Immediate-release Oral Dosage Forms Research Articles

Knowledge-based: facilitating access to medicines in Latin America

The World Health Organization (WHO), with the scientific support of the International Pharmaceutical Federation (FIP), guides the development of multisource pharmaceutical products for market authorization using in vivo bioequivalence studies or, where applicable, in vitro biowaiver strategies based on the Biopharmaceutical Classification System (BCS). A review of the regulatory framework guiding generic medicines approval in Latin American countries revealed that less than 50% of regional health authorities offer a generic medicines development pathway utilizing a BCS-based biowaiver strategy. Aligned with the ONE FIP Strategy to facilitate access to medicines, a regional case study was carried out to implement and harmonize BCS-based biowaiver knowledge in Latin American countries. A steering committee involving regional representatives from health authorities, the pharmaceutical industry, and universities were established to coordinate to develop activities. A series of digital engagement events were held in Spanish and English with representatives from Latin America to share knowledge on BCS-based regulatory strategy, promote collaborations, and explore the alignment of biowaiver approval and regulatory pathways among Latin American countries. Feedback from diverse Latin American stakeholders demonstrated inconsistent implementation of bioequivalence testing within the region. However, there is support for a synergistic approach among countries to reduce duplication and increase efficiency in market authorization for generic medicines. This includes alignment with the WHO Prequalification of Medicines program as well as the development of a computational database for the classification of active pharmaceutical ingredients to demonstrate therapeutic interchangeability of immediate-release oral dosage forms according to the BCS. FIP-facilitated digital learning opportunities raised awareness of the BCS-based biowaiver regulatory strategy among Latin American stakeholders. It resulted in a plan to continually strengthen collaborative efforts in the region to harmonize regulations relevant to drug development generics medicines to introduce cost-effective medicines products that benefit public health.

A Rational Approach to Predicting Immediate Release Formulation Behavior in Multiple Gastric Motility Patterns: A Combination of a Biorelevant Apparatus, Design of Experiments, and Machine Learning.

Gastric mechanical stress often impacts drug dissolution from solid oral dosage forms, but in vitro experiments cannot recreate the substantial variability of gastric motility in a reasonable time. This study, for the first time, combines a novel dissolution apparatus with the design of experiments (DoE) and machine learning (ML) to overcome this obstacle. The workflow involves the testing of soft gelatin capsules in a set of fasted-state biorelevant dissolution experiments created with DoE. The dissolution results are used by an ML algorithm to build the classification model of the capsule's opening in response to intragastric stress (IS) within the physiological space of timing and magnitude. Next, a random forest algorithm is used to model the further drug dissolution. The predictive power of the two ML models is verified with independent dissolution tests, and they outperform a polynomial-based DoE model. Moreover, the developed tool reasonably simulates over 50 dissolution profiles under varying IS conditions. Hence, we prove that our method can be utilized for the simulation of dissolution profiles related to the multiplicity of individual gastric motility patterns. In perspective, the developed workflow can improve virtual bioequivalence trials and the patient-centric development of immediate-release oral dosage forms.

Formulation, Optimization and Evaluation of Nanofiber Based Fast Dissolving Drug Delivery System of Colchicine for Pediatrics

Systemic toxicity is an obstacle against the oral administration of colchicine. The high body surface area to mass ratio in pediatrics would dramatically enhance the toxicity risk. This issue could be jettisoned by formulation of an optimized nanofiber-based fast dissolving delivery system. It could enhance the drug's bioavailability, reduce the administered dose, and bring more convenience and compliance for pediatrics with the problem of consuming conventional dosage forms. The optimized colchicine loaded nanofibers of polyvinyl alcohol 10%w/v with 220.47±16.87 nm mean diameter size exhibits smooth surface and continuous structure in SEM micrographs. No incompatibility was seen in FT-IR analyses. The thermal study illustrated stability enhancement by colchicine loading. The water angle analysis demonstrated its superhydrophilicity and the in vitro release profile illustrated a quick release of colchicine in 30 seconds. As a conclusion, nanofiber-based fast dissolving formulation of colchicine could be suggested as a localized and systemic transmucosal delivery system, immediate-release oral dosage form, and even topical colchicine delivery system that may reduce the risk of systemic toxicity in pediatrics. The antitumor property of CL may also suggest it in rapid neoadjuvant or adjuvant localized chemotherapy protocols for the management of topical tumors in pediatrics.

Implementing the Biopharmaceutics Classification System in Drug Development: Reconciling Similarities, Differences, and Shared Challenges in the EMA and US-FDA-Recommended Approaches.

The US-FDA recently posted a draft guideline for industry recommending procedures necessary to obtain a biowaiver for immediate-release oral dosage forms based on the Biopharmaceutics Classification System (BCS). This review compares the present FDA BCS biowaiver approach, with the existing European Medicines Agency (EMA) approach, with an emphasis on similarities, difficulties, and shared challenges. Some specifics of the current EMA BCS guideline are compared with those in the recently published draft US-FDA BCS guideline. In particular, similarities and differences in the EMA versus US-FDA approaches to establishing drug solubility, permeability, dissolution, and formulation suitability for BCS biowaiver are critically reviewed. Several case studies are presented to illustrate the (i) challenges of applying for BCS biowaivers for global registration in the face of differences in the EMA and US-FDA BCS biowaiver criteria, as well as(ii) challenges inherent in applying for BCS class I or III designation and common to both jurisdictions.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Nifedipine

