A Novel Approach to Justify Dissolution Differences in an Extended Release Drug Product using Physiologically Based Biopharmaceutics Modeling and Simulation

Dr Reddy's Laboratories Ltd. developed generic version of XYZ extended release tablets (ER) and achieved bioequivalence as per criteria mentioned by USFDA in both fasting and fed conditions for higher strength formulation (1200 mg). However, on comparison of multimedia dissolution profiles in pH 4.5 acetate media, the f2 similarity value was <50. The lower strength formulation (600 mg) demonstrated faster dissolution profile. This was identified as strength-dependent sink condition difference and in vitro multiunit dissolution studies were used to justify sink differences between the higher and lower strengths. Additionally, a Physiologically Based Biopharmaceutics Model (PBBM) was developed using GastroPlus^TM. The validity of this model was established using in-house human pharmacokinetic data. Further, this model was used to justify the insignificant in vivo impact of the faster dissolution profile for the lower strength formulation. This work provides a novel and less explored approach that can be used to obtain biowaiver for lower strength formulations when the standard biowaiver criteria cannot be met. This work also demonstrates the usefulness of PBBM to justify dissolution dissimilarity between dose proportional formulations and to evaluate its biopharmaceutics risk without the need for actual in vivo studies.     

On the Heterogeneity of Drug Dissolution and Release

Pharmaceutical Research -     

Predictive Drug Release Modeling Across Dissolution Apparatuses I and II using Computational Fluid Dynamics

A modeling process is developed and validated with which active pharmaceutical ingredient (API) release is predicted across the United States Pharmacopeia (USP) dissolution apparatuses I and II based on limited experimental dissolution data (at minimum two dissolution profiles at different apparatus settings). The process accounts for formulation-specific drug release behavior and hydrodynamics in the apparatuses over the range of typical agitation rates and medium volumes. This modeling process involves measurement of experimental mass transfer coefficients via a conventional mass balance and the relationship of said mass transfer coefficients to hydrodynamics and apparatus setting via computational fluid dynamics (CFD). A novel 1-D model is hence established, which provided calibration data for a particular formulation, can model mass transfer coefficients and their corresponding drug release at apparatus configurations of interest. Based on validation against experimental data produced from five erosion-based formulations over a range of apparatus configurations, accuracy within 8 %LA (labelled amount of API) and an average root mean square deviation of 3 %LA is achieved. With this predictive capability, minimizing the number of dissolution experiments and the amount of chemical materials needed during method development appears feasible.     

The Development of USP Dissolution and Drug Release Standards

Dissolution tests have been in use in the pharmaceutical industry for over 20 years, and they are official in The United States Pharmacopeia since the early 1960s. The dissolution test, reviewed primarily as a quality control tool, replaced the use of disintegration tests which had been official in The United States Pharmacopeia since 1950. Refinements in the dissolution test equipment and methodology have occurred over the years in order to enhance its relevance. The Subcommittees of the USP Committee of Revision dealing with these issues have developed and refined compendial dissolution standards and policies for conventional solid-oral dosage forms and modified-release dosage forms.     

Push-Pull Controlled Drug Release Systems: Effect of Molecular Weight of Polyethylene Oxide on Drug Release

First, an elementary osmotic pump (EOP) with a simple structure was prepared using polyethylene oxide (PEO) and NaCl as an excipient, and the influence of the molecular weight (Mw) of PEO on drug release was investigated. In the dissolution test of EOP, it was observed that the gelated core tablet was pushed out through the orifice. The dissolution profile of EOP was sigmoidal, and despite the short time, a zero-order release region was observed. The gel swelling rate in the zero-order region was independent of the Mw of PEO. It was also found that higher the Mw of PEO, the larger the saturated swelling amount. Next, a push-pull pump (PPP) with almost identical formulation to that of EOP was prepared, and its drug release characteristics were investigated. PPPs were prepared by varying the combination of Mws of PEO in both layers, and their dissolution profiles were compared. It was found that PPP using a low-Mw PEO for the drug layer and PEO with a high-Mw in the push layer showed the longest dissolution profile of the linear region. The obtained findings suggested that the properties of PEO and its hydrogel play a crucial role in the drug release of PPP.     

