Mechanical Properties of Dry and Wet Cellulosic and Acrylic Films Prepared from Aqueous Colloidal Polymer Dispersions Used in the Coating of Solid Dosage Forms

The mechanical properties of dry and wet polymeric films prepared from various aqueous polymeric dispersions were evaluated by a puncture test. They were studied with respect to type of polymer dispersion [cellulosic: Aquacoat and Surelease; acrylic: Eudragit NE, L, RS, and RL 30 D], plasticizer type (water-soluble or water-insoluble), drying or curing conditions, method of film preparation (pseudolatex- vs solvent casting) and ratio of Eudragit RS/RL 30 D in mixed Eudragit RS/RL films. Dry and wet mechanical strengths of the polymeric films depended primarily on the types of the colloidal polymer dispersion and the plasticizer. Films prepared from ethylcellulose dispersions resulted in very weak and brittle films when compared to the acrylic films. Pseudolatex-cast ethylcellulose films showed lower puncture strength and elongation values when compared to those of the solvent-cast films. Curing of the pseudolatex-cast ethylcellulose films had minimal effects on their mechanical properties. Eudragit L 30D, an enteric polymer dispersion, resulted in brittle films in the dry state, but in very flexible films in the wet state because of the plasticization effect of water. Wet Eudragit RS 30 D polymer films plasticized with water-insoluble plasticizers were significantly more flexible than the corresponding wet films plasticized with water-soluble plasticizers. The water-soluble plasticizers leached from the films during exposure to the aqueous medium, while the water-insoluble plasticizers were almost completely retained within the wet films. The low permeability of a water-soluble drug, chlorpheniramine maleate, and the weak mechanical properties of Aquacoat films could suggest osmotic driven/rupturing effects as the release mechanisms from Aquacoat-coated dosage forms.     

Constant Potassium Chloride Release from Microporous Membrane-Coated Tablets Prepared with Aqueous Colloidal Polymer Dispersions

To achieve constant drug release and to avoid the use of organic solvents, potassium chloride tablets were coated with aqueous latexes containing dispersed pore-formers with pH-dependent solubility characteristics. The pore-forming agent, dibasic calcium phosphate, was insoluble in the latex but soluble at low pH. Upon contact with simulated gastric fluids, it leached out rapidly to form a rate-controlling, microporous membrane. The release of potassium chloride was linear with time up to 75–80% drug released. It increased with increasing level of pore-former and decreasing membrane thickness but was independent of the degree of agitation and the pH of the dissolution medium after leaching of the pigments. Upon storage at different relative humidities, moisture uptake of the film coat and variations in the release profiles over time were minimal.     

聚合物水性分散体在茶碱控释小丸包衣上的应用

将Ｓｕｒｃｌｅａｓｅ、Ｓｕｒｅｔｅｒｉｃ、Ｏｐａｒｌｒｙ等聚合物水性分散体应用于茶碱小丸的包衣,得到释放度符合美国药典要求的控释小丸。     

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.     

Mechanisms to Control Drug Release from Pellets Coated with a Silicone Elastomer Aqueous Dispersion

The mass transport of two different compounds through polydi-methylsiloxane (PDMS)–silica films was investigated to demonstrate qualitatively how this coating system can alter the release of various compounds. Various ratios of PDMS elastomer and silica were used to coat monodisperse particle-sized pellets layered with an ionizable compound (tartrazine) and a nonionized compound (acetaminophen). The 2:1 PDMS–silica composition containing the polyethylene glycol (PEG) 8000 pore former allowed mainly pore transport through void spaces in the PDMS films. Both compounds rapidly diffused through the film as a result of the solubilization and subsequent removal of the PEG 8000 from the film matrix. As the PDMS–silica ratios in the films changed from a 1:1 to a 2:1 to a 4:1 (all without polyethylene glycol 8000) coating formulation, the differences in release rate between acetaminophen and tartrazine changed. The lower ratio of PDMS–silica allowed much faster tartrazine diffusion compared to acetaminophen. As the ratio increased from 1:1 to 2:1, the two compounds were released at similar rates. When the ratio reached 4:1, acetaminophen was released significantly faster than tartrazine. Explanations for these differences and the mechanisms controlling the drug release are discussed in the text. In some circumstances, osmolality and pH affected drug release from dosage forms coated with this polymer system. This study demonstrated that utilization of this polymer system offers a useful tool for the formulation scientist to modify release rates of ionic and nonionic drug substances.     

