Microdialysis for evaluating the entrapment and release of a lipophilic drug from nanoparticles

The aim of the study was to evaluate the microdialysis (MD) as a tool to determine entrapment efficiency and drug release of a lipophilic drug model, diclofenac (DIC), from nanocapsules, nanospheres, and nanoemulsions. Factors that could interfere with the MD probe recovery were investigated: perfusion fluid composition, concentration and form of the drug in the perfusate, and recovery method. DIC entrapment efficiency to nanoparticles and the drug release in phosphate buffer pH 7.4 after different dilutions were evaluated by MD and ultrafiltration/centrifugation (UC). DIC recovery for the 5 μL/min flux was concentration and pH dependent. DIC sodium was used for the recoveries determination since it did not differ from the DIC acid recovery for the same media. DIC entrapment efficiency determined applying both techniques were equivalent and close to 100% for all nanoparticles. In pH 7.4 DIC release from the nanoparticles was partial for the dilution rate 1:1 (v/v), around 50–60%. A complete release was observed from 1:10 (v/v) dilution. Only nanocapsules presented a incomplete release for 1:5 (v/v) dilution, around 86%. MD and UC techniques were equivalent for the evaluation of DIC entrapment efficiency and drug release from the nanoparticles.     

Catanionic mixtures involving a drug: a rather general concept that can be utilized for prolonged drug release from gels

The aim of this work was to study at what extent mixtures of drug substances and oppositely charged surfactants form catanionic aggregates and to apply these as a means of obtaining prolonged drug release from a gel. The properties of traditional catanionic mixtures are relatively well known, but only recently we found that not only traditional surfactants form these mixtures, but also structurally more complex surface active drug compounds. In this study, several different compositions of catanionic mixtures were studied visually, by cryogenic transmission electron microscopy (cryo-TEM) and rheologically using a Bohlin VOR Rheometer. Some of the catanionic vesicle and micelle phases were incorporated in and released from gels using the USP paddle method. The drug compounds investigated were lidocaine, ibuprofen, naproxen, alprenolol, propranolol, and orphenadrine. Of the six drug molecules used in this study, five, both positively and negatively charged, were capable of forming catanionic vesicles and/or micelles with oppositely charged surfactants. The drug release studies show that catanionic drug surfactant mixtures are beneficial for obtaining prolonged release from gels, as the drug release using catanionic vesicles and micelles was prolonged between 10 and 100 times compared to the release of pure drug substance from the gel.     

Release characteristics of anionic drug compounds from liquid crystalline gels I: Passive release across non-rate-limiting membranes

Liquid crystalline gels (LCG) offer the formulator dynamic and flexible vehicles, into which actives, enhancers and other adjuvants with a wide range of physicochemical properties can be incorporated. This is achievable because of the biphasic oil/water composition of the gel. In this paper, the suitability of an isotropic liquid crystalline gel is investigated for a range of anionic drug molecules, with particular emphasis on sodium diclofenac. Parameters, which have been investigated, include the mode of vehicle preparation, the effect of the concentration of the drug and how buffering the gel and/or the receptor medium affect the release profiles. Such profiles have been measured for the sodium salts of benzoate, salicylate and indomethacin. The passive release from the standard system was found to adhere to matrix-controlled diffusion. An increase in concentration leads to a non-linear increase in the cumulative release of sodium diclofenac from the gels. In direct contrast to the result reported for cationic salbutamol base, optimum release from the gel was achieved when neither the receptor medium nor the aqueous phase of the gel was buffered. The percentages released of the sodium salts of benzoate, salicylate and indomethacin, after 24 h, were determined to be 25, 26 and 19%, respectively, and these are significantly greater than the release of sodium diclofenac. This suggests that diclofenac undergoes ion-pairing or complexation within the gel, which inhibits its diffusion from the vehicle. Future papers will report on the incorporation of enhancers and the effects of iontophoresis on the release profiles of drugs from these gels, and ultimately on the transdermal transport of drugs from these vehicles across human and porcine skin.     

Controlled drug release from polymeric delivery devices V: Hydroxy group effects on drug release kinetics and thermodynamics.

