Relationship between diffusivity of water molecules inside hydrating tablets and their drug release behavior elucidated by magnetic resonance imaging

We reported previously that sustained release matrix tablets showed zero-order drug release without being affected by pH change. To understand drug release mechanisms more fully, we monitored the swelling and erosion of hydrating tablets using magnetic resonance imaging (MRI). Three different types of tablets comprised of polyion complex-forming materials and a hydroxypropyl methylcellulose (HPMC) were used. Proton density- and diffusion-weighted images of the hydrating tablets were acquired at intervals. Furthermore, apparent self-diffusion coefficient maps were generated from diffusion-weighted imaging to evaluate the state of hydrating tablets. Our findings indicated that water penetration into polyion complex tablets was faster than that into HPMC matrix tablets. In polyion complex tablets, water molecules were dispersed homogeneously and their diffusivity was relatively high, whereas in HPMC matrix tablets, water molecule movement was tightly restricted within the gel. An optimal tablet formulation determined in a previous study had water molecule penetration and diffusivity properties that appeared intermediate to those of polyion complex and HPMC matrix tablets; water molecules were capable of penetrating throughout the tablets and relatively high diffusivity was similar to that in the polyion complex tablet, whereas like the HPMC matrix tablet, it was well swollen. This study succeeded in characterizing the tablet hydration process. MRI provides profound insight into the state of water molecules in hydrating tablets; thus, it is a useful tool for understanding drug release mechanisms at a molecular level.     

Design and optimization of a new self-nanoemulsifying drug delivery system

To improve the dissolution rate of ibuprofen, a model poorly water soluble drug, self-nanoemulsifying drug delivery systems (SNEDDS) were developed. Various surfactants and oils were screened as candidates for SNEDDS on the basis of droplet size of the resulting emulsions. The influence of the constituent structure, concentration and the composition of SNEDDS formulations, and the emulsifier HLB value, on the properties of the resulting emulsions was systematically investigated. Several SNEDDS formulations were employed to study the relationship between the emulsion droplet size and the dissolution rate of ibuprofen. The dissolution rate was accelerated by decreasing the nanoemulsion droplet size, and was significantly faster than that from a conventional tablet. The optimal SNEDDS formulation had a mean nanoemulsion droplet diameters of 58 nm in phosphate buffer, pH 6.8 (simulated intestinal fluid), and released ibuprofen more than 95% within 30 min. Therefore, these novel SNEDDS carriers appear to be useful for controlling the release rate of poorly water soluble drugs.     

Effect of formulated ingredients on rapidly disintegrating oral tablets prepared by the crystalline transition method

The aim of this article was to determine the optimal ingredients for the rapidly disintegrating oral tablets prepared by the crystalline transition method (CT method). The effect of ingredients (diluent, active drug substance and amorphous sugar) on the characteristics of the tablets was investigated. The ingredients were compressed and the resultant tablets were stored under various conditions. The oral disintegration time of the tablet significantly depended on diluents, due to differences in the penetration of a small amount of water in the mouth and the viscous area formed inside the tablet. The oral disintegration time was 10-30 s for tablets with a tensile strength of approximately 1 MPa, when erythritol, mannitol or xylitol was used as the diluent. The increase in the tensile strength of tablets containing highly water-soluble active drug substances during storage was as large as that of tablets without active drug substances, while the increase in the tensile strength of tablets containing low water-soluble active drug substances was small. It was therefore found that highly water-soluble active drug substances were more suitable for the formulation prepared by the CT method than low water-soluble active drug substances. Irrespective of the type of amorphous sugar (amorphous sucrose, lactose or maltose) used, the porosity of tablets with 1 MPa of tensile strength was 30-40%, and their oral disintegration time was 10-20 s. The optimal ingredients for rapidly disintegrating oral tablets with reasonable tensile strength and disintegration time were therefore determined from these results.     