Development of Extended-Release Solid Dispersions of Nonsteroidal Antiinflammatory Drugs with Aqueous Polymeric Dispersions: Optimization of Drug Release via a Curve-Fitting Technique

Extended-release solid dispersions of nonsteroidal antiinflammatory drugs were prepared by using aqueous polymeric dispersions of Eudragit RS30D and Eudragit RL30D as the inert carriers. The effects of different polymer ratios of Eudragit RS30D and Eudragit RL30D, different particle sizes, and different combination of various formulations of solid dispersions on the in vitro release kinetics of drugs from the dosage forms were investigated. A computer curve-fitting process was developed to choose the optimum formulation of the solid dispersion with the desired drug release profile. This process might offer the advantages of efficiency and simplicity in the formulation development of extended-release solid dispersions.     

Polymer Blends Used for the Coating of Multiparticulates: Comparison of Aqueous and Organic Coating Techniques

PURPOSE: The purpose of this study was to use polymer blends for the coating of pellets and to study the effects of the type of coating technique (aqueous vs. organic) on drug release. METHODS: Propranolol HCl-loaded pellets were coated with blends of a water-insoluble and an enteric polymer (ethyl cellulose and Eudragit L). Drug release from the pellets as well as the mechanical properties, water uptake, and dry weight loss behavior of thin polymeric films were determined in 0.1 M HCI and phosphate buffer, pH 7.4. RESULTS: Drug release strongly depended on the type of coating technique. Interestingly, not only the slope, but also the shape of the release curves was affected, indicating changes in the underlying drug release mechanisms. The observed effects could be explained by the higher mobility of the macromolecules in organic solutions compared to aqueous dispersions, resulting in higher degrees of polymer-polymer interpenetration and, thus, tougher and less permeable film coatings. The physicochemical properties of the latter were of major importance for the control of drug release, which was governed by diffusion through the intact polymeric films and/or water-filled cracks. CONCLUSIONS: The type of coating technique strongly affects the film microstructure and, thus, the release mechanism and rate from pellets coated with polymer blends.     

Effect of Polymer Blending on the Release of Ganciclovir from PLGA Microspheres

Purpose The aim of the study is to investigate the effect of polymer blending on entrapment and release of ganciclovir (GCV) from poly(d,l-lactide-co-glycolide) (PLGA) microspheres using a set of empirical equations. Methods Two grades of PLGA, PLGA 7525 [d,l-lactide:glycolide(75:25), MW 90,000–126,000 Da] and Resomer RG 502H [d,l-lactide:glycolide(50:50), MW 8000 Da], were employed in the preparation of PLGA microspheres. Five sets of microsphere batches were prepared with two pure polymers and their 1:3, 1:1, and 3:1 blends. Drug entrapment, surface morphology, particle size analysis, drug release, and differential scanning calorimetric studies were performed. In vitro drug-release data were fitted to a set of empirical sigmoidal equations by nonlinear regression analysis that could effectively predict various parameters that characterize both diffusion and degradation cum diffusion-controlled release phases of GCV. Results Entrapment efficiencies of GCV ranged from 47 to 73%. Higher amounts of GCV were entrapped in polymer blend microspheres relative to individual polymers. Triphasic GCV release profiles were observed, which consisted of both diffusion and degradation cum diffusion-controlled phases. In vitro GCV release was shortest for Resomer RG 502H microsphere (10 days) and longest for PLGA 7525 microspheres (90 days). Upon blending, the duration of release gradually decreased as the content of Resomer RG 502H in the matrix was raised. Equations effectively estimated the drug-release rate constants during both the phases with high R² values (>0.990). GCV release was slower from the blend microsphere during the initial diffusion phase. Majority of entrapped drug (70–95%) was released during the matrix degradation cum diffusion phase. Conclusions Drug entrapment and release parameters estimated by the equations indicate more efficient matrix packing between PLGA 7525 and Resomer RG 502H in polymer-blended microspheres. The overall duration of drug release diminishes with rising content of Resomer RG 502H in the matrix. Differential scanning calorimetry studies indicate stronger binding between the polymers in the PLGA 7525/Resomer RG 502H∷ 3:1 blend. Polymer blending can effectively alter drug-release rates of controlled delivery systems in the absence of any additives.     

