Recent Advances in the development of Modified Release Tablets by amalgamating both Solubility Enhancement and Polymer Matrix Sintering Technologies.

Background: The fact that about 90 % of newly discovered API’s or new molecular entity(NME) have little or no aqueous solubility, causes a significant protest to the initialization of development and their scale up of dosage form in the Pharma Industry. Aqueous solubility of API’s has critical role in drug dissolution or availability of drug at the site of action or bioavailability, when a dosage form is administered orally.Objective: The object of this study is to formulate a modified release tablet dosage form of a poorly aqueous soluble drug, which not only have higher aqueous solubility or bioavailability but also have sustained release characteristics with high mechanical strength &their commercial viability. Numerous techniques are available for the solubility enhancement but all individual techniques have its own limitations for commercialization.Method: Aqueous solubility of drugs is improved by the known Solubility enhancement techniques like Micronization &Solid dispersions. After successful solubility enhancement, sustained release or modified release tablets of poorly aqueous soluble drug can be easily formulated into a suitable shape or size by using a known Polymer Matrix Sintering Technology with commercial feasibility. Micronization of poorly water-soluble drugs can be performed by Air Jet Mill or Ball Mill. Whereas Solid dispersion technique involves, molecular dispersion of poorly soluble drug in a suitable inert carrier, to form an amorphous and highly soluble compounds. Sintering Technology is defined as the bonding of adjacent particle surfaces in a mass of powder, or in compact, by the application of heat. Conventional sintering technique involves the heating of compact at a temperature below the melting point of the solid constituents in a controlled environment under atmospheric pressure.Results: Enhanced solubility of poorly soluble API’s by these proposed techniques is due to either conversion of crystalline compound in to amorphous form or reduction of particle size to its molecular level by the application of Micronization or solid dispersion techniques. The developed modified release tablets will show a sustained release characteristic due to Sintering aspect and provides enhanced solubility of BCS class II or IV drugs.Conclusion: Novel modified release tablets have been designed through consolidation of Solubility enhancement and Polymer Matrix Sintering technologies. Simultaneous exploitation of well-known and established approaches- Micronization (optimum particle size reduction) or solid dispersion, optional surfactant and Polymer Matrix Sintering Technique in the recent concept, produces significant enhancement of solubility of poorly water soluble API’s without compromising the content uniformity of dosage form and also provide a modified or sustained release characteristics with high mechanical strength. The release profile of drug can be easily tailored by using combination of both techniques where challenges of low solubility are prominent.

Advances in Hormone Replacement Therapy for Adult Adrenal Insufficiency / 罕见病研究

Adrenal insufficiency is a disease characterized by insufficient secretion of adrenocortical hormones, usually treated with glucocorticoid replacement therapy. The routine drugs have two forms-short-acting and long-acting. The shorter one should be taken 2-3 times a day resulting hormone level of patients fluctuating greatly within a day. Although long-acting drugs reduce the frequency of administration, it is easy to lead to excessive replacement, resulting in adverse effects on metabolism. New alternative treatments for adult patients have emerged, including modified-release hydrocortisone and hydrocortisone subcutaneous infusion pumps. In this review, we briefly introduce these new therapies, emphasizing the pharmacodynamics and pharmacokinetics of the replacement, the effects on metabolism and drug safety, aiming at contributing to the future clinical practice.

Pharmacokinetics of a Novel Sustained-Release Vitamin C Oral Tablet: A Single Dose, Randomized, Double-Blind, Placebo-Controlled Trial

Objectives To evaluate the pharmacokinetics of a novel sustained-release oral tablet (C-Fence, Inventia Healthcare Limited, Mumbai, India). Methods We conducted a randomized, placebo controlled, parallel-design, 500 mg single-dose pharmacokinetic study of this new preparation in 18 healthy adult human subjects (nine in each group) under fasting conditions. The concentration-time profile and pharmacokinetic parameters of L-ascorbic acid, including Cmax (maximum plasma concentration), Tmax (time to reach Cmax), and AUC0-24h (area under the plasma concentration versus time curve from time 0 h to 24 h) were calculated using baseline-corrected values. Results The sustained-release tablets resulted in mean Cmax and AUC0-24h, respectively, of 1.39 ± 1.21 µg/mL and 11.72 ± 10.73 µg.h/mL against 0.18 ± 0.10 µg/mL and 0.89 ± 0.27 µg.h/mL, respectively, in the placebo group. The mean Tmax with the sustained-release tablets was 4.3 ± 2.5 h. At 12, 16, and 24 h from dosing, the concentrations were 0.6, 0.4, and 0.3 µg/mL, respectively, above baseline values. Conclusion Novel sustained-release formulations of vitamin C are expected to help achieve plasma vitamin C values above the homeostatic saturation level and result in higher steady-state plasma concentration, which might result in better cellular uptake.

