Sustained Release Formulation of Salbutamol Sulphate

Abstract

Sustained release tablets containing salbutamol sulphate has been prepared by wax matrix granulation method and were evaluated for in vitro release profile and in vivo availability studies in dogs. Out of the release retarding waxy materials used combinations of carnauba wax and stearyl alcohol in concentration range between 60 to 70% of the weight of the tablet were found to be optimum in fabricating sustained release tablets for twentyfour hours duration of action. The formulations were also compared with marketed products of salbutamol for in vitro release profile.     

Controlled Release Salbutamol Sulphate Molded Tablets Using Eudragit Retard

Permeable acrylic resins were used as efficient retarding materials to prepare controlled release salbutamol sulphate molded tablets. The formulation is simple, efficient, economic and is easily shaped into molded tablets. The effects of two types of acrylic resins, namely: Eudragit RL100 ad Eudragit RS100 in concentrations 1, 2 and 5% w/w on the physical characteristics as well as on the in vitro release patterns of salbutamol sulphate from molded tablets prepared with either polyethylene glycol (PEG) 4000 or 6000 were studied. It was revealed that, as the molecular weight of the PEG increased, the hardness of the tablets increased. Considerable retardation in the drug release was observed by using Eudragit RS100 as compared to Eudragit RL100. The formulation prepared with PEG 6000 and 5% Eudragit RS100 produced much more release time prolongation than the other tested formulations. On the other hand, tablets prepared by the direct compression technique produced a faster release of salbutamol sulphate than those prepared by molding.     

Controlled Release Salbutamol Sulphate Molded Tablets Using Eudragit Retard

Abstract

Permeable acrylic resins were used as efficient retarding materials to prepare controlled release salbutamol sulphate molded tablets. The formulation is simple, efficient, economic and is easily shaped into molded tablets. The effects of two types of acrylic resins, namely: Eudragit RL100 ad Eudragit RS100 in concentrations 1, 2 and 5% w/w on the physical characteristics as well as on the in vitro release patterns of salbutamol sulphate from molded tablets prepared with either polyethylene glycol (PEG) 4000 or 6000 were studied. It was revealed that, as the molecular weight of the PEG increased, the hardness of the tablets increased. Considerable retardation in the drug release was observed by using Eudragit RS100 as compared to Eudragit RL100. The formulation prepared with PEG 6000 and 5% Eudragit RS100 produced much more release time prolongation than the other tested formulations. On the other hand, tablets prepared by the direct compression technique produced a faster release of salbutamol sulphate than those prepared by molding.     

Evaluation of Stereoselective Dissolution of Racemic Salbutamol Matrices Prepared with Commonly Used Excipients and 1H-NMR Study

The purpose of this work was to examine the in vitro enantioselective dissolution of salbutamol from matrix tablets containing various chiral excipients, such as γ-cyclodextrin (γ-CD), heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), sulfobutyl-β-cyclodextrin (SBE-β-CD), hydroxypropylmethylcellulose (HPMC), and egg albumin. In this study, two types of tablets were prepared; the coated tablet contained the complex of racemic salbutamol and cyclodextrin (γ-CD, DM-β-CD, and SBE-β-CD), and the uncoated tablet was composed of the drug with either HPMC or egg albumin. Subsequently, these formulations were evaluated for enantioselective release. The results revealed that the formulations containing either SBE-β-CD, HPMC, or egg albumin had no enantioselective release, while the formulation with DM-β-CD gave slightly different release of the two enantiomers at the end of the dissolution profile. The formulation containing γ-CD provided significant stereoselectivity throughout the dissolution profile. The release of the eutomer R-salbutamol was higher than that of the distomer S-salbutamol from the γ-CD tablet. In addition, the enantioselective interaction for the γ-CD inclusion complex was investigated by ¹H-NMR (nuclear magnetic resonance) spectroscopy and gave evidence to support the enantioselectivity obtained on dissolution.     

