Functional Category:
Bioadhesive material; controlled-release agent; emulsifying agent; emulsion stabilizer; rheology modifier; stabilizing agent; suspending agent; tablet binder.
Applications in Pharmaceutical Formulation:
Carbomers are used in liquid or semisolid pharmaceutical formulations as rheology modifiers. Formulations include creams, gels, lotions and ointments for use in ophthalmic,(5–7) rectal,(8–10) topical(11–20) and vaginal(21,22) preparations. Carbomer grades with residual benzene content greater than 2 ppm do not meet the specifications of the PhEur 6.4 monograph. However, carbomer having low residuals of other solvents than the ICH-defined ‘Class I OVI solvents’ may be used in Europe. Carbomer having low residuals of ethyl acetate, such as Carbopol 971P NF or Carbopol 974P NF, may be used in oral preparations, in suspensions, capsules or tablets.(23–35) In tablet formulations, carbomers are used as controlled release agents and/or as binders. In contrast to linear polymers, higher viscosity does not result in slower drug release with carbomers. Lightly crosslinked carbomers (lower viscosity) are generally more efficient in controlling drug release than highly crosslinked carbomers (higher viscosity). In wet granulation processes, water, solvents or their mixtures can be used as the granulating fluid. The tackiness of the wet mass may be reduced by including talc in the formulation or by adding certain cationic species to the granulating fluid.(36) However, the presence of cationic salts may accelerate drug release rates and reduce bioadhesive properties. Carbomer polymers have also been investigated in the preparation of sustained-release matrix beads,(26–39) as enzyme inhibitors of intestinal proteases in peptide-containing dosage forms,(40–42) as a bioadhesive for a cervical patch(43) and for intranasally administered microspheres,(44) in magnetic granules for site-specific drug delivery to the esophagus,(45) and in oral mucoadhesive controlled drug delivery systems.(46–49) Carbomers copolymers are also employed as emulsifying agents in the preparation of oil-in-water emulsions for external administration. Carbomer 951 has been investigated as a viscosity-increasing aid in the preparation of multiple emulsion microspheres.(50) Carbomers are also used in cosmetics. Therapeutically, carbomer formulations have proved efficacious in improving symptoms of moderate-to-severe dry eye syndrome.(51,52)
Description:
Carbomers are white-colored, ‘fluffy’, acidic, hygroscopic powders with a characteristic slight odor. A granular carbomer is also available
Stability and Storage Conditions
Carbomers are stable, hygroscopic materials that may be heated at temperatures below 1048C for up to 2 hours without affecting their thickening efficiency. However, exposure to excessive temperatures can result in discoloration and reduced stability. Complete decomposition occurs with heating for 30 minutes at 2608C. Dry powder forms of carbomer do not support the growth of molds and fungi. In contrast, microorganisms grow well in unpreserved aqueous dispersions, and therefore an antimicrobial preservative such as 0.1% w/v chlorocresol, 0.18% w/v methylparaben–0.02% w/v propylparaben, or 0.1% w/v thimerosal should be added. The addition of certain antimicrobials, such as benzalkonium chloride or sodium benzoate, in high concentrations (0.1% w/v) can cause cloudiness and a reduction in viscosity of carbomer dispersions. Aqueous gels may be sterilized by autoclaving(7) with minimal changes in viscosity or pH, provided care is taken to exclude oxygen from the system, or by gamma irradiation, although this technique may increase the viscosity of the formulation.(54,55) At room temperature, carbomer dispersions maintain their viscosity during storage for prolonged periods. Similarly, dispersion viscosity is maintained, or only slightly reduced, at elevated storage temperatures if an antioxidant is included in the formulation or if the dispersion is stored protected from light. Exposure to light causes oxidation that is reflected in a decrease in dispersion viscosity. Stability to light may be improved by the addition of 0.05–0.1% w/v of a water-soluble UV absorber such as benzophenone-2 or benzophenone-4 in combination with 0.05–0.1% w/v edetic acid. Carbomer powder should be stored in an airtight, corrosionresistant container and protected from moisture. The use of glass, plastic, or resin-lined containers is recommended for the storage of formulations containing carbomer.
Incompatibilities:
Carbomers are discolored by resorcinol and are incompatible with phenol, cationic polymers, strong acids, and high levels of electrolytes. Certain antimicrobial adjuvants should also be avoided or used at low levels, see Section 11. Trace levels of iron and other transition metals can catalytically degrade carbomer dispersions. Certain amino-functional actives form complexes with carbomer; often this can be prevented by adjusting the pH of the dispersion and/or the solubility parameter by using appropriate alcohols and polyols. Carbomers also form pH-dependent complexes with certain polymeric excipients. Adjustment of pH and/or solubility parameter can also work in this situation.
Safety:
Carbomers are used extensively in nonparenteral products, particularly topical liquid and semisolid preparations. Grades polymerized in ethyl acetate may also be used in oral formulations; see Section 18. There is no evidence of systemic absorption of carbomer polymers following oral administration.(56) Acute oral toxicity studies in animals indicate that carbomer 934P has a low oral toxicity, with doses up to 8 g/kg being administered to dogs without fatalities occurring. Carbomers are generally regarded as essentially nontoxic and nonirritant materials;(57) there is no evidence in humans of hypersensitivity reactions to carbomers used topically. LD50 (guinea pig, oral): 2.5 g/kg for carbomer 934(58) LD50 (guinea pig, oral): 2.5 g/kg for carbomer 934P LD50 (guinea pig, oral): 2.5 g/kg for carbomer 940 LD50 (mouse, IP): 0.04 g/kg for carbomer 934P LD50 (mouse, IP): 0.04 g/kg for carbomer 940 LD50 (mouse, IV): 0.07 g/kg for carbomer 934P LD50 (mouse, IV): 0.07 g/kg for carbomer 940 LD50 (mouse, oral): 4.6 g/kg for carbomer 934P LD50 (mouse, oral): 4.6 g/kg for carbomer 934 LD50 (mouse, oral): 4.6 g/kg for carbomer 940 LD50 (rat, oral): 10.25 g/kg for carbomer 91 LD50 (rat, oral): 2.5 g/kg for carbomer 934P LD50 (rat, oral): 4.1 g/kg for carbomer 934 LD50 (rat, oral): 2.5 g/kg for carbomer 940 LD50 (rat, oral): > 1g/kg for carbomer 941 No observed adverse effect level (NOAEL) (rat, dog, oral): 1.5 g/kg for carbomer homopolymer type B.(59)