A controlled porosity osmotic pump system with biphasic release of theophylline

A controlled porosity osmotic pump system with biphasic release of theophylline was developed for the nocturnal therapy of asthma. The developed system was composed of a tablet-in-tablet (TNT) core and a controlled porosity coating membrane. Release pattern of the developed system was influenced by amount of pore former (18.2-45.5%, w/w of polymer), weight gain (16-26 mg per tablet) of the coating membrane and osmotic agents used in inner layer of the TNT core. When sodium phosphate and sodium chloride were selected as the osmotic agents in inner and outer layer of the TNT core respectively, target release profile was obtained with coating solution cellulose acetate-polyethylene glycol 400-diethyl phthalate (54.5-36.4-9.1%, w/w) at a weight gain of 16-22 mg per tablet. To examine the mechanism of drug release, release profiles of osmotic agents, micro-environmental osmotic pressure and micro-environmental pH of the formulation during dissolution were studied. Micro-environmental osmotic pressure decreased and micro-environmental pH increased continuously during the whole dissolution process, theophylline release was dominated by the successive dissolution of sodium chloride and sodium phosphate. Theophylline solubility increased as environmental pH exceeded 10.8. At the last stage of the biphasic release, micro-environmental pH in the developed formulation reached 10.9, and theophylline release was promoted by its elevated solubility despite of the decrease of micro-environmental osmotic pressure in the developed formulaiton.     

高效液相色谱法测定喘静片的3种主要成分

 采用高效液相色谱法同时测定喘静片中的3种主要成分：茶碱、异戊巴比妥和盐酸甲基麻黄碱。以ODS作固定相,通过均匀设计方法选择的最佳流动相为V（0.015 mol/L磷酸二氢钠缓冲液,含体积分数为0.3%的三乙胺,pH 4.9 )∶V（甲醇）=35∶65,检测波长为215 nm,用程序调节检测器的灵敏度,以咖啡因作内标物。茶碱、异戊巴比妥、盐酸甲基麻黄碱的回收率分别为99.7%～102.6%,98.5%～100.2%,98.0%～102.7%,日间RSD分别为0.23%～1.2%,0.35%～2.5%,0.33%～1.6%。该方法简便、快速、准确。     

pH-enzyme di-dependent chronotherapeutic drug delivery system of theophylline for nocturnal asthma

The purpose of this research work was to develop and evaluate a chronotherapeutic based colon-targeted drug delivery system of theophylline (THEO) exploiting pH-enzyme sensitive property for the prevention of episodic attack of asthma in early morning. Guar gum microspheres of theophylline were prepared by emulsification technique. Coating of microspheres was performed using solvent evaporation method with pH sensitive Eudragit(?) polymers. The particle size and surface morphology, entrapment efficiency and degree of swelling of microspheres were examined. The in vitro drug release studies were performed in pH progression medium and also in the presence of 2% rat caecal content. Theophylline was efficiently microencapsulated in guar gum microspheres at different polymer concentrations (1-4%). Fourier transform infrared (FT-IR)-spectroscopy confirmed the intermolecular interactions between guar gum and glutaraldehyde. Coating of guar gum microspheres by Eudragit led to decelerate the in vitro drug release of THEO. Moreover in vitro drug release studies also performed with 2% rat caecal content showed marked increment in drug release. The controlled release of THEO after a lag time was achieved with developed formulation for chronotherapeutic delivery. The pH dependent solubility behavior of Eudragit and gelling properties of guar gum are found to be responsible for delaying the release.     

