Solidification Studies of Polyethylene Glycols,Gelucire 44/14 or their Dispersions with Triamterene or Temazepam

The solidification of polyethylene glycols (PEG 1500, PEG 2000, PEG 4000, PEG 6000), gelucire 44/14 or their dispersions containing triamterene or temazepam were studied to assess the feasibility of using these dispersions to liquid-fill hard gelatin capsules. Solidification from melts, investigated by differential scanning calorimetry using cooling cycles, showed a tendency of the drugs, carriers or their dispersions to supercool. The degree of supercooling depended on the rate of cooling, the drug content and, for the PEGs, on the molecular weight. PEG 1500 and PEG 2000 gave one morphological form, irrespective of cooling rate; PEG 4000 and PEG 6000 solidified into at least two forms, depending on the cooling rate. Incorporation of drugs affected the morphology of the PEGs during solidification. The rate of crystal growth was, furthermore, influenced by the fusion temperature, molecular weight and the degree of supercooling. The degree of crystallinity, as measured by the enthalpies of solidification, decreased with increasing cooling rate. The results show that reducing the rate of solidification could lead to incomplete solidification, giving products that are liable to change on storage.     

Solubilization behavior of poorly soluble drugs with combined use of Gelucire 44/14 and cosolvent

Gelucire 44/14 is a surface-active excipient that can solubilize poorly soluble drugs. We investigated its solubilization behavior when coexisting with dimethylacetoamide (DMA) or dimethylsulfoxide (DMSO), both of which are also expected to enhance drug solubility. Gelucire was confirmed to form micelles by surface tension and fluorescence measurements both in water and water/cosolvent mixtures. Light-scattering measurements revealed that DMA and DMSO affect the micellar morphology in a different manner. DMA helped form large structures by being entrapped in the hydrophobic region of the micelles and/or inducing the aggregation. DMSO was likely to be anchored to the interfacial layer and did not induce micelle growth. Two model drugs, phenytoin and indomethacin, were employed to observe the solubilization behavior of poorly soluble drugs in Gelucire/cosolvent mixtures. The solubility of these drugs in the mixtures could be explained very well by using the new solubility model introduced in this article. Addition of cosolvents to the Gelucire solution did not enhance the solubility very much, and thus the combined use of cosolvents with Gelucire offered only little advantage from the viewpoint of solubility.     

Preparation and in vitro characterization of a semi-solid dispersion of flurbiprofen with Gelucire 44/14 and Labrasol

Flurbiprofen is characterized by low solubility in water and has been implicated in causing gastro intestinal ulceration. The purpose of this study was to increase the dissolution characteristics of flurbiprofen by preparing a semi-solid dispersion with Gelucire 44/14 and Labrasol (F1) in hard gelatin capsules. The results were evaluated by comparing several in vitro parameters with powdered drug filled into hard gelatin capsules. The in vitro dissolution testing of the dosage forms was performed in different media (simulated gastric fluid, pH 1.2; citrate buffer pH 4.5; phosphate buffers pH 6.8 and 7.2, and water). Characterization of semi-solid dispersions and physical mixtures was performed using Fourier transform-infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC), particle size analysis and turbidity measurement. The results suggest that all semi-solid dispersions of flurbiprofen showed a remarkable improvement in the rate and extent of drug dissolution. The dissolution of F1 exhibited significant improvement in all dissolution media at different pH. The dissolution of flurbiprofen within 30 min in pH 1.2 was (55%), in pH 4.5 67%, pH 6.8 96%, pH 7.2 98% and in water 88%. FT-IR indicated no strong drug: excipient interactions, and DSC studies indicated a loss of crystalline nature of the drug. The particle size analysis revealed an average size diameter from 194 to 278 nm. Therefore, a semi-solid dispersion of flurbiprofen with Gelucire and Labrasol may have the potential of improved bioavailability because of the enhanced in vitro properties.     