pH-Sensitive Polymer Blends Used as Coating Materials to Control Drug Release from Spherical Beads: Elucidation of the Underlying Mass Transport Mechanisms

Purpose To elucidate the drug release mechanisms from pellets coated with pH-sensitive polymer blends.Methods Verapamil hydrochloride-loaded beads were coated with various blends of a water-insoluble and an enteric polymer, ethylcellulose:Eudragit L and Eudragit NE:Eudragit L, respectively. Both experimental and theoretical techniques were used to characterize the systems before and upon exposure to 0.1 M HCl and phosphate buffer (pH 7.4).Results Using analytical solutions of Fick’s second law of diffusion, optical and scanning electron microscopy, and mechanical and gravimetric analysis, new insight into the underlying drug release mechanisms could be gained. More importantly, the latter can be effectively altered by varying the type of polymer blend and blend ratio. For example, at low pH drug release is primarily controlled by diffusion through the intact film coatings in Eudragit NE:Eudragit L blends, whereas crack formation is of major importance in ethylcellulose:Eudragit L-coated systems. At high pH, the (partial) leaching of the enteric polymer out of the coatings plays an important role. In all cases, the observed drug release profiles could be explained based on the occurring mass transport processes.Conclusions The obtained new knowledge can be used to effectively adjust desired drug release mechanisms and, thus, release patterns.     

Controlled Release of DSBP from Genipin-Crosslinked Gelatin Thin Films

Controlled release of a marker drug, 4,4′-bis(2-sulfostyryl) biphenyl (DSBP) from genipin crosslinked gelatin thin films, with application to drug delivery by transdermal patches is studied in this paper. A simple method for fabrication of nano-thin films, using basic lab equipment is introduced. This method consists of two steps: dipping of the substrate in a deposition solution, followed by centrifugation of the substrate. Also, swelling and drug release from thin films is modeled, using the Fick's second law of diffusion. The effect of genipin concentration on release of DSBP molecules from thin films is investigated, experimentally and numerically. The results show that controlled release of DSBP from the genipin-crosslinked gelatin thin films is achieved, using various concentrations of genipin in gelatin.     

Sustained Local Anesthetic Release from Bioerodible Polymer Matrices: A Potential Method for Prolonged Regional Anesthesia

Polyanhydride polymer matrices have been used successfully for sustained release of a number of drugs in vitro and in vivo. Dibucaine free base, dibucaine HC1, and bupivacaine HC1 were incorporated into polymer matrices with copolymer l,3-bis(p-carboxyphenoxy)propane-sebacic acid anhydride (1:4). Drug release was measured in vitro following incubation of the drug-polymer matrices in phosphate buffered solution, pH 7.4, at 37°C, to approximate in vivo conditions. Local anesthetics were released in a sustained manner yielding 90% cumulative drug release over periods ranging from 3 to 14 days. The kinetics of release varied with both the choice of local anesthetic and the method of drug incorporation into the matrix (hot melt versus compression molding). Polymer local anesthetic matrix devices (PLAM), loaded by hot melt incorporation with 20% bupivacaine, were implanted in vivo adjacent to the sciatic nerve in three rats. Reversible neural blockade was observed for 4 days in all animals. Polymer implants without local anesthetic showed no neural blockade. This technology could lead to methods of prolonged blockade of peripheral nerves or of sympathetic ganglia, which may be utilized for the management of postoperative pain, sympathetically maintained pain, or certain forms of chronic pain.     

Physicochemical and release properties of pellets coated with Kollicoat SR 30 D, a new aqueous polyvinyl acetate dispersion for extended release

Kollicoat^® SR 30 D is a new aqueous colloidal polyvinyl acetate dispersion used for extended release coatings. Kollicoat^® SR 30 D is stable against sedimentation, has a low viscosity (54 mPas) and a negative zeta potential of −23.2 mV because of the presence of the anionic surfactant, sodium dodecyl sulfate. Because of its low minimum film formation temperature (MFT = 18 °C), plasticizer addition and a thermal after-treatment (curing) of coated pellets was not required. Coated pellets showed no aging or curing effect. The rate of release could be easily adjusted by varying the coating level. A subcoating layer of the hydrophilic polymer, polyvinyl alcohol, between an ibuprofen-containing core and the Kollicoat^® SR coating prevented the diffusion of the lipophilic, low melting ibuprofen into the polymer coating during storage. The drug release from Kollicoat^® SR 30 D coated pellets was almost independent of the pH and ionic strength of release medium.     

