Studies on the In Vitro Release of Theophylline from Polyethylene Glycol-Polyvinyl Acetate Mixtures Liquid Filled into Hard Gelatin Capsules

The release of theophylline from mixtures of polythylene glycol (PEG) with polyvinyl acetate (PVAc) liquid filled into hard gelatin capsules has been studied in vitro. Results indicate that theophylline release can be controlled over a relative wide range by varying the concentration of PVAc, and that the reproducibility of the release profile is improved considerably if the PVAc concentration exceeds 2% w/w. Other results show that drug load, molecular weight of PEG, and pH of the dissolution medium also affect release profiles. In general, the experimental data are well described by a simple equation derived from Fickian diffusion kinetics, thus supporting the suggestion that drug release from this type of formulation is controlled by diffusion in solution through water-filled pores in a network of precipitated PVAc.     

Physicochemical characterization of nimodipine–polyethylene glycol solid dispersion systems

This study investigates the solid–solid interactions between nimodipine (NIM) and polyethylene glycol (PEG) of different mean molecular weights (PEG 2000, 4000 and 6000), in solid dispersion systems, applying differential scanning calorimetry (DSC), Fourier-Transform infrared spectroscopy, powder X-ray diffraction (PXRD), hot stage microscopy (HSM) and theoretical modeling by the Flory–Huggins (FH) solution theory. Phase diagrams constructed with the aid of DSC and FH solution theory showed sensitivity on the estimated values of the FH interaction parameter (χ). When χ is considered a constant number (χ?=?α, α?≠?0), formation of a eutectic mixture is predicted in the 70–80% w/w PEG concentration region, while when χ was considered as a function of concentration and temperature (χ?=?f(φ,Τ)), the model predicts the formation of monotectic systems. Construction of more precise phase diagrams by HSM to the aid of Kofler’s “contact preparation” method confirmed the monotectic nature of the examined systems. Studies on NIM’s re-crystallization process in the solid dispersions revealed a strong dependence of the crystallization rate, as well as the resulting crystal form, on the mean molecular weight and concentration of PEG: NIM crystallization rates decrease as PEG’s MW increases, while NIM mod II crystals predominate in dispersions prepared at temperatures above NIM’s liquidus and growth of NIM mod I prevailing in PEG-rich samples.     

Enhanced dissolution of ibuprofen using solid dispersion with polyethylene glycol 20000

To improve its dissolution, ibuprofen solid dispersions (SDs) were prepared in a relatively easy and simple manner, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), and evaluated for solubility and in vitro drug release. Loss of individual surface properties during melting and re-solidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting toward the lower melting temperature of the drug peak in SDs in DSC study indicated the possibilities of drug-polymer interactions. FTIR spectra showed the presence of drug crystalline in SDs. The effect of improved dissolution on the oral absorption of ibuprofen in rats was also studied. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C(max), and a significant decrease in T(max) over pure ibuprofen. Preliminary results from this study suggested that the preparation of fast dissolving ibuprofen SDs by low-temperature melting method using polyethylene glycol 20000 as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution, and absorption rate of ibuprofen.     

Enhanced Dissolution of Ibuprofen Using Solid Dispersion with Polyethylene Glycol 20000

To improve its dissolution, ibuprofen solid dispersions (SDs) were prepared in a relatively easy and simple manner, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), and evaluated for solubility and in vitro drug release. Loss of individual surface properties during melting and re-solidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting toward the lower melting temperature of the drug peak in SDs in DSC study indicated the possibilities of drug–polymer interactions. FTIR spectra showed the presence of drug crystalline in SDs. The effect of improved dissolution on the oral absorption of ibuprofen in rats was also studied. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C_max, and a significant decrease in T_max over pure ibuprofen. Preliminary results from this study suggested that the preparation of fast dissolving ibuprofen SDs by low-temperature melting method using polyethylene glycol 20000 as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution, and absorption rate of ibuprofen.     

