Design, in vitro stability, and ocular hypotensive activity of t-butalone chemical delivery systems.

The objective of this work was to synthesize two bioreversible diacyl derivatives of t-butalone (chemical delivery systems), determine their chemical and in vitro stability, and investigate their potential use as topical antiglaucoma agents. The stability of these compounds was determined in isotonic phosphate buffers (pH range 5-8) and in selected biological media, including human whole blood, rabbit and rat blood, and the anterior segment tissues of rabbit. The ocular hypotensive activity of these compounds in unrestrained, normotensive albino rabbits was determined with a pneumatonometer. The two compounds were stable at lower pH. The stability decreased as the pH increased, suggesting their lability to base-catalyzed hydrolysis. These compounds exhibited significant differences in the hydrolytic rates in the whole blood among species examined (rat > rabbit > human). The observed rates of disappearance in different ocular tissues were indicative of relative enzyme activity in these media (iris-ciliary body > cornea > aqueous humor). The two compounds exhibited a significant ocular hypotensive activity (P < 0.01) at 2% dose level. The peak activity was found between 2 and 4 h, and the activity was maintained for 4.5 to 7 h. The dipivalyl derivative of t-butalone exhibited more pronounced decrease in intraocular pressure than that of diisovaleryl derivative. The present study suggests the possible use of diacyl derivatives of t-butalone as ocular hypotensive agents.

Intraocular pressure-lowering activity and in vivo disposition of dipivalyl terbutalone in rabbits.

The ocular hypotensive activity and in vivo disposition of dipivalyl terbutalone, a chemical delivery system for terbutaline, were investigated in the albino rabbit model. The dose-response relationship was assessed at drug concentrations ranging from 0.5 to 4% in normal saline. Intraocular pressure (IOP)-lowering activity of dipivalyl terbutalone was compared with epinephrine in equal concentrations. The in vivo disposition was investigated after topical administration of dipivalyl terbutalone at 4% dose level for which two metabolic products, terbutaline, and terbutalone, were monitored in different anterior segment tissues/fluid of albino rabbits, including corneal and iris-ciliary body homogenates and aqueous humor. The instillation of 0.5, 1, 2, and 4% solutions (1 drop of 50 microL) significantly decreased the IOP of normotensive rabbits in a dose-dependant manner. At the highest dose, the maximum reduction (5.6 +/- 0.65 mm Hg) was observed at 3 h. In a comparative efficacy study, dipivalyl terbutalone was found to be more effective than epinephrine. In the in vivo distribution after the topical administration of dipivalyl terbutalone, terbutaline was found only in the iris-ciliary body, whereas terbutalone was found in all parts of the eye studied. This work suggests the potential use of dipivalyl terbutalone as an antiglaucoma agent, representing a new chemical delivery system for terbutaline.

Chemical delivery systems: evaluation of physicochemical properties and enzymatic stability of phenylephrone derivatives.

The physicochemical properties and enzymatic stability of esters of phenylephrone, synthesized on the basis of the chemical delivery system (CDS) concept, were studied as a new class of mydriatic agents. Potentiometrically determined ionization constants (pKa) of the novel compounds were in the range 7.19-7.21. The three esters of phenylephrone (isovaleryl, phenylacetyl, and pivalyl) were more lipophilic than phenylephrone as indicated by n-octanol/pH 7.4 buffer partition coefficients (log Papp) and the chromatographic capacity factors (log k'). The chemical stability of the esters of phenylephrone was evaluated in hydrochloric acid, citrate, and phosphate buffers (with pH ranging between 2.0 and 8.0), and the enzymatic hydrolysis in rat and human plasma. The samples were analyzed using HPLC assay procedures. The phenylephrone esters were found to undergo comparatively slow hydrolytic degradation in buffer with pH 3.0 and 4.0, with half-lives ranging from 1136 to 1980 hr at 37 degrees C. The novel esters were readily hydrolyzed in human plasma with half-lives ranging between 16.2 and 47.8 min. The hydrolytic degradation rates were higher in rat plasma than in human plasma, in which the half-lives were in the range of 9.8-38.3 min. In the present investigations, only phenylephrone, not the active species phenylephrine, was detected. Among the esters studied, isovaleryl ester was the most labile. Pivalyl ester, having a tertiary carbon, showed relatively high resistance to chemical and enzymatic hydrolysis because of the steric hindrance, followed by phenyl and isovaleryl esters. The results suggest that the duration of action of the phenylephrone CDS can be controlled with proper chemical manipulations.

