Selective coating of cylindrical matrices with a central hole. II. An interpretation of the release process

A swellable perforated matrix was prepared and coated on one or more of its surfaces. Two drugs having different water solubility were chosen to load the matrix. To clarify the effect of the matrix swelling on the release process, the release rate was analysed according to the swelling area i.e., the surface area from which the drugs could be released. According to the experimental release data, the drug solubility usually predominated at the beginning and the matrix swelling at the end of the release process. When the interior hole was the only uncoated surface, pseudo-zero order kinetics were obtained when the drug solubility allows the control of the drug release by the matrix swelling.     

Perforated coated tablets for controlled release of drugs at a constant rate

Tablets with a central hole and a water-impermeable coating were prepared. These perforated coated tablets (PCTs) dissolve and release drug through the central hole only. In vitro release of the model drugs sodium benzoate and benzamide from PCTs occurred at a constant rate up to 80% release. The zero-order release rate varies with hole size, drug solubility, drug concentration, diluent solubility, and binder concentration. These results demonstrate that the PCT design can be used to prepare drug delivery devices which release at controllable constant rates.     

Controlled release from hydrogel-based solid matrices. A model accounting for water up-take, swelling and erosion

Design and realization of drug delivery systems based on polymer matrices could be greatly improved by modeling the phenomena which take place after the systems administration. Availability of a reliable mathematical model, able to predict the release kinetic from drug delivery systems, could actually replace the resource-consuming trial-and-error procedures usually followed in the manufacture of these latter. In this work, the complex problem of drug release from polymer (HPMC) based matrices systems was faced. The phenomena, previously observed and experimentally quantified, of water up-take, system swelling and erosion, and drug release were here described by transient mass balances with diffusion. The resulting set of differential equations was solved by using finite element methods. Two different systems were investigated: cylindrical matrices in which the transport phenomena were allowed only by lateral surfaces ("radial" case), and cylindrical matrices with the overall surface exposed to the solvent ("overall" case). A code able to describe quantitatively all the observed phenomena has been obtained.     

Release Characteristics of Implantable Cylindrical Polyethylene Matrices

The geometrical relationship between a hemisphere and a cylinder has been investigated for controlled-release systems. The relationship was tested by comparing dissolution results with results from mathematical calculation based on the principles of diffusion for matrix systems. A procedure has been developed for producing implantable, cylindrical, low-density polyethylene matrices, uncoated or coated with a thin impermeable film and a thick paraffin layer except for a hole on the flat faces of the cylinder. Drug matrices were prepared from a blend of sodium salicylate and polymer compressed in an appropriately designed stainless-steel mould at 150°C. Differential scanning calorimetry revealed that no decomposition product was formed in the matrix. When the surface area and the number of holes is increased, drug release also increases. When density is increased, however, drug release decreases significantly. Zero-order drug release was obtained from high-density covered one-hole and two-hole matrices. The diffusion coefficient was calculated as 0.067 day^?1. The study suggested that true zero-order drug release could be obtained by drug diffusion from a hole, rather than from geometric shapes in the matrix systems. In addition, for constant release the diffusion area has to increase by approximately 25 mm² every day, compared to the area of the previous day, because the diffusion distance increases logarithmically.     

Solute release from a porous polymeric matrix: inwardly tapered disk with a central releasing hole

Diffusional solute release from an inert porous polymeric matrix was evaluated using sodium salicylate released from fused, inwardly tapered, polyethylene disk matrices (1.27 cm in diameter) with a central releasing hole. Two types of matrix were made by compressing (175 MPa) a sodium salicylate-melt polyethylene mixture with two different sets of circular conical punches having angles of 20 degrees and 30 degrees, with an axis perpendicular to the cone. The matrix sodium salicylate loading was greater than its solubility limit in the release medium. The fused matrices were coated with wax and perforated in their center to create a surface available for solute release. Flat disks with a central cylindrical hole were also made to compare the release profiles. An approximate solution was developed for these inwardly tapered disks and tested against experimental results. The theoretical model and experimental results showed good agreement and indicated that this type of matrix geometry may be useful as a pharmaceutical dosage form to approximate zero-order release.     

Analysis of surface properties of cellulose ethers and drug release from their matrix tablets.

