Effects of solid dispersion and self-emulsifying formulations on the solubility,dissolution, permeability and pharmacokinetics of isorhamnetin,quercetin and kaempferol in total flavones of Hippophae rhamnoides L.

The aim of this study was to investigate the effects of solid dispersions (SD) and self-emulsifying (SE) formulations on the solubility and absorption properties of active components in total flavones of Hippophae rhamnoides L. (TFH). The solubility, dissolution rate, permeability and pharmacokinetics of isorhamnetin, quercetin and kaempferol in TFH SD/SE formulations and TFH were compared. The results showed that the solubility and dissolution rate of isorhamnetin, quercetin and kaempferol in SD/SE formulations were significantly enhanced compared to those in TFH, however, their intestinal permeability was comparable. The bioavailability of isorhamnetin, quercetin and kaempferol in rats remarkably increased after oral administration of TFH SD formulations compared to TFH, but there was no significant increase after oral administration of TFH SE formulations. The results of this study indicated the SD formulations on the improvement of pharmacokinetic properties of isorhamnetin, quercetin and kaempferol in TFH were much better than those of SE formulations. The improvement of pharmacokinetic properties of isorhamnetin, quercetin and kaempferol in TFH by SD formulations was probably ascribed to the enhancement of the solubility and dissolution of the three components, but was not relevant to the intestinal permeability. Therefore, as for herb extracts containing multiple components, especially for their major components with poor water solubility, solid dispersion formulations might have the better potential to enhance their bioavailability.     

Preparation, characterization, and stability of liposome-based formulations of mitoxantrone

The preparation, characterization, and stability of lyophilized liposome-based formulation of mitoxantrone was investigated. Mitoxantrone was entrapped inside small, unilamellar liposomes composed of dioleoylphosphocholine (DOPC), cholesterol, and cardiolipin. The mean vesicle size and drug entrapment efficiency of the liposomes were ~ 150 nm and ~ 99%, respectively. Less than 1% of drug was lost and mean vesicle size remained unchanged after sterile filtration. The pre-lyophilized (pre-lyo) formulations were characterized by a differential scanning calorimetric (DSC) method. Results showed that the glass transition temperatures (Tg') increased as the molar ratios of sucrose:lipid and trehalose:lipid in the formulations were increased. The maximum Tg' of the pre-lyo formulations containing 10:1 sucrose:lipid and trehalose:lipid molar ratios were - 37°C and - 41°C, respectively. After reconstitution of the lyophilized cake of the sucrose-containing formulation, the mean vesicle size was comparable to pre-lyo liposome size. In vitro release studies showed that less than 2% of mitoxantrone was released after an extensive dialysis against phosphate buffered saline (PBS) at 37°C, indicating that the mitoxantrone was highly associated and retained inside the liposomes. Short-term stability studies of the sucrose-containing formulations revealed that the reconstituted and eight-fold diluted formulations were stable for up to 8 hours at room temperature. Long-term stability studies of lyophilized liposomal mitoxantrone showed that the lyophilized formulation was stable for up to 13 months after storage at refrigerated condition.     

On continuous,discontinuous, mixed,and primal hybrid finite element methods for second‐order elliptic problems

Finite element formulations for second‐order elliptic problems, including the classic H¹‐conforming Galerkin method, dual mixed methods, a discontinuous Galerkin method, and two primal hybrid methods, are implemented and numerically compared on accuracy and computational performance. Excepting the discontinuous Galerkin formulation, all the other formulations allow static condensation at the element level, aiming at reducing the size of the global system of equations. For a three‐dimensional test problem with smooth solution, the simulations are performed with h‐refinement, for hexahedral and tetrahedral meshes, and uniform polynomial degree distribution up to four. For a singular two‐dimensional problem, the results are for approximation spaces based on given sets of hp‐refined quadrilateral and triangular meshes adapted to an internal layer. The different formulations are compared in terms of L²‐convergence rates of the approximation errors for the solution and its gradient, number of degrees of freedom, both with and without static condensation. Some insights into the required computational effort for each simulation are also given.     

