TR2021021389A1 - INHIBITORY EFFECTS OF ROSMARINIC ACID ON COX-1, COX-2 AND LOX ENZYMES - Google Patents
INHIBITORY EFFECTS OF ROSMARINIC ACID ON COX-1, COX-2 AND LOX ENZYMESInfo
- Publication number
- TR2021021389A1 TR2021021389A1 TR2021/021389 TR2021021389A1 TR 2021021389 A1 TR2021021389 A1 TR 2021021389A1 TR 2021/021389 TR2021/021389 TR 2021/021389 TR 2021021389 A1 TR2021021389 A1 TR 2021021389A1
- Authority
- TR
- Turkey
- Prior art keywords
- cox
- rosmarinic acid
- inflammatory agent
- inflammatory
- inhibitory effects
- Prior art date
Links
- DOUMFZQKYFQNTF-WUTVXBCWSA-N (R)-rosmarinic acid Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-WUTVXBCWSA-N 0.000 title claims abstract description 50
- ZZAFFYPNLYCDEP-HNNXBMFYSA-N Rosmarinsaeure Natural products OC(=O)[C@H](Cc1cccc(O)c1O)OC(=O)C=Cc2ccc(O)c(O)c2 ZZAFFYPNLYCDEP-HNNXBMFYSA-N 0.000 title claims abstract description 25
- DOUMFZQKYFQNTF-MRXNPFEDSA-N rosemarinic acid Natural products C([C@H](C(=O)O)OC(=O)C=CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-MRXNPFEDSA-N 0.000 title claims abstract description 25
- TVHVQJFBWRLYOD-UHFFFAOYSA-N rosmarinic acid Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=Cc2ccc(O)c(O)c2)C=O TVHVQJFBWRLYOD-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 title claims description 6
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 title claims description 6
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 title claims description 3
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 title claims description 3
- 102000004190 Enzymes Human genes 0.000 title description 3
- 108090000790 Enzymes Proteins 0.000 title description 3
- 230000002401 inhibitory effect Effects 0.000 title description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims abstract description 26
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 239000002552 dosage form Substances 0.000 claims description 5
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 4
- 229960001259 diclofenac Drugs 0.000 claims description 4
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 4
- 229960001680 ibuprofen Drugs 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims description 2
- 229940125532 enzyme inhibitor Drugs 0.000 claims 1
- 239000002532 enzyme inhibitor Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- -1 0.5% - 99% Chemical compound 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007942 layered tablet Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
Abstract
Mevcut buluş, antienflamatuvar ajan olarak kullanım için rosmarinik asit maddesi ile ve bu maddeyi içeren farmasötik bileşimlerle ilgilidir.The present invention relates to rosmarinic acid for use as an anti-inflammatory agent and to pharmaceutical compositions containing it.
Description
TARIFNAME ROSMARINIK ASITIN COX-l, COX-2 VE LOX ENZIMLERINI INHIBE EDICI ETKILERI Teknik Alan Mevcut bulus, antienflamatuvar ajan olarak kullanim için rosmarinik asit maddesi ile ve bu maddeyi içeren farmasötik bilesimlerle ilgilidir. Teknigin Bilinen Durumu Entlamasyon kaynakli rahatsizliklar siklikla karsimiza çikmaktadir. Vücudun farkli bölgelerinde farkli nedenlerle meydana gelen enflamasyonlarin tedavisi çesitli konvansiyonel ilaçlarla saglanmaya çalisilmaktadir. Ancak kullanilan bu ajanlarla tedavi zaman zaman yetersiz kalmakla beraber yeni ve dogal antienflamatuar aj anlarin kesfi büyük Önem tasimaktadir. Dogal kaynakli terapötik ajanlarin ticari kullaniminda en çok karsilasilan problemlerden biri dogal ürünlerden elde edilen ekstrelerin içerisindeki farmasötik etkiye sahip madde miktarinin sabit olmamasidir. Bitkinin toplandigi bölgeye veya toplandigi döneme göre degisiklik gösterebilen burn iktar degisikligi, bitkisel kökenli ekstreler kullanilarak etkinligi tekrar edilebilir ve standardize edilebilir formülasyonlar gelistirilmesini engellemektedir. Teknigin bilinen durumu göz önüne alindiginda hem bitkisel veya dogal kaynaklardan elde edilen hem de içerisinde bulunan farmasötik etkinlik