CN113712895A - 经口腔粘膜吸收的s-氯胺酮药物 - Google Patents
经口腔粘膜吸收的s-氯胺酮药物 Download PDFInfo
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- CN113712895A CN113712895A CN202011081969.8A CN202011081969A CN113712895A CN 113712895 A CN113712895 A CN 113712895A CN 202011081969 A CN202011081969 A CN 202011081969A CN 113712895 A CN113712895 A CN 113712895A
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- Prior art keywords
- ketamine
- oral mucosa
- tabletting
- mixing
- medicine
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Classifications
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
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Abstract
经口腔粘膜吸收的S‑氯胺酮药物，以S‑氯胺酮为有效药物成分，与口腔粘膜药物中可以接受的辅助成分共同组成，该药物对口腔无刺激性，起效更快，生物利用度更高，使患者具有满意的依从性。
Description
技术领域
本发明涉及一种经口腔粘膜吸收的药物，具体讲是一种可经口腔粘膜吸收的S-氯胺酮药物，包括舌下片/胶囊/颗粒/丸/散/膜、口颊含片/胶囊/颗粒/丸/散/膜、含片/胶囊/颗粒/丸/散/膜、口腔粘附片/膜和口腔贴片/膜等可全部或主要由舌下粘膜和/或口颊粘膜等口腔粘膜吸收的药物制剂。
背景技术
消化道肿瘤如食管癌、胃癌、肝癌等恶性肿瘤，中国的发病和死亡人数约占全球的一半，胃癌、结直肠癌、食管癌分别排名恶性肿瘤发病率第二、第三和第六。
口服给药途径需要经过消化道吸收，起效时间较慢，无法满足不能口服给药的消化道晚期癌症患者和术后消化道疾病患者的镇痛需求，以及锐痛或急性疼痛患者迅速镇痛的临床需求。
透皮贴剂由于无法及时调整剂量，有过量导致呼吸抑制的风险。
不能口服给药的消化道晚期癌症、消化道疾病术后的住院患者营养支持及治疗的日常输液量很大，进一步输液镇痛易导致循环负荷过重反应、静脉炎等输液反应。取消门诊输液的大趋势将导致锐痛或急性疼痛门诊患者无法进行输液镇痛。由于无法自主注射给药，急诊患者的疼痛症状也无法及时得到缓解。
约1/3的晚期癌症患者伴有不能常规控制的呼吸困难，急诊中需镇痛的患者、创伤性医疗如骨折复位及烧伤的治疗原因引起的锐痛或急性疼痛的患者，可能由于疼痛无法维持正常的呼吸深度及呼吸频率，导致无法通过鼻黏膜给药。
氯胺酮是2种旋光异构体即左旋氯胺酮和右旋氯胺酮等量混合而成的消旋体混合物，是唯一一种兼有意识消失、镇痛和遗忘作用的麻醉药物，但用药后出现的幻觉、噩梦等不良反应使其应用受限。右旋氯胺酮镇痛、催眠强度是消旋体氯胺酮的2倍，给药剂量仅为氯胺酮的1/2，药物消除更快、苏醒更快、神经系统不良反应轻、呼吸道分泌物少。S-氯胺酮鼻喷剂在欧美均已上市，适应症为抑郁症，S-氯胺酮注射液在英国及欧盟已上市，国内由恒瑞公司于2019年获批上市，适应症均为麻醉。后多项研究报道了S-氯胺酮具有良好的镇痛效果，机理为通过对中枢神经系统NMDA受体的非竞争性阻滞，与现有晚期癌症病人镇痛常用药物吗啡、芬太尼等相比，S-氯胺酮具有以下优势：
