The Experts below are selected from a list of 177 Experts worldwide ranked by ideXlab platform
Eva Roblegg - One of the best experts on this subject based on the ideXlab platform.
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development of an abuse and alcohol resistant formulation based on hot melt extrusion and film coating
Aaps Pharmscitech, 2016Co-Authors: Nicole Jedinger, Simone Schrank, Johannes Khinast, Johannes M Fischer, Karlheinz Breinhalter, Eva RobleggAbstract:This study focused on the development of flexible (i.e., deformable) multiple-unit pellets that feature (i) a prolonged drug release, (ii) drug abuse deterrence, and (iii) a minimal risk of alcohol-induced Dose Dumping (ADD). Deformable pellets were prepared via an advanced continuous one-step hot-melt extrusion (HME) technique, with the drug (i.e., antipyrine and codeine phosphate) fed as an aqueous solution into the molten matrix material (i.e., cornstarch, gum arabic, and xanthan). Formulations that had suitable mechanical characteristics (i.e., high compression strength) were coated with a flexible Aquacoat® ARC film to ensure prolonged release and to avoid ADD. The pellets were characterized in terms of their mechanical properties and in vitro drug release behavior in alcoholic media. All formulations were abuse deterrent: they had a high compression strength and grinding the pellets into powder was impossible. Since the pellets comprising gum arabic and xanthan as a matrix did not remain intact during dissolution testing, they had a very fast drug release rate. Cornstarch-based pellets that swelled but remained intact in the dissolution media had a slower drug release. Coated cornstarch-based pellets had a prolonged release over 8 h and resistance to Dose Dumping in 20 and 40% ethanol. Our results indicate that cornstarch-based pellets manufactured via the advanced HME process followed by coating are a promising formulation that makes tampering difficult due to a high compression strength combined with robustness in alcoholic media.
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alcohol Dose Dumping the influence of ethanol on hot melt extruded pellets comprising solid lipids
European Journal of Pharmaceutics and Biopharmaceutics, 2015Co-Authors: Nicole Jedinger, Simone Schrank, Stefan Mohr, Andrea Feichtinger, Johannes Khinast, Eva RobleggAbstract:The objective of the present study was to investigate interactions between alcohol and hot-melt extruded pellets and the resulting drug release behavior. The pellets were composed of vegetable calcium stearate as matrix carrier and paracetamol or codeine phosphate as model drugs. Two solid lipids (Compritol® and Precirol®) were incorporated into the matrix to form robust/compact pellets. The drug release characteristics were a strong function of the API solubility, the addition of solid lipids, the dissolution media composition (i.e., alcohol concentration) and correspondingly, the pellet wettability. Pellets comprising paracetamol, which is highly soluble in ethanol, showed alcohol Dose Dumping regardless of the matrix composition. The wettability increased with increasing ethanol concentrations due to higher paracetamol solubilities yielding increased dissolution rates. For pellets containing codeine phosphate, which has a lower solubility in ethanol than in acidic media, the wettability was a function of the matrix composition. Dose Dumping occurred for formulations comprising solid lipids as they showed increased wettabilities with increasing ethanol concentrations. In contrast, pellets comprising calcium stearate as single matrix component showed robustness in alcoholic media due to wettabilities that were not affected by the addition of ethanol. The results clearly indicate that the physico-chemical properties of the drug and the matrix systems are crucial for the design of ethanol-resistant dosage forms. Moreover, hydrophobic calcium stearate can be considered a suitable matrix system that minimizes the risk of ethanol-induced Dose Dumping for certain API's.