Physical,Chemical, and Bioavailability Studies of Parenteral Diazepam Formulations Containing Propylene Glycol and Polyethylene Glycol 400

Abstract

Parenteral diazepam formulations (10 mg/ml), XXV and XXX were prepared using propylene glycol and/or polyethylene glycol 400. The viscosity of formulations XXV and XXX was found to be 9.72 and 11.13 Cps., respectively using Stormer viscosimeter at 22° C. The accelerated stability studies indicated shelf-life of formulations XXV and XXX to be 132     

Effects of pigeon pea and plantain starches on the compressional, mechanical, and disintegration properties of paracetamol tablets

A study has been made of the effects of pigeon pea starch obtained from the plant Cajanus cajan (L) Millisp. (family Fabaceae) and plantain starch obtained from the unripe fruit of Musa paradisiaca L. (family Musaceae) on the compressional, mechanical, and disintegration properties of paracetamol tablets in comparison with official corn starch BP. Analysis of compressional properties was done by using density measurements, and the Heckel and Kawakita equations, whereas the mechanical properties of the tablets were evaluated by using tensile strength (T--a measure of bond strength) and brittle fracture index (BFI--a measure of lamination tendency). The ranking for the mean yield pressure, P(y), for the formulations containing the different starches was generally corn < pigeon pea < plantain starch while the ranking for P(k), an inverse measure of the amount of plasticity, was pigeon pea < plantain < corn starch, which indicated that formulations containing corn starch generally exhibited the fastest onset of plastic deformation, whereas those formulations containing pigeon pea starch exhibited the highest amount of plastic deformation during tableting. The tensile strength of the tablets increased with increase in concentration of the starches while the Brittle Fracture Index decreased. The ranking for T was pigeon pea > plantain > corn starch while the ranking for BFI was corn > plantain > pigeon pea starch. The bonding capacity of the formulations was in general agreement with the tensile strength results. The disintegration time (DT) of the formulation increased with concentration of plantain and corn starches but decreased with concentration of pigeon pea starch. The general ranking of DT values was plantain < pigeon pea < corn starch. Notably, formulations containing pigeon pea starch exhibited the highest bond strength and lowest brittleness, suggesting the usefulness of pigeon pea starch in producing strong tablets with minimal lamination tendency. Plantain starch, on the other hand, would be more useful where faster disintegration of tablet is desired. The results show that the starches could be useful in various formulations depending on the intended use of the tablets with the implication that the experimental starches can be developed for commercial purposes.     

Development of an Implantable,Biodegradable, Controlled Drug Delivery System for Local Antibiotic Therapy

Abstract

A novel drug delivery system was developed using a monoglyceride (Glycerol Monostearate) and a water-soluble release rate modifier as the matrix. Cefuroxime sodium (Zinacef®) was chosen as a model drug in this study. Formulations (cylindrical implants 6 × 6 mm) were prepared by a melt-dispersion method. Dissolution studies were performed using USP paddle method. The effect of glycerol, PEG 400 and their combination on drug release profiles was studied. Two assay methods (UV and HPLC) for cefuroxime analysis were compared. Percent recovery from four formulations (A-D) was higher with UV than HPLC assay. While both UV and HPLC assay methods were developed for cefuroxime, only HPLC assay is stability indicating. Glycerol showed higher accelerating effect than PEG 400 on the drug release. All formulations exhibited extended release of cefuroxime. Degradation of cefuroxime occurred mainly during dissolution suggesting drug stability in the formulations.     

Effects of Pigeon Pea and Plantain Starches on the Compressional,Mechanical, and Disintegration Properties of Paracetamol Tablets

