Nimodipine Solid Dispersions Research Articles

Formulation and Evaluation of Nimodipine Tablets Using Solid Dispersion Technique

The present study is an attempt to develop immediate release tablets of Nimodipine using solid dispersion technique to achieve rapid release in GIT which might result in enhanced absorption and thereby improved bioavailability. Various batches of Nimodipine solid dispersion (SD1-SD6) were prepared using fusion method, solvent evaporation and combination of these two methods (melt evaporation method/melting solvent method). PEG 6000 and PVP K30 were used as polymeric carrier in (drug: carrier) 1:1 ratio for all the formulations. Docusate sodium was used as surfactant in 0.025% to 0.085%. Drug-excipients interactions were carried out for pure drug and optimized formulations using FTIR studies. Six batches of Nimodipine immediate release tablets (F1 to F6) were developed by wet granulation method using its solid dispersion. Crospovidone was selected as super disintegrant and acetone as an organic solvent. All the batches of immediate release tablets were evaluated for different pre-compression and post-compression parameters including stability study of the optimized formulation. Among all formulations, F6 prepared by melt evaporation method with a high surfactant content showed the greatest drug release (101.49% ± 0.31%). The stability studies (formulation F6) showed there was no major differences in physical parameters and was stable even after a period of 3 months. % CDR of the accelerated time stability batch was 94.41% ± 0.265% of its content in 30 min which is showing immediate release and the drug content of the same stability batch was 99.87% ± 0.119%.

Formulation and characterization of nimodipine in situ gels for oral delivery

To formulate and evaluate Nimodipine floating in situ gels for oral delivery in order to enhance its residence time and to overcome the inherent drawbacks associated with conventional oral formulations like tablets and capsules. As Nimodipine is a BCS Class II drug, first Nimodipine solid dispersions were made to enhance its solubility. Solvent evaporation method was employed for this. Then in situ gel formulations were prepared using the optimized solid dispersion formulations. Sodium alginate and HPMC K100M were used as gelling agent and viscosifying agent respectively. In vitro characterization like gelling capacity, floating time, drug content, viscosity, % cumulative drug release studies were performed. In vivo pharmacokinetic parameters were studied. Infrared spectroscopy ruled out drug-excipient interactions. The release pattern showed a burst effect in the first 30 minutes followed by a moderate steady release for 12 hours. Stability testing indicated that the formulation remained stable with no significant changes in percent cumulative drug release and viscosity. In vivo pharmacokinetic study results were satisfactory. A promising, stable, sustained release, liquid oral floating in-situ gelling systems of Nimodipine were successfully developed and evaluated. Oral in situ gels could be good alternative for geriatric and pediatric population who have trouble swallowing solid medications.

Enhancement of the solubility and the dissolution rate of oral nimodipine formulation with solid dispersion

The present study was an attempt to enhance the dissolution rate of nimodipine (a poorly water-soluble drug), The objective of this study was to evaluate poloxamer 407 as a carrier for nimodipine solid dispersions. The solid dispersions of nimodipine with poloxamer 407 were prepared by the hot melting technique, the molar ratio (3:1). The physicochemical properties of Solid dispersion were investigated by Differential Scanning Calorimetry (DSC), powder x-ray diffraction (PXRD), and Fourier Transform Infrared (FT-IR) spectroscopy. The FT-IR spectra indicated there was no chemical interaction between nimodipine and poloxamer 407 in the solid dispersion. DSC analysis indicated a decrease in the melting point of nimodipine and poloxamer 407 in solid dispersion. The tablet form was prepared by wet granulation of nimodipine with a binder solution of poloxamer 407 and compressed the dried granules of nimodipine into non-friable, stable tablets. The other objective, the performance of two classes of super disintegrates as croscarmellose sodium (Ac-Di-Sol), and polyvinyl pyrrolidone K30 in the dissolution of nimodipine immediate release and promoting disintegration tablets was evaluated. The in-vitro dissolution was determined by using United States Pharmacopeia (USP) type II dissolution test apparatus. All the results indicated that enhancement of the dissolution rate of nimodipine has been done successfully and drug release Kinetics indicated that the drug dissolution was a diffusion equation.

