CN1324236A - △9-四氢大麻酚(△9thc)溶液的定量吸入器及其使用方法 - Google Patents
△9-四氢大麻酚(△9thc)溶液的定量吸入器及其使用方法 Download PDFInfo
- Publication number
- CN1324236A CN1324236A CN99812654.3A CN99812654A CN1324236A CN 1324236 A CN1324236 A CN 1324236A CN 99812654 A CN99812654 A CN 99812654A CN 1324236 A CN1324236 A CN 1324236A
- Authority
- CN
- China
- Prior art keywords
- thc
- aerosol
- pharmaceutical composition
- described method
- disperses
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
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
- A61K9/12—Aerosols; Foams
-
- 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
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
本发明提供了用定量吸入器输送的Δ9-四氢大麻酚(Δ9THC)溶液的药用制剂。该制剂使用非-CFC推进剂,提供了可用于治疗多种疾病的稳定的Δ9THC可气雾分散的来源。治疗的多种疾病包括化疗引起的恶心和呕吐;肌肉痉挛;疼痛;AIDS衰竭综合症引起的食欲不振;以及癫痫;青光眼;支气管哮喘和情感障碍。
Description
发明背景
发明领域
本发明主要涉及△9-四氢大麻酚(△9THC)的治疗应用。特别是,本发明为因肿瘤化疗引起的恶心和呕吐;肌肉痉挛;疼痛;由爱滋病衰竭综合症引起的缺乏食欲;以及患有癫痫、青光眼、支气管哮喘、情感障碍等其它相关疾病的患者提供了一种定量吸入器用于△9THC的气雾化施用。
技术背景描述
“大麻药用”是当前公众日益广泛关注的一个时尚和有争议的话题。尽管大麻一直以来通常被认定是一种非法的“消遣”用毒品,同时它作为一种药物也已有很长的使用历史了。1997年,国立健康研究院(NIH)发表了一篇关于大麻潜在药学应用科研数据的综述。在这篇综述中,NIH认为大麻可能确实具有有益的药理作用并建议研究人员开发出该药的适宜给药剂量及形式,例如一种通过“烟雾”吸入的输送系统。表1总结了一些研究的结论(参考文献2-18),这些文献对大麻的主要活性成分△9-四氢大麻酚(△9THC)的治疗作用给以了证实。
表1△9THC对各种临床疾病治疗的应用情况 | |||
病症及患者数量 | 给药途径及剂量 | 结论 | 参考文献 |
爱滋病引起的食欲缺乏及恶病质;94名患者;12个月 | 口服安慰剂,2.5mg THC每日一或两次直至增至每日20mg | THC的长期使用耐受性良好;THC可提高食欲,与对照组相比仅有体重增加趋势 | Beal等,1997 |
爱滋病引起的食欲缺乏及恶病质;139名患者;42天 | 口服安慰剂,或口服2.5mgTHC,每日两次 | 57%服用赋形剂的对照组和69%的服用THC的患者具有统计学意义。THC服用组的食欲与基线相比提高了38%,比较而言,服用安慰剂的对照组的食欲仅提高了8%。同时THC还缓解了恶心。在两组之间,体重的改变没有明显差异。 | Beal等,1995 |
肿瘤化疗引起的恶心和呕吐;36名用丙氯拉嗪或三乙基啦嗪无法治愈的重度恶心和呕吐患者 | 口服THC,15mg/m2 | 与丙氯拉嗪相比,64%因化疗引起恶心和呕吐的患者在服用THC后有所改善;副反应有烦躁不安等;作者建议的THC起始服用剂量是5mg/m2 | McCabe等,1988 |
表1△9THC对各种临床疾病治疗的应用情况 | |||
病症及患者数量 | 给药途径及剂量 | 结论 | 参考文献 |
肿瘤化疗引起的恶心和呕吐;53名用其它止吐剂无法治愈的恶心和呕吐患者 | 口服5或15mg/m2 THC,每日四次 | 由于THC的作用,72%的患者部分或完全达到止吐作用 | Lucas及Laszlo,1980 |
肿瘤化疗引起的恶心和呕吐;84名患者 | 口服10mg/m2的THC或丙氯拉嗪 | THC效果比丙氯拉嗪更为显著 | Sallan等,1980 |
肿瘤化疗引起的恶心和呕吐;116名患者 | 口服15mg THC,10mg丙氯拉嗪,或安慰剂 | THC和丙氯拉嗪的止吐效果相近,均强于服用安慰剂的对照组;THC的中枢神经系统副作用大于丙氯拉嗪 | Frytak等,1979 |
肿瘤化疗引起的恶心和呕吐;15名患者 | 口服安慰剂或10mg/m2的THC,每3小时共5次,一旦发生呕吐,即给予掺有THC(17mg)的香烟为安慰剂 | 93%的患者恶心和呕吐的症状有所缓解,其中53%的疗效确切,40%没有确切反应;血浆中THC含量为7.1±6.9(平均值±标准偏差)ng/ml。副反应有镇静,心动过速,少见的其它副反应 | Chang等,1979 |
表1△9THC对各种临床疾病治疗的应用情况 | |||
病症及患者数量 | 给药途径及剂量 | 结论 | 参考文献 |
晚期癌症带来的疼痛;34名患者 | 安慰剂,10或20mg THC,60或120mg可待因 | THC的镇痛作用与可待因相近但效力强于可待因。THC的中枢神经系统副作用包括镇静,精神恍惚,共济失调和定向力障碍 | Noyes等,1975 |
多发性硬化引起的痉挛;2名患者 | 口服10或15mgTHC,直肠给药5或10mg THC | 被动机动性提高,行走能力增强 | Brenneisen等,1996 |
多发性硬化引起的痉挛;13名患者 | 口服2.5至15mgTHC,每日一或两次,或服用安慰剂 | 服用7.5mg或更高剂量的THC时主观上痉挛感受大大改善,客观测量数据并未显示出明显改善 | Ungerleider等,1987 |
多发性硬化引起的痉挛;8名患者,单盲实验 | 口服5至15mgTHC | 8位患者中5位对震颤有轻微的主观改善,其中2位患者主观与客观均有所改善 | Clifford,1983 |
多发性硬化引起的痉挛;9名患者 | 安慰剂,或5或10mgTHC | 与安慰剂对照组相比,治疗组痉挛缓解,最低的副反应 | Petro及Ellenberger1981 |
表1△9THC对各种临床疾病治疗的应用情况 | |||
病症及患者数量 | 给药途径及剂量 | 结论 | 参考文献 |
青光眼6名患者 | 口服安慰剂或5,10,15,20mg THC | 疼痛减轻,情绪高涨,增进食欲兴奋,困倦,吐字不清,精神恍惚 | Merritt等1980 |
10名眼内压正常的受试者 | THC静脉给药(0.022或0.044mg/kg) | 眼内压平均降低37% | Cooler及Gregg1977 |
肿瘤化疗引起的恶心和呕吐;其它止吐剂治疗无效者 | 口服10mg/m2 THC或安慰剂 | 在服用THC的20例中,5例不再呕吐,9例呕吐症状减轻,3例呕吐症状未见减轻,2例没有统计意义。THC比安慰剂能更显著地缓解呕吐反应 | Sallan等1975 |
当大麻被用作非法的消遣用精神毒品时,其中的活性成分△9THC通常以大麻燃烧的烟雾中不纯的非药用气雾剂形式输送到肺。裹在被吸入烟雾中的气雾化的△9THC在数秒内被吸收并被有效地输送到大脑。表2及文献19-20描述了△9THC给药的药物动力学特性。可以清楚地看出,吸入法是△9THC给药的优选途径。与口服给药方式相比,吸入法提供了更迅速的药理作用和血药浓度峰值。与其它给药途径相比,吸入法给药的疗效可与通过静脉注射给药相比拟,但吸入法是一和更低侵入性的技术。
表2.△9THC口服给药,静脉给药或通过烟雾吸入给药时的药物动力学 | |||||