(1)吗啡、芬太尼、氯胺酮均具有较强的呼吸抑制作用。S-氯胺酮克服了吗啡、芬太尼和氯胺酮的呼吸抑制不良反应，且有选择性增加呼吸频率的效果。
(2)S-氯胺酮起效较吗啡和芬太尼更快，且镇痛作用是消旋体氯胺酮的2倍，R-氯胺酮的2～4倍。
(3)给药S-氯胺酮的受试者注意力集中的受损程度和主要记忆力受损的程度较给药R-异构体和消旋体的受试者更低。
(4)在长期使用阿片类药物(如吗啡、芬太尼)后，机体会对其产生耐受性，且易引发痛觉过敏。小剂量S-氯胺酮给药还具有改善上述症状的效果。
已上市的S-氯胺酮给药途径有口服、静脉注射和鼻内给药等。由于首过效应，S-氯胺酮口服生物利用度仅8％～24％，且易受到药物相互作用的影响；鼻内给药后可迅速达到血药浓度峰值，生物利用度高达48％，但其给药剂量不易控制；消化道肿瘤患者静脉注射S-氯胺酮易导致输液反应。
发明内容
针对上述情况，本发明将在此基础上提供一种经口腔粘膜吸收的S-氯胺酮药物，以提高生物利用度和患者顺应性，提升镇痛效果，降低不良反应风险。
本发明经口腔粘膜吸收的S-氯胺酮药物，同样以S-氯胺酮为有效药物成分，与口腔粘膜药物中可以接受的辅助成分共同组成。其中，所说的口腔粘膜药物中可以接受的辅助成分，可以选择目前在口腔粘膜药物制剂中通常需要和/或使用的多种辅料成分，包括：
稀释剂：如微晶纤维素、乳糖、乳糖复合物Ludipress(由乳糖、Kollidon 30和Kollidon CL组成)、Ludipress LCE(由乳糖和Kollidon 30组成)、Ludiflash(由90％Mannitol、5％
CL-SF和5％
SR 30D组成)、Cellactose 80、Tablettose80、MicroceLac 100、StarLac、Prosolv HD 90、淀粉、预胶化淀粉、糖粉、葡萄糖、硫酸钙、糊精、甘露醇、赤藓糖醇、麦芽糖、麦芽糖醇、麦芽糖糊精、山梨醇、木糖醇中的一种或几种；
粘合剂：如常用的聚维酮类成分(如Kollidon VA 64、Kollidon VA 64 Fine、Plasdone S-630)、淀粉浆、羟丙基甲基纤维素、甲基纤维素、角叉菜胶、卡波姆、瓜尔胶、明胶、阿拉伯胶、黄原胶、海藻酸或如海藻酸钠、海藻酸钾、海藻酸钙等其盐类成分、海藻酸丙二醇酯等各种成分中的一种或几种、磷酸淀粉钠、壳聚糖、糊精和糖浆中的一种或几种；
润湿剂：如常用的水、乙醇、无水乙醇及不同浓度的乙醇溶液中的一种或几种；
崩解剂：如交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素、微晶纤维素、微晶纤维素-微粉硅胶、预胶化淀粉、干淀粉、淀粉、海藻酸钠、海藻酸、羟丙基淀粉、羧甲基纤维素钙中的一种或几种，用量一般可为片剂总重量的0.1％～50％；
pH调节成分：可以选择药学中允许使用的常用成分，包括可以改变/调节溶液pH值的碳酸盐或碳酸氢盐成分(如碳酸钠、碳酸钾、碳酸钙、碳酸氢钠、碳酸氢钾等)、磷酸盐或其酸式盐成分(如磷酸钙、磷酸氢钙、磷酸氢二钠、磷酸氢二钾、磷酸二氢钠、磷酸二氢钾等)、枸橼酸盐成分(如枸橼酸钠、枸橼酸钠二水合物、枸橼酸钾等)、乳酸盐成分(如乳酸钠、乳酸钾等)、苹果酸盐成分(如苹果酸钠、苹果酸钾、苹果酸钙等)、酒石酸盐成分(如酒石酸钾、酒石酸钾钠等)、维生素C盐类成分(如维生素C钠、维生素C钾、维生素C钙、维生素C磷酸酯钠等)、海藻酸盐类成分(如海藻酸钠、海藻酸钾、海藻酸钙等)、琥珀酸盐成分(如琥珀酸钠)、醋酸盐成分(如醋酸钠等)、氨基酸类成分(如精氨酸、组氨酸、赖氨酸、半胱氨酸等)中的至少一种。
掩味(矫味)剂：如常用的甘草甜素、阿斯巴甜、晶状麦芽糖、处理琼脂(TAG)、甜菊苷、三氯蔗糖、黄原胶、糖精、维生素C、果糖、葡聚糖、甜蜜素、索马甜、糖精、薄荷醇等允许使用的甜味剂和/或食用香精成分中的一种或几种。
润滑剂：如常用的硬脂酸镁、硬脂酸、硬脂富马酸钠、十二烷基硫酸钠、聚乙二醇4000(或聚乙二醇6000)、微粉硅胶、滑石粉等成分中的一种或几种。
