Plasma enhanced chemical vapor depositions to encapsulate crystals in thin polymeric films: a new approach to controlling drug release rates

An RF plasma discharge was employed to deposit thin polymeric films on drug particles. This study utilized acetylsalicylic acid (aspirin) crystals and allyl alcohol as polymerizable monomer for this new approach to controlling drug release rates. Release rates of coated and uncoated particles were measured in aqueous solution at a pH of 1.0. The drug release rates could be varied over wide ranges by appropriate control of the polymeric films. These controls included film composition, extent of polymer cross-linking and film thickness. A 360 degrees rotating plasma reactor was employed to provide effective agitation and mixing of the drug particles during the coating operation. The plasma discharge was operated in a pulsed mode to provide improved control of the polymer film compositions and, at the same time, minimize undesirable decomposition of drug molecules. Overall, the results obtained clearly indicate that the pulsed RF plasma coating process developed represents a viable, one-step, solventless route to controlled drug release.     

Modulating pH-independent release from coated pellets: Effect of coating composition on solubilization processes and drug release

The aim of the study was to clarify the influences of three coating parameters on the drug release from chlorpheniramine maleate (CPM) pellets, coated with blends of poly(vinyl acetate) (PVAc) and poly(vinyl alcohol)-poly(ethylene glycol) (PVA-PEG) graft copolymer. A central composite design was implemented to investigate the effect of the polymer blend ratio, the film coat thickness and the plasticizer concentration on the drug release. The solubilization inside the pellets was monitored by EPR spectroscopy. The blending ratio of both the polymers and the film thickness were found to have a major influence on the drug release and the solubilization speed, in contrast to the plasticizer concentration. A pH-independent release profile was adjustable via modulating the polymer blend ratio and the coating thickness. A mathematical model was developed, providing a good predictability of the release profile, based on the film coat composition. This model offers the possibility to achieve a defined drug-release profile by selective adaptation of the film coat composition, in view of process times, feasibility or polymer costs.     

Controlled release reservoir mini tablets approach for controlling the drug release of Galantamine Hydrobromide

The objective of this study is to explore and investigate the reservoir mini tablets approach to control the release of Galantamine Hydrobromide in comparison to desired release profile to the Innovator formulation Razadyne ER capsules as disclosed in US Patent 7,160,559 which is granted to Janseen Pharmaceutica NV. The core mini tablets were prepared using the direct compression and wet granulation methods. These core mini tablets were further coated with Galantamine Hydrobromide in two different portions; 70% as controlled release and 30% as immediate release and then filled in empty hard gelatin capsule shells. The dissolution profiles of each formulation were compared to those of Razadyne ER capsules and the mean dissolution time (MDT), dissolution efficiency (DE%) and dissolution similarity (f2 factor) were calculated. It was observed that core formulation plays an important role in controlling the drug release as well as maintaining pH independent drug release profile. The release mechanism of GAH from reservoir mini tablet formulation follows Higuchi and first order. These results imply that controlled release reservoir mini tablets which further filled into empty hard gelatin capsule shells can be a suitable method to formulate controlled release Galantamine hydrobromide.     

Controlled release reservoir mini tablets approach for controlling the drug release of Galantamine Hydrobromide

The objective of this study is to explore and investigate the reservoir mini tablets approach to control the release of Galantamine Hydrobromide in comparison to desired release profile to the Innovator formulation Razadyne^® ER capsules as disclosed in US Patent 7,160,559 which is granted to Janseen Pharmaceutica NV. The core mini tablets were prepared using the direct compression and wet granulation methods. These core mini tablets were further coated with Galantamine Hydrobromide in two different portions; 70% as controlled release and 30% as immediate release and then filled in empty hard gelatin capsule shells. The dissolution profiles of each formulation were compared to those of Razadyne^® ER capsules and the mean dissolution time (MDT), dissolution efficiency (DE%) and dissolution similarity (f2 factor) were calculated. It was observed that core formulation plays an important role in controlling the drug release as well as maintaining pH independent drug release profile. The release mechanism of GAH from reservoir mini tablet formulation follows Higuchi and first order. These results imply that controlled release reservoir mini tablets which further filled into empty hard gelatin capsule shells can be a suitable method to formulate controlled release Galantamine hydrobromide.     

