Drug Physicochemical Properties and Capsule Fill Determine Extent of Premature Gastric Release from Enteric Capsules.

Intrinsically, enteric capsule shells offer several advantages compared to coating of dosage forms with enteric polymers. We undertook a systematic investigation to elucidate capsule-fill parameters that may result in premature gastric drug release from Vcaps® Enteric capsules (Lonza CHI, Morristown, NJ, USA). Four model drugs with different ionization and solubility profiles were investigated: acetaminophen, ketoprofen, trimethoprim and atenolol. Different fill loads, diluents and drug-to-diluent ratios were explored. Enteric capsules were filled with drug or drug and diluent powder mix and underwent USP II dissolution testing using mini-vessels and paddles. Capsules were tested in pH 2 (0.01 M HCl) or pH 4.5 (3.2 × 10-5 M HCl) 200 mL acid media to simulate normal, fasted or hypochlorhydric gastric pH, respectively. Acetaminophen, trimethoprim and atenolol displayed premature gastric drug release from enteric capsules. The extent of premature release was dependent on drug solubility, ionization profile and capsule-fill level. At 100 mg drug-fill level, acetaminophen, trimethoprim and atenolol gave rise to 10.6, 12.2 and 83.1% drug release, respectively, in normal, fasted, gastric fluids. Diffusion layer pH of trimethoprim and atenolol in pH 2 media was determined to be pH 6.3 and 10.3, respectively. Upon increasing capsule-fill load using microcrystalline cellulose as a diluent, a significant reduction in premature gastric release was observed. However, including mannitol as a diluent was only effective at decreasing premature drug release at a low drug-to-diluent ratio. Systematic in vitro screening of enteric capsule fills needs to be conducted to ensure that drug product performance is not compromised.

Intra- and inter-subject variability in gastric pH following a low-fat, low-calorie meal.

Food can alter drug bioavailability through gastric pH changes. Time spent at gastric pH ranges is reported here, including variability data following ingestion of a light, mixed, 260 kcal meal. pH data was obtained for 20 healthy subjects undergoing SmartPill™ wireless motility capsule investigations on three separate visits. Gastric phase pH was sorted into pH < 2, 2-3, 3-4, 4-5 and > 5. All visits and all subjects were pooled to determine median time (25-75th percentiles) in minutes. Gastric emptying time was 176 (137-205) min with the majority of time, 111 (67 - 163), spent at pH < 2. Times spent at pH 2-3 and 3-4 were similar: 17 (5.7 - 35.6) and 18 (7.2-29.3). Time spent at pH 4-5 was 9 (1.3-20.6) and at pH > 5 was 0.7 (0-4.4). Intra-subject variability as determined by robust coefficient of variation (RCV)% was 30 % for pH < 2, 57 % for pH 2-3, 71 % for pH 3-4, 106 % for pH 4-5 and 144 % for pH > 5. Inter-subject variability RCV% was 49 % for pH < 2, 89 % for pH 2-3, 54 % for pH 3-4, 97 % for pH 4-5 and 148 % for pH > 5. Inter-subject variability can be up to approximately twofold higher than intra-subject variability at the lower pH ranges.

Vitamin C Improves Dasatinib Concentrations Under Hypochlorhydric Conditions of the Simulated Stomach Duodenum Model.

PURPOSE: pH-dependent drug-drug interactions (DDIs) with poorly soluble, weakly basic drugs may lead to clinical implications. Dasatinib is a tyrosine kinase inhibitor with reduced absorption in patients on acid-reducing agents (ARAs). The objective of this study is to investigate the influence of gastric pH on dasatinib supersaturation and determine if vitamin C (L-ascorbic acid) can improve dasatinib concentrations under simulated hypochlorhydric gastric conditions. METHODS: A dynamic, in vitro, multi-compartment, simulated stomach duodenum (SSD) model mimicking fluid volumes and transfer rates was used to investigate the concentration of BCS class IIb drugs versus time curves. Dasatinib and lamotrigine were explored under normal, fasted, simulated gastric fluids (pH 2) (FaSGF), hypochlorhydric simulated gastric fluids (pH 4.5) (FaSGFhypo) and FaSGFhypo with 1000 mg of vitamin C. RESULTS: Significant supersaturation of dasatinib was observed in the duodenum compartment of the SSD model in FaSGF. A 90% reduction in dasatinib AUC∞ was observed in FaSGFhypo. Upon addition of vitamin C to FaSGFhypo, drug concentrations were restored to those observed in FaSGF. Lamotrigine AUC∞ in the duodenal compartment were similar in both FaSGF and FaSGFhypo. The in vitro trends observed for dasatinib and lamotrigine are reflective of the trends observed in vivo in subjects receiving treatment with ARAs. CONCLUSIONS: The SSD model serves as a good in vitro tool for assessing the effect of pH-dependent DDIs on bioavailability of weakly basic drugs with solubility/ dissolution limited absorption. Vitamin C provides a promising approach for improving bioavailability of poorly soluble, weakly basic drugs in hypochlorhydric patients.

