Capsule (drug)
A capsule is a solid dosage form that provides a fixed dose of a drug. Capsules are mostly used orally , but there are also capsules for vaginal or rectal use, as well as a pre-dosage option for powder inhalers .
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Capsules consist of a capsule shell and a filling. Today, the shell is mostly made of gelatine , occasionally cellulose or carrageenan , and in the past also made of starch or glue . Both the shell and the filling material can be made gastric juice-resistant with coatings or other formulation techniques. Such enteric capsules (rarely also called enteric capsules ) only release the active ingredient in the intestine and not in the stomach. This is in contrast to the bite capsule , the contents of which are already released in the mouth and, depending on the physicochemical properties , can be absorbed through the oral mucous membranes .
While hard capsules are preferably filled with solid goods such as powders , granules , tablets or even smaller capsules, soft capsules are usually filled with liquid or pasty systems. Capsules are more costly to produce than tablets. However, capsules have some advantages over tablets. This includes the protective effect of the capsule shell, which on the one hand protects the active ingredient from external conditions (e.g. light ), but on the other hand also protects the patient from e.g. B. can protect the smell or taste of the active ingredient . Thanks to the many design options for the capsule shell in terms of shape, size and color (and in some cases printing), the placebo effect and recognition value can be strengthened. Furthermore, hard capsules are a relatively easy-to-manufacture drug form that is occasionally made individually in the pharmacy . The disadvantage of the capsule compared to a tablet is that it is more complicated to take and the shorter shelf life. It is best for patients to take capsules standing up with plenty of liquid to prevent the gelatin from sticking to the esophagus.
Related dosage forms: tablet , dragee , pill , film-coated tablet
history
Since most people are reluctant to take drugs that taste and / or smell bad, gelatine and starch capsules and dragees were developed. In 1834 Joseph Gerard Auguste Dublanc and his assistant Francois Achille Barnabe Mothes patented the production of so-called capsules gelatineuses . The latter filled Balsamum Copaivae into small, egg-shaped glue vesicles with an airtight seal. In 1837 the Viennese pharmacist Karl Schürer von Waldheim was granted the privilege to produce gelatine capsules, which the pharmacist Johann Eduard Simon sold in Berlin four years later. In 1847, Mathilde Winkler was commissioned to produce "elastic capsules" for wrapping foul-tasting medicines . The gelatine or glue capsules were included in DAB 3 in 1890. It turned out that these capsules were well suited for the administration of fatty or essential oils.
In contrast, starch capsules were used to encase powders. As early as 1730, Christof de Pauli (1683–1754) tried to wrap such bad-tasting substances in wafers. At that time, however, this procedure was not yet well received. It was not until the 1870s that Stanislas Limousin (1831–1887) developed two-part cachets made of starch for powdered medicines. With the help of Marie Fasser , owner of a wafer company, he tried to improve the manufacturing processes and the quality of the capsules. They developed a new locking device that reduced fragility. After that, the " Capsula amylaceae " quickly became established and were also included in the DAB .
Capsule types
Hard capsules
They are mainly made from a gelatin mass. Due to ethical and cultural influences, other film formers such as hydroxypropylmethyl cellulose are also increasingly being used. In contrast to soft capsules, hard capsules do not contain any plasticizers. Hard capsules consist of two prefabricated, cylindrically shaped hollow shapes with a hemispherical bottom. These nested capsule halves are available in eight different sizes (from large to small: 000, 00, 0, 1, 2, 3, 4, 5), sizes 0–3, most often size 1. To preserve the The strength and elasticity of the capsules must not be stored too dry or too moist (residual moisture 12–14%). Hard capsules are almost exclusively used to absorb solid preparations (powder, granules, pellets, microcapsules). For uniform dosing, the most uniform possible grain size and good flowability of the preparation are required. In order for hard gelatine capsules to have mechanical stability, they are closed using a groove-cam mechanism. This prevents unintentional opening of a capsule. This system is known as SNAP-FIT ® . Other locking systems are STAR-LOCK ® and LOK-CAPS ® . If the content of the capsule is particularly sensitive to moisture, the capsule can also be glued, welded or provided with a band.
Filling
Hard capsules are usually filled in a volume-dosed manner. For this purpose, a capsule machine is used in pharmacies and various metering devices in industry. In the double slide process, two slide valves are used to pre-dose the product and then fill it into an empty capsule. In the screw process, a dosing screw transports the product to the bottom of the capsule. The tamping process is characterized by tamping punches that first compress the product inside a metering disc and then slide it into the empty capsule via a deflector. With the tube dispenser, too, the product is first compacted by being dipped into the product several times. The metering plunger is then not only used to set the desired volume, but also pushes the active ingredient mixture into the capsule shell.
