TR201820952A2 - GRANULOCYTE COLONY A COMBINATION WITH A STIMULATING FACTOR - Google Patents
GRANULOCYTE COLONY A COMBINATION WITH A STIMULATING FACTOR Download PDFInfo
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- TR201820952A2 TR201820952A2 TR2018/20952A TR201820952A TR201820952A2 TR 201820952 A2 TR201820952 A2 TR 201820952A2 TR 2018/20952 A TR2018/20952 A TR 2018/20952A TR 201820952 A TR201820952 A TR 201820952A TR 201820952 A2 TR201820952 A2 TR 201820952A2
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- 230000004936 stimulating effect Effects 0.000 title 1
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
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Abstract
Mevcut buluş; kanserli hastaların kemoterapiler ile kombinasyon halinde bir hedeflenen terapi ile tedavi edilmesi için granülosit-koloni uyarıcı faktör (G-CSF) ve bir biguanid bileşiği içeren bir farmasötik kombinasyon ile ilgilidir.The present invention; It relates to a pharmaceutical combination comprising granulocyte-colony stimulating factor (G-CSF) and a biguanide compound for treating cancer patients with a targeted therapy in combination with chemotherapies.
Description
TARIFNAME GRANÜLOSIT KOLONI UYARICI FAKTÖR IÇEREN BIR KOMBINASYON Bulusun Alani Mevcut bulus; kanserli hastalarin kemoterapiler ile kombinasyon halinde bir hedeflenen terapi ile tedavi edilmesi için granülosit-koloni uyarici faktör (G-CSF) ve bir biguanid bilesigi içeren bir farmasötik kombinasyon ile ilgilidir. DESCRIPTION A COMBINATION CONTAINING GRANULOCYTE COLON SIGNIFICANT FACTOR Field of Invention The present invention; A targeted treatment of cancer patients in combination with chemotherapies granulocyte-colony stimulating factor (G-CSF) and a biguanide compound for treatment with therapy relates to a pharmaceutical combination containing
Teknigin Bilinen Durumu Kanser, anormal hücre büyümesi gösteren ve vücudun diger bölgelerine siçrama veya yayilma potansiyeli olan bir grup hastaliktir. Bu anormal hücreler; kanser hücreleri, malign hücreler veya tümör hücreleri olarak adlandirilir. Tedavi protokolleri kanserin tipine ve evresine göre degiskenlik göstermektedir. Çogu tedavi protokolü, her hastanin hastaligina uyacak sekilde tasarlanmaktadir. Bununla birlikte, çogu tedavi sunlardan en az birini içermektedir ve hepsini içerebilir: cerrahi, kemoterapi ve radyasyon terapisi. State of the Art Cancer that shows abnormal cell growth and spreads to other parts of the body or It is a group of diseases with the potential to spread. These abnormal cells; cancer cells, malignant are called cells or tumor cells. Treatment protocols depend on the type of cancer and varies according to the stage. Most treatment protocols depend on each patient's disease. is designed to fit. However, most treatments have at least one and may include all: surgery, chemotherapy and radiation therapy.
Kemoterapi, vücutta hizla bölünen kanser hücrelerinin büyümesini yavaslatmak veya durdurmak için tasarlanmis antikanser ilaçlarin kullanilmasidir. Ancak diger tedaviler gibi, yan etkilere neden olur. En yaygin görülen advers etkilerden biri dolasimdaki nötrofil sayilarinda belirgin bir düsüsü (nötropeni) içeren miyelosüpresyondur. Miyelosüpresyon, hastanede kalis süresini arttirabilecek siddetli enfeksiyonlar gibi potansiyel olarak tehlikeli sonuçlarla iliskilidir. Ayrica, nihayetinde genel tedavi etkililigini azaltacak olsa da kemoterapinin geçici olarak kesilmesine veya dozunun azaltilmasina neden olabilir. Chemotherapy slows the growth of rapidly dividing cancer cells in the body or is the use of anticancer drugs designed to stop it. However, like other treatments, causes side effects. One of the most common adverse effects is circulating neutrophil is myelosuppression with a marked decrease in their number (neutropenia). myelosuppression, potentially dangerous, such as severe infections that can increase hospital stay associated with results. Also, although it will ultimately reduce the overall treatment efficacy may result in temporary cessation or dose reduction of chemotherapy.
