European Journal of Pharmaceutics and Biopharmaceutics (v.60, #1)
Mucoadhesives in the gastrointestinal tract: revisiting the literature for novel applications
by Dimitra Dodou; Paul Breedveld; Peter A. Wieringa (pp. 1-16).
This article investigates applying mucoadhesives to manipulate friction and to achieve locomotion of an alternative colonoscopic device through the large intestine. Considering that such an application of mucoadhesives is new, the authors recognised the need to revisit the different aspects of mucoadhesion in the gastrointestinal tract on the basis of the literature and to re-evaluate them according to the requirements for intestinal locomotion. First, the material properties, which are critical for the locomotion mechanism and specific categories of mucoadhesives characterised by those critical properties were identified. The next step was to examine the structural characteristics of those categories to specify which of the already synthesised mucoadhesives are promising candidates for friction manipulation. Then, the response of those mucoadhesives to a number of environmental stimuli was examined. At the end, two in vitro experiments were carried out to study the potential of mucoadhesives for intestinal locomotion. A comparative analysis of the role of mucoadhesives in drug delivery and in intestinal locomotion leads to the conclusion that the two applications can be approached to one extent with common principles, but crucial differences are present as well.
Keywords: Mucoadhesion; Gastrointestinal tract; Colon; Drug delivery; Locomotion; Friction
Pharmacokinetics of an immediate release, a controlled release and a two pulse dosage form in dogs
by Raimar Löbenberg; Jae Seung Kim; Gordon L. Amidon (pp. 17-23).
Clinical studies have shown that circadian patterns influence the pharmacokinetics of certain drugs used in the treatment of different diseases. For such drugs, the bioavailability is influenced by the time of administration. The objective of this study was to investigate differences in the pharmacokinetic patterns between a pulsatile drug delivery system using a pulsatile capsule, an immediate release tablet and a controlled release tablet. Metoprolol was chosen as a model drug because of its high solubility and high permeability pattern throughout the GI tract. The dosage forms were administered to four dogs and the plasma levels were measured using LC-MS/MS. Pharmacokinetic parameters were determined for each dosage form. Fluctuations in the plasma time curves over the observation period indicated that physiological factors like motility have an influence on the drug absorption. The comparison of the plasma time curves of the dosage forms showed that each dosage form caused significant differences in the drug plasma levels. The pulsatile drug delivery capsule caused two defined Cmax values for each dose between 1â€“1.75 and 2.5â€“3.5h. Implications for the use of a pulsatile drug delivery device for chronopharmacotherapy are discussed. Pulsatile drug delivery offers a promising way for chronopharmacotherapy if the time of administration and pulse time are adjusted to the circadian pattern.
Keywords: Metoprolol; LC-MS/MS; Pulsatile drug delivery; Chronopharmacotherapy; Pharmacokinetics; Beta blocker; Dog study; In vivo study; Immediate release; Controlled release; Sustained release; Pulsatile release
Topical delivery of cyclosporin A: an in vitro study using monoolein as a penetration enhancer
by Luciana B. Lopes; John H. Collett; M. Vitória L.B. Bentley (pp. 25-30).
Topical delivery of cyclosporin A (CysA) is of great interest for the treatment of autoimmune skin disorders, but it is frequently ineffective due to poor drug penetration in the skin. The present study was aimed at investigating whether the presence of monoolein (a lipidic penetration enhancer) in a preparation of propylene glycol can improve CysA delivery to the skin. CysA was incorporated in a propylene glycol preparation containing 5â€“70% (w/w) of monoolein. The topical (to the skin) and transdermal (across the skin) delivery of CysA were evaluated in vitro using porcine ear skin mounted in a Franz diffusion cell. CysA was quantified by UV-HPLC. At 5%, monoolein increased only the transdermal delivery of CysA. At 10%, it increased both topical and transdermal delivery. When the concentration of monoolein was further increased (20â€“70% w/w), an interesting phenomenon was observed: the topical delivery of CysA was still elevated but its transdermal delivery was substantially reduced. It was concluded that monoolein (in propylene glycol formulations) can promote the topical delivery of CysA, with reduced transdermal delivery.