Permeability of a soft steroid, loteprednol etabonate, through an excised rabbit cornea.

The objective of this work was to study the in vitro permeability characteristics of a "soft" steroid, loteprednol etabonate 1 in different vehicles across excised rabbit cornea using a transcorneal permeation system. The vehicles studies were aqueous solutions of beta-cyclodextrin derivatives; 2-hydroxypropyl beta-cyclodextrin (HPCD) and heptakis (2,6-di-O-methyl) beta-cyclodextrin (DMCD); and DMCD together with 5 and 10% propylene glycol (PG) or dimethyl sulfoxide (DMSO). Two experimental suspension products of the steroid, 0.1% and 0.5%, and the suspensions of the steroid in commercial lubricant ophthalmic solutions which include Liquifilm Tears and Tears Plus were also studied for their possible use as vehicles to deliver the steroid across the cornea. The observed permeability rate of the soft steroid from DMCD was found to be 13-fold greater than from HPCD. The presence of varying percentages of PG and DMSO with DMCD decreased the flux of the steroid. Transcorneal permeability of the steroid was found to be insignificant from aqueous buffer (pH 7.4) and commercial lubricant ophthalmic solutions. The flux of the steroid in 20% DMCD (23 micrograms/hr/cm2) was found to be comparable with 0.5% commercial suspension (20.5 micrograms/hr/cm2). The barrier function of corneal epithelium for the steroid in 0.5% experimental suspension was also investigated. When the corneal epithelium was removed, the lag time of the lipophilic soft steroid decreased but the flux value did not change.

Tissue distribution of LY231617, an antioxidant with neuroprotectant activity, in the rat.

The tissue distribution of a butylated phenol antioxidant, LY231617, which has been shown to exert potent neuroprotection action was examined. Preliminary pharmacokinetic examination suggests that LY231617 was eliminated in a biphasic fashion after iv administration to the rat with a distribution half-life of 5 min and an elimination half-life of close to 2.5 h. The volume of distribution of the compound was large (7.4 L), consistent with its lipophilic structure. Dosing paradigms that have historically resulted in pharmacologically relevant activity were examined and were found to generate brain tissue levels of LY231617 of approximately 45 micrograms/g.

Theoretical studies on the structures of natural and alkylated cyclodextrins.

A series of semiempirical molecular orbital calculations using the AM1 method have been performed on isolated natural and alkylated alpha- and beta-cyclodextrins. For natural cyclodextrins, three geometries were considered: (i) molecular mechanics (MM2); (ii) AM1 fully optimized geometry; (iii) X-ray structures based on the experimental coordinates for heavy atoms with positions of hydrogen atoms optimized by AM1. Large differences between AM1 calculated properties of geometries i-iii were found. The differences between ii and iii are smaller and reflect the intermolecular, crystal packing forces. Comparisons are made between ii and iii and properties determined therefrom, such as cavity diameter, outer diameter, and height. In addition, AM1 semiempirical calculations were performed on the mixed (2,3,6) (hydroxyprophyl)-beta-cyclodextrin, 2,6-dimethyl-beta-cyclodextrin, and 2,6-bis(hydroxypropyl)-beta-cyclodextrin. The results were compared with the substituent effects on monoglucose. It was found that the alkylation and methyl and 2-(hydroxypropyl) functions on beta-cyclodextrin does not introduce significant steric hindrance.

In vitro evaluation of a controlled-release site-specific diisovaleryl tert-butalone chemical delivery system for the eye.

