Comparison of neurofuzzy logic and decision trees in discovering knowledge from experimental data of an immediate release tablet formulation.

Understanding of the cause-effect relationships between formulation ingredients, process conditions and product properties is essential for developing a quality product. However, the formulation knowledge is often hidden in experimental data and not easily interpretable. This study compares neurofuzzy logic and decision tree approaches in discovering hidden knowledge from an immediate release tablet formulation database relating formulation ingredients (silica aerogel, magnesium stearate, microcrystalline cellulose and sodium carboxymethylcellulose) and process variables (dwell time and compression force) to tablet properties (tensile strength, disintegration time, friability, capping and drug dissolution at various time intervals). Both approaches successfully generated useful knowledge in the form of either "if then" rules or decision trees. Although different strategies are employed by the two approaches in generating rules/trees, similar knowledge was discovered in most cases. However, as decision trees are not able to deal with continuous dependent variables, data discretisation procedures are generally required.     

Probability of passing dissolution acceptance criteria for an immediate release tablet

During development of solid dosage products, a pharmaceutical manufacturer is typically required to propose dissolution acceptance criteria unless the product falls into Biopharmaceutics Classification System (BCS) class I, in which case a disintegration test may be used. At the time of filing the new drug application (NDA) or common technical document (CTD), the manufacturer has already met with regulatory agencies to discuss and refine dissolution strategy. The dissolution acceptance criteria are based on stability and batch history data and are often arrived at by considering the percentage of batches that pass United States Pharmacopeia (USP) criteria at Stage 1 (S(1)), when in fact, the product is deemed unacceptable only when a batch fails USP criteria at Stage 3 (S(3)) [H. Saranadasa, Disso. Technol. 7 (2000) 6-7, 18 [1]]. Calculating the probability of passing (or failing) dissolution criteria at S(1), S(2), or S(3) can assist a manufacturer in determining appropriate acceptance criteria. This article discusses a general statistical method that was developed to assess the probability of passing the multistage USP test for dissolution and how it was applied to an immediate release tablet formulation. In this case, acceptance criteria were set and the analysis was conducted to assess the probabilities of passing or failing based on this acceptance criterion. Whether the acceptance criteria were relevant to the product was also considered. This mathematical approach uses a Monte Carlo simulation and considers a range of values for standard deviation and mean of historical data.     

New immediate release formulation for deterring abuse of methadone

Context. Drug abusers are known to take a dosage form containing an opioid analgesic and crush, shear, grind, chew, or dissolve it in water or in alcohol, in order to extract the opioid component.

Objective. Develop an anti abuse immediate release formulation using methadone as model drug.

Materials and Methods. Tablets combining methadone and alkalizing agents were manufactured. A methadone assay was used to determine extraction efficiency from tablets in aqueous and alcohol solvents. In vitro dissolution testing was used to determine drug release in different media.

Results and Discussions. Meglumine-based formulations prevented extraction of 70 to 100% of methadone from tablets. Addition of this alkalizing agent caused methadone to precipitate out of a solution along with other ingredients and be retained on standard filters. Meglumine-containing and control tablets showed similar dissolution profiles in acidic media, suggesting adequate solubilisation of the drug early in the gastrointestinal tract. Finally, stability upon storage of the formulations for 6 months at 25°C/60%RH and 40°C/75%RH was confirmed.

Conclusion. Incorporation of an alkalizing agent into methadone tablets significantly reduced the preparation of a methadone solution for intravenous administration and abuse, while allowing the formulation to release methadone in gastric media and provide desired pharmacological effect.     

