Preservatives ophthalmic formulations

Regardless of the cause, the mainstay of treatment for dry eye is artificial tears. Artificial tears augment the tear film topically and provide relief. If a patient uses artificial tears more than four times daily, recommend a preservative-free formulation. Preservative-free formulations are also appropriate if the patient develops an allergy to ophthalmic preservatives. Artificial tears are available in gel, ointment, and emulsion forms that provide a longer duration of relief and may allow for less frequent instillation. Ointment use is appropriate at bedtime.30... 

This preservative is also comparatively new to ophthalmic formulations and has been used as a disinfectant in contact lens solutions. Polyaminopropyl biguanide (polyhexamethyl biguanide) also is a polymeric compound that has a low toxicity potential at the concentrations generally used in these solutions [141, 149, 150]. 

Presoaked lenses are considered a more efficient and reliable delivery system. However, the soaking of lenses in ophthalmic formulations to incorporate the drag into the lens may cause toxicity to corneal epithelium because preservatives, such as benzalkonium chloride, have a great affinity for the hydrophilic contact lens material and are concentrated in the contact lens. Contact lens for sensitive wearers may also cause foreign-body sensation, blurring and decreased oxygen tension on the corneal surface resulting from occlusion by contact lens. 

A solution containing tropicamide 1% and benzalkonium chloride 0.01% (Mydriaticum) was introduced in 1979 to obtain mydriasis and cycloplegia for diagnostic purposes. Contact dermatitis from ophthalmic formulations is common, preservatives being the most frequent causes (3). Allergic contact dermatitis has been reported, implicating tropicamide as a sensitizer (4). 

Chlorhexidine and its salts are widely used, primarily as topical disinfectants. As excipients, chlorhexidine salts are mainly used as antimicrobial preservatives in ophthalmic formulations. 

A list of regulatory approved antimicrobial preservatives used in ophthalmic formulations with recommended concentration ranges is shown in Table 12.7. The use of methyl- and propylparabens, thimerosal and other mercurial preservatives has decreased in recent years due to adverse reactions associated with their use (Wade and Weller 1994). 

By far, the most widely used antimicrobial preservative used in ophthalmics is BKC (70 percent of all commercial products). It is often used in combination with disodium ede-tate because of the synergistic effects, allowing lower concentrations of BKC to be used. Even the use of BKC has been questioned because of some evidence of eye toxicity in rabbits (Dormans and van Logten 1982), and some people have developed hypersensitivity to this preservative. However, BKC does possess good pharmaceutical properties, being stable in solution, stable to autoclaving, and at the usual concentration of 0.01 percent, is an effective preservative over the range of pH values typically used in ophthalmic formulations. 

Each gram of ophthalmic ointment, 1%, contains 10 mg chloramphenicol in a special base of liquid petrolatum and polyethylene. It contains no preservatives. Another formulation contains active ingredients chloramphenicol 11%... 

Other quaternary ammonium germicides, ben-zethonium chloride and benzalkonium bromide, have been used in several ophthalmic solutions. While these have the advantage of not being a chemical mixture, they do not possess the bactericidal effectiveness of benzalkonium chloride and are subject to the same incompatibility limitations. In addition, the maximum concentration for benzethonium chloride is 0.01%. Several new products that form gels in the eye, like Timolol Gel Forming Solution and Timoptic-XE, employ another quaternary preservative, BDAB, in the formulation. 

This aromatic alcohol has been an effective preservative and still is used in several ophthalmic products. Over the years it has proved to be a relatively safe preservative for ophthalmic products [138] and has produced minimal effects in various tests [99,136,139]. In addition to its relatively slower rate of activity, it imposes a number of limitations on the formulation and packaging. It possesses adequate stability when stored at room temperature in an acidic solution, usually about pH 5 or below. If autoclaved for 20-30 minutes at a pH of 5, it will decompose about 30%. The hydrolytic decomposition of chlorobutanol produces hydrochloric acid (HC1), resulting in a decreasing pH as a function of time. As a result, the hydrolysis rate also decreases. Chlorobutanol is generally used at a concentration of 0.5%. Its maximum water solubility is only about 0.7% at room temperature, which may be lowered by active or excipients, and is slow to dissolve. Heat can be used to increase dissolution rate but will also cause some decomposition and loss from sublimation. Concentrations as low as 0.125% have shown antimicrobial activity under the proper conditions. 

This preservative is comparatively new to ophthalmic preparations and is a polymeric quaternary ammonium germicide. Its advantage over other quaternary ammonium seems to be its inability to penetrate ocular tissues, especially the cornea. It has been used at concentrations of 0.001-0.01% in contact lens solutions as well as dry eye products. At clinically effective levels of preservative, POLYQUAD is approximately 10 times less toxic than benzalkonium chloride [87,137], Various in vitro tests and in vivo evaluations substantiate the safety of this compound [137,141,142], This preservative has been extremely useful for soft contact lens solutions because it has the least propensity to adsorb onto or absorb into these lenses, and it has a practically nonexistent potential for sensitization. Its ad-sorption/absorption with high water and high ionic lenses can be resolved by carefully balancing formulation components [143],... 