A dual pH and microbiota-triggered coating (Phloral™) for fail-safe colonic drug release.

Enteric-coated dosage forms are widely used for targeting the ileo-colonic region of the gastrointestinal (GI) tract. However, accurate targeting is challenging due to intra- and inter-individual variability in intestinal paramaters such as fluid pH and transit times, which occasionally lead to enteric coating failure. As such, a unique coating technology (Phloral™), which combines two independent release mechanisms - a pH trigger (Eudragit® S; dissolving at pH 7) and a microbiota-trigger (resistant starch), has been developed, offering a fail-safe approach to colonic targeting. Here, we demonstrate that the inclusion of resistant starch in the coating does not affect the pH mediated drug release mechanism or the robustness of the coating in the upper GI tract. In order to make the resistant starch more digestible by bacterial enzymes, heat treatment of the starch in the presence of butanol was required to allow disruption of the crystalline structure of the starch granules. Under challenging conditions of limited exposure to high pH in the distal small intestine fluid and rapid transit through the colon, often observed in patients with inflammatory bowel disease, particularly in ulcerative colitis, this dual-trigger pH-enzymatic coating offers a revolutionary approach for site specific drug delivery to the large intestine.

The Route to Palatable Fecal Microbiota Transplantation.

The community of symbiotic microorganisms that reside in our gastrointestinal tract is integral to human health. Fecal microbiota transplantation (FMT) has been shown to be highly effective in treating recurrent Clostridioides difficile infection (rCDI) and is now recommended by medical societies for patients suffering from rCDI who have failed to respond to conventional therapy. The main challenges with FMT are its accessibility, acceptability, lack of standardization, and regulatory complexity, which will be discussed in this review. Access to FMT is being addressed through the development of frozen and lyophilized FMT preparations that can be prepared at stool banks and shipped to the point of care. Both access and patient acceptance would be enhanced by oral FMT capsules, and there is potential to reduce capsule burden by utilizing colonic release capsules, targeting the site of disease. This review compares the efficacy of different FMT routes of administration: capsules, nasal feeding tubes, enemas, and colonoscopic infusions. FMT is considered investigational by the Food and Drug Administration. In effort to improve access to FMT, physicians may perform FMT outside of an investigational new drug application for treating CDI infections not responsive to standard therapies. The majority of FMT studies report only minor adverse effects; however, there is risk of transmission of infections.

Correction to: Fecal Microbiota Transplantation Capsules with Targeted Colonic Versus Gastric Delivery in Recurrent Clostridium difficile Infection: A Comparative Cohort Analysis of High and Low Dose.

The original version of the article unfortunately contained an error in article title. The corrected title is 'Fecal Microbiota Transplantation Capsules with Targeted Colonic Versus Gastric Delivery in Recurrent Clostridium difficile Infection: A Comparative Cohort Analysis of High and Low Dose'.

Community pharmacists' understanding and perceptions of FDA therapeutic equivalence standards.