Characterization of Solid Dispersion Phase Transitions Using a New Optical Thermal Analyzer

The phase transitions occurring during the heating of progesterone PEG6000, and progesterone-PEG6000 solid dispersions (3% and 20% w/w) were studied. Investigations were performed by differential scanning calorimetry (DSC) and optical thermal analysis (OTA). For complex systems, such as solid dispersions, the use of OTA allow a new interpretation of the DSC results. For instance, we have shown that peaks which were at first appearance identified as two superposed endothermic peaks, were in fact the result of a more complex set of reactions including a melting, a devitrification, and a second melting reaction.     

Thermal Behavior and Dissolution Properties of Naproxen From Binary and Ternary Solid Dispersions

Solid dispersions of 10% w/w naproxen (NAP) in poly(ethylene glycol) (PEG) (4000, 6000, or 20,000) as a carrier with or without incorporation of anionic (sodium dodecyl sulfate; SDS) or nonionic (Tween 80; Tw80) surfactant were prepared by the melting method. Physicochemical characteristics were determined by differential scanning calorimetry (DSC) and X-ray diffraction analysis. The results of dissolution studies showed that drug dissolution properties were better from ternary systems than from binary systems since in the former the wetting and solubilizing effects of surfactant and polymer were additive. No influence of the PEG molecular weight was found. The best performance given by anionic surfactant has been attributed to several factors, such as higher hydrophilicity, better solubilizing power, and most facile interaction with both drug and PEG. No important changes in solid-state characteristics or in drug dissolution properties were found after 30 months storage for dispersions with or without surfactant. Only a slight decrease in initial drug dissolution rate was observed at the highest concentration (10% w/w) of SDS.     

Thermal behavior and dissolution properties of naproxen from binary and ternary solid dispersions

Solid dispersions of 10% w/w naproxen (NAP) in poly(ethylene glycol) (PEG) (4000, 6000, or 20,000) as a carrier with or without incorporation of anionic (sodium dodecyl sulfate; SDS) or nonionic (Tween 80; Tw80) surfactant were prepared by the melting method. Physicochemical characteristics were determined by differential scanning calorimetry (DSC) and X-ray diffraction analysis. The results of dissolution studies showed that drug dissolution properties were better from ternary systems than from binary systems since in the former the wetting and solubilizing effects of surfactant and polymer were additive. No influence of the PEG molecular weight was found. The best performance given by anionic surfactant has been attributed to several factors, such as higher hydrophilicity, better solubilizing power, and most facile interaction with both drug and PEG. No important changes in solid-state characteristics or in drug dissolution properties were found after 30 months storage for dispersions with or without surfactant. Only a slight decrease in initial drug dissolution rate was observed at the highest concentration (10% w/w) of SDS.     

Characterization of ibuproxam binary and ternary dispersions with hydrophilic carriers

This work investigates the possibility of increasing the dissolution properties of ibuproxam (a poorly water-soluble anti-inflammatory drug) using hydrophilic carriers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), or urea, alone or in combination. Phase-solubility studies showed that the carrier solubilizing power was in the order PEG>PVP>urea and evidenced a synergistic effect in drug solubility improvement when using carrier combinations. Binary and ternary systems, at 20/80 or 20/40/40 (w/w) drug/carrier(s) ratios, prepared by coevaporation of their ethanolic solutions or by cogrinding physical mixtures in a high-energy vibrational micromill, were characterized by differential scanning calorimetry (DSC), hot stage microscopy (HSM), and scanning electron microscopy (SEM) analyses. The results of dissolution tests (USP paddle method), in terms of Dissolution Efficiency, indicated that ternary systems were up to 35% more effective than the corresponding binary preparations and coevaporated products were up to 45% more efficacious than the corresponding coground ones. The IBUX-PEG-PVP coevaporated was the best product, allowing a more than three-times increase in Dissolution Efficiency with respect to drug alone; moreover, t50% (> 60 min for pure ibuproxam) was < 10 min, and 90% dissolution was achieved after 30 min, whereas only 40% was obtained after 60 min for pure drug. The best performance of this system was attributed to a joined effect of the strong amorphizing power of PVP (as demonstrated by solid state analyses) with the high solubilizing efficacy of PEG (as emerged from phase-solubility studies). The drug dissolution rate from solid dispersions remained practically unchanged after one-year storage at room temperature in closed containers.     

