TR201905678A2 - TREATMENT APPLICATIONS OF SOLID LIPID EMULSIONS CONTAINING NATURAL COMPONENTS OF CURCUMIN AND PIPER - Google Patents

TREATMENT APPLICATIONS OF SOLID LIPID EMULSIONS CONTAINING NATURAL COMPONENTS OF CURCUMIN AND PIPER Download PDF

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TR201905678A2
TR201905678A2 TR2019/05678A TR201905678A TR201905678A2 TR 201905678 A2 TR201905678 A2 TR 201905678A2 TR 2019/05678 A TR2019/05678 A TR 2019/05678A TR 201905678 A TR201905678 A TR 201905678A TR 201905678 A2 TR201905678 A2 TR 201905678A2
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curcumin
piperine
cancer
solid lipid
piper
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TR2019/05678A
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Nur Yilmaz Eli̇f
Bolat Zeynep
Demi̇r Bi̇lun
İşlek Zeynep
Şahi̇n Fi̇kretti̇n
Hi̇kmet Üçişik Mehmet
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Univ Istanbul Medipol
Univ Yeditepe
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Priority to PCT/TR2020/050322 priority patent/WO2020214125A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/12Ketones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51Nanocapsules; Nanoparticles
    • A61K9/5107Excipients; Inactive ingredients
    • A61K9/5123Organic compounds, e.g. fats, sugars

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  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Dispersion Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Mevcut buluş kurkumin ve piperin doğal bileşenlerini ihtiva eden katı lipid emülsiyon formülasyonlarına (emülsomlara) ve söz konusu emülsomların neoplastik hastalıkların tedavisinde kullanımına ilişkindir.The present invention relates to solid lipid emulsion formulations (emulsomes) containing natural components of curcumin and piperine and the use of said emulsomes in the treatment of neoplastic diseases.

Description

TARIFNAME KURKUMIN VE PIPERIN DOGAL BILESENLERINI IHTIVA EDEN KATI LIPIT EMULSIYONLARININ TEDAVI AMAÇLI UYGULAMALARI TEKNIK ALAN Mevcut bulus kurkumin ve piperin dogal bilesenlerini ihtiva eden kati lipid emülsiyon formülasyonlarina (emülsomlara) ve söz konusu emülsomlarin neoplastik hastaliklarin tedavisinde kullanimina iliskindir. TEKNIGIN BILINEN DURUMU Kurkuinin, zerdeçal bitkisinin; piperin ise karabiber bitkisinin anamaddesini olusturmaktadir. Bu dogal iki aktif bilesigin çesitli tedavi edici etkileri eski medeniyetlerden günümüze bilinmektedir. Modern tip uygulamalarinda ise özellikle son yillarda kullanimlari arastirilmakta ve belirli hastalik modellerine karsi (çesitli kanser türleri ve Alzheimer gibi) etkili olduklari gözlemlenmektedir. Bilhassa kurkumin (zerdeçal), anti-inflamatuvar, anti-kanserojen, anti-bakteriyal, anti- romatizmal ve rejeneratif özellikleri dolayisiyla büyük bir kullanim potansiyeli olusturmaktadir. Ancak kurkuminin suda yeterince çözünmemesi ve sudaki kararsizligi (hizla alt bilesenlerine ayrilmasi), terapötik uygulamalarda kullanimini engellemektedir. Vücut emilimi düsük olan kurkumin, yüksek dozlarda (örn. günde 8- mg) kullanilsa bile kandaki miktari terapötik etki gösterecek konsantrasyon degerlerinin çok altinda kalmaktadir. Bu durum, saglik sorununun bulundugu dokuya kurkumininin yeterli miktarda iletilememesi sonucunu dogurmaktadir. Yapilan çalismalarda karabiberin (piper nigrum) içerisinde bulunan piperin etken maddesinin zerdeçal ile birlikte kullaniminin, zerdeçalin çözünürlügünü ve biyoyararlanimini arttirmak suretiyle sinerjik bir etki olusturdugu görülmüstür. Buna göre kurkumin ile piperin maddelerinin birarada kullanimi daha yüksek biyoyararlanima sahip formülasyonlarin elde edilmesini saglamaktadir. Teknigin bilinen durumu dikkate alindiginda kurkuminden maksimum fayda saglamak için bu maddenin özellikte bagirsaklarda emilimini arttiran ve/veya direkt kana enjeksiyonunu saglayan çesitli nanotasiyici sistemlere ihtiyaç duyuldugu görülmektedir. Bu özelliklere sahip