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Uzun yıllardır ilacın vücuda alınmasında kullanılan yöntemler arasında oral ve parenteral yöntem ön plana çıkmaktadır. Bu yöntemlerin dezavantajları göz önünde bulundurulduğunda farklı yöntem arayışları bir gereklilik oluşturmuştur. Deriye yapışan bir bant yardımıyla ilacın dolaşım sistemine verilmesi ise bu konuya önemli bir boyut kazandırmıştır. Transdermal yama adı verilen bu bantlar ile deri vasıtasıyla ilaç etken maddesi dolaşım sistemine verilir ve kontrollü salım için kararlı bir plazma düzeyi oluşturulur. Günümüzde transdermal yolla kontrollü ilaç salımı ilgi çekici ve üzerinde yoğun çalışmalar yürütülen bir konu olarak karşımıza çıkmaktadır.
Yürütülen bu çalışmada pektin temelli filmler hazırlanmıştır. Pektin, doğal bir polisakkarit olmasından ve ilaç salımında gösterdiği üstün özelliklerden dolayı tercih edilmiştir. Hazırlanan filmlerde deriden geçişi arttırması amacıyla, her bir film için farklı oranlarda; hint yağı (HY), polietilen glikol (PEG 600) ve benzil alkol (BA) eklenmiştir. İçinde penetrasyon arttırıcı bulunmayan standart ilaç yüklü film hazırlanıp kontrol grubu olarak kullanılmıştır. Çalışmada kullanılan prokain, lokal anestezik bir ilaçtır. İlaç, penetrasyon arttırıcılarla birlikte 5 saat manyetik karıştırıcıda karışmıştır. Ardından bu karışım pektin temeli matrise karıştırma yöntemiyle 24 saatte yüklenmiştir. Karışım çapraz bağlayıcının bulunduğu petri kaplarına dökülerek orbital karıştırıcı yardımıyla oda sıcaklığında 24 saat boyunca kurumaya bırakılmıştır.
Sentezlenen filmlerin yapısal karakterizasyonu için Fourier transform infrared spektroskopisi kullanılmıştır. Termal karakterizasyon için diferansiyel taramalı kalorimetre kullanılmıştır. Filmler, yapısında kullanılan farklı HY ve PEG miktarı nedeniyle, farklı hidrofilite değerlerine sahiptir. Filmlerin hidrofiliteleri temas açısı ölçerle belirlenmiştir. Şişme deneyi; oda sıcaklığında pH 7.4 tampon çözelti ortamında yapılmıştır. Ayrıca su buharı ile şişme değeri de belirlenmiştir.
Franz difüzyon hücreleri kullanılarak filmlerin ilaç difüzyonu gözlenmiştir. Reseptör hacmi pH değeri 7.4 olan tampon çözelti ile doldurulmuştur. Difüzyon alanına tampon çözeltiyle ıslatılmış, selüloz nitrattan yapılmış bir membran yerleştirilmiştir. İlaç yüklü filmler bu membran üzerine yerleştirilmiş ve 37 ± 2 °C sıcaklığında 24 saat ilaç nüfuzyonu tayin edilmiştir.
Çalışmada elde edilen sonuçlara göre filmlerin temas açısı değerleri HY/PEG oranı arttıkça artmıştır.
Şişme davranışlarına bakıldığında HY miktarı artınca şişmenin azaldığı görülmüştür. Burada HY' nin hidrofobik karakteri rol oynamaktadır. Literatür verileri de göz önünde bulundurulduğunda PEG ile su molekülleri arasında hidrojen bağlarının oluşmasının PEG içeren filmlerin şişmesinde etkili olduğu sonucuna varılmıştır.
Franz difüzyon hücrelerde yapılan difüzyon sonuçları; BA etkisi, HY etkisi, PEG etkisi ve pH etkisi olarak farklı başlıklar altında incelenip değerlendirilmiştir. HY' nin artışının difüzyonu azalttığı, BA'nın ise kontrollü salımı olumsuz yönde etkilediği sonucuna varılmıştır. Literatürdeki verilere de uygun olarak PEG' in salımı hızlandırırken kontrolü de sağladığı görülmüştür. pH değeri 6.4 olan tampon çözeltide pH 7.4' e göre ilaç difüzyonunun arttığı tespit edilmiştir.
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For many years, oral and parenteral methods have emerged about taking medicines to body. Along with this growth in drug delivery, however, there is increasing concern over the disadvantages of taking medicines. Therefore, the search for different methods has created a necessity. Transdermal patches make a major contribution to the field of drug delivery. By using these bands which are called transdermal patches, the drug active substance is delivered to the circulatory system through the skin and a stable plasma level is created for controlled release. Recently, researchers have shown an increased interest in transdermal drug delivery.
Despite its long clinical success, TD patches have a major problem with this kind of application is the outermost barrier of skin. To better understand the mechanisms of the stratum corneum (SC) and its effects, the skin structure is analysed. The SC, the outermost barrier of the skin against foreign materials, shows an obstacle to the transdermal diffusion of drugs. Only a few small-molecule drugs with high lipophilicity can naturally permeate through the stratum corneum, a vast majority of hydrophilic drugs have been ruled out against transdermal delivery.