Keywords: Monoolein; Cyclosporin A; Topical delivery; Penetration enhancer; In vitro permeation
In vitro availability of kaempferol glycosides from cream formulations of methanolic extract of the leaves of Melilotus elegans
by Tsige Gebre-Mariam; Kaleab Asres; Melkamu Getie; Abebe Endale; Reinhard Neubert; Peter C. Schmidt (pp. 31-38).
In Ethiopian traditional medicine, Melilotus elegans Salzm. ex Ser. (Leguminosae) is used for the treatment of haemorrhoids and lacerated wounds. In view of its wide spread use and proven anti-inflammatory activity, 80% methanolic extract of the leaves was formulated into creams. HPLC/UV and MS studies revealed the presence of flavonoids, of which kaempferol was the major aglycone. Quantitative estimation of kaempferol in the hydrolyzed extract as determined by HPLC/UV was found to be 16.3Â±0.93Î¼g/mg ( n=6, range) of extract. The in vitro release profiles of kaempferol glycosides (quantified as kaempferol equivalent) from the cream formulations in a multilayer membrane system indicated that a lipophilic cream of the extract provides higher release of kaempferol glycosides than hydrophilic and amphiphilic ones. Over a study period of 4h, the lipophilic cream released 66Â±5.70% of kaempferol glycosides, while the hydrophilic and amphiphilic creams resulted in 55Â±2.77 and 38Â±2.30% release, respectively.
Keywords: Melilotus elegans; Flavonoids; Kaempferol glycosides; Kaempferol; Multilayer membrane; Creams; In vitro availability
Cyclodextrin complexes of valdecoxib: properties and anti-inflammatory activity in rat
by Kale Rajendrakumar; Saraf Madhusudan; Tayade Pralhad (pp. 39-46).
The influence of natural Î²-cyclodextrin and its hydrophilic derivatives (HPÎ²Cd and SBE7Î²Cd) on the in vitro dissolution rate, in vivo absorption and oral bioavailability of a poorly water soluble anti-inflammatory agent, valdecoxib (VALD) was studied. Equimolar drugâ€“cyclodextrin solid complexes were prepared by kneading and coevaporation methods and characterized by infrared spectroscopy, differential scanning calorimetry, X-ray diffraction. In the liquid state, the cyclodextrin complexes were studied using phase solubility analysis,1H nuclear magnetic resonance and circular dichroism spectroscopy. Drug solubility and dissolution rate in distilled water were notably improved by employing the Î²Cds. The DP15 (i.e. percent of dissolved VALD at 15min) was 10.5% for the pure drug and 50, 91 and 93% for VALD-Î²Cd, VALD-HPÎ²Cd and VALD-SBE7Î²Cd complexes, respectively. Moreover, it was found that in the, the cyclodextrin complexes of drug showed significant improvement in the anti-inflammatory activity.
Keywords: Valdecoxib; Cyclodextrin complexation; Modified Î²-cyclodextrins; Anti-inflammatory activity
The effect of liposomes with superoxide dismutase on A2182 cells
by RuÅ¾ica GaloviÄ‡ Rengel; Jelena FilipoviÄ‡-GrÄ?iÄ‡; Ivana ÄŒepelak; Tihana Å½aniÄ‡-GrubiÅ¡iÄ‡; Karmela BariÅ¡iÄ‡ (pp. 47-51).
Differently charged liposomes were examined for the efficiency of delivery of Cu/Zn superoxide dismutase (CuZnSOD) to human lung epithelial cells, A2182, and their prospects of cell protection from oxidative agents. A2182 cells were treated with cationic, neutral and anionic liposomes with encapsulated CuZnSOD. Untreated cells and cells pre-treated with liposome-encapsulated CuZnSOD were exposed to oxidative stress caused by xanthine/xanthine oxidase. Cellular antioxidant response was monitored for 4 or 24h after the beginning of oxidative stress induced by the activity of superoxide dismutase (SOD) and total glutathione concentration. CuZnSOD-loaded liposomes increased the SOD activity of A2182 cells 24h after treatment. The highest increase of cellular SOD, by 108%, was achieved using anionic liposomes. Neutral and cationic liposomes increased cellular SOD by 83 and 85%, respectively. Cationic liposomes were the most cytotoxic. Exposure of untreated cells to oxidative stress increased the cellular glutathione level after 24h. Cells pre-treated with liposome-encapsulated CuZnSOD were protected from oxidative stress, as shown by the unchanged concentration of cellular glutathione.
