Preparation and Evaluation of Sustained-Release Solid Dispersions of Drugs with Eudragit Polymers

Coevaporates of paracetamol and rifampicin with Eudragit polymers of different natures (anionic, cationic, and zwitterionic) were prepared. Determination of dissolution rate of these coevaporates in dissolution media simulating those of the gastrointestinal tract (GIT) revealed that the release rate of paracetamol is retarded from all the coevaporates studied. In this respect, Eudragit L100-SS shows the highest sustainment of drug release, while Eudragit E100 shows the lowest. Conversely, the release of rifampicin from its coevaporates with the anionic Eudragit S100 polymer is more retarded than the corresponding coevaporate with the zwitterionic Eudragit RL100 or from coevaporates with equal mixtures of the two polymers.

Increasing the polymer weight fraction in rifampicin coevaporates with Eudragit S100 up to 0.5 resulted in a corresponding decrease in the dissolution rate. However, beyond this weight fraction, the polymer effect on the dissolution rate of the drug becomes minimized. The results confirmed that the process of dissolution of the two drugs from their coevaporates is a diffusion-controlled release process.

The biological performance of paracetamol coevaporates was monitored in rabbits; paracetamol level in plasma was found to follow first-order kinetics. for all the investigated paracetamol coevaporates, the peak plasma level was less than 50 μg/ml compared to a value of 60, μg/ml for the drug per se. The coevaporates of the drug with Eudragit L100-55 showed slowest rates of absorption and elimination as well as greatest half-peak and half-life times. Biological peformance of rifampicin coevaporates was assessed in human subjects receiving a single oral dose equivalent to 300 mg of the drug. The results depicted sustainment of drug release as a function of polymer weight fraction. A strict correlation was shown to exist between the total amount of drug excreted during 24 hr post dosing of the coevaporates and its in vitro dissolution rate.

The results depicted that paracetamol can be formulated in the form of a coevaporate with Eudragit L100-55 to prepare a more safe sustained-release formulation with minimal side effects, and also revealed the advantages of administration of rifampicin in the form of a coevaporate with Eudragit S100 (4:1) at a single oral dose equivalent to 600 mg of drug.     

Preparation,Characterization and In Vitro Evaluation of Solid Dispersions Containing Docetaxel

Solid dispersions using water-soluble carriers were studied for improving the dissolution of docetaxel, a poorly soluble compound. In order to obtain the most optimized formulation, we prepared many solid dispersions with different carriers, different solvents, or at a series of drug-to-carrier ratios, and compared their dissolution. The accumulative dissolution of docetaxel from poloxamer 188 was more excellent than that from PVP_k30 and glyceryl monostearate, and the dissolution of docetaxel from solid dispersion was markedly higher than that of pure docetaxel; meanwhile the increased dissolution was partly dependent on the ratios of docetaxel and poloxamer 188. The ethanol used to prepare solid dispersion is of more significant effect on the dissolution of docetaxel than that of acetone. The docetaxel/poloxamer 188 system was characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and environmental scanning electron microscope (ESEM). The results of DSC, XRD, and ESEM analyses of docetaxel/poloxamer 188 system showed that there are intermolecular interactions between docetaxel and poloxamer, and the crystallinity of docetaxel disappeared. These results show that solid dispersion is a promising approach of developing docetaxel drug formulates.     

