TR201410320A2 - Development of dry powder inhaler formulation containing netilmicin. - Google Patents
Development of dry powder inhaler formulation containing netilmicin. Download PDFInfo
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- TR201410320A2 TR201410320A2 TR2014/10320A TR201410320A TR201410320A2 TR 201410320 A2 TR201410320 A2 TR 201410320A2 TR 2014/10320 A TR2014/10320 A TR 2014/10320A TR 201410320 A TR201410320 A TR 201410320A TR 201410320 A2 TR201410320 A2 TR 201410320A2
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Abstract
Bu buluş, hastane kökenli enfeksiyonların tedavisinde kullanılan aminoglikozid grubu bir antibiyotik olan netilmisin sülfatın etkili bir şekilde uygulanmasını sağlayan bir formülasyonun üretim metodu ile ilgilidir. Buluşun amacı, hastane kökenli enfeksiyonların iyileştirilmesi amacıyla kullanılan netilmisinin hedef lokasyona en uygun şekilde ulaşması ve en etkin şekilde bu lokasyonda işlev görmesi için bir formülasyon oluşturulmasını sağlayan bir kuru toz inhaler formülasyonu üretim metodu gerçekleştirmektir.The present invention relates to a method of producing a formulation which provides effective administration of netilmicin sulfate, an aminoglycoside group antibiotic used in the treatment of nosocomial infections. SUMMARY OF THE INVENTION The object of the invention is to provide a dry powder inhaler formulation production method which provides the formulation of netilmicin used for the treatment of nosocomial infections in order to reach the target location in the most appropriate way and to function effectively in this location.
Description
TARIFNAME NETILMISIN IÇEREN KURU TOZ INHALER FORMÜLASYONU GELISTIRILMESI Teknik Alan Bu bulus, hastane kökenli enfeksiyonlarin tedavisinde kullanilan aminoglikozid grubu bir antibiyotik olan netilmisin sülfatin etkili bir sekilde uygulanmasini saglayan bir formülasyonun üretim metodu ile ilgilidir. Önceki Teknik Çagimizin en önemli hastaliklari arasinda yer alan hastane kökenli enfeksiyonlar, hastanede yatan hastalarin yatis süresini ve tedavi giderlerini arttirmaktadir. Bu durum, ülke ekonomisine yük getiren, yüksek oranda morbidite, mortaliteye neden olmaktadir. Hastane enfeksiyonlarindan birisi olan pnömoni, dünyadaki enfeksiyonlara bagli ölümler arasinda ikinci sirayi, yogun bakim ünitesi enfeksiyonlari içerisinde ise ilk sirayi almaktadir. Bu sebeple son yillarda, özellikle gelismekte olan ülkelerde, pnömoni hastaligina çözüm arayisi üzerinde yogun olarak durulan önemli bir konu haline gelmistir. DESCRIPTION DRY POWDER INHALER FORMULATION WITH NETILMISIN IMPROVEMENT Technical Area This invention is an aminoglycoside used in the treatment of hospital-acquired infections. effective application of netilmicin sulfate, a group of antibiotics It relates to the production method of a formulation that provides Prior Art Hospital-acquired infections, which are among the most important diseases of our age, It increases the length of stay and treatment costs of hospitalized patients. This This situation causes a high rate of morbidity and mortality, which imposes a burden on the country's economy. causes. Pneumonia, one of the hospital infections, the second place among deaths due to infections, the intensive care unit It takes the first place among infections. For this reason, in recent years, on the search for a solution to pneumonia disease, especially in developing countries It has become an important issue that has been heavily focused on.
Pnömoni, servis ve yogun bakim ünitelerinde en sik rastlanan ve en siddetli nozokomiyal (hastane kökenli) enfeksiyon olup, önemli bir mortalite ve morbidite nedeiiidir. Pnömoni, erken teshis konulmasi gereken ve ciddi tedavi gerektiren bir hastaliktir. Antibiyotiklerin varligina ve destek tedavilerdeki gelismelere ragmen hastanede yatan hastalar için halen öneinli bir inorbidite ve inortalite nedenidir. Pneumonia is the most common and most severe disease in service and intensive care units. It is a nosocomial (hospital-acquired) infection with a significant mortality and morbidity. the reason is. Pneumonia is a condition that requires early diagnosis and serious treatment. is a disease. Despite the availability of antibiotics and developments in supportive treatments, It is still an important cause of inorbidity and inortaliness for hospitalized patients.
Aminoglikozid grubu antibiyotiklerin pnömoni tedavisinde tek basina kullanildiklarinda etkinligi düsük oldugu için, daha çok kombine kullaniini tercih edilmektedir. Öte yandan uzun süre antibiyotik kullanimindan dolayi bu antibiyotiklere direnç gelismekte ve tedavi basarisizlikla sonuçlanmaktadir. Aminoglycoside antibiotics alone in the treatment of pneumonia Since their effectiveness is low when used, they prefer more combined use. is being done. On the other hand, due to long-term use of antibiotics, this Resistance to antibiotics develops and treatment results in failure.
Acinetobacter baumannii ve Pseudomonas aeruginosa hastane ortaminda uzun süre canli kalabilen, hastadan hastaya kolaylikla bulasabilen, öncelikle hastane kaynakli enfeksiyonlara yol açabilen patojenlerdir. Son yillarda hastalarin iyilestirmesi amaciyla kullanimi hizla artan antibiyotiklerin siklikla ve yanlis kullanimlari sebebiyle; A. baumannii ve P. aeruginosa patojenleri, aminoglikozid tipi antibiyotikler de dâhil hemen hemen tüm antibiyotiklere karsi direnç gelistirmislerdir. Bu yüzden A. bauinannii ve P. aeruginosa patojenlerinin yarattigi enfeksiyonlar, halk sagligi problemi olarak kabul edilmektedir. Bunlarin yani sira, yüksek oranda nefrotoksik ve ototoksik yan etkileri bulunan aminoglikozidler, enfeksiyonlarin tedavisinde esas olarak parenteral yolla uygulanir, ancak parenteral yolla verildiklerinde brons sekresyonlarina az miktarda geçtikleri için biyoyararlanimlari çok düsüktür. Bir baska deyisle, aminoglikozidlerin parenteral uygulamasi pnömoni tedavisinde etkin ve güvenilir bir yol degildir. Sonuç olarak, morbidite ve mortalitenin azaltilmasi, yasam kalitesinin yükseltilmesi, yatis ve hastane disi tedavi süresinin azaltilmasi, toplam tedavi maliyetinin ve direnç sikliginin düsürülmesi akilci antibiyotik kullanimi ile saglanabilir. Acinetobacter baumannii and Pseudomonas aeruginosa in the hospital setting for a long time. that can stay alive for a long time, can easily be transmitted from patient to patient, are pathogens that can cause infections. In recent years, patients Antibiotics, the use of which is rapidly increasing for the purpose of healing, is frequently and incorrectly used. due to their use; A. baumannii and P. aeruginosa pathogens, aminoglycoside Resistance to almost all antibiotics, including type antibiotics they have developed. Therefore, the pathogens of A. bauinannii and P. aeruginosa The infections it causes are accepted as a public health problem. These In addition, it has a high rate of nephrotoxic and ototoxic side effects. Aminoglycosides are mainly administered parenterally in the treatment of infections. administered, but little effect on bronchial secretions when given parenterally. Their bioavailability is very low as they pass through in large amounts. In other words, Parenteral administration of aminoglycosides is effective and safe in the treatment of pneumonia. it is not a way. As a result, reducing morbidity and mortality, improving the quality of life, reducing the length of hospitalization and out-of-hospital treatment, total Reducing the cost of treatment and the frequency of resistance with the rational use of antibiotics can be provided.