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the design of controlled release formulations resistant to alcohol induced Dose Dumping a review
European Journal of Pharmaceutics and Biopharmaceutics, 2014Co-Authors: Nicole Jedinger, Johannes Khinast, Eva RobleggAbstract:The concomitant intake of alcoholic beverages together with oral controlled-release opioid formulations poses a serious safety concern since alcohol has the potential to alter the release rate controlling mechanism of the dosage form which may result in an uncontrolled and immediate drug release. This effect, known as alcohol-induced Dose Dumping, has drawn attention of the regulatory authorities. Thus, the Food and Drug Administration (FDA) recommends that in vitro drug release studies of controlled-release dosage forms containing drugs with narrow therapeutic range should be conducted in ethanolic media up to 40%. So far, only a limited number of robust dosage forms that withstand the impact of alcohol are available and the development of such dosage forms is still a challenge. This review deals with the physico-chemical key factors which have to be considered for the preparation of alcohol-resistant controlling dosage forms. Furthermore, appropriate matrix systems and promising technological strategies, which are suitable to prevent alcohol-induced Dose Dumping, are discussed.
Nicole Jedinger - One of the best experts on this subject based on the ideXlab platform.
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development of an abuse and alcohol resistant formulation based on hot melt extrusion and film coating
Aaps Pharmscitech, 2016Co-Authors: Nicole Jedinger, Simone Schrank, Johannes Khinast, Johannes M Fischer, Karlheinz Breinhalter, Eva RobleggAbstract:This study focused on the development of flexible (i.e., deformable) multiple-unit pellets that feature (i) a prolonged drug release, (ii) drug abuse deterrence, and (iii) a minimal risk of alcohol-induced Dose Dumping (ADD). Deformable pellets were prepared via an advanced continuous one-step hot-melt extrusion (HME) technique, with the drug (i.e., antipyrine and codeine phosphate) fed as an aqueous solution into the molten matrix material (i.e., cornstarch, gum arabic, and xanthan). Formulations that had suitable mechanical characteristics (i.e., high compression strength) were coated with a flexible Aquacoat® ARC film to ensure prolonged release and to avoid ADD. The pellets were characterized in terms of their mechanical properties and in vitro drug release behavior in alcoholic media. All formulations were abuse deterrent: they had a high compression strength and grinding the pellets into powder was impossible. Since the pellets comprising gum arabic and xanthan as a matrix did not remain intact during dissolution testing, they had a very fast drug release rate. Cornstarch-based pellets that swelled but remained intact in the dissolution media had a slower drug release. Coated cornstarch-based pellets had a prolonged release over 8 h and resistance to Dose Dumping in 20 and 40% ethanol. Our results indicate that cornstarch-based pellets manufactured via the advanced HME process followed by coating are a promising formulation that makes tampering difficult due to a high compression strength combined with robustness in alcoholic media.
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alcohol Dose Dumping the influence of ethanol on hot melt extruded pellets comprising solid lipids
European Journal of Pharmaceutics and Biopharmaceutics, 2015Co-Authors: Nicole Jedinger, Simone Schrank, Stefan Mohr, Andrea Feichtinger, Johannes Khinast, Eva RobleggAbstract:The objective of the present study was to investigate interactions between alcohol and hot-melt extruded pellets and the resulting drug release behavior. The pellets were composed of vegetable calcium stearate as matrix carrier and paracetamol or codeine phosphate as model drugs. Two solid lipids (Compritol® and Precirol®) were incorporated into the matrix to form robust/compact pellets. The drug release characteristics were a strong function of the API solubility, the addition of solid lipids, the dissolution media composition (i.e., alcohol concentration) and correspondingly, the pellet wettability. Pellets comprising paracetamol, which is highly soluble in ethanol, showed alcohol Dose Dumping regardless of the matrix composition. The wettability increased with increasing ethanol concentrations due to higher paracetamol solubilities yielding increased dissolution rates. For pellets containing codeine phosphate, which has a lower solubility in ethanol than in acidic media, the wettability was a function of the matrix composition. Dose Dumping occurred for formulations comprising solid lipids as they showed increased wettabilities with increasing ethanol concentrations. In contrast, pellets comprising calcium stearate as single matrix component showed robustness in alcoholic media due to wettabilities that were not affected by the addition of ethanol. The results clearly indicate that the physico-chemical properties of the drug and the matrix systems are crucial for the design of ethanol-resistant dosage forms. Moreover, hydrophobic calcium stearate can be considered a suitable matrix system that minimizes the risk of ethanol-induced Dose Dumping for certain API's.
