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Investigation of mixing time and relative concentration effects in adhesive mixtures for drug inhalation

Åslund, Simon LU (2015) MAM720 20142
Ergonomics and Aerosol Technology
Abstract
A common approach to treat respiratory diseases is with adhesive powder mixtures. These are dispersed into an aerosol upon inhalation. It has been found that the performance of such mixtures can be improved by adding fine particle lactose, but exactly why is yet to be established. Several theories have been proposed by previous studies, but the fundamental mechanism is still unknown.

This study was done in order to examine the impact of lactose fines (LF) in adhesive mixtures. This was approached by manufacturing different formulations using a high shear mixer. The concentration of added fines was kept at a constant 8% for all batches, whereas the relative concentration between the active pharmaceutical ingredient (API) Beclomethasone... (More)
A common approach to treat respiratory diseases is with adhesive powder mixtures. These are dispersed into an aerosol upon inhalation. It has been found that the performance of such mixtures can be improved by adding fine particle lactose, but exactly why is yet to be established. Several theories have been proposed by previous studies, but the fundamental mechanism is still unknown.

This study was done in order to examine the impact of lactose fines (LF) in adhesive mixtures. This was approached by manufacturing different formulations using a high shear mixer. The concentration of added fines was kept at a constant 8% for all batches, whereas the relative concentration between the active pharmaceutical ingredient (API) Beclomethasone Dipropionate (BDP) and LF was varied systematically. Two sets of formulations were made, one containing a force control additive (1% Magnesium Stearate), referred to as coated formulations, whereas the other contained no such additive, referred to standard formulations. Several samples were extracted at different time points during the mixing stage in order to get a better understanding on how the mixing process influences the dispersion properties.

The aerodynamic particle size distributions of the API and LF were assessed using a Next Generation Impactor (NGI), which is a widely practiced technique within pharmaceutical development work. Quantification of BDP component was done using a well-developed method consisting of an ultra-performance liquid chromatography -system and an internal standard solution. However, this technique is not suitable to quantify the LF component. Overall, the analysis of lactose intended for inhalation is poorly described in literature. Therefore, one objective of this thesis was to find and evaluate such method. Two techniques were tried out; the first one being LC-PAD system based on electrochemical analysis. This was however disregarded due to instrumental errors and instead, a high pressure liquid chromotography system coupled with a mass spectrometer was used. However, this technique needs more tuning to be as good as the one used for BDP, as the assessed results did sometime display unreasonably high values and it is still unclear how much impact the carriers have on the analysis.

Regarding the performance of the manufactured batches, it was observed that the Fine Particle Fraction (FPF) for the coated formulations were consistently higher than for the standard formulations, as was expected. The coated formulations did also show a dependency on the mixing process as regards the FPF values. No such effect could be seen for the standard formulations. It was also found that the FPF of LF were consistently higher than the FPF of BDP. The FPF of BDP was consistently higher for formulations with a higher amount of LF. It was proposed that the LF and BDP form co-agglomerates during mixing, which lies in agreement with one of the existing theories that explains the behavior of LF.

The NGI is, despite yielding high quality results, a rather time consuming method which bottlenecks the pharmaceutical development process. A faster method to assess the PSD of an adhesive mixture is by the usage of Laser Diffraction (LD). This technique is however chemically non-specific, which render analysis of adhesive mixtures including both LF and API a bit troublesome. It would be favorable for future work if there was a way of correcting for LF when analyzing using LD, and a second part of this thesis was thus to evaluate how well data assessed from the NGI correlated with data assessed with LD setups.

It was found that it is possible to screen a formulation using LD if an appropriate dispersion method is used. However, in order to correct for LF in LD measurements, more research is needed as the LF seems to disperse differently in different formulations. Formulations with only LF as added fines correlated well with data assessed by the NGI. (Less)
Popular Abstract (Swedish)
Laktos – astmamedicinens bästa vän?

Att leverera medicin till lungan är en krånglig process då en stor del av den verksamma substansen riskerar att fastna i svalget. Ny forskning har dock gett bredare förståelse för hur små partiklar av laktos kan användas till att öka effektiviteten hos inhalerbara läkemedel.

