International Journal of Pharmaceutics (v.310, #1-2)
TITLE PAGE (EDI BOARD) (iii).
Influence of deposition and spray pattern of nasal powders on insulin bioavailability by E. Pringels; C. Callens; C. Vervaet; F. Dumont; G. Slegers; P. Foreman; J.P. Remon (1-7).
The influence of the deposition pattern and spray characteristics of nasal powder formulations on the insulin bioavailability was investigated in rabbits. The formulations were prepared by freeze drying a dispersion containing a physical mixture of drum dried waxy maize starch (DDWM)/Carbopol® 974P (90/10, w/w) or a spray-dried mixture of Amioca® starch/Carbopol® 974P (25/75, w/w). The deposition in the nasal cavity of rabbits and in a silicone human nose model after actuation of three nasal delivery devices (Monopowder, Pfeiffer and experimental system) was compared and related to the insulin bioavailability. Posterior deposition of the powder formulation in the nasal cavity lowered the insulin bioavailability.To study the spray pattern, the shape and cross-section of the emitted powder cloud were analysed. It was concluded that the powder bulk density of the formulation influenced the spray pattern. Consequently, powders of different bulk density were prepared by changing the solid fraction of the freeze dried dispersion and by changing the freezing rate during freeze drying. After nasal delivery of these powder formulations no influence of the powder bulk density and of the spray pattern on the insulin bioavailability was observed.
Keywords: Powder formulation; Deposition; Spray pattern; Bulk density; Nasal bioavailability; Insulin;
Evaluation of human serum albumin as a substitute of foetal bovine serum for cell culture by M. De Castro; G. Orive; A.R. Gascón; R.M. Hernandez; J.L. Pedraz (8-14).
Cell microencapsulation requires clinically approved materials for their use in pharmaceutical and/or biomedical applications. The overwhelming majority of the literature has used the classical alginate-poly-l-lysine-alginate (APA) capsules for cell immobilization. Although alginate is granted with the medical approval, some of the remaining components such as foetal bovine serum (FBS), an essential ingredient of cell culture media, are not in accordance with the guidelines affirmed by the American Society for Testing and Materials (ASTM) and Food and Drug Administration (FDA). In this paper, human serum albumin (HSA), a medically approved substance, was evaluated as a potential substitute of FBS. The effect of different percentages of FBS and HSA was studied on the proliferation rate, viability and protein production of two different cell lines (C2C12 and baby hamster kidney (BHK) cells), maintained in culture and immobilized in APA microcapsules. Results show that substitution of FBS by HSA reduced the functionality of both non-encapsulated and encapsulated BHK cells. However, immobilized C2C12 cells presented the highest level of viability and a reduction in protein production of 25% when 1% HSA was used. It can be concluded that HSA might be a possible substitute of FBS in order to maintain or transport encapsulated C2C12 cells for short periods of time before implantation.
Keywords: Encapsulation; Human serum albumin; Foetal bovine serum; C2C12 cells; BHK cells; Culture medium;
An in vitro study of the design and development of a novel doughnut-shaped minitablet for intraocular implantation by Yahya E. Choonara; Viness Pillay; Trevor Carmichael; Michael P. Danckwerts (15-24).
A novel doughnut-shaped minitablet (DSMT) was developed and evaluated as a biodegradable intraocular drug delivery system for rate-modulated delivery of antiviral bioactives. The DSMT device was manufactured using a special set of punches fitted with a central-rod in a Manesty tableting press. The DSMT device released the antiretrovirals foscarnet and ganciclovir at a first-order rate. The erosion kinetics was assessed by gravimetric analysis and scanning electron microscopy. The device gradually eroded when immersed in simulated vitreous humor (SVH) (pH 7.4, 37 °C) and released bioactives in a sustained manner. The novel geometric design and veracity of the DSMT device was retained even after 24 weeks of erosion. When considering the duration of the bioactive released from the DSMT device, it was found that by the careful selection of the type and concentration of polymer employed in formulating the DSMT device, it was possible to produce a device that could release drug for any period up to 12 months.
Keywords: Cytomegalovirus retinitis; Doughnut-shaped minitablet (DSMT); Extended release; Polylactide-co-glycolide (PLGA); Biodegradation; Intraocular implantation;
Quantitative estimation of film forming polymer–plasticizer interactions by the Lorentz–Lorenz Law by J. Dredán; R. Zelkó; Á.Z. Dávid; I. Antal (25-30).
Molar refraction as well as refractive index has many uses. Beyond confirming the identity and purity of a compound, determination of molecular structure and molecular weight, molar refraction is also used in other estimation schemes, such as in critical properties, surface tension, solubility parameter, molecular polarizability, dipole moment, etc.In the present study molar refraction values of polymer dispersions were determined for the quantitative estimation of film forming polymer–plasticizer interactions.Information can be obtained concerning the extent of interaction between the polymer and the plasticizer from the calculation of molar refraction values of film forming polymer dispersions containing plasticizer.
Keywords: Molar refraction; Polymer–plasticizer interaction; Film coating;
Synthesis and transdermal properties of acetylsalicylic acid and selected esters by Minja Gerber; Jaco C. Breytenbach; Jonathan Hadgraft; Jeanetta du Plessis (31-36).
