Modified-release Drug Products Research Articles

Retrospective analysis of the biopharmaceutics characteristics of solid oral Modified-Release drug products in approved US FDA NDAs designated as Extended-Release or Delayed-Release formulations

BackgroundModified Release (MR) orally administered drugs products [Extended-Release (ER) and Delayed-Release (DR)] differ from Immediate-Release (IR) drug products in their drug release site and/or rate to offer therapeutic advantages. It is important to understand the biopharmaceutics factors that determine how a drug works in the gastrointestinal tract and the various pharmacokinetic properties that determine a drug’s rate of absorption and release in the human body. To better understand the biopharmaceutics characteristics of ER and DR drug products, this study retrospectively analyzed submissions approved by the US Food and Drug Administration (FDA), from 2001 to 2021, and their corresponding review documents. This review work is expected to enhance the readers’ understanding regarding the biopharmaceutics properties that supported approval of these products’ ER claims, as per 21 CFR 320.25(f), and DR claims. MethodsA comprehensive search was conducted using the FDA’s internal New Drug Application (NDA) database for ER and DR oral drug products approved between 2001 and 2021. The search yielded 87 ER applications (23 ER capsules and 64 ER tablets) and 21 DR applications (10 DR capsules, 11 DR tablets) for which electronic records were accessible. These products were analyzed for overall drug product design, dosing frequency compared to the reference (if applicable), degree of fluctuation, dissolution method, and alcohol dose-dumping. ResultsOut of 87 total applications for ER drug products that were assessed, 62% of the ER tablets contained a polymer matrix formulation, and hypromellose (HPMC) was used in 50% of these products. 52% of the ER capsules consisted of polymer beads while about half of the DR drug products contained a non-bead formulation with a combination of polymers. The majority of ER drug products were found to have a reduction in dosing frequency and a decrease in the degree of fluctuation when compared to the IR reference product. The 13 ER drug products that exhibited an increase in degree of fluctuation exhibited general and pharmacodynamic benefits, such as reduced dosing frequency and reduced pill burden. The majority of DR formulations were developed to prevent drug degradation in the stomach, followed by to decrease potential stomach irritation, and lastly for localized release in the colon. The majority of ER drug products had 1:1 ratios of dissolution duration compared to dosing frequency (i.e., the majority of ER drug products had a dissolution duration of 24 h and were dosed every 24 h while those with a dissolution duration of 12 h were dosed every 12 h). The majority of ER applications had single-stage dissolution methods while most DR drug products used biphasic dissolution methods. All of the DR dissolution methods incorporated an acid stage of 2 h and a buffer stage with various timeframes. 53% the DR drug products had a ratio of dissolution duration to dosing frequency of 1:4 (e.g. a dissolution duration of 2 h to a dosing frequency of 8 h) or 1:8 (e.g. a dissolution duration of 2 h to a dosing frequency of 16 h). Of the ER tablets and DR drug products, 72% exhibited no alcohol dose-dumping under in vitro testing conditions. ER capsules, however, did not yield similar results—most of which exhibited alcohol induced dose-dumping. Alcohol dose dumping was mitigated by either in vivo studies or warnings on the drug product label. ConclusionThe results of this study help the reader understand the design, characteristics, and pharmacological advantages of the ER and DR drug products for patient benefit; as well as the regulations governing the FDA’s assessment of ER claims.

A Review on Modified Release Dosage Form

Among the various routes of drug delivery oral route is most preferred route. But conventional dosage form offers few limitations which could be resolved by modifying the existing dosage form. Sustained and controlled drug delivery system helps in maintaining of constant plasma drug concentration and retards the release rate of drug thereby extending the duration of action. Modified release drug products allow at least a two-fold reduction in dosing when compared to a drug that is presented in a conventional immediate release form. Modified release drug products are designed to release active pharmaceutical ingredient over a longer duration of time; At least, longer than an Immediate release (I.R) formulation. Many Pharmaceutical companies also utilize the proprietary advantages of Modified release formulations to extend the patent life cycle of commercial products thereby bringing in new business.