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the design of controlled release formulations resistant to alcohol induced Dose Dumping a review
European Journal of Pharmaceutics and Biopharmaceutics, 2014Co-Authors: Nicole Jedinger, Johannes Khinast, Eva RobleggAbstract:The concomitant intake of alcoholic beverages together with oral controlled-release opioid formulations poses a serious safety concern since alcohol has the potential to alter the release rate controlling mechanism of the dosage form which may result in an uncontrolled and immediate drug release. This effect, known as alcohol-induced Dose Dumping, has drawn attention of the regulatory authorities. Thus, the Food and Drug Administration (FDA) recommends that in vitro drug release studies of controlled-release dosage forms containing drugs with narrow therapeutic range should be conducted in ethanolic media up to 40%. So far, only a limited number of robust dosage forms that withstand the impact of alcohol are available and the development of such dosage forms is still a challenge. This review deals with the physico-chemical key factors which have to be considered for the preparation of alcohol-resistant controlling dosage forms. Furthermore, appropriate matrix systems and promising technological strategies, which are suitable to prevent alcohol-induced Dose Dumping, are discussed.
Johannes Khinast - One of the best experts on this subject based on the ideXlab platform.
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development of an abuse and alcohol resistant formulation based on hot melt extrusion and film coating
Aaps Pharmscitech, 2016Co-Authors: Nicole Jedinger, Simone Schrank, Johannes Khinast, Johannes M Fischer, Karlheinz Breinhalter, Eva RobleggAbstract:This study focused on the development of flexible (i.e., deformable) multiple-unit pellets that feature (i) a prolonged drug release, (ii) drug abuse deterrence, and (iii) a minimal risk of alcohol-induced Dose Dumping (ADD). Deformable pellets were prepared via an advanced continuous one-step hot-melt extrusion (HME) technique, with the drug (i.e., antipyrine and codeine phosphate) fed as an aqueous solution into the molten matrix material (i.e., cornstarch, gum arabic, and xanthan). Formulations that had suitable mechanical characteristics (i.e., high compression strength) were coated with a flexible Aquacoat® ARC film to ensure prolonged release and to avoid ADD. The pellets were characterized in terms of their mechanical properties and in vitro drug release behavior in alcoholic media. All formulations were abuse deterrent: they had a high compression strength and grinding the pellets into powder was impossible. Since the pellets comprising gum arabic and xanthan as a matrix did not remain intact during dissolution testing, they had a very fast drug release rate. Cornstarch-based pellets that swelled but remained intact in the dissolution media had a slower drug release. Coated cornstarch-based pellets had a prolonged release over 8 h and resistance to Dose Dumping in 20 and 40% ethanol. Our results indicate that cornstarch-based pellets manufactured via the advanced HME process followed by coating are a promising formulation that makes tampering difficult due to a high compression strength combined with robustness in alcoholic media.
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alcohol Dose Dumping the influence of ethanol on hot melt extruded pellets comprising solid lipids
European Journal of Pharmaceutics and Biopharmaceutics, 2015Co-Authors: Nicole Jedinger, Simone Schrank, Stefan Mohr, Andrea Feichtinger, Johannes Khinast, Eva RobleggAbstract:The objective of the present study was to investigate interactions between alcohol and hot-melt extruded pellets and the resulting drug release behavior. The pellets were composed of vegetable calcium stearate as matrix carrier and paracetamol or codeine phosphate as model drugs. Two solid lipids (Compritol® and Precirol®) were incorporated into the matrix to form robust/compact pellets. The drug release characteristics were a strong function of the API solubility, the addition of solid lipids, the dissolution media composition (i.e., alcohol concentration) and correspondingly, the pellet wettability. Pellets comprising paracetamol, which is highly soluble in ethanol, showed alcohol Dose Dumping regardless of the matrix composition. The wettability increased with increasing ethanol concentrations due to higher paracetamol solubilities yielding increased dissolution rates. For pellets containing codeine phosphate, which has a lower solubility in ethanol than in acidic media, the wettability was a function of the matrix composition. Dose Dumping occurred for formulations comprising solid lipids as they showed increased wettabilities with increasing ethanol concentrations. In contrast, pellets comprising calcium stearate as single matrix component showed robustness in alcoholic media due to wettabilities that were not affected by the addition of ethanol. The results clearly indicate that the physico-chemical properties of the drug and the matrix systems are crucial for the design of ethanol-resistant dosage forms. Moreover, hydrophobic calcium stearate can be considered a suitable matrix system that minimizes the risk of ethanol-induced Dose Dumping for certain API's.