Antibiyotikler günümüzde, tüm dünyada en çok kullanilan ilaçlarin basinda gelmektedir. Özellikle gelismekte olan ülkelerde toplam saglik giderlerinin pazarinin yaklasik %20”sini antibiyotikler olusturmaktadir. Bu kadar yüksek oranda antibiyotik kullanimi, bakterilerde antibiyotiklere karsi direnç gelisimine imkan saglamakta ve ülkemizde oldugu gibi tüm dünyada enfeksiyon hastaliklarinin tedavisinde güçlüklere neden olmaktadir. Yeni bir antibiyotik molekülünün tasarimi ve tedaviye sunulmasi çok masrafli olup, uzun zaman almaktadir. Bunun yerine bilinen bir antibiyotigin tedavide farkli uygulama yolu ile etkin bir sekilde kullanilmasi, oldukça tercih edilen bir yaklasimdir. Ayrica çoklu ilaç dirençli (ÇID) Aeinetobacter ve Pseudomonas türlerine etkili antibiyotik sayisinin azligina paralel olarak bir diger sorun da, enfeksiyon bölgesine yani akcigerlere ulasan antibiyotik miktarinin yetersizligidir. Bu durumda olasi en iyi çözüm, pulmoner yol ile tedavinin yapilmasidir. Ancak bu sekilde yeterli miktarda antibiyotik akcigerlere ulastirilabilecektir. Bundan dolayi yeni ve etkin bir formülasyon gelistirerek pnömoni için akilci bir tedavi saglanmalidir. Antibiotics are one of the most used drugs all over the world today. is coming. In particular, in developing countries, the total health expenditures Antibiotics constitute about 20% of the market. that high The use of antibiotics at a high rate leads to the development of resistance to antibiotics in bacteria. provides an opportunity and infection all over the world as in our country. causes difficulties in the treatment of diseases. a new antibiotic The design of the molecule and its presentation to treatment is very costly and takes a long time. takes. Instead, a different way of application of a known antibiotic in the treatment Using it effectively is a highly preferred approach. Moreover effective against multi-drug resistant (MDR) Aeinetobacter and Pseudomonas species Parallel to the low number of antibiotics, another problem is infection. It is the inadequacy of the amount of antibiotics reaching the region, namely the lungs. This In this case, the best possible solution is treatment by the pulmonary route. However, this In this way, sufficient amount of antibiotics can be delivered to the lungs. Therefore a rational treatment for pneumonia by developing a new and effective formulation should be provided.
Hastanede gelisen pnömonilerin en önemli alt grubunu ventilatör iliskili pnömoni (VIP) olusturmaktadir. Farkli nedenlerle (medikal veya cerrahi) hastaneye yatirilan hastalarda, altta yatan hastaliga veya yatis süresinde eklenen komplikasyonlara bagli olarak inekanik ventilasyon tedavisi gerekebilmektedir. Ventilator-associated pneumonia is the most important subgroup of hospital-acquired pneumonia. (VIP). Hospitalized for different reasons (medical or surgical) in hospitalized patients, the underlying disease or during the hospitalization period. Depending on the complications, incanic ventilation treatment may be required.
Mekanik ventilasyon süresinin 48 saati asmasini takiben ortaya çikan akciger enfeksiyonlari VIP olarak adlandirilmaktadir. Özellikle mekanik ventilasyon tedavisinin 4. gününden sonra olusan pnömoniler geç VIP olarak adlandirilmaktadir. Bu enfeksiyonlarda ÇID bakteri riski çok yüksektir. P. aeruginosa patojenlerinde; florokinolon ve karbapenemlere karsi direnç oranlarinin arttigi bilinmektedir. Acinetobacter türlerinin ise üçte birinde karbapenemlere karsi direnç söz konusudur. Çoklu ilaç dirençli Acinetobacter türlerinin büyük çogunlugu tlorokinolon, aminoglikozid ve b-laktamlara karsi da direnç göstermektedirler. Çoklu ilaç dirençli Acinetobacter türlerinin tedavisinde neredeyse tek seçenek durumuna gelen, kolistinin tek basina kullanimi, ilaç direnci gelisimi nedeniyle önerilmemektedir. Ulusal Hastane Enfeksiyonlari Sürveyans Agi (UHESA) 2013 yili sonuçlarina göre; Türkiye'de VIP yayilma hizi, Gögüs Hastaliklari yogun bakim üniteleri için 1000 ventilatör gününde 15.8 olarak bildirilmektedir. Ege Üniversitesi Tip Fakültesi Gögüs Hastaliklari Klinigi yayilma hizi 8-75.3 olarak belirlenmistir. Bu çalismada en sik saptanan etken patojenler; %826 oraniyla Gram negatif basiller olup, bunlarin da %50.4”ünü A. baumannii ve %19.0”m1 P. aeruginosa olusturrnaktadir. Bu etkenlere bagli VIP”lerin tedavisinde kullanilan en önemli antibiyotik seçeneklerine direnç oranlari ise sirasiyla, genisletilmis spektrumlu beta laktam/beta laktamaz inhibitörleri için %629, antipsödomonal sefalosporinler için %722 ve karbapenemler için %63.8 olarak bulunmustur. Kombinasyon tedavisinde kullanilan önemli bir antibiyotik seçenegi olan aminoglikozitlere direnç orani ise sadece %37.0,din Ancak bu ilaç grubunun en önemli yan etkisi nefrotoksisite olup, nefrotoksisite gelismesi prognozu olumsuz yönde etkilemektedir. Yanisira aminoglikozitlerin akcigerlere geçisinin kötü olmasi, bu grup antibiyotiklerin kullanimini önemli ölçüde kisitlamakta ve bu önemli tedavi seçenegini devre disi birakmaktadir. Ventilatör iliskili pnömoni yogun bakim ve hastanede kalis sürelerini uzatarak maliyetini önemli ölçüde artirmaktadir. Ege Üniversitesi Tip Fakültesi Gögüs Hastaliklari yogun bakim ünitesinde 2011-2013 yillari arasinda VlP”e bagli olarak yogun bakimda kalis süresi 21.5 (3-85) gün, hastanede yatis süresi 26 (3-110) gün olarak bulunmus, mortalite orani ise %736 olarak çok yüksek saptanmistir. Aminoglikozidlerin paranteral uygulanmasinda akcigere geçis orani düsüktür. Bu durum göz önüne alindiginda, pulmoner yol ile kullanilmalari halinde akcigerlerde yüksek konsantrasyonlara kolayca ulasilabilecektir. Yüksek oranda nefrotoksik ve ototoksik yan etkileri de böylelikle azaltilabileeektir. Sistemik enfeksiyonlarin tedavisi için aminoglikozidlerin sadece parenteral kullanimi vardir ve parenteral yolla verildiginde brons sekresyonlarina çok az oranda (~%1) geçerler. Bundan dolayi biyoyararlanimlari düsüktür. Çoklu ilaç uygulamalarina