Detailed knowledge based on new developments, especially in analytical techniques, is needed for characterizing polymer excipients. Inverse gas chromatography (IGC) is a useful method for investigating polymer surfaces in terms of thermodynamic parameters. The aim of our work was to study the correlation between polymer surface properties determined with IGC and the mechanisms of release of water-soluble pentoxifylline and vancomycin hydrochloride from cellulose ether matrices. Tablets were made of hydroxypropyl (HPC), hydroxyethyl (HEC) or hydroxypropylmethyl (HPMC) cellulose and contained 25% of drug. Differences in dispersive component of the surface free energy for these polymers were relatively small and ranged from 26 to 33mN/m. However, polar properties, expressed as specific component of the enthalpy of adsorption and as acid-base properties show larger differences between the polymers and demonstrate their relative polarity in the order HEC>HPMC>HPC, which correlates well with water sorption on bulky polymers and with the swelling degree of polymer matrices. The release of pentoxifylline and vancomycin from HPC is governed mainly by Fickian diffusion, whereas from HEC the relaxation of polymer chains is important too. The analysis of the release profiles in the light of Peppas-Sahlin model lead to the conclusion that the surface properties of the cellulose ethers influence the interactions with water and the release mechanisms of the drug. It was found out, that data obtained by IGC enable rapid inference about the behaviour of polymers in water and the release of water-soluble drugs.     

Evaluation of the Properties of Ethylcellulose-Cellulose Triacetate Microcapsules Containing Theophylline Prepared by Different Microencapsulation Techniques

Abstract

Using cellulose triacetate as an added complementary coating material in preparing sustained-release ethylcellulose-cellulose triacetate microcapsules of theophylline, three microencapsulation techniques were investigated. Ethylcellulose-cellulose triacetate composite microcapsules, ethylcellulose-cellulose triacetate dual-walled microcapsules and ethylcellulose microcapsules containing cellulose triacetate matrices were prepared using the non-solvent addition phase separation method. The effects of cellulose triacetate on the release of theophylline from the different ethylcellulose-cellulose triacetate microcapsules were obtained from dissolution studies. The results showed that the release rates of ethylcellulose-cellulose triacetate microcapsules were slower than those obtained from the ethylcellulose microcapsules prepared with similar core to wall ratios. The ethylcellulose microcapsules containing cellulose triacetate matrices had longer release half-times and smaller surface areas than the other capsule preparation. The release patterns of theophylline from the different ethylcellulose-cellulose triacetate microcapsules fitted first-order kinetics. Scanning electron micrographs showed that the surfaces of various ethylcellulose-cellulose triacetate microcapsules were different from those of theophylline, cellulose triacetate matrices of cellulose triacetate microcapsules, and that the surface morphology of ethylcellulose-cellulose triacetate microcapsules was affected by the preparative method.     

制备工艺对骨架片释放的影响

以盐酸氢吗啡酮为模型药物，制备了6种不同类型的骨架片，研究了工艺参数对骨架片释放行为的影响。结果表明：(1)HPMC与十八醇或EC合用能明显减小压片压力对释放的影响；(2)对于HPMC亲水凝胶骨架片，用含1％HPMC K4M的50％乙醇湿法制粒的效果与粉末直接压片相当；对于HPMC—十八醇混合骨架片，湿法制粒的释药快于熔融制粒法；(3)HPMC—十八醇混合骨架片释放受片径或(和)片重改变的影响小于HPMC—CMC—Na—十八醇混合骨架片；(4)包薄膜衣、制粒大小及工艺放大对HPMC—十八醇混合骨架片的释放基本无影响。     

Dissolution processes and surface alteration. 4. Determination of the "effective" surface

A method is described for measuring the "effective" surface of a drug by means of dissolution parameters using the Paddle-model or a resorption-model respectively. The obtained values were compared with the specific surface which was determined by BET-technique. The "effective" surfaces obtained by means of the dissolution parameters are smaller than those determined BET-technique.     

