Twin screw granulation as a simple and efficient tool for continuous wet granulation

The modification of a twin screw extruder for continuous wet granulation was investigated. Modification of the extruder setup as well as the screw design allowed the continuous wet granulation of alpha-lactose monohydrate without the need of a wet sieving step. The robustness of twin screw granulation was evaluated by studying the influence of processing parameters and formulation variables on the process performance and on the properties of alpha-lactose monohydrate granules and tablets. The process reproducibility during long term production was evaluated. Screw speed (200-450 rpm) and total input rate (5.5-9.5 kg/h) had no significant influence on the granule properties, while the water concentration during granulation influenced the process as well as the granule properties. At a water concentration (calculated on wet granule basis) of 5.5-8.5%, continuous twin screw granulation of alpha-lactose monohydrate 200 M was feasible and the granules obtained had good properties. PVP addition mainly affected tablet properties. Tablets made from granules containing 2.5% PVP had a tensile strength above 0.94 MPa, a friability below 1% and a disintegration time ranging between 495 and 576 s. Tablets containing hydrochlorothiazide complied with the dissolution requirements as 60% was released after 5 and 15 min from tablets without PVP and with 2.5% PVP, respectively. No problems were observed during continuous twin screw granulation over a period of 8h and the granule and tablet properties were reproducible throughout the process. These results indicated that twin screw granulation is an efficient tool for continuous wet granulation.     

A new method to obtain and present complete information on the compatibility: study of its validity for eight binary mixtures of morphine with drugs frequently used in palliative care

Parenteral administration of mixtures of morphine with other drugs has become common practice in palliative care. Such mixtures are sometimes found to be incompatible but compatibility data are scarce. An attempt was made to develop a quick and simple investigation strategy to obtain complete information on the compatibility of two drugs. This strategy was then used to study the physical and chemical compatibility of morphine HCl with alizapride HCl, atropine sulphate, dexamethasone sodium phosphate, hyoscine butylbromide, metoclopramide HCl, octreotide lactate, ranitidine HCl and hyoscine hydrobromide. These compatibility data are presented in such a way that they are easy to use in clinical practice. The investigation strategy outlined here allows the collection of complete information on the compatibility of morphine with another drug by studying a limited number of carefully selected mixtures per combination. The mixtures to be studied are selected using a scheme in which all possible mixtures prepared by mixing morphine solutions of varying concentrations with a drug solution in different volume ratios can be visualized. Applying this strategy to the eight combinations revealed, except for ranitidine HCl, no physical (visual) or chemical (HPLC; >90%) incompatibility in any of the mixtures studied for seven days at 22 and 32 degrees C. This indicates that all possible mixtures of these drug solutions with morphine HCl are compatible. For the combination with ranitidine incompatibility was observed only when using morphine HCl solutions containing >40 mg/ml and at certain ratios (drug/morphine HCl [D/M]: 4/42, 10/6 and 8/8, v/v), but all physically compatible mixtures were chemically stable (>90%). Studying extra mixtures in addition to those required to be studied according to the strategy revealed no discrepancies for any of the eight combinations studied. Adaptation of the layout of the scheme and the design of a decision tree resulted in an easy tool to check compatibility in daily practice. The scheme designed in this study is a useful tool for research and for daily practice. It simplifies and thereby encourages investigation of the compatibility of drugs. The availability of data on the physical as well as chemical compatibility in daily practice will contribute to a better quality of the mixtures used in palliative care and help to avoid complications and inadequate symptom control.     

Laparoscopic ablation of peripelvic renal cysts

Recently, laparoscopic surgery has been reported for symptomatic renal cysts. A 60-year-old female was referred to Toyama Medical and Pharmaceutical University Hospital with a chief complaint of general fatigue and left back pain. CT demonstrated bilateral peripelvic renal cysts, and DIP demonstrated left hydronephrosis and a medical shift of the left renal pelvis. Laparoscopic ablation of bilateral peripelvic renal cysts was performed under general anesthesia and a round excision was made in the cyst wall via the peritoneum. After surgery, the left back pain disappeared and CT demonstrated resolution of peripelvic renal cysts. Laparoscopic ablation of peripelvic renal cyst is a highly effective and minimally morbid procedure.     

