International Journal of Pharmaceutics (v.234, #1-2)
Evaluation of modified gum karaya as carrier for the dissolution enhancement of poorly water-soluble drug nimodipine by G.V Murali Mohan Babu; Ch.D.S Prasad; K.V Ramana Murthy (1-17).
Modified gum karaya (MGK), a recently developed excipient was evaluated as carrier for dissolution enhancement of poorly soluble drug, nimodipine (NM). The advantages of MGK over the parent gum karaya (GK) were illustrated by differences in the in vitro dissolution profiles of respective solid mixtures prepared by co-grinding technique. The influence of process variable, such as polysaccharide concentration and method of preparation of solid mixture on dissolution rate was studied. Solubility studies were also performed to explain the differences in dissolution rate. Solid mixtures were characterized by differential scanning calorimetry (DSC), X-ray diffraction studies (XRD) and scanning electron microscopy (SEM). The dissolution rate of NM was increased as the MGK concentration increased and optimum ratio was found to be 1:9 w/w ratio (NM:MGK). It is found that method of preparation of solid mixtures was significantly effected the dissolution rate of NM from solid mixtures. The order of method of preparation in according to their Dissolution Efficiency is physical mixture<co-grinding mixture<swollen carrier mixture<kneading mixture (water as kneading agent)<kneading mixture (70% v/v ethanol as kneading agent)<solid dispersion. Though, the solid mixtures prepared by other methods like solid dispersion, swollen carrier mixture and kneading technique gave faster release, co-grinding mixture prepared in 1:9 w/w ratio (NM:MGK) was found to exhibit a significant improvement in dissolution rate without requiring addition of organic solvents or high temperatures for its preparation and the process is less cumbersome. Hence, co-grinding technique appears to be more easier and the most convenient method from a practical point of view.
Keywords: Gum karaya; Modified gum karaya; Nimodipine; Dissolution enhancement; Solid dispersion; Kneading; Co-grinding; Swollen carrier mixture;
Solid state characterization of an neuromuscular blocking agent—GW280430A by Haijian (Jim) Zhu; Mark Sacchetti (19-23).
GW280430A is an ultrashort-acting neuromuscular blocking agent and is targeted for muscle relaxation as part of the intubation surgical procedure. The objective of this work was to perform solid state characterization on GW280430A and to evaluate the relationship between water content and glass transition temperature (T g). GW280430A was characterized by differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction (PXRD), microscopy and moisture sorption. The effect of water content on the T g of GW280430A was evaluated by equilibrating the material over saturated salt solutions at a range of relative humidities (6.4–72.6%) and determining the T g by DSC using hermetically sealed aluminum pans. GW280430A undergoes dehydration at 40 °C, glass transition at 130 °C and decomposition at 190 °C by differential scanning calorimetry. By PXRD and moisture sorption, GW280430A is an amorphous material and deliquesces at about 70% RH at room temperature. Water acts as a potent plasticizer for GW280430A and the T g decreases significantly as the water content increases. No measurable decomposition of GW280430A was observed after 4 weeks at 40 °C/75% RH.
Keywords: GW280430A; Neuromuscular blocking agent; Solid state characterization; Glass transition temperature; Differential scanning calorimetry; Thermogravimetric analysis; Powder X-ray diffraction; Moisture sorption; Solid state stability;
Finite element analysis of slow drug release through deformed coating film: effects of morphology and average thickness of coating film by B.-H Chen; D.J Lee (25-42).
This paper, a continuation of our previous work, is a presentation of the effect of the morphology and the average thickness of the deformed coating films on the slow diffusional release characteristics analyzed numerically under the constraints of the constant volume of the drug matrices and the coating films, if the films have the same average thickness. Increasing the average thickness of the coating films slows down the fractional release and the average release rate of the drug and smoothen the initial burst of the drug, as well as increase the initial lag time. The effect due to deformation of the coating films on these diffusional release characteristics are found to be less significant with the increasing average thickness of the coating films. Interestingly initial lag times are found to be the same for the coated particles having the same smallest thickness but different average thickness of coating films. The effect due to the change in the average thickness of the coating films on the characteristics of the slow controlled-release is discussed to shed light on the design of a better controlled-release device.
Keywords: Controlled-release; Deformation; Morphology; Film thickness; Coating film; Diffusional release;
Application of time-dependent sessile drop contact angles on compacts to characterise the surface energetics of sulfathiazole crystals by Tim H Muster; Clive A Prestidge (43-54).