A Marginal Structural Modeling Approach to Assess the Cumulative Effect of Drug Treatment on the Later Drug Use Abstinence

In this article, we applied a marginal structural model (MSM) to estimate the effect on later drug use of drug treatments occurring over 10 years following first use of the primary drug. The study was based on the longitudinal data that were collected in three projects among 421 subjects and covered 15 years since first use of their primary drug. The cumulative treatment effect was estimated by the inverse-probability of treatment weighted estimators of MSM as well as the traditional regression analysis. Contrary to the traditional regression analysis, results of the MSM showed that the cumulative treatment occurring over the 10 years significantly increased the likelihood of drug use abstinence in the subsequent 5-year period. From both the statistical and empirical point of view, MSM is a better approach to assessing cumulative treatment effects, considering its advantage of controlling for self-selection bias over time.     

DDSolver: An Add-In Program for Modeling and Comparison of Drug Dissolution Profiles

In recent years, several mathematical models have been developed for analysis of drug dissolution data, and many different mathematical approaches have been proposed to assess the similarity between two drug dissolution profiles. However, until now, no computer program has been reported for simplifying the calculations involved in the modeling and comparison of dissolution profiles. The purposes of this article are: (1) to describe the development of a software program, called DDSolver, for facilitating the assessment of similarity between drug dissolution data; (2) to establish a model library for fitting dissolution data using a nonlinear optimization method; and (3) to provide a brief review of available approaches for comparing drug dissolution profiles. DDSolver is a freely available program which is capable of performing most existing techniques for comparing drug release data, including exploratory data analysis, univariate ANOVA, ratio test procedures, the difference factor f ₁, the similarity factor f ₂, the Rescigno indices, the 90% confidence interval (CI) of difference method, the multivariate statistical distance method, the model-dependent method, the bootstrap f ₂ method, and Chow and Ki’s time series method. Sample runs of the program demonstrated that the results were satisfactory, and DDSolver could be served as a useful tool for dissolution data analysis.     

A Two-Stage Response Surface Approach to Modeling Drug Interaction

Studies of drug combinations have become increasingly important, especially in treating malignant cancers. Researchers are interested in identifying compounds that act synergistically when combined. Such synergy is usually measured through an interaction index. The existing statistical methods, in general, estimate the interaction index using pooled data from compounds administered individually and in combination. In this article, we propose a two-stage response surface approach. Parameters of monotherapy dose–response curves are estimated and then incorporated in estimating the interaction index through a quadratic response surface model. Using multiple simulation studies, we demonstrate that the new method gives less biased estimates for both monotherapy dose–response curves and interaction index. Also developed is a bootstrapping method that allows constructing a confidence interval for interaction index at any combination dose levels. An example is provided to illustrate the method.     

Modeling of Drug Release from Bioerodible Polymer Matrices

Models for drug release from bioerodible polymer matrices are proposed in this article. We consider that drug is released continually by diffusion that is influenced by polymer chain degradation, and polymer matrix erosion starts and enhances the drug release at a certain time. The models give excellent reproduction of drug release profiles within the whole release period, and the parameters can be correlated to various factors such as γ-irradiation dose, copolymer composition, and initial drug loading, this correlation indicates that the new models can be used to predict the effects of various factors on drug release profiles based on limited experimental data.     

Microspheres of Human Serum Albumin with Barbiturates: Effect of Drug Partition Coefficient on Preparation and Drug Release

Abstract— Human serum albumin microspheres were prepared with a series of barbiturates by the thermal denaturation method. The barbiturates were of similar general physicochemical properties but different partition coefficients. The total drug content of microspheres was dependent on the partition coefficient, and an increase in the partition coefficient caused a decrease in the drug content of finished microspheres due to drug migration to the outer organic phase during preparation. The ensemble drug release from microspheres was followed by the paddle method and by potentiometric titration with a pH-stat. Nonlinear regression analysis showed the best fit for the spherical Higuchi equation, especially first-order kinetics (bi-phasic). The drug partition coefficient affected the release in such a way that drugs with higher partition coefficients were released faster and to a greater extent than those with lower coefficients.     

