Nutritional status and anxious and depressive symptoms in anorexia nervosa: a prospective study.

The interweaving of malnutrition and symptoms of anxiety and depression in anorexia Nervosa (AN) is mentioned without any consensus regarding the course of anxious-depressive symptoms in relation to nutritional status in the course of treatment of patients with AN. The objectives of the current study in a large sample of AN inpatients were to assess the relationships between anxiety and depression symptoms and nutritional status both over the course of inpatient treatment and at discharge. 222 consecutive inpatients with AN (DSM-IV TR) were assessed (entrance and discharge) for duration of illness, psychiatric treatments, sociodemographic data and with psychometric scales for different psychopathological symptoms [depressive (BDI), anxiety and depressive (HAD scale), obsessive-compulsive (MOCI) and social phobia (LSAS fear score)]. Nutritional status was assessed with Body Mass Index (BMI) and body composition by bioelectrical impedance. The Fat free mass index [FFMI = FFM (kg)/height (m2)] was considered for the analysis. Two models were developed where the dependent variables were each psychopathological score at discharge (BDI, HAD anxiety, MOCI, and LSAS fear) in the cross-sectional model, and their variation in the longitudinal model (where a positive score reflected symptom decrease at discharge). A fixed set of predictors, defined on presumed clinical and statistical relevance (FFMI in the cross-sectional model and Variation of FFMI in the longitudinal model), were considered in each model, without any model selection procedure. This is the first study to confirm a positive relationship between the course of eating disorder symptoms and that of anxious-depressive symptoms during inpatient treatment of AN even after adjustment on a vast array of possibly confounding factors.

Preparation and investigation of P28GST-loaded PLGA microparticles for immunomodulation of experimental colitis.

The aim of this work was to prepare and characterize (in vitro and in vivo) PLGA-based microparticles loaded with an enzymatic protein derived from the helminth parasite Schistosoma haematobium: glutathione S-transferase P28GST (P28GST). This protein is not only a promising candidate vaccine against schistosomiasis, it also exhibits interesting immunomodulating effects, which can be helpful for the regulation of inflammatory diseases. Helminths express a regulatory role on intestinal inflammation, and immunization by P28GST has recently been shown to be as efficient as infection to reduce inflammation in a murine colitis model. As an alternative to the combination with a classical adjuvant, long acting P28GST microparticles were prepared in order to induce colitis prevention. PLGA was used as biodegradable and biocompatible matrix former, and a W/O/W emulsion/solvent extraction technique applied to prepare different types of microparticles. The effects of key formulation and processing parameters (e.g., the polymer molecular weight, drug loading, W/O/W phase volumes and stirring rates of the primary/secondary emulsions) on the systems' performance were studied. Microparticles providing about constant P28GST release during several weeks were selected and their effects in an experimental model of colitis evaluated. Mice received P28GST-loaded or P28GST-free PLGA microparticles (s.c.) on Day 0, and optionally also on Days 14 and 28. Colitis was induced on Day 35, the animals were sacrificed on Day 37. Interestingly, the Wallace score (being a measure of the severity of the inflammation) was significantly lower in mice treated with P28GST microparticles compared to placebo after 1 or 3 injections. As immunogenicity markers, increased anti-P28GST IgG levels were detected after three P28GST PLGA microparticle injections, but not in the control groups. Thus, the proposed microparticles offer an interesting potential for the preventive treatment of experimental colitis, while the underlying mechanism of action is still to be investigated.

Mood disorders in eating disorder patients: Prevalence and chronology of ONSET.

OBJECTIVES: In a clinical population, we estimated the frequency of mood disorders among 271 patients suffering from Anorexia Nervosa (AN) and Bulimia Nervosa (BN) in comparison to a control group matched for age and gender. METHOD: The frequency of mood disorders was measured using the Mini International Neuropsychiatric Interview (MINI), DSM-IV version. RESULTS: Mood disorders were more frequent among eating disorder (ED) patients than among controls, with a global prevalence of the order of 80% for each ED group. The majority of the mood disorders comorbid with ED were depressive disorders (MDD and dysthymia). The relative chronology of onset of these disorders was equivocal, because mood disorders in some cases preceded and in others followed the onset of the eating disorders. LIMITATIONS: Our sample was characterized by patients with severe ED and high comorbidities, and thus do not represent the entire population of AN or BN. This also may have resulted in an overestimation of prevalence. CONCLUSION: Mood disorders appear significantly more frequently in patients seeking care for ED than in controls. These results have implications for the assessment and treatment of ED patients, and for the aetio-pathogenesis of these disorders.

