Preclinical study of an oral controlled release naltrexone complex in mice

Naltrexone, a long-acting, orally effective, opioid antagonist which blocks opioid effects as well as the development of physical dependence, would appear to be a drug ideally suited to addiction treatment. An optimal dosage regimen is critical for the treatment patient compliance in ambulatory opiate detoxification programs. The ideal dosage regimen would be an oral controlled-release system of naltrexone that allowed once-a-day administration providing stable plasma levels. A naltrexone-Eudragit L complex was produced in aqueous medium from naltrexone hydrochloride solution and Eudragit L30D (30% w/v) previously diluted (6% w/v) and partially neutralized. The antagonistic activity of naltrexone-Eudragit L on morphine-induced thermal antinociception, in comparison with conventional naltrexone, was evaluated, using the mouse hot-plate model. Mice were administered 10 mg kg(-1) morphine subcutaneously, 10 min before test, and the antagonist products, either naltrexone-Eudragit L or naltrexone hydrochloride, were administered orally at 0.5, 1, 2, 4, 6, 8, 10, 12, 14 and 16h before the test. The results showed that the antagonism induced by naltrexone-Eudragit L was effective until 12 h after drug administration, while that induced by naltrexone hydrochloride disappeared 10 h after its administration. A 23.47% increase of the area under curve was obtained when naltrexone-Eudragit L was administered, compared with that induced by conventional naltrexone. The time taken to decrease the inhibition of analgesic activity to 50% was delayed by 51.80%. This complexation technique can be considered as a useful tool in the design of oral controlled-release systems capable of inducing a long-lasting effect in-vivo.     

Preclinical assessment of the feasibility of applying controlled release oral drug delivery to a lead series of atypical antipsychotics

In this paper, we present a preclinical approach for evaluating the feasibility of applying controlled-release (CR) oral drug delivery to increase the duration of exposure and lower the C(max) of compounds in a lead series of short half-life atypical antipsychotics. Three lead compounds in the series had demonstrated potential pharmacological benefits for the treatment of psychosis, in preclinical studies. However, the compounds showed evidence of insufficient half-lives to enable a once-a-day (QD) product using immediate-release (IR) oral delivery. To evaluate and compare the potential for oral CR delivery to extend the duration of action and thereby enable QD administration, the in vitro solubility and permeability, and the duodenal and colonic absorption of three compounds in the series were measured. Based on the results, one candidate was selected for advancement that showed moderate in vitro solubility, but had the highest in vitro permeability and ratio of colonic to duodenal bioavailability (0.9) in the rat. The results from this study provided evidence that a CR drug delivery system could be used to extend the duration of exposure of the compounds in the series and a scientific basis for selecting one of the three compounds as a candidate.     

Assessment of the drug level in bronchial secretion with patient's noncompliance and oral dosage forms with controlled release

The drug level was calculated in the plasma, the lung tissue and bronchial secretion using ciprofloxacin as the drug with erosion-controlled dosage forms. A numerical model was built and tested for this calculation. It takes into account the following stages: the kinetics of drug release along the gastrointestinal tract time, the absorption into and elimination out of the plasma, the diffusion through the lung tissue and convection into the bronchial secretion. Emphasis is placed upon the effect of patient's non-compliance on the drug levels, with intake omission, intake omission followed by double dosing, wrong frequency. Calculation with erosion-controlled dosage form with a long time of full erosion able to remain in the gastrointestinal over a period of time much longer than the usual gastrointestinal tract time shows the interest of bioadhesion.     

Acrylic microspheres for oral controlled release of the biguanide buformin

Spherical microparticles based on methacrylic acid-methyl methacrylate copolymer have been developed. The method chosen for the preparation of such microparticles was suspension radical copolymerization of acrylic comonomers in the presence of the ethyleneglycol dimethacrylate as crosslinking agent. The microparticles obtained were characterised by inverse size exclusion chromatography, scanning electron microscopy, swelling degree and exchange capacity. The porous volume of the microspheres ranged from 0.086 ml/g for the microparticles produced by a methacrylic acid/methyl methacrylate ratio of 1/3 and a 10% degree of crosslinking, to 8.57 ml/g for the microparticles produced by a methacrylic acid/methyl methacrylate ratio of 3/1 and 2% degree of crosslinking (in 0.1 N NaCl in phosphate buffer pH 7.4). Also the pore diameter of the swollen microparticles ranged from a few to 120 A. Buformin tosylate - a classical hypoglycaemic drug - was included in the polymer network of the microparticles during the polymerization process. Due to the water solubility of the drug and its low solubility in the organic phase, the entrapment yield did not exceed 15%. However the amount of encapsulated drug as well as the drug released from the microparticles, was dependent on the methacrylic acid/methyl methacrylate ratio, the degree of crosslinking and solvent/comonomers ratio.     