The time-dependent wetting of sulfathiazole compacts with sessile water drops was evaluated using video microscopy. The influence of sulfathiazole crystalline form, particle size, pre-saturation with water, humidity and compaction pressure on the droplet spreading kinetics and contact angles are reported. The rate and extent of droplet spreading decreased for compact surfaces of high microscopic roughness; this was determined by atomic force microscopy (AFM). Pre-saturation of powder compacts with water (pre-saturated with sulfathiazole) enhanced droplet spreading and enabled pseudo-equilibrium contact angles to be determined for up to 10 min. Sessile-drop contact angles on both sulfathiazole powder compacts and single crystals are compared with particle contact angles determined by liquid penetration. This study has led to an improved understanding of the influence of physical heterogeneities and the face-specific surface chemistry of individual crystals on the wetting characteristics of pharmaceutical compacts.
Keywords: Sulfathiazole; Compacts; Wettability; Contact angle; Sessile drop; Porosity; Surface roughness;
A new method to determine discoloration kinetics of uncoated white tablets occurring during stability testing—an application of instrumental color measurement in the development pharmaceutics by J Berberich; K.-H Dee; Y Hayauchi; C Pörtner (55-66).
The tristimulus color coordinates CIELAB and associated parameter Color Intensity (CI) have been shown to be a quantifiable variable for whiteness of uncoated tablets. Whereas any of L*, a* or b* indicates the discoloration of white tablets to a certain degree, it alone cannot reflect the full extent of discoloration. The CI has been defined which is able to describe the discoloration kinetics with acceptable regression coefficients. The evaluation of the CIELAB values from the stability data has shown that the discoloration of the white tablets means an intensification of yellowish or brownish color which is manifested by more or less constant hue angle (hab) values and increasing chroma (Cab*) values. In the view of these data the discoloration kinetics can physically be expressed by the CI. With the CI values the discoloration kinetics can be calculated by linear or polynomial regression with acceptable confidence intervals. The discoloration rates determined under several storage temperatures follow the Arrhenius equation and the activation energy can be estimated for the products. The CI values are unambiguously connected to the visual perception of the corresponding tablets. By means of the discoloration kinetics based on the CI values, it has become possible to statistically determine, the period of time uncoated tablets remain white.
Keywords: Tristimulus color; CIELAB; L*a*b*; Discoloration kinetics; Color measurement; Color intensity (CI); White tablets; Stability testing;
Enhanced bioavailability of triprolidine from the transdermal TPX matrix system in rabbits by Sang-Chul Shin; Jun-Shik Choi (67-73).
The pharmacokinetics and bioavailability of triprolidine, antihistamines, were studied to determine the feasibility of enhanced transdemal delivery of triprolidine from the poly(4-methyl-1-pentene) (TPX) matrix system containing polyoxyethylene-2-oleyl ether in rabbits. The triprolidine–TPX matrix (50 mg/kg) was applied to abdominal skin of rabbits. Blood samples were collected via femoral artery for 36 h and the plasma concentrations of triprolidine were determined by HPLC. Pharmacokinetic parameters was calculated using the lagran computer program. The area under the curve (AUC) was significantly higher in the enhancer group (4058±1420 ng/ml h) than that (1902±857 ng/ml h) in control group (P<0.05), showing about 235% increased bioavailability. The average C max was increased significantly in the enhancer group (216±44.3 ng/ml) compared with control group (130±25.8 ng/ml) (P<0.05). The mean T max was increased in the enhancer group (8.0±2.55 h) compared with the control (6.0±2.28 h) but was not significant. The relative bioavailability was 23.1% in the control group and 49.3% in the enhancer group compared to the oral route. As the triprolidine–TPX matrix containing polyoxyethylene-2-oleyl ether as an enhancer and tiethyl citrate as a plasticizer was administered to rabbits via the transdermal routes, the relative bioavailability increased by about 2.13-fold compared to the control group, showing a relatively constant, sustained blood concentration with minimal fluctuation. The results of this study shows that triprolidine–TPX matrix could be developed as a transdermal delivery system providing consistent plasma concentration.
Keywords: Bioavailability; Pharmacokinetics; TPX matrix; Triprolidine; Enhancer; Transdermal administration; Histological change;
Tetanus toxoid microspheres consisting of biodegradable poly(lactide-co-glycolide)- and ABA-triblock-copolymers: immune response in mice by Tobias Jung; Regina Koneberg; Klaus-D. Hungerer; Thomas Kissel (75-90).