formülasyonlarin gelistirilmesi amaciyla yapilan çesitli çalismalarda sinerjik etki gösteren kurkumin ve piperin moleküllerinin lipozom, misel, kati lipid nanopartiküller, polimerler, dendrimerler gibi çesitli makromoleküler platformlar üzerinde tasinmasina yönelik çalismalar gerçeklestirilmistir. Ancak, su ana kadar yapilan bu tip formülasyonlarda temel olarak düsük ilaç yükleme kapasitesi, formülasyonun hazirlanmasina kullanilan organik çözücü ve sürfaktana bagli olarak istenmeyen toksisite ve yan etkiler görülmesi, düsük kararlilik orani, hücre içine alimda yetersizlik, hizli ilaç salinim problemi ve yüksek ekonomik maliyet gibi problemler görülmektedir. Bulus sahipleri teknigin bilinen durumunda var olan bu problemlerin, 'ozellikle sürfaktan kullanimindan kaynaklanan toksisite probleminin, üstesinden gelmeyi amaçlamakta ve var olan bu formülasyonlara alternatif bir kurkumin-piperin formülasyonu gelistirmeyi hedeflemektedir. BULUSUN KISA AÇIKLAMASI Bulus; bir fosfolipid katman ve piperin ve kurkuminin içerisinde dagildigi bir trigliserit kati çekirdekten olusan emulsomlara ve söz konusu emulsomlarin neoplastik hastaliklarin tedavisinde kullanimina iliskindir. BULUSUN DETAYLI AÇIKLAMASI Mevcut bulus, piperin ve kurkuinin içeren farmasötik formülasyonlara iliskin olup özelligi; - çekirdegi trigliserit türevlerinden olusan ve hem çekirdeginde hem de dis katmaninda kolesterol veya ester türevleri bulunan emulsom formunda olmasidir. Bulus sahipleri yaptiklari çalismalarda; yukarida verilen özelliklere sahip emulsomlar içerisinde formüle edilen kurkumin ve piperin formülasyonlarinin (i) yapisinda organik çözücü ve sürfaktan içermemesi sayesinde toksik etki göstermemesi; (ii) yapi içerisine yüksek miktarda kurkuinin ve piperin yüklenmesine olanak saglamasi; (iii) kendine özgü kati fazdaki yapisi sayesinde salinim süresini arttirarak kurkumin ve piperinin etki süresini uzatmasi; ve (iv) emulsomlarin dis yüzeyini olusturan fosfolipidlerin modifiye edilebilir yapilar olmasi sayesinde protein, polimer, çesitli hedefleyici ligandlar V.b. moleküllerin baglanmasiyla hedeflendirilmis veya salinim veya emilim özellikleri degistirilmis kurkumin ve piperin formülasyonlarinin hazirlanmasina olanak saglamasi avantajlarina sahip oldugunu bulmuslardir. Bulusun bir uygulamasinda bulusa uygun kurkumin ve piperin içeren emulsom formülasyonlarin çekirdegini olusturan triglisterit türevleri; 25 DC sicaklikta kati veya likit kristal formda olan yaglardan, trikaprin, trilaurin, trimiyristin, tripalmitin ve tristearin gibi dogal, çift sayili, dalsiz trigliseritlerden, mono doymamis yag asitlerinden, kismi hidrojene bitkisel yaglardan olusan bir grubun içerisinden seçilir. Bulusun tercih edilen bir uygulamasinda kurkumin ve piperin içeren einulsom formülasyonlarinin çekirdegini olusturan trigliserit türevi madde olarak tripalmitin, diger adiyla trigliserin palmitat, kullanilir. Bulusun bir uygulamasinda kurkumin ve piperin içeren emulsom formülasyonlarin dis yüzeyini olusturan fosfolipidler, soya lesitini, yumurta lesitini, fosfatidil gliserol, fosfatidil inostol, fosfatidil etaiiolamin, fosfatidik asit, sfingomiyelin, di fosfatidilgliserol, fosfatidil serin, fosfatidil kolin, kardiyolipin gibi dogal fosfolipidlerden veya dimiyristoyl fosfatidilgliserol, diiniyristoyl fosfatidilkolin, 1,2- dipalmitol-rak-glisero-3- fosfatidilkolin (DPPC) gibi sentetik fosfolipidlerden veya hidrojene veya kismi hidrojene lesitinler ve fosfolipidlerden olusan bir grubun içerisinden seçilebilir. Bulusun tercih edilen bir uygulamasinda fosfolipid olarak 1,2- dipalmitol-rak-glisero-3- fosfatidilkolin (DPPC) kullanilir. Bulusun bir uygulamasinda kurkumin ve piperin içeren emulsom formülasyonlarin çekirdeginde ve dis katmaninda bulunan kolesterol; kolesterol, palmitoyl kolesterol, oleoyl kolesterolden olusan bir grubun içerisinden seçilir. Bulusun bir uygulamasinda emulsom yapisini olusturan trigliserit, fosfolipid ve kolesterol türevlerinin