Chronopharmaceutical drug delivery from a pulsatile capsule device based on programmable erosion

We report the development of a chronopharmaceutical capsule drug delivery system capable of releasing drug after pre-determined time delays. The drug formulation is sealed inside the insoluble capsule body by an erodible tablet (ET). The release time is determined by ET erosion rate and increases as the content of an insoluble excipient (dibasic calcium phosphate) and of gel-forming excipient (hydroxypropylmethylcellulose; HPMC) increases. The time-delayed release of a model drug (propranolol HCI) was investigated by dissolution testing (USP XXIII paddle method). Both composition and weight of ET influence the time of drug release. Moreover it was found that drug release was controlled by the quantity of HPMC, irrespective of lactose content within the tablet weight range 80-160 mg, when above a threshold concentration of 20% HPMC. Programmable pulsatile release has been achieved from a capsule device over a 2-12-h period, consistent with the demands of chronotherapeutic drug delivery. The time of drug release can be controlled by manipulation of tablet formulation.     

The effect of oil as a dietary component on in vitro dissolution of an acid-labile drug

The non-benzodiazepine-like anxiolytic agent deramiclane fumarate (EGIA-3886) was used to demonstrate that the presence of high oil/fat content in dissolution media serves as a barrier against accelerated drug degradation in acidic media.     

The effect of tablet formulation on the haemodynamic properties of glyceryl trinitrate.

A non-invasive haemodynamic study was carried out in 13 normal subjects to compare the pharmacodynamics of glyceryl trinitrate when formulated as a moulded tablet ('Nitrostat') rather than as a generic compressed tablet. The glyceryl trinitrate moulded tablet, with a much more rapid and predictable dissolution time, produced an earlier onset of systolic blood pressure fall (p less than 0.01) and a greater maximum percentage change in peripheral blood flow (p less than 0.02). No other significant differences in effect on pulse rate, blood pressure or peripheral blood flow were noted.     

The effect of some excipients on the physical properties of a paracetamol tablet formulation

The effects of the addition of the excipients sorbitol, sodium lauryl sulphate and Aerosil on the physical properties of a paracetamol tablet formulation have been evaluated. Increase in the concentration of sorbitol and sodium lauryl sulphate caused a decrease in the hardness with a corresponding increase in the friability, disintegration and dissolution rates of the tablets. The mode of incorporation of the excipient, Aerosil, greatly influenced the physical properties of the paracetamol tablets. When added internally, the tablets' strength decreased while the friability, disintegration and dissolution rates increased. However, when Aerosil was added externally, the strength of the tablets increased while their friability, disintegration and dissolution rates decreased.     

Binder-substrate interactions in wet granulation. 3: The effect of excipient source variation

The effect of excipient source variation on the interactions during wet granulation between microcrystalline cellulose and aqueous solutions of two molecular weight grades of two polymer binders has been studied using an instrumented mexer torque rheometer. The wet massing data confirmed previous observations that dissimilar polymers interact differently with cellulose substrates during the wet massing process. In addition, for a second cellulose material, variations were also observed in the pattern of interaction between the binders and the excipient. An examination of particulate and surface energetic properties revealed differences in the cellulose materials which were then related to the observed rheological behaviour.     

Abacavir/lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with each component administered concurrently and the effect of food on absorption

