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 PDFInfo
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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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- Turkey
- Prior art keywords
- cancer
- cholesterol
- curcumin
- piperine
- emulsom
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- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 title claims abstract description 76
- 229940109262 curcumin Drugs 0.000 title claims abstract description 38
- 235000012754 curcumin Nutrition 0.000 title claims abstract description 38
- 239000004148 curcumin Substances 0.000 title claims abstract description 38
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 239000007787 solid Substances 0.000 title claims abstract description 7
- 239000002960 lipid emulsion Substances 0.000 title abstract description 3
- 229940075559 piperine Drugs 0.000 claims abstract description 37
- MXXWOMGUGJBKIW-YPCIICBESA-N piperine Chemical compound C=1C=C2OCOC2=CC=1/C=C/C=C/C(=O)N1CCCCC1 MXXWOMGUGJBKIW-YPCIICBESA-N 0.000 claims abstract description 36
- WVWHRXVVAYXKDE-UHFFFAOYSA-N piperine Natural products O=C(C=CC=Cc1ccc2OCOc2c1)C3CCCCN3 WVWHRXVVAYXKDE-UHFFFAOYSA-N 0.000 claims abstract description 36
- 235000019100 piperine Nutrition 0.000 claims abstract description 36
- 239000000203 mixture Substances 0.000 claims abstract description 32
- 238000009472 formulation Methods 0.000 claims abstract description 31
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 34
- 235000012000 cholesterol Nutrition 0.000 claims description 18
- 150000003904 phospholipids Chemical class 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 11
- 150000003626 triacylglycerols Chemical class 0.000 claims description 10
- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 claims description 10
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 9
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 6
- -1 tricaprine Chemical class 0.000 claims description 6
- 229960001947 tripalmitin Drugs 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 201000009030 Carcinoma Diseases 0.000 claims description 4
- 150000001841 cholesterols Chemical class 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N trilaurin Chemical compound CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 3
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- 238000000265 homogenisation Methods 0.000 claims description 3
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- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 3
- 238000000527 sonication Methods 0.000 claims description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 3
- DUXYWXYOBMKGIN-UHFFFAOYSA-N trimyristoyl-sn-glycerol Natural products CCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCC DUXYWXYOBMKGIN-UHFFFAOYSA-N 0.000 claims description 3
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims description 3
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 2
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims description 2
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
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- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
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- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
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- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 2
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010027406 Mesothelioma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 206010061934 Salivary gland cancer Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 208000004354 Vulvar Neoplasms Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- RJECHNNFRHZQKU-RMUVNZEASA-N cholesteryl oleate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)C1 RJECHNNFRHZQKU-RMUVNZEASA-N 0.000 claims description 2
- 239000008344 egg yolk phospholipid Substances 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 239000000787 lecithin Substances 0.000 claims description 2
- 235000010445 lecithin Nutrition 0.000 claims description 2
- 239000004973 liquid crystal related substance Substances 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 239000003921 oil Substances 0.000 claims description 2
- 235000019198 oils Nutrition 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 125000001095 phosphatidyl group Chemical group 0.000 claims description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 2
- 201000003804 salivary gland carcinoma Diseases 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 2
- 239000008347 soybean phospholipid Substances 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 201000005102 vulva cancer Diseases 0.000 claims description 2
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims 2
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 claims 1
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 claims 1
- FRKBLBQTSTUKOV-UHFFFAOYSA-N diphosphatidyl glycerol Natural products OP(O)(=O)OCC(OP(O)(O)=O)COP(O)(O)=O FRKBLBQTSTUKOV-UHFFFAOYSA-N 0.000 claims 1
- 235000021281 monounsaturated fatty acids Nutrition 0.000 claims 1
- 235000015112 vegetable and seed oil Nutrition 0.000 claims 1
- 239000008158 vegetable oil Substances 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 16
- 244000163122 Curcuma domestica Species 0.000 description 4
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- 239000000126 substance Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 235000013976 turmeric Nutrition 0.000 description 4
- 244000203593 Piper nigrum Species 0.000 description 3
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- 230000003217 anti-cancerogenic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 235000013614 black pepper Nutrition 0.000 description 1
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- 229960005160 dimyristoylphosphatidylglycerol Drugs 0.000 description 1
- ZGSPNIOCEDOHGS-UHFFFAOYSA-L disodium [3-[2,3-di(octadeca-9,12-dienoyloxy)propoxy-oxidophosphoryl]oxy-2-hydroxypropyl] 2,3-di(octadeca-9,12-dienoyloxy)propyl phosphate Chemical compound [Na+].[Na+].CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COP([O-])(=O)OCC(O)COP([O-])(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC ZGSPNIOCEDOHGS-UHFFFAOYSA-L 0.000 description 1
- BPHQZTVXXXJVHI-AJQTZOPKSA-N ditetradecanoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-AJQTZOPKSA-N 0.000 description 1
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- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules 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
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
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. DESCRIPTION SOLID CONTAINING NATURAL COMPONENTS OF CUCUMIN AND PIPER THERAPEUTIC APPLICATIONS OF LIPIT EMULSIONS TECHNICAL FIELD The present invention is a solid lipid emulsion containing natural components of curcumin and piperine. formulations (emulsomes) and the neoplastic related to its use in the treatment of diseases.