Tetanus toxoid (TT) was microencapsulated using poly(lactide-co-glycolide) (PLGA) with molar compositions of 50:50, 75:25 or an ABA-triblock-copolymer consisting of PLGA A-blocks attached to a central polyoxyethylene-B-block with a W/O/W (water/oil/water) double emulsion technique. The TT microspheres (MS) were evaluated with respect to protein integrity during antigen release in-vitro and compared with aluminum-adsorbed TT in a mouse model for in-vivo induction of tetanus-specific antibodies as well as protection against a subcutaneous tetanus toxin challenge. The more hydrophilic ABA-triblock-copolymer protected the TT against the deleterious microenvironmental conditions in the degrading MS and provided a prolonged antigen release. In spite of the distinct differences in the in-vitro release patterns MS from PLGA and ABA-triblock-copolymer did not show significant differences in the in-vivo induction of tetanus-specific antibodies. Both preparations elicited antibody titers nearly as high as conventional aluminum-adsorbed TT, which lasted for 29 weeks and were protective against a challenge with 100×LD50 tetanus toxin. TT-MS boosted mice which were preimmunized with aluminum-adsorbed as well as with microencapsulated TT. TT-MS are suitable candidates for single shot vaccine delivery systems which elicit a long lasting and protecting immune response.
Keywords: Tetanus toxoid; Biodegradable microspheres; Polyesters; Single-shot vaccine;
Polymer–cysteamine conjugates: new mucoadhesive excipients for drug delivery? by Constantia E Kast; Andreas Bernkop-Schnürch (91-99).
In the present study, the features of two new thiolated polymers—the so-called thiomers—were investigated. Mediated by a carbodiimide cysteamine was covalently attached to sodium carboxymethylcellulose (Na-CMC) and neutralised polycarbophil (Na-PCP). Depending on the weight-ratio polymer to cysteamine during the coupling reaction, the resulting CMC–cysteamine conjugate and PCP–cysteamine conjugate showed in maximum 43±15 and 138±22 μmole thiol groups per g polymer (mean±S.D.; n=3), respectively, which were used for further characterisation. Tensile studies carried out with the CMC–cysteamine conjugate on freshly excised porcine intestinal mucosa displayed no significantly (P<0.01) improved mucoadhesion, whereas, the mucoadhesive properties of the PCP–cysteamine conjugate were increased 2.5-fold compared with the unmodified polymer. The swelling behaviour of the CMC–cysteamine conjugate was uninfluenced by the covalent attachment of the sulfhydryl compound. In contrast the swelling behaviour of the PCP–cysteamine conjugate was improved significantly (P<0.01) versus unmodified PCP. Furthermore, in aqueous solutions the disintegration time of tablets based on the CMC– and PCP–cysteamine conjugates was prolonged 1.5 and 3.2-fold, respectively, in comparison to tablets containing the corresponding unmodified polymers. According to these results, especially the PCP–cysteamine conjugate represents a promising new pharmaceutical excipient for various drug delivery systems.
Keywords: Sodium carboxymethylcellulose; Polycarbophil; Thiomers; Mucoadhesion;
Intestinal transport of cefuroxime axetil in rats: absorption and hydrolysis processes by N Ruiz-Balaguer; A Nacher; V.G Casabo; M Merino Sanjuan (101-111).
Studies were performed using three cefuroxime axetil solutions (11.8, 118 and 200 μM) in three selected intestinal segments and one cefuroxime axetil solution (118 μM) in colon of anaesthetized rats. First-order absorption rate pseudoconstants, k ap and effective permeability coefficients, P eff, were calculated in each set. Absorption of cefuroxime axetil can apparently be described as a carrier-mediated transport, which obeys Michaelis–Menten and first order kinetics in the proximal segment of the small intestine and a passive diffusion mechanism in the mean and distal segments. The absorption kinetic parameters for cefuroxime axetil were obtained: V m=0.613 (0.440) μM min−1; K m=31.49(28.31) μM and k a=0.011(0.003) min−1. Parameters characterizing degradation of the prodrug were obtained in each intestinal segment: proximal segment k dp=0.0049(0.0003) min−1, mean segment, k dm=0.0131(0.0007) min−1 and distal segment k dd=0.019(0.0009) min−1. Therefore, in situ intestinal absorption of cefuroxime axetil in the proximal segment of the rat in the presence of variable concentrations of cefadroxil has been investigated in order to examine the inhibitory effect of cefadroxil on cefuroxime axetil transport. The data suggest that cefadroxil and cefuroxime axetil share the same intestinal carrier.
Keywords: Carrier-mediated; Cefadroxil; Cefuroxime axetil absorption; Competitive inhibition; Intestinal permeability;
Intestinal absorption characteristics of the low solubility thiocarboxanilide UC-781 by S Deferme; J Van Gelder; F Ingels; G Van den Mooter; S De Buck; J Balzarini; L Naesens; E De Clercq; R Kinget; P Augustijns (113-119).
