Development of Subcutaneous and Intramuscular Formulations of Calcium Alendronate Salts

Abstract

Poorly soluble calcium-alendronate salts were prepared and investigated as potential candidates for subcutaneous or intramuscular formulations. Three such formulations containing calcium-alendronate salts with different stoichiometries were developed for testing in safety, disposition and efficacy studies in animals. All formulations demonstrated a drastic reduction in pain on injection and tissue damaging propensity compared to the soluble salts of ABP. All three were efficacious and showed prolonged absorption from the injection site with the deposition of a large percentage of the dose into the bone. Complex formation between alendronate and calcium was also studied.     

Preformulation Selection of a Proper Salt for a Weak Acid-Base (Rs-82856) - A New Positive Inotropic Agent

The solubility, hygroscopicity and intrinsic dissolution rate of the various salts of a weak acid-base (RS-82856) were evaluated. The phosphate salt was a mixture of monobasic and dibasic salts and was not physically stable. The hydrogen sulfate, and chloride salts were less hygroscopic and more soluble in water than the cation salts tested (sodium and potassium). All salts studied showed only slightly better intrinsic dissolution rates (~two-fold) than the parent drug at pH 3.1 and 7.0; only the hydrogen sulfate salt and the potassium salt had better dissolution rates at pH 1.2. This unusual dissolution behavior of the salts can be explained by the extremely low buffering effect of the salts in the dissolution medium. The hydrogen sulfate salt was recommended for development and was supported by the ~two-fold increase in bioavailability in a dog study when compared to the parent drug.     

Muco-Adhesive Liquid Ophthalmic Vehicles - Evaluation of Macromolecular Ionic Complexes of Pilocarpine

Abstract

Pilocarpine (Pi), a widely used anti-glaucoma drug, is characterized by a very low bioavailability, due to poor corneal penetration and extensive precorneal loss. Purpose of the present study was the preparation and “in vivo” evaluation of a series of liquid formulations containing salts (or ionic complexes) of Pi with soluble polyanionic polymers of natural, synthetic or semi-synthetic origin. It was speculated that since to some of the polymers have been attributed muco-adhesive properties, they might favour the preocular retention of the ionically bound drug, and enhance its bioavailability. The polymers submitted to investigation were a) hyaluronic acid (HA); b) poly-(galacturonic acid) (PGA); c) Mesoglycan (MG, a complex mixture of mucopolysaccharides); d) Carboxymethylchitin (CMCh) and d) two poly(acrylic acids) of different molecular weight (PAA1 and PAA2). Aqueous solutions of the Pi polymer salts, each containing 1.53% w/w Pi base (equivalent to 2.0% Pi nitrate) were tested for miotic activity in albino rabbits, using as reference an aqueous, 2% solution of Pi nitrate, either as such or viscosized with 1.5 and 5.0% poly(vinyl alcohol), (PVA). All polymeric solutions enhanced, in some cases to a statistically significant extent, the bioavailability of the drug with respect to the reference solutions. The relevance of viscosity effects, and of possible muco-adhesive phenomena to the bioavailability of Pi from the salt-vehicles are discussed     

Muco-Adhesive Liquid Ophthalmic Vehicles - Evaluation of Macromolecular Ionic Complexes of Pilocarpine

Pilocarpine (Pi), a widely used anti-glaucoma drug, is characterized by a very low bioavailability, due to poor corneal penetration and extensive precorneal loss. Purpose of the present study was the preparation and “in vivo” evaluation of a series of liquid formulations containing salts (or ionic complexes) of Pi with soluble polyanionic polymers of natural, synthetic or semi-synthetic origin. It was speculated that since to some of the polymers have been attributed muco-adhesive properties, they might favour the preocular retention of the ionically bound drug, and enhance its bioavailability. The polymers submitted to investigation were a) hyaluronic acid (HA); b) poly-(galacturonic acid) (PGA); c) Mesoglycan (MG, a complex mixture of mucopolysaccharides); d) Carboxymethylchitin (CMCh) and d) two poly(acrylic acids) of different molecular weight (PAA1 and PAA2). Aqueous solutions of the Pi polymer salts, each containing 1.53% w/w Pi base (equivalent to 2.0% Pi nitrate) were tested for miotic activity in albino rabbits, using as reference an aqueous, 2% solution of Pi nitrate, either as such or viscosized with 1.5 and 5.0% poly(vinyl alcohol), (PVA). All polymeric solutions enhanced, in some cases to a statistically significant extent, the bioavailability of the drug with respect to the reference solutions. The relevance of viscosity effects, and of possible muco-adhesive phenomena to the bioavailability of Pi from the salt-vehicles are discussed     

Some formulation factors influencing the rate of drug release from bioadhesiw matrices

The development of monolithic matrices with controlled release and mucosa-adhesive properties was investigated. After an initial screening procedure for formulations that showed stability and minimal swelling, the rate of release of a model water soluble drug from various polyacrylic acid containing matrices was evaluated. All the formulations gave a prolonged drug release relative to a lactose containing control formulation. A formulation containing Carbopol 934P and CaCl₂, was found to give the slowest rate of drug release (t_50% of 7.77h), with release kinetics nearest to the ideal zero order. When tested in a modified tensiometer it was found that the inclusion of a relatively high loading of a model drug did not adversely affect the adhesive properties of these formulations.     