Cellulosic polymers such as cellulose acetate (CA), cellulose acetate butyrate (CAB), and hydroxypropyl methyl cellulose phthalate (HPMCP) and hydrogels (hydroxyethyl/hydroxypropyl acrylate and hydroxypropyl methacrylate monomers) were used to sustain/control the release of diisovaleryl tert-butalone, a novel site-specific chemical delivery system (CDS) for potential antiglaucoma treatment. Diisovaleryl tert-butalone was incorporated into cellulosic polymers by the method of "solution casting" and into hydrogels by the method of "impregnation." In vitro release-rate kinetics from these systems were studied using a closed sink kinetic model. The release rate of CDS from the polymers chosen followed first-order kinetics and the release was sustained for about 2-6 h. In the case of hydrogels a pronounced "burst release" was observed. Increasing the percentage of cross-linker in the linear monomers of the hydrogel was shown to sustain the release longer. When the diisovaleryl tert-butalone CDS was incorporated into one of the cellulosic polymers, cellulose acetate butyrate, as the CDS-beta-cyclodextrin [heptakis(2,6-di-O-methyl)-beta-cyclodextrin] inclusion complex, the release pattern approximated Higuchi's expression for a monolithic matrix system, where the amount of CDS released from the polymer was proportional to the square-root of time. Further, the stability of the CDS in the polymer was improved when it was dispersed in the polymer as the CDS-beta-cyclodextrin CD complex.

Improved delivery through biological membranes. LXI: Design, synthesis, and evaluation of a lipolol-based intradermal drug targeting system for 5-fluorouracil.

This report describes initial studies with the lipolyl ester of 1-carboxypropylcarbamoyl-FU (LE-CPCFU) which was designed to enhance the dermal delivery of the antitumor agent 5-fluorouracil (FU). The design of LE-CPCFU was based upon our previous observation that sulfur-based chemical drug targeting systems were localized within the skin and improved the delivery of the parent drug to the dermal tissue (Chikhale et al., 1993; Bodor et al., 1982; Bodor and Sloan, 1982). In the in vitro test system that used freshly-excised guinea-pig skin, LE-CPCFU was found to enhance FU delivery to the skin 2- to 5-fold compared to underivatized FU. Neither LE-CPCFU nor its acid metabolite 1-carboxypropylcarbamoyl-FU (CPCFU) could be detected in the skin or receiver during the diffusion experiments even though LE-CPCFU and CPCFU were found to be reasonably stable in aqueous pH 7.4 buffer and during the analytical procedure. FU which was released from LE-CPCFU in the skin subsequently diffused into the receiver. Thus, LE-CPCFU was observed to improve FU delivery to the skin during the initial time period of the study (0-4 hr). This study indicates that LE-CPCFU in the guinea-pig skin was hydrolyzed to form FU in the skin serving as an intradermal drug delivery system for the antitumor agent. Thus, LE-CPCFU could prove to reduce the systemic toxicity of FU by enhancing the local skin concentration and minimizing the systemic concentration of the antitumor agent as compared to underivatized FU.

Soft drugs--XVI. Design, evaluation and transdermal penetration of novel soft anticholinergics based on methatropine.

Atropine has been reported to produce unwanted systemic side effects on topical administration into the eye. The same problem could arise when atropine is used topically as a suppressant of eccrine sweating. In this study, the principles of soft drug design were applied to methatropine. A hypothetical carboxylate metabolite of methatropine was reactivated by esterification with cyclic and alicyclic alcohols to yield a series of compounds (3a-g). In vitro evaluation by guinea pig ileum assay indicated that the compounds are potent anticholinergics and the lead carboxylate metabolite is about 60 times less potent than the most active compound of the series. The activity was found to decrease with the increasing side chain length. The n-octanol/water partition coefficients were found to be directly dependent on the chain length for the compounds made with straight chain alcohols. The transdermal permeability coefficients across the hairless mice skin were found to be directly dependent on the partition coefficients. The soft drugs are found to metabolize extensively during the penetration process compared to the unmetabolizable nature of methatropine. The soft drugs reported in this study will probably be able to elicit a local action at the site of application but will probably be metabolized rapidly in the systemic circulation, thereby avoiding the systemic side effects with a consequent increase in the therapeutic index.

