Formulation study for lansoprazole fast-disintegrating tablet. I. Effect of compression on dissolution behavior

Lansoprazole fast-disintegrating tablet (LFDT) is a new patient-friendly formulation of lansoprazole. Since lansoprazole is an antiulcer agent and is unstable under acidic conditions, we have developed LFDT as an orally disintegrating tablet containing enteric-coated microgranules. The effect of compression on dissolution behavior was investigated, as compression affected cleavage and crushing of the enteric layer. To decrease cleavage and crushing of the enteric layer, the effects of the combined ratio of methacrylic acid copolymer dispersion to ethyl acrylate-methyl methacrylate copolymer dispersion and the concentration of triethyl citrate on the dissolution in the acid stage and the dissolution in the buffer stage were evaluated. By adjusting the ratio of methacrylic acid copolymer dispersion to ethyl acrylate-methyl methacrylate copolymer dispersion to 9 : 1 and adding a 20% triethyl citrate concentration, sufficient flexibility of the enteric layer and sufficient stability against compression forces were achieved. Agglomeration of enteric-coated microgranules during the coating process was decreased at the optimized concentration of triethyl citrate and glyceryl monostearate. We compared the absorption properties of LFDT and lansoprazole capsules in dogs. The absorption profiles of LFDT were similar to those of lansoprazole capsules.     

Formulation study for lansoprazole fast-disintegrating tablet. III. Design of rapidly disintegrating tablets

Lansoprazole fast-disintegrating tablets (LFDT) are a patient-friendly formulation that rapidly disintegrates in the mouth. LFDT consist of enteric-coated microgranules (mean particle size, approximately 300 microm) and inactive granules. In the design of the inactive granules, mannitol was used as a basic excipient. Microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), and crospovidone were used as binders and disintegrants. A new grade of L-HPC (L-HPC-33), with a hydroxypropoxy group content of 5.0-6.9%, was developed and it has no rough texture due to a decrease in water absorption. It was clarified that L-HPC-33 could be useful as a binder and disintegrant in rapidly disintegrating tablets. LFDT contain enteric-coated microgranules in tablet form. The enteric-coated microgranule content in LFDT affect qualities such as tensile strength, disintegration time in the mouth, and dissolution behavior in the acid stage and in the buffer stage of LFDT. The 47.4% content of the enteric-coated microgranules was selected to give sufficient tensile strength (not less than 30 N/cm(2)), rapid disintegration time in the mouth (not more than 30 s), and dissolution behavior in the acid stage and buffer stage similar to current lansoprazole capsules. Compression force affected the tensile strength and the disintegration time in the mouth, but did not affect the dissolution behavior in the acid and buffer stages.     

Formulation and optimization of orally disintegrating tablets of sumatriptan succinate

The aims of the present research were to mask the intensely bitter taste of sumatriptan succinate and to formulate orally disintegrating tablets (ODTs) of the taste masked drug. Taste masking was performed by coating sumatriptan succinate with Eudragit EPO using spray drying technique. The resultant microspheres were evaluated for thermal analysis, yield, particle size, entrapment efficiency and in vitro taste masking. The tablets were formulated by mixing the taste masked microspheres with different types and concentrations of superdisintegrants and compressed using direct compression method followed by sublimation technique. The prepared tablets were evaluated for weight variation, thickness, hardness, friability, drug content, water content, in vitro disintegration time and in vitro drug release. All the tablet formulations disintegrated in vitro within 37-410 s. The optimized formulation containing 5% Kollidon CL-SF released more than 90% of the drug within 15 min and the release was comparable to that of commercial product (Suminat?). In human volunteers, the optimized formulation was found to have a pleasant taste and mouth feel and disintegrated in the oral cavity within 41 s. The optimized formulation was found to be stable and bioequivalent with Suminat?.     

Development and evaluation of orally disintegrating tablets (ODTs) containing Ibuprofen granules prepared by hot melt extrusion

In the current study Ibuprofen was embedded in a methacrylate copolymer (Eudragit^® EPO) matrix to produce solid dispersions by hot-melt extrusion (HME) processing. The obtained granules were incorporated in orally disintegrating tablets (ODTs). The tablets were developed by varying the ratio of superdisintegrants such as sodium croscarmellose and crosslinked polyvinylpyrrolidone grades while a direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets which included porosity, hardness, friability and dissolution profiles were further evaluated and compared with Nurofen^® Meltlet ODTs. The taste and sensory evaluation in human volunteers demonstrated excellence in masking the bitter active and improved tablet palatability.     

Preparation and evaluation of tablets rapidly disintegrating in saliva containing bitter-taste-masked granules by the compression method.