Electrochemical determination of dissolution rates of lyophilized pharmaceutical formulations.

We present a method to measure dissolution times for rapidly dissolving lyophilized formulations. K4Fe(CN)6 was lyophilized in formulations containing sucrose, salts, and Tween 20. Dissolution of the lyophilized powders was measured by monitoring the time dependence of the oxidation of Fe(CN)6(4-) ion at the surface of a platinum rotating disk electrode. Reconstitution of lyophilized K4Fe(CN)6 formulations with aqueous solutions of 0.03% Tween 20 altered the time of dissolution for all cases. Salt and sucrose formulations without Tween 20 dissolved more slowly in a Tween 20 solution than in water alone. In contrast, formulations containing Tween 20 dissolved faster in the Tween 20 solution when compared to dissolution in water.     

Properties of ceramic injection-moulding formulations

Five ceramic injection moulding formulations with 65vol% powder and polypropylene as the main organic component were injection -moulded under identical conditions. The extent of mould filling and the production of moulding defects in thick sections were examined in the light of rheological and shrinkage properties of the formulations.     

Some Aspects of Developer and Fixing Bath Concentrates Based on Potassium and Ammonium Salts Respectively

The limited solubility of some potassium salts in comparison to corresponding sodium salts is known from analytical chemistry; the analytical behaviour of ammonium salts is similar to that of potassium salts.

On the other hand, potash and potassium sulphite which are of interest for photographic developers ore several times as soluble as soda and sodium sulphite. Most developer concentrates, therefore, contain potassium salts. However, certain processing conditions may lead to turbidity or precipitation in the developers, due to the formation of sparingly soluble potassium hydroquinone disulphonate.

Commercial fixing bath concentrates contain ammonium thiosulphate which is much more soluble than sodium thiosulphate. Potassium thiosulphate is only slightly more soluble than sodium thiosulphate and, moreover, proves useless as a fixing agent. Fixing baths on the basis of ammonium thiosulphate are superior to those based on the corresponding sodium compound in the processing of films containing silver iodide.

In practical use the formation of crystalline deposits containing ammonium, silver, iodide and thiosulphate ions may occur.     

Characteristics of air pollution control residues of MSW incineration plant in Shanghai

A unique type of waste--air pollution control (APC) residues--has received increasing attention in China since the first large-scale incinerator, Shanghai Yuqiao municipal solid waste (MSW) incineration plant, was installed in the country in 2002. The APC residues of this particular plant are similar to other residues that will be produced in other incineration plants under construction in China. This work examines for the first time the benchmark contaminants of APC residues from the Yuqiao Plant, with reference to soluble salts, heavy metals and dioxins. Experimental findings reveal that the residues contained a marked amount of soluble salts, of up to 17.4-21.9% (mostly chlorides), 0.98-1.5 ngTEQ/gash of dioxins and various heavy metals. Lead is of particular concern, and requires stabilization before disposal. Heavy metal speciation schemes were implemented herein to determine the leaching characteristics. The correlation between the amounts of soluble salts or chemical speciation of the heavy metals and the leaching toxicity of these heavy metals in the residues is considered.     

Mineralogical study of the deterioration of granite stones of two Portuguese churches and characterization of the salt solutions in the porous network by the presence of diatoms

Two Portuguese churches were built with stones of different types of two-mica fine to coarse grained granites. The stones in both monuments were previously submitted to a natural weathering process in the quarries leading to a homogeneous and very well interconnected porous network composed of very thin fissures, allowing a fast capillary transfer of rain water and salt solutions. Therefore, the stones presently exhibit several types of stone decay. A mineralogical study of the deteriorations was carried out in the two churches that permitted the identification of several minerals of soluble salts responsible for stone decay. Some forms of diatoms have been identified in samples of deteriorated stones in both monuments. Several ions in the salt solutions present in the porous networks of the granites, which are in conformity with the minerals of soluble salts associated with the deterioration of the granite, permit the development of several forms of diatoms.     