The aim of this study was to determine the intestinal absorption characteristics of the antiviral agent UC-781 and to optimize the experimental conditions of the in vitro system for low solubility compounds. The absorption potential of UC-781 was studied with the Caco-2 system and with the rat intestinal perfusion technique. The low solubility of UC-781 required the use of solubility/dissolution rate enhancing agents (e.g. VitE-TPGS, Gelucire 44/14). The creation of sink conditions in the receiver compartment of the Caco-2 system was a prerequisite to reliably study the transport of this poorly soluble compound. After inclusion of VitE-TPGS in the acceptor solution, UC-781 could be characterized as a class II drug of the Biopharmaceutical Classification System (low solubility, high permeation across membranes). A significant concentration-dependent decrease in transport of UC-781 was observed upon increasing the concentration of VitE-TPGS in the apical compartment. This observation contrasts to the absorption enhancing properties of VitE-TPGS, and can probably be attributed to a decrease in the concentration of free UC-781 when using higher concentrations of the solubility/dissolution rate enhancing agents. The use of Gelucire 44/14 as a solubilizing agent resulted in a batch-dependent degradation of UC-781. The inclusion of the solubility/dissolution rate-enhancing agent VitE-TPGS did not result in absorption enhancement in the intestinal perfusion technique.
Keywords: HIV; UC-781; NNRTI; Caco-2; Vitamin E-TPGS; Gelucire;
Enhancement of skin permeation of miconazole by phospholipid and dodecyl 2-(N,N-dimethyl amino)propionate (DDAIP) by M Fujii; S Büyüktimkin; N Büyüktimkin; J.H Rytting (121-128).
Miconazole (MCZ) has very low solubility in both water and oil. Permeation rates through shed snakeskin from an aqueous suspension and a mineral oil suspension were 0.5 μg/cm2/h and almost none, respectively. When hydrogenated phosphatidylcholine (HPC) was added to mineral oil and heated to 95 °C, the solubility of MCZ increased in proportion to the HPC concentration. DSC measurements also indicated an interaction between them. Thus, a gel formed by hydrogenated phospholipid and mineral oil, as vehicle was prepared. The solubility of MCZ in the gel was around 1% and the permeation rate was 1.3 μg/cm2/h, which was about 2.5 times that from an aqueous suspension. As an alternative approach, a skin permeation enhancer, dodecyl 2-(N,N-dimethyl amino)propionate (DDAIP) was applied 2 h before a skin permeation study. The permeation from an aqueous suspension became 11 times that of the suspension without DDAIP pretreatment. The concentration of MCZ in the skin increased 8-fold, indicating that the enhancement effect involved high partition of MCZ into the skin. On the other hand, when a gel formulation was used, pretreatment with DDAIP was not as effective as incorporation of DDAIP in the gel formulation. Following pretreatment, permeation was only two times that of the gel without DDAIP pretreatment, and half that of the water suspension with DDAIP pretreatment. This suggested that release from the gel was the rate-limiting step with the gel formulation. When DDAIP was added to the gel, the permeation rate of MCZ was 3.3 μg/cm2/h. It was also a release limited type permeation. The gel with DDAIP is potentially a useful formulation, because of relatively high permeation while possibly avoiding overdosing.
Keywords: Miconazole; Skin permeation; Dodecyl 2-(N,N-dimethyl amino)propionate; Phospholipid; Shed snakeskin; Enhancer;
Co-delivery of an antisense oligonucleotide and 5-fluorouracil using sustained release poly (lactide-co-glycolide) microsphere formulations for potential combination therapy in cancer by Majad Hussain; Gary Beale; Marcus Hughes; Saghir Akhtar (129-138).
Antisense oligonucleotides (AODNs) can selectively inhibit oncogene expression by Watson–Crick hybridisation to target mRNA and are being increasingly considered for use in combination with conventional drugs for potential anticancer therapy. Combination therapy of AODNs and cytotoxic agents using biodegradable polymeric delivery systems potentially offers several advantages including site-specific or organ-directed targeting, protection from digesting enzymes, and improved pharmacokinetics/pharmacodynamics resulting from sustained delivery of the entrapped drugs. Using a model AODN targeting the epidermal growth factor receptor (that is over-expressed in several cancers including breast and brain cancer) and the commonly used cytotoxic agent, 5-fluorouracil (5-FU), we have examined the use of poly (lactide-co-glycolide) (P(LA-GA)) microsphere formulations for co-delivery of these agents. Both agents were either co-entrapped in a single microsphere formulation or individually entrapped in two separate microsphere formulations and release profiles determined in vitro. Using a double emulsion method for preparing the P(LA-GA) microspheres suitable entrapment and sustained release over 35 days was observed in both types of formulation. Release of AODN and 5-FU from all formulations appeared to be biphasic. However, the release rates of the two agents were significantly slower when co-entrapped as a single microsphere formulation compared to those obtained with the separate formulations. Electrophoretic mobility shift assays suggested that this might be, in part, due to an interaction of 5-FU with the oligodeoxynucleotide (ODN). Further, our data suggest that by mixing individual formulations of 5-FU and ODNs at different mass ratios allowed greater flexibility in achieving the desired release profile as well as avoiding potential drug–drug interactions. Thus, co-administration of individual P(LA-GA) microsphere formulations of AODNs and 5-FU, at appropriate mass ratios, appears worthy of further investigation for the potential co-delivery of these anti-cancer agents in vivo.