Nötropeni ile mücadelede önemli bir gelisme, rekombinant granülosit koloni uyarici faktör (G- CSF) formlari kullanilarak rutin hemopoietik büyüme faktörü destegi kullanimidir. G-CSF uygulamasi, kemik iliginden elde edilmis hücrelerin (BMDC'Ier) mobilizasyonunu arttirarak kemoterapiden sonra nötrofilleri artirabilir, böylece nötropeninin hem siddetini hem de süresini azaltabilir. (Voloshin T., Gingis-Velitski S., Bril R., Benayoun L., Munster M., Milsom Granülosit koloni uyarici faktör (G-CSF), rekombinant DNA teknolojisi ile üretilen 175 amino asit proteinidir. G-CSF, insan granülosit koloni uyarici faktör geninin içine eklenmis Escherichia coli (E. coli.) bakterileri tarafindan üretilir. Protein, E. coli'de ekspresyon için gerekli bir N-terminal metiyonin eklenmesi disinda, insan DNA dizilimi analizinden öngörülen dogal dizilim ile özdes bir amino asit dizilimine sahiptir. G-CSF, E. coli'de üretildiginden, ürün glikosile degildir ve bu nedenle bir insan hücresinden izole edilen G-CSF'den farklidir. An important development in the fight against neutropenia is recombinant granulocyte colony stimulating factor (G- Routine use of hemopoietic growth factor supplementation using CSF) forms. G-CSF administration, by increasing the mobilization of bone marrow-derived cells (BMDCs). may increase neutrophils after chemotherapy, thereby increasing both the severity and can reduce the time. (Voloshin T., Gingis-Velitski S., Bril R., Benayoun L., Munster M., Milsom Granulocyte colony stimulating factor (G-CSF), 175 amino acids produced by recombinant DNA technology. acid protein. G-CSF inserted into the human granulocyte colony stimulating factor gene It is produced by the bacteria Escherichia coli (E. coli.). Protein for expression in E. coli predicted from human DNA sequencing analysis, except for a necessary N-terminal methionine addition. It has an amino acid sequence identical to the natural sequence. Since G-CSF is produced in E. coli, the product It is not glycosylated and therefore different from G-CSF isolated from a human cell.
G-CSF, flakonda veya önceden doldurulmus hazir enjektörlerde tedarik edilir. Ürün, tek kullanimlik flakonlarda ve önceden doldurulmus hazir enjektörlerde mevcuttur. Tek mcg G-CSF içermektedir. Tek kullanimlik önceden doldurulmus hazir enjektörler sirasiyla 0,5 ml veya 0, 8 mI'Iik bir dolum hacminde 300 mcg veya 480 mcg G-CSF içermektedir. G-CSF is supplied in vial or pre-filled pre-filled syringes. product, single Available in reusable vials and pre-filled pre-filled syringes. Only Contains mcg of G-CSF. Disposable pre-filled pre-filled syringes 0.5, respectively Contains 300 mcg or 480 mcg of G-CSF in a fill volume of 1 ml or 0.8 ml.
E. coli içinde sentezlenen rekombinant insan G-CSF ekspresyon sistemine filgrastim adi verilir. Filgrastimin yapisi dogal glikoproteinden biraz farklidir. Yayinlanan çalismalarin çogunda filgrastim kullanilmistir ve filgrastim, pazarlama için onaylanan ilk G-CSF formdur. patent dokümaninda açiklanmistir. Rekombinant G-CSF'ye dayanan ilk ticari olarak temin edilebilen G-CSF preparasyonu, 1991 yilinda Almanya'da kabul edilmis ve Neupogen® ticari ismi altinda Amgen tarafindan üretilmekte ve dagitilmaktadir. Ürün formülasyonu, intravenöz ve subkutan uygulamaya uygun bir formda filgrastim, asetat, sorbitol, polisorbat 80, sodyum ve su içermektedir. granülosit koloni uyarici faktörün (G-CSF) izole edilmesi ve saflastirilmasi prosesi açiklanmaktadir. The expression system of recombinant human G-CSF expressed in E. coli is called filgrastim. is given. The structure of filgrastim is slightly different from the natural glycoprotein. Your published work most have used filgrastim, and filgrastim was the first form of G-CSF approved for marketing. explained in the patent document. First commercially available based on recombinant G-CSF The G-CSF preparation, which can be produced in Germany, was accepted in 1991 and Neupogen® is commercially available. It is produced and distributed by Amgen under the name Product formulation, intravenous and filgrastim, acetate, sorbitol, polysorbate 80, sodium in a form suitable for subcutaneous administration and contains water. The process of isolating and purifying granulocyte colony stimulating factor (G-CSF) is explained.