birbirine agirlikça orani (trigliseritfosfolipid:kolesterol) 17: 1 :1 Buna göre bulusun tercih edilen bir uygulamasinda mevcut bulus kurkumin ve piperin içeren farmasötik formülasyonlarma yönelik olup özelligi; - çekirdegin trigliserin palmitattan - dis katmanin l,2-dipalmitol-rak-glisero-3- fosfatidilkolin (DPPC) olusmasi ve hem çekirdeginde hem de dis katmaninda kolesterol bulunan emulsom formunda olmasidir. Bulusun bir uygulamasinda emulsom yapisini olusturan trigliserin palmitat, 1,2- dipalmitol-rak-glisero-3- fosfatidilkolin (DPPC) ve kolesterolün birbirine agirlikça orani (trigliserin palmitatzDPPC:kolesterol) 17:1:1 ile 21:3:1 araliginda, tercihen Buna göre bulusun özellikle tercih edilen bir uygulamasinda mevcut bulus kurkumin ve piperin içeren farmasötik formülasyonlarina yönelik olup özelligi; - çekirdegin trigliserin palmitattan - dis katmanin olusmasi ve hein çekirdeginde hem de dis katmaninda kolesterol bulunan emulsoin formunda olmasi ve trigliserin palmitat:DPPC:kolesterol oraninin 1711:] ile 21:31] araliginda, tercihen 18:1.5z1 ile 20:2:1 araliginda olmasidir. Bulusun bir uygulamasi bulusa uygun kurkumin ve piperin içeren emulsomlarin hazirlanmasinda kullanilacak bir yönteme iliskin olup söz konusu yöntem; - triglisterit, fosfolipid ve kolesterol türevlerinin bir organik çözücü, tercihen kloroform içerisinde çözülmesi - kurkumin ve piperinin bir organik çözücü, tercihen kloroform içerisinde çözülmesi - Elde edilen çözeltilerin karistirilmasi ve düsük basinç altinda organik çözücünün uzaklastirilmasiyla film yapisinin elde edilmesi - Elde edilen film yapisinin suda çözülmesiyle kurkumin ve piperin içeren emulsom formülasyonlarinin elde edilmesi adimlarini içerir. Bulusun tercih edilen bir uygulamasinda elde edilen kurkumin ve piperin içeren emulsoin formülasyonu, formülasyonu olusturan emulsomlarin partikül büyüklügü dagiliminin homojen hale getirilmesi amaciyla sonikasyon banyosu, filtrasyon (ekstrüzyon) veya homojenizasyon islemine tabi tutulur. Bulusun tercih edilen bir uygulamasinda söz konusu yöntemde organik çözücü, tercihen kloroforrn oda sicakliginda, veya 40-60 UC arasinda bir sicaklikta uzaklastirilabilir. Bulus bir diger açidan, bulusa uygun kurkumiii ve piperin içeren emulsom formüasyonlarinin neoplastik hastaliklarin tedavisi için ilaç olarak kullanilmasina yöneliktir. Mevcut bulus kapsaminda kullanilan "neoplastik hastaliklar" ifadesi habis (malign) tümörlere veya kontrolsüz hücre büyümesi ile karakterize olan bir fizyolojik duruma, örnegin kanser hastaligina isaret eder. Bulus kapsaminda "neoplastik hastalik" ve karsinoma, lenfoma, blastoma sarkoma ve lösemiyi içermekte olup bunlarla sinirli degildir. Karsinoma, burada kullanildigi sekliyle, epitel hücrelerden olusan bir kanser türünü ifade etmektedir. Lenfoma, burada kullanildigi sekliyle, lenfositlerden gelisen bir kanser türünü anlatmaktadir. Blastoma, burada kullanildigi sekliyle, blast hücre adiyla da bilinen öncü hücrelerden gelisen bir kanser türünü anlatmaktadir. Sarkoma, burada kullanildigi sekliyle, mezenkimal kökenli degismis hücrelerden kaynaklanan kanser türünü anlatmaktadir. Lösemi, burada kullanildigi sekliyle, kemik iliginde baslayan ve yüksek sayida anormal akyuvar hücresi olusumuna neden olan kanser türünü ifade etmektedir. Kanser türlerine ait daha özel örnekler meme kanseri, prostat kanseri, kolorektal kanser, deri kanseri, küçük hücreli akciger kanseri, küçük hücreli olmayan akciger kanseri, mezotelyom, gastrointestinal kanser, pankreas kanseri, gliyoblastom, vulva kanseri, rahim agzi kanseri, endometriyal karsinom, yumurtalik kanseri, karaciger kanseri, hepatom, mesane kanseri, böbrek kanseri, tükürük bezi karsinomu, tiroid kanseri ve çesitli bas ve boyun kanserlerini içerir. Bu tarifname baglaminda içerir ifadesinin kapsar ifadesini belirtmesi amaçlanmistir. Teknik açidan uygun olan yerlerde, bulusun uygulamalari birlestirilebilir. Uygulamalar burada belirli özellikler/elemanlar içerecek