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the design of controlled release formulations resistant to alcohol induced Dose Dumping a review
European Journal of Pharmaceutics and Biopharmaceutics, 2014Co-Authors: Nicole Jedinger, Johannes Khinast, Eva RobleggAbstract:The concomitant intake of alcoholic beverages together with oral controlled-release opioid formulations poses a serious safety concern since alcohol has the potential to alter the release rate controlling mechanism of the dosage form which may result in an uncontrolled and immediate drug release. This effect, known as alcohol-induced Dose Dumping, has drawn attention of the regulatory authorities. Thus, the Food and Drug Administration (FDA) recommends that in vitro drug release studies of controlled-release dosage forms containing drugs with narrow therapeutic range should be conducted in ethanolic media up to 40%. So far, only a limited number of robust dosage forms that withstand the impact of alcohol are available and the development of such dosage forms is still a challenge. This review deals with the physico-chemical key factors which have to be considered for the preparation of alcohol-resistant controlling dosage forms. Furthermore, appropriate matrix systems and promising technological strategies, which are suitable to prevent alcohol-induced Dose Dumping, are discussed.
Mary Bond - One of the best experts on this subject based on the ideXlab platform.
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assessment of alcohol induced Dose Dumping with a hydrocodone bitartrate extended release tablet formulated with cima abuse deterrence technology
Clinical Drug Investigation, 2015Co-Authors: Mona Darwish, Mary Bond, Ronghua Yang, William Tracewell, Philmore RobertsonAbstract:Greater drug content requirements for extended-release (ER) opioids necessitate greater protection against Dose Dumping. Hydrocodone ER employs the CIMA® Abuse-Deterrence Technology platform, which provides resistance against rapid release of the active moiety when the tablet is manipulated or taken with alcohol. Assess effects of alcohol on hydrocodone ER pharmacokinetics. Open-label, crossover (January 25–April 30, 2010). Single center. Forty healthy adults. Subjects received all four treatments in a randomized manner (separated by a minimum 5-day washout): hydrocodone ER 15 mg with 240 mL water and 240 mL orange juice containing 4, 20, and 40 % alcohol in a fasted state. Naltrexone was administered to minimize opioid-related adverse events. Effect of alcohol on pharmacokinetics of hydrocodone ER assessed by comparing systemic exposure [maximum plasma drug concentration (C max) and area under the plasma drug concentration-versus-time curve from time 0 to infinity (AUC0–∞)] after administration with alcohol or with water. Geometric means ratios of hydrocodone ER with 4, 20, and 40 % alcohol relative to water were 1.05, 1.09, and 1.14, respectively, for C max and 1.07, 1.13, and 1.17, respectively, for AUC0–∞. All 90 % confidence intervals for these geometric means ratios fell within the limits of 0.8 and 1.25. Increasing alcohol concentrations did not notably affect systemic exposure but were associated with increased adverse events. Hydrocodone ER tablets were resistant to Dose Dumping when administered with alcohol in healthy subjects based on similar systemic exposures observed across all treatments.
