Capsule (dosage form)

Among the capsules distinguish:

• solid
• soft
• microcapsules
• gastro-resistant capsules (enteric-soluble)
• spansules - capsules containing pellets

Soft - whole capsules of various shapes (spherical, ovoid, oblong, etc.) with liquid or pasty substances.

Solid - capsules of cylindrical shape with hemispherical ends, consisting of two parts, which enter one another, without forming gaps.

Capsules may be filled with:

• powders
• granules
• microcapsules
• pellets
• pills
• liquid "ointment" mixtures
• live lyophilized bacteria

From the point of view of patients, capsules have a large number of advantages that serve as the reason that this dosage form is one of the most popular in the pharmaceutical market ^[1] . According to studies, most patients believe that capsules, thanks to their smooth, sliding shells, are much easier to swallow than tablets ^[1] . In addition, the material of the capsule itself completely eliminates contact between the substance and the human oral cavity , which eliminates the bitter taste and unpleasant odor that most active substances possess ^[1] . This factor significantly facilitates the patient's compliance , which in turn increases the therapeutic effect of the prescribed therapy ^[1] . Capsules can also be made with a clean glossy shell, attractive to the consumer, which improves the aesthetic perception of this dosage form ^[1] . In case of additional difficulties in swallowing, some geriatric and pediatric capsules provide the possibility of opening and mixing their contents with food ^[1] . There are a number of advantages of capsules as a dosage form in terms of ensuring the bioavailability of the drug, since they are most effective for immediate release forms of the active substance ^[1] . When using pellets as an encapsulate in the case of some formulations, prolonged plasma concentration profiles of the active substance can be achieved ^[2] . One of the most important advantages of capsules is the simplicity of their use, which does not require any special skills from the patient (compared to injections ) ^[2] .

A number of advantages make capsules an attractive form for drug manufacturers. Capsules can be used throughout the entire process of studying the effectiveness of a drug (both in animal experiments and in clinical studies ), without the need to transfer them to another form for patients to take ^[2] . Despite the lower cost-effectiveness of capsule production compared to tablets, this dosage form still has a relatively low cost and provides high stability for encapsulated active substances ^[2] . Capsules are simple enough to develop their production technology, since the main requirement for the material of the encapsulate is only to ensure uniformity of dosage, which allows manufacturers to quickly bring new products to the market ^[2] . From the point of view of marketing, capsules as a dosage form provide the manufacturer with great opportunities to use a wide range of colors, various sizes, applying inscriptions and logos, which contribute to increasing brand awareness among patients ^[2] .

Despite all the advantages, capsules also have a number of significant disadvantages. This dosage form is poorly suited for the creation of preparations intended for absorption in the small intestine , since the standard capsule material undergoes strong hydrolytic decomposition during their stay in the stomach and requires the introduction of special acid-resistant compounds ^[3] . A number of hygroscopic excipients It is impossible to use in the encapsulate, as they can dry the material of the capsules and make them brittle. The capsule body itself, on the contrary, is prone to absorb moisture from the environment, which can adversely affect the stability of the drug and lead to stickiness of the shell ^[3] . Gelatin , which is used as a capsule material, needs additional control in order to avoid getting the causative agents of mad cow disease ^[3] . Capsules are much smaller than tablets suitable for creating herbal remedies , because due to the lack of a pressing stage, a finished capsule containing vegetable raw materials will have a very large size, which is inconvenient for the patient to take ^[3] . The complexity of manufacturing and validation of the capsule shell production process forces manufacturers to buy ready-made cases, which increases the cost of finished products ^[3] . The speed of filling the capsules is also inferior to tabletting , and the filling machines themselves are more complex in design, which increases their service time compared to tablet presses ^[3] . The transition from filling capsules of one size to another requires a complete replacement of the entire dispensing mechanism, which can take several hours, while similar maintenance of tablet presses consists only of replacing punches and dies ^[3] .

The first mention of capsules as a dosage form is contained in the Ebers papyrus (about 1550 BC), where they are presented as one of the possible ways of dispensing pharmaceutical substances ^[4] . Nevertheless, the ancient Egyptian text does not contain a detailed description of what exactly was used in the role of these capsules and what kind they had ^[4] . In the modern sense of this dosage form, capsules are first found in the records of the Vienna pharmacist de Pauli, dated 1730. De Pauli's invention described oval capsules filled with turpentine , which was prescribed for patients with gout ^[4] . The goal of the pharmacist when creating a new dosage form was the desire to hide the unpleasant taste of the active substance ^[4] .

