TW201725041A - The pharmaceutical composition for reduction of skin irritation - Google Patents

The pharmaceutical composition for reduction of skin irritation Download PDF

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TW201725041A
TW201725041A TW105143951A TW105143951A TW201725041A TW 201725041 A TW201725041 A TW 201725041A TW 105143951 A TW105143951 A TW 105143951A TW 105143951 A TW105143951 A TW 105143951A TW 201725041 A TW201725041 A TW 201725041A
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hydrochloride
pharmaceutical composition
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skin
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李伊俐
鄭建新
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懷特生技新藥股份有限公司
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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

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Abstract

A method for reduction of skin irritation in a subject, wherein the method comprising a pharmaceutical composition including a nalbuphine hydrochloride and a pharmaceutically acceptable excipient.

Description

治療皮膚癢之醫藥組合物 Medical composition for treating skin itching

本發明係提供一種用於製備治療皮膚癢醫藥組合物之用途，其中該醫藥組合物包含一有效劑量的鹽酸納布芬及一藥物可接受的賦形劑所組成。 The present invention provides a use for the preparation of a pharmaceutical composition for treating skin itching, wherein the pharmaceutical composition comprises an effective amount of nebufen hydrochloride and a pharmaceutically acceptable excipient.

發炎反應在維持生理功能的恆定上有著重要的作用，而且和許多慢性皮膚疾病的發生有著一定的關係。嗜中性白血球(Neutrophils)和巨噬細胞(macrophages)釋出的蛋白酵素、活性氧屬前趨物、細胞激素和neutrophil extracellular traps(NETs)，除了能夠清除微生物外，也會造成周圍組織的損傷。最近幾年的研究證實，嗜中性白血球和巨噬細胞不僅有先天免疫的能力，也具有後天免疫的功能。化療藥物的治療，無論是單獨或合併使用，都會引起許多嚴重的副作用。最近的研究指出，化療藥物會引起發炎反應，而發炎反應也可能造成癌細胞的增生或轉移。研究證據顯示，抑制嗜中性白血球和巨噬細胞(macrophages)的發炎反應可能有助於抗癌作用和降低化療藥物引起的副作用。 The inflammatory response plays an important role in maintaining a constant physiological function and has a certain relationship with the occurrence of many chronic skin diseases. Neutrophils and macrophages release protein enzymes, ROS precursors, cytokines and neutrophil extracellular traps (NETs), in addition to scavenging microorganisms, can also cause damage to surrounding tissues. . Recent studies have confirmed that neutrophils and macrophages not only have the ability to innate immunity, but also have the function of acquired immunity. The treatment of chemotherapeutic drugs, either alone or in combination, can cause many serious side effects. Recent studies have pointed out that chemotherapy drugs can cause inflammatory reactions, and inflammatory reactions may also cause cancer cells to proliferate or metastasize. Research evidence suggests that inhibition of inflammatory responses by neutrophils and macrophages may contribute to anticancer effects and reduce side effects caused by chemotherapy drugs.

嗜中性白血球釋放的NETs會引發T細胞的啟動(priming)；嗜中性白血球和TH17細胞有cross-talk的作用，而TH17細胞已被證實與異位性皮膚 炎(atopic dermatitis)以及乾癬(psoriasis)的有關。越來越多研究提出，嗜中性白血球過度或不當活化和皮膚發炎疾病，如：乾癬、異位性皮膚炎及光老化(photoaging)，有重要的關係。 NETs released by neutrophils trigger priming of T cells; neutrophils and TH17 cells have cross-talk effects, while TH17 cells have been shown to be associated with atopic skin Atopic dermatitis and related to psoriasis. More and more studies have suggested that neutrophilic excessive or inappropriate activation and skin inflammatory diseases such as dryness, atopic dermatitis and photoaging have important relationships.

發炎小體是細胞內的多蛋白複合體，具有感應及調控功能，為人體免疫系統中重要的一環。當巨噬細胞受到病源分子或是危險分子刺激時，發炎小體會快速組裝並活化，進而產生免疫反應來抵禦攻擊。發炎小體的活化可以激活caspase-1，進而催化促發炎激素IL-1β及IL-18蛋白裂解並釋放於細胞外。近年來，許多研究指出，發炎小體的失調涉及了許多免疫疾病的產生，像是：癌症、阿茲海默症、糖尿病等。抑制發炎小體的IL-1β及IL-18活化或製造，具有抗癌作用。許多化療藥物，如：melphalan,cisplatin,vincristine,etoposide,paclitaxel,methotrexate,and cytarabine，會造成巨噬細胞發炎小體的活化。所以，抑制巨噬細胞發炎小體的活化將能降低化療藥物引起的副作用。 The inflammatory body is a multi-protein complex in the cell, which has an induction and regulation function and is an important part of the human immune system. When macrophages are stimulated by pathogenic molecules or dangerous molecules, the inflamed bodies assemble and activate rapidly, which in turn produces an immune response against the attack. Activation of inflammatory bodies activates caspase-1, which in turn catalyzes the cleavage of the inflammatory hormones IL-1β and IL-18 and releases them extracellularly. In recent years, many studies have pointed out that the dysregulation of inflammatory bodies involves the production of many immune diseases, such as: cancer, Alzheimer's disease, diabetes and so on. It inhibits the activation or production of IL-1β and IL-18 of inflammatory bodies and has an anticancer effect. Many chemotherapy drugs, such as melphalan, cisplatin, vincristine, etoposide, paclitaxel, methotrexate, and cytarabine, cause activation of macrophage inflammatory bodies. Therefore, inhibition of the activation of macrophage inflammatory bodies will reduce the side effects caused by chemotherapy drugs.

