Enhancement of griseofulvin release from liquisolid compacts

The potential of hydrophilic aerogel formulations and liquisolid systems to improve the release of poorly soluble drugs was investigated using griseofulvin as model drug. The in vitro release rates of this drug formulated as directly compressed tablets containing crystalline griseofulvin were compared to aerogel tablets with the drug adsorbed onto hydrophilic silica aerogel and to liquisolid compacts containing the drug dissolved or suspended in PEG 300. Furthermore, the commonly used carrier and coating materials in liquisolid systems Avicel® and Aerosil® were replaced by Neusilin®, an amorphous magnesium aluminometasilicate with an extremely high specific surface area of 339 m²/g to improve the liquisolid approach.Both the liquisolid compacts containing the drug dissolved in PEG 300 and the aerogel tablets showed a considerably faster drug release than the directly compressed tablets. With liquisolid compacts containing the drug suspended in PEG 300, the release rate increased with rising fraction of dissolved drug in the liquid portion. It could be shown that Neusilin® with its sevenfold higher liquid adsorption capacity than the commonly used Avicel® and Aerosil® allows the production of liquisolid formulations with lower tablet weights.     

Hydrophilic silica aerogels as dermal drug delivery systems - Dithranol as a model drug.

A special class of porous silica materials, silica aerogels, was recently shown to be a potential candidate for oral drug delivery systems. It was demonstrated, that stability of drugs and their dissolution rate can essentially be improved through the adsorption on to these materials. In this work, drug loaded silica aerogels are firstly applied as dermal drug delivery systems. Dithranol is used as a representative drug since there is a need to enhance its dermal availability. The unstable and nearly water-insoluble drug exhibits a poor penetration. Release of dithranol from aerogels into various semi-solid formulations and its dissolution as well as the release and penetration into artificial membranes were investigated by Fourier-transform infrared attenuated total reflection (FTIR-ATR) spectroscopy. Two model membranes (one hydrophilic and one lipophilic) were applied. Several formulations were tested and the most promising one was used in order to study the penetration of dithranol into human stratum corneum (SC). Dithranol adsorbed on hydrophilic silica aerogels exhibited superior penetration behaviour compared to that of the standard ointment (dithranol in white soft paraffin).     

Enhancement of the dissolution rate and oral absorption of a poorly water soluble drug by formation of surfactant-containing microparticles

The slow dissolution rate exhibited by poorly water-soluble drugs is a major challenge in the drug development process. Following oral administration, drugs with slow dissolution rates generally show erratic and incomplete absorption which may lead to therapeutic failure. The aim of this study was to improve the dissolution rate and subsequently the oral absorption and bioavailability of a model poorly water-soluble drug. Microparticles containing the model drug (griseofulvin) were produced by spray drying the drug in the absence/presence of a hydrophilic surfactant. Poloxamer 407 was chosen as the hydrophilic surfactant to improve the particle wetting and hence the dissolution rate. The spray dried particles were characterized and in vitro dissolution studies and in vivo absorption studies were carried out. The results obtained showed that the dissolution rate and absolute oral bioavailability of the spray dried griseofulvin/Poloxamer 407 particles were significantly increased compared to the control. Although spray drying griseofulvin alone increased the drug's in vitro dissolution rate, no significant improvement was seen in the absolute oral bioavailability when compared to the control. Therefore, it is believed that the better wetting characteristics conferred by the hydrophilic surfactant was responsible for the enhanced dissolution rate and absolute oral bioavailability of the model drug.     

Design of Alginate-Based Aerogel for Nonsteroidal Anti-Inflammatory Drugs Controlled Delivery Systems Using Prilling and Supercritical-Assisted Drying