Properties of gastroretentive sustained release tablets prepared by combination of melt/sublimation actions of L-menthol and penetration of molten polymers into tablets

A novel floating sustained release tablet having a cavity in the center was developed by utilizing the physicochemical properties of L-menthol and the penetration of molten hydrophobic polymer into tablets. A dry-coated tablet containing famotidine as a model drug in outer layer was prepared with a L-menthol core by direct compression. The tablet was placed in an oven at 80°C to remove the L-menthol core from tablet. The resulting tablet was then immersed in the molten hydrophobic polymers at 90°C. The buoyancy and drug release properties of tablets were investigated using United States Pharmacopeia (USP) 32 Apparatus 2 (paddle 100 rpm) and 900 ml of 0.01 N HCl. The L-menthol core in tablets disappeared completely through pathways in the outer layer with no drug outflows when placed in an oven for 90 min, resulting in a formation of a hollow tablet. The hollow tablets floated on the dissolution media for a short time and the drug release was rapid due to the disintegration of tablet. When the hollow tablets were immersed in molten hydrophobic polymers for 1 min, the rapid drug release was drastically retarded due to a formation of wax matrices within the shell of tablets and the tablets floated on the media for at least 6 h. When Lubri wax? was used as a polymer, the tablets showed the slowest sustained release. On the other hand, faster sustained release properties were obtained by using glyceryl monostearate (GMS) due to its low hydrophobic nature. The results obtained in this study suggested that the drug release rate from floating tablets could be controlled by both the choice of hydrophobic polymer and the combined use of hydrophobic polymers.     

雪松醇纳米乳的配方设计及表征

为改善雪松醇水溶性,研究制备了雪松醇纳米乳(Cedrol Nanoemulsion,CE-NE),优化其配方,并对其理化性质进行考察。本研究采用低能乳化法制备纳米乳,在伪三元相图筛选配方的基础上,以粒径及多分散系数(polydispersity,PDI)作为评价指标,利用单形网格设计法(Simplex Lattice Design,SLD)进一步优化纳米乳配方。利用透射电镜观察最优配方纳米乳的形貌,利用粒度仪测定纳米乳粒径及Zeta电位,并考察pH以及离心稳定性等理化性质。结果表明CE-NE最优处方组成为:1.2g蓖麻油聚氧乙烯醚、0.2g肉豆蔻酸异丙酯、0.6g聚乙二醇400、2.0g水,优化得到的纳米乳透射电镜观察其形貌呈大小均一球形,粒径为16.66nm、多分散系数为0.087、Zeta电位为-6.14mV,具有良好的离心稳定性。本研究成功的制备了雪松醇纳米乳,且具有良好的理化性质,为纳米乳载体的进一步应用奠定了基础。     

Development water in oil nanoemulsion of diethylcarbamazine for enhanced the characteristics for lymphatic targeting: A proof of concept study

As an antifilariasis drug, oral administration of diethylcarbamazine (DEC) could not effectively deliver the drug to the lymphatic system. Hydrophobic formulation with a particle size of <100 nm could improve the delivery of drug. Accordingly, we developed water in oil nanoemulsion encapsulating DEC. The nanoemulsion was less than 100 nm with negative charge, showing its suitability for lymphatic targeting. The nanoemulsion could sustain the release of DEC and improve the retention in intestinal tissue in comparison with DEC solution. Importantly, this approach did not cause any hemolysis in in vitro study and any irritation in in vivo study.     

Floating and sustained-release characteristics of effervescent tablets prepared with a mixed matrix of Eudragit L-100-55 and Eudragit E PO

The aim of this study was to evaluate the influence of Na-bicarbonate as an effervescent agent on the floating and sustained-release characteristics in 0.1 M HCl of tablets made of Eudragit E PO (EE) and/or Eudragit L-100-55 (EL) as matrix formers at different EE:EL weight ratios: 0:100, 25:75, 50:50, 75:25, and 100:0. The tablets were made by direct compression utilizing metronidazole as a model drug. Effervescent tablets with 50EE/50EL (w/w) showed the best floating and sustained drug release properties in the dissolution medium. The corresponding noneffervescent tablets were nonfloating and showed significantly faster drug release. Effervescent tablets with single polymers showed an immediate drug release pattern. These results were explained by Fourier-transform infrared spectroscopy and elemental analysis, which showed strong evidence of interpolyelectrolyte complexation between EE and EL when they were exposed to 0.1 M HCl as an effervescent hybrid matrix, but not as a noneffervescent hybrid matrix. The role of Na-bicarbonate in allowing EE-EL complexation during dissolution was explained as due to raising the pH around EL particles for sufficient polymer ionization and ionic-interaction with the ionized EE.     