A single-center, open-label, three-way crossover study was conducted in 24 healthy subjects to assess (1) the bioequivalence of a combined abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg (A/L/Z) combination tablet relative to the separate brand-name components administered simultaneously and (2) the effect of food on the bioavailability of the drugs from the combination tablet. The subjects were randomly assigned to receive each of the following three treatments, separated by a 2-day washout period: one A/L/Z combination tablet after an overnight fast, one abacavir 300 mg tablet + one lamivudine 150 mg tablet + one zidovudine 300 mg tablet sequentially after an overnight fast, or one A/L/Z combination tablet 5 minutes after completing a standardized high-fat breakfast (67 g fat, 58 g carbohydrate, and 33 g protein). Serial blood samples were collected up to 24 hours postdose for determination of abacavir, lamivudine, and zidovudine serum concentrations. Standard pharmacokinetic parameters were estimated. Treatments were considered bioequivalent if 90% confidence intervals (CI) for geometric least squares (GLS) mean ratios for abacavir, lamivudine, and zidovudine area under the serum concentration-time curve (AUC(infinity)) and maximum observed serum concentration (Cmax) fell entirely within 0.80 to 1.25 for log-transformed parameters. The combined A/L/Z tablet was bioequivalent in the extent (AUC) and rate of absorption (Cmax and time of Cmax [tmax]) to the individual brand-name drug components administered concurrently under fasted conditions. GLS ratios and 90% CI for AUC(infinity) and Cmax were 0.99 (0.96, 1.03) and 1.00 (0.90, 1.11), respectively, for abacavir; 0.95 (0.91, 0.99) and 0.90 (0.84, 0.99), respectively, for lamivudine; and 0.95 (0.89, 1.02) and 0.96 (0.80, 1.15), respectively, for zidovudine. The extent of absorption of abacavir, lamivudine, and zidovudine from the combination tablet was not altered by administration with meals, indicating that this formulation may be administered with or without food. However, food slowed the rate of absorption, delayed the tmax, and reduced the Cmax of abacavir, lamivudine, and zidovudine. These changes, which were consistent with those observed with the individual reference formulations when administered with food, were not considered clinically important. All formulations were well tolerated underfasted and fed conditions.     

Degradation of a fluoropyridinyl drug in capsule formulation: degradant identification, proposed degradation mechanism, and formulation optimization

The purpose of this paper was to investigate the degradation chemistry of a fluoropyridinyl drug candidate in capsule formulation and to optimize the formulation based on a proposed degradation mechanism. Small developmental batches of capsules were made by tituration of drug substance and excipients using a mortar and pestle, followed by manual encapsulation. Degradants were identified by LC-MS/MS and LC-photodiode array detector (PDA) and were monitored by LC-ultraviolet detector (UVD) during stability studies. It was found that the drug could undergo a nucleophilic substitution reaction in which hydroxyl groups replace the fluorine substituents on the pyridine rings. The initial degradation rate is independent of the drug concentration but dependent on the temperature, the pH of the microenvironment, and the excipient type. On the basis of these experimental results, a nucleophilic substitution reaction mechanism for the degradation was proposed and a successful capsule formulation was developed.     

Physical stability and solubility of the thermotropic mesophase of fenoprofen calcium as pure drug and in a tablet formulation

The aim of this study was to investigate and compare the physical stability and solubility of the liquid crystalline form of fenoprofen calcium as pure drug and in a proprietary tablet formulation (Nalfon), and to investigate if a simple heat treatment of a proprietary tablet containing fenoprofen calcium may lead to a physically stable formulation with enhanced dissolution rate and apparent solubility. The liquid crystalline form of fenoprofen calcium (thermotropic mesophase) was prepared by heating the crystalline drug to 125 degrees C to remove the water of crystallisation. Differential scanning calorimetry investigation revealed an endothermic peak at 89 degrees C upon heating (liquid crystal formation) attributable to water loss from the crystalline dihydrate. The liquid crystalline order was maintained upon cooling. No interference of tablet excipients with the thermal behaviour of the drug in the tablet formulation was observed. The crystalline dihydrate and liquid crystalline forms of fenoprofen calcium could be differentiated by diffuse reflectance infra-red spectroscopy and X-ray powder diffraction, both as pure drug and in tablet formulation. The supercooled liquid crystal (thermotropic reversed hexagonal phase) alone and in preheated and ground tablets was physically stable when stored in a dry environment or at 33% relative humidities (RH) at both 20 and 40 degrees C for 2 months. At 40 degrees C and 75% RH the supercooled mesophase extensively converted to the crystalline dihydrate within 6 days. Liquid crystalline fenoprofen calcium stored at 20 degrees C and 75% RH showed only partial dihydrate conversion after 2 months of storage. The solubility of the crystalline dihydrate alone and from the tablet formulation was 2.8+/-0.2 mg/ml and 3.0+/-0.2 mg/ml (mean+/-s.d.), respectively, (not significantly different), whereas the maximum solubility of the liquid crystal was 5.0+/-0.3 mg/ml (mean+/-s.d.) and 6.9+/-0.6 mg/ml (mean+/-s.d.), respectively (significantly different). The difference in maximum solubility between the crystalline dihydrate form of fenoprofen calcium and the fenoprofen calcium mesophase was highly significant, for both the pure drugs and the tablet formulations. The dissolution rate of the liquid crystalline fenoprofen calcium in preheated, intact tablets was significantly lower than that of the crystalline form in non-preheated tablets. Gross visual changes and scanning electron microscopy indicated that the disintegration properties of the tablet may be detrimentally effected by heating the tablet to 125 degrees C, diminishing the beneficial effect of improved solubility of the liquid crystal. The study has shown that conversion of the crystalline form of fenoprofen calcium to the liquid crystal can enhance the apparent solubility of the pure drug and the drug in presence of tablet excipients, but that the conversion should be performed before tablet formulation in order to increase dissolution of this poorly water-soluble drug.     