Melt granulation and heat treatment for wax matrix-controlled drug release

The purpose of this study was to evaluate sustained drug release after melt granulation and heat treatment. Theophylline (anhydrous) and phenylpropanolamine hydrochloride (PPA) were used as model drugs. Compritol® 888 ATO (Glyceryl Behenate NF) was incorporated as the wax matrix material. Formulations with drug:wax in 3:1 and 1:1 ratios were evaluated. Tablets were made by dry blending or melt granulation; some of the tablets were heat treated at 80°C for 30 min. Tablets with or without heat treatment were tested for drug release using in vitro drug dissolution. The results showed that melt granulation gave slower drug release than dry blending. Heat treatment further retarded drug release for both dry blending and melt granulation. The drug release rates for theophylline were slower than for PPA at the same wax level and processing method. The drug release profiles were linear using a square root of time scale. In conclusion, melt granulation and heat treatment slowed drug release for the wax matrix-controlled release tablets. Heat treatment of the tablets made by melt granulation further retarded drug release. Heat treatment redistributed the wax, forming a new matrix system with higher tortuosity. The application of melt granulation or heat treatment can successfully retard drug release.     

Evaluation of Stereoselective Dissolution of Racemic Salbutamol Matrices Prepared with Commonly Used Excipients and 1H-NMR Study

The purpose of this work was to examine the in vitro enantioselective dissolution of salbutamol from matrix tablets containing various chiral excipients, such as γ-cyclodextrin (γ-CD), heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), sulfobutyl-β-cyclodextrin (SBE-β-CD), hydroxypropylmethylcellulose (HPMC), and egg albumin. In this study, two types of tablets were prepared; the coated tablet contained the complex of racemic salbutamol and cyclodextrin (γ-CD, DM-β-CD, and SBE-β-CD), and the uncoated tablet was composed of the drug with either HPMC or egg albumin. Subsequently, these formulations were evaluated for enantioselective release. The results revealed that the formulations containing either SBE-β-CD, HPMC, or egg albumin had no enantioselective release, while the formulation with DM-β-CD gave slightly different release of the two enantiomers at the end of the dissolution profile. The formulation containing γ-CD provided significant stereoselectivity throughout the dissolution profile. The release of the eutomer R-salbutamol was higher than that of the distomer S-salbutamol from the γ-CD tablet. In addition, the enantioselective interaction for the γ-CD inclusion complex was investigated by ¹H-NMR (nuclear magnetic resonance) spectroscopy and gave evidence to support the enantioselectivity obtained on dissolution.     

Effect of diluents on tablet integrity and controlled drug release

The objective of this study was to evaluate the effect of diluents and wax level on tablet integrity during heat treatment and dissolution for sustained-release formulations and the resultant effect on drug release. Dibasic calcium phosphate dihydrate (DCPD), microcrystalline cellulose (MCC), and lactose were evaluated for their effect on tablet integrity during drug dissolution and heat treatment in wax matrix formulations. A newly developed direct compression diluent, dibasic calcium phosphate anhydrous (DCPA), was also evaluated. Compritol® 888 ATO was used as the wax matrix material, with phenylpropanolamine hydrochloride (PPA) as a model drug. Tablets were made by direct compression and then subjected to heat treatment at 80°C for 30 min. The results showed that MCC, lactose, and DCPA could maintain tablets intact during heat treatment above the melting point of wax (70°C-75°C). However, DCPD tablets showed wax egress during the treatment. MCC tablets swelled and cracked during drug dissolution and resulted in quick release. DCPD and lactose tablets remained intact during dissolution and gave slower release than MCC tablets. DCPA tablets without heat treatment disintegrated very quickly and showed immediate release. In contrast, heat-treated DCPA tablets remained intact through the 24-hr dissolution test and only released about 80% PPA at 6 hr. In the investigation of wax level, DCPD was used as the diluent. The drug release rate decreased as the wax content increased from 15% to 81.25%. The dissolution data were best described by the Higuchi square-root-of-time model. Diluents showed various effects during heat treatment and drug dissolution. The integrity of the tablets was related to the drug release rate. Heat treatment retarded drug release if there was no wax egress.     

Development of a Formulation of Sustained Release Potassium Chloride

Abstract

The purpose of this work has been the designing and “in vitro” evaluation of a potassium chloride tablet using a wax matrix.

Camauba wax, stearyl alcohol and stearic acid ware employed to prepare granulates at different drug/wax ratios. Fran dissolution kinetic studies and technological performances a 75/25 – KCl/camauba wax granulates was selected. The rheolqgical properties of granulates were characterized and tablets were manufactured employing ccrrmun tablets excipients. Also a coating procedure was developed. The coated tablet formulation selected release the potassium chloride according to the USP requirements.