给药途径 | 剂量 | 血药浓度(%) | 开始显效时间 | 血药浓度峰值出现时间 | 参考文献 |
口服,溶于芝麻油填入明胶胶囊中 | 2.5,5或10mg | 10-20% | 0.5到1小时 | 120-480分钟 | (PDR,1995) |
口服,于甜饼干中 | 20mg | 4-12% | 120-180分钟 | 60-90分钟 | (Ohlsson等,1980) |
静脉注射,大丸剂 | 5mg | 100% | 10分钟 | 3分钟 | (Ohlsson等,1980) |
烟雾(THC有部分随烟逸失或热解) | 13mg | 8-24% | 10分钟 | 3分钟 | (Ohlsson等,1980) |
目前对于那些可能受益于△9THC的患者来说,药物的来源非常有限。△9THC的一种口服制剂(MARINOL)市场上有售,主要是用来治疗肿瘤化疗引起的恶心和呕吐并使爱滋病衰竭综合症的患者增进食欲。在MARINOL中,药用等级的△9THC是溶解在芝麻油中,再填入用来口服的明胶胶囊中的。然而,药物口服要比吸入法吸收缓慢而且易变质,口服的起效时间介于30分钟到2小时之间(表2)。一些肿瘤患者为了减轻化疗带来的恶心和呕吐而吸食大麻,这是不得已的选择,但毕竟是违法的,而且显然也不是一种理想的治疗方案。目前没有可供药用的△9THC气雾剂形式。
如果能有一种可以气雾剂形式给药的药用级的△9THC是十分有利的。它能提供一种迅速吸入药物的途径而又不必违法去吸食大麻。而且可以避免吸食大麻带来的严重副作用。此外,药用纯度的△9THC的气雾制剂可以已知的控制剂量给药。
在1976年,Olsen等描述了以一种氯氟烃(CFC)推进的△9THC定量吸入制剂(21)。然而,据知△9THC在储藏过程中发生分解,而且△9THC在这个制剂中的稳定性是值得怀疑的。另外,在制剂中乙醇含量如此之高(~23%),以至于形成的气雾状液滴太大,无法被有效吸入(22)。这种△9THC的CFC制剂在治疗哮喘的试验中仅仅显示了一定的疗效(23,24)。而且,以CFC作为推进剂已经被禁止,所以现在这种制剂已经毫无用处。显而易见,开发出一种新的气雾剂制剂,保证△9THC在其中的稳定性,液滴的大小又适于被高效吸收,是非常有利的。
发明概要
本发明的目的是提供一种由非CFC推进剂和以药用有效浓度存在的△9THC组成的稳定的可气雾分散的药物组合物。更具体地说,本发明的目的是提供由氢氟烷烃(如HFA 227或HFA 134a)推进剂和△9THC组成的稳定可气雾分散的药物组合物。推进剂以约78到100重量%的量存在,更特别的是,推进剂以约85到100重量%的量存在。象乙醇这样的有机溶剂可以用作△9THC在推进剂中的助溶剂,但不是必需的。如果使用有机溶剂,要求优选用量低于20重量%,更优选低于15重量%。△9THC的药用有效浓度范围优选为0.05到10重量%;最优选为0.1到6重量%。本发明的药物组合物可以用来治疗多种疾病,如肿瘤化疗引起的恶心和呕吐;肌肉痉挛;疼痛;爱滋病衰竭综合症引起的食欲不振;肿瘤化疗引起的食欲不振以及癫痫,青光眼,支气管哮喘,情感障碍,偏头痛。
附图详述
图1.△9THC定量吸入器在40℃,相对湿度(RH)82%条件下储藏前后的特性
图2.△9THC定量吸入器简图
本发明优选的实施方式的详述
本发明提供了一系列非臭氧增压驱动的△9THC定量吸入器制剂。在本发明的优选实施方式中,所述制剂包含非臭氧驱动的氢氟烷烃推进剂HFA 134a(1,1,1,2-四氢氟代乙烷)和HFA 227(1,1,1,2,3,3,3-七氟代丙烷)或二者的混合物。
当以氢氟烷烃为推进剂时,发现该推进剂可以与如乙醇溶剂一起使用或不使用溶剂。溶剂的比例越高,△9THC的溶解量也越大。但高比例的溶剂也会导致液滴的粒径增加。在本发明优选的实施方式中,如表3所示,推进剂的组成可以从100%的推进剂和0%的溶剂到85%的推进剂和15%的溶剂之间变动。在这个比例范围内,可获得△9THC的药用有效浓度,而且液滴的粒径(<5.8μm)小到足以提供极好的药物的气雾剂输送。本领域的技术人员可以从这些优选实施方式反映的情况中看出,推进剂和溶剂(如乙醇)的精确比例可以根据设计的△9THC最终浓度及液滴粒径的不同而加以改变。在实际使用中,每种推进剂与溶剂的比例均有其对应的粒径及△9THC溶解量,通常使用的比例范围是推进剂100至80%,溶剂0至20%。据估计,很多溶剂如乙醇、丙醇、丙二醇、甘油、聚乙二醇等,均可以考虑用于本发明制剂的制备中。
本领域的技术人员同样能够认识到,“可吸入剂量”(或具有空气动力学粒径小至足以输送到肺并被肺吸收的微粒中△9THC的质量)(图1)可以通过选择不同式样的喷嘴和更小的喷嘴管径加以提高。可吸入剂量也可以通过延长定量吸入器的管嘴的方法提高,按照这种方式可以提供与定量吸入器的管嘴相连的整体的或分体的气雾剂分隔器或储存器。这样做能够促进液滴的挥发,因此增加了更小的“可吸入”的微粒或者液滴的剂量比例。通常,可被吸入的液滴的最佳粒径小于10μm。
表3.△9THC在乙醇/HFA推进剂混合物中的表观溶解度 | ||||
制剂 | 样品中△9THC的质量(g) | 样品质量(g) | 表观溶解度平均值(±标准偏差) | 注释 |
△9THC在100%的HFA134a中 | 0.000240 | 0.1071 | 0.224%w/w(±0.063) | 过量的△9THC加在推进剂混合物中(在加压的定量吸入器中),溶解样品通过喷雾吸收器排出,n=5 |
△9THC在5%的乙醇/95%的HFA134a中 | 0.00144 | 0.0914 | 1.585%w/w(±0.321) | 同上 |
△9THC在10%的乙醇/90%的HFA134a中 | 0.00363 | 0.1036 | 3.511%w/w(±0.249) | 同上 |
△9THC在15%的乙醇/85%的HFA134a中 | 0.00536 | 0.1098 | 4.883%w/w(±0.224) | 同上 |
△9THC在100%的HFA227中 | 0.00021 | 0.1451 | 0.147%w/w(±0.008) | 同上 |
△9THC在5%的乙醇/95%的HFA227中 | 0.00134 | 0.0979 | 1.339%w/w(±0.169) | 同上 |
△9THC在10%的乙醇/90%的HFA227中 | 0.00454 | 0.1267 | 3.240%w/w(±0.161) | 同上 |
△9THC在15%的乙醇/85%的HFA227中 | 0.00623 | 0.1062 | 5.940%w/w(±0.191) | 同上 |
令人惊奇的是,本发明制剂的一个明显的好处是不需要用表面活性剂作为增溶剂和阀门润滑剂。这与Purewal和Greenleaf的发明(欧洲专利0,372,777;参考文献#25)形成了鲜明的对比,他们是在亲脂类表面活性剂存在下提供HFA134a/乙醇混合物以产生稳定的药物制剂。在那项发明中,亲脂类表面活性剂的作用是使不溶物质形成混悬液以满足定量吸入器阀门的润滑需要。如果阀门的润滑不能满足,不仅定量吸入器的使用寿命缩短,其准确地输送药物的能力也会大大降低。然而,可能是由于本发明制剂的内在润滑功能,表面活性剂的使用是非必需的。这样就简化了组成,降低了成本,而且也排除了制剂组分间可能发生的有害的相互作用。
任何药物制剂的一个重要着眼点是制剂稳定性。△9THC据知在储存过程中会发生分解,导致药用有效浓度降低,纯度下降。本发明制剂的稳定性按照加速的储藏试验原则进行了测试。结果见图1及表4A和4B。经过加速的储藏试验后,本发明的制剂在气雾化的△9THC释放的剂量重现性方面是稳定的。很显然,本发明的非水制剂溶液中的△9THC化学降解稳定性良好,可以用来制造多种剂量的、具有良好的预测储存寿命的吸入器。