In this study, a novel preparation method for alginate‐based aerogels charged with nonsteroidal anti‐inflammatory drugs (NSAIDs) was developed using prilling in combination with supercritical fluid technique. Nanoporous carriers were prepared by laminar jet breakup of drug/alginate solutions or suspensions followed by cross‐linking in ethanol or aqueous CaCl₂ solutions, water replacement, and supercritical‐CO₂‐assisted drying. A substantial drug loss was observed for highly soluble ketoprofen lysinate, whereas encapsulation efficiency was satisfying for slightly soluble ketoprofen. The tandem technique successfully produced almost spherical aerogels (sphericity coefficient 0.97–0.99) in narrow size distribution with reduced particle shrinkage and smooth surface (surface roughness 1.10–1.13); the internal porous texture of the parent hydrogels was preserved and appeared as a network of nanopores with diameters around 200 nm. Drug release profiles were monitored using a pH change method to evaluate the possible application of the aerogels as fast dissolving NSAIDs formulation. Aqueous cross‐linking led to aerogels encapsulating ketoprofen in the amorphous form and with an enhanced burst effect in simulated gastric fluid (75% in 30 min), whereas ethanol cross‐linking produced aerogels embedding drug in crystal clusters with slower dissolution rate. The system appears an interesting potential carrier for the fast delivery of slightly soluble drugs in the upper gastrointestinal tract.     

Fast-dissolving microparticles fail to show improved oral bioavailability

Oral dosage forms are the preferred means of delivering drugs for systemic absorption. However, development problems occur for drugs with poor water solubility and/or gastrointestinal permeability. It is generally believed that the in-vivo bioavailability of poorly water-soluble drugs from Class II of the Biopharmaceutics Classification System can be improved by increasing the dissolution rate. We have attempted to increase the in-vivo oral bioavailability of a model Class II drug (griseofulvin) by preparing rapidly-dissolving particles. The solvent-diffusion method was used to prepare particles with hydrophilic surfactants (Brij 76/Tween 80 surfactant blend) and in-vivo studies were conducted in rats. The griseofulvin particles produced were bipyramidal in habit with a particle size of 2.18 +/- 0.12 microm; they contained crystalline drug and a relatively large proportion (12% w/w) of hydrophilic surfactant. The latter and the small particle size ensured rapid particle dispersion and dissolution in-vitro. Thus, within 30 min of the in-vitro dissolution test, the bipyramidal particles had released approximately 70% of drug compared with approximately 10% from the starting material (particle size 12.61 +/- 1.11 microm). However, the rapid and increased drug dissolution in-vitro was not translated to rapid and enhanced absorption in-vivo, and the oral bioavailability of the model drug was found to be the same from the control and from the bipyramidal particles. The poor in-vivo performance of the bipyramidal particles showed that although the dissolution rate of a Class II drug is thought to be a good indicator of its in-vivo bioavailability, this is not always the case.     

Development of biodegradable porous starch foam for improving oral delivery of poorly water soluble drugs

A biodegradable porous starch foam (BPSF) was developed for the first time as a carrier in order to improve the dissolution and enhance the oral bioavailability of lovastatin - defined as a model poorly water soluble BCS type II drug. In this paper, BPSF was prepared by the solvent exchange method and characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis in order to perform the morphological and structural characterization of BPSF. Lovastatin was loaded by immersion/solvent evaporation into the BPSF which provided a stable hydrophilic matrix with a nano-porous structure. The solid state properties of the loaded BPSF samples were characterized by SEM, Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). In vitro and in vivo drug release studies showed that when BPSF was used as a carrier it allowed immediate release of lovastatin and enhanced the dissolution rate in comparison with crystalline lovastatin and commercial capsules. These results provide important information about the mechanism of drug adsorption and release from BPSF as a carrier. Accordingly, BPSF has a promising future as a device for the oral delivery of poorly water soluble drugs.     

Effect of Hydrophilic Diluents on the Release Profile of Griseofulvin from Tablet Formulations

Studies have shown that when compressing drugs with low aqueous solubility, the solubility of diluents selected is very crucial as it influences the disintegration, dissolution and bioavailability of such drugs. Based on these reports, the present study was undertaken to investigate the effect of some commonly used hydrophilic tablet diluents (lactose, sucrose, mannitol and dextrose) on the in vitro release properties of griseofulvin from compressed tablets. Griseofulvin granules and tablets were prepared using the wet granulation method. Tablet properties evaluated as a function of the diluents used include, hardness, friability, dissolution profile and dissolution efficiency at 60 min. Results obtained indicated variability in griseofulvin release in the presence of the diluents. The relative enhanced dissolution effects of the four hydrophilic diluents is in the order of dextrose>sucrose>lactose>mannitol. All the griseofulvin tablet batches produced exhibited a better drug release (in terms of rate and extent of release) than a commercially available tablet sample of griseofulvin (Fulcin^®). The results of the dissolution efficiency (DE_60min) are 91.7, 83.5, 48.7, 35.3 and 15.6% for dextrose, sucrose, lactose, mannitol and fulcin^®, respectively. The overall results indicated that dextrose or sucrose can be utilised to improve the in vitro release profile and hence in vivo bioavailability of griseofulvin from compressed tablets.     