吸收促进剂：聚山梨酸酯；聚氧乙烯与烷基形成的醚类；聚氧乙烯与脂肪酸形成的酯类；脂肪酸；脂肪醇；胆酸及其与制药学上可接受的阳离子形成的盐类；C1-C6脂肪醇与脂肪酸形成的酯类；多元醇与脂肪酸形成的酯类，所述的多元醇含有2-6个羟基功能基团；聚乙二醇化的甘油酯；十二烷基硫酸钠等成分中的一种或几种。
本发明上述经口腔粘膜吸收药物中的S-氯胺酮，是在口腔的舌下、口颊或口腔的其它部位含化，全部或基本上是由包括舌下粘膜和口颊粘膜等口腔内的粘膜组织吸收起效，其具体制剂形式，可以包括目前已有使用的舌下片/胶囊/颗粒/丸/散/膜、口颊含片/胶囊/颗粒/丸/散/膜、含片/胶囊/颗粒/丸/散/膜、口腔粘附片/膜和口腔贴片/膜等。
本发明上述药物中，所说有效药物成分S-氯胺酮在药物制剂中的含量，一般可以为药物总重量的0.1％～100％，上述辅助成分的用量则可分别按目前各相应制剂的常规方式使用。
本发明上述经口腔粘膜吸收药物的制备，可以采用目前同类药物制剂的常规方式制备得到。以片剂为例，其典型的制备方式可以有：
a.干法制粒压片方式：将有效药物成分S-氯胺酮与所选择的辅助成分混合均匀，直接压成块，再破碎成颗粒，压片，制得成品。
b.湿法制粒压片方式：将有效药物成分S-氯胺酮与内加的辅助成分混合均匀，加入粘合剂和/或润湿剂制粒并干燥后，再加入(或不加入)外加辅料(润滑剂和/或崩解剂)，充分混匀，压片，制得成品。
c.粉末直接压片方式：将有效药物成分S-氯胺酮与所选择的辅助成分混合均匀，直接压片，制得成品。
d.半干法制粒压片方式：将所选择的辅助成分混合均匀，加入粘合剂和/或润湿剂制粒并干燥后，再加入有效药物成分(也可以与外加润滑剂和/或崩解剂等辅料一并加入)充分混匀，压片，制得成品。
本发明上述形式的药物可以满意地解决其他剂型所存在的消化道肿瘤患者无法给药，无法调整剂量等缺点，具有理想的患者依从性，避免了大量静脉输液导致的不良反应，让术后消化道肿瘤患者能够安全有效的镇痛。同时，该片剂的制备方法简单，无需特殊设备，易于产业化，生产效率高，成本低。
以下通过实施例的具体实施方式再对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。在不脱离本发明上述技术思想情况下，根据本领域普通技术知识和惯用手段做出的各种替换或变更，均应包括在本发明的范围内。
具体实施方式
实施例1(含片)
组成：
制备方法：将S-氯胺酮原料与淀粉、预胶化淀粉等辅助成分混合均匀后，加入10％淀粉浆制粒，流化床干燥，整粒，加入硬脂酸镁和滑石粉，混合均匀，压片，即得。崩解时限：10分钟
实施例2(含片)
组成：
制备方法：将S-氯胺酮原料与预胶化淀粉、木糖醇等辅助成分混合均匀后，用30％乙醇制粒，烘箱干燥，整粒，加入硬脂酸混合均匀，压片，即得。
崩解时限：9分钟
实施例3(含片)
组成：
制备方法：将S-氯胺酮原料与乳糖、微晶纤维素等辅助成分混合均匀后，加入硬脂酸镁，混合均匀，直接压片即得。崩解时限：8分钟
实施例4(含片)
组成：
制备方法：将S-氯胺酮原料与预胶化淀粉、淀粉等辅助成分混合均匀后，置流
化床中，用纯化水制粒，干燥，整粒，加入硬脂酸混合均匀，压片，即得。崩解时限：6分钟
实施例5(口颊含片)
组成：
制备方法：将S-氯胺酮原料与预胶化淀粉、碳酸氢钠等辅助成分混合均匀后，加入硬脂酸镁混合，直接压片即得。崩解时限：5分钟
实施例6(口腔贴片或口腔粘附片)
组成：
制备方法：将处方量的S-氯胺酮与麦芽糖、甘露醇、卡波姆和羟丙基甲基纤维素等辅助成分混合均匀，压片即得。崩解时限：20分钟
实施例7(舌下片)
组成：
制备方法：将处方量的S-氯胺酮与预胶化淀粉和甘露醇等辅助成分混合均匀，置高效湿法制粒机中，加入8％淀粉浆制粒，流化床干燥，整粒，加入外加辅料羧甲基淀粉钠和微粉硅胶，总混，压片即得。崩解时限：4分钟
实施例8(舌下片)
组成：