Keywords: A2182 cells; Glutathione; Liposomes; Superoxide dismutase; Oxidative stress
Carboxymethyl high amylose starch (CM-HAS) as excipient for Escherichia coli oral formulations
by Carmen Calinescu; Jérôme Mulhbacher; Éric Nadeau; John Morris Fairbrother; Mircea Alexandru Mateescu (pp. 53-60).
Carboxymethyl high amylose starch (CM-HAS) is proposed as a novel excipient for oral tablet formulation of bioactive agents ensuring their protection in the stomach and delivery in the intestine. Three variants of CM-HAS, with different degrees of substitution, were synthesized by starch treatment with various amounts of monochloroacetic acid. The products were dried in powder form and tablets were obtained by direct compression of mixed powders of polymeric excipient and lyophilized Escherichia coli ( E. coli) bacteria. Dosage forms of CM-HAS are unswollen and compact in acidic medium, ensuring protection of active agents against acidity. Release of bacteria from CM-HAS tablets is based on the fast swelling of the tablets during the passage from gastric acidity to alkaline intestinal medium, enzymatic hydrolysis triggering their rapid, almost total dissolution. The bacteria thus formulated displayed higher survival rates in acidic gastric conditions and for longer periods than the free bacteria or than the bacteria formulated with the non-derivatized starch. The CM-HAS selected matrix also assured a good viability of bacteria after 6 months under refrigeration.
Keywords: Carboxymethyl high amylose starch; Oral administration; Drug delivery; Gastric resistance; Intestinal matrix dissolution; Escherichia coli; Probiotics; VaccinAbbreviations; CM-HAS; non-cross-linked Carboxymethyl High Amylose Starch; CM; carboxymethyl; HAS; High Amylose Starch; ETEC; Enterotoxigenic; Escherichia coli; SGF; simulated gastric fluid; SIF; simulated intestinal fluid; DNS; 35-dinitrosalicylic acid; DS; degree of substitution; CF; compression force; CFU; colony forming units
Polymethacrylates as crystallization inhibitors in monolayer transdermal patches containing ibuprofen
by Francesco Cilurzo; Paola Minghetti; Antonella Casiraghi; Leila Tosi; Stefania Pagani; Luisa Montanari (pp. 61-66).
The feasibility of a monolayer patch based on polydimethylsiloxane pressure sensitive adhesive containing ibuprofen (IB) in supersaturated condition was studied. The efficacy of three low molecular weight excipients (propylene glycol, PG, Cremophor EL and Cremophor RH) and of two copolymers of methacrylic acid (EudragitÂ® E, EuE, and EudragitÂ® RL, EuRL) as IB crystallization inhibitors was tested. The performances of the patches were evaluated in terms of drug release and human stratum corneum and epidermis (SCE) permeation profile. The interactions between IB and the other excipients were investigated by ATRâ€“FT-IR spectroscopy. The stability of the patches, prepared without adding crystallization inhibitors, was unsatisfactory because crystals grew in less than 1 month. Among the low molecular weight molecules, only PG inhibited the IB crystallization up to 50 days without affecting the IB skin permeation profile. The addition of EuE or EuRL in the matrices prevented drug crystallization for more than 12 months. EuE significantly reduced the IB in vitro release rate and the IB permeated amount through the SCE compared to other formulations. These phenomena are attributed to a stronger association between IB and EuE than IB and EuRL.
Keywords: Transdermal patches; Crystallization inhibitors; Ibuprofen; Eudragit; ®; Silicon PSA
Development of tretinoin gels for enhanced transdermal delivery
by Sang-Chul Shin; Hee-Jung Kim; In-Joon Oh; Cheong-Weon Cho; Kyu-Ho Yang (pp. 67-71).