Evaluation of Solid Dispersions of Clofazimine

ABSTRACT

Clofazimine (CLF) was formulated with polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) as a solid solid dispersion (SSD) to increase the aqueous solubility and dissolution rate of the drug. Different molecular weights of PEG (1500, 4000, 6000, and 9000 Da) and PVP (14,000 and 44,000 Da) were used in different drug:carrier weight ratios (1:1, 1:5, and 1:9) and their effect on the dissolution performance of the drug was evaluated in USP Type 2 apparatus using 0.1 N HCl medium. The dissolution rate was compared with corresponding physical mixtures, a currently marketed soft gelatin capsule product, and free CLF. The effect of different methods of preparation (solvent/melt) on the dissolution rate of CLF was evaluated for PEG solid dispersions. Saturation solubility and phase solubility studies were carried out to indicate drug:carrier interactions in liquid state. Infrared (IR) spectroscopy and X-ray diffraction (XRD) were used to indicate drug:carrier interactions in solid state. Improvement in the drug dissolution rate was observed in solid dispersion formulations as compared to the physical mixtures. The dissolution rate improved with the decreasing weight fraction of the drug in the formulation. Polyvinyl pyrrolidone solid dispersion systems gave a better drug release profile as compared to the corresponding PEG solid dispersions. The effect of molecular weight of the PEG polymers did not follow a definite trend, while PVP 14,000 gave a better dissolution profile as compared to PVP 44,000. Improvement in saturation solubility of the drug in the solid dispersion systems was noted in all cases. Further, IR spectroscopy indicated drug:carrier interactions in solid state in one case and XRD indicated reduction in the crystallinity of CLF in another. It was concluded that solid-dispersion formulations of Clofazimine can be used to design a solid dosage form of the drug, which would have significant advantages over the currently marketed soft gelatin capsule dosage form.     

Preparation and Characterization of Solid Dispersions of Piroxicam with Hydrophilic Carriers

ABSTRACT

The objective of this study was to improve the dissolution rate of a poor water soluble drug, piroxicam, by solid dispersion technique. Solid dispersions were prepared by three different methods depending on the type of carrier. The dissolution rate of piroxicam was markedly increased in solid dispersion of myrj 52, Eudragit® E100 and mannitol. Solubility studies revealed a marked increase in the solubility of piroxicam with an increase in myrj 52 and Eudragit® E100 concentrations. Data from the X-ray diffraction and FT-IR spectroscopy showed that piroxicam was amorphous in the solid dispersions prepared with dextrin and Eudragit® E100.     

Chemometric Modelling of Dissolution Rates of Griseofulvin From Solid Dispersions With Polymers

The quantitative relationship between the release rate of griseofulvin and the chemical and physical properties of a series of polymers, used for the preparations of solid dispersions, was investigated by the application of multiple regression analysis (MRA), partial least square analysis (PLS) and a new non linear chemometric procedure called CARSO (Computer Aided Response Surface Optimization).

It was confirmed that the degree of crystallinity of griseofulvin and the wettability of the powder samples are important in the dissolution mechanism and in the prediction of dissolution profiles of griseofulvin from these solid dispersions.     

Chemometric Modelling of Dissolution Rates of Griseofulvin From Solid Dispersions With Polymers

Abstract

The quantitative relationship between the release rate of griseofulvin and the chemical and physical properties of a series of polymers, used for the preparations of solid dispersions, was investigated by the application of multiple regression analysis (MRA), partial least square analysis (PLS) and a new non linear chemometric procedure called CARSO (Computer Aided Response Surface Optimization).

It was confirmed that the degree of crystallinity of griseofulvin and the wettability of the powder samples are important in the dissolution mechanism and in the prediction of dissolution profiles of griseofulvin from these solid dispersions.     

Preparation and Evaluation of Eudragit E Microspheres Containing Bacampicillin

Abstract

Microspheres with bacampicillin were prepared by the solvent evaporation method using systems methanol, acetone and methyl acetate/liquid paraffin and Eudragit E as polymer. Sieve analysis showed that the particle size of the microspheres follows log - normal distribution with average size of 123, 206 and 300 μm, respectively. Scanning electron microscopy was used to prove that all chosen systems provided the particles of regular spherical shape without aggregation

HPLC method was developed for testing drug content, drug stability and dissolution. The results of HPLC analysis showed the exisistence of degradation products of bacampicillin in microspheres prepared by the use of all three solvents. The degree of degradation was the lowest in the case of methyl acetate. The experimental values of dissolution profiles fit well to 0. order and combined 0. and t^½ order. The comparison of dissolution profiles of microspheres and bacampicillin itself shows that microspheres produce retard effect and therefore bacampicillin is not expected to be released in saliva after peroral administration of microspheres     