The primary aim of this study was to determine the transdermal penetration of acetylsalicylic acid and some of its derivatives, to establish a correlation, if any, with selected physicochemical properties and to determine if transdermal application of acetylsalicylic acid and its derivatives will give therapeutic drug concentrations with respect to transdermal flux. Ten derivatives of acetylsalicylic acid were prepared by esterification of acetylsalicyloyl chloride with ten different alcohols. The experimental aqueous solubility, log D and transdermal flux values were determined for acetylsalicylic acid and its derivatives at pH 4.5. In vitro penetration was measured through excised female human abdominal skin in diffusion cells. The experimental aqueous solubility of acetylsalicylic acid (6.56 mg/ml) was higher than that of the synthesised acetylsalicylate derivatives (ranging from 1.76 × 10−3 to 3.32 mg/ml), and the log D of acetylsalicylic acid (−0.85) was lower than that of its derivatives (ranging from −0.25 to 1.95). There was thus an inverse correlation between the aqueous solubility data and the log D values. The experimental transdermal flux of acetylsalicylic acid (263.83 nmol/cm2 h) was much higher than that of its derivatives (ranging from 0.12 to 136.02 nmol/cm2 h).
Keywords: Acetylsalicylic acid; Skin penetration; Transdermal delivery;
Synthesis and characterization of membranes obtained by graft copolymerization of 2-hydroxyethyl methacrylate and acrylic acid onto chitosan by K.S.C.R. dos Santos; J.F.J. Coelho; P. Ferreira; I. Pinto; S.G. Lorenzetti; E.I. Ferreira; O.Z. Higa; M.H. Gil (37-45).
Chitosan based membranes to be applied on wound healing as topical drug delivery systems were developed by graft copolymerization of acrylic acid (AA) and 2-hydroxyethyl methacrylate (HEMA) onto chitosan using cerium ammonium nitrate as chemical initiator. Evidence for graft copolymerization of the vinyl monomers onto chitosan was obtained by FTIR and DMTA. Swelling degree, cytotoxicity, thrombogenicity and haemolytic activity of these membranes were evaluated. Chitosan-graft-AA-graft-HEMA showed to be the best matrix for drug delivery systems than chitosan-graft-AA because it retains good swelling properties, but the content in HEMA has improved cytocompatibility, hemocompatibility and thrombogenic character.
Keywords: Chitosan; Acrylic acid; 2-Hydroxyethyl methacrylate; Membranes; Wound healing;
Pharmacokinetic and pharmacodynamic studies following oral administration of erythropoietin mucoadhesive tablets to beagle dogs by N. Venkatesan; J. Yoshimitsu; Y. Ohashi; Y. Ito; N. Sugioka; N. Shibata; K. Takada (46-52).
Oral administration of mucoadhesive tablets containing erythropoietin (EPO) and an absorption enhancer Labrasol was studied in rats and dogs. Mucoadhesive tablets were prepared using Sylysia 550 holding the absorption enhancer and Carbopol 974P as a mucoadhesive agent. Mucoadhesive tablets were covered with a water-insoluble backing layer made of cellulose acetate and a pH-sensitive covering layer made of Eudragit L/Eudragit S. Tablet was administered into the rat jejunum at EPO dose of 100 IU/kg and serum samples were collected for 6 h. Serum EPO level was analysed with a standard ELISA procedure. After administration, rats showed a maximum serum EPO level of C max 70.6 ± 8.9 mIU/ml. Oral administration of a single tablet containing 100 IU/kg EPO to beagle dogs showed a C max of 24.6 ± 4.1. When EPO dose was increased to 500 IU/kg and the number of tablets was also increased to 5, the C max was 54.8 ± 9.0 mIU/ml. However, when EPO, 100 IU/kg dose was divided into five tablets, the C max was 15.5 ± 1.8 mIU/ml. In the absence of absorption enhancer, the C max was 35.8 ± 3.8 with 500 IU/kg dose distributed among five tablets. Pharmacodynamic studies were carried out following oral administration of mucoadhesive tablets for 6 consecutive days at an EPO dose of 500 IU/kg. Whole blood samples were collected and percent circulating reticulocytes were counted using Miller technique. The increase in percent circulating reticulocytes was found to be 1.7% on day 8 following oral administration. As a control study, EPO was administered by i.v. route at a dose of 300 IU/kg for 3 consecutive days and the percent circulating reticulocytes were counted. Mucoadhesive tablets showed promising results as an oral drug delivery system for protein therapeutics.
Keywords: Erythropoietin; Labrasol; Mucoadhesive tablets; Oral; Reticulocytes;
Enhancement of drug affinity for cell membranes by conjugation with lipoamino acids by Rosario Pignatello; Salvatore Guccione; Francesco Castelli; Maria G. Sarpietro; Laura Giurato; Massimo Lombardo; Giovanni Puglisi; Istvan Toth (53-63).
Lipoamino acids (LAAs) are promoieties able to enhance the amphiphilicity of drugs, facilitating their interaction with cell membranes. Experimental and computational studies were carried out on two series of lipophilic amide conjugates between a model drug (tranylcypromine, TCP) and LAA or alkanoic acids containing a short, medium or long alkyl side chain (C-4 to C-16). The effects of these compounds were evaluated by monolayer surface tension analysis and differential scanning calorimetry using dimyristoylphosphatidylcholine monolayers and liposomes as biomembrane models. The experimental results were related to independent calculations to determine partition coefficient and blood–brain partitioning. The comparison of TCP–LAA conjugates with the related series of TCP alkanoyl amides confirmed that the ability to interact with the biomembrane models is not due to the mere increase of lipophilicity, but mainly to the amphipatic nature and the kind of LAA residue.
