The effect of polymer properties on direct compression and drug release from water-insoluble controlled release matrix tablets

The objective of this study was to identify and evaluate key polymer properties affecting direct compression and drug release from water-insoluble matrices. Commonly used polymers, such as Kollidon^® SR, Eudragit^® RS and ethyl cellulose, were characterized, formulated into tablets and compared with regard to their properties in dry and wet state. A similar site percolation threshold of 65% v/v was found for all polymers in dry state. Key parameters influencing polymer compactibility were the surface properties and the glass transition temperature (T_g), affecting polymer elasticity and particle size-dependent binding. The important properties observed in dry state also governed matrix characteristics and therefore drug release in wet state. A low T_g (Kollidon^® SR < Eudragit^® RS) decreased the percolation threshold, particle size effect and tortuosity, but increased permeability and sensitivity to heat/humidity treatment. Hence, lower permeability and higher stability are benefits of a high-T_g polymer (ethyl cellulose). However, release retardation was observed in the same order as matrix integrity (Eudragit^® RS < ethyl cellulose < Kollidon^® SR), as the high permeability was counteracted by PVP in case of Kollidon^® SR. Therefore, the T_g and composition of a polymer need to be considered in polymer design and formulation of controlled-release matrix systems.     

Properties of Free Films Prepared from Aqueous Polymers by a Spraying Technique

A spray method for the preparation of free films from aqueous polymeric dispersions was investigated. Free films were prepared from aqueous dispersions of methacrylic acid-ethyl methacrylate copolymer (Eudragit^® L 30D), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), and ethyl cellulose (EC) by a spray method and a cast method, and their mechanical properties and reproducibility were investigated. Uniform films were obtained from the dispersions of Eudragit^® L 30D, HPMCAS, and EC by the spray method, but films could not be formed by spraying the CAP dispersion. The tensile strength, elongation, and elastic modulus of the sprayed Eudragit^® L 30D films were similar to the properties of the cast films, and good reproducibility was obtained from both methods. Marked within-run variation in the mechanical properties was observed for the cast HPMCAS and CAP films, which could be due to a settling of the solid particles during the drying step. The variation in the mechanical properties of the sprayed HPMCAS films was lower and the tensile strength significantly higher than that of the cast films. There were also significant differences in tensile strength and elongation of EC films between products of the two methods. The results indicated that the spray method used to prepare the free films from aqueous polymeric dispersions provided uniform films with consistent and reproducible properties.     

Fabrication and evaluation of Eudragit® polymeric films for transdermal delivery of piroxicam

The aims of this work were to develop and characterize the prolonged release piroxicam transdermal patch as a prototype to substitute oral formulations, to reduce side effects and improve patient compliance. The patches were composed of film formers (Eudragit^®) as a matrix backbone, with PVC as a backing membrane and PEG200 used as a plasticizer. Results from X-ray diffraction patterns and Fourier transform-infrared spectroscopy indicated that loading piroxicam into films changed the drug crystallinity from needle to an amorphous or dissolved form. Piroxicam films were prepared using Eudragit^® RL100 and Eudragit^® RS100 as film formers at various ratios from 1:0 to 1:3. Films prepared solely by Eudragit^® RL100 showed the toughest and softest film, while other formulations containing Eudragit^® RS100 were hard and brittle. Drug release kinetic data from the films fitted with the Higuchi model, and the piroxicam release mechanism was diffusion controlled. Among all formulation tested, Eudragit^® RL100 films showed the highest drug release rate and the highest drug permeation flux across human epidermal membrane. Increasing drug loading led to an increase in drug release rate. Eudragit^® can be used as a film former for the fabrication of piroxicam films.     