Preparation and in Vitro Dissolution Profiles of Tolazamide-Polyethylene Glycol Solid Dispersions

The objective of this study is to prepare solid dispersions of tolazamide (TLZ) using polyethylene glycol (PEG) and measure the dissolution of TLZ. PEG 8000 was used as carrier to prepare solid dispersions by melt and solvent methods. Dissolution studies indicated a remarkable increase in the rate of dissolution of TLZ when dispersed in PEG as well as with physical mixture of TLZ and PEG. The rate of dissolution of TLZ was faster with solid dispersions containing TLZ:PEG (1:5) and (1:10) compared to physical mixtures and pure TLZ. The effect of buffer on dissolution was studied. In general the dissolution of TLZ was less in phosphate buffered saline (PBS, pH 7.4) compared to Tris buffer. However, there was no significant difference in the extent of dissolution of TLZ from solid dispersions and physical mixture compared to pure TLZ. Solid dispersions prepared by solvent method showed faster dissolution rates compared to melt method. These results suggest that the rate of dissolution can be increased by improving the wetting property of tolazamide.     

Lonidamine Solid Dispersions: In Vitro and In Vivo Evaluation

ABSTRACT

Solid dispersions of lonidamine in PEG 4000 and PVP K 29/32 were prepared by the spray-drying method. Then, the binary systems were studied and characterized using differential scanning calorimetry, hot stage microscopy, and x-ray diffractometry. In vitro dissolution studies of the solid dispersed powders were performed to verify if any lonidamine dissolution rate or water solubility improvement occurred. In vivo tests were carried out on the solid dispersions and on the cyclodextrin inclusion complexes to verify if this lonidamine water solubility increase was really able to improve the in vivo drug plasma levels. Drug water solubility was increased by the solid dispersion formation, and the extent of increase depended on the polymer content of the powder. The greater increase of solubility corresponded to the highest content of polymer. Both the solid dispersions and the cyclodextrin complexes were able to improve the in vivo bioavailability of the lonidamine when administered per os. Particularly, the AUC of the drug plasma levels was increased from 1.5 to 1.9-fold depending on the type of carrier.     

Preparation and Evaluation of A Sustained-Release Ophthalmic Vehicle for Dapiprazole

Abstract

The present investigation is concerned with the development and “in vivo” evaluation of a long-acting ocular vehicle for the α-adrenergic blocking drug dapiprazole (DAP). The approaches tested for prolonging the activity were a) salification of the drug base with polygalacturonic acid (PGA), and b) formulation as a highly viscous hydrogel. The vehicles prepared by applying (singly or in combination) these techniques, and two reference aqueous vehicles containing DAP-HCl were submitted to a series of biological tests on rabbits (miosis and reversion of mydriasis). When compared with an aqueous solution an aqueous solution, reconstituted prior to use from a freeze-dried formulation (marketed in Italy as Glamidolo^R, Angelini)

The topical administration of ophthalmic drugs from aqueous solutions (collyria) is characterized by a poor bioavailability and a short duration of action, as a result of a series of concomitant physiological factors (induced lacrimation, tear turnover, solution drainage etc.) which concur in removing the solution from the eye. These factors have been widely investigated and detailed in the relevant literature, and several approaches to extend the ocular residence time of topically applied medications have been reported (4). In the present study two such approaches, namely, a) salification of the basic drug with a polyanionic polymer and b) increased vehicle viscosity, were applied to the development of a long-acting ocular formulation for DAP. The effect of the said manipulations on the biological activity of a series of DAP vehicles was submitted to a preliminary verification “in vivo”, by performing miosis and reversion of tropicamide-induced mydriasis tests in rabbits     

Dissolution, Bioavailability and Ulcerogenic Studies on Solid Dispersions of Indomethacin in Water Soluble Cellulose Polymers

