Percutaneous absorption of cyclizine and its alkyl analogues.

Cyclizine (I) alkyl analogues (II-IV) were synthesized and their skin permeation parameters evaluated in vitro. It was hoped that these compounds would possess physicochemical properties more favourable for percutaneous delivery than (I). The identification and levels of purity for the compounds were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry, and infrared spectrometry (IR) while melting points were determined by an electrothermal digital Bupsilonchi melting point apparatus. Aqueous solubilities (25 degrees C) and partition coefficients were determined and in vitro permeation studies were performed in buffer (37 degrees C) at pH 7.4 over a period of 24 h, using Franz diffusion cells fitted with human epidermal membranes. Generally, the analogues were more lipophilic, but nevertheless possessed higher aqueous solubilities as compared to (I). (II) and (IV) exhibited two- to three-fold increase in aqueous solubility and their melting temperatures dropped by more than 55 degrees C. Compound (III) had similar aqueous solubility to (I), but its melting point dropped by about 35 degrees C. Measured steady-state fluxes indicated that (II) is a far better penetrant (J=6.95 microg/cm(2)/h) of human epidermis than (I). Although fluxes of (III) and (IV) drop off markedly from that of (II), they remained above the flux of (I), which is (0.132 microg/cm(2)/h). In conclusion, (II) was the best skin permeant and also exhibited the highest aqueous solubility and lowest level of crystallinity as compared to (I) and other analogues. (III) and (IV) were more lipophilic. The overall permeation data of this series indicated that the more water-soluble and the lowest melting point compound was the best skin permeant.

Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats.

The intranasal route of administration provides a potential useful way of administering a range of systemic drugs. In order to assess the feasibility of this approach for the treatment of nausea and vomiting, doxylamine succinate was studied in rats for the pharmacokinetics (AUC, C(max), t(max)) following intranasal, oral and intravenous administrations. Subjects (six male Sprague-Dawley rats per time interval for each route of administration) received 2-mg doses of doxylamine succinate orally and I-mg doses intranasally and intravenously, respectively. The various formulations were formulated in isotonic saline (0.9% w/v) at 25 +/- 1 degrees C. Doxylamine succinate concentrations in plasma were determined with a high-performance liquid chromatographic assay and a liquid-liquid extraction procedure. Intranasal and oral bioavailabilities were determined from AUC values relative to those after intravenous dosing. Intranasal bioavailability was greater than that of oral doxylamine succinate (70.8 vs 24.7%). The intranasal and oral routes of administration differed significantly from the intravenous route of administration. Peak plasma concentration (C(max)) was 887.6 ng/ml (S.D. 74.4), 281.4 ng/ml (S.D. 24.6) and 1296.4 ng/ml (S.D. 388.9) for the intranasal, oral and intravenous routes, respectively. The time to achieve C(max) for the intranasal route (t(max)=0.5 h) was faster than for the oral route (t(max)=1.5 h), but no statistically significant differences between the C(max) values were found using 95% confidence intervals. The results of this study show that doxylamine succinate is rapidly and effectively absorbed from the nasal mucosa.

Chemical stabilities and biological activities of thalidomide and its N-alkyl analogs.

UNLABELLED: PURPOSE. To determine whether the N-alkyl analogs of the thalidomide are active and stable, their stabilities in buffer and their abilities to inhibit tumor necrosis factor alpha (TNF-alpha) in vitro in human peripheral blood mononuclear cell cultures were investigated. METHODS: TNF-alpha concentrations were determined with the aid of ELISA kits. Chemical stabilities of the compounds were determined in three phosphate buffer solutions (pH 6, 6.4, and 7.4) at 25 and 32 degrees C by high-pressure liquid chromatography, and half-lives were calculated. RESULTS: The addition of N-alkyl groups to the glutarimide ring of the thalidomide molecule had little effect on the ability such compounds have to inhibit TNF-alpha production. There was no statistical difference between the activity of thalidomide and its N-alkyl analogs at a 95% confidence level. Like thalidomide, the N-alkyl analogs in this series inhibit an average of 60% of the TNF-alpha synthesis in lipopolysaccharide-stimulated peripheral blood mononuclear cell cultures. Thalidomide and its N-alkyl analogs are hydrolyzed at very similar rates, with half-lives ranging from 25 to 35 h at 32 degrees C at pH 6.4 and an average rate constant of 2.35 x 10(-2)/h. CONCLUSION: Alkylating thalidomide had little effect on its ability to inhibit the production of TNF-alpha in these cell cultures. All of the compounds tested seem to have some, perhaps comparable, therapeutic potential.

Percutaneous delivery of thalidomide and its N-alkyl analogs.

PURPOSE: The purpose of this study was to determine the permeation parameters of thalidomide and three of its N-alkyl analogs and to establish a correlation between the physicochemical properties of these compounds and their percutaneous rates of absorption. METHODS: In vitro permeation studies were performed from buffer, n-alkanols and various mixed components using vertical Franz diffusion cells fitted with human epidermal membranes. RESULTS: Measured steady-state fluxes indicate that N-methyl thalidomide is a far better penetrant of human skin than the "parent molecule". However, fluxes through skin drop off markedly from that of the methylated compound when the chain length is extended to propyl and pentyl. However, they remain well above the flux of thalidomide, which is less than 0.025 microg/cm2/h. CONCLUSIONS: The best skin permeant of this series was the N-methyl analog, which also exhibited the highest water (buffer) solubility compared to thalidomide, and the N-propyl and N-pentyl analogs. The N-propyl and N-pentyl analogs were more lipid soluble and exhibited higher partition coefficient values than the N-methyl analog. From all the permeability data using buffer, a series of n-alkanols and various combinations of solvents and enhancers as vehicles, the more water-soluble compound and not the more lipid soluble one was the best skin permeant.

Physicochemical characterization and solubility analysis of thalidomide and its N-alkyl analogs.

PURPOSE: The present study was primarily aimed at exploring the feasibility of improving percutaneous delivery via chemical manipulation of the thalidomide molecule to form analogs with improved physicochemical properties. N-Alkyl analogs were synthesized with the belief that these would be suitably hydrophobic and far less crystalline than the reference compound. This article presents their physicochemical properties. METHODS: Thalidomide and three of its N-alkyl analogs were synthesized. Identification and levels of purity (>96%) were assured through element analysis, fast atom-bombardment mass spectrometry, nuclear magnetic resonance spectroscopy, and high-performance liquid chromatography. N-Octanol/water partition coefficients were determined at pH 6.4. Solubilities in water and a series of n-alkanols were obtained. Best-fit solubility parameters were determined from the solubilities of the respective compounds in London solvents and were also calculated from respective hexane solubilities. melting points and heats of fusion. RESULTS: Methylation of the thalidomide molecule at its acidic nitrogen led to an aqueous solubility about 6-fold higher than thalidomide but, because the alkyl chain length was further extended from methyl to pentyl. aqueous solubilities decreased essentially exponentially. The destabilization of the crystalline structure with increasing alkyl chain length led to an increased solubility in nonpolar media. The log partition coefficient increased linearly with increasing alkyl chain length and the solubility parameters declined systematically through this series. By adding a methyl group to the thalidomide structure, the melting point dropped by more than 100 degrees C. Adding to the alkyl chain length led to further, more modest decreases. Heats of fusion decreased dramatically upon thalidomide's alkylation as well. CONCLUSION: Alkylation of the thalidomide molecule resulted in compounds with physicochemical properties that appear to be markedly better suited for percutaneous delivery.