芬太尼口腔贴膜的制备及质量评价

制备了以壳聚糖和羟丙纤维素为基质的芬太尼口腔贴膜,并评价了贴膜的粘附力、体外释药行为及对金黄地鼠离体颊粘膜的渗透性能.结果表明,以壳聚糖-羟丙纤维素4:1制得的贴膜口腔滞留时间约50min,释药性能及颊膜渗透能力较好,在室温、相对湿度75%环境放置3个月质量稳定.     

奥氮平口溶膜的制备与质量评价

摘 要 目的：制备奥氮平口溶膜处方并评价其质量。方法: 采用溶剂浇铸法制备奥氮平口溶膜,分别以羟丙甲基纤维素（HPMC）和聚乙二醇400（PEG400）用量作为考察因素,以口溶膜的拉伸强度、延展率、10 min药物溶出度作为评价指标,通过Box Behnken效应面法优化了奥氮平口溶膜的处方;评价口溶膜的拉伸强度、延展率、耐折度、崩解时限和药物溶出度,并与市售奥氮平口崩片进行体外溶出度对比研究。结果:当HPMC和PEG400用量分别为11.0%和2.3%,制得的奥氮平口溶膜成膜性能较强,具有较高的硬度和柔韧性,50 s内可迅速溶解,药物溶出速度较快,与市售奥氮平口崩片体外溶出相似。结论:奥氮平口溶膜处方设计合理,工艺可行,质量稳定可控,值得进一步开发研究。     

Tensile Properties of Free Films Cast from Aqueous Ethylcellulose Dispersions

Free films of two commercially available formulations of aqueous ethylcellulose dispersion differing only in plasticizer content (Surelease/E-7-7050 without silica and E-7-7060 containing dibutyl sebacate and glyceryl tricaprylate/caprate as plasticizers, respectively) were cast and coalesced at temperatures ranging between 30 and 70°C. Mechanical properties of these films were measured using tensile stress analysis. Three mechanical parameters, namely, tensile strength, work of failure, and elastic modulus, were computed from the load-time profiles of these films. The results showed that the tensile strength and elastic modulus values of the films cast from both formulations increased with the corresponding increase in coalescence temperature up to 60°C, beyond which no significant differences were observed. In the case of work of failure, however, the difference between the two formulations was observed above 60°C. The films cast from Surelease/E-7-7050 formulation without silica (dibutyl sebacate as the plasticizer) were relatively softer than those from Surelease/E-7-7060 formulation (glyceryl tricaprylate/caprate as the plasticizer). At coalescence temperatures above 50°C, the films cast from both formulations exhibited temperature-dependent plastic deformation.     

Development and In vitro Evaluation of Mucoadhesive Buccal Films of Nebivolol

Nebivolol, a cardioselective β-blocker undergoes extensive metabolism in the liver after its oral administration resulting in low bioavailability. Oral administration of nebivolol also causes gastrointestinal disturbances characterised by stomach ache. To overcome these short comings, mucoadhesive buccal films of nebivolol were prepared using different concentrations of hydroxypropyl methylcellulose and hydroxyl ethylcellulose in the ratios of 2:1, 4:1 and 6:1 and hydroxypropyl methylcellulose and methylcellulose in the ratio of 2:2, 4:3 and 6:4 by solvent casting technique. All the prepared films were found to be smooth, elegant and uniform in thickness and weight. Among the three polymer combinations used, 6:4 (BFN₆) showed increased in vitro residence time, which appeared to be mainly due to mucoadhesive nature of hydroxylpropyl methylcellulose and methylcellulose. Evaluation of the films showed uniform dispersion of the drug throughout the formulation (96.21±0.71 to 97.02±0.12%). In vitro drug release studies showed better results at the end of 8 h. The release profile of all the formulations was subjected to kinetic analyses, which suggested that the drug was released by diffusion mechanism following super case-II transport.     

Evaluation of Moisture Sorption by Tablet Cores Containing Superdisintegrants During the Aqueous Film Coating Process

A physical-chemical analysis of the extent of sorption of water by tablets containing superdisintegrants was carried out following the aqueous film coating of formulated tablets. Characterization of the uncoated and coated tablet properties was conducted using thermo-gravimetric analysis, differential scanning calorimetry, mercury intrusion porosimetry, and measurement of the tablet tensile strength. Tablet residual moisture content, pore system characteristics, tensile strength, and glass transition temperature of the amorphous polymer components of the tablet matrix were significantly affected after the coating operation. These findings were attributed to the penetration of water from the aqueous film coating solution into the tablet matrix.     