Dimensions of hard capsules
| size | External dimensions | Content (density dependent) | Weight | volume | 1 teaspoon of powder fits in | Pieces / dm³ |
|---|---|---|---|---|---|---|
| 000 | 2.6 cm x 0.97 cm | 800 mg - 1600 mg | 158 mg | 1.4 ml | 4 capsules | |
| 00 | 2.3 cm x 0.84 cm | 600 mg - 1200 mg | 123 mg | 0.91 ml | 5 capsules | 510 capsules |
| 0 | 2.16 cm x 0.75 cm | 400 mg - 800 mg | 100 mg | 0.68 ml | 7 capsules | 600 capsules |
| 1 | 1.94 cm x 0.68 cm | 290 mg - 580 mg | 76 mg | 0.50 ml | 10 capsules | 950 capsules |
| 2 | 1.76 cm x 0.62 cm | 220 mg - 440 mg | 61 mg | 0.37 ml | 13 capsules | 1100 capsules |
| 3 | 1.57 cm x 0.57 cm | 160 mg - 320 mg | 47 mg | 0.30 ml | 18 capsules | 1400 capsules |
| 4th | 1.43 cm x 0.52 cm | 120 mg - 240 mg | 41 mg | 0.21 ml | 25 capsules | 2100 capsules |
Soft capsules
Soft capsules come in many different forms. Mainly soft capsules are based on the Process Rotary made . But there is also the Globex - Accogel or Norton process. Compared to hard capsules, soft capsules have a thicker, but more elastic, soft shell. The elasticity is achieved by adding plasticizers such as sorbitol or glycerol with a content of approx. 25%. Soft capsules are preferably used to hold liquid and semi-solid preparations. Only aqueous or hygroscopic liquids are excluded from use because of the dissolution of the gelatin shell. Rectal and vaginal capsules have the same properties.
Occasionally, the active ingredient is worked into the capsule shell instead of the filling (lozenges).
Filling of soft capsules
Soft capsules are shaped, filled and sealed in one operation. Liquid products can be filled directly, while solid products are first dissolved or dispersed in a suitable auxiliary material, so that a paste-like consistency is obtained. Pumpable solutions , suspensions or emulsions are mainly used as filling material . Depending on which substances are used as the filling material, the filling material and capsule shell can migrate. Water or water-containing mixtures are therefore not used to fill soft gelatine capsules, ethanol and glycerol only in small quantities. Vegetable oil / wax , paraffin oil / hard paraffin and macrogols are suitable filling goods . By lecithin supplements the pumping ability of the filling material can be improved further. Make sure that the active ingredients and other components have a particle size of less than 100 μm, as otherwise the filling channels can become clogged. The filling of soft capsules can be carried out with certain industrial processes, such as e.g. B. the drip process, the Norton process, the Accogel process or with the Scherer process.
Soft gelatine capsules without a seam are produced using the drop process, also known as the Globex or blown process. With the help of a concentric double capillary, the lipophilic filling material can flow out of the nozzles. A warm gelatin solution flows out of a tube that surrounds this nozzle. At the mouth of the capillary, the filling material and gelatin solution flow together. When the product cools down, a seamless soft gelatin capsule forms due to the favorable interfacial tension. The capsule then drips into a cool paraffin solution. Round capsules are created that do not contain any air pockets. In most cases, the Globex process is used to encapsulate oils. The capsule size can be determined by varying the machine. With the drip process, up to 5000 capsules can be produced per hour.
The Accogel process can be used to encapsulate liquids, pastes and even powders. The forming roller has channels in the base through which a vacuum can be applied and which form elongated pockets. The vacuum enables the gelatine to be sucked into a depression in the roller. These pockets hold the contents. With the help of a second forming roller, another gelatine band is placed on the first and closed by pressing and welded. Due to the vacuum, the seam is created on the side. The Accogel process can produce 25,000 to 60,000 soft capsules per hour.
Elongated, bag-like capsules can be formed using the Norton process. Here, too, gelatine tapes are used, which are fed from both inner sides of the capsule forming machine. The filling material is filled into the pockets of the capsule molding with the help of filling cannulas, at the same time two gelatine bands are advanced by one capsule length so that both molded parts are pressed together. The molded parts move alternately together and apart again and gradually punch out the soft gelatin capsules.
