Oral Solid Controlled Release Dosage Forms: Role of GI-Mechanical Destructive Forces and Colonic Release in Drug Absorption Under Fasted and Fed Conditions in Humans

Purpose. This study was undertaken to examine the effects of mechanical destructive forces on drug release from controlled release (CR) dosage forms in vitro and in vivo and their colonic release, using two CR tablets of acetaminophen A and B, showing slower and faster erosion rates, respectively. Methods. In vitro release rates were determined by several official methods. Tablets were administered to healthy volunteers under fasting and fed conditions. Results. Both tablets showed similar release rates under mild destructive conditions (e.g., paddle method at 10 rpm) but CR-B showed faster release under highly destructive conditions (e.g., rotating basket method at 150 rpm), where the tablet was eroded. The in vivo release from CR-B was faster than from CR-A, possibly because of enhanced erosion. The variable in vivo release from CR-B indicated large inter-subject differences in destructive GI forces. The fastest in vivo release from CR-B among individuals was approximated by the in vitro dissolution determined by destructive methods such as the rotating basket at 150 rpm. The slowest in vivo release from tablets A and B was lower than the dissolution by the paddle method at 10 rpm. The release from both tablets was markedly reduced at 3–4 hrs after dosing irrespective of feeding conditions which can be attributed to release inhibition in the colon. Conclusions. Effects of GI destructive forces on the tablet erosion and the release inhibition in the colon must be considered in the development of CR dosage forms.     

Correlation of in Vitro Release Rate and in Vivo Absorption Characteristics of Four Chlorpheniramine Maleate Extended-Release Formulations

An in vitro/in vivo correlation was established for four formulations of chlorpheniramine maleate (histamine, H₁-blocker) extended-release tablets exhibiting different in vitro release rate characteristics. In vitro release rate data were obtained for 12 individual tablets of each formulation using the USP Apparatus 2, paddle stirrer at 50 rpm in 1000 ml of distilled water at 37.0 ± 0.5°C. Inspection of the individual and mean release rate data indicated that the in vitro release rate of chlorpheniramine maleate was consistent with the intended design of the four extended-release formulations. The in vivo bioavailability and pharmacokinetics of these formulations were evaluated in 24 healthy subjects under fasting conditions. Wagner Nelson analyses of the in vivo data revealed extended release absorption profiles for all four formulations. Linear regression analyses of the mean percentage of dose absorbed versus the mean in vitro release resulted in a statistically significant correlation (r ² > 0.98, P < 0.001) for each formulation. Qualitative rank-order correlations were observed among all combinations of in vitro and in vivo parameters. These data support a Level A correlation between the in vitro release rate profiles and the in vivo absorption for chlorpheniramine maleate determined under fasting conditions.     

Suitability of the cynomolgus monkey as an animal model for drug absorption studies of oral dosage forms from the viewpoint of gastrointestinal physiology

To determine the usefulness of the monkey as an animal model, which can predict in vivo performance of humans, the major gastrointestinal physiological parameters of this animal were evaluated. The pH of gastric juice collected by a fiberscope from the stomach in fasted cynomolgus monkeys showed a high acidity level, which ranged from 1.2 to 4.3. The gastric emptying time of oral dosage forms (solution, granules and tablets) showed that the larger size dosage forms seemed to be emptied more slowly, and three dosage forms were prolonged by feeding. The gastrointestinal agitation intensity of monkeys was estimated using controlled-release tablets of acetoaminophen, which showed a slow erosion rate. The in vivo release amount-time profiles of the tablet in fasted monkeys corresponded to their in vitro profiles with paddle agitation conditions of between 10 rpm and 50 rpm of the paddle method; this result was smaller than in dogs (100 rpm) but equivalent to that in humans (10 rpm). Further, the small intestinal transit time (SITT), estimated using a double marker method, ranged from 2.2 to 4.2 h in the fasting state and from 2.2 to 3.2 h in the fed state; the SITT was not significantly delayed by feeding. Comparison with the published data about dogs and humans showed these gastrointestinal physiological parameters of monkeys to be more similar to those of humans. Consequently, it is assumed that the monkey is useful as an animal model for bioavailability studies of oral dosage forms.     