The effects of progesterone hydroxylation on silicone matrix drug release kinetics and thermodynamics were investigated. Hydroxylation at positions 11, 17, and/or 21 substantially reduced progesterone release. The magnitude of this reduction depended on the number and position of the hydroxy groups and could be attributed to decreased polymer matrix diffusivity (Dm) and polymer solubility (Cp). Thermodynamically, hydroxy group addition to positions 11 and/or 21 reduced the activation energy for matrix diffusion (Ed,m) but increased the solvation energy for dissolution in silicone polymer (delta HT,m)). Adding an hydroxy group to position 17 increased the Ed,m but decreased the delta HT,m. The overall (Ed,m) + delta H(T,m)) values were relatively constant and independent of hydroxylation.     

Controlled drug release from pellets containing water-insoluble drugs dissolved in a self-emulsifying system.

The aim of the study was to provide a controlled release system, which could be used for the oral administration of highly water-insoluble drugs. Pellets have been prepared by extrusion/spheronization containing two model drugs (methyl and propyl parabens) of low water solubility. One type of pellets contained the drugs mixed with lactose and microcrystalline cellulose (MCC) and the other types of pellets contained the model drugs dissolved in a self-emulsifying system (4.8%) consisting of equal parts of mono-diglycerides and polysorbate 80 and MCC. Pellets of all types in the same size fraction (1.4-2.0 mm) were coated to different levels of weight gain, with ethylcellulose, talc and glycerol. A sample of pellets containing methyl parabens in the self-emulsifying system was pre-coated with a film of hydroxypropylmethyl cellulose from an aqueous solution and then coated as above. Dissolution experiments established that the presence of the self-emulsifying system enhanced the drug release of both model drugs and that the film coating considerably reduced the drug release from pellets made with just water, lactose and MCC. The coating reduced the drug release from the pellets containing the self-emulsifying system to a lesser extent but in relation to the quantity of coat applied to the pellets. The application of a sub-coating of hydroxypropylmethyl cellulose was able to reduce the release rate of methyl parabens self-emulsifying system ethyl cellulose coated pellets. Thus, the formulation approach offers the possibility of formulating and controlling the in vitro release of water-insoluble drugs from solid oral dosage forms.     

Effect of curing conditions and plasticizer level on the release of highly lipophilic drug from coated multiparticulate drug delivery system

The study aimed to investigate the effect of triethyl citrate (TEC) plasticizer level (10, 15, and 20%), curing temperature (40, 50, and 60 degrees C) and time (0 to 168 h) on the release of a highly lipophilic drug bumetanide from pellets coated with methacrylate ester copolymer (Eudragit RS). Bumetanide was layered onto sugar pellets followed by coating with 6% Eudragit RS with and without hydroxypropyl methyl cellulose (HPMC) seal coat using Wurster Fluid Bed equipment. Coated pellets were stored for 3 months at room temperature and the release was tested in USP purified water. At 10% TEC level, increasing curing time and temperature lead to slower drug release. At 15 and 20% TEC levels, curing initially decreased drug release followed by increase in the release at longer curing time and higher temperature. Drug release from coated pellets plasticized with 15% TEC and completely cured followed zero order kinetic models. At plasticizer level of 20%, bumetanide release from the completely cured pellets was better modeled using the Higuchi's equation reflecting possible drug migration during curing. Storage led to an increase in drug release. The use of HPMC seal coat stabilized drug release after storage. It was concluded that bumetanide migration into Eudragit RS film coat was the main cause of the accelerated release after curing and storage. The drug migration during storage at room temperature was prevented by seal coating the pellets with HPMC.     

Controlled loading and release of a model drug from polypeptide multilayer nanofilms

A major concern of medicine today is the sustained release of therapeutic compounds. Delivery vehicles for such compounds must be biocompatible. Ideally, loading a drug into the delivery vehicle will be a simple process, and vehicle properties will allow control over the drug release profile under desired conditions. Here, polypeptide multilayer nanofilms have been prepared by electrostatic layer-by-layer self-assembly to study the post-fabrication loading and release of a model therapeutic, methylene blue (MB). Drug loading and release have been characterized by optical spectroscopy for different peptide designs at different pH values, and film surface morphology has been characterized by atomic force microscopy (AFM). Differences in peptide structure have been found to influence MB loading and release under otherwise fixed conditions. Release is also influenced by pH, salt concentration, and number of "capping" layers. Although more research will be needed to exhaust the potential of polypeptide multilayer films, present results would suggest that the technology holds considerable promise for applications in medicine.     