Zero-order release profile of metoclopramide hydrochloride sublingual tablet formulation

This report describes zero-order approximation for metoclopramide hydrochloride sublingual tablet formulation. Effects of type and concentration of excipients on release were investigated. Study revealed that highest rate of dissolution was attained with crosspovidone and decreased in the order crosspovidone > sodium starch glycolate > ac-di-sol. All formulations demonstrated flush release, except the one containing 10% crosspovidone where a lag time of 0.5?min. was depicted. Increasing the concentration of crosspovidone from 5 to 10% gave the same half-life, whereas kinetics of release changed to zero order. Differential scanning colorimetry and infrared spectroscopy did not reveal any sign of physical or chemical interaction between drug and crosspovidone. In order to study the alignment of polymeric network inside tablet matrix, scanning electron microscopy was performed on the tablet and its cross-section. Matrix with 10% crosspovidone showed higher density of interconnections extending to the interior of core enabling fast and constant release. Hence physicochemical characteristics of crosspovidone could be tailored by varying its concentration, in a way that provided a porous matrix with tight arrangement of polymeric chains, resembling to an assemblage of cylinders with constant apertures, from which zero-order release was approached.     

Gastrointestinal transit of a controlled release naproxen tablet formulation

The gastrointestinal transit of a controlled release naproxen tablet formulation has been measured in healthy young and old subjects using the technique of gamma scintigraphy. Gastric emptying of the tablet was affected by food (mean emptying times for fasted subjects were 0.64 h (young) and 0.86 h (old) increased to 3.0 h (young) and 3.3 h (old) following a light breakfast). The small intestinal transit times for both fed and fasted states was about 3.2 h. There were no significant differences that could be attributed to subject age for gastric emptying and small intestinal transit.     

Surfactant effects upon dissolution patterns of carbamazepine immediate release tablet

The objective of this study was to investigate the effects of sodium lauryl sulfate upon the saturation solubility of carbamazepine, its dissolution kinetics, and T50% defined as the time required for dissolving 50% of carbamazepine. Water, 0.1 N-HCl, and phosphate buffers at pH 4.0 and 6.8 containing 0.1, 0.5, 1, and 2% sodium lauryl sulfate were used as dissolution media. The dissolution study was conducted by using the USP dissolution apparatus II with an agitation rate of 75 rpm. Samples of the dissolution media were taken in 7, 15, 30, 45, 60, 75, and 90 min, and the amounts of carbamazepine were determined spectrophotometrically at 285 nm. All dissolution data were fitted well into a four-parameter exponential equation: Q = a(1 - e(-b x t)) + c(1 - e(-d x t)). In this equation Q represented % carbamazepine dissolved at a time t, and a, b, c, and d were constants. This equation led to the calculation of dissolution rates at various time points and T50%. It was found that the dissolution rate of carbamazepine was directly proportional to the aqueous concentration of sodium lauryl sulfate. In addition, under our experimental conditions T50% values ranged from 37.8 to 4.9 min. It was interesting to note that T50% declined rapidly as the surfactant concentration increased from 0.1 to 0.5%, whereas it declined more slowly at concentrations greater than 1%. These results clearly demonstrated that the dissolution rate of carbamazepine and duration of its dissolution test could be tailored by optimizing the amount of sodium lauryl sulfate in a dissolution medium.     

氢溴酸加兰他敏口服液及片剂的人体生物等效性研究

目的:采用HPLC-RF检测法测定氢溴酸加兰他敏的血药浓度,研究其在人体内的药动学和生物等效性。方法:24例健康男性志愿者单剂量随机交叉口服5 mg加兰他敏口服液(受试制剂)和片剂(参比制剂)。血浆样品经碱化后用乙醚提取,采用反相HPLC-RF法测定血浆中加兰他敏浓度,检测波长:激发波长290 nm,发射波长320 nm。采用3P97药动学软件计算药动学参数和相对生物利用度,并对参数进行方差分析和双单侧t检验。结果:加兰他敏口服液和片剂的主要药动学参数:Cmax分别为(31．53±5．59)和(33．44±5．72)μg·L-1;Tmax分别为(1．66±0．79)和(1．51±0．72)h;t1/2分别为(7．06±2．16)和(6．64±2．30)h;AUC0～∞分别为(340．6±77．2)和(325．5±77．7)μg·h·L-1。氢溴酸加兰他敏口服液相对生物利用度为105．6％。结论:加兰他敏口服液和片剂生物等效。     

Controlled-release tablet formulation of isoniazid.