Formulation of stomach-specific floating microparticles of nizatidine and their radiographic evaluation

Nizatidine is an anti-secretogogue and a gastroprotective drug with a half-life of 1-2 h and is well absorbed in the stomach. This study aimed to optimize the process and develop floating microparticles of nizatidine that are based on low methoxyl pectin. Oil-in-oil dispersion method and Taguchi orthogonal array design were employed, and the prolonged residence time of the microparticles in the stomach was demonstrated. The constraints for independent variables, viz. A-polymer, B-internal solvent volume, C-surfactant, D-stirring rate and E-stirring time were set to generate the experimental runs. Particle size, percentage yield, micromeritic properties, entrapment efficiency, in vitro buoyancy and in vitro release were characterized. Surface morphology, zeta potential, in vitro release kinetics and in vivo floating performance of the optimized formulation was examined. The microparticles were free-flowing, irregular in shape and had a mean particle size distribution of 73-187 µ. Low methoxyl pectin played a predominant role in achieving buoyancy and optimum gastric retention for the modified release of the drug, suggesting Korsmeyer-Peppas model as the possible release mechanism. In vivo radiographic study in rabbits revealed that the drug was retained in the stomach for a period of 6 h. These results indicate that nizatidine floating microparticulate system provides modified drug release for the effective treatment of gastric ulcer

Effects of physiological factors on small intestinal transit time / 解放军医学杂志

Objective: To explore the influence of gender, age and body mass index (BMI) on small intestinal transit time (SITT). Methods: A total of 181 patients admitted to in the Third Medical Center of Chinese PLA General Hospital during September 2012 to December 2018 for capsule endoscopy were selected and their age, gender, BMI and SITT were analyzed. The Mann-Whitney U test was utilized to compare the differences of SITT in patients of different genders. Spearman ρ test and multiple linear regression analysis were adopted to explore the relationship between different physiological variables age, gender, BMI and patient SITT. Results: The median SITT were 267.5 minutes for females and 252.0 minutes for males. Although the median SITT was 15.5 minutes longer in women than men, no statistical significance was found (P=0.360). There was positive correlation between age and SITT (ρ=0.22, P=0.002), and negative correlation between BMI and SITT (ρ=-0.17, P=0.02). Conclusion: The differences in drug bioavailability of modified-release preparations can not be attributed to SITT among patients of different genders, but may be related to SITT among patients of different ages and BMI.

Development and characterization of pullulan-polymethacrylate free films as potential material for enteric drug release

ABSTRACT Free films of pullulan-polymethacrylate associations were produced by casting process to develop a novel target-specific material. For characterization, tests of water vapor permeability, swelling index, infrared absorption spectroscopy, thermogravimetric analysis, scanning electron microscopy and mechanical analysis were performed. The polysaccharide concentration directly influenced vapor permeability and swelling, increasing the values of the latter up to five times when added in a proportion of 20% (per weight). The individual properties of each polymer were maintained, and chemical interactions were not detected. The films were found to be thermally stable and they had unaltered mechanical properties with the addition of the polysaccharide. The microscopic analysis revealed rugosity that was proportional to pullulan and disorganization of the polymer network at pH 6.8. These results suggest that this novel material has potential for enteric drug release because of synergism between pH and enzyme dependence.

Impact of CYP3 A5 genetic polymorphism on modified releasing tacrolimus pharmacokinetics in Chinese renal transplant recipients / 中国药理学通报

Aim To investigate the impact of CYP3 A5 genetic polymorphism on modified releasing tacrolimus pharmacokinetics in Chinese stable renal transplant re-cipients. Methods Pharmacokinetics of once daily-ta-crolimus( tac-q. d. ) and twice daily-tacrolimus( tac-b. i. d. ) were determined by CLIA, CYP3A5 genotype was measured by PCR-RFLP. Each 10 patients receiv-ing tac-q. d. and tac-b. i. d. respectively were en-rolled, and each 5 patients receiving tac-q. d. were matched to poor metabolizer ( PM ) and extensive me-tabolizer ( EM ) group respectively according to CYP3A5 genotypes. Results AUC0~24 h for tac-q. d. was 1. 78 folds higher than AUC0~12 h for tac-b. i. d. , and dose-adjusted C0 was 40% lower for tac-q. d. than for tac-b. i. d. There were no significant differences for other parameters between the two groups; Cmax, AUC0~24 h and C0 were 1. 75, 1. 96 and 2. 49 folds higher for PM than for EM, and dose-adjusted Cmax, AUC0~24 h and C0 were 1. 80, 2. 34 and 2. 64 folds higher for PM than for EM. There were good correla-tions between AUC0~24 h and C0 for tac-q. d. Conclu-sion Conversion from tac-b. i. d. to tac-q. d. results in requirement of increased tacrolimus dose and detec-tion of CYP3A5 genotype, which is necessary for ensu-ring C0 in the range of therapeutic window.