dirençli pnömoniler için halen en önemli tedavi seçeneklerinin basinda gelen aminoglikozitler için hedef bölgesi olan akcigerlere dogrudan ulasmasini saglayacak kuru toz formunda bir formülasyon gelistirilememistir. Lung emerging after the duration of mechanical ventilation exceeds 48 hours infections are called VIP. especially mechanical ventilation Pneumonias occurring after the 4th day of treatment are classified as late VIP. is named. The risk of MDR bacteria in these infections is very high. p. in aeruginosa pathogens; resistance to fluoroquinolones and carbapenems rates are known to increase. One third of Acinetobacter species There is resistance to carbapenems. Multi-drug resistant Acinetobacter The majority of species are also active against chloroquinolones, aminoglycosides and b-lactams. they show resistance. In the treatment of multi-drug resistant Acinetobacter species the use of colistin alone, which has become almost the only option, Not recommended due to the development of resistance. National Hospital Infections According to the Surveillance Network (UHESA) 2013 results; VIP expansion in Turkey rate is 15.8 per 1000 ventilator days for chest diseases intensive care units. reported as. Ege University Faculty of Medicine Chest Diseases Clinic spreading rate was determined as 8-75.3. The most common factor in this study pathogens; Gram negative bacilli with a rate of 826%, of which 50.4% are A. baumannii and 19.0”m1 P. aeruginosa. Depends on these factors Resistance to the most important antibiotic options used in the treatment of VIPs ratios of extended-spectrum beta-lactam/beta-lactamase, respectively. 629% for inhibitors, 722% for antipseudomonal cephalosporins and It was found as 63.8% for carbapenems. In combination therapy The rate of resistance to aminoglycosides, which is an important antibiotic option used, is only 37.0%,din However, the most important side effect of this drug group is nephrotoxicity. and development of nephrotoxicity negatively affects the prognosis. Besides the poor lung passage of aminoglycosides, this group of antibiotics significantly restricts its use and disables this important treatment option. is leaving. Ventilator-associated pneumonia ICU and hospital stay extends the time, significantly increasing the cost. Ege University Type Faculty of Chest Diseases in the intensive care unit between 2011-2013 Depending on VLP, the duration of stay in the intensive care unit is 21.5 (3-85) days, hospitalization The duration was found to be 26 (3-110) days, and the mortality rate was 736%. high detected. Parenteral administration of aminoglycosides to the lung the pass rate is low. Given this situation, the pulmonary route easily reach high concentrations in the lungs if used can be reached. High rates of nephrotoxic and ototoxic side effects thus it can be reduced. For the treatment of systemic infections aminoglycosides have only parenteral use and are administered parenterally. When given, they pass into bronchial secretions at a very small rate (~1%). Therefore their bioavailability is low. For pneumonia resistant to multidrug administration target for aminoglycosides, which is still at the forefront of the most important treatment options. It is a dry powder form that will allow it to reach the lungs directly. formulation has not been developed.
Hastanede gelisen pnömoni ve bir alt grubu olan ventilatör iliskili pnömonilerin büyük çogunlugu, çoklu antibiyotik dirençli Gram negatif bakterilere bagli olarak gelismektedir. Bu enfeksiyonlarin tedavisinde önemli bir antibiyotik seçenegi olan aminoglikozitler, kombinasyon tedavisinin bir parçasi olarak ve sadece parenteral yolla kullanilmaktadir. Ancak bu ilaç grubunun en önemli yan etkisi nefrotoksisite olup, hastalarin yas ortalamasinin da yüksek olmasi bu riski artirmaktadir. Ayrica aminoglikozitlerin akcigerlere geçisinin kötü olmasi, bu grup antibiyotiklerin tek basina kullanimi mümkün olmamaktadir. Kombinasyon tedavisinin bir parçasi olarak kullanilmasi durumunda ise, ilaç etkilesimine bagli olarak nefrotoksisite oranlari daha da yükselmektedir. Bu durum, bu grup antibiyotiklerin kullanimini büyük ölçüde kisitlamakta ve bu önemli tedavi seçenegini devre disi birakmaktadir. Oysa patojenlerin aminoglikozitlere karsi direnç oranlari, bu enfeksiyonlarin tedavisinde sik olarak kullanilan diger antibiyotiklere göre daha düsüktür. Aminoglikozitlerin hedef organ olan akcigerlere dogrudan ulasmasini saglayabilecek bu formülasyon, etkin ve güvenli bir sekilde tedavi saglayabilmektedir. Bunun sonucu olarak da, insan hayatina mal olan bu komplikasyon, daha fazla tedavi edilebilir hale gelecek ve bu nedenle ortaya çikan aci kayiplarin önlenmesi mümkün olacaktir. Hospital-acquired pneumonia and its subgroup, ventilator-associated pneumonia. mostly due to multi-antibiotic resistant Gram-negative bacteria is developing. It is an important antibiotic option in the treatment of these infections. aminoglycosides as part of combination therapy and parenterally only way is used. However, the most important side effect of this drug group is nephrotoxicity. and the high mean age of the patients increases this risk. Moreover the poor passage of aminoglycosides to the lungs, this group of antibiotics is the only It is not possible to use it on its own. Part of combination therapy If used as a drug, nephrotoxicity due to drug interaction rates are getting higher. This situation discourages the use of this group of antibiotics. greatly restricts and disables this important treatment option. is leaving. However, the rates of resistance of pathogens to aminoglycosides than other antibiotics commonly used in the treatment of infections. is low. Direct access of aminoglycosides to the target organ, the lungs This formulation, which can provide effective and safe treatment can provide. As a result, this complication will become more treatable and therefore It will be possible to prevent painful losses.