The dissolution kinetics of the potassium chloride from both coated and uncoated tablets fit the Higuchi diffusion model, giving a straight line when the amount dissolved is plotted against the square root of time.     

Statistical Comparison of the Dissolution curves of Controlled-Release Solid Oral Dosage Forms

This paper shows how the Box method, based on the statistical technique known as “split-plot” in general use for replicate measurements, may be used to quantify and compare in vitro dissolution curves of controlled release solid oral dosage forms. In this case, it is applied to the interpretation of the findings of a stability test on controlled-released lithium tablets formulated with a wax matrix and containing 10.8 mEq lithium per tablet. The findings showed that the total amount of lithium dissolved after the tablets had been stored for a period of six months was slightly greater than before storage; the dissolution mean rate went from 1.06 mEq/h to 1.17 mEq/h and the dissolution rate curve profile apparently registered less variation.

The method described here for the comparison of dissolution curves is particularly useful when the curves do not follow a set kinetic process and has proved sensitive to slight changes in the dissolution profile.     

Statistical Comparison of the Dissolution curves of Controlled-Release Solid Oral Dosage Forms

Abstract

This paper shows how the Box method, based on the statistical technique known as “split-plot” in general use for replicate measurements, may be used to quantify and compare in vitro dissolution curves of controlled release solid oral dosage forms. In this case, it is applied to the interpretation of the findings of a stability test on controlled-released lithium tablets formulated with a wax matrix and containing 10.8 mEq lithium per tablet. The findings showed that the total amount of lithium dissolved after the tablets had been stored for a period of six months was slightly greater than before storage; the dissolution mean rate went from 1.06 mEq/h to 1.17 mEq/h and the dissolution rate curve profile apparently registered less variation.

The method described here for the comparison of dissolution curves is particularly useful when the curves do not follow a set kinetic process and has proved sensitive to slight changes in the dissolution profile.     

Formulation and evaluation of controlled-release transdermal patches of theophylline-salbutamol sulfate.

Transdermal formulations containing theophylline and salbutamol sulfate (SS) were formulated using hydroxypropylmethylcellulose. Theophylline was loaded by adsorption with the aid of the coadsorbate sodium chloride. The formulations were subjected to in vitro release studies, and the dose of salbutamol and theophylline was optimized to yield the desired flux. The films were uniform and 93 +/- 5.4 microm thick. The in vitro fluxes of theophylline and salbutamol sulfate from the formulation were 1.22 +/- 0.4 mg/h/cm2 and 13.36 +/- 1.02 microg/h/cm2, respectively. The formulation was subjected to pharmacodynamic studies in guinea pigs. The preconvulsive time (PCT) of guinea pigs increased significantly after 4 h, and the same was observed even after 24 h Pharmacokinetic studies were carried out in healthy human volunteers. Theophylline was analyzed in saliva, and salbutamol was analyzed in the blood plasma. The Tmax of the drugs was 3 h, and appreciable concentrations of the drugs above their MEC could be analyzed even after 12 h. The elimination half-life of the drugs was significantly prolonged compared to that for tablets. There were no signs of erythema or edema in the volunteers during observation for a period of 7 days.     

Release of a Low Dose Water Soluble Medicinal Agent from Inert Wax Matrix Tablets

Directly compressible wax matrix tablets have been developed for a low dose medicinal agent (Chloropheniramine maleate). A mixture of castor wax NF and Hydrogenated Vegetable Oil NF, was optimized in the ratio of 50:50 as matrix based on their bulk density and particle size distribution and compression properties The compression properties indicated that the increase in compression forces resulted in a tablet of higher hardness up to 8 Kp. However further increase in compression forces resulted in the decrease in hardness and capping was apparent.

The result of dissolution studies indicated no significant effect of hardness and tablet shape (Round and rectangular shaped) on the dissolution properties of wax matrix tablets. A plot of percent drug released various square root of time exhibited a linear relationship. The release rates of CPM from wax matrix tablets were found to be independent of the rotational speed of paddles between 50-75 RPM. From these results, the release mechanism of CPM from wax matrix tablets appears to be primarily diffusion controlled rather than matrix erosion.     