The aim of this study was to prepare, using taste-masked granules, tablets which can rapidly disintegrate in saliva (rapidly disintegrating tablet), of drugs with bitter taste (pirenzepine HCl or oxybutynin HCl). The taste-masked granules were prepared using aminoalkyl methacrylate copolymers (Eudragit E-100) by the extrusion method. None of the drugs dissolved from the granules (% of dissolved, < 5%) even at 480 min at pH 6.8 in the dissolution test. However, the drugs dissolved rapidly in the medium at pH 1.2 in the dissolution test. Rapidly disintegrating tablets were prepared using the prepared taste-masked granules, and a mixture of excipients consisting of crystalline cellulose (Avicel PH-102) and low-substituted hydroxypropylcellulose (L-HPC, LH-11). The granules and excipients were mixed well (mixing ratio by weight, crystalline cellulose: L-HPC = 8:2) with 1% magnesium stearate, and subsequently compressed at 500-1500 kgf in a single-punch tableting machine. The prepared tablets (compressed at 500 kgf) containing the taste-masked granules have sufficient strength (the crushing strength: oxybutynin tablet, 3.5 kg; pirenzepine tablet, 2.2 kg), and a rapid disintegration time (within 20 s) was observed in the saliva of healthy volunteers. None of the volunteers felt any bitter taste after the disintegration of the tablet which contained the taste-masked granules. We confirmed that the rapidly disintegrating tablets can be prepared using these taste-masked granules and excipients which are commonly used in tablet preparation.     

Development, characterization and performance evaluation of oro-dispersible tablet containing aceclofenac hydroxypropyl-β-cyclodextrin binary system

The purpose of this research was to mask the intensely bitter taste of aceclofenac (ACF) and to formulate oro dispersible tablet (ODT) of the taste-masked drug. Taste masking was done by complexing aceclofenac with Hydroxypropyl-β-Cyclodextrin (HPβCD) by different methods. Phase solubility studies indicated complex with possible stoichiometry of 1:1 and a stability constant of 221.11 M^?1. The complexes were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry studies. The characterization studies confirmed inclusion of the ACF within the nonpolar cavity of HPβCD in the neutralization method (NM). Remarkable improvement in the in vitro drug release profiles in pH 6.8 phosphate buffer was observed with all complexes, especially the neutralization. The complexes of ACF–HPβCD (1:1) was compressed into tablet and properties of tablets such as tensile strength, wetting time, in vitro disintegration time, and disintegration in the oral cavity were investigated to elucidate the wetting and disintegration characteristics of tablets. Polyplasdone XL-10 7% wt/wt gave the minimum disintegration time. Tablets of batch F4 containing Avicel 200 and 7% wt/wt Polyplasdone XL-10 showed faster disintegration, within 12 s, than the marketed tablet (128 s). Good correlation between in vitro disintegration with in-house developed method and in the oral cavity was recognized. Taste evaluation of ODT in human volunteers revealed considerable taste masking with the degree of bitterness below threshold value. Thus, results conclusively demonstrated successful masking of taste and rapid disintegration of the formulated tablets in the oral cavity.     

High-performance liquid chromatographic assay for prostaglandin E1 in various ointment vehicles. Separation and stability testing

A high-performance liquid chromatographic method for the determination of prostaglandin E1 (PGE1) incorporated in white petrolatum, white ointment, hydrophilic petrolatum and Plastibase was investigated. The prostaglandin was separated from the oleaginous vehicles with n-hexane-aqueous acetonitrile. Most of white petrolatum, which is a principal component in the vehicles, remained in the n-hexane layer, and the recovery of the drug from any vehicle attained 100%. The method was applied to stability studies of PGE1 in white petrolatum and macrogol ointment. In which pure PGE1 and PGE1-alpha-cyclodextrin complex (PGE1-CD) were incorporated. The drug remained intact for up to 6 months when stored at 5 degrees C. At 25 and 40 degrees C, pure PGE1 was more stable than PGE1-CD and both PGE1 species were more stable in white petrolatum than in macrogol ointment.     

Determination of Plasticizers Commonly Used In Pharmaceutical Dosage Forms by High Performance Liquid Chromatography

Abstract

A simple reversed-phase HPLC method was developed to identify and quantify plasticizers commonly used with polymers present in sustained or controlled release dosage forms. the plasticizers investigated included triethyl citrate, tributyl citrate, acetyl triethyl citrate, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, and triacetin. the plasticizers were detected at 220 nm, the mobile phase being methanol:water (70:30 v/v%). the peak area response was linear over the studied concentration range of 0.5–5.0 mM/L for triethyl citrate, acetyl triethyl citrate, dibutyl sebacate, and triacetin, and 0.005 ? 0.05 mM/L for diethyl phthalate. the recovery from solvent-cast ethyl cellulose and Eudragit RS 100 films was complete. Two pharmaceutical applications of this assay included the quantitation of plasticizers in polymer-coated sugar beads and a leaching study of a water-soluble plasticizer, triethyl citrate, from polymeric films into simulated intestinal fluids.     