To develop the new gel formulations that show sustained release for a period of time, the bioadhesive carbopol gels containing tretinoin were prepared. The release characteristics of drug from the carbopol gel were studied according to temperature, receptor medium and drug concentration. For the enhancement of its percutaneous absorption, some kinds of penetration enhancer were used. As the concentration of drug increased, the release of drug from the gel increased, showing concentration dependency. The increase of temperature showed the increased drug release, depending on the activation energy of permeation. Among the enhancers used such as the glycols and the non-ionic surfactants, polyoxyethylene 2-oleyl ether showed the best enhancing effect. The carbopol gels of tretinoin containing an enhancer could be developed for the enhanced transdermal delivery of drug.
Keywords: Tretinoin; Penetration enhancer; Diffusion; Carbopol gels; Transdermal delivery
Effect of SBE7-Î²-cyclodextrin complexation on carbamazepine release from sustained release beads
by J.S. Smith; R.J. MacRae; M.J. Snowden (pp. 73-80).
The effect of SBE7-Î²-cyclodextrin together with hydroxypropylmethyl cellulose (HPMC) or polyvinylpyrrolidone (PVP) on the saturated solubility and delivery of carbamazepine (a poorly soluble drug) from sustained release (SR) beads was investigated. Carbamazepine solubility at room temperature increased from 0.1 to 5.4mg/ml by forming an inclusion complex with SBE7-Î²-cyclodextrin (15%w/v). HPMC (0.1%w/v) also increased the aqueous solubility of carbamazepine, acting both alone and synergistically with SBE7-Î²-cyclodextrin, to produce solubility values of 0.26 and 8.1mg/ml respectively. PVP (0.1â€“0.5%w/v) had no effect on carbamazepine solubility, either alone or in combination with SBE7-Î²-cyclodextrin. The addition of SBE7-Î²-cyclodextrin to SR beads increased the rate of carbamazepine release. In addition, comparable release rates where obtained when lower ratios of SBE7-Î²-cyclodextrin together HPMC were incorporated in the SR bead. Therefore this ternary drug cyclodextrin polymer system was considered preferable over the binary drug cyclodextrin system for SR beads, as less cyclodextrin was required. However, both binary and ternary approaches were considered suitable techniques to improve the release rate and potentially the in vivo bioavailability of poorly soluble drugs that had previously exhibited slow or incomplete release from SR beads.
Keywords: Beads; Carbamazepine; Cyclodextrin; Hydroxypropyl methylcellulose; Sustained release
Comparison of powder produced by evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) technologies using novel Z-contrast STEM and complimentary techniques
by Jason M. Vaughn; Xiaoxia Gao; Miguel-Jose Yacaman; Keith P. Johnston; Robert O. Williams III (pp. 81-89).
The objective of this study was to compare the properties of particles formed by nucleation and polymer stabilization (e.g. evaporative precipitation into aqueous solution (EPAS)) versus rapid freezing (e.g. spray freezing into liquid (SFL)). Powders formed by EPAS and SFL, composed of danazol and PVP K-15 in a 1:1 ratio, were characterized using X-ray powder diffraction, modulated differential scanning calorimetry (MDSC), contact angle determination, dissolution, scanning electron microscopy (SEM), environmental scanning electron microscopy (ESEM), BET specific surface area, and Z-contrast scanning transmission electron microscopy (STEM). Large differences in particle morphologies and properties were observed and explained in terms of the particle formation mechanisms. Both techniques produced amorphous powders with high Tg and low contact angle values. However, STEM analysis showed highly porous bicontinuous nanostructured 30nm particles connected by narrow bridges for SFL versus aggregated 500nm primary particles for EPAS. The combination of STEM and other characterization techniques indicates solid solutions were formed for the SFL powders consistent with rapid freezing. In contrast, the EPAS particle cores are enriched in hydrophobic API and the outer surface is enriched in the hydrophilic polymer, with less miscibility than in the SFL powders. Consequently, dissolution rates are faster for the SFL particles, although both techniques enhanced dissolution rates of the API.
Keywords: Particle engineering processes; Precipitation; Freezing
Design of a phytosphingosine-containing, positively-charged nanoemulsion as a colloidal carrier system for dermal application of ceramides
by Erol Yilmaz; Hans-Hubert Borchert (pp. 91-98).