Novel films for drug delivery via the buccal mucosa using model soluble and insoluble drugs

Bioadhesive buccal films are innovative dosage forms with the ability to adhere to the mucosal surface and subsequently hydrate to release and deliver drugs across the buccal membrane. This study aims to formulate and characterize stable carrageenan (CAR) based buccal films with desirable drug loading capacity. The films were prepared using CAR, poloxamer (POL) 407, various grades of PEG (plasticizer) and loaded with paracetamol (PM) and indomethacin (IND) as model soluble and insoluble drugs, respectively. The films were characterized by texture analysis, thermogravimetric analysis (TGA), DSC, scanning electron microscopy, X-ray powder diffraction (XRPD), and in vitro drug release studies. Optimized films were obtained from aqueous gels comprising 2.5% w/w κ-CAR 911, 4% w/w POL 407 and 6% w/w (PM) and 6.5% w/w (IND) of PEG 600 with maximum drug loading of 1.6% w/w and 0.8 % w/w for PM and IND, respectively. TGA showed residual water content of approximately 5% of films dry weight. DSC revealed a T(g) at 22.25 and 30.77°C for PM and IND, respectively, implying the presence of amorphous forms of both drugs which was confirmed by XRPD. Drug dissolution profiles in simulated saliva showed cumulative percent release of up to 45 and 57% of PM and IND, respectively, within 40?min of contact with dissolution medium simulating saliva.     

The Effect of Processing Variables on the Release of Ibuprofen and Caffeine from Controlled-Release Nonswellable Core-in-Cup Compressed Tablets

An aqueous soluble polymer such as hydroxypropyl methylcellulose (HPMC), which is widely used in oral sustained-release drug delivery systems, swells when it comes into contact with an aqueous environment. In core-in-cup systems the swelling of the HPMC splits open the cup portion of the tablet. This study investigated the use of acacia, tragacanth, polyethylene glycol 6000 (PEG 6000), and hydroxyethyl-cellulose (HEC) as possible alternatives to the use of HPMC to control the release of caffeine (soluble) and ibuprofen (insoluble) from core-in-cup compressed tablets. It also investigated the possibility of producing a core-in-cup system that had the ability to release caffeine and ibuprofen for a maximum time of constant release of 8-12 hr. A preliminary study revealed that acacia was most effective for the release of caffeine from the core-in-cup compressed tablets, and that PEG 6000 was most effective for the release of ibuprofen from the core-in-cup compressed tablets. On further investigation it was found that by means of adjusting the hardness of compression and the concentration of polymers used, it was possible to formulate a core-in-cup system that could release drug at a constant rate from the core-in-cup compressed tablets for 8 to 12 hr.     

The Effect of Processing Variables on the Release of Ibuprofen and Caffeine from Controlled-Release Nonswellable Core-in-Cup Compressed Tablets

Abstract

An aqueous soluble polymer such as hydroxypropyl methylcellulose (HPMC), which is widely used in oral sustained-release drug delivery systems, swells when it comes into contact with an aqueous environment. In core-in-cup systems the swelling of the HPMC splits open the cup portion of the tablet. This study investigated the use of acacia, tragacanth, polyethylene glycol 6000 (PEG 6000), and hydroxyethyl-cellulose (HEC) as possible alternatives to the use of HPMC to control the release of caffeine (soluble) and ibuprofen (insoluble) from core-in-cup compressed tablets. It also investigated the possibility of producing a core-in-cup system that had the ability to release caffeine and ibuprofen for a maximum time of constant release of 8-12 hr. A preliminary study revealed that acacia was most effective for the release of caffeine from the core-in-cup compressed tablets, and that PEG 6000 was most effective for the release of ibuprofen from the core-in-cup compressed tablets. On further investigation it was found that by means of adjusting the hardness of compression and the concentration of polymers used, it was possible to formulate a core-in-cup system that could release drug at a constant rate from the core-in-cup compressed tablets for 8 to 12 hr.     