單純皮膚癢，基本上為單純來自皮膚疾病的癢，常見的異位性皮膚炎、蕁麻疹、慢性濕疹或乾癬等疾病，由黴菌、蚊蟲及寄生蟲叮咬後所產生的癢症均屬於範疇之內。內臟疾病造成的癢，身體器官病變或疾病，也可導致皮膚出現癢感，例如：洗腎患者、B型肝炎、C型肝炎、愛滋病患、甲狀腺疾病、副甲狀腺疾病、慢性腎病以及缺鐵性貧血的患者，其中膽汁肝膽類及腎臟型病患為難治型的皮膚癢。神經性的癢，源自於神經本身的癢感，分為中樞神經癢與周邊神經癢。中樞神經癢，最常見的微帶狀皰疹痊癒後，部分患者會有神經癢或神經痛等症狀；周邊神經癢，則為腦瘤或癌症病人施打嗎啡之後遺症。精神性的癢，為患者幻想出的癢，屬於身體 的幻想。 Simple skin itching, basically itchy from skin diseases, common atopic dermatitis, urticaria, chronic eczema or dryness. The itch caused by mold, mosquitoes and parasites is a category. within. Itching caused by visceral diseases, body organ diseases or diseases can also cause skin itching, such as: dialysis patients, hepatitis B, hepatitis C, AIDS, thyroid disease, parathyroid disease, chronic kidney disease and iron deficiency Anemia patients, in which bile hepatobiliary and kidney-type patients are refractory skin itching. Neurotic itching originates from the itchiness of the nerve itself and is divided into central nervous system itch and peripheral nerve itching. Central nervous system itch, the most common micro-shingles after healing, some patients will have symptoms such as nerve itching or neuralgia; peripheral nerve itching, for patients with brain tumors or cancer, morphine sequelae. Mental itching, itching for the patient, belongs to the body Fantasy.

舒緩癢症的分法，包括外用藥物、口服藥物與照光。常用外用藥物為含有薄荷腦(醇)或使用痱子膏，主要用以降低表皮溫度，但無法根治解決癢的問題，屬於症狀治療。然而於醫師處方簽中常使用含抗組織胺的藥膏或局部麻醉劑做為紓緩癢症的方法。口服藥物則以抗組織胺藥物為主，少部分情況下則使用口服抗憂鬱劑，使中樞神經的癢感被壓抑。照光，對於排斥服用藥物之病患則藉由特殊波長的紫外光照射使引起皮膚癢的介質降低。 The classification of soothing itch, including topical drugs, oral medications and illuminating. Commonly used topical drugs are menthol (alcohol) or scorpion cream, which is mainly used to reduce the temperature of the epidermis, but can not cure the problem of itching. It belongs to symptom treatment. However, ointment containing antihistamine or local anesthetic is often used as a method for relieving itching in physician prescriptions. Oral drugs are mainly antihistamine drugs, and in some cases, oral antidepressants are used, so that the central nervous system's itching is suppressed. According to the light, for patients who are taking drugs, the medium causing itching of the skin is lowered by irradiation with ultraviolet light of a specific wavelength.

舉例而言，如前述洗腎患者容易有搔癢的症狀，而洗腎患者搔癢的原因有尿毒毒素太高、皮膚乾燥以及維他命A、副甲狀腺素、組織胺及鈣、鎂、磷等離子在洗腎時，不易被洗出體外，堆積在體內，也會引發強烈癢感。 For example, patients with dialysis are prone to have itching symptoms, and pruritus patients have itchy urinary toxins, dry skin, and vitamin A, parathyroid hormone, histamine, and calcium, magnesium, and phosphorus in dialysis. When it is not easy to be washed out of the body and accumulated in the body, it will also cause a strong itching.

換句話說，因洗腎患者於接受透析過程中所使用的各種類透析膜，易造成透析期間不同程度的補體活化，促使患者肥大細胞和嗜鹼細胞釋放出組織胺，進而造成患者搔癢症狀。而目前臨床上主要是使用肝素等藥物來減緩洗洗腎患者的發炎反應，但長期使用肝素，易增加出血的風險。另外，臨床上亦有使用.Thalidomide緩解***之洗腎患者患者的搔癢，但會造成患者免疫抑制之副作用。 In other words, because of the various types of dialysis membranes used by dialysis patients during the dialysis process, it is easy to cause different degrees of complement activation during dialysis, prompting the release of histamine from mast cells and basophils, which may cause itching symptoms. At present, the main clinical use of heparin and other drugs to slow the inflammatory response of patients with kidney washing, but long-term use of heparin, easy to increase the risk of bleeding. In addition, clinical use of Thalidomide to relieve uremia in patients with dialysis patients with pruritus, but it will cause side effects of immunosuppression.

然而，上述舒緩皮膚癢之藥物或治療方法無法長期或有效地舒緩皮膚癢之症狀且僅能由患者自我評分來界定皮膚癢之程度。因此，極需具較長效型效果之藥物方法有效地舒緩皮膚癢之症狀以及輔助檢測皮膚癢的程度的方法，特別是能應用於具特殊病症的患者如洗腎患者而減緩其搔癢 症狀的藥物與方法。 However, the above-mentioned drugs or treatments for relieving skin itching cannot relieve the symptoms of itchy skin for a long time or effectively and can only define the degree of skin itching by the patient self-scoring. Therefore, there is a great need for a drug method having a long-acting effect to effectively relieve the symptoms of itchy skin and a method for assisting in detecting the degree of itchy skin, in particular, it can be applied to patients with special diseases such as dialysis patients to slow itching. Symptoms of drugs and methods.

有鑑於此，本發明提供一種用於製備治療皮膚癢醫藥組合物之用途，其中該醫藥組合物包含一有效劑量的鹽酸納布芬(nalbuphine hydrochloride)及一藥物可接受的鹽類所組成。 In view of the above, the present invention provides a use for the preparation of a pharmaceutical composition for treating skin itching, wherein the pharmaceutical composition comprises an effective amount of nalbuphine hydrochloride and a pharmaceutically acceptable salt.

有鑑於此，本發明提供一種舒緩皮膚癢之方法，其中該舒緩皮膚癢之方法包含提供皮膚癢之洗腎疾病患者一含有鹽酸納布芬之醫藥組合物，一天2次，每次劑量為60mg~180mg。 In view of the above, the present invention provides a method for relieving skin itch, wherein the method for relieving skin itch comprises providing a diarrhea dialysis patient, a pharmaceutical composition containing nabfen hydrochloride, twice a day, each dose of 60 mg ~180mg.

較佳的，其中該皮膚癢係由於洗腎所引起的。 Preferably, the skin itching is caused by dialysis.

