Pilocarpine complexation

MF Saettone, D Monti, MT Torracca, P Chetoni, B Giannaccini. (1989). Muco-adhesive liquid ophthalmic vehicles—Evaluation of macromolecular ionic complexes of pilocarpine. Drug Dev Ind Pharm 15 2475-2489. 

A complex example of activation, aimed at improving ocular delivery, has been reported for prodrugs of pilocarpine (8.87, Fig. 8.6) [123][124], The prodrugs are, in fact, lipophilic diesters of pilocarpic acid (8.86, Fig. 8.6). The first step is enzymatic O-acyl hydrolysis to remove the acyl carrier (Fig. 8.6, Reaction a). In a second step, intramolecular nucleophilic attack leads to loss of the alcohol carrier and ring closure to pilocarpine (Fig. 8.6, Reaction b). 

Nondegradable polymers are also useful as matrices for ocular implants. This application requires the polymer to be hydrophilic, to minimize local tissue irritation. Need for ocular implants stems from the challenges posed to conventional ocular medicines (i.e., eye drops) such as rapid dilution, tear washout, poor patient compliance, and limited bioavailability. Ocular implants from hydrophilic polymer matrices that provide localized sustained release may overcome the above limitations. The first polymeric sustained release product to reach the market was Ocusert , a pilocarpin sustained release ocular implant developed by Alza. Ocusert has the drug reservoir as a thin disc of pilocarpine-alginate complex sandwiched between two transparent discs of microporous membrane fabricated from ethylene-vinyl acetate copolymer. The microporous membranes permit the tear fluid to penetrate into the drug reservoir compartment to dissolve pilocarpine from the complex. Pilocarpine molecules are then released at a constant rate of 20 or 40 pg/hr for a four- to seven-day management of glaucoma. 

A polarographic study on complexes formed between pilocarpine and various imidazoles and copper was carried out. The half-wave potentials of reduction waves of pilocarpine in a copper citrate medium were recorded and found to be a function of the imidazole concentration at low copper concentrations (83). 

The complexation reactions of pilocarpine with cobalt(II), nickel(II), copper(II), and zinc(II) ions were investigated (84). The complexes were characterized by spectrophotometry, conductivity, ESR, NMR, and magnetic susceptibility measurements. In each case, the metal ion was pseudo-tetrahedrally coordinated. Pilocarpine interacts with the metal ion through the imidazole ring. 

In this controlled-release ocular insert, the drug reservoir is a thin disc of pilocarpine-alginate complex sandwiched between two transparent discs of micro-porous membrane fabricated from ethylene-vinyl acetate copolymer (Fig. 5). The microporous membranes permit the tear fluid to penetrate into the drug... 

Likewise, animal models characteristically discern three types of activity activity against electrically induced convulsions correlates with activity again.st generalized tonic-clonic and partial seizures, and activity against penty-Icnetetrazole (PTZ)-induced. seizures correlates with antiabsence activity. Of late, a fourth model, activity against pilocarpine and kainic acid seizures, is said to predict protection against temporal lobe epilep.sy (a complex partial seizure). 

The film formation and thickening actions of povidone, and sometimes also its ability to form complexes with active ingredients, keep the solution in the eye for a longer time,increasing its therapeutic effect. Pilocarpine [86], timolol [166] and... 

A number of new methodological developments in the analysis and purification of pilocarpine (22) hydrochloride have been published.A microcrystallo-scopic determination of imidazole derivatives using antimony acid complexes has been studied. 

The administration of morphine is followed by a series of complex events. Analgesia, euphoria, addiction, and respiratory depression are stressed in the literature, but if morphine had only its effect on carbohydrate metabolism it would rank wdth insulin and phloridzin in interest if it had only its effect on smooth muscle it would rank with pilocarpine and physostigmine and if it had only its effect on gastric secretion and salivation it wmuld rank with histamine. But consideration of some effects is lost in the importance of analgesia and only possible counter indications to its use as an analgesic remain continuously on the experimental horizon. 

In this formnlation, pilocarpine is bound to a polymeric material and this complex makes up the internal, dispersed phase of the emulsion system, in vitro studies have indicated that the release time of 80% of the pilocarpine from this system is 6 h compared to 80% released in only 1 h from pilocarpine hydrochloride solntion thus, the prolonged therapeutic effect is apparently due to both an enhanced pnlse entry of drng and to a prolongation of drug release from the vehicle. 

Dysfunction of Complex 1 respiratory chain enzyme and ultrastructural damage in the hippocampal mitochondria is seen in kainite-induced SE in rats (Chuang et al., 2(X)4). A key player in mitochondrial oxidative phosphorylation. Complex I is a major source of superoxide and its dysfunction may increase mitochondrial reactive oxygen species (ROS) production and redox signaling (Taylor et al., 2(X)3). The perforant path stimulation model shows mitochondrial dysfunction and decreased brain glutathione (Cock et al., 2002). Pilocarpine-treated rats show selective decline in Complexes 1 and IV activity in hippocampal CAland CA3 subfields (Kudin et al., 2002). This pattern of complex 1 deficiency in CA3 region is also seen in humans (Kunz et al., 2000). 

Saettone M F, Giannaccini B, Chetoni P, et al. Evaluation of highmolecular- weight and low-molecular-weight fractions of sodium hyaluronate and an ionic complex as adjuvants for topical ophthalmic vehicles containing pilocarpine. IntJPharm 1991 72 131-139. 

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