Improvement of the dissolution rate of poorly soluble drugs by solid crystal suspensions

We present a novel extrusion based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin and spironolactone) is significantly accelerated. The drug and highly soluble mannitol are coprocessed in a hot melt extrusion operation. The obtained product is an intimate mixture of the crystalline drug and crystalline excipient, with up to 50% (w/w) drug load. The in vitro drug release from the obtained solid crystalline suspensions is over 2 orders of magnitude faster than that of the pure drug. Since the resulting product is crystalline, the accelerated dissolution rate does not bear the physical stability concerns inherent to amorphous formulations. This approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug. Being thermodynamically stable, the dissolution profile and the solid state properties of the product are maintained after storage at 40 °C, 75% RH for at least 90 days.     

Application of simulated intestinal fluid on the phospholipid vesicle-based drug permeation assay

The compatibility of fasted state simulated intestinal fluid (FaSSIF) in drug permeation studies employing the phospholipid vesicle-based permeation assay (PVPA) model was confirmed by a set of different integrity indicators. Neither calcein permeability nor electrical resistance were found significantly changed indicating unaffected barrier tightness. Furthermore, the release of phospholipid from the barriers in contact with FaSSIF was negligible, although sodium taurocholate disappeared from the donor - possibly due to transfer into the barrier. Visual examination of the barrier structure by confocal laser scanning microscopy (CLSM) revealed no changes. The model drugs, cimetidine, nadolol, ketoprofen and griseofulvin showed either slightly enhanced or unchanged permeability values in the presence of FaSSIF. This may be attributed to micellar encapsulation and/or slight changes in barrier characteristics. Particularly for poorly soluble drugs, FaSSIF appeared favourable in terms of markedly improved recovery. Moreover, utilisation of BSA in the receiver compartment seems to augment this beneficial effect on recovery rate. It is likely that this experimental set-up affords better sink conditions in the receiver phase, which results in higher fluxes. Overall, a combination of FaSSIF in the donor phase and BSA in the receiver phase facilitates improved experimental output.     

Nanoparticle layers controlling drug release from emulsions.

The influence of interfacial layers of silica nanoparticles on the release kinetics of a model lipophilic drug (di-butyl-phthalate (DBP)) from polydimethylsiloxane droplets in water is reported. The nanoparticle layers are formed by self-assembly from solution and their structure is controlled by nanoparticle hydrophobicity and the solution conditions. For DBP loading levels resulting in released concentrations below the solubility limit, release is rapid from uncoated droplets whereas significant sustained release is facilitated by rigid interfacial layers of hydrophobic silica nanoparticles. Activation energies for release are in the range 580-630kJmol(-1), which is ten times greater than for barriers introduced by typical polymeric stabilisers. In contrast, at higher DBP loading levels (total concentration greater than the solubility level), both hydrophilic and hydrophobic nanoparticle layers increase the rate and extent of dissolution compared with uncoated droplets and pure DBP solutions. Nanoparticle layers are shown to significantly influence the release kinetics of lipophilic drugs from oil in water emulsions: either sustained or enhanced release properties can be introduced depending on the nanoparticle layer type and drug loading level. Thus, nanoparticle layers may be engineered to facilitate a range of release behaviours and offer great potential in the delivery of poorly soluble drugs.     

