Effect of curing conditions and plasticizer level on the release of highly lipophilic drug from coated multiparticulate drug delivery system

The study aimed to investigate the effect of triethyl citrate (TEC) plasticizer level (10, 15, and 20%), curing temperature (40, 50, and 60 degrees C) and time (0 to 168 h) on the release of a highly lipophilic drug bumetanide from pellets coated with methacrylate ester copolymer (Eudragit RS). Bumetanide was layered onto sugar pellets followed by coating with 6% Eudragit RS with and without hydroxypropyl methyl cellulose (HPMC) seal coat using Wurster Fluid Bed equipment. Coated pellets were stored for 3 months at room temperature and the release was tested in USP purified water. At 10% TEC level, increasing curing time and temperature lead to slower drug release. At 15 and 20% TEC levels, curing initially decreased drug release followed by increase in the release at longer curing time and higher temperature. Drug release from coated pellets plasticized with 15% TEC and completely cured followed zero order kinetic models. At plasticizer level of 20%, bumetanide release from the completely cured pellets was better modeled using the Higuchi's equation reflecting possible drug migration during curing. Storage led to an increase in drug release. The use of HPMC seal coat stabilized drug release after storage. It was concluded that bumetanide migration into Eudragit RS film coat was the main cause of the accelerated release after curing and storage. The drug migration during storage at room temperature was prevented by seal coating the pellets with HPMC.     

The influence of core materials and film coating on the drug release from coated pellets

The objective of this study was to analyse the influence of the composition of the core of the pellets on the in vitro drug release profile. The different materials (drugs and fillers) were chosen according to their relative solubility. Pellets were prepared by a standardised process of extrusion/spheronisation. A selected fraction size (1-1.4 mm diameter) of pellets of each preparation was coated with Surelease (an aqueous dispersion of ethyl cellulose) to give 5% weight gain. The dissolution studies were performed and data analysed in terms of the Area under the Curve (AUC) of the % dissolved as function of time and Mean Dissolution Time (MDT). ANOVA was applied in order to identify the influence factors and the relationship of cross effects. Canonical analysis and multiple regression were employed to quantify these relationships. The film coat was found to be the major factor controlling the drug release. The results however, show that both drug and filler solubility influenced the drug release profile. Some of the unusual results could only be explained if consideration was given to the physical characteristics of both powder and pellets. In particular, the specific surface area of calcium phosphate compared with other fillers played an important role on the release profile of the model drug.     

Preparation and in vitro evaluation of a novel combined multiparticulate delayed-onset sustained-release formulation of diltiazem hydrochloride

A combined delivery system, containing two kinds of diltiazem hydrochloride multi-layer coated pellets with different release characteristics, was developed to meet chronotherapeutic requirements. The dissolution studies in vitro indicated that the combined system could constantly release drug at a predetermined time in synchrony with the biologic rhythm of disease activity. These two kinds of pellets were mixed at the ratio 1:1. Pellet 2 could provide drug during the later phase of drug release from pellet 1, because the amount released was insufficient in the later phase (about 14-24 h after administration) for pellet 1. Addition of Tween 20 in the HPMC swelling layer was able to modify the hydration rate of HPMC layer which controlled the delayed time of the release system. It was found that the drug release kinetics followed Hixson-Crowell equation and this indicated that the main drug-transport mechanism inside the pellets was an erosion mechanism. The drug release rate was independent of the hydrodynamic conditions and pH of the external environment, and showed a decrease with increasing of osmotic pressure of the dissolution medium. These release characteristics indicated that the drug release from this system was driven by osmotic-pressure gradient.     

The influence of pellet shape and surface properties on the drug release from uncoated and coated pellets

The crystallisation of amorphous salbutamol sulphate prepared by spray drying was monitored using a humidity controlled microbalance (Dynamic Vapour Sorption apparatus, Surface Measurement Systems) combined with a near-infrared probe. Amorphous salbutamol sulphate was prepared by spray drying from a solution in water. The particles were then analysed using scanning electron microscopy, thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, isothermal microcalorimetry and water vapour sorption analysis combined with near-infrared spectroscopy (NIR). Isothermal microcalorimetry and water vapour sorption combined with NIR spectroscopy were able to detect the transition from the amorphous to crystalline state. However while the isothermal microcalorimeter showed only a classic crystallisation exotherm when the material was exposed at 75% RH, the DVS-NIR results at the same humidity highlighted a more complex process. When exposed at 75% RH, the uptake of water was followed by crystallisation that was detected using NIR. The expulsion of water after crystallisation was very slow and at a constant rate whether the material was exposed to 75 or 0% RH. The NIR and DVS studies indicated that the material had crystallised very soon after exposure to high RH. The water that was expelled during crystallisation was not displaced from the particles and remained associated with the particles for many days. This study showed that the use of gravimetric analysis together with NIR spectroscopy provided valuable information on the dynamics of the crystallisation of salbutamol sulphate. The retention of water within recently crystallised salbutamol is potentially important to the behaviour of dosage forms containing the amorphous (or partially amorphous) form of this drug.     