Physiologically Based Biopharmaceutics Model of Vildagliptin Modified Release (MR) Tablets to Predict In Vivo Performance and Establish Clinically Relevant Dissolution Specifications.

The objective of the study was to predict pharmacokinetic (PK) and pharmacodynamic (PD) parameters of matrix-based modified release (MR) drug product of vildagliptin. Physiologically based biopharmaceutics modeling (PBBM) was developed using GastroPlus™ based on the available data including immediate-release (IR) drug product of vildagliptin. In vitro-in vivo correlation (IVIVC) was developed using mechanistic deconvolution to predict plasma concentration-time profile and PK parameters for a MR drug product planned for clinical use. Both methods, i.e., PBBM and IVIVC, were compared for the predicted PK parameters. Integration of DDDPlus™ and GastroPlus™ modeling was performed to explore clinically relevant dissolution specifications for vildagliptin MR tablets. The bioequivalence (BE) between batches with different dissolution specifications was evaluated using virtual clinical trials. The PD effect of dipeptidyl peptidase-IV (DPP-IV) inhibition was simulated utilizing PDPlus™ model in GastroPlus™. The results indicated that IVIVC best correlated the simulated PK parameters with those observed with the clinical study. The outcomes highlight the importance of integration of in vitro and in silico tools towards predictability of PK and PD parameters for a MR drug product. However, the post absorptive phase was found to be more dependent on the demographics of the healthy subjects.

Design of experiments and multivariate analysis approach to study dissolution stability of a modified-release drug product to support lean design strategies

Objective The purpose of this paper is to present the use of Design of Experiments and multivariate analysis for evaluation of a modified-release drug product stability to support post-approval lean stability approaches. The focus of the paper was to investigate potential root-causes for acceleration of dissolution upon stability. Methods For statistical evaluation of stability data, multiple linear regression statistics was used. The design space of the stability study was modeled using MODDE 12.1 software. For experimental set-up, parameters such as Temperature, Time, Packaging, Batch, and Active Pharmaceutical Ingredient supplier were selected. Results With multiple linear regression modeling of the all generated stability data until six months, we were able to identify or confirm the Stability-related quality attributes and Shelf life limiting attributes. From the multiple linear regression correlation coefficients, we have evaluated that decrease of an antioxidant upon stability could cause potential shift in dissolution. However, main factors for accelerated dissolution can be attributed to other material and process variables. In the last part of the study, we have shown the usefulness of these methodologies for supporting lean stability approaches. With enhanced drug product knowledge, we designed two reduced long-term stability studies and showed that with ‘One-half’ reduced design, we would still be able to confirm 24-month shelf life. Conclusions Implementing Quality by design approaches on stability studies could reduce the need for excessive analytical testing, help to evaluate meaningfulness of the data and set a risk-based stability testing strategy.

Melt extrusion deposition (MED™) 3D printing technology – A paradigm shift in design and development of modified release drug products

Three-dimensional printing (3DP) technology offers unique advantages for pharmaceutical applications. However, most of current 3D printing methods and instrumentations are not specifically designed and developed for pharmaceutical applications. To meet the needs in pharmaceutical applications for precision, compatibility with a wide range of pharmaceutical excipients and drug materials without additional processing, high throughput and GMP compliance, an extrusion-based 3D printer based on Melt Extrusion Deposition (MED™) 3D printing technology was developed in this study. This technology can process powder pharmaceutical excipients and drugs directly without the need of preparing filament as required by FDM 3D printing. Six different tablet designs based on compartment models were used to demonstrate the precision and reproducibility of this technology. The designed tablets were fabricated using the GMP-compliant MED™ 3D printer and were evaluated in vitro for drug release and in vivo for selected designs using male beagle dogs. Tablet designs with one or more compartments showed versatile release characteristics in modulating the release onset time, release kinetics, duration of release and mode of release. Multiple drugs or formulations were fabricated into a single tablet to achieve independent release kinetics for each drug or to fine-tune the pharmacokinetic profile of a drug. Building upon the theoretical analysis of models, precision and reproducibility of MED™ 3D printing technology, a novel product development approach, 3D printing formulation by design (3DPFbD®) was developed to provide an efficient tool for fast and efficient pharmaceutical product development. The MED™ 3D printing represents a novel and promising technology platform encompassing design and development of modified drug release products and has potential to impact the drug delivery and pharmaceutical product development.

