Surface responses and desirability functions to determine optimal granulation domains.

BACKGROUND: Single pot mixer-granulator-dryer (high-shear granulator with in situ double jacket vacuum drying) and multiphase equipment (high-shear granulator associated with fluid bed dryer) are classically used for wet granulation. At present time, industrial production imperatives may require to switch one formulation from one equipment to another. METHOD: To compare the two processes and to define, for each of them, the optimal formulation domain, experiments were organized according to Doehlert experimental designs. Response surfaces were used to identify the levels of each factor (binder and filler ratios) inducing the more satisfying responses. The contribution of binder and filler ratios to granule properties was highlighted according to the process. Then the desirability function was used to determine and compare the optimal formulation domain for each process. RESULTS AND CONCLUSION: In the studied formulation domain and for the considered equipment, the transposition from a single pot to a multiphase high-shear granulation process did not seem to raise difficulties; the same formulations were out of specification for both processes and other trials, the technological properties were maintained or improved in the Fielder/Niro equipment.

Comparison of single pot and multiphase granulation. Part 1: Effect of the high shear granulator on granule properties according to the drug substance and its concentration.

Pharmaceutical granulations are usually developed with regard to a specific manufacturing process but switching from one piece of equipment to another can be necessary to comply with the available industrial equipment. Investigations were undertaken on formulations differing in the drug substance and in its concentration. Our aim was to highlight the effect of the granulation process on granules manufactured in a pilot scale Moritz Turbosphere TS50 or in Fielder PMA 65 and dried in a Glatt GPCG1 fluid bed dryer. The granulation process and formulation parameters showed a significant impact on granule size distribution, behaviour under pressure, and on tablet mechanical properties and dissolution kinetics.

Comparison of single pot and multiphase granulation. Part 2: Effect of the drying process on granules manufactured in a single pot granulator and dried either in situ or in a fluid bed dryer.

The aim of this study was to highlight the effect of the drying process on granules manufactured in a pilot scale single pot granulator and dried either in situ or in a fluid bed dryer, for formulations differing in drug substance and its concentration (1%; 25%). Although most of raw data were within specifications, single pot drying tended to improve granule comprimability and seemed less sensitive to formulation. Moreover, it was demonstrated that the formulation impacted on granule median diameter, packing ability, comprimability, residual lower punch pressure and tablet dissolution kinetics. Interactions between process and formulation were highlighted concerning tablet tensile strength and uniformity of mass.

Comparison of single pot and multiphase high shear wet granulation processes related to excipient composition.

At present time, industrial production imperatives can require the transposition of a formulation from one equipment to another. In order to evaluate the impact of such a switch on the properties of granules and tablets, investigations were undertaken on formulations manufactured both in a single pot mixer-granulator-dryer (high shear granulator with in situ double jacket vacuum drying) and in a multiphase equipment (high shear granulator/fluid bed dryer). Principal component analysis highlighted the major contribution of the binder ratio on granule size distribution, flow and packing ability whereas the relative ratio of mannitol and lactose, used as fillers, mainly impacted on compressibility and tablet cohesion. In the studied domain, the lubricant ratio did not explain the considered responses. Statistical analysis (comparison of means, analysis of variance and PCA) showed that both processes led to products with similar characteristics which demonstrated the ability of the processes to produce granules with close quality. However, Fielder/Niro granule characteristic data were found to be more dispersed, thus demonstrating a higher sensitivity of the multiphase process to formulation changes. Technological properties of granules and tablets were found to be maintained or improved therefore securing the switch from single pot to multiphase equipments.

Drug/lactose co-micronization by jet milling to improve aerosolization properties of a powder for inhalation.