Starch-based coatings for colon-specific delivery. Part II: Physicochemical properties and in vitro drug release from high amylose maize starch films

This work reports an investigation into free-film properties of a high amylose maize starch-based film coating that has been used in the preparation of formulations for drug delivery to the colon (WO 2008/012573 A1) and relates these properties to in vitro drug release from pellets.Maize starch/ethylcellulose free films were prepared and characterised by scanning electron microscopy (SEM), light microscopy, modulated differential scanning calorimetry (mDSC), Fourier-transform infrared (FT-IR), X-ray and % swelling in aqueous fluids with pH conditions similar to the stomach and small intestine. 5-ASA release from film-coated pellets was tested in enzyme free simulated gastric fluid and phosphate buffer pH 7.2. Selected formulations were further assessed in simulated gastric and intestinal fluids containing pepsin and pancreatin, respectively.The free films prepared were smooth and homogeneous in their appearance. The two polymers are immiscible, and neither mDSC nor FT-IR could detect interactions between them. Films made from high amylose starches were found to have a considerably lower swelling ability than high amylopectin-based films, and they suppressed drug release in the enzyme free media successfully.5-ASA release from pellets coated with mixtures of high amylose starches (Hylon^® VII, Hylon^® V or LAPS) and Surelease^® in a ratio of 1 to 2 w/w was found to be minimal in simulated gastric and intestinal fluids. This suggests that these mixed films provide starch domains that are resistant to the enzymes present in the upper GI tract and thus can potentially be used in the preparation of colon-specific delivery devices. Starches with a minimum amylose content of 56% such as the starches used in this study (Hylon^® VII and Hylon^® V) are preferred, and although pure amylose can also be used this is not essential.     

Electrochemical standardization of sustained-release coating material, II (author's transl)]

Electrochemical Standardization of Sustained-Release Coating Material, II The permeability of sustained-release coating material (zein, shellac, Eudragit^R retard 1, Eudragit^R retard s) for nitroglycerine is determined using a mercury-membrane-electrode. The influence of film forming materials, their proportions, concentration of nitroglycerine, film thickness, temperature, ionic strength and pH of solutions on the permeability of free films was evaluated.     

Properties of theophylline tablets dry powder coated with Eudragit® E PO and Eudragit® L 100-55

The aim of the present study was to investigate the influence of Eudragit^® E PO on the drug release mechanism of Eudragit^® L 100-55 film coatings applied to theophylline tablets by a dry powder coating technique. The process was entirely liquid-free. Calculation of the Flory-Huggins interaction parameter based on solubility parameters suggested immiscibility of the two copolymers. MDSC thermograms were characterized by two glass transitions for the investigated Eudragit^® E PO/Eudragit^® L 100-55 ratios and confirmed incomplete miscibility of the copolymers at processing conditions. FT-IR analysis was employed to study binding interactions of the polymers. Due to the higher affinity of the plasticizer, triethyl citrate, for Eudragit^® E PO compared to Eudragit^® L 100-55, redistribution of the plasticizer was observed during the curing phase of the process. Plasticizer migration also affected the initial phase of drug release from powder-coated theophylline tablets that were stored for four weeks. Drug release from powder-coated tablets was dependent on the polymer blend ratio, coating thickness, and the pH of the dissolution medium. A broad range of pH dependent theophylline release profiles were obtained as a function of the polymer blend ratio. The particle size of the coating powder influenced the microstructure of the film coating.     

Eudragit? Microparticles for the Release of Budesonide: A Comparative Study

This study compares the behaviour of budesonide-containing microparticles made of Eudragit^®RS or Eudragit^®RS/Eudragit^®RL 70:30 (w/w) prepared either by solvent evaporation or spray-drying technique. The loading efficiency of budesonide within microparticles was about 72% for microparticles prepared by solvent evaporation and around 78% for spray-dried microparticles. Thermal analyses were assessed to collect information about the structural stability of budesonide within the polymeric microspheres. The in vitro release was performed using simulating gastric (fasted state simulated gastric fluid) and intestinal (fasted state simulated intestinal fluid) fluids as the receiving solutions. After 3 h the drug release from Eudragit^®RS/Eudragit^®RL microparticles was about 6-fold higher than that obtained in the case of monopolymer microparticles. Using fasted state simulated intestinal fluid the drug was released between 4 and 30% in both types of preparations. Eudragit^®RS microparticles showed a better protection of the drug from gastric acidity than those of Eudragit^®RS/Eudragit^®RL allowing us to propose Eudragit^®RS microparticles as a hypothetical system of colon specific controlled delivery.     