Pulmoner yol ile ilaç uygulamasi, parenteral yol kadar hizli etki gösteren ve agri faktörü olmadigi için hastalar için daha iyi tolere edilebilen önemli bir yoldur. Drug administration via the pulmonary route is as fast-acting and painful as the parenteral route. It is an important way that can be tolerated better for patients because it does not have a factor.
Ilacin sistemik dolasima geçisinin daha az ve yavas olmasi nedeniyle diger organlar üzerindeki yan etkilerin azalmasi ve de akcigerlerde daha yüksek ilaç konsantrasyona ulasilmasi, pulmoner yolla ilaç uygulamanin non-invaziv bir metot olarak avantajli yönlerini olusturmaktadir. Akcigerlerden ilaç salimi, gastrointestinal absorpsiyona etki eden beslenme komplikasyonlarindan, gastrointestinal sistemde olusan ilaç irritasyonundan, sindirim enzimlerinden ve hastalar arasi metabolik farkliliklanndan bagimsizdir. Bu nedenlerden dolayi ilaçlarin pulmoner yol ile uygulanmasi etkili ve güvenilir bir yol olup, pnömoni tedavisinde oldukça ümit vericidir. Due to the fact that the drug's passage into the systemic circulation is less and slow, other reduced side effects on organs and higher drug exposure in the lungs concentration is a non-invasive way of administering drugs by the pulmonary route. constitutes its advantageous aspects as a method. Drug release from the lungs, nutritional complications that affect gastrointestinal absorption, from drug irritation in the gastrointestinal tract, digestive enzymes and is independent of metabolic differences between patients. For these reasons Administering drugs by the pulmonary route is an effective and safe way, very promising in treatment.
Inhaler seklinde uygulanan ilaçlarin dozu, sistemik olarak kullanilan ilaç dozlarindan çok daha düsüktür. Etkilerinin daha erken baslamasi yaninda, sistemik kullanilan ilaçlara göre de daha az yan etkilere sahiptirler. ilaçlarin brons mukozasindaki klirensi yavas oldugu için etkileri daha uzun sürer. Özellikle bu uygulama yöntemi ile ilaçlarin dogrudan hedef organa yüksek miktarlarda verilmesi durumunda bile düsük yan etki gözlemlenmektedir. Yan etkilerin sinirli olmasi, ilacin hava yollarinda yüksek konsantrasyonlara ulasmasina ve ilacin kandaki konsantrasyonunun düsük olmasina baglidir. The dose of drugs administered in the form of inhalers, the drug used systemically much lower than their dose. Besides the earlier onset of its effects, They also have fewer side effects than systemic drugs. bronchi of drugs Since its clearance in the mucosa is slow, its effects last longer. Especially this With the method of administration, high amounts of drugs are directly injected into the target organ. Even in the case of administration, low side effects are observed. Frustrated by the side effects may cause the drug to reach high concentrations in the airways and It is due to its low concentration in the blood.
Günümüzde inhalasyon tedavisinde, Ölçülü Doz lnhaler (ÖDI), Kuru Toz Inhaler (KTI) ve nebulizatörler kullanilmaktadir. KTI sisteinlerinin üretimine kadar ÖDI°ler, tasinabilir ve çok doz uygulama kapasitesine sahip olmalarindan dolayi inhalasyon ilaç uygulama piyasasinda uzun süre önemli bir yer tutmustur. Ancak ÖDI”lerden farkli olarak; - KTI sistemlerinin püskürtücü gaz içennemesi, - ilacin sikilmasi ile birlikte ayni anda nefes alinmasinin gerekmemesi (el ve soluk koordinasyon uyumu), e ara cihaz (spacer) gerektirmedigi için tasinmalarinin ve kullanimlarinin kolay olmasi, - hem lipofilik hem de hidrofilik etkin maddelere uygulanabilmesi, - formülasyon problemleri tasimamalari ve formülasyonlarin stabilitelerinin daha iyi olmasi, - kolay çalismasi: - bes yasin üzerindeki çocuklarda, ergen ve artritli hastalarin kolaylikla kullanabilmesi gibi avantajlarindan dolayi KTI formülasyonlarinin hazirlanmasi uygun görülmüstür. Today, in inhalation therapy, Metered Dose Inhaler (ODI), Dry Powder Inhaler (KTI) and nebulizers are used. Until the production of KTI cysteines ODI°s are portable and multi-dose because they are has taken an important place in the inhalation drug application market for a long time. However Unlike ODIs; - KTI systems do not contain propellant gas, - no need to breathe at the same time as the drug is squeezed (hand and breath coordination harmony), e Since it does not require an intermediate device (spacer), it is easy to carry and use it. to be easy, - applicable to both lipophilic and hydrophilic active substances, - formulation problems and stability of formulations to be better, - easy operation: - children over the age of five, adolescents and patients with arthritis can be easily KTI formulations can be used preparation was deemed appropriate.