Literature data relevant to the biopharmaceutical properties of the active pharmaceutical ingredient (API) nifedipine are reviewed to evaluate whether a waiver of in vivo bioequivalence (BE) testing of immediate-release (IR) dosage forms formulated as tablets and soft gelatin capsules is warranted. Nifedipine's solubility and permeability, its therapeutic use and index, pharmacokinetics, food drug interactions, and any reported BE/bioavailability problems were all taken into consideration. Solubility and BA data indicate conclusively that nifedipine is a class II substance of biopharmaceutics classification system (BCS) and that the formulation of drug product plays a key role on the dissolution characteristics of the API. Therefore, a BCS biowaiver-based approval of nifedipine containing IR oral dosage forms cannot be recommended for reformulated/new multisource drug products or for major scale-up and postapproval changes to the existing drug products.

In Vitro–In Vivo Correlation Strategy Applied to an Immediate-Release Solid Oral Dosage Form with a Biopharmaceutical Classification System IV Compound Case Study

The ability to predict in vivo response of an oral dosage form based on an in vitro technique has been a sought after goal of the pharmaceutical scientist. Dissolution testing that demonstrates discrimination to various critical formulations or process attributes provides a sensitive quality check that may be representative or may be overpredictive of potential in vivo changes. Dissolution methodology with an established in vitro-in vivo relationship or correlation may provide the desired in vivo predictability. To establish this in vitro-in vivo link, a clinical study must be performed. In this article, recommendations are given in the selection of batches for the clinical study followed by potential outcome scenarios. The investigation of a Level C in vitro-in vivo correlation (IVIVC), which is the most common correlation for immediate-release oral dosage forms, is presented. Lastly, an IVIVC case study involving a biopharmaceutical classification system class IV compound is presented encompassing this strategy and techniques.

Agglomeration of Mesoporous Silica by Melt and Steam Granulation. Part I: A Comparison Between Disordered and Ordered Mesoporous Silica

The objective of this study was to compare agglomerations by melt and steam granulation of ordered, COK-12, and disordered, Syloid(®) 244 FP (244), mesoporous silica material. Poloxamer 188 (P188) and polyvinylpyrrolidone K25 (PVP) were chosen as binders for melt and steam granulation, respectively. The poorly water-soluble compound, itraconazole (ITZ), was selected for the development of an immediate-release oral dosage form. Steam granulation resulted in the largest granules, however, the slowest release. Compression behavior and tablet properties of steam-granulated material prepared with COK-12 and 244 were similar. As determined by X-ray powder diffraction, melt granulation resulted in the most ITZ to extract from the pores during processing. However, the enhanced release rate was still maintained when compared with the crystalline form. Moreover, no additional drug extraction was observed following the 6 month storage in 25°C/60% relative humidity (RH) and 40°C/75%RH. P188 diffraction peaks were present in the 244 melt-granulated material, but disappeared because of the degradation following 1 week in 40°C/75%RH conditions. The differential scanning calorimetry analysis indicated that the degradation of P188 already occurred during the granulation process itself. Based on these results, steam granulation with PVP is the preferred method over melt granulation with P188.

The Clinical Pharmacokinetics of Darifenacin

Darifenacin hydrobromide is a selective muscarinic M(3) receptor antagonist that is indicated for use in treatment of overactive bladder disorder. Darifenacin was found to have a short terminal elimination half-life after intravenous and immediate-release oral dosage forms (3-4 hours) but this increased with a prolonged-release (PR) formulation (14-16 hours). The absolute bioavailability of darifenacin from 7.5 and 15 mg PR tablets was estimated to be 15.4% and 18.6%, respectively. With repeated once-daily oral administration of the PR formulation, peak plasma concentrations of darifenacin are achieved approximately 7 hours post-dose. After oral administration, darifenacin is well absorbed from the gastrointestinal tract and very little unchanged drug (<2%) is recovered in the faeces. Steady state is achieved after 6 days of once-daily administration of the PR formulation. As expected, values of peak plasma concentration (C(max)) and area under the plasma concentration-time curve are dose dependent, although the increase in plasma concentrations is proportionally greater than the increase in dose owing to saturation of presystemic metabolism. From intravenous administration, it has been established that darifenacin possesses a moderate-to-high hepatic extraction ratio, with high plasma clearance (36-52 L/h) and a volume of distribution (165-276L) that exceeds total body water. It is highly protein bound (98%), primarily to alpha(1)-acid glycoprotein. Darifenacin is subject to extensive hepatic metabolism, with 3% of unchanged drug excreted in urine and faeces. Metabolism is mediated by hepatic cytochrome P450 2D6 and 3A4, the main metabolic routes being monohydroxylation in the dihydrobenzfuran ring, dihydrobenzfuran ring opening, and N-dealkylation of the pyrrolidine nitrogen. Several possibly important drug-drug interactions have been identified with darifenacin, including ketoconazole, erythromycin and fluconazole, each of which increases darifenacin mean C(max) by 9.52-, 2.28- and 1.88-fold, respectively. When given with imipramine, darifenacin causes 1.6-fold higher plasma concentrations of the antidepressant and its major metabolite. Moderate hepatic impairment, but not renal insufficiency, has been shown to increase plasma concentrations of the drug. The pharmacokinetic profile of darifenacin is not affected by food.