Development, Solubility Enhancement and Characterization of Nimodipine Solid Dispersions

The main aim of this study was to formulate and characterize nimodipine solid dispersions using various novel polymers. Solid dispersions were prepared by solvent evaporation method in order to improve the solubility and overall bioavailability of nimodipine. Solubility and dissolution studies indicate that Kolliwax RH 40 is the most suitable polymer. The solubility studies was corresponded with dissolution data and the formulation SD15 was found to be having highest drug release of about 98.96 ± 5.15% in about 90 minutes. In vitro release data from several formulations containing Nimodipine was determined kinetically using different mathematical models like Zero order, First order, Higuchi, and Korsmeyer–Peppas model. XRD and SEM studies indicate no crystallinity in the optimized formulation SD15. FTIR studies suggested good drug excipient compatibility between all components of prepared formulation. These results confirm the viability of enhancing the solubility of nimodipine by formulating the drug as solid dispersions in Kolliwax.

Cooperative effect of polyvinylpyrrolidone and HPMC E5 on dissolution and bioavailability of nimodipine solid dispersions and tablets

Solid dispersion (SD) systems have been extensively used to increase the dissolution and bioavailability of poorly water-soluble drugs. To circumvent the limitations of polyvinylpyrrolidone (PVP) dispersions, HPMC E5 was applied in the formulation process and scaling-up techniques, simultaneously. In this study, SD of nimodipine (NMP) and corresponding tablets were prepared through solvent method and fluid bed granulating one step technique, respectively. Discriminatory dissolution media were used to obtain reliable dissolution results. Meanwhile, the stability study of SDs was investigated with storage under high temperature and humidity conditions. Moreover, the solubility of SDs was measured to explore the effect of carriers. The preparations were characterized by DSC, PXRD, and FTIR. Dramatical improvements in the dissolution rate of NMP were achieved by the ingenious combination of the two polymers. Binary NMP/PVP/HPMC-SDs released steadily, while the dissolution of single NMP/PVP-SDs decreased rapidly in water. The fluid-bed tablets (FB-T) possessed a similar dissolution behavior to the commercial Nimotop™ tablets. The characterization patterns implied that NMP existed in an amorphous state in our SDs. Furthermore, the results of stability tests suggested a better stability of the binary SDs. A special cooperative effect of PVP and HPMC was discovered on dissolution characteristics of NMP SDs and tablets, which could be extended to other drugs henceforth. Finally, the bioavailability of FB-T was evaluated in beagle dogs with Nimotop™ as the reference, and the results showed a higher AUC0–12hvalue for FB-T.

Effect of HPMCAS on recrystallization inhibition of nimodipine solid dispersions prepared by hot-melt extrusion and dissolution enhancement of nimodipine tablets.

In current study, a novel nimodipine solid dispersion (NM-SD) was prepared by hot-melt extrusion (HME) with Hypromellose methylcellulose acetate succinate (H type and fine grades, HPMCAS-HF) for its excellent recrystallization inhibition effects. NM was confirmed to exist as an amorphous state in NM-SD by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), hot stage microscopy (HSM) and scanning electron micrographs (SEM). FT-IR analysis illustrated hydrogen bond interaction between drugs and excipients in NM-SD. The release behavior of NM-SD tablets was investigated in the dissolution medium of pH 6.8 for the in vitro study, which showed that the release of nimodipine could be realized in vitro without recrystallization within two hours. The in vivo pharmacokinetic profiles study in Sprague-Dawley rats was also determined. It was obvious that the Cmax value of NM-SD tablets made by dry granulation was slightly higher than Nimotop®, while the area under the curve, AUC(0-t) exhibited no significant difference between them. In conclusion, the solubility of NM and dissolution rate of NM-SD tablets were greatly improved by HME due to the recrystallization inhibition characteristic of HPMCAS-HF.

Preparation and In Vivo Evaluation of Nimodipine Solid Dispersions

Preparation and In Vivo Evaluation of Nimodipine Solid Dispersions

HSA induced HCPT nanocrystal for high-performance antitumor therapy

The aim of this study was to prepare solid dispersion of nimodipine (NMD) by solvent evaporation method to overcome the poor water solubility of NMD, and to formulate controlled-release (CR) tablets containing the NMD solid dispersion. NMD is a dihydropyridine calcium-channel antagonist that is practically insoluble in water. Owing to the short half-life of the drug in the plasma, NMD immediate-release tablets should be administered frequently for the treatment and prevention of ischemic disorders following aneurysmal subarachnoid hemorrhage. In this study, solid dispersion technique was applied to increase the low solubility of NMD. Carriers for solid dispersions were prepared with different kinds of hydrophilic polymers. Kinetic solubility studies were performed for the prepared solid dispersions, using sodium acetate buffer (pH 4.5). Solid dispersions were then characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectrometry (FT-IR). CR tablets containing the NMD-PVP K30 solid dispersions were designed to reduce the dosing interval and increase patient compliance. Hydroxypropyl methylcelluloses (HPMC) were used as release-modifiers, and lactose anhydrous as a diluent.

