Stability ophthalmic solutions

Behind the relatively straightforward compositional nature of ophthalmic solutions, suspensions, and ointments, however, lie many of the same physicochemical parameters that affect drug stability, safety, and efficacy, as they do for most other drug products. But additionally, specialized dosage forms present the ophthalmic product designer with some extraordinary compositional and manufacturing challenges. These... 

The therapeutically inactive ingredients in ophthalmic solution and suspension dosage forms are necessary to perform one or more of the following functions adjust concentration and tonicity, buffer and adjust pH, stabilize the active ingredients against decomposition, increase solubility, impart viscosity, and act as solvent. The use of unnecessary ingredients is to be avoided, and the use of ingredients solely to impart a color, odor, or flavor is prohibited. 

Stablizers. Stabilizers are ingredients added to a formula to decrease the rate of decomposition of the active ingredients. Antioxidants are the principal stabilizers added to some ophthalmic solutions, primarily those containing epinephrine and other oxidizable drugs. Sodium bisulfite or metabisulfite are used in concentration up to 0.3% in epinephrine hydrochloride and bitartrate solutions. Epinephrine borate solutions have a pH range of 5.5 7.5 and offer a more difficult challenge to formulators who seek to prevent oxidation. Several patented antioxidant systems have been developed specifically for this compound. These consist of ascorbic acid and acetylcysteine, and sodium bisulfite and 8-hydroxyquinoline. Isoascorbic acid is also an effective antioxidant for this drug. Sodium thiosulfate is used with sodium sulfacetamide solutions. 

When the stability of dorzolamide hydrochloride was studied in 2% ophthalmic solutions over two years, photodegradation was not observed. However, when solutions were exposed to daylight, a degradant identified as the 45,65 de-ethylated analog was formed. 

Mechanism of Action A mast cell stabilizer that prevents the activation and release of inflammatory mediators, such as histamine, leukotrienes, mast cells, eosinophils, andmonocytes.T herapeuticEffect Prevents both early and late asthmatic responses. Pharmacokinetics The extent of absorption is 7% to 9% of a single inhaled dose of 3.5 to 4 mg and 17% of multiple inhaled doses, with absorption largely from the respiratory tract. Although most of the inhaled dose is subsequently swallowed, only 2% to 3% is absorbed from the G1 tract. Less than 4% of the total dose is systemically absorbed following multiple doses of ophthalmic solution. Protein binding 89%. Not metabolized. Excreted in urine. Half-life 1.5-3.3 hr. 

G. Parhizkani, R. B. Miller, and C. Chen, A stability-indicating HPLC method for the determination of benzalkonium chloride in phenylephrine HG 10% ophthalmic solution, J. Liquid Chromatogr., 78 553 (1995). 

While the metastable forms offer higher dissolution rates, many manufacturers use a particular amorphous, crystalline, salt, or ester form of a drug with the solubility needed to be dissolved in the established conditions, for instance, to prepare a chloramphenicol ophthalmic solution [39]. Thus, the selection of amorphous or crystalline form of a drug may be of considerable importance to facilitate the formulation, handling, and stability [37]. 

Nedocromil sodium has been found to be effective in treating SAC and GPC. In SAC, there was found to be significant improvement in itching, conjimctival injection, and overall disease when compared with placebo. In treatment of contact lens-induced GPC, when compared with placebo, the medication reduces itching and mucous discharge. Nedocromil is available as a clear, yellow, 2% ophthalmic solution, and it differs from other mast cell stabilizers by having a twice-daily dosage. 

Contraindications for all mast cell stabilizers include patients sensitive to the ophthalmic solution or any of its components. 

The inclusion of a phosphate buffer in homatropine hydrobromide ophthalmic solution enabled formula-tors to fix the solution pH at 6.8, enabling the product to be lyophilized. ° This lyophilized product could be stored for extended periods without degradation. Tro-methamine was found to effect a stabilizing effect on A-nitrosoureas (such as lomustine, carmustine, and tauromustine) in aqueous solutions. ... 

Garrell, R.K. King, R.E. Stabilization of homatropine hydrobromide ophthalmic solution at pH 6.8 by lyophiliza-tion. J. Parenter. Drug Assoc. 1982, 36, 452-462. 