Keywords: Lipoamino acids; Tranylcypromine; Lipophilicity; Amphiphilicity; Differential scanning calorimetry (DSC); Biomembrane model; Langmuir–Blodgett film balance;
The expulsion of lipophilic drugs from the cores of solid lipid microspheres in diluted suspensions and in concentrates by Justyna Pietkiewicz; Malgorzata Sznitowska; Marcin Placzek (64-71).
The aim of the study was to compare incorporation of bupivacaine base, bupivacaine stearate and indomethacin in diluted suspensions of lipospheres (10%, w/w of lipid) and in concentrates (50%, w/w of lipid). The lipid cores were composed of a mixture of solid and liquid triglycerides (Precirol and Miglyol 4:1). The lipospheres sizing between 0.5–10 μm (suspensions) and 0.5–20 μm (concentrates) were prepared using a hot emulsification with high-shear mixing and cold resolidification method. None of the studied drugs was successfully incorporated in the lipid core. The increased incorporation of drugs determined in the concentrated lipospheres was only apparent, since in fact all the dose was only attached to the surface of the lipid particles and was transferred to the aqueous phase in the course of an intensive agitation. The presence of hydrophilic polymers in the aqueous phase did not prevent the expulsion effect although drug precipitation was retarded. The expulsion effect did not correlate with the solubility of drugs determined in the bulk lipids.
Keywords: Lipospheres; Concentrated lipospheres; Bupivacaine; Bupivacaine stearate; Indomethacin; Expulsion; Incorporation;
Air classifier technology (ACT) in dry powder inhalation by A.H. de Boer; P. Hagedoorn; D. Gjaltema; J. Goede; H.W. Frijlink (72-80).
In this study, the design of a multifarious classifier family for different applications is described. The main design and development steps are presented as well as some special techniques that have been applied to achieve preset objectives. It is shown by increasing the number of air supply channels to the classifier chamber (from 2 to 8), that the fine particle losses from adhesion onto the classifier walls can be reduced from 75% to less than 5% of the real dose for soft (spherical) agglomerates. By applying a bypass flow that is arranged as a co-axial sheath of clean air around the aerosol cloud from the classifier, the airflow resistance of the classifier can be controlled over a relatively wide range of values (0.023–0.041 kPa0.5 min l−1). This, without affecting the fine particle dose or increasing the fine particle losses in the inhaler. Moreover, the sheath flow can be modelled to reduce the depositions in the induction port to the cascade impactor or in the patient's mouth, which are the result of back flows in these regions. The principle of powder induced pressure drop reduction across a classifier enables assessment of the amount of powder in the classifier at any moment during inhalation, from which classifier loading (from the dose system) and discharge rates can be derived. This principle has been applied to study the residence time of a dose in the classifier as function of the carrier size fraction and the flow rate. It has been found that this residence time can be controlled in order to obtain an optimal balance between the generated fine particle fraction and the inhalation manoeuvre of the patient. A residence time between 0.5 and 2 s at 60 l/min is considered favourable, as this yields a high fine particle dose (depending on the type of formulation used) and leaves sufficient inhaled volume for particle transport into the deep lung.
Keywords: Dry powder inhalation; Air classifier technology; Novolizer®; Adhesive mixtures; Carrier lactose; Spherical pellets;
Air classifier technology (ACT) in dry powder inhalation by A.H. de Boer; P. Hagedoorn; D. Gjaltema; J. Goede; H.W. Frijlink (81-89).
In this study, the in vitro fine particle deposition from a multi dose dry powder inhaler (Novolizer®) with air classifier technology has been investigated. It is shown that different target values for the fine particle fraction (fpf < 5 μm) of the same drug can be achieved in a well-controlled way. This is particularly relevant to the application of generic formulations in the inhaler. The well-controlled and predictable fpf is achieved through dispersion of different types of formulations in exactly the same classifier concept. On the other hand, it is shown that air classifier-based inhalers are less sensitive to the carrier surface and bulk properties than competitive inhalers like the Diskus®. For 10 randomly selected lactose carriers for inhalation from four different suppliers, the budesonide fpf (at 4 kPa) from the Novolizer® varied between 30 and 46% (of the measured dose; R.S.D. = 14.2%), whereas the extremes in fpf from the Diskus® dpi were 7 and 44% (R.S.D. = 56.2%) for the same formulations. The fpf from a classifier-based inhaler appears to be less dependent of the amount of lactose (carrier) fines (<15 μm) in the mixture too. Classifier-based inhalers perform best with coarse carriers that have relatively wide size distributions (e.g. 50–350 μm) and surface discontinuities inside which drug particles can find shelter from press-on forces during mixing. Coarse carrier fractions have good flow properties, which increases the dose measuring accuracy and reproducibility. The fpf from the Novolizer® increases with increasing pressure drop across the device. On theoretical grounds, it can be argued that this yields a more reproducible therapy, because it compensates for a shift in deposition to larger airways when the flow rate is increased. Support for this reasoning based on lung deposition modelling studies has been found in a scintigraphic study with the Novolizer®. Finally, it is shown that this inhaler produces a finer aerosol than competitor devices, within the fpf < 5 μm, subfractions of particles (e.g. <1, 1–2, 2–3, 3–4 and 4–5 μm) are higher.
Keywords: Air classifier technology; Dry powder inhalation; Carrier lactose; Fine particle fraction; Novolizer®; Adhesive mixtures;
Properties of sustained release hot-melt extruded tablets containing chitosan and xanthan gum by Mamoru Fukuda; Nicholas A. Peppas; James W. McGinity (90-100).