sekilde açiklanmistir. Tarifname ayrica esas olarak bahsi geçen özellikleri/elemanlari içeren ya da bunlardan meydana gelen diger uygulamalari da kapsamaktadir. Patentler ve basvurular benzeri teknik referanslar referans yolu ile bu dokümana dahil edilmistir. Burada spesifik olarak ve açikça anlatilan uygulamalar tek basina ya da bir veya birkaç diger uygulama ile birlikte bir feragatnameye esas teskil edebilir. Simdi bulus sadece örnek amaçli olan ve bu bulusun kapsamini herhangi bir sekilde kisitlar olarak yonimlanmamasi gereken asagidaki örneklere atifta bulunularak açiklanacaktir. ÖRNEKLER: Ornek l: Piperin ve Kurkumin Içeren Emulsomlarin Hazirlanmasi Tablo 1: Emulsoin olusturan bilesenler ve miktarlari Moleküler Miktari Agirligi K'i'itle Kesiri Mol Kesiri Tablo 1`de yer alan miktarlarda tripalmitin, DPPC ve kolesterol kloroform içerisinde çözülür. Ayri bir yerde kurkumin ve piperin de kloroform içerisinde çözülür. Elde edilen iki karisim birlestirilir ve düsük basinç altinda 60 0C sicaklikta çözücü olarak kullanilan kloroform uzaklastirilir. Elde edilen filmin suda çözülmesiyle piperin ve kurkumin içeren emulsom formülasyonlari elde edilir. Daha sonra istege bagli olarak elde edilen emulsomlarin boyutlarinin homojen hale getirilmesini saglamak amaciyla sonikasyon, filtrasyon (ekstrüzyon) veya homojenizasyon uygulanir. Ornek 2: HCT116 Hücreleri ile Hücre Canliligi Testi HCT116 hücrelerinin kurkumin ve piperin yüklü emulsomlar ile muamelesi sonrasi hücre canliliklari MTS hücre canliligi teknigi yardimiyla saptanmistir. 96 kuyucuklu tabaklar kullanilarak yapilan analizde, HCTl 16 hücre hatti için kuyucuk basina 10 bin hücre ekilmistir. Hücrelerin oturmasi gözlemlendikten sonra 2,8 uM piperin yüklü emulsom ve 25 uM kurkumin yüklü emulsom ile ayri ayri ve birlikte muamele edilmistir. Negatif kontrol olarak muamele görmemis hücreler kullanilmistir. 24, 48 ve 72 saatlik muamele sürelerinin ardindan hücreler MTS ("CellTiter96 AQueousOne Solution Cell Proliferation Assay") kolorimetrik hücre ajani ile muamele edilmistir (Sekil 1). Karanlikta iki saat inkübasyonu sonucunda mikrotabak spektrofotometre kullanilarak hücrelerin 490 nm dalga boyundaki absorbans degerleri ölçülmüstür. Bu prosedür 24 saat, 48 saat ve '72 saat zaman dilimlerinde tekrarlanmistir. Alinan sonuçlarin analizleri negatif kontrol hücrelerinin canlilik oraninin %100 kabul edilmesiyle hesaplanmistir. Elde edilen hücre canlilik oranlari HCT116 hücreleri için Sekil 1`de verilen grafikte görülmektedir. Buna göre sadece piperin yüklü emulsom ile muamele edilen hücrelerde hücre canliligi kontrol grubundan farklilik göstermezken; kurkumin yüklü emulsom ile muamele edilenler hücrelerde hücre canliligi 48. saatte %65, 72. saatte %49 olurken; kurkumin arti piperin yüklü emulsomlar ile muamele edilen hücreler için bu degerler %56 ve %46 olarak belirlenmistir. Kurkumin ve piperin yüklü emulsomlar ile muamele edilen HCT116 hücreleri ile kontrol grubu arasinda anlamli bir farklilik oldugu görülmektedir. TR TRDESCRIPTION THERAPEUTIC APPLICATIONS OF SOLID LIPID EMULSIONS CONTAINING THE NATURAL COMPONENTS CURCUMIN AND PIPERIN TECHNICAL FIELD This invention relates to solid lipid emulsion formulations (emulsifiers) containing the natural components curcumin and piperine and their use in the treatment of neoplastic diseases. STATE OF ART Curcumin is the main component of the turmeric plant; piperine is the main component of the black pepper plant. The various therapeutic effects of these two natural active compounds have been known since ancient civilizations. In modern medical practice, their use has been investigated, especially in recent years, and they have been observed to be effective against certain disease models (such as various types of cancer and Alzheimer's). Curcumin (turmeric), in particular, has great potential for use due to its anti-inflammatory, anti-carcinogenic, antibacterial, anti-rheumatic, and regenerative properties. However, curcumin's