A Gelucire 44/14 and labrasol based solid self emulsifying drug delivery system: formulation and evaluation

A solid self emulsifying formulation (S-SEF) has been developed with an intention to improve the dissolution characteristics of poorly water soluble lercanidipine hydrochloride (LH). Suitable components for the formulation of liquid self emulsifying drug delivery systems (SEDDS) were selected after screening various vehicles via solubility studies. Formulations were designed with Gelucire^® 44/14 as oil, labrasol as surfactant and transcutol-P as co surfactant. The prepared formulations were evaluated for self emulsifying efficiency and ternary phase diagram was used to designate optimum systems in the emulsifying domain. These systems were further investigated for robustness towards different pH conditions, globule size, thermodynamic stability, surface morphology, cloud point and in vitro drug release. The optimized LH loaded formulation possessed a mean globule size of 142.5 ± 5.37 nm and cloud point of 72 ± 2.66 °C. The liquid SEDDS was transformed into free flowing S-SEF by adsorbing on to an inert carrier, Neusilin US2^®. The results revealed no difference in globule size and emulsification characteristics between liquid SEDDS and S-SEF. The solid state characterization studies indicated loss of crystallinity for the drug. Significant improvement in dissolution characteristics of LH for prepared S-SEF was observed compared with pure drug.     

Development and physicochemical characterization of saquinavir mesylate solid dispersions using Gelucire 44/14 or PEG 4000 as carrier

Solid dispersions of saquinavir mesylate containing either Gelucire^® 44/14 or poly(ethylene glycol) (PEG) 4000, or mixtures of each carrier with Tween 80 or polyvinyl pyrrolidone (PVP) K30 were prepared in order to enhance the drug dissolution rate. These systems were prepared by the melting method and characterized by X-ray powder diffraction, microscopical techniques, and Raman spectroscopy aiming to establish a relationship between physicochemical and dissolution properties under different cooling conditions. Modifications in degree of crystalline order/disorder over time were observed in preparations with both carriers. Overall, formulations cooled and stored at ?20 °C showed less variation in dissolution rates than those at 25 °C. Although Tween 80 has enhanced the known self-emulsifying properties of Gelucire^® 44/14, its combination with PEG 4000 displayed miscibility problems. The addition of PVP K30 was not the most effective approach in enhancing the dissolution in early steps; however, the drug dissolution was stable after 7 days of storage at 25 °C. The combination of PEG 4000 and PVP K30 maintained the dissolution properties for 60 and 90 days at 25 °C/95 % relative humidity and 40 °C/75 % (f ₂ values >50), respectively.     

Enhanced bioavailability of piroxicam using Gelucire 44/14 and labrasol: in vitro and in vivo evaluation.

Piroxicam is a non-steroidal anti-inflammatory drug that is characterized by low solubility and high permeability. The purpose of the study was to investigate the in vitro and in vivo performance of the semi-solid dispersion prepared with Gelucire 44/14 and Labrasol into hard gelatin capsules (GL) for enhancing the dissolution rate of the drug. The results were evaluated by comparing with pure piroxicam filled into hard gelatin capsules (PP) and a commercially available tablet dosage form containing a piroxicam:beta-cyclodextrin complex (CD). The in vitro dissolution testing of the dosage forms was performed in different media (simulated gastric fluid, pH 1.2; phosphate buffers, pH 4.5 and 6.8; and water). Amongst the dosage forms, GL provided at least 85% piroxicam dissolution within 30 min in each of the media, behaving like a fast-dissolving immediate release drug product. Oral bioavailability of 20 mg piroxicam in GL, CD, and PP was compared after administration of a single dose to eight healthy volunteers. Three treatments were administered in crossover fashion, separated by a washout period of 2 weeks. Piroxicam was monitored in plasma by high-performance liquid chromatography. The apparent rate of absorption of piroxicam from GL (Cmax=2.64 micrograms/ml, tmax=82.5 min) was significantly higher than that of the PP (Cmax=0.999 micrograms/ml, tmax=144 min) (P<0.05) and similar to that of CD (Cmax=2.44 micrograms/ml, tmax=120 min) (P>0.05). The relative bioavailability values as the ratios of mean total AUC for GL relative to PP and CD, were 221 and 98.6%. Piroxicam is characterized by a slow and gradual absorption via the oral route and this causes a delayed onset of therapeutic effect. Thus, plain piroxicam preparations are not indicated for analgesia. The results of the in vivo study revealed that the GL dosage form would be advantageous with regards to rapid onset of action, especially in various painful conditions where an acute analgesic effect is desired.     

Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14

The purpose of this study was to prepare and characterize solid dispersions of the antiviral thiocarboxanilide UC-781 with PEG 6000 and Gelucire 44/14 with the intention of improving its dissolution properties. The solid dispersions were prepared by the fusion method. Evaluation of the properties of the dispersions was performed using dissolution studies, differential scanning calorimetry, Fourier-transform infrared spectroscopy and X-ray powder diffraction. To investigate the possible formation of solid solutions of the drug in the carriers, the lattice spacings [d] of PEG 6000 and Gelucire 44/14 were determined in different concentrations of UC-781. The results obtained showed that the rate of dissolution of UC-781 was considerably improved when formulated in solid dispersions with PEG 6000 and Gelucire 44/14 as compared to pure UC-781. From the phase diagrams of PEG 6000 and Gelucire 44/14 it could be noted that up to approximately 25% w/w of the drug was dissolved in the liquid phase in the case of PEG 6000 and Gelucire 44/14. The data from the X-ray diffraction showed that the drug was still detectable in the solid state below a concentration of 5% w/w in the presence of PEG 6000 and Gelucire 44/14, while no significant changes in the lattice spacings of PEG 6000 or Gelucire 44/14 were observed. Therefore, the possibility of UC-781 to form solid solutions with the carriers under investigation was ruled out. The results from infrared spectroscopy together with those from X-ray diffraction and differential scanning calorimetry showed the absence of well-defined drug–polymer interactions.     

Physical stability of solid dispersions of the antiviral agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K30

This paper describes the physical stability of solid dispersions of UC-781 with PEG 6000, Gelucire 44/14 and PVP K30 prepared by the solvent and melting methods. The concentration of the drug in the solid dispersions ranged from 5 to 80% w/w. The solid dispersions were stored at 4-8 and 25 degrees C (25% RH), then their physicochemical properties were analysed by differential scanning calorimetry (DSC), X-ray powder diffraction and dissolution studies as a function of storage time. The DSC curves of solid dispersions of UC-781 with PVP K30 did not show any melting peaks corresponding to UC-781 after storage, indicating no recrystallization of the drug. The DSC data obtained from PEG 6000 and Gelucire 44/14 showed some variations in melting peak temperatures and enthalpy of fusion of the carriers. It was shown that the enthalpy of fusion of PEG 6000 in the dispersions increased after storage; it was more pronounced for samples stored at 25 degrees C compared to those at 4-8 degrees C indicating the reorganization of the crystalline domains of the polymer. Similarly, the enthalpy of fusion of Gelucire 44/14 in the solid dispersions increased as a function of time. Dissolution of UC-781 from all solid dispersions decreased as a function of storage time. While these observations concurred with the DSC data for all solid dispersions, they were not reflected by X-ray powder diffraction data. It was concluded that it is the change of the physical state of the carriers and not that of the drug, which is responsible for the decreased dissolution properties of the solid dispersions investigated.     

Gelucire44/14 as a novel absorption enhancer for drugs with different hydrophilicities: in vitro and in vivo improvement on transcorneal permeation

The objective of this study was to investigate the application of Gelucire44/14 as a novel absorption enhancer in ophthalmic drug delivery system. Six compounds, namely ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin in the order of increasing lipophilicity were selected as model drugs. The effect of Gelucire44/14 on transcorneal permeation was evaluated across excised rabbit cornea. Ocular irritation and precorneal retention time were assessed. Additionally, aqueous humor pharmacokinetic test was performed by microdialysis. The results indicated that Gelucire44/14, at a concentration of 0.05% or 0.1% (w/v), was found to maximally increase the apparent permeability coefficient by 6.47-, 4.14-, 3.50-, 3.97-, 2.92-, and 1.86-fold for ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin, respectively (p < 0.05). Moreover, Gelucire44/14 was nonirritant at broad concentrations of 0.025%-0.4% (w/v). Pharmacokinetic tests showed that Gelucire44/14 promoted ocular bioavailability of the compounds as indicated by 5.40-, 4.03-, 3.46-, 3.57-, 2.77-, and 1.77-fold maximal increase in the area under the curve for the drugs aforementioned, respectively (p < 0.01). Therefore, Gelucire44/14 exerted a significant improvement on the permeation of both hydrophilic and lipophilic compounds, especially hydrophilic ones. Hence, Gelucire44/14 can be considered as a safe and effective absorption enhancer for ophthalmic drug delivery system.     