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. KNOWN STATE OF THE TECHNIQUE Curcuin, the turmeric plant; Piperine is the main ingredient of the black pepper plant. forms. The various therapeutic effects of these two natural active compounds are ancient. known from civilizations to the present. In modern type applications, especially Their use has been investigated in recent years and has been used against certain disease models (various cancer types and Alzheimer's) are observed to be effective. Especially Curcumin (turmeric), anti-inflammatory, anti-carcinogenic, anti-bacterial, anti- It has a great potential for use due to its rheumatic and regenerative properties. forms. However, curcumin is not sufficiently soluble in water and instability (rapidly breaking down into subcomponents), its use in therapeutic applications hinders. Curcumin, which is low in body absorption, can be administered in high doses (e.g. 8-day mg) at the concentration in the blood that will have a therapeutic effect, even if it is used. remains well below its values. This situation is related to the tissue where the health problem is located. This results in insufficient delivery of curcumin.
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. In the studies, piperine, which is in black pepper (piper nigrum), is the active ingredient. The use of the substance together with turmeric, turmeric solubility and It has been observed that it creates a synergistic effect by increasing its bioavailability. This The combination of curcumin and piperine substances is higher than It enables to obtain formulations with bioavailability.
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. Maximum benefit from curcumin considering the state of the art To ensure that this substance increases its absorption in the intestines and / or directly various nanocarrier systems that provide blood injection are needed. is seen.
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. Various studies have been carried out to develop formulations with these properties. In studies, curcumin and piperine molecules, which have synergistic effects, were found in liposomes, various macromolecules such as micelles, solid lipid nanoparticles, polymers, dendrimers Studies have been carried out to transport it on platforms. However, water basically low drug loading capacity in this type of formulations made so far, depending on the organic solvent and surfactant used to prepare the formulation. undesirable toxicity and side effects, low stability rate, intracellular such as insufficient intake, rapid drug release problem and high economic cost. problems appear. The inventors are aware of this existing state of the art. problems, 'especially the toxicity problem caused by the use of surfactant, aims to overcome these existing formulations and aims to develop the curcumin-piperine formulation.
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. BRIEF DESCRIPTION OF THE INVENTION Meet; a phospholipid layer and a layer in which piperine and curcumin are dispersed. emulsomes consisting of triglyceride solid core and the aforementioned emulsomes related to its use in the treatment of neoplastic diseases.
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. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical formulations containing piperine and curcuin. feature; - from derivatives of triglyceride nuclei cholesterol or ester derivatives in both the core and the outer layer It is in the form of emulsom found.
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. The inventors in their work; emulsomes with the above properties in the structure (i) of curcumin and piperine formulations formulated in It does not have a toxic effect due to the fact that it does not contain organic solvents and surfactants; (ii) structure it allows the loading of high amounts of curcuin and piperine into it; (iii) curcumin and curcumin by increasing the release time thanks to its unique solid phase structure. prolonging the duration of action of piperine; and (iv) forming the outer surface of emulsomes Since phospholipids are modifiable structures, proteins, polymers, various targeting ligands etc. targeted or release by binding of molecules or of curcumin and piperine formulations with altered absorption properties. They have found that it has the advantages of enabling the preparation of
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. In one embodiment of the invention, emulsom containing curcumin and piperine according to the invention triglyceride derivatives forming the core of the formulations; solid at 25 DC or oils in liquid crystal form, tricaprin, trilaurin, trimyristin, tripalmitin and monounsaturated fat from natural, even, unbranched triglycerides such as tristearin acids, partially hydrogenated vegetable oils.
Bulusun tercih edilen bir uygulamasinda kurkumin ve piperin içeren einulsom formülasyonlarinin çekirdegini olusturan trigliserit türevi madde olarak tripalmitin, diger adiyla trigliserin palmitat, kullanilir. In a preferred embodiment of the invention, einulsom containing curcumin and piperine tripalmitin as the triglyceride derivative substance forming the core of its formulations, also known as triglycerin palmitate, is used.