Influence of film additives on stabilizing drug release rates from pellets coated with acrylic polymers.

The objective of this study was to investigate the influence of talc and triethyl citrate (TEC) on stabilizing the drug release rates following curing and storage at elevated temperature of pellets coated with an aqueous acrylic polymeric dispersion. Core pellets containing anhydrous theophylline (20%), microcrystalline cellulose, and polyvinylpyrrolidone were prepared by extrusion-spheronization. The aqueous dispersions were prepared by adding up to 30% TEC as a plasticizer and talc up to 200% as an antiadherent to a mixture of Eudragit RS 30D/RL 30D (95:5). The theophylline pellets were coated in a fluidized-bed coating unit and then cured at elevated temperatures. Theophylline pellets were successfully coated with the Eudragit dispersions that contained up to 200% talc, based on the dry polymer weight, and the coating efficiency was greater than 93%. Our results demonstrated that the polymer, which was plasticized by TEC, was able to function as a film-forming agent for dispersions containing high levels of talc. No sticking of the coated pellets was observed during the coating process or during the curing or equilibrating phase, even with high levels of TEC in the film. The dissolution rate of theophylline from the coated pellets was delayed when the film coating dispersion contained high levels of talc. Additionally, the stability of the drug release profiles from the coated pellets after storage was significantly improved. Furthermore, a modified dissolution testing used to simulate mechanical stresses that may be encountered in vivo showed the film coated pellets would have sufficient strength. The results of this study demonstrated that high levels of film additives in the acrylic dispersion contributed to the stabilization of the drug release rates as well as the reproducibility of the coating process.     

Controlled release multiparticulate beads coated with starch acetate: material characterization, and identification of critical formulation and process variables

The objectives of the present investigation were to prepare and characterize starch acetate (SA) with high degree of substitution (dS) and to study its prospect as film-forming agent in a controlled-release multiparticulate drug delivery system. As a part of the development process by quality by design, the objectives also included identification of critical formulation and process variables that affect the release of a drug. SA, a relatively new polymer, was characterized because it showed good film-forming properties. SA with dS 2.9 was synthesized from corn starch by paste disruption technique. It was compared with the raw material, starch, by Fourier transform infrared spectroscopy, X-ray diffraction, and molecular mass analysis. Viscosity of SA solution increased logarithmically with the polymer concentration. At higher polymer concentrations (1.5-5.0%), the solutions showed pseudoplastic behavior. Among the plasticizers tested, triacetin and triethyl citrate yielded free films with acceptable mechanical properties. The glass transition temperature (Tg) of the films could be well controlled by these plasticizers. Unplasticized film showed a Tg of 31.8 degrees C. A trend was found that increase in triacetin concentration in SA films resulted in increase in permeability coefficient for tritiated water. Scanning electron microscopic photographs showed a clear and smooth plasticized film compared to rough unplasticized film. Dyphylline-loaded beads were coated with highly substituted SA to evaluate the main effects of the formulation and process variables on the release of the drug and to figure out the reliability of the screening design. A seven-factor, twelve-run Plackett-Burman screening design was used. The response variables were cumulative percent of drug released in 0.5, 1, 4, 8, and 12 hr. Quantitative evaluation of the design revealed that coating weight gain, plasticizer concentration, and post-drying temperature had greater influence on the drug release than the others. The main effects on drug release after 12 hr decreased in the following order: coating weight gain (-7.81), plasticizer concentration (4.96), postdrying temperature (-2.51), SA concentration (-0.80), inlet temperature (0.51), postdrying time (-0.31), and atomizing pressure (-0.28).     

pH-independent drug release of an extremely poorly soluble weakly acidic drug from multiparticulate extended release formulations.