The aim of this work was to formulate a powder for inhalation with fusafungine, a drug substance initially highly cohesive. The classical approach based on micronization by jet milling to prepare respirable drug particles and then blending with a carrier was first applied. A fractional factorial experimental design was implemented to screen six formulation parameters. The effect of drug/lactose co-micronization on aerosolization was then evaluated. In vitro deposition studies were performed with the twin stage glass impinger and the inhaler Spinhaler. Micronization did not induce DSC-detectable amorphization and gave a highly cohesive, poor flowable powder with a theoretical aerodynamic diameter of 5 microm. The powder was then blended with coarse lactose and optionally fine lactose. Unfortunately, the respirable fraction could not be optimized and remained below 10%. On the other hand, a co-micronized powder drug/fine lactose 50:50 gave a respirable fraction of 16%. Following blending with a carrier, the respirable fraction and the emitted dose fraction reached 23% and 69%, respectively. The use of a fine lactose grade for co-micronization was essential. In conclusion, this study demonstrated that co-micronization with a fine lactose is an efficient and simple strategy to formulate a powder for inhalation with enhanced aerosolization properties, especially for highly cohesive drug substance.

Multiphase versus single pot granulation process: influence of process and granulation parameters on granules properties.

High-shear wet granulation is widely used for the production of pharmaceutical dosage forms. Different equipment is available for high-shear granulation and drying. This review focuses on two main processes for granules production: multiphase consisting of high-shear granulation followed by drying in a separate apparatus, and single pot granulation/drying. At present, formulas are specifically developed with regard to the production equipment, which raises many problems when different industrial manufacturing equipment is used. Indeed, final granules properties are likely to depend on equipment design, process, and formulation parameters. Therefore, a good understanding of these parameters is essential to facilitate equipment changes. The aim of this review is to present the influence of equipment, process, and formulation parameters on granules properties, considering both the granulation and the drying steps of multiphase and single pot processes.

[Post-mortem evaluation following oncologic treatment of the functional and bacteriologic status of 25 permanent venous access devices]. / Evaluation post-mortem après traitement oncologique de l'état fonctionnel et bactériologique de 25 accès veineux permanents.

Permanent venous access devices allow long-term parenteral treatment under relatively safe and comfortable conditions. Nevertheless, this use is associated with some degree of (particularly infectious) morbidity. 25 permanent access devices were removed surgically in immediate autopsies and cultured. Some half were infected, with a clear prevalence (40%) for Staphylococcus coagulase negative. The results were related to clinical history and compared with the figures and conclusions of other studies. It is proposed that in certain situations cultures of native blood should be carried out more frequently through the permanent venous access, with a view to possible specific targeted antibiotic therapy associated with the heparinized lock.

[A rare complication of permanent venous access: constriction, fracture and embolization of the catheter]. / Une complication rare des accès veineux permanents: laminage, fracture et embolisation du catheter.

The pinch off syndrome due to squeezing of the implanted catheter is a rare complication of permanent venous access devices (0.1 to 1% of the cases). The cause is a mechanical catheter's compression in the costo-clavicular space, when implanted too medially in the subclavian vein. In case of lack of venous reflux or injection difficulties, sometimes complicated by local pain, a radiological control must be obtained to demonstrate signs of compression or beginning of fracture. Significant damage to the system is shown be extravasation of radioopaque contrast medium. The suspicion of catheter damage justifies early replacement of the system to avoid right heart or pulmonary artery embolism. The electron microscopic scanning tends to prove that the catheter's rupture is caused by a fatigue process.

[Effect of postoperative retransfusion of autologous blood products on hemostasis in heart surgery]. / Einfluss der postoperativen Retransfusion von autologen Blutprodukten auf die Hämostase in der Herzchirurgie.

In cardiac surgery a reduction of homologous blood products is mainly achieved by autologous blood salvage. Unprocessed retransfusion of autologous blood may induce changes in hemostasis. We assessed changes of activated clotting times (ACT) after retransfusion of unprocessed (1) oxygenator blood and (2) shed mediastinal blood. In 41 patients undergoing cardiac surgery (37 revascularization and 4 valve procedures) with a mean cardiopulmonary bypass time of 116.3 min, ACT was measured at the following time points: pre- and postoperatively, and before and after retransfusion of oxygenator blood and shed mediastinal blood. A significant prolongation of ACT values was only seen between pre- to postoperative blood (p < 0.003). Retransfusion of oxygenator blood changed ACT from 120 +/- 25 vs 116 +/- 17 sec and retransfusion of shed mediastinal blood showed a mean ACT of 118 +/- 14 vs 115 +/- 20 sec from before to after transfusion. There was a significant correlation between the ACT value in the unprocessed oxygenator blood and the ACT value measured in the patient after retransfusion (r = 0.41, p < 0.02). 6 patients receiving over 1 litre of unprocessed autologous blood (either from the oxygenator or the mediastinum) in less than 60 minutes showed a significant increase of ACT value after transfusion (p < 0.05). Hence, under normal conditions, retransfusion of unprocessed autologous blood will not significantly alter hemostasis measured by the ACT test in patients undergoing cardiac surgery.

