A new rapidly absorbed paracetamol tablet containing sodium bicarbonate. I. A four-way crossover study to compare the concentration-time profile of paracetamol from the new paracetamol/sodium bicarbonate tablet and a conventional paracetamol tablet in fed and fasted volunteers

The primary objective of this four-way crossover study was to compare the concentration-time profile of paracetamol from a new rapidly absorbed paracetamol tablet containing sodium bicarbonate (PS) with a conventional paracetamol tablet (P), in a panel of 28 fed and fasted healthy volunteers. The results demonstrated that paracetamol was absorbed more rapidly from tablets containing sodium bicarbonate compared to conventional tablets, as indicated by a shorter tmax in both the fed and fasted state and a higher Cmax in the fasted state. The two formulations were bioequivalent with respect to area under curve (AUC). Food did not affect the extent of absorption from either formulation, as indicated by AUC, however, food did reduce the rate of absorption from both formulations, as indicated by a longer tmax and a lower Cmax. Metabolic activation of paracetamol to its oxidation metabolites, as assessed by combined partial clearances to subsequent secondary metabolites cysteine and mercapturic acid conjugates, indicated that the two formulations were bioequivalent in this respect.     

A new in vitro/in vivo kinetic correlation method for nitrofurantoin matrix tablet formulations

The kinetic distributions of in vitro percentage release and in vivo percentage urinary excretion rates of nitrofurantoin from matrix tablets were plotted using a kinetic program. In vitro release rates were determined using the USP paddle and half-change methods. Urinary excretion curves of the drug were characterized by means of the statistical moments. The individual linear correlations between each in vitro and in vivo kinetic distribution were established, and regression equations were calculated. The application results of the best correlations obtained were evaluated according to in vivo results. A reversed kinetic procedure was applied for transformation of the correlated kinetic values to the drug percentage release rates. The modified Langenbucher kinetic showed excellent linear correlation (r = .9985). The method that is proposed in this study, the kinetic correlation program, is simple, independent of time, and suggests that it is possible to use kinetic distributions in the in vitro/in vivo correlation. This study also suggests using kinetic correlation to investigate the suitability of the in vitro dissolution methods with the in vivo drug dissolution.     

A new rapidly absorbed paediatric paracetamol suspension. A six-way crossover pharmacokinetic study comparingthe rate and extent of paracetamol absorption from a new paracetamol suspension with two marketed paediatric formulations

The objective of this study was to compare the rate and extent of paracetamol absorption from the new Paracetamol pediatric suspension (PPS) with two marketed paracetamol suspensions: Children’s panadol (CP) and Panodil baby & infant (PBI). The study also assessed the effect on paracetamol absorption of light-calorie, low-fat food consumed 2?h before dosing. Twenty eight male adult volunteers received a single oral dose of 1000?mg of paracetamol from each of three treatments, in both fasted and fed states according to a randomized, single-center, open-label, six-way crossover study design. PPS was bioequivalent to both CP and PBI for AUC_{0–10 h}, AUC_0–inf and C_max in both fasted and fed state. However, PPS had greater rate of paracetamol absorption and a faster speed of onset. T_max for PPS was significantly shorter than for PBI in both fasted (p?=?0.0005) and fed state (p?=?0.0001). Median T_max for PPS was also 10?min shorter than CP in fasted state. Time to reach minimum effective concentration (MEC) for PPS was significantly shorter than CP and PBI. Early paracetamol exposure of PPS was significantly higher than that of the two existing paracetamol products. Food had a significant effect in the early exposure and onset of therapeutic level of paracetamol from PPS. AUC_{0–30 min} was significantly higher and time to reach plasma paracetamol at MEC level was significantly shorter than in the fasted state.     