Sodium hyaluronate as a mucoadhesive component in nasal formulation enhances delivery of molecules to brain tissue

Intranasal administration of molecules has been investigated as a non-invasive way for delivery of drugs to the brain in the last decade. Circumvention of both the blood-brain barrier and the first-pass elimination by the liver and gastrointestinal tract is considered as the main advantages of this method. Because of the rapid mucociliary clearance in the nasal cavity, bioadhesive formulations are needed for effective targeting. Our goal was to develop a formulation containing sodium hyaluronate, a well-known mucoadhesive molecule, in combination with a non-ionic surfactant to enhance the delivery of hydrophilic compounds to the brain via the olfactory route. Fluorescein isothiocyanate-labeled 4 kDa dextran (FD-4), used as a test molecule, was administered nasally in different formulations to Wistar rats, and detected in brain areas by fluorescent spectrophotometry. Hyaluronan increased the viscosity of the vehicles and slowed down the in vitro release of FD-4. Significantly higher FD-4 transport could be measured in the majority of brain areas examined, including olfactory bulb, frontal and parietal cortex, hippocampus, cerebellum, midbrain and pons, when the vehicle contained hyaluronan in combination with absorption enhancer. The highest concentrations of FD-4 could be detected in the olfactory bulbs, frontal and parietal cortex 4 h after nasal administration in the mucoadhesive formulation. Intravenous administration of a hundred times higher dose of FD-4 resulted in a lower brain penetration as compared to nasal formulations. Morphological examination of the olfactory system revealed no toxicity of the vehicles. Hyaluronan, a non-toxic biomolecule used as a mucoadhesive in a nasal formulation, increased the brain penetration of a hydrophilic compound, the size of a peptide, via the nasal route.     

Oxytetracycline tablet formulations: the effect of wet mixing time, particle size and batch variation on granule and tablet properties.

The wet mixing time has been shown to influence the properties of an oxytetracycline dihydrate tablet formulation, wet granulated with PVP solution. Increased time of wet mixing produced larger, stronger and more dense granules, which compressed into tablets with longer disintegration and dissolution times. Decreased drug particle size aggravated these trends. A decrease in drug particle size also produced larger, stronger and more dense granules. Above an oxytetracycline mean particle diameter of about 6 mum, the tablet dissolution was satisfactory. As the oxytetracycline particle size was decreased further, however, the distintegration and dissolution of the corresponding tablets was markedly slower.     

盐酸维拉帕米脉冲释放片体内外释药特性

目的：研究盐酸维拉帕米脉冲释放片体内外释药特性。方法：用干法压制包衣技术制备盐酸维拉帕米脉冲释放片，调整包衣中致孔剂用量，通过体外释放度试验考查时滞，并用HPLC法测定家兔血药浓度，考查体内外时滞的相关性。结果：体内外时滞基本相符。结论：可用体外时滞预测体内的时滞。     

The effect of breathing pattern on nebulizer drug delivery.