In vivo efficacy of microbiota-sensitive coatings for colon targeting: a promising tool for IBD therapy.

The first proof of concept in vivo for a new type of microbiota-sensitive film coatings allowing for colon targeting is presented. The efficacy of these polysaccharide barriers to optimize drug release for the treatment of inflammation is demonstrated in an experimental colitis model with Wister rats. 5-Aminosalicylic acid (5-ASA) pellets were prepared by extrusion-spheronization and coated with Nutriose:ethylcellulose (EC) 1:4 or peas starch:ethylcellulose 1:2 blends. The pellets were mixed with standard chow, and the daily drug dose was 150mg/kg. For reasons of comparison, also commercially available Pentasa pellets and placebo pellets were studied. At day 3 after the beginning of the treatment, colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS). Animals were sacrificed on day 6. Macroscopic and histological evaluations of colitis were performed blindly. In addition, inflammatory markers were evaluated using ELISA and real-time PCR. Rats receiving TNBS and placebo pellets developed a severe colitis in the distal half of the colon. 5-ASA administered in the form of Pentasa pellets reduced macroscopic inflammation by only 5%. In contrast, the colon lesions were much less severe upon treatment with Nutriose:EC- and peas starch:EC-coated pellets: The macroscopic score was reduced by 25 and 24%, respectively. Decreases of 37 and 38% of the histological lesions confirmed the efficacy of these new colon targeting systems. Also, inflammatory markers (MPO, IL-1ß mRNA, TNF mRNA) were significantly decreased in rats receiving Nutriose:EC- and peas starch:EC-coated pellets compared to Pentasa pellets. Furthermore, real-time PCR analysis indicated increased activation of the target receptor PPAR-γ and the HMGCS2 gene in rats upon administration of 5-ASA loaded Nutriose:EC- and peas starch:EC pellets compared to the commercial product. Also, HPLC-MS/MS analysis of plasma samples demonstrated that the level of the main metabolite of the drug (N-acetyl-5-ASA) was much lower upon administration of Nutriose:EC or peas starch:EC coated pellets compared to Pentasa pellets, indicating that undesired premature drug release in the upper gastrointestinal tract was more effectively hindered. In addition to the rat study, in vivo imaging of transgenic mice expressing the luciferase gene evidenced much more pronounced PPAR-γ activation upon 5-ASA administration in the form of Nutriose:EC-coated pellets versus Pentasa pellets. All these results clearly demonstrate the superiority of these microbiota-sensitive polysaccharide-based film coatings for colon targeting in vivo.

The effects on children of depressed mothers' remission and relapse over 9 months.

BACKGROUND: The high rate of depression among children of depressed mothers is well known. Suggestions that improvement in maternal acute depression has a positive effect on the child have emerged. However, data on the mechanisms of change have been sparse. The aim was to understand how remission and relapse in the mother might explain the changes in the child's outcome. METHOD: Participants were 76 depressed mothers who entered into a medication clinical trial for depression and 135 of their eligible offspring ages 7-17 years. The mothers and children were assessed at baseline and periodically over 9 months by independent teams to understand the relationship between changes in children's symptoms and functioning and maternal remission or relapse. The main outcome measures were, for mothers, the Hamilton Depression Rating Scale (HAMD), the Social Adjustment Scale (SAS) and the Parental Bonding Instrument (PBI) and, for children, the Children's Depression Inventory (CDI), the Columbia Impairment Scale (CIS), the Multidimensional Anxiety Scale for Children (MASC) and the Children's Global Assessment Scale (CGAS). RESULTS: Maternal remission was associated with a decrease in the child's depressive symptoms. The mother's subsequent relapse was associated with an increase in the child's symptoms over 9 months. The effect of maternal remission on the child's improvement was partially explained by an improvement in the mother's parenting, particularly the change in the mother's ability to listen and talk to her child, but also reflected in her improvement in parental bonding. These findings could not be explained by the child's treatment. CONCLUSIONS: A depressed mother's remission is associated with her improvement in parenting and a decrease in her child's symptoms. Her relapse is associated with an increase in her child's symptoms.

