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Among solid dosage forms, the capsule is second only to the compressed tablet in terms of frequency of use. Given the unique advantages of this dosage form, the popularity of the capsule is not surprising. Because the medication is contained within the capsule shell, the capsule provides a tasteless, odourless delivery system that doesn't require a secondary coating step. Many patients find that swallowing capsules is easier than swallowing tablets. From the formulator's point of view, hard-shell capsules provide unique capabilities and options for dosage form design and formulation. Therefore, with the appropriate choice of excipients, it may be possible to direct-fill into capsules many large-dose actives that could not be tableted without a granulation step. Modern capsule-filling machines also enable the multiple filling of beads, granules, tablets, powders, and liquids into hard shells. This capability provides the formulator with numerous options for designing unique delivery systems or simply for separating incompatible substances within the same capsule.
Capsules and soft gels have undergone several significant transformations over the years, resulting in improved formulations and delivery of ingredients. Capsule technologies continue to develop and expand. The traditional powder-fill hard capsule (hard-shell) and the liquid-fill soft capsule (softgel) still represent a significant percentage of the capsule market. However, the continuing development of materials and processing technologies for liquid-fill capsules offer increased options for formulators and manufacturers, and offers further opportunities for marketing groups. Materials development includes capsule-forming components and excipients that can affect product bioavailability and stability. Manufacturing technologies include machine development for new capsule-based units. These advances have been coupled with increasing manufacturing expertise and facilities to provide new product formats that can provide formulators and marketers with new options.
Gelatine continues to be the main capsule-forming material, with ongoing activity in developing alternatives. One major development lies in non-gelatine softgel capsules that use modified starch in combination with carrageenans. These are sulphated polysaccharides derived from the cell walls of red algae, and are widely used in the food industry. Capsule forming uses the so-called iota and kappa carrageenans that have specific chemical and physical properties. The kappa carrageenan provides gel strength whereas the iota carrageenan provides flexibility. They are suitable for concentrated fills or for salts of weak acids and strong bases, as shown in 18-month stability samples with ibuprofen. It is likely that these materials will be exploited widely for non-gelatine softgel products.
Capsule coating has represented low-volume manufacture for many years, with restricted market opportunities. It has been aimed primarily at pharmaceuticals that required protection of the active against gastric acid. Commercial exploitation has been partly restricted by technological difficulties in ensuring robust processing and in adopting non-aqueous systems. For example, it is difficult to coat softgels because of low coat adhesion on the plasticized capsule shell surface; hence, coating is done using solvent systems. The use of hard shells minimizes this issue as there is no plasticizer present and the capsule surface provides for good shell/ coat adhesion. The cap/body edge can represent a mechanical weak-point for the coat but can be minimized by capsule banding. It provides a non-stepped surface for coat adhesion and is suited for use with industry standard aqueous-coat materials. The enteric-coat components which are standard to the pharmaceutical industry are not allowed in nutritional supplements. They could be useful in certain nutraceutical applications, such as for probiotics or other acid-sensitive components. An alternative approach that uses shellac in an aqueous-based system has been described. It meets pharmacopoeial standards for enteric coat performance while meeting the acceptability requirements for non-pharmaceuticals.
The developments in aqueous-based coating systems have led to an increase in the amount of unique colour coatings. In addition, requests for vegetarian products have increased leading to use of more vegetarian capsules and use of excipients, which meet vegetarian standards. Also, fast-melt formulas, which do not require water for administration, certainly have appeal for paediatric and geriatric populations, where swallowing can be problematic. Other considerations that will continue to drive capsule preference include ease-of swallowing, as well as an elegant visual appearance.
There have been difficulties concerning the development and manufacture of combination products. The Duocap system, developed for multi-component and multiphase products, is based on hard-capsule liquid-fill technology and presents formulators with a means of solving these complex formulation issues, together with a way of implementing manufacture. Potential uses include:
the development of multiphase release products using specific excipients (macrogol glyceridesl) or technologies (microemulsions)
the co-presentation of compatible actives
the co-presentation of incompatible actives
the avoidance of site-specific degradation in the gastrointestinal tract
the formulation of fixed-combination products
meeting marketing needs for line extensions
Based on manufacture using a modified Bosch 1500 L filling machine, the Duocap system enables a capsule to be filled into a larger liquid-filled capsule. As a further sophistication, either or both capsules may be coated. The approach is well suited to pharmaceuticals when there is a need to manipulate release profiles and to high-end nutraceuticals, particularly when there is a need to deliver product to different parts of the intestine or to avoid compatibility issues. The presentation may also have marketing advantage.