Guar (GG) and Karaya gums (KG) alone and in combination with hydroxy-propylmethylcellulose (HPMC) were evaluated as release retarding materials to formulate a controlled-release tablet dosage form of isoniazid (1). In vitro release of 1 from tablets followed non-Fickian release profile with rapid initial release. Urinary excretion studies in normal subjects showed steady-state levels of 1 for 13 h. In vitro and in vivo data correlated (r = 0.9794). The studies suggested the potentiality of GG and KG as release retarding materials in formulating controlled-release tablet dosage forms of 1.     

Concentration-effect relationship of levodopa in patients with Parkinson's disease after oral administration of an immediate release and a controlled release formulation.

1. The relationship between plasma concentration of levodopa and motor-response was investigated in 12 patients with Parkinson's disease who showed marked response fluctuations, after a single oral dose of an immediate release (IR) formulation (100 mg levodopa/25 mg genserazide) and a controlled release (CR) formulation (300 mg levodopa/75 mg benserazide), using a double-blind, randomized, cross-over design. 2. The sum score of the Columbia University Rating Scale (CURS sigma) was used for pharmacodynamic assessment. A sigmoidal Emax-model was fitted to the data using a semiparametric pharmacokinetic/dynamic approach. 3. The dose-corrected AUC of levodopa after the IR-formulation was 27.5 (+/- 9.1 s.d.) ng ml-1 h per mg and 23.2 (+/- 4.6 s.d.) ng ml-1 h per mg after the CR-formulation. Cmax was 1714 (+/- 1027 s.d.) ng ml-1 after the IR-formulation and 1494 (+/- 383 s.d.) ng ml-1 after the CR-formulation. 4. With both preparations, the maximal response to levodopa (Emax) was a decrease in the CURS sigma rating of about 27 scores. Estimates of the EC50 of levodopa were 495 (+/- 144 s.d.) ng ml-1 (IR) and 1024 (+/- 502 s.d.) ng ml-1 (CR), respectively (95%-CI: 1.51-2.66, point estimator 1.95). The mean duration of the motor response was 1.9 (+/- 0.5 s.d.) h (IR) and 2.8 (+/- 0.7 s.d.) h (CR), respectively (95%-CI: 1.12-2.04, point estimator 1.53).(ABSTRACT TRUNCATED AT 250 WORDS)     

人工智能在毒性病理学中的应用

毒性病理学是临床前药物安全性评价的重要组成部分。随着计算机科学的发展和全切片数字扫描切片技术的发展,人工智能（AI）已经广泛应用于药物安全性评价领域,也包括病理学的各个方面,如诊断病理学、兽医诊断学、病理学研究、监管毒理学和病理学初级阅片及同行评议等。AI病理学平台的应用逐渐影响精准医学和个性化医学的未来发展。然而,与其他重要的科学技术进步一样,AI在毒性病理学领域的实施和应用也面临巨大的挑战。通过简要综述数字病理学的发展、算法类型、AI在毒性病理学中的应用概况、AI的监管环境等,以期为AI在毒性病理学中的研究发展及广泛应用提供新的思路。     

Standardization of sulaharan yoga: an ayurvedic tablet formulation

Quality assurance of herbal products may be ensured by proper quality control of the herbal ingredients and by means of good manufacturing practice. We have developed a simple scheme for the standardization and authentication of Sulaharan Yoga a poly herbal formulation. Sulaharan Yoga was prepared as per Ayurvedic Formulary of India. In-house and marketed preparation has been standardized on the basis of organoleptic characters, physical characteristics and physico-chemical properties. The set parameters were found to be sufficient to standardize the Sulaharan Yoga and can be used as reference standards for the quality control/ quality assurance study.     