Positively charged oil/water (o/w) nanoemulsions (PN) are effective vehicles to change the permeability of the skin. This study focused on the preparation and characterisation of phytosphingosine (PS) containing PN (PPN) which serve as colloidal carriers for the dermal application of ceramide IIIB (CIIIB) and the stratum corneum (SC) lipids (PPNSC) such as ceramide III (CIII), cholesterol, and palmitic acid. The investigations were conducted using appropriate emulsification and homogenisation processing conditions to optimise PPNSC with regard to droplet size, physical stability, and solubility of PS, CIII and CIIIB. A decrease in droplet size was observed through eight homogenisation cycles at a pressure of 500 bar and a temperature of 50°C. Above these optimal values, an increase in droplet size was observed. PS and ceramides have low solubilities in oil and water. When Lipoid E-80® (LE80) was added to the oil phase, the solubility of PS and ceramides increased, indicating some interactions shown by DSC measurements. SC lipids and CIIIB could be successfully incorporated in PPN without producing any physical instability. The high stability of PPNSC is probably due to the presence of a hydrophilic (Tween 80) and a lipophilic surfactant (LE80), supported by the lipophilic cosurfactant PS, at the o/w interface. It was shown that PS was responsible for the positive charge and thus supported the high physical stability of PPNSC. This optimised emulsion was selected for further skin absorption evaluation.
Keywords: Positively charged oil/water nanoemulsion; Dermal application; Lipoid E-80; ®; Phytosphingosine; Ceramide; Stability of nanoemulsion
Diclofenac salts, II. Solid dispersions in PEG6000 and Gelucire 50/13
by Adamo Fini; José R. Moyano; Juan M. Ginés; José I. Perez-Martinez; Antonio M. Rabasco (pp. 99-111).
A number of systems were prepared at five compositions (5, 10, 20, 30 and 40% w/w) of diclofenac/ N-(2-hydroxyethyl) pyrrolidine salt and acidic diclofenac in PEG6000 and Gelucire 50/13, as physical mixtures and as solid dispersions. Powder X-ray diffractograms for the systems examined show shifted and normal peaks, suggesting that the drug is present inside the samples in different physical states. Differential scanning calorimetry does not offer important information, since drug solubility into the carriers increases with temperature and thermograms show only the melting point peak of the carriers. Hot-stage microscopy examination explains that, in high concentration samples, the drug is present either dissolved into the carriers, or precipitated as microcrystals, or undissolved crystals of larger size. Gelucire 50/13 allows the formation of larger crystals than PEG, using both the chemical forms of the drug. The release percentage of the drug from PEG6000/acidic diclofenac reaches 50% after few minutes in the most favourable case and appears to be dependent on the composition of the samples: the more diclofenac is present as dissolved in the pre-treated samples, the higher is the release. The optimum composition was found in the range of 5â€“10% w/w.
Keywords: Diclofenac/-(2-hydroxyethyl) pyrrolidine and acidic diclofenac; PEG6000 and Gelucire 50/13; Solid dispersions; SEM; XRD; HSM and DSC; Dissolution profiles
Novel nanoparticulate carrier system based on carnauba wax and decyl oleate for the dispersion of inorganic sunscreens in aqueous media
by J.R. Villalobos-Hernández; C.C. Müller-Goymann (pp. 113-122).
The purpose of this study was to characterize carrier systems for inorganic sunscreens based on a matrix composed of carnauba wax and decyl oleate. Ultraviolet radiation attenuators like barium sulfate, strontium carbonate and titanium dioxide were tested. The lipid matrices were used either as capsules or as accompanying vehicles for the pigments in aqueous dispersions. Manufacturing was performed using high pressure homogenization at 300bar and a temperature of 75Â°C. To evaluate the effect of the pigments on the crystalline structure of the waxâ€“oil mixture, X-ray diffraction and differential scanning calorimetry were used. Further parameters determined were particle size, polydispersity index, z-potential, viscosity and sun protection factor (SPF). Transmission electron microscopy was also applied for visualization of nanoparticles. The X-ray diffraction patterns and the melting points of the lipid mixtures remained unchanged after the pigments were added. The particle sizes of the encapsulated species ranged from 239 to 749.9nm showing polydispersity values between 0.100 and 0.425. Surface charge measurements comprising values up to âˆ’40.8mV denoted the presence of stable dispersions. The formulations could be described as ideal viscous presenting viscosities in a range of 1.40â€“20.5mPas. Significant increases in SPF up to about 50 were reported after the encapsulation of titanium dioxide. Freeze fracture micrographs confirmed the presence of encapsulated inorganic crystals.