Using a combination of lipids and nanoparticles, researchers from the University of Illinois at Urbana-Champaign (UIUC) have devised a potentially new variant of drug delivery systems with their nano-size capsules.
"This is a new way to make nano-size capsules of a biologically-friendly material. The hollow, deformable and bio-functional capsules could be used in drug delivery, colloidal-based biosensors, and enzyme-catalyzed reactions," adds Steve Granick, lead project researcher.
This process was achieved by first preparing a dilute solution of lipid capsules of a particular size. After encapsulating chemicals in the capsules or adsorbing molecules on their surfaces, the team added charged nanoparticles to the solution. The nanoparticles then adhered to the capsules to prevent further growth, freezing them at the desired size. The lipid concentration can then be increased without limits.
Oral delivery of peptide hormones
Oral delivery of therapeutic peptide hormones offers the promise of greater patient compliance when compared to injectable formulations. Success is difficult to achieve because the hormones are relatively large and vulnerable to degradation in the gastrointestinal tract. An enteric-coated solid dosage form with excipients that modulate intestinal proteolytic activity and enhance peptide transport was developed.
Alternate routes of delivery for macromolecule drugs have been a topic of intense R&D to improve patient acceptance and adherence to chronic dosing regimens. Many companies and research groups have developed alternate delivery methods, including nasal, pulmonary, buccal, and transdermal administration and depot injection. However, oral delivery formulations in capsules or tablets offer the greatest convenience and patient compliance.
Therapeutic peptide hormones represent a major challenge for oral delivery. Developers of commercially viable oral peptide products face four obstacles:
strongly acidic gastric environment
high levels of intestinal proteolytic activity
high intestinal permeability barrier
need for large quantities of the active pharmaceutical ingredient because of the inherently low bioavailability of an orally delivered peptide.
Unigene Laboratories proprietary technology, which meets all the goals of orally active formulations, involves the preparation of a solid dosage form that contains the peptide along with other excipients in enteric-coated capsules or tablets. The excipients consist of up to three groups of compounds, depending on the peptide to be delivered. The Group A additive is a general inhibitor or modulator of intestinal protease activity. The Group B additive is a detergent that improves the solubility of the peptide, decreases interactions with intestinal mucus, and enhances paracellular transport. The Group C additive is a specific inhibitor of the primary enzymes that degrade the peptide. The Group C additives increase the stability of the molecule in the GI tract.
The enteric coating makes the capsule stable in acidic pH and allows it to pass through the stomach intact. As the pH in the intestine increases above 5.5, the coating dissolves and releases the peptide and excipients into a localized area of the intestine, where proteases with neutral to alkaline pH optima are inhibited.
This technology is applicable to a variety of peptides and small proteins, and it can achieve relative bioavailabilities ranging from 1 to 10%, depending on the size, charge, and structure of the peptide. No chemical modification or derivatization of the peptide is necessary to achieve peptide absorption.
Capsules against diabetes
A UK company, Diabetology and Cardiff University experts may have solved the previous setback on oral insulin with their capsules special coating that protects the drug from acids in the stomach, which will allow it to pass into the small intestine where it is absorbed.
Biotechnologists at The Norwegian University of Science and Technology (NTNU) have developed a new type of alginate capsule -called TAM (the Trondheim Alginate Microcapsule) - that could solve the problem of the body's immune system recognizing and attacking alien, implanted insulin cells. They say that the gel capsule is designed with a view to camouflage the insulin-producing cells to the body's immune system.
Capsule development continues across a broad spectrum of activities, from the introduction of new materials, new formulation and processing systems and up to meeting the security needs of the current marketplace. These reflect engineering and formulation innovations and the market's needs to resolve increasingly demanding technical issues in the development and manufacture of products containing new chemical entities or drug combinations.