較佳的，其中該有效劑量為60mg~180mg。 Preferably, the effective dose is from 60 mg to 180 mg.

較佳的，其中該鹽酸納布芬醫藥組物係早晚各服用1次。 Preferably, the nabufen hydrochloride medical group is taken once in the morning and evening.

較佳的，其中該鹽酸納布芬醫藥組物係為口服或塗抹。 Preferably, the naprofamine hydrochloride pharmaceutical group is orally or smeared.

較佳的，其中該鹽酸納布芬醫藥組物為該口服劑型時，該賦形劑係選自由1,2-二羥基丙烷、醣醛酸、二甘醇***、角鯊烯、丙烯酸甘油酯、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯和水所組成之群組。 Preferably, wherein the naprofamine hydrochloride pharmaceutical composition is the oral dosage form, the excipient is selected from the group consisting of 1,2-dihydroxypropane, uronic acid, diethylene glycol ethyl ether, squalene, glyceryl acrylate. a group consisting of methylparaben, propylparaben and water.

較佳的，其中該鹽酸納布芬醫藥組物為該塗抹劑型時，該賦形劑係選自由1,2-二羥基丙烷、醣醛酸、二甘醇***、角鯊烯、丙烯酸甘油酯、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯和水所組成之群組。 Preferably, wherein the naprofamine hydrochloride pharmaceutical composition is the application form, the excipient is selected from the group consisting of 1,2-dihydroxypropane, uronic acid, diethylene glycol ethyl ether, squalene, glyceryl acrylate. a group consisting of methylparaben, propylparaben and water.

第1圖為鹽酸納布芬醫藥組合物抑制在被fMLF/CB活化的人類嗜中性白血球之超氧化物結果。 Figure 1 is a graph showing the results of inhibition of superoxide in human neutrophils activated by fMLF/CB by a drug composition of nabuffine hydrochloride.

第2圖為鹽酸納布芬醫藥組合物抑制在被fMMYALF/CB活化的人類嗜中性白血球之超氧化物結果。 Figure 2 is a graph showing the inhibition of superoxide in human neutrophils activated by fMMYALF/CB by a drug composition of nabufen hydrochloride.

第3圖為鹽酸納布芬醫藥組合物抑制在被PMA活化的人類嗜中性白血球之超氧化物結果。 Figure 3 is a graph showing the results of inhibition of superoxide in human neutrophils activated by PMA by a pharmaceutical composition of Nabuffine Hydrochloride.

第4圖為鹽酸納布芬醫藥組合物無顯著抑制在被fMLF/CB活化的人類嗜中性白血球之彈性蛋白酶(elastase)的釋放結果。 Figure 4 is a graph showing the release of elastase from human neutrophils activated by fMLF/CB without significant inhibition of the naprofene hydrochloride pharmaceutical composition.

第5圖為經鹽酸納布芬醫藥組合物處理的人類嗜中性白血球釋放LDH測試結果。 Figure 5 is a graph showing the results of human neutrophil LDH release by treatment with a drug composition of nabuff hydrochloride.

第6圖為鹽酸納布芬醫藥組合物在cell-free xanthine/xanthine oxidase系統中清除超氧化物測試。 Figure 6 is a graph showing the removal of superoxide in a cell-free xanthine/xanthine oxidase system of nabuffine hydrochloride pharmaceutical composition.

第7圖為鹽酸納布芬醫藥組合物抑制在被fMLF/CB活化的人類嗜中性白血球之細胞貼合效果測試結果。 Fig. 7 is a graph showing the results of cell adhesion test of human neutrophils inhibited by fMLF/CB by a drug composition of nabuffine hydrochloride.

第8圖為鹽酸納布芬醫藥組合物抑制在被PMA活化的人類嗜中性白血球之NET形成測試結果。 Figure 8 is a graph showing the results of NET formation test for inhibition of human neutrophils induced by PMA by a drug composition of Nabuffine Hydrochloride.

第9圖為鹽酸納布芬醫藥組合物沒有造成在LPS-primed THP-1巨噬細胞之LDH的釋放測試。 Figure 9 is a graph showing that the naprofamine hydrochloride pharmaceutical composition did not cause release of LDH in LPS-primed THP-1 macrophages.

第10圖為鹽酸納布芬醫藥組合物抑制在LPS-primed THP-1的巨噬細胞之NLRP3-dependent發炎體活化。 Figure 10 is a graph showing the inhibition of NLRP3-dependent inflammatory body activation of macrophages in LPS-primed THP-1 by a drug composition of nabuffine hydrochloride.

第11圖4種不同配方的鹽酸納布芬(nalbuphine hydrochloride)醫藥組合物抑制在被fMLF/CB活化的嗜中性白血球之細胞內ROS產生，利用流式細胞儀測量螢光量來代表細胞內所被標定ROS含量，與對照相比*代表P<0.05，**代表P<0.01，***代表P<0.001。。 Figure 11 Figure 4 nalbuphine hydrochloride pharmaceutical composition of different formulations inhibits ROS production in neutrophils of fMLF/CB-activated neutrophils, and the amount of fluorescence is measured by flow cytometry to represent intracellular sites. The ROS content was calibrated, * represents P < 0.05 compared with the control, ** represents P < 0.01, and *** represents P < 0.001. .

第12圖4種不同配方的鹽酸納布芬(nalbuphine hydrochloride)醫藥組合物抑制在被fMLF/CB活化的嗜中性白血球之細胞內ROS產生，為典型的螢光啟動細胞分選概況的直方圖，平均熒光強度顯示為平均值±S.E.M(n=4)，與對照相比*代表P<0.05，**代表P<0.01，***代表P<0.001。 Figure 12: 4 different formulations of nalbuphine hydrochloride pharmaceutical composition inhibits intracellular ROS production in fMLF/CB-activated neutrophils, a histogram of a typical fluorescent-primed cell sorting profile. The mean fluorescence intensity is shown as mean ± SEM (n = 4), * represents P < 0.05 compared to the control, ** represents P < 0.01, and *** represents P < 0.001.

1. 鹽酸納布芬醫藥組合物抑制活化態嗜中性白血球所造成的氧化壓力。1. The naprofamine hydrochloride pharmaceutical composition inhibits the oxidative stress caused by activated neutrophils.