Preparation of rapidly disintegrating tablets containing itraconazole solid dispersions

The disintegratability of tablets prepared from two types of solid dispersions containing the water-soluble polymer TC-5 and the enteric polymer HP-55 as an excipient were compared. The disintegratability was better in the tablets of solid dispersions containing non-water-soluble HP-55 than those containing TC-5. In consideration of the dissolubility of solid dispersions containing HP-55, the mean diameter of the solid dispersion (coating powder) must be controlled to 120 microm or less, but as this markedly increases the adhesion/aggregation tendency of the particles (angle of repose: 47 degrees ), control of the adhesion/aggregation tendency emerged as another problem. Therefore, surface-modification was performed in a high-speed agitating granulator using 0.1% light anhydrous silicic acid as a surface modifier, and marked improvement in the flowability was observed. This made continuous tableting using a rotary tablet machine possible even with the poorly flowable solid dispersions. Also, in tableting of the solid dispersions, no recrystallization of amorphous itraconazole by the tableting pressure was observed, and the tablets maintained satisfactory dissolubility. Moreover, it was possible to obtain the rapidly disintegrating tablets with very satisfactory properties, i.e., a tablet hardness of 30 N or higher and a disintegration time of 30 s or less, by the addition of croscarmellose as a disintegrant at 2% to the surface-modified solid dispersion and selection of the tableting pressure at 4.5 kN.     

Enhancement effect of lauric acid on the rectal absorption of propranolol from suppository in rats.

In a previous paper, we have demonstrated that medium chain fatty acids significantly enhance the in vitro rectal absorption of propranolol (PL) and that the enhancement may be partly due to the formation of a complex with a fatty acid at a 1:1 molar ratio. To confirm in vivo the enhancement effect of lauric acid on PL absorption, PL suppositories with lauric acid at various molar ratios were administered to rat rectum. PL absorption from Witepsol and macrogol suppositories with lauric acid at a 1:1 molar ratio was much larger than that after PL alone and the 1:2 or 1:3 molar ratio ones. The bioavailability (BA) after administration of the 1:1 molar ratio suppository (PL, 4 mg/kg) was 1.6- and 2.1-fold for the Witepsol and macrogol formulations respectively, compared with that after PL alone. A similar result was obtained with the PL solid dispersion suppository with lauric acid at a 1:1 molar ratio, showing a 1.7-fold higher BA compared with PL alone. The release of PL from the macrogol suppository was significantly faster at a 1:1 molar ratio than that of other preparations, but not so in the solid dispersion suppository. There was not good agreement between the release rates of PL from the suppositories and the plasma levels after dosing. These results supported the concept that a portion of PL, by forming a 1:1 complex with lauric acid, would penetrate across the rectal mucosa more easily than PL alone.     

Tabletting of solid dispersion particles consisting of indomethacin and porous silica particles

We attempted to make the rapidly dissolving tablet (Tab) containing solid dispersion particles (SD) with indomethacin (IMC) and porous silica (Sylysia350) as carrier prepared by using spray-drying technique. Rapidly dissolving tablet was formulated with mannitol as a diluent and low substituted hydroxypropylcellulose (L-HPC) or partly pre-gelatinized starch (PCS) as a disintegrant. The percent dissolved from Tab (SD) was higher than that of tablet containing physical mixture (PM) at 20 min. Nearly 100% of drug in Tab (SD) was dissolved within 60 min, while the drug dissolution of Tab (PM) was not completed at the same time period. In addition, the tensile strength of Tab (SD) was much higher than that of Tab (PM). Adding L-HPC in Tab (SD) (Tab (SD-L-HPC)), the percent dissolved from Tab (SD-L-HPC) at 5 min became much higher than that from Tab (SD). The dissolution profile of IMC from Tab (SD-L-HPC) was almost the same irrespective of the compression pressure, while the tensile strength of tablet increased with increasing the compression pressure. In comparing the compaction property of these tablets by observing the ratio of residual die wall pressure (RDP) to maximum die wall pressure (MDP) (RDP/MDP), it was found that addition of L-HPC in the tablet formulation improved compactibility. In case that PCS was formulated as disintegrant, Tab (SD-PCS), similar improvement in the dissolution profile and tensile strength was observed, though the dissolution rate of IMC from Tab (SD-PCS) was slightly lower than that from Tab (SD-L-HPC) irrespective of the compression pressure.     

