James D Pipkin

Controlled drug delivery devices for experimental ocular studies with timolol 2. Ocular and systemic absorption in rabbits

Controlled drug delivery was tested as a means to decrease the potentially dangerous systemic drug concentrations which are associated with timolol eyedrop therapy. l-Tumolol (125 μg) was administered in 0.5% eyedrops (25 μl, pH 6.86) and in controlled release silicone tubing devices (dose 57.6 μ;g; release rate 7.2 μgh for 8 h) in the eyes of pigmented rabbits. [3H]Timolol tracer was used in ocular absorption studies and unlabeled timolol dosage forms in systemic absorption studies. [3H]Timolol concentrations were determined in ocular tissues and tear fluid. Beta blocking activity in plasma was determined using a radioreceptor assay. Comparable timolol concentrations were achieved in the iris-ciliary body with silicone tubing devices (57.6 μg) and with eyedrops (125 μg). The relative ocular timolol bioavailability after controlled drug delivery was about 2-fold greater than from eyedrops. In plasma, peak beta-blocking activity was much higher after eyedrop administration (17.16 ± 2.40 ng/ml) than during controlled timolol delivery (< 1.0 ngml). The results indicate that controlled drug delivery is a viable alternative in improving the therapeutic index of glaucoma therapy with timolol.

Controlled drug delivery devices for experimental ocular studies with timolol 1. In vitro release studies

Abstract Controlled drug delivery devices which can be easily tailored and conveniently prepared to release ocular drugs at specified controlled rates can be useful in studies of ocular drug delivery and drug response. The devices were fabricated by injecting 6.0, 9.0 or 12.5 μl of aqueous borate buffered solutions of timolol (2.5–20.0 mg ml ) into end-plugged pieces of silicone tubing and the release of timolol was studied in vitro. An initial lag in timolol release was avoided by storing the devices for an appropriate time (3–9 h) after filling the devices. The appropriate storage time was dependent on the steady-state flux of timolol, indicating that timolol was binding to the silica filler in the silicone tubing. Timolol was released at a constant rate (0.7–7.2 μg h ) for 8 h from the devices when the initial core pH was 8.64 and when the devices were stored for an appropriate time before an experiment. The steady-state release rate of timolol was increased 2.4-fold when the pH inside the device was increased from 8.34 to 9.24, As expected, the observed release rate increased with increased drug concentration in the device core and with increased length of the device. The permeability of timolol in the silicone membrane walls was 2.48−6.03 × 10 −9 cm 2 s −1 depending on the composition of the inner core solution. Thickness of the end-plugs (0.5 or 3.5 mm) did not affect timolol release from the devices, when the volume of timolol solution in the devices was 12.5 μl.

Effect of sulfobutyl ether-β-cyclodextrin on bioavailability of insulin glargine and blood glucose level after subcutaneous injection to rats

Insulin glargine is the first long-acting basal insulin analogue used for subcutaneous administration once daily in patients with type 1 or type 2 diabetes mellitus. To obtain the further bioavailability and the sustained glucose lowering effect of insulin glargine, in the present study, we investigated the effect of sulfobutyl ether-β-cyclodextrin (SBE4-β-CyD), with the degree of substitution of sulfobutyl ether group of 3.9, on pharmaceutical properties of insulin glargine and the release of insulin glargine after subcutaneous injection to rats. SBE4-β-CyD increased the solubility and suppressed aggregation of insulin glargine in phosphate buffer at pH 9.5, probably due to the interaction of SBE4-β-CyD with aromatic amino acid residues such as tyrosine of insulin glargine. In addition, SBE4-β-CyD accelerated the dissolution rate of insulin glargine from its precipitates, compared to that of insulin glargine alone. Furthermore, we revealed that subcutaneous administration of an insulin glargine solution with SBE4-β-CyD to rats enhanced the bioavailability of insulin glargine and sustained the glucose lowering effect, possibly due to the inhibitory effects of SBE4-β-CyD on the enzymatic degradation at the injection site. These results suggest that SBE4-β-CyD can be a useful excipient for sustained release of insulin glargine.

Slow-release of famotidine from tablets consisting of chitosan/sulfobutyl ether β-cyclodextrin composites

An intermolecular complex formed from a 1:1 weight ratio of chitosan (CS, molecular weight 30 kDa) and sulfobutyl ether β-cyclodextrin (SBE-β-CyD, degree of substitution 7) was less soluble than either of the original components. The release of famotidine from tablets composed of a simple mixture of CS and SBE-β-CyD is slower in media at pH 1.2 than at 6.8. Macroscopic observation of tablets and a kinetic analysis of release profiles suggested that, at pH 1.2, the drug was slowly released from the less-soluble CS/SBE-β-CyD complex formed on the surface of the tablet immediately after exposure to water, accompanied by the dissolution of the interpolymer complex and, ultimately, the erosion and disintegration of the tablet. In the case of the medium at pH 6.8, the formation of a gel by CS was the cause of the slow release, especially for CS/SBE-β-CyD tablets which were significantly gelated and both the diameter and thickness of the tablet had expanded. The in vitro slow releasing characteristic of the CS/SBE-β-CyD tablet was reflected in the in vivo absorption of the drug after oral administration to rats. These results suggest that a simple mixing of CS and SBE-β-CyD is potentially useful for the controlled release of a drug.

Effects of Selected Anionic β-Cyclodextrins on Persistence of Blood Glucose Lowering by Insulin Glargine after Subcutaneous Injection to Rats

Insulin glargine is a synthetic long-acting insulin product used for patients with diabetes mellitus. In this study, to obtain the further desirable blood-glucose lowering profile of insulin glargine, we investigated the effects of β-cyclodextrin sulfate (Sul-β-CyD) and sulfobutylether β-cyclodextrin (SBE7-β-CyD) on physicochemical properties of insulin glargine and pharmacokinetics/pharmacodynamics of insulin glargine after subcutaneous injection to rats. Sul-β-CyD and SBE7-β-CyD increased solubility of insulin glargine. SBE7-β-CyD suppressed the formation of oligomer and enhanced the dissolution rate of insulin glargine from its precipitate, compared to that of Sul-β-CyD. Additionally, we revealed that after subcutaneous administration of an insulin glargine solution, SBE7-β-CyD, but not Sul-β-CyD, increased bioavailability and sustained the blood-glucose lowering effect, possibly due to the inhibitory effects of SBE7-β-CyD on the enzymatic degradation at the injection site. These results suggest that SBE7-β-CyD could be a useful excipient for sustained release of insulin glargine.

Phenindione solubility in mixed organic solvents: analysis of the role of specific hydrogen and non-hydrogen bonding interactions

Abstract Phenindione, 2-phenyl-1,3-indanedione, exists predominantly in its diketo (I) rather than its enol (II) form in hydrocarbon solvents. Basic molecules interact with phenindione in cyclohexane resulting in formation of a tautomeric enol-complex (III). The solubility of hydrogen bond donor molecules in the presence of bases can often be defined by specific “chemical” or hydrogen bond interactions. In the present study the solubility of phenindione in cyclohexane in the presence of increasing concentrations of a number of dipolar bases, cosolvents, was studied. The purpose was to see if the increased solubility of phenindione in the presence of the bases was predictable from an earlier independently, spectrophotometrically determined hydrogen bonding interaction constants. In the presence of strong bases the solubility was predicted well by the increased presence of the enol-complex: however, in the presence of weak bases it was obvious that the non-specific “chemical” and/or “physical” effects were also operative.