Wax-matrix tablet for time-dependent colon-specific delivery system of sophora flavescens Aiton: preparation and in vivo evaluation

A wax-matrix time-dependent colon-specific tablet (WM-TDCS) was studied. Wax-matrix tablet core consisting of semi-synthetic glycerides, as a wax polymeric expanding agent, carboxymethyl starch sodium (CMS-Na), and NaCl was prepared, and Sophora flavescens Aiton (ASF, extracts of traditional Chinese medicine) was used as model drug. The wax-matrix ASF tablets core was coated with Eudragit NE 30 D as the inner coating materials and with Opadry OY-P-7171 as the outer coating materials. The in vitro release behaviors of the coated tablets were examined and then in vivo absorption kinetics of the coated tablets in dogs was further investigated. The volume of the tablet core was markedly increased at 37 degrees C because of the expand effect of polymer semi-synthetic glycerides and CMS-Na. The drug release from WM-TDCS was more stable than TDCS in vitro and in vivo. The lag time of ASF release was also controlled by the thickness of the inner coating layer. In vivo evaluation demonstrated that in vivo lag time of absorption was in a good agreement with in vitro lag time of release. ASF wax-matrix tablets coated with Eudragit NE 30 D and Opadry OY-P-7171 using the regular coating technique could be designed to achieve a lag time of 3 h in the small intestinal tract.     

Release of a Low Dose Water Soluble Medicinal Agent from Inert Wax Matrix Tablets

Abstract

Directly compressible wax matrix tablets have been developed for a low dose medicinal agent (Chloropheniramine maleate). A mixture of castor wax NF and Hydrogenated Vegetable Oil NF, was optimized in the ratio of 50:50 as matrix based on their bulk density and particle size distribution and compression properties The compression properties indicated that the increase in compression forces resulted in a tablet of higher hardness up to 8 Kp. However further increase in compression forces resulted in the decrease in hardness and capping was apparent.

The result of dissolution studies indicated no significant effect of hardness and tablet shape (Round and rectangular shaped) on the dissolution properties of wax matrix tablets. A plot of percent drug released various square root of time exhibited a linear relationship. The release rates of CPM from wax matrix tablets were found to be independent of the rotational speed of paddles between 50–75 RPM. From these results, the release mechanism of CPM from wax matrix tablets appears to be primarily diffusion controlled rather than matrix erosion.     

Wax-Matrix Tablet for Time-Dependent Colon-Specific Delivery System of Sophora Flavescens Aiton: Preparation and In Vivo Evaluation

A wax-matrix time-dependent colon-specific tablet (WM-TDCS) was studied. Wax-matrix tablet core consisting of semi-synthetic glycerides, as a wax polymeric expanding agent, carboxymethyl starch sodium (CMS-Na), and NaCl was prepared, and Sophora flavescens Aiton (ASF, extracts of traditional Chinese medicine) was used as model drug. The wax-matrix ASF tablets core was coated with Eudragit NE 30 D as the inner coating materials and with Opadry OY-P-7171 as the outer coating materials. The in vitro release behaviors of the coated tablets were examined and then in vivo absorption kinetics of the coated tablets in dogs was further investigated. The volume of the tablet core was markedly increased at 37°C because of the expand effect of polymer semi-synthetic glycerides and CMS-Na. The drug release from WM-TDCS was more stable than TDCS in vitro and in vivo. The lag time of ASF release was also controlled by the thickness of the inner coating layer. In vivo evaluation demonstrated that in vivo lag time of absorption was in a good agreement with in vitro lag time of release. ASF wax-matrix tablets coated with Eudragit NE 30 D and Opadry OY-P-7171 using the regular coating technique could be designed to achieve a lag time of 3 h in the small intestinal tract.     

Formulation and Evaluation of Controlled-Release Transdermal Patches of Theophylline–Salbutamol Sulfate

Transdermal formulations containing theophylline and salbutamol sulfate (SS) were formulated using hydroxypropylmethylcellulose. Theophylline was loaded by adsorption with the aid of the coadsorbate sodium chloride. The formulations were subjected to in vitro release studies, and the dose of salbutamol and theophylline was optimized to yield the desired flux. The films were uniform and 93 ± 5.4 μm thick. The in vitro fluxes of theophylline and salbutamol sulfate from the formulation were 1.22 ± 0.4 mg/h/cm² and 13.36 ± 1.02 μg/h/cm², respectively. The formulation was subjected to pharmacodynamic studies in guinea pigs. The preconvulsive time (PCT) of guinea pigs increased significantly after 4 h, and the same was observed even after 24 h. Pharmacokinetic studies were carried out in healthy human volunteers. Theophylline was analyzed in saliva, and salbutamol was analyzed in the blood plasma. The T_max of the drugs was 3 h, and appreciable concentrations of the drugs above their MEC could be analyzed even after 12 h. The elimination half-life of the drugs was significantly prolonged compared to that for tablets. There were no signs of erythema or edema in the volunteers during observation for a period of 7 days.     

