International Numbering System (INS) for Food Additives: 407
Food additives Europe numbers: E407
Functional Category
Emulsifying agent; gel base; stabilizing agent; suspending agent; sustained-release agent; viscosity-increasing agent
Applications in Pharmaceutical Formulation:
Carrageenan is used in a variety of nonparenteral dosage forms, including suspensions (wet and reconstitutable), emulsions, gels, creams, lotions, eye drops, suppositories, tablets, and capsules. In suspension formulations, usually only the i-carrageenen and lcarrageenan fractions are used. l-Carrageenan is generally used at levels of 0.7% w/v or less, and provides viscosity to the liquid. Carrageenan has been shown to mask the chalkiness of antacid suspensions when used as a suspending agent in these preparations.(2) When used in concentrations of 0.1–0.5%, carrageenan gives stable emulsions. Carrageenan is used in hand lotions and creams to provide slip and improved ‘rub out’. i-Carrageenan develops a shear-thinning thixotropic gel, which can be easily poured after shaking. When i-carrageenan is used, the presence of calcium ions is required for the gel network to become established. With pure i-carrageenan, about 0.4% w/v is required for most suspensions plus the addition of calcium. However, if SeaSpen PF is used, it must be at about 0.75% w/v level, although no additional calcium is required as this is already present in the product to control the rate of gelation. Studies on the effect of carrageenan and other colloids on mucoadhesion of drugs to the oropharyngeal areas(3,4) have shown that carrageenan had the greatest propensity for adhesion and can be used in formulations for oral and buccal drug delivery. The application of carrageenan in topical gel bases has been examined,(5–7) and the findings indicate that the use of carrageenan in these dosage forms is most likely to be dependent on the active drug, owing to the potential for ionic interactions. In the case of topical gels, a combination of i, k-, and lcarrageenans produces a spreadable gel with acceptable tactile sensation, resulting in drug release that is more likely to follow diffusion kinetics. Incorporation of carrageenan into tablet matrices with various drugs and other excipients to alter release profiles has been studied, illustrating that the carrageenans have good tablet-binding properties.(8–12) Furthermore, the inclusion of calcium or potassium salts into the tablet creates a microenvironment for gelation to occur, which further controls drug release. There have also been several references to the use of carrageenan in chewable tablets having a confectionary texture.(13,14) This approach to creating a novel dosage form requires the use of both icarrageenan and k-carrageenan, to prevent moisture loss and texture changes that occur over time. See also Section 10. Carrageenan has been used for the microencapsulation of proteins(15) and probiotic bacteria.(16) Hydrogels have also been prepared by crosslinking with gelatin and k-carrageenan for oral delivery of probiotic bacteria.(17) It has also been used as beads in the preparation of controlled release systems.(18,19) Hydrogel beads based on k-carrageenan and sodium alginate/chitosan are being used as new carriers for drug loading and controlled delivery systems.(20,21) k-Carrageenan is known as a novel pelletization aid in the manufacture of pellets by extrusion/spheronization and has the best pelletization behavior.(22–25) l-Carrageenan is also able to nanoencapsulate drug molecules spontaneously, hence controling drug release.(26) The presence of carrageenan induces the formation of smaller particles compared to those formed in the absence of polymer, and their average size depends on the nature and concentration of the polysaccharide used.(27) Studies have shown that carrageenan compounds block infections by the herpes simplex virus;(28) human cytomegalovirus; human papilloma virus;(29) Sindbis virus; vesicular stomatitis virus; and HIV.(30) A combined k- and l-carrageenan formulation is currently being investigated as the active ingredient in a topical microbicide used to prevent the sexual transmission of HIV.(31–33) In combination with chitosan, agar and polyvinyl pyrrolidone, carrageenan forms a water-insoluble complex which is able to absorb large amounts of body fluids, and is used as an effective wound dressing.(34–36) Carrageenan is used in the preparation of hard and soft capsule shells.(37) It is also used in toothpastes and cosmetic preparations such as conditioners and shampoos.(38,39)
Description
Carrageenan, when extracted from the appropriate seaweed source, is a yellow-brown to white colored, coarse to fine powder that is odorless and tasteless.
Stability and Storage Conditions
Carrageenan is a stable, though hygroscopic, polysaccharide and should be stored in a cool, dry place. Carrageenan in solution has maximum stability at pH 9 and should not be heat processed at pH values below 3.5. Acid and oxidizing agents may hydrolyze carrageenan in solution leading to loss of physical properties through cleavage of glycosidic bonds. Acid hydrolysis depends on pH, temperature and time. The acid hydrolysis takes place only when the carrageenan is dissolved, and the hydrolysis is accelerated as the processing temperature and/or the processing time is increased. However, when the carrageenan is in its gelled state the acid hydrolysis no longer takes place; see Table IV
Incompatibilities
Carrageenan can react with cationic materials. If complexation of cationic materials, with associated modification of the active compound’s solubility, is undesirable, the use of carrageenan is not recommended. Carrageenan may interact with other charged macromolecules, e.g. proteins, to give various effects such as viscosity increase, gel formation, stabilization or precipitation
Safety
Carrageenan is widely used in numerous food applications and is increasingly being used in pharmaceutical formulations. Carrageenan is generally regarded as a relatively nontoxic and nonirritating material when used in nonparenteral pharmaceutical formulations. However, carrageenan is known to induce inflammatory responses in laboratory animals, and for this reason it is frequently used in experiments for the investigation of anti-inflammatory drugs.(41–45) Animal studies suggest that degraded carrageenan (which is not approved for use in food products) may be associated with cancer in the intestinal tract, although comparable evidence does not exist in humans.(46) The WHO has set an acceptable daily intake of carrageenan of ‘not specified’ as the total daily intake was not considered to represent a hazard to health.(47) In the UK, the Food Advisory Committee has recommended that carrageenan should not be used as an additive for infant formulas.(48) LD50 (rat, oral): >5 g/kg LD50 (rabbit, skin): >2 g/kg/4 h LC50 (rat, inhalation): >0.93 mg/L(49