另外,众所周知,象△9THC这样的亲脂的物质在定量吸入器制剂中会扩散到阀门的弹性体中(△9THC是高亲脂性的,这从它高达6000∶1的辛醇∶水分配系数可以看出)。经过一段时间,这种扩散就会导致亲脂性的药物的喷出或输送剂量减少。这种现象也会缩短制剂的有效储存寿命。然而,从图1和表4的数据看来本发明的制剂没有出现这种情况。在经过一段时间后,喷出或输送的剂量仍是恒定的。这可能主要归功于所选择的△9THC制剂的自身特性,而不是阀门弹性体的作用。
表4A.乙醇/氢氟烷烃(HFA)推进剂混合物中△9THC压力定量吸入器的制剂及喷雾性能
吸入器 | 组成(%w/w) | 描述 | ||
△9THC | 乙醇 | 推进剂 | ||
1 | 0.13% | ~5% | 95%HFA 134a | 3/98淡黄色溶液 |
2 | 0.13% | ~5% | 95%HFA 227 | 3/98淡黄色溶液 |
3 | 0.12% | ~5% | 95%HFA 134a | 3/98淡黄色溶液 |
4 | 0.18% | ~5% | 95%HFA 134a | 3/98淡黄色溶液 |
5 | 0.27% | ~5% | 95%HFA 227 | 3/98淡黄色溶液 |
6 | 0.25% | ~5% | 95%HFA 134a | 3/98淡黄色溶液 |
7 | 0.57% | ~5% | 95%HFA 134a | 3/98黄色溶液 |
8 | 0.58% | ~5% | 95%HFA 227 | 3/98黄色溶液 |
9 | 0.49% | ~5% | 95%HFA 134a | 3/98黄色溶液 |
10 | 1.02% | ~5% | 95%HFA 134a | 3/98黄色溶液 |
11 | 1.11% | ~5% | 95%HFA 227 | 3/98黄色溶液 |
12 | 0.97% | ~5% | 95%HFA 134a | 3/98黄色溶液 |
SS*#1起始 | 1.07% | 4.94% | 94.0%HFA 134a | 6/98黄色溶液 |
SS*#1在40℃/82%RH条件下存放28天后** | 1.07% | 4.94% | 94.0%HFA 134a | 7/98黄色溶液 |
SS*#2在40℃/82%RH条件下存放21天后** | 1.00% | 5.01% | 95%HFA 134a | 7/98黄色溶液 |
SS*#3更换调节器*** | 1.02% | 5.15% | 93.8%HFA 134a | 10/98黄色溶液 |
a5次测定的平均值(标准偏差)
b空气动力学直径<5.8μm的气雾微粒中△9THC的质量
*SS:稳定性样品 **RH:相对湿度
***喷嘴直径大约=0.2mm
表4B.乙醇/氢氟烷烃(HFA)推进剂混合物中△9THC压力定量吸入器的制剂及喷雾性能
吸入器 | 喷雾性能 | ||
定量剂量(mg)a | 喷出剂量(mg)a | 小微粒剂量(mg)a,b | |
11 | 1.72(0.25) | 1.32(0.17) | ND |
12 | 0.94(0.23) | 0.97(0.10) | 0.38(0.02) |
SS*#1起始 | 1.10(0.07) | 0.90(0.03) | 0.22(0.03) |
SS*#1在40℃/82%RH条件下存放28天后** | 1.06(0.03) | 0.92(0.04) | 0.23(0.02) |
SS*#2在40℃/82%RH条件下存放21天后** | 1.02(0.05) | 0.90(0.05) | 0.21(0.02) |
SS*#3更换调节器*** | ND | ND | 0.40(n=1) |
a5次测定的平均值(标准偏差)
b空气动力学直径<5.8μm的气雾微粒中△9THC的质量
*SS:稳定性样品 **RH:相对湿度 ND:不确定
***喷嘴直径约=0.2mm
所述制剂中△9THC的最终浓度可以通过改变推进剂和溶剂的比例,从而改变△9THC溶解度的方法加以调节。通常溶剂(如乙醇)的含量越高就可以溶解越多的△9THC。例如,在本发明优选的实施方式中,随着推进剂的组成从100%HFA 227变成85%的HFA 227和15%的乙醇,△9THC的表观溶解度也由0.147%w/w变成了5.94%w/w。这样,体积一定的条件下,△9THC的剂量可以通过改变组分配比加以选择。
此外,如上所述,用MDI分散的药物的“小微粒剂量”或“可吸入剂量”是喷嘴直径的函数。在图1和表4A,4B中喷嘴口直径是0.4mm。本发明的制剂的“小微粒剂量”或“可吸入剂量”不受储存的影响。
本发明中的△9THC是药用纯的,也就是说它的形式是非离子化的树脂样药物(6aR-反式)-6a,7,8,10a-四氢-6,6,9-三甲基-3-戊基-6氢-二苯并[b,d]-吡喃-1-醇。尽管本发明的优选的实施方式中使用的不是它的盐或酯,那些本领域的技术人员肯定明白其它适宜形式的△9THC(如盐和酯)可以合成并用于本发明的应用中。
对于不同的患者,△9THC在患者血浆中的所期望的最终浓度不尽相同,它取决于,如被治疗病症的性质和严惩程度,以及患者的全面状况,体重,性别,对药物的敏感程度等等。通常在吸入15分钟后所需的浓度范围达到10-100ng/ml。在患者血浆中的△9THC的浓度可以通过气相色谱/质谱联用(GC/MS)迅速准确地检出。
确切的治疗方案应该随着情况的不同,针对不同患者做出相应的改变。比如说,在本发明一个优选实施方式中,一位接受化疗的患者可以在化疗前15分钟吸入一个剂量的△9THC,在化疗后再每天吸入4-8次。在另一个优选实施方式中,一位因患有爱滋病衰竭综合症而食欲不振的患者可以每天吸入△9THC 3-5次,在每顿正餐或小吃30分钟之前吸入。在另一个优选实施方式中,一位因患肿瘤疼痛,或是因多发性硬化或者脊索损伤而引起的痉挛的患者可以根据处方每天吸3-6次△9THC。那些本领域的技术人员很清楚,为了满足不同的患者的个人需要,治疗方案是可以调整的。
△9THC既可以单独使用也可以与其它药物配伍使用。本领域的技术人员都明白,如,在一个爱滋病衰竭综合症的病例中,患者同时还要服用对抗爱滋病病毒的药物。与之相类的,本领域的技术人员也同样可以理解,接受肿瘤化疗的患者同时也可能服用其它止吐剂,为了减轻疼痛,肿瘤患者也会服用鸦片样物质和非甾体类消炎剂。
本发明制剂的容器可以是适于气雾吸入剂有效传质的任何一种形式。有几种容器和它们的使用方法是本领域的技术人员所熟知的。比如说,定量吸入器可以应用各种定量室腔,各种塑料调节器及管嘴,和各种气雾剂的贮存室腔(如分隔器或储存器装置),以便于使适宜剂量的△9THC到达并沉积在肺部,然后被吸收进入血液循环。另外一种如Burns和Marshak在美国专利5,284,133中所描述的止动器,也可以用来防止△9THC的过量逸出,该文献在此引入作为参考。图2展示了一种盛有本发明组合物的定量吸入器简图,并展示了反复使用的基础上,输送定量△9THC的优点。所述定量吸入器包括了一个容器100用于贮存所述组合物,和一个阀输送装置102用于气雾化的THC的输送。
尽管本发明描述了优选的实施方式,但本领域的技术人员能认识到,在不偏离本发明附加的权利要求书的精神和范围内可以对本发明进行修改。
参考文献
1.大麻药用研究工作组(Workshop on the madical utility ofmarijuana).国立健康研究院(National Institutes of Health)August,1997
2.Beal,J.A.,Olson,R.,Lefkowitz,L.,Laubenstein,L.,Bellman,P.,Yangco,B.,Morales,J.O.,Murphy,R.,Powderly,W.,Plasse,T.F.,Mosdell,K.W.及Shepard,K.W.(1997)屈大麻酚用于治疗获得性免疫缺陷综合症引起的食欲不振作用的长期效果及安全性评价(Long-term efficacy and safety ofdronabinol for acquired immunodeficiency syndrome-associatedanorexia.),疼痛综合症治疗杂志(J.Pain.Symptom Manage.)14:7-14