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. In one embodiment of the invention, the external use of emulsom formulations containing curcumin and piperine. phospholipids forming its surface, soy lecithin, egg lecithin, phosphatidyl glycerol, phosphatidyl inostol, phosphatidyl ethanolamine, phosphatidic acid, sphingomyelin, di natural, such as phosphatidylglycerol, phosphatidyl serine, phosphatidyl choline, cardiolipin from phospholipids or dimyristoyl phosphatidylglycerol, diiniyristoyl phosphatidylcholine, 1,2- synthetic phospholipids such as dipalmitol-rac-glycero-3-phosphatidylcholine (DPPC), or a group of hydrogenated or partially hydrogenated lecithins and phospholipids can be selected from. In a preferred embodiment of the invention, the phospholipid 1,2- dipalmitol-rac-glycero-3-phosphatidylcholine (DPPC) is used.
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. In one embodiment of the invention, emulsom formulations containing curcumin and piperine cholesterol found in its core and outer layer; cholesterol, palmitoyl cholesterol, selected from the group consisting of oleoyl cholesterol.
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. In an application of the invention, triglyceride, phospholipid and weight ratio of cholesterol derivatives to each other (triglyceridephospholipid:cholesterol) 17: 1 :1 Accordingly, in a preferred embodiment of the invention, the present invention contains curcumin and piperine. It is intended for pharmaceutical formulations containing; - from the core triglycerin palmitate - 1,2-dipalmitol-rac-glycero-3-phosphatidylcholine (DPPC) of the outer layer emulsom, which is formed and contains cholesterol in both its core and outer layer. is in form.
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. In an application of the invention, triglycerin palmitate, which forms the emulsom structure, is 1,2- by weight of dipalmitol-rac-glycero-3-phosphatidylcholine (DPPC) and cholesterol ratio (triglycerine palmitatzDPPC:cholesterol) in the range of 17:1:1 to 21:3:1, preferably Accordingly, in a particularly preferred embodiment of the invention, the present invention contains curcumin. and piperine containing pharmaceutical formulations. - from the core triglycerin palmitate - outer layer emulsoin, which is formed and contains cholesterol in both the hein core and the outer layer and the triglycerin palmitate:DPPC:cholesterol ratio between 1711:] and 21:31] in the range, preferably between 18:1.5z1 and 20:2:1.
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. One application of the invention is the use of emulsoms according to the invention containing curcumin and piperine. It is related to a method to be used in the preparation of the said method; - an organic solvent of triglycerides, phospholipids and cholesterol derivatives, preferably dissolving in chloroform - curcumin and piperine in an organic solvent, preferably chloroform unravel - Mixing the solutions obtained and organic under low pressure Obtaining the film structure by removing the solvent - Containing curcumin and piperine by dissolving the obtained film structure in water includes the steps of obtaining emulsom formulations.
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. Containing curcumin and piperine obtained in a preferred embodiment of the invention emulsoin formulation, particle size of emulsoms that make up the formulation sonication bath, filtration to make the distribution homogeneous (extrusion) or homogenization process.
Bulusun tercih edilen bir uygulamasinda söz konusu yöntemde organik çözücü, tercihen kloroforrn oda sicakliginda, veya 40-60 UC arasinda bir sicaklikta uzaklastirilabilir. In a preferred embodiment of the invention, in said method, the organic solvent is preferably chloroform at room temperature, or at a temperature between 40-60 UC can be removed.
Bulus bir diger açidan, bulusa uygun kurkumiii ve piperin içeren emulsom formüasyonlarinin neoplastik hastaliklarin tedavisi için ilaç olarak kullanilmasina yöneliktir. In another aspect of the invention, emulsomal containing curcumin and piperine according to the invention formulations to be used as drugs for the treatment of neoplastic diseases. oriented.
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. The expression “neoplastic diseases” used in the present invention is malignant. tumors or a physiological condition characterized by uncontrolled cell growth, For example, it refers to the disease of cancer. Within the scope of the invention, “neoplastic disease” and includes and is limited to carcinoma, lymphoma, blastoma, sarcoma, and leukemia is not.
Karsinoma, burada kullanildigi sekliyle, epitel hücrelerden olusan bir kanser türünü ifade etmektedir. Carcinoma, as used herein, is a type of cancer composed of epithelial cells. means.
Lenfoma, burada kullanildigi sekliyle, lenfositlerden gelisen bir kanser türünü anlatmaktadir. Lymphoma, as used herein, is a type of cancer that develops from lymphocytes. it tells.
Blastoma, burada kullanildigi sekliyle, blast hücre adiyla da bilinen öncü hücrelerden gelisen bir kanser türünü anlatmaktadir. Blastoma, as used herein, is one of the progenitor cells, also known as blast cells. describes a developing type of cancer.