The significance of using breathing patterns with simplified functional shapes in vented jet nebulizer research is examined. This study is comprised of three parts: (1) The measurement and analysis of human breathing patterns, (2) the subsequent in vitro testing of the effects of breathing pattern differences using a consistent bench test method, and (3) a computer modeling of these effects on the estimated regional drug deposition in the human lung. Breathing through a Pari LC-Star nebulizer caused statistically significant changes (p < or = 0.05) in measured human breathing patterns when compared to normal breathing. Observed changes included an increase in the tidal volume (34%) and period (39%). Additionally, the average duty cycle shifted 12% towards a more symmetrical breath due to the unequal increase in the inhalation and exhalation times (55% and 28%, respectively). The position of the point of maximum flow in each breath phase shifted towards the beginning and end of the breath for the inhale and exhale by 28% and 48%, respectively. The bench testing revealed that breathing pattern shape variation caused statistically significant differences in nebulizer output only in two cases. Decreasing duty cycles and shifting the point of maximum flow towards the beginning of the breath both result in a decrease in output efficiency. Square flow patterns produced slight but consistently higher output efficiencies (average 2.1% higher) and a constant output particle size over the course of each breath, different from the other non-square patterns. Numerical simulations revealed no significant dosage differences resulting from breathing pattern shape variations. However, square wave patterns consistently produced slight overpredictions in comparison with real nebulizer patterns. In contrast, sine wave patterns were found to produce essentially the same results as nebulizer patterns in both the bench tests and in the deposition simulations. This suggests that sine wave shapes are preferable for simulating breathing when bench testing drug delivery using vented jet nebulizers.     

Effect of formulation solubility and hygroscopicity on disintegrant efficiency in tablets prepared by wet granulation, in terms of dissolution

The effect of tablet formulation solubility and hygroscopicity on the dissolution efficiency of three "super disintegrants" (sodium starch glycolate, crospovidone, and croscarmellose sodium) in tablets prepared by wet granulation was investigated. Lactose, calcium phosphate dibasic, sorbitol, and naproxen sodium, alone or in combination, provided varying degrees of solubility and hygroscopicity in the formulations. To monitor in vitro dissolution, 1% p-aminobenzoic acid was added to the formulation as a tracer. The results indicate that highly soluble and/or hygroscopic ingredients decrease the effectiveness of super disintegrants in promoting in vitro dissolution. The greater the overall hygroscopicity and solubility of the tablet formulation, the larger the decrease in the efficiency of the super disintegrant.     

Studies on cyclodextrin polymer. Part 1: The effect of CDP on indomethacin tablet formulation

Cyclodextrin polymer (CDP), which is a cross-linked derivative of beta-cyclodextrin, has been used as binder and disintegrating agent in tablet formulation. In this study different tablet formulations of indomethacin, which is a nonsteroid anti-inflammatory drug were prepared by direct compression method. Corn starch, lactose and Esma-Spreng were used besides CDP as disintegrating agent. The hardness, friability, disintegration time and dissolution rate of the tablet were determined. The data were also evaluated kinetically. It was found that CDP is a good disintegrating agent and significantly increased the dissolution rate of the poorly soluble indomethacin.     

Effect of food intake on the delivery of fluorescein as a model drug in colon delivery capsule after oral administration to beagle dogs

Abstract

The effect of food on the release time of a model drug, fluorescein (FL), has been studied after oral administration to beagle dogs in colon delivery capsule in comparison to conventional gelatin capsule and enteric capsules. The dose of FL was 30 mg for each animal. After oral administration of each test preparation in fasted or postprandial condition (100 grams of commercial solid food was given at 30 min before drug administration), blood samples were collected and plasma FL concentrations were measured spectrofluorometrically. Pharmacokinetic analysis was performed with plasma FL concentration vs. time data and the following parameters were determined; Tmax (the time when plasma FL concentration reaches to its maximum concentration), Cmax (peak plasma FL concentration), Tlag (the time when FL appeared at first into the systemic circulation), AUC (area under the plasma FL concentration vs. Time curve) and MRT (mean residence time). For gelatin capsule, mean Tmax appeared at 0.83 ± 0.33 (S.E.) h after administration and MRT was 2.67 ± 0.21 h in fasted condition. By feeding, Tmax and MRT increased to 1.50 ± 0.76 h and 3.09 ± 0.49 h. For two enteric HPMCP and Eudragit S capsules, MRTs were 2.90 ± 0.48 h and 5.24 ± 0.32 h in fasted condition, and 11.30 ± 1.10 h and 12.83 ± 0.34 h in postprandial condition, respectively. Tlag also increased by postprandial administration. As colon delivery capsule, time-controlled release capsule (TCC) and two types of intestinal inner pressure-controlled release capsules (PCC) (#1 is a separate type and #2 is a seamless one) were tested. MRT of TCC was 4.76 ± 0.29 h and 6.43 ± 0.66 h in fasted and postprandial conditions, respectively. This capsule did not receive the effect of food intake. For #1 PCC, MRTs were 5.32 ± 0.22 h and 12.28 ± 0.26 h in fasted and postprandial conditions, respectively. For #2 PCC, MRTs were 5.51 ± 0.26 h and 13.36 ± 0.84 h in fasted and postprandial conditions, respectively. In addition, the effect of two times feedings was studied with two PCCs and longer MRTs, 28.44 ± 1.39 h and 26.32 ± 1.64 h, were obtained. The release time of FL from PCCs increased by postprandial administration. As compared to the results on two enteric capsules, these PCCs are thought to disintegrate in the colon. However, TCC is thought to disintegrate in the stomach after postprandial administration.     