3.Beal,J.A.,Olson,R.,Laubenstein,L.,Morales,J.O.,Bellman,B.,Yangco,B.,Lefkowitz,L.,Plasse,T.F.,及Shepard,K.V.(1995)屈大麻酚作为对爱滋病患者的体重减轻、食欲下降症状的治疗(Dronabinol as atreatment for anorexia associated with weight loss in patients withAIDS),疼痛综合症治疗杂志(J.Pain.Symptom Manage.)10:89-97
4.McCabe,M.,Smith,F.P.,MacDonald,J.S.,Wooley,P.V.,Goldberg,D.及Schein,P.S.(1988)对普通止吐疗法无效患者使用四氢大麻酚的疗效(Efficacy of tetrahydrocannabinol in patients refractory to standardantiemetic therapy)新药调查(Invest.New Drugs)6:243-246
5.Lucas,V.S.及Laszlo,J.(1980)△9-THC用于肿瘤化疗引起的难以治愈的呕吐反应(△9-THC for refractory vomiting induced by cancerchemotherapy)美国医学联合会会志(JAMA)243:1241-1243
6.Sallan,S.E.,Cronin,C.,Zelen,M.及Zinberg,N.E.(1980)接受肿瘤化疗患者使用的止吐剂:△9THC与丙氯拉嗪的随机比较(Antiemetics inpatients receiving chemotherapy for cancer:a randomized comparison of△9THC and prochlorperazine)新英格兰医学杂志(N.Engl.J.Med.)302:135-138
7.Frytak,S.,Moertel,C.G.,O’Fallon,J.R.,Rubin,J.,Creagan,E.T.,O’Connell,M.J.,Schutt,A.J.及Schwartau,N.W.(1979)接受肿瘤化疗患者使用的△9THC为止吐剂:与丙氯拉嗪及安慰剂的比较(Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancerchemotherapy:a comparison with prochloperazine and a placebo)内服药物年报(Ann.Intr.Med.)91:825-830.
8.Chang,A.E.,Shiling,D.J.,Stillman,R.C.,Goldgerg,N.H.,Seipp,C.A.,Barofdky,I.,Simon,R.M.及Rosenberg SA(1979)以△9THC作为服用大剂量甲氨蝶呤的肿瘤患者的止吐剂(△9THC as an antiemetic in cancerpatients receving high-dose methotrexate)内服药物年报(Ann.Internal.Med).91:819-824。
9.Sallan,S.E.,Zinberg,N.E.及Frei,I.E.(1975)△9THC对接受肿瘤化疗的患者的止吐疗效(Antiemetic effect of△9THC in patients recevingcancer chemotherapy)新英格兰医学杂志(New Engl.J.Mad)293:795-797。
10.Noyes,J.R.,Brunk,S.F.,Baram,D.A.及Canter,A.(1975)△9THC及可待因的止吐性(The analgesic properties of △9THC and codeine)临床药理杂志(J.Clin.Pharmacol)15:139-143。
11.Noyes,R.,Jr.,Brunk,S.F.,Baram,D.A.及Canter,A.(1975)△9THC的止吐效果(Analgesic effect of △9-tetrahydrocannabinol)临床药理杂志(J.Clin.Pharmacol)15:139-143。
12.Brenneisen,R.,Egli,A.,Elosohlly,M.A.,Henn,V.及Spiess,Y.(1996)△9THC对两名患者的解痉试点研究,口服或直肠给药(The effect oforally and rectally administered △9THC on spasticity:a pilot study with 2patients)国际临床药物治疗杂志(Int.J.Clin.J.Pharmocol.Ther)34:446-452。
13.Ungerleider,J.T.,Andyrsiak,T.F.L.,Ellison,G.W.及Myers,L.W.(1987)△9THC对多发性硬化引起的痉挛的疗效(△9THC inthe treatment of spasticity associated with multiple sclerosis)酒精物质滥用进展(Adv.Alcohol Subst.Abuse)7:39-50
14.Clifford,D.B.(1983)△9THC对多发性硬化引起的震颤的疗效(Tetrahydrocannabinol for tremor in multiple sclerosis)神经病学年报(Ann.Neurol).13:669-171
15.Petro,D.J.,及Ellenberger,C.(1981)△9THC用于治疗人的痉挛(Treatment of human spasticity with delta 9-tetrahydrocannabinol)临床药理杂志(J.Clin.Pharmacol)21:413S-416S.
16.Maurer,M.,Henn,V.,Dittrich,A.及Hofman,A.(1990)在单一双盲实验中△9THC显示有解痉、止痛疗效(Delta 9-tetrahydrocannabinolshows antispastic and analgesic effects in a single case double-blind trial)欧洲精神病科学(Eur.Arch.Psychiatry Neurol.Sci)240:1-4.
17.Merritt,J.,Crawford,W.,Alexander,P.,Anduze,A.及Gelbart,S.1980)大麻对青光眼患者眼内压及血压的影响(Effects of marihuana on intraocular and blood pressure in glaucoma)眼科学(Opht.)87:222-228.
18.Cooler,P.及Gregg,J.M.(1977)△9THC对人眼内压的影响(Effect of △9THC on intra ocular pressure in humans)南方医学杂志(South.Med.J)70:951-954.
19.PDR(1995)医师工作参考书(Physician’s Desk Reference)(49)Montvalek,NewJersey:Medical Economics Data Production Co.,pp.2787.
20.Ohlsson,A.,Lindgren,J.E.,Wahlen,A.,Agurall,S.,Hollister,L.E.andGillespie,H.K.(1980)口服和静脉注射、通过吸烟吸入后△9THC在血浆中的浓度及效果(Plasma△9THC concentrations and effects after oral andintravenous administration and smoking)临床药理学及治疗学(Clin.Pharmacol.Ther)28:409-416.