Thermal stability of polymer compositions with modified alumina

Thermal stability and combustibility of polymer compositions: foam plastic (trade mark PEN-I) based on an epoxide novolak block copolymer, and poly(methyl methacrylate, containing modified alumina of various dispersion as a filler, were investigated.     

Masking mechanisms of bitter taste of drugs studied with ion selective electrodes

The masking mechanisms of the bitter taste of propantheline bromide (PB) and oxyphenonium (OB) bromide by native and modified cyclodextrins, saccharides, surfactants, organic acids, nonionic and anionic polymers, and other compounds were investigated with ion selective electrodes. The intensity of the bitter taste for a mixed solution of cyclodextrin with PB or OB was quantitatively explained from the observed electromotive force with the following assumptions: the complex and the masking agent do not have any tastes and the bitter taste is independent of other tastes. Sodium dodecyl sulfate reduced the bitter taste remarkably, and this reduction was also explicable on the basis of the same mechanism. Sodium taurodeoxycholate enhanced the bitter taste, because of its strong bitterness, although it formed 1 : 1 complexes with PB and OB. The masking mechanism of saccharides was ascribed to overcoming the weak bitterness of the drug by the strong sweetness. Lambda-carrageenan suppressed the bitter taste remarkably. This suppression was ascribed to the binding of PB and OB to lambda-carrageenan, the effect of the solution viscosity on the bitter taste, and the covering of the bitter taste receptor by lambda-carrageenan. It was suggested that the moderate masking by other polymers was attributable to the effect of the solution viscosity or the receptor covering. Native and modified beta-cyclodextrins, sodium dodecyl sulfate, lambda-carrageenan, Tween 20, and sodium carboxymethyl cellulose are good masking agents for the bitter tastes of PB and OB. The drug ion selective electrode is a useful tool for understanding of the masking mechanism of the bitter taste, screening of masking agents, and estimation of appropriate concentrations of the masking agents.     

Thermal study of ethyl cellulose coating films used for modified release (MR) dosage forms

The aim of our research was to investigate the effect of the length of the polymer chain and the concentration of triethyl citrate used as a plasticizer on the thermal stability of the film structure in the case of two ethyl cellulose films (EC 10 and EC 45) used for preparing MR dosage forms. The influence of storage time was studied by monitoring the changes in the thermoanalytical parameters and by performing TG–MS examinations. It was found that the decomposition of the plasticizer from the arising film structure is retarded and a more homogeneous sample, therefore a better film can be prepared from EC 45. Mass spectrography performed as a coupled technique also proved that the films stayed stable until approximately 200 °C. Based on the above results, the composition prepared from EC 45 polymer with 5% triethyl citrate as plasticizer is recommended for making MR dosage forms.     

Chemical investigation of the bitter substances of the fruit of Lonicera caerulea

Esters of malic and citric acids have been isolated from an ethyl acetate fraction of an ethanolic extraction ofLonicera caerulea L.: dibutyl malate (I), 4-butyl 1-methyl malate (II), 1-butyl 4-methyl malate (III), tributyl citrate (IV), 1,5-dibutyl citrate (V), 1,1-dibutyl citrate (VI), 1,5-dibutyl 1-methyl citrate (VII), 1,1-dibutyl 5-methyl citrate (VIII), 1-butyl citrate (IX), 1-butyl citrate (X), 1-butyl 1,5-dimethyl citrate (XI), and 1-butyl 1,5-dimethyl citrate (XII). Compounds (I-IV, VII, VIII, XI, and XII) had a bitter taste and were the main components of the bitter substances of the fruit ofLonicera caerulea. The structures of compounds (I-XII) were established on the basis of their¹H and¹³C NMR spectra, by FAB mass spectrometry and chromato-mass spectrometry.Irkutsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the USSR. Sverdlovsk Institute of the National Economy. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 338–342, May–June; 1989.     

HPLC Determination of Lansoprazole and Method Application for the Formulation Development of Enteric‐coated Lansoprazole Pellets

The aim of this study was to develop a validated HPLC method for the determination of lansoprazole in dissolution medium and pellets. For the formulation development, we investigated the role of 2‐hydroxypropyl‐β‐cyclodextrin (HPβCD) on the dissolution of enteric‐coated pellets of lansoprazole prepared by the solution layering technique using a fluid bed coater. Dissolution results demonstrated the coating using Acryl‐Eze protected the formulations from releasing lansoprazole in acid medium for the first 2 h, and the addition of HPβCD improved the dissolution performance by 189%, compared with the group without HPβCD. The DSC analysis displaced an absence of the endothermic peak for the lyophilized products lansoprazole and HPβCD, and FTIR analysis demonstrated the band broadening, shifting or disappearance compared to the spectra of the physical mixture, which indicated the formation of the inclusion complex between lansoprazole and HPβCD. This study has developed a validated HPLC method to measure lansoprazole in test media and pellets, which was applied successfully to the formula tion development of enteric‐coated pellets.     