The dissolution rate, bioavailability and ulcerogenic activity of indomethacin dispersed in water soluble cellulose polymers was investigated. Solid dispersions of indomethacin in hydroxypropyl cellulose-SL (HPC-SL), hydroxypropylmethyl cellulose (HPMC) and hydroxyethyl cellulose (HEC) were prepared by common solvent method with a view to improve its dissolution and absorption characteristics. The dispersions were evaluated by X-ray diffraction, TLC, IR, dissolution rate, bioavailability and ulcerogenic studies. TLC and IR studies indicated no interaction between indomethacin and carriers. Indomethacin in the dispersions was found to be in amorphous form. Marked increase in the dissolution rate and efficiency of indomethacin was observed in the case of solid dispersions. HPC-SL gave the highest dissolution improvement. A 30-fold increase in dissolution was observed with indomethacin-HPC-SL (9:1) dispersion.

In vivo studies in human subjects showed a significant increase in absorption rate (k_a) and serum levels of indomethacin with solid dispersions when compared to indomethacin alone. However, the extent of bioavailabilty was the same with both indomethacin and its solid dispersions. About 70-80 per cent reduction in ulcerogenic activity was observed with solid dispersions and the dispersions were found to have negligible ulcerogenic activity.     

Preparation and Evaluation of a Sustained-Release Formulation of Nifedipine HPMC Tablets

A nifedipine (NF) polyethylene glycol (PEG) solid dispersion was prepared. Using this solid dispersion, NF hydroxypropylmethylcellulose (HPMC) matrix tablets were prepared. Both the high-viscosity grade HPMC (Methocel K15M) and low-viscosity grade HPMC (Methocel K100) were applied in the tablets to form the matrix. The dissolution and absorption of NF from the tablet were evaluated as a formulation that had a sustained release over 24 hr. The Hixson-Crowell equation and Higuchi equation were used to investigate the dissolution mechanism, and the erosion and diffusion codependent mechanism was established. Adalat GITS 30 was used as a reference dosage form. Each beagle dog was also administered an intravenous injection to obtain the pharmacokinetics parameters. The Loo-Riegelman method was applied to study the in vitro/in vivo correlation of the tested tablets and Adalat GITS 30, and significant correlation was proved. Absolute bioavailability and comparative bioavailability of the tested tablet were studied. The results indicated that the NF HPMC tablet could be an ideal 24-hr sustained-release formulation.     

Preparation,Characterization, and Evaluation of Liposomal Dispersions of Lidocaine

Abstract

Lidocaine, a local anesthetic agent, was encapsulated into liposomes employing the conventional lipid-film hydration technique. An attempt was made to freeze dry the aqueous liposomal dispersions. The prepared liposomal dispersions were investigated by differential scanning calorimetry (DSC), transmission electron microscopy (TEM), scanning electron microscopy (SEM), ³¹ P-nuclear magnetic resonance (NMR) spectroscopy, and laser counting studies for characterization. The skin partition coefficient for liposomal lidocaine was calculated. The results showed that lidocaine incorporated into the liposomes got selectively partitioned and localized in the skin to a great extent. A topical liposomal gel formulation containing 2% w/w lidocaine was prepared using Carbopol-934 as the gelling agent. The prepared formulation was tested for its local anesthetic efficacy employing the pinprick test. The liposomal preparation of lidocaine gave a much longer duration of action compared to the conventional topical formulation.     

Preparation, Characterization, and Evaluation of Liposomal Dispersions of Lidocaine

Lidocaine, a local anesthetic agent, was encapsulated into liposomes employing the conventional lipid-film hydration technique. An attempt was made to freeze dry the aqueous liposomal dispersions. The prepared liposomal dispersions were investigated by differential scanning calorimetry (DSC), transmission electron microscopy (TEM), scanning electron microscopy (SEM), ³¹ P-nuclear magnetic resonance (NMR) spectroscopy, and laser counting studies for characterization. The skin partition coefficient for liposomal lidocaine was calculated. The results showed that lidocaine incorporated into the liposomes got selectively partitioned and localized in the skin to a great extent. A topical liposomal gel formulation containing 2% w/w lidocaine was prepared using Carbopol-934 as the gelling agent. The prepared formulation was tested for its local anesthetic efficacy employing the pinprick test. The liposomal preparation of lidocaine gave a much longer duration of action compared to the conventional topical formulation.     