A new rapidly absorbed paediatric paracetamol suspension. A six-way crossover pharmacokinetic study comparingthe rate and extent of paracetamol absorption from a new paracetamol suspension with two marketed paediatric formulations

The objective of this study was to compare the rate and extent of paracetamol absorption from the new Paracetamol pediatric suspension (PPS) with two marketed paracetamol suspensions: Children's panadol (CP) and Panodil baby & infant (PBI). The study also assessed the effect on paracetamol absorption of light-calorie, low-fat food consumed 2?h before dosing. Twenty eight male adult volunteers received a single oral dose of 1000?mg of paracetamol from each of three treatments, in both fasted and fed states according to a randomized, single-center, open-label, six-way crossover study design. PPS was bioequivalent to both CP and PBI for AUC(0-10 h), AUC(0-inf) and C(max) in both fasted and fed state. However, PPS had greater rate of paracetamol absorption and a faster speed of onset. T(max) for PPS was significantly shorter than for PBI in both fasted (p?=?0.0005) and fed state (p?=?0.0001). Median T(max) for PPS was also 10?min shorter than CP in fasted state. Time to reach minimum effective concentration (MEC) for PPS was significantly shorter than CP and PBI. Early paracetamol exposure of PPS was significantly higher than that of the two existing paracetamol products. Food had a significant effect in the early exposure and onset of therapeutic level of paracetamol from PPS. AUC(0-30 min) was significantly higher and time to reach plasma paracetamol at MEC level was significantly shorter than in the fasted state.     

Development of sustained-release tablets containing sodium valproate: in vitro and in vivo correlation

We have developed a 200 mg and 400 mg sustained-release sodium valproate tablet that allows effective blood concentration of the active drug with once-a-day dosing. The controlled dissolution or sustained release of the drug was attained by a membrane-controlled system. A single-coating system did not adequately control the dissolution rate, and therefore double-coated tablets were prepared and a human pharmacokinetic study was conducted. With the 200 mg VPA-Na tablets, the nonfasting C_max was only 20% higher than the fasting C_max. An in vitro dissolution test was conducted to predict the effects of food on drug dissolution after administration of this tablet. A relatively good correlation was observed between the absorption profiles and the dissolution profiles of the drug.     

Preparation and in vitro/in vivo evaluation of a ketoprofen orally disintegrating/sustained release tablet

Context: Orally disintegrating tablets (ODTs) with sustained release profiles are a new generation of ODTs called orally disintegrating/sustained release tablets (ODSRTs), which are convenient in use and able to slowly release drugs to maintain effective blood concentrations over a prolonged period of time. Ketoprofen, one of non-steroidal anti-inflammatory drugs, is an ideal model drug for ODSRTs.

Methods: We designed a simple two-step process to develop novel ketoprofen orally disintegrating/sustained release tablets (KODSRTs). Firstly, sustained release ketoprofen fine granules were developed by spray drying the aqueous dispersions composed of Eudragit RS-30D, Starch 1500 and PEG 6000. The optimal parameters of spray drying were 100°C for inlet air temperature and 1.5 mL/min for feed rate. Subsequently, the obtained granules were directly compressed into KODSRTs after mixing with lactose, mannitol and a superdisintegrant, crosslinked polyvinylpyrrolidone (PVPP). The characteristics of KODSRTs, especially their potential for extended drug release, were evaluated.

Results: Results of an in vitro release test demonstrated that KODSRTs could slowly release ketoprofen for 24 h after disintegrating within 30 s. Extended release properties of KODSRTs were decided by the ketoprofen sustained release fine granules in tablets. Besides, the disintegration time of KODSRTs depended on the percentage of PVPP in tablets. In vivo pharmacokinetic studies in beagles also showed that KODSRTs possessed a significantly extended release profile compared with ketoprofen normal capsules.

Conclusion: KODSRTs were successfully prepared using a simple two-step process: spray drying and direct compression.     