Radioimmunoassay of Antarelix, a luteinizing hormone releasing-hormone antagonist, in plasma and its application for pharmacokinetic study in dogs.

A procedure for the radioimmunoassay (RIA) of Antarelix (teverelix) in plasma has been developed for the pharmacokinetic study of this potent LHRH antagonist in dogs. Antiserum was produced by coupling the deamidated Antarelix analog to bovine serum albumin by a carbodiimide reaction and immunizing rabbits with the conjugate. The crossreactivity of the antiserum with LHRH, LHRH agonist Metereline and LHRH antagonists tested was negligible, except for Antide which displayed a crossreactivity of 33%. No crossreactivity with Antarelix metabolites could be detected. The RIA is suitable for the direct determination of Antarelix in plasma, with a minimum detectable level of 1.12 fmol/assay. The accuracy and precision of the method were assessed with plasma samples spiked with Antarelix at concentrations ranging from 0.4 to 6.4 pmol/ml. The recovery was 104.8% with intra- and interassay CV between 1 and 3.7%. Pharmacokinetic profiles of Antarelix in dogs were established following an i.v. or a s.c. dose of 10 micrograms/kg.

Radioimmunoassay for hexarelin, a peptidic growth hormone secretagogue, and its pharmacokinetic studies.

A radioimmunoassay (RIA) method for hexarelin, a peptidic growth hormone secretagogue, has been developed and applied to pharmacokinetic studies in dogs following an IV dose of 1 microgram/kg, and three SC doses of 1, 10, and 100 micrograms/kg. The sensitivity of the assay was determined to be 1.34 fmol/assay. Cross-reactivity of the antiserum with nine hexarelin analogues was less than 1% upon modification of positions 3, 4, or 5 of the peptide. No apparent cross-reaction with endogenous hexarelin metabolites were observed. Intra- and interassay coefficients of variation were less than 3% and 4%, respectively. Intravenous bolus pharmacokinetics of hexarelin displayed a high terminal half-life of 120 min, a fractional plasma clearance of 4.28 ml/min/kg, and a volume of distribution at steady state of 387.7 ml/kg. Following SC administration of hexarelin, despite the increase in dose administered, both clearance (3.93-5.17 ml/min/kg) and volume of distribution (316-544 ml/kg) parameters remained constant over the dose range studied.

Growth hormone releasing activity by intranasal administration of a synthetic hexapeptide (hexarelin).

OBJECTIVE: Hexarelin is a new synthetic growth hormone releasing peptide. We have tested the efficacy of intranasal (i.n.) administration of hexarelin to stimulate plasma GH and have compared this to the intravenous (i.v.) administration of the peptide. PATIENTS: Ten children with familial short stature (FSS) aged 5.5-15.5 years and two known GH deficient patients aged 24 and 28 years without GH treatment. METHODS: All 12 subjects were submitted to i.v. (1 microgram/kg) and i.n. (20 micrograms/kg) hexarelin tests with a one-week interval between tests. Blood samples for GH, TSH, fT4 and T3 were obtained at 0, 15, 30, 60, 90 and 120 minutes. The hormone determinations were made by standard radio-immunoassays (RIA). RESULTS: Both the i.n. and i.v. administration of hexarelin induced a large GH response, the mean (+/- SD) being 72.2 +/- 35.5 mU/l for the i.n. test and 79.6 +/- 53.0 mU/l for the i.v. test. The peak GH in the i.v. test occurred at 15-30 minutes and in the i.n. test between 30 and 60 minutes. The GH deficient patients showed no GH response in either test. Plasma TSH decreased in the FSS children from a mean (+/- SD) of 1.0 +/- 0.26 to 0.64 +/- 0.2 mU/l (P < 0.005) during the i.n. test and from 1.0 +/- 0.3 to 0.7 +/- 0.3 mU/l (P < 0.05) during the i.v. test. In the isolated GH deficient patient, plasma TSH decreased from 1.06 +/- 0.38 mU/l to 0.86 +/- 0.17 during the i.v. test and from 1.60 +/- 0.01 to 1.11 +/- 0.06 mU/l during the i.n. test. There were no significant changes in plasma fT4 or T3 in any of the tests. CONCLUSIONS: The synthetic hexapeptide hexarelin is a potent pituitary GH stimulator when administered intranasally. The GH response was similar to that observed after intravenous hexarelin. Simultaneously, there was a significant decrease in plasma TSH but the concentrations remained in the normal range. These findings appear to be of theoretical and practical relevance to the investigation and management of short children.