insufficiency in water and its instability (rapid breakdown into its components) hinder its use in therapeutic applications. Curcumin, which has low body absorption, remains far below the therapeutic concentration levels even when used in high doses (e.g., 8 mg/day). This results in insufficient delivery of curcumin to the affected tissue. Studies have shown that the use of piperine, an active ingredient in black pepper (Piper nigrum), in combination with turmeric creates a synergistic effect by increasing the solubility and bioavailability of turmeric. Accordingly, the combined use of curcumin and piperine allows for the creation of formulations with higher bioavailability. Considering the current state of the technology, it is evident that maximizing the benefit from curcumin requires various nanocarrier systems that enhance its absorption, particularly in the intestines, and/or facilitate its direct injection into the bloodstream. Various studies aimed at developing formulations with these properties have focused on the synergistic transport of curcumin and piperine molecules on various macromolecular platforms such as liposomes, micelles, solid lipid nanoparticles, polymers, and dendrimers. However, to date, formulations of this type have faced problems such as low drug loading capacity, undesirable toxicity and side effects depending on the organic solvent and surfactant used in the preparation of the formulation, low stability rate, insufficient intracellular uptake, rapid drug release problems, and high economic costs. The inventors aim to overcome these problems, especially the toxicity problem arising from surfactant use, that exist in the current state of the art, and to develop an alternative curcumin-piperine formulation to these existing formulations. BRIEF DESCRIPTION OF THE INVENTION The invention relates to emulsifiers consisting of a phospholipid layer and a triglyceride solid core in which piperine and curcumin are dispersed, and the use of these emulsifiers in the treatment of neoplastic diseases. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical formulations containing piperine and curcunin, characterized by: - being in the form of an emulsion whose core consists of triglyceride derivatives and which contains cholesterol or ester derivatives in both the core and the outer layer. In their studies, the inventors found that the curcumin and piperine formulations formulated in emulsions with the above-mentioned properties (i) do not exhibit toxic effects due to the absence of organic solvents and surfactants in their structure; (ii) allow for the loading of high amounts of curcunin and piperine into the structure; (iii) extend the duration of action of curcumin and piperine by increasing the release time thanks to its unique solid-phase structure; and (iv) the phospholipids forming the outer surface of the emulsions are modifiable structures, allowing for the use of proteins, polymers, various targeting ligands, etc. They found that the invention has the advantage of enabling the preparation of curcumin and piperine formulations that are targeted by molecular binding or whose release or absorption properties are altered. In one application of the invention, the triglyceride derivatives forming the core of curcumin and piperine-containing emulsion formulations are selected from a group consisting of oils that are in solid or liquid crystal form at 25°C, natural, even-numbered, unbranched triglycerides such as tricaprine, trilaurine, trimyristin, tripalmitin and tristearin, monounsaturated fatty acids, and partially hydrogenated vegetable oils. In a preferred application of the discovery, tripalmitin, also known as triglyceride palmitate, is used as the triglyceride derivative that forms the core of einulsom formulations containing curcumin and piperine. In one application of the invention, the phospholipids forming the outer surface of emulsion formulations