TR201612233A1 - OPHTHALMIC PHARMACEUTICAL COMPOSITIONS - Google Patents
OPHTHALMIC PHARMACEUTICAL COMPOSITIONS Download PDFInfo
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- TR201612233A1 TR201612233A1 TR2016/12233A TR201612233A TR201612233A1 TR 201612233 A1 TR201612233 A1 TR 201612233A1 TR 2016/12233 A TR2016/12233 A TR 2016/12233A TR 201612233 A TR201612233 A TR 201612233A TR 201612233 A1 TR201612233 A1 TR 201612233A1
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- cyclosporine
- ophthalmic
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Abstract
Mevcut buluş, keratokonjunktivitis sikka ile ilişkili oküler enflamasyona bağlı olarak gözyaşı yapımının baskılandığı öngörülen hastalarda gözyaşı yapımının artırılmasında profilaktik ve/veya semptomatik ve/veya terapötik tedavisinde kullanılmak üzere siklik bir polipeptit olan immünosüpresif özellikteki uygun etken maddeyi ve/veya farmasötik olarak kabul edilebilir türevlerini içeren farmasötik bileşim/ler ile ilgilidir.The present invention relates to a pharmaceutical composition comprising an immunosuppressive active agent and / or a pharmaceutically acceptable active ingredient comprising a cyclic polypeptide suitable for use in prophylactic and / or symptomatic and / or therapeutic treatment for enhancing tear formation in patients predicted to suppress tear formation due to ocular inflammation associated with keratoconjunctivitis cycka. composition (s).
Description
TARIFNAME OFTALMIK FARMASÖTIK BILESIMLER BULUSUN ILGILI OLDUGU ALAN Mevcut bulus, keratokonjunktivitis sikka ile iliskili oküler enflamasyona bagli olarak gözyasi yapiminin baskilandigi öngörülen hastalarda gözyasi yapiminin artirilmasinda profilaktik ve/veya semptomatik ve/veya terapötik tedavisinde kullanilmak üzere siklik bir polipeptit olan immünosüpresit` özellikteki uygun etken maddeyi ve/veya farmasötik olarak kabul edilebilir türevlerini içeren farmasötik bilesim/ler ile ilgilidir. DESCRIPTION OPHTHALMIC PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention is related to ocular inflammation associated with keratoconjunctivitis sicca. in increasing tear production in patients who are predicted to have suppressed tear production. cyclic therapy for use in the prophylactic and/or symptomatic and/or therapeutic treatment the appropriate active substance with immunosuppressive properties, which is a polypeptide, and/or pharmaceutically relates to pharmaceutical composition(s) containing acceptable derivatives.
Mevcut bulus; siklik bir polipeptit olan immünosüpresif özellikteki etken maddenin ve/veya farmasötik olarak kabul edilebilir türevleri oldugu ve uygun farmasötik formlarda etken madde olarak kullanildigi farmasötik bilesim/ler ile ilgilidir. The present invention; The active substance with immunosuppressive properties, which is a cyclic polypeptide and/or pharmaceutically acceptable derivatives and in suitable pharmaceutical forms relates to the pharmaceutical composition(s) in which it is used as an active ingredient.
Formül 1: Ayrica bulus, Siklosporin ve/veya farmasötik olarak kabul edilebilir türevlerini içeren farmasötik bilesimlerin oftalmik uygulama için uygun olan formülasyonlarini ve profilaktik ve/veya semptomatik ve/veya terapötik kullanimlarini da kapsamaktadir. ÖNCEKI TEKNIK (TEKNIGIN BILINEN DURUMU) Kuru göz sendromu, oküler yüzey hasari ile birlikte görme bozuklugu ile sonuçlanabilen gözyasi Iilmi ve oküler yüzeyin multifaktoriyel bir hastaligidir. Bu tabloya artmis gözyasi osmolaritesi ve oküler yüzey inflamasyonu eslik etmektedir. Kuru göz hastaliginin her bir formu farkli tedavi protokolü gerektirmektedir ve dogru taniyi koymak bu nedenle çok önemlidir. Hastaligin tedavisinde kuru göze neden olan faktörlerin ortaya çikarilmasi ve semptomlari arttiran durumlarin engellenmesi önemlidir. Tedavi, medikal, anti-inflamatuar tedavi, kan ürünleri ile tedavi, girisimsel tedaviler, cerrahi tedavi ve halen gelistirilmekte Kuru göz sendromuna (KGS) neden olan faktörlerin ortaya çikarilmasi kuru göz tedavisinde çok önemlidir ve ilk basamaktir. Kuru göz hastalarinda gerek altta yatan nedenlere, gerek hastaligin kendisine ve gerekse komplikasyonlara yönelik