Keywords: Nanoparticulate carriers; High pressure homogenization; Inorganic sunscreens; Carnauba wax; Decyl oleate; Sun protection factor
Synthesis and characterisation of novel nanospheres made from amphiphilic perfluoroalkylthio- Î²-cyclodextrins
by Sandrine Péroche; Ghania Degobert; Jean-Luc Putaux; Marie-Geneviève Blanchin; Hatem Fessi; Hélène Parrot-Lopez (pp. 123-131).
This work describes the synthesis of new amphiphilic perfluorohexyl- and perfluorooctyl-propanethio- Î²-cyclodextrins and the comparison of the ability of these molecules and alkyl analogue, nonanethio- Î²-cyclodextrin to form nanospheres. Nanospheres were prepared using nanoprecipitation method (perfluoroalkylthio- Î²-cyclodextrin in THF [0.11Ã—10âˆ’3M], stirring rate 700rpm, addition of aqueous phase at 64Â°C into organic phase at 50Â°C). They were characterised by Photon Correlation Spectroscopy (PCS) and by electron microscopy (SEM and cryo-TEM). The nanospheres prepared from these new Î²-cyclodextrin derivatives have an average size of 260nm, and appear to be spherical in cryo-TEM images. Whereas alkyl analogue forms polydisperse aggregates with sizes in the range 60â€“350nm.
Keywords: Amphiphilic cyclodextrins; Fluoroalkylthio-Î²-cyclodextrins; Alkylthio-Î²-cyclodextrins; Nanospheres; PCS; SEM; Cryo-TEM
The difficulty in the assessment of the compression behaviour of powder mixtures: Double layer tablets versus arithmetic additivity rule
by Petra M. Belda; Jobst B. Mielck (pp. 133-145).
The weighted arithmetic mean from values of a feature derived from the individual components is often used to calculate the theoretically expected compression behaviour of powder mixtures if no interparticulate interactions between the components occur. Alternatively, simulated and experimental double layer tablets are presented. The suitability of the various methods to serve as a reference for the assessment of the compression behaviour of powder mixtures shall be compared. Narrow and similar sieve fractions of maltitol and metamizol were mixed in various ratios of true volumes. Constant total true volumes of the single substances, powder mixtures, and layered powders of the same composition were compressed on an eccentric tabletting machine to a constant maximum geometric mean punch force. In addition, the compression of double layer tablets was mathematically simulated from the dynamic relative densityâ€“force data of the pure materials. At a given momentary force, the relative density of a simulated double layered powder bed is given by the harmonic mean of the relative density values of the pure materials weighted by their true volume fractions. The results show that the total, the net, and the expansion work change indeed almost linearly with the true volume fraction of the components in the double layer tablets, with the consequence that the plasticity index (=net work/total workÃ—100) proceeds non-linearly. The slope of the Heckel plot â€˜at pressureâ€™ and the apparent mean yield pressure obtained from these Heckel data are non-linearly related to the true volume fraction. If the weighted arithmetic mean is used to analyse the compression behaviour of the powder mixtures, results are obtained which are incompatible or even contradictory between interrelated features. On the other hand, the double layer model provides a consistent evaluation. A good agreement between the results of the experimental and the simulated double layer tablets is found.
Keywords: Tabletting of powder mixtures; Double layer tablets; Relative density; Work of compression; Heckel parameters
The influence of bile salts and mixed micelles on the pharmacokinetics of quinine in rabbits
by Gerhard Dongowski; Bertram Fritzsch; Jochen Giessler; Albert Härtl; Olaf Kuhlmann; Reinhard H.H. Neubert (pp. 147-151).