Bu zamana kadar kanser için bilinen tamamen iyilestirici bir kür bulunmamaktadir. Mevcut tedaviler, tipik olarak kemoterapi semptomlarini kisitlayarak, kemoterapi sonrasi hastanin iyilesmesini hizlandirmaya odaklanmaktadir. Tek basina G-CSF yeterli tedavi saglamaz. To date, there is no known fully curative cure for cancer. Available treatments, typically by limiting chemotherapy symptoms, focuses on accelerating recovery. G-CSF alone does not provide adequate treatment.
Mevcut bulusta strateji, adjuvan kanser tedavisinin su anki durumunun kombinasyon tedavisi ile iyilestirilmesidir. In the present invention, the strategy is combination therapy of the current state of adjuvant cancer therapy. with improvement.
Ancak laboratuvar modelleri, biguanidlerin hem kanser tedavisi hem de kemoprevensiyondaki aktivitesi için bagimsiz etkileyici kanitlarlar sunmaktadir. (Michael Mevcut bulusta, kemoprevensiyon ve kanser tedavisinin suanki durumunu iyilestirmeye yönelik strateji, tedavilerin kombine edilmesidir. Ek olarak, önceki teknikte, G-CSF ile biguanid kombinasyonu bulunmamaktadir. However, laboratory models suggest that biguanides can be used as both cancer treatment and provides compelling independent evidence for its activity in chemoprevention. (Michael The present invention seeks to improve the current status of chemoprevention and cancer therapy. The strategy for treatment is to combine treatments. Additionally, in the prior art, with G-CSF There is no biguanide combination.
Biguanid terimi, karacigerde glukoz üretimini önleyerek, vücudun insüline karsi duyarliligini artirip, bagirsaklardan emilen seker miktarini azaltarak etki gösteren bir oral tip 2 diyabet ilaçlari grubuna atifta bulunmaktadir. Biguanid, formülü HN(C(NH)NH2)2 olan organik bilesiktir. Biguanid örnekleri, metformin, fenformin, buformindir. Çok sayida klinik öncesi, epidemiyolojik ve klinik çalismanin bulgulari, diger biguanid kullanicilari ile karsilastirildiginda metformin kullaniminin, kanser hücresi büyümesi ve çogalmasi inhibisyonu ile ve tüm kanser vakalarinda azalma ile iliskili oldugunu göstermistir. The term biguanide reduces the body's sensitivity to insulin by inhibiting the production of glucose in the liver. an oral type 2 diabetes mellitus that acts by increasing the amount of sugar absorbed from the intestines It refers to the group of drugs. Biguanide, organic with the formula HN(C(NH)NH2)2 is compound. Examples of biguanides are metformin, phenformin, buformin. Findings from numerous preclinical, epidemiological, and clinical studies, other biguanide Compared with users of metformin, cancer cell growth and showed that it was associated with inhibition of proliferation and a reduction in all cancer cases.
Son on yilda, metforminin çesitli kanserler üzerindeki önleyici ve terapötik etkileri ile ilgili sayisiz epidemiyolojik çalisma yayinlanmistir. In the last decade, there has been a lot of interest in the preventive and therapeutic effects of metformin on various cancers. Numerous epidemiological studies have been published.
Metformin, oral yoldan uygulanan bir biguanid yapisina sahip bir antidiyabetiktir. Metformin hidroklorür beyaz ila beyazimsi kristalin bir bilesiktir ve suda kolaylikla çözünür ve aseton, eter ve kloroformda hemen hemen çözünmez. Metforminin oral dozlarinin genellikle günde degisebilir. Metformin is an orally administered antidiabetic with a biguanide structure. metformin hydrochloride is a white to off-white crystalline compound and readily soluble in water and acetone, It is practically insoluble in ether and chloroform. Oral doses of metformin are usually it can change.
Metformin hidroklorürün IUPAC (Uluslararasi Saf ve Uygulamali Kimya Birligi) adi, 1,1- dimetilbiguanid hidroklorürdür ve kimyasal yapisi asagida Formül I”de gösterilmektedir. IUPAC (International Union of Pure and Applied Chemistry) name of metformin hydrochloride, 1,1- dimethylbiguanide hydrochloride and its chemical structure is shown in Formula I below.
