Püskürtmeli kurutucu tekniği ile farklı taşıyıcılar kullanılarak sentezlenmiş montelukast etkeni içeren kuru toz inhalasyon ürünlerinin karakterizasyonu
Characterization of dry powder inhalation products containing montelukast synthetized using different carriers by spray dryer technique
Yazar: ELİF ŞAHİN
Danışman: PROF. DR. GÜLHAYAT SAYGILI ; DOÇ. DR. PELİN BARAN
İstanbul Teknik Üniversitesi / Lisansüstü Eğitim Enstitüsü / Kimya Mühendisliği Ana Bilim Dalı / Kimya Mühendisliği Bilim Dalı
Derece: Yüksek Lisans, 2023
Konu: Kimya Mühendisliği = Chemical Engineering

Özet:
Astım hastalığı sıkça karşılaşılan kronik bir akciğer rahatsızlığıdır. Astım hastalarının düzenli olarak ilaç kullanmaları ve astım nöbetleri esnasında hızla müdahale edebilmek için tedavi sürecinde kullandıkları ilaçları sürekli olarak yanlarında bulundurmaları gerekmektedir.
Astım ataklarında inhalasyon yoluyla alınan ilaçların etkinliğinin geleneksel ilaç yöntemlerinin etkinliğine göre daha yüksek olduğu yapılan çalışmalar ile kanıtlanmıştır. Direkt olarak hedef bölgeye uygulanması, buna bağlı olarak hızlı etki göstermesi ve sistemik yan etkilerinin daha az olması, akciğer hastalıklarının tedavisinde inhaler ürünlerin kullanımına olanak sağlayan en önemli özelliklerdendir. İnhaler ürünlerin içereceği etken maddeler için en kritik noktalardan bir tanesi etken madde boyutudur. Etken maddelerin akciğer yüzeyinden absorpsiyonunun gerçekleşmesi için boyutunun 5 µm'den küçük olması gerekmektedir.
Astım hastalarına en çok reçete edilen ilaç etken maddelerden bir tanesi de montelukast sodyum etkenidir. Bu etken maddeye ait tek etken veya başka bir etken madde ile tek bir dozaj formu içerisinde birleştirilip çift etken şeklinde üretildiği birçok dozaj formu mevcuttur. 
Yapılan bu çalışmada, kuru toz inhalasyon ürünleri için ilaç taşıyıcısı olarak kullanılabilecek montelukast sodyum etken maddesi içeren yeni bir taşıyıcı sistem geliştirilmiştir. Taşıyıcı sisteme ait malzemeler mannitol, laktoz monohidrat ve beta siklodekstrin olarak belirlenmiştir. Bu malzemeler, Amerikan İlaç ve Gıda Dairesi (FDA) ve Avrupa İlaç Ajansı (EMA) gibi otoritelerin inhalasyon ürünlerinde kullanılmasını onayladığı ve kullanılması durumunda malzemelerin sahip olduğu özellikler nedeniyle üretim proseslerini kolaylaştırabileceğini belirttiği malzemelerdir. Minitab programında 3 faktör, 3 seviye Box Behnken deney tasarım modeli kullanılarak 15 farklı formülasyon belirlenmiştir. Belirlenen formülasyonlar kütlece farklı kombinasyonlarda yardımcı malzemeler içermesine karşılık sabit miktarda montelukast sodyum içermektedir. Formülasyonlara ait plasebo ve numune çözeltileri hazırlanarak püskürtmeli kurutucu cihazına beslenmiştir. UV-Visible spektroskopisi kullanılarak elde edilen kuru tozlara ait absorbans değerleri 284 nm'de ölçülmüştür. Ölçüm sonuçları hazırlanan kalibrasyon grafiğine yerleştirilip mikropartikül yapıda etken maddenin tutunma oranı hesaplanmıştır. Optimum tutunma oranına sahip olan formülasyon belirlenmiş ve sonrasında bu formülasyona ait plasebo ve numuneye Sıvı Kromatografisi Analizi, X-Işınları Kırınımı (XRD) Analizi, Fourier Transform Infrared Spektroskopisi (FTIR) ve Partikül Boyut Dağılım (PSD) analizleri uygulanmıştır. Elde edilen sonuçlar değerlendirildiğinde kuru toz inhalasyon ürünlerinde kullanılmak üzere yeni geliştirilen bu yaklaşımın mikropartikül yapıda etken maddenin tutunma oranının kullanım için uygun olduğunu göstermiştir. Sonuçlara göre formülasyonlarda yardımcı malzemelerin kütlesinin artması ile etken maddenin tutunma oranının arttığı gözlemlenmiştir. Bu durumun yardımcı malzemelerin kütlesinin artmasıyla yapılarında bulunan hidrojenlerin sayısının da artması ve montelukast sodyum etken maddesinde bulunan hidrojenler ile hidrojen bağları oluşturmasından kaynaklı olduğu düşünülmektedir. Buna bağlı olarak da daha fazla etken madde tutunma yüzdeli sonuçlar elde edilmiştir.

Abstract:
Asthma is a common chronic lung disease. Asthma patients need to be treated quickly during asthma attacks. Otherwise, asthma attacks can lead to death of the patient. It has been proven that the effectiveness of inhalers in asthma attacks is higher than the effectiveness of traditional drug methods. Inhalers have many features that make it advantageous to use in the treatment of asthma. Some of these are applied directly to the target area, thus showing a rapid effect and having less systemic side effects. These opportunities show that inhalers are of critical importance in the treatment of asthma.