嗜中性白血球NADPH oxidase產生的氧化壓力不僅會造成周邊組織的傷害，也會進一步全面啟動自己的發炎反應，所以針對發炎性疾病的藥物開發而言，嗜中性白血球NADPH oxidase是一個非常有重要的治療標靶。NADPH oxidase生成的超氧自由基會由噬菌體或granules的膜釋放到細胞內或是經由細胞膜直接釋出到細胞外，超氧自由基會被分解成hydrogen peroxide(H2O2)，hydroxyl radical(OH)，和hypochlorous acid(HOCl)，這些反應和許多發炎性疾病有重要的關係。目前研究認為plasma membrane和phagosome or granule membrane上的NADPH oxidase的調控機制不同，功能也不同。所以研究藥物抑制嗜中性白血球造成的氧化壓力時，須能區分細胞內或細胞外來源。 The oxidative stress produced by neutrophil NADPH oxidase not only causes damage to surrounding tissues, but also further activates its own inflammatory response. Therefore, neutrophil NADPH oxidase is very important for drug development of inflammatory diseases. Therapeutic targets. The superoxide radical generated by NADPH oxidase is released into the cell by the membrane of phage or granules or directly released into the cell via the cell membrane, and the superoxide radical is decomposed into hydrogen peroxide (H 2 O 2 ), hydroxyl radical ( OH), and hypochlorous acid (HOCl), these reactions have important relationships with many inflammatory diseases. At present, it is considered that the regulation mechanism of NADPH oxidase on plasma membrane and phagosome or granule membrane is different and its function is different. Therefore, when the study drug inhibits the oxidative stress caused by neutrophils, it must be able to distinguish between intracellular or extracellular sources.

細胞外O2 ‧-釋放之測定：將含有0.5mg/ml ferricytochromec的嗜中性白血球懸浮液，預熱5分鐘使達37℃，加入鹽酸納布芬醫藥組合物作用後，再以不同的化學趨化物活化細胞。使用紫外光分光光度計，於波長550nm下測量其吸光值。實驗中評估嗜中性白血球所釋出O2‧-的量(extinction coefficient 21.1/mM/cm)可以經由superoxide dismutase(SOD,20U/ml)抑制ferricytochrome c還原，計算得知。 Determination of extracellular O 2 ‧- release: a neutrophil suspension containing 0.5 mg/ml ferricytochromec was preheated for 5 minutes to reach 37 ° C, added to the drug composition of Nabuffine hydrochloride, and then treated with different chemistry Chemotides activate cells. The absorbance was measured at a wavelength of 550 nm using an ultraviolet spectrophotometer. Evaluation experiment neutrophil O2 ‧- the amount of release (extinction coefficient 21.1 / mM / cm ) can be inhibited by superoxide dismutase (SOD, 20U / ml ) ferricytochrome c reduction, that is calculated.

2. 鹽酸納布芬醫藥組合物抑制活化態嗜中性白血球的彈性蛋白酶釋放。2. The naprofene hydrochloride pharmaceutical composition inhibits elastase release from activated neutrophils.

嗜中性白血球被活化時會經去顆粒反應釋放彈性蛋白酶。彈性蛋白酶不僅會造成發炎反應，也和癌症有關。將含Ms-Ala-Ala-Pro-Val-pNA的嗜中性白血球懸浮液，預熱5分鐘使達37℃，加入鹽酸納布芬醫藥組合物作用後，再加入不同的化學趨化物造成彈性蛋白酶釋放。使用紫外光分 光光度計，於波長405nm下測量其吸光值。 When the neutrophils are activated, they release the elastase via a degranulation reaction. Elastase not only causes an inflammatory response, but is also associated with cancer. The neutrophil suspension containing Ms-Ala-Ala-Pro-Val-pNA was preheated for 5 minutes to reach 37 ° C. After adding the drug composition of Nabuffine hydrochloride, different chemical chemotactic compounds were added to cause elasticity. Protease release. Using ultraviolet light The photometer was measured for its absorbance at a wavelength of 405 nm.

3. 鹽酸納布芬醫藥組合物降低嗜中性白血球NETs形成現象。3. Nabufen hydrochloride pharmaceutical composition reduces the formation of neutrophil NETs.

受到細菌感染或特定刺激物活化的嗜中性白血球會將染色體結構和抗微生物分子，已類似網狀的形式釋放出去，這個過程稱為NETosis。NETs的主要組成有DNA，修飾的histones，和一些顆粒蛋白。NETs是一種能幫助宿主抵禦病源入侵的抗微生物防禦性結構，但是越來越多的研究證據證實，某些肺部發炎疾病、自體免疫皮膚病、類風濕性關節炎以及系統性紅斑狼瘡等也和NETs的有關[24-27]。嗜中性白血球懸浮液與不具細胞膜通透性的DNA染劑SYTOX Green混於37℃，再加入刺激劑反應。使用TECAN infinite 200Pro螢光讀盤儀，偵測螢光數值的變化或以顯微鏡分析螢光影像。 Neutrophilic white blood cells, which are activated by bacterial infections or specific stimuli, release the chromosomal structure and antimicrobial molecules, which are already reticulated, a process called NETosis. The main components of NETs are DNA, modified hisons, and some granule proteins. NETs are an antimicrobial defensive structure that helps the host fight against pathogen invasion, but more and more research evidence confirms certain lung inflammatory diseases, autoimmune skin diseases, rheumatoid arthritis, and systemic lupus erythematosus. Also related to NETs [24-27]. The neutrophil suspension was mixed with SYTOX Green, a DNA stain that does not have cell membrane permeability, at 37 ° C, and then added with a stimulant. Use the TECAN infinite 200Pro Fluorescent Reader to detect changes in fluorescent values or to analyze fluorescent images with a microscope.

4. 鹽酸納布芬醫藥組合物改變嗜中性白血球吸附能力。4. Nabufen hydrochloride pharmaceutical composition changes the neutrophil adsorption capacity.