HSC\TJLHJJ\NH2 Formül I Metformin, p53 gen eksikligi olan bir kanser hastasina uygulandiginda, metformin tedavisinin, kanser hücrelerinin enerji metabolik yolunda degisikliklere yol açtigi ve antikanser aktivitesinin metformin dozu ile orantili olarak arttigi, böylece metforminin, diabetes mellitus tedavisi için olan normal dozda kanser tedavisi için etkili oldugu bulunmustur. HSC\TJLHJJ\NH2 Formula I When metformin is administered to a cancer patient with a p53 gene deficiency, metformin treatment leads to changes in the energy metabolic pathway of cancer cells and anticancer activity increased proportionally with the dose of metformin, thus metformin, It is effective for the treatment of cancer at the usual dose for the treatment of diabetes mellitus. has been found.
Bu bulusta, bir dozaj formunda birden fazla molekülün birlestirilmesi hasta uyumunu arttirmaktadir. Bununla birlikte, bu kombinasyon hastalarin yasam kalitesini arttirirken, bir dozaj formunda birden fazla molekülün kombine edilmesi, nötropeni gibi kemoterapi semptomlarini azaltmaktadir. In this invention, combining more than one molecule in a dosage form improves patient compliance. is increasing. However, while this combination improves patients' quality of life, combining more than one molecule in dosage form, chemotherapy such as neutropenia reduces symptoms.
Bulusun Ayrintili Açiklamasi Mevcut bulusun esas amaci, granülosit-koloni uyarici faktörü (G-CSF) ile biguanid bilesigi kombine edilerek, kemoterapi semptomlarinin ortadan kaldirilmasi, hizli ve etkili tedavi sunulmasi ve ilgili önceki teknige ek avantajlar getirilmesidir. Detailed Description of the Invention The main aim of the present invention is to combine granulocyte-colony stimulating factor (G-CSF) with biguanide. combination, elimination of chemotherapy symptoms, rapid and effective treatment and to bring additional advantages over the relevant prior art.
Mevcut bulusun bir baska amaci, toksisitelerin azaltilmasi, daha iyi çözünürlük ve stabilite sunulmasi ve terapötik ajanlarin bölgeye özgü olarak iletilmesidir. Another object of the present invention is the reduction of toxicities, better solubility and stability. delivery and site-specific delivery of therapeutic agents.
Mevcut bulusun bir diger amaci, kanser tedavisinde kullanilmak üzere sinerjik etkiye sahip, stabil bir kombinasyon formülasyonu elde etmektedir. Another object of the present invention is to have a synergistic effect for use in cancer treatment, obtains a stable combination formulation.
Spesifikasyon boyunca kullanildigi sekliyle “biguanid” terimi, metformin, fenformin veya buformine atifta bulunmaktadir. The term "biguanide" as used throughout the specification includes metformin, phenformin, or It refers to buformin.
Spesifikasyon boyunca kullanildigi sekliyle "metformin" terimi, yalnizca metformini degil, ayni zamanda metforminin diger farmasötik olarak kabul edilebilir tuzunu, farmasötik olarak kabul edilebilir solvatlarini, farmasötik olarak kabul edilebilir hidratlarini, farmasötik olarak kabul edilebilir enantiyomerlerini, farmasötik olarak kabul edilebilir türevlerini, farmasötik olarak kabul edilebilir polimorflarini veya farmasötik olarak kabul edilebilir prodrug”larini da kapsamaktadir. The term "metformin" as used throughout the specification refers to the same Also, other pharmaceutically acceptable salt of metformin pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable acceptable polymorphs or pharmaceutically acceptable prodrugs. covers.
Burada kullanildigi sekliyle kombinasyon, ajanlarin ayni veya farkli dozaj formlarinda eszamanli olarak uygulanmasini veya ajanlarin ayri olarak uygulanmasini (örnegin sirali uygulama) içermektedir. Örnegin, ajanlar, ayri uygulama için formüle edilebilir ve eszamanli veya sirali olarak uygulanabilir. Bu tür eszamanli veya sirali uygulamalarda ajanlarin tercihen tedavi edilen hastalarda ayni anda mevcut olmalari amaçlanir. Combination, as used herein, is the combination of agents in the same or different dosage forms. simultaneous administration or separate administration of agents (e.g. sequential application) included. For example, agents may be formulated for separate administration and may be used simultaneously. or sequentially. In such simultaneous or sequential applications, agents are preferably They are intended to be present at the same time in treated patients.
Mevcut bulusun bir uygulamasina göre, bir farmasötik kombinasyon granülosit-koloni uyarici faktör (G-CSF) ve bir biguanid bilesigi içermektedir. According to one embodiment of the present invention, a pharmaceutical combination granulocyte-colony stimulant factor (G-CSF) and a biguanide compound.