tedaviler esas tedavi yöntemlerini olusturmaktadir. ” grubunun tanimladigi sekilde kum göz aslinda “Oküler yüzey hasari ile birlikte rahatsizlik hissi, görme bozuklugu ve stabil olmayan gözyasi film tabakasina neden olan gözyasi ve oküler yüzeyin multifaktoriyel disfonksiyonu” olarak belirtilmistir. Bu nedenle etyolojiye baktigimizda aslinda birçok farkli mekanizmanin rol oynadigini görmekte ve tedavi planlarken de bu mekanizmalar göz önünde bulundurulmaktadir. Uzun yillardir devam eden arastirmalara ragmen kuru göz tanisi ve tedavisi halen zorluk tasimaktadir. Tanida semptomlarin ayrintili degerlendirilmesi ve tanisal testlerin uygun kombinasyonlari ile hastaya yaklasilmasi çok önemlidir. Tedavinin basarisini, konulan taninin dogrulugu ve olgularin kuru göz etyopatogenezine göre uygun sinitlandirilmasi belirlemektedir (Akova Kuru göz patogenezinde intlamasyonun öneminin farkedilmesi ile yeni tedavi yaklasimlari gündeme gelmistir. 19987de Stem ve arkadaslarinin ileri sürdügü gözyasi fonksiyonel ünitesi kuru göz patogenezindeki inflamasyon modelini destekler niteliktedir (Stem ve ark,, 1998), Hiperosmolar gözyasi inflamatuar medyatörlerin salinimi ve inflamatuar kaskadin aktive olmasi ile yüzey epitelini hasara ugratabilir ve goblet hücre kaybi ile müsin üretiminde azalmaya neden olabilir (Djalilian ve ark., 2005). Suni gözyasi preparatina ragmen konjonktivadaki hipereminin, korneadaki boyanmanin ve iritasyon sikayetlerinin devam ettigi olgular antiinflamatuar tedavi için adaydirlar. Formula 1: In addition, the invention includes Cyclosporine and/or its pharmaceutically acceptable derivatives. formulations of pharmaceutical compositions suitable for ophthalmic administration and It also includes prophylactic and/or symptomatic and/or therapeutic uses. PRIOR ART (KNOWN STATE OF THE ART) Dry eye syndrome can result in visual impairment with ocular surface damage. Tear is a multifactorial disease of the lens and ocular surface. Increased tears for this painting osmolarity and ocular surface inflammation. Dry eye disease form requires a different treatment protocol and making the correct diagnosis is therefore very important. is important. In the treatment of the disease, revealing the factors that cause dry eye and It is important to prevent situations that increase symptoms. Treatment, medical, anti-inflammatory treatment, treatment with blood products, interventional treatments, surgical treatment and still under development. Revealing the factors that cause dry eye syndrome (KGS) dry eye It is very important in the treatment and is the first step. In dry eye patients, both the underlying Treatments for the causes, both the disease itself and the complications, are essential. form treatment methods. ” group, sand eye is actually “Discomfort with ocular surface damage. sensation, visual impairment, and unstable tear film causing multifactorial dysfunction of the ocular surface. Therefore, the etiology When we look at it, we actually see that many different mechanisms play a role and the treatment These mechanisms are taken into account when planning. continue for many years Despite the researches, the diagnosis and treatment of dry eye is still difficult. in diagnosis detailed assessment of symptoms and appropriate combinations of diagnostic tests. Approaching the patient is very important. The success of the treatment, the accuracy of the diagnosis and Appropriate stratification of the cases according to the etiopathogenesis of dry eye determines (Akova Recognizing the importance of inflammation in the pathogenesis of dry eye, new treatment approaches has come to the fore. In 1998, Stem et al. suggested that the tear is functional. unit supports the inflammation model in the pathogenesis of dry eye (Stem and et al, 1998), Hyperosmolar tear release of inflammatory mediators and inflammatory With the activation of the cascade, it can damage the surface epithelium and cause goblet cell loss. may cause a decrease in mucin production (Djalilian et al., 2005). artificial tear hyperemia of the conjunctiva, staining of the cornea and irritation Cases with ongoing complaints are candidates for anti-inflammatory therapy.
