Aim of the study is to establish physiologically-based in vitro in vivo correlation (IVIVC) of azithromycin, a biopharmaceutics classification system (BCS) class II drug (high permeability/ low solubility). In vitro dissolution was done using USP apparatus II in pH 6 phosphate buffer at 50 rpm. In vivo pharmacokinetic study was done on 28 healthy humans after IRB and Jordan FDA approvals. Plasma sampling was collected up to 72 hours. Non compartmental analysis was done using Kinetica program V 5. Physiologically based IVIVC was conducted using linear IVIVC module of SimCYP program V 13. Physiological parameter of effective intestinal permeability was optimized along with IVIVC calculations. IVIVC dissolution prediction matched in vivo profile with 1% and 7.7% prediction errors for AUC 72 and Cmax, indicating proper physiologically based IVIVC. This is in agreement with IVIVC expectation for class II drugs according to (BCS) when in vitro dissolution rate is similar to in vivo dissolution rate. This is important for drug formulators to predict in vivo bioavailability from in vitro dissolution, which can save time and money.
The N-ethoxycarbonylmorpholine moiety was evaluated as a novel prodrug moiety for carboxylic acid containing drugs represented by diclofenac (1). Compound 2, the N-ethoxycarbonylmorpholine ester of diclofenac was synthesized and evaluated as a potential prodrug. The stability of the synthesized prodrug was evaluated in solutions of pH 1 and 7.4, and in plasma. The ester’s half lives were found to be 8 h, 47 h and 21 min in pH 1, pH 7.4 and plasma, respectively. Equimolar doses of diclofenac sodium and its synthesized prodrug were administered orally to a group of rabbits in a crossover study to evaluate their pharmacokinetic parameters. The prodrug 2 shows a similar rate and extent of absorption as the parent drug (1). The ulcerogenicity of the prepared prodrug was evaluated and compared with the parent drug. The prodrug showed less ulcerogenicity as detected by fewer number and smaller size of ulcers. In conclusion, the newly synthesized N-ethoxycarbonylmorpholine ester of diclofenac prodrug showed appropriate stability properties at different pHs, similar pharmacokinetic profile, and much less ulcerogenecity at the GIT compared to the parent drug diclofenac.
2-(4-Chlorophenyl)-5-benzoxazoleacetic acid (CBA) and its ester, methyl-2-(4-chloro-phenyl)-5-benzoxazoleacetate (MCBA), were synthesized, and their structures were confirmed by 1HNMR, IR, and mass spectrophotometry. The anti-psoriatic activities of CBA and MCBA were tested using an imiquimod (IMQ)-induced psoriatic mouse model, in which mice were treated both topically (1% w/w) and orally (125 mg/kg) for 14 days. The erythema intensity, thickness, and desquamation of psoriasis were scored by calculating the psoriasis area severity index (PASI). The study also included the determination of histopathological alterations in the skin tissues of treated mice. Topical and oral administration of CBA and MCBA led to a reduction in erythema intensity, thickness, and desquamation, which was demonstrated by a significant decrease in the PASI value. In addition, skin tissues of mice treated with CBA and MCBA showed less evidence of psoriatic alterations, such as hyperkeratosis, parakeratosis, scale crust, edema, psoriasiform, and hyperplasia. After administration of either topical or oral dosing, the anti-psoriatic effects were found to be stronger in MCBA-treated than in CBA-treated mice. These effects were comparable to those produced by Clobetasol propionate, the reference drug. This drug discovery could be translated into a potential new drug for future clinical use in psoriasis treatment.
Background: The free carboxylic acid group present in the mefenamic acid (MFA) structure plays a potential role in developing various neuromuscular side effects after MFA administration. In this study, the hydroxypropyl promoiety was added to the carboxylic acid group of MFA in an attempt to reduce the neuromuscular side effects of MFA and improve its therapeutic effects. Methods: Hydroxypropylester of MFA (HPEMA) was synthesized and subjected to various in vivo investigations compared to MFA. The neuromuscular toxicity was conducted following high doses administration in mice and was evaluated at various measuring parameters, such as the percentage of catalepsy, clonic-tonic seizure, and death. In addition, the anti-inflammatory and antinociceptive effects of HPEMA were evaluated in the carrageenan-induced paw edema test and acetic acid-induced writhing test, respectively. Results: The finding of this study reveal that the percentage of catalepsy, clonic-tonic seizure, and death is significantly lower in mice treated with HPEMA than those treated with equimolar doses of MFA. In addition, treatment with HPEMA caused a comparable anti-inflammatory activity in the carrageenan-induced paw edema test and a significantly higher antinociceptive effect in the acetic acid-induced writhing test than the MFA treatment. Conclusion: This study’s findings suggest that HPEMA is a promising prodrug for MFA.
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