Effect of Various Polymers Concentrations on Physicochemical Properties of Floating Microspheres

Floating microspheres have emerged as a potential candidate for gastroretentive drug delivery system. For developing a desired intragastric floatation system employing these microspheres, it is necessary to select an appropriate balance between buoyancy and drug releasing rate. These properties mainly depend on the polymers used in the formulation of the microspheres. Hence it is necessory to study the effect of these polymer concentrations on the various physicochemical properties of the microspheres. Floating microspheres were prepared by emulsion solvent evaporation technique utilising different polymers such as ethyl cellulose, Eudragit^® RS and Eudragit^® RL by dissolving them in a mixture of dichloromethane and methanol. Release modifiers studied were hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose E50 LV and Eudragit^® EPO. Prepared microspheres were analysed for particle size, surface morphology, entrapment efficiency, buoyancy, differential scanning calorimetry and in-vitro drug release. Ethyl cellulose and Eudragit^® EPO resulted microspheres with high percentage yield, excellent spherical shape but had very less buoyancies with a high cumulative drug release. Ethyl cellulose microspheres prepared using hydroxypropyl methylcellulose K4M showed more sustained drug release and high buoyancies than that of the microspheres formulated with the hydroxypropyl methylcellulose E50 LV. Amongst these hydroxypropyl methylcellulose E50 LV showed good balance between buoyancy and the drug release.     

Preparation and evaluation of tamsulosin hydrochloride sustained-release pellets modified by two-layered membrane techniques

The aim of the present study was to develop tamsulosin hydrochloride sustained-release pellets using two-layered membrane techniques. Centrifugal granulator and fluidized-bed coater were employed to prepare drug-loaded pellets and to employ two-layered membrane coating respectively. The prepared pellets were evaluated for physicochemical characterization, subjected to differential scanning calorimetry (DSC) and in vitro release of different pH. Different release models and scanning electron microscopy (SEM) were utilized to analyze the release mechanism of Harnual^® and home-made pellets. By comparing the dissolution profiles, the ratio and coating weight gain of Eudragit^® NE30D and Eudragit^® L30D55 which constitute the inside membrane were identified as 18:1 and 10%–11%. The coating amount of outside membrane containing Eudragit^® L30D55 was determined to be 0.8%. The similarity factors (f₂) of home-made capsule and commercially available product (Harnual^®) were above 50 in different dissolution media. DSC studies confirmed that drug and excipients had good compatibility and SEM photographs showed the similarities and differences of coating surface between Harnual^® and self-made pellets before and after dissolution. According to Ritger-Peppas model, the two dosage form had different release mechanism.     

Mucoadhesive platforms for targeted delivery to the colon

A novel platform system, comprising a mucoadhesive core and a rapid release carrier, was designed for targeted drug delivery to the colon. Prednisolone pellets containing different carbomers, including Carbopol 971P, Carbopol 974P and Polycarbophil AA-1, with or without organic acids, were produced by extrusion-spheronization. Mucoadhesive pellets were coated with a new enteric double-coating system, which dissolves at pH 7. This system comprises an inner layer of partially neutralized Eudragit^® S and buffer salt and an outer coating of standard Eudragit^® S. A single layer of standard Eudragit S was also applied for comparison purposes. Dissolution of the coated pellets was assessed in USP II apparatus in 0.1 N HCl followed by Krebs bicarbonate buffer pH 7.4. Visualization of the coating dissolution process was performed by confocal laser scanning microscopy using fluorescent markers in both layers. The mucoadhesive properties of uncoated, single-coated and-double coated pellets were evaluated ex vivo on porcine colonic mucosa. Mucoadhesive pellets coated with a single layer of Eudragit^® S release its cargo after a lag time of 120 min in Krebs buffer. In contrast, drug release from the double-coated mucoadhesive pellets was significantly accelerated, starting at 75 min. In addition, the mucoadhesive properties of the core of the double coated pellets were higher than those from single-coated pellets after the core had been exposed to the buffer medium. This novel platform technology has the potential to target the colon and overcome the variability in transit and harmonize drug release and bioavailability.     