The use of Thermal Analysis in the Study of Solid Dispersions

Abstract

Differential thermal analysis (DTA) has been used to study the properties of seven drug-polyethylene glycol 6000 solid dispersions immediatley after preparation by rapid cooling. PEG 6000 displayed a melting point of 64°C but other, second order transitions occurred at 29 to 40°C and at ～ -50°C. Melts of chloramphenicol, glutethimide, griseofulvin, indomethacin and paracetamol solidifed to glasses, but phenacetin and phenylbutazone recrystallised. By examining the dispersions at various drug:PEG 6000 ratios, ranges were estimated which corresponded to PEG recrystallisation, PEG fusion, drug recrystallisation and drug fusion. It was predicted that systems which displayed PEG melting endotherms at drug contents of 0 to > 70% drug and drug melting endotherms at contents in excess of 50% drug, made unsuitable solid dispersions because increases in dissolution rate occurred over a limited range of low drug content. Graphs of reciprocal glass transition temperatures (T_g) and dispersion content indicated a transition temperature for PEG 6000 at -71°C. Using this value and the observed T_g values of the drugs, estimates of T- values were compared with observed values throughout the drug:PEG 6000 phase diagrams. Systems where the observed T_g values were higher than calculated T_g values (paracetamol or chloramphenicol) were less prone to age-mediated dissolution changes than those systems where the calculated T_g values exceeded the observed values (glutethimide, griseofulvin or indomethacin).     

Physical and chemical characterization of thermosoftened bases for molten filled hard gelatin capsule formulations

Dynafill, Dynasan-114, Lutrol-F68, PEG-10000 and PEG-20000 have been examined as potential bases for the preparation of fusion formed solid dispersions for molten filling into hard gelatin capsules. Investigations included, an examination of thermal effects on crystal structure by DSC and XRD, a theological study to evaluate capsule filling characteristics, dissolution studies on drug/base formulations, chemical analysis for free fatty acid impurities in Dynafill and Dynasan-114, and detailed studies on selected drug/base formulations. PEG-20000 and Dynasan-114 were not examined in detail, after preliminary investigations had shown high viscosity and poor filling characteristics for PEG-20000 and poor dissolution characteristics for Dynasan-114. Dynafill provided good release profiles when formulated with a variety of model drugs (Acetohexamide, Ibuprofen, Indomethacin, Quinidine sulphate and Theophylline). Results from hot stage photomicrography supported by DSC and XRD were used to construct a phase diagram of the Ibuprofen/Lutrol-F68 system. The evidence from the phase diagram indicated the formulation of a simple eutectic system with no solid solubility and a eutectic composition at approximately 35% w/w Ibuprofen.     

Formulation studies on ibuprofen sodium–cationic dextran conjugate: effect on tableting and dissolution characteristics of ibuprofen