21.Olsen,J.L.,Lodge,J.W.,Shapiro,B.J.及Tashkin,D.P.(1976)一种△9THC的吸入气雾剂(An inhalation aerosol of △9-tetrahydrocannabinol)药剂学及药理学杂志(J.Pharmacy andPharmacol)28:86.
22.Dalby,R.N.及Byron,P.R.(1988)制成溶液或悬浊液时压力气雾剂喷出的液滴大小分布了比较(Comparison of output particle sizedistributions from pressurized aerosols formulated as solutions orsuspensions)药剂研究(Pharm.Res)5:36-39.
23.Tashkin,D.P.,Reiss,S.,Shapiro,B.J.,Calvarese,B.,Olsen,J.L.及Lidgek,J.W.(1977)气雾化的△9THC对健康受试者和哮喘病人的支气管作用(Bronchial effects of aerosolized △9-tetrahydrocannabinol inhealthy and asthmatic subjects)美国呼吸道疾病综述(Amer.Rev.ofResp.Disease)115:57-65
24.Williams,S.J.,Hartley,J.P.R.及Graham,J.D.P.(1976)气雾剂给用△9THC对哮喘患者的支气管扩张作用(Bronchodilator effect of delta-9-THC administered by aerosol to asthmatic patients)胸科学(Thorax)31:720-723.
25.欧洲专利0,372,777(Riker Laboratories)医用气雾剂制剂(Medicinal aerosol formulations)
Claims (23)
1.一种可气雾分散的药物组合物,该组合物含有:氢氟烷烃推进剂;和以可药用形式存在的△9-四氢大麻酚,其以药用有效浓度溶解在所说的氢氟烷烃中。
2.权利要求1所述的可气雾分散的药物组合物,其中所说的△9-四氢大麻酚是在没有使用选自溶剂和表面活性剂的增溶剂下溶解在所述的氢氟烷烃推进剂中。
3.权利要求1所述的可气雾分散的药物组合物,其中所说的氢氟烷烃选自HFA134a和HFA227。
4.权利要求3所述的可气雾分散的药物组合物,其中所说的氢氟烷烃以大于85重量%的量存在。
5.权利要求1所述的可气雾分散的药物组合物,其中还包含一种有机溶剂。
6.权利要求5所述的可气雾分散的药物组合物,其中所说的有机溶剂是以不高于15重量%的量存在的乙醇。
7.权利要求1所述的可气雾分散的药物组合物,其中所说的△9-四氢大麻酚的药用有效浓度的范围为0.05-10重量%。
8.权利要求1所述的可气雾分散的药物组合物,其中所说的△9-四氢大麻酚的药用有效浓度的范围为0.1-6重量%。
9.权利要求1所述的可气雾分散的药物组合物,其中的△9-四氢大麻酚以纯品的形式存在。
10.一种无溶剂的药物组合物,该组合物主要由1,1,1,2,3,3,3-七氟代丙烷(HFA227)和△9-四氢大麻酚组成。
11.一种无溶剂的药物组合物,该组合物主要由1,1,1,2-四氟代乙烷(HFA134a)和△9-四氢大麻酚组成。
12.用△9-四氢大麻酚的气雾化可药用形式对患者进行治疗的方法,包括步骤:
将气雾剂量的可药用形式的△9-四氢大麻酚作为可吸入的液滴用药到患者的肺部,所述△9-四氢大麻酚来自由氢氟烷烃推进剂和所说的可药用形式的△9-四氢大麻酚组成的组合物中。
13.权利要求12所述的方法,其中所说的组合物含有可药用的溶剂。
14.权利要求12所述的方法,其中所说的组合物无溶剂。
15.权利要求12所述的方法,其中所说的气雾化剂量足以缓解恶心。
16.权利要求12所述的方法,其中所说的气雾化剂量足以缓解呕吐。
17.权利要求12所述的方法,其中所说的气雾化剂量足以缓解疼痛。
18.权利要求12所述的方法,其中所说的气雾化剂量足以缓解肌肉痉挛。
19.权利要求12所述的方法,其中所说的气雾化剂量足以缓解偏头痛。
20.权利要求12所述的方法,其中所说的气雾化剂量足以缓解运动失调。
21.权利要求12所述的方法,其中所说的气雾化剂量足以提高患有恶病质的患者的食欲。
22.权利要求12所述的方法,其中所说的△9-四氢大麻酚的可药用形式是纯的△9-四氢大麻酚,所说的氢氟烷烃选自HFA134a和HFA227。
23.一种定量吸入器,包括:
外壳;
与所说外壳相连的定量阀门;
及可气雾分散的药用组合物,该组合物含有氢氟烷烃推进剂及以药用有效浓度溶解于所说氢氟烷烃推进剂中的形式存在的△9-四氢大麻酚。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10585098P | 1998-10-27 | 1998-10-27 | |
US60/105,850 | 1998-10-27 | ||
US09/273,766 | 1999-03-22 | ||
US09/273,766 US6509005B1 (en) | 1998-10-27 | 1999-03-22 | Δ9 Tetrahydrocannabinol (Δ9 THC) solution metered dose inhaler |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1324236A true CN1324236A (zh) | 2001-11-28 |
CN1214789C CN1214789C (zh) | 2005-08-17 |
Family
ID=26803013
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN99812654.3A Expired - Fee Related CN1214789C (zh) | 1998-10-27 | 1999-10-20 | △9-四氢大麻酚溶液的定量吸入器及其使用方法 |
Country Status (14)
Country | Link |
---|---|
US (3) | US6509005B1 (zh) |
EP (1) | EP1124551B1 (zh) |
JP (1) | JP2002528399A (zh) |
KR (1) | KR100636854B1 (zh) |
CN (1) | CN1214789C (zh) |
AT (1) | ATE391501T1 (zh) |
AU (1) | AU764119B2 (zh) |
BR (1) | BR9915095A (zh) |
CA (1) | CA2344637A1 (zh) |
DE (1) | DE69938505T2 (zh) |
ES (1) | ES2308855T3 (zh) |
HK (1) | HK1042846B (zh) |
MX (1) | MXPA01004188A (zh) |
WO (1) | WO2000024362A2 (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100592903C (zh) * | 2002-04-03 | 2010-03-03 | 索尔瓦药物有限公司 | 稳定的天然大麻素制剂及其制备方法 |
CN101198324B (zh) * | 2005-06-16 | 2011-06-08 | 欧洲凯尔特公司 | 用于改进剂型的大麻素活性药物成分 |
CN110200953A (zh) * | 2019-06-15 | 2019-09-06 | 汉义生物科技(北京)有限公司 | 大麻素在制备吸入给药药物中的应用 |
CN111587111A (zh) * | 2017-08-27 | 2020-08-25 | 罗得技术公司 | 用于治疗眼科病症的药物组合物 |
Families Citing this family (81)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU779324B2 (en) * | 1999-08-20 | 2005-01-20 | Abbott Laboratories | Composition for inhalation comprising delta-9-tetrahydrocannabinol in a semiaqueous solvent |
US7648696B2 (en) * | 1999-08-20 | 2010-01-19 | Unimed Pharmaceuticals, Llc | Composition for inhalation comprising delta-9-tetrahydrocannabinol in a semiaqueous solvent |
US6747058B1 (en) | 1999-08-20 | 2004-06-08 | Unimed Pharmaceuticals, Inc. | Stable composition for inhalation therapy comprising delta-9-tetrahydrocannabinol and semiaqueous solvent therefor |
AU3580001A (en) * | 2000-03-01 | 2001-09-12 | University College London | Modulators of the endocannabinoid uptake and of the vallinoid receptors |
GB2361869B (en) * | 2000-03-09 | 2004-09-22 | Pharmasol Ltd | Sublingual delivery of cannabis |
EP1280515B1 (en) | 2000-03-09 | 2007-02-14 | GW Pharma Limited | Pharmaceutical compositions comprising cannabis |
US6503894B1 (en) | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
GB0025092D0 (en) * | 2000-10-13 | 2000-11-29 | Glaxo Group Ltd | Medicament dispenser |
US10004684B2 (en) | 2001-02-14 | 2018-06-26 | Gw Pharma Limited | Pharmaceutical formulations |
US7905230B2 (en) | 2001-05-09 | 2011-03-15 | Novartis Ag | Metered dose inhaler with lockout |
US7458374B2 (en) * | 2002-05-13 | 2008-12-02 | Alexza Pharmaceuticals, Inc. | Method and apparatus for vaporizing a compound |
US7090830B2 (en) * | 2001-05-24 | 2006-08-15 | Alexza Pharmaceuticals, Inc. | Drug condensation aerosols and kits |
JP2005503425A (ja) | 2001-05-24 | 2005-02-03 | アレックザ モレキュラー デリヴァリー コーポレイション | 所定の吸入ルートによる薬剤エステルの送出 |
US7645442B2 (en) | 2001-05-24 | 2010-01-12 | Alexza Pharmaceuticals, Inc. | Rapid-heating drug delivery article and method of use |
US20030051728A1 (en) | 2001-06-05 | 2003-03-20 | Lloyd Peter M. | Method and device for delivering a physiologically active compound |
US20070122353A1 (en) * | 2001-05-24 | 2007-05-31 | Hale Ron L | Drug condensation aerosols and kits |