BACKGROUND: Pharmacists need to demonstrate knowledge of and have confidence in Food and Drug Administration (FDA) therapeutic equivalence (TE) standards to improve acceptance of generic medicines amongst patients and other healthcare professionals. OBJECTIVE: To evaluate community pharmacists' understanding, interpretation and perceptions of the FDA TE standards to identify if further education is needed on this topic. METHODS: An anonymous, 13-item survey was piloted and then distributed by e-mail to a random sample of 287 Indiana community pharmacists. The 5-min survey included demographic, knowledge-based, and perception-based questions on FDA TE criteria that participants were given one week to complete. Participants completed the survey using a Web-based survey tool (Qualtrics). RESULTS: 192 pharmacists completed the survey achieving a response rate of 66.9%. Only 7.3% of respondents correctly identified FDA bioequivalence criteria for approval of generic drug products. Two questions presented TE codes from the Orange Book and asked respondents to identify if a pair of drug products were therapeutically equivalent: 62.6% and 61.0% of respondents answered correctly. However, 89.4% of respondents correctly indicated that the Orange Book is the location of FDA TE evaluations. 74.9% of responding pharmacists indicated a positive perception of the rigor of FDA approval standards associated with generic medications and 66.0% believed that generic drug products made by different manufacturers are of similar quality. CONCLUSIONS: The results suggest that community pharmacists need additional education on the interpretation of TE codes and FDA bioequivalence criteria for approval of generic drug products. The safety and efficacy of generics are often questioned by patients and physicians. It is important for pharmacists to be knowledgeable of FDA TE standards as they are experts in medicines and need to be confident with the criteria to effectively convey them to patients and healthcare professionals.

A Simulated Stomach Duodenum Model Predicting the Effect of Fluid Volume and Prandial Gastric Flow Patterns on Nifedipine Pharmacokinetics From Cosolvent-Based Capsules.

Nifedipine is a Biopharmaceutics Classification System class II drug displaying large variability in absorption even when administered as immediate-release soft gelatin capsules of a cosolvent formulation. This in vitro study sought to understand the reasons behind variability in nifedipine absorption, how it can be minimized, and if it can be predicted using in vitro models. A dynamic in vitro simulated stomach duodenum model was used to explore drug concentration-time profiles of nifedipine soft gelatin capsules under conditions simulating how patients take their medicines. Specifically, the effect of prandial gastric emptying patterns and fluid volume administration (250 mL vs. 50 mL water) were investigated. Significant supersaturation of nifedipine was observed. While administration of large and small water volumes gave rise to a similar Cmax and area under the curve (AUC∞), the coefficient of variation in AUC was 4.8% and 49%, respectively, which can be attributed to differences in precipitation kinetics. Fasting and fed gastric emptying patterns also gave rise to a similar AUC; however, Cmax was significantly lower in the fed state. These trends are consistent with previously published in vivo results in healthy volunteers. The simulated stomach duodenum provides a good discriminative screening tool for predicting trends in drug concentration profiles of Biopharmaceutics Classification System class II drugs.

Fecal Microbiota Transplantation Capsules with Targeted Colonic Versus Gastric Delivery in Recurrent Clostridium difficile Infection: A Comparative Cohort Analysis of High and Lose Dose.

BACKGROUND: Fecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridium. difficile infection (rCDI). FMT capsules have emerged, and it is unknown if delivery location and dose impact efficacy. METHODS: We compared two cohorts of patients receiving two capsule formulations: gastric release (FMTgr) and targeted colonic release (FMTcr) at two different sites. Cohort A received FMTgr at (1) high dose: 60 capsules and low dose: 30 capsules. Patients in Cohort B received FMTcr at (1) high dose: 30 capsules (2) low dose: 10 capsules. Clinical cure rates and adverse events were monitored through week 8. Paired t-tests were used to compare diversity pre- and post-FMT. RESULTS: 51 rCDI patients were enrolled. Cohort A contained n = 20 and Cohort B contained n = 31. Overall cure at week 8 for FMTgr was 75% (15/20) compared to 80.6% for FMTcr, (25/31), p = 0.63. Both formulations were safe with no serious adverse events. FMTcr was superior at increasing gut microbial diversity. DISCUSSION: To our knowledge, this is the first study to compare targeted delivery of FMT capsules. While both capsules were safe and efficacious, microbial engraftment patterns were superior in FMTcr.

Risk Factors for Rescue Therapy in Crohn's Patients Maintained on Infliximab After Withdrawal of the Immunomodulator: A Long-Term Follow-Up.