Siklosporinin en belirgin 2 etkisi T lenfosit aktivasyonunu baskilamak ve çesitli hücre tiplerinde apoptozisi önlemektir. Bu etkileri sitoplazmada bulunan siklofilin A ve D denilen iki sitoplazmik protein yardimi ile olusturmaktadir. Siklofilin A ile Cs A'nin birlesmesi ile T lenfosit aktivasyonu sirasinda özellikle IL-2 salinimi önlenmis olur ve hücresel bagisiklik cevabi baskilanir. Siklofilin D”nin Cs A ile birlesmesi sonucu hücrede apoptozis baskilanir. Cs A°nin konjonktiva epitelinde apoptozisi azalttigi farelerdeki kuru göz modelinde gösterilmistir (Strong ve ark., 2005). Yapilan çok merkezli 877 olguyu içeren bir Faz III çalismasinda %0,05 ve %0,l,lik Cs A kullanimi karsilastirilmis ve 6 aylik tedavi sonrasinda her iki doz grubunda belirgin olarak gözyasi fonksiyonlarinda ve subjektif sikayetlerde düzelme olmustur (Sall ve ark., 2000). Bir baska çalismada da aköz yetmezlik ile birlikte olan kuru göz olgularinda topikal Cs A uygulamasinin azalmis goblet hücre sayisinda ve bu hücrelerden salgilanan TGF°de artisa neden oldugu saptaninistir (Pflugfelder ve ark., 2008). Topikal siklosporin A kuru gözün yarattigi inflamasyonu baskilamanin yanisira meibomian bezlerinin salgi kanallarini tikayan tikayan meibum içindeki serbest yag asitlerinin polar lipidlere dönüstürülmesinden kaynaklanan inflamasyonu, bakteri kolonizasyonunun ürettigi bakteri lipazlarini da baskilamaktadir (Perry ve ark., 2006). The two most prominent effects of cyclosporine are suppressing T lymphocyte activation and inhibiting various cell types. types to prevent apoptosis. These effects are caused by cyclophilin A and D in the cytoplasm. It is formed with the help of two cytoplasmic proteins called of cyclophilin A and Cs A IL-2 release is prevented during T lymphocyte activation and the cellular immune response is suppressed. As a result of the combination of cyclophilin D with Cs A, apoptosis is suppressed. Dry mice in which Cs A decreased apoptosis in the conjunctival epithelium. shown in the eye model (Strong et al., 2005). Multicenter 877 cases were performed. The use of 0.05% and 0.1% Cs A was compared in a Phase III study involving 6 After one month of treatment, there was significant improvement in tear function and in both dose groups. subjective complaints improved (Sall et al., 2000). In another study, aqueous Decreased goblet effect of topical Cs A application in dry eye cases with regurgitation It has been determined that it causes an increase in the number of cells and TGF° secreted from these cells. (Pflugfelder et al., 2008). Topical cyclosporine A for inflammation of dry eye In addition to suppression, the meibum that blocks the secretory ducts of the meibomian glands resulting from the conversion of free fatty acids into polar lipids. It also suppresses inflammation and bacterial lipases produced by bacterial colonization. (Perry et al., 2006).
Siklosporinler, birçok farmakolojik özellige sahip polar olmayan, halkali oligopeptitlerin bir simfindandir. Bunlar özellikle, bagisiklik bastirici ( immünosüpresif) ve iltihap önleyici (antienflamatuvar) etkinlikleriyle taninir ve diger yandan, bagisiklik (immün) kökenli kuru keratokonjonktivit hastalarinda, gözyasi bezi tarafindan gözyasi salgilanmasini arttirmalari ya da eski durumuna getirmeleri bakimindan etkilidirler. Cyclosporins are non-polar, cyclic oligopeptides with many pharmacological properties. is a simfindan. These are particularly immunosuppressive (immunosuppressive) and anti-inflammatory known for its (anti-inflammatory) activities and, on the other hand, increase tear secretion by the lacrimal gland in patients with keratoconjunctivitis or they are effective in reinstatement.
W0890l772 nolu patent belgesinde siklosporin ve bir dolgu maddesi içeren, gözyasi bezlerindeki bir bozukluk nedeniyle gözyasi eksikliginden sikayetçi hastalarda gözyasi üretimini arttirmaya yönelik, haricen kullanilan bir göz bilesiminden bahsedilmektedir. Özellikle sözü edilen dolgu maddeleri zeytin yagi, yerfistigi yagi, hintyagi, polioksietilenlenmis hint yagi, mineral yaglar, vazelinler, dimetilsülfoksit, bir alkol, lipozomlar, silisyum yaglari yada bunlarin karisimlaridir. In the patent document W0890l772, teardrops containing cyclosporine and a filler Tears in patients who complain of a lack of tears due to a disorder in their glands An externally used eye compound is mentioned to increase its production. Particularly mentioned fillers are olive oil, peanut oil, castor oil, polyoxyethyleneated castor oil, mineral oils, petrolatum, dimethylsulfoxide, an alcohol, liposomes are silicon oils or their mixtures.