Predictors of newly diagnosed atrial fibrillation in cryptogenic stroke: a cohort study.

BACKGROUND AND PURPOSE: A significant proportion of cryptogenic ischaemic strokes are due to paroxysmal atrial fibrillation (AF). As paroxysmal AF appears to inexorably progress to persistent or permanent AF, this study with long-term follow-up was designed to establish the profile of patients who developed AF after hospital discharge. METHODS: All patients with cryptogenic ischaemic stroke over a 1-year period were included (n = 164). Patients were prospectively followed up at the outpatient clinic. Information on long-term outcome included the presence of newly diagnosed AF (NDAF). A specific NDAF assessment was performed at least 2 years after the index stroke using a structured telephone interview. Baseline clinical, laboratory, and echocardiographic data of these patients were retrospectively recorded. Independent predictive factors were then used to produce a predictive grading score for NDAF, derived by logistic regression analysis. RESULTS: With a median follow-up of 854 days, 22 cases of NDAF (13%) were observed. On multivariate analysis, factors associated with NDAF were age ≥72 years (two points), history of coronary artery disease (one point) or stroke (one point), and left atrial area ≥16 cm(2) (two points) (total score ranging from 0 to 6). Patients with a score ≤1 point did not have NDAF during follow-up. CONCLUSIONS: In cryptogenic ischaemic stroke, the NDAF score can be used to target patients at high risk of developing AF after hospital discharge, as a score of 0-1 was highly predictive of the absence of NDAF during follow-up. These results need to be confirmed in prospective studies.

The Attitudes and Patterns of Eating (APE) Questionnaire: development and factor analysis in a U.S. adolescent community sample.

OBJECTIVE: This paper describes the creation and demonstrates the internal consistency of the Attitudes and Patterns of Eating (APE) Questionnaire, English version, which assesses adolescent food beliefs and eating habits and can be used for comparative studies on various cultures and lifestyles. The questionnaire is intended for use in a study comparing French and U.S. adolescents, the details of which will be presented in a future article. METHOD: A research team composed of French and American researchers observed eating behaviors in community samples from each country and reviewed previous studies comparing Europe and North America regarding eating attitudes/practices. Common eating-related themes were identified and corresponding questionnaire items were constructed, then a group of U.S. high school students (N=1230) was administered the questionnaire. RESULTS: A principal components analysis (PCA) identified 5 components: "Eating Diet/Light Foods," "Unhealthy/Increased Eating," "Homemade Meals," "Skipping Meals" and "Healthy Eating". DISCUSSION: The testing and factor analysis of the APE (English) Questionnaire demonstrated its internal consistency. Further validity and reliability studies will be needed to complete the global validation process for both the French and English versions.

Dry powder inhalers: study of the parameters influencing adhesion and dispersion of fluticasone propionate.

Interactions between particles are dependent on the physicochemical characteristics of the interacting particles but it is also important to consider the manufacturing process. Blending active pharmaceutical ingredient (API) with carrier is a critical stage that determines the blend homogeneity and is the first step towards obtaining the final quality of the powder blend. The aim of this work was to study parameters that influence the interactions between API and carrier in adhesive mixtures used in DPI and their effect on API dispersion. The study was done with fluticasone propionate blended with lactose 'Lactohale 200'. The study was based on the influence of the operating conditions (speed, mixing time, resting steps during mixing), the size of the carrier and the storage conditions on the blend properties and on the API dispersion. The quality of the blends was examined by analysing the API content uniformity. Adhesion characteristics were evaluated by submitting mixtures to a sieving action by air depression with the Alpine air-jet sieve. Aerodynamic evaluation of fine particle fraction (FPF) was obtained using a Twin Stage Impinger; the FPF being defined as the mass percentage of API below 6.4 µm. For good dispersion and therefore good homogeneity of the API in the carrier particles, speed and powder blending time have to be sufficient, but not too long to prevent the appearance of static electricity, which is not favourable to homogeneity and stability. The FPF increases with the decrease in the carrier size. The storage conditions have also to be taken into consideration. Higher humidity favours the adhesion of API on the carrier and decreases the FPF.