受到化學趨化物活化的嗜中性白血球會藉由integrin(CD11/CD18)相關吸附(adhesion)作用，轉移(migration)至發炎損傷區域。將嗜中性白血球懸浮液，預熱5分鐘使達37℃，加入鹽酸納布芬醫藥組合物作用後，將細胞加入含有fibrinogen(0.1mg/ml)的培養皿內，再加入fMLF反應10分鐘，最後加入Hoechst反應10分鐘。利用20倍物鏡顯微鏡(OLYMPUS IX81)觀察嗜中性白血吸附現象。 Neutrophilic white blood cells activated by chemotactic compounds will migrate to the inflamed lesion area by integrin (CD11/CD18)-associated adsorption. The neutrophil suspension was preheated for 5 minutes to reach 37 ° C. After adding the drug composition of nabuff hydrochloride, the cells were added to a petri dish containing fibrinogen (0.1 mg/ml), and then fMLF was added for 10 minutes. Finally, add Hoechst reaction for 10 minutes. Neutrophil white blood adsorption was observed using a 20x objective microscope (OLYMPUS IX81).

5. 鹽酸納布芬醫藥組合物抑制巨噬細胞釋放IL-1β的作用。5. The naprofamine hydrochloride pharmaceutical composition inhibits the release of IL-1β by macrophages.

發炎小體的活化可以激活caspase-1，進而催化促發炎激素IL-1β及IL-18蛋白裂解並釋放於細胞外。THP-1先以phorbolmyristate acetate(PMA)刺激3小時後，靜置21小時，使其分化成巨噬細胞，再加入nigercin等刺激劑來造成發炎小體的活化。收取上清液，以ELISA分析IL-1β的濃度。 Activation of inflammatory bodies activates caspase-1, which in turn catalyzes the cleavage of the inflammatory hormones IL-1β and IL-18 and releases them extracellularly. THP-1 was stimulated with phorbolmyristate acetate (PMA) for 3 hours, then allowed to stand for 21 hours to differentiate into macrophages, and then stimulant such as nigercin was added to cause activation of the inflammatory body. The supernatant was collected and analyzed for IL-1β concentration by ELISA.

6. 4種鹽酸納布芬醫藥組合物配方抑制活化態嗜中性白血球之細胞內ROS產生6. Four nabufen hydrochloride pharmaceutical composition formulations inhibit intracellular ROS production in activated neutrophils

細胞內ROS之測定：將標定DHR123的嗜中性白血球，加入鹽酸納布芬醫藥組合物反應後，以不同的化學趨化物來活化細胞。利用流式細胞儀測量螢光量來代表細胞內所被標定ROS含量。 Determination of intracellular ROS: The neutrophils of DHR123 were spiked and added to the Nabuffine hydrochloride pharmaceutical composition to react, and the cells were activated with different chemotactic compounds. Fluorescence is measured by flow cytometry to represent the amount of ROS that is calibrated within the cell.

7. 搔癢的數值等級(NRS)量表(Numerical rating scale(NRS)score)7. Iterative numerical rating scale (NRS) score (Numerical rating scale (NRS) score)

癢，是一種主觀感受，除主觀上可觀察患者持續搔抓身體上的某個部位外，醫師於看診時透過1~10分的量表並由病患界定癢的程度。然而同樣屬於「好癢」，部分病患給出5分，但部分病患則給出1分。本次主要測試的病患為洗腎的患者。目前對癢症的分類為對皮膚是否有病灶做為分類，第一類為皮膚出現病灶的皮膚癢，如異位性皮膚炎、乾癬及慢性濕疹等原發病症所引起的癢感，第二類為無病灶的癢，皮膚外觀無病灶，但病患會覺得癢，第三類為已出現病灶，但此類病灶則為病患因前兩類的癢所抓而造成的病灶。另一種癢症的分類法，則藉由癢的來源區分，例如：單純皮膚癢、內臟疾病造成的癢、神經性的癢、精神病的癢及其他原因引起的癢。 Itching is a subjective feeling. Except that subjectively observable patients continue to scratch a certain part of the body, the physician uses a scale of 1 to 10 points at the time of the visit and defines the degree of itching by the patient. However, it is also a "good itch". Some patients give 5 points, but some patients give 1 point. The patient who was tested this time was a patient who was dialysis. At present, the classification of itching is classified as whether the skin has lesions. The first type is the itchy skin of the skin, such as atopic dermatitis, dryness and chronic eczema. The second type is itchy without lesions, the skin has no lesions, but the patients will feel itchy. The third type has lesions, but these lesions are caused by the first two types of itching. Another classification of itch is distinguished by the source of itching, such as: itchy skin, itching caused by visceral diseases, itching of nerves, itching of mental illness and itching caused by other causes.

8. 實驗結果8. Experimental results

利用fMLF(外源性FPR1刺激劑)以及fMMYALF(內生性FPR1刺激劑)活化嗜中性白血球，鹽酸納布芬醫藥組合物具有濃度相關性抑制超氧自 由基產生的作用，IC50值分別是55.96±20.64μM以及76.53±27.95μM(圖1 and圖2)。再者，利用PMA刺激嗜中性白血球產生超氧自由基，鹽酸納布芬醫藥組合物在高濃度的情況下才具顯著抑制(圖3)。另外，在彈性蛋白酶釋放反應測試結果，鹽酸納布芬醫藥組合物無顯著抑制fMLF刺激造成的彈性蛋白酶釋放(圖4)。鹽酸納布芬醫藥組合物在實驗濃度，不論是短時間或長時間皆不會影響細胞存活率，結果顯示在試驗過程中，鹽酸納布芬醫藥組合物沒有細胞毒性(圖5)。根據這些實驗結果，推論鹽酸納布芬醫藥組合物選擇性抑制NADPH oxidase活化作用。 Activation of neutrophils using fMLF (exogenous FPR1 stimulator) and fMMYALF (endogenous FPR1 stimulator), a concentration-dependent inhibition of superoxide from nabuffine hydrochloride The IC50 values were 55.96 ± 20.64 μM and 76.53 ± 27.95 μM (Fig. 1 and Fig. 2), respectively. Furthermore, the use of PMA to stimulate neutrophils to produce superoxide radicals, the naprofene hydrochloride pharmaceutical composition was significantly inhibited at high concentrations (Fig. 3). In addition, in the elastase release reaction test, the naprofene hydrochloride pharmaceutical composition did not significantly inhibit elastase release caused by fMLF stimulation (Fig. 4). The naprofamine hydrochloride pharmaceutical composition did not affect cell viability at the experimental concentrations, either for a short period of time or for a long period of time, and the results showed that the naprofene hydrochloride pharmaceutical composition was not cytotoxic during the test (Fig. 5). Based on these experimental results, it is inferred that the naprofamine hydrochloride pharmaceutical composition selectively inhibits the activation of NADPH oxidase.

