Atenolol yüklenmiş poli(akrilik asit) bazlı hidrojel sistemlerinin kontrollü salımının incelenmesi ve karakterizasyonu
Investigation and characterization of the controlled release of atenolol loaded poly(acrylic acid) based hydrojel systems
Yazar: SİNEM DEMİR
Danışman: PROF. DR. AYŞEGÜL GÖLCÜ
İstanbul Teknik Üniversitesi / Lisansüstü Eğitim Enstitüsü / Kimya Ana Bilim Dalı / Kimya Bilim Dalı
Derece: Yüksek Lisans, 2021
Konu: Kimya = Chemistry
Dizin: Hidrojeller = Hydrogels ; Kontrollü ilaç salımı = Controlled drug release

Özet:
Son yıllarda, yeni bir etken madde geliştirme çalışmaları yerini var olan etken maddenin vücuda veriliş yöntemlerinin iyileştirilmesine bırakmıştır. Klasik yollarla vücuda alınan ilaçların, kullanılan dozuna, dozaj sıklığına ve bireysel kullanım hatalarına da bağlı olarak etken maddenin, etkin plazma konsantrasyonundaki süresi kısalabilmektedir. Tüm bu faktörlere bağlı olarak etken madde, toksik düzeyin üzerine çıkarak kişiyi ciddi yan etkilere maruz bırakabilmekte ve/veya minimum etkili düzeyin altında kalarak sisteme yararsız hale gelebilmektedir. Olumsuz bu durumların üstesinden gelebilmek amacıyla, etken maddenin vücuda verilmesi için kontrollü ilaç salım sistemleri son zamanlarda önemli bir araştırma konusu haline gelmiştir. Etken maddelerin vücuda verilişi için, kontrollü ilaç salım sistemlerinde kullanılan polimerik ilaç taşıyıcı sistem olarak sentezlenen hidrojeller etkili bir yöntem olarak tercih edilmektedir. Hidrojellerin yapısını korurken su absorplayabilme yetenekleri, çeşitli uyaranlara karşı yapılarında meydana gelen şişme ve büzüşme gibi mekanik davranışları etken maddenin salımı için kontrollü bir salım olanağı sağlamak amacıyla kullanılabilmektedir. 
Hipertansiyon ileriki yaşlarda görülme olasılığı yüksek olan, kan basıncının artmasına bağlı olarak inme, kalp yetmezliği, böbrek yetmezliği, beyin kanaması gibi ciddi bir çok hastalıktan ölüme kadar varan sonuçlar doğuran önemli bir risk faktörüdür. İlerleyen yaşlarda ortaya çıkan bu hastalığın klasik ilaç kullanım yöntemleri ile tedavisinde, uzun süreli ve tekrarlanan dozlarda uzun süreli tedavi uygulanmaktadır. İlaçların düzenli ve vaktinde kullanılması önem taşımaktadır ancak yaşa bağlı olarak bireyde gelişen unutkanlık, birden fazla ilaç kullanımına bağlı olarak  ilaçların karıştırılması, zaman açısından karıştırılması, eksik veya fazla dozda ilacı kullanma gibi sorunlara bağlı olarak etkili bir tedavi sağlanamayabilmektedir. Kontrollü salım sitemleri ile hem etkili konsantrasyonda hem de tekrarlanan dozlara ihtiyaç duymadan tedavi sağlanması önem taşımaktadır.
Bu çalışmada, hipertansiyon tedavisinde kullanılan antihipertansif ilaçların arasında yer alan atenolol ile çalışılmıştır. Atenololün poli(akrilik asit) bazlı hidrojel sistemlerinden salımı takip edilmiştir. Başlangıç ilaç konsantrasyonu ve çapraz bağlayıcı konsantrasyonu bakımından karşılaştırılmak üzere üç farklı ilaç yüklü hidrojel formülasyonları ve bunlara uygun olarak ilaç yüklü olmayan formülasyonları oluşturulmuştur. Hidrojellerden ilaç salımı, temsili olarak hazırlanan mide (pH = 1.2), bağırsak (pH = 7.4) ve vücut sıvısı (pH = 7.4) ortamlarında gerçekleştirilmiştir. Elde edilen sonuçlara bakıldığında, düşük pH değerine sahip temsili mide ortamında, bağırsak ve vücut sıvısına kıyasla ilaç korunarak, daha az miktarda ilaç salımının gerçekleştiği gözlenmiştir. Nötr pH değerlerine sahip temsili bağırsak ve vücut sıvısında ise iyonizasyona bağlı olarak, daha etkin bir konsantrasyonda salım gerçekleştiği gözlenmiştir. Elde edilen sonuçlar kinetik modellemelere yerleştirildiğinde R2 değerleri sırasıyla 0.959 ve 0.9434 olarak hesaplanan, birinci dereceden ve Higuchi kinetik modellerinin en uygun modeller olduğu tespit edilmiştir. Şişme değerleri hesaplandığın da, bu sonuçlarında salım profilleri ile uyumlu oldukları tespit edilmiştir. Salım deneylerinde gözlendiği üzere, temsili mide ortamında düşük salım gösteren jellerin şişme davranışı da diğer ortamlara kıyasla daha az olmuştur. Temsili bağırsak sıvısında en yüksek salım değerini gösteren jeller, en büyük şişme oranına da bağırsak içerisinde sahip olmuştur. Temsili bağırsak sıvısına en yakın salım profiline sahip olan vücut sıvısı, şişme olarakta bağırsak ortamındaki jelleri takip etmiştir. Infrared spektrumları alınan ilaç ve jellere (ilaçlı ve ilaçsız) ait spektrumlar karşılaştırıldığında ilaca ait temel piklerin hidrojel sistemlerde de gözlendiği tespit edilmiştir.