BULUSUN AÇIKLAMASI Mevcut bulus, keratokonjunktivitis sikka ile iliskili oküler enflamasyona bagli olarak gözyasi yapiminin baskilandigi öngörülen hastalarda gözyasi yapiminin artirilmasinda profilaktik ve/veya semptomatik ve/veya terapötik tedavisinde kullanilmak üzere siklik bir polipeptit olan immünosüpresit` özellikteki uygun etken maddeyi ve/veya farmasötik olarak kabul edilebilir türevlerini içeren farinasötik bilesim/ler ile ilgilidir. DESCRIPTION OF THE INVENTION The present invention is related to ocular inflammation associated with keratoconjunctivitis sicca. in increasing tear production in patients who are predicted to have suppressed tear production. cyclic therapy for use in the prophylactic and/or symptomatic and/or therapeutic treatment the appropriate active substance with immunosuppressive properties, which is a polypeptide, and/or pharmaceutically relates to pharmaceutical composition(s) containing acceptable derivatives.
Mevcut bulusun bir diger yönü; oftalmik kullanilmak üzere siklik bir polipeptit olan immünosüpresif özellikteki uygun etken maddeyi ve/veya farmasötik olarak kabul edilebilir türevlerini ve farmasötik olarak kabul edilebilir yardimci maddeleri içeren farmasötik bilesim/ ler ile ilgilidir. Another aspect of the present invention is; a cyclic polypeptide for ophthalmic use Accept the appropriate active substance with immunosuppressive properties and/or pharmaceutical containing derivatives and pharmaceutically acceptable excipients. relates to pharmaceutical composition/s.
Bulusta siklik bir polipeptit olan immünosüpresif özellikteki uygun etken madde bunlarla sinirli olmamakla birlikte, Takrolimus, Siklosporin, Piinekroliinus, Abetimus, Gusperimus ve/veya fannasötik olarak kabul edilebilir türevlerinin arasindan tercihen Siklosporin olarak seçilir. In the invention, the appropriate active substance with immunosuppressive properties, which is a cyclic polypeptide, but not limited to Tacrolimus, Cyclosporine, Piinecroliinus, Abetimus, Gusperimus and/or pharmaceutically acceptable derivatives, preferably Cyclosporine is selected as.
Bulusta “farmasötik olarak kabul edilebilir türevleri” terimi ile farmasötik olarak kabul edilebilir uygun tuzlar, esterler, solvatlar, hidratlar, kompleksler, polimorflar, enantiyomerler, önilaçlar, asit adisyon tuzlari, analoglar, izomerler, rasematlar, amidler, enantiyomer tuzlari, bazik tuzlar, konjugeler, tautomerler, anhidratlar, anhidritler, bazlar, asitler, eterler, kristal ve amorf formlar veya serbest formlarindan bir veya daha fazlasi ifade edilmektedir. In the invention, the term "pharmaceutically acceptable derivatives" is defined as pharmaceutically acceptable. Suitable salts, esters, solvates, hydrates, complexes, polymorphs, enantiomers, prodrugs, acid addition salts, analogs, isomers, racemates, amides, enantiomer salts, basic salts, conjugates, tautomers, anhydrates, anhydrides, bases, one or more of acids, ethers, crystalline and amorphous forms or free forms is expressed.
Oftalmik uygulama için hazirlanan farmasötik bilesim/ler damla (solüsyon, süspansiyon), krem, jel, merhem, losyon, liniment (sivi merhem), solüsyon, süspansiyon, emülsiyon (su/yag, yag/su) ve sivi çözelti gibi dozaj forinlarinda olabilir. Pharmaceutical composition(s) prepared for ophthalmic administration, drops (solution, suspension), cream, gel, ointment, lotion, liniment (liquid ointment), solution, suspension, emulsion (water/oil, oil/water) and can be in dosage forms such as liquid solution.
Bulusta oftalmik uygulama için hazirlanan farmasötik bilesim/ler tercihen farmasötik emülsiyon formundadir. Oftalmik emülsiyon tek kullanimlik flakon/lar halinde ve/Veya çoklu kullanima uygun olacak sekilde hazirlanir. The pharmaceutical composition(s) prepared for ophthalmic administration in the invention is preferably pharmaceutical in emulsion form. Ophthalmic emulsion in single-use vials/s and/or It is prepared to be suitable for multiple uses.