In vitro- In vivo Correlation Studies of Modified Release Tolterodine Tablet Dosage form in Rabbits.

Tolterodine is an antimuscarnic drug that is used for sympathetic treatment of urinary incontinence. Tolterodine modified release tablet, was investigated in rabbit for pharmacokinetic and in vitro–in vivo correlation studies. Tablets were prepared and in vitro release was studied in simulated gastric fluid at 150RPMs. New Zealand albino male rabbits have been used as animal model for in vivo study. A sensitive and simple HPLC method was developed for the determination of Tolterodine content in rabbit plasma. In vitro release studies showed that release patterns followed zero order for around 24h. The in vivo–in vitro correlation coefficients obtained from point-to-point analysis were greater than 99% between concentrations at certain time points obtained from release study in simulated gastric fluid and HPLC analysis of rabbit’s plasma. From the in vitro–in vivo correlation prediction it was evident that the Tolterodine matrix assisted tablet is a good for controlled delivery of Tolterodine.

Development of a multiparticulate system containing enteric-release mini-tablets of omeprazole

The main aim of this study was to develop a multiparticulate system containing mini-tablets of omeprazole formulated with an enteric polymer with pH-dependent solubility. Pre-formulation studies showed good flow and compaction capacity, leading to the production ofhigh quality mini-tablets. The mini-tablets were coated in a fluidized bed with hydroxypropylmethylcellulose /Eudragit(r) L30D55 and packed into hard gelatin capsules. The dissolution profile showed gastro-resistance and zero-order kinetics. The dissolution profile for the formulation containing lactose as the diluent and coated with 12% (tablet weight gain) of polymer was similar to that ofthe reference drug.

O presente trabalho teve como objetivo desenvolver e avaliar um sistema multiparticulado de liberação modificada, composto por mini-comprimidos revestidos com polímero de liberação pH-dependente, utilizando como fármaco modelo o omeprazol. Os mini-comprimidos (diâmetro de 2,5 mm) foram obtidos em máquina de compresssão excêntrica, revestidos em leito fluidizado com hidroxipropilmetilcelulose/Eudragit(r)L30D55 e, em seguida, acondicionados em cápsulas gelatinosas duras. A partir dos resultados obtidos no perfil de dissolução foi possível demonstrar a liberação gastro-resistente e comportamento cinético de ordem zero. A formulação contendo lactose como diluente, com revestimento de 12% de polímero, demonstrou semelhança com o medicamento referência.

Sistemas farmacêuticos gastrorretentivos flutuantes / Pharmaceutical gastro-retentive systems

Freqüentemente recorre-se à produção de sistemas gastrorretentivos para modular a liberação de fármacos a partir de sistemas farmacêuticos com vistas ao aumento do tempo de permanência do fármaco no trato gastrointestinal. Umas das estratégias mais interessantes passa pela produção de sistemas flutuantes. Estes podem ser classificados em dois grupos: sistemas flutuantes efervescentes e sistemas flutuantes não-efervecentes. Neste artigo apresenta-se uma revisão bibliográfica do que tem sido produzido nesta área nos últimos anos.

Gastro-retentive systems are often produced in order to modulate drugs release from pharmaceutical forms and in this way to increase drug residence time in the gastrointestinal tract. One of the most interesting strategies consists in the preparation of floating devices. These can be classified into two groups: effervescent systems and non-effervescent systems. A review of what has been done in the last years is presented in this article.

Pentoxifylline Modified Release Capsules' Preparation and Its in Vitro Drug Release Characteristics / 中国药房

OBJECTIVE: To prepare pentoxifylline(PTX) modified release capsule and to investigate its in vitro drug release characteristics. METHODS: The orthogonal design was adopted to optimize the formula and the preparation technics; and the contents of PTX were determined by UV - spectrophotometry. RESULTS: The optimized formula and preparation technics were as follows: PTX 200mg, hydroxy propyl methylcellulose 90mg, stearic acid 60mg, octadecyl alcohol 50mg, flu-idization for 25min at 80℃;PTX assumed linear relationship with absorbability at the range of 1.0-10.0?g /ml(r = 0.9 995), the average recovery was 101.24% , RSD = 1.27% (n = 6) . CONCLUSION: The optimized technics is simple and easy to handle; PTX modified release capsules prepared in the technics were of good stability and which have an obvious in vitro slow release property.