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The influence of (Pseudo)polymorphic forms of lactose on dry powder inhaler performance
Relating to Invited Lecture j-Material
A major complication associated with orthopaedic implants is the occurrence of device-related infection. This is a particular problem with bone external fixation pins since the implant surface is open to colonisation by commensal skin bacteria. Recently the use of silver as a means of controlling microbial colonisation of biomaterials has been reported for medical devices such as ureteric stents.1 In this study the ability of clinical isolates to adhere lo silver-coated stainless steel external fixation pins was assessed. Heat-sterilized stainless steel and silver-coated stainless steel pins (Orthofix Sri, ltaly) were pretreated with human serum or phosphate buffered saline (PBS). Clinical wound isolates (Eschetichia co/i SC1, Pseudomonas aeruginosa SC2, Staphylococcus aureus SC4, S.aureus SC5 and S.haemolyticus SC7) were cultured in peptone Bacterial water supplemented with 3% (v/v) human serum. suspensions (3 x 10 cells/ml PBS) were incubated with the pins and the adenosine trfphosphate (ATP) from the bound bacteria was extracted and quantified by a luciferase bioluminescent method. The number of adherent cells was calculated from standard curves. The findings of this study indicated that generally there was a significant reduction in adhesion to silver-coated pins when compared lo the uncoated surface (Mann-Whitney rank-sum test; P < 0.05), although this differential effect was lost following scum conditioning. In practice, the initial stage of infection is likely to be caused by colonisation of the external portion of the pin which will not have a serum-derived protein conditioning film. Therefore the ability of silver to reduce initial bacterial attachment may have an important clinical application in controlling infection of external fixation pins.
Science (P3.03l-P3.0891
Sl79
Rubber closures form a critical barrier in the protection of freeze-dried products against the uptake of moisture. In this study. the moisture absorption of different rubber closures at different temperatures and relative humidities was evaluated. using a Karl Fischer titration - oven combination. Besides, the moisture absorption during steam sterilisation and the moisture desorption during drying of the stoppers was investigated. The stoppers studied were bromobutyl stoppers 1092 W4018 (Pharma Gummi); FM357 V9032 SNl, FM257 V9032 SNO and FM257 V9032 Omniflex (Helvoet Pharma) and chlorobutyl stoppers 1319 PH701/50 and 1097 W1888 (Pharma Gummi) and FM140 V9032 SAFI (Helvoet Pharma). The moisture levels of the closures stored during 80 days at 95%RH-40’C was in the range 0.85-1.4996 for the bromobutyl stoppers and in the range 1.66-1.97% for the chlorobutyl stoppers, dependent on the coating treatmentThe same trend in moisture absorption was seen during steam sterilisation. where the moisture uptake of the chlorobutyl rubber closures was higher (0.820.90%). compared to the bromobutyl rubber closures (0.40-0.54%). Moisture desorption after steam sterilisation, during drying at 100 ‘C. depended on the treatment of the stopper. e.g. siliconation. The moisture absorption of a freeze-dried 10% w/v maltodextrin DE22 solution was evaluated after venting the lyophilization chamber with air or nitrogen or closing the vials under vacuum with FM140 and FM357 closures (Helvoet Pharma). There was no moisture desorption in the rubber closures during the lyophilization process. Moisture uptake of the freeze-dried cakes at 95%RH_40’C depended on the venting procedure of the lyophilization chamber after freeze-drying.
1. J.W.C.Leung et al. Gastrointestinal Endoscopy.1992. 38:338-340
The principle of an ultrasonic nebuliser is based on the vibrations of a piezo-ektrii crystal driven by an alternating electrfcal field . These fModiil vibrations are characterised by theii frequency , their amplii and their intensity whii correspondsto the energy transmitted per surface unit. When the vibration intensity is suffffnt , cavitation appears and generates droplets Ventilation enables an airflow to cross thenebukrandtocarryouttheaemsoldroplets. For a given nebuliser , the vibration frequency of the pieze electric aystal is fixed and is otten in the range of l-2.5 MHz In most cases , an adjustment in vibration intensity is possible by modiiing vibration amplitude The ventilation level is adjustable. We studied the influence of these two parameters on the effiiiency of ultrasonic nebuliition Our study was carried out with a protein solution that had to be administered intothelungs.Thesolution~presentedaviscosityd1.25 mPas and a sufface tension of 53 mN I m We checked the integrity of the protein which was submitted to different vibration conditions The efficiency of nebulisation was evaluated by determining droplet size , the percentage of nebulfsed drug and nebuffsaticn time. The rise in vibration intensity does not modii the size of droplets emitted , it decreases nebulisatfoa time and raises the quantity of protein nebulised thus improving performance. On the other hand, the i&ease in ventilation increases the size of droplets emitted decreases nebulisation time and the quantity of @o&in nebulised becauee more drug is bst on the walls of the nebuliser. Hiih intensityassociated with low ventilation favours drug delivery deepintothelurgs.