A novel approach for the control of drug release rate through hydrogel membrane: I. Effect of drug immobilization on drug release rate by copolymerization method.

Precise control of drug release rate in hydrogel drug delivery systems to better mimic physiological condition is a challenging research topic in development of Advanced Drug Delivery Systems. One of the major issues with bioresponsive drug delivery systems is the excessive 'leakage' of drug while the system is in the 'off' state, which leads to shortening of the device life-time and potential overdose problem for the patient. In the present study, a new approach, based on partition effects, termed drug immobilization via copolymerization, is proposed to control the drug release rate of membrane-based drug delivery systems. In this method, a certain level of drug is pre-immobilized in the membrane through copolymerization. The immobilized drug contributes to the overall chemical potential of drug molecules in the membrane but their mobility is restricted, hence will not be released. At equilibrium, the amount of drug from donor that dissolved in the membrane is reduced due to contribution of immobilized drug, resulting in an effective reduction in partition coefficient and hence the release rate. The testing of the method by bovine serum albumin (BSA) as a model drug confirmed the controllability of the method: almost 35% reduction of the drug leakage in the 'off-state' was observed when 20mg BSA was immobilized in the pH-sensitive hydrogel membrane. The mathematical model of the drug partition in the membrane was modified to describe the new partition phenomenon (mobile drug and immobilized drug in the membrane) in this study.     

Controlled drug release from polymeric delivery devices. III: In vitro-in vivo correlation for intravaginal release of ethynodiol diacetate from silicone devices in rabbits.

Forty female rabbits were implanted with silicone vaginal devices containing ethynodiol diacetate for up to 8 weeks. As predicted from in vitro studies, a Q - t1/2 (matrix-controlled) release profile was observed in vivo. The in vivo drug release profile was compared with in vitro data measured at three hydrodynamic conditions, and the diffusional resistance across the vaginal wall was estimated. Drug released from silicone devices yielded a prolonged plasma level when compared with data following intravaginal or intravenous administration of a solution dose. The rate constant for elimination was unchanged. The plasma concentration of the drug was related to the intravaginal drug release profile both theoretically and experimentally and was above the concentration required to inhibit fertilization.     

Effect of formulation parameters and drug–polymer interactions on drug release from starch acetate matrix tablets

The aim of this study was to determine, whether interactions between a drug and hydrophobic polymer matrix are present, and if so, how they affect the drug release. In addition, the most important formulation parameters, for example porosity or structure of the tablet, which have the greatest impact on drug release, were defined. Six different drug compounds, that is allopurinol, acyclovir, metronidazole, paracetamol, salicylamide and theophylline, were used in different formulations with hydrophobic starch acetate (DS 2.7) as a matrix forming polymer. Results indicate that the formulation parameters describing directly or indirectly the structure of the matrix, such as porosity, compaction force and the particle size fraction of the filler-binder, have the strongest impact on drug release. The contribution of drug property based variables is not as high as formulation parameters, but they cannot be overlooked. The contribution of water solubility and dissolution rate of the compound are obvious, but there are other significant parameters, which describe the hydrophobic and hydrophilic regions of the molecule, that also affect the drug release. This can be seen especially with the salicylamide: compound which appears to have a strong and sufficiently high hydrophobic region that interacts with starch acetate and impairs the drug release. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3676–3690, 2009     

Controlled drug release from polymeric delivery devices IV: in vitro--in vivo correlation of subcutaneous release of norgestomet from hydrophilic implants.

The in vitro and in vivo releases of norgestomet from hydrophilic implants were found to follow a matrix-controlled (Q - t1/2) process. The sorption of drug onto the implants was observed to obey the same mechanism but with a much smaller magnitide of the Q/t1/2 value. The effect of the extent of cross-linking on the magnitude of drug release (Q/t1/2) profiles was analyzed both theoretically and experimentally. The release of norgestomet from hydrophilic implants was found to be an energy-linked process. Two energy terms were calculated; the activation energy for matrix diffusion was 7.71 kcal/mole, and the heat of drug crystal solvation was 25-28.6 kcal/mole.     

Matrix type controlled release systems: I. Effect of percolation on drug dissolution kinetics.