為了瞭解鹽酸納布芬醫藥組合物的抑制能力是透過直接清除自由基或是透過影響嗜中性白血球的活化訊號，設計實驗評估鹽酸納布芬醫藥組合物直接清除superoxide anion的能力。鹽酸納布芬醫藥組合物在濃度高達300μM時，仍不具顯著抑制xanthine/xanthine oxidase系統產生超氧自由基的能力(圖6)，實驗結果說明，鹽酸納布芬醫藥組合物應該是直接抑制嗜中性白血球的活化。自由基的產生會誘導嗜中性白血球integrin的表現。透過抑制CD11b的表現，我們也證實鹽酸納布芬醫藥組合物會抑制嗜中性白血球的吸附作用(圖7)。 In order to understand the inhibitory ability of the naprofene hydrochloride pharmaceutical composition, the ability to directly remove the superoxide anion by the nabufen hydrochloride pharmaceutical composition was evaluated by direct scavenging of free radicals or by activation signals affecting neutrophils. Nabuffine hydrochloride pharmaceutical composition does not significantly inhibit the ability of the xanthine/xanthine oxidase system to produce superoxide free radicals at concentrations up to 300 μM (Fig. 6). The experimental results indicate that the naprofene hydrochloride pharmaceutical composition should be directly inhibited. Activation of neutrophils. Free radical production induces the performance of neutrophil integrin. By inhibiting the performance of CD11b, we also confirmed that the naproxen hydrochloride pharmaceutical composition inhibits the adsorption of neutrophils (Fig. 7).

嗜中性白血球NETs是被嗜中性白血球釋放出去限制病原體移動並加以破壞分解病原體的物質。然而，若是NETs不當釋出或作用後清除不乾淨，可能造成許多嗜中性白血球為主的發炎反應所引起的疾病，包括系統性紅斑狼瘡、類風溼性關節炎、阿茲海默症等等。鹽酸納布芬醫藥組合物在濃度30-300μM時具有抑制由PMA刺激嗜中性白血球形成NETs的效果(圖8)。 Neutrophilic white blood cells, NETs, are substances that are released by neutrophils to limit the movement of pathogens and destroy the pathogens. However, if NETs are improperly released or removed, it may cause many neutrophil-induced inflammatory reactions, including systemic lupus erythematosus, rheumatoid arthritis, Alzheimer's disease, etc. . The nabfen hydrochloride pharmaceutical composition has an effect of inhibiting the formation of NETs by neutrophil leukocytes by PMA at a concentration of 30-300 μM (Fig. 8).

另一部分，鹽酸納布芬醫藥組合物在不影響LPS-primed THP-1細胞存活率的濃度下(圖9)，具有抑制nigericin刺激下形成和釋放IL-1β的作用。有趣地，鹽酸納布芬醫藥組合物(3-300μM)在這個實驗的抑制能力有biphasic的現象，在濃度30μM時有最強抑制能力(圖10)。 In another part, the naprofamine hydrochloride pharmaceutical composition has the effect of inhibiting the formation and release of IL-1β under the stimulation of nigericin at a concentration that does not affect the survival rate of LPS-primed THP-1 cells (Fig. 9). Interestingly, the inhibitory ability of the naprofene hydrochloride pharmaceutical composition (3-300 μM) in this experiment was biphasic, with the strongest inhibitory ability at a concentration of 30 μM (Fig. 10).

嗜中性白血球在急性發炎的重要性已經被廣為了解，而且越來越多的研究證實，它們在慢性發炎和自體免疫疾病過程中，也有著重要的關鍵角色。所以，針對發炎性疾病的治療而言，嗜中性白血球是一個極為重要的治療標靶。然而直到現在，只有少數臨床用藥是針對抑制嗜中性白血球的活化來治療發炎性疾病。在本計畫中，我們證明鹽酸納布芬醫藥組合物選擇性抑制NADPH oxidase活化作用；而且有具有抑制inflammasome活化的能力。NADPH oxidase是負責超氧自由基產生的酵素，而超氧自由基是ROS的前驅物。在人類嗜中性白血球中，NADPH oxidase是由細胞質中的p47phox、p67phox、p40phox以及small GTP-binding protein Rac2與細胞膜上的flavocytochromeb558的複合物所組成的。在嗜中性白血球相關的發炎疾病中，NADPH oxidase的不當控制有著非常絕對的影響。總而言之，嗜中性白血球的NADPH oxidase是一個非常有意義的治療標靶。鹽酸納布芬醫藥組合物抑制FPR1刺激嗜中性白血球，活化NADPH oxidase，產生超氧自由基的作用，具有臨床重要性。 The importance of neutrophils in acute inflammation has been widely recognized, and more and more studies have confirmed that they also play an important role in the process of chronic inflammation and autoimmune diseases. Therefore, neutrophils are an extremely important therapeutic target for the treatment of inflammatory diseases. However, until now, only a small number of clinical drugs have been used to treat inflammatory diseases by inhibiting the activation of neutrophils. In this project, we demonstrate that the naproxen hydrochloride pharmaceutical composition selectively inhibits the activation of NADPH oxidase; and it has the ability to inhibit the activation of inflammasome. NADPH oxidase is the enzyme responsible for superoxide radical production, and superoxide radical is the precursor of ROS. In human neutrophils, NADPH oxidase is composed of a complex of p47phox, p67phox, p40phox, and small GTP-binding protein Rac2 in the cytoplasm and flavocytochromeb558 on the cell membrane. In neutrophil-associated inflammatory diseases, the inappropriate control of NADPH oxidase has a very absolute effect. In summary, NADPH oxidase in neutrophils is a very interesting therapeutic target. Nabuffine hydrochloride pharmaceutical composition inhibits FPR1 stimulation of neutrophils, activates NADPH oxidase, and produces superoxide free radicals, which is of clinical importance.