KTI”ler, ilacin akcigerlere ulasmasi için yüksek inspiratuar akim gerektirir, yani hastanin kendi inspiratuar gayreti gereklidir. KTI kullanimini en çok kisitlayan faktör, hastanin inspiratuar efor kapasitesine bagli olarak alinabilmesi, yani olusturulan inspiratuar akim hizlarindan etkilenmesidir. inspiratuar akim hizi, obstrüktif hastaliklarin siddetlerine göre degiskenlik göstermektedir. Bazi hastalar sadece aerosol bulutu olusturabilecek kadar düsük akim hizi olustururlar. Bunun sonucunda ilacin bogaz bölgesinde depolanmasi nedeniyle etkin bir tedavi saglanamaz. Yogun bakim ünitesinde yatan hastalar gerekli inspiratuar akimi saglayamayacaklari için ventilatör destekli uygulama, modifiye KTI cihazlari kullanilarak KTI”1erin hastaya verilmesi seklinde ya da Exubera, Airmax aktif KTI cihazlari ile gerçeklestirilmektedir. KTIs require high inspiratory flow for the drug to reach the lungs, i.e. The patient's own inspiratory effort is required. most restrictive to the use of KTI factor is that it can be taken depending on the inspiratory effort capacity of the patient, that is It is affected by the inspiratory flow rates created. inspiratory flow rate, It varies according to the severity of obstructive diseases. some patients they only generate a flow rate low enough to form an aerosol cloud. This As a result, effective treatment is not possible due to the storage of the drug in the throat area. cannot be provided. Patients in the intensive care unit required inspiratory flow ventilator-assisted application, modified KTI devices in the form of giving KTIs to the patient by using or using Exubera, Airmax active It is carried out with KTI devices.
Teknigin bilinen durumunda yapilmis olan bazi basvurular sunlardir: Bulusun Kisa Açiklamasi Bulusun amaci, hastane kökenli hastaliklarin iyilestirilmesi amaciyla kullanilan netilmisinin hedef lokasyona en uygun sekilde ulasmasi ve en etkin sekilde bu lokasyonda islev görmesi için bir formülasyon olusturulmasini saglayan bir kuru toz inhaler formülasyonu üretim metodu gerçeklestirmektir. Some applications made in the state of the art are as follows: Brief Description of the Invention The aim of the invention is to use drugs used for the treatment of hospital-acquired diseases. to reach the target location in the most appropriate way and to do this in the most effective way. a dry substance that allows a formulation to be created to function at the location powder inhaler formulation production method is to realize.
Bulusun diger amacia daha düsük dozda etkin madde içeren bir formülasyona sahip olmasi sayesinde tedaviye geleneksel uygulamalara kiyasla daha fazla etkinlik kazandiran ve hastane maliyetlerini azaltan bir kuru toz inhaler fomiülasyonu üretim metodu gerçeklestinnektir, Bulusun bir diger amaci, aminoglikozidlerin biyoyararlanimini artirmak için pulmoner yoldan kullanildigi, böylelikle etkin inaddenin daha düsük dozla verilerek akcigerlerde terapötik konsantrasyonun lokalize edilmesini ve aminoglikozidlerin yan etkilerinin azaltilmasin saglayan bir kuru toz inhaler forrnülasyonu üretim metodu gerçeklestirmektir. It is another object of the invention to provide a formulation containing a lower dose of active ingredient. It has more treatment compared to traditional applications, thanks to its a dry powder inhaler that adds effectiveness and reduces hospital costs The production method of the formulation is to be carried out, Another object of the invention is to increase the bioavailability of aminoglycosides. It is used by the pulmonary route, so that the effective inert can be administered at a lower dose. localization of the therapeutic concentration in the lungs and a dry powder inhaler that helps reduce the side effects of aminoglycosides The formulation is to realize the production method.
Bulusun Ayrintili Açiklamasi Bulus konusu netilmisin içeren kuru toz inhaler fonnülasyonu üretim metodu, hastane kökenli enfeksiyonlarin tedavisinde kullanilan aminoglikozid grubu bir antibiyotik olan netilinisin sülfatin etkili bir sekilde uygulanmasini saglayan bir formülasyonun üretim metodu olup, - asetik asit çözeltisinin hazirlanmasi, - oda sartlarinda çözelti içerisinde kitosanin çözündürülmesi, - çözeltinin içerisine netilmisin ilave edilmesi, - Çözeltinin içerisine mannitol ilave edilmesi, - çözeltinin içerisine lösin ilave edilmesi, - çözeltinin bir filtreden geçirilerek süzülmesi, - süzülen çözeltinin nano boyutlu bir püskürterek kurutucu cihazi tarafindan püskürtülmesiyle kuru toz inhaler formülasyonun hazirlanmasi adimlarini içermektedir. Detailed Description of the Invention Production method of dry powder inhaler formulation containing netilmicin which is the subject of the invention, A group of aminoglycosides used in the treatment of hospital-acquired infections. an effective application of the antibiotic netilinicin sulfate. is the production method of the formulation, - preparation of acetic acid solution, - dissolving chitosan in solution at room conditions, - adding netilmicin to the solution, - Adding mannitol to the solution, - adding leucine to the solution, - filtering the solution through a filter, - by a nano-sized spray dryer device of the filtered solution the steps of preparing the dry powder inhaler formulation by spraying contains.
Bulusun tercih edilen uygulamasinda asetik asit çözeltisinin hazirlanmasi adiminda glasiyel asetik asit kullanilarak %1”lik (h/h) asetik asit çözeltisinin hazirlanmaktadir. Preparation of acetic acid solution in the preferred embodiment of the invention 1% (v/v) acetic acid solution using glacial acetic acid in the step is being prepared.
Bulusun tercih edilen uygulamasinda asetik asit çözeltisi içerisinde çözündürülen kitosan dogal bir polimer olarak tercih edilmis olup kuru toz içerisinde %0-45 (aL/a) araliginda kullanilmaktadir. In the preferred embodiment of the invention, dissolved in acetic acid solution Chitosan is preferred as a natural polymer and 0-45% in dry powder It is used in the range of (aL/a).
Bulusun tercih edilen uygulamasinda asetik asit çözeltisi içerisine eklenen ve etkin madde olarak tercih edilen netilinisin sülfat kuru toz içerisinde %10-50 (a/a) araliginda kullanilmaktadir. In the preferred embodiment of the invention, added into acetic acid solution and netilincin sulfate, which is preferred as active ingredient, in dry powder 10-50% (w/w) used in the range.
Bulusun tercih edilen uygulamasinda asetik asit çözeltisi içerisine eklenen ve yardimci madde olarak tercih edilen mannitol kuru toz içerisinde %0-75 (a/a) araliginda kullanilmaktadir. In the preferred embodiment of the invention, added into acetic acid solution and 0-75% (w/w) in dry powder of mannitol preferred as auxiliary used in the range.