Surfactants. The use of surfactants is greatly restricted in formulating ophthalmic solutions. The order of surfactant toxicity is anionic > cationic >> nonionic. Several nonionic surfactants are used in relatively low concentrations to aid in dispersing steroids in suspensions and to achieve or to improve solution clarity. Those principally used are the sorbitan ether esters of oleic acid (Polysorbate or Tween 20 and 80), polymers of oxyethylated octyl phenol (Tyloxapol), and polyoxyl 40 stearate. The lowest concentration possible is used to perform the desired function. Their effect on preservative efficacy and their possible binding by macromolecules must be taken into account, as well as their effect on ocular irritation. The use of surfactants as cosolvents for an ophthalmic solution of chloramphenicol has been described [271]. This com-... 

The combination of active drug, preservative, and vehicle usually results in a hypotonic formulation (< 290 mOsm). Simple or complex salts, buffering agents, or certain sugars are often added to adjust osmolarity of the solution to the desired value. An osmolarity of 290 mOsm is equivalent to 0.9% saline, and this is the value sought for most ophthalmic and intravenous medications.The ocular tear film has a wide tolerance for variation in osmotic pressure. However, increasing tonicity above that of the tears causes immediate dilution by osmotic water movement from the eyelids and eye. Hypotonic solutions are sometimes used to treat dry eye conditions and to reduce tear osmolarity from abnormally high values. 

Recognizing that long-term therapy with frequently applied preserved solutions can be toxic to the ocular surfece, manufecturers have formulated some ophthalmic solutions in imit-dose dispensers without preservatives (Figure 3-7). 

Levobunolol is suppUed as a 0.25% and 0.5% sterile ophthalmic solution of the levo-isomer of the hydrochloride salt.The formulation contains a viscosity agent, 1.4% polyvinyl alcohol, and is preserved with BAG 0.004% (see Table 10-1). 

Ototoxicity can occur when benzalkonium chloride is applied to the ear and prolonged contact with the skin can occasionally cause irritation and hypersensitivity. Benzalkonium chloride is also known to cause bronchoconstriction in some asthmatics when used in nebulizer solutions. Toxicity experiments with rabbits have shown benzalkonium chloride to be harmful to the eye in concentrations higher than that normally used as a preservative. However, the human eye appears to be less affected than the rabbit eye and many ophthalmic products have been formulated with benzalkonium chloride 0.01% w/v as the preservative. 

Benzethonium chloride is a quaternary ammonium compound used in pharmaceutical formulations as an antimicrobial preservative. Typically, it is used for this purpose in injections, ophthalmic and otic preparations at concentrations 0.01-0.02% w/v. Benzethonium chloride may also be used as a wetting and solubilizing agent, and as a topical disinfectant. 

Chlorobutanol is primarily used in ophthalmic or parenteral dosage forms as an antimicrobial preservative at concentrations up to 0.5% w/v see Section 10. It is commonly used as an antibacterial agent for epinephrine solutions, posterior pituitary extract solutions, and ophthalmic preparations intended for the treatment of miosis. It is especially useful as an antibacterial agent in nonaqueous formulations. Chlorobutanol is also used as a preservative in cosmetics [see Section 16) as a plasticizer for cellulose esters and ethers and has been used therapeutically as a mild sedative and local analgesic. 

Chlorocresol is used primarily as a preservative in topical pharmaceutical formulations but has also been used in nebulized solutions and ophthalmic and parenteral preparations. It should not, however, be used in formulations for intrathecal, intracisternal, or peridural injection. 

Methylparaben and other parabens are widely used as antimicrobial preservatives in cosmetics and oral and topical pharmaceutical formulations. Although parabens have also been used as preservatives in injections and ophthalmic preparations, they are now generally regarded as being unsuitable for these types of formulations owing to the irritant potential of the parabens. These experiences may depend on... 

Phenylethyl alcohol is used as an antimicrobial preservative in nasal, ophthalmic, and otic formulations at 0.25-0.5% v/v concentration it is generally used in combination with other preservatives.Phenylethyl alcohol has also been used on its own as an antimicrobial preservative at concentrations up to 1% v/v in topical preparations. At this concentration, mycoplasmas are inactivated within 20 minutes, although enveloped viruses are resistant. " Phenylethyl alcohol is also used in flavors and as a perfumery component, especially in rose perfumes. 

Phenylmercuric salts are used as antimicrobial preservatives mainly in ophthalmic preparations, but are also used in cosmetics see Section 16), parenteral, and topical pharmaceutical formulations see Table I. 

Sodium acetate is used as a buffering agent in various intramuscular, intravenous, topical, ophthalmic, nasal, oral, otic, and subcutaneous formulations. It may be used to reduce the bitterness of oral pharmaceuticals. It can be used to enhance the antimicrobial properties of formulations it has been shown to inhibit the growth of S. aureus and E. coli, but not C. albicans in protein hydrolysate solutions. It is widely used in the food industry as a preservative. Sodium acetate has also been used therapeutically for the treatment of metabolic acidosis in premature infants, and in hemodialysis solutions. ... 

Sulfobutylether P-cyclodextrin can form noncovalent complexes with many types of compounds including small organic molecules, peptides, and proteins. It can also enhance their solubility and stability in water. The first application of sulfobutylether P-cyclodextrin was in injectable preparations it can also be used in oral solid and liquid dosage forms, and ophthalmic, inhalation, and intranasal formulations. Sulfobutylether P-cyclodextrin can function as an osmotic agent and/or a solubilizer for controlled-release delivery, and has antimicrobial preservative properties when present at sufficient concentrations. 

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