制备方法：将处方量的S-氯胺酮与麦芽糖糊精、微晶纤维素、羧甲基淀粉钠等辅助成分过100目筛，混合均匀，直接压片即得。崩解时限：4.5分钟
实施例9(舌下片)
组成：
制备方法：将S-氯胺酮与淀粉、交联羧甲基纤维素钠等内加辅料过100目筛，混合均匀，加入6％淀粉浆制粒后，干燥、整粒，加入硬脂酸镁总混、压片即得。崩解时限：3分钟
实施例10(舌下片)
组成：
制备方法：将S-氯胺酮与山梨醇、羟丙基纤维素等辅助成分过100目筛，混合均匀，加入干法制粒机制粒，整粒，加入硬脂酸镁总混，压片即得。崩解时限：3分钟
实施例11(舌下片)
组成：
制备方法：将乳糖、微晶纤维素等辅助成分过100目筛，加入湿法制粒机，用纯化水制粒，干燥，整粒，加入处方量S-氯胺酮混合，加入硬脂酸镁总混，压片即得。崩解时限：3分钟
实施例12(舌下片)
组成：
制备方法：将微晶纤维素、三氯蔗糖等辅助成分过100目筛，加入湿法制粒机，用5％聚维酮水溶液制粒，干燥，整粒，加入处方量S-氯胺酮混合，加入硬脂酸镁总混，压片即得。崩解时限：3分钟
实施例13(舌下片)
组成：
制备方法：将微晶纤维素、三氯蔗糖等辅助成分过100目筛，加入湿法制粒机，用聚维酮乙醇溶液制粒，干燥，整粒，加入处方量S-氯胺酮混合，加入硬脂酸镁总混，压片即得。崩解时限：3分钟
实施例14(舌下片)
组成：
制备方法：将乳糖、微晶纤维素等辅助成分过100目筛，加入纯化水，制粒，干燥，整粒，加入处方量S-氯胺酮混合，加入硬脂酸镁总混，压片即得。崩解时限：4分钟
实施例15(舌下片)
组成：
制备方法：将乳糖、微晶纤维素等辅助成分过100目筛，加入湿法制粒机，用纯化水制粒，干燥，整粒，等量递加法加入处方量S-氯胺酮混合，加入硬脂酸镁总混，压片即得。崩解时限：3.5分钟
实施例16(舌下片)
组成：
制备方法：将S-氯胺酮和蔗糖、微晶纤维素等辅助成分过100目筛，加入挤出滚圆机，用纯化水挤出，滚圆，整粒，加入硬脂酸镁及三氯蔗糖总混，压片即得。崩解时限：4分钟
实施例17(舌下片)
组成：
制备方法：将S-氯胺酮和蔗糖、微晶纤维素等辅助成分过100目筛，加入挤出滚圆机，用纯化水挤出，滚圆，整粒，加入硬脂酸镁及三氯蔗糖总混，压片即得。崩解时限：4分钟
实施例18(舌下片)
组成：
制备方法：按照处方量称取药物活性成分和辅料溶于水中，然后放入冻干机内低温迅速冻结成型，将冻结后的药物在高真空低温条件下升华，除去水分并适当干燥除去残余水分，制片。
崩解时限：3分钟
实施例19(舌下含服微丸)
组成：
制备方法：将空白丸芯加入流化床，底喷加入S-氯胺酮的水溶液，干燥后整粒，欧巴代水溶液包薄膜衣。崩解时限：2分钟
实施例20(舌下含服颗粒)
组成：
制备方法：将S-氯胺酮与淀粉、交联羧甲基纤维素钠等内加辅料过100目筛，混合均匀，加入6％淀粉浆制粒后，干燥、整粒、装袋即得。崩解时限：2分钟
实施例21(膜剂)
组成：
制备方法：称取处方量S-氯胺酮盐酸美金刚加入纯化水中，搅拌分散均匀，再称取处方量二氧化钛、甘油加入纯化水中，搅拌分散均匀，再称取处方量聚乙烯吡咯烷酮加入分散均匀的溶液中，充分搅拌溶解形成胶液，胶液通过抽真空离心脱泡。将胶液注入涂布机，涂膜。按规格剪裁，包装。
以上虽然以实施例描述了本发明的精神，但是只用于说明目的而不是限制本发明，实施例的变化对于本领域一般的技术人员，在阅读本发明的技术路线后或者实施例后变得显而易见。因此，在不背离本发明范围和精神的情况下，可以对本发明的实施例进行调整和改变，这些调整和改变都属于本发明的等同替换。
Claims (3)
1.经口腔粘膜吸收的S-氯胺酮药物，以S-氯胺酮为有效药物成分，与口腔粘膜药物中可以接受的辅助成分共同组成，其特征是每单位剂量中所含S-氯胺酮为1-200mg。
2.如权利要求1所述的经口腔粘膜吸收的S-氯胺酮药物，其特征是剂型为片剂、胶囊剂(微囊剂)、颗粒剂、丸剂、散剂和膜剂等剂型。