Abstract:
Medicines are natural and synthetic substances that are used to protect people from diseases and to eliminate existing diseases. In recent years, studies to develop a new drug have been replaced by the improvement of existing drug delivery methods. The duration of the active substance in the effective plasma concentration may be shortened depending on the dose used, the dosage frequency and individual usage errors of the drugs taken into the body by classical means. Depending on all these factors, the active substance may rise above the toxic level and expose the person to serious side effects and/or become useless to the system by remaining below the minimum effective level. In order to overcome these negative situations, controlled drug release systems for the delivery of the active substance to the body have recently become an important research topic. In order to enhance their therapeutic effects and reduce the associated side effects, active drug molecules must selectively accumulate at the disease site over a long period of time with high controllability. Drug delivery refers to approaches, formulations, technologies and systems for the delivery of therapeutics into the body to safely and effectively achieve their desired therapeutic effects. Compared with conventional drug delivery systems, controlled drug delivery systems can effectively reduce dosing frequency while maintaining drug concentration in targeted organs or tissues for a longer period of time.
Controlled drug release systems exist to deliver drugs more effectively than conventional methods. Controlled drug release system refers to a drug loading system that can delay the release rate of drugs from preparations and release drugs into target tissues, organs and cells at a constant rate. In this sense, controlled drug release systems offer extensive information and fascinating features to reduce drug concentration fluctuations, reduce drug toxicities, and increase therapeutic efficacy. It can reduce the human body's drug absorption rate, delay the effect of drugs, and reduce drug administration times. So it can achieve better therapeutic effect. Drug delivery system refers to a new way of drug delivery that can release drugs at a fixed time, target location and specified dosage by regulating the internal structure of drug carriers. These systems are preferred due to many advantages such as high efficiency, low toxicity, release to target location and high safety. In addition, some clinical studies of the active substance need to be completed in order to develop a new drug. Considering the time taken for the development of a new drug in the clinical drug research and development process, making existing drugs applicable to controlled release systems provides an advantage in terms of time.
Controlled drug release systems, which aim to increase drug efficacy and patient compliance, and reduce the frequency of administration and dosing-related side effects, are an important issue for developing more effective products. For this purpose, the use of mathematical modeling is very useful because this approach, in the best case, allows the estimation of the release kinetics before the release systems are performed. More often, it allows some important physical parameters to be measured, such as the drug diffusion coefficient, and to apply model fitting to experimental release data. Therefore, mathematical modeling, the development of which requires an understanding of all phenomena affecting drug release kinetics, is of crucial value in the process optimization of this formulation.
Hydrogels synthesized as polymeric drug delivery systems used in controlled drug release systems are preferred as an effective method for the delivery of active substances to the body. Hydrogels are used in many fields. This is due to their special nature and compatibility with different conditions of use. The flexibility of hydrogels, due to their water content, makes it possible to use them in different conditions ranging from industrial to biological, and the biocompatibility of the materials used to manufacture them, as well as their chemical behavior in non-toxic biological environments, extend their application to the medical sciences. Controlled drug delivery systems, which are used to deliver certain rates of drug over predetermined times, have been used to overcome the limitations of regular drug formulations. Hydrogels can store and protect various drugs from hostile environments and release them at desired release kinetics. These properties of hydrogels make them an excellent choice for drug delivery applications. Hydrogels are a hydrophilic polymer network that can swell in water and retain large amounts of water while preserving the structure. A three-dimensional network is formed by cross-linking the polymer chains and the hydrogel is insoluble in water due to the cross-links in this network structure. While preserving the structure of hydrogels, their ability to absorb water, their mechanical behavior such as swelling and shrinkage that occur in their structures against various stimuli can be used to provide a controlled release opportunity for the release of the active substance. Due to the hydrophilic groups in its structure, the cross-linked polymeric network begins to swell with the increase in volume and mass, depending on the amount of water attached. The cross-linked polymeric network shows different swelling properties depending on the amount of hydrophilic groups. Due to the presence of more hydrophilic groups, more swelling occurs in the network structure. It has the ability to change the hydrogel structure with a stimulus applied by the environment on the obtained hydrogel. Thanks to these reactive actions, the drug is made to be released in the desired target area. This situation has accelerated the studies on bringing various drugs into forms suitable for controlled drug release systems in the treatment of many diseases.
