure can be chemically and structurally modified to produce required characteristics.³

Enteric Coated Capsules:

They are the capsules that are formulated to protect the formulation ingredients from degrading in stomach which in turn absorbed in small intestine. They are also termed as gastro retentive coatings. Enteric coatings are applied when the active ingredient used may get deactivated or degraded in stomach acid. Polymer coatings which are insoluble in gastric pH, but which are soluble in intestinal fluids are selected as suitable candidates for formulation. Enteric coatings are utilized for decreasing irritation of drugs such as Aspirin, Omeprazole and Ammonium chloride. They are widely used for protecting either pharmaceutical or nutraceutical substances.

The composition of enteric coating contains 0.01% - 10% of resin and 0.01% - 10% polymer.⁴

Enteric coating capsules are used for delayed release of drug substances. They are activated in intestinal pH of around 5.5. These types of capsules do not dissolve in mouth nor get activated by acid exposure.

FIG:3 Drug substance coated with enteric coatings to protect from degradation.

Various polymers used for enteric coatings are

• pH dependent enteric coating polymers.
• Gel forming polymers.

Other excipients present in capsule shell formulations are copolymers, plasticizers, and gelling substances. Size ranges from largest size 00 to smallest size 5.⁵ Coating techniques are characterized by several variables such as spray rate of coating solution, temperature, pressure, volume of drying air and equipment dimensions. Methods used for manufacturing these types of capsules are spray drying, pan coating, fluid bed coating and hot melt extrusion method.

3D Printed Capsules

FIG:4 3D printed capsules along with capsule forming machine.

3D printing in capsules refers to the manufacturing process that proceeds by stacking different types of layers on top of another to produce different geometrical figures. It is utilized for fabrication of capsules. It is also referred as additive manufacturing. By utilizing 3D printing technology batches can be manufactured with varying designs by using wide varieties of chemicals with different shapes and sizes. Two 3D printing technologies include stereo lithography apparatus (SLA) and fused deposition modelling (FDM). Compared to SLA, FDM has low performance as it degrades heat liable active pharmaceutical ingredients because of generation of high amount of heat. The hydrophilic matrix material HPMC has been utilized as thickening agent, binder and as film forming agent in 3D printed capsules. 3D printed capsules are used for delayed release of medicaments. They also help in masking unpleasant taste of medicaments.

AI in Capsule Formulation:

Artificial intelligence is a upcoming approach in product process development. It contains various algorithms that is applied in wide range of circumstances. It has been lately recognized as emerging technologies in pharmaceutical product development. Challenges that occur during process development are poor powder flowability, stability during manufacturing development and chemical degradation of products. All these challenges can be overcome by using artificial intelligence. AI is a process simulating human intelligence using computers. Several learning algorithms such as logistic regression, linear regression, decision tree, Random Forest, K-Nearest Neighbors (KNN), LightGBM, XGBoost and Support Vector Machine are extensively used for developing solid dosage formulations.⁶ AI techniques in capsule formulation is developed to find defects in physical and chemical stability along with dissolution rate and dissolution profile. Various algorithms used in capsule formulation development are KNN, SVM and CNN for wide range of applications such as identifying capsule defects and detecting defects in pellets forms which are present inside capsules.⁷

Special Types of Capsules:

Capsules are usually classified as soft gelatin capsules and hard gelatin capsules.  Hard gelatin capsules contain dry powdered ingredients or ingredients in the form of pellets. These capsules comprise of 2 parts such as body and cap. ⁸ Soft gelatin capsules are known as soft gels which are used to encapsulate non aqueous liquid and semi solid formulations.⁹ Apart from these 2 types, capsules are further classified into various classes based on their pattern of release and shell composition. Special types of capsules are classified based on release patterns of drug substance by utilizing excipients having different properties.Instance for water soluble drugs, hydrophilic excipients are preferred for fast release and hydrophobic excipients for slow release. For water insoluble drugs, hydrophilic excipients are used for faster release and hydrophobic excipients for slow release. Rapid capsule release can be achieved by adding sodium bicarbonate or citric acid which facilitates opening of capsule through carbon dioxide evolution.¹⁰

Coating Capsules:

These are the capsules which enhance appearance, conceal taste and help in modification of drug release. They are prepared by coating with specific polymers by using traditional coating techniques. Coating has disadvantages such as chipping and peeling of coat.

