Pharmaceutical Technology: Controlled Drug Release, Volume 2

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15 Preparation and evaluation of a sustained release ophthalmic vehicle for dapiprazole M.F.Saettone, C.Alderigi and B.Giannaccini Department of <strong>Pharmaceutical</strong> <strong>Technology</strong>/Biopharmaceutics, University of Pisa, I– 56100 Pisa, Italy, and D.Galli-Angeli ACRAF SpA, I–60100 Ancona, Italy SUMMARY The present investigation is concerned with the development and in vivo evaluation of a longacting ocular vehicle for the α-adrenergic blocking drug dapiprazole (DAP). The approaches tested for prolonging the activity were (a) using the drug base with polygalacturonic acid (PGA) and (b) formulation as a highly viscous hydrogel. The vehicles prepared by applying (singly or in combination) these techniques, and two reference aqueous vehicles containing DAP-HCl, were submitted to a series of biological tests on rabbits (miosis and reversion of mydriasis). When compared with an aqueous solution containing an equivalent amount of DAP-HCl, the polyanionic complex DAP-base-PGA increased significantly some activity parameters (maximal miotic intensity, duration, AUC) of the drug, while the hydrogel vehicle containing DAP-HCl prolonged the apparent absorption and elimination phases of the drug, mainly by virtue of a prolonged ocular retention. The combination of the two approaches, as in the hydrogels containing the DAP-PGA complex, permitted the best control of pharmacological activity parameters, which corresponded to a prolonged-pulse release of the drug. In the miosis test, the AUC values did not show any dose-dependent increase, while this effect was evident in the mydriasis-reversion experiments. The possible mechanism(s), by which the examined techniques may influence the activity parameters and the overall ocular bioavailability of DAP are discussed. INTRODUCTION Dapiprazole hydrochloride (DAP-HCl; 5, 6, 7, 8-tetrahydro-3-[2-(4-o-tolyl-1-piperazinyl)ethyl;]-striazole[4,3-α]pyridine monohydrochloride) is an α-adrenergic block-ing agent, mainly used for
162 CH. 15] A SUSTAINED RELEASE OPHTHALMIC VEHICLE FOR DAPIPRAZOLE the treatment of chronic simple glaucoma in cases where a miotic effect coupled to reduction of intraocular pressure (IOP) is desired [1]. Other therapeutic applications are the induction of preoperative miosis in specified cases of eye surgery and the reversion of pharmacologically induced mydriasis [2,3]. The drug is clinically used as an aqueous solution, reconstituted prior to use from a freeze-dried formulation Glamidolo ® , Angelini). The topical administration of ophthalmic drugs from aqueous solutions (collyria) is characterized by a poor bioavailability and a short duration of action, as a result of a series of concomitant physiological factors (induced lacrimation, tear turnover, solution drainage etc.) which remove the solution from the eye. These factors have been widely investigated, and several approaches to extending the ocular residence time of topically applied medications have been reported [4]. In the present study two such approaches, namely (a) complexing the basic drug with a polyanionic polymer and (b) increased vehicle viscosity, were applied to the development of a long-acting ocular formulation for DAP. The effect on the biological activity of a series of DAP vehicles was submitted to preliminary in vivo tests by performing miosis and reversion of tropicamide-induced mydriasis tests in rabbits. EXPERIMENTAL Materials Dapiprazole base, DAP-B (melting point, 163–164°C), and hydrochloride, DAP-HCL (melting point, 192–193°C), were purified samples supplied by Acraf SpA (Ancona); high molecular weight hydroxypropylcellulose, HPC (Klucel HF, Her-cules Inc., Wilmington, DE), and polyglacturonic acid, PGA (4.89 mEq/g, Prion Chemicals, Milano), were commercial samples, used without prior purification. Benzalkonium chloride, USP grade (BZ), was purchased from Carlo Erba SpA; Nylon 6 (Capran 77C, thickness 27±0.3 µm) was obtained from Allied Chemical Corp., Morristown, NJ. Vehicles The DAP-B-PGA ionic complex was prepared by adding portionwise, at room temperature, 0.68g PGA to a stirred solution of FDAP-B (l.0g) in methanol (50 ml). The solvent was then evaporated to give a highly water soluble creamy white powder, containing 59.52% DAP-B. The pH of a 1. 68% w/v solution of the complex (corresponding to 1.0% DAP-B) was 5.4. The composition of all DAP vehicles is shown in Table 1. Gel vehicles 5–8 were prepared by adding a water solution of DAP-HCl or PGA complex to a preformed HPC gel containing BZ as the preservative. As an example, the preparation of vehicle 5 is described. A solution of the ionic complex DAP-B-PGA (0.84 g) in water (35 ml) was slowly added, while stirring, to a gel prepared by hydrating overnight 4.5 g HPC in water (60 ml) containing benzalkonium chloride (0.01 g). The mixture was then brought to the final weight, and was stored at 5°C until used.
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Pharmaceutical Technology: Controlled Drug Release, Volume 2

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