Keywords: Oligonucleotides; Cytotoxic agent; 5-Fluorouracil; Combination therapy; Cancer; Biodegradable polymer; Controlled release; Drug delivery;
Application of a factorial design to the study of specific parameters of a Carbopol ETD 2020 gel. Part I. Viscoelastic parameters by M.D Contreras; R Sánchez (139-147).
This work studies the application of a 23 factorial design to a cosmetic gel with the aim of simplifying the analysis of the influence of the concentration of Carbopol ETD 2020 (cb), of ethanol (et) and of glycerin (gl) on the viscoelastic parameters: equilibrium modulus (Gn), critical molecular weight (M c), degree of structuring (log G′/log ν) and viscous modulus (G″). We have obtained high linear polynomial correlations among the components and the response factors determined. The results obtained evidence the usefulness of this type of technique in detecting interactions among the components that would be difficult to foresee otherwise. M c, log G′/log ν and G″ depend on the interaction cb–et. Gn depends on the interaction of cb–et–gl. That is, an increase in gl can increase or decrease the elasticity (Gn) of the gels, depending on the concentrations of cb and et.
Keywords: Carbopol ETD 2020; Cosmetic; Factorial design; Gels; Viscoelasticity;
Application of a factorial design to the study of the flow behavior, spreadability and transparency of a Carbopol ETD 2020 gel. Part II by M.D Contreras; R Sanchez (149-157).
A factorial design (23) is applied to study the influence of three of the components of a cosmetic gel (the concentrations of Carbopol ETD 2020, ethanol and glycerine) on flow parameters (Casson's yield value (τ c), Casson's viscosity (η c) and apparent viscosity at 125 s−1 (η ap. 125 s−1)), spreadability, and transparency. The first-order polynomial equation allowed by the model suitably accounts for the τ c and spreadability. Both depend on the concentrations of Carbopol and ethanol, and τ c also depends on the ethanol–glycerine interaction. The model explains to a certain extent the complex relationships that are established between the components and that influence η c y η ap. 125 s−1. Transparency is independent of the Carbopol concentration and it is also thought to be independent of the ethanol concentration. In addition, a high linear correlation has been found between the τ c and spreadability and other viscoelastic parameters of the gels that were previously determined (Int. J. Pharm. (2001)). The application of the technique of experimental design has been shown to be a very useful tool for formulating gels.
Keywords: Carbopol ETD 2020; Factorial design; Flow; Gels; Spreadability; Transparency;
The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers by Gary H Kamimori; Chetan S Karyekar; Ronald Otterstetter; Donna S Cox; Thomas J Balkin; Gregory L Belenky; Natalie D Eddington (159-167).
Objective:The purpose of this study was to evaluate the rate of absorption and relative bioavailability of caffeine from a Stay Alert® chewing gum and capsule formulation. Methods: This was a double blind, parallel, randomized, seven treatment study. The treatment groups were: 50, 100, and 200 mg gum, 50, 100, and 200 mg capsule, and a placebo. Subjects consisted of 84 (n=12 per group); healthy, non-smoking, males who had abstained from caffeine ingestion for at least 20 h prior to dosing and were randomly assigned to the treatment groups. Blood samples were collected pre-dose and at 5, 15, 25, 35, 45, 55, 65, 90 min and 2, 3, 4, 6, 8, 12, 16 and 29 h post administration. Plasma caffeine levels were analyzed by a validated UV-HPLC method. Results: Mean T max for the gum groups ranged from 44.2 to 80.4 min as compared with 84.0–120.0 min for the capsule groups. The T max, for the pooled data was significantly lower (P<0.05) for the gum groups as compared with the capsule groups. Differences in T max were significant for the 200 mg capsule versus 200 mg gum (P<0.05). The mean k a values for the gum group ranged from 3.21 to 3.96 h−1 and for the capsule groups ranged from 1.29 to 2.36 h−1. Relative bioavailability of the gum formulation after the 50, 100 and 200 mg dose was 64, 74 and 77%, respectively. When normalized to the total drug released from the gum (85%), the relative bioavailability of the 50, 100 and 200 mg dose were 75, 87, and 90%, respectively. No statistical differences were found for C max and AUCinf for comparisons of the gum and capsule formulations at each dose. Within each dose level, there were no significant formulation related differences in C max. No significant differences were observed in the elimination of caffeine after the gum or capsule. Conclusions: The results suggest that the rate of drug absorption from the gum formulation was significantly faster and may indicate absorption via the buccal mucosa. In addition, for the 100 and 200 mg groups, the gum and capsule formulations provide near comparable amounts of caffeine to the systemic circulation. These findings suggest that there may be an earlier onset of pharmacological effects of caffeine delivered as the gum formulation, which is advantageous in situations where the rapid reversal of alertness and performance deficits resulting from sleep loss is desirable.