BACKGROUND: Usefulness of thiopurine and scheduled infliximab combination therapy in non-immunomodulator (IM)-naïve Crohn's disease (CD) patients and the optimal length of dual therapy are still debated. AIMS: To determine proportion of patients developing disease flare requiring rescue therapy and risk factors associated with disease flare after de-escalation of IM from combination therapy. METHODS: Adult CD patients in clinical remission on combination therapy were identified from a large single-center database between 2002 and 2009. Patients who had their IM stopped in the absence of adverse events were included. Association between clinical and demographic variables and time until rescue therapy was analyzed using Cox-proportional hazard models. RESULTS: Forty-three CD patients on combination therapy in clinical remission at time of IM de-escalation were identified and followed up for a median duration of 61.6 months (range 5.4-129.5). Median duration of remission on combination therapy prior to IM de-escalation was 12.0 months (range 4-74). Thirty-one patients (72.1%) required rescue therapy during follow-up. On multivariable analysis, age at diagnosis < 16 years versus > 40 years (HR 4.55, 95% CI 1.18-17.62, p = 0.028), using methotrexate instead of azathioprine in combination with infliximab (HR 3.37, 95% CI 1.14, 9.96, p = 0.028), and duration of combination therapy < 6 months (HR 5.68, 95% CI 1.58, 20.36, p = 0.007) increased risk for rescue therapy. CONCLUSIONS: A large proportion of CD patients on combination therapy experienced a flare following IM withdrawal. Young age at diagnosis, short duration of combination therapy, and methotrexate use were independent predictors of the need for rescue therapy.

Sustained release ophthalmic dexamethasone: In vitro in vivo correlations derived from the PK-Eye.

Corticosteroids have long been used to treat intraocular inflammation by intravitreal injection. We describe dexamethasone loaded poly-DL-lactide-co-glycolide (PLGA) microparticles that were fabricated by thermally induced phase separation (TIPS). The dexamethasone loaded microparticles were evaluated using a two-compartment, in vitro aqueous outflow model of the eye (PK-Eye) that estimates drug clearance time from the back of the eye via aqueous outflow by the anterior route. A dexamethasone dose of 0.20±0.02mg in a 50µL volume of TIPS microparticles resulted in a clearance t1/2 of 9.6±0.3days using simulated vitreous in the PK-Eye. Since corticosteroids can also clear through the retina, it is necessary to account for clearance through the back of the eye. Retinal permeability data, published human ocular pharmacokinetics (PK) and the PK-Eye clearance times were then used to establish in vitro in vivo correlations (IVIVCs) for intraocular clearance times of corticosteroid formulations. A t1/2 of 48h was estimated for the dexamethasone-TIPS microparticles, which is almost 9 times longer than that reported for dexamethasone suspension in humans. The prediction of human clearance times of permeable molecules from the vitreous compartment can be determined by accounting for drug retinal permeation and determining the experimental clearance via the anterior aqueous outflow pathway using the PK-Eye.

Methotrexate Polyglutamate Monitoring in Patients With Crohn's Disease.

Methotrexate is an efficacious immunosuppressant for induction and maintenance of remission in Crohn's disease. The goal of this pilot study was to determine whether total or individual methotrexate glutamate levels (MTXGlun ) in red blood cells correlate with disease activity and adverse events in Crohn's disease. A cross-sectional study was undertaken with 12 patients on a stable dose of 25 mg weekly methotrexate (oral or subcutaneous). Clinical disease activity was assessed by the Harvey-Bradshaw Index (HBI), and biologic disease activity was measured by inflammatory markers. Concentrations of individual MTXGlun levels were measured in red blood cells (RBCs) using high-performance liquid chromatography-mass spectrometry. No association was observed between RBC individual (MTXGlun ) or total methotrexate glutamate concentrations and clinical disease activity (HBI score) or inflammatory markers or adverse events. Although Crohn's disease patients in remission appeared to generally have higher RBC total longer-chain methotrexate polyglutamate (MTXGlu3+4+5 ) concentrations compared with those with active disease, a definitive association between RBC MTXGlu3+4+5 levels and clinical disease activity could not be established. Larger longitudinal studies in patients with diverse disease activity are needed to establish the value of MTXGlun levels as indicators of treatment efficacy and clinical outcome.

Assessment of Small Intestinal Transit Times in Ulcerative Colitis and Crohn's Disease Patients with Different Disease Activity Using Video Capsule Endoscopy.