Effect of Destruction Force on Drug Release from Multiple Unit Controlled Release Dosage Forms in Humans

Purpose. This study examined the effects of mechanical destructive forces on drug release from controlled release (CR) multiple unit dosage forms in vitro and in vivo and their colonic release, using two CR granules of acetaminophen, AG and BG, which differed in hardness (AG was hard and BG was soft), but which did not depend on agitation speed or pH for their release. Methods. In vitro release rates were determined using several official methods and the rotating dialysis cell method. Granules were administered to healthy volunteers under fasting and fed conditions. Results. Both granules showed similar release rates under mild destructive conditions in official dissolution tests, but BG showed a faster release rate in the rotating dialysis cell method. In the fasting state, the drug absorption-time profiles of AG and BG were almost equal. In the fed state, the drug release rate of BG increases whereas that of AG is almost equal to the fasted state. The food effect on BG could be caused by an increase in the mechanical stress of the GI tract due to food intake judging from the findings in vitro and in dogs. The colonic release from multiple unit CR products was larger than that from single unit ones. Conclusions. In vivo release of drug from a multiple unit CR product that is structurally weak is affected by mechanical stresses, which differ among human subjects but are increased by food ingestion. Colonic release from multiple unit CR products is larger than that from single unit products.     

THEOPHYLLINE CONTROLLED-RELEASE FORMULATIONS: IN VIVO--IN VITRO CORRELATIONS

Four experimental controlled-release oral solid dosage formulations were developed and the in vitro dissolution characteristics of theophylline from these formulations were studied in USP apparatus I. Pharmacokinetic evaluation of these formulations was carried out in eight beagle dogs under fasting conditions. Theophylline in a 5% dextrose injection USP, oral solution, and Slo-Phyllin® were used as controls to estimate the in vivo dissolution of these four formulations in the GI tract. The percentage cumulative amounts of drug absorbed and the percentage cumulative amounts of drug released into the GI tract from these four controlled-release formulations were obtained by numerical deconvolution methods. The in vivo and in vitro dissolution data demonstrated good correlation indicating that in vitro dissolution tests can be used to optimize the further design of controlled drug release oral solid dosage formulations for theophylline.     

Release and Absorption Characteristics of Novel Theophylline Sustained-Release Formulations: In Vitro-in Vivo Correlation

Five new experimental sustained-release (SR) formulations of theophylline, T-l, T-l-A, T-2, T-2-A, and T-2-E, in a matrix tablet form with a protein were developed. The in vitro release of theophylline from these novel experimental formulations and two commercial (Theotrim and Theo-Dur) SR formulations, was studied for 2 hr immersed in simulated gastric fluid TS, followed by an additional 10 hr immersed in simulated intestinal fluid TS. Like Theotrim and Theo-Dur, theophylline release profiles from all the novel experimental formulations were smooth, controlled, and unaffected by changes in the pH and the proteolytic enzyme content of the incubation media. Pharmacokinetic evaluation of T-l, T-l-A, T-2-A, Theotrim, and Theo-Dur was carried out in five dogs and six healthy human volunteers under fasting conditions, using immediate-release aminophylline tablets as controls. Pharmacokinetic analysis by the Wagner–Nelson procedure revealed sustained-release absorption characteristics for all the formulations with the exception of the immediate release aminophylline tablet. For each of the formulations tested, the regression analysis results of the percentage of theophylline absorbed in dogs or humans against the mean percentage released in vitro, at the corresponding times, indicated a high correlation. These data imply that the in vivo release profiles under fasting conditions in the gastrointestinal tract of dogs and humans may be similar to those in the in vitro studies.     