The most well-known process for the production of soft gelatine capsules today is the Scherer process. This process can produce 100,000 capsules per hour. Capsule filling and manufacture take place in one operation. The production of oval, oblong, teardrop-shaped and ampoule-shaped capsules is possible. However, it cannot be used to encapsulate powders; these must first be processed into a suspension or paste. The machine has two forming rollers that rotate together. Gelatin ribbons, which consist of 40% gelatin, 30% glycerol and 30% water, run on these forming rollers. The filling material is added between the two forming rollers and the two halves of the gelatine ribbon are welded to one another through the development of heat. The produced soft gelatin capsule is cooled. It is then washed with organic solvents and dried at 30% humidity and room temperature.
Microcapsules
Microcapsules are solid particles or liquid droplets that are coated with a gelatin coating or other substances ( gum arabic or other polymers e.g. starch, cellulose). They range in size from nanometers to a few millimeters. Microencapsulated substances are free-flowing powders and are mostly used as an intermediate product in drug formulation. The advantages of microencapsulation are that liquids can be converted into dry powders and processed into solid preparations without difficulty. In this way, unpleasant smells or tastes can be concealed and volatile substances are fixed. The shell material of the microcapsules offers protection against external influences (light, air, moisture). Thanks to the microencapsulation, incompatible drugs can also be processed with one another. Appropriate processing enables gastric juice-resistant capsules or capsules with delayed release of active ingredients to be produced.
Gastro-resistant capsules
The European Pharmacopoeia defines enteric capsules as capsules with delayed release . They are therefore assigned to capsules with a modified release of active ingredients. Gastric juice- resistant capsules are stable in an acidic environment, such as gastric juice . The active ingredients are only released after passage through the stomach in the duodenum , jejunum or ileum , where a more neutral environment is present. Both hard and soft capsule shells can have an enteric coating. As a rule, however, the capsules are filled with enteric granules , tablets or pellets . The exact location of the release is determined by the type of coatings used. In so-called colon targeting , coatings are used that dissolve in even higher pH values than in the duodenum.
Enteric coatings consist of synthetic polymers such as polymethacrylates, vinyl acetate-vinylpyrrolidone copolymers, polyvinyl acetate phthalates or PEG-polyvinyl alcohol copolymers. In addition, semi-synthetic polymers in the form of cellulose derivatives such as cellulose ethers or esters are also used. Natural polymers such as shellac are rarely used due to the rapid aging process and varying composition.
The European Pharmacopoeia prescribes different tests depending on the type of gastric juice resistance. Enteric coated envelopes must correspond to a modified test for disintegration time (2.9.1). The apparatus used has a frame made of a sieve bottom with 6 test tubes into which the dosage forms are added. The apparatus heats one liter of the medium prescribed in the respective monograph (here: 0.1 N hydrochloric acid) to approx. 37 ° C. The frame is immersed in the medium, oscillating, for two hours. After the time has elapsed, the dosage forms are examined. The gastric juice-resistant capsules must not show any damage that would indicate the release of the content. The medium is now replaced by phosphate buffer with a pH value of 6.8, a disk is placed on each capsule and put into operation for one hour, each capsule having to disintegrate.
Starch capsules
Starch capsules are made in special wafer bakeries from wheat starch and wheat flour. There are two different forms. The first form consists of a bowl and a lid (larger diameter). The second form consists of two equal parts that are glued together at the edge after filling. The capacity of starch capsules is between 0.2 and 1.5 g powder. To make it easier to take the capsules, they are briefly immersed in water. This makes the capsule slippery but does not disintegrate. Starch capsules are only suitable for the absorption of dry powder. Because of their sensitivity to moisture and mechanical stress, and above all because of their unsatisfactory disintegration properties, starch capsules are almost no longer used today.
Individual evidence
- ↑ Official German edition: European Pharmacopoeia . In: Deutscher Apotheker Verlag (Hrsg.): Grundwerk . 8th edition. tape 1 . Govi-Verlag, 2014, ISBN 978-3-7692-6253-7 , pp. 1714 .
- ^ A b Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Ed. Wiss. Verl.-Ges, Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 32 f .
- ^ Drug Development and Industrial Pharmacy. Retrieved November 8, 2017 .
- ^ Bauer Frömming Führer: Textbook of Pharmaceutical Technology . Ed .: Wissenschaftliche Verlagsgesellschaft mbH Stuttgart. 8th edition. Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, Stuttgart, ISBN 978-3-8047-2222-4 , p. 487 .
- ^ Rudolf Voigt: Pharmaceutical Technology . Ed .: Deutscher Apotheker Verlag Stuttgart. 10th edition. Deutscher Apotheker Verlag Stuttgart, Stuttgart, ISBN 978-3-7692-3511-1 , p. 716 .