Measurement of multiple drugs in urine,water, and on surfaces using fluorescence covalent microbead immunosorbent assay

There are a range of applications that require the measurement of multiple drugs such as urine analysis, drug determination in water, and screening for drug contamination on surfaces. Some of the procedures used such as enzyme-linked immunosorbent assay (ELISA) are simple but can only determine one drug at a time, and others such as GC-MS or LC-MS are complex, time-consuming, and expensive. In this study, fluorescence covalent microbead immunosorbent assay (FCMIA) was investigated as a simple method for the measurement of multiple drugs simultaneously in three matrices: diluted urine, water, and on surfaces. Five different drugs of abuse or their metabolites (methamphetamine, caffeine, benzoylecgonine (a metabolite of cocaine), tetrahydrocannabinol (THC), the active ingredient in marijuana, and oxycodone) were studied over the range 0–15?ng/ml. There was no measureable cross-reactivity among the drugs at the concentrations studied. Urine dilutions from 1/50 to 1/2.5 were studied and dilutions less than 1/20 had a significant effect on the methamphetamine assay but limited effects on the benzoylecgonine and oxycodone assays and almost no effect on the THC assay. For assays performed in 1/20 urine dilution, water, and diluted surface sampling buffer, least detectable doses (LDD) were 1?ng/ml or less for the drugs. Surfaces spiked with drugs were sampled with swabs wetted with surface sampling buffer and recoveries were linear over the range 0–100?ng/100?cm² surface loading for all drugs. FCMIA has potential to be used for the measurement of multiple drugs in the matrices studied.     

Measurement of multiple drugs in urine, water, and on surfaces using fluorescence covalent microbead immunosorbent assay

There are a range of applications that require the measurement of multiple drugs such as urine analysis, drug determination in water, and screening for drug contamination on surfaces. Some of the procedures used such as enzyme-linked immunosorbent assay (ELISA) are simple but can only determine one drug at a time, and others such as GC-MS or LC-MS are complex, time-consuming, and expensive. In this study, fluorescence covalent microbead immunosorbent assay (FCMIA) was investigated as a simple method for the measurement of multiple drugs simultaneously in three matrices: diluted urine, water, and on surfaces. Five different drugs of abuse or their metabolites (methamphetamine, caffeine, benzoylecgonine (a metabolite of cocaine), tetrahydrocannabinol (THC), the active ingredient in marijuana, and oxycodone) were studied over the range 0-15?ng/ml. There was no measureable cross-reactivity among the drugs at the concentrations studied. Urine dilutions from 1/50 to 1/2.5 were studied and dilutions less than 1/20 had a significant effect on the methamphetamine assay but limited effects on the benzoylecgonine and oxycodone assays and almost no effect on the THC assay. For assays performed in 1/20 urine dilution, water, and diluted surface sampling buffer, least detectable doses (LDD) were 1?ng/ml or less for the drugs. Surfaces spiked with drugs were sampled with swabs wetted with surface sampling buffer and recoveries were linear over the range 0-100?ng/100?cm(2) surface loading for all drugs. FCMIA has potential to be used for the measurement of multiple drugs in the matrices studied.     

Role of epithelium in agonist-induced contractile responses of guinea-pig trachealis: influence of the surface through which drug enters the tissue.

1. A method has been used in guinea-pig isolated tracheal rings to achieve selective drug entry from the adventitial or mucosal surface. A study has been made of the effects of epithelium removal on responses to spasmogens entering the tissue solely from the adventitial or the mucosal surface. 2. Cumulative concentration-response curves for KCl (1 to 100 mM), acetylcholine (0.1 microM to 10 mM) and histamine (1 microM to 1 mM) were constructed in intact and epithelium-denuded tracheal rings in circumstances where drug entry was unrestricted or restricted to the adventitial or mucosal surface. 3. Epithelium removal did not alter the responsiveness or sensitivity of tracheal rings to KCl either when drug entry was unrestricted or when drug entry was restricted to the adventitial or mucosal surface. 4. When acetylcholine entered from the mucosal or adventitial surfaces of intact tracheal rings its concentration-response curve was displaced to the right with respect to that obtained for unrestricted drug entry. A greater rightward shift was observed for mucosal drug entry than for adventitial drug entry. Epithelium removal potentiated acetylcholine entering from the mucosal surface to a greater extent (27.5 fold) than it potentiated acetylcholine entering from both surfaces (4 fold). Epithelium removal did not potentiate effects of acetylcholine entering from the adventitial surface alone. 5. In intact tracheal segments, concentration-response curves for histamine entering from the mucosal surface were displaced to the right compared with those for histamine entering in an unrestricted fashion or from the adventitial surface alone. This displacement was absent in epithelium-denuded preparations.(ABSTRACT TRUNCATED AT 250 WORDS)     