Preparation and evaluation of orally rapidly disintegrating tablets containing taste-masked particles using one-step dry-coated tablets technology

In this study, in order to address the problems with manufacturing orally rapidly disintegrating tablets (ODT) containing functional (taste masking or controlled release) coated particles, such as the low compactability of coated particles and the rupture of coated membrane during compression, a novel ODT containing taste-masked coated particles (TMP) in the center of the tablets were prepared using one-step dry-coated tablets (OSDrC) technology. As a reference, physical-mixture tablets (PM) were prepared by a conventional tableting method, and the properties of the tablets and the effect of compression on the characteristics of TMP were evaluated. OSDrC was found to have higher tensile strength and far lower friability than PM, but the oral disintegration time of OSDrC is slightly longer than that of PM following high compression pressure. Consequently, OSDrC approaches the target tablet properties of ODT, whereas PM does not. The deformation of TMP in OSDrC due to compression is slight, and the release rate of acetaminophen (AAP) from OSDrC is the same as from TMP. However, TMP on the surface of PM are considerably deformed, and the release rate of AAP from PM is faster than from TMP. These findings suggest that OSDrC technology is a useful approach for preparing ODT containing functional coated particles. Furthermore, we demonstrate that the elastic recovery of tablets can affect differences in the properties of OSDrC, PM and placebo tablets (PC).     

MULTIPLE EMULSIONS. PART II: PROPOSED TECHNIQUE TO OVERCOME UNPLEASANT TASTE OF DRUGS

Multiple emulsions of water in oil in water (W/O/W) have been used as a novel technique to overcome unpleasant taste of drugs. The drug is dissolved in the inner water phase and is released throughout the oil phase in the presence of synthetic gastric juice

Yield of preparation and stability have been studied using various sets of different inner (emulsifier I) and outer (emulsifier II)emulsifiers

Combination of anionic-nonionic emulsifiers yielded optimal results: High yield of preparation, high stability and complete release of the drug in synthetic gastric juice.     

The organization of the surface of multicomponent plasma-electrolytic anode layers on aluminum

The elemental composition of characteristic formations on the surface of anodic films containing transition metal compounds (Ni, Cu, Co, Mn, and W) and formed on an aluminum alloy in aqueous electrolytes under the conditions of the action of electric spark and arc discharges (plasma-electrolytic or plasmaelectrochemical oxidation) was studied. The main formations on the surface were fritted structures, pores, caverns covered by “lids” on top, and disperse particles (microgranules). Electrolyte transition metals largely concentrated in caverns, pores, and microgranules. The composition of microgranules was different from that of caverns, pores, and fritted structures. The main elements that formed microgranules were nickel and carbon. Cobalt and manganese were differently built into surface formations. Cobalt replaced nickel in micro-granules, and manganese replaced aluminum in fritted surface structures.     

Electrochemical studies and differential pulse polarographic analysis of lansoprazole in pharmaceuticals

The electrochemical reduction of lansoprazole was investigated by cyclic voltammetry and direct current and differential pulse polarography. The reduction potential was -1.32 V vs. Ag/AgCl with a dropping mercury electrode in a supporting electrolyte consisting of phosphate buffer (pH 9.0)-tetramethylammonium iodide (4 + 1). The reversibility of the electrode reaction and the type of limiting current were studied. The temperature coefficient and the diffusion constant were determined. A mechanism for the electrode reaction was proposed. A new simple and sensitive differential pulse polarographic method was also developed for the quantification of lansoprazole. A linear calibration graph was obtained in the range 0.04-11.35 micrograms ml-1. The limit of detection was 0.03 microgram ml-1 and the intra- and inter-day precisions were 0.84-2.32 and 0.72-3.09%, respectively. The developed method was applied to six different commercial pharmaceutical capsule preparations containing enteric-coated granules. The relative standard deviations ranged from 1.36 to 2.85%. Recovery studies for the accuracy of the method were performed by adding a synthetic mixture to known amounts of lansoprazole and the mean recovery was 100.45%. The data obtained from commercial preparations were compared with those from a published spectrophotometric method. No difference was found statistically.