In vitro drug release and in vivo human X-ray studies of ileo-cecal targeting budesonide fast disintegrating tablet

Crohn's disease is a type of inflammatory bowel disease that frequently affects the ileo-cecal region of the gastrointestinal tract. For effective treatment of this disease, a site-targeting drug in the ileo-cecal region is essential. Budesonide (BD) is a synthetic, non-halogenated glucocorticoid and is the drug of choice for the treatment of Crohn's disease. The present study is an attempt to develop the dosage form of a BD tablet to achieve targeted drug release in the ileo-cecal region. The BD tablets are coated with Eudragit FS 30 D, which is a polymer that specifically dissolves at and above pH 6.8. The in vitro drug release and in vivo tablet disintegration (using X-ray radiography) were carried out. The coating process was optimized successfully. The in vitro performance of the tablet with coating thickness showed that the tablet did not disintegrate till 4.5 hours, which represents the transit time to the ileo-cecal region. In vivo studies also established that the tablet lasted till 4.5 hours. The tablet containing 0.5%?superdisintegrant and 10%?coating thickness was able to deliver BD effectively to the ileo-cecal region, thus making it a promising drug delivery system for the treatment of Crohn's disease.     

Preparation, characterization and in vivo studies of proliposomes containing Cyclosporine A

The present study was undertaken to prepare proliposomes of Cyclosporine A (CsA) to increase its oral bioavailability. The proliposomes were prepared by spraying a solution of CsA, egg lecithin and cremophor EL in methanol-chloroform mixture onto directly compressible lactose (carrier) in a rotary evaporator. A dry free flowing powder of proliposomes was obtained. The dry proliposomal powder was characterized for surface morphology by scanning electron microscopy (SEM). Then the proliposomes were hydrated with distilled water to produce liposomes, which were characterized for particle size distribution, % drug entrapment, and morphological characteristics by transmission electron microscopy (TEM). The liposomes exhibited good entrapment of about 99%. The entrapment of CsA in liposomes was found to be dependent mainly on the drug:lipid ratio. Bioavailability studies were carried out for three different formulations of CsA i.e., free drug suspension; proliposomes derived liposomes and marketed formulation (Pannimun Bioral, Microemulsion) on male SD rats. The results of bioavailability studies indicated that the difference in the mean drug concentration of the free drug and the liposomes was found to be statistically significant (p < 0.05, p value is 0.032). The absorption constant for liposomal product was much greater (10.26 h(-1)) than for free drug solution (1.2 h(-1)) or the marketed sample of microemulsion (2.51 h(-1)) and the volume of distribution was found to be less for liposomes (7629.88 ml/kg) than that of the free drug solution (10971.92 ml/kg) and marketed microemulsion (9012.07 ml/kg). The results of these studies have shown that a stable proliposomal formulation of CsA for oral administration can be prepared which can be easily hydrated into liposomes from which CsA can exert its clinical effects with a better oral bioavailability.     

Evaluation of monolithic osmotic tablet system for nifedipine delivery in vitro and in vivo

The aim of this study was to evaluate the monolithic osmotic tablet system (MOTS) containing a solid dispersion with the practically water-insoluble drug nifedipine in vitro and in vivo. In the drug release study in vitro, the release profiles of this system had almost zero-order kinetics. The influences of tablet formulation variables, sizes of the delivery orifice, membrane variables, and values of pH in the dissolution medium on nifedipine release from MOTS have been investigated. The results provided evidence that the tablet core played an important role in MOTS. While orifice sizes and membrane variables affected the nifedipine release rate, MOTS was independent of the dissolution medium. The appropriate orifice size was found to be in the range of 0.5-1.0 mm. The coating membrane incorporating hydrophilic polyethylene glycol (PEG) formed a porous structure. The human pharmacokinetics and relative bioavailability of MOTS containing nifedipine were compared with a commercial Adalat® osmotic tablet system containing an equivalent dose of nifedipine following an oral single dose of 30 mg given to each of 11 healthy volunteers in an open, randomized crossover study in vivo. The relative bioavailability for MOTS was 112%. There was no statistically significant difference in the pharmacokinetic parameters between two dosage forms. It is concluded that the monolithic osmotic tablet controlled release system is feasible for a long-acting preparation as a once-daily treatment.     