Prediction of in vivo drug release behavior of controlled-release multiple-unit dosage forms in dogs using a flow-through type dissolution test method

A newly designed flow-through type dissolution test method (FT method) was applied to predict in vivo drug release behaviors in dogs of controlled-release multiple unit dosage forms. The in vivo drug release behaviors were directly observed by measuring the residual amount of drugs in preparations recovered from the gastrointestinal (GI) tract after oral administration. Theophylline (TP), acetaminophen (AA), and phenylpropanolamine hydrochloride (PPA), which have different solubility, were used as model drugs. In vivo drug release behaviors in the gastrointestinal (GI) tract of dogs were similar to the results of the Wagner-Nelson method. In vivo release behaviors of TP and AA, until 2h after administration, were well correlated to in vitro behaviors obtained by the paddle method at 100 rpm. However, the in vivo release rates of TP and AA were gradually decreased because of a lack of fluid in the lower region of the GI tract, their poor solubility, the difference of the release rates, and so on. Non-sink conditions, which would reflect TP and AA release in the lower region of the GI tract, were obtained by the FT method at a cell volume of 0.5 ml and a flow rate of 0.37 ml/h (TP), 0.48 ml/h (AA), respectively. The in vitro release profiles obtained by the FT method combining sink and non-sink conditions were similar to their in vivo profiles. On the other hand, in the case of PPA, the in vivo release profiles were considerably similar to the in vitro ones obtained by both the paddle method and the FT method. In conclusion, the FT method combining sink and non-sink conditions will give a good in vitro/in vivo correlation regarding release behavior for controlled-release multiple unit dosage forms.     

Comparison of WHO and US FDA biowaiver dissolution test conditions using bioequivalent doxycycline hyclate drug products

Objectives The dissolution characteristics of immediate‐release doxycycline hyclate products with certified in‐vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver‐based approval. Methods Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin‐ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy‐Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.2, acetate buffer, pH 4.5, and simulated intestinal fluid without pancreatin, pH 6.8. Results were obtained at two paddle speeds recommended for biowaiver applications: 75 rpm (World Health Organization; WHO) and 50 rpm (US Food and Drug Administration; US FDA). Key findings The results for the tablets and hard gelatin capsules indicate that a paddle speed of 75 rpm is more representative than 50 rpm, since 75 rpm generates dissolution profiles corresponding more closely to the in‐vivo profiles than those at 50 rpm. For evaluating soft gelatin capsule formulations with lipid fill, both US FDA and WHO methods were found to be over‐discriminating. Conclusions Bioequivalence of immediate‐release doxycycline hyclate tablets and hard gelatin capsules, but not soft gelatin capsules, can be evaluated in vitro using the biowaiver dissolution test conditions specified by the WHO.     

Influence of physical factors in gastrointestinal tract on acetaminophen release from controlled-release tablets in fasted dogs

Four types of controlled-release (CR) acetaminophen (AAP) tablets, namely A, B, C and D, were prepared to investigate the influence of physical factors in the gastrointestinal (GI) tract on AAP release in fasted dogs. CR-A was designed as a completely resistant formulation to mechanical destructive force but to show an agitation speed-dependent dissolution rate. CR-B, CR-C and CR-D were designed to have different wet strengths but to show similar dissolution rates. The absorption profiles of the four CR forms in dogs showed biphasic patterns, with phase change about 2 h after oral dosing. The first phase of the absorption profile of CR-A and in vivo release directly observed were close to its in vitro profiles at a speed of 25–50 revs./min, indicating that agitation intensity in the dog GI tract may be relatively low. The first phase of the absorption profiles of the CR-B, CR-C and CR-D differed from each other, despite the fact that dissolution rates in vitro were similar. The tablet with low wet strength showed a faster absorption rate, indicating that it would be destructed by GI mechanical forces. Furthermore, absorption during the second phase was extremely low for all CR tablets. We confirmed on necroscopy that the suppression of drug absorption in the second phase was caused by the termination of AAP release from the tablets in the colon. These results will be useful in evaluating the in vivo performance of CR tablets in fasted dogs.     