Göz damlalari bir veya daha fazla etkin madde içeren, lokal uygulanarak kullanilan, steril sulu çözelti, yagli çözelti ve süspansiyon yapisindaki preparatlardir. Preparatin stabilite problemi varsa etkin ve yardimci madde karisimi steril toz halinde ambalajlanir ve kullanimdan hemen önce uygun steril çözücü ile çözelti veya süspansiyon haline getirilerek uygulanir. Eye drops containing one or more active ingredients, used by local application, sterile They are preparations in the form of aqueous solution, oily solution and suspension. Stability of the preparation If there is a problem, the mixture of active and auxiliary substances is packaged as sterile powder and into solution or suspension with suitable sterile solvent just before use. brought and applied.
Göz damlalarinin formülasyonu sirasinda etkin madde/maddelerin yanisira, tonisite ayarlamak, viskozite ayarlamak, preparati en stabil oldugu pH'ya getirmek ve etkin maddenin çözünürlügünü artirmak amaciyla bazi yardimci maddelerden de yararlanilir. Çözücüsü su olan göz preparatlari çok dozluk kaplarda hazirlanacagi zaman uygun bir antimikrobiyal madde içermelidir. Eger antimikrobiyal inadde konulmasi uygun degilse preparat tek dozluk kaplarda hazirlanabilir. Örnegin; göz ameliyatlarinda kullanilan göz damlalari koruyucu içermez ve tek dozluk kaplarda hazirlanir. During the formulation of eye drops, besides the active substance(s), tonicity adjust the viscosity, bring the preparation to the pH where it is most stable and Some auxiliary substances are also used to increase the solubility of the substance. When eye preparations with water solvent are to be prepared in multi-dose containers, an appropriate should contain antimicrobial agents. If it is not appropriate to add an antimicrobial agent The preparation may be prepared in single-dose containers. For example; eye used in eye surgery The drops do not contain preservatives and are prepared in single-dose containers.
Ayrica bazi durumlarda göz damlalalari içinde bulunan koruyucu (prezervan) maddeler gözü irrite edebilir. Böyle durumlarda koruyucu maddelere karsi duyarliligi olan veya kontakt lens kullanan kisiler koruyucu madde içermeyen göz damlalari kullanabilirler. Çözücüsü su olan damlalarin steril olmasinin yanisira partiküllerinden arindirilmis ve berrak olmasi, süspansiyon halinde olan göz damlalarinin ise çalkalama ile tekrar hoinojen olarak dagilmasi (redisperse olmasi) ve her bir damlatma ile verilen doz homojenliginin dogru ve yeterli olmasi gerekmektedir. Çok dozlu kaplarda hazirlanan göz damlalarinin baska bir sekilde önerilmedikçe hacminin en fazla 10 ml olmasi gerekir. Göz preparatlari, özel bir ambalaj materyali içerrniyorsa, kullanilmak üzere açildiktan kisa bir süre sonra kontamine olur. Bu nedenle ambalajlari açildiktan sonraki maksimum kullanim zamanlari ambalajlarinda belirtilmelidir. In addition, in some cases, preservatives contained in eye drops. may irritate the eye. In such cases, those who are sensitive to preservatives or Contact lens wearers can use preservative-free eye drops. In addition to being sterile, the drops with water solvent are free of particles and clear, the suspension of eye drops is homogenous by shaking. dispersion (redispersion) and the homogeneity of the dose given with each drop. It must be accurate and sufficient. Eye drops prepared in multi-dose containers Its volume should not exceed 10 ml unless recommended otherwise. eye preparations, if it does not contain a special packaging material, shortly after opening for use. becomes contaminated. Therefore, the maximum usage times after unpacking should be stated on the packaging.
Bulusta kullanilan oftalmik uygulamaya yönelik oftalmik emülsiyon formülasyonu; uygun etken madde/ler yaninda en az bir çözünürlük arttirici, en az bir tonisite ajani, en az bir Viskozite arttirici ajan, en az bir pH ayarlayici ajan ve en az bir çözücünün de dahil oldugu gruptan seçilen bir veya daha fazla yardimci madde içerebilen bir bilesimi tanimlar. The ophthalmic emulsion formulation for ophthalmic administration used in the invention; appropriate In addition to the active ingredient/s, at least one solubilizer, at least one tonicity agent, at least one Viscosity increasing agent, at least one pH adjusting agent and at least one solvent defines a composition that may contain one or more excipients selected from the group.