9. 鹽酸納布芬(nalbuphine hydrochloride)醫藥組合物口服劑型改良測試9. Nalbuphine hydrochloride pharmaceutical composition oral dosage form improvement test

鹽酸納布芬醫藥組合物的傳輸劑型，其包括藥學上可接受的賦形劑。這一提法包括鹽酸納布芬醫藥組合物。一種或多種藥學上可接受的 賦形劑的加入各種實施例。 A delivery form of a naproxen hydrochloride pharmaceutical composition comprising a pharmaceutically acceptable excipient. This formulation includes a naproxen hydrochloride pharmaceutical composition. One or more pharmaceutically acceptable Various embodiments of the excipients were added.

本發明之鹽酸納布芬醫藥組合物亦可包含口服劑型，以增加鹽酸納布芬的口服吸收，適用口服劑型包含：鹽酸納布芬、1,2-二羥基丙烷、醣醛酸、二甘醇***、角鯊烯、丙烯酸甘油酯、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯。 The nabuffine hydrochloride pharmaceutical composition of the present invention may further comprise an oral dosage form for increasing the oral absorption of nabfen hydrochloride, and the oral dosage form comprises: nabufen hydrochloride, 1,2-dihydroxypropane, uronic acid, digan Alcohol ether, squalene, glyceryl acrylate, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate.

其具有下列優點：因直接進入血液中而避開肝臟首度效應，大幅減低鹽酸納布芬醫藥組合物之副作用，方便使用，適用於長期使用，對肝臟影響較小，適用於肝功能不良的使用者，藥物交互作用小，適用於需同時使用多種藥物的患者皮膚刺激性比貼劑輕微甚多。 It has the following advantages: it avoids the first effect of the liver by directly entering the blood, greatly reduces the side effects of the naproxen hydrochloride pharmaceutical composition, is convenient to use, is suitable for long-term use, has less influence on the liver, and is suitable for liver dysfunction. Users, the drug interaction is small, suitable for patients who need to use multiple drugs at the same time, the skin irritation is much lighter than the patch.

鹽酸納布芬醫藥組合物口服劑型改良配方比例：Nabuffine Hydrochloride Pharmaceutical Composition Oral Formulation Modified Formula Ratio:

1. 配方1. 1. Formula 1.

2. 配方2 2. Formula 2

3. 配方3 3. Formula 3

4. 配方4 4. Formula 4

評估鹽酸納布芬醫藥組合物的4種配方是否抑制在被fMLF活化的嗜中性白血球細胞膜之CD11b的表現，使用DHR123螢光標的細胞內ROS，利用流式細胞儀偵測儀螢光的變化情形。實驗結果顯示，鹽酸納布芬醫藥組合物的4種配方具有抑制嗜中性白血球細胞膜上CD11b表現的作用(圖11和圖12)，即使用DHR123標記人嗜中性粒細胞，並用H2O(0.1%，作為對照組)或鹽酸納布芬醫藥組物(4組配方)作用5分鐘，然後通過fMLF/CB活化另外5分鐘，平均螢光強度顯示為平均值±S.E.M(n=4)，試驗結果以配方2鹽酸納布芬醫藥組合物抑制在被fMLF活化的嗜中性白血球細胞膜上CD11b表現的效果最佳。 To evaluate whether the four formulations of the naproxen hydrochloride pharmaceutical composition inhibit the expression of CD11b in the neutrophil cell membrane activated by fMLF, the intracellular ROS using the DHR123 cursor, and the change in fluorescence by flow cytometry situation. The results of the experiment showed that the four formulations of the naprofene hydrochloride pharmaceutical composition have the effect of inhibiting the expression of CD11b on the neutrophil cell membrane (Fig. 11 and Fig. 12), that is, using DHR123 to label human neutrophils and using H 2 O (0.1%, as a control group) or Nabuffine hydrochloride drug group (4 groups of formulas) for 5 minutes, then activated by fMLF/CB for another 5 minutes, the average fluorescence intensity is shown as mean ± SEM (n = 4) The test results were the best in inhibiting the expression of CD11b on the fMLF-activated neutrophil cell membrane by the formulation 2 Nabuffine hydrochloride pharmaceutical composition.

3個洗腎病患使用配方2鹽酸納布芬醫藥組合物後早晚填寫搔癢的數值等級(NRS)量表，服用此組合物後能有效降低2-5等級。 Three dialysis patients used the formula 2 Nabuffine hydrochloride pharmaceutical composition to fill in the pruritus numerical rating (NRS) scale in the morning and evening, and the composition can effectively reduce the grade 2-5.

最佳實施例為口服配方2鹽酸納布芬醫藥組合物早晚各服用1次，口服劑量從60mg~180mg。 The preferred embodiment is oral formulation 2 Nabuffine hydrochloride pharmaceutical composition is taken once in the morning and evening, and the oral dose is from 60 mg to 180 mg.

10. 鹽酸納布芬(nalbuphine hydrochloride)醫藥組合物皮膚穿透劑型改量測試10. Nalbuphine hydrochloride pharmaceutical composition skin penetrant dosage type test

本發明之鹽酸納布芬醫藥組合物亦可包含皮膚穿透促進劑，亦即鹽酸納布芬醫藥組合物之皮膚塗抹劑型，以增加鹽酸納布芬的皮膚穿透作用，適用皮膚穿透促進劑包含：鹽酸納布芬、1,2-二羥基丙烷、醣醛酸、二甘醇***、角鯊烯、丙烯酸甘油酯、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯，其具有下列優點：因直接進入血液中而避開肝臟首度效應，大幅減低鹽酸納布芬之副作用，方便使用，適用於長期使用，對肝臟影響較小，適用於肝功能不良的使用者，藥物交互作用小，適用於需同時使用多種藥物的患者皮膚刺激性比貼劑輕微甚多。 The nabuffine hydrochloride pharmaceutical composition of the present invention may further comprise a skin penetration enhancer, that is, a skin application form of the nabuffine hydrochloride pharmaceutical composition, to increase the skin penetration effect of nabuffine hydrochloride, and is suitable for skin penetration promotion. The agent comprises: nAbfen hydrochloride, 1,2-dihydroxypropane, uronic acid, diethylene glycol ethyl ether, squalene, glyceryl acrylate, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, which has the following Advantages: Avoiding the liver's first effect by directly entering the blood, greatly reducing the side effects of naproxen hydrochloride, convenient for use, suitable for long-term use, less impact on the liver, suitable for users with liver dysfunction, drug interaction Small, suitable for patients who need to use multiple drugs at the same time, the skin irritation is much lighter than the patch.