gösteren madde miktari yönünden standardize edilebilen antienflamatuar ajanlara ihtiyaç oldugu görülmektedir. Bulusun Amaci Bulus sahipleri, bitkisel veya dogal kaynaklardan elde edilen ve içerisinde bulunan farmasötik etkinlik gösteren madde miktari yönünden standardize edilebilen antientlamatuar ajanlar gelistirmeyi amaçlamaktadir. Bulusun Kisa Açiklamasi Mevcut bulus antienflamatuvar ajan olarak kullanim için rosmarinz'k asit maddesine yönelikrz'r. Ayrica, COX ve LOX enzimlerini selektif olarak inhibe eden çok fazla ajan olmamasi nedeniyle, bulusa uygun antientlamatuvar ajan olarak kullanim için rosmarinik asit ile hastalara dogal bir antientlamatuar ajan saglanmaktadir. Bulusun Detayli Anlatimi Bulusun bir uygulamasi antientlamatuvar ajan olarak kullanim için en az %95 satlikta rosmarinik asite veya herhangi bir oranda örnegin %0,5 - %99 oraninda rosmarinik asit içeren bilesiklere, tercihen "00,5 - %99 oraninda rosmarinik asit içeren bitki esktrelerine, özellikle tercihen "00,5 ile iliskindir. Bulusun tercih edilen bir uygulamasi antienflamatuar ajan olarak kullanim için % 95-99 satlikta rosmarinik asite iliskindir. Bulusun özellikle tercih edilen bir uygulamasi antienflamatuar ajan olarak kullanim için % 97-99 satlikta rosmarinik asite iliskindir. Bulus kapsaminda bahsedilen % satlikta rosmarinik asit miktari, standardize ekstrenin Türk Farmakopesi-II monogratlar (Avrupa farmaskopesi adaptasyonu) - 2016 isimli kaynakta (TC. Saglik Bakanligi, Türkiye Ilaç ve Tibbi cihaz kurumu, 1. Baski, 2016) rosmarinik asit tayininde kullanilan herhangi bir analiz yöntemi örnegin HPLC ve/veya HPTLC cihazi analizleri ile belirlenmektedir. Bu bulus kapsaminda bahsi geçen % orani relatif` bir oran olup, analize tabi tutulan rosmarinik asit numunesindeki toplam madde miktarina kiyasla rosmarinik asit miktarini ifade etmektedir. Örnegin, bir rosmarinik asit numunesinin HPLC analizinde elde edilen tüm pik alani 100 ile ifade edilecek olursa, bulusa uygun bir rosmarinik asit numunesinde rosmarinik asit"e karsilik gelen pikin alani en az 95 olmalidir. Burada kullanilan antientlamatuar ajan ifadesi, COX-l ve/veya COK-2 ve/veya LOX inhibitörü etkisi gösteren aj anlari da kapsamaktadir. Bulus bir diger açidan, antienflamatuvar ajan olarak kullanima uygun etken madde olarak en az Bulusun bir diger unsuru, etken madde olarak en az %95 saflikta, tercihen %95-99 satlikta, özellikle tercihen %97-99 saflikta rosmarinik asit içeren farmasötik bilesimlerde bahsi geçen bu etken maddeye ilave olarak bir diger antienflamatuar ajan kullanilmasidir. Bulusun bir uygulamasinda bahsi geçen ilave antienflamatuar ajan ibuprofen veya diklofenak olabilir. Bulusa uygun kombinasyonlar, ayni dozaj formunda veya farkli dozaj fonnlarinda formüle edilebilir. Bulusa uygun kombinasyon formülasyonlarinin farkli dozaj formlarinda formüle edilmesi durumunda bahsi geçen formülasyonlar farkli zamanlarda veya ayni anda veya sirali olarak kullanilabilir. Bulusa uygun formülasyonlar oral veya topikal kullanima uygun bir dozaj formunda formüle edilebilir. Oral formülasyonlar, tablet, kapsül, uzun salinimli kapsül, geciktirilmis salinimli kapsül, surup, emülsiyon, süspansiyon, kaplamali tablet, katmanli tablet, agizda dagilan tablet, efervesan tablet, sase, dil alti tablet forrnlarindan herhangi birinde olabilir. Topikal formülasyonlar, merhem, krem, jel, hidrojel, losyon formlarindan herhangi birinde olabilir. Bulusa uygun formülasyonlar içerisinde rosmarinik asite ek olarak farmasötik olarak kabul edilebilir en az bir yardimci madde olabilir. Bahsi geçen yardimci madde, herhangi bir terapötik etkisi olmayip, formülasyonun hazirlanmasi veya korunmasi veya kullanimi esnasinda ortaya çikan bir gereksinimi karsilamak için kullanilabilir. Endüstriye Uygulanabilirlik Bulus sayesinde antienflamatuar ajan olarak kullanima uygun dogal kökenli ajanlar gelistirilmistir. Bu yönüyle bulus hem saglik sektöründeki son kullanicilari hem de ilaç gelistiricilerini il gilendirmektedir. Örnekler Örnek 1: Bulusa uygun en