Bulusta “çözünürlük arttirici ajan” ilacin sudaki çözünürlügünü ve göz içerisine ilacin absorbsiyonunu arttirir, aköz stabiliteyi iyilestirir, lokal irritasyonu azaltirlar. Bu nedenle bulusta çözünürlük arttirici ajan olarak; hidroksi propil betasiklodesktrin gibi siklo dekstrinler, polietoksillenmis hint yagi, yerfistigi yagi, mineral yaglar, vazelinler, dimetilsülfoksit, makrogol gliserol hidroksi stearat (kolliphor RH 40), hintyagi (Castor Oil), povidon, sorbitan trioleat, sorbitan monooleat, sorbitan monolaurat; polioksietilen (20) sorbitan monolaurat (polisorbat 20), polioksietileii (20) sorbitaii monopalmitat (polisorbat 40), polioksietilen (20) sorbitaii moiiostearat (polisorbat 60), polioksietilen (20) sorbitan monooleat (polisorbat 80) gibi polisorbatlar kullanilabilir. Bulusta tercihen inakrogol gliserol hidroksi stearat ve/veya hintyagi kullanilmaktadir. Bulusta kullanilan çözünürlük arttirici ajan miktari %0.01-15 agirlik/hacim oranindadir. In the invention, “solubility enhancing agent” means the solubility of the drug in water and the injection into the eye. They increase absorption, improve aqueous stability, reduce local irritation. Because as a solubilizing agent in the invention; cyclone, such as hydroxypropyl betacyclodesktrin dextrins, polyethoxylated castor oil, peanut oil, mineral oils, petroleum jelly, dimethylsulfoxide, macrogol glycerol hydroxy stearate (kolliphor RH 40), castor oil (Castor) Oil), povidone, sorbitan trioleate, sorbitan monooleate, sorbitan monolaurate; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethyleii (20) sorbitaii monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitaii moiiostearate (polysorbate 60), polyoxyethylene (20) Polysorbates such as sorbitan monooleate (polysorbate 80) can be used. preferably in the invention Inacrogol glycerol hydroxy stearate and/or castor oil are used. used in the invention The amount of solubility enhancing agent is 0.01-15% w/v.
Bulusta “tonisite ajani” terimi, standart referans madde ile ayni osmotik basinca sahip maddeleri ifade etmektedir. Tonisite ajani olarak; sodyum klorür, mannitol, sorbitol, gliserin (gliserol), borik asit, potasyum nitrat, glukoz ve/Veya bunlarin karisimlari kullanilabilir. Bulusta tercihen gliserin kullanilmaktadir. Bulusta kullanilan tonisite ajani miktari %0. l -20 agirlik/hacim oranindadir. In the invention, the term "tonicity agent" means having the same osmotic pressure as the standard reference substance. means items. As a tonicity agent; sodium chloride, mannitol, sorbitol, glycerin (glycerol), boric acid, potassium nitrate, glucose and/or mixtures thereof can be used. Glycerin is preferably used in the invention. Tonicity agent used in the invention amount of 0%. l -20 weight/volume ratio.
Bulusta “viskozite arttirici ajan” terimi, sivinin kalinligini arttirarak yavas akmasini saglayan bir ajan veya ajan karisimini belirtmektedir. Viskozite ajani olarak karbomer, ksantan gami, guar gam, akasya, povidon, aljinik asit, etilselüloz, jelatin, hidroksietil selüloz, hidroksipropil selüloz, polivinil pirolidon, hidroksipropil metilselüloz (HPMC), polidekstroz, karragenan, metil selüloz, sukroz, sorbitol, ksilitol, polivinil alkol, ketearil alkol, kolloidal silikon dioksit ve/veya bunlarin karisimlari kullanilabilir. Bulusta tercihen polivinil pirolidon kullanilmaktadir. Bulusta kullanilan viskozite arttirici ajan miktari Bulusta pH ayarlayici ajan olarak; sülfürik asit, sodyum hidroksit, hidroklorik asit, sodyum klorit, asetik asit, borik asit, anhidröz sodyum sülfît, sodyum sitrat, sodyum karbonat ve/veya bunlarin karisimlari kullanilabilir. Bulusta tercihen sodyum hidroksit ve/veya hidroklorik asit kullanilmaktadir. In the invention, the term "viscosity increasing agent" means that it increases the thickness of the liquid and causes it to flow slowly. denotes an agent or agent mixture that provides Carbomer as viscosity agent, xanthan gum, guar gum, acacia, povidone, alginic acid, ethylcellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methylcellulose (HPMC), polydextrose, carrageenan, methyl cellulose, sucrose, sorbitol, xylitol, polyvinyl alcohol, ketaryl alcohol, colloidal silicon dioxide and/or their mixtures can be used. preferably in the invention polyvinyl pyrrolidone is used. The amount of viscosity increasing agent used in the invention As a pH adjusting agent in the invention; sulfuric acid, sodium hydroxide, hydrochloric acid, sodium chloride, acetic acid, boric acid, anhydrous sodium sulfite, sodium citrate, sodium carbonate and/or mixtures thereof may be used. In the invention preferably sodium hydroxide and/or hydrochloric acid is used.