High efficiency dry coating of non-subcoated pellets for sustained drug release formulations using amino methacrylate copolymers

Abstract

Dry coating utilizing a fluidized bed was evaluated in order to produce films with sustained drug release using amino methacrylate copolymers as film former. In contrast to other dry coating procedures using amino methacrylate copolymers, the described method enables an appropriate polymer adhesion by the selection of a plasticizer additive mixture in combination with the use of a three-way nozzle for simultaneous application. Well spreading fatty acid esters were found to increase the coating efficiency from 73% to approximately 86%, when they were used in conjunction with the plasticizer. Pellets were used as drug cores without previous treatment. After a curing step at 55?°C, the pellets exhibited a prolongation of the drug release over a period of about 6?h. Mainly the three parameters, coating level, composition of the polymers in the coating mixture, and the type of plasticizer, were found to exert distinct influence on the dissolution profile. Despite the differences in the coating procedure, the dissolution profiles of the coated pellets as well as the influencing parameters were similar to those known from conventional coating techniques.     

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.     

Modifying rates of reductive elimination of leaving groups from indolequinone prodrugs: a key factor in controlling hypoxia-selective drug release

3-(4-Methylcoumarin-7-yloxy)methylindole-4,7-diones were synthesised as model prodrugs in order to investigate the correlation between rates of reductive elimination from the (indolyl-3-yl)methyl position with reductive metabolism by hypoxic tumor cells and NADPH: cytochrome P450. Rates of elimination of the chromophore/fluorophore (7-hydroxy-4-methylcoumarin) following one-electron reduction of indolequinones to their semiquinone radicals (Q*-) was measured by pulse radiolysis utilising spectrophotometric and fluorometric detection. Incorporation of a thienyl or methyl substituent at the (indol-3-yl)CHR-position (where R=thienyl or methyl adjacent to the phenolic ether linking bond) significantly shortened the half-life of reductive elimination from 87 to 6 and 2 ms, respectively. Elimination from the methyl substituted analogue can thus compete effectively with the reaction of the semiquinone radical with oxygen at levels typically present in tumours (half-life approximately 1.8 ms at 0.5% O2). Chemical kinetic predictions were confirmed by metabolism in breast tumour MCF-7 cells between 0-2.1% O2. Rates of reductive release of the fluorophore from the non-fluorescent parent indolequinones (R=H, Me, thienyl) were similar under anoxia ( approximately 1.7 nmol coumarinmin(-1)mg protein(-1)) reflecting the similarity in one-electron reduction potential. Whereas coumarin release from the indolequinone (R=H) was completely inhibited above 0.5% O2, the enhanced rate of reductive elimination when R=thienyl or Me increased the metabolic rate of release to approximately 0.35 and 0.7 nmol coumarinmin(-1)mg protein(-1), respectively at 0.5% O2; complete inhibition occurring by 2.1% O2. Similar 'oxygen profiles' of release were observed with NADPH: cytochrome P450 reductase. In conclusion, it is possible to modify rates of reductive elimination from indolequinones to control the release of drugs over a range of tumour hypoxia.     

Testing of drug release from film pellets with special consideration of the thickness of the polymer coating

The influence of the thickness of polymer films on drug release was studied by means of an apparatus, developed especially for the examination of film-coated pellets. To show the direct dependence of the thickness of the polymer layer on the process of liberation a sequence of ten coating steps was chosen. On the contrary the release of active ingredients of varying dissolution behaviour was synchronous and didn't depend on the pH-value of the medium. The results show, that by using the proper coating material the thickness of the layer can be used to control the drug liberation process. The comparison of the release from different coating steps in the apparatus described makes it possible to produce mixtures of pellets with both a quick onset and a long duration of action by using only one type of coating material.     