The effect of electrostatic interaction between ibuprofen sodium (IbS) and cationic diethylaminoethyl dextran (Ddex), on the tableting properties and ibuprofen release from the conjugate tablet was investigated. Ibuprofen exhibits poor flow, compaction (tableting) and dissolution behavior due to its hydrophobic structure, high cohesive, adhesive and viscoelastic properties therefore it was granulated with cationic Ddex to improve its compression and dissolution characteristics. Electrostatic interaction and hydrogen bonding between IbS and Ddex was confirmed with FT-IR and DSC results showed a stepwise endothermic solid–solid structural transformation from racemic to anhydrous forms between 120 and 175?°C which melted into liquid form at 208.15?°C. The broad and diffused DSC peaks of the conjugate granules as well as the disappearance of ibuprofen melting peak provided evidence for their highly amorphous state. It was evident that Ddex improved the flowability and densification of the granules and increased the mechanical and tensile strengths of the resulting tablets as the tensile strength increased from 0.67?±?0.0172 to 1.90?±?0.0038?MPa with increasing Ddex concentration. Both tapping and compression processes showed that the most prominent mechanism of densification were particle slippage, rearrangement and plastic deformation while fragmentation was minimized. Ddex retarded the extent of dissolution in general, indicating potentials for controlled release formulations. Multiple release mechanisms including diffusion; anomalous transport and super case II transport were noted. It was concluded that interaction between ibuprofen sodium and Ddex produced a novel formulation with improved flowability, tableting and dissolution characteristics with potential controlled drug release characteristics dictated by Ddex concentration.     

Synthesis and evaluation of novel polyester-ibuprofen conjugates for modified drug release

Ibuprofen was conjugated at different levels to a novel polyester, poly(glycerol-adipate-co-omega-pentadecalactone) (PGA-co-PL), via an ester linkage to form a prodrug. The conjugates were characterized by differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), infrared (IR), gel permeation chromatography (GPC), ultraviolet (UV), and high-performance liquid chromatography (HPLC). The conjugates had a molecular weight between 18 and 24 kDa, and there was a suppression of the free hydroxyl groups within the conjugated polymer. DSC scans showed a lowering of the melting point (T(m)) when compared with the polyester alone and a difference in the number and area of T(m) peaks. Drug release studies showed an initial burst release (13-18%) followed thereafter by very slow release (maximum 35% after 18 days). Continuous work may produce ester-linked conjugates that are sufficiently labile to allow for complete release of ibuprofen over the time period studied.     

Release Kinetics of Acyclovir from a Suspension of Acyclovir Incorporated in a Cubic Phase Delivery System

Acyclovir is a widely used agent in the treatment of herpes virus infections of the skin, but owing to its poor physicochemical properties in terms of bioavailability and suboptimal formulations, the treatment is far from optimal. The liquid crystalline cubic phase system has been reported to act as a bioadhesive drug delivery system. In the present study, acyclovir was suspended in a cubic phase of glycerol monooleate (GMO) and water 65%:35% w/w, and the phase behavior and release kinetics were examined. X-ray diffraction and differential scanning calorimetry (DSC) measurements demonstrated that the cubic phase containing 1%-10% (w/w) acyclovir retains its phase condition in the temperature range investigated (20°C-70°C). Acyclovir can be incorporated in high amounts (∼40% w/w) without causing phase transition, as is shown in polarized light. This is probably because of its low solubility (∼0.1% w/w) in the cubic phase. The release characteristics of acyclovir incorporated as a suspension (1%-5% w/w) into a cubic phase were investigated using Franz diffusion cells. Acyclovir was quantified by high-performance liquid chromatography (HPLC). The drug was readily released from the system, and the release increased with the initial drug load concentration. About 25%-50% was released after 24 h. The release is dependent on the square root of time, and the kinetics can be described by the Higuchi theory. The rate-limiting step in the release process is most likely diffusion. The suggested theory is further supported by identical release data obtained for micronized and nonmicronized acyclovir. The fluxes for 1% and 5% w/w were 380 and 900 μg/h^1/2, respectively. Comparison of the release rates of acyclovir delivered from a cubic phase and from the commercial product, Zovir® cream, showed the rate to be six times faster from the cubic phase. The results indicate that the cubic phase is a promising drug delivery system for acyclovir.     