az %95 safliga sahip rosmarinik asit numunesinin COX-l ve COX-Z inhibisyonu için ICso degerleri ve bilinen antienflamatuar ajanlarla karsilastirilmasi Asagida sonuçlari verilen çalismada kullanilan rosmarinik asit numunesi içerisinde % 95 Madde No. ICsu (ug/mL) SI Örnek 1°de yer alan sonuçlar degerlendirildiginde bulusa uygun en az %95 rosmarinik asit içeren numunenin dogal bir madde olmasina ragmen ticari olarak uzun sürelerdir kullanilan diklofenak ve ibuprofen gibi antienflamatuvar ajanlardan daha iyi antienflamatuar etki gösterdigi görülmektedir. Burada görüldügü üzere, bulusa uygun dogal ajan diklofenaktan hem COX-l hem de COX-Z inhibisyonu açisindan daha iyi etkinlik göstermektedir. Diger yandan bulusa uygun ekstrenin ibuprofen7den COX-Z inhibisyonu bakimindan önemli ölçüde daha iyi etki gösterdigi görülmektedir. Antientlamatuar ajanlarda COX-Z inhibisyonu seçiciligi bahsi geçen ajanin mide tahris edici yan etkilerinin az olmasiyla iliskilendirilmektedir. Bu baglamda bulusa uygun dogal ajan ile beklenmeyen bir sekilde daha az yari etkiye sahip antienflamatuar ajan hazirlamanm mümkün oldugu sonucuna ulasilmaktadir. Tüm bu deney verileri bu dogal kaynakli bir bilesenin önemli bir antieflamatuar ajan olabilecegini ortaya koymaktadir. TR TR TR TR DESCRIPTION INHIBITORY EFFECTS OF ROSMARIINIC ACID ON COX-1, COX-2 AND LOX ENZYMES Technical Field The present invention relates to the substance rosmarinic acid for use as an anti-inflammatory agent and to pharmaceutical compositions containing this substance. Known Status of the Technique Disorders caused by entlamination occur frequently. Inflammations that occur in different parts of the body for different reasons are tried to be treated with various conventional drugs. However, although treatment with these agents is sometimes insufficient, the discovery of new and natural anti-inflammatory agents is of great importance. One of the most encountered problems in the commercial use of naturally derived therapeutic agents is that the amount of substances with pharmaceutical effects in the extracts obtained from natural products is not constant. Variation in nose quantity, which may vary depending on the region where the plant is collected or the period in which it is collected, prevents the development of reproducible and standardizable formulations using plant-derived extracts. Considering the known state of the art, it seems that there is a need for anti-inflammatory agents that are obtained from herbal or natural sources and can be standardized in terms of the amount of pharmaceutically active substances they contain. Purpose of the Invention The inventors aim to develop anti-inflammatory agents that are obtained from herbal or natural sources and can be standardized in terms of the amount of pharmaceutically active substances they contain. Brief Description of the Invention The present invention is directed to rosmarinzic acid for use as an anti-inflammatory agent. Additionally, since there are not many agents that selectively inhibit COX and LOX enzymes, a natural anti-inflammatory agent is provided to patients with rosmarinic acid for use as an anti-inflammatory agent according to the invention. Detailed Description of the Invention An embodiment of the invention is based on compounds containing at least 95% commercial rosmarinic acid or any amount of rosmarinic acid, such as 0.5% - 99%, preferably plant extracts containing 0.5 - 99% rosmarinic acid, for use as an anti-inflammatory agent. , particularly preferably relating to "00.5". A preferred embodiment of the invention relates to 95-99% available rosmarinic acid for use as an anti-inflammatory agent. A particularly preferred embodiment of the invention relates to 97-99% available rosmarinic acid for use as an anti-inflammatory agent. The % amount of rosmarinic acid on sale mentioned within the scope of the invention is compared to any of the standardized extracts used in the determination of rosmarinic acid in the source named Turkish