Extended release mini matrix tablets for 8-Prenylnaringenin (8-PN), an extremely poorly soluble weakly acidic drug, were developed by using polyvinylacetate/polyvinylpyrrolidone as matrix former. Mini matrix tablets were manufactured by direct compression or wet granulation technique. With conventional modified release formulations, the drug demonstrated pH-dependent release due to pH-dependent solubility of the drug substance (i.e., increasing solubility at higher pH-values). In order to achieve pH-independent drug release two classes of pH-modifying agents (water-soluble vs. water-insoluble) were studied with respect to their effect on the dissolution of 8-PN. Addition of water-soluble salts of weak acids (sodium carbonate and sodium citrate) failed in order to achieve pH-independent 8-PN release. In contrast, addition of water insoluble salts of a strong base (magnesium hydroxide and magnesium oxide) was found to maintain high pH-values within the mini matrix tablets during release of 8-PN at pH 1 over a period of 10 h. The micro-environmental conditions for the dissolution of the weakly acidic drug were kept almost constant, thus resulting in pH-independent drug release. Compound release from mini matrix tablets prepared by wet granulation was faster compared to the drug release from tablets prepared by direct compression.     

Development and validation of a non-linear IVIVC model for a diltiazem extended release formulation

To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a diltiazem multi-particulate bead extended release formulation. In vitro dissolution of diltiazem capsules was examined using the following methods: USP Apparatus II (paddle) at 100 rpm and USP Apparatus III at 30 dpm. Seven healthy subjects received three diltiazem formulations (90 mg): slow (S), moderate (M), fast (F) releasing and an oral solution (90 mg). Serial blood samples were collected over 48 h and analyzed by a validated HPLC assay using ultraviolet detection. The f(2) metric (similarity factor) was used to analyze the dissolution data. Linear and non-linear (quadratic, cubic, and sigmoid functions) correlation models were developed using pooled fraction dissolved (FRD) and fraction absorbed (FRA) data from various combinations of the formulations. Predicted diltiazem concentrations were obtained by convolution of the in vivo dissolution rates. Prediction errors were estimated for C(max) and AUC to determine the validity of the correlation. Apparatus II using purified water was found to be the most discriminating dissolution method. Significant intersubject (CV%>50) was observed for C(max) and AUC. The quadratic M/F IVIVC model provided a significant relationship between FRD and FRA when using either two or three of the formulations. An average percent prediction error for C(max) and AUC for all formulations was 12.4% and 9.2%, respectively. The prediction errors observed for C(max) and AUC suggest that the predictability of the quadratic IVIVC model is inconclusive, as such, external validation studies are required.     

Absorption of doxycycline from a controlled release pellet formulation: The influence of food on bioavailability

A three-way crossover study was performed to compare the bioavailability of a new pelletised doxycycline product administered either with food or without food and a reference product taken without food. Four different methods were used to calculate pharmacokinetic parameters from the data. The sums of squares, Akaike's Information Criterion (AIC), and the ranges for the parameters obtained were used for comparison. Good fits to the data were obtained when all four methods were used, each with a lag time. The two compartment open model was the most efficient method for describing the data. The one compartment open model was the least efficient, particularly with respect to predicting the peak concentration of doxycycline in plasma. All the models gave similar rank order results with respect to bioavailability differences between the three treatments. Analysis of the data by different methods suggests that pelletised doxycycline is bioequivalent to the reference product when taken in the absence of food. A standardized feeding regimen affected the rate, but not extent of absorption of doxycycline from the pelletised formulation.     

The influence of cationic lipid type on in-vitro release kinetic profiles of antisense oligonucleotide from cationic nanoemulsions.

Novel formulations of cationic nanoemulsions based on three different lipids were developed to strengthen the attraction of the polyanionic oligonucleotide (ODN) macromolecules to the cationic moieties on the oil nanodroplets. These formulations were developed to prolong the release of the ODN from the nanoemulsion under appropriate physiological dilutions as encountered in the eye following topical application. Increasing the concentration of the new cationic lipid exhibiting two cationic amine groups (AOA) in the emulsion from 0.05% to 0.4% did not alter markedly the particle size or zeta potential value of the blank cationic nanoemulsion. The extent of ODN association did not vary significantly when the initial concentration of ODN remained constant at 10muM irrespective of the cationic lipid nature. However, the zeta potential value dropped consistently with the low concentrations of 0.05% and 0.1% of AOA in the emulsions suggesting that an electrostatic attraction occurred between the cationic lipids and the polyanionic ODN molecules at the o/w interface. Only the nanoemulsion prepared with N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium salts (DOTAP) remained physically stable over time. DOTAP cationic lipid nanoemulsion was the most efficient formulation capable of retaining the ODN despite the high dilution of 1:100 with simulated tear solution (STS). Less than 10% of the ODN was exchanged in contrast to 40-50% with the other cationic nanoemulsions. The in-vitro release kinetic behavior of ODN exchange with physiological anions present in the STS appears to be complex and difficult to characterize using mathematical fitting model equations. Further pharmacokinetic studies are needed to verify our kinetic assumptions and confirm the in-vitro ODN release profile from DOTAP cationic nanoemulsions.     