Chemotherapeutic Drugs Released from Polymers: Distribution of 1,3-bis(2-chloroethyl)-l-nitrosourea in the Rat Brain

Purpose. The distribution of [³H]BCNU following release from polymer implants in the rat brain was measured and evaluated by using mathematical models. Methods. [³H]BCNU was loaded into p(CPP:SA) pellets, which were subsequently implanted intracerebrally in rats; [³H]BCNU was also directly injected into the brains of normal rats and rats with intracranially transplanted 9L gliomas. Concentrations of [³H]BCNU on coronal sections of the brain were measured by autoradiography and image processing. For comparison, the kinetics of [³H]BCNU release from the p(CPP:SA) polymer discs into phosphate-buffered saline were also measured. Results. High concentrations of BCNU (corresponding to ~1 mM) were measured near the polymer for the entire 30-day experiment. The penetration distance, defined as the distance from the polymer surface to the point where the concentration of [³H]BCNU in the tissue had dropped to 10% of the maximum value, was determined: penetration distance was ~5 mm at day 1 and ~1 mm at days 3 through 14. Local concentration profiles were compared with a mathematical model for estimation of the modulus ², an indicator of the relative rate of elimination to diffusion in the brain. From day 3 to 14, ² was ~7, indicating that BCNU elimination was rapid compared to the rate of diffusive penetration into tissue. The enhanced penetration observed on day 1 appears to be due to convection of extracellular fluid caused by transient, vasogenic edema, which disappears by day 3. Conclusions. Polymer implants produce very high levels of BCNU in the brain, but BCNU penetration into brain tissue is limited due to rapid elimination.     

Effect of Different Tensoactives on the Morphology and Release Kinetics of PLA-b-PEG Microcapsules Loaded With the Natural Anticancer Compound Perillyl Alcohol

Perillyl alcohol is a natural compound that has attracted a significant interest due to its potent antitumor activity. However, clinical trials have exhibited poor tolerance by oral administration, mainly due to gastrointestinal side effects. We propose the entrapment of perillyl alcohol into poly(D,L-lactic acid)-block-poly(ethylene glycol) (PLA-b-PEG) as delivery platform (entrapment efficiency of 63%-68%). The influence of different concentrations of the tensoactives poly(vinyl alcohol) and sodium cholate (SC) on shear strength and morphology was evaluated by confocal laser scanning microscopy and interfacial tension studies. Only the microcapsules formulated with SC maintained their sphericity when submitted to shear stress. These results indicate that the interface is better organized with SC, conferring mutual stacked packing that is able to better stabilize the organic drop. The in vitro release profile of the drug from the microcapsules was correlated with pore formation and polymer degradation, best fitted to the Baker-Lonsdale model. The loaded microcapsules showed an IC₅₀ equivalent to that of the free drug (80 μg/mL) after 72 h of exposure. However, after 24 h of exposure, loaded microcapsules showed an IC₅₀ almost two-fold higher (220 μg/mL) suggesting gradual release.     

Evaluation of Pyrrolobenzodiazepine-Loaded Nanoparticles: A Targeted Drug Delivery Approach

We describe the development and evaluation of pyrrolobenzodiazepines (PBDs) in poly(dl-lactide-co-glycolide) and lipid nanoparticle drug delivery systems. We have established that the partition coefficient (LogP) of PBD is a key influencer of the encapsulation efficiency in nanoparticle systems, with higher LogP values associated with higher encapsulation efficiencies toward increased drug payload delivery and better antitumor efficacy. Cytotoxicity assays demonstrated that compounds with higher LogP values demonstrated higher 50% inhibitory concentration values than the free drug. In vivo efficacy studies in mice demonstrated that a single injection of nanoparticle PBD formulations could inhibit tumor growth for nearly 3 weeks, whereas the free drug failed to inhibit growth. Importantly, mice treated with PBD-loaded nanoparticles did not experience significant loss of body weight. These data demonstrate that nanoparticles containing PBD molecules can be used as an alternative to the widely used antibody drug conjugate approach in delivering cytotoxic PBDs.