In vitro and in situ evidence for the contribution of Labrasol and Gelucire 44/14 on transport of cephalexin and cefoperazone by rat intestine.

In vitro and in situ intestinal transport of beta-lactam antibiotics in the presence of two novel pharmaceutical excipients, caprylocaproyl and lauroyl macrogolglycerides (Labrasol and Gelucire 44/14), is described. The objective was to compare the effects of both macrogolglycerides on the intestinal transport of cephalexin, a substrate of oligopeptide transporters, and cefoperazone, a non-substrate of them. The in vitro transport studies were performed using a sheet of rat jejunum mounted in Ussing-type diffusion chambers. The in situ studies used an isolated internal loop model in the rat. Labrasol and Gelucire 44/14 were used as the excipients at low concentrations (0.01-0.5%, w/v). The membrane permeability of both drugs was compared by apparent permeability coefficients (P(app)) determined from changes in the amount of permeation vs. time in in vitro studies and by apparent absorptive clearance (CL(app)) determined from changes in the steady state drug concentration of perfusate in in situ studies. The P(app) value of cephalexin increased with an increase in the concentration of Labrasol (0.05-0.5%) compared to the value without Labrasol. The enhancing effect of Labrasol on cephalexin transport was similarly observed in in situ studies, and when 0.5% Labrasol was used in the presence of glycyl-L-leucine or L-alanyl-L-alanine, 60 or 46% enhancement of the active transport of cephalexin by Labrasol was obtained. On the other hand, Gelucire 44/14 did not affect the P(app) and CL(app) of either drug. The different effects of the excipients on cephalexin transport were thought to be due to the influences of size parameters such as a polydispersity index and particle size, and the change in the short-circuit current of jejunum by the addition of the excipient.     

Physico-chemical characterization of an amphiphilic cyclodextrin/genistein complex

Specific recognition of cell-targeting systems as host-carriers modified with receptor targeting groups, is a major ambition in the application of supramolecular science to medicine and life science. Genistein (Gen), an isoflavone belonging to the class of phytoestrogens, is of great interest because it has been considered as potential remedy for many kinds of disease. In this work, Genistein in aqueous medium and in the presence of an host nanocarrier as amphiphilic cyclodextrin (CyD) modified in the upper rim with oligoethylene hydroxyl groups [(2-oligo(ethyleneoxide)-6-hexylthio)-β-CyD, SC6OH] at 1:1 molar ratio, has been firstly investigated by UV–vis measurements coupled with circular dichroism data, in order to characterize the drug/macrocycle binding affinity through the formation of the complex.     

Effect of carrier excipient and processing on stability of indorenate hydrochloride/excipient mixtures.