Effect of Hydrodynamic Environment on Tablets Dissolution Rate

The main objective of this research was to develop an experimental method to apply well‐defined flow fields to solid dosage forms, to study the rate process underlying tablet dissolution, and to better understand the role of external hydrodynamic condition on mass transfer rate and film thickness during dissolution. Two drugs models, Theophylline (class 1) and Naproxen (class 2), were selected and formulated into conventional tablets containing 105 mg Theophylline or 300 mg Naproxen using the wet granulation method. Tablets were tested for dissolution using both the basket and paddle methods at different rotational speed of 25, 50, 75, and 100 rpm. In general, the paddle method gave higher dissolution rates than the basket method and as the velocity of rotation was increased, drug release was also increased. Six different paddles and a tablet holder were designed and used to test dissolution rate. The rate of dissolution was dependent on the tablet surface area exposed to the dissolution medium, and on the shape, diameter, and area of the paddles used. Theophylline tablets showed increased mass transfer rate and decreased film thickness as basket rotation speed was increased. At 25 rpm, the mass transfer coefficient was 0.684 × 10^{? 4} cm/sec and film thickness was 12.003 × 10^{? 2} cm; at 100 rpm, the mass transfer coefficient was 3.884 × 10^{? 4} cm/sec and film thickness was 2.114 × 10^{? 2} cm. Paddle values tested at the same speed showed higher mass transfer coefficient and lower film thickness for Theophylline and Naproxen tablets. P values obtained by modification of the Stokes‐Einstein equation showed that diffusion is the rate‐limiting step to drug release and not mass transfer. This study demonstrated that hydrodynamic condition, type of dissolution testing used, and design of the paddles have an effect on dissolution rate, mass transfer rate, and the film thickness underlying the dissolution process.     

Dosage form design and in vitro/in vivo evaluation of cevimeline extended-release tablet formulations

The objective of the present work is to develop an extended-release dosage form of cevimeline. Two types of extended-release tablets (simple matrix tablets and press-coated tablets) were prepared and their potential as extended-release dosage forms were assessed. Simple matrix tablets have a large amount of hydroxypropylcellulose as a rate-controlling polymer and the matrix is homogeneous throughout the tablet. The press-coated tablets consisted of a matrix core tablet, which was completely surrounded by an outer shell containing a large amount of hydroxypropylcellulose. The simple matrix tablets could not sustain the release of cevimeline effectively. In contrast, the press-coated tablets showed a slower dissolution rate compared with simple matrix tablets and the release curve was nearly linear. The dissolution of cevimeline from the press-coated tablets was not markedly affected by the pH of the dissolution medium or by a paddle rotating speed over the range of 50–200 rpm. Furthermore, cevimeline was constantly released from the press-coated tablets in the gastrointestinal tract and the steady-state plasma drug levels were maintained in beagle dogs. These results suggested that the designed PC tablets have a potential for extended-release dosage forms.     

Study on dissolution and absorption of four dosage forms of isosorbide mononitrate: Level A in vitro–in vivo correlation

The objective of the present study was to develop a novel in vitro system to simulate the process of dissolution and permeation of oral solid dosage forms in vivo, and to establish a correlation between in vitro permeation and in vivo absorption that could predict the bioavailability (BA) and bioequivalence (BE) of congeneric products. The in vitro dissolution and absorption kinetics of four dosage forms of isosorbide mononitrate (ISMN) were evaluated by the USP basket/paddle system and drug dissolution/absorption simulating system (DDASS). The corresponding pharmacokinetic study was performed in beagle dogs. A comparative study was carried out between the classical and the novel method to estimate the effectiveness of the modified DDASS in simulating the course of dissolution and absorption in vivo. Indeed, the correlation coefficients of in vitro dissolution and in vivo absorption obtained from DDASS and dogs were higher. Moreover, a higher level A in vitro–in vivo correlation (IVIVC) between DDASS permeation and dog absorption was established, with correlation coefficients of 0.9968, 0.9872, 0.9921, and 0.9728. The DDASS method was more accurate at modeling the process of dissolution and absorption in vivo for both immediate-release (IR) and sustained-release (SR) dosage forms of ISMN.     

Controlled Release of Paracetamol from Amylodextrin Tablets: In Vitro and in Vivo Results

Amylodextrin is a suitable excipient for the design of solid controlled-release systems. The release of paracetamol from tablets containing 30% drug and 70% amylodextrin was studied in vitro and in vivo. In vitro dissolution profiles showed almost-constant drug release rates during 8 hr, when measured in 0.05 M buffer, pH 6.8. Peroral administration of the tablets to man showed almost-constant paracetamol plasma levels up to 14 hr, as compared to fast absorption and fast elimination of a reference paracetamol solution. The plasma profiles of eight volunteers demonstrated a small intersubject variability during the first day after tablet administration. Increasing variability and decreasing plasma levels during the second day were caused by excretion of tablets from the bodies. Cumulative input as a function of time showed near-zero-order drug release during the first day. The in vivo results indicate that amylodextrin tablets are not hydrolyzed by -amylase, present in the gastrointestinal tract.     