Pharmacokinetics of a new sustained-release formulation of theophylline sodium glycerinate in healthy subjects with a new asymmetric dosage regimen

Pharmacokinetics of a new sustained-release formulation of theophylline sodium glycerinate in healthy subjects was studied. In this study, a new asymmetric dosage regimen was presented to achieve a better accordance with the chronotherapy of asthma. Each of 10 subjects was administered one tablet (equivalent to 0.1 g anhydrous theophylline) in the morning and four tablets in the evening for a consecutive 6 days and blood samples were collected at the predetermined time and analyzed by a validated HPLC method. This new regimen produced a steady and effective level of theophylline in plasma for the whole day, especially in the evening. A lower dose in the morning could reach the effective level (C(min)4.97 +/- 1.60 microg/mL and C(max)10.68 +/- 1.80 micro g/mL over the a.m. dosing interval) and a higher dose in the evening did not result in toxic levels but led to a reasonable concentration range (C(max)9.72 +/- 1.56 microg/mL over p.m. dosing interval), which could maintain a higher plasma theophylline concentration without the risk of serious adverse events and control asthmatic symptoms probably occurring during the night or early in the morning. The results suggested that the proposed asymmetric regimen was necessary, practicable and safe for twice daily sustained-release tablets of theophylline sodium glycerinate and also provides the basis for the clinical dosage regimen of other theophylline formulated products.     

Controlled release from directly compressible theophylline buccal tablets

The aim of the current study was the development of theophylline buccal adhesive tablets using direct compression. Buccal adhesive formulations were developed using a water soluble resin with various combinations of mucoadhesive polymers. The prepared theophylline tablets were evaluated for tensile strength, swelling capacity and ex vivo mucoadhesion performance. Ex vivo mucoadhesion was assessed using porcine gingival tissue and the peak detachment forces were found to be suitable for a buccal adhesive tablet with a maximum of 1.5 N approximately. The effect of formulation composition on the release pattern was also investigated. Most formulations showed theophylline controlled release profiles depended on the grade and polymer ratio. The release mechanisms were found to fit Peppas’ kinetic model over a period of 5 h. In general the majority of the developed formulations presented suitable adhesion and controlled drug release.     

Colon targeted delivery systems of metronidazole based on osmotic technology: development and evaluation

Colon targeted delivery systems of metronidazole (MTZ) based on osmotic technology were developed. The developed systems consisted of osmotic core (drug, osmotic agent and wicking agent), coated with semipermeable membrane (SPM) containing guar gum as pore former, coated core were then further coated with enteric coating to protect the system from acidic environment of stomach. The effect of various formulation variables namely the level of wicking agent (sodium lauryl sulphate), osmotic agent in the osmotic core, the level of pore former (guar gum) in SPM, and the thickness of SPM, were studied on physical parameters and drug release characteristics of developed formulations. MTZ release was inversely proportional to SPM thickness, but directly related to the level of pore former, wicking agent and osmotic agent. On the other hand burst strength of the exhausted shells was decreased with the increase in level of pore former in the membrane but increased with the increase in the thickness of SPM. The drug release from the developed formulations was independent of pH, and agitation intensity, but dependent on the osmotic pressure of the release media. The thickness of enteric coating could prevent formation of delivery pores before contact with simulated colonic fluid, but had no effect on drug release. Result of SEM studies showed the formation of in-situ delivery pores in the membrane from where the drug release occurred, and the number of pores formed were directly related to the initial level of pore former (guar gum) in SPM. The manufacturing procedure was found to be reproducible and formulations were found to be stable during 3 months of accelerated stability studies.     

A new drug delivery system using plasma-irradiated pharmaceutical aids. IX. Controlled-release of theophylline from double-compressed tablet composed of cellulose derivatives as wall material.

The rapid release from a double-compressed tablet containing theophylline with the water-soluble polymer, hydroxypropylmethylcellulose (HPMC) or hydroxypropylmethylcellulose phthalate (HPMCP), used as a wall material can be suppressed by argon plasma-irradiation and changed into the sustained-release system due to a decrease in solubility of the outer layer. It was shown that the release profiles can be varied so as to cause theophylline release at different rates, depending on the set of conditions chosen for tablet manufacture and for plasma operation.     