The aim of this study was to investigate the influence of pH, buffer species and ionic strength on the release mechanism of chlorpheniramine maleate (CPM) from matrix tablets containing chitosan and xanthan gum prepared by a hot-melt extrusion process. Drug release from hot-melt extruded (HME) tablets containing either chitosan or xanthan gum was pH and buffer species dependent and the release mechanisms were controlled by the solubility and ionic properties of the polymers. All directly compressed (DC) tablets prepared in this study also exhibited pH and buffer species dependent release. In contrast, the HME tablets containing both chitosan and xanthan gum exhibited pH and buffer species independent sustained release. When placed in 0.1N HCl, the HME tablets formed a hydrogel that functioned to retard drug release in subsequent pH 6.8 and 7.4 phosphate buffers even when media contained high ionic strength, whereas tablets without chitosan did not form a hydrogel to retard drug release in 0.1N HCl. The HME tablets containing both chitosan and xanthan gum showed no significant change in drug release rate when stored at 40 °C for 1 month, 40 °C and 75% relative humidity (40 °C/75% RH) for 1 month, and 60 °C for 15 days.
Keywords: Chitosan; Xanthan gum; Hot-melt extrusion; Sustained release; Hydrogel; pH independent release; Buffer species independent release;
Evaluation of rapidly disintegrating tablets containing glycine and carboxymethylcellulose by Jinichi Fukami; Etsuo Yonemochi; Yasuo Yoshihashi; Katsuhide Terada (101-109).
A rapidly disintegration tablet in the oral cavity was prepared using a glycine as a disintegrant. Effect of disintegrant on the disintegration behavior of the tablet in the oral cavity was evaluated. Wetting time prepared from carboxymethylcellulose (NS-300) having the hardness of 4 kg was 3 s. Tablet containing NS-300 showed fastest disintegration compared to other formulations. These results suggested that NS-300 possessed excellent wetting nature and resulted in the rapid disintegration of tablet. Ethenzamide and ascorbic acid were added to the formulation, and their disintegration behavior were evaluated. Ethenzamide did not affect the disintegration property, however, ascorbic acid prolonged disintegration time. It was suggested that the tablet formulation containing NS-300 and glycine was highly applicable to water-insoluble drug, such as ethenzamide.
Keywords: Rapidly disintegrating tablets; Glycine; Carboxymethylcellulose;
In vitro permeation of repellent DEET and sunscreen oxybenzone across three artificial membranes by Tao Wang; Sreeneeranj Kasichayanula; Xiaochen Gu (110-117).
DEET and oxybenzone are two essential active ingredients in repellent and sunscreen products. We performed a series of in vitro diffusion studies to evaluate the transmembrane permeation of DEET and oxybenzone across three artificial membranes, low-density polyethylene (LDPE), low fouling composite (LFC) and mixed cellulose esters (MCE), from concurrent use of commercial repellent and sunscreen preparations. Permeation of DEET and oxybenzone across the test membranes was synergistically increased when both the repellent and the sunscreen formulations were applied simultaneously. Different application sequences and formulation types also resulted in variable permeation profiles of DEET and oxybenzone. Compared to biological piglet epidermis under the identical experimental conditions, transmembrane permeation of DEET was suppressed in LDPE and LFC membranes, but enhanced in MCE membrane; transmembrane permeation of oxybenzone was reduced in LFC membrane, but increased in LDPE and MCE membranes. Permeability coefficients of DEET and oxybenzone in all three artificial membranes were significantly different from those in piglet skin. It was concluded that the permeation profiles of the compounds were dependent upon physicochemical characteristics of the membranes and the formulations.
Keywords: Diffusion; Membrane transport; Permeability; Concurrent use; Insect repellents; Sunscreens;
Taste masking analysis in pharmaceutical formulation development using an electronic tongue by Jack Y. Zheng; Melissa P. Keeney (118-124).
The purpose of this study is to assess the feasibility for taste masking and comparison of taste intensity during formulation development using a multichannel taste sensor system (e-Tongue). Seven taste sensors used in the e-Tongue were cross-selective for five basic tastes while having different sensitivity or responsibility for different tastes. Each of the individual sensors concurrently contributes to the detection of most substances in a complicated sample through the different electronic output. Taste-masking efficiency was evaluated using quinine as a bitter model compound and a sweetener, acesulfame K, as a bitterness inhibitor. In a 0.2 mM quinine solution, the group distance obtained from e-Tongue analysis was reduced with increasing concentration of acesulfame K. This result suggests that the sensors could detect the inhibition of bitterness by a sweetener and could be used for optimization of the sweetener level in a liquid formulation. In addition, the bitterness inhibition of quinine by using other known taste-masking excipients including sodium acetate, NaCl, Prosweet® flavor, and Debittering® powder or soft drinks could be detected by the e-Tongue. These results further suggest that the e-Tongue should be useful in a taste-masking evaluation study on selecting appropriate taste-masking excipients for a solution formulation or a reconstitution vehicle for a drug-in-bottle formulation. In another study, the intensity of the taste for several drug substances known to be bitter was compared using the e-Tongue. It was found that the group distance was 695 for prednisolone and 686 for quinine, which is much higher than that of caffeine (102). These results indicate that the taste of prednisolone and quinine is stronger or more bitter than that of caffeine as expected. Based on the group distance, the relative intensity of bitterness for these compounds could be ranked in the following order: ranitidine HCl > prednisolone Na > quinine HCl∼phenylthiourea > paracetamol ≫ sucrose octaacetate > caffeine. In conclusion, the multichannel taste sensor or e-Tongue may be a useful tool to evaluate taste-masking efficiency for solution formulations and to compare bitterness intensity of formulations and drug substances during pharmaceutical product development.