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 drug release from Gelucire-based matrix pellets: experiment and theory

The aim of this work was to elucidate the underlying drug release mechanisms from lipidic matrix pellets, using theophylline and Gelucire 50/02 as model drug and carrier material, respectively. Pellets were prepared by two different techniques: melt-solidification and extrusion-spheronization. The effects of different formulations and processing parameters on the resulting drug release kinetics in 0.1N HCl and phosphate buffer pH 7.4 were studied and the obtained results analyzed using adequate mathematical models in order to get further insight into the underlying mass transport mechanisms. The type of preparation technique was found to strongly affect the underlying drug release mechanisms. Drug release from pellets prepared by the melt-solidification method was primarily controlled by pure diffusion, whereas drug release from pellets prepared by the extrusion-spheronization method was purely diffusion-controlled only at early time points. After approximately 2h, the pellets started to disintegrate, resulting in decreased diffusion pathway lengths and, thus, increased drug release rates. Furthermore, the curing conditions significantly affected the theophylline release kinetics, whereas varying the initial drug loading from 20 to 50% (w/w) resulted only in a slight increase in the relative drug release rate. Interestingly, the effects of the size of pellets prepared by the melt-solidification method on the resulting drug release kinetics could be quantitatively predicted using an analytical solution of Fick's second law of diffusion. These predictions could be verified by independent experiments.     

Water-mediated solid-state transformation of a polymorphic drug during aqueous-based drug-layer coating of pellets

During aqueous drug-layer coating, drug substance(s) are exposed to water and elevated temperatures which can lead to water-mediated process induced transformations (PITs). The effects of aqueous drug-layer coating of pellets (Cellets^®) on the anhydrous piroxicam, PRX, were investigated in the miniaturized coating equipment and with free films. Hydroxypropyl methylcellulose (HPMC) was used as a carrier coating polymer. Free films were prepared by using an in-house small-scale rotating plate system equipped with an atomization air nozzle. Raman spectroscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) were used to characterize the solid-state properties and surface morphology of the pellets and free films. The results showed that anhydrous PRX form I (AH) and monohydrate (MH) were stable during drug-layer coating, but amorphous PRX in solid dispersion (SD) crystallized as MH already after 10 min of coating. Furthermore, the increase in a dissolution rate was achieved from the drug-layer coated inert pellets compared to powder forms. In conclusion, water-mediated solid-state PITs of amorphous PRX is evident during aqueous-based drug-layer coating of pellets, and solid-state change can be verified using Raman spectroscopy.     

Aqueous ethyl cellulose dispersions containing plasticizers of different water solubility and hydroxypropyl methylcellulose as coating material for diffusion pellets. I. Drug release rates from coated pellets

The present work investigates release mechanisms of theophylline pellets coated with an aqueous ethyl cellulose (EC) dispersion containing plasticizers and hydroxypropyl methylcellulose (HPMC) as a water soluble pore former. Three different drug release mechanisms from coated pellets can be determined as a function of the water solubility of the plasticizers and the ionic strength of the release medium. Coated pellets with the addition of more hydrophilic plasticizers such as triethyl citrate (TEC) or diethyl phthalate (DEP) show an approximate zero-order-release rate. In contrast, two-phase release profiles can be observed from pellets coated with dispersions containing hardly soluble plasticizers such as dibutyl phthalate (DBP) or dibutyl sebacate (DBS). Only in a release medium of high ionic strength the water soluble pore former will remain in the coating. Thus the drug diffuses through a hydrated swollen membrane containing EC, HPMC and insoluble plasticizer. The release mechanisms depend on the glass transition temperature of the ethyl cellulose and therefore on the migration of the plasticizers and the pore former. This was shown by investigation of the migration of the additives and the influence of the temperature of the release medium on the release. Additionally, the study investigates the effect of curing and storage conditions of coated pellets on the drug release rate.     

Gastroretentive raft liquid delivery system as a new approach to release extension for carrier-mediated drug

Gabapentin (GBP), an antiepileptic and anti-neuropathic agent, suffers from short half-life (5–7?h), has narrow absorption window, and is absorbed via carrier-mediated mechanism resulting in frequent dosing, poor compliance, and poor bioavailability (<60%). Moreover, GBP is a freely water-soluble drug, thus it is considered a challenging candidate to be formulated as extended release dosage form. In this study, raft forming systems were investigated as a potential drug delivery system for prolonging gastric residence time of GBP. A 2³ full factorial design was adopted to study the effect of formulation variables (% gellan gum, % GMO, and % LM-pectin 101), on the percent of GBP released at different time intervals (1, 5, and 8?h) as well as the gel strength, and thus was achieved an optimized formula with zero-order release profile suitable for once-daily administration. In vivo assessment was performed in rats to evaluate gastric residence of the gel formed. In addition, the oral bioavailability of GBP relative to commercially available Neurontin^® immediate release oral solution was also investigated. Significant increase was observed for C_max, AUC_(0–t), and AUC_(0–∞). The increase in relative bioavailability of GBP from the optimized formula was 1.7 folds.     