Mevcut bulusun bir uygulamasina göre, biguanid bilesigi; metformin veya fenformin veya buformindir. Tercihen, biguanid bilesigi; metformin veya metforminin farmasötik olarak kabul edilebilir bir tuzu, solvati veya polimorfudur. According to one embodiment of the present invention, the biguanide compound; metformin or phenformin or is buformin. Preferably, the biguanide compound; metformin or metformin pharmaceutically acceptable a salt, solvate or polymorph thereof.
Metformin ve G-CSF'nin kombine kullanimi, sinerjik bir etki yaratabilir. Kombinasyon, kemoterapi ile eszamanli veya sirali olarak birlikte uygulanir. The combined use of metformin and G-CSF may produce a synergistic effect. Combination, It is administered simultaneously or sequentially with chemotherapy.
Ayrica, mevcut bulusa göre hem metformin hem de G-CSF içeren kombinasyon, mükemmel farmakolojik etkilere sahiptir ve hastalarda medikasyon komforu saglayabilmektedir. Moreover, according to the present invention, the combination containing both metformin and G-CSF is an excellent It has pharmacological effects and can provide medication comfort in patients.
Bu kombinasyon, kemoterapiden sonra nötropeni ile iliskili riskleri azaltmaya yardimci olur, böylece kombinasyon, kanser tedavisi için destekleyici tedavi saglamis olur. This combination helps reduce the risks associated with neutropenia after chemotherapy. thus the combination provides supportive therapy for cancer treatment.
Mevcut bulusun bir uygulamasina göre, kanser; bas ve boyun kanserleri, özofagus kanseri, mide kanseri, kolorektal kanser, kolon kanseri, rektum kanseri, karaciger kanseri, safra kesesi kanseri, kolanjiokarsinom, safra yolu kanseri, pankreas kanseri, akciger kanseri, meme kanseri, yumurtalik kanseri, serviks kanseri, endometrium kanseri, vajina kanseri, vulva kanseri, böbrek kanseri, ürotelyal kanser, prostat kanseri, testis tümörü, osteosarkom, yumusak doku sarkomu, lösemi, miyelodisplastik sendrom, malign Ienfoma, yetiskin T hücreli lösemi, multipl miyelom, cilt kanseri, beyin tümörü, plevral mezotelyoma ve primeri bilinmeyen kanseri içeren gruptan seçilmektedir. According to one embodiment of the present invention, cancer; head and neck cancers, esophageal cancer, stomach cancer, colorectal cancer, colon cancer, rectum cancer, liver cancer, bile bladder cancer, cholangiocarcinoma, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, kidney cancer, urothelial cancer, prostate cancer, testicular tumor, osteosarcoma, soft tissue sarcoma, leukemia, myelodysplastic syndrome, malignant Ienfoma, adult T-cell leukemia, multiple myeloma, skin cancer, brain tumor, pleural mesothelioma and primary selected from the group containing unknown cancer.
Mevcut bulusun bir uygulamasina göre, biguanid bilesigi; metformin hidroklorür veya metformin bütirat veya metformin glisinat veya metformin pamoattir. According to one embodiment of the present invention, the biguanide compound; metformin hydrochloride or metformin butyrate or metformin glycinate or metformin pamoate.
Mevcut bulusun bir uygulamasina göre, metforminin G-CSF'ye agirlik orani 0.1 - 8.0, tercihen 0.3 - 2.0 arasindadir. According to one embodiment of the present invention, the weight ratio of metformin to G-CSF is 0.1 - 8.0, preferably It is between 0.3 - 2.0.
Mevcut bulusun bir uygulamasina göre, kanser tedavisi ihtiyaci olan bir kiside kanseri tedavi etmeye yönelik bir farmasötik kombinasyon, metformin ve G-CSF içermekte olup, burada; metformin ve G-CSF, etkili miktarda uygulanmaktadir. According to one embodiment of the present invention, the treatment of cancer in a person in need of cancer treatment. A pharmaceutical combination for treatment includes metformin and G-CSF, wherein; metformin and G-CSF are administered in effective amounts.
Mevcut bulusun bu uygulamasina göre farmasötik kombinasyon, 0.2 mg/ml ila 1.0 mg/ml, tercihen 0.6 mg/ml ila 0.96 mg/ml G-CSF içermektedir. The pharmaceutical combination according to this embodiment of the present invention is 0.2 mg/ml to 1.0 mg/ml, preferably 0.6 mg/ml to 0.96 mg/ml G-CSF.