Controlled-release oral dosage forms containing nimodipine solid dispersion and hydrophilic carriers

The aim of this study was to prepare solid dispersion of nimodipine (NMD) by solvent evaporation method to overcome the poor water solubility of NMD, and to formulate controlled-release (CR) tablets containing the NMD solid dispersion. NMD is a dihydropyridine calcium-channel antagonist that is practically insoluble in water. Owing to the short half-life of the drug in the plasma, NMD immediate-release tablets should be administered frequently for the treatment and prevention of ischemic disorders following aneurysmal subarachnoid hemorrhage. In this study, solid dispersion technique was applied to increase the low solubility of NMD. Carriers for solid dispersions were prepared with different kinds of hydrophilic polymers. Kinetic solubility studies were performed for the prepared solid dispersions, using sodium acetate buffer (pH 4.5). Solid dispersions were then characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectrometry (FT-IR). CR tablets containing the NMD-PVP K30 solid dispersions were designed to reduce the dosing interval and increase patient compliance. Hydroxypropyl methylcelluloses (HPMC) were used as release-modifiers, and lactose anhydrous as a diluent.

Enhanced hypotensive effect of nimodipine solid dispersions produced by supercritical CO2 drying

Solid dispersions of nimodipine and PVP K-30 were prepared by supercritical fluid technology at three drug:carrier ratios (1:9, 2:8, 3:7, w/w). The samples were characterized by X-ray powder diffraction, infrared spectroscopy and scanning electron microscopy, and evaluated by means of their solubility, dissolution rate and hypotensive effect. The solid dispersion with the highest amount of PVP K-30 (SD 1:9) presented an amorphous state, a porous surface and hydrogen bonds between nimodipine and the carrier. On the other hand, the other solid dispersions were semicrystalline. All formulations enhanced the solubility and dissolution rate of nimodipine and the best results were found for SD 1:9. This formulation promoted an increase of more than 1300% in the solubility of nimodipine, besides releasing 100% of the drug within 5min. When submitted to in vivo studies SD 1:9 decreased significantly the mean arterial pressure and also reduced its phenylephrine-induced increase.

Dissolution Enhancement and Characterization of Nimodipine Solid Dispersions with Poloxamer 407 or PEG 6000

The solid dispersion approach is an alternative to increase drug solubility. Many carriers have been studied, but there is few information about poloxamer 407 (P407). Consequently, the objective of this study was to evaluate P407 as a carrier for nimodipine solid dispersions and to compare its solubility and dissolution rates with those from polyethylene glycol (PEG 6000). The solid dispersions were prepared by the hot melting and solvent methods and they were characterized by FTIR, DSC, solubility, and dissolution tests. The results indicated a three-fold increase in solid dispersions solubility in the presence with P407 than those prepared with PEG.

The Inhibition Effect of High Storage Temperature on the Recrystallization Rate During Dissolution of Nimodipine–Kollidon VA64 Solid Dispersions (NM–SD) Prepared by Hot-Melt Extrusion

Nimodipine (NM) solid dispersions (SD) were prepared by hot-melt extrusion with polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA; Kollidon VA64) as the carrier, then the extrudate was stored at different temperatures (20°C, 40°C, 60°C) after milling. Conventional differential scanning calorimetry and powder X-ray diffraction revealed that the drug was present as an amorphous state in the carrier. The dissolution curves of NM from SD at 37°C in water showed that the rate of recrystallization for NM from SD stored at high temperatures was slower than that from room temperature. The single glass transition temperature (T(g) ) measured by modulated temperature DSC remained constant around 89°C and indicated that the amorphous state of the compound was not altered by heating. However, the C=O vibration of the amide function of Kollidon VA64 increased from 1658 to 1675 cm(-1) was observed in infrared spectra and implied the weakness of H-bonding between the compound and the polymer. The above-mentioned experiments clued to us that suitable postcooking for a short time is good for SD; however, the mechanisms of the changes were still not clear and need further investigation.