ABSTRACT

A study has been made of the effects of pigeon pea starch obtained from the plant Cajanus cajan (L) Millisp. (family Fabaceae) and plantain starch obtained from the unripe fruit of Musa paradisiaca L. (family Musaceae) on the compressional, mechanical, and disintegration properties of paracetamol tablets in comparison with official corn starch BP. Analysis of compressional properties was done by using density measurements, and the Heckel and Kawakita equations, whereas the mechanical properties of the tablets were evaluated by using tensile strength (T-a measure of bond strength) and brittle fracture index (BFI-a measure of lamination tendency). The ranking for the mean yield pressure, P_y, for the formulations containing the different starches was generally corn < pigeon pea < plantain starch while the ranking for P_k, an inverse measure of the amount of plasticity, was pigeon pea < plantain < corn starch, which indicated that formulations containing corn starch generally exhibited the fastest onset of plastic deformation, whereas those formulations containing pigeon pea starch exhibited the highest amount of plastic deformation during tableting. The tensile strength of the tablets increased with increase in concentration of the starches while the Brittle Fracture Index decreased. The ranking for T was pigeon pea > plantain > corn starch while the ranking for BFI was corn > plantain > pigeon pea starch. The bonding capacity of the formulations was in general agreement with the tensile strength results. The disintegration time (DT) of the formulation increased with concentration of plantain and corn starches but decreased with concentration of pigeon pea starch. The general ranking of DT values was plantain < pigeon pea < corn starch. Notably, formulations containing pigeon pea starch exhibited the highest bond strength and lowest brittleness, suggesting the usefulness of pigeon pea starch in producing strong tablets with minimal lamination tendency. Plantain starch, on the other hand, would be more useful where faster disintegration of tablet is desired. The results show that the starches could be useful in various formulations depending on the intended use of the tablets with the implication that the experimental starches can be developed for commercial purposes.     

Stresses,stress sensitivities and shape optimization in two-dimensional linear elasticity by the Boundary Contour Method

This paper presents new formulations for computing stresses as well as their sensitivities in two-dimensional (2-D) linear elasticity by the Boundary Contour Method (BCM). Contrary to previous work (e.g. Reference 1), the formulations presented here are established directly from the boundary contour version of the Hypersingular Boundary Integral Equation (HBIE) which can provide accurate numerical results and is very efficient with regard to numerical implementation as well as computational time. The Design Sensitivity Coefficients (DSCs) computed from the above formulations are then coupled with a mathematical programming method, here the Successive Quadratic Programming (SQP) algorithm, in order to solve shape optimization problems. Numerical examples are presented to demonstrate the validity of the new formulations for calculation of DSCs. Also, based on these formulations, shape optimization examples by the BCM are presented here for the first time. © 1998 John Wiley & Sons, Ltd.     

Preparation,characterization, sterility validation,and in vitro cell toxicity studies of microemulsions possessing potential parenteral applications

Context: Water-in-oil microemulsions (w/o ME) are ideal for parenteral drug delivery. However, no such formulations have been tested for biocompatibility in in vitro cell cultures. Furthermore, sterilization of w/o MEs is a challenging process that has not been previously developed and validated.

Purpose: To formulate pharmaceutically relevant water-in-oil (w/o) microemulsion’s systems suitable for use as a parenteral formulation.

Methods: w/o MEs were prepared using dioctyl sodium sulfosuccinate (DOSS), ethyl oleate (EO), and water. Formulations were characterized using polarized light microscopy, electrical conductivity, rheology, and dynamic light scattering. An aseptic filtration method for sterilization was developed using membrane filtration. The biocompatibility of selected MEs were evaluated in NIH3T3 cell cultures. Dissolution studies were performed on microemulsions containing methylene blue to evaluate the drug release profile.

Results: The maximum amount of water incorporated in the formulations was 14% w/w. DOSS/EO/water microemulsions exhibited Newtonian flow. Particle sizes for these MEs were less than 30 nm in size. Formulations filtered aseptically were free of bacteria when gram-stained and visualized under a microscope. All MEs showed no toxicity to NIH 3T3 cells.

Discussion: The absence of birefringence and low conductivity values indicated that the formulations were w/o microemulsions. The filtration method of sterilization was validated by the absence of microbial growth on blood agar plates over a 14-day period. In vitro dye release studies demonstrate sustained release of the model drug over a 72-h time period.

Conclusion: Characteristics delineated in this study demonstrate the potential for these formulations to be used as parenteral preparations.     