Keywords: Taste sensor; e-Tongue; Bitterness; Quinine; Caffeine; Formulation; Solution; Excipients; Principal component analysis; Bitterness inhibition; Preformulation;
Radiopharmacokinetic and dosimetric parameters of 188Re-lanreotide in athymic mice with induced human cancer tumors by Eva M. Molina-Trinidad; Consuelo Arteaga de Murphy; Guillermina Ferro-Flores; Eduardo Murphy-Stack; Helgi Jung-Cook (125-130).
Radiolabeled peptides, like the somatostatin analogs, have been used for peptide receptor-mediated radionuclide therapy (PRMRT) in metastatic neuroendocrine tumors.The eight amino acid peptide 3-(2-naphthalenyl)-d-alanyl-l-cysteinyl-l-tyrosyl-d-tryptophyl-l-lysyl-l-valyl-l-cysteinyl-l-threoninamide,cyclic(2 → 7)-disulfide (9Cl) (lanreotide) was found to bind to the five somatostatin tumor receptors. Lanreotide has been labeled via the bifunctional chelating agent, DOTA, to 111In, and 90Y. A direct labeling method was used to label lanreotide with 188Re. Athymic mice with implanted human cancer tumors (uterine-cervix, renal, and neuroblastoma) were injected with radiochemically pure 188Re-lanreotide (1.11 MBq). The percent injected activity (%IA/g) from serial blood samples was the input data for the WinNonlin computer program to obtain radiopharmacokinetic parameters. The organs’ percent injected activity per gram of tissue (%IA/g) was extrapolated to the weights of a 70 kg male model organs and the number of nuclear transitions (N) were the input for the OLINDA/EXM program to obtain dosimetry estimates. Induced uterine-cervix tumors (HeLa cells) show a mean 2.4 %IA/g uptake up to 24 h and the tumor/blood ratio was over 1.85 (1.5–24 h post-injection) confirming 188Re-lanreotide remains bound to the tumor. The estimated tumor absorbed dose was 460 mGy/MBq. Human effective dose was 0.0182 mSv/MBq. Therefore, 188Re-lanreotide is a good candidate for PRMRT and a clinical trial is being planned in order to acquire individual dosimetric data.
Keywords: 188Re-lanreotide; Implanted tumors in athymic mice; Pharmacokinetics; Dosimetry; OLINDA code;
Enhancement of the transdermal delivery of catechins by liposomes incorporating anionic surfactants and ethanol by Jia-You Fang; Tsong-Long Hwang; Yen-Ling Huang; Chia-Lang Fang (131-138).
The aim of this study was to develop and evaluate liposomal formulations encapsulating tea catechins, which possess antioxidant and chemopreventive activities. Liposomes were characterized for size, zeta potential, and entrapment efficiency. Both in vitro and in vivo skin permeation were examined using nude mouse skin as a model. The results suggested that the liposomal composition plays an important role in affecting the efficiency of transdermal catechin delivery. Incorporation of anionic surfactants such as deoxycholic acid (DA) and dicetyl phosphate (DP) in the liposomes in the presence of 15% ethanol increased the (+)-catechin permeation by five to seven-fold as compared to the control. The flexibility of bilayers is suggested as an important factor governing the enhancing effect of liposomes. Intercellular spaces within the stratum corneum but not shunt routes are the major pathways for catechin delivery from liposomes. (+)-Catechin and (−)-epicatechin are isomers which showed similar encapsulation efficiencies and skin permeation in liposomes. (−)-Epigallocatechin-3-gallate showed the highest encapsulation rate and in vivo skin deposition level in liposomes among all catechins tested. The stability and in vitro tranepidermal water loss test indicated the safety of the practical use of liposomes developed in this study.
Keywords: Catechins; Transdermal delivery; Liposomes; Ethanol;
Floating matrix dosage form for phenoporlamine hydrochloride based on gas forming agent: In vitro and in vivo evaluation in healthy volunteers by Xiaoqiang Xu; Minjie Sun; Feng Zhi; Yiqiao Hu (139-145).
Phenoporlamine hydrochloride is a novel compound that is used for the treatment of hypertension. The purpose of this study was to develop a sustained release tablet for phenoporlamine hydrochloride because of its short biological half-life. Three floating matrix formulations of phenoporlamine hydrochloride based on gas forming agent were prepared. Hydroxypropyl methylcellulose K4M and Carbopol 971P NF were used in formulating the hydrogel drug delivery system. Incorporation sodium bicarbonate into matrix resulted in the tablet floating over simulated gastric fluid for more than 6 h. The dissolution profiles of all tablets showed non-Fickian diffusion in simulated gastric fluid. Moreover, release of the drug from these tablets was pH-dependent. In vivo evaluations of these formulations of phenoporlamine hydrochloride were conducted in six healthy male human volunteers to compare the sustained release tablets with immediate release tablets. Data obtained in these studies demonstrated that the floating matrix tablet containing more Carbopol was capable of sustained delivery of the drug for longer periods with increased bioavailability and the relative bioavailability of formulation (containing 25% Carbopol 971P NF, 8.3% HPMC K4M) showed the best bioequivalency to the reference tablet (the relative bioavailability was 1.11 ± 0.19).