Assessing Food Effects on Oral Drug Absorption Based on the Degree of Renal Excretion.

Food intake influences the pharmacokinetics of orally administered drugs by altering drug absorption, metabolism, and excretion. A drug which is mainly excreted into urine as parent drug is usually highly water-soluble and metabolically stable. Food intake is not expected to significantly affect its extent of oral absorption, metabolism, and excretion. Therefore, we hypothesize that an orally administered drug with significant renal excretion should not have a dramatic food effect (FE). To test our hypothesis, we summarized the FE for orally administered immediate-release (IR) and modified-release (MR) formulations approved by the US FDA from 1998 to 2019, focusing on drugs undergoing significant renal excretion. Totally, 98 active pharmaceutical ingredients (APIs) in IR formulations and 34 APIs in MR formulations were selected. The results demonstrate that the area-under-the-curve (AUC) for IR drug products with fur_unchanged_po > 10% is unlikely to be affected by food, although the peak plasma concentration (Cmax) may increase or decrease by up to 50%. Compared with IR drug products with fur_unchanged_po > 10%, MR drug products with fur_unchanged_po > 10% tend to have more significant FE. Although our proposed approach cannot substitute a clinical FE study, it could be a useful addition to early drug development to get an initial sense of the potential for FE for a drug candidate.

Physiologically Based Biopharmaceutics Modeling of Regional and Colon Absorption in Dogs.

Colon absorption is a key determinant for the successful development of modified-release (MR) formulations, and the risk that colon absorption may limit the in vivo performance of an MR product can be assessed early by various in vitro tests or by preclinical in vivo regional absorption studies in dogs. Mechanistic physiologically based biopharmaceutics modeling (PBBM) is becoming increasingly accepted to predict in vivo performance and guide formulation development; however, no evaluation of the ability to predict colon absorption has been performed. The purpose of this study was to investigate if regional and colon absorption of drugs in dogs could be predicted with sufficient accuracy using PBBM to enable the replacement of in vivo dog studies in the early assessment of colon absorption limitation risks. This was done by predicting the regional and colon absorption and plasma exposure of 14 drugs after administration to the dog colon according to an a priori approach using the in silico absorption models GI-Sim and GastroPlus. Predictive performance was primarily assessed by comparing observed and predicted plasma concentration–time profiles, AUC0-t, and the relative bioavailability in the colon (Frel,colon) as compared to an oral/duodenal reference. Trends in dependency of prediction performance on predicted fraction absorbed, permeability, and solubility/dissolution rate were also investigated. For GI-Sim, the absolute average fold error (AAFE) values for AUC0-t and Frel,colon were within a 2-fold prediction error for both solutions (1.88 and 1.51, respectively) and suspensions (1.58 and 1.99, respectively). For GastroPlus, the AAFE values for AUC0-t and Frel,colon were outside the set 2-fold prediction error limit for accurate predictions for both solutions (3.63 and 2.98, respectively) and suspensions (2.94 and 2.09, respectively). No trends for over- or underprediction were observed for GI-Sim, whereas GastroPlus showed a slight trend for underprediction of both AUC0-t and Frel,colon for compounds with low permeability. In addition, regional differences in the plasma profiles were qualitatively predicted in the majority of cases for both software. Despite the differences in prediction performance, both models can be considered to predict regional differences in absorption as well as AUC0-t and Frel,colon with acceptable accuracy in an early development setting. The results of this study indicate that it is acceptable to replace in vivo regional absorption studies in dogs with the evaluated models as a method for the early assessment of the risk for colon absorption limitation of MR drug product candidates.