Drug formulations intended for the global market should be tested for stability under tropical climatic conditions

RATIONALE OBJECTIVE: The quality of drugs imported into developing countries having a tropical climate may be adversely affected if their formulations have not been optimized for stability under these conditions. The present study investigated the influence of tropical climate conditions (class IV: 40 degrees C, 75% relative humidity) on the drug content, in vitro dissolution and oral bioavailability of different formulations of two essential drugs marketed in Tanzania: diclofenac sodium and ciprofloxacin tablets. METHODS: Before and after 3 and 6 months storage under class IV conditions the drug content and in vitro dissolution were evaluated using United States Pharmacopoeia (USP) 24 methods. Following a randomized four-period cross-over study, the pharmacokinetic parameters of drug formulations stored for 3 months under class IV conditions were compared with those stored at ambient conditions. RESULTS: Drug content and drug release from all tested ciprofloxacin formulations were within USP-24 requirements and remained stable during storage at simulated tropical conditions. Oral bioavailability was also not influenced by tropical conditions. The dissolution rate of two diclofenac formulations (Diclo 50 manufactured by Camden and Dicloflame 50 manufactured by Intas) reduced significantly during storage under class IV conditions. After oral administration Camden tablets stored for 3 months under class IV conditions showed a reduction in C(max) (90% CI of C(max) ratio: 0.59 - 0.76). This reduction was smaller than expected based on the in vitro tests. CONCLUSIONS: Some drug formulations imported into Tanzania are not optimized for stability in a tropical climate. Manufacturers and regulatory authorities should pay more attention to the WHO recommendations for testing the stability of drugs under tropical climate conditions. Efforts should be made to improve the in vitro tests to better predict the bioavailability.     

Compatibility and stability of ternary admixtures of morphine with haloperidol or midazolam and dexamethasone or methylprednisolone

The concentration range over which compatible admixtures of morphine hydrochloride with haloperidol lactate (Haldol) or midazolam hydrochloride (Dormicum) and dexamethasone-21-sodium phosphate (Decadron and Decadron Pack) or methylprednisolone-21-sodium succinate (Solu-Medrol) can be prepared was determined by visual evaluation of the solutions at 22 degrees C. The compatibility was evaluated for admixtures prepared in a ratio morphine hydrochloride (D1)/drug 2 (D2)/drug 2 (D3) in a ratio 10/1/1 to 10/1/10 (v/v/v). The solutions of morphine hydrochloride used were 10, 20, 30, 40 and 50 mg/ml prepared in water and isotonized with sodium chloride or dextrose. The drug solutions were used undiluted and diluted 1/5 (v/v) in water. All admixtures were prepared by adding the corticosteroid as D2 and as D3 in order to evaluate the influence of the order of mixing on the compatibility. The stability of the drugs in the compatible admixtures was evaluated during storage for 28 days at 22 degrees C and protected from light. Visual inspection, high performance liquid chromatography (HPLC) analysis, pH and osmolality determinations were performed. For each drug combination incompatibility was observed with increasing ratio and/or concentration of the drug solutions. Within the range of compatibility the concentrations of the three drugs could be increased so to allow adequate symptom control with all drug combinations. For a similar admixture a higher concentrations of corticosteroid could be obtained using dexamethasone-21-sodium phosphate versus methylprednisolone-21-sodium succinate and a higher concentration of dexamethasone-21-sodium phosphate could be obtained without incompatibility using Decadron Pack versus Decadron. The admixtures for which the stability was evaluated were stable for 28 days (> 95% of the initial concentration). None of these admixtures showed any visual changes during storage, except for some of the admixtures prepared using undiluted Decadron, in which small crystals were seen after 1-28 days. The initial pH of the admixture ranged from 3.99 to 6.06 and varied less than 0.10 during storage. The initial osmolality of the admixtures ranged from 170 to 323 mOsm/kg and remained almost constant during storage.     