The influence of excipients on drug release from hydroxypropyl methylcellulose matrices

The influence of commonly used excipients, spray-dried lactose (SDL), microcrystalline cellulose (MCC), and partially pregelatinized maize starch (Starch 1500) on drug release from hydroxypropyl methylcellulose (HPMC, hypromellose) matrix system has been investigated. A model formulation contained 30%w/w drug, 20%w/w HPMC, 0.5%w/w fumed silica, 0.25%w/w magnesium stearate, and 49.25%w/w filler. Chlorpheniramine maleate and theophylline were used as freely (1 in 4) and slightly (1 in 120) water-soluble drugs, respectively. It was found that for both drugs, addition of 20 to 49.25%w/w Starch 1500 resulted in a significant reduction in drug release rates compared to when MCC or SDL was used. The study showed that using lactose or microcrystalline cellulose in the formulations resulted in faster drug release profiles. Partially pregelatinized maize starch contributed to retardation of both soluble and slightly soluble drugs. This effect may be imparted through synergistic interactions between Starch 1500 and HPMC and the filler actively forming an integral part within the HPMC gel structure.     

Compression of coated drug beads for sustained release tablet of glipizide: formulation,and dissolution

Abstract

A promising glipizide formulation comprising compression of four-layer coated beads into tablets was prepared. The tablet offered the advantages of: a two-hour lag time before drug release, retaining sustained release characteristics and providing approximately zero-order drug release. Drug release was nearly independent of paddle speeds of 50 and 100?rpm releasing 80% over 14?h similar to the commercial glipizide osmotic pump tablet during dissolution testing while keeping the benefits of multiparticular dosage forms. The tablets contain beads with four layers: (1) the innermost layer consists of 2.5?g glipizide and 3.75?g solid ethylcellulose (Surelease®) coated onto 71.25?g of sugar beads; (2) next a hardening layer of 5?g of hypromellose; (3) the controlled release layer of 7.5?g of Surelease®:lactose at a solids ratio of 100:7 and (4) an outermost layer of 20?g of lactose:sodium starch glycolate (Explotab®) at a 2:1 ratio. Then, beads were compressed into tablets containing 11?mg of glipizide using 1500?lbs of compression pressure. The dissolution test similarity factor (f₂) was above 50 for all test conditions for formulation F13 and Glucotrol® with a high of 69.9. The two Surelease® layers both aid controlling drug release, with the Surelease®-drug layer affecting drug release to a greater extent.     

Kinetic analysis of drug release from hydrogels containing amphoteric surfactants

A one compartment open model was used in order to describe chloramphenicol release from hydrogels containing amphoteric surfactants as gelling agents. Such interpretation seems to be more profitable than that based on Higuchi's root square equation. Using the proposed model it is possible to consider that drug release takes place from the water phase near the surface of membrane, rather than from the micellar phase in which drug seems to be immobilized.     

盐酸地尔硫卓延迟缓释微丸的制备及处方优化

目的制备盐酸地尔硫卓延迟缓释微丸并对其处方进行优化。方法采用挤出滚圆法制备含药丸芯。采用流化床双层包衣技术以乙基纤维素为内层包衣材料,乙基纤维素与丙烯酸树脂的混合膜材为外层包衣材料制备延迟缓释微丸。以释放度为考察指标对其进行单因素考察,采用星点设计-效应面法优化处方,并对模型处方进行验证。结果单因素考察结果表明内层包衣增重、外层包衣增重以及外层包衣材料配比对释放度影响显著。通过所建立优化模型的效应面图可知,内层包衣增重X1=4.5%⁷.0%,外层包衣增重X2=7.0%7.0%,外层包衣增重X2=7.0%¹8.5%时所得的模型处方具有理想的释放时滞和释药速率。处方验证结果的f2相似因子为69.24>50,表明3批自制微丸的释药曲线与理论释药曲线具有良好的相似性。结论制备了具有理想释药时滞和释药速率的盐酸地尔硫卓延迟缓释微丸,所建数学模型具有良好的预测效果。     