Development of a Clinically Relevant Dissolution Approach to Simulate Physiological Forces with a USP 2 Apparatus: “Peristaltic Dissolution”

Gastrointestinal hydrodynamics are poorly replicated in vitro and can significantly alter the release kinetics of drug products due to compressive forces in the stomach and peristaltic movement in the intestines. In this work, we describe the development and application of a predictive in vitro dissolution device that simulates gastrointestinal forces for the testing of oral drug products. The peristaltic dissolution device developed herein is designed as an addition to the common USP Apparatus 2 that applies repetitive compressive forces via a piston during dissolution testing of a product to replicate in vivo conditions. A dissolution testing device was designed, fabricated, and evaluated against human in vivo pharmacokinetic data to better mimic the physical forces present in the gastrointestinal tract. An optimized compression protocol to predict in vivo dissolution was developed using clinical data from two modified release carvedilol drug products. The apparatus was further evaluated using data from an additional modified release drug product. Finally, additional dissolution studies were performed to evaluate the utility of the apparatus for in vitro analysis of medicated gums, gastric retentive formulations, and long-acting injectable drug depots. The device was successfully implemented and the protocol to use the device was optimized using two initial drug products and further evaluated using an additional three drug products. The optimized protocol included a 1-h lag time (applicable in the fed state), followed by a cycle of 3 s of compression with 6 s intervals between compressions. Additional applications of the peristaltic dissolution device were also demonstrated through small exploratory studies, with continued potential for further optimization of the testing protocols following further research. This simple compressive device referred to as the “peristaltic dissolution device” was successfully proven to better predict in vivo performance of modified release drug products, as gastrointestinal mechanical forces have been observed to significantly impact and occasionally cause complete dose dumping of controlled release formulations. In addition, it has proven to be easily adapted for evaluation of other drug products such as medicated gums, gastric retentive formulations, and ex vivo long-acting injectable drug depots.

On the usefulness of compendial setups and tiny-TIM system in evaluating the in vivo performance of oral drug products with various release profiles in the fasted state: Case example sodium salt of A6197

We evaluated the usefulness of quality control dissolution data collected with compendial Apparatus I and II, biorelevant dissolution data collected with compendial apparatus IV, and bioaccessibility data collected with the non-compendial tiny-TIM system in screening modified release formulations during the development of BCS Class I compounds using a Boehringer Ingelheim model experimental compound, A6197. Four products were investigated: an immediate release tablet, an extended release tablet, modified release mini-tablets, and extended release pellets. Data with modified release products collected with the compendial apparatus were evaluated vs. the average intraluminal dissolution estimated after deconvoluting clinical data collected in healthy adults. Data collected with the tiny-TIM system were evaluated vs. the average AUC and Cmax values estimated from the clinical data. Unlike with the quality control data collected with Apparatus I and II, data collected with Apparatus IV data and Level I biorelevant media adequately described the intraluminal dissolution process of the three modified release products. Data deviated less than 10% from the actual average deconvoluted intraluminal dissolution profiles, illustrating the usefulness of Apparatus IV biorelevant data in understanding the intraluminal dissolution process of BCS class I small molecules administered as modified release products in the fasted state. Total bioaccessibility data and maximum bioaccessibility data collected using the tiny-TIM and the immediate release tablet and the three modified release drug products correctly reproduced the ranking of A6197 AUC values (R2 = 0.989) and Cmax values (R2 = 0.962), respectively, illustrating tiny-TIM as a useful system for formulation selection of BCS class I small molecules administered in the fasted state.

In vitro-In vivo Relationship and Bioequivalence Prediction for Modified-Release Capsules Based on a PBPK Absorption Model.