Bulusun tercih edilen uygulamasinda asetik asit çözeltisi içerisine eklenen ve yardimci madde olarak tercih edilen lösin kuru toz içerisinde %10-50 (a/a) araliginda kullanilmaktadir. In the preferred embodiment of the invention, added into acetic acid solution and 10-50% (w/w) leucine in dry powder, which is preferred as an auxiliary substance used in the range.
Bulusun tercih edilen uygulamasinda karisimin Iitreden geçirilerek süzülmesi adiminda, karisim por genisligi 0.8 - 5 um araliginda olan bir filtreden geçirilerek süzülmektedir. In the preferred embodiment of the invention, the mixture is filtered through a filter. In step 1, the mixture is passed through a filter with a pore width of 0.8 - 5 µm. is floating.
Bulusun tercih edilen uygulamasinda çözeltinin püskürtülerek kurutulmasi adiminda çözelti 4, 5.5 ya da 7 um mesh”lik bir püskürtme basligina sahip bir kurutucu cihazi tarafindan püskürtülmektedir. In the preferred embodiment of the invention, the solution is spray dried. In step 4, the solution is sprayed with a nozzle of 4, 5.5, or 7 µm mesh. is sprayed by the dryer device.
Bulusun tercih edilen uygulamasinda çözeltinin püskürtülerek kurutulmasi adiminda sistemde giris sicakligi 80-] 20 °C araligindadir. In the preferred embodiment of the invention, the solution is spray dried. The inlet temperature in the system is in the range of 80-] 20 °C.
Bulusun tercih edilen uygulamasinda çözeltinin püskürtülerek kurutulmasi adiminda sistemde gaz akis hizi 110-150 L/dk°dir. In the preferred embodiment of the invention, the solution is spray dried. The gas flow rate in the system is 110-150 L/min.
Bulusun tercih edilen uygulamasinda çözeltinin püskürtülerek kurutulmasi adiminda sistemde basinç degeri 30-50 mBar°dir. In the preferred embodiment of the invention, the solution is spray dried. The pressure value in the system at step is 30-50 mBar°.
Bulusun bir diger uygulamasinda elde kuru toz inhaler formülasyon, bir iiihaler cihaz vasitasiyla hastaya pulmoner yolla uygulanmaktadir. In another embodiment of the invention, the handheld dry powder inhaler formulation is It is administered to the patient via the pulmonary route via the device.
Bulus konusu bir kuru toz inhaler formülasyonu üretim metodunda öiicelikle glasiyel asetik asitten hareketle %1 asetik asit çözeltisi hazirlanmaktadir. Bu çözelti içerisinde kitosan -oda sartlarinda- çözündürülür ve karisim içerisine netilmisin, mannitol ve lösin ilave edilir. Elde edilen karisim 0.8 - 5 um araliginda por büyüklügüne sahip bir tiltreden süzülür. Süzülen çözelti nano boyutlu püskürterek kurutucu cihazinda (Nano Spray Dryer BUCHI, B-90) 4, 5.5 ya da 7' um mesh”lik püskürtme basligi ile püskürtülerek kuru toz inhaler fomiülasyonlar hazirlandi. Bulus konusu bir kuru toz inhaler formülasyonu üretim metodu ile hazirlanan kuru toz inhaler formülasyonlarda, etkin madde (netilmisin sülfat) içerigi %10-50 (a/a); yardimci madde olarak mannitol %0-75 (a/a) ve lösin %10- 50 (a/a); polimer olarak, dogal bir polimer olan farkli molekül agirliklarindaki kitosan (%0-45 (a/a)) kullanildi. A dry powder inhaler formulation which is the subject of the invention is especially used in the production method. 1% acetic acid solution is prepared starting from glacial acetic acid. This Chitosan -at room conditions- is dissolved in the solution and added into the mixture. netilmicin, mannitol and leucine are added. The resulting mixture is in the range of 0.8 - 5 µm. It is filtered through a filter with a pore size. The filtered solution is nanosized. in spray dryer (Nano Spray Dryer BUCHI, B-90) 4, 5.5 or 7' Dry powder inhaler formulations by spraying with a um mesh spray head was prepared. The subject of the invention is a dry powder inhaler formulation production method. In dry powder inhaler formulations prepared, the active substance (netilmicin sulfate) content of 10-50% (w/w); mannitol 0-75% (w/w) and leucine 10%- 50 (w/w); As a polymer, it is a natural polymer of different molecular weights. chitosan (0-45% (w/w)) was used.