Enteric coated insulin pellets: development, drug release and in vivo evaluation

Pellets with human insulin as a model drug were prepared by an extrusion and spheronization process to investigate the oral application of peptides. The described process proved suitable for preparing small batches of about 50 g in laboratory scale. The developed formulation was completed by the addition of aprotinin as protease inhibitor and sodium cholate as an intestinal absorption promoter to enhance oral bioavailability of insulin. In order to protect the peptide against the gastric juice the pellets were coated with shellac in a fluid-bed ball coater. Pharmaceutical properties of the produced batches were examined by analysis of contents and dissolution tests. Dissolution of insulin in simulated gastric juice of pH 1.2 was prevented by shellac. On the other hand, a rapid and complete release of the molecular-dispersed insulin from the pellets was found in simulated intestinal fluid (pH 7.5) with simultaneous efficiency of the protease inhibitor against added enzyme activity. Despite promising in vitro results no significant absorption of insulin was detected in vivo after oral application of the pellets to streptozotocin diabetic rats. High sensitivity to enzymatic degradation and low ability to cross the intestinal wall are discussed as limiting factors for the insufficient absorption of insulin in vivo.     

Controlled drug release from pellets containing water-insoluble drugs dissolved in a self-emulsifying system.

The aim of the study was to provide a controlled release system, which could be used for the oral administration of highly water-insoluble drugs. Pellets have been prepared by extrusion/spheronization containing two model drugs (methyl and propyl parabens) of low water solubility. One type of pellets contained the drugs mixed with lactose and microcrystalline cellulose (MCC) and the other types of pellets contained the model drugs dissolved in a self-emulsifying system (4.8%) consisting of equal parts of mono-diglycerides and polysorbate 80 and MCC. Pellets of all types in the same size fraction (1.4-2.0 mm) were coated to different levels of weight gain, with ethylcellulose, talc and glycerol. A sample of pellets containing methyl parabens in the self-emulsifying system was pre-coated with a film of hydroxypropylmethyl cellulose from an aqueous solution and then coated as above. Dissolution experiments established that the presence of the self-emulsifying system enhanced the drug release of both model drugs and that the film coating considerably reduced the drug release from pellets made with just water, lactose and MCC. The coating reduced the drug release from the pellets containing the self-emulsifying system to a lesser extent but in relation to the quantity of coat applied to the pellets. The application of a sub-coating of hydroxypropylmethyl cellulose was able to reduce the release rate of methyl parabens self-emulsifying system ethyl cellulose coated pellets. Thus, the formulation approach offers the possibility of formulating and controlling the in vitro release of water-insoluble drugs from solid oral dosage forms.     

The ATPases: a new family for a family-based drug design approach

The rapid discovery of new drugs is greatly facilitated when a family of related proteins is targeted with a similar approach in chemistry. Few protein families have so far been investigated using this kind of 'family-based' approach. Therefore, to increase the size of our Pharmacopeia and to cure human diseases more efficiently, new druggable protein families must be identified. It is shown in this review that ATPases are very good candidates for a family-based approach. The human proteome contains many ATPases, which are involved in several diseases. All the ATPases contain a nucleotide-binding site, and it is therefore possible to target all of them with a single strategy in chemistry; the design of competitive ATP inhibitors. Moreover, because a similar approach has been conducted with the protein kinases, the compound libraries and the knowledge developed in the kinase field can be directly applied to the ATPases.     