Agglomerate behaviour of fluticasone propionate within dry powder inhaler formulations.

Due to their small size, the respirable drug particles tend to form agglomerates which prevent flowing and aerosolisation. A carrier is used to be mixed with drug in one hand to facilitate the powder flow during manufacturing, in other hand to help the fluidisation upon patient inhalation. Depending on drug concentration, drug agglomerates can be formed in the mixture. The aim of this work was to study the agglomeration behaviour of fluticasone propionate (FP) within interactive mixtures for inhalation. The agglomerate phenomenon of fluticasone propionate after mixing with different fractions of lactose without fine particles of lactose (smaller than 32 µm) was demonstrated by the optical microscopy observation. A technique measuring the FP size in the mixture was developed, based on laser diffraction method. The FP agglomerate sizes were found to be in a linear correlation with the pore size of the carrier powder bed (R(2)=0.9382). The latter depends on the particle size distribution of carrier. This founding can explain the role of carrier size in de-agglomeration of drug particles in the mixture. Furthermore, it gives more structural information of interactive mixture for inhalation that can be used in the investigation of aerosolisation mechanism of powder. According to the manufacturing history, different batches of FP show different agglomeration intensities which can be detected by Spraytec, a new laser diffraction method for measuring aerodynamic size. After mixing with a carrier, Lactohale LH200, the most cohesive batch of FP, generates a lower fine particle fraction. It can be explained by the fact that agglomerates of fluticasone propionate with very large size was detected in the mixtures. By using silica-gel beads as ball-milling agent during the mixing process, the FP agglomerate size decreases accordingly to the quantity of mixing aid. The homogeneity and the aerodynamic performance of the mixtures are improved. The mixing aid based on ball-milling effect could be used to ameliorate the quality of inhalation mixture of cohesive drug, such as fluticasone propionate. However, there is a threshold where an optimal amount of mixing aids should be used. Not only the drug des-aggregation reaches its peak but the increase in drug-carrier adhesion due to high energy input should balance the de-agglomeration capacity of mixing process. This approach provides a potential alternative in DPI formulation processing.

Influence of the lactose grade within dry powder formulations of fluticasone propionate and terbutaline sulphate.

Dry powder formulations are often composed of fine drug particles and coarser carrier particles, typically alpha-lactose monohydrate. However, the performance of a powder formulation may be highly dependent on the lactose quality and source. This study investigated the characteristics of lactose that influence the drug-to-carrier interaction and the performance of lactose-based dry powder inhaler formulations. The selected lactoses differed in the preparation processes and the content of fine lactose particles. Efficiency testing was done using fluticasone propionate and terbutaline sulphate as model drugs. Inverse gas chromatography was used to determine the surface heterogeneity distribution of different energy sites of the lactose and to understand the mechanism by which the fine carrier particles can improve the performance of dry powder inhalers. To assess the adhesion of respirable-sized drug to carrier particles, a simple method was developed based on aspiration and considering the whole blend as it is used in dry powder inhalers. When the percentage of fine lactose is high, a lower quantity of drug adheres to the lactose and/or the adhesion force is also lower. This was confirmed by the aerosolization assays done in the TSI (twin stage impinger). A correlation was observed between adhesion characteristics and inertial impaction. For both drugs, the fine particle fractions were highest in blends that present a greater proportion of lactose fine particles. A fairly good correlation between the fine particle fractions of both drugs and the peak max value and the AUC (area under curve) were found by inverse gas chromatography. With higher fine particle fraction values, which correspond to higher content of fines, the peak maxima determined by inverse gas chromatography were shifted to higher adsorption potentials, which supports the agglomeration hypothesis.

In vitro evaluation of powders for inhalation: the effect of drug concentration on particle detachment.