Preparation of Budesonide-Poly (Ethylene Oxide) Solid Dispersions Using Supercritical Fluid Technology

The purpose of this study was to investigate the possibility of preparing solid dispersions of the poorly soluble budesonide by supercritical fluid (SCF) technique, using poly (ethylene oxide) (PEO) as a hydrophilic carrier. The budesonide-PEO solid dispersions were prepared, using supercritical carbon dioxide (SC CO₂) as the processing medium, and characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), solubility test and dissolution test in order to understand the influence of the SCF process on the physical status of the drug. The endothermic peak of budesonide in the SCF-treated mixtures was significantly reduced, indicating that budesonide was in amorphous form inside the carrier system. This was further confirmed by SEM and PXRD studies. The enhanced dissolution rates of budesonide were observed from SCF-treated budesonide-PEO mixtures. The amorphous characteristic of the budesonide, the better mixing of drug and PEO powders in the presence of SC CO₂, together with the improved wettability of the drug in PEO, produced a remarkable enhancement of the in vitro drug dissolution rate. Thus, budesonide-PEO solid dispersions with enhanced dissolution rate can be prepared using organic solvent-free SCF process.     

Carbamazepine and Polyethylene Glycol Solid Dispersions: Preparation, in Vitro Dissolution, and Characterization

The objective of this study was to prepare solid dispersions of carbamazepine (CBZ) using polyethylene glycol (PEG) 4000 and PEG 6000, measure the dissolution, and characterize using x-ray diffraction, DSC, and IR spectroscopy. Solid dispersions were prepared by either the melt or solvent methods. A comparison of dissolution profiles of the solid dispersions indicated dramatic increases in the rate and extent of CBZ dissolution from solid dispersions. The dissolution of physical mixtures provided evidence of the solubilizing effects of PEGs. Untreated CBZ exhibited 10.09 ± 2.92% dissolution in 10 min (D_l0); whereas, a melt of PEG 6000 and CBZ at a ratio of 6: 1 provided 36.49 ± 1.97% and a melt of PEG 4000 and CBZ at a ratio of 6: 1 gave a D₁₀ of 23.59 ± 1.45%. The rate and extent of dissolution of CBZ were significantly higher when blends of the PEGs were employed to prepare solid dispersion. The melt method provided significantly higher rate and extent of dissolution of CBZ than the solvent method. Also, the rate and extent of dissolution of CBZ were significantly greater when the solid dispersion was cooled at room temperature as opposed to with ice (faster). X-ray diffractometry revealed almost a complete loss of crystallinity of CBZ in solid dispersions. IR spectrometry indicated an increase in amorphocity of the PEGs after melting. IR spectra suggested that no complexation occurred between the PEGs and CBZ. Alterations in the crystallinity of the system were also supported by the DSC thermograms. Decreasing heats of fusion implied decrease in crystallinity, which would be expected to provide greater dissolution rates. Peak melting temperatures obtained from the thermograms ruled out the possibility of the formation of a eutectic mixture. However, the formation of solid solution could also be a possible mechanism for the increase in dissolution.     

Carbamazepine and Polyethylene Glycol Solid Dispersions: Preparation,in Vitro Dissolution,and Characterization