Small intestinal transit times (SITT) influence drug bioavailability. This study aimed to compare SITT in Crohn's disease and ulcerative colitis patients with non-inflammatory bowel disease (IBD) and to determine influence of disease activity on transit times, and in addition, to establish the utility of small bowel video capsule endoscopy (SB-VCE) in investigation of SITT in IBD patients. A retrospective review was performed on consecutive patients who had undergone SB-VCE at a university hospital out-patient clinic. In total, 125 non-IBD patients, 55 Crohn's disease patients, and 23 ulcerative colitis patients were included. SITT were calculated from the first duodenal image to the first cecal image. Disease activity was assessed based on endoscopy results and inflammatory markers (calprotectin, C-reactive protein, erythrocyte sedimentation rate). SITT were longer in ulcerative colitis patients compared to non-IBD patients (median 264 min vs. 216 min, p = 0.010). Patients with active Crohn's disease (n = 33) also displayed prolonged SITT compared to non-IBD patients (median 253 min vs 216 min, p = 0.017) and patients with quiescent Crohn's disease (n = 22) (p = 0.005). SITT can be prolonged in IBD patients depending on disease activity which may alter the drug release profiles and clinical response to colonic drug delivery systems. SB-VCE is a simple, non-invasive tool that can be utilized in pharmacokinetic studies to understand drug bioavailability in different patient groups. Moreover, this variability in transit times needs to be simulated in dissolution testing for in vitro in vivo correlations.

Effect of Gastric Fluid Volume on the In Vitro Dissolution and In Vivo Absorption of BCS Class II Drugs: a Case Study with Nifedipine.

Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large inter-patient variability in nifedipine absorption results in variable exposure among different patients. We conducted in vitro dissolution studies to compare nifedipine dissolution from immediate release (IR) capsules with different volumes of dissolution media. Results from dissolution studies were used to design a crossover study in healthy volunteers to evaluate the effect of coadministered water volume with nifedipine 10 mg IR capsules on nifedipine pharmacokinetics, especially absorption (C max, t max, and AUC0-6). Dissolution studies demonstrated that larger gastric fluid volumes result in enhanced nifedipine dissolution from 10 mg IR cosolvent capsules (73 vs. 17% in 200 and 100 mL simulated gastric fluid, respectively, at 30 min). The pharmacokinetic crossover study in healthy volunteers (N = 6) did not show a significant effect of the water volume administered with the capsule (50 vs. 250 mL) on C max, t max, or AUC0-6 of orally administered nifedipine IR capsules (10 mg). However, administration of large water volumes resulted in lower variability in nifedipine C max (47 vs. 70% for 250 and 50 mL, respectively). Administration of large water volumes with nifedipine 10 mg IR cosolvent capsules may reduce inter-individual variability in plasma exposure. Evaluation of similar effects in other BCS Class II drugs is recommended.

The Effect of Sex and Age on Small Intestinal Transit Times in Humans.

This study utilizes a novel approach of small bowel video capsule endoscopy for investigating the influence of sex and age on small intestinal transit times (SITT) in humans. A total of 81 outpatients undergoing investigations with the small bowel video capsule endoscope (SB-VCE) and meeting inclusion criteria were included in this study. Following an overnight fast, patients swallowed the SB-VCE with a glass of water. SITT were calculated from the first duodenal image to the first cecal image. This study showed that the SB-VCE provides accurate and reliable measurements of SITT under real-life conditions. A large inter-individual variability in SITT was observed, with times ranging from 50 to 460 min. This variability can have implications on drug absorption and bioavailability. The median SITT were 219 min for females and 191 min for males. Although SITT were 28 min longer in females than males, this difference was not found to be statistically significant (p = 0.66). No correlation was found between age and SITT (Pearson correlation coefficient 0.19). Therefore, any drug bioavailability differences of modified release dosage preparations that are observed between adult patient groups of different age or sex are unlikely to be attributable to SITT.

Leveraging BCS in Development: A Case Study.