Limited information on the effect of the drug concentration on the performance of powders for inhalation is currently published. The aim of this work was to study the influence of drug concentration on the adhesion between drug and carrier and on the drug detachment from the carrier. The study was done with formoterol fumarate and fluticasone propionate blended with lactose Lactohale 200. To assess the adhesion of respirable-sized drug to carrier particles, a simple method was developed based on aspiration and considering the whole blend as it is used in dry powder inhalers. Adhesion characteristics were evaluated by submitting the mixtures to a sieving action by air depression with an Alpine air-jet sieve. Aerodynamic evaluation of fine particle dose and emitted dose was obtained using a Twin Stage Impinger (TSI). Drug concentration of powder blends used in dry powder inhalers influenced adhesion, content uniformity and in vitro deposition of the drug. For the higher concentration of formoterol, it seemed that a lower quantity of drug adhered to the lactose. This was confirmed by the aerosolization assays done in the TSI. The fine particle fraction increased linearly with the formoterol concentration. A correlation was observed between adhesion characteristics and inertial impaction. In the case of fluticasone, the influence of the concentration was different. First, the fine particle fraction increased with the concentration and then decreased with a further increase of the fluticasone concentration. This could be explained by the lack of homogeneity when the fluticasone concentration was high because of agglomerates of pure drug which can not be redispersed, or by the physico-chemical characteristics of this drug.

Non-coated multiparticulate matrix systems for colon targeting.

BACKGROUND: Colon specific drug delivery can significantly improve the efficacy of local treatments of inflammatory bowel diseases. Film coatings containing the starch derivative Nutriose have recently been reported to minimize 5-ASA release in media simulating the upper gastro intestinal tract (GIT), while releasing the drug in a time-controlled manner upon contact with feces from Crohn's Disease and Ulcerative Colitis patients. It was the aim of this study to prepare Nutriose-containing matrix pellets and mini tablets in order to avoid a film coating step. METHODS: Highly dosed matrix pellets were prepared by extrusion-spheronization, highly dosed mini tablets by compression. Various types of lipids were added and drug release measured in 0.1 N HCl and phosphate buffer pH 6.8, optionally containing pepsin and pancreatin. RESULTS: The type of added lipid and the preparation technique, in particular the curing conditions, significantly affected the resulting drug release kinetics. Glyceryl palmitostearate containing pellets and mini tablets showed the most promising results upon appropriate curing, minimizing premature drug release in media simulating the upper GIT. CONCLUSION: The proposed novel multiparticulates do not require a film coating step and show an interesting potential for site-specific drug delivery to the colon of inflammatory bowel disease patients.

Bone implants modified with cyclodextrin: study of drug release in bulk fluid and into agarose gel.

The aim of this work was to better understand the importance of the type of experimental setup used to monitor antibiotic release from functionalized hydroxyapatite implants. Microporous hydroxyapatite discs were prepared by sintering and subsequently functionalized with hydroxypropyl-ß-cyclodextrin (HPßCD) polymer crosslinked with butanetetracarboxylic acid. On one hand, polymerization was performed within the implant after its impregnation with the monomers (CD-HA-M implant). On the other hand, a pre-synthesized HPßCD polymer was loaded and fixed onto the HA discs (CD-HA-P implant). Both types of implants were soaked with ciprofloxacin hydrochloride or vancomycin hydrochloride solution and dried at 37°C. The DSC study highlighted that the cyclodextrin polymer could interfere with both drugs, due to the carboxylic groups carried by the crosslinks. Drug release was measured into phosphate buffered saline pH 7.4 in agitated vials, or into agarose gels to more realistically mimic in vivo conditions. Importantly, in all cases, drug release into agarose gels was much slower than into well-agitated phosphate buffer. Non-functionalized discs displayed faster drug release because no complex could be formed and/or due to the absence of the HPßCD polymer network hindering drug diffusion within the implant pores. In the case of ciprofloxacin hydrochloride, drug release from the CD-HA-M implants was faster than drug release from the CD-HA-P implants due to the different polymer structures resulting in different complexation strengths, whereas in the case of vancomycin hydrochloride the release patterns were similar because vancomycin hydrochloride was not included into the cyclodextrin. The agarose gel method seems more biorelevant and discriminatory than the vial method for drug release measurements from bone implants.

Air permeability of powder: a potential tool for Dry Powder Inhaler formulation development.