Matrix type controlled release tablets were prepared by compression of binary mixtures of a soluble brittle model drug (caffeine) and a plastic matrix substance (ethyl cellulose). The drug content of the tablets was varied from 10% to 100% (weight/weight) and the drug dissolution from one flat side of the tablets was studied. By means of percolation theory the release kinetics could be explained over the whole range of drug loadings. For low drug concentrations up to the lower percolation threshold the release was incomplete because most of the drug was encapsulated by the matrix substance. For drug loadings between the lower and the upper percolation threshold the release was matrix-controlled. For high drug loadings a change to zero order dissolution kinetics was observed. Close to the percolation threshold the diffusion coefficient obeys a scaling law, from which a simple equation to estimate the value of the lower percolation threshold was derived and applied to the measured dissolution data. The critical porosity (lower percolation threshold) was found to be 0.35, corresponding to a drug content of about 28% (weight/weight).     

Calcium alginate microparticles for oral administration: I: Effect of sodium alginate type on drug release and drug entrapment efficiency.

The natural polymers alginate and chitosan were used for the preparation of controlled release nicardipine HCl gel microparticles. The effect of the mannuronic/guluronic acid content and the alginate viscosity on the prolonged action of the microparticles, which were prepared with different types of alginates, were investigated. The mean particle sizes and the swelling ratios of the microparticles were also determined. The in vitro release studies were carried out with a flow-through cell apparatus in different media (pH 1.2, 2.5, 4.5, 7 and 7.5 buffer solutions). The release of nicardipine was extended with the alginate gel microparticles prepared with guluronic acid rich alginate. After the determination of the most appropriate alginate type, the effect of alginate-chitosan complex formation was studied on the release pattern of drug incorporated. It was observed that the alginate-chitosan complex formation reduced the erosion of the alginate-chitosan matrix at pH 7-7.5. The release of drug from the chitosan-alginate gel microparticles took place by both diffusion through the swollen matrix and relaxation of the polymer at pH 1.2-4.5.     

Review article: mechanisms of drug release from tablets and capsules. I: Disintegration

Variable drug release from solid oral dosage forms has been an important cause of bioavailability problems in the past, and is a factor now carefully controlled in pharmaceutical products. In two reviews, we describe briefly the composition and manufacture of tablets and capsules, and the two main processes by which they release drugs; disintegration and dissolution. We will explain what is presently understood of the actual mechanisms of drug release and the physico-chemical factors that affect the release process. The strategies adopted by pharmaceutical scientists in designing modern oral solid dose forms to release drugs at reproducible and therapeutically optimal rates will be discussed. Finally, the role of gamma scintigraphy in assessing dosage form performance in vivo will be described.     

Investigation of drug release from suspension using FTIR-ATR technique: part I. Determination of effective diffusion coefficient of drugs

Fourier transform infrared attenuated total reflectance (FTIR-ATR) spectroscopy was used to study directly the release of drug particles (ketoconazole) in a liquid medium (paraffinum liquidum). In the case of the release experiment, the formulation is placed on the ATR crystal and the acceptor membrane on the top of the ointment. The decrease of the drug content in the sediment near the interface ATR crystal-formulation in the course of the release process was quantified by monitoring the changes of the IR spectrum in relevant spectral ranges using multivariate analysis. A mathematical model based on Fick's second law with appropriate initial and boundary conditions was applied in order to determine the diffusion coefficient of the drug in the liquid medium. Knowing this value, it is possible to calculate the effective diffusion coefficient of the drug in heterogeneous semisolid formulation (Vaseline) as a function of the volume fraction of the solid phase.     

Controlled release of tramadol hydrochloride from matrices prepared using glyceryl behenate.

An inert matrix to control the release of tramadol HCl was prepared using glyceryl behenate as a matrix-forming agent. The matrices were prepared by either direct compression of a physical mixture of the drug and the matrix-forming agent or by compression of granules prepared by hot fusion of the drug and the matrix-forming agent. The hot fusion method was found to be more effective than compression of physical mixtures in retarding the release of the drug from the matrix. Drug release was adjusted by using release enhancers, such as microcrystalline cellulose and lactose, and the results showed that higher release rates were obtained using lactose. However, the release of the drug was independent of the compression force and the pH of the dissolution medium. This study showed that glyceryl behenate is an appropriate waxy material that can be used as a matrix-forming agent to control the release of a water-soluble drug such as tramadol HCl.