Ophthalmic vehicles containing polymer-solubilized tropicamide: "in vitro/in vivo" evaluation

Commercial 1.0% aqueous tropicamide (TR) eyedrops are buffered to pH 4.4-5.0 to produce sufficiently stable solutions of the weakly basic, poorly soluble drug. These acidic solutions, however, are irritants and may induce copious lachrimation, thus reducing the drug bioavailability. The aim of the present study was to evaluate some solubilizing agents for the preparation of 1.0% TR ophthalmic solutions adjusted at physiologically compatible pH, potentially showing increased eye tolerance, activity, and stability when compared with standard commercial eyedrops. The tested solubilizers were two non-ionic surfactants—Tyloxapol (TY) and Cremophor EL (CR)—and one polymer, Pluronic P85 (PL). Four stable 1% TR formulations, containing 3% TY, 7.5% CR, 15% PL, or 5% CR + 10% PL were submitted to mydriatic activity tests in rabbits. They improved to a small but statistically significant extent the AUC for mydriatic effect of TR in the test animals when compared with commercial 1.0% TR eyedrops.     

In vitro and in vivo evaluation of hydrophilic and hydrophobic polymers-based nicorandil-loaded peroral tablet compared with its once-daily commercial sustained-release tablet

Context: Hydrophilic and hydrophobic polymer-based nicorandil (10 mg)-loaded peroral tablets were prepared using the wet granulation technique. The influence of varying amounts of hydroxypropyl methylcellulose (HPMC) (30–50 mg), ethylcellulose (2–4 mg), microcrystalline cellulose (5–20 mg) and Aerosil^® (5–12 mg) in conjunction with the constant amounts (3 mg) of glidant and lubricant (magnesium stearate and talc) on the in vitro performances of the tablets (hardness, friability, weight variation, thickness uniformity, drug content, and drug release behavior) were investigated. Objective: The objectives of this study were (i) to select a nicorandil-loaded peroral tablet that matched the in vitro dissolution profile of once-daily commercial sustained-release tablet, and (ii) to compare the in vivo sustaining/controlling efficacy of the selected peroral tablet with that of its commercial counterparts. Results and Discussion: Because the nicorandil (10 mg)-loaded tablet prepared based on F-IX composition (50 mg HPMC, 4 mg ethylcellulose, 10 mg MCC and 3 mg glidant and lubricant) showed a release profile comparable to that of the Nikoran^® OD SR tablet release profile, the tablet with this composition was considered to be the optimized/selected formulation and, therefore, was subjected to stability study and in vivo study in rabbits. Despite of the higher C_max and AUC values obtained with the optimized tablet, there was no sign of difference between the optimized- and Nikoran^® OD SR- tablets following a single-dose crossover oral administration into rabbit. Conclusion: The optimized tablet could be used as an alternative to the commercial once-daily tablet.     

The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance

Abstract

The use of soluble cocrystal for delivering drugs with low solubility, although a potentially effective approach, often suffers the problem of rapid disproportionation during dissolution, which negates the solubility advantages offered by the cocrystal. This necessitates their robust stabilization in order for successful use in a tablet dosage form. The cocrystal between carbamezepine and succinic acid (CBZ-SUC) exhibits a higher aqueous solubility than its dihydrate, which is the stable form of CBZ in water. Using this model system, we demonstrate an efficient and material-sparing tablet formulation screening approach enabled by intrinsic dissolution rate measurements. Three tablet formulations capable of stabilizing the cocrystal both under accelerated condition of 40?°C and 75% RH and during dissolution were developed using three different polymers, Soluplus® (F₁), Kollidon VA/64 (F₂) and Hydroxypropyl methyl cellulose acetate succinate (F₃). When compared to a marketed product, Epitol® 200?mg tablets (F₀), drug release after 60?min from formulations F₁ (～82%), F₂ (～95%) and F₃ (～95%) was all higher than that from Epitol® (79%) in a modified simulated intestinal fluid. Studies in albino rabbits show correspondingly better bioavailability of F₁–F₃ than Epitol.     

Formulation development and in vitro evaluation of solidified self-microemulsion in the form of tablet containing atorvastatin calcium

Aim: The objective of our present study was to prepare solid self-microemulsion in the form of tablet of a poorly water soluble drug, Atorvastatin calcium (ATNC) to increase the solubility, dissolution rate, and minimize the hazards experienced from liquid emulsions.