鹽酸納布芬(nalbuphine hydrochloride)醫藥組合物皮膚穿透劑型(塗抹劑型)改量配方比例：Nalbuphine hydrochloride pharmaceutical composition skin penetrant dosage form (smear dosage form) modified formula ratio:

1. 配方1 Formula 1

2. 配方2 2. Formula 2

3. 配方3 3. Formula 3

4. 配方4 4. Formula 4

3個洗腎病患使用配方2鹽酸納布芬醫藥組合物後早晚填寫搔癢的數值等級(NRS)量表，服用此組合物後能有效降低2-5等級。 Three dialysis patients used the formula 2 Nabuffine hydrochloride pharmaceutical composition to fill in the pruritus numerical rating (NRS) scale in the morning and evening, and the composition can effectively reduce the grade 2-5.

最佳實施例為塗抹納布配方2芬鹽酸醫藥組合物早晚各使用1次。 The preferred embodiment is the application of the Nabu formulation 2 fen hydrochloric acid pharmaceutical composition once in the morning and evening.

Claims (10)

一種用於製備治療皮膚癢醫藥組合物之應用，其中該醫藥組合物包含一有效劑量的鹽酸納布芬及一藥物可接受的賦形劑所組成。 A use for the preparation of a pharmaceutical composition for treating skin itching, wherein the pharmaceutical composition comprises an effective amount of nebufen hydrochloride and a pharmaceutically acceptable excipient. 如申請專利範圍第1項所述之應用，其中該皮膚癢係由於洗腎所引起的。 The application of claim 1, wherein the itchy skin is caused by dialysis. 如申請專利範圍第1項所述之應用，其中該有效劑量為60mg~180mg。 The application of claim 1, wherein the effective dose is 60 mg to 180 mg. 如申請專利範圍第1項所述之應用，其中該鹽酸納布芬醫藥組物係早晚各服用1次。 The application of claim 1, wherein the nabufen hydrochloride drug group is administered once in the morning and evening. 如申請專利範圍第1項所述之應用，其中該鹽酸納布芬醫藥組物係為一口服劑型或一塗抹劑型。 The application of claim 1, wherein the nabufen hydrochloride pharmaceutical group is an oral dosage form or a smear dosage form. 如申請專利範圍第5項所述之應用，其中該鹽酸納布芬醫藥組物為該口服劑型時，該賦形劑係選自由1,2-二羥基丙烷、醣醛酸、二甘醇***、角鯊烯、丙烯酸甘油酯、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯和水所組成之群組。 The application of claim 5, wherein the nabufen hydrochloride pharmaceutical composition is selected from the group consisting of 1,2-dihydroxypropane, uronic acid, and diethylene glycol diethyl ether. a group consisting of squalene, glyceryl acrylate, methyl paraben, propyl paraben and water. 如申請專利範圍第6項所述之應用，其中該鹽酸納布芬比例為5~15%、1,2-二羥基丙烷比例為30~50%、醣醛酸比例為30~50%、二甘醇***比例為15~25%、角鯊烯比例為4~6%、丙烯酸甘油酯比例為0.05~10%、對羥基苯甲酸甲酯比例為0.5~1%、對羥基苯甲酸丙酯比例為0.5~1%、水比例為0~15%。 For example, the application of the scope of claim 6 wherein the ratio of nappo hydrochloride is 5 to 15%, the ratio of 1,2-dihydroxypropane is 30 to 50%, and the ratio of uronic acid is 30 to 50%. The ratio of glycol ether is 15~25%, the ratio of squalene is 4~6%, the ratio of glyceryl acrylate is 0.05~10%, the proportion of methylparaben is 0.5~1%, and the ratio of propylparaben is It is 0.5~1% and the water ratio is 0~15%. 如申請專利範圍第5項所述之應用，其中該鹽酸納布芬醫藥組物為該塗抹劑型時，該賦形劑係選自由1,2-二羥基丙烷、醣醛酸、二甘醇***、角鯊烯、丙烯酸甘油酯、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯和水所組成之群組。 The application of claim 5, wherein the nabufen hydrochloride pharmaceutical composition is selected from the group consisting of 1,2-dihydroxypropane, uronic acid, and diethylene glycol diethyl ether. a group consisting of squalene, glyceryl acrylate, methyl paraben, propyl paraben and water. 如申請專利範圍第8項所述之應用，其中該鹽酸納布芬比例為5~15%、1,2-二羥基丙烷比例為30~50%、醣醛酸比例為30~50%、二甘醇***比例為15~25%、角鯊烯比例為4~6%、丙烯酸甘油酯比例為0.05~10%、對羥基苯甲酸甲酯比例為0.5~1%、對羥基苯甲酸丙酯比例為0.5~1%、水比例為0~15%。 For example, the application of the scope of claim 8 wherein the ratio of nappo hydrochloride is 5 to 15%, the ratio of 1,2-dihydroxypropane is 30 to 50%, and the ratio of uronic acid is 30 to 50%. The ratio of glycol ether is 15~25%, the ratio of squalene is 4~6%, the ratio of glyceryl acrylate is 0.05~10%, the proportion of methylparaben is 0.5~1%, and the ratio of propylparaben is It is 0.5~1% and the water ratio is 0~15%. 一種舒緩皮膚癢之方法，其中該舒緩皮膚癢之方法包含提供皮膚癢之洗腎疾病患者一含有鹽酸納布芬之醫藥組合物，一天2次，每次劑量為60mg~180mg。 A method for relieving skin itching, wherein the method for relieving skin itch comprises providing a pharmaceutical composition containing diazepine hydrochloride in a patient with diarrhea of the skin, twice a day, each dose being 60 mg to 180 mg.
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