Giovanni Caponetti

Drying a tuberculosis vaccine without freezing

With the increasing incidence of tuberculosis and drug resistant disease in developing countries due to HIV/AIDS, there is a need for vaccines that are more effective than the present bacillus Calmette–Guérin (BCG) vaccine. We demonstrate that BCG vaccine can be dried without traditional freezing and maintained with remarkable refrigerated and room-temperature stability for months through spray drying. Studies with a model Mycobacterium (Mycobacterium smegmatis) revealed that by removing salts and cryoprotectant (e.g., glycerol) from bacterial suspensions, the significant osmotic pressures that are normally produced on bacterial membranes through droplet drying can be reduced sufficiently to minimize loss of viability on drying by up to 2 orders of magnitude. By placing the bacteria in a matrix of leucine, high-yield, free-flowing, “vial-fillable” powders of bacteria (including M. smegmatis and M. bovis BCG) can be produced. These powders show relatively minor losses of activity after maintenance at 4°C and 25°C up to and beyond 4 months. Comparisons with lyophilized material prepared both with the same formulation and with a commercial formulation reveal that the spray-dried BCG has better overall viability on drying.

Delivery of Nasal Powders of β-Cyclodextrin by Insufflation

AbstractPurpose. Delivery of nasal powders of granulated β-cyclodextrin by insufflation was studied in order to find the relationship between powder properties and delivery behavior. Methods. Three nasal powder formulations, prepared by granulating β-cyclodextrin with different binders, were delivered from a powder insufflation device, in which the dose to be emitted was loaded in a gelatin capsule. The delivery sequence of powder was recorded and characterized using an image analysis program. Results. Particle size was the main parameter affecting nasal powder delivery, both as to the amount of dose sprayed and the aspect of cloud produced. Between 50–150 µm of particle size a substantial change in delivery behavior of powders was observed. Powder of around 100 µm in size showed useful insufflation characteristics for nasal delivery. Bioavailability of nasal formulations of progesterone/β-cyclodextrin powders was discussed in term of delivery behavior. Conclusions. The formulation approaches for improving nasal delivery of powders require the use of size optimized carriers. Insufflation of powders over 50 µm can favour the particle deposition by impaction, whereas for powders below 50 µm, deposition by sedimentation is moved. β-cyclodextrin is a suitable carrier for achieving high systemic availability following nasal administration of powder formulations.

Sterilization of corticosteroids for ocular and pulmonary delivery with supercritical carbon dioxide

Glucocorticosteroids, a class of drugs widely used in the treatment of allergies, airways inflammation and inflammatory ocular diseases, are often difficult to sterilize due to their inherent sensibility to heat or irradiation induced degradation. Being often in form of suspension, obviously the final medicinal product cannot be sterilized by filtration. The effectiveness of supercritical CO2 (SC-CO2) based method for the sterilization of food and biomedical materials is well documented in the literature. Few reports are available on the sterilization of drugs especially in powder form with SC-CO2. The aim of the present work was to investigate the suitability of SC-CO2 at mild temperature for the decontamination of two model corticosteroid powders (beclometasone dipropionate and budesonide) both in dry or wet form. We found that SC treatment in wet environment reduces by at least six orders of magnitude the contamination of micronized steroidal drugs while retaining the particle size distribution. The findings of this work are of particular interest for the application in the case of aqueous suspension of steroids for aerosol therapy or ocular delivery, where the sterilization process with SC-CO2 could be carried out directly on the bulk of the final formulation.

Influence of layer position on in vitro and in vivo release of levodopa methyl ester and carbidopa from three-layer matrix tablets

A versatile oral controlled release system for the simultaneous delivery of levodopa methyl ester and carbidopa, consisting of a three-layer matrix tablet, has been studied and developed. Each individual layer of the matrix exhibited a different release mechanism, i.e. the first layer was swellable (S), the second one was erodible (E) and the third one was disintegrating (D). The three layers have been assembled in the monolithic matrix in different relative positions. It was found that in the monolith the three layers could interact, producing in vitro release profiles depending on their relative position. The monoliths having the configurations DSE and SDE were administered to human volunteers in order to determine the plasma profiles. The pharmacokinetic data showed a significant difference between the early time plasma curves: the monolith DSE, having the fast release profile, gave rise to a rapid appearance of a high levodopa plasma level, whereas the slower releasing monolith SDE produced a smoothed plasma concentration profile.

Edry™ an innovative dry powder technology evaluated via functional respiratory imaging (FRI)

INTRODUCTION: Recent DPI development focussed on new inhalation devices and better chemicals. An little explored option is particle engineering. E dry is a spray drying platform to engineer powder particles with optimal size and deagglomeration characteristics. The aim of this work was to evaluate the E dry technology utilizing a new product candidate, Z7200 (budesonide (BUD)/formoterol fumarate (FF) 80/2.25µg) compared to its reference product (Symbicort 160/4.5µg). METHODS In vitro aerosol properties were tested using a Multi Stage Liquid Impinger (MSLI) at 4 different pressure drops (1-2-3-4kPa). FRI lung deposition calculations were based on CT scans of 5 asthmatic patients. The lower airways were coupled to 2 upper airway geometries (average and narrow) and DPI device. Deposition of BUD and FF was calculated via FRI at the above mentioned pressure drops by using the aerodynamic characterization from MSLI. RESULTS Results showed consistent aerosolization performances for each active moiety of Z7200 at every flow rate both in vitro and in silico. On the contrary, Symbicort requires an optimal inhalatory effort in order to deposit therapeutic amounts of drug in the lung. CONCLUSIONS This work indicates that E dry powders are potentialy offering significant benefits in lung deposition and inhalation flow rate independency with respect to a conventional reference product like Symbicort, both for BUD and FF.