Mevcut bulusun bu uygulamasina göre farmasötik kombinasyon, 0.1 mg/ml ila 1.5 mg/ml, tercihen 0.3 mg/ml ila 1.2 mg/ml metformin içermektedir. The pharmaceutical combination according to this embodiment of the present invention is 0.1 mg/ml to 1.5 mg/ml, preferably 0.3 mg/ml to 1.2 mg/ml metformin.
Mevcut bulusun bir uygulamasina göre, farmasötik kombinasyon, ayrica, tampon maddeleri, stabilizatörler, seyrelticiler, selatlama ajanlari, nanotasiyicilar, koruyucular, çözündürücüler veya bunlarin karisimlarini içeren gruptan seçilen farmasötik olarak kabul edilebilir eksipiyanlar içermektedir. According to one embodiment of the present invention, the pharmaceutical combination also includes buffers, stabilizers, diluents, chelating agents, nanocarriers, preservatives, solubilizers or pharmaceutically acceptable selected from the group consisting of mixtures thereof Contains excipients.
Uygun tampon maddeleri, alkali metal sitrat, sitrik asit, sodyum sitrat, tartarik asit, fumarik asit, sorbik asit, süksinik asit, adipik asit, askorbik asit, glutarik asit, potasyum hidrojen tartrat, sodyum hidrojen tartrat, potasyum hidrojen ftalat, sodyum hidrojen ftalat, potasyum dihidrojen fosfat, sodyum dihidrojen fosfat, disodyum hidrojen fosfat, hidroklorik asit, sodyum hidroksit veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable buffers are alkali metal citrate, citric acid, sodium citrate, tartaric acid, fumaric acid, sorbic acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid, sodium hydroxide or mixtures thereof.
Uygun stabilizatörler; sitrik asit, fumarik asit, tartarik asit, sodyum sitrat, sodyum klorür, sodyum benzoat, sodyum dihidrojen fosfat, kalsiyum karbonat, magnezyum karbonat, polisorbatlar 20 ve 80, arginin, Iisin, meglamin, askorbik asit, gallik asit esterleri veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable stabilizers; citric acid, fumaric acid, tartaric acid, sodium citrate, sodium chloride, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, polysorbates 20 and 80, arginine, Iisin, meglamine, ascorbic acid, gallic acid esters or their selected from the group containing the mixtures.
Uygun seyrelticiler, mikrokristalin selüloz, manitol, spreyle kurutulmus manitol, Iaktoz, Iaktoz monohidrat, nisasta, dekstroz, sukroz, fruktoz, maltoz, sorbitol, ksilitol, inositol, kaolin, inorganik tuzlar, kalsiyum tuzlari, polisakkaritler, dikalsiyum fosfat, sodyum klorür, dekstratlar, bikarbonat, kalsiyum karbonat veya bunlarin karisimlarini Içeren gruptan seçilmektedir. Suitable diluents are microcrystalline cellulose, mannitol, spray-dried mannitol, Iactose, Ilactose. monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, bicarbonate, calcium carbonate or mixtures thereof.
Uygun selatlama ajanlari; etilendiamin tetraasetik asit (EDTA) veya etilendiamin-N, N'- disüksinik asit (EDDS) veya bunlarin karisimlarini içeren gruptan seçilmektedir. Saklama stabilitesini arttirmak için uygulama için güvenli seviyelerde eklenebilir. Suitable chelating agents; ethylenediamine tetraacetic acid (EDTA) or ethylenediamine-N, N'- disuccinic acid (EDDS) or mixtures thereof. Storage can be added at levels safe for application to increase stability.
Nano tasiyicilar, mikron alti partikül boyutu tipik olarak <500 nm olan kolloidal ilaç tasiyici sistemleridir. Yüksek yüzey alani/hacim oranlari sayesinde ano tasiyicilar, ilaçlarin temel özelliklerini ve biyoaktivitesini degistirme kabiliyetine sahiptir. Daha iyi farmakokinetik ve biyodagilim, daha az toksisite, gelismis çözünürlük ve stabilite, terapötik ajanlarin kontrollü salinimi ve bölgeye özgü iletime, nano tasiyicilarin ilaç dagitim sistemlerine katabilecegi özelliklerden bazilaridir. Nanocarriers are colloidal drug carriers with a submicron particle size typically <500 nm. systems. Thanks to their high surface area/volume ratio, ano carriers are the mainstay of drugs. It has the ability to change its properties and bioactivity. better pharmacokinetics and biodistribution, less toxicity, improved solubility and stability, controlled use of therapeutic agents release and site-specific delivery, that nanocarriers can add to drug delivery systems. are some of the features.