WO2003006010A1 (en) * | 2001-07-10 | 2003-01-23 | Norton Healthcare Limited | Aerosol formulations of δ8 tetrahydrocannabinol |
WO2003051367A1 (en) * | 2001-12-18 | 2003-06-26 | Alexza Molecular Delivery Corporation | Parental analgesic formulations comprising fentanyl and a cannabinoid receptor agonist |
EP1321159A1 (en) | 2001-12-21 | 2003-06-25 | CHIESI FARMACEUTICI S.p.A. | Pressurized metered dose inhaler (pMDI) actuators with laser drilled orifices |
IL148244A0 (en) * | 2002-02-19 | 2002-09-12 | Yissum Res Dev Co | Anti-nausea and anti-vomiting activity of cannabidiol compounds |
US6900317B2 (en) * | 2002-02-19 | 2005-05-31 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Salts of the CGRP antagonist BIBN4096 and inhalable powdered medicaments containing them |
DE10206770A1 (de) * | 2002-02-19 | 2003-08-28 | Boehringer Ingelheim Pharma | Verfahren zur Herstellung eines Pulverinhalativums enthaltend ein Salz des CGRP-Antagonisten BIBN4096 |
US20040014679A1 (en) * | 2002-02-20 | 2004-01-22 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | Inhalation powder containing the CGRP antagonist BIBN4096 and process for the preparation thereof |
US20060193788A1 (en) * | 2002-11-26 | 2006-08-31 | Hale Ron L | Acute treatment of headache with phenothiazine antipsychotics |
DE10226494A1 (de) * | 2002-06-14 | 2004-01-08 | Lts Lohmann Therapie-Systeme Ag | Filmförmige mucoadhäsive Darreichungsformen zur Verabreichung von Cannabis-Wirkstoffen |
EP1515711A1 (en) * | 2002-06-22 | 2005-03-23 | Norton Healthcare Limited | Pharmaceutical composition |
US6946150B2 (en) | 2002-08-14 | 2005-09-20 | Gw Pharma Limited | Pharmaceutical formulation |
US10538373B2 (en) | 2002-08-14 | 2020-01-21 | Gw Pharma Limited | Pharmaceutical formulation |
US20040105818A1 (en) * | 2002-11-26 | 2004-06-03 | Alexza Molecular Delivery Corporation | Diuretic aerosols and methods of making and using them |
US7913688B2 (en) | 2002-11-27 | 2011-03-29 | Alexza Pharmaceuticals, Inc. | Inhalation device for producing a drug aerosol |
WO2004104490A1 (en) | 2003-05-21 | 2004-12-02 | Alexza Pharmaceuticals, Inc. | Self-contained heating unit and drug-supply unit employing same |
WO2005044093A2 (en) * | 2003-11-05 | 2005-05-19 | Unimed Pharmaceuticals, Inc. | Delta-9- the treatment of multiple sclerosis |
US7540286B2 (en) | 2004-06-03 | 2009-06-02 | Alexza Pharmaceuticals, Inc. | Multiple dose condensation aerosol devices and methods of forming condensation aerosols |
TWI369203B (en) | 2004-11-22 | 2012-08-01 | Euro Celtique Sa | Methods for purifying trans-(-)-△9-tetrahydrocannabinol and trans-(+)-△9-tetrahydrocannabinol |
KR20070118069A (ko) * | 2004-12-09 | 2007-12-13 | 인시스 테라퓨틱스, 인코포레이티드 | 실온에서 안정한 드로나비놀 제형 |
CA2599213A1 (en) * | 2005-02-25 | 2006-08-31 | Unimed Pharmaceuticals, Inc. | Dronabinol compositions and methods of using same |
EP1881757A4 (en) * | 2005-05-13 | 2008-09-10 | Unimed Pharmaceuticals Inc | DRONABINOL TREATMENT OF CHEMOTHERAPY-INDUCED POSSIBLE INCOMPATIBILITY AND ILLUSTRATION |
TWI366460B (en) * | 2005-06-16 | 2012-06-21 | Euro Celtique Sa | Cannabinoid active pharmaceutical ingredient for improved dosage forms |
EP1898877A1 (en) * | 2005-06-20 | 2008-03-19 | Unimed Pharmaceuticals, Inc. | Dronabinol treatment for migraines |
AU2007281918A1 (en) * | 2006-08-04 | 2008-02-14 | Insys Therapeutics Inc. | Aqueous dronabinol formulations |
GB0702895D0 (en) * | 2007-02-14 | 2007-03-28 | Resolution Chemicals Ltd | Delta 9 tetrahydrocannabinol derivatives |
GB0703284D0 (en) * | 2007-02-20 | 2007-03-28 | Resolution Chemicals Ltd | Delta 9 - tetrahydrocannabinol processing |
JP2008212436A (ja) | 2007-03-06 | 2008-09-18 | Canon Inc | 吸入装置 |
EP2121088B1 (en) | 2007-03-09 | 2016-07-13 | Alexza Pharmaceuticals, Inc. | Heating unit for use in a drug delivery device |
US8222292B2 (en) | 2007-08-06 | 2012-07-17 | Insys Therapeutics, Inc. | Liquid cannabinoid formulations |
WO2009020666A1 (en) * | 2007-08-06 | 2009-02-12 | Insys Therapeutics Inc. | Oral cannabinoid liquid formulations and methods of treatment |
JP2009106467A (ja) | 2007-10-30 | 2009-05-21 | Canon Inc | 吸入装置 |
US20110038915A1 (en) * | 2009-08-14 | 2011-02-17 | Eduardo Jose Gonzalez | Chewing Gum Formula for Enhancing Psycho-Spirituality |
WO2012006125A1 (en) * | 2010-06-28 | 2012-01-12 | Palliatech | Vaporizable substance drug delivery and monitoring system |
US8910630B2 (en) | 2010-06-28 | 2014-12-16 | Palliatech, Inc. | Cannabis drug delivery and monitoring system |
CA2822738C (en) | 2010-12-22 | 2021-06-08 | Exonoid Medical Devices Ltd. | Method and system for drug delivery |
US9345771B2 (en) | 2012-10-04 | 2016-05-24 | Insys Development Company, Inc. | Oral cannabinoid formulations |
US11253472B2 (en) | 2012-10-04 | 2022-02-22 | Benuvia Therapeutics Llc | Oral cannabinoid formulations |
US10265293B2 (en) | 2012-10-04 | 2019-04-23 | Insys Development Company, Inc. | Oral cannabinoid formulations |
WO2015195711A2 (en) * | 2014-06-16 | 2015-12-23 | Shurtleff, James, Kevin | Method and devices for manufacturing and delivering of aerosolized formulations |
WO2015200049A1 (en) * | 2014-06-26 | 2015-12-30 | Island Breeze Systems Ca, Llc | Mdi related products and methods of use |
KR20230117250A (ko) | 2014-06-30 | 2023-08-07 | 사이키 메디컬 엘티디. | 흡입기 장치용 약물 투약 카트리지 |
BR112016030955B1 (pt) | 2014-06-30 | 2022-03-22 | Syqe Medical Ltd. | Dispositivo inalador |
US11298477B2 (en) | 2014-06-30 | 2022-04-12 | Syqe Medical Ltd. | Methods, devices and systems for pulmonary delivery of active agents |