In order to increase the permeation, there are many kinds of techniques. These techniques are called in mainly 2 different way. The first method is physical methods. It can be catagorized such as ultrasonic wave, electrical vibrations, iontophoresis and laser. On the other hand, there is chemical method to increse the penetration of drug through the skin. Prior studies that have noted the importance of chemical penetration enhancers. It is interesting to note that in a number of studies show that physical methods are able to have some negative results after application on the skin surface. These methods have a risk to cause an irritation on skin. A comparison of the two methods reveals that chemical enhancers have superior features than physical methods.
The aim of the thesis is investigate the transdermal drug delivery with chemical penetration enhancers. In this thesis, films based on pectin are prepared. The purpose of preferring pectin is pectin is a natural polysaccaride and it has superior feature in drug delivery. To increase the penetration, castor oil (CO), polyethylene glycol (PEG 600) and benzyl alcohol (BA) are used at different ratios for every films. Standard drug loaded film without any penetration enhancers is prepared at the same condition and used as control group. In this study, procaine is used as a model drug. Procaine is a local anesthetic of the ester type. To eliminate the moisture, CO and PEG are kept for 24 h at 80° C under vacuum. Firstly, low methoxy pectin is dissolved with the ultra deionized water at 25° C, stirred at 100 rpm for 24 h. Drug with penetration enhancers are stirred for 5 h under magnetic stirring. For the preparation of td patches, the drug solution with penetration enhancers is added successively to mixture based on pectin. The resulting mixture is stirred overnight using a magnetic stirring. Thereafter all this process, in order to obtain crosslinked films, the resulting mixture is added to solution into a petri plate. To dry crosslinked films, orbital shaker is used at room temperature for 1 day at room temperature.
To determine structural characterization of the drug loaded td films Fourier transform infrared spectroscope is used. For thermal characterization differential scaning calorimeter is used. This experiment is repeated at least 2 times for each film. Contact angle measurements are made for determining the hydrophilic/hydrophobic character on the td films. This experiment is repeated at least 3 times for each film. The average and standard deviation are calculated. Swelling experiments are carried out at room temperature as swelling experiment and at 37 °C as water vapor swelling, respectively. pH 7.4 buffer solution is used in all swelling experiments. 4 drug loaded films are used for this experiment. All performs for each film are repeated 3 times. The average and standard deviation are calculated.
The transdermal films are inspected for brittleness. In addition to brittleness test, film thickness is measured at least at six randomly selected areas by means of a digital micrometer. The average and standard deviation are calculated.
For permeation studies, Franz diffusion cells are used. The receptor compartment is filled with pH 7.4 buffer solution. Through the experiment, cellulose nitrate membrane which is wetted by buffer solution before drug- loaded film application is used. The drug loaded films are applied to the diffusion area on the membrane. The experiment is performed at 37 ± 2 °C. For this way, a skin epidermal surface temperature is mimicked and the situation is maintained. The permeation studies are conducted a period of 7 h which samples are collected every 60 min and the last sample is collected on 24. h. In this diffusion experiment, 8 films are used. All performs for each film are repeated 3 times. The average and standard deviation are calculated.
The findings of the contact angle measurements further support the idea of increasing hydrofobic character as CO/PEG ratio increase. The formulation of C30P5-PC has the maximum amount of CO. The most suprising aspect of the data is the formulation of C10-PC has lower contact angle result than the standard film. With the decrease of hydrophilic character, it can be said that lipophilic character will increase. This is a desired result for TD studies. Lipophilic, that is, fat-soluble substances easily pass the membranes of the lipid structure; hydrophilic ones, water-soluble substances pass less than the lipid membrane.
Swelling results are observed. As the amount of CO increase, swelling decreases. The mean of this result is the hydrophobic character of CO plays a significant role. This study confirms that hydrophobic character is associated with swelling. These results agree with the findings of other studies, in which has been concluded that the formation of hydrogen bonds between PEG and water molecules are effective in swelling films containing PEG.
According to the result of the franz diffusion, the maximum drug release a period of 24 h is observed in the case of formulation C10P5-PC within 12.7 mg drug/g film. Following this, the drug release a period of 24 h is observed in the case of formulation C30P5-PC within 11.4 mg drug/g film. The results of franz diffusion are examined and assessed under different headings as the effect of BA, the effect of CO, the effect of PEG and the effect of pH. The results from the diffusion experiment show that there is no increase of drug diffusion in case of increasing the amount of CO. A clear benefit of BA in the experiment of drug diffusion is not be able to identified in this analysis. Interestingly, BA has a negative effect on controlled drug release. As mentioned in the literature review, there is a significant increase of drug diffusion in the case of formulations contain PEG. The results indicate that PEG has a positive effect in controlled drug release. The formulation C10P5-PC releases more than 7.8 mg drug/g film (1.6 times) than pH 7.4 at pH 6.4. It is determined that the diffusion in the buffer solution with pH value of 6.4 is more than the diffusion in the buffer solution with pH value of 7.4. |
