Pilocarpine formulation

Bucolo C, Mangiafico P. Pharmacological profile of a new topical pilocarpine formulation. J OculPharmacol Ther 1999 15 567- 573. 

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. 

Scholz M, Lin JE, Lee VE1, Keipert S. Pilocarpine permeability across ocular tissues and cell cultures Influence of formulation parameters. J Ocul Pharmacol Ther 18 455-468 (2002). 

Tegtmeyer S, Papantoniou I, Miiller-Goymann CC. Reconstruction of an in vitro cornea and its use for drug permeation studies from different formulations containing pilocarpine hydrochloride. Eur J Pharm Biopharm 51 119-125 (2001). 

Ocular formulations of pilocarpine have caused visual blurring that may result in decreased visual acuity, especially at night and in patients with central lens changes, and impairment of depth perception. Advise caution while driving at night or performing hazardous activities in reduced lighting. 

Garty, N., and M. Lusky. 1994. Pilocarpine in submicron emulsion formulation for treatment of ocular hypertension A phase II clinical trial. Invest Ophthalmol Vis Sci 35 2175. 

Figure 12.7 The Ocusert pilocarpine system is a thin multilayer membrane device. The central sandwich consists of a core containing the drug pilocarpine. The device is placed in the eye, where it releases the drug at a continuous rate for 7 days. Devices with release rates of 20 or 40 p,g/h are used. Controlled release of the drug eliminates the over- and under-dosing observed with conventional eyedrop formulations, which must be delivered every 4-6 h to maintain therapeutic levels of the drug in the eye tissue [18]...

Emulsions have been used for centuries for the oral administration of medical oils and vitamins and as dermatological vehicles. Recently, their application has been extended as drug carriers in the delivery and targeting of ophthalmic drags. An indomethacin emulsion has been reported to increase ocular bioavailability and efficacy compared to commercially available formulation in rabbits. 0.4% indomethacin emulsion showed 2.2 fold increase in the area under the anterior aqueous drag concentration/time curve compared to a 1% indomethacin suspension. The emulsion formulation also reduced ocular surface irritation caused by indomethacin Similar advantages have been shown for a pilocarpine emulsion which produced a prolonged therapeutic effect in comparison with pilocarpine hydrochloride eyedrops in man. It can be administered only twice a day, rather than four times daily for conventional formulation. 

The first nanoparticulate delivery system studied was Piloplex, consisting of pilocarpine ionically bound to poly(methyl)methacrylate-acrylic acid copolymer nanoparticles [44], Klein et al. [1,98] found that a twice-daily application of Piloplex in glaucoma patients was just as effective as three to six instillations of conventional pilocarpine eye drops. However, the formulation was never accepted for commercialization due to various formulation-related problems, including the nonbiodegradability, local toxicity, and difficulty of preparing a sterile formulation [208],... 

Another early attempt to formulate a nanoparticulate system for the delivery of pilocarpine was made by Gurny [99], This formulation was based on pilocarpine dispersed in a hydrogen CAP pseudolatex formulation. Gurny and co-workers [101] compared the formed nanoparticles to a 0.125% solution of hyaluronic acid some years after their first investigation and found that the viscous hyaluronic acid system showed a significantly longer retention time in front of the eye than the pseudolatex formulation. 

Various lecithin-based MEs were also characterized by Hasse and Keipert [131]. The formulations were tested in terms of their physicochemical parameters (pH, refractive index, osmolality, viscosity, and surface tension) and physiological compatibility (HET-CAM and Draize test). In addition, in vitro and in vivo evaluations were performed. The tested MEs showed favorable physicochemical parameters and no ocular irritation as well as a prolonged pilocarpine release in vitro and in vivo. 

An example of a degradable matrix system is the pilocarpine-containing inserts formulated by Saettone et al. [148]. Pilocarpine nitrate and polyacrylic acid were incorporated into a matrix containing polyvinyl alcohol and two types of hydroxy-propyl methylcellulose. It was shown that all inserts significantly increased the pharmacological effect (miotic response) compared to a solution of pilocarpine nitrate. 

Miyazaki, S., Suzuki, S., Kawasaki, N., Endo, K.,Takahashi, A., and Attwood, D. (2001), In situ gelling xyloglucan formulations for sustained release ocular dehvery of pilocarpine hydrochloride, Int. J. Pharm., 229(1-2), 29-36. 

Diepold, R., Kreuter, I, Himber, J., Gurny, R., Lee, V. H., Robinson, J. R., et al. (1989), Comparison of different models for the testing of pilocarpine eyedrops using conventional eyedrops and a novel depot formulation (nanoparticles), Graefes Arch. Clin. Exp. Ophthalmol., 227(2), 188-193. 

Garty, N, Lusky, M., Zalish, M., Rachmiel, R., Greenbaum, A., Desatnik, H., Neumann, R., Howes, J. F., and Melamed, S. (1994), Pilocarpine in submicron emulsion formulation for treatment of ocular hypertension A phase II clinical trial, Investigative Ophthalmol. Vis. Sci., 35,2175. 

Formulations of pilocarpine in clinical usage — mainly for the treatment of glaucoma—are given in a pocket handbook issued jointly by the British Medical Association and The Pharmaceutical Society of Great Britain (107). 

Drugs (e.g., pilocarpine) that cause rapid lacrimation by stinging or by stimulation of lacrimal glands in normal individuals are formulated at high concentration to offset the dilution and washout that occur from tear flow. Patients with dry eyes that do not tear readily can absorb greatly exaggerated doses of topically applied medications. In children, who cry and lacrimate more easily than do adults, rapid drug washout can prevent adequate absorption of topically applied medications. 

Ocular distribution and elimination of biodegradable polyalkylcyanoacrylate nanoparticles has been examined in a number of reports. " " Pilocarpine containing polybutylcyanoacrylate nanoparticles alone or in gel type formulations are capable of enhancing and prolonging the miosis and pressure lowering response in various animal models. ... 

Deshpande SG, Shirolkar S. Sustained release ophthalmic formulations of pilocarpine. / Pharm Pharmacol 1989 41 197-200. 

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