Sarkoma, burada kullanildigi sekliyle, mezenkimal kökenli degismis hücrelerden kaynaklanan kanser türünü anlatmaktadir. Sarcoma, as used herein, consists of altered cells of mesenchymal origin. describes the type of cancer caused.
Lösemi, burada kullanildigi sekliyle, kemik iliginde baslayan ve yüksek sayida anormal akyuvar hücresi olusumuna neden olan kanser türünü ifade etmektedir. Leukemia, as used herein, is bone marrow-onset and high-number refers to the type of cancer that causes abnormal white blood cell formation.
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. More specific examples of cancer types are breast cancer, prostate cancer, colorectal cancer, skin cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, gastrointestinal cancer, pancreatic cancer, glioblastoma, vulva 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.
Bu tarifname baglaminda içerir ifadesinin kapsar ifadesini belirtmesi amaçlanmistir. In the context of this specification, the phrase includes is intended to indicate the phrase includes.
Teknik açidan uygun olan yerlerde, bulusun uygulamalari birlestirilebilir. Where technically feasible, applications of the invention may be combined.
Uygulamalar burada belirli özellikler/elemanlar içerecek sekilde açiklanmistir. Applications are described here to include certain features/elements.
Tarifname ayrica esas olarak bahsi geçen özellikleri/elemanlari içeren ya da bunlardan meydana gelen diger uygulamalari da kapsamaktadir. The specification also includes or includes essentially said properties/elements. It covers other applications as well.
Patentler ve basvurular benzeri teknik referanslar referans yolu ile bu dokümana dahil edilmistir. Technical references such as patents and applications are included in this document by reference. has been made.
Burada spesifik olarak ve açikça anlatilan uygulamalar tek basina ya da bir veya birkaç diger uygulama ile birlikte bir feragatnameye esas teskil edebilir. The applications specifically and expressly described herein can be used alone or in one or together with several other applications may serve as the basis for a disclaimer.
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. The invention is now for illustrative purposes only and does not in any way extend the scope of this invention. with reference to the following examples, which should not be construed as constraints. will be disclosed. EXAMPLES: Example 1: Preparation of Emulsoms Containing Piperine and Curcumin Table 1: Emulsoin-forming components and their amounts Molecular Quantity Weight by Weight Fraction Molecular Fraction Tripalmitin, DPPC and cholesterol in the amounts listed in Table 1 in chloroform is resolved. In a separate place, curcumin and piperine are also dissolved in chloroform. in hand The two mixtures obtained are combined and used as a solvent at 60 0C under low pressure. The chloroform used is removed.
Elde edilen filmin suda çözülmesiyle piperin ve kurkumin içeren emulsom formülasyonlari elde edilir. Emulsom containing piperine and curcumin by dissolving the resulting film in water. formulations are obtained.
Daha sonra istege bagli olarak elde edilen emulsomlarin boyutlarinin homojen hale getirilmesini saglamak amaciyla sonikasyon, filtrasyon (ekstrüzyon) veya homojenizasyon uygulanir. Then, the dimensions of the optionally obtained emulsomes become homogeneous. sonication, filtration (extrusion) or homogenization is applied.
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.Example 2: Cell Viability Test with HCT116 Cells After treatment of HCT116 cells with curcumin and piperine loaded emulsomes Cell viability was determined by the MTS cell viability technique. 96 wells In analysis using plates, 10 thousand per well for HCTl 16 cell lines cells were planted. Loaded with 2.8 µM piperine after the cells were observed to settle emulsom and 25 µM curcumin-loaded emulsom, separately and together. has been made. Untreated cells were used as negative control. 24, 48 and after 72 hours of treatment, cells MTS (“CellTiter96 AQueousOne Solution Cell Proliferation Assay“) was treated with a colorimetric cell agent. (Figure 1). Microplate spectrophotometer after two hours of incubation in the dark The absorbance values of the cells at a wavelength of 490 nm were measured using This the procedure was repeated at 24 hour, 48 hour and '72 hour time zones. received analysis of the results showed that the viability of the negative control cells was 100% accepted. is calculated by. Obtained cell viability rates for HCT116 cells It can be seen in the graph given in Figure 1. Accordingly, only piperine loaded emulsom Cell viability differed from the control group in cells treated with while not showing; cells treated with curcumin-loaded emulsom its vitality was 65% at the 48th hour and 49% at the 72nd hour; loaded with curcumin plus piperine For cells treated with emulsomes, these values were 56% and 46%. has not been determined. HCT116 treated with curcumin and piperine loaded emulsomes It is seen that there is a significant difference between the cells and the control group.
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