A century later, in 1834, a patent was issued to pharmacist Joseph Gerard Dublain and his student Francois Motet in Paris , confirming their invention of a method for producing capsules from gelatin ^{[1] [5]} . This method itself consisted in immersing a small leather bag filled with mercury in molten gelatin ^[4] . After removing the bag from the melt, it was dried to form a hard gelatin film, which was then removed from the mold ^[4] . The finished capsules were filled using a pipette with various liquid dosage forms and were finally sealed from the open end with a drop of molten gelatin ^[4] . In modern terms, due to the unstable shape, Dublan capsules would be classified as soft ^[6] .

The invention did not go unnoticed by doctors, and only a year later the production of this dosage form was started outside of France. Soon there were a large number of patent applications for capsules from other researchers who wanted to circumvent the claims of Mote and Dublan ^[4] . One of these experimenters was Jules Cesar Leyubi, who registered in 1846 a patent for the first fully hard capsule, which consisted of two gelatin parts, which were obtained by immersion of silver-coated pins mounted on a holder frame ^[6] . Leyubi himself described his capsules as “cylindrical in the form of a silkworm pupa and consisting of two parts that connect to each other to form a box”, and this method was the basis of the entire modern production of hard gelatin capsules ^[4] . Despite this, the difficulties in manufacturing individual cases and capsule caps limited the distribution of this dosage form only by manual production at pharmacies at that time ^[4] . In 1847, in Great Britain, a similar patent for two-part capsules was obtained by patent agent James Murdoch, who was also called the inventor of this type of capsule in a number of sources ^[6] .

The transition to the industrial level of production occurred in 1888, after John Russell created the capsule making machine based on Leuby technology, which was introduced at the Parke-Davis plant in Detroit ^[4] . Further development of capsule machines went towards increasing productivity - in 1895 Arthur Colton patented an apparatus capable of producing from 6 to 10 thousand capsules per hour ^[4] . In 1924, Colton's company introduced and in 1931 introduced a machine for Parke-Davis, capable of producing two-tone capsules and at the same time form both caps and cases of hard capsules ^[4] . It was this apparatus that became the basis for all modern industrial machines for the manufacture of hard gelatin capsules ^[4] . In 1933, the first soft capsules invented by American Robert Pauli Scherer were launched on the market.

By the beginning of the XXI century, the global production of capsules became the third largest among all dosage forms, second only to tablets and injectable drugs ^[2] . According to forecasts, from 2014 to 2019, the empty capsule market was to expand by 7% annually, due to an increase in the consumption of drugs by the aging population of developed countries and the emergence of a large number of innovative substances that required new delivery methods ^[7] .

Capsule Shell

Capsule Content

Flow Chart

Encapsulate

Hard capsule shells

Soft capsule shells

Capsule Filling

Finishing and packaging

• Larry L. Augsburger. Hard- and Soft-Shell Capsules // Modern Pharmaceutics: Volume 1. Basic Principles and Systems: [ eng. ] . - N. Y .: Informa Healthcare , 2006. - P. 499-564. - (Drugs and the Pharmaceutical Sciences). - ISBN 978-1420065640 .
• Georg Schwedt. Chemie der Arzneimittel: Einfache Experimente mit Medikamenten aus der Apotheke: [ him. ] . - Mannheim: Wiley , 2018 .-- 166 S. - ISBN 978-3527345038 .
• Developing Solid Oral Dosage Forms: Pharmaceutical Theory & Practice: [ eng. ] / Yihong Qiu, Yisheng Chen, Geoff GZ Zhang, Lawrence Yu, Rao V. Mantri. - San Diego, CA: Elsevier , 2017 .-- 1176 p. - ISBN 978-0128024478 .
• Pharmaceutical Dosage Forms: Capsules: [ eng. ] / Larry L. Augsburger, Stephen W. Hoag. - Boca Raton, FL: CRC Press , 2018 .-- 435 p. - ISBN 978-1841849768 .