Uygun nanotasiyicilar; altin nanopartiküller, polilaktik asit, poli (siyano) akrilatlar, polietilenimin, blok kopolimerler, polikaprolakton veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable nanocarriers; gold nanoparticles, polylactic acid, poly (cyano) acrylates, from the group consisting of polyethyleneimine, block copolymers, polycaprolactone or mixtures thereof is selected.
Uygun koruyucular; alkol, kuaterner amonyum bilesikleri, benzetanyum klorür, benzoksonyum klorür, benzododesiyum bromür, alkiltrimetilamonyum bromür, setrimonyum bromür, benzalkonyum klorür, feniletil alkol, benzoik asit ve esterleri ve bunlarin tuzlari, metil 4-hidroksibenzoat, sodyum metil 4-hidroksibenzoat veya propil 4-hidr0ksibenzoat, butillenmis hidroksil tolüen, butillenmis hidroksisilol, setilpiridinyum klorür, setirimid, propilparaben veya metilparaben, alkil asitler, potasyum sorbat, sorbik asit, kalsiyum sorbat, sodyum sorbat, klorheksidin diglükonat, klorheksidin asetat, klorheksidin klorür, 2-fenoik asit, klorit asit klorür, fenoller, 4-klorosresol, 4-kloroksilenol, diklorofen, heksaklorofen veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable preservatives; alcohol, quaternary ammonium compounds, benzetanium chloride, benzoxonium chloride, benzododesium bromide, alkyltrimethylammonium bromide, cetrimonium bromide, benzalkonium chloride, phenylethyl alcohol, benzoic acid and their esters and their salts, methyl 4-hydroxybenzoate, sodium methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate, butylated hydroxyl toluene, butylated hydroxysilol, cetylpyridinium chloride, cetirimide, propylparaben or methylparaben, alkyl acids, potassium sorbate, sorbic acid, calcium sorbate, sodium sorbate, chlorhexidine digluconate, chlorhexidine acetate, chlorhexidine chloride, 2-phenoic acid, chloric acid chloride, phenols, 4-chlorocresol, 4-chloroxylenol, dichlorophene, hexachlorophene or mixtures thereof selected from the group containing
Uygun çözücüler; propanol, 1-bütanol, 2-bütanol, etil asetat, etil eter, heptan, pentan, 1- pentanol, 1-pr0panol, 2-propan0l, metilen klorit, aseton, etanol, diklorometan, n-heksan, dioksan veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable solvents; propanol, 1-butanol, 2-butanol, ethyl acetate, ethyl ether, heptane, pentane, 1- pentanol, 1-propanol, 2-propanol, methylene chloride, acetone, ethanol, dichloromethane, n-hexane, dioxane or mixtures thereof.
Yukarida tarif edilen eksipiyanlarin olasi tüm varyasyonlarindaki herhangi bir kombinasyonu, burada aksi belirtilmedikçe veya baglamla açikça çelismedikçe mevcut bulus kapsamindadir. Any combination of the excipients described above in all possible variations, is within the scope of the present invention, unless otherwise stated herein or unless it clearly conflicts with the context.
Farmasötik kombinasyon, intravenöz, subkutan, intradermal veya intramüsküler gibi parenteral olarak uygulanabilir. Bu nedenle mevcut bulus, sulu ve sulu olmayan izotonik steril enjeksiyon çözeltileri dahil olmak üzere parenteral uygulamaya uygun kabul edilebilir bir tasiyici içinde çözünmüs veya süspanse edilmis bir metformin ve G-CSF çözeltisi veya süspansiyonu içeren parenteral uygulamaya yönelik kompozisyonlar sunmaktadir. Pharmaceutical combination, such as intravenous, subcutaneous, intradermal or intramuscular can be administered parenterally. Therefore, the present invention is sterile, aqueous and non-aqueous, isotonic. acceptable for parenteral administration, including injection solutions. a solution of metformin and G-CSF dissolved or suspended in the carrier or provides compositions for parenteral administration containing a suspension.