Development and characterization of extended release Kollidon SR mini-matrices prepared by hot-melt extrusion

Kollidon^® SR as a drug carrier and two model drugs with two different melting points, ibuprofen and theophylline, were studied by hot-melt extrusion. Powder mixtures containing Kollidon^® SR were extruded using a twin-screw extruder at temperatures 70 and 80 °C for ibuprofen and 80 and 90 °C for theophylline. The glass transition temperature (T_g) and maximum torque were inversely related to ibuprofen concentrations, indicating its plasticizing effect. The results of differential scanning calorimetry (DSC) and X-ray diffraction analysis showed that ibuprofen remained in an amorphous or dissolved state in the extrudates containing drug up to 35%, whereas theophylline was dispersed in the polymer matrix. The increase in amounts of ibuprofen or theophylline in the hot-melt extrudates resulted in the increase in the drug release rates. Theophylline release rate in hot-melt extruded matrices decreased as the extrusion temperature increased. In contrast, a higher processing temperature caused the higher ibuprofen release. This was a clear indication of the plasticizing effect of ibuprofen on Kollidon^® SR and a result from water uptake. Theophylline release rate from hot-melt extrudates decreased with increasing triethyl citrate (TEC) level because of the formation of a denser matrix. By adding of Klucel^® LF as a water-soluble additive to the hot-melt extruded matrices, an increase in ibuprofen and theophylline release rates was obtained.     

An approach to a cold chain free oral cholera vaccine: in vitro and in vivo characterization of Vibrio cholerae gastro-resistant microparticles

The present work describes the formulation of Eudragit^® L30 D-55 microparticles (MP) alone or with mucoadhesive agents, alginate or Carbopol^®, as an approach for the development of an oral cholera vaccine. In the first part, a spray drying technique was optimized for microparticle elaboration, obtaining a microparticle size ranging from 7 to 9 μm with high encapsulation efficiencies. Moreover, gastro resistant properties and Vibrio cholerae (VC) antigenicity were maintained, but for Eudragit^®-Carbopol^® microparticles which showed low antigenicity values, ≈25%. Next, a stability study was performed following ICH Q1 A (R2) guidelines, i.e. 25 °C-60% relative humidity (RH) for 12 months, and 30 °C-65% RH and 40 °C-75% RH for 6 months. Upon storage, microparticle size changed slightly, 1 μm for Eudragit^®-alginate MPs and 0.36 μm for Eudragit^®MP. However, gastro resistance and antigenicity values were kept in an acceptance range. In the third stage of this work, in vivo experiments were performed. The immune response evoked was measured by means of vibriocidal titer quantification, observing that Eudragit^®-alginate MPs were able to induce stronger immune responses, comparable to the free VC. Therefore, microencapsulation of VC by spray drying could be proposed as an approach to a cold chain free and effective oral cholera vaccine.     

Inhibition of surface crystallisation of amorphous indomethacin particles in physical drug–polymer mixtures

Surface coverage may affect the crystallisation behaviour of amorphous materials. This study investigates crystallisation inhibition in powder mixtures of amorphous drug and pharmaceutical excipients. Pure amorphous indomethacin (IMC) powder and physical mixtures thereof with Eudragit^® E or Soluplus^® in 3:1, 1:1 and 1:3 (w/w) ratios were stored at 30 °C and 23 or 42% RH. Samples were analysed during storage by X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, and scanning electron microscopy (SEM). IMC Eudragit^® mixtures showed higher physical stability than pure IMC whereas IMC Soluplus^® mixtures did not.     