In-vivo and In-vitro Correlation for Delayed-release Behaviour of a Molsidomine/O-carboxymethyl-O-ethyl-β-cyclodextrin Complex in Gastric Acidity-controlled Dogs

The in-vivo absorption behaviour of molsidomine from the delayed-release tablets of an O-carboxy-methyl-O-ethyl-β-cyclodextrin complex was investigated using gastric acidity-controlled dogs under fasted and non-fasted conditions. The in-vitro release profiles were generated by changing the pH of the dissolution medium at different rotation paddle speeds. The absorptivity of molsidomine in the high acidity dog was correlated with the pH-changed release profile (pH 1·2 to 7·0 after 2 h), whereas that in the low acidity dog was correlated with the release profile at a constant pH of 7·0. The absorption in fasted dogs was well correlated with the in-vitro release at the low-rotation paddle speed (< 5 rev min^?1), whereas that in the non-fasted dogs was correlated with that of high rotation (100 rev min^?1). The present results suggested that the in-vivo delayed-release behaviour of the complex is predictable from the in-vitro release profiles generated using pH-variable dissolution testing apparatus at different rotation speeds of the paddle.     

A biorelevant dissolution stress test device – background and experiences

Importance of the field: The prediction of the in vivo drug release characteristics of modified release (MR) oral dosage forms by in vitro dissolution tests is a prerequisite for successful product development.

Areas covered in this review: To improve the predictive power of dissolution testing, the authors recently developed a new dissolution test apparatus that simulates physical conditions of the gastrointestinal (GI) passage of MR dosage forms. The simulation includes pressure force exerted by GI motility, shear stress force generated during phases of GI transport and intermittent contact with intestinal fluids while the dosage form is located in an intestinal air pocket.

What the reader will gain: The article briefly describes selected aspects of GI tract physiology, evolution and goals of dissolution testing as well as the development and use of test devices that are intended to simulate GI tract conditions. The data are discussed in the light of the test results obtained with the new dissolution stress test device developed by the authors' group. Achievements reported from 1986 to 2010 are referred to.

Take home message: The new apparatus was evaluated using extended release (ER) tablets of nifedipine and diclofenac. The dissolution characteristics of some of the tested products were strongly dependent on the test conditions and could be distinctly influenced by the mechanical stress events of biorelevant intensity. Results of these experiments thus indicated that a high sensitivity of dosage forms to GI-specific physical conditions has to be regarded as a major cause of irregularities in the drug release profiles, which may result in fluctuations of the individual drug plasma concentration profiles, as, for example, caused by dose dumping.     

硝苯地平控释片体内外相关性溶出方法研究

目的 开发相应的能区分和反映参比制剂与自研制剂之间释放差异的溶出方法,使自研制剂与参比制剂体外释放达到最大程度的匹配,从而为生物等效性试验提供体内外更具相关性的研究。方法 采用美国药典(USP)溶出2法(桨法)作为质量控制方法;另采用流池法作为溶出区分性方法,评估不同实验参数下的溶出结果。结果 优化并确立方法为开环系统,流速3.0 mL·min^-1,加1/2勺玻璃珠。该方法可以有效区分处方和生产工艺变化对产品溶出的影响。以此法为基础所得到的体外溶出速率和溶出度与体内药动学研究结果一致。结论 本研究所开发的流池法适合作为硝苯地平控释片的溶出区分性方法,并具备一定的体内体外相关性。     

Application of hot-melt extrusion technology for designing an elementary osmotic pump system combined with solid dispersion for a novel poorly water-soluble antidepressant

TP1 is a novel antidepressant with poor solubility. To reduce fluctuations in blood concentration and increase oral bioavailability, a controlled-release system was developed by combining a solid dispersion (SD) and an elementary osmotic pump (EOP). The study compared different methods of preparing SDs. Hot-melt extrusion (HME) exhibited clear advantages over the traditional melting technique. An in vitro release study demonstrated that HME-EOP tablets released TP1 in a zero-order manner over 12?h and the drug release was in dependent of the release medium and agitation speed, whereas release from molten-EOP tablets lasted only 8?h. In contrast to immediate-release tablets, the HME-EOP tablets exhibited less fluctuation in blood concentration and higher bioavailability in vivo. In summary, the osmotic pump system combined with an HME-based SD of TP1 presented controlled release in vitro, high bioavailability in vivo and a good in vivo–in vitro correlation.     