Design and Development of Oral Oil-in-Water Nanoemulsion Formulation Bearing Atorvastatin: In Vitro Assessment

The objective of the present investigation was to design a thermodynamically stable and dilutable nanoemulsion formulation of AT-Ca with minimum surfactant concentration that could improve its solubility as well as its oral bioavailability. The composition of optimized nanoemulsion formulation was Sefsol 218 and oleic acid (1:1) 10% w/w, as an oil phase, Tween-20 (19% w/w) as a surfactant, Carbitol (19% w/w) as a cosurfactant and distilled water (52% w/w) as an aqueous phase, containing 10 mg of AT. The optimized formulation showed higher% drug release (99.34%), lower droplet size (42.8 ± 0.42 nm) with low polydispersity index (0.237 ± 0.012), less viscosity (27.51 ± 1.01 cP) and infinite dilution capability. In vitro drug release from the nanoemulsion formulations was highly significant (p < 0.01) as compared to drug suspension.     

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 validation of HPLC method for simultaneous estimation of piperine and guggulsterones in compound Unani formulation (tablets) and a nanoreservoir system

An attempt has been made to develop and validate a simultaneous HPLC method for novel approach of drug release via oil‐in‐water (o/w) nanoemulsion formulation and Habb‐e‐Khardal Unani tablet containing piperine and guggul sterones E and Z as main ingredients. Nanoemulsion was prepared by titration method using sefsol‐218 as an oily phase, cremophor‐EL as a surfactant, transcutol as a co‐surfactant and distilled water as an aqueous phase. The formulation was optimized on the basis of thermodynamic stability and dispersibilty test. The nanoformulation was evaluated for particle size, surface morphology, electrical conductivity and viscosity determination. The in vitro dissolution was carried out by dialysis bag method. Drugs were quantified using an HPLC method developed in‐house with a C₁₈ column as stationary phase and acetonitrile and water as mobile phase at λ_max of 240 nm. The optimized formulation showed higher drug release, lower droplet size and less viscosity as compared with the conventional Habb‐e‐Khardal Unani tablet. The present study illustrated the potential of nanoemulsion dosage form in improving biopharmaceutic performance of piperine and guggul sterone. The HPLC method was also found to be quite sufficient for the routine quality control of formulations containing piperine and guggul sterone E and Z as ingredients and also for in vitro drug release studies. Copyright © 2011 John Wiley & Sons, Ltd.     

Improved skin delivery and validation of novel stability-indicating HPLC method for ketoprofen nanoemulsion

Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) widely used to treat rheumatoid arthritis and other inflammatory diseases. Normally used by oral route, this drug presents numerous side effects related to this administration route, such as nausea, dyspepsia, diarrhea, constipation and even renal complications. To avoid that, topical administration of ketoprofen represents a good alternative, since this drug has both partition coefficient and aqueous solubility suitable for skin application, compared to other NSAIDs. In this study, we describe the production of a nanoemulsion containing ketoprofen, its skin permeation and in vitro release study and a novel validation method to analyze this drug in the permeation samples and a forced degradation study using skin and nanoemulsion samples. The new HPLC method was validated, with all specifications in accordance with validation parameters and with an easy chromatographic condition. Forced degradation study revealed that ketoprofen is sensitive to acid and basic hydrolysis, developing degradation peaks after exposure to these factors. Concerning in vitro release from the nanoemulsion, release curves presented first order profile and were not similar to each other. After 8 h, 85% of ketoprofen was release from the nanoemulsion matrix while 49% was release from control group. In skin permeation study, nanoemulsion enabled ketoprofen to pass through the skin and enhanced retention in the epidermis and stratum corneum, layer on which the formulation presented statistically different values compared to the control group.     

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.     