Development of a Formulation of Sustained Release Potassium Chloride

The purpose of this work has been the designing and “in vitro” evaluation of a potassium chloride tablet using a wax matrix.

Camauba wax, stearyl alcohol and stearic acid ware employed to prepare granulates at different drug/wax ratios. Fran dissolution kinetic studies and technological performances a 75/25 - KCl/camauba wax granulates was selected. The rheolqgical properties of granulates were characterized and tablets were manufactured employing ccrrmun tablets excipients. Also a coating procedure was developed. The coated tablet formulation selected release the potassium chloride according to the USP requirements.

The dissolution kinetics of the potassium chloride from both coated and uncoated tablets fit the Higuchi diffusion model, giving a straight line when the amount dissolved is plotted against the square root of time.     

Soluble filler as a dissolution profile modulator for slightly soluble drugs in matrix tablets

The purpose of this experimental work was the development of hydrophilic–lipophilic matrix tablets for controlled release of slightly soluble drug represented here by diclofenac sodium (DS). Drug dissolution profile optimization provided by soluble filler was studied. Matrix tablets were based on cetyl alcohol as the lipophilic carrier, povidone as the gel-forming agent, and common soluble filler, that is lactose or sucrose of different particle size. Physical properties of tablets prepared by melt granulation and drug release in a phosphate buffer of pH 6.8 were evaluated. In vitro studies showed that used filler type, filler to povidone ratio and sucrose particle size influenced the drug release rate. DS dissolution profile could be changed within a wide range from about 50% per 24 hours to almost 100% in 10 hours. The release constant values confirmed that DS was released from matrices by the diffusion and anomalous transport. The influence of sucrose particle size on the drug release rate was observed. As the particle size decreased, the drug release increased significantly and its dissolution profile became more uniform. Soluble fillers participated in the pore-forming process according to their solubility and particle size. Formulations containing 100 mg of the drug, 80 mg of cetyl alcohol, 40 mg of povidone, and 80 mg of either lactose or sucrose (particle size 250–125 μm) were considered optimal for 24-hour lasting dissolution of DS.     

The Control of Drug Release from Conventional Melt Granulation Matrices

Abstract

Sustained release potassium chloride tablets were prepared using a melt granulation formulation in a Baker Perkins Granulator. Parts of the validation for this manufacturing process are highlighted in this paper including granulation end point temperature, incorporation of extragranular excipients, amount of wax in the formulation, granule cooling rate and scale of the operation. A number of other factors have been studied which are not Included here although they are no less important. The release of potassium chloride from tablets was found to be dependent on the wax level and the amount of extragranular excipients (“wicklng agent”). Within the controlled production process, any variation in granulation end point temperature and granule cooling rate should not have any significant effect.     

Microencapsulation of a hydrophilic drug into a hydrophobic matrix using a salting-out procedure. II. Effects of adsorbents on microsphere properties

Wax microspheres of the hydrophilic drug guaifenesin were prepared by the congealable disperse-phase method using a salting-out procedure. In order to improve the particle properties of the microspheres, adsorbents (colloidal silica, magnesium stearate, and talc) were used during preparation. The effects of adsorbents on microsphere properties such as the angle of repose (AR), compressibility index (CI), geometric mean diameter (GMD), loading efficiency (LE), and in vitro drug release (DR) were determined. The AR, CI, and GMD of the microspheres were significantly reduced in the presence of the adsorbents. Increase in the concentrations of colloidal silica and magnesium stearate led to lower LE and faster DR, while talc showed no effect, which could be due to the particle diameter and specific surface area of the adsorbents. The microspheres prepared with colloidal silica were chosen to be compressed into tablets since they were smaller, more uniform, and had better flow properties than those made with magnesium stearate and talc. The in vitro drug release profile of the microsphere tablets was compared with that of commercially available Mucinex®, sustained release guaifenesin matrix tablets. Similar release profiles were observed between the two tablets. Scanning electronic microscopy (SEM) studies of the broken tablets revealed that the deformation of the microspheres caused by compression was minimal.