Effect of low-molecular-weight beta-cyclodextrin polymer on release of drugs from mucoadhesive buccal film dosage forms

We investigated the effect of low-molecular-weight beta-cyclodextrin (beta-CyD) polymer on in vitro release of two drugs with different lipophilicities (i.e., lidocaine and ketoprofen) from mucoadhesive buccal film dosage forms. When beta-CyD polymer was added to hydroxypropylcellulose (HPC) or polyvinylalcohol (PVA) film dosage forms, the release of lidocaine into artificial saliva (pH 5.7) was reduced by 40% of the control. In contrast, the release of ketoprofen from the polymer film was enhanced by addition of beta-CyD polymer to the vehicle. When lidocaine and ketoprofen was incubated with beta-CyD polymer in the artificial saliva, concentration of free lidocaine molecules decreased in a beta-CyD polymer concentration-dependent manner. The association constant with beta-CyD polymer was 6.9+/-0.6 and 520+/-90 M(-1) for lidocaine and ketoprofen, respectively. Retarded release of the hydrophilic lidocaine by beta-CyD polymer might be due to the decrease in thermodynamic activity by inclusion complex formation, whereas enhanced release of the lipophilic ketoprofen by the beta-CyD polymer might be due to prevention of recrystallization occurring after contacting the film with aqueous solution. Thus, effects of low-molecular-weight beta-CyD polymer to the drug release rate from film dosage forms would vary according to the strength of interaction with and the solubility of active ingredient.     

Development of poly(glycerol adipate) nanoparticles loaded with non-steroidal anti-inflammatory drugs

The aim of this study was to assess acylated and non-acylated poly(glycerol adipate) polymers (PGA) as suitable nanoparticulate systems for encapsulation and release of ibuprofen, ibuprofen sodium salt (IBU-Na) and ketoprofen as model drugs. Drug encapsulated nanoparticles were prepared using the interfacial deposition method in the absence of surfactants. Physicochemical characterisation studies of the produced loaded nanoparticles showed that drug-polymer interactions depend on the characteristics of the actual active substance. IBU-Na showed strong interactions with the polymers and it was found to be molecularly dispersed within the polymer matrix while ibuprofen and ketoprofen retained their crystalline state. The drug release profiles showed stepwise patterns which involve an initial burst release effect, diffusion of the drug from the polymer matrix and eventually drug release possibly via a combined mechanism. PGA polymers can be effectively used as drug delivery carriers for various active substances.     

Amorphization and modified release of ibuprofen by post-synthetic and solvent-free loading into tailored silica aerogels

Promising active pharmaceutical ingredients (APIs) often exhibit poor aqueous solubility and thus a low bioavailability that substantially limits their pharmaceutical application. Hence, efficient formulations are required for an effective translation into highly efficient drug products. One strategy is the preservation of an amorphous state of the API within a carrier matrix, which leads to enhanced dissolution. In this work, mesoporous silica aerogels (SA) were utilized as a carrier matrix for the amorphization of the poorly water-soluble model drug ibuprofen. Loading of tailored SA was performed post-synthetically and solvent-free, either by co-milling or via the melting method. Thorough analyses of these processes demonstrated the influence of macrostructural changes during the drying and grinding process on the microstructural properties of the SA. Furthermore, interfacial SA-drug interaction properties were selectively tuned by attaching terminal hydrophilic amino- or hydrophobic methyl groups to the surface of the gel. We demonstrate that not only the chemical surface properties of the SA, but also formulation-related parameters, such as the carrier-to-drug ratio, as well as process-related parameters, such as the drug loading method, decisively influence the ibuprofen adsorption efficiency. In addition, the drug-loaded SA formulations exhibited a remarkable physical stability over a period of 6 months. Furthermore, the release behavior is shown to change considerably with different surface properties of the SA matrix. Hence, the reported results demonstrate that utilizing specifically processed and modified SA offers a compelling technique for enhancement of the bioavailability of poorly-water soluble APIs and a versatile adjustment of their release profile.     

Development of poly(glycerol adipate) nanoparticles loaded with non-steroidal anti-inflammatory drugs

The aim of this study was to assess acylated and non-acylated poly(glycerol adipate) polymers (PGA) as suitable nanoparticulate systems for encapsulation and release of ibuprofen, ibuprofen sodium salt (IBU-Na) and ketoprofen as model drugs. Drug encapsulated nanoparticles were prepared using the interfacial deposition method in the absence of surfactants. Physicochemical characterisation studies of the produced loaded nanoparticles showed that drug–polymer interactions depend on the characteristics of the actual active substance. IBU-Na showed strong interactions with the polymers and it was found to be molecularly dispersed within the polymer matrix while ibuprofen and ketoprofen retained their crystalline state. The drug release profiles showed stepwise patterns which involve an initial burst release effect, diffusion of the drug from the polymer matrix and eventually drug release possibly via a combined mechanism. PGA polymers can be effectively used as drug delivery carriers for various active substances.     