Preparation,Characterization, and Pharmacokinetics of Sterically Stabilized Nimodipine-Containing Liposomes

ABSTRACT

Nimodipine is a dihydropyridine calcium antagonist used in clinical trials in the treatment of ischemic damage in subarachnoid hemorrhage and commercially available as nimotop® intravenous infusion solution and tablets. However, due to its poor solubility in water, intravenous administration depends on the use of the dehydrated alcohol to achieve a clinically relevant concentrated infusion solution while the low bioavailability of the nimotop® tablets were far away from content. We have prepared a well-characterized novel lyophilized liposome-based nimodipine formulation that is sterile and easy-to-use. Of the several formulations examined, nimodipine-liposomes composed of ePC/CHOL 20:3 and co-surfactant poloxamer 188/sodium deoxycholate/ePC/3:0.3:5 were chosen for further studies. This composition was found to give more stable liposomes than other formulations. It gave 89.9% entrapment efficiency and particle size of 200 nm after lyophilization. The pharmacokinetic parameters following orally and intravenously administration to New Zealand rabbits were determined and compared with those of commercial nimodipine formulations. Encapsulation of nimodipine in liposomes produced marked differences over those of commercial preparations with an increased C_max, prolonged elimination half-life, and an increased value for AUC. The obtained values for mean residence time (MRT) indicated that nimodipine remains longer for liposomal formulation. Thus an optimum i.v. liposome formulation for nimodipine can be developed for an alternative to the commercial nimodipine preparations.     

Design of novel urogenital pharmabiotic formulations containing lactobacilli,salivaricin CRL 1328 and non-microbial compounds with different functionalities

Context: The administration of pharmabiotics is a promising alternative to antimicrobial drugs for the treatment and/or prevention of female urogenital infections.

Objective: To design pharmabiotic formulations including bioactive ingredients of microbial origin combined with non-microbial substances and then to evaluate the stability of the combinations during freeze-drying and storage.

Materials and methods: Different formulations including Lactobacillus gasseri CRL 1263, Lactobacillus salivarius CRL 1328, salivaricin CRL 1328 (a bacteriocin) and non-microbial compounds (lactose, inulin and ascorbic acid) were assayed, and the ingredients were freeze-dried together or separately. The formulations were stored in gelatin capsules at 4?°C for 360?d.

Results: The viability of lactobacilli was affected to different extents depending on the strains and on the formulations assayed. L. salivarius and ascorbic acid were successfully combined only after the freeze-drying process. Salivaricin activity was not detected in formulations containing L. gasseri. However, when combined with ascorbic acid, lactose, inulin or L. salivarius, the bacteriocin maintained its activity for 360?d. The selected microorganisms proved to be compatible for their inclusion in multi-strain formulations together with lactose, inulin and ascorbic acid. Salivaricin could be included only in a L. salivarius CRL 1328 single-strain formulation together with non-microbial substances.

Conclusions: This study provides new insights into the design of urogenital pharmabiotics combining beneficial lactobacilli, salivaricin CRL 1328 and compounds with different functionalities.     

Influences of copolymers (Copovidone,Eudragit RL PO and Kollicoat MAE 30 DP) on stability and bioactivity of spray-dried and freeze-dried lysozyme

Protein stability is the most crucial factor in protein pharmaceutical preparations. Various techniques were applied for producing stable protein formulations such as spray-drying and freeze-drying. However, heating and freezing stresses are disadvantages for proteins using these methods, respectively. Accordingly, excipients have been used to preserve therapeutic effects of proteins during processing and for long period of time. Therefore, influences of Copovidone, Eudragit^® RL-PO and Kollicoat^® MAE-30 DP (as excipients) on stability and integrity of lysozyme (as a model protein) in spray-dried and freeze-dried forms were investigated. Protein formulations in both dried forms were prepared without and with the addition of mentioned excipients at different concentrations. Protein formulations were characterized for yield determination, morphology using scanning electron microscopic (SEM), thermal analysis by Differential Scanning Calorimetry (DSC), secondary structure stability using Fourier transform infrared (FT-IR) spectroscopy and biological activity. All protein formulations were subjected to a stability study as solid protein formulations for 3 weeks at 24?°C/76% relative humidity and aqueous protein samples were stored at 50?°C for 30?min in a water bath. Results showed that Copovidone successfully preserved integrity and biological activity of lysozyme before and after storage in both spray-dried and freeze-dried forms with more advantage for using higher concentration of the same excipient. Smooth spheres of spray-dried lysozyme formulations with Copovidone were smaller than spray-dried lysozyme without and with Kollicoat^® MAE-30 DP, which affected %yield produced. Copovidone has demonstrated valuable protection ability for lysozyme.     