MX2017000057A (es) | 2014-06-30 | 2017-06-30 | Syqe Medical Ltd | Procedimiento y dispositivo para vaporizacion e inhalacion de sustancias aisladas. |
WO2016001922A1 (en) | 2014-06-30 | 2016-01-07 | Syqe Medical Ltd. | Methods, devices and systems for pulmonary delivery of active agents |
PL3160565T3 (pl) | 2014-06-30 | 2022-01-10 | Syqe Medical Ltd. | Urządzenia i systemy do dopłucnego dostarczania środków aktywnych |
WO2016054268A1 (en) | 2014-09-30 | 2016-04-07 | MJAR Holdings, LLC | Methods of growing cannabaceae plants using artificial lighting |
CA2966710A1 (en) | 2014-11-03 | 2016-05-12 | Ramot At Tel Aviv University Ltd. | Methods for treatment of cognitive decline |
EP3297710A4 (en) * | 2015-05-21 | 2019-05-01 | Island Breeze Systems Ca, LLC | DRILL-BASED INGREDIENTS WITH APPROPRIATE DOSE AND FOOD APPLICATORS AND APPLICATORS |
US20170038184A1 (en) * | 2015-08-06 | 2017-02-09 | Charles E. Ankner | Formulation delivery system |
US9585867B2 (en) | 2015-08-06 | 2017-03-07 | Charles Everett Ankner | Cannabinod formulation for the sedation of a human or animal |
EP3399972B1 (en) | 2016-01-06 | 2021-03-31 | Syqe Medical Ltd. | Low dose therapeutic treatment |
ES2926186T3 (es) | 2016-06-28 | 2022-10-24 | Trichomeshell Ltd | Una forma de dosificación para vaporización y fumar |
US9717683B1 (en) | 2016-06-29 | 2017-08-01 | Ep Pharma, Llc | Low-temperature inhalation administration of cannabinoid entities |
US10231948B2 (en) | 2017-02-27 | 2019-03-19 | Jason Ty Nguyen | Metered dose inhaler compositions, systems, and methods |
GB2567240B (en) | 2017-10-09 | 2022-04-06 | Senzer Ltd | An inhaler particularly a cannabinoid inhaler and a method of assembling such an inhaler |
WO2020016659A2 (en) | 2018-07-18 | 2020-01-23 | Glatt Gmbh | Multiparticulate formulations of cannabinoids |
US20220040141A1 (en) * | 2018-10-01 | 2022-02-10 | Blue Harvest, Llc | Ultrapure phenol compositions |
US11806645B1 (en) | 2019-05-07 | 2023-11-07 | Cannaceutical Extractions LLC | Methods of producing CBD/THC oils |
US20230117531A1 (en) * | 2020-03-19 | 2023-04-20 | Tff Pharmaceuticals, Inc. | Dried particle inhalation for delivery of cannabis |
US11542226B2 (en) * | 2020-04-23 | 2023-01-03 | Axim Biotechnologies, Inc. | Polyfunctional cannabinoids |
EP3919046A1 (en) | 2020-06-02 | 2021-12-08 | Athenion AG | Method for solubilizing natural, endogenous and synthetic cannabinoids |
GB2595692A (en) | 2020-06-03 | 2021-12-08 | Senzer Ltd | A refill for an inhaler particularly a cannabinoid inhaler |
CA3183864A1 (en) * | 2020-06-22 | 2021-12-30 | Glynn Wilson | Oronasal cbd formulations and uses thereof |
WO2022115718A1 (en) * | 2020-11-29 | 2022-06-02 | Castor Trevor P | Extraction, separation and purification of cannabinoids from cannabis staiva and other marijuana biomass |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3728360A (en) * | 1971-08-31 | 1973-04-17 | Little Inc A | Ester derivatives of tetrahydrocannabinol |
US4087546A (en) * | 1976-02-17 | 1978-05-02 | Eli Lilly And Company | Hexahydro-dibenzo[b,d]pyran-9-ones as antiasthmatic drugs |
US4087547A (en) * | 1976-02-17 | 1978-05-02 | Eli Lilly And Company | Hexahydro-dibenzo[b,d]pyran-9-ones in treatment of glaucoma |
US4635651A (en) * | 1980-08-29 | 1987-01-13 | Jacobs Allen W | Process for the inclusion of a solid particulate component into aerosol formulations of inhalable nicotine |
US4464378A (en) * | 1981-04-28 | 1984-08-07 | University Of Kentucky Research Foundation | Method of administering narcotic antagonists and analgesics and novel dosage forms containing same |
US4476140A (en) * | 1983-05-16 | 1984-10-09 | Yale University | Composition and method for treatment of glaucoma |
US5192528A (en) * | 1985-05-22 | 1993-03-09 | Liposome Technology, Inc. | Corticosteroid inhalation treatment method |
US4847290A (en) * | 1987-08-17 | 1989-07-11 | Sumner Burstein | Delta 1-thc-7-oic acid and analgesic and anti-inflammatory agents |
US5538993A (en) * | 1991-09-12 | 1996-07-23 | Yissum Research Development Company | Certain tetrahydrocannabinol-7-oic acid derivatives |
US5916540A (en) * | 1994-10-24 | 1999-06-29 | Glaxo Group Limited | Aerosol formulations containing P134A and/or P227 and particulate medicament |
CA2125666C (en) * | 1991-12-12 | 2002-07-16 | Rachel Ann Akehurst | Medicaments |
US5736124A (en) * | 1991-12-12 | 1998-04-07 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicament |
US5683676A (en) * | 1991-12-12 | 1997-11-04 | Glaxo Group Limited | Canister containing aerosol formulations containing P134a and particulate medicaments |
US5284133A (en) * | 1992-07-23 | 1994-02-08 | Armstrong Pharmaceuticals, Inc. | Inhalation device with a dose-timer, an actuator mechanism, and patient compliance monitoring means |
US5492688A (en) * | 1993-04-28 | 1996-02-20 | The Center For Innovative Technology | Metered dose inhaler fomulations which include the ozone-friendly propellant HFC 134a and a pharmaceutically acceptable suspending, solubilizing, wetting, emulsifying or lubricating agent |
EP0735884B1 (en) * | 1993-12-20 | 2000-04-26 | Minnesota Mining And Manufacturing Company | Flunisolide aerosol formulations |
US5502076A (en) * | 1994-03-08 | 1996-03-26 | Hoffmann-La Roche Inc. | Dispersing agents for use with hydrofluoroalkane propellants |
US5653961A (en) * | 1995-03-31 | 1997-08-05 | Minnesota Mining And Manufacturing Company | Butixocort aerosol formulations in hydrofluorocarbon propellant |
US6017963A (en) * | 1995-11-14 | 2000-01-25 | Euro-Celtique, S.A. | Formulation for intranasal administration |