Effect of the melt granulation technique on the dissolution characteristics of griseofulvin

This work describes a melt granulation technique to improve the dissolution characteristics of a poorly water-soluble drug, griseofulvin. Melt granulation technique is a process by which pharmaceutical powders are efficiently agglomerated by a meltable binder. The advantage of this technique compared to a conventional granulation is that no water or organic solvents is needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation. Granules were prepared in a lab scale high shear mixer, using a jacket temperature of 60 degrees C and an impeller speed of approximately 20,000 rpm. The effect of drug loading (2.5/5%), binder (PEG 3350/Gelucire 44/14), filler (starch/lactose), and HPMC on the dissolution of griseofulvin was investigated using a half two level-four factor factorial design. The granules were characterized using powder XRD, DSC and SEM techniques. A significant enhancement in the in vitro dissolution profiles of the granules was observed compared to the pure drug and drug excipient physical mixtures. The factorial design results indicated that higher drug loading and the presence of HPMC reduced the extent of dissolution of the drug, whereas, the presence of starch enhanced the dissolution rate. XRD data confirmed crystalline drug in formulation matrices. DSC results indicated monotectic mixtures of griseofulvin with PEG in the granulated formulations. In conclusion, the results of this work suggest that melt granulation is a useful technique to enhance the dissolution rate of poorly water-soluble drugs, such as, griseofulvin.     

Ketoprofen sustained-release suppositories containing hydroxypropylmethylcellulose phthalate in polyethylene glycol bases

In this study, conventional and sustained-release suppositories of ketoprofen (KP) were prepared and the effects of suppository bases and the inert matrix material (hydroxypropylmethylcellulose phthalate, HP 55) on in vitro release of ketoprofen suppositories were investigated. Suppositories containing 100 mg ketoprofen were prepared by the fusion method. Witepsol H15, Massa Estarinum B, and polyethylene glycols (PEG) were used as examples of hydrophobic and hydrophilic bases, respectively. Sustained-release suppositories of KP were prepared by using HP 55. Weight variation, content uniformity, breaking (hardness) and melting range tests were then conducted on these formulations. In vitro release and diffusion rate tests were also carried out according to the USP XXII basket method and the Muranishi method, respectively. The results show that the rate of release of KP is very slow for Witepsol H15 and Massa Estarinum B bases. However, KP was released very rapidly from the PEG bases in the conventional suppositories. On the other hand, HP 55 might be useful as a vehicle for sustained release preparations of ketoprofen in suppository form. It was shown from the kinetic assessment of release data that the best fit was achieved with zero-order kinetics.     

Adsorption of ketoprofen and bumadizone calcium on aluminium-containing antacids and its effect on ketoprofen bioavailability in man

The present study reports the adsorption of ketoprofen and bumadizone calcium, two non-steroidal anti-inflammatory drugs, on three aluminium-containing antacids. The type of aluminium antacid, the initial drug concentration and the pH of the medium were found to influence drug adsorption. At pH 3–4, binding of both drugs to aluminium hydroxide and dihydroxyaluminium sodium carbonate indicated co-operative adsorption, while adsorption profiles of bumadizone calcium on aluminium glycinate suggested a constant partitioning pattern. pH (1–8) adsorption profiles for ketoprofen and bumadizone calcium binding to aluminium hydroxide and dihydroxyaluminium sodium carbonate passed through a maximum in the pH range 3.5–4.5. Antacid dissolution during the adsorption runs was also investigated at different pH values. The effect of coadministration of ketoprofen and aluminium hydroxide on the bioavailability of ketoprofen was investigated in healthy volunteers. Urine was collected for 24 h following drug administration and samples were analyzed by HPLC for ketoprofen and its conjugates. The urinary excretion data indicated a decrease in drug bioavailability upon coadministration with aluminium hydroxide.     