Alginate-based in situ gelling suspensions and emulsions comprising N4-alkyloxycarbonyl derivatives of cytosine: zero-order release and effect of physicochemical properties

As an alternative to incorporation of various excipients, N⁴-alkyloxycarbonyl-cytosine derivatives possessing various physicochemical properties and cytosine regeneration rates have been examined to modify release rate and kinetics from in situ gelling alginate formulations, e.g., liquid formulations that gel in acidic gastric juice and release the entrapped derivative or parent cytosine. Linear relationships were obtained between the release rate constants and the square root of the solubility for suspension formulations. Calculated diffusion coefficients were observed to be similar for suspension and solution formulations; however, for in situ gelling emulsion formulations, diffusivity correlated linearly to log P. Zero-order release of parent cytosine was observed from in situ gelling suspensions of the poorly soluble acid-labile N⁴-adamantyloxycarbonyl-cytosine prodrug.     

Binding Efficiencies of Strach N. F. and Modified Starches in Formulations of Poorly Water Soluble Drugs

Active and excipient ingredients were granulated in planetary and high intensity mixers. Compression properties of single and multi-drug formulations were evaluated with an insturmented single punch tablet press interfaced with a digitial computer. Dissolution rates were measured using the USP Apparatus #I. Binding efficiency was found directly proportional to granule coarseness for equally well-lubricated granulations. Some differences were observed between the starches, in the manner of their incorporation (dry or as slurry) and between the single and multi-drug formulations. The fromulations containing the pregelatinized starches allowed faster release of a poorly water soluble drug than did those containing starch, N.F.     

The effect of water soluble salts on the nucleating ability of the Agl-AgBr-Cul system

Experiments have been done to determine the extent to which the nucleating ability of 50: 25: 25 mol% composition of Agl, AgBr and Cul fusion material is influenced by the presence of soluble salts. Using a bulk freezing technique, the freezing nucleation temperatures are measured for each salt combination with the nucleant, at salt concentrations of 0.01, 0.1 and 0.5 M. For this, 21 soluble salts have been considered. These salts are found, in general, to increase the supercooling to varying amounts depending upon the salt type and the concentration. But NaCl, at 0.01 M concentration significantly improved the nucleation ability of the material and the nucleation temperature was found to be as high as –0.35° C. The combination of chlorides as well as some sulphates are found to exhibit a decrease in nucleation activity of the material.     

Bile salt/lecithin mixed micelles optimized for the solubilization of a poorly soluble steroid molecule using statistical experimental design

Bile salts and lecithin combine physiologically to form mixed micelles which aid the solubilization and absorption of dietary fats and drug molecules. In this series of experiments, we have shown how experimental design procedures aid the optimization of a formulation incorporating a bile salt, lecithin, and water with fluticasone propionate (FP) as the model poorly soluble drug. The initial inclusion of a categorical variable ruled out the use of classic response surface designs; therefore the experimental design was constructed using a d-optimal selection from a candidate set of all possible experimental combinations. A separate 2-factor central composite design was used to determine the optimum lecithin and bile salt concentrations over an extended range after the categorical variable had been eliminated. It has been demonstrated that an increase in either lecithin or cholic acid concentration produces an increase in solubility of FP, while sodium taurocholate appears to depress the solubility of FP compared with the other two bile salts. The increase in solubility associated with the increase in bile salt and lecithin is further demonstrated by a linear relationship between FP solubility and the total lipid in the formulation. The influence of molar ratio of lecithin to bile salt in the formulation is also significant. The physical properties of the mixed micellar system (solution turbidity and viscosity ranking) were used to further discriminate between formulations. The optimization showed that the dominant effect was the lecithin, which improves the solubilizing characteristics of the formulation with increasing concentration. The effect of salt concentration is less marked though slightly quadratic in nature. The overall increase in solubility demonstrated was from <1 microg/mL in water to 205 microg/mL in the optimized mixed micellar system.     

水显影光固化材料的制备及其各组分对感光性能的影响

利用热塑性酚醛环氧树脂的环氧基，依次用丙烯酸及叔胺盐进行开环反应，合成了水溶性丙烯酸酯类感光高分子，将其配制成水显影光固化材料，并研究了叔胺盐的种类，不同光引发剂和光谱效剂以及稀释性单体对其感光性能的影响。     

Evaluation of sorghum starch as a tablet excipient

The suitability of sorghum starch as a binder and disintegrant at various concentrations in diverse tablet formulations have been investigated. Sodium bicarbonate and calcium carbonate were used as soluble and insoluble inorganic medicinal substances in various tablet formulations.

The effect of sorghum starch on the physical properties of the tablets were compared with those formulated with maize starch using the same concentrations of binder and disintegrant under the same experimental conditions.