a-lactose monohydrate is the most commonly employed carrier in dry powder inhaler formulations. In this study the in!luence of diffarem (pseudo)polymorphic forms of lactose on entrainment and drug deposition from a dry powder inhaler was investigated Separate powder blends were prepared containing both an inhaled steroid marker and three crystal forms of lactose: a-monohydrate, a-stable anhydrous and p-anhydrous lactose. Stable a-anhydrous lactose was formed by the chemical dehydration of a-lactose monohydrate. All other materials were of commercial origin, pharmacopoeial quality and separated into the size range 63-90~ The presence of stable a-anhydrous lactose was confirmed by differential scanningcalorimetry Fractal analysis of digital images, obtained from scanning electron microscopy, was used to character& the surface morphology of each crystal type It wss found that crystals of both a-monohydrate and b-anhydrous lactose possessedfractal dimensionsin the order of 1.OI to 1.05 whilst those of a-anhydrous lactose ranged from I 06 to I 16, reflecting their higher surface roughness Powder aerosol characteristics, determined using a specially constructed entrainment tube, reflected the differences in surface texture The rougher a-anhydrous lactose was less readily entrained than the smoother amonohydrate and @-anhydrouspowders The respirable dose of drug from the different blends was daennined using a twin stage liquid impinger (B.P. Apparatus A). Initial data suggeststhat there are no appreciable difTerences between the fine particle deposition characteristics of the powder blends despite their variations in particle morphology However, it is considered that the different arrangement of crystal lattices and consequent morphologicaldifferences may influence the entrainmentof lactose particles
A major complication associated with orthopaedic implants is the occurrence of device-related infection. This is a particular problem with bone external fixation pins since the implant surface is open to colonisation by commensal skin bacteria. Recently the use of silver as a means of controlling microbial colonisation of biomaterials has been reported for medical devices such as ureteric stents.1 In this study the ability of clinical isolates to adhere lo silver-coated stainless steel external fixation pins was assessed. Heat-sterilized stainless steel and silver-coated stainless steel pins (Orthofix Sri, ltaly) were pretreated with human serum or phosphate buffered saline (PBS). Clinical wound isolates (Eschetichia co/i SC1, Pseudomonas aeruginosa SC2, Staphylococcus aureus SC4, S.aureus SC5 and S.haemolyticus SC7) were cultured in peptone Bacterial water supplemented with 3% (v/v) human serum. suspensions (3 x 10 cells/ml PBS) were incubated with the pins and the adenosine trfphosphate (ATP) from the bound bacteria was extracted and quantified by a luciferase bioluminescent method. The number of adherent cells was calculated from standard curves. The findings of this study indicated that generally there was a significant reduction in adhesion to silver-coated pins when compared lo the uncoated surface (Mann-Whitney rank-sum test; P < 0.05), although this differential effect was lost following scum conditioning. In practice, the initial stage of infection is likely to be caused by colonisation of the external portion of the pin which will not have a serum-derived protein conditioning film. Therefore the ability of silver to reduce initial bacterial attachment may have an important clinical application in controlling infection of external fixation pins.