Sustained Release Capsules:

Conventional dosage forms require frequent dosing of medicaments to achieve required therapeutic effect. To overcome this drawbacks, sustained release formulations have come into existence. These are defined as capsules which contains finely powdered drugs in form of pellets for control drug release. Then these pellets are filled in appropriate doses into capsules. These are designed to release medication over extended period of time to provide steady and prolonged therapeutic effect. This helps in increased patient compliance.  They employ different drug release mechanisms such as matrix system, reservoir system, osmotic system and multi-particulate systems.¹¹

Liquid Filled Hard Gelatin Capsules:

FIG:5 Hard gelatine capsule filled with liquid formulation.

Large number of drug substances which are available currently are water insoluble. Formulation of these kinds of drug substances in traditional manner offers various disadvantages. Hence these capsules have come into existence. They are defined as dosage forms which contain capsule shell made up of gelatin which contains drug substances along with excipients either in liquid form or semi-solid form. ¹² Drugs with poor bioavailability and low melting point are suitable candidates for filling into this type of capsule. This kind of dosage form offers more stability. This offers various advantages such as increased scalability, ease of production, faster action and high product stability. ¹³ They are highly transparent, heat resistant and moisture resistant. They contain various excipients such as plasticizers, antioxidants, wetting agents, suspending agents, diluents and solubilizing agents.¹⁴They are developed in various shapes and sizes.

Recent Advancements In Capsule Technology:

Advances in capsule technology have increased patient compliance and therapeutic efficacy. Innovations in capsule technology include Novel floating ring capsule, Telemetric capsules, CODAS, Capsule-in-Capsule technology, SODAS and DUOCAP. Capsules are available in a wide variety which includes soft and hard gelatin capsules. Furthermore, development in capsule shell formation includes the use of non-gelatin alternatives such as HPMC, PVA and starch. This enhanced technology allows for precise drug release at regular time intervals, enhance bioavailability and increase in drug absorption. They even increase the stability and shelf life of medications.

These technological innovations include:

Novel Floating Ring Capsule:

FIG:6 Floating ring capsule observed in stomach after drug intake.

The main aim of formulating this dosage form is stomach specific target for extending presence of medication to improve therapeutic efficacy. It is developed using various polymers such as HPMC and Sodium CMC. Drug release from capsules is controlled by using varying concentrations of polymers. This type of dosage form retains in stomach for providing required therapeutic effects. They contain both soluble and insoluble components. These capsules can be customized for drug release. Gastrointestinal retention depends upon variety of factors such as density, size of dosage form and fasting or fed condition of patient.

Telemetric Capsules:

FIG:7 Capsules containing sensors which produces electrical signals.

These are the recent advances in the medical sector. These are the capsules which are ingestible devices that are equipped with sensors and communication systems to monitor various physiochemical properties. They are utilized for diagnostic and therapeutic purposes. It consists of location detectors, lithium battery, transmitter and interchangeable drug reservoir tips. These capsules have a cylindrical form of standard 000 capsule size.¹⁵ It offers non-invasive monitoring of physiochemical parameters. They offer early detection of various abnormalities. They are expensive to produce and use which limit their accessibility to patients. Currently they are  used for monitoring in gastrointestinal areas, their use in other areas is limited. Transmission of sensitive data raises concern for data privacy and security. It even faces safety issues. Various types of telemetric capsules are hydrogen sensing capsules, pH sensing capsules, temperature sensing capsule, pressure sensing capsule, imaging capsule, drug delivery capsule etc.

Eg: Hemo Pill acute, are pill shaped devices that are administered orally for real-time blood detection in  upper gastrointestinal tract.