Soft drugs--XIV. Synthesis and anticholinergic activity of soft phenylsuccinic analogs of methatropine.

Three soft drug analogs and a metabolite of methatropine based on phenylsuccinic structural moiety were synthesized and tested for activity. In an in vivo assay, the soft drugs were found to be two orders of magnitude less potent than methatropine while the carboxylate metabolite was found to be one order of magnitude less potent than the soft drugs. A structural isomer of compound 4a was found to be less potent. All the soft drugs tested elicited shorter durations of mydriatic action in rabbit eyes compared to atropine. The untreated eye was dilated in the atropine treated animals while no dilation occurred in the soft drug treated animals indicating facile systemic metabolism of the soft drugs to inactive moieties, possibly the carboxylate metabolite. In in vitro stability studies, the soft drugs have been found to be more hydrolytically labile than atropine. The shorter duration of mydriatic action of compound 4a coupled with increased hydrolytic lability make this a candidate for further study.

Soft drugs 15: mydriatic activity and transcorneal penetration of phenylsuccinic soft analogs of methscopolamine as short acting mydriatics.

Soft drug analogs of methscopolamine (4 a-c) were tested for mydriatic activity in rabbits' eyes. After unilateral administration of equieffective doses, the AUC24hrs and the mydriatic recovery times were found to be significantly lower with the soft drugs compared to methscopolamine. At equieffective doses, the AUC24hrs for soft drugs ranged from 22.4% to 60% of that of methscopolamine. Significant dilation of the untreated eye was observed with methscopolamine but not with the soft drugs after unilateral administration. Soft drug 4a exhibited only 10.4% of the AUC6hrs (untreated eye) of that of methscopolamine. Shorter durations of mydriatic action combined with potentially reduced systemic side effects make these compounds candidates for further study. In vitro rabbit transcorneal penetration of soft analog 4a was found to be significantly higher than methscopolamine.

Synthesis and in vitro dopaminergic activity of (2-aminoethyl)-1-hydroxy-2-pyridone type dopamine analogs.

Two isoteric/isoelectronic dopamine analogs based of (2'-aminoethyl)-1-hydroxy-2-pyridone without having the COMT vulnerable m-hydroxy group were synthesized via ten synthetic steps. Their dopaminergic activities were evaluated by measuring the inhibitory effects of prolactin secretion from the anterior pituitary in rats. The compounds 1 and 2 caused a reduction of prolactin secretion at the 10(-6) M concentration. Semiempirical MO calculations (at the AM-1 level) were performed on 1 and 2 in order to understand the structural and electronic features as compared to dopamine.

Soft drugs. 13: Design and evaluation of phenylsuccinic analogs of scopolamine as soft anticholinergics.

Concepts involved in the design of soft drugs (drugs which, after achieving their therapeutic role, are metabolized in a predictable manner and at a controlled rate to non-toxic moieties) have been applied to methscopolamine. Selected aliphatic and cycloaliphatic esters (4a-e) of a hypothetical metabolite (2a) of methscopolamine with a phenylsuccinic acid basic structural moiety were designed and found to have anticholinergic activity and to revert to the original hypothetical metabolite in biological media with fairly short half lives. The pA2 values of the soft drugs were determined and the hypothetical metabolite was found 100 times less potent than the most potent compound (4a) of the series. The anticholinergic activities were found to be dependent on the length of the side chain alcohol.

Soft drugs. 12: Design, syntheses and evaluation of soft anticholinergics.