Alternate polyelectrolyte coating of chitosan beads for extending drug release

In the present study, we addressed the factors modifying ciprofloxacin release from multiple coated beads. Beads were prepared by simple ionic cross-linking with sodium tripolyphoshate and coated with alginate and/or chitosan to prepare single, double, or multilayered beads. The water uptake capacity depended on the nature of beads (coated or uncoated) and pH of test medium. The number of coatings given to the beads influenced ciprofloxacin release rate. The coating significantly decreased the drug release from the beads in comparison to uncoated beads (p < 0.001). When the beads were given three coatings, viz., alginate, chitosan, and again alginate, the drug release appeared to follow the pattern exhibited by colon-targeted drug delivery systems with time dependent release behavior. The increase in coating formed a barrier for easy ingress of dissolution medium into the bead matrix, reducing the diffusion of drug.     

Fluid bed coating: the utility of dual programmable pumps for controlled gradient drug deposition on pellets

The objective of this study was to demonstrate the potential use of dual programmable pumps in a fluid bed coating process to manufacture pellets coated with gradient layers of a drug. To achieve this goal, two matrix forming dispersions with an equivalent amount of solids, one containing verapamil HCl as a model drug, and the other without the drug, were forced in a gradient pattern into a fluid bed coater using two pumps joined at Y junction. The two pumps were operated at opposing flow rates via a computer guided program to maximize drug concentration in the inner layers around the core. The difference between gradient and non-gradient drug coating was demonstrated by dissolution studied. Depending on the drug to polymer ratio, verapamil HCl release from gradient layered pellets was delayed over an extended period of time and was significantly different from the non-gradient coated pellets.     

Influence of an enteric polymer on drug release rates of theophylline from pellets coated with Eudragit RS 30D

The purpose of this research study was to investigate the influence of an enteric polymer on the drug release properties of theophylline pellets coated with Eudragit RS 30D. Theophylline pellets were coated with aqueous colloidal dispersions of Eudragit RS 30D containing various amounts of Eudragit L 100-55. The effect of storage conditions on the release of drug from coated pellets was determined as a function of the pH of the dissolution medium. The results from the dissolution study showed significant changes in the dissolution rate of theophylline from pellets coated with Eudragit RS 30D when cured at 40 degrees C for 4 days. No change in the drug release rate was observed when Eudragit L100-55 was present in the Eudragit RS 30D dispersion. Increasing the ratio of Eudragit L100-55 to Eudragit RS 30D resulted in faster drug release rates from the coated pellets. An increase in the pH of the dissolution medium was found to enhance drug release from the pellets coated with Eudragit RS 30D containing Eudragit L 100-55. Theophylline pellets when coated with Eudragit RS 30D containing the enteric polymer Eudragit L100-55 demonstrated no aging effects when stored at elevated temperatures. The overcoating of the pellets with Eudragit RD 100 did not affect the drug release profiles and prevented the particles from agglomerating during curing and storage.     

Slow release of drug through deformed coating film: effects of morphology and drug diffusivity in the coating film.

The effects of the morphology and drug diffusivity in the coating film on the slow release characteristics have been analyzed numerically under the constraint that the volume of the coating film and the drug matrix is maintained constant. Two different systems of coated particles with deformed coating films were studied and their release characteristics compared with those of the coated particles having spherical coating films. The average release rate, fractional release, drug concentration profiles, and the initial burst of drug were found to be strongly influenced by the ratio of drug diffusivity in the coating film to that in the drug matrix D(r) (i.e., dimensionless drug diffusivity in the coating film). Increasing D(r) always increased the release rate, the fractional release, and the initial burst of drug, but reduced the initial lag times of drug release. The effect of shape deformation was very significant in the drug concentration profiles and the initial lag times; in contrast, it was not so substantial on the fractional release and the average release rates. The morphology difference in the deformed systems was also found to affect the release characteristics to different extents. Increasing the degree of the shape deformation, represented by the perturbation parameter epsilon, always reduced the effective surface area for the controlled release of drug. Because of the compensation effects between decreasing surface area and the non-uniform mass flux distribution, even though the heterogeneity of surface mass flux distribution would become more considerable, the effects of increasing shape deformation to the overall release rate would be less than expected unless the coating film was deformed significantly enough. The effect of the shape deformation and the morphology difference become less effective to differentiate the release characteristics with increasing D(r).