by Leticia Ely , Wilson Roa , Warren H. Finlay , Raimar Lo¨benberg

In recent past pulmonary drug delivery has become a major interested involving systemic drug absorption and treatment methods for diseases such as diabetes mellitus, pain relief, cystic fibrosis, asthma, lung cancer, and tuberculosis. Delivering drugs through pulmonary system comes with challenges. These are tackled with the help of nanoparticles, aerosols and delivering drugs in the form of dry powder.

Use of nanoparticles in pulmonary drug delivery helps bypass mucocillary clearance, phagocyte clearance and translocation by epithelium cells. Drawbacks include the size of the nanoparticles that limit lung deposition, limited sedimentation lead the aresole to be cleared by lung quicly after inhalation. Aerosoles are incorporated with carrier particles and the increase in size helps increase the amount of drug deposition to the lungs.

Effervescent drug delivery has been widely used in oral drug treatments, especially for treatments of stomach distress, vitamin supplements and analgesics. However, the authors states by year 2006 none has attempted use of effervescent formulations for treatment of pulmonary drug delivery. Therefore this study is the first attempted to investigate the suitability of effervescent technology along with nanonparticles for pulmonary drug delivery.

Polybutlycyanoacrylate (PBC) nonoparticle and ciprofloxacin hydrocholiride hydrate (CHH) are used as the model substance in this study to investigate suitability of active release mechanism of effervescent for pulmonary drug delivery. The new effervescent formulation was tested by comparing it with dispersion time of lactose particle carriers.

Both PBC nanoparciels and CHH nanoparticle was prepared using standard procedure as explained in brief in the article. The derived particle were then tested for loading efficiency by dissolving lactose or effervescent powder in water and analyzed using UV spectroscopy at 271nm before and after loading. Dissolved drug content was then calculated with the help of calibration curve and liner regression. To tag the particles with flourcent labeling, 7 ml of suspension of PBC was added to 7% lactose containing solution or to 7% lactose solution with either PEG 6000 and L-leucine or 7% lactose solution with an effervescent solution contacting PEG 6000 and L-Leucine. The solutions were then spray dried under standard conditions used in this study.

The particle size was determined using the photon spectroscopy. Mass, median diameter ( MMA) was determined with help of Mark II Anderson cascade Impactor and with new high efficiency inhaler. Sample were also investigated using confocal laser microscopy and scanning electron microscopy . Different compositions of the powders were tested and spray dried to analyze an appropriate size that will help pulmonary delivery.

To formulate a novel effervescent formulation different concentrations of citric acid, and carbonates in different rations of 50% sodium carbonate, 50% sodium bicarbonate was analyzed in tablet formulation. Two components in an aqueous environment are shown in the following formulation.

R–COOH þ XHCO3 H2O R–COOX þ CO2 þ H2O

As seen effervescent formulation releases carbon dioxide, when disintegration is increased and absorption is increased the phase transition between solid phase and gas phase result in an increase of volume and drug dissolution. The basic effervescent formulation contains citric acid, water and sodium carbonate, since this formulation has to be spray dried in order to be used for pulmonary delivery the Ph of solution was increased at 8 by adding ammonia. To active the expected MMD and particle size polysorbate 80, L-leucine and PEG 6000 were added to the basic formulation along with different amounts of lactose were added.

Change in amounts of lactose resulted in changes in size and morphology of the career particles. Smaller particle sizes were achieved increasing the lactose and visa versa. They were dense and spherical in shape.

The particle sizes data indicates by lactose was found to be 73.38 +/-13% and for powders containing the L-leucine/PEG 6000 effervescent formulation was 68.55+/- 23.90%, therefore the researchers conclude using PEG 6000 powder would be the most ideal for formation of inhalable particles. Comparison of the releases of drug from drug ciprofloxacin( poorly water soluble) was compared between lactose particles and effervescent formulation. Results indicated effervescent carrier particles released 56+/-8% while lactose particle released 32+/-3. The significance was noted at t-test, P < 0.05.

Polybutylcyanoacrylate nanoparticles were also compared with lactose and effervescent formulation. Four different powders with constant of L-lucin and PEG were created to test the effervescent formulation. Data indicated there was significant increase in particle size P < 0.05 if only lactose was used but when lactose contained PEG and L-Leucin no statistical different was observed in particle sizes.

Effervescent property of carrier particle was tested by exposing to water. Data indicated that nanoparticle was actively distributed in the gas bubbles. When effervescent powder was dispersed in water immediate gas bubbles and dispersion was observed.

A new effervescent formulation was formed for the model drugs. The formulations formulated including lactose containing L-leucin and PEG 6000 was able to release nonpartiles seem to have been better compared to career particles made of just lactose by reducing agglomeratiotion and had better active releases. Results indicted releases of nanoparticle were affected by both the effervescent formulation and coic of excipients used. The force made by the effervescent reaction helped disperser the nonparticle efficiently and reduced particle aggregation and increase disintegration and drug dissolution. Researches also state more studies are needed to determine if the effervescent formulation was inhalable. With further studies the effervescent carrier particle could possibly be used for number of drug delivery to the lung with better efficient compared to the conventional carrier particles.

by Möller et al. 2009

This paper discusses, sinusitis and rhinosinusitis. The was to develop a better treatment method for these infections. Sinusitis is a commonly diagnosed illnesses in European population, it is also estimated that over 10 -15% of the European population suffers from rhinosinusitis. Sinusitis and chronic rhinosinusitis a result of inflamed nasal lining due to bacterial, fungal and allergic infections. Inflammation of nasal mucus lining will result in an increased mucus secretion, loss of cilia, obstructed air pathway and blockage of nasal drainage. This will lead to loss of mucus drainage and in turn sinusitis while chronic rhinosinusitis is observed in an environment with reduced ventilation.