Hypertension is a risk factor with a high probability of being seen in the future. It is an important disease that can lead to death from many serious diseases such as stroke, heart failure, kidney failure, cerebral hemorrhage due to increased blood pressure. The heart of individuals with high blood pressure has to work against a pressure. When the heart works with this pressure in the arteries for a long time, thickening occurs in the heart wall. The hardening of the arterial wall increases the workload of the heart. Blood comes to the heart through the arteries, but due to the narrowing of the vessels, not enough blood can reach the heart. As a result, the work force of the heart increases. The passage of blood through the narrowed artery causes high pressure. In the treatment of this disease, which occurs in advancing ages, with classical drug use methods, long-term and repeated doses of long-term treatment are applied. Regular and timely use of drugs is important for successful treatment. However, an effective treatment may not be provided due to problems such as forgetfulness that develops in the individual due to age, mixing of drugs due to the use of more than one drug, confusion in terms of time, use of missing or excessive doses of drugs. It is important to provide treatment with controlled release systems both at an effective concentration and without the need for repeated doses. The fact that there is no need for repeated doses in the treatment eliminates many problems. Mixing the drugs, not using them on time, intake of the missing or excessive dose of the drug into the body is prevented.
In this study, atenolol, which is among the antihypertensive drugs used in the treatment of hypertension, was studied. Atenolol is a selective β-blocker. It is effective in patients with all degrees of hypertension and is generally well tolerated. When given orally, atenolol reduces blood pressure to a similar extent. Atenolol effectively lowers blood pressure in elderly patients with hypertension and in women with pregnancy-related hypertension. An effective treatment can be provided by using atenolol, a beta-blocker, in the prevention of these damages caused by hypertension in the arteries leading to the heart. Beta blockers affect receptors in the heart and blood vessels. There is also encouraging evidence that mortality from cardiovascular disease is reduced during long-term treatment with atenolol in patients with hypertension. As a result of these positive developments, it is aimed to develop a hydrogel system in which the concentration of the active ingredient atenolol can be kept at a controllable level.
The release of atenolol from poly(acrylic acid) based hydrogel systems has been monitored. For this purpose, pH sensitive poly(acrylic acid) based hydrogels were synthesized. The release experiments of the synthesized hydrogels were followed in representatively prepared stomach, intestinal and body fluid environments. Percent cumulative drug release was started by measuring the absorbance of the liquids taken from these environments at certain time intervals. By evaluating the results obtained with this method, it is aimed to develop a hydrogel system suitable for the most effective and ideal treatment. The hydrogel obtained by using poly(acrylic acid) has gained a pH sensitive feature. At high pH values, they become ionized and show more swelling. Three different drug-loaded hydrogel formulations and corresponding non-drug-loaded formulations were created to be compared in terms of initial drug concentration and crosslinker concentration. Drug release from hydrogels was performed in representatively prepared stomach (pH = 1.2), intestinal (pH = 7.4) and body fluid (pH = 7.4) media. Looking at the results obtained, it was observed that in the representative gastric environment with a low pH value, the drug was preserved and less drug release occurred compared to the intestinal and body fluids. In the representative intestinal and body fluids with basic pH values, it was observed that a more effective concentration was released due to ionization. When the results obtained were placed in the kinetic models, it was determined that the first-order and Higuchi kinetic models, whose R2 values were calculated as 0.959 and 0.9434, respectively, were the most suitable models. When the swelling values were calculated, it was determined that these results were compatible with each other with the release profiles. As observed in the release experiments, the swelling behavior of the low-release gels in the representative gastric medium was also less than in the other mediums. The gels showing the highest release value in the representative intestinal fluid also had the greatest swelling rate in the intestine. The body fluid, which has the closest release profile to the representative intestinal fluid, followed the gels in the intestinal environment as swelling. When the spectra of drugs and gels (with and without drugs) whose infrared spectra were taken were compared, it was determined that the main peaks of the drug were also observed in hydrogel systems.