The sorption of nitroglycerin by infusion sets

The sorption of nitroglycerin, from 5% glucose solution, by infusion sets was investigated under simulated perfusion conditions. Several burettes, sets and catheters were evaluated. The stability of the drug in the presence of glucose was also determined. High density polyethylene and glass proved satisfactory for its perfusion in solutions. A method for the evaluation of its uptake under simulated perfusion conditions is described.     

Spray-dried powders of starch and crosslinked poly(acrylic acid) as carriers for nasal delivery of inactivated influenza vaccine

Mucosal vaccination has several advantages over parenteral vaccination. In this study, viscosity-enhancing mucosal delivery systems for the induction of an adaptive immune response against viral antigen were investigated. Powder formulations based on spray-dried mixtures of starch (Amioca^®)/poly(acrylic acid) (Carbopol^® 974P) in different ratios were used as carriers of the viral antigen. A comparison of these formulations for intranasal delivery of heat-inactivated influenza virus combined with LTR192G adjuvant was made in vivo in a rabbit model. Individual rabbit sera were tested for seroconversion against hemagglutinin (HA), the major surface antigen of influenza. The powder vaccine formulations were able to induce systemic anti-HA IgG responses. The presence of Carbopol^® 974P improved the kinetics of the immune responses and the level of IgG titers in a dose-dependent way which was correlated with moderately irritating capacities of the formulation. In contrast, mucosal IgA responses were not detected. In conclusion, it was demonstrated that the use of bioadhesive carriers based on Amioca^® starch and poly(acrylic acid) facilitates the induction of a systemic anti-HA antibody response after intranasal vaccination with a whole virus influenza vaccine.     

Optimisation of an in vitro procedure for the determination of the enzymatic inhibition potency of multifunctional polymers.

An in vitro procedure for the determination of the inhibition potency of multifunctional polymers towards the proteolytic enzyme trypsin was optimised. Carbopol((R)) 934P was used as the reference polymer. The enzymatic reaction was optimised and the HPLC method was validated. The optimal substrate concentration and enzymatic activity were determined aiming at extracting the linear or steady-state part of the metabolite concentration versus time curve of the enzymatic degradation reaction. A substrate concentration of 20 mmol/l N-alpha-benzoyl-L-arginine-ethylester and an enzymatic activity of 30 enzymatic units trypsin/ml were used. The degree of trypsin inhibition was expressed by the inhibition factor (IF), defined as the ratio of the enzymatic reaction rate without a polymer (control) to the reaction rate in the presence of a polymer. During the optimisation of the trypsin inhibition assay, formation of an ion complex between the substrate and the poly(acrylic acid) was observed. The complex formation was concentration dependent, but the influence on the enzymatic reaction was negligible as long as an excessive substrate concentration was present in the reaction medium. The optimised method allows to characterize, evaluate and compare the in vitro trypsin inhibition strength for most multifunctional polymers.     

Starch/Carbopol spray-dried mixtures as excipients for oral sustained drug delivery.

The present study evaluated if mixtures prepared by spray-drying an aqueous dispersion of Amioca starch and Carbopol 974P could be used as matrix for oral sustained drug delivery. The influence of the Amioca/Carbopol 974P ratio (0/100, 25/75, 50/50, 60/40, 85/15, 90/10, 95/5 and 100/0) and the pH and ionic strength (mu) of the dissolution medium on the drug release was investigated. The matrices composed of the spray-dried mixtures with 10% or 15% Carbopol 974P sustained the drug release over the longest time period. At this Carbopol concentration, shear viscosity measurements indicated the formation of an optimal network between the polymer chains of Amioca starch and Carbopol 974P, forming a rigid gel layer offering resistance to erosion during the dissolution experiments.