PLA-PEG-PLA copolymer-based polymersomes as nanocarriers for delivery of hydrophilic and hydrophobic drugs: preparation and evaluation with atorvastatin and lisinopril

Tri-block poly(lactide)–poly(ethylene glycol)–poly(lactide) (PLA–PEG–PLA) copolymers were synthesized and used to prepare polymersomes loaded separately by the hydrophobic and hydrophilic model drugs, atorvastatin and lisinopril, respectively. The resulting nanostructures were characterized by various techniques such as FTIR, DSC, PCS and AFM. The polymersomes exhibited high encapsulation efficiencies of almost 78% and 70.8% for atorvastatin and lisinopril, respectively. Investigation on FTIR and DSC results revealed that such a high encapsulation efficiency is due to strong interaction between atorvastatin and the copolymer. The impact of drug/copolymer ratio and copolymer composition on drug-loading efficiency and drug release behavior were also studied. The results showed that in case of lisinopril, polymersomes exhibited a triphasic drug release, while for atorvastatin a biphasic release profile was obtained. Overall, the results indicated that PLA–PEG–PLA polymersomes can be considered as a promising carrier for both hydrophilic and hydrophobic drugs.     

Physical and chemical characterization of thermosoftened bases for molten filled hard gelatin capsule formulations

Abstract

Dynafill, Dynasan-114, Lutrol-F68, PEG-10000 and PEG-20000 have been examined as potential bases for the preparation of fusion formed solid dispersions for molten filling into hard gelatin capsules. Investigations included, an examination of thermal effects on crystal structure by DSC and XRD, a theological study to evaluate capsule filling characteristics, dissolution studies on drug/base formulations, chemical analysis for free fatty acid impurities in Dynafill and Dynasan-114, and detailed studies on selected drug/base formulations. PEG-20000 and Dynasan-114 were not examined in detail, after preliminary investigations had shown high viscosity and poor filling characteristics for PEG-20000 and poor dissolution characteristics for Dynasan-114. Dynafill provided good release profiles when formulated with a variety of model drugs (Acetohexamide, Ibuprofen, Indomethacin, Quinidine sulphate and Theophylline). Results from hot stage photomicrography supported by DSC and XRD were used to construct a phase diagram of the Ibuprofen/Lutrol-F68 system. The evidence from the phase diagram indicated the formulation of a simple eutectic system with no solid solubility and a eutectic composition at approximately 35% w/w Ibuprofen.     

Incorporation of paclitaxel solid dispersions with poloxamer188 or polyethylene glycol to tune drug release from poly(ϵ-caprolactone) films

Here we report the application of solid dispersion (SD) technique to improve paclitaxel (PTX) release from poly(?-caprolactone) (PCL)-based film. Paclitaxel solid dispersions (SDs) with either poloxamer188 (PXM) or polyethylene glycol (PEG) were successfully prepared by a melting method and then incorporated into PCL films, which were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and In vitro drug release/dissolution studies. It was found that PTX was faster released from the SDs than the corresponding physical mixtures (PMs) or PTX alone. For the PCL films with almost the same PTX loading, drug release from films containing SDs was remarkably faster than that from the film directly incorporated with PTX particles, and the films containing SDs with PXM exhibited a faster drug release than those with PEG. An increase In the content of PXM had no significant influence on PTX release from the films containing SDs. Incorporation of a higher content of SDs led to slower drug release from PCL films, indicating that PTX loading had a dominating effect on drug release. Through this study, we demonstrated the feasibility of the application of SD technique on the improvement of PTX release from PCL films and offered some beneficial information on modulating drug release behavior by changing the compositions and contents of the SDs-loaded PCL films.     

尼龙1010／66共聚物的热力学研究

本文研究了尼龙1010/66共聚物的熔点、熔程、熔融热和熔融熵等热力学参数与其组成的关系,其相图中最低共熔点时尼龙1010重量比为60～70％,与理论值相近,此时熔点、熔融热和熔融熵最低,熔程最大。