Materials and methods: Self-microemulsifying ATNC tablet was formulated mainly by using self-emulsifying base, solidifying agent silicon dioxide and sodium starch glycolate as tablet disintegrant. Self-emulsifying base containing Transcutol P, Gelucire 44/14, and Lutrol F68 with their ratios in the formulation, were best selected by solubility study and ternary phase diagram in different vehicles. Particle size of microemulsion from tablet, physical parameters of the tablet and drug content has been checked. In vitro drug release rate has been carried out in phosphate buffer medium (pH 6.8). Physicochemical characterization of the drug in the optimized formulation has been performed to check drug-excipient incompatibility, if any.

Results: Average particle diameter of the emulsions formed from the tablet was found to be below 100?nm in case of formulation F4 and F5, which indicated microemulsions has been formed. In vitro drug release from the formulations F3, F4, and F5 was found to be >90%, indicated the enhancement of solubility of ATNC compared to parent drug. Differential thermal analysis (DTA), Powder X-ray Diffraction (X-RD) and Fourier transform infra red (FTIR) study proved the identity of the drug in the optimized formulation.

Conclusion: The tablet form of self-microemulsifying (SME) drug delivery is good for solubility enhancement.     

A Nifedipine Coground Mixture with Sodium Deoxycholate. II. Dissolution Characteristics and Stability

Nifedipine is a poorly water soluble drug that demonstrates low bioavailability. In a previous study, a coground mixture of nifedipine with sodium deoxycholate (DCNa), a bile salt, immediately produced colloidal particles when dispersed in water. In this study, the effect of the weight fraction of DCNa, grinding time, dissolution media, and storage conditions on colloidal particle formation in solution was investigated. The coground mixture was prepared with a vibration rod mill, and its solid state was characterized using powder X-ray diffraction. A laser diffraction particle size analyzer was used to determine the particle size distribution curve in water. The size of particles formed in solution decreased with an increase in the weight fraction of DCNa and grinding time. A nifedipine-DCNa (1 : 2 w/w) mixture coground for 30 min was used in the experiments. Colloidal particle formation from the coground mixture was also observed in dissolution media of water and a pH 6.8 buffer solution at 37°C. Most precipitates passed through a filter with a pore size of 0.8 μm, but the particle size distribution in water was different from that in the pH 6.8 buffer solution. DCNa exhibited not only micellar solubilization for drug crystals, but also a retarding effect on drug crystal growth in a supersaturated solution. The latter effect could serve to form colloidal particles in solution. When stored under 75% relative humidity at 40°C for 1 month, the amorphous coground mixture crystallized, and the particle size in water markedly increased. Therefore, the weight fraction of DCNa, grinding time, dissolution media, and humidity during storage influence the dissolution characteristics of nifedipine from a coground mixture.     

A Nifedipine Coground Mixture with Sodium Deoxycholate. II. Dissolution Characteristics and Stability

Nifedipine is a poorly water soluble drug that demonstrates low bioavailability. In a previous study, a coground mixture of nifedipine with sodium deoxycholate (DCNa), a bile salt, immediately produced colloidal particles when dispersed in water. In this study, the effect of the weight fraction of DCNa, grinding time, dissolution media, and storage conditions on colloidal particle formation in solution was investigated. The coground mixture was prepared with a vibration rod mill, and its solid state was characterized using powder X-ray diffraction. A laser diffraction particle size analyzer was used to determine the particle size distribution curve in water. The size of particles formed in solution decreased with an increase in the weight fraction of DCNa and grinding time. A nifedipine-DCNa (1 : 2 w/w) mixture coground for 30 min was used in the experiments. Colloidal particle formation from the coground mixture was also observed in dissolution media of water and a pH 6.8 buffer solution at 37°C. Most precipitates passed through a filter with a pore size of 0.8 μm, but the particle size distribution in water was different from that in the pH 6.8 buffer solution. DCNa exhibited not only micellar solubilization for drug crystals, but also a retarding effect on drug crystal growth in a supersaturated solution. The latter effect could serve to form colloidal particles in solution. When stored under 75% relative humidity at 40°C for 1 month, the amorphous coground mixture crystallized, and the particle size in water markedly increased. Therefore, the weight fraction of DCNa, grinding time, dissolution media, and humidity during storage influence the dissolution characteristics of nifedipine from a coground mixture.     