In Vitro and in Vivo Evaluation in Rabbits of a Controlled Release 5-fluorouracil Subconjunctival Implant Based on Poly(D,L-lactide-co-glycolide)

Purpose. To design a controlled release 5-fluorouracil (5-FU) implant to provide prolonged antifibroblast concentrations of 5-FU in the sub-conjunctival tissues but low concentrations of 5-FU in other ocular tissues. Methods. Implants (5 mg; 2.5 mm diameter × 1.2 mm thickness) of 5-FU or 9:1, 8:2, 7:3 5-FU to polymer mass ratios were made by compression. Poly(D,L-lactide-co-glycolide) polymers with 50:50 and 75:25 lactide to glycolide ratios were used. In vitro release characteristics of four types of implants were studied: 5-FU alone (CT), 5-FU/ polymer matrices (MT), coated 5-FU/polymer matrices with a central hole drilled through the matrix and coating (CM1), and with a central hole in the coating (CM2). MT and CM1 (9:1 drug/polymer) were selected for subconjunctival implantation in rabbits. ¹⁴C-5-FU levels in various ocular tissues and retrieved pellets were monitored. Results. First-order release was observed from CT, MT and CM1 implants. Zero-order release profiles were observed from CM2 implants. Drug release was retarded by formulating 5-FU in a matrix comprising poly(D,L-lactide-co-glycolide) which in turn could be modified by the lactide/glycolide ratio of the polymer, the drug to polymer ratio, coating, and hole dimensions. First-order release kinetics were observed for MT and CM1 implants in the in vivo study in rabbits. A correlation between in vitro and in vivo release was established which allowed in vivo release to be predicted from in vitro release data. For CM1, therapeutic tissue concentrations of 35.2 µg/g (conjunctiva) and 17.7µLg/g (sclera) were found at the implantation site up to 200 hours post-implantation. Tracer levels were undetectable in other ocular tissues. Conclusions. The CM1 implant maintained steady antifibroblast levels in target tissues and minimized levels in nontarget tissues.     

Modeling of adhesion in tablet compression--I. Atomic force microscopy and molecular simulation

Adhesion problems during tablet manufacturing have been observed to be dependent on many formulation and process factors including the run time on the tablet press. Consequently, problems due to sticking may only become apparent towards the end of the development process when a prolonged run on the tablet press is attempted for the first time. It would be beneficial to predict in a relative sense if a formulation or new chemical entity has the potential for adhesion problems early in the development process. It was hypothesized that favorable intermolecular interaction between the drug molecules and the punch face is the first step or criterion in the adhesion process. Therefore, the rank order of adhesion during tablet compression should follow the rank order of these energies of interaction. The adhesion phenomenon was investigated using molecular simulations and contact mode atomic force microscopy (AFM). Three model compounds were chosen from a family of "profen" compounds. Silicon nitride AFM tips were modified by coating a 20-nm iron layer on the surfaces by sputter coating. Profen flat surfaces were made by melting and recrystallization. The modified AFM probe and each profen surface were immersed in the corresponding profen saturated water during force measurements using AFM. The work of adhesion between iron and ibuprofen, ketoprofen, and flurbiprofen in vacuum were determined to be -184.1, -2469.3, -17.3 mJ. m(-2), respectively. The rank order of the work of adhesion between iron and profen compounds decreased in the order: ketoprofen > ibuprofen > flurbiprofen. The rank order of interaction between the drug molecules and the iron superlattice as predicted by molecular simulation using Cerius(2) is in agreement with the AFM measurements. It has been demonstrated that Atomic Force Microscopy is a powerful tool in studying the adhesion phenomena between organic drug compounds and metal surface. The study has provided insight into the adhesion problems occurring during tablet compression and a direction for continued study.     