Bulus konusu bir kuru toz inhaler formülasyonu üretim metodu ile üretilen netilmisin içeren uzun etkili kuru toz inhaler formülasyonlari, 4, 5.5 ya da 7' pm mesh”lik püskürtme basligina sahip nano boyutlu püskürtücülü bir kurutucu cihazi (Nano Spray Dryer BUCHI, B-90) kullanilarak hazirlanmaktadir. Cihazin optimum çalisma sartlari: I Püskürtme basligi (Nozzle): 4, 5 .5 ya da 7 umllik mesh - Giris sicakligi (lnlet temperature): 80-120°C - Sprey: %50-100 (cihazdaki Spray orani/hizi) - Gaz akis hizi: 110-150 L/dk - Basinç: 30-50 mBar - Pompa: 4 (cihazda yer alan peristaltik pompa hiz kademesi) Netilmisinin bir aminoglikozid antikoru grubu üyesi olup, bulus konusu bir kuru toz inhaler formülasyonu üretim metodu sayesinde ilk kez mikropartiküler kuru toz inhaler (KTI) formülasyonlari gelistirilmis, etkinlikleri optimize edilmis ve güvenle kullanilabilecek bir formülasyonu tasarlanmistir. Teknikte bilinen diger uygulama yollari ile karsilastirildiginda, daha düsük dozda etkin madde kullanilarak, akcigerlerde terapötik konsantrasyon saglanmakta ve böylelikle netilmisinin yan etkileri de azaltilmaktadir. Bu nedenle, aminoglikozidlerin biyoyararlanimini artirmak için pulmoner yol ile verilmesi, ideal bir seçim olacaktir. Buna ek olarak, hastanin yogun bakim ünitesinde yatis süresi kisaltilabileeek böylelikle hastane giderlerinde azalma saglanabilecek ve yogun bakim ünitesinde çalisan saglik ekibinin is yükü azaltilabilecektir. Bulus konusu bir kuru toz inhaler formülasyonu üretim metodu sayesinde ilaçlarin etkin uygulanmasina engel olan ve tibbi tedaviyi basarisiz kilan konvansiyonel dozaj sekillerine iyi bir alternatif olabilecek yenilikçi bir formülasyon tasarlanmistir. The subject of the invention is a dry powder inhaler formulation produced by the production method. long-acting dry powder inhaler formulations containing netilmicin, 4, 5.5 or 7' pm A nano-sized spray dryer with a mesh spray head (Nano Spray Dryer BUCHI, B-90). your device Optimum working conditions: I Nozzle: 4, 5.5 or 7 µm mesh - Inlet temperature (lnlet temperature): 80-120°C - Spray: 50-100% (Spray rate/speed on the device) - Gas flow rate: 110-150 L/min - Pressure: 30-50 mBar - Pump: 4 (peristaltic pump speed level in the device) Netilmicin is a member of the aminoglycoside antibody group and is a dry matter of the invention. Thanks to the powder inhaler formulation production method, for the first time, microparticulate dry powder inhaler (KTI) formulations have been developed, their efficacy optimized and A formulation that can be used safely has been designed. Other known in the art lower dose of active substance compared to routes of administration By using it, therapeutic concentration is achieved in the lungs and thus The side effects of netilmicin are also reduced. Therefore, aminoglycosides To increase bioavailability, pulmonary delivery is an ideal choice. will be. In addition, the length of stay of the patient in the intensive care unit can be shortened so that hospital expenses can be reduced and intensive The workload of the healthcare team working in the care unit will be reduced. subject of the invention effective method of producing a dry powder inhaler formulation. conventional dosage that precludes administration and fails medical treatment An innovative formulation has been designed that can be a good alternative to their shapes.
Bu baglamda, aminoglikozidlerin biyoyararlanimini artirmak için pulmoner yoldan kullanilmasi suretiyle, etkin maddenin daha düsük dozla verilerek diger uygulama yollarina göre akcigerlerde terapötik konsantrasyonda lokalize olabildigi ve yan etkilerinin de azaltildigi görülmektedir. In this context, to increase the bioavailability of aminoglycosides, pulmonary route, the active substance is given in a lower dose and the other localized at therapeutic concentration in the lungs according to the routes of administration It is seen that it can be possible and the side effects are also reduced.
Bulus konusu bir kuru toz inhaler formülasyonu üretim metodunda, netilinisin içeren mikropartiküler KTI formülasyonu hazirlanmistir. Bu sunulan formülasyon ile daha etkin, güvenilir ve ayni zamanda da yenilikçi bir tedavi yaklasimi saglanmaktadir. Olusturulan netilmisin yüklü KTI formülasyonlari ile pnömoni tedavisinde daha etkili bir uygulama saglanmakta ve KTI formülasyonlari yogun bakim ünitelerinde de kullanilabilir hale getirilmektedir. In a dry powder inhaler formulation production method, which is the subject of the invention, netilinicin A microparticular KTI formulation containing This presented formulation A more effective, reliable and at the same time innovative treatment approach with is provided. Pneumonia with netilmicin loaded KTI formulations A more effective application is provided in the treatment of It is also made usable in maintenance units.
Akilci bir antibiyotik kullanimi, etkin maddenin etkinligini artirabilen, bu sayede kombine kullanima gerek kalinadan kontrollü ve lokal ilaç salimi saglayacak olan ilaç tasiyici sistemler ile mümkündür. Bu yüzden, tedavinin etkinligi için uygun bir ilaç tasiyici sistemin gelistirilmesi gerekmektedir. Akcigerlerde bakterilerin eradikasyonu için, özellikle pnömoni tedavisinde etkin maddenin oral veya intravenöz yol ile uygulamaya daha iyi bir alternatif olan pulmoner yol ile verilmesinin dogru bir yaklasim olacagi düsünülmektedir. Böylece akcigerlerde yüksek terapötik konsantrasyona ulasilirken etkin maddenin sisteinik yan etkileri de azaltilinis olacaktir. The rational use of antibiotics, which can increase the effectiveness of the active substance, which will provide controlled and local drug release without the need for combined use. possible with drug delivery systems. Therefore, it is appropriate for the efficacy of the treatment. A drug delivery system needs to be developed. Bacteria in the lungs For the eradication of the active substance, especially in the treatment of pneumonia, oral or with the pulmonary route, which is a better alternative to administration by the intravenous route. is thought to be a correct approach. Thus in the lungs Cysteinic side effects of the active substance when reaching a high therapeutic concentration will also be reduced.
Bulus konusu bir kuru toz inhaler formülasyonu üretim metodunda kullanilan mikropartiküller; - düsük dozda ilaç kullanimina olanak saglamasi, - etkin maddenin yapisini ve aktivitesini degistirmemesi, - etkin maddeyi kontrollü olarak salmasi, - hedef organ, doku ve hücrelere etkin maddeyi tasiinasi gibi avantajlari açisindan oldukça önemli ilaç tasiyici sistemlerdir. The subject of the invention is a dry powder inhaler formulation used in the production method. microparticles; - enabling low-dose drug use, - does not change the structure and activity of the active substance, - controlled release of the active substance, - Advantages such as transporting the active substance to target organs, tissues and cells They are very important drug delivery systems in terms of
Bunlara ek olarak, ilacin inikropartikül içerisinde sunulmasi sonucu etkin maddenin stabilitesinin artmasini saglamaktadir. Uygun özelliklerde hazirlanmasi halinde akcigerlerde iyi bir dagilim ve yeterli depolanma saglamakta ve akcigerlerde etkin maddenin etkisini arttirici özellik göstermektedir. Bulus kapsaminda yapilan çalismalar, mikropartiküllerin pulmoner yol ile ilaç uygulamada da iyi bir tasiyici sistem oldugunu göstermistir. Mikropartiküler KTl°ler ile netilmisinin uzayan etkili formülasyonu sayesinde akcigerlerde etkin maddenin depolanmasi artirilarak, pnömoni hastaliginin tedavisine yenilikçi bir bakis açisi ile çözüm sunulmaktadir. In addition, as a result of the presentation of the drug in inoparticle, it is effective. It increases the stability of the substance. Preparation with appropriate features It provides a good distribution and adequate storage in the lungs and It shows the effect of increasing the effect of the active substance in the lungs. Meet The studies conducted within the scope of the study revealed that microparticles are transported via the pulmonary route. It has also shown that it is a good carrier system in practice. microparticular Effective in the lungs thanks to its prolonging effective formulation with KTl°s an innovative approach to the treatment of pneumonia disease by increasing the storage of the substance. A solution is presented from the point of view.