3.如权利要求1、2所述的经口腔粘膜吸收的S-氯胺酮药物，其特征是采用干法制粒、湿法制粒、半干法制粒、挤出滚圆、微丸上药后干燥、压片(制丸或填装胶囊)、粉末直接压片和冷冻干燥法制片等工艺制备。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023207728A1 (zh) * | 2022-04-26 | 2023-11-02 | 宜昌人福药业有限责任公司 | 艾司氯胺酮液体制剂及其用途 |
| WO2023207730A1 (zh) * | 2022-04-26 | 2023-11-02 | 宜昌人福药业有限责任公司 | R-氯胺酮液体制剂及其用途 |
| WO2024033910A1 (en) * | 2022-08-09 | 2024-02-15 | Vitalmelt Ltd. | Freeze-dried bite with single dose psychedelic |
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| US20140079740A1 (en) * | 2012-08-02 | 2014-03-20 | ClinPharm Support GmbH | Oral transmucosal adminstration forms of s-ketamine |
| WO2015051259A1 (en) * | 2013-10-04 | 2015-04-09 | Impax Laboratories, Inc. | Pharmaceutical compositions and methods of use |
| WO2020086673A1 (en) * | 2018-10-26 | 2020-04-30 | Guangzhou Dazhou Biomedicine Ltd. | Ketamine oral transmucosal delivery system |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20140079740A1 (en) * | 2012-08-02 | 2014-03-20 | ClinPharm Support GmbH | Oral transmucosal adminstration forms of s-ketamine |
| WO2015051259A1 (en) * | 2013-10-04 | 2015-04-09 | Impax Laboratories, Inc. | Pharmaceutical compositions and methods of use |
| WO2020086673A1 (en) * | 2018-10-26 | 2020-04-30 | Guangzhou Dazhou Biomedicine Ltd. | Ketamine oral transmucosal delivery system |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023207728A1 (zh) * | 2022-04-26 | 2023-11-02 | 宜昌人福药业有限责任公司 | 艾司氯胺酮液体制剂及其用途 |
| WO2023207730A1 (zh) * | 2022-04-26 | 2023-11-02 | 宜昌人福药业有限责任公司 | R-氯胺酮液体制剂及其用途 |
| WO2024033910A1 (en) * | 2022-08-09 | 2024-02-15 | Vitalmelt Ltd. | Freeze-dried bite with single dose psychedelic |
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