Formulation and evaluation of a bioadhesive patch for buccal delivery of tizanidine

Tizanidine hydrochloride (THCl) is an antispasmodic agent which undergoes extensive first pass metabolism making it a possible candidate for buccal delivery. The aim of this study was to prepare a monolayered buccal patch containing THCl using the emulsification solvent evaporation method. Fourteen formulations were prepared using the polymers Eudragit^® RS 100 or Eudragit^® RL 100 and chitosan. Polymer solutions in acetone were combined with a THCl aqueous solution (in some cases containing chitosan) by homogenization at 9000 rpm for 2 min in the presence of triethyl citrate as plasticizer and cast in novel Teflon molds. Physicochemical properties such as film thickness, in vitro drug release and in vitro mucoadhesion were evaluated after which permeation across sheep buccal mucosa was examined in terms of flux and lag time. Formulations prepared using a Eudragit^® polymer alone exhibited satisfactory physicomechanical properties but lacked a gradual in vitro drug release pattern. Incorporation of chitosan into formulations resulted in the formation of a porous structure which did exhibit gradual release of drug. In conclusion, THCl can be delivered by a buccal patch formulated as a blend of Eudragit^® and chitosan, the latter being necessary to achieve gradual drug release.     

Chitosan films incorporated with nettle (Urtica Dioica L.) extract-loaded nanoliposomes: II. Antioxidant activity and release properties

Chitosan films were loaded with NE nettle (Urtica dioica L.) extract (NE) at concentrations of 0, 0.5, 1 and 1.5%w/w in the free or nanoliposomal form to obtain active and nanoactive films, respectively. The antioxidant potential of the films containing NE-loaded nanoliposomes was decreased in comparison of free NE incorporated films. Diffusion of NE to soybean oil was enough to delay the induction of the oxidation of soybean oil stored for 60 days in contact with chitosan based films. Release studies indicated that the release rate of NE in 95% ethanol simulant significantly decreased by the nanoencapsulation of NE. The diffusion coefficient (D) for chitosan films containing 1.5%w/w of free and encapsulated NE at 25?°C was 18.80 and 3.68?×?10^?7 cm² s^?1, respectively. Moreover, the formation of nanoliposomes diminished the increasing effect of temperature on the release rate as when storage temperature increased from 4?°C to 40?°C.     

Development of a novel tablet-in-capsule formulation of mesalamine for inflammatory bowel disease

Objective: The objective of the present work was to develop a tablet-in-capsule type of multiunit system, which releases the drug in a controlled manner at pre-programmed time intervals.

Methods: The system consists of an enteric-coated hydroxypropyl methylcellulose capsule filled with four units of mesalamine minitablets, each of which was further coated with different ratios of Eudragit^® E100 and Eudragit^® RS100.

Results: In vitro evaluation of tablets coated with Eudragit^® E100 and Eudragit^® RS100 at different pH conditions revealed that at lower pH levels (2.0, 3.6 and 5.5 pH), the drug release is mainly governed by the dissolution of Eudragit^® E100 from the Eudragit^® E100 and Eudragit^® RS100 coat. In vitro evaluation of capsules enteric coated with Eudragit^® L100 and Eudragit^® S100 revealed that a maximum lag time of 3?h and 4?h was obtained, respectively. In vivo roentgenographic evaluation in rabbits revealed that the developed system remained intact until it reaches the targeted region of the gastrointestinal tract, i.e. ileum and colon, where the tablets were released after the dissolution of the enteric coat Eudragit^® L100 and Eudragit^® S100, respectively.

Conclusion: The developed system exhibited a promising targeting behavior and hence may be used for the treatment of inflammatory bowel disease.     