Enhanced gentamicin loading and release of PLGA and PLHMGA microspheres by varying the formulation parameters

The purpose of this study was to develop a suitable formulation for gentamicin sulfate (GS) that gives a sustained release of the drug. Therefore this drug was loaded into poly(D,L-lactide-co-glycolide) (PLGA) and poly(lactic-co-hydroxymethyl glycolic acid) (PLHMGA) microspheres. The effects of various formulation parameters (ethanol, surfactant, osmotic value of the external phase, polymer type and concentration) on particle characteristics (size, loading and release) were investigated. The GS loaded microspheres were prepared using a double emulsion evaporation technique. The results demonstrate that neither ethanol nor surfactants had beneficial effects on the drug loading efficiency (around 4-10%). However, an increase in buffer concentration (and thus osmotic pressure) of the external phase resulted in a substantial increase of GS-loading (from 10 to 28%). Further, an increase of concentration of PLGA in DCM from 10% to 15/20% caused a 4-time increase of the drug loading. The best formulation identified in this study had a loading efficiency of around 70% resulting in PLGA microspheres with a 6% (w/w) loading. The particles showed a burst release of the drug depending on their porosity, followed by a phase of 35 days where hardly any release occurred. The drug was then slowly released for around 25 days likely due to degradation of the microspheres. The drug loading efficiency of GS in PLHMGA was not significantly different from PLGA microspheres (64%). The release of GS from PLHMGA microspheres was faster than that of PLGA because the degradation rate of PLHMGA is more rapid than PLGA. This study shows that prolonged release of gentamicin can be obtained by loading this drug into microspheres made of biodegradable aliphatic polyesters.     

The Pharmaceutical Use of Captisol®: Some Surprising Observations

The purpose of this paper is to share some recent observations on the pharmaceuticaluses and properties of Captisol^® or SBE_7M--CD in controlled porosity osmotic pump tablets (CP-OPT) and the underlying mechanism/sthat lead to apparent zero-order drug release pattern. It would have been simple toattribute the apparent zero-order release mechanism/s of poorly water-soluble drugsfrom CP-OPTs and pellets utilizing Captisol^®as both a solubilizing andosmotic agent, to purely osmotic and diffusional components. However, the mechanismmay be more related to a counterbalancing of physical properties as the concentration of Captisol^®changes within the matrix. Specifically, the initial concentration of Captisol^®within a core is 0.3–0.4M. When this drops to lower values an osmotic pressure drop occurs across the membrane. Therefore, drug release should not follow apparent zero-order kinetics if all the drug is solubilized. However, as the viscosity within the tablet also drops, the apparent diffusion coefficient of both Captisol^® and drug increases. Therefore, it appears that there is an initial resistance (hydraulic pressure) to fluid flow from the tablet through the rate-limiting microporous membrane. This resistance decreases so that even as osmotic pressure and concentration differences drop with time, counterbalancing faster release occurs. Osmotic driving force appears to be the most important initial driving force but a diffusional component becomes more significant with time.     

Osmotic-driven mass transport of water: Impact on the adhesiveness of hydrophilic polymers

Adhesion is an important property for the functionality of many medical devices. One reason for the development of adhesive forces is dehydration caused by mass transport of water. Osmotic pressure is one main driving force for mass transport and the correlation between osmotic pressure and adhesive force has not been studied yet, which was the aim of the present study. A model system was used where a Carbopol tablet was lowered onto a 1% (w/w) agarose gel. The force required to detach the tablet (adhesive force) and the weight gain of the tablet (as a measure of transported water) were determined. Sodium chloride and mannitol were added to the agarose gel to decrease the osmotic pressure difference between the agarose gel and the partially hydrated Carbopol tablet. This resulted in a decrease of both mass transport and adhesive force. In addition, experiments with restricted water transport within the agarose gel were performed by preparing gels with different agarose concentrations. An increase of the agarose concentration resulted in decreased water transport and higher adhesive forces. Hence, the results confirmed our hypothesis that osmotic-driven mass transport and restricted mass transport of water correlate very well with the adhesive force.     

Dissolution assay of theophylline, diprophylline and proxyphylline from a sustained release dosage form by high performance thin layer chromatography.