The observations show that sorghum starch can be used as binder and disintegrant in tablet formulations. The indication is that the starch exhibit about twice the disintegrant power and about the same binding efficacy compared to maize starch.     

Early development evaluation of AZD2738, a substrate for the NK receptors

The purpose of this study was to investigate whether AZD2738, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development with an oral immediate release solid dosage form as a possible final product. The neutral form of AZD2738 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Mostly crystalline material of fumarate, maleate and chloride salt of AZD2738 were obtained. X-ray powder diffractometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the salts. Based on the physicochemical properties, the chloride salt is preferred for continued product development. The chloride salt of AZD2738 is an anhydrate, the crystallization is reproducible, the hygroscopicity is acceptable and just one polymorph was obtained. Notably is that the two obtained polymorphs of the fumarate salt of AZD2738 are monotropically related, whereas the two identified polymorphs for the maleate salt of the compound are enantiotropic. The dissolution behavior and the stability (in aqueous solutions, formulations and solid state) of the salts were also studied and found to be satisfactory, at least at pH >3. Liquid formulations should preferable be stored frozen at pH >3.     

Alginate-Based In Situ Gelling Suspensions and Emulsions Comprising N4-Alkyloxycarbonyl Derivatives of Cytosine: Zero-Order Release and Effect of Physicochemical Properties

As an alternative to incorporation of various excipients, N⁴-alkyloxycarbonyl-cytosine derivatives possessing various physicochemical properties and cytosine regeneration rates have been examined to modify release rate and kinetics from in situ gelling alginate formulations, e.g., liquid formulations that gel in acidic gastric juice and release the entrapped derivative or parent cytosine. Linear relationships were obtained between the release rate constants and the square root of the solubility for suspension formulations. Calculated diffusion coefficients were observed to be similar for suspension and solution formulations; however, for in situ gelling emulsion formulations, diffusivity correlated linearly to log P. Zero-order release of parent cytosine was observed from in situ gelling suspensions of the poorly soluble acid-labile N⁴-adamantyloxycarbonyl-cytosine prodrug.     

Modified phosphate pigments as high performance reinforcing materials for rubber vulcanizates

This study is focusing on the synthesis of novel modified micronized phosphate pigments as reinforcing materials for the vulcanizates of styrene-butadiene rubber (SBR), natural rubber (NR) and their blends. The metal phenyl phosphate pigments were prepared via co-precipitation process from the reaction of equimolar ratios of the disodium phenyl phosphate solution and the water soluble salts of the investigated metals. The white prepared phosphate pigments were introduced in the rubber formulations to replace carbon black the highly common and commercial reinforcing material in rubber vulcanizates. The rheometric characteristics, physico-mechanical properties in addition to the accelerated aging properties of the rubber vulcanizates were investigated, discussed and interpreted in the light of previous studies. The results showed that, phenyl phosphate pigments exercised a great effect on the rheological characteristics (scorch time, cure time…etc.), and achieved high performance and pronounced mechanical properties. The stress and strain at yield and at rupture of the loaded rubber with modified phosphates are better than that loaded with carbon black and Hisil e.g. tensile strength data were (20.0–23.4), 18.01 MPa and 15.05 for rubber blend vulcanizates loaded with 30 phr of modified phosphate pigments, carbon black and Hisil, respectively.     

Design of self-microemulsifying drug delivery systems using a high-throughput formulation screening system

Purpose: A high-throughput formulation screening (HTFS) system that enabled to rapidly and efficiently select self-microemulsifying drug delivery system (SMEDDS) formulations has been developed in our previous study. The purpose of this study was to investigate the applicability of the HTFS system to SMEDDS designs. Methods: A poorly soluble drug (Nilvadipine), an oil (Sefsol-218), 11 hydrophilic surfactants (HS), and 10 lipophilic surfactants (LS) were used. Formulations were prepared and SMEDDS formulations were chosen by the HTFS system. A HS with the largest number of SMEDDS formulations was selected. In the selected HS system, a LS with the largest number of SMEDDS formulations was selected. Formulations with minimum turbidity at each ratio of the selected HS/LS were chosen as optimized formulations. Results: A total of 2455 formulations were prepared and SMEDDS formulations were selected using the HTFS system. From the screening data, HCO60 was selected as a superior emulsifiable HS, and Plurol (PLUROL OLEIQUE CC497) was selected as a suitable LS to HCO60. Five optimized formulations were chosen from the HCO60/Plurol system. The formulations formed fine microemulsions (<33.6 nm) without phase separation and drug precipitation. These formulation designs were conducted using 600 mg of the drug at a rate of 400 formulations/person/day. Conclusion: SMEDDS formulations could be rapidly and efficiently designed using the HTFS system.