Abstract

The objective of this study was to prepare solid dispersions of carbamazepine (CBZ) using polyethylene glycol (PEG) 4000 and PEG 6000, measure the dissolution, and characterize using x-ray diffraction, DSC, and IR spectroscopy. Solid dispersions were prepared by either the melt or solvent methods. A comparison of dissolution profiles of the solid dispersions indicated dramatic increases in the rate and extent of CBZ dissolution from solid dispersions. The dissolution of physical mixtures provided evidence of the solubilizing effects of PEGs. Untreated CBZ exhibited 10.09 ± 2.92% dissolution in 10 min (D_l0); whereas, a melt of PEG 6000 and CBZ at a ratio of 6: 1 provided 36.49 ± 1.97% and a melt of PEG 4000 and CBZ at a ratio of 6: 1 gave a D₁₀ of 23.59 ± 1.45%. The rate and extent of dissolution of CBZ were significantly higher when blends of the PEGs were employed to prepare solid dispersion. The melt method provided significantly higher rate and extent of dissolution of CBZ than the solvent method. Also, the rate and extent of dissolution of CBZ were significantly greater when the solid dispersion was cooled at room temperature as opposed to with ice (faster). X-ray diffractometry revealed almost a complete loss of crystallinity of CBZ in solid dispersions. IR spectrometry indicated an increase in amorphocity of the PEGs after melting. IR spectra suggested that no complexation occurred between the PEGs and CBZ. Alterations in the crystallinity of the system were also supported by the DSC thermograms. Decreasing heats of fusion implied decrease in crystallinity, which would be expected to provide greater dissolution rates. Peak melting temperatures obtained from the thermograms ruled out the possibility of the formation of a eutectic mixture. However, the formation of solid solution could also be a possible mechanism for the increase in dissolution.     

Preparation and Preliminary Evaluation of Eudragit RL and RS Pseudolatices for Controlled Drug Release

Eudragit RL and RS pseudolatices were prepared by the solvent change technique, which consisted of dissolving the polymer in a water miscible organic solvent or in a mixed water miscible organic solvent system, followed by dispersian in deionized water under mild agitation. The organic solvent (s) was removed from the aqueous organic solution to leave a stable Eudragit latex.

Eudragit pseudolatex coated theophylline pellets were prepared in a fluidized-bed coating machine. The effects of polymer type and coating level, plasticizer concentration, and PH of the dissolution medium on drug release were investigated. The higher content of quaternary ammonium groups attached to the polymer backbone make the coatings produced from Eudragit RL too water sensitive; and hence unsuitable for controlling theophylline release. On the other hand, Eudragit RS films retarded theophylline release. On the other hand, Eudragit RS films retarded theophylline release over a wide pH range. Release of the drug was found to be a function of the polymer coating level, plasticizer concentration and dependent on pH of the dissolution medium.     

The Release Rate of Indomethacin from Solid Dispersions with Eudragite

Abstract

The coprecipitates were prepared by a solvent technique using Eudragit E as carrier and indomethacin as a model drug.

X-Ray diffractometry, differential scanning calorimetry (DSC) and wettability tests were employed to investigate the physical state of the studied formulations. Up to 50% of indomethacin can be dispersed in an amorphous state in Eudragit E.

The influence of the pH on the in vitro release of solid dispersions has been evaluated. Because of the good solubility of Eudragit E at pH 1.2 a fast dissolution rate of the drug was observed while a marked delay was noticed at pH 7.5 where the polymer is only permeable to water. At pH 5.8 the kinetics of drug release can be modulated by the drug/polymer ratio. The dissolution rate of the drug can be increased by decreasing its amount in the coevaporate.     

The Release Rate of Indomethacin from Solid Dispersions with Eudragite

The coprecipitates were prepared by a solvent technique using Eudragit E as carrier and indomethacin as a model drug.

X-Ray diffractometry, differential scanning calorimetry (DSC) and wettability tests were employed to investigate the physical state of the studied formulations. Up to 50% of indomethacin can be dispersed in an amorphous state in Eudragit E.

The influence of the pH on the in vitro release of solid dispersions has been evaluated. Because of the good solubility of Eudragit E at pH 1.2 a fast dissolution rate of the drug was observed while a marked delay was noticed at pH 7.5 where the polymer is only permeable to water. At pH 5.8 the kinetics of drug release can be modulated by the drug/polymer ratio. The dissolution rate of the drug can be increased by decreasing its amount in the coevaporate.