Nimodipine (NM) tablets with high dissolution containing NM solid dispersions prepared by hot-melt extrusion

Using a mixture of Eudragit® EPO and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) (Kollidon VA64) as carriers, a nimodipine solid dispersion (NM-SD) was prepared by hot-melt extrusion (HME) to achieve high dissolution. The dissolution profiles in 900 mL 0.1 mol/L HCl showed that the drug release of NM-SD reached 90% in 1 h. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) were used to characterize the state of NM. The results obtained showed that NM was in an amorphous form in the solid dispersion (SD). NM-SD tablets (NM-T-SD) were compressed by wet granulation and direct compression, respectively. The stability of NM-T-SD was examined during a 2-month storage period (40°C, RH 75%). The results showed that the dissolution of NM-T-SD was slightly reduced after 2 months storage (40°C, RH 75%), which implied that aging occurred to some degree. However, no NM crystals could be observed by PXRD after 2 months storage for NM-T-SD (F11) prepared by direct compression.

Nimodipine semi-solid capsules containing solid dispersion for improving dissolution

The aim of this study was to improve the dissolution and, therefore, bioavailability of the poorly water-soluble and highly permeable drug nimodipine (NMD). Present research involved the preparation of a solid dispersion (SD) consisting of NMD, Eudragit-E100 and Plasdone-S630 by hot-melt extrusion (HME). Compared with pure drug and physical mixture, the dissolution of NMD was enhanced dramatically (about 80% within 30 min). Adding the nimodipine solid dispersion (NMD-SD) powder to a mixture of Plasdone-S630 and PEG400, and then transferring it to hard HPMC capsules, resulted in nimodipine semi-solid capsules (NMD-SSC). The dissolution from NMD-SSC was increased further (about 95% in 20 min). In addition, the relative bioavailability of the NMD-SSC (test) and Nimotop ® (reference) was determined in beagle dogs after a single dose (120 mg NMD) in a randomized crossover, own-control study. The results suggested that there was no significant difference in the areas under the plasma concentration–time curve and the mean peak concentration between NMD-SSC (AUC 0–∞ = 2488 ± 433 ng h mL −1, C max = 321 ± 78 ng ml −1) and Nimotop ® (AUC 0–∞ = 2272 ± 398 ng h mL −1, C max = 293 ± 73 ng mL −1) ( P > 0.05). However, the apparent rate of absorption of NMD from NMD-SSC ( t max = 1.3 h) was markedly faster than that from Nimotop ® ( t max = 3.1 h) ( P < 0.05), which indicates that as a fast release preparation, NMD-SSC is well absorbed.

Part II: Bioavailability in Beagle Dogs of Nimodipine Solid Dispersions Prepared by Hot-Melt Extrusion

ABSTRACTThe aim of the present work was to investigate the in vitro dissolution properties and oral bioavailability of three solid dispersions of nimodipine. The solid dispersions were compared with pure nimodipine, their physical mixtures, and the marketed drug product Nimotop®. Nimodipine solid dispersions were prepared by a hot-melt extrusion process with hydroxypropyl methylcellulose (HPMC, Methocel E5), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA, Plasdone S630®), and ethyl acrylate, methyl methacrylate polymer (Eudragit® EPO). Previous studies of XRPD and DSC data showed that the crystallinity was not observed in hot-melt extrudates, two Tgs were observed in the 30% and 50% NMD-HPMC samples, indicating phase separation. The weakening and shift of the N–H stretching vibration of the secondary amine groups of nimodipine as determined by FT-IR proved hydrogen bonding between the drug and polymers in the solid dispersion. The dissolution profiles of the three dispersion systems showed that the release was improved compared with the unmanipulated drug. Drug plasma concentrations were determined by HPLC, and pharmacokinetic parameters were calculated after orally administering each preparation containing 60 mg of nimodipine. The mean bioavailability of nimodipine was comparable after administration of the Eudragit® EPO solid dispersion and Nimotop®, but the HPMC and PVP/VA dispersions exhibited much lower bioavailability. However, the AUC0–12 hr values of all three solid dispersions were significantly higher than physical mixtures with the same carriers and nimodipine powder.