A Parallelogram Approach for Safety Evaluation of Ingested Acetaldehyde

Route-specific carcinogenicity data are often lacking for compounds of regulatory importance. Acetaldehyde (AA), for example, a natural constituent in foods, is a rodent carcinogen via the inhalation route, but oral carcinogenicity data are not available. In the absence of such data, a parallelogram approach can be used to estimate the oral carcinogenic potency of this chemical. The relative potency of AA to the structurally related compound formaldehyde (FA) in the nose and the relative potency of FA in the nose and stomach serve as the basis for estimating the potency of AA in the stomach. On a dosimetric basis, inhaled AA is 14- to 35-fold less potent than FA in producing nasal DNA–protein crosslinks (DPX), subchronic tissue injury, and tumors. Ingested AA is also considerably (∼5-fold) less potent than FA in producing gastric injury and DPX. Compared to the nose, the stomach is 10- to 60-fold less sensitive to both AA- and FA-induced DPX and subchronic tissue injury. The parallelogram approach will not supplant long-term oral carcinogenicity studies with AA; however, the consistent pattern of decreased sensitivity of acetaldehyde compared to formaldehyde, lower sensitivity of the stomach to the nose, and the lack of gastric tumorigenicity of orally ingested formaldehyde strongly suggests that ingested acetaldehyde is not likely to be carcinogenic. Successful estimation of the carcinogenic potency of ingested glutaraldehyde, for which chronic oral and inhalation data are available, provides further support that the parallelogram approach can provide a reasonable estimate of the carcinogenic potency of closely related aldehydes, such as AA.     

Drug-Polymer Mixed Coating: A New Approach for Controlling Drug Release Rates in Pellets

A new approach to developing a drug-polymer mixed coat for highly water-soluble diltiazem pellets was investigated at different coating levels. Drug layering and the coating procedures were performed using a bottom spray fluidized bed coater. Drug pellets were coated with Eudragit NE40 (NE40) alone and in combination with diltiazem and hydrophilic cellulose derivatives. Dissolution studies revealed that incorporation of hydrophilic substances such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), and the drug itself considerably increased the release rates. The release from mixed polymer coatings was fast compared to pellets coated with NE40 only. The major portion of the drug was released in about 2 hours in case of MC and NE40 mixed coat compared to hours from coated pellets containing HPMC or diltiazem. Incorporation of 15% to 25% drug with respect to the polymer coat helped to achieve a drug-release profile at a desirable rate over a 12 hour period. Moreover, the test formulation comprising 25% diltiazem with respect to 7% NE40 had a dissolution profile that matched the commercial product, Herbesser SR capsules. The release of diltiazem from the coated pellets was slightly affected by the pH of dissolution media.     

沉降篮对盐酸罗匹尼罗缓释片释放度的影响

目的 研究沉降篮对盐酸罗匹尼罗缓释片释放度的影响。方法 在FDA推荐的释放度检测方法基础上,比较增加沉降篮前后,盐酸罗匹尼罗缓释片在各取样时间点释放度的变化情况。结果 增加沉降篮后,盐酸罗匹尼罗缓释片释放度结果没有明显变化,但相同时间点不同片之间RSD明显变小。结论 沉降篮可以有效控制盐酸罗匹尼罗缓释片位置,得到稳定的结果,更有利于产品质量控制。     

Simultaneous FTIR Spectroscopic Imaging and Visible Photography to Monitor Tablet Dissolution and Drug Release

Purpose Previous studies of hydroxypropyl methylcellulose (HPMC)-based tablet during exposure to water showed a number of ‘fronts’ moving into the tablet but led to contradictory interpretations. These fronts are related to water penetration into and dissolution of the tablet, but the exact nature can not be derived from visible photographic evidence. A method to study tablet dissolution simultaneously by Fourier transform infrared-attenuated total reflection (FTIR-ATR) imaging and macro-photography can assist in providing correct interpretation of the observed fronts. Methods Therefore, the combination of macro-photography and FTIR-ATR spectroscopic imaging was developed and used to interpret the physical changes leading to the observed fronts. Buflomedyl pyridoxal phosphate (BPP), a coloured drug, was used as a model drug. Results The quantitative results obtained by FTIR-ATR imaging enabled the attribution of the three observed fronts (inside to outside) to: (1) true water penetration, possibly combined with (partial) dissolution of buflomedyl pyridoxal phosphate (BPP); (2) total gellification of HPMC; (3) erosion front. Conclusions The method to study dissolution of a tablet simultaneously by FTIR-ATR imaging and macro-photography has been developed and used to obtain reliable interpretation of the fronts observed during tablet dissolution.     

Predicting the Effect of Fed-State Intestinal Contents on Drug Dissolution

Purpose  

There are several endogenous and exogenous species in the gastrointestinal (GI) tract which can act as solubilizing agents and thereby affect drug dissolution. The purpose of this study is to understand food effects on drug dissolution and provide insight into their anticipated overall effect on absorption and bioavailability.     

Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Immediate Release Dosage Forms

Dissolution tests are used for many purposes in the pharmaceutical industry: in the development of new products, for quality control and, to assist with the determination of bioequivalence. Recent regulatory developments such as the Biopharmaceutics Classification Scheme have highlighted the importance of dissolution in the regulation of post-approval changes and introduced the possibility of substituting dissolution tests for clinical studies in some cases. Therefore, there is a need to develop dissolution tests that better predict the in vivo performance of drug products. This could be achieved if the conditions in the gastrointestinal tract were successfully reconstructed in vitro. The aims of this article are, first, to clarify under which circumstances dissolution testing can be prognostic for in vivo performance, and second, to present physiological data relevant to the design of dissolution tests, particularly with respect to the composition, volume, flow rates and mixing patterns of the fluids in the gastrointestinal tract. Finally, brief comments are made in regard to the composition of in vitro dissolution media as well as the hydrodynamics and duration of the test.     

甲壳素对双氯灭痛缓释片溶出的影响

以pH 6.8磷酸盐缓冲液为释放介质,采用转蓝法测定了不同甲壳素含量的双氯灭痛缓释片的体外累体释放度。结果表明,随着片剂中壳素含量的增高、片剂溶出变慢,且溶出越符合零级释放。     

高于饱和装填量时的平板混合药膜体系释放动力学模型

针对最一般的情况建立了Ｃｄ＞Ｃｓ时的混合药膜的释放动力学模型,用拉氏变换求得了解析解,该模型可通过相应简化而获得一些特定情况的解;用５－氟脲嘧啶／ＥＶＡＬ混合药膜体系的释放实验数据对所提出的模型进行了验证并与Ｈｉｇｕｃｈｉ模型进行了比较。结果表明：在中等装填量的情况下如：１５.５＜Ｃｄ＜１２３.６ｍｇ·ｃｍ(－３)时,本文模型与实验数据符合的很好,预测精度比Ｈｉｇｕｃｈｉ模型高,特别是在Ｃｄ＜１５．５ｍｇ·ｃｍ(－３)时;这两个模型均不能较好描述较高装填量的情况,如Ｃｄ＞２１０ｍｇ．ｃｍ(－３),这种情况我们在别处已经作过讨论（８,９）。     

Effects of Dissolution Medium pH and Simulated Gastrointestinal Contraction on Drug Release From Nifedipine Extended-Release Tablets*

In contrast to nifedipine matrix-based extended-release dosage forms, the osmotic pump drug delivery systems have a zero-order drug release independent of external variables such as pH, agitation rate, and dissolution media. The objective of this study focuses on the in vitro evaluation of the mechanical properties of osmotic pump and polymer matrix-based formulations in dissolution media, and the potential impacts that media pH and simulated gastrointestinal contraction have on drug release. Two strengths of osmotic pump product A and polymer matrix-based product B were used in this study. An in-house system was developed with the capability of applying mechanical compression and monitoring mechanical properties of sample during dissolution testing. A United States Pharmacopeia or an in-house apparatus was used for dissolution testing under various conditions. Compared to the product A, the mechanical properties of the product B change significantly at various pHs and mechanical compressions. The results suggest that polymer matrix-based products bear a risk of formulation-related interactions with the gastrointestinal tract during in vivo drug dissolution, especially in the case of concomitant pH and gastric contractile changes. Modified dissolution testing devices may help formulation scientists in product development and provide regulatory agencies with an additional metric for quality assurance of drug products.     

Physiologically Based Pharmacokinetic Modeling of Drug Disposition in Rat and Human: A Fuzzy Arithmetic Approach

PURPOSE: Probabilistic methods are insufficient for dealing with the vagueness inherent in human judgment of minimal data available during early drug development. We sought to use fuzzy set theory as a basis for quantifying and propagating vague judgment in a physiologically based pharmacokinetic (PBPK) model for diazepam disposition. MATERIALS AND METHODS: First, using diazepam distribution data in rat tissues and fuzzy regression, we estimated fuzzy rat tissue-to-plasma partition coefficients (Kp's). We scaled the coefficients prior to human PBPK modeling. Next, we constructed the fuzzy set of hepatic intrinsic clearance (CLint) by integrating CLint values measured in vitro from human hepatocytes. Finally, we used these parameters, and other physiological and biochemical information, to predict human diazepam disposition. We compared the simulated plasma kinetics with published concentration-time profiles. RESULTS: We successfully identified rat Kp's by fuzzy regression. The predicted rat tissue concentration-time contours enveloped the animal tissue distribution data. For the human PBPK model, the mean in vivo plasma concentrations were contained in the simulated concentration-time envelopes. CONCLUSIONS: We present a novel computational approach for handling information paucity in PBPK models using fuzzy arithmetic. Our methodology can model the vagueness associated with human perception and interpretation of minimal drug discovery data.