Pharmacopoeia-II monogrades (European pharmacopoeia adaptation) - 2016 (Turkish Ministry of Health, Turkish Medicine and Medical Device Agency, 1st Edition, 2016). The analysis method is determined by, for example, HPLC and/or HPTLC device analysis. Within the scope of this invention, the percentage mentioned is a relative ratio and expresses the amount of rosmarinic acid compared to the total amount of substance in the rosmarinic acid sample subjected to analysis. For example, if the entire peak area obtained in the HPLC analysis of a rosmarinic acid sample is expressed as 100, the area of the peak corresponding to rosmarinic acid in a rosmarinic acid sample according to the invention should be at least 95. The term anti-inflammatory agent used here means COX-1 and/or In another aspect, the invention also includes agents that have COK-2 and/or LOX inhibitor effects, as an active ingredient suitable for use as an anti-inflammatory agent, with at least 95% purity, preferably 95-99% purity. In one embodiment of the invention, the said additional anti-inflammatory agent may be ibuprofen or diclofenac, especially in pharmaceutical compositions containing 97-99% purity rosmarinic acid, in the same dosage form or in different dosage forms. If the combination formulations according to the invention are formulated in different dosage forms, said formulations can be used at different times or simultaneously or sequentially. The formulations according to the invention can be formulated in a dosage form suitable for oral or topical use. Oral formulations can be in any of the forms of tablet, capsule, extended-release capsule, delayed-release capsule, syrup, emulsion, suspension, coated tablet, layered tablet, orodispersible tablet, effervescent tablet, sachet, or sublingual tablet. Topical formulations can be in any of the forms of ointment, cream, gel, hydrogel or lotion. In addition to rosmarinic acid, the formulations according to the invention may contain at least one pharmaceutically acceptable excipient. Said excipient does not have any therapeutic effect and may be used to meet a need arising during the preparation or preservation of the formulation or during its use. Industrial Applicability Thanks to the invention, natural origin agents suitable for use as anti-inflammatory agents have been developed. In this respect, the invention interests both end users in the healthcare sector and drug developers. Examples Example 1: IC50 values for COX-1 and COX-Z inhibition of the rosmarinic acid sample with at least 95% purity according to the invention and its comparison with known anti-inflammatory agents. In the rosmarinic acid sample used in the study whose results are given below, 95% Substance No. ICwater (ug/mL) SI When the results in Example 1 are evaluated, it is seen that the sample containing at least 95% rosmarinic acid in accordance with the invention has a better anti-inflammatory effect than anti-inflammatory agents such as diclofenac and ibuprofen, which have been used commercially for a long time, even though it is a natural substance. As seen here, the natural agent according to the invention shows better efficacy than diclofenac in terms of both COX-1 and COX-Z inhibition. On the other hand, it appears that the extract according to the invention has a significantly better effect than ibuprofen in terms of COX-Z inhibition. The selectivity of COX-Z inhibition in anti-inflammatory agents is associated with the low stomach irritating side effects of the said agent. In this context, it is concluded that it is possible to prepare an anti-inflammatory agent with unexpectedly less half-effects with the natural agent in accordance with the invention. All these experimental data reveal that this naturally occurring ingredient may be an important anti-inflammatory agent. TR TR TR TR
Claims (8)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TR2021021389A1 true TR2021021389A1 (en) | 2023-07-21 |
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