Design and evaluation of an oral controlled release delivery system for melatonin in human subjects

Six human subjects were given an oral formulation designed to provide an immediate and controlled release of melatonin (MT). The controlled release formulation consisted of MT-loaded sugar beads coated with 20% Aquacoat^®. A computer simulation program (MAXSIM^®) was used to estimate the MT dose and ratio of immediate and controlled release MT based on average population pharmacokinetics of MT. When 0.5 mg of MT (immediate release portion of MT, 0.1 mg) was administered to four subjects, average peak plasma MT concentration was reached at about 600 pg/ml and maintained at about 100 pg/ml over 8 h. Observed peak plasma MT concentrations were 3-times greater than predicted by simulation. These results suggest that the MT dose, ratio of immediate release MT to controlled release MT, and the controlled release dosage form must all be considered in order to closely mimic the endogenous plasma MT concentration-time curve. Deconvolution and pharmacokinetic analysis suggested that less than 20% of the orally administered controlled release MT dose reached the systemic circulation from time 0 to 8 h. A good correlation was observed between plasma MT concentration and urinary excretion rate of 6-sulphatoxymelatonin (6-STMT), a major metabolite of MT. As plasma MT concentration increased, the urinary excretion rate of 6-STMT increased concomitantly. This suggests that the urinary excretion rate of 6-STMT may be used as an index of human plasma MT concentration.     

Minimizing bioavailability variations with oral controlled release formulations

Despite various routes of drug delivery being explored, the oral route has continued to be the most popular route of drug administration. However, the complexities associated with the gastrointestinal tract lead to variations in the rate and extent of bioavailability of drugs administered as oral dosage forms. This variation in the bioavailability of drugs is responsible for the majority of adverse effects, lack of efficacy, and development of tolerance, etc. This review explores the possibilities of minimizing these bioavailability variations with the use of oral controlled release (CR) dosage forms. The use of CR preparations, in lieu of the immediate preparations in itself, leads to better control over plasma levels. Furthermore, the additional benefits offered by CR products, such as the reduction in first-pass metabolism, enhanced and reproducible bioavailability with gastro retentive preparations, overcoming circadian rhythm variations, and the lesser effect of fed condition on bioavailability, can be effectively utilized for bioavailability variation minimization. However, CR products cannot be use indiscriminately. The use of CR products to serve the purpose of bioavailability variation minimization should be based on due consideration to the role of metabolizing enzymes, the permeability variations, and the area available for absorption.     

Modeling microstructure development and release kinetics in controlled drug release coatings

In recent years, controlled release coatings, comprised of drug-polymer composites, have been integrated with medical devices, improving device functionality and performance. However, relationships between material properties, manufacturing environment, composite (micro)structure, and subsequent release kinetics are not well established. We apply a thermodynamically consistent model to probe the influence of drug-polymer chemistry (phobicity), drug loading, and evaporation rate on microstructure development during fabrication. For these structures, we compute release profiles for exposure to polymer-insoluble media and media in which the polymer readily dissolves. We find that with increasing drug-polymer phobicity, structural heterogeneities form at lower loadings and more rapid rates. The heterogeneities remain isolated and compact at low loadings and become interconnected as the drug to polymer ratio approaches 1.0. Release into polymer-insoluble media was dramatically enhanced by heterogeneities, resulting in up to a fourfold increase in drug release. In polymer-soluble media, however, heterogeneities diminished release. Although reductions of only 30% were typically observed, the absolute changes were much larger than observed in polymer-insoluble media. Our results suggest that improved comprehension and quantification of the physico-chemical properties in controlled release systems will enable the microstructure to be tailored to achieve desired responses that are insensitive to manufacturing variations.     

Design and study of rifampicin oral controlled release formulations

Oral controlled release formulations of rifampicin have been developed by using hydroxypropyl methylcellulose polymer at different ratios. From in vitro release data, we found that the release was extended with an increase of polymer proportion from 20% to 40%. However, increase in polymer beyond 40% resulted in no significant change in the release rate. There was a distinct difference in the release rate and release character due to variation in the compression force. The release kinetics were analyzed using Ritger and Peppas exponential equation. Stability studies at ambient storage conditions for 1 year showed that formulations were stable.     

Guar gum as platform for the oral controlled release of therapeutics

Introduction: The past decade of research has witnessed a huge advancement in research efforts on guar gum (GG)-based polymers as controlled release (CR) formulations for the delivery of therapeutics.