The purpose of this investigation was to determine the solid-state chemical stability of a model drug, indorenate hydrochloride, as a function of carrier excipient and mixing process. Physical mixtures and granules were prepared by tumble mixing and alcoholic granulation with and without binder. Stability of the mixtures was estimated using differential scanning calorimetry and isothermal degradation studies at 40, 50, and 60 degrees C. Average first-order degradation constants at 25 degrees C, extrapolated from isothermal studies, were much lower for indorenate hydrochloride after tumbling mixing with microcrystalline cellulose (3.45 x 10(-5) day-1) than those obtained after tumbling mixing with lactose (112.0 x 10(-5) day-1). Distribution of the drug on the excipient's surface, through granulation with and without Povidone, increased the average drug degradation rates in granules with microcrystalline cellulose (36.2 x 10(-5) day-1) as well as in granules with lactose (326 x 10(-5) day-1). Partially amorphous lactose (spray-dried lactose) showed higher average degradation rates (310.5 x 10(-5) day-1) than crystalline lactose (199.3 x 10(-5) day-1). It appears that the amorphous portion of the drug as well as that of reacting excipients play a major role in affecting the reaction rate. The calorimetric studies showed a strong solid-solid interaction between indorenate hydrochloride and lactose, suggesting chemical incompatibility. This strong solid-solid interaction was characterized by disappearance of typical transition peaks of lactose at temperatures above 200 degrees C and the development of new peaks at about 130-170 degrees C. No major changes in transition peaks were observed in mixtures of microcrystalline cellulose and indorenate hydrochloride, suggesting chemical compatibility. Calorimetric results allow the prediction of the chemical incompatibility between indorenate hydrochloride and lactose observed in isothermal degradation studies.     

Ethylenediamine,profile of a sensitizing excipient

Ethylenediamine is an excipient with many industrial and pharmaceutical uses. It is included in creams as a stabilizer and in aminophylline as the counter ion of theophylline. Ethylenediamine is one of the most frequent contact sensitizers, producing local and generalized reactions. Besides, many cases of systemically induced dermatitis have also been described both after oral, rectal and intravenous use. Inhalation of ethylenediamine or aminophylline dust may provoke rhinitis and asthmatic reactions. In contrast to these delayed reactions only one immediate reaction of the urticarial type after intravenous use has been described. Ethylenediamine shows cross-reactions with antihistamines of the ethylenediamine derivative group, with edetate, other amines, piperazine and hydroxyzine. Ethylenediamine shows a short half-life of about 0.55 h and a small volume of distribution of 0.133 l/kg. After oral administration its bioavailability is about 0.34, due to a substantial first-pass effect. Renal excretion of the unchanged substance amounts to only about 18% after intravenous and 3% after oral administration. It behaves independently from theophylline after administration of aminophylline. Good alternatives are now available for the pharmaceutical applications of ethylenediamine. Theophylline itself is well absorbed orally; for the intravenous administration theN-methylglucamine salt is sufficiently soluble. Suppositories containing pure theophylline are commercially available in some countries, but the experience with this product is relatively small.     

Diclofenac salts, II. Solid dispersions in PEG6000 and Gelucire 50/13.

A number of systems were prepared at five compositions (5, 10, 20, 30 and 40% w/w) of diclofenac/N-(2-hydroxyethyl) pyrrolidine salt and acidic diclofenac in PEG6000 and Gelucire 50/13, as physical mixtures and as solid dispersions. Powder X-ray diffractograms for the systems examined show shifted and normal peaks, suggesting that the drug is present inside the samples in different physical states. Differential scanning calorimetry does not offer important information, since drug solubility into the carriers increases with temperature and thermograms show only the melting point peak of the carriers. Hot-stage microscopy examination explains that, in high concentration samples, the drug is present either dissolved into the carriers, or precipitated as microcrystals, or undissolved crystals of larger size. Gelucire 50/13 allows the formation of larger crystals than PEG, using both the chemical forms of the drug. The release percentage of the drug from PEG6000/acidic diclofenac reaches 50% after few minutes in the most favourable case and appears to be dependent on the composition of the samples: the more diclofenac is present as dissolved in the pre-treated samples, the higher is the release. The optimum composition was found in the range of 5-10% w/w.     

Preparation and evaluation of floating risedronate sodium Gelucire 39/01 matrices

Incorporation of bisphosphonates in the lipid reduces gastric irritation. Only gastric retention with sustained release allows the drug to reach the duodenum and jejunum and improves the availability of bisphosphonates. Risedronate sodium and Gelucire 39/01 floating matrices were prepared using melt solidification. The sustained release floating matrices were evaluated for in vitro and in vivo floating ability and in vitro drug release. Ageing of the matrices was studied by differential scanning calorimetry, hot stage polarizing microscopy, scanning electron microscopy and in vitro drug release. Ageing causes changes in the crystal structure of Gelucire, which is responsible for an increase in drug release.