Keywords: Caffeine; Chewing gum; Relative bioavailability; Rate of absorption;
Principal component analysis of dissolution data with missing elements by E Adams; B Walczak; C Vervaet; P.G Risha; D.L Massart (169-178).
The use of principal component analysis (PCA) for incomplete dissolution data sets is examined. The PC space is constructed using a reference set and the test set is projected in that space. Several cases such as a reference set with missing data, an incomplete test set and both sets measured at different time points, are discussed using two examples: one simulation and one obtained from the pharmaceutical practice. From the many possibilities to deal with missing data, the expectation–maximization algorithm in combination with PCA was chosen. The influence on the similarity or f 2 factor is examined too. The sampling with replacement or bootstrap technique, which can be used to obtain confidence limits, can also be used when missing data are present in one of the data sets.
Keywords: Dissolution; Missing data; Expectation–maximization algorithm; Principal component analysis;
Optimization and characterization of controlled release multi-particulate beads formulated with a customized cellulose acetate butyrate dispersion by Siva Vaithiyalingam; Mansoor A Khan (179-193).
The objectives of the present investigation were: (1) to model the effect of process and formulation variables viz., coating weight gain, duration of curing, and plasticizer concentration on in-vitro release profile of verapamil HCl from multi-particulate beads formulated with a novel aqueous-based pseudolatex dispersion; (2) to optimize the formulation by response surface methodology (RSM) and artificial neural network (ANN); and (3) to characterize the optimized product by thermal and X-ray analyses. Inert beads (Nupareil®) were loaded with verapamil HCl and subsequently coated with a custom designed aqueous-based pseudolatex dispersion of cellulose acetate butyrate (CAB). Experiments were designed and data was collected according to a three factor, three level face centered central composite design. Data was analyzed for modeling and optimizing the release profile using both RSM and ANN. Model fitted the data and explained 90% of variability in response in the case of RSM and at least 70% in the case of ANN. Release profile was optimized for a zero-order model. Optimized formulations were prepared according to the factor combinations dictated by RSM and ANN. In each case, the observed drug release data of the optimized formulations was close to the predicted release pattern. However, the modeling and optimization abilities of RSM as evaluated by the R-squared values, were found to be higher than that of ANN. X-ray and drug content analysis suggested the absence of any degradation of verapamil HCl and excipients incorporated in the formulation.
Keywords: Cellulose acetate butyrate; Pseudolatex; Multi-particulate beads; Excipient compatibility; Central composite-face centered design; ANN; Mathematical modeling;
Preparation and characterization of fentanyl-loaded PLGA microspheres: in vitro release profiles by Hak Soo Choi; Sun-Ah Seo; Gilson Khang; John M. Rhee; Hai Bang Lee (195-203).
We developed several kinds of fentanyl-loaded poly(l-lactide-co-glycolide) (PLGA) microspheres (FMS) for sustained release of fentanyl. FMS were prepared by an emulsion solvent-evaporation method. In this study, the influences of several preparation parameters, such as initial drug loading, polymer concentration, and solvent volume on the release patterns of fentanyl were investigated. Furthermore, it has been well noted that the detection of fentanyl is extremely difficult because its clinical dose level is very low, about 1–3 ng/ml, in cancer-patient treatment. Therefore, we also developed a rapid and sensitive determination method for fentanyl in systemic circulation by employing gas chromatography (GC) system. Fentanyl was slowly released from FMS over 15 days with a quasi-zero order property. From the results, our FMS may be good formulations to deliver the analgesics and suitable for the treatment of severe pain over long periods.