Oral controlled drug administration,Pharmacokinetic Considerations

Abstract

A reversed phase high-performance liquid chromatographic method was developed for simultaneous quantitation of dextropropoxyphene napsylate in three different formulations. The first contains caffeine and aspirin while the others are combinations with acetaminophene. The mobile phase consisted of acetonitrile (30%) in acetate buffer. The assay was carried at 28Onm wavelength. The method is precise and does not require sample manipulation prior to analysis. The applicability of the assay procedure in studying dissolution rate of capsule formulations is described.     

Preparation, characterization, and pharmacokinetics of sterically stabilized nimodipine-containing liposomes

Nimodipine is a dihydropyridine calcium antagonist used in clinical trials in the treatment of ischemic damage in subarachnoid hemorrhage and commercially available as nimotop^® intravenous infusion solution and tablets. However, due to its poor solubility in water, intravenous administration depends on the use of the dehydrated alcohol to achieve a clinically relevant concentrated infusion solution while the low bioavailability of the nimotop^® tablets were far away from content. We have prepared a well-characterized novel lyophilized liposome-based nimodipine formulation that is sterile and easy-to-use. Of the several formulations examined, nimodipine-liposomes composed of ePC/CHOL 20:3 and co-surfactant poloxamer 188/sodium deoxycholate/ePC/3:0.3:5 were chosen for further studies. This composition was found to give more stable liposomes than other formulations. It gave 89.9% entrapment efficiency and particle size of 200 nm after lyophilization. The pharmacokinetic parameters following orally and intravenously administration to New Zealand rabbits were determined and compared with those of commercial nimodipine formulations. Encapsulation of nimodipine in liposomes produced marked differences over those of commercial preparations with an increased C_max, prolonged elimination half-life, and an increased value for AUC. The obtained values for mean residence time (MRT) indicated that nimodipine remains longer for liposomal formulation. Thus an optimum i.v. liposome formulation for nimodipine can be developed for an alternative to the commercial nimodipine preparations.     

Development of a Lyophilized Formulation for (R,R)-Formoterol (L)-Tartrate

(R,R)-formoterol is a β-agonist for inhalation. Aqueous instability suggested the need for a reconstitutable lyophilized dosage form. The objective of these studies was to devise a stable, rapid-dissolving, therapeutically compatible dosage form. The effects of diluents and residual moisture on the stability of thermally stressed formoterol formulations were investigated. Drug and various excipients (acetate, lactose, and mannitol) were lyophilized and placed in humidity chambers (0 to 90% relative humidity) at 25 to 50°C. Stability was characterized by time-dependent changes using HPLC, pH, and XRD. Residual moistures were determined by Karl Fisher methods. Regression models were developed to quantify the effects of formulation and environmental variation on drug stability. Solid-state instability was observed as a function of high residual moisture and diluent type. Although the residual moistures in mannitol formulations were typically below 1%, the degradation rate (50°C) varied from 2 to 10 mcg/day, which was 1.3- to 20-fold high than observed for lactose formulations under the same relative humidity conditions. At high relative humidity, the presence of acetate significantly increased the degradation rate (p < 0.04). The critical residual moisture content for lactose formulations was 3%. The amount of lactose was optimized by evaluating the degradation over the temperature range 25 to 50°C. Mannitol and acetate were shown to be unsuitable excipients, and an optimal lactose amount was 50 mg for vials containing 50 mcg of drug.     