Tablet‐effervescence‐assisted dissolved carbon flotation for the extraction of four triazole fungicides in water by gas chromatography with mass spectrometry

A pretreatment method named tablet‐effervescence‐assisted dissolved carbon flotation was introduced for the determination of four triazole fungicides in environmental water. In this method, the use of effervescent tablet composed of nontoxic sodium carbonate and sodium dihydrogen phosphate could generate CO₂ in situ to assist the dispersion of extraction solvent and to accelerate mass transfer of target analytes. In addition, the simple phase separation simply based on the rising of low‐density organic solvent from the aqueous phase was applied rather than the application of apparatus, which demonstrated the potential for on‐site extraction in the field. The experimental variables, including the composition of effervescent tablets, amount of effervescent tablets, types and volume of extraction solvent, were investigated. Under the optimized conditions, the method showed good linearity for myclobutanil, tebuconazole, epoxiconazole, and difenoconazole in the range of 1–100 μg/L. The limits of detection and the limits of quantification were within the range of 0.15–0.26 and 0.49–0.86 μg/L, respectively. The obtained correlation coefficients varied from 0.997 to 0.999, and suitable enrichment factors were 422–589. The recoveries were 82.5–112.9% with relative standard deviations of 4.7–13.5%.     

A study of physicochemical and biopharmaceutical properties of amoxicillin tablets using full factorial design and PCA biplot

The variables that influence the tablets obtained by direct compression method deserve to be studied to minimize formulations costs and to improve the physicochemical and biopharmaceutical properties of the compacts. Here, we explore the adjuvants effects on amoxicillin tablet formulations considering multiple responses, and indicate the most suitable formulation composition. A 2(3) full factorial design was built to different amoxicillin formulations, each one containing three replicate batches, and eight responses (physicochemical and biopharmaceutical parameters) were obtained. The microcrystalline cellulose (MCC) type Avicel PH-102 (low) or PH-200 (high), the absence (low) or presence (high) of spray-dried lactose (LAC), and the absence (low) or presence (high) of disintegrant (DIS) were the levels investigated. The more relevant responses to the distinct formulations from the experimental design were hardness, friability, and the amount of amoxicillin dissolved during the first hour. PCA biplot indicated high values of amount of drug dissolved in 60 min as advantageous responses for the investigated amoxicillin tablet formulations and high values of friability as not desirable. Considering the individual response evaluation, the most suitable amoxicillin tablet formulation should present in its composition the MCC type Avicel PH-102 (low level) and the superdisintegrant agent (DIS high level), croscarmellose sodium, but no LAC (low level).     

Application of nilvadipine solid dispersion to tablet formulation and manufacturing using crospovidone and methylcellulose as dispersion carriers

Nilvadipine (NIL) solid dispersion using crospovidone (Cross-linked-N-vinyl-2-pyrolidone, cl-PVP) and methylcellulose (MC) as carriers was applied to tablet formulation. Several grades of cl-PVP and MC were used, and their influence on tablet properties such as hardness, disintegration, dissolution and chemical stability were investigated. The agitation granulation method was used for preparation of solid dispersion granules, and the granules were compressed using a rotary tableting machine, and finally the obtained tablets were coated with film. As the particle size of cl-PVP decreased, hardness and apparent solubility were increased, while dissolution rate was lowered. When a higher viscosity grade of MC was used, hardness and dissolution rate were increased, and apparent solubility did not change. All batches of tablets were chemically stable at 40 degrees C, 75% relative humidity (R.H.) for six months. Finally, tablets with enhanced dissolution properties were obtained by using Polyplasdone XL-10 and Metolose SM-25 as the grades of cl-PVP and MC, respectively. These formulation tablets showed higher solubility and dissolution rate during storage as well as initial indicating good physical stability.     