Dry Powder Inhalers have drawn great attention from pharmaceutical scientists in recent years in particular those consisting of low-dose micronized drug particles associated with larger carrier particles and called interactive mixtures. However, there is little understanding of the relation between bulk powder properties such as powder structure and its aerodynamic dispersion performance. The aim of this work was to develop a simple method to measure the air permeability of interactive mixtures used in Dry Powder Inhalers by using Blaine's apparatus--a compendial permeameter and to relate it to the aerodynamic behaviour. The study was done with fluticasone propionate and terbutaline sulphate as drug models that were blended with several lactoses having different particle size distribution thus containing different percentages of fine particle lactose. The quality of the blends was examined by analysing the drug content uniformity. Aerodynamic evaluation of fine particle fraction was obtained using a Twin Stage Impinger. A linear correlation between a bulk property--air permeability of packed powder bed--and the fine particle fraction of drug was observed for the tested drugs. The air permeability reflects the quantity of the free particle fraction in the interparticulate spaces of powder bed that leads to fine particle fraction during fluidization in air flow. A theoretical approach was developed in order to link the air permeability of powder bed and drag force acting on powders during aerosolization process. The permeability technique developed in this study provides a potential tool for screening Dry Powder Inhaler formulations at the development stage.

Curing of aqueous polymeric film coatings: Importance of the coating level and type of plasticizer.

The aim of this study was to better understand the effects of the curing conditions on the resulting drug release patterns from pellets coated with aqueous polymer dispersions. Diltiazem HCl was used as model drug, ethylcellulose as polymer, triethyl citrate (TEC), dibutyl sebacate (DBS), and distilled acetylated monoglycerides (Myvacet) as plasticizers. Interestingly, the effects of the curing conditions strongly depended on the coating level and the type of plasticizer: in the case of TEC, the drug release rate monotonically decreased with increasing harshness of the curing conditions (time, temperature, and relative humidity), irrespective of the coating level. In contrast, in the case of DBS and Myvacet, this type of relationship was only observed at low coating levels (5%). At intermediate coating levels (around 7.5%), the curing conditions had virtually no effect on drug release. At high coating levels (10%), the release rate initially increased and then decreased with increasing harshness of the curing conditions. This more complex behavior might be attributable to the superposition of two competing phenomena: improved film formation and drug migration into the polymeric membrane. Furthermore, it could be shown that the type of plasticizer had a major effect on drug release in not fully coalesced and equilibrated film coatings, whereas the release profiles were similar for all plasticizers in the case of completely formed and equilibrated film coatings. Importantly, the latter systems were stable for long term even during storage under stress conditions.

Nandrolone excretion in sedentary vs physically trained young women.

We investigated the effects of the menstrual cycle, oral contraception and physical training on exhaustive exercise-induced changes in the excretion of nandrolone metabolites [19-norandrosterone (19-NA), and 19-noretiocholanolone (19-NE)] in young women. Twenty-eight women were allocated to an untrained group (n=16) or a trained group (n=12), depending on their physical training background. The untrained group was composed of nine oral contraceptive users (OC+) and seven eumenorrheic women (OC-), while the trained group was entirely composed of OC+ subjects. Three laboratory sessions were conducted in a randomized order: a prolonged exercise test, a short-term exercise test and a control session. Urine specimens were collected before and 30, 60 and 90 min after the exercise test and at the same times of the day during the control session. Urinary concentrations of nandrolone metabolites were determined by gas chromatography coupled to mass spectrometry. Urinary concentrations of 19-NA and 19-NE ranged from undetectable levels to 1.14 and 0.47 ng/mL, respectively. Nandrolone excretion was not affected by the menstrual cycle phase (early follicular vs mid-luteal), prior physical training, oral contraception or acute physical exercise. Therefore, a urinary concentration of 2 ng/mL of 19-NA appears to be fair as the upper acceptable limit in doping control tests for female athletes.

Comorbidity studies of eating disorders and mood disorders. Critical review of the literature.