Science (P3.03l-P3.0891
Sl79
Rubber closures form a critical barrier in the protection of freeze-dried products against the uptake of moisture. In this study. the moisture absorption of different rubber closures at different temperatures and relative humidities was evaluated. using a Karl Fischer titration - oven combination. Besides, the moisture absorption during steam sterilisation and the moisture desorption during drying of the stoppers was investigated. The stoppers studied were bromobutyl stoppers 1092 W4018 (Pharma Gummi); FM357 V9032 SNl, FM257 V9032 SNO and FM257 V9032 Omniflex (Helvoet Pharma) and chlorobutyl stoppers 1319 PH701/50 and 1097 W1888 (Pharma Gummi) and FM140 V9032 SAFI (Helvoet Pharma). The moisture levels of the closures stored during 80 days at 95%RH-40’C was in the range 0.85-1.4996 for the bromobutyl stoppers and in the range 1.66-1.97% for the chlorobutyl stoppers, dependent on the coating treatmentThe same trend in moisture absorption was seen during steam sterilisation. where the moisture uptake of the chlorobutyl rubber closures was higher (0.820.90%). compared to the bromobutyl rubber closures (0.40-0.54%). Moisture desorption after steam sterilisation, during drying at 100 ‘C. depended on the treatment of the stopper. e.g. siliconation. The moisture absorption of a freeze-dried 10% w/v maltodextrin DE22 solution was evaluated after venting the lyophilization chamber with air or nitrogen or closing the vials under vacuum with FM140 and FM357 closures (Helvoet Pharma). There was no moisture desorption in the rubber closures during the lyophilization process. Moisture uptake of the freeze-dried cakes at 95%RH_40’C depended on the venting procedure of the lyophilization chamber after freeze-drying.
1. J.W.C.Leung et al. Gastrointestinal Endoscopy.1992. 38:338-340
The principle of an ultrasonic nebuliser is based on the vibrations of a piezo-ektrii crystal driven by an alternating electrfcal field . These fModiil vibrations are characterised by theii frequency , their amplii and their intensity whii correspondsto the energy transmitted per surface unit. When the vibration intensity is suffffnt , cavitation appears and generates droplets Ventilation enables an airflow to cross thenebukrandtocarryouttheaemsoldroplets. For a given nebuliser , the vibration frequency of the pieze electric aystal is fixed and is otten in the range of l-2.5 MHz In most cases , an adjustment in vibration intensity is possible by modiiing vibration amplitude The ventilation level is adjustable. We studied the influence of these two parameters on the effiiiency of ultrasonic nebuliition Our study was carried out with a protein solution that had to be administered intothelungs.Thesolution~presentedaviscosityd1.25 mPas and a sufface tension of 53 mN I m We checked the integrity of the protein which was submitted to different vibration conditions The efficiency of nebulisation was evaluated by determining droplet size , the percentage of nebulfsed drug and nebuffsaticn time. The rise in vibration intensity does not modii the size of droplets emitted , it decreases nebulisatfoa time and raises the quantity of protein nebulised thus improving performance. On the other hand, the i&ease in ventilation increases the size of droplets emitted decreases nebulisation time and the quantity of @o&in nebulised becauee more drug is bst on the walls of the nebuliser. Hiih intensityassociated with low ventilation favours drug delivery deepintothelurgs.
a-lactose monohydrate is the most commonly employed carrier in dry powder inhaler formulations. In this study the in!luence of diffarem (pseudo)polymorphic forms of lactose on entrainment and drug deposition from a dry powder inhaler was investigated Separate powder blends were prepared containing both an inhaled steroid marker and three crystal forms of lactose: a-monohydrate, a-stable anhydrous and p-anhydrous lactose. Stable a-anhydrous lactose was formed by the chemical dehydration of a-lactose monohydrate. All other materials were of commercial origin, pharmacopoeial quality and separated into the size range 63-90~ The presence of stable a-anhydrous lactose was confirmed by differential scanningcalorimetry Fractal analysis of digital images, obtained from scanning electron microscopy, was used to character& the surface morphology of each crystal type It wss found that crystals of both a-monohydrate and b-anhydrous lactose possessedfractal dimensionsin the order of 1.OI to 1.05 whilst those of a-anhydrous lactose ranged from I 06 to I 16, reflecting their higher surface roughness Powder aerosol characteristics, determined using a specially constructed entrainment tube, reflected the differences in surface texture The rougher a-anhydrous lactose was less readily entrained than the smoother amonohydrate and @-anhydrouspowders The respirable dose of drug from the different blends was daennined using a twin stage liquid impinger (B.P. Apparatus A). Initial data suggeststhat there are no appreciable difTerences between the fine particle deposition characteristics of the powder blends despite their variations in particle morphology However, it is considered that the different arrangement of crystal lattices and consequent morphologicaldifferences may influence the entrainmentof lactose particles