In this work, we discuss leveraging the Biopharmaceutics Classification System (BCS) in the development of edivoxetine HCl, a selective norepinephrine reuptake inhibitor. First, the biopharmaceutical and in vivo data are presented and discussed. Solubility studies indicate that edivoxetine HCl meets the BCS "highly soluble" criteria. To determine permeability classifications, in vitro intestinal Caco-2 epithelial cell model with and without cyclosporin A (CsA), a common P-glycoprotein (P-gp) inhibitor, were conducted. Pharmacokinetic (PK) data obtained across phase 1 and 2 clinical studies where single and multiple doses range from the lowest to the highest strength are presented. Neither the Caco-2 nor the in vivo data on their own were sufficient to conclusively classify edivoxetine as highly permeable. However, collectively the data were utilized to support high permeability and consequently BCS1 classification of edivoxetine HCl. BCS1 classification was leveraged throughout development to assess the risk associated with not conducting relative bioavailability (RBA) studies and avoiding bioequivalence (BE) studies. Examples are presented where formulation changes were made between phase I (drug in capsule/drug in bottle formulations) and phase II (tablet) trials in addition to phase III (tablet) and commercial (smaller tablet) without having to conduct any in vivo comparability studies. For the first change, BCS was leveraged to avoid conducting a RBA study even before obtaining official BCS classification. For the later change, official BCS1 classification was relied upon to avoid conducting a BE study.

Cosolvency approach for assessing the solubility of drugs in poly(vinylpyrrolidone).

The log-linear cosolvency model was applied for estimating the solubility of four drugs: ritonavir, griseofulvin, itraconazole and ketoconazole in poly(vinylpyrrolidone) (PVP). Cosolvent mixtures consisted of PVP mixed in different proportions with N-ethylpyrrolidone, which served as the monomeric analogue of the repeating unit of the polymer. Solubility in the monomer-polymer mixtures was determined by HPLC. As the configuration of the solvating unit in the solvent mixture changed from entirely monomeric to increasingly polymeric, the solubility of the drugs decreased in a fashion that follows the log-linear cosolvency model. The linear relationship was used to obtain estimates for the solubility of the drugs in the different grades of PVP. The solubility of the drugs in PVP is low (from <1% to ∼15% w/w). Among the set of drug solutes, ritonavir exhibited the highest solubility in PVP (w/w). Mixing with the monomer is most favorable for griseofulvin among the four drugs. However, the detrimental effect of polymerization on its solubility is more pronounced than for ritonavir. The mixing of itraconazole with the monomer is more favorable than the mixing of ketoconazole. However, despite the molecular similarity between ketaconazole and itraconazole, the solubility of the latter is particularly affected by the polymeric configuration of the solvating unit, to the point of exhibiting differences in solubility resulting from the chain length of the grade of PVP used. The log-linear cosolvency model is a useful tool for estimating the solubility of the drugs in the polymer at room temperature, while providing quantitative information on the differences in mixing behavior of the four model compounds.

A novel method for determining the solubility of small molecules in aqueous media and polymer solvent systems using solution calorimetry.

PURPOSE: 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. METHODS: A semi-adiabatic solution calorimeter was used to measure the heat of dissolution of prednisolone and chlorpropamide in aqueous solvents and of griseofulvin and ritonavir in viscous solutions containing polyvinylpyrrolidone and N-ethylpyrrolidone. RESULTS: Dissolution end point was clearly ascertained when heat generation stopped. The heat of solution was a linear function of dissolved mass for all drugs (<10% RSD, except for chlorpropamide). Heats of solution of 9.8 ± 0.8, 28.8 ± 0.6, 45.7 ± 1.6 and 159.8 ± 20.1 J/g were obtained for griseofulvin, ritonavir, prednisolone and chlorpropamide, respectively. Saturation was identifiable by a plateau in the heat signal and the crossing of the two linear segments corresponds to the solubility limit. The solubilities of prednisolone and chlopropamide in water by the calorimetric method were 0.23 and 0.158 mg/mL, respectively, in agreement with the shake-flask/HPLC-UV determined values of 0.212 ± 0.013 and 0.169 ± 0.015 mg/mL, respectively. For the higher solubility and high viscosity systems of griseofulvin and ritonavir in NEP/PVP mixtures, respectively, solubility values of 65 and 594 mg/g, respectively, were obtained. CONCLUSION: Solution calorimetry offers a reliable method for measuring drug solubility in organic and aqueous solvents. The approach is complementary to the traditional shake-flask method, providing information on the solid properties of the solute. For highly viscous solutions, the calorimetric approach is advantageous.

Molecular dynamic simulations of ocular tablet dissolution.

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.

Characterisation of ilomastat for prolonged ocular drug release.

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.