Design and in vitro evaluation of adhesive matrix for transdermal delivery of propranolol

Propranolol hydrochloride, a water-soluble drug, was incorporated in three transdermal delivery systems using three polymers (hydroxypropylmethylcellulose, polyisobutylene and Ucecryl MC808). The influence of different factors (polymeric material, matrix thickness, drug content, thickness of the adhesive layer and presence of a dissolution enhancer) was investigated. Microscopic observations and DSC thermograms have permitted to demonstrate that propranolol was essentially dissolved in the HPMC matrix and dispersed in the two other matrix types. In vitro dissolution study was carried out according to European Pharmacopoeia. Release from HPMC matrices without adhesive coating was fast. Release from these matrices became more regular (reduction of the burst effect) and slow when they are coated with a 12 microm thick Ucecryl layer. Release from different PIB matrices was too slow to be suitable as TDDS for propranolol. The best release modulation was obtained from Ucecryl matrices. In all matrices types, propylene glycol accelerated propranolol release rate. The kinetic of drug release from most matrix types was more closely described by the square-root model (Higuchi).     

Inhibition of a solid phase reaction among excipients that accelerates drug release from a solid dispersion with aging

Hydrophobic drug substances can be formulated as a solid dispersion or solution using macromolecular matrices with high glass transition temperatures to attain satisfactory dissolution. However, very few marketed products have previously relied on solid dispersion technology due to physical and chemical instability problems, and processing difficulties. In the present study, a modified release product of a therapeutic drug for hypertension, Barnidipine hydrochloride, was developed. The drug product consisted of solid dispersion based on a matrix of carboxymethylethylcellulose (CMEC), which was produced using the spray-coating method. An enteric coat layer was sprayed on the surface of the solid dispersion to control drug release. Interestingly, the release rate accelerated as the drug product aged, while there were no indications of deceleration of the release rate which was due to crystallization of the drug substance. To prevent changes in the dissolution kinetics during storage periods, a variety of processing conditions were tried. It was found that not only use of non-aqueous solvents but also a reduction in coating temperatures consistently resulted in stable solid dispersions. The molecular bases of dissolution of the drug substance from those matrices were investigated. The molecular weight of CMEC was found to be a dominant factor that determined dissolution kinetics, which followed zero-order release, suggesting an involvement of an osmotic pumping mechanism. While dissolution was faster using a higher molecular weight CMEC, the molecular weight of CMEC in the drug product slowly increased with aging (solid phase reaction) depending on the processing conditions, causing the time-induced elevation of dissolution. While no crystalline components were found in the solid dispersion, the amorphous structure maintained a degree of non-equilibrium by nature. Plasticization by water in the coating solution relaxed the amorphous system and facilitated phase separation of the drug substance and CMEC upon production. The solid phase reaction advanced differentially in the solid dispersion depending on the degree of phase separation set initially. The use of non-aqueous solvents and/or a decrease in the coating temperatures inhibited the occurrence of phase separation upon production, thereby preventing the formation of CMEC-rich phases where the solid phase reaction occurred during storage.     

Improving Dissolution Performance and Drug Loading of Amorphous Dispersions Through a Hierarchical Particle Approach

Co-precipitation is an emerging manufacturing strategy for amorphous solid dispersions (ASDs). Herein, the interplay between processing conditions, surface composition, and release performance was evaluated using grazoprevir and hypromellose acetate succinate as the model drug and polymer, respectively. Co-precipitated amorphous dispersion (cPAD) particles were produced in the presence and absence of an additional polymer that was either dissolved or dispersed in the anti-solvent. This additional polymer in the anti-solvent was deposited on the surfaces of the cPAD particles during isolation and drying to create hierarchical particles, which we define here as a core ASD particle with an additional water soluble component that is coating the particle surfaces. The resultant hierarchical particles were characterized using X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, and X-ray photoelectron spectroscopy (XPS). Release performance was evaluated using a two-stage dissolution test. XPS analysis revealed a trend whereby cPAD particles with a lower surface drug concentration showed improved release relative to particles with a higher surface drug concentration, for nominally similar drug loadings. This surface drug concentration could be impacted by whether the secondary polymer was dissolved in the anti-solvent or dispersed in the anti-solvent prior to isolating final dried hierarchical cPAD powders. Grazoprevir exposure in dogs was higher when the hierarchical cPAD was dosed, with ∼1.8 fold increase in AUC compared to the binary cPAD. These observations highlight the important interplay between processing conditions and ASD performance in the context of cPAD particles and illustrate a hierarchical particle design as a successful approach to alter ASD surface chemistry to improve dissolution performance.     