OBJECTIVE: We conducted a critical literature review of studies assessing the prevalence of mood disorders (MD) in subjects with eating disorders (ED; anorexia nervosa and bulimia nervosa). In the first part of this article, we discuss methodological issues relevant to comorbidity studies between ED and MD. In the second part, we summarize the findings of these studies in light of the methodological considerations raised. METHOD: A manual computerised search (Medline) was performed for all published studies on comorbidity between ED and MD. In order to have sufficiently homogeneous diagnostic criteria for both categories of disorders, this search was limited to articles published between 1985 and 2006. RESULTS: Too few studies include control groups, few studies compared diagnostic subgroups of ED subjects, and results are scarce or conflicting. DISCUSSION: The results are discussed in the light of the methodological problems observed. The implications when reviewing the results of published studies and planning future research are set out.

Influence of carrier on the performance of dry powder inhalers.

The aim of this work is to study carriers which can become alternatives to monohydrate lactose in dry powder inhalers and to consider particle parameters that influence adhesion between drug and carrier in dry powder inhalers. Different forms of mannitol, lactose and maltitol were mixed with either terbutaline sulphate or formoterol fumarate. The blends were submitted to different adhesion tests where drug detachment from the carrier was obtained either through mechanical vibration or by aspiration. Parameters like particle shape, roughness, amorphous content and cristalline form may affect interactions between drug and carrier. In our case, crystallized forms of the carrier offered lower adhesion but better release of the active ingredient than spray-dried forms. The crystallized mannitol produced maximal fine particle dose. The blends of the mannitols and the two active ingredients gave different results. The two techniques used to assess the adhesion of drugs to carrier particles provide complementary information about drug/carrier interactions and detachment. The mechanical sieving allows to assess blend stability and the air-jet sieving makes it possible to determine how easily the drug separates from carrier. For the drugs tested, the results of fine particle doses are in agreement with the Alpine air-jet sieve results. The tests used are helpful for the choice of a new carrier in the field of the development of new carriers for dry powder inhalers.

Aerosolization potential of cyclodextrins--influence of the operating conditions.

The aim of this work is to characterize the aerosols obtained by jet nebulization with cyclodextrin solutions and to study the influence of operating conditions on nebulization efficiency. Two cyclodextrins, an hydroxypropyl cyclodextrin (Kleptose HP) and a polydisperse methyl beta cyclodextrin (Crysmeb), were tested with 14 nebulizers that differ geometrically. We first determined the physicochemical properties of density, viscosity, and surface tension for the cyclodextrin solutions. Nebulization efficiency was evaluated by measuring droplet size, nebulization rate, quantity of solution nebulized, and nebulization time. We studied the influence of the technological parameters of pressure and nebulizer type and the influence of the formulation on performance efficiency. The use of different nebulizers and different pressure conditions results in variable efficiency. Regardless of the type of nebulizer, an increase in pressure decreases droplet size and increases nebulization rate. The influence of the nebulizer design is considerable. The aqueous cyclodextrin solutions studied can generate aerosols in particle size ranges suitable for pulmonary deposition. Large quantities of aerosol can be nebulized in acceptable nebulization times. The cyclodextrin concentration does not modify nebulization efficiency in the range tested.

Influence of granulation and compaction on the particle size of ibuprofen--development of a size analysis method.

The aim of this work was to study the impact of the process on drug particle size. We chose ibuprofen, practically insoluble in water, as granulometry greatly influences its dissolution rate. We developed an original method using a laser granulometer to assess the size of ibuprofen within a blend before and after granulation and then compression. Wet granulation was performed with a Lodige and a Diosna granulator. The granules were then compressed. The evolution of ibuprofen particle size after these operations was checked. Two grades of ibuprofen differing in size were studied: ibuprofen 25 and ibuprofen 50. After the wet granulation of ibuprofen 50 with a Lodige or a Diosna granulator, a decrease in size was observed. This could be caused by shocks occurring in the granulator. On the other hand, after compression of the granules, ibuprofen particle size increased and was greater than that measured before granulation. Compression could induce some fragmentation of ibuprofen associated with the plastic deformation and then, under pressure, a closeness of the fragments or deformed particles which could bind or associate with one another because the melting point of ibuprofen is not very high. In the case of ibuprofen 25, the same phenomena were observed after compression. But, after granulation, particle size was not modified. There was little breaking of ibuprofen particles in the granulator because they are much smaller than those of ibuprofen 50. This work shows the impact of the process on drug particle size when producing tablets. The method developed made it possible to differentiate and measure the size of ibuprofen particles in a blend.