Keywords: Phenoporlamine hydrochloride; Floating matrix; Sustained release; Bioavailability; In vitro–in vivo correlation;
Dissolution characteristics of cylindrical particles and tablets by Tadashi Fukunaka; Yoshiko Yaegashi; Taku Nunoko; Ryusei Ito; Boris Golman; Kunio Shinohara (146-153).
In this paper, dissolution characteristics of primary-particles and compressed tablets were investigated by experiments using a mathematical model. For the primary-particle, it was found that the dissolution rate increased with a decrease in the particle size. Assuming that primary-particles of size distribution were of cylindrical shape and that the dissolution occurs from the total external surface, an extended Nernst–Noyes–Whitney equation fitted to the experimental data well. As the influences of particle size and shape on thickness of a diffusion-boundary film were found to be quite low, the dissolution rate was considered to be affected by the specific surface area dominantly. Furthermore, the same model was applied to a compressed tablet and fitted to the data well. Though the rate constant obtained were not affected by the properties of primary-particles forming the tablet, it was found to increase with the apparent voidage which occupies the inter-particle volume of tablet diluent among less soluble particles. Consequently, an increase in the apparent voidage is presumed to accelerate penetration of water into the internal voids of the tablet. Thus, the dissolution going, the effective surface area inside the tablet is considered to be extended.
Keywords: Dissolution; Mathematical model; Tablet; Particle shape; Particle size; Active pharmaceutical ingredients;
A new hydrogel for the extended and complete prednisolone release in the GI tract by G. Di Colo; A. Baggiani; Y. Zambito; G. Mollica; M. Geppi; M.F. Serafini (154-161).
The issue of incomplete release of poorly soluble drugs from sustained-release oral formulations is addressed using prednisolone (PDS) as the model drug and a novel highly swelling hydrogel as the rate-controlling material. The hydrogel was formed by heating N-carboxymethylchitosan (CMC) to 80 °C for 24 h. Swelling, alkalimetry, FTIR, DSC, and solid-state NMR studies showed that the treatment produced physical crosslinking, i.e., polymer chain entanglement. A controlled-release system was prepared by coating an inert compacted support of ethylcellulose (50 mg; diameter, 6 mm) with a CMC layer containing dispersed PDS powder (10–50 μm). The system was heated to crosslink the CMC coating, then drug release to simulated GI fluids was studied in vitro. The drug release pattern and term were modulated via the layer mass (LM) (10 or 14 mg cm−2) and/or the drug–polymer wt ratio (D/P) (1:5 or 2:5). The rate parameter, K, and the time exponent, n, of the Peppas equation were: K = 26.6 ± 0.3 h−n , n = 0.78 ± 0.02 (LM, 10 mg cm−2; D/P, 1:5); K = 24.7 ± 0.7 h−n , n = 0.56 ± 0.02 (LM, 14 mg cm−2; D/P, 1:5); K = 20.7 ± 0.3 h−n , n = 0.76 ± 0.01 (LM, 10 mg cm−2; D/P, 2:5). Hydrogel swelling was faster than drug release. This was controlled, in a first stage, by drug dissolution–diffusion in the swollen gel, and subsequently, by diffusion. The drug release rate was unaffected by the GI pH variations, and slightly affected by the environmental hydrodynamics. The system promises an extended and complete release of poorly soluble drugs in the GI tract.
Keywords: Prednisolone; Controlled-release system; Hydrogel; N-Carboxymethylchitosan; Solid-state NMR; Release mechanism;
Effects of incorporated drugs on degradation of novel 2,2′-bis(2-oxazoline) linked poly(lactic acid) films by Tommy Tarvainen; Minna Malin; Isabel Barragan; Jukka Tuominen; Jukka Seppälä; Kristiina Järvinen (162-167).
Earlier studies have indicated that the degradation rate of poly(lactic acid) (PDLLA) can be modified by using 2,2′-bis(2-oxazoline) as a chain extender in polymer synthesis to form a lactic acid-based poly(ester-amide) (PEA). In the present study, the effect of an incorporated drug on the degradation rate of the PEA was evaluated. The model drugs, neutral guaifenesin, acidic sodium salicylate (pK a 3.0) and basic timolol (pK a 9.2), were incorporated into solvent cast PDLLA and PEA films. The drug content in the films was 2% (w/w). The degradation studies were carried out in PBS (pH 7.4, 37 °C); the resulting decrease in molecular weight of polymers was determined by size exclusion chromatography and the weight loss of films was measured. In addition, the drug release from the films in PBS (pH 7.4, 37 °C) was studied. The model drugs were released from the PDLLA and PEA films in a biphasic or triphasic manner. The final fast release phase of the drugs from both PDLLA and PEA films started when the molecular weight (M n) of the polymer had decreased close to 15,000 g/mol. The degradation rate of the PDLLA films was clearly enhanced by incorporated sodium salicylate or timolol. Whereas, the degradation rate of the PEA film was not enhanced by the incorporated drugs. The present results indicate that when compared to the PDLLA film, degradation rate of the PEA film in the presence of the drug is more predictable.
Keywords: Hydrolysis; Degradation; 2,2′-Bis(2-oxazoline) chain extender; Poly(lactic acid); Poly(ester-amide);
Effect of drug particle size in ultrasound compacted tablets by Mónica Millán; Isidoro Caraballo (168-174).