药物树脂复合物的表面包衣法微囊化工艺

以马来酸氯苯那敏为模型药物,采用离子交换树脂(Amberlite IRP-69)为载体制备药物树脂复合物。再以丙烯酸树脂(Eudragit RS100)为包衣材料,通过离子交换的方式对氯苯那敏树脂复合物进行表面包衣,并对表面包衣工艺参数的影响进行单因素考察,以期制备具有良好缓释性能的氯苯那敏树脂复合物微囊。在本试验范围内,药物树脂复合物的载药量越高、Eudragit RS100浓度越高、反应介质(95%乙醇)用量越多以及反应温度越高,药物释放越慢。上述结果提示,表面包衣法制备药物树脂复合物缓释微囊的生产操作简单,工艺重现性好,可进一步作制剂加工。     

The effect of a PEG versus a chitosan coating on the interaction of drug colloidal carriers with the ocular mucosa.

The influence of the surface characteristics of colloidal drug carriers in their interaction with different biological surfaces is becoming increasingly evident. In order to investigate the importance of these characteristics in their interaction with the ocular mucosa, we developed three types of nanocapsules that differ in their surface properties: poly- epsilon -caprolactone (PECL) nanocapsules, chitosan (CS)-coated PECL nanocapsules and poly(ethylene glycol) (PEG)-coated PECL nanocapsules. Two different approaches were used to form these polymer coated nanocapsules: (i) the electrostatic anchorage of the coating onto the PECL nanocapsules-in the case of CS-and (ii) the use of the previously synthesized copolymer PECL-PEG for the formation of the nanocapsules. In both cases, the systems, prepared by the interfacial deposition technique, were loaded with a fluorescent dye (rhodamine) in order to quantify and visualize their interaction with the ocular surface ex vivo and in vivo. An important conclusion from the ex vivo studies is that the developed systems, and specially the CS-coated ones, enhanced the penetration of the encapsulated dye through the cornea. This effect was not simple due to the physical presence of the nanocapsules but to their ability to carry the encapsulated compound. The second conclusion from the confocal laser scanning microscopy (CLSM) studies is that the systems were able to enter the corneal epithelium by a transcellular pathway and that the penetration rate was dependent on the coating composition. The images suggest that the PEG coating accelerates the transport of the nanocapsules across the whole epithelium, whereas the CS coating favours the retention of the nanocapsules in the superficial layers of the epithelium. The specific behaviour of CS-coated systems was also corroborated in vivo. These results indicate that the surface composition of colloidal drug carriers affects their biodistribution in the eye. Therefore, this surface modification approach can be used as a targeting strategy in ocular drug delivery.     

Aerodynamic sizing of metered dose inhalers: an evaluation of the Andersen and Next Generation pharmaceutical impactors and their USP methods

The particle sizing performance of a Next Generation Pharmaceutical Impactor (NGI) was compared to that of an Andersen cascade impactor (ACI). A single lot of Vanceril MDIs containing beclomethasone dipropionate (BDP) was used throughout. MDIs were sampled into NGI and ACI in accordance with USP recommendations, at 30.0 and 28.3 L/min, respectively, following 1, 2, 6, and 30 actuations with or without a silicone cup or stage coating, to determine the apparent particle size distributions (PSD) of BDP. The mass balance and the statistical comparability of drug deposits were assured on a "per actuation basis" across all experiments, demonstrating "good cascade impactor practices." Interstage deposition or "wall losses" in NGI were found to be lower than those in ACI, although their determination was laborious in NGI. The PSD profiles for Vanceril from a single actuation were distinguishable between NGI and ACI, when uncoated collection surfaces were used, most specifically for drug mass <4-microm aerodynamic diameter (p < 0.05). Silicone coating of collection surfaces and an increased number of actuations were shown to result in PSD profile shifts for both NGI and ACI. Such effects were most pronounced for NGI, although coating the collection surfaces and/or increasing the number of actuations improved drug retention significantly on the upper stages of NGI, and thereby, minimized the effects of particle bounce of BDP from Vanceril MDIs. PSD profiles from a single actuation could be determined reliably in either of these impactors, provided that coated collection surfaces were employed; also, cumulative % mass undersize profiles were similar between instruments. However, small differences in PSD profiles still existed to support NGI's design claims for reduced "overlap" in its stage collection efficiency curves.