Vid behandling av sjukdomar som drabbar luftvägarna, så som astma, finns det olika sätt att gå tillväga. Det vanligaste sättet är att andas in verksamma substansen, dvs själva medicinen, i form av ett pulver. Partiklarna följer då med ner i luftvägarna, som en så kallad aerosol. Beroende på dessa partiklars storlek kommer de fastna i olika delar av luftrören och ju mindre partikel, desto längre ner i lungorna kan den komma.... (More)
Laktos – astmamedicinens bästa vän?

Att leverera medicin till lungan är en krånglig process då en stor del av den verksamma substansen riskerar att fastna i svalget. Ny forskning har dock gett bredare förståelse för hur små partiklar av laktos kan användas till att öka effektiviteten hos inhalerbara läkemedel.

Vid behandling av sjukdomar som drabbar luftvägarna, så som astma, finns det olika sätt att gå tillväga. Det vanligaste sättet är att andas in verksamma substansen, dvs själva medicinen, i form av ett pulver. Partiklarna följer då med ner i luftvägarna, som en så kallad aerosol. Beroende på dessa partiklars storlek kommer de fastna i olika delar av luftrören och ju mindre partikel, desto längre ner i lungorna kan den komma. Genom att avgränsa partikelstorleken på den verksamma substansen kan man i princip bestämma var i lungan denna partikel ska hamna. Ett vanligt mål att sikta på är i de nedre delerna av lungan. För att träffa dessa delar brukar man använda partiklar som är ungefär 1-5 μm i diameter, dvs en hundradel till en tjugondel av diametern på ett vanligt hårstrå.

Partiklar av denna storlek vill dock väldigt gärna klumpa ihop sig med varandra, vilket leder till en dålig medicinering då det mesta fastnar i de övre luftvägarna. Ett sätt att lösa detta är att blanda den verksamma substansen med betydligt större partiklar, bestående av ett inaktivt material, t.ex. laktos. De mindre partiklarna, som består av den verksamma substansen, fastnar då på laktosen istället och kan enklare frisättas vid inandning. Dessa större partiklarna kallas för bärare, då de ”bär” på de mindre partiklarna.

För att öka andelen partiklar som frisätts kan man också blanda i ett ett pulver av partiklar som sätter sig på ytan av de stora laktospartiklarna, så att den ytbeläggning som erhålls gör det lättare för de mindre partiklarna att lossna vid inandning. För att ytterligare underlätta för den verksamma substansen att frigöras från bäraren kan man blanda i små partiklar av laktos i pulvermixen. Dock är förklaringen till varför detta förbättrar spridningsförmågan fortfarande ett mysterium, men en nyligen utfört studie har stärkt en av de teorier som har förslagits av tidigare forskning. Genom att tillverka olika pulverblandningar med olika koncentrationer av verksam substans och små partiklar av laktos kunde man undersöka hur och om dessa samverkade. I vissa pulverblandningar blandade man även ett pulver som ger den ytbeläggningen på bärarna som nämndes tidigare.

Pulveregenskaperna utvärderades sedan med hjälp av en specialdesignad teknik som är skapad för att efterlikna de villkor som finns i en lunga. Via den kan man se hur mycket av den verksamma substansen som lossnar från bärarpartiklarna. Om många partiklar lossnar har pulvermixen en hög effektivitet, och det visade sig smörjmedlet både ökade denna effektivitet samt gav olika effektivitet för olika blandningstider.