The bioavailability of orally administered drugs can be influenced by interactions with food components and by physico-chemical conditions in the upper gastrointestinal tract. Normally, bile salts enhance the transport of lipophilic drugs across mucosal membranes. Bile salts are able to form stable mixed micelles consisting of fatty acids and phospholipids. Conventional micellar systems are known to solubilize lipophilic drugs having a low bioavailability. The influence of bile salts and mixed micelles on the pharmacokinetics of the lipophilic drug quinine was investigated in rabbits. Female rabbits were given intraduadenally quinine (5mg/kg body weight) without and with incorporation into the micellar or mixed micellar systems. Blood was collected every 30min for 6h. In plasma, concentration of quinine was measured using HPLC. The plasma concentrationâ€“time profiles of quinine were significantly lower within the first 2h after administration in presence of both the sodium salt of glycodeoxycholic acid (above the critical micellar concentration) as well as of mixed micellar systems consisting of glycodeoxycholic acid and palmitic acid and/or lecithin. The pharmacokinetic parameters AUC (relative bioavailability) and cmax of quinine were significantly decreased by micellar systems in rabbits. These mixed micellar systems lower and not as expected, increase the absorption of quinine in vivo. Therefore, quinine should be orally administered at least 1h before food intake, particularly before fat intake.
Keywords: Quinine pharmacokinetics; Bile salts; Mixed micelles; Rabbits
Compressibility of floating pellets with verapamil hydrochloride coated with dispersion Kollicoat SR 30 D
by WiesÅ‚aw Sawicki; RafaÅ‚ Å?unio (pp. 153-158).
The purpose of this study was to work out a method of compression of floating pellets with verapamil hydrochloride (VH) in a dose of 40mg. It was assumed that this form should reside in the stomach floating for several hours and gradually release the drug in a controlled way. Compression of pellets into tablets, being a modern technological process, is much more perfect than enclosing them in a hard gelatin capsule. KollicoatÂ® SR 30 D was selected for coating. In experiments three plasticizers were examinedâ€”propylene glycol, triethyl citrate and dibuthyl sebecate (all at concentration of 10%). It was found that VH release from pellets coated by the films of the same thickness (70Î¼m), however, containing plasticizers is considerably different. Pellets were prepared by wet granulation of powder mixture, spheronization of the granulated mass and coating of the cores with a sustained release film. Two kinds of cellulose, microcrystalline and powdered, and sodium hydrocarbonate were the main components of pellet core. Proper pellet coating film thickness, ensuring obtaining desirable VH release profile and flotation effect, was defined. X compositions of tablets with pellets were examined in order to obtain formulation, from which VH release would mostly approximate pellets before compressing. The best formulation was evaluated taking into account the effect of compression force an tablet hardness and friability, and pellet agglomeration and flotation. Tablet cross-section photographs were taken confirming necessary coating film thickness preventing their deformation caused by compressing into tablets.
Keywords: Verapamil hydrochloride; Floating pellets; Coating compressibility; Plasticizers; Controlled release
Quantification of the leaching of triethyl citrate/polysorbate 80 mixtures from Eudragit® RS films by differential scanning calorimetry
by Ronny Gruetzmann; Karl G. Wagner (pp. 159-162).
The influence of triethyl citrate and polysorbate 80 (TweenÂ® 80) on the glass transition temperature ( TG) of EudragitÂ® RS membranes was investigated using differential scanning calorimetry (DSC). The TG-decreasing effect of TEC and TweenÂ® 80 displayed an almost identical performance in extent at a linear relationship between weight proportion and TG resulting in a specific TG-decrease ( TG,spec.) of âˆ’1.98( K/%TEC) and âˆ’1.86( K/%Tween), respectively. Thus, the proportion of each adjuvant could be summarized as the plasticizer complex weight proportion (PC) with TG,spec.=1.96( K/%PC). Vice versa this linear relationship could be used to determine the proportion of plasticizer complex within the polymer membrane after swelling and diffusion processes, i.e. plasticizer leaching. For membranes containing 20% (w/w) TEC and 8% (w/w) TweenÂ® 80 as plasticizer complex a fast leaching resulted during the dissolution test reaching an equilibrium at 6.08% (Â±0.5) PC after 30min in demineralised water. The DSC method proved to be a simple method to determine plasticizer leaching via TG, however, without respect on the film forming properties of the two different excipients. Plasticizing with TEC or TEC/TweenÂ® 80 mixtures led to smooth and continuous films, while plasticizing with TweenÂ® 80 only resulted in mosaic like fissured films.
Keywords: Eudragit; ®; RS; Plasticizer leaching; Triethyl citrate; Polysorbate 80; Glass transition temperature