The main objective of this work is to study the influence of the drug particle size on the pharmaceutical availability of ultrasound compacted tablets. Inert matrix systems containing different drug particle sizes were prepared using both, an ultrasound-assisted press and a traditional eccentric machine. Potassium chloride was used as drug model and Eudragit® RS-PM as matrix forming excipient. The excipient particle size was kept constant. The cross-sectional microphotographs of ultrasound tablets show the existence of a quasi-continuum medium. Keeping constant the drug load, US-tablets showed very similar release rates, whereas for traditional tablets, an increase in the particle size resulted in a clear decrease in the release rate. In these tablets, the excipient forms an almost continuum medium. In an infinite theoretical system of these characteristics, the size of the drug particles will not modify the percolation threshold. The percolation of the excipient in this system can be assimilated to a continuum percolation model. In accordance with the proposed model, a lower influence of the drug particle size on the drug release rate was obtained for the US-tablets in comparison with traditional tablets. This fact can be indicative of the similarity of the drug percolation thresholds in these systems.
Keywords: Matrix tablet; Ultrasound-assisted press; Continuum percolation; Percolation threshold;
Calorimetric investigation of protein/amino acid interactions in the solid state by Fei Tian; Samir Sane; J. Howard Rytting (175-186).
Possible protein/amino acid interactions and the physical states of amino acids after freeze-drying have been studied using isoperibol calorimetry and differential scanning calorimetry (DSC). Good linear correlations (R 2 = 0.99) between the enthalpies of solution and the percentage of antibody in all physical mixtures, as well as unchanging melting temperatures of amino acids for physical mixtures demonstrated that there is no interaction between the antibodies and amino acids studied upon physical mixing. On the other hand, positive deviations for antibody/histidine and antibody/arginine freeze-dried samples obtained from the isoperibol calorimetry results demonstrated that molecular level interactions, such as ion–dipole or electrostatic interactions or hydrogen bonding, occur between antibodies and histidine or arginine. The values of ΔH interaction for antibody/histidine (1:1, w/w) and antibody/arginine (1:1, w/w) lyophilized samples were approximately 8 kJ/mol. These interactions were also confirmed by decreased and/or the disappearance of melting temperatures of the amino acids with DSC measurements. A negative deviation from linearity was detected for antibody/aspartic acid lyophilized samples which indicated partial amorphization of aspartic acid. No deviation from linearity as well as similar melting temperatures of antibody/glycine lyophilized samples indicated the absence of interactions between the antibodies and glycine upon freeze-drying.
Keywords: Antibody/amino acid interactions; Calorimetry; Freeze-dried state;
Zinc(II) phthalocyanine loaded PLGA nanoparticles for photodynamic therapy use by Eduardo Ricci-Júnior; Juliana Maldonado Marchetti (187-195).
Sophisticated delivery systems, such as nanoparticles, represent a growing area in biomedical research. Nanoparticles (Np) were prepared using a solvent emulsion evaporation method (SEEM) to load zinc(II) phthalocyanine (ZnPc). Np were obtained using poly (d,l latic-co-glycolic acid) (PLGA). ZnPc is a second generation of photoactive agents used in photodynamic therapy.ZnPc loaded PLGA nanoparticles were prepared by SEEM, characterized and available in cellular culture. The process yield and encapsulation efficiency were 80 and 70%, respectively. The nanoparticles have a mean diameter of 285 nm, a narrow size distribution with polydispersive index of 0.12, smooth surface and spherical shape. ZnPc loaded nanoparticles maintains its photophysical behavior after encapsulation. Photosensitizer release from nanoparticles was sustained with a moderate and burst effect of 15% for 3 days. The photocytotoxicity of ZnPc loaded PLGA Np was evaluated on P388-D1 cells what were incubated with ZnPc loaded Np (5 μM) by 6 h and exposed to red light (675 nm) for 120 s, and light dose of 30 J/cm2. After 24 h of incubation, the cellular viability was determined, obtaining 61% of cellular death. All the physical–chemical, photophysical and photobiological measurements performed allow us conclude that ZnPc loaded PLGA nanoparticles is a promising drug delivery system for photodynamic therapy.
Keywords: Nanoparticles; PLGA; ZnPc; Preparation; Characterization; Phototoxicity assay;
Preparation of immuno-stimulating complexes (ISCOMs) by ether injection by H.L. Pham; P.N. Shaw; N.M. Davies (196-202).
This study investigated the application of the solvent dispersion technique, specifically ether injection, which has been successfully used in the preparation of liposomes, as a new, continuous and potentially scaleable method for the preparation of ISCOMs. Phosphatidylcholine (PC) and cholesterol (Chol) were dissolved in ether, which was injected into an aqueous solution, maintained at 55 °C, containing Quil A. The influences of the following variables on ISCOM formation were investigated: ratio of PC:Quil A:Chol used, pumping rate, total lipid mass and concentration of buffer salts and Quil A in the aqueous phase. All samples were characterized by negative stain transmission electron microscopy, photon correlation spectroscopy and sucrose ultracentrifugation gradient. It was demonstrated that ISCOMs could be produced by this method but the homogeneity of the preparation was influenced by the conditions used. Homogeneous ISCOM preparations were consistently produced only when the weight ratio of PC:Quil A:Chol was 5:3:2 with a total lipid mass of 20 mg, the Quil A dissolved in a 0.01 M phosphate buffer at a concentration of 6 mg in 4 ml, and the ether solution injected into the warmed buffer solution at a rate of 0.2 ml/min. Changing any of these variables resulted in more heterogeneous preparations in which ISCOMs typically co-existed with other colloidal structures such as worm-like and helical micelles, liposomes, lamellae and lipidic particles.