Keywords: Fentanyl; Poly(l-lactide-co-glycolide); Microspheres; Solvent-evaporation method; Gas chromatography;
Impact of deep freezing on the stability of 25 mg/ml vancomycin ophthalmic solutions by V. Sautou-Miranda; F. Libert; A. Grand-Boyer; C. Gellis; J. Chopineau (205-212).
For the treatment of certain eye infections, ophthalmic solutions ‘laced’ with 25 mg/ml vancomycin are sometimes prepared. Their physical and chemical stability and the maintenance of their sterility were studied after deep freezing at −20±2 °C and thawing, followed or not by refrigeration for 48 h at 4±2 °C. Physical and chemical analysis comprised visual inspection turbidity, determination of pH and osmolality, and assay of vancomycin by high performance liquid chromatography with ultraviolet detection. For microbiological analysis a 25 mg/ml vancomycin ophthalmic solution was filtered through two membranes and cultured on trypticase-soy and Sabouraud-glucose solid media. Any colonies were then counted. These physical, chemical and microbiological analyses demonstrated the stability of 25 mg/ml vancomycin ophthalmic solutions in 5% glucose deep frozen at −20±2 °C for 3 months. The vancomycin concentration varied by no more than 5% of the initial concentration, and no breakdown product was evidenced. Neither pH (mean=3.8±0.1) nor osmolality (mean=318.3±5.6 mOsm/kg) varied significantly, and remained compatible with intraocular administration. No particle or bacterial combination was found in the course of the study. The thawing procedure (at ambient temperature or under warm running water from a tap) did not modify the stability of the eye drops. Likewise, storage in a refrigerator for 48 h after thawing did not modify stability. The advantage of storing vancomycin 25 mg/ml ophthalmic solutions for 3 months in deep freeze is that a stock of chemically and microbiologically controlled preparations can be held ready for administration to patients, thereby allowing prompter dispensing, as the eye drops are not made up extemporaneously, while the improved control over production ensures that patients receive solutions of constant quality, as every batch prepared is systematically inspected.
Keywords: Vancomycin; Ophthalmic solutions; Stability; Deep freezing;
Development of sustained release matrix tablets of didanosine containing methacrylic and ethylcellulose polymers by Carla Sánchez-Lafuente; M. Teresa Faucci; Mercedes Fernández-Arévalo; Josefa Álvarez-Fuentes; Antonio M. Rabasco; Paola Mura (213-221).
Didanosine, a nucleoside analog used in the treatment of acquired immuno deficiency syndrome (AIDS), has been incorporated into directly compressed monolythic matrices whose excipients were mixtures at different ratios of a methacrylic resin (Eudragit RSPM) and an ethylcellulose (Ethocel 100), both water-insoluble and pH-independent polymers. Technological characterization (drug particle morphology, mean weight, diameter, thickness and hardness of tablets) was carried out and in vitro drug release behaviour was measured using the USP basket apparatus. The effect of varying the Eudragit–Ethocel ratio, as well as the drug–polymeric matrix ratio, was evaluated. The results showed the suitability of Eudragit–Ethocel mixtures as matrix-forming material for didanosine sustained release formulations. Combination of the moderate swelling properties of Eudragit RSPM with the plastic properties of the more hydrophobic Ethocel 100 allowed suitable modulation of didanosine release.
Keywords: Didanosine; Eudragit; Ethocel; Sustained release; Matrix tablets;
Diethyl ether fraction of Labrasol having a stronger absorption enhancing effect on gentamicin than Labrasol itself by Zhaopeng Hu; Rama Prasad Yv; Riichi Tawa; Takahiro Konishi; Makoto Ishida; Nobuhito Shibata; Kanji Takada (223-235).
In our previous study, we had reported that Labrasol has a good gastrointestinal (GI) absorption enhancing effect on poorly absorbable drugs. In order to improve further absorption enhancing effect of Labrasol on gentamicin (GM), which is a representative water-soluble, poorly absorbable drug, Labrasol was fractionated with hexane, diethyl ether, ethyl acetate and water. The absorption enhancing effect of each fraction of Labrasol and Labrasol alone were evaluated in vivo using rats. Each test formulation of GM was administered into the rat colon at a dose of 5.0 mg/kg and plasma GM concentrations were measured by a HPLC method. Among the four fractions of Labrasol and Labrasol, diethyl ether fraction showed the strongest absorption enhancing effect on GM. When the doses of diethyl ether fraction were 1.0, 0.5 and 0.1 ml/kg, the C max values were 8.95±1.46, 8.02±2.14 and 7.41±1.25 μg/ml, respectively. Moreover, AUC0–6 values were also maintained at high level, i.e. 27.28±5.90, 20.32±3.79 and 19.61±2.09 μg h/ml. Based on the AUC0–6 values obtained with each fraction, the rank order of absorption enhancing effect on GM was diethyl ether>ethyl acetate≒hexane>aqueous fraction.