Formulation and in vitro studies of a fixed-dose combination of a bilayer matrix tablet containing metformin HCl as sustained release and glipizide as immediate release

The emerging new fixed dose combination of metformin hydrocholride (HCl) as sustained release and glipizide as immediate release were formulated as a bilayer matrix tablet using hydroxy propyl methyl cellulose (HPMC) as the matrix-forming polymer, and the tablets were evaluated via in vitro studies. Three different grades of HPMC (HPMC K 4M, HPMC K 15M, and HPMC K 100M) were used. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. In vitro release studies were carried out at a phosphate buffer of pH 6.8 with 0.75% sodium lauryl sulphate w/v using the apparatus I (basket) as described in the United States Pharmacopeia (2000). The release kinetics of metformin were evaluated using the regression coefficient analysis. There was no significant difference in drug release for different viscosity grade of HPMC with the same concentration. Tablet thus formulated provided sustained release of metformin HCl over a period of 8 hours and glipizide as immediate release.     

Development and evaluation of rapidly dissolving buccal films of naftopidil: in vitro and in vivo evaluation

Abstract

Objectives: Development and evaluation of rapidly dissolving film for intra-oral administration of naftopidil.

Significance: Formulation of naftopidil in the form of rapidly dissolving buccal film can eliminate the dissolution problem of naftopidil and provide a greater chance for direct absorption into the systemic circulation bypassing the presystemic metabolism. This can improve the oral bioavailability. In addition, this film guarantees patient compliance and is suitable for geriatric patients.

Methods: Rapidly dissolving film utilized hydroxypropyl methylcellulose E5 and polyvinylpyrrolidone K30 as the main components. The drug was loaded in pure form or after co-grinding with citric and/or tartaric acid. A solution of naftopidil in plurol oleique, labrasol, and tween 80 self-microemulsifying drug delivery systems (SMEDDS) was also loaded. The interactions of the drug with the excipients were monitored using thermal analysis, Fourier transform infrared spectroscopy, and X-ray diffraction. Naftopidil dissolution was monitored and selected films were used to assess the bioavailability after buccal administration to rabbit. Unprocessed drug suspension was administered orally and used as a reference.

Results: Incorporation of naftopidil in the film developed a new crystalline structure. The crystallinity of drug was abolished in the presence of organic acids or SMEDDS. The rapidly dissolving films showed fast liberation of the drug irrespective to the composition. Those films enhanced the bioavailability of naftopidil compared to orally administered suspension with SMEDDS containing film being superior.

Conclusion: The study introduced rapidly dissolving buccal film for enhanced dissolution and bioavailability of naftopidil.     

In vitro and in vivo studies on biocompatibility of carbon fibres

In the present study we focused on the in vitro and in vivo evaluation of two types of carbon fibres (CFs): hydroxyapatite modified carbon fibres and porous carbon fibres. Porous CFs used as scaffold for tissues regeneration could simultaneously serve as a support for drug delivery or biologically active agents which would stimulate the tissue growth; while addition of nanohydroxyapatite to CFs precursor can modify their biological properties (such as bioactivity) without subsequent surface modifications, making the process cost and time effective. Presented results indicated that fibre modification with HAp promoted formation of apatite on the fibre surface during incubation in simulated body fluid. The materials biocompatibility was determined by culturing human osteoblast-like cells of the line MG 63 in contact with both types of CFs. Both tested materials gave good support to adhesion and growth of bone-derived cells. Materials were implanted into the skeletal rat muscle and a comparative analysis of tissue reaction to the presence of the two types of CFs was done. Activities of marker metabolic enzymes: cytochrome c oxidase (CCO) and acid phosphatase were examined to estimate the effect of implants on the metabolic state of surrounding tissues. Presented results evidence the biocompatibility of porous CFs and activity that stimulates the growth of connective tissues. In case of CFs modified with hydroxyapatite the time of inflammatory reaction was shorter than in case of traditional CFs.