A physiologically based pharmacokinetic (PBPK) absorption model was developed in GastroPlus™ based on data on intravenous, immediate-release (IR), and modified-release (MR) drug products. The predictability of the model was evaluated by comparing predicted and observed plasma concentration profiles; average prediction errors (PE) were below 10%. IVIVR was developed using mechanistic deconvolution for a MR drug product to evaluate the in vivo effect of a proposed change in dissolution specification. The predictability of the IVIVR was evaluated and PE were below 10%; however, external validation was not possible due to the lack of data. The developed PBPK absorption model and IVIVR were used to predict plasma concentration profiles and pharmacokinetic (PK) parameters for a hypothetical formulation with 0% of drug dissolved in 2h in in vitro dissolution test. Both methods predicted the insignificant effect of a change in in vitro dissolution profile on in vivo product performance. The bioequivalence of a hypothetical formulation to the test product was evaluated using virtual clinical trial. The performed analysis supported the proposed change in dissolution specification. A validated PBPK absorption model was proposed as an adequate alternative to IVIVC, when IVIVC could not have been developed according to the guidelines.

Approval of modified-release products by FDA without clinical efficacy/safety studies: A retrospective survey from 2008 to 2017

In principle, approval of a modified-release (MR) drug product is based on evidence from pharmacokinetic (PK) and/or pharmacodynamic studies and clinical efficacy/safety studies. The purpose of this survey is (i) to explore the number of new drug applications (NDAs) of MR drug products, approved by the FDA, employ the PK study as a bridge to already-approved immediate-release drug products without conducting their own clinical efficacy/safety studies; and (ii) to understand the type of PK studies are required for such NDAs. To this end, we surveyed the approved records of MR drug products from 2008 to 2017 from the Drug@FDA website, and filtered pertinent information from FDA's assessment reports. A total of five out of 79 products were found. A single dose PK study was conducted to investigate the underlying drug release mechanisms in four of these products. For these products, the applicants also performed multiple dose PK equivalence studies, but the PK parameters used to support the equivalence were different among studies. Information regarding the exposure-response relationship was available for all selected products, which is fundamental for such cases. Although the difference in PK curve shapes is recognized as being critical for the clinical effectiveness, this evaluation was not performed in all selected cases, as indicated in FDA's assessment reports.

FORMULATION AND EVALUATION OF VENLAFAXINE HYDROCHLORIDE SUSTAINED RELEASE MATRIX TABLET

Aim: The term modified-release drug product is used to describe products that alter the timing and/or the rate of release of the drug substance.Objective: The objective of the present study was to formulate and evaluate the sustained release matrix tablet of venlafaxine hydrochloride.Methods: Venlafaxine hydrochloride is a structurally novel antidepressant for oral administration. It is widely prescribed for the treatment of depression, generalized anxiety disorder, and social anxiety disorder. Venlafaxine hydrochloride is currently available as immediate release tablet and as an extended release capsules under the brand names of Effexor (WYETH AYERST) and Effexor XR (WYETH AYERST). The biological half-life of venlafaxine very short (5 h) and the dose is to be taken 2–3 times a day and the recommended maximum daily dose is 75–450 mg/day. Venlafaxine hydrochloride is an antidepressant and so it is to be taken for quite a long period. Hence, to reduce the dosing frequency, simple, lower cost sustained release tablets of venlafaxine were preferred for the development.Conclusion: The venlafaxine hydrochloride sustained release matrix tablets shown controlled release profile as per the release profile ofthe innovator is EffexorTm_XR. The sustained release of this matrix tablet reduces the dosing frequency and reduces the side effects, bywhich in a long-term therapy, it may be useful as a product with patient compliance for the treatment of major depression disorder.