Codas Technology:

It is termed as the chronotherapeutic oral drug absorption system. It is utilized for controlled and extended release of drug substances. This drug release is aligned with circadian rhythms which help in increased therapeutic effect by reducing side effects. In this type of system intentional release timing of drug substance is scheduled. It was developed by Elan Drug Technology. This approach is beneficial for conditions like hypertension, asthma and arthritis where symptoms may worsen at specific times. This uses a system which delays drug release by 4 to 5 hours. This improves patient compliance, treatment efficacy and improves safety by avoiding intake of high dose of drug substances at inappropriate times. They have several applications such for treatment of cardiovascular diseases, treatment of diabetes and used in menopausal hormone therapy. It is single-unit system in which, the lag time is controlled by a plug, which gets pushed away by erosion and the drug is released as a ‘Pulse’ from the insoluble capsule body.¹⁶

Example: Pulsincap system.

Sodas Technology:

They are known as the Spheroidal oral drug absorption system. They optimize drug release by enhancing drug bioavailability and increasing therapeutic efficacy. They provide immediate release of drug substances followed by sustained release to provide fast onset of action.  They provide controlled absorption of drug substances and target release of drug substance to specific areas. One or more amount of active drug substances can be formulated into these dosage forms.¹⁷ Dosing frequency can be reduced by utilizing this technology. They offer flexibility in designing dosage form which enables production of customized dosage form.  It produces uniform spherical beads of 1-2 mm in diameter containing drug and excipients which are coated with product specific controlled release polymers. ¹⁸ Marketed formulation available are Fluvoxamine maleate extended-release capsules and Dexmethylphenidate hydrochloride extended-release capsules.

Capsule- In -Capsule Technology:

FIG:8 Single capsule encapsulated into other capsule.

• It is a novel development in capsule formation. This type of formulation consists of formulated capsules which are either of liquid filled or dry filled and nested in an outer filled liquid capsule. ¹⁹
• They consist of two phases one is immediate release and one is sustained release. The obtained formulation may be non-aqueous solutions, suspensions, semisolid matrices or microemulsions.
• Advantages include increase patient compliance, reduced dosing frequency, increased bioavailability, increased absorption, product stability, safety for potent and cytotoxic drugs.
• Its limitations include risk of dose dumping, all drugs can’t be formulated, inflexible dosing schedule and high cost of production.
• This type of formulation is used to treat various GI disorders. It provides fast and control release of drug substances.²⁰

Tablet In Capsule:

FIG:9 Tablets that are encapsulated into capsule shell.

It is newly developed approach in pharmaceutical industry that combines the benefits of both tablet and capsule in single dosage form. This involves encapsulating mini tablets into capsule shell. They can be designed to provide initial rapid therapeutic effect followed by extended release. They protect sensitive drug from degradation and improves stability. Tablets are generally manufactured by traditional methods such as direct compression and are encapsulated into hard gelatin capsules. Encapsulation is performed using automated machinery. They even offer personalized medications by tailoring treatment approaches to patients by utilizing genetic behaviour, disease characterized and treatment responses. The use of various kinds of excipients can modulate drug release profile and acts as protecting agents. They even use biodegradable polymers which are environmental friendly materials.  Incorporation of smart sensors inside minitablets enables real time monitoring of patient adherence. They can also detect ingestion events, measure biomarkers and track drug release kinetics. ²¹ Marketed formulation available are Lamisil for antifungal treatment, Paradaxa as anti-coagulant.

Advancements In Capsule Shell:

Recent advances in polymer systems have enabled the production of a wide variety of capsules for performing the required functions. The functional properties of polymers has incresed development of versatility in capsule formulation. Properties of polymers determine the capsule’s performance. Examples of specialized polymers used for the development of capsules are-

Hydroxy Propyl Methyl Cellulose Capsule:

HPMC capsules are an alternative to traditional gelatin capsules, which offer numerous advantages. They exhibit greater stability under various environmental conditions. They are compatible with a wide range of formulations including hygroscopic materials. They are tasteless and odorless, which increases patient interest.  HPMC lacks gelling properties on its own, hence requires an additional gelling agent. The presence or absence of an external gelling agent determines the dissolution profile of capsules. Various types of gelling agents used are carrageenan, pectin, gellan gum, agar agar. When used in specific concentration, they can impart delayed release.  HPMC capsules which are designed without utilizing gelling agent can dissolve in either acidic or basic environment. They are designed for immediate, delayed or enteric release of active ingredients.