Keywords: Gentamicin sulfate (GM); Absorption enhancement; Labrasol; Diethyl ether fraction of Labrasol; Extraction; Rat colon;
Niosomes as carriers for tretinoin. I. Preparation and properties by Maria Manconi; Chiara Sinico; Donatella Valenti; Giuseppe Loy; Anna M Fadda (237-248).
Tretinoin-loaded niosomes were prepared from polyoxyethylene (4) lauryl ether, sorbitan esters and a commercial mixture of octyl/decyl polyglucosides, in the presence of cholesterol and dicetyl phosphate. Liposomes made of hydrogenated and non-hydrogenated phosphatidylcholine were also prepared as a comparison reference. A study was made of the influence of vesicle composition and preparation method on the vesicle structure (MLV, LUV, SUV), size distribution, entrapment efficiency and in vitro release of incorporated tretinoin. Results showed that in the presence of cholesterol all the amphiphiles used were able to form stable vesicle dispersions with or without tretinoin. Vesicle sizes were dependent on the preparation method, bilayer composition and drug load. Multilamellar (MLV) vesicles were larger than extruded (LUV) and sonicated (SUV) vesicles while drug-loaded vesicles were generally smaller than empty ones. Entrapment efficiencies of tretinoin were always very high especially for multilamellar (91–99%) and extruded (88–98%) vesicles. The in vitro release of tretinoin from the prepared vesicular formulations was studied using the vertical Franz diffusion cells. The rate of drug release through a Silastic membrane from a liposomal and niosomal tretinoin dispersion was generally faster than from a tretinoin solution. Release data showed that tretinoin delivery is mainly affected by the vesicular structure and that tretinoin delivery increased from MLVs to LUVs to SUVs.
Keywords: Niosomes; Non-ionic surfactant vesicles; Liposomes; Tretinoin; In vitro release;
Spectrophotometric investigation of the binding of vitamin E to water-containing reversed micelles by G Avellone; D Bongiorno; L Ceraulo; M Ferrugia; V Turco Liveri (249-255).
The distribution constants of vitamin E partitioned between apolar organic phase and water-containing reversed micelles of sodium bis (2-ethylhexyl) sulfosuccinate (AOT), didodecyldimethylammonium bromide (DDAB), soybean phosphatidylcholine (lecithin) and tetraethylene glycol monododecyl ether (C12E4) have been evaluated by a spectrophotometric method. The results suggest that in the presence of domains from apolar organic solvent to surfactant and to water, vitamin E is partitioned between the micellar palisade layer and the organic solvent and also that its binding strength to reversed micelles depends mainly by specific interactions between the head group of vitamin E and that of the surfactant. Moreover, in addition to the advantageous interactions between vitamin E and water, the dependence of the distribution constants upon the molar ratio R (R=[water]/[surfactant]) indicates a competition between water and vitamin E for the binding sites at the water/surfactant interface. The biological implications of the preferential location and confinement of vitamin E in water-containing reversed micelles are discussed.
Keywords: Vitamin E; Reversed micelles; Membrane models; UV–vis spectroscopy;
Effect of an external resistance to airflow on the inspiratory flow curve by J.P de Koning; Th.W van der Mark; P.M.J Coenegracht; Th.F.J Tromp; H.W Frijlink (257-266).
Inhalation is a convenient way to deliver drugs to the respiratory tract in the treatment of respiratory diseases. For dry powder inhalers (DPI's), the principle of operation is to use the patient-generated inspiratory flow as energy source for emptying of the dose system and the delivery of fine drug particles into the respiratory tract. Resistance to airflow of the inhaler device is a major determinant for the inspiratory flow profile through the dry powder inhaler that can be generated by the patient. Therefore, resistance to airflow is one of the design parameters for DPI's, that could be used to control the inspiratory flow profile, and is one of the parameters to optimise particle deposition in the airways. In this study the effect of resistance to airflow on different parameters of the inspiratory flow curves as generated by healthy subjects, asthmatics and COPD patients was determined. As a result of increased resistance to airflow, the peak inspiratory flow (PIF), the flow increase rate (FIR) and the inhaled volume to reach PIF is decreased. On the other hand, the total inhalation time as well as the 80% dwell time is increased. In general, tuning of the resistance to airflow in the design of a dry powder inhaler may improve the drug deposition in the respiratory tract.
Keywords: Dry powder inhaler; Resistance to airflow; Inspiratory flow curve; Pulmonary drug delivery; Peak inspiratory flow; Flow increase rate;