3D printed capsules for quantitative regional absorption studies in the GI tract

Drug development is a long process which requires careful evaluation of the drug substance (active pharmaceutical ingredient, API), drug product (tablet, capsule etc.) and the bioperformance (both pre-clinical and clinical) before testing the efficacy of the final dosage form. The earliest assessment of a new drug substance requires an understanding of the safety and clinical performance (Phase 1) wherein faster processes (like on-site formulation strategy) have been set in place for quick clinical read-outs. One key gap that exists in this early assessment is the ability to evaluate modified release drug products. Here, an additive manufacturing approach is used to prepare polyvinyl alcohol (PVA) capsule shells using 3D printing (3DP), where the shells can be filled with either a solid or a liquid vehicle containing the API. In this work we demonstrate how we can delay the release of the API from the printed capsules allowing us to evaluate regional absorption in pre-clinical studies. By using 3DP, a new method to provide a series of release profiles is demonstrated, where the induction time of a delayed burst release is controlled by the wall thicknesses of printed capsules. New hanging baskets were also designed and 3D printed for the dissolution tests to better understand the rupturing of these capsules in an USP 2 dissolution apparatus. By controlling the wall thickness of the capsule, the induction time of drug release can be controlled from 12 to 198 min. This wide range of induction times demonstrated with this 3DP strategy is not currently available in a commercially available oral drug product form. Varying the induction times to the drug release to interrogate different regions of the GI tract is exhibited in vivo (beagle dogs) and initial analysis suggested a good in vitro/in vivo relationship (IVIVR).

AN UPDATED REVIEW ON MODIFIED RELEASE TABLETS

For some time now modified drug release has been studied and used extensively during the development of pharmaceutical drug products because of its advantages over immediate release formulations. As per the forecasting by Global Business Intelligence (GBI) research, the growth in oral drug delivery market will uplift in the coming years. Modified release drug products allow at least a two-fold reduction in dosing when compared to a drug that is presented in a conventional immediate release form. Modified release drug products are designed to release active pharmaceutical ingredient over a longer duration of time; At least, longer than an immediate release (I.R) formulation. Many Pharmaceutical companies also utilize the proprietary advantages of Modified release formulations to extend the patent life cycle of commercial products thereby bringing in new business. Keywords: Immediate release (I.R), Modified release (M.R), Novel drug delivery systems (NDDS), Loading doze (LD), Maintenance doze (MD), New Drug Application (NDA)

New Approach for the Application of USP Apparatus 3 in Dissolution Tests: Case Studies of Three Antihypertensive Immediate-Release Tablets.

The USP Apparatus 3 is a compendial dissolution Apparatus that has been mainly used to assess the performance of modified-release drug products. However, this Apparatus can be applied to dissolution testing of immediate-release tablets as well, with several advantages such as lower consumption of dissolution media, reduced setup time in quality control routine, and minimized hydrodynamic issues. In this work, three immediate-release (IR) tablets containing antihypertensive drugs of different Biopharmaceutic Classification System (BCS) classes were evaluated in order to assess the possible interchangeability between the official dissolution method using typical USP Apparatus 1 or 2 and the proposed methods using USP Apparatus 3. Depending on the selection of the appropriate operational conditions, such as dip rate and sieve mesh size, it was observed that USP Apparatus 3 could provide similar dissolution profiles compared to USP Apparatus 1 or 2 to the drug products tested. In addition, USP Apparatus 3 avoided conning issues related to USP Apparatus 2. The successful application of USP Apparatus 3 in dissolution tests for IR drug products depends on the definition of specific test conditions for each product, considering all the equipment variables, as well as drug and formulation characteristics.

Biopharmaceutical Evaluation and CMC Aspects of Oral Modified Release Formulations.

This article discusses the range of outcomes from biopharmaceutical studies of specific modified release (MR) product examples in preclinical models and humans. It touches upon five major biopharmaceutical areas for MR drug products: (1) evidence for regional permeability throughout the GI tract, (2) susceptibility to food-effect, (3) susceptibility to pH-effect, (4) impact of chronopharmacology in designing MR products, and (5) implications to narrow therapeutic index products. Robust bioperformance requires that product quality is met through a thorough understanding of the appropriate critical quality attributes that ensure reliable and robust manufacture of a MR dosage form. The quality-by-design (QbD) aspects of MR dosage form design and development are discussed with the emphasis on the regulatory view of the data required to support dosage form development.