大黄素固体分散体制备、表征与释药机制研究

摘要：目的 制备大黄素固体分散体，提高其体外溶出度并探究其释药机制。方法 采用分子对接技术，辅助筛选聚合物载体。以大黄素为原料药，Kollidon VA64为聚合物载体，采用热熔挤出工艺制备大黄素固体分散体。通过溶出仪测定其体外溶出，利用SEM，DCS和PXRD对原料药和固体分散体的表面形态和晶型进行表征，最后采用FTIR，NMR和分子动力学模拟对固体分散体的释药机制进行探究。结果 相较于大黄素原料药，大黄素固体分散体在4种介质中的溶出被明显改善，大黄素由结晶态转化为无定形态，药物与聚合物载体间形成了氢键。结论 固体分散体中药物晶型的转变和氢键的产生是改善药物体外溶出的主要因素。     

Buccal films of prednisolone with enhanced bioavailability

Abstract

The conventional formulation of prednisolone is considered to be low in efficacy, primarily on account of their failure in providing and maintaining effective therapeutic drug levels. This study aims to focus on development of a mucoadhesive buccal delivery system with a twofold objective of offering a rapid as well as a prolonged delivery of prednisolone coupled with enhanced therapeutic efficacy. Buccoadhesive films of prednisolone were prepared by solvent-casting method using hydroxyl propyl methyl cellulose (K100), Carbopol 940 and/or Eudragit® NE 40?D. Placebo films possessing the most desirable physicomechanical properties were selected for drug loading. The effect of polymer and its content on film properties, i.e. mucoadhesive strength, swelling and hydration, in vitro drug release was studied. Based on these studies, film F7D was selected for ex vivo permeation across porcine cheek mucosa. The steady state flux of prednisolone across the buccal mucosa was found to be 105.33?±?32.07?µg/cm²/h. A comparative pharmacokinetic study of prepared film (F7D) and oral suspension of prednisolone was conducted. In vivo data of buccal film show greater bioavailability (AUC_0–α: 24.26?±?4.06?µg.h/ml versus 10.65?±?2.15?µg.h/ml) and higher C_max (2.70?±?0.38?µg/ml versus 2.29?±?0.32?µg/ml) value when compared to oral suspension. The data observed from this study highlight the feasibility of the buccal route as a viable option for delivery of prednisolone.     

Formulation of 3D Printed Tablet for Rapid Drug Release by Fused Deposition Modeling: Screening Polymers for Drug Release,Drug-Polymer Miscibility and Printability

The primary aim of this study was to identify pharmaceutically acceptable amorphous polymers for producing 3D printed tablets of a model drug, haloperidol, for rapid release by fused deposition modeling. Filaments for 3D printing were prepared by hot melt extrusion at 150°C with 10% and 20% w/w of haloperidol using Kollidon^® VA64, Kollicoat^® IR, Affinsiol^?15 cP, and HPMCAS either individually or as binary blends (Kollidon^® VA64 + Affinisol^? 15 cP, 1:1; Kollidon^® VA64 + HPMCAS, 1:1). Dissolution of crushed extrudates was studied at pH 2 and 6.8, and formulations demonstrating rapid dissolution rates were then analyzed for drug-polymer, polymer-polymer and drug-polymer-polymer miscibility by film casting. Polymer-polymer (1:1) and drug-polymer-polymer (1:5:5 and 2:5:5) mixtures were found to be miscible. Tablets with 100% and 60% infill were printed using MakerBot printer at 210°C, and dissolution tests of tablets were conducted at pH 2 and 6.8. Extruded filaments of Kollidon^® VA64-Affinisol^? 15 cP mixtures were flexible and had optimum mechanical strength for 3D printing. Tablets containing 10% drug with 60% and 100% infill showed complete drug release at pH 2 in 45 and 120 min, respectively. Relatively high dissolution rates were also observed at pH 6.8. The 1:1-mixture of Kollidon^® VA64 and Affinisol^?15 cP was thus identified as a suitable polymer system for 3D printing and rapid drug release.