Optimization of primaquine diphosphate tablet formulation for controlled drug release using the mixture experimental design

A tablet formulation based on hydrophilic matrix with a controlled drug release was developed, and the effect of polymer concentrations on the release of primaquine diphosphate was evaluated. To achieve this purpose, a 20-run, four-factor with multiple constraints on the proportions of the components was employed to obtain tablet compositions. Drug release was determined by an in vitro dissolution study in phosphate buffer solution at pH 6.8. The polynomial fitted functions described the behavior of the mixture on simplex coordinate systems to study the effects of each factor (polymer) on tablet characteristics. Based on the response surface methodology, a tablet composition was optimized with the purpose of obtaining a primaquine diphosphate release closer to a zero order kinetic. This formulation released 85.22% of the drug for 8 h and its kinetic was studied regarding to Korsmeyer–Peppas model, (Adj-R² = 0.99295) which has confirmed that both diffusion and erosion were related to the mechanism of the drug release. The data from the optimized formulation were very close to the predictions from statistical analysis, demonstrating that mixture experimental design could be used to optimize primaquine diphosphate dissolution from hidroxypropylmethyl cellulose and polyethylene glycol matrix tablets.     

Compression of coated drug beads for sustained release tablet of glipizide: formulation,and dissolution

Abstract

A promising glipizide formulation comprising compression of four-layer coated beads into tablets was prepared. The tablet offered the advantages of: a two-hour lag time before drug release, retaining sustained release characteristics and providing approximately zero-order drug release. Drug release was nearly independent of paddle speeds of 50 and 100?rpm releasing 80% over 14?h similar to the commercial glipizide osmotic pump tablet during dissolution testing while keeping the benefits of multiparticular dosage forms. The tablets contain beads with four layers: (1) the innermost layer consists of 2.5?g glipizide and 3.75?g solid ethylcellulose (Surelease®) coated onto 71.25?g of sugar beads; (2) next a hardening layer of 5?g of hypromellose; (3) the controlled release layer of 7.5?g of Surelease®:lactose at a solids ratio of 100:7 and (4) an outermost layer of 20?g of lactose:sodium starch glycolate (Explotab®) at a 2:1 ratio. Then, beads were compressed into tablets containing 11?mg of glipizide using 1500?lbs of compression pressure. The dissolution test similarity factor (f₂) was above 50 for all test conditions for formulation F13 and Glucotrol® with a high of 69.9. The two Surelease® layers both aid controlling drug release, with the Surelease®-drug layer affecting drug release to a greater extent.     

Novel amorphous microporous silica spheres for controlled release applications

A new synthesis route for large spherical particles of amorphous microporous silica (AMS) was developed. These novel spherical porous particles with diameter of around 100 µm and pore diameter smaller than 2 nm were prepared using an oil drop method. Molten ibuprofen was successfully loaded into the AMS pores. In vitro release experiments revealed that ibuprofen was released from the spheres via a slow pore diffusion process lasting up to 14 days. Experimentally determined diffusion coefficients of ibuprofen in the porous spheres were of the order of 10^?15–10^?16 m² s^?1. The present findings reveal the potential of AMS spheres for controlled release of small drug molecules over long time periods. The spherical shape of the AMS particles is advantageous in formulation processes as it provides adequate powder flow properties and reliable release profiles. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4295–4301, 2011     

Multiple dose pharmacokinetics of a new once daily extended release tolterodine formulation versus immediate release tolterodine

OBJECTIVE: To determine the multiple dose pharmacokinetics of a new extended release (ER) capsule formulation of tolterodine, compared with the existing immediate release (IR) tablet, in healthy volunteers. DESIGN: Nonblind, randomised, 2-way crossover trial. PARTICIPANTS: 19 healthy volunteers (7 females, 12 males), mean age 33 years (range 18 to 55 years). Prior to the study, all volunteers were classified as either extensive or poor metabolisers by cytochrome P450 2D6 genotyping. METHODS: Volunteers received tolterodine ER 4mg once daily or tolterodine IR 2mg twice daily for 6 days (all doses given as the L-tartrate salt). A washout period of 7 days separated the 2 treatments. Serum concentrations of tolterodine, its active 5-hydroxymethyl metabolite (5-HM) and the active moiety (extensive metabolisers: sum of unbound tolterodine + 5-HM; poor metabolisers: unbound tolterodine) were measured for up to 48 hours post-dose on day 6 (steady state). Tolerability was also determined. RESULTS: 17 volunteers (13 extensive metabolisers, 4 poor metabolisers) completed the study and were evaluable for both treatment periods. The 90% confidence interval for the geometric mean ratio of area under the serum concentration-time curve to 24 hours (AUC24) of the active moiety, for all volunteers combined, indicated equivalence for the 2 formulations. Pooled analysis also demonstrated that the peak serum concentration (Cmax) of the active moiety following administration of tolterodine ER was around 75% of that observed for the IR tablet, whereas the trough concentration was around 1.5-fold higher. Overall, the pharmacokinetics of tolterodine (irrespective of genotype) and 5-HM (extensive metabolisers only) were consistent with sustained drug release over 24 hours. Tolterodine ER was well tolerated. CONCLUSIONS: The new once daily ER formulation of tolterodine 4mg shows pharmacokinetic equivalence (AUC24) to the existing IR tablet given at a dose of 2mg twice daily. Findings of lower Cmax for tolterodine ER may explain the significantly lower rate of dry mouth subsequently observed in patients with overactive bladder.     