Areas covered: The unique structure and beneficial properties of GG makes it an attractive biomaterial in CR applications. Current status on GG-based polymers has been addressed as a CR formulation in the form of microspheres, nanoparticles, hydrogels and matrix tablets for the delivery of various types of therapeutics having a wide range of physicochemical properties. Majority of literature on GG as a platform technology has dealt with oral route of drug administration as it is the most convenient, patient-compliant and preferred approach. Recent reports on GG-based polymers are summarized and critically discussed to narrate their usefulness as oral delivery systems.

Expert opinion: The research on GG-based formulations has been focused on optimization of the therapy by designing CR dosage forms with a minimum number of excipients. In this context, GG-based polymers are quite attractive. The present review summarizes published reports on these systems and offers expert opinion relevant to oral delivery of therapeutics.     

Steady-state pharmacokinetics of controlled release oral morphine sulphate in healthy subjects

The pharmacokinetics of oral morphine sulphate as controlled release tablets ('MS-Contin') and solution were compared at steady-state. Plasma morphine concentrations were determined over 24 hours following the last dose of each drug when given in a randomised, crossover fashion to healthy subjects. Radioimmunoassay was used, which was sensitive yet provided good specificity relative to high-performance liquid chromatography. Controlled release tablets had 86% the bioavailability of the solution. Although each dose of controlled release tablets was double that of the solution, their peak plasma concentrations were the same. Time to maximum concentration was 3 times longer for controlled release tablets with an absorption half-life twice that of the solution. Elimination of both drugs was similar and biphasic with the minor terminal portion at 10 times the half-life of the major early process. These data explain the analgesic duration of 12 hours observed in clinical studies and the lack of accumulation with morphine compared with methadone.     

Physical chemical properties of oral drug candidates in the discovery and exploratory development settings

The advent of automated in vitro screening of hundreds of thousands of compounds has introduced biases into the drug discovery process that have significant implications for subsequent drug development. Screening biases that impact oral absorption adversely are discussed, and approaches are suggested for the prediction, assessment and communication of absorption-related physical chemical properties in drug discovery and exploratory development.     

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)     

Assessment of bioavailability of experimental controlled release microcapsules of nifedipine

Experimental controlled release nifedipine microcapsules composed of ethylcellulose and eudragit RL were explored for the assessment of bioavailability on rabbit. The pharmacokinetic parameters were compared between the formulations and with the pure drug material. A statistically significant difference between the formulations was noticed in the parameters, K, T1/2, AUC (0-->infinity), MRT and bioavailability but not in Vd, Cmax and Tmax and in each case a highly significant difference was observed with reference drug material. Controlled release absorption profiles in vivo were observed from the experimental microcapsules as revealed by the Wagner-Nelson method. The absorption lag time, absorption rate constant, and absorption half life were calculated by using the back projection method of residuals. A good correlation demonstrated between in vivo absorption and in vitro release data for both the products merits specific attention. There was no loss in bioavailability of the experimental ethylcellulose microcapsule (drug content 75.8%), even though nifedipine undergoes extensive first pass metabolism.     

Application of organogels as oral controlled release formulations of hydrophilic drugs

We previously demonstrated that organogels prepared from soybean oil using 12-hydroxy stearic acid as a gelator can slowly release ibuprofen, a model lipophilic drug. In this study, we investigated the applicability of organogels as controlled release formulations of hydrophilic drugs. The release rates of theophylline and ofloxacin, which are used as model hydrophilic drugs, were significantly slower than those of ibuprofen and antipyrine (model lipophilic drugs). Furthermore, no erosion was noted during drug release from organogels. Lipophilic drug molecules are released after diffusion in organogels because all molecules fully dissolve in the gel. On the other hand, hydrophilic drug molecules need to be dissolved before they diffuse in the organogel, prior to their release from the gel. Therefore, it is speculated that the release rates of hydrophilic drugs are slower than those of lipophilic drugs. To confirm the usefulness of organogels in controlled release formulations in vivo, organogels containing ibuprofen, ofloxacin, theophylline or antipyrine were intraduodenally administered to rats. All drugs used in this study were rapidly absorbed when administered in aqueous suspensions. In contrast, the drug concentrations in plasma after administration in organogels were lower; however, the lower concentrations of drugs sustained for 10h after administration. With organogel administration, the mean residence time of drugs was longer than that with aqueous suspension administration. In conclusion, organogels are potential candidates for controlled release formulations of not only lipophilic drugs, but also hydrophilic drugs.     