Keywords: ISCOM; Immuno-stimulating complex; Quil A; Adjuvant; Ether injection;
Cryo-TEM investigation of phase behaviour and aggregate structure in dilute dispersions of monoolein and oleic acid by Denise Alves Ferreira; Maria Vitória L.B. Bentley; Göran Karlsson; Katarina Edwards (203-212).
Cryo-transmission electron microscopy (cryo-TEM) was used to image the microstructure in dilute sonicated dispersions of monoolein and oleic acid. The aim of the study was to explore how different experimental parameters, such as sample composition, total lipid concentration, pH, and ageing affect the phase behaviour and aggregate structure. Our investigations show that a rich variety of lamellar and non-lamellar structures, including liposomes and particles of cubic and inverted hexagonal phase, may form depending on the experimental conditions. The results are analyzed and discussed in relation to existing phase diagrams and earlier investigations concerning phase- and structural behaviour in monoolein/oleic acid/water systems.
Keywords: Monoolein; Oleic acid; Aggregate structure; Liposomes; Dispersed liquid crystalline phases; Cryo-TEM; Vaccines;
Influence of particle size on transport of methotrexate across blood brain barrier by polysorbate 80-coated polybutylcyanoacrylate nanoparticles by Kepan Gao; Xinguo Jiang (213-219).
Transports of methotrexate-loaded polybutylcyanoacrylate nanoparticles with different sizes across blood brain barrier were investigated in this experiment. The drug-loaded nanoparticles were prepared by emulsion polymerization method. After coating with polysorbate 80, nanoparticles with the size 70, 170, 220, 345 nm were, respectively, i.v. injected into rats at the dose of 3.2 mg/kg. Uncoated nanoparticles and methotrexate solution were also i.v. injected at the same dosage as controls. 0.5, 1, 1.5, 2, 3, 4 h after injection, cerebrospinal fluids and brain tissues were collected for tests. Drug level in all biological samples was determined by HPLC. It was found out that nanoparticles overcoated by polysorbate 80 could significantly improve the drug level in both brain tissues and cerebrospinal fluids compared with uncoated ones and simple solution. Seventy-nanometer nanoparticles could deliver more drugs into brain while no significant difference was observed among the other three size ranges. In conclusion, polysorbate 80-coated polybutylcyanoacrylate nanoparticles could be used to overcome blood brain barrier especially those whose diameter was below 100 nm.
Keywords: Polybutylcyanoacrylate; Methotrexate; Nanoparticles; Blood brain barrier;
Characterization of the molecular distribution of drugs in glassy solid dispersions at the nano-meter scale, using differential scanning calorimetry and gravimetric water vapour sorption techniques by D.J. van Drooge; W.L.J. Hinrichs; M.R. Visser; H.W. Frijlink (220-229).
The molecular distribution in fully amorphous solid dispersions consisting of poly(vinylpyrrolidone) (PVP)–diazepam and inulin–diazepam was studied. One glass transition temperature (T g), as determined by temperature modulated differential scanning calorimetry (TMDSC), was observed in PVP–diazepam solid dispersions prepared by fusion for all drug loads tested (10–80 wt.%). The T g of these solid dispersions gradually changed with composition and decreased from 177 °C for pure PVP to 46 °C for diazepam. These observations indicate that diazepam was dispersed in PVP on a molecular level. However, in PVP–diazepam solid dispersions prepared by freeze drying, two T g's were observed for drug loads above 35 wt.% indicating phase separation. One T g indicated the presence of amorphous diazepam clusters, the other T g was attributed to a PVP-rich phase in which diazepam was dispersed on a molecular level. With both the value of the latter T g and the ΔC p of the diazepam glass transition the concentrations of molecular dispersed diazepam could be calculated (27–35 wt.%). Both methods gave similar results. Water vapour sorption (DVS) experiments revealed that the PVP-matrix was hydrophobised by the incorporated diazepam. TMDSC and DVS results were used to estimate the size of diazepam clusters in freeze dried PVP–diazepam solid dispersions, which appeared to be in the nano-meter range. The inulin–diazepam solid dispersions prepared by spray freeze drying showed one T g for drug loads up to 35 wt.% indicating homogeneous distribution on a molecular level. However, this T g was independent of the drug load, which is unexpected because diazepam has a lower T g than inulin (46 and 155 °C, respectively). For higher drug loads, a T g of diazepam as well as a T g of the inulin-rich phase was observed, indicating the formation of amorphous diazepam clusters. From the ΔC p of the diazepam glass transition the amount of molecularly dispersed diazepam was calculated (12–27 wt.%). In contrast to the PVP–diazepam solid dispersions, DVS-experiments revealed that inulin was not hydrophobised by diazepam. Consequently, the size of diazepam clusters could not be estimated. It was concluded that TMDSC enables characterization and quantification of the molecular distribution in amorphous solid dispersions. When the hygroscopicity of the carrier is reduced by the drug, DVS in combination with TMDSC can be used to estimate the size of amorphous drug clusters.
Keywords: Mode of incorporation; Amorphous drug clusters; Solid solution; Solid suspension; Molecular incorporation; Carrier; Non-proportional water vapour sorption;