Role of an isomorphic desolvate in dissolution failures of an erythromycin tablet formulation

The investigation of dissolution failures for erythromycin dihydrate tablet formulation over a 12-month period using a near-infrared spectroscopy technique revealed the role of a desolvated dihydrate in the retardation of dissolution. Near infrared spectroscopy (NIR) indicated a dehydrated dihydrate of erythromycin is produced during formulation and gradually binds with Mg(OH)2. The binding delays the process of dissolution. NIR was used to successfully predict that humidifying the tablets would reverse the binding and increase the dissolution rate.     

Effects of a bezafibrate sustained release formulation on plasma lipoproteins in patients with hypercholesterolemia. Importance of timing of tablet intake for efficacy

The therapeutic effect of a single sustained release tablet of bezafibrate (Cedur retard, 400 mg) in primary hypercholesterolemia type IIa and type IIb was investigated in a placebo-controlled randomised study comparing the efficacy of morning vs. evening intake. The decrease in total cholesterol with the morning intake was 18.5% vs. 16.5% for the evening intake (n.s.). HDL-cholesterol increased more in patients taking bezafibrate retard at morning (29.6% vs. 22.4%, p less than 0.05). Bezafibrate was well tolerated. Animal experiments and precursor studies of cholesterol synthesis in man indicate peak activity of HMG-CoA reductase between 1 a.m. and 3 a.m. The data suggest that with normal eating habits during day time other modes of action of bezafibrate besides HMG-CoA reductase inhibition such as reduction of VLDL-synthesis in the liver and an increased fractional catabolic rate, could contribute to the therapeutic effect.     

Evaluation of food effect on the oral absorption of clarithromycin from immediate release tablet using physiological modelling

Background: Food may affect the oral absorption of drugs. Purpose: The aim of the present study was to investigate the influence of food on the oral absorption of clarithromycin by evaluating the effect of media parameters, such as pH, bile secretions and food composition, on the release of the drug from immediate release tablets, using in vitro and in silico assessments. Method: The solubility, disintegration and dissolution profiles of clarithromycin 500 mg immediate release tablets in compendial media with/without the addition of a homogenized FDA meal as well as in biorelevant simulated intestinal media mimicking fasting and fed conditions were determined. These in vitro data were input to GastroPlus?, which was used for developing a physiological absorption model capable of anticipating the effect of food on clarithromycin absorption. Level A in vitro–in vivo linear correlations were established using a mechanistic absorption modelling based deconvolution approach. Results: The pH of the media has a profound effect on clarithromycin solubility, tablet disintegration and drug release. Clarithromycin has lower solubility in biorelevant media compared with other media, due to complex formation with bile salts. Clarithromycin tablets exhibited prolonged disintegration times and reduced dissolution rates in the presence of the standard FDA meal. The simulation model predicted no significant food effect on the oral bioavailability of clarithromycin. The developed IVIVC model considered SIF, acetate buffer and FaSSIF media to be the most relevant from the physiological standpoint. Conclusion: The intake of a standard FDA meal may have no significant effect on the oral bioavailability of clarithromycin immediate release tablet.