An oral controlled release matrix pellet formulation containing nanocrystalline ketoprofen

A controlled release pellet formulation using a NanoCrystal colloidal dispersion of ketoprofen was developed. In order to be able to process the aqueous NanoCrystal colloidal dispersion into a hydrophobic solid dosage form a spray drying procedure was used. The in vitro dissolution profiles of wax based pellets loaded with nanocrystalline ketoprofen are compared with the profiles of wax based pellets loaded with microcrystalline ketoprofen and of a commercial sustained release ketoprofen formulation. Pellets were produced using a melt pelletisation technique. All pellet formulations were composed of a mixture of microcrystalline wax and starch derivatives. The starch derivatives used were waxy maltodextrin and drum dried corn starch. Varying the concentration of drum dried corn starch increased the release rate of ketoprofen but the ketoprofen recovery remained problematic. To increase the dissolution yield surfactants were utilised. The surfactants were either added during the production process of the NanoCrystal colloidal dispersion (sodium laurylsulphate) or during the pellet manufacturing process (Cremophor RH 40). Both methods resulted in a sustained but complete release of nanocrystalline ketoprofen from the matrix pellet formulations.     

The effect of metoclopramide on the absorption of oral controlled release morphine.

The pharmacokinetics of oral controlled release morphine and metoclopramide were investigated in 20 patients in a double-blind, randomly allocated study. The concurrent administration of metoclopramide and oral controlled release morphine led to a faster onset and increased level of sedation compared with the administration of oral controlled release morphine alone. Whilst the increased sedation may be advantageous in anaesthetic practice, it may be a potential problem in patients starting longer term therapy with these drugs.     

Development of controlled release oral drug delivery system by membrane-coating method-I

In order to develop a controlled-release oral drug delivery system (DDS) which sustains the plasma acetaminophen (AAP) concentration for a certain period of time, microporous membrane-coated tablets were prepared and evaluatedin vitro. Firstly, highly water-soluble core tablets of AAP were prepared with various formulations by wet granulation and compression technique. Then the core tablets were coated with polyvinylchloride (PVC) in which micronized sucrose particles were dispersed. Effect of formula compositions of core tablets and coating suspensions on the pharmaceutical characteristics such as drug release kinetics and membrane stability of the coated tablets was investigatedin vitro. AAP was released from the coated tablets at a zero-order rate in a pH-independent manner. This independency of AAP release to pH change from 1.2 to 7.2 is favorable for the controlled oral drug delivery, since it will produce a constant drug release in the stomach and intestine regardless of the pH change in the GI tract. Drug release could be extended upto 10 h according to the coating condition. The release rate could be controlled by changing the formula compositions of the core tablets and coating suspensions, coat weight per each tablet, and especially PVC/sucrose ratio and particle size of the sucrose in the coating suspension. The coated tablets prepared in this study had a fairly good pharmaceutical characteristicsin vitro, however, overall evaluation of the coated tablets should awaitin vivo absorption study in man.     

口服缓控释制剂研究概况

本文综述了口服缓控释制剂研究概况。缓控释制剂有三种释药类型：定时、定速、定位释药。有多种剂型：包括骨架缓控释制剂、薄膜包衣缓控释制剂、渗透泵型缓控释制剂、胃内漂浮缓控释制剂、缓控释微丸、缓控释液体制剂等。口服缓控释释放系统的迅猛发展，为新药物的研制、老药新用途的开发提供了更为广阔的前景。     

Investigating the feasibility of temperature-controlled accelerated drug release testing for an intravaginal ring

The objective of the present study was to investigate if temperature can be utilized to accelerate drug release from Nuvaring®, a reservoir type intravaginal ring based on polyethylene vinyl acetate copolymer that releases a constant dose of contraceptive steroids over a duration of 3 weeks. The reciprocating holder apparatus (USP 7) was utilized to determine real-time and accelerated etonogestrel release from ring segments. It was demonstrated that drug release increased with increasing temperature which can be attributed to enhanced drug diffusion. An Arrhenius relationship of the zero-order release constants was established, indicating that temperature is a valid parameter to accelerate drug release from this dosage form and that the release mechanism is maintained under these accelerated test conditions. Accelerated release tests are particularly useful for routine quality control to assist during batch release of extended release formulations that typically release the active over several weeks, months or even years, since they can increase the product shelf life. The accelerated method should therefore be able to discriminate between formulations with different release characteristics that can result from normal manufacturing variance. In the case of Nuvaring®, it is well known that the process parameters during the extrusion process strongly influence the polymeric structure. These changes in the polymeric structure can affect the permeability which, in turn, is reflected in the release properties. Results from this study indicate that changes in the polymeric structure can lead to a different temperature dependence of the release rate, and as a consequence, the accelerated method can become less sensitive to detect changes in the release properties. When the accelerated method is utilized during batch release, it is therefore important to take this possible restriction into account and to evaluate the accelerated method with samples from non-conforming batches that are explicitly “out of specification” under real-time test conditions.