The pH is the most important factor in the stability of sulfacetamide sodium solutions. Among the 20% ophthalmic solutions of the drug, the greatest stability (to two years) is shown by the solutions with a pH of 8-8.5 (112). The addition of 200mg/100 ml of sulfacetamide to 30% ophthalmic solutions of sulfacetamide sodium decreases the pH from 9.3-9.6 to 7.3-8.4 and increases the shelf life of the solution after sterilization at 100°C for 30 minutes to more than one year (113). 

Although tyrothricin is too toxic for parenteral therapy, it was formerly sold in the United States as oral lozenges. Modem tyrothricin formulations are composed of 70—80% tyrocidines and 30—20% linear gramicidins. Tyrocidines are not as active as linear gramicidins and are too toxic for any therapeutic use by themselves. The bactericidal linear gramicidins are used in the United States solely as an ophthalmic solution in combination with polymyxin B sulfate and neomycin sulfate. The linear gramicidin is used in this aqueous product as a substitute for bacitracin, which lacks stability under such conditions. 

Miller, R.B. Chen, C. A stability-indicating HPLC method for the determination of 17P-estradiol-3-phosphate in an ophthalmic solution. Chromatographia, 1995, 40, 204-206... 

After this, the complex of BCDAC and hydroquinone was selected, because the surfactant BCDAC has been used previously in ophthalmic solutions. First, the stability of the complex was checked when it was mixed with several ointments. The complex was mixed with hydrophilic ointment (HO), hydrophilic petrolatum (HP), white petrolatum (WP), plastibase (PB) and zinc oxide ointment (ZO). The colour value. 

Al-Badriyeh D, Li J, Stewart K et al (2009) Stability of extemporaneously prepared vOTiconazole ophthalmic solution. Am J Health-Syst Pharm 66 1478-83... 

Anaizi NH, Swenson CF, Dentinger PJ (1997) Stability of acetylcysteine in an extemporaneously compounded ophthalmic solution. Am J Health Syst Pharm 54 549-553... 

Adler, C.A., Maurice, D.M. and Paterson, M.E., 1971, The effect of viscosity of the vehicle on the penetration of fluorescein into the human eye. Exptl. Eye Res. 11 34 Blaug, S.M. and Canada, A.T., 1965, Relationship of viscosity, contact time and prolongation of action of methylcellulose-containing ophthalmic solutions. Amer. J. Hosp. Pharm., 22 662 Bungaard, H., Buur, A., Chang, S-C. and Lee, V.H.L., 1988, Timolol prodrugs synthesis, stability and lipophilicity of various alkyl, cycloalkyl and aromatic esters of timolol. Int J. Pharm., 46 77 Chrai, S.S. and Robinson, J.R., 1974, Ocular evaluation of methylcellulose vehicle in albino rabbits. 

Elrod, L., T. G. Golich, J. A. Morley, Benzalkonium chloride in eye care products by HPLC and solid-phase extraction or on-line column switching, J. Chromatogr., 1992,625, 362-367. Parhizkari, G., G. Delker, R. B. Miller, C. Chen, Stability-indicating HPLC method for determination of benzalkonium chloride in Tramadol ophthalmic solution, Chromatographia, 1995,40,155-158. 

Co-administration of ofloxacin and chitosan in eyedrops increased the bioavailabUity of the antibiotic [290]. Trimethyl chitosan was more effective because of its solubility (plain chitosan precipitates at the pH of the tear fluid). On the other hand, N-carboxymethyl chitosan did not enhance the corneal permeability nevertheless it mediated zero-order ofloxacin absorption, leading to a time-constant effective antibiotic concentration [291]. Also W,0-carboxymethyl chitosan is suitable as an excipient in ophthalmic formulations to improve the retention and the bioavailability of drugs such as pilocarpine, timolol maleate, neomycin sulfate, and ephedrine. Most of the drugs are sensitive to pH, and the composition should have an acidic pH, to enhance stability of the drug. The delivery should be made through an anion exchange resin that adjusts the pH at around 7 [292]. Chitosan solutions do not lend themselves to thermal sterilization. A chitosan suspension, however. 

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. 

---