Effect of formulation additives upon the intranasal bioavailability of a peptide drug: tetracosactide (ACTH1-24).

Nasal absorption of tetracosactide (ACTH1-24; Synacthen) was evaluated in anesthetized rats and compared to intravenous and intramuscular (i.m.) administration. The effect of formulation additives on tetracosactide bioavailability was studied following modification of nasal saline solution. Poloxamer 407 (Pluronic F-127) was used as a vehicle for drug sustained release, whereas sodium glycocholate and bacitracin were used as enhancers. Tetracosactide plasma levels were monitored with radioimmunoassay. Nasal bioavailability was low (4.4%) compared to i.m. (24%). Poloxamer 407 addition did not improve drug kinetics profiles and showed a non-significant decrease in bioavailability (4%). On the other hand, both enhancers effectively increased tetracosactide nasal absorption. The sodium glycocholate effect was very fast (Tmax = 5 min), but did not last long. Moreover, absorption was increased threefold compared to the simple formulation. On the other hand, maximum tetracosactide levels in plasma were reached after 15 min for the formulation containing bacitracin as enhancer, and tetracosactide bioavailability was strongly increased, to 24%, i.e., as much as after an i.m. injection.

Growth hormone-releasing activity of hexarelin in humans. A dose-response study.

Hexarelin is a new hexapeptide (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2.micrograms.kg-1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (Cmax) were 3.9, 26.9, 52.3, 55.0 ng.ml-1 after 0, 0.5, 1 and 2 micrograms.kg-1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC0-180) were 0.135, 1.412, 2.918 and 3.695 micrograms.min.ml-1. The theoretical maximum response (Emax) and the dose that produces half of the maximum response (ED50) were estimated using logistic regression. The calculated ED50 values were 0.50 and 0.64 microgram.kg-1 for Cmax and AUC0-180, respectively. The corresponding Emaxs were 55.1 ng.ml-1 and 3936 ng.min.ml-1, thus indicating that the effect after the 2 micrograms.kg-1 dose is very close to the maximal response.(ABSTRACT TRUNCATED AT 250 WORDS)

Antarelix (EP 24332) a novel water soluble LHRH antagonist.

A novel water soluble LHRH antagonist (EP 24332-Antarelix) is described. Its activity in vitro and in vivo in several animal models is given. Antarelix (Ac-D-Nal, D-Cpa, D-Pal, Ser, Tyr, D-Hci, Leu, Lys-(iPr), Pro, D-Ala-NH2) in view of its potency, modest histamine-liberating activity and high water solubility has been selected for further development.

[The transnasal route of drug administration. Aspects of nasal anatomy and physiology]. / Intérêt de la voie transnasale pour l'administration des médicaments. Première partie. Aspects de l'anatomie et de la physiologie nasale.

The use of transnasal administration of drugs has gained interest with the synthesis of new polypeptidic biologically active substances. Since few years an increasing number of therapeutical hormones delivered through the nose are now available to treat disorders that only used to require parenteral injections to be effective. In its first part the present review describes the anatomy and physiology of the nose in order to gain insight in this site of delivery. The second part deals more specifically with models used to study transnasal absorption and describes parameters that modify drug absorption in relation with the model chosen.