Suitability of Spray Dried Powder containing Lipids for Inhalation Formulation based on Fine Particle Fraction and Particle Size Distribution

Abstract

The aim of this master thesis is to provide an indication of the suitability, or otherwise usage, of spray-drying for production of powder aimed for inhalation formulation and comparing the characteristics of the product, with and without lipids. Lipids have a proven effect of delaying release of active drug substances in the cardiovascular system and pulmonary systemic delivery has a number of advantages, chiefly among them being bypassing the first pass metabolism. Incorporating lipids in an inhalation formulation would therefore be advantageous. Spray-drying is one of the proposed methods for production of such powder.

There are numerous measurements needed to ascertain whether the product is suitable for a given formulation or not. This project will focus on the fine particle fraction and the particle size distribution, as well as miscellaneous measurements (for example, water activity and general particle shape).
Two ingredients were essential in the formulation: The active pharmaceutical ingredient (API) and the lipid excipient. Lysozyme from egg white substituted for an API. Two lipids were tested, labeled “mixed lipid” and “pure lipid” respectively. The project was divided into three production trials and two analysis phases to gain information of how variations of different factors affect the properties.

Obtained results show that the production system is robust and addition of lipids does not affect the properties adversely. Spray-drying produces spherical particles with low water content, if a high drying temperature and low feed rate is chosen. The fine particle fraction of the produced batches does not exceed 30 % and the size distribution shows the produced powder has no uniform particle size. The majority of the particle population have a large diameter with declining amount in lower diameters.

Analysis of the results indicate an inhomogeneity in the final product, due to several irregularities and a large spread with the measured data. While no definite data was measured, possibilities of the discrepancies could be due to the preparation of the encapsulated substance rather than due to production via spray-drying.

Popular Abstract

Formulating drugs require numerous issues to be tackled in order to optimize the effectivity. All forms of formulations have their own challenges that scientists and companies try to work around. For example, metabolism of the drug by the liver, called the first-pass effect, greatly reduces the drug concentration and, in worst cases, even alter it to toxic forms. This could be a great concern. Pulmonary drug delivery bypasses this by transporting the drug, in powder form, from the respiratory tract to the blood, using the alveoli as a gateway. The minimum requirement to transport to the lungs is a particle size of less than 5 µm in diameter.

Many techniques exist to produce powder and a particular popular one is spray-drying. In spray-drying, a pharmaceutical solution, containing all substances to be incorporated in the powder, is divided into a spray of millions of droplets. Each droplet is dried with the heat provided by a warm gas and forms a single particle. And so, in one single operation, powder is produced. The question is then how to optimize the production process for maximum amount of fine particles in the powder.

The master thesis presents the data of production trials of spray-dried powder and evaluation of how the fine particle fraction is affected by variations in the production process. The formulation consisted of lysozyme, lactose, and lipids. Analyzing powder properties based on size is common when formulating inhalable drugs. For this, cascade impactors are a convenient tool, specifically made for that purpose. Larger particles are caught early in the plates in impactor and smaller particles continue further down in the impactor. The dynamics involved when a patient uses dry powder inhaler is simulated to distribute the powder in different size ranges. This gives information of where the powder should be deposited in the respiratory tract.

Results showed that spray-drying is a very robust production method. Addition of lipids in the process does not change the fine particle fraction in the powder. A repeating pattern found in the results is a discrepancy and lack of reproducibility in data for samples containing lipids versus samples containing no lipids. Production via spray-drying often leads to a homogeneous matrix in the powder particles. However, as presented in the thesis, the presented method seems to have been affected when including lipids in the formulation. #

Popular Abstract (Swedish)

Formulering av läkemedel kräver att man tar tag i ett flertal problem för att optimera effektiviteten. All former av formuleringar har sina egna utmaningar som vetenskapsmän och företag försöker lösa. Till exempel, leverns nedbrytning av läkemedlet, det så kallade första-passage-metabolismen, minskar koncentrationen av den aktiva substansen och, i värsta fall, förändrar den till en giftig form. Detta kan vara ett stort bekymmer. Ett sätt att kringgå detta är att transportera läkemedlet, i pulverform, från luftvägarna till blodet, genom att använda alveolerna som en ingångsport. Det minimala kravet för att en produkt skall nå längst ner i lungorna är en partikelstorlek på mindre än 5 µm i diameter.

Många produktionsmetoder för pulver finns och ett av de mer populära sätten är sprejtorkning. En lösning, innehållande substanserna som ska inkorporeras i pulvret, finfördelas till miljontals droppar i en sprejtork. Varenda droppe torkas av värme tillförd från het luft och formas till en partikel. Det krävs därför bara en enda process för att producera pulver från lösning. Frågan är sedan hur processen kan optimeras för att få maximal mängd finpartiklar i pulvret.

Examensarbetet presenterar resultat från produktionsförsök av sprejtorkat pulver och utvärdering om hur finpartikel fraktionen påverkas av variationer i produktionsprocessen. Formuleringen består av lysozym (ett protein), laktos och lipider. Analysering av pulvrets egenskaper baserat på storlek är vanligt vid formulering av inhalerbara läkemedel. Kaskadimpaktorer är praktiska verktyg som används för detta ändamål. Kaskadimpaktorer försöker likna luftvägarna och gör att stora partiklar fastnar tidigt på plattor i impaktorn medan små partiklar transporteras vidare i impaktorn precis som de gör i luftvägarna. Förhållande för när en patient använder en torrpulver inhalator simuleras för att distribuera pulvret i olika storlekarordningar. Metoden ger information om vart pulvret skulle hamna i luftvägarna.

Resultaten visar att sprejtorkning är en robust metod. Tilsats av lipider i processen förändrar inte finpartikel fraktionen i pulvret. Ett upprepande mönster i resultatet är avvikelser and brist på reproducerbarhet i proverna som innehåller lipider gentemot proverna som inte innehåller lipider. Sprejtorkningsproduktion leder i många fall till ett homogent matrix i pulverpartiklarna. Resultaten presenterad i rapporten visar dock att den presenterade metoder verkar ha blivit påverkad av lipidtillsatserna i formuleringen. #

• author: Nguyen, Hung
• supervisor: Ingegerd Sjöholm; Ian Harwigsson; Mårten Svensson
• organization: Food Technology and Nutrition (M.Sc.)
• alternative title: Lämpligheten hos sprejtorkat pulver innehållande lipider för inhalation baserat på finpartikelfraktion och partikelstorleksfördelning
• course: KLG920 20161
• year: 2016
• type: H3 - Professional qualifications (4 Years - )
• subject: Technology and Engineering
• keywords: Fine Particle Fraction: Particle Size Distribution, Drying, Inhalation, DPI, Dry Powder Inhaler, Powder, Inhaler, Spray drying, Lipids, Inhalation Formulation, Lysozyme, Pharmaceutical Technology, läkemedelsteknologi
• language: English
• id: 8877966
• date added to LUP: 2016-06-10 10:45:29
• date last changed: 2016-06-10 10:45:29