The content and dissolution rate of theophylline, diprophylline and proxyphylline from a sustained release formulation were determined by UV in situ densitometry. After separation the chromatographic zones corresponding to the spots of theophylline, diprophylline and proxyphylline on the high performance thin layer chromatographic plates were scanned in reflectance/absorbance mode at 275 nm. Quantification was performed with a second degree polynomial function over the range 40-200 ng for theophylline and 60-300 ng for diprophylline and proxyphylline. Percentages of dissolved theophylline, diprophylline and proxyphylline were monitored over 1, 3 and 6 h. The method was found to be simple, accurate, reliable, time-saving (up to 18 samples can be determined simultaneously) and low-cost.     

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?.     

基于HPMCP包覆介孔SBA-15的pH敏感药物缓释系统

以肠溶性包衣材料羟丙甲纤维素邻苯二甲酸酯(HPMCP)为原料,在负载法莫替丁(Famo)的SBA-15药片表面包覆聚合物膜,成功制备了一种新型的pH敏感药物缓释系统, 并考察了此缓释系统在不同pH释放环境中的释放行为. 结果表明: 在模拟胃液中(SGF, pH=1.2),HPMCP能致密包覆在药片表面,从而明显延缓Famo的释放速度;而在模拟肠液中(SIF, pH=7.5),HPMCP能够迅速溶于缓释溶液中,因而对Famo释放速度的影响甚微. 因此,可以将这种新型智能药物缓释系统应用于肠道靶向给药.     

Antihormonal agents. Part 1: HPLC of RU 38486 and its metabolites

Procedures are described for the TLC and reverse phase HPLC analysis of the antihormonal steroid RU 38486 and its metabolites. Conditions are developed for the HPLC of the pure drug substance and a tablet formulation, and also for following its pharmacokinetics and metabolism.     

Formulation variation and in vitro-in vivo correlation for a rapidly swellable three-layered tablet of tamsulosin HCl

In order to develop a preferable once-a-day oral tablet formulation, various formulations of three-layered tablets containing tamsulosin HCl as a hydrophilic model drug were evaluated and compared with a commercial reference, tamsulosin OCAS?. When the test tablet was exposed to a release medium, the medium quickly permeated to the mid-layer and the two barrier layers swelled surrounding the mid-layer rapidly. Volume expansion showed faster and enough swelling of the three-layered tablet up to 2 h. Larger amount of barrier layers caused reduced release kinetics and a high molecular weight polymer showed more resistance against agitation force. A formulation with water-soluble mid-layer showed fast erosion decreasing its volume significantly. On the pharmacokinetic study, the mean ratio of area under the curve (AUC) and C(max) for the test formulation to the reference was 0.69 and 0.84, respectively, showing that the absorption of the drug was less complete than the reference. Plasma concentration at 24 h of the test formulation was higher than the reference. The Wagner-Nelson method showed that decreased initial dissolution rate might be the cause of the less complete absorption. On considering in vitro-in vivo correlation (IVIVC), level A, the reference (R2=0.981) showed more linear relationship than the test (R2=0.918) due to the decreased dissolution and absorption rate of the formulation. This result suggests that the in vitro dissolution profiles and release kinetics might be useful in correlating absorption kinetics as well as overall plasma drug concentration-time profiles for formulation studies.     

A new drug delivery system using plasma-irradiated pharmaceutical aids. VIII. Delayed-release of theophylline from double-compressed tablet composed of eudragit as wall material.

The rapid release from a double-compressed tablet containing theophylline as a core drug with the pH-dependent water-soluble polymers, Eudragit L100, S100 or L100-55 used as a wall material was suppressed by argon plasma-irradiation due to an effect of inter-segmental cross-link reactions on the decrease in the surface polymer solubility of outer layer. In addition, the rapid theophylline release from the double-compressed tablet of Eudragit L100-55 with a lower glass transition temperature (Tg) has converted into the delayed-release system under a set of plasma operational conditions due to an additional effect of plasma heat flux on softening of Eudragit L100-55 surface resulting in the formation of the film-like surface with a particle-particle interlinking of the outer layer.     