The influence of chitosan and sodium alginate and formulation variables on the formation and drug release from pellets prepared by extrusion/spheronisation

The influence of the incorporation of two oppositely charged hydrophilic natural polymers, chitosan and sodium alginate, alone and in combination, on the ability of formulations containing a model drug (paracetamol) to form spherical pellets by the process of extrusion/spheronisation and the properties of the pellets, has been undertaken. A statistically experimental design was employed to allow the major factors which determined the properties of the pellets, to be identified. A standardised procedure was used to prepare the pellets with a ram producing the extrudate for spheronisation. Statistical analysis of the results indicated that the formulation variables of the type and level of the polymer, the proportion of the model drug, and the proportion of the microcrystalline cellulose influenced (a) the quantity of liquid binder required to produce a good formulation (narrow size range and high value for the shape factor indicating sphericity), (b) the steady-state extrusion force, (c) the pellet perimeter, (d) the apparent pellet density and (e) the porosity of the pellets. The median size of the pellets of the "good formulation" could only be related to the chitosan and sodium alginate content of the formulations. The proportion of the drug, chitosan and sodium alginate content of the formulation significantly influenced the in vitro dissolution of the model drug (paracetamol). The drug release mechanism differed with the formulation variables, although if the pellets remained intact during the dissolution test, diffusion was the controlling mechanism. There was no significant advantage to be gained by using a mixture of the two polymers in terms of retarding drug release.     

The influence of additives on the in vitro release of drugs from hard gelatin capsules

A factorially designed experiment has been used to assess the total percentage of drug released from hard gelatin capsules in vitro as a function of (a) the drug—the drugs being nitrofurantoin, nitrofurazone, oxytetracycline dihydrate and tetracycline hydrochloride; (b) the diluent—the diluents being lactose, Primojel and Dry-Flow starch; (c) the quantity of diluent, either 20 or 80%; (d) the presence (at a 1 % level) and absence of magnesium stearate and (e) the presence (at a 1 % level) and absence of sodium lauryl sulphate. Treatment of the results by analysis of variance, in 5,4, 3 and 2 factor combinations, indicates that the influence of a given factor is often dependent on the other factors. These interdependencies take the form of either a variation in the extent of an effect or the reversal of an effect. The influence of drug and level of diluent show interdependencies of the former kind. Hence, whilst the overall average for drug release indicates that the drugs can be ranked in the ascending order: nitrofurantoin < nitrofurazone < oxytetracycline < tetracycline, the interactions predict that the quantitative ratios of 1:1·8:2·7:5·1 for the drugs above will vary when an additive is present and according to the additive. The rank order will, however, remain unchanged. Similarly, the higher level of diluent will usually increase drug release but not by a constant ratio between drugs. A reversal of an effect is shown by the addition of magnesium stearate, which in some instances increases rather than decreases drug release (its more usual effect). The addition of 1 % sodium lauryl sulphate does not provide a major enhancement of drug release, and in certain cases can be detrimental. There is no consistent order of effectiveness of the three diluents, and thus a universal capsule diluent, which will always improve drug release, does not appear to be a possibility.     

The influence of drug type on the release profiles from Surelease-coated pellets

The release of metoclopramide hydrochloride (a water-soluble cationic drug) and diclofenac sodium (a sparingly soluble anionic drug) from pellets coated with ethylcellulose from an aqueous ethylcellulose dispersion (Surelease) at different coating loads was investigated. The release rates of each drug decreased as the coating load of Surelease increased. However, despite its lower water solubility, diclofenac sodium was released slightly faster than metoclopramide hydrochloride at equivalent coating loads. Changes in the release rates after curing were more pronounced for metoclopramide hydrochloride and the release rates of diclofenac sodium were lower than those of metoclopramide hydrochloride after curing. Differences between the release behaviour of the two drugs were probably due to an interaction between the cationic metoclopramide and the anionic ammonium oleate present in the Surelease. The slower release of metoclopramide hydrochloride may be due to an in situ formation of a poorly soluble complex of the drug and the ammonium oleate. This complex, because of its large molecular size, may diffuse more slowly through the film, causing a reduction in the release rate of metoclopramide hydrochloride. This interaction may also account for the differences in release characteristics of the drugs after curing. During curing the surfactant, due to its unstable nature in heat, may be converted to its constituent components. The interaction of drug with the surfactant was reduced as the residue of the ammonium oleate decreased during curing. However, a relatively low volume flow rate of air, and therefore, slower removal of ammonia in the modified side-vented Manesty Accela-cota 10 may also have affected the coating process of the pellets.