Parenteral formülasyonlar genellikle bir tasiyici olarak su, fizyolojik salin, dengeli tuz çözeltileri, sulu dekstroz, gliserol veya benzeri gibi farmasötik olarak ve fizyolojik olarak kabul edilebilir sivilari içeren enjektabl sivilari içermektedir. Parenteral formulations are usually water, physiological saline, balanced salt as a carrier. solutions are pharmaceutically and physiologically acceptable, such as aqueous dextrose, glycerol or the like. Includes injectable liquids, including injectable liquids.
Nihai üründeki etkin maddelerin stabilitesi, formülasyonu yapan için büyük bir endise kaynagidir. Genel olarak, etkin maddeler sulu ortamlarda kati dozaj formlarindan daha az stabildir ve sivi sulu formülasyonlarin uygun sekilde stabilize edilmesi ve korunmasi önemlidir. Bu ürünlerde asit-baz reaksiyonlari, asit veya baz katalizi, oksidasyon ve indirgenme olusabilir. Bu türden reaksiyon, etkin madde-bilesen etkilesimlerinden, bilesen- bilesen etkilesimlerinden veya kap-ürün etkilesimlerinden kaynaklanabilir. PH'a duyarli bilesikler söz konusu oldugunda, bu gibi etkilesimler pH'yi degistirebilir ve çökelmeye neden olabilir. The stability of the active ingredients in the final product is a major concern for the formulator. is the source. In general, active ingredients are less common in aqueous media than in solid dosage forms. stable and suitable stabilization and protection of liquid aqueous formulations is important. In these products, acid-base reactions, acid or base catalysis, oxidation and downgrade may occur. This type of reaction is caused by active substance-component interactions, component-to-component interactions. may result from component interactions or container-product interactions. sensitive to pH In the case of compounds, such interactions can change the pH and cause precipitation. it could be.
Mevcut bulusun bir uygulamasina göre, kompozisyonun pH degeri tamponlanir ve 4.0 ila 6.0 araligindadir. According to one embodiment of the present invention, the pH of the composition is buffered and is 4.0 to 6.0. is in the range.
Mevcut bulusun bir uygulamasina göre farmasötik kombinasyon, kanser tedavisinde kullanilmak üzere tasarlanmistir. According to one embodiment of the present invention, the pharmaceutical combination is used in the treatment of cancer. It is designed to be used.
Mevcut bulusun bir uygulamasina göre, farmasötik kombinasyon, kanserli bir kisinin, kemoterapiler ile kombinasyon halinde uygulanan bir hedeflenen terapi ile tedavi edilmesi için kullanilmaktadir. According to one embodiment of the present invention, the pharmaceutical combination allows a person with cancer, be treated with a targeted therapy administered in combination with chemotherapies is used for.
Bir baska uygulamada, bulus, ayni birim dozaj formlarinda G-CSF ve bir biguanid olarak metformin içeren bir farmasötik kit ile ilgili olup, söz konusu formlar, etkili miktarlarda ayri ayri, sirali veya eszamanli uygulanmaya uygundur. Ambalaj ayni zamanda kullanma talimati da içermektedir. Kit, opsiyonel olarak polyester bobin ambalaj malzemesi ve nem tutucu da içerebilir. In another embodiment, the invention is used as G-CSF and a biguanide in the same unit dosage forms. relates to a pharmaceutical kit containing metformin, said forms separately in effective amounts. It is suitable for separate, sequential or simultaneous application. The packaging is also the instructions for use. also includes. The kit includes optional polyester bobbin packing material and a desiccant. may contain.
Claims (1)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2018/20952A TR201820952A2 (en) | 2018-12-28 | 2018-12-28 | GRANULOCYTE COLONY A COMBINATION WITH A STIMULATING FACTOR |
| PCT/TR2019/051223 WO2020139300A2 (en) | 2018-12-28 | 2019-12-26 | A combination comprising granulocyte colony stimulating factor |
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| Application Number | Priority Date | Filing Date | Title |
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| TR2018/20952A TR201820952A2 (en) | 2018-12-28 | 2018-12-28 | GRANULOCYTE COLONY A COMBINATION WITH A STIMULATING FACTOR |
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| GB0603252D0 (en) * | 2006-02-17 | 2006-03-29 | Axcess Ltd | Dissolution aids for oral peptide delivery |
| CN103917224A (en) * | 2011-07-19 | 2014-07-09 | Stc·Unm公司 | Intraperitoneally-administered nanocarriers that release their therapeutic load based on inflammatory environment of cancers |
| US20180064662A1 (en) * | 2015-03-05 | 2018-03-08 | The General Hospital Corporation | Novel compositions and uses of metformin agents |
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