Mass variation tests for coating tablets and hard capsules: rational application of mass variation tests

The mass variation test is a simplified alternative test version of the content uniformity test. In the case of coating tablets and capsules, the mass variation test is principally applied to test the inner cores or fillings containing the active ingredient. However, some exceptions exist in pharmacopoeias. The effects of tablet coating and capsule shell on the results of the mass variation test were studied. The mass variation of outer crusts (coatings, capsule shells) and inner cores (core tablets, fillings) was measured separately in several products. The effects of coating on weight variability were very large for sugar-coated tablets. Relative standard deviation (RSD) of the formulation weight (RSD(W)) of sugar-coated tablets (2.73%) was larger than that of plain tablets (0.77%). The cause of the large RSD(W) is the large variation the weight of sugar-coating accounting for 44% of formulation weight. In the case of film-coated tablets, the effect of coating weight on the mass variation test was very small because the rate of coating in comparison to the whole weight was small. In the case of hard capsules, the usage of whole formulation weight resulted in underestimation of variations of filling weight. The differences between dosage forms in the applicability of the mass variation test are caused by differing weight proportions and variability of the outer coatings or shells. To avoid the underestimation of mass variation for hard capsules, a corrected acceptance value is useful. For all the dosage units, the mass variation test can principally be applied to determine which mass is expected to be proportional to the content of the active ingredient. However, some modification of acceptance values enables application of the mass variation tests to inapplicable cases, such as when the RSD of drug concentration (RSD(C)) is larger than 2%.     

Rapid and sensitive LC-MS/MS method for the determination of metoprolol in Beagle dog plasma with a simple protein precipitation treatment and its pharmacokinetic applications

A rapid LC-MS/MS method with good accuracy and sensitivity was developed and validated for the pharmacokinetics study of metoprolol (MP) in beagle dogs. The plasma samples were simply precipitated by methanol and then analyzed by LC-MS/MS. An Ultimate XB-C?? column (150 × 2.1 mm ID, 5 μm) was used for separation, with methanol-water containing 0.2% formic acid (65:35, v/v) as the mobile phase at a flow rate of 0.2 mL/min. Monitoring ions of MP and internal standard (hydroxypioglitazone) were m/z 268.1/115.6 and m/z 373.1/150.2, respectively. The linear range was 3.03-416.35 ng/mL with an average correlation coefficient of 0.9996, and the limit of quantification was 3.03 ng/mL. The intra- and inter-day precision was less than 15%. At low, middle and high concentrations, the recovery, the matrix effect and the accuracy was in the range of 76.06%-95.25%, 93.67%-104.19% and 95.20%-99.96% respectively. The method was applied for the pharmacokinetics study of MP tartrate tablets (50 mg). The AUC(0-t), T(max) and C(max) were respectively 919.88 ± 195.67 μg/L·h, 0.96 ± 0.33 h, 349.12 ± 78.04 ng/mL.     

In Vitro–In Vivo Correlation of Tianeptine Sodium Sustained-Release Dual-Layer Tablets

Tianeptine tablets are currently marketed to be designed for immediate-release tablets. The tianeptine has a short half-life, making it difficult to design for sustained-release tablets and achieve bioequivalence with the tianeptine immediate-release tablet (Stablon^®). We established the in vitro–in vivo correlation (IVIVC) of three formulations of tianeptine sustained-release tablets according to their granule size. To evaluate sustained drug release, in vitro tests were performed in pH 1.2 media for 24 h. In vivo pharmacokinetic analysis was performed following oral administration of reference drug and test drug to beagle dogs. The dissolution profile revealed delayed release as the size of the granules increased. The dissolution results were confirmed in pharmacokinetic analysis, showing that the half-life was delayed as granule size increased. The final formulation and reference drug showed an equivalent area under the curve (AUC). Through this, IVIVC was established according to the size of the tianeptine sodium granules, which is the purpose of this study, and was used to predict in vivo pharmacokinetics from the formulation composition. This approach may be useful for determining optimal formulation compositions to achieve the desired pharmacokinetics when developing new formulations.