containing curcumin and piperine can be selected from natural phospholipids such as soy lecithin, egg lecithin, phosphatidylglycerol, phosphatidylinostol, phosphatidylethanolamine, phosphatidic acid, sphingomyelin, disphosphatidylglycerol, phosphatidylserine, phosphatidylcholine, cardiolipin, or from synthetic phospholipids such as dimyristoyl phosphatidylglycerol, diiniristoyl phosphatidylcholine, 1,2-dipalmitol-rac-glycero-3-phosphatidylcholine (DPPC), or from a group of hydrogenated or partially hydrogenated lecithins and phospholipids. In one application of the invention, 1,2-dipalmitol-rak-glycero-3-phosphatidylcholine (DPPC) is used as a phospholipid. In another application of the invention, the cholesterol found in the core and outer layer of curcumin and piperine-containing emulsion formulations is selected from a group consisting of cholesterol, palmitoyl cholesterol, and oleoyl cholesterol. In yet another application of the invention, the weight ratio of triglycerides, phospholipids, and cholesterol derivatives forming the emulsion structure (triglycerides:phospholipids:cholesterol) is 17:1:1. Accordingly, in one application of the invention, the present invention is directed towards pharmaceutical formulations containing curcumin and piperine, and its characteristic is; - The core consists of triglyceride palmitate, the outer layer is 1,2-dipalmitol-rak-glycero-3-phosphatidylcholine (DPPC), and it is in the form of an emulsion containing cholesterol in both the core and the outer layer. In one application of the invention, the ratio by weight of triglyceride palmitate, 1,2-dipalmitol-rak-glycero-3-phosphatidylcholine (DPPC), and cholesterol forming the emulsion structure (triglyceride palmitate to DPPC:cholesterol) is between 17:1:1 and 21:3:1, preferably. Accordingly, a particularly preferred application of the invention is related to pharmaceutical formulations containing curcumin and piperine; - The core consists of triglyceride palmitate, the outer layer is formed from it, and it is in the form of an emulsion containing cholesterol in both the core and the outer layer, and the triglyceride palmitate:DPPC:cholesterol ratio is between 17:11 and 21:31, preferably between 18:1.5 and 20:2.1. An application of the invention relates to a method for preparing curcumin and piperine-containing emulsions that conform to the invention; The invention involves the following steps: - dissolving triglyceride, phospholipid, and cholesterol derivatives in an organic solvent, preferably chloroform; - dissolving curcumin and piperine in an organic solvent, preferably chloroform; - mixing the resulting solutions and removing the organic solvent under low pressure to obtain a film structure; - obtaining curcumin and piperine-containing emulsion formulations by dissolving the resulting film structure in water. In a preferred application of the invention, the obtained curcumin and piperine-containing emulsion formulation is subjected to sonication bath, filtration (extrusion), or homogenization to homogenize the particle size distribution of the emulsions comprising the formulation. In a preferred application of the invention, the organic solvent, preferably chloroform, can be removed at room temperature or at a temperature between 40-60°C. The invention, from another perspective, is directed towards the use of curcumin and piperine-containing emulsion formulations as drugs for the treatment of neoplastic diseases. The term "neoplastic diseases" as used within the scope of this invention refers to malignant tumors or a physiological condition characterized by uncontrolled cell growth, such as cancer. Within the scope of this invention, "neoplastic disease" includes, but is not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. Carcinoma, as used herein, refers to a type of cancer originating from epithelial cells. Lymphoma, as used herein, describes a type of cancer developing from