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single and multiple Dose pharmacokinetics of a hydrocodone bitartrate extended release tablet formulated with abuse deterrence technology in healthy naltrexone blocked volunteers
Clinical Therapeutics, 2015Co-Authors: Mona Darwish, Ronghua Yang, William Tracewell, Philmore Robertson, Mary BondAbstract:Abstract Purpose A hydrocodone extended-release (ER) formulation was developed to provide sustained pain relief with twice-daily dosing. Developed using the CIMA abuse-deterrence technology platform (CIMA Labs Inc, Brooklyn Park, Minnesota), this formulation also provides resistance against rapid release of hydrocodone when tablets are comminuted and resistance against Dose Dumping when tablets are taken with alcohol. Two open-label studies evaluated hydrocodone ER pharmacokinetics (PK) after single- and multiple-Dose administration in healthy, naltrexone-blocked subjects. Methods In the single-Dose period of both studies, healthy subjects aged 18 to 45 years of age received hydrocodone ER (study 1, 45 mg; study 2, 90 mg). In the multiple-Dose period of study 1, subjects received one 45-mg hydrocodone ER tablet twice daily from the morning of day 1 through the morning of day 6. In the multiple-Dose period of study 2, subjects received hydrocodone ER twice daily, titrated to 90 mg over 10 days (days 1 and 2, 45 mg; days 3 and 4, 60 mg; days 5–10, 90 mg). All subjects received naltrexone to block opioid receptors. Blood samples were collected pre-Dose and through 72 hours post-Dose in the single-Dose period and after the final Dose in the multiple-Dose period. PK measures included maximum observed plasma drug concentration (C max ), area under the plasma drug concentration by time curve from time 0 to the time of the last measurable drug concentration (AUC 0–t ), time to C max (T max ), observed accumulation ratio (R obs ), and steady-state plasma concentration (C ss ). Safety and tolerability were assessed. Findings The PK analyses included 36 subjects from study 1 and 33 from study 2. Plasma hydrocodone PK parameters after single- and multiple-Dose administration of hydrocodone ER 45 mg (study 1) were Dose-normalized to 90 mg and pooled with data from study 2. As expected, C max was higher (125.4 vs 57.2 ng/mL), AUC 0–t was higher (2561 vs 1095 ng·h/mL), and T max occurred earlier (5.0 vs 8.0 hours) with multiple-Dose administration. Mean R obs after multiple-Dose administration of hydrocodone ER was also slightly higher than predicted from single-Dose data (2.8 vs 2.4). C ss were achieved within 5 days of twice-daily administration of both Doses. Mean fluctuation with hydrocodone ER 45 or 90 mg was 36.4% and 33.9%, respectively, and mean swing was 46.9% and 43.5%, respectively. The incidence of adverse events was similar in the single-Dose (33%) and multiple-Dose (29%) periods in study 1 and slightly higher in the multiple-Dose (76%) than in the single-Dose (53%) period in study 2. Implications The PK profile of hydrocodone ER was qualitatively similar after single- and multiple-Dose administration. The steady-state profile demonstrated sustained exposure with limited swing and fluctuation. Single and multiple Doses of hydrocodone ER (45 and 90 mg) were generally well tolerated in healthy subjects receiving naltrexone; however, exposure to naltrexone may have confounded the interpretation of safety findings.
Aliasgar Shahiwala - One of the best experts on this subject based on the ideXlab platform.
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multiparticulate formulation approach to pulsatile drug delivery current perspectives
Journal of Controlled Release, 2009Co-Authors: Aliasgar ShahiwalaAbstract:In the body under physiological conditions, many vital functions are regulated by transient release of bioactive substances at a specific time and site. Thus, to mimic the function of living systems and in view of emerging chronotherapeutic approaches, pulsatile delivery, which is meant to release a drug following programmed lag phase, has attracted increasing interest in recent years. In pursuit of pulsatile release, various design strategies have been proposed, broadly categorized into single-unit and multiple-unit systems. However, in recent pharmaceutical applications involving pulsatile delivery, multiparticulate dosage forms are gaining much favor over single-unit dosage forms because of their potential benefits like predictable gastric emptying, no risk of Dose Dumping, flexible release patterns and increased bioavailability with less inter- and intra-subject variability. Based on these premises, the aim of the present review is to survey the main multiparticulate pulsatile delivery systems, for which the swelling and rupturing; dissolution or erosion; and changed permeability of the coating membrane are primarily involved in the control of release. The development of low density floating multiparticulate pulsed-release dosage forms possessing gastric retention capabilities has also been addressed with increasing focus on the upcoming multiparticulate-pulsatile technologies being exploited on an industrial scale.