Dissolution Failure of Solid Oral Drug Products in Field Alert Reports

From 2005 to 2014, 370 data entries of dissolution failures of solid oral drug products were assessed with respect to the solubility of drug substances, dosage forms [immediate release (IR) vs. modified release (MR)], and manufacturers (brand name vs. generic). The study results show that the solubility of drug substances does not play a significant role in dissolution failures; however, MR drug products fail dissolution tests more frequently than IR drug products. When multiple variables were analyzed simultaneously, poorly water-soluble IR drug products failed the most dissolution tests, followed by poorly soluble MR drug products and very soluble MR drug products. Interestingly, the generic drug products fail dissolution tests at an earlier time point during a stability study than the brand name drug products. Whether the dissolution failure of these solid oral drug products has any in vivo implication will require further pharmacokinetic, pharmacodynamic, clinical, and drug safety evaluation. Food and Drug Administration is currently conducting risk-based assessment using in-house dissolution testing, physiologically based pharmacokinetic modeling and simulation, and post-market surveillance tools. At the meantime, this interim report will outline a general scheme of monitoring dissolution failures of solid oral dosage forms as a pharmaceutical quality indicator.

Bioavailability and Bioequivalence Aspects of Oral Modified-Release Drug Products.

Oral modified-release (MR) products are dosage forms administered through the mouth and designed to release drug in a controlled manner to achieve maximum efficacy, minimal side effects, and better patient compliance. With significant progress in pharmaceutical technologies and favored therapeutic benefit, more and more oral MR products including the generic versions of these products are being developed, marketed, and used in the USA. Because different types of MR products may exhibit unique drug release modes and specific pharmacokinetic profiles, a better understanding of the regulation and evaluation of these generic MR products can help development and marketing of generic MR products that are therapeutically equivalent to the corresponding reference product. This review summarizes the general regulatory requirements for establishing bioequivalence between generic and reference oral MR products. In addition, some special regulatory considerations for bioequivalence evaluation are highlighted with examples of specific oral MR drug products.

Scientific and Regulatory Considerations in Solid Oral Modified Release Drug Product Development.

This review presents scientific and regulatory considerations for the development of solid oral modified release (MR) drug products. It includes a rationale for patient-focused development based on Quality-by-Design (QbD) principles. Product and process understanding of MR products includes identification and risk-based evaluation of critical material attributes (CMAs), critical process parameters (CPPs), and their impact on critical quality attributes (CQAs) that affect the clinical performance. The use of various biopharmaceutics tools that link the CQAs to a predictable and reproducible clinical performance for patient benefit is emphasized. Product and process understanding lead to a more comprehensive control strategy that can maintain product quality through the shelf life and the lifecycle of the drug product. The overall goal is to develop MR products that consistently meet the clinical objectives while mitigating the risks to patients by reducing the probability and increasing the detectability of CQA failures.

Gastrointestinal release behaviour of modified-release drug products: Dynamic dissolution testing of mesalazine formulations

The aminosalicylate mesalazine (mesalamine) forms the mainstay of treatment in ulcerative colitis (UC), a disease for which many commercial modified-release products have been developed with the aim of providing targeted gastrointestinal release. The release profiles of five of these commercial formulations were evaluated in bicarbonate buffer using a novel dissolution model that mimics the dynamic conditions of the gastrointestinal tract. Monolithic and multi-particulate mesalazine formulations with pH-dependent and/or independent release mechanisms were evaluated (Asacol® 800, Octasa®, Mezavant® XL, Salofalk®, Pentasa®), and each of the products displayed a distinctive dissolution profile. The dissolution results for Mezavant® XL (Lialda®) (lag time 290min) demonstrated good correlation with previously reported in vivo disintegration times assessed by gamma-scintigraphy in humans. Octasa® showed a similar lag time to Mezavant® XL. Drug release from Asacol® 800 (Asacol® HD) showed a wide standard deviation, reflecting the great variability in vivo. Salofalk® displayed both delayed release and extended release characteristics. Pentasa® released more than 50% of its drug load in the stomach compartment of the model, which is attributed to the absence of a gastro-resistant coating in this product. The new dissolution method provided a realistic and discriminative in vitro assessment of mesalazine release from different formulations. These results demonstrate that this strategy can be used to predict intestinal release behaviour, and potentially aid the rational design of products developed to target different sites of the gut.