Bulusta çözücü olarak; saflastirilmis su, enjeksiyonluk su, fizyolojik serum, sterilize damitilmis su gibi uygun sulu çözeltiler ve/veya bunlarin karisimlari kullanilabilir. Bulusta tercihen enj eksiyonluk su kullanilmaktadir. As a solvent in the invention; purified water, water for injection, physiological saline, sterilized Suitable aqueous solutions such as distilled water and/or mixtures thereof may be used. in the find preferably injection water is used.
Bulusta, Siklosporin ve/veya farmasötik olarak kabul edilebilir türevlerinin kullanildigi fannasötik bilesimlerin oftalmik uygulamasina yönelik oftalmik emülsiyon formülasyonu asagidakileri içermektedir; - yaklasik %0.001-10 agirlik/hacim oraninda Siklosporin - yaklasik %0.0l-15 agirlik/hacim oraninda bir veya daha fazla çözünürlük arttirici ajan - yaklasik %0. 1-20 agirlik/hacim oraninda bir veya daha fazla tonisite ajani - yaklasik %0.001-10 agirlik/hacim oraninda bir veya daha fazla viskozite arttirici ajan - kafi miktar pH ayarlayici ajan - kafi miktar çözücü. In the invention, cyclosporine and/or pharmaceutically acceptable derivatives are used. ophthalmic emulsion formulation for ophthalmic administration of pharmaceutical compositions It includes the following; - Cyclosporine at a rate of approximately 0.001-10% w/v - one or more solubility enhancing agents at a weight/volume ratio of approximately 0.01-15% - about 0%. One or more tonicity agents in a weight/volume ratio of 1-20 - one or more viscosity-increasing agents of approximately 0.001-10% w/v - sufficient amount of pH adjusting agent - sufficient amount of solvent.
Bulus esas olarak oftalmik kullanilmak üzere siklik bir polipeptit olan immünosüpresif özellikteki Siklosporin ve/veya farmasötik olarak kabul edilebilir türevlerini ve farmasötik olarak kabul edilebilir uygun yardimci maddeleri içeren farmasötik bilesim/lerin hazirlanmasi ile ilgilidir. Bulusuri farmasötik bilesimlerinin oftalmik emülsiyon formunda olmasi temeldir. Bulusun bir diger özelligi hazirlanan farmasötik oftalmik emülsiyonun koruyucu içermemesidir. Böylece Siklosporin ve/Veya farmasötik olarak kabul edilebilir türevlerini ve farmasötik olarak kabul edilebilir uygun yardimci maddeleri içeren farmasötik dozaj form/lari tahris edici özelliklerinin düsük olmasi, çabuk etki etmesi, gözde kuruluk yapmamasi, kullanimlarinin daha kolay olmasi gibi üstünlüklere sahiptir ve bu farmasötik bilesimler fiziksel ve kimyasal kararlilik açisindan oldukça stabil bir davranis sergilemistir. The invention is primarily an immunosuppressive, a cyclic polypeptide for ophthalmic use. Cyclosporine and/or its pharmaceutically acceptable derivatives and pharmaceutical pharmaceutical composition(s) containing suitable excipients acceptable as relates to preparation. Bulusuri pharmaceutical compositions in ophthalmic emulsion form it is fundamental. Another feature of the invention is that the prepared pharmaceutical ophthalmic emulsion does not contain preservatives. Thus Cyclosporine and/or pharmaceutically acceptable derivatives and suitable pharmaceutically acceptable excipients. pharmaceutical dosage form/s have low irritant properties, act quickly, It has advantages such as not being dry in the eyes, being easier to use, and These pharmaceutical compositions are highly stable in terms of physical and chemical stability. behaved.
Asagidaki örnekler bulusu açiklamaktadir, fakat hiçbir suretle kisitlamamaktadirlar. The following examples illustrate the invention, but in no way limit it.