Formation of physically stable amorphous drugs by milling with Neusilin

Each of four drugs (ketoprofen, indomethacin, naproxen, and progesterone) was milled with Neusilin (amorphous magnesium aluminosilicate) to effect conversion from crystalline to amorphous states, and the physical stability of the resultant drugs was investigated. Ball milling the drugs alone for 48 h resulted in no amorphization. X-ray powder diffractometry (XPD), birefringence, and differential scanning calorimetry (DSC) data indicated amorphization of all the four drugs on ball milling with Neusilin. Fourier transform infrared spectroscopy (FTIR) data showed a reduction in the absorbance of the free and the hydrogen-bonded acid carbonyl peaks accompanied by a corresponding increase in the absorbance of the carboxylate peak, indicating an acid-base reaction between the carboxylic acid-containing drugs and Neusilin on milling. On storage of milled powders (at 40 degrees C and 75% RH for 4 weeks), XPD, birefringence, and DSC data showed the absence of reversion to the crystalline state, and FTIR data revealed continued absence of the carbonyl peaks. Whereas the carboxylic acid-containing drugs convert from their crystalline acid form to amorphous salt form on milling with Neusilin, progesterone seems to interact with Neusilin via hydrogen bonding. The amorphous Neusilin-bound states of all four drugs were physically stable during storage. The water of adsorption seems to mediate the conversion of the crystalline state to an amorphous Neusilin-bound state.     

Solubilisation capacity of Brij surfactants

The aim of this study was to investigate the potential of selected Brij non-ionic surfactants for enhancing the solubility of poorly water-soluble drugs. Griseofulvin was selected as a model drug candidate enabling comparisons to be made with the solubilisation capacities of other poly(ethylene oxide)-based copolymers. UV/Vis and (1)H NMR spectroscopies were used to quantify the enhancement of solubility of griseofulvin in 1wt% aqueous micellar solutions of Brij 78 (C(18)H(37)E(20)), Brij 98 (C(18)H(35)E(20)) and Brij 700 (C(18)H(37)E(100)) (where E represents the OCH(2)CH(2) unit of the poly(ethylene oxide) chain) at 25, 37 and 40°C. Solubilisation capacities (S(cp) expressed as mg griseofulvin per g Brij) were similar for Brij 78 and 98 (range 6-11mgg(-1)) but lower for Brij 700 (3-4mgg(-1)) as would be expected for the surfactant with the higher ethylene oxide content. The drug loading capacity of micelles of Brij 78 was higher than many di- and triblock copolymers with hydrophilic E-blocks specifically designed for enhancement of drug solubility.     

Nanoparticle encapsulation of emulsion droplets

The overall aim of this study is to coat emulsion droplets with nanoparticles using a simple heterocoagulation process in aqueous dispersion and determine: the adsorption behavior and interfacial layer microstructure, droplet physical stability against flocculation and coalescence, and the release profile of a model lipophilic molecule (dibutylphtalate (DBP)) from within the droplets. Polydimethylsiloxane (PDMS) droplets were used as a model emulsion due to their colloidal stability in the absence of added stabilisers. Aerosil type silica nanoparticles with different hydrophobicity levels were used as the model nanoparticles. The adsorption behavior of silica nanoparticles at the droplet-water interface was studied using adsorption isotherms and SEM imaging. Adsorption of hydrophilic nanoparticles is weakly influenced by pH, but significantly influenced by salt addition, whereas for hydrophobically modified nanoparticles a balance of hydrophobic and electrostatic forces controls adsorption over a wide range of pH and salt concentrations. The coalescence kinetics (determined under coagulation conditions at high salt concentration) and the physical structure of coalesced droplets were determined from optical microscopy. Adsorbed layers of hydrophilic nanoparticles introduced a barrier to coalescence of approximately 1kT and form kinetically unstable droplet networks at high salt concentrations. The highly structured and rigid adsorbed layers significantly reduce coalescence kinetics. Significant sustained release of DBP can be achieved using rigid layers of hydrophobic silica nanoparticles at the interface. Activation energies for release are in the range 580-630 kJ mol(-1), 10 times higher than for barriers introduced by Pluronic stabilisers.