lymphocytes. Blastoma, as used herein, describes a type of cancer developing from precursor cells, also known as blast cells. Sarcoma, as used herein, describes a type of cancer arising from altered cells of mesenchymal origin. Leukemia, as used herein, refers to a type of cancer that originates in the bone marrow and causes the formation of a high number of abnormal white blood cells. More specific examples of cancer types include breast cancer, prostate cancer, colorectal cancer, skin cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, gastrointestinal cancer, pancreatic cancer, glioblastoma, vulvar cancer, cervical cancer, endometrial carcinoma, ovarian cancer, liver cancer, hepatoma, bladder cancer, kidney cancer, salivary gland carcinoma, thyroid cancer, and various head and neck cancers. In the context of this specification, the term "includes" is intended to indicate "covers". Where technically feasible, applications of the invention may be combined. Applications are described here to include specific features/elements. The specification also covers other applications that primarily involve or comprise the aforementioned features/elements. Patents and applications, and similar technical references, are included in this document by way of reference. Applications specifically and explicitly described here may, alone or in combination with one or more other applications, form the basis of a disclaimer. The invention will now be described by reference to the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of this invention in any way. EXAMPLES: Example 1: Preparation of Emulsifiers Containing Piperine and Curcumin Table 1: Components and Quantities of Emulsifiers Molecular Amount Weight Mass Fraction Mole Fraction Tripalmitine, DPPC, and cholesterol are dissolved in chloroform in the amounts given in Table 1. Separately, curcumin and piperine are also dissolved in chloroform. The two resulting mixtures are combined, and the chloroform used as a solvent is removed under low pressure at 60°C. Emulsifier formulations containing piperine and curcumin are obtained by dissolving the resulting film in water. Then, depending on the preference, sonication, filtration (extrusion), or homogenization is applied to ensure the homogenization of the dimensions of the obtained emulsifiers. Example 2: Cell Viability Test with HCT116 Cells Cell viability of HCT116 cells after treatment with curcumin and piperine-loaded emulsions was determined using the MTS cell viability technique. In the analysis performed using 96-well plates, 10,000 cells were seeded per well for the HCT116 cell line. After observing cell settlement, the cells were treated separately and together with 2.8 µM piperine-loaded emulsion and 25 µM curcumin-loaded emulsion. Untreated cells were used as a negative control. After 24, 48, and 72 hours of treatment, the cells were treated with the MTS ("CellTiter96 AQueousOne Solution Cell Proliferation Assay") colorimetric cell agent (Figure 1). After two hours of incubation in the dark, the absorbance values of the cells at a wavelength of 490 nm were measured using a microplate spectrophotometer. This procedure was repeated at 24, 48, and 72-hour intervals. The analysis of the obtained results was calculated by assuming a 100% viability rate for negative control cells. The obtained cell viability rates for HCT116 cells are shown in the graph in Figure 1. Accordingly, while cell viability did not differ from the control group in cells treated only with piperin-loaded emulsion; in cells treated with curcumin-loaded emulsion, cell viability was 65% at 48 hours and 49% at 72 hours; and for cells treated with curcumin plus piperin-loaded emulsions, these values were determined as 56% and 46%, respectively. A significant difference was observed between HCT116 cells treated with curcumin and piperine-loaded emulsifiers and the control group.

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