Siklosporin ve/veya farmasötik olarak kabul edilebilir türevlerinin kullanildigi farmasötik bilesimlerin oftalmik uygulamasina yönelik oftalmik emülsiyon formülasyonu asagidakileri içermektedir; - yaklasik %0.001-10 agirlik/hacim oraninda Siklosporin - yaklasik %0.0l-15 agirlik/hacim oraninda makrogol gliserol hidroksi stearat ve/veya hintyagi - yaklasik %0. 1-20 agirlik/hacim oraninda gliserin - yaklasik %0.00l-10 agirlik/hacim oraninda polivinil pirolidon - kafi miktar sodyum hidroksit ve/veya hidroklorik asit - kafi miktar en jeksiyonluk su Siklosporin ve/veya farmasötik olarak kabul edilebilir türevlerinin kullanildigi farmasötik bilesimlerin oftalmik uygulamasina yönelik oftalmik emülsiyon formülasyonu asagidakileri içermektedir (mg/mL); - yaklasik 0.01-15mg Siklosporin - yaklasik 0.1-90mg makrogol gliserol hidroksi stearat ve/veya hintyagi - yaklasik l-100mg gliserin - yaklasik 0.1-50mg polivinil pirolidon - kafi miktar sodyum hidroksit ve/Veya hidroklorik asit - kafi miktar en jeksiyonluk su Üretim prosesi: Siklosporin, makrogol gliserol hidroksi stearat, hint yagi, polivinil pirolidon ve gliserin belirlenen miktarlarda tartilir. Makrogol gliserol hidroksi stearat ve hint yagi bir kazana alinir ve karistirilir. Karistirma devain ederken belirli bir sicakliga kadar isitilir. Üzerine Siklosporin ilave edilir, karistirilir ve oda sicakligina gelene kadar beklenir. Karisim otoklav yöntemi ile steril hale getirilir (Karisim 1). Enjeksiyonluk suyun belirli bir kismi ayri bir kazana alinir. Karistirma altinda polivinil pimlidon ilave edilir ve berrak bir sivi elde edilene kadar karistirilir. Üzerine gliserin ilave edilir ve karistirilir. Karisim 0t0klav yöntemi ile steril hale getirilir (Karisim II). Karisim I, Karisim II” ye karistirma altinda oldukça yavas bir sekilde ilave edilir. pH kontrolü yapilir (pH 5.5-6.5 arasinda olmalidir) (Karisim HI). Enjeksiyonluk su ilavesi ile final hacme tamamlama yapilir. pH kontrolü yapilir (pH 5.5-6.5 arasinda olmalidir). Bitmis ürün uygun siselere doldurulur. Pharmaceutical use of cyclosporine and/or its pharmaceutically acceptable derivatives ophthalmic emulsion formulation for ophthalmic administration of compounds It includes the following; - Cyclosporine at a rate of approximately 0.001-10% w/v - macrogol glycerol hydroxy stearate and/or approximately 0.01-15% w/v Indian Oil - about 0%. 1-20 weight/volume glycerin - polyvinyl pyrrolidone approx. 0.00l-10% w/v - sufficient sodium hydroxide and/or hydrochloric acid - sufficient amount of water for injection Pharmaceutical use of cyclosporine and/or its pharmaceutically acceptable derivatives ophthalmic emulsion formulation for ophthalmic administration of compounds Contains (mg/mL); - about 0.01-15mg of Cyclosporine - about 0.1-90mg macrogol glycerol hydroxy stearate and/or castor oil - about 1-100mg of glycerin - about 0.1-50mg polyvinyl pyrrolidone - sufficient sodium hydroxide and/or hydrochloric acid - sufficient amount of water for injection Production process: Cyclosporine, macrogol glycerol hydroxy stearate, castor oil, polyvinyl pyrrolidone and glycerine weighed in specified quantities. Macrogol glycerol hydroxy stearate and castor oil in a cauldron taken and mixed. It is heated to a certain temperature while stirring. Over Add cyclosporine, mix and wait until it reaches room temperature. Mixture It is sterilized by autoclave method (Mixture 1). A certain portion of water for injection taken into a separate boiler. Polyvinyl pimlidone is added under stirring and a clear liquid mixed until obtained. Add glycerin and mix. Mix 0t0clav It is sterilized by the method (Mix II). Mixture I under mixing to “Mixture II” It is added very slowly. pH control is done (pH should be between 5.5-6.5) (Karisim HI). The final volume is completed by adding water for injection. pH control (pH should be between 5.5-6.5). The finished product is filled into suitable bottles.
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