För att undersöka de små partiklarna av laktos testade man en metod som tidigare inte har testats i dessa sammanhang. Det visade sig då att ju mer små partiklar av laktos och mindre verksam substans i en pulverblandning, desto högre effektivitet fick den. En möjlig förklaring till detta är att laktosen och den verksamma substansen delvis klumpar ihop sig med varandra i stora kluster, som enklare går sönder när pulvret sprids i luften.
De tekniker som användes för att komma fram till resultatet ovan är väldigt tidskrävande. Därför testades också en annan, snabbare, teknik som baseras på hur partiklar av olika storlek sprider ljus olika. Resultatet här var lovande och visar på att man kan använda denna teknik som ett komplement till den ovan. Vidare forskning inom området behövs dock, men genom denna studie har man tagit ett steg närmare mot att lösa laktosens gåta. (Less)
Please use this url to cite or link to this publication:
author
Åslund, Simon LU
supervisor
organization
course
MAM720 20142
year
type
H2 - Master's Degree (Two Years)
subject
keywords
Aerosol Drug Inhalation Adhesive mixtures Next Generation Impactor Laser diffraction
language
English
id
5367947
date added to LUP
2015-06-09 09:47:13
date last changed
2015-06-09 09:47:13
@misc{5367947,
  abstract     = {A common approach to treat respiratory diseases is with adhesive powder mixtures. These are dispersed into an aerosol upon inhalation. It has been found that the performance of such mixtures can be improved by adding fine particle lactose, but exactly why is yet to be established. Several theories have been proposed by previous studies, but the fundamental mechanism is still unknown.

This study was done in order to examine the impact of lactose fines (LF) in adhesive mixtures. This was approached by manufacturing different formulations using a high shear mixer. The concentration of added fines was kept at a constant 8% for all batches, whereas the relative concentration between the active pharmaceutical ingredient (API) Beclomethasone Dipropionate (BDP) and LF was varied systematically. Two sets of formulations were made, one containing a force control additive (1% Magnesium Stearate), referred to as coated formulations, whereas the other contained no such additive, referred to standard formulations. Several samples were extracted at different time points during the mixing stage in order to get a better understanding on how the mixing process influences the dispersion properties.

The aerodynamic particle size distributions of the API and LF were assessed using a Next Generation Impactor (NGI), which is a widely practiced technique within pharmaceutical development work. Quantification of BDP component was done using a well-developed method consisting of an ultra-performance liquid chromatography -system and an internal standard solution. However, this technique is not suitable to quantify the LF component. Overall, the analysis of lactose intended for inhalation is poorly described in literature. Therefore, one objective of this thesis was to find and evaluate such method. Two techniques were tried out; the first one being LC-PAD system based on electrochemical analysis. This was however disregarded due to instrumental errors and instead, a high pressure liquid chromotography system coupled with a mass spectrometer was used. However, this technique needs more tuning to be as good as the one used for BDP, as the assessed results did sometime display unreasonably high values and it is still unclear how much impact the carriers have on the analysis.

Regarding the performance of the manufactured batches, it was observed that the Fine Particle Fraction (FPF) for the coated formulations were consistently higher than for the standard formulations, as was expected. The coated formulations did also show a dependency on the mixing process as regards the FPF values. No such effect could be seen for the standard formulations. It was also found that the FPF of LF were consistently higher than the FPF of BDP. The FPF of BDP was consistently higher for formulations with a higher amount of LF. It was proposed that the LF and BDP form co-agglomerates during mixing, which lies in agreement with one of the existing theories that explains the behavior of LF.

The NGI is, despite yielding high quality results, a rather time consuming method which bottlenecks the pharmaceutical development process. A faster method to assess the PSD of an adhesive mixture is by the usage of Laser Diffraction (LD). This technique is however chemically non-specific, which render analysis of adhesive mixtures including both LF and API a bit troublesome. It would be favorable for future work if there was a way of correcting for LF when analyzing using LD, and a second part of this thesis was thus to evaluate how well data assessed from the NGI correlated with data assessed with LD setups.

It was found that it is possible to screen a formulation using LD if an appropriate dispersion method is used. However, in order to correct for LF in LD measurements, more research is needed as the LF seems to disperse differently in different formulations. Formulations with only LF as added fines correlated well with data assessed by the NGI.},
  author       = {Åslund, Simon},
  keyword      = {Aerosol Drug Inhalation Adhesive mixtures Next Generation Impactor Laser diffraction},
  language     = {eng},
  note         = {Student Paper},
  title        = {Investigation of mixing time and relative concentration effects in adhesive mixtures for drug inhalation},
  year         = {2015},
}