Kuru toz inhaler sistemlerin basarisi ilaç pazarinda da bu sistemleri kullanan bazi ürünlerin yer almasini saglamistir. Netilmisin için gelistirilen kuru toz inhaler formülasyon, mevcut formülasyonlarin dezavantajlarini ortadan kaldirarak, alternatif` bir seçenek olusturmaktadir. Ayrica bulus konusu bir kuru toz inhaler formülasyonu üretim metodu ilaç sanayisinde halihazirda var olan altyapi ile üretilebilecek bir üründür. Bu sebeple, ek maliyet gereksinimleri de ortadan kaldirilmaktadir. The success of dry powder inhaler systems is also in the pharmaceutical market, some of which use these systems. ensured that the products were included. Dry powder inhaler developed for netilmicin formulation, eliminating the disadvantages of existing formulations, constitutes an alternative option. Also, the subject of the invention is a dry powder inhaler. The production method of the formulation is combined with the existing infrastructure in the pharmaceutical industry. It is a product that can be produced. Therefore, additional cost requirements are eliminated. is being removed.
Pnömoni, mortalite ve morbiditesi yüksek olan, hastanede yatis süresini ve tedavi maliyetini yükselten, ülke ekonomisine önemli oranda yük getiren bir enfeksiyon hastaligidir. Girisimsel tip alanindaki ilerlemelere bagli olarak, yapilan ameliyatlarin artmasi ile uzun süreli yogun bakim destegi sonucu, hastanede kalim süresinin uzamasina paralel olarak, pnömoni riski her yil giderek artan oranlarda karsimiza çikmaktadir. Dünya Saglik Örgütü verilerine göre, hastanede yatarak tedavi gören yaklasik her 10 hastadan birinde hastane enfeksiyonu ve siklikla pnömoninin ortaya çiktigi ve üçüncü dünya ülkelerinde yilda yaklasik 6.000 kisinin pnömoni nedeniyle yasamini yitirdigi, hastanede kalis süresinin hasta basina 7-10 gün uzadigi ve 2-6 milyar dolar ek maliyete neden oldugu vurgulanmaktadir. Ülkemizde saglik için ayrilan bütçe sinirlidir. Mevcut kaynaklar sinirli oldugundan, bunlari mümkün olan en iyi sekilde kullanmak gereklidir. Bu nedenle, ilaçlarin akilci bir biçimde kullanilabilmesi için, etkinlik ve güvenilirligin yani sira uygulanabilirligi ve maliyetini de gözden geçirmek dogru olacaktir. Yapilan literatür arastirmasinda. pnömoni tedavisinde çok kullanilan aminoglikozid grubu antibiyotiklerin alveol ve bronslara penetrasyonunun iyi olmamasi nedeniyle parenteral yolla verilisinin hayal kirikligi yarattigi ve yan etkileri yüzünden kullanimlarinin sinirli oldugu hildirilmektedir. Pneumonia, which has high mortality and morbidity, length of hospital stay and treatment an infection that increases its cost and puts a significant burden on the country's economy. is the disease. Depending on the advances in the field of interventional medicine, As a result of increased surgeries and long-term intensive care support, hospital stay Parallel to the prolongation of the duration of the pneumonia, the risk of pneumonia is increasing at an increasing rate every year. is coming our way. According to the World Health Organization data, hospitalization hospital infection in approximately one in 10 patients treated and frequently approximately 6,000 per year in third world countries where pneumonia occurs the person died due to pneumonia, the length of hospital stay It takes 7-10 days per head and causes an additional cost of 2-6 billion dollars. is emphasized. The budget allocated for health in our country is limited. Available Since resources are limited, use them in the best possible way. is necessary. Therefore, in order for drugs to be used rationally, efficacy must be and to review the feasibility and cost as well as the reliability it will be true. In the literature search. in the treatment of pneumonia the aminoglycoside group antibiotics used in the alveoli and bronchi Due to poor penetration, parenteral administration is unreasonable. It causes irritation and its use is limited due to its side effects. is being deceived.
Bulus kapsaminda, farmakovijilans ve farmakoekonomik kriterler göz önüne alinarak, pulmoner yol ile uygulamada daha düsük doz kullanilarak geleneksel uygulamalara göre daha etkin ve daha az yan etkiye neden olan netilmisin yüklü kuru toz inhaler (KTI) formülasyonu gelistirilmistir. Bulus konusu bir kuru toz inhaler formülasyonu üretim metodundaki formülasyon ile akcigerlerde etkin maddenin lokalizasyonu artirilarak, uzatilmis etkin madde salimi saglanabilecek, tedavi giderleri azaltilabilecek ve hastalarin kisa sürede iyilesebilmesi mümkün olabilecektir. Bulus kapsaminda gelistirilen netilinisin yüklü mikropartiküler KTI formülasyonu, pnömoni tedavisinde ileriye dönük klinik katki saglayabilecektir. Within the scope of the invention, pharmacovigilance and pharmacoeconomic criteria are considered. by using a lower dose in the pulmonary route. It is loaded with netilmicin, which is more effective and causes less side effects than other applications. dry powder inhaler (KTI) formulation has been developed. The subject of the invention is a dry powder The inhaler formulation is effective in the lungs with the formulation in the production method. By increasing the localization of the substance, extended release of the active substance can be achieved, treatment costs can be reduced and it is possible for patients to recover in a short time. can be. Microparticular KTI loaded with netilinsin developed within the scope of the invention formulation may provide a prospective clinical contribution to the treatment of pneumonia.
Bulus kapsaminda hazirlanan netilmisin KTI formülasyonu endüstri açisindan uygulanabilir özelliktedir. Gelistirilen formülasyon, kolaylikla seri üretimi gerçeklestirilebilir olup7 piyasaya sunulabilir niteliktedir. Netilmicin KTI formulation prepared within the scope of the invention has been used in terms of industry. is applicable. The developed formulation is easily mass-produced. feasible and can be put on the market7.
Claims (13)
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