Concepts involved in the design of soft drugs (drugs which, after achieving their therapeutic role, are metabolized in a predictable manner and at a controlled rate to non-toxic moieties) have been applied to methscopolamine (1). Selected aliphatic and cycloaliphatic esters (3) of a hypothetical carboxylic acid metabolite (2) of methscopolamine were designed and found to have anticholinergic activity. Six soft drug analogs of methscopolamine were tested for mydriatic activity in rabbit eye. At equieffective doses, the AUC24 hrs and the mydriatic recovery time were found to be significantly less with some of the soft drugs compared to methscopolamine and soft drug 3a was found to be shorter acting than tropicamide. At equieffective doses the AUC24 hrs for soft drugs ranged from 23.2% to 187% of that of methscopolamine. Significant dilation of the untreated eye was observed with scopolamine but not with the soft drugs after unilateral administration. Soft drug 3a exhibited only 2.3% of the AUC6 hrs (untreated eye) of that of methscopolamine.

A redox-based chemical delivery system that enhances estradiol distribution to the brain: disposition studies in the rat.

The disposition of a chemical delivery system for estradiol (E2-CDS) which is based on a redox dihydropyridine-pyridinium salt conversion was investigated in rats. Tissue and plasma concentrations of E2-CDS and the oxidized metabolite (E2-Q+) were evaluated at times ranging from 1 to 14 days after intravenous administration of E2-CDS formulated as a modified cyclodextrin inclusion complex. While E2-CDS levels were below HPLC assay detection limits for all samples by 1 day postdosing, E2-Q+ was readily quantified. The calculated half-life of E2-Q+ was longest in brain tissue, significantly shorter in heart, lung, and kidney tissues, and shortest in plasma. There was a linear relationship between administered E2-CDS dose and oxidized metabolite measured in brain as well as in other tissues collected 24 hr after drug administration. Coadministration of high doses of a similarly oxidizable dihydropyridine, 1-methyl-1,4-dihydronicotinamide (NMN), in a dimethylsulfoxide (DMSO) vehicle decreased E2-Q+ measured in brain and other tissues without significantly affecting the relative patterns of distribution in these tissues. Brain tissue E2Q+ levels were not detected after dosing with the oxidized metabolite.

Novel soft steroids: effects on cell growth in vitro and on wound healing in the mouse.

Evaluation of three "soft" steroids is described. The test compounds were compared with the standard anti-inflammatory steroids betamethasone and prednicarbate in two studies. Soft steroids are designed based on the "inactive metabolite approach" to be rapidly inactivated by predictable metabolism after performing their therapeutic function. Consequently, lower circulating (peripheral) levels of potentially harmful steroids result, and undesirable systemic and local side effects are minimized. The soft and standard steroids behaved similarly in an in vitro cell culture model, whereas in a whole animal study the advantages of the soft steroids were evident.

A redox-based system that enhances delivery of estradiol to the brain: pharmacokinetic evaluation in the dog.

The pharmacokinetics of a dihydropyridine-pyridinium salt-type chemical delivery system (CDS) for brain-targeted delivery of estradiol (E2) were examined in dogs. Parameters evaluated in vitro included stability in buffers and biological fluids and plasma protein binding. In vivo studies examined drug and metabolite concentrations in plasma, urine, and cerebrospinal fluid as well as in selected brain regions. The administered lipophilic E2-CDS disappeared very quickly from plasma and was not detected in urine. The oxidized drug form, E2-Q+, was excreted unchanged or as a conjugate in the urine for as long as 2 weeks. Plasma levels were below assay detection limits at later times. Pharmacokinetic analysis of urine E2-Q+ levels allowed estimation of a half-life of 2.2 days. Amounts of E2-Q+ excreted into the urine were proportional to the dose but averaged only 13.9% of the dose, indicating that other routes of excretion must be considered. CSF levels were below the limit of detection for both E2-CDS and E2-Q+, however, brain tissue concentrations of E2-Q+ were similar in several brain regions of individual animals examined 1 or 3 days after drug dosing.

Improved anticonvulsant activity of phenytoin by a redox brain delivery system. III: Brain uptake and pharmacological effects.