In vivo and in vitro studies have indicated that paranasal sinus could be reached through nebulized drugs but it was noted that it only had a low efficiency, therefor the main treatment method for chronic sinusitis and rhinosinusitis still remains as surgery. It is important to find a better treatment and transportation method of drugs for treatment of these infections.
This study aims to analyse the ventilation efficiency of the sinus of three healthy volunteers, using dynamic 81mKr-gas imaging along with pulsating airflows. The researchers also study and investigate the deposition efficiency by radiolabeling the aerosols with DTPA(diethylenetriaminepentaacetic acid) and retention of 99mTc-DTPA aerosol particles after a period of 24 hours was assessed.

Three healthy male volunteers (non-smokers) with a mean age of 46+/- 12 were recruited to participate in this study. All three volunteer’s has normal lung functions and had no history of allergic diseases. Nasal anatomies of the three subjects were investigated with use of MRT imaging and fibre optic rhinoscopy.
Pulsating aerosol delivery system.

PARI SINUS system with 45Hz frequency with amplitude of 24mbar was used to generate a pulsating aerosol generating system based on PARI BOY N aerosol drug delivery device. The rate of mass output was at 0.2ml/min, There was no significance difference between pulsating aerosol output and non-pulsating aerosol output was noted.
Kr-gas ventilation studies. Contineous ventilation of Kr-gas through nasal airway was given in front of a single head gamma camera with the use of PARI SINUS system the air supply has 82mKr- gas generator output channel. Kr-gas ventilation imaged was taken with and without pulsation for comparison.

The aerosol was produced using a solution composed of 99mTc- DTPA (diethylenetriaminepentaacetic acid) with nanocolloid of 500 Dalton in size. DTPA aerosols constructed were used for ventilation imaging and measurement of alveolar transmembrane permeability. Passive diffusion results in clearing out of 99mTc-DTPA within 90 minfrom the lungs into circulation. Nebulizer was filled with DTPA solution containing about 600 MBq of 99mTc-activity. Total nasal deposition rate was assessed by measuring the output rate of the nebulizer all particles on PALL BB50 filter before the aerosol delivery. Post DTPA delivery was measured during 24hours by investigating the nasal deposition, retention and clearance along with low energy collimator. Images of anterior and lateral gamma camera were coded just after inhalation, and after 1.5, 3, 6 and 24 hours post inhalation respectively. DTPA Translocate to blood after 24 hours was assessed by urine analysis. Statistical analyses of group difference of with or without pulsation were performed and calculated by two-sided t-Test with a significance level of p < 0.05.

There is only little Kr- gas pentration to the paranasal sinus is seen, this is clearer since sinus do not appear on this image.

Images suggest negligible Kr- gas activity in the maxillary sinuses. Kr-gas penetration was seen in the nasal airway when administrated without pulsation while with pulsating the gas penetration was seen to front sinus resulting in activity above the nasal airways and Kr-gas penetration to maxillary sinuses shows activity to central nasal activity region and below. The images demonstrate Kr-gas activity in central nasal cavity and the frontal and maxillary sinus in all three volunteers. There were no difference in activity was visualized in central nasal cavity due to pulsating air flow after normalization for the activity of the nebulizer, But a 5 fold incur of activity in four sinus with pulsation air flow was observed.

Aerosol deposition in the nasal airways and in the nasal sinuses
Aerosol deposition was not recovered in the first image obtained after immediate aerosol deliver confirming tight closure of the soft plate during aerosol delivery. Three subject showed total aerosol deposition (% of nebulized dose) of 25 ± 16% without pulsation and 58 ± 17% with pulsation (p < 0.01) in the nasal cavitiy. Pentration to the sinuse was ovserved at 4.2 ± 0.3% with plkkusation with 1% was seen for without pulsation.

DTPA clearance from the nasal cavity
Aerosols delivered with and without pulsation deposited were cleared with half time of 1 hours according for nearly 30% of the aerosols. The remained were cleared with half time 6.9 and 7.9 hours for both with and without pulsation aerosol delivery. Retention of aerosol without and with pulsating delivery in nasal cavity after 24 hours were observed at 5.4 ± 1.8% and 8.6 ± 1.3% respectively while a( p < 0.01) DTPA was excreted into the urine within 24 hours.

Ventilation of maxillary and frontal sinuses was observed by gamma camera was observed with pulsating air flow with an deposited aerosol penetration of 3% to 5% into the paranasal sinus with pulsating delivery system where as only 1% was seen when administrated via non pulsation. There for pulsation has increased aerosol deposit in the nasal airway by factor of three.
The data suggests that paranasal sinus ventilation air flow and aerosolized drug delivery showed high efficiency when given via pulsating air flow. The data therefore suggest that topical drug delivery to paranasal sinus in relevant quantities could be a possible future treatment instead of surgery with further investigations. The data presented in this study only uses three volunteer’s which is not a sufficient number of test subjects there for further investigation should be recommended. The three subjects were healthy with clear air pathways; therefore for treatment of chronic rhinosinusitis the data may not be applicable.