In vitro evaluation of mucoadhesive vaginal tablets of antifungal drugs prepared with thiolated polymer and development of a new dissolution technique for vaginal formulations

The main objective of this work was to develop antifungal matrix tablet for vaginal applications using mucoadhesive thiolated polymer. Econazole nitrate (EN) and miconazole nitrate (MN) were used as antifungal drugs to prepare the vaginal tablet formulations. Thiolated poly(acrylic acid)-cysteine (PAA-Cys) conjugate was synthesized by the covalent attachment of L-cysteine to PAA with the formation of amide bonds between the primary amino group of L-cysteine and the carboxylic acid group of the polymer. Vaginal mucoadhesive matrix tablets were prepared by direct compression technique. The investigation focused on the influence of modified polymer on water uptake behavior, mucoadhesive property and release rate of drug. Thiolated polymer increased the water uptake ratio and mucoadhesive property of the formulations. A new simple dissolution technique was developed to simulate the vaginal environment for the evaluation of release behavior of vaginal tablets. In this technique, daily production amount and rate of the vaginal fluid was used without any rotational movement. The drug release was found to be slower from PAA-Cys compared to that from PAA formulations. The similarity study results confirmed that the difference in particle size of EN and MN did not affect their release profile. The release process was described by plotting the fraction released drug versus time and n fitting data to the simple exponential model: M(t)/M(∞)=kt(n). The release kinetics were determined as Super Case II for all the formulations prepared with PAA or PAA-Cys. According to these results the mucoadhesive vaginal tablet formulations prepared with PAA-Cys represent good example for delivery systems which prolong the residence time of drugs at the vaginal mucosal surface.     

Thermal stability of metronidazole drug and tablets

TG and DSC data were used to determine the thermal parameters of metronidazole drug and tablets. Three tablets A, B and C were analysed. The TG curves of metronidazole drug and tablets A and B displayed five and C four thermal decomposition processes, respectively. Analysis of the DSC data pointed to chemical interactions between metronidazole drug and the excipients of tablets, suggested by alterations in the melting point of metronidazole. The rate constants obtained from the isothermal TG data presents following sequence of the thermal stability: tablet A>tablet C>metronidazole drug>tablet B. This revised version was published online in July 2006 with corrections to the Cover Date.     

Sodium mefenamate as a solution for the formulation and dissolution problems of mefenamic acid

Sodium salt formation of mefenamic acid (MA) was studied as a way to solve the formulation and dissolution problems of MA. For this purpose, sodium salt of mefenamic acid (Na-MA) was prepared by reacting MA powder with equimolar sodium hydroxide in an aqueous phase, and consequently, Na-MA solution was obtained. The resultant solution was lyophilized and Na-MA powder was collected. The salt formation was confirmed by the results of fourier transformation-infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) studies on Na-MA powder in comparison to MA powder. Na-MA powder was assessed for direct compressibility, in comparison to MA powder, when formulated as a mixture with minimum amount of Avicel((R)) pH 101 and then compressed into tablets using a hydraulic tablet press. Na-MA tablets exhibited satisfactory hardness and friability, and did not show capping or lamination. On the other hand, some MA tablets showed capping or lamination upon compression and all the tested MA tablets for friability capped. Na-MA tablets were also studied for drug dissolution, in comparison to MA tablets, in water, a pH 7.4 phosphate buffer, and a pH 7.4 phosphate buffer after soaking in 0.1 m HCl. Under these different dissolution conditions, Na-MA tablets showed much higher dissolution rate and extent than MA tablets. The results of the study suggested that Na-MA can be considered as a solution form for the formulation and dissolution problems of MA.     

High amounts of 17-methylated anabolic-androgenic steroids in effervescent tablets on the dietary supplement market

In numerous studies it has been demonstrated that several nutritional supplements contain prohormones not declared on the label. In the current study two products (effervescent tablets) containing high amounts of the 17-methylated anabolic androgenic steroids metandienone (product 1: 16.8 mg/tablet) and stanozolol (product 2: 14.5 mg/tablet) were identified. Additionally in both products norandrostenedione was detected, in product 2 with minor amounts of several other steroids. The substances identified can cause enormous health risks. In addition, the use of the analyzed tablets can lead to positive doping results for metabolites of the respective steroids in sports. This study again shows the insufficient surveillance of the production and trade of dietary supplements. Consumers should be aware of the enormous health and doping risks connected with the use of such products. For GC-MS identification of the analytes the trimethylsilyl derivatives of the steroids and the mixed N-t-butyldimethylsilyl,O-trimethylsilyl derivatives were used. The quantitation of metandienone, norandrostenedione, and stanozolol was performed using HPLC-DAD.