Using Computational Fluid Dynamics to Compare Shear Rate and Turbulence in the TIM-Automated Gastric Compartment With USP Apparatus II

We use computational fluid dynamics to compare the shear rate and turbulence in an advanced in vitro gastric model (TIMagc) during its simulation of fasted state Migrating Motor Complex phases I and II, with the United States Pharmacopeia paddle dissolution apparatus II (USPII). A specific focus is placed on how shear rate in these apparatus affects erosion-based solid oral dosage forms. The study finds that tablet surface shear rates in TIMagc are strongly time dependant and fluctuate between 0.001 and 360 s^?1. In USPII, tablet surface shear rates are approximately constant for a given paddle speed and increase linearly from 9 s^?1 to 36 s^?1 as the paddle speed is increased from 25 to 100 rpm. A strong linear relationship is observed between tablet surface shear rate and tablet erosion rate in USPII, whereas TIMagc shows highly variable behavior. The flow regimes present in each apparatus are compared to in vivo predictions using Reynolds number analysis. Reynolds numbers for flow in TIMagc lie predominantly within the predicted in vivo bounds (0.01-30), whereas Reynolds numbers for flow in USPII lie above the predicted upper bound when operating with paddle speeds as low as 25 rpm (33).     

A comparative study of different release apparatus in generating in vitro–in vivo correlations for extended release formulations

The importance of hydrodynamics in the development of in vitro–in vivo correlations (IVIVCs) for a BCS Class II compound housed in a hydrophilic matrix formulation and for a BCS Class I compound housed in an osmotic pump formulation was assessed. In vitro release data were collected in media simulating the fasted state conditions in the stomach, small intestine and the ascending colon using the USP II, the USP III and the USP IV release apparatuses. Using the data collected with the USP II apparatus, the plasma profiles were simulated and compared with human plasma profiles obtained after administration of the same dosage forms to healthy fasted volunteers. Data obtained with the USP III and USP IV apparatuses were directly correlated with the deconvoluted human plasma profiles. In vitro hydrodynamics affected the release profile from the hydrophilic matrix. For both formulations, based on the values of the difference factor, all three apparatuses were equally useful in predicting the actual in vivo profile on an average basis. Although some hydrodynamic variability is likely with low solubility drugs in hydrophilic matrices, the hydrodynamics of USP II, III and IV may all be adequate as a starting point for generating IVIVCs for monolithic dosage forms in the fasted state.     

Evidence for Site-Specific Absorption of a Novel ACE Inhibitor

Moexipril {2-[(l-ethoxycarbonyl)-3-phenylpropyl]amino-l-oxopropyl]-6,7-dimethoxy-1,2,3,4-tetra-hydroisoquinoline-3-carboxylic acid (S,S,S)}, an ester prodrug of an ACE inhibitor, was formulated in controlled-release preparations with a range of in vitro release rates, to provide a prolonged input of drug in vivo. However, pharmacokinetic studies with the controlled-release dosage forms in humans produced plasma profiles with the same characteristics and time to peak as an immediate-release capsule. In vitro dissolution data from the controlled-release dosage form, as well as the known characteristics of the polymer used to control drug release from the dosage form, suggest no reason to suspect an abrupt halt to the in vivo release of the drug after 1–2 hr. The lack of sustained blood levels is, therefore, most likely due to failure of the GI tract to absorb the drug beyond some location in the upper small intestine, i.e., site-specific absorption. This theory is supported by a series of computer simulations involving moexipril and the active moiety, moexipril diacid. Possible mechanisms include poor drug permeability, a pH effect whereby the zwitterionic form of the drug is more rapidly absorbed, and esterase cleavage of moexipril to the poorly absorbed moexipril diacid.