Vitamin B12 buccoadhesive tablets: auspicious non-invasive substitute for intra muscular injection: formulation,in vitro and in vivo appraisal

Attempting to prepare a convenient bioavailable formulation of vitamin B₁₂ (cyanocobalamin), 17 tablet formulations were prepared by direct compression. Different concentrations of hydroxypropyl methyl cellulose (HPMC), carbopol 971p (CP971p), and chitosan (Cs) were used. The tablets were characterized for thickness, weight, drug content, hardness, friability, surface pH, in vitro drug release, and mucoadhesion. Kinetic analysis of the release data was conducted. Vitamin B₁₂ bioavailability from the optimized formulations was studied on rabbits by the aid of enzyme-linked immunosorbent assay. Neurotone^® I.M. injection was used for comparison. HPMC (F1-F4), CP971p (F5-F8), and HPMC/CP971p (F12-F15)-based formulations showed acceptable mechanical properties. The formulated tablets showed maximum swelling indices of 232?±?0.13. The surface pH values ranged from 5.3?±?0.03 to 6.6?±?0.02. Bioadhesive force ranged from 66?±?0.6 to 150?±?0.5?mN. Results showed that CP971p-based tablets had superior in vitro drug release, mechanical, and mucoadhesive properties. In vitro release date of selected formulations were fitted well to Peppas model. HPMC/CP971p-based formulations showed bioavailability up to 2.7-folds that of Neurotone^® I.M. injection.     

Optimization of Direct Compression Tablet Formulations for Use in Tropical Countries

Abstract

With the aid of a combined mixture- and factorial- design, 2 standard tablet formulations were selected suitable for use in tropical countries. The formulations were based on native ingredients or ingredients that are available worldwide. The selection of the standard formulations was based on both the initial tablet properties of the formulations one day after preparation as well as the physical stability after storage under tropical conditions.

The selected formulations were evaluated by adding model drugs (diazepam, 2 mg per tablet or hydrochlorthiazide, 100 mg per tablet) and measuring tablet properties, not only one day after preparation, but also after storage under tropical conditions. Both selected tablet formulations were suitable standard formulations for tablets prepared by direct compression for use in tropical countries.     

Comparison of an experimental bone cement with a commercial control, Hydroset™

Glass polyalkenoate cements based on strontium calcium zinc silicate glasses (Zn-GPCs) and high molecular weight polyacrylic acids (PAA) (MW; 52,000–210,000) have been shown to exhibit mechanical properties and in vitro bioactivity suitable for arthroplasty applications. Unfortunately, these formulations exhibit working times and setting times which are too short for invasive surgical applications such as bone void filling and fracture fixation. In this study, Zn-GPCs were formulated using a low molecular weight PAA (MW; 12,700) and a modifying agent, trisodium citrate dihydrate (TSC), with the aim of improving the rheological properties of Zn-GPCs. These novel formulations were then compared with commercial self-setting calcium phosphate cement, Hydroset™, in terms of compressive strength, biaxial flexural strength and Young’s modulus, as well as working time, setting time and injectability. The novel Zn-GPC formulations performed well, with prolonged mechanical strength (39 MPa, compression) greater than both vertebral bone (18.4 MPa) and the commercial control (14 MPa). However, working times (2 min) and rheological properties of Zn-GPCs, though improved, require further modifications prior to their use in minimally invasive surgical techniques.     

Improved initial burst of estradiol organogel as long-term in situ drug delivery implant: formulation,in vitro and in vivo characterization

Objective: The present investigation was aimed at optimizing of estradiol (E2) loaded l-amino acid derivatives organogel formulations resulting in improved the high initial release problems and sustained release of E2.

Methods: The visco-elastic properties of blank organogels were measured by rheometer. The E2 organogel formulations were optimized using a central composite design. Also, the effect of gelator structure and composition of the gel formulations on release behavior (in vitro and in vivo) had been studied.

Results: The change of the gelator structure could affect significantly the stiffness of the implants. The release behavior of gel without N-Methyl-2-pyrrolidinone (NMP) was controlled by gel corrosion only. While the drug release of the gel with NMP was controlled by both corrosion and diffusion. The high initial release problems of the organogels were improved by optimizing the formulations. The system consisting by N-Lauroyl l-lysine methyl ester (LLM) derivative in the oil indicated the lowest initial drug release, showed a much lower blood drug level and maintained a steady state for nearly 1 month.

Conclusion: Organogels based on l-lysine methyl ester derivative were ideal carriers for long-term parenteral administration of E2.