Phenytoin (DPH) was delivered to the brain by a dihydropyridine in equilibrium pyridinium salt redox system, which was evaluated for anticonvulsant activity. Following iv injection of the lipophilic delivery system of DPH (2) to rats, concentrations of DPH were lower but sustained and, after 30 min, essentially the same as the levels after equimolar administration of DPH. While 2 delivered the same levels of DPH to the brain as DPH did, it was twice as potent as DPH in rats (ED50 was 7.5 mumol/kg for 2 and 14.2 mumol/kg for DPH) and mice (2: 10.5; DPH: 23.9) against maximal electroshock seizures (MES), and seven times more potent in mice (2: 10.0, DPH: 70.6) against maximal pentylenetetrazole seizures (MPS). Moreover, 2 was active against pentylenetetrazole threshold seizures (PTS) in mice and rats (ED50 = 44.1 and 40.5 mumol/kg, respectively), while DPH was ineffective (up to a dose of 79.2 mumol/kg). After evaluation of acute neurological toxicity in rats, 2 was found to possess 1.5 times higher a protective index (for MES) than DPH. It appeared also that while DPH was 2.9 times less sensitive to MPS than to MES, 2 was equally potent to both types of convulsions. Thus, the data indicate that 2 delivered DPH more efficiently to the brain. The better anticonvulsant activity (quantitatively as well as qualitatively) of 2 can be explained on the basis of an improved distribution in the brain due to its higher lipophilicity, and by favorable regional differences in the rates of conversion of 2 to DPH at the convulsing foci.

Improved anticonvulsant activity of phenytoin by a redox brain delivery system I: Synthesis and some properties of the dihydropyridine derivatives.

Nine chemical delivery systems (CDSs) were synthesized for the efficient transport of phenytoin (DPH) across the blood-brain barrier. The CDSs were based on a dihydropyridine in equilibrium quaternary pyridinium ion redox system which relies on chemistry similar to the NADH in equilibrium NAD interconversion for activity. The chemical carriers, derivatives of trigonelline, 1-alkylcarboxynicotinamide, 3-pyridylacetic acid, and N-methylpicolinic acid, were esterified with 3-(hydroxymethyl)phenytoin. The CDSs proved to be more lipophilic (5-23 times) than DPH. The 1-alkylcarboxydihydronicotinamide CDSs, excluding the sterically hindered one (11e), were quite unstable in rat tissue homogenates and hydrolyzed to release DPH. In human blood, however, they were found to be much more stable (75 times) toward hydrolysis. All other CDSs were oxidized quantitatively to the corresponding pyridinium ion in rat brain homogenates. These compounds were found to possess the required physicochemical characteristics for delivering DPH into rat brain.

Evidence for prolonged suppression of stress-induced release of adrenocorticotropic hormone and corticosterone with a brain-enhanced dexamethasone-redox delivery system.

We have developed a redox system for brain-enhanced delivery of dexamethasone based on an interconvertible dihydropyridine in equilibrium pyridinium salt carrier. Dexamethasone, when combined with the lipoidal carrier, readily crosses the blood-brain barrier. The carrier, when oxidized, reduces its rate of exit from the brain. The aim of the study was to evaluate the capacity of a dexamethasone-chemical delivery system (DX-CDS) and dexamethasone (DEX) to suppress stress-induced elevations of plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Adult male Sprague-Dawley (CD) rats were administered either DX-CDS (10 mg/kg), an equimolar dose of DEX or the drug vehicle (2-hydroxypropyl-beta-cyclodextrin) by a single tail vein injection. Rats then received either no stress or a restraint stress for a 5- or 15-min duration on days 1, 3, 5 or 7 after drug administration and trunk blood was rapidly collected. To assess peripheral effects of DX-CDS and DEX, 1 ml of blood was removed via orbital puncture and evaluated for total and differential leukocyte counts in a separate group of animals. Both DX-CDS and DEX were effective on day 1 in suppressing, by greater than 95%, ACTH secretion induced by a 5-min stress. However, DX-CDS was effective through day 5 (44% suppression) while DEX was not effective after 24 h. When 15 min of stress was applied, DX-CDS effected a significant ACTH suppression through 7 days while DEX was effective for only 3 days. DX-CDS was effective through day 7 (55%) in suppressing CORT after a 15-min stress while DEX was effective for 3 days only.(ABSTRACT TRUNCATED AT 250 WORDS)