Observations on the dissolution behavior of a tablet formulation: effect of compression forces

Two test drugs, hydrochlorothiazide and phenylbutazone, were separately incorporated into a standard formulation to study their disintegration and dissolution properties as a function of compression force. The increase in dissolution with force was attributed to the manner in which tablets disintegrated while dissolving. At a fixed press setting, tablets from the same compression cycle showed variations in their dissolution which were in agreement with the observed effects of force on dissolution. A linear correlation between dissolution efficiency and the logarithm of force was found to exist over the compression range studied.     

The effect of experimental design on the modeling of a tablet coating formulation using artificial neural networks

The aim of this study was to investigate the effect of experimental design strategy on the modeling of a film coating formulation by artificial neural networks (ANNs). Box-Behnken, central composite and pseudo-random designs of 102, 90 and 100 simulated records, respectively were used to train a multilayer perceptron (MLP) ANN comprising six input and two output nodes separated by a single hidden layer of five nodes. Network over-training was limited by using a test set of 40 pseudo-randomly distributed records. The models were validated using a set of 60 pseudo-randomly distributed records. Crack velocity was highly curved with respect to pigment particle size and size distribution. Similarly, film opacity was highly curved in response to pigment concentration and film thickness. The Box-Behnken and central composite designs generated models that were unable to predict crack velocity and showed extensive bias in prediction of film opacity. The pseudo-random design was unable to predict crack velocity of the test data set but yielded acceptable predictions for the validation set. Film opacity was well predicted by the pseudo-random design model. The poor predictive ability of the Box-Behnken and central composite models was attributed to poor interpolation of the high curvature of the response surfaces. In contrast, the pseudo-random design mapped the interior of the design space allowing improved interpolation and predictive ability. It is concluded that Box-Behnken and central composite experimental designs are inappropriate for ANN modeling of highly curved responses and that extensive internal mapping of the design space is essential to generate predictive ANN models.     

The effect of powder type, free moisture and deformation behaviour of granules on the kinetics of fluid-bed granulation.

The effects of two types of powder, lactose and corn starch, and of free moisture on the kinetics of fluid-bed granulation have been investigated using population balance modelling. A coalescence kernel that considered the deformation behaviour of the granules was used. The best fit of the experimental data was obtained for both materials by assuming that the granules underwent plastic deformation. The predicted cumulative number fractions were in very good agreement with the experimental data. The effect of free moisture (in the range of 5-10%) was investigated with lactose. The process was independent of the statistical distribution in free moisture within the approximate range 5-10%. The results suggest a local plasticity in fluid-bed spray granulation caused by the deposition of spray droplets onto the granules, with their subsequent absorption into the voids leading to regions of saturated voids.     

The effect of flow rate on drug delivery from the Pulvinal, a high-resistance dry powder inhaler.

Dry powder inhalers vary widely in their resistance to flow. When the resistance is high, airway resistance can be neglected and inspiration rates will be determined primarily by the device. Provided that the patient can generate adequate flow rates to aerosolize the dose, variability of emitted dose and fine particle dose should be reduced. For in vitro simulation, these concepts are explored using a Pulvinal device. In conditions likely to be encountered in patient use, the emitted dose showed little dependence (80-102 micrograms) as the flow rate increased from 28 to 63 L/min. The fine particle dose was more sensitive, increasing by a factor of 1.6 from 22 to 35 micrograms. These variations are less than those observed with the Turbohaler, a device of intermediate resistance and very much lower than those observed with the Rotahaler, a low-resistance device.