To explore the application of solution calorimetry for measuring drug solubility in experimentally challenging situations while providing additional information on the physical properties of the solute material.
Small tablets for implantation into the subconjunctival space in the eye are being developed to inhibit scarring after glaucoma filtration surgery (GFS). There is a need to evaluate drug dissolution at the molecular level to determine how the chemical structure of the active may correlate with dissolution in the nonsink conditions of the conjunctival space. We conducted molecular dynamics simulations to study the dissolution process of tablets derived from two drugs that can inhibit fibrosis after GFS, 5-fluorouracil (5-FU) and the matrix metalloprotease inhibitor (MMPi), ilomastat. The dissolution was simulated in the presence of simple point charge (SPC) water molecules, and the liquid turnover of the aqueous humor in the subconjunctival space was simulated by removal of the dissolved drug molecules at regular intervals and replacement by new water molecules. At the end of the simulation, the total molecular solvent accessible surface area of 5-FU tablets increased by 60 times more than that of ilomastat as a result of tablet swelling and release of molecules into solution. The tablet dissolution pattern shown in our molecular dynamic simulations tends to correlate with experimental release profiles. This work indicates that a series of molecular dynamic simulations can be used to predict the influence of the molecular properties of a drug on its dissolution profile and could be useful during preformulation where sufficient amounts of the drug are not always available to perform dissolution studies.
Bicarbonate media are reflective of the ionic composition and buffer capacity of small intestinal luminal fluids. Here we investigate methods to stabilise bicarbonate buffers which can be readily applied to USP-II dissolution apparatus. The in vitro drug release behaviour of three enteric coated mesalazine (mesalamine) products is investigated. Asacol 400 mg and Asacol 800 mg (Asacol HD) and the new generation, high dose (1200 mg) delayed and sustained release formulation, Mezavant (Lialda), are compared in pH 7.4 Krebs bicarbonate and phosphate buffers. Bicarbonate stabilisation was achieved by: continuous sparging of the medium with 5% CO(2)(g), application of a layer of liquid paraffin above the medium, or a specially designed in-house seal device that prevents CO(2)(g) loss. Each of the products displayed a delayed onset of drug release in physiological bicarbonate media compared to phosphate buffer. Moreover, Mezavant displayed a zero-order, sustained release profile in phosphate buffer; in bicarbonate media, however, this slow drug release was no longer apparent and a profile similar to that of Asacol 400 mg was observed. These similar release patterns of Asacol 400 mg and Mezavant displayed in bicarbonate media are in agreement with their pharmacokinetic profiles in humans. Bicarbonate media provide a better prediction of the in vivo behaviour of the mesalazine preparations investigated.
The transit of dosage forms through the small intestine is considered to be constant at around 3 h, and unaffected by the presence of food. Here we address this assumption and examine how the timing of tablet and food administration can influence small intestine transit time.
We are developing tablet dosage forms for implantation directly into the subconjunctival space of the eye. The matrix metalloproteinase inhibitor, ilomastat, has previously been shown to be efficacious at suppressing scarring following glaucoma filtration surgery (GFS). We report on the physical characterisation of ilomastat which is being developed for ocular implantation. Since ilomastat is being considered for implantation it is necessary to examine its polymorphs and their influence on aspects of the in vitro drug release profile. X-ray powder diffraction identified two polymorphs of ilomastat from different commercial batches of the compound. Tablets were prepared from the two different polymorphs. Isothermal perfusion calorimetry was used to show that amorphous content is not increased during tablet formulation. The melting points of the two polymorphs are 188 and 208°C as determined by differential scanning calorimetry. Utilising single crystal X-ray diffraction, the structural conformations and packing arrangements of the different polymorphs were determined. The orthorhombic crystal crystallised as a monohydrate while the second monoclinic crystal form is non-solvated. Ilomastat tablets prepared from the two different solid forms exhibited similar drug release profiles in vitro under conditions mimicking the aqueous composition, volume and flow of the subconjunctival space after GFS. This suggests that a reproducible dose at each time point during release after implantation should be achievable in vivo with ilomastat tablets prepared from the two polymorphs identified.
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