AU727416C (en) * | 1996-05-14 | 2001-07-19 | Glaxo Group Limited | Benzofurans and benzopyrans as chronobiological agents |
US6039932A (en) * | 1996-09-27 | 2000-03-21 | 3M Innovative Properties Company | Medicinal inhalation aerosol formulations containing budesonide |
AU726510B2 (en) * | 1996-12-04 | 2000-11-09 | Consort Medical Plc | Pharmaceutical compositions and devices for their administration |
JP2001507702A (ja) * | 1996-12-31 | 2001-06-12 | インヘイル・セラピューティックス・システムズ・インコーポレテッド | 親水性賦形剤を有する疎水性薬剤の水性懸濁液を噴霧乾燥させる方法およびその方法によって作製された組成物 |
US5804592A (en) * | 1997-05-30 | 1998-09-08 | Unimed Pharmaceuticals, Inc. | Method for improving disturbed behavior and elevating mood in humans |
US7025992B2 (en) * | 2001-02-14 | 2006-04-11 | Gw Pharma Limited | Pharmaceutical formulations |
-
1999
- 1999-03-22 US US09/273,766 patent/US6509005B1/en not_active Expired - Lifetime
- 1999-10-20 EP EP99965726A patent/EP1124551B1/en not_active Expired - Lifetime
- 1999-10-20 AT AT99965726T patent/ATE391501T1/de not_active IP Right Cessation
- 1999-10-20 BR BR9915095-6A patent/BR9915095A/pt not_active Application Discontinuation
- 1999-10-20 WO PCT/US1999/024486 patent/WO2000024362A2/en active IP Right Grant
- 1999-10-20 ES ES99965726T patent/ES2308855T3/es not_active Expired - Lifetime
- 1999-10-20 CA CA002344637A patent/CA2344637A1/en not_active Abandoned
- 1999-10-20 CN CN99812654.3A patent/CN1214789C/zh not_active Expired - Fee Related
- 1999-10-20 MX MXPA01004188A patent/MXPA01004188A/es not_active IP Right Cessation
- 1999-10-20 AU AU21430/00A patent/AU764119B2/en not_active Ceased
- 1999-10-20 KR KR1020017004513A patent/KR100636854B1/ko not_active IP Right Cessation
- 1999-10-20 DE DE69938505T patent/DE69938505T2/de not_active Expired - Fee Related
- 1999-10-20 JP JP2000577974A patent/JP2002528399A/ja active Pending
-
2001
- 2001-09-04 US US09/944,221 patent/US6713048B2/en not_active Expired - Lifetime
-
2002
- 2002-05-28 HK HK02103979.7A patent/HK1042846B/zh not_active IP Right Cessation
-
2004
- 2004-01-20 US US10/759,280 patent/US20040258622A1/en not_active Abandoned
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100592903C (zh) * | 2002-04-03 | 2010-03-03 | 索尔瓦药物有限公司 | 稳定的天然大麻素制剂及其制备方法 |
CN101198324B (zh) * | 2005-06-16 | 2011-06-08 | 欧洲凯尔特公司 | 用于改进剂型的大麻素活性药物成分 |
CN111587111A (zh) * | 2017-08-27 | 2020-08-25 | 罗得技术公司 | 用于治疗眼科病症的药物组合物 |
US11786463B2 (en) | 2017-08-27 | 2023-10-17 | Rhodes Technologies | Pharmaceutical compositions for the treatment of ophthalmic conditions |
CN111587111B (zh) * | 2017-08-27 | 2023-12-19 | 罗得技术公司 | 用于治疗眼科病症的药物组合物 |
CN110200953A (zh) * | 2019-06-15 | 2019-09-06 | 汉义生物科技(北京)有限公司 | 大麻素在制备吸入给药药物中的应用 |
Also Published As
Publication number | Publication date |
---|---|
BR9915095A (pt) | 2002-01-15 |
KR20010075610A (ko) | 2001-08-09 |
EP1124551A2 (en) | 2001-08-22 |
MXPA01004188A (es) | 2002-06-04 |
CA2344637A1 (en) | 2000-05-04 |
DE69938505T2 (de) | 2009-07-09 |
HK1042846A1 (en) | 2002-08-30 |
WO2000024362A2 (en) | 2000-05-04 |
WO2000024362A3 (en) | 2000-08-24 |
KR100636854B1 (ko) | 2006-10-20 |
EP1124551A4 (en) | 2004-10-13 |
US20040258622A1 (en) | 2004-12-23 |
ES2308855T3 (es) | 2008-12-01 |
AU764119B2 (en) | 2003-08-07 |
ATE391501T1 (de) | 2008-04-15 |
DE69938505D1 (de) | 2008-05-21 |
US20020031480A1 (en) | 2002-03-14 |
EP1124551B1 (en) | 2008-04-09 |
HK1042846B (zh) | 2006-01-20 |
AU2143000A (en) | 2000-05-15 |
JP2002528399A (ja) | 2002-09-03 |
US6713048B2 (en) | 2004-03-30 |
CN1214789C (zh) | 2005-08-17 |
US6509005B1 (en) | 2003-01-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1214789C (zh) | △9-四氢大麻酚溶液的定量吸入器及其使用方法 | |
Kowal et al. | Review on clinical studies with cannabis and cannabinoids 2010-2014 | |
Wetli et al. | Death caused by recreational cocaine use | |
Walsh et al. | Established and potential therapeutic applications of cannabinoids in oncology | |
US20050079136A1 (en) | Aerosol formulations of delta tetrahydrocannabinol | |
AU2002319422A1 (en) | Aerosol formulations of delta8 tetrahydrocannabinol | |
Cervellin et al. | Bad news about an old poison. A case of nicotine poisoning due to both ingestion and injection of the content of an electronic cigarette refill | |
Raybuck et al. | Varenicline ameliorates nicotine withdrawal-induced learning deficits in C57BL/6 mice. | |
US5989582A (en) | Administration of ketamine for detoxification and to treat substance addiction, and compositions therefor | |
Hollister | Marijuana (cannabis) as medicine | |
JP2003520237A (ja) | 鬱病及び関連疾患を治療するためのミルトラザピン及びジェピロンを含有する配合剤 | |
EP0814790B1 (en) | Administration of ketamine for detoxification | |
Pajai et al. | Pharmacotherapy in tobacco cessation: a narrative review | |
Ashton | Biomedical benefits of cannabinoids? | |
CN110200953B (zh) | 大麻素在制备吸入给药药物中的应用 | |
Pace et al. | The Medical Use of Marihuana and THC in Perspective | |
Balkisson | Drugs of Abuse and the implications for Anaesthesia and Critical Care | |
Hollister | Marijuana (Cannabis) As Medicine | |
Grinspoon | Cannabis, The Wonder Drug | |
Grinspoon | Cannabis: Wonder drug of the'90s | |
Moccia | Medical uses of marijuana | |
CN113573710A (zh) | 基于大麻素受体激动剂和丝氨酸水解酶抑制剂的抗焦虑治疗产品 | |
MXPA97006456A (en) | Nasal and eye administration of ketamine to manage pain and to detoxify | |
Araujo et al. | Effects of the different population densities in the home cage on behavioral sensitization induced by repeated administration of ethanol |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050817 Termination date: 20091120 |