Inhalation products are divided into 3 different classes. These are classified as Metered-Dose Inhalers, Dry Powder Inhaler and Soft Mist Inhalers. According to the treatment, the appropriate inhaler is selected for the patient. Each inhalation product has advantages and disadvantages over other types. However, when a general comparison is made, the systems with the highest stability and the highest amount of drug delivery are dry powder inhalers (DPI). Since the active pharmaceutical ingredient is in solid form, advantages are provided in terms of stability of the active pharmaceutical ingredient, ease of use and the amount of dose applied. The risks of disintegration, decomposition and microbiological contamination are less compared to liquid formulations. Considering all these advantages, DPI products are more preferred.
One of the most critical points of inhaler products is the size of the active substance it contains. Particles must be smaller than 5 μm in order for the active substances to be absorbed from the lung surface and penetrate deep into the lung. Active substances with larger particle sizes are not preferred in the treatment because the active substance cannot reach the lungs.
In the production of inhaler powders, the most preferred production method is the spray dryer. Spray drying method is one of the suitable methods both in terms of industrial applicability and for the production of particles below 5 μm. By changing the production parameters; criteria such as particle size, particle size distribution, density, shape, charge, release rate can be optimized. With spray drying method, it is possible to obtain particles with appropriate size and morphological properties by changing the production parameters As a result, DPIs are a frequently preferred system with many advantages.
Montelukast sodium is one of the most prescribed drugs for asthma patients. There are many dosage forms available in which montelukast sodium is produced as a mono or in combination with another active ingredient (combo). These dosage forms are in the form of film tablets, sachets or syrup.  These oral dosage forms act more slowly than the inhaled dosage forms. They are also exposed to systematic side effects and the effectiveness of treatment is reduced.
By using various excipients during the production process, several parameters such as flow properties of powders and ease of manufacture can be improved.  However, since the selected excipients will penetrate directly into the lungs, biocompatibility of excipients is extremely critical for human health.
Carrier materials such as lactose can support flowability and also uniformity of a blend during manufacturing process. Also, carrier materials can increase the reproducibility of the dry powder inhaler products by reducing agglomeration of the active pharmaceutical ingredients. Sometimes lactose cannot be used as a carrier, for example, in diabetic patients and in systems where drugs and proteins that interact with lactose are used, alternative carriers such as mannitol, trehalose, erythritol and sorbitol are used.
Mannitol inhalation is used to improve lung function in patients with cystic fibrosis. It is known that the hard capsule inhalation powder product containing mannitol has been approved by the EMA. Although lactose is by far the most widely used carrier in DPI applications, there are some limitations for patients with lactose intolerance. In addition, carrier compatibility with emerging new APIs, for example APIs carrying primary amino groups such as peptides and proteins, is important. For these reasons, the search for alternative carriers such as mannitol for DPI formulations is of great interest. Mannitol is a non-reducing, non-hygroscopic compound with promising aerosolization properties. Moreover, its safety in lung application has been proven.
β-CD increases drug solubility and permeability by penetrating the drug through the lipophilic surface of biological membranes. Because of its improved dispersibility and drug permeability, β-CD can be used to prepare spray-dried powders for pulmonary drug delivery. Cyclodextrins are poorly absorbed through mucous membranes, but at higher concentrations of drugs, cyclodextrins may also facilitate their own absorption and increase drug absorption and/or bioavailability.
In this study, a new drug delivery system containing the active ingredient montelukast sodium was developed for dry powder inhalers. Excipients of the carrier system were selected as mannitol, lactose monohydrate and beta cyclodextrin. The use of these materials in inhalers is approved by authorities such as the American Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
In the Minitab program, 15 different formulations were determined by using 3 factor, 3 levels Box Behnken experimental design model. The specified formulations contain a fixed amount of montelukast sodium and excipients in different combinations by weight. Placebo and sample solutions of the formulations were prepared and fed to the spray dryer. The absorbance values of dry powders obtained using UV-Visible spectroscopy were measured at 284 nm. The measurement results were placed on the prepared calibration chart and the results were calculated as % drug holding capacity.
After measuring the drug holding capacity of all samples, the formulation with the optimum drug holding capacity was determined. High Performans Liquid Chromatography (HPLC) analyzes, X-Ray Diffraction (XRD) analyzes, Fourier Transform Infrared Spectroscopy (FTIR) and Particle Size Distribution (PSD) analyzes were applied to the placebo and sample of this optimum formulation.
As a result of the studies, it was observed that the HPLC results were similar to the UV-Visible results. With XRD chromatograms, information was obtained about the crystallinity of the active substance and the sample. The FTIR spectrum showed an increase in the number of O-H bonds in the sample according to the active substance and supported the theories that the drug holding capacity increased as the auxiliary material increased. When these results obtained are evaluated, it has been shown that the drug holding capacity of this newly developed approach for use in dry powder inhalation products is suitable for use.
As a result of the studies, although the approach of dry powder inhalers containing montelukast sodium is promising, stability problems are experienced due to the hygroscopic structure of the active substance. For this reason, studies should be developed for that the sample remains as a dry powder without losing its flow properties throughout its shelf life.