Pullulan And Other Modified Polymer Capsules:

Other than HPMC polymer pullulan and other organic solvents have acquired the market. Pullulan capsules are originated from natural fermentation of starch by fungus Aureobasidium pullulans, that are eco-friendly.  Pullulan capsules have oxygen barrier properties, which acts as shield for protecting oxygen sensitive active ingredients like vitamins and probiotics. Pullulan capsule can offer 250 times higher oxygen protecting properties compared to traditional capsules. They possess clear in appearance which are odourless and tasteless. They are known for rapid dissolution which offers increase in bioavailability. Another polymer used is Polyvinyl alcohol. They are combined with starch which offers excellent water solubility and film forming properties. They are highly moisture resistant and stable formulation. As their availability is regional specific, their usage is limited. Usage of wide variants of polymers in capsule formulation not only increased the drug development but also support sustainability by reducing environmental hazards by utilizing biodegradable materials.²²

Current Trends in Capsule Formulation:

Capsules are one of the preffered oral dosage form next to tablets. Out of 22 approved oral medications by FDA in 2022, 10 are capsule dosage forms and 12 are tablets.  Although gelatin capsules have taken a wide market previously, HPMC capsules are now being replaced for gelatin capsules because of their sustainability offering wide variety of properties. Plant based HPMC capsules are used which offer wide range of advantages as they offer high stability. Hydrogel based capsules are used for targeted drug delivery and sustained release of medications. They are made up of hydrogels which are 3-dimensional network of polymers capable of absorbing and retaining water. They possess high level of biocompatibility with biological tissues.  There is rising demand for enteric coated and delayed release capsules. As the burden of chronic disorders are increasing which requires long term of treatment, these kinds of medications offer solution to this problem. Usage of multicomponent and pelletized capsules. Patients requiring multiple medications or supplements make use of these multicomponent capsules. Formulation of active ingredients along with excipients into free-flowing species is known as pellets and technique is known as pelletization. They may be coated or uncoated. They exhibit enhanced physical and dispositional characteristics. They offer fixed dose combination of incompatible drugs without facing stability issues.  Newly emerging trend in nutraceutical industry of pelletized dosage forms are combining liquids and semi-solids with solids in a single capsule.  Recently capsules have been designed for pH determination and environmental monitoring. The Alpha and Bravo capsules are used in the measurement of gut pH.23 Recently approved capsule formulations are Prussian blue insoluble capsule which are used for treating patients who are contaminated with radioactive substances such as caesium or thallium. Magnesium hydroxide capsules are extensively used for this purpose which acts as osmotic agents. Treatment duration and dosage depends on level of contamination.

CONCULSION:

Capsules are one of the most widely used solid oral dosage form which offer several advantages. They are widely accepted by various categories of patients to acquire desired effects. The global capsule market valued at USD 2.96 billion in 2022, which is expected to reach USD 7.28 billion by 2032. As market expands, companies are aiming for advancements in capsule forming technologies to meet the consumers’ requirements aiming for betterment of drug release mechanisms. Capsule forming technology is undergoing rapid advances by utilizing advanced materials, smart designs and sustainability. It is even focusing on personalized health care medications. Capsule filling is becoming more stringent in terms of manufacturing process by utilizing various polymers for capsule shell preparation such as HPMC which offers several advantages and becomes attractive. Innovations have been developed to replace the traditional gelatin capsule shell which has major processing drawbacks which in turn impact on the shelf life of the product. The innovations in the field of pharmaceutical science have led to the outcome of safer, more efficient and sustainable types of capsule forms for patients worldwide.

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