CN1938027A - Opioid delivery system - Google Patents

Opioid delivery system Download PDF

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CN1938027A
CN1938027A CN 200480042669 CN200480042669A CN1938027A CN 1938027 A CN1938027 A CN 1938027A CN 200480042669 CN200480042669 CN 200480042669 CN 200480042669 A CN200480042669 A CN 200480042669A CN 1938027 A CN1938027 A CN 1938027A
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opioid
formulation
fentanyl
concentration
onset
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CN 200480042669
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奥兰多-里卡多·亨
史蒂文-路易斯·谢弗
黛安娜-海伦·普柳拉
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德莱克斯疗法公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/007Pulmonary tract; Aromatherapy
    • A61K9/0073Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4468Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/007Pulmonary tract; Aromatherapy
    • A61K9/0073Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00Sprayers or atomisers specially adapted for therapeutic purposes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators

Abstract

An opioid formulation for pulmonary administration in the treatment or management of pain, a pulmonary drug delivery device containing, method of administering, kit containing, and uses of same. The formulation contains at least one rapid-onset opioid and preferably also contains a sustained-effect opioid to reduce the frequency of administration. The invention employs the side effects of the opioid formulation to permit patients to self-limit drug intake, thereby avoiding toxicity while achieving analgesia. A pharmacokinetic and pharmacodynamic model is employed to determine optimum drug formulations and optimum parameters for administration.

Description

阿片样物质递送系统 Opioid delivery system

技术领域 FIELD

本发明涉及药物制剂及其施用方法,更具体而言,涉及基于阿片样物质的止痛剂及其施用方法。 The present invention relates to pharmaceutical formulations and methods of administration, and more particularly, relates to a method based on the administration of analgesics and opioid.

背景技术 Background technique

阿片样物质是现有的最古老药物之一,且一直是主要的控制疼痛的物质。 Opioids are one of the oldest existing drugs, and has been a major pain control substances. 最初的阿片样物质阿片来自罂粟植物。 The initial opioid-opioid from the poppy plant. “阿片剂”是阿片的天然衍生物,包括吗啡、美沙酮和海洛因。 "A tablet" is a natural derivative of opium, comprising morphine, methadone and heroin. “阿片样物质”是一类范围更宽的药物,包括阿片、阿片剂以及具有与阿片相同的药理学效应的合成药物。 "Opioid" is a class of a wider range of drugs, including opium, opiates, and synthetic drugs with the same pharmacological opioid effects. 通常使用的合成类阿片样物质包括杜冷丁、芬太尼、阿芬太尼、舒芬太尼和瑞芬太尼。 Usually synthetic opioids include meperidine, fentanyl, alfentanil, sufentanil and remifentanil.

现认为阿片样物质通过结合脊髓和脑以及外周组织中的mu受体发挥作用。 It is believed that the opioid act by binding spinal cord and brain and peripheral tissues of mu receptors. 与mu受体结合诱发了广泛的药理学效应,包括诸如痛觉丧失等治疗作用,在不同的情况下可能被认为是副作用或治疗作用,包括镇静以及减少肠道动力,副作用有恶心、呕吐、尿潴留、瘙痒(pruritis)、呼吸减缓、成瘾和毒性如严重呼吸减缓、意识丧失和死亡等。 Binding to mu receptor induces a wide range of pharmacological effects, including therapeutic effects such as analgesia and the like, in different situations may be considered as side effects or therapeutic effects, including sedation and reduced intestinal motility, side effects are nausea, vomiting, urinary retention, itching (pruritis), slowed breathing, addiction and toxicity such as severe breathing slow, loss of consciousness and death.

阿片样物质在许多方面相互有差异,包括它们的递送途径、它们的物化组成、它们的药物吸收速率、它们的药动学及它们的药效学。 Opioid have mutual differences in many ways, including their route of delivery, their physicochemical composition, their drug absorption rate, their pharmacokinetics, and their pharmacodynamics. 阿片样物质的非侵入性递送途径包括口服、直肠、透皮、透粘膜以及经吸入施用。 Non-invasive routes of opioid delivery include oral, rectal, transdermal, transmucosal, and via inhalation. 阿片样物质的侵入性递送途径包括静脉注射、肌肉注射、硬膜外注射、脊椎注射以及关节注射。 Invasive routes of opioid delivery include intravenous, intramuscular, epidural injection, intraarticular injection and spinal injection. 静脉注射时,某些阿片样物质迅速进入脑和脊髓并由此极快的发挥药效(例如,阿芬太尼和瑞芬太尼),而其它一些被缓慢吸收至作用位点并具有极慢起效的药物作用(例如吗啡)。 When injected intravenously, some opioids quickly enter the brain and spinal cord and thus fast play efficacy (e.g., alfentanil and remifentanil), while others are absorbed slowly to the site of action and has a very slow-start acting drugs (e.g., morphine). 相似的,对于某些阿片样物质,由于非常迅速的代谢,药物作用时间很短暂(例如瑞芬太尼),而另一些阿片样物质可能具有非常慢的代谢并因而延长了作用时间(例如美沙酮)。 Similarly, for some opioids, due to the very rapid metabolism, drug action time is very short (eg remifentanil), while other opioids may have very slow metabolism and thus prolong the duration of action (such as methadone ). 就药效学而言,阿片样物质的效力跨越约5个数量级,从诸如卡芬太尼和埃托啡(均用于麻醉大象)等非常强效的阿片样物质到诸如美沙酮和吗啡等效力相对较弱的药物。 To pharmacodynamics, the potency of opioids spans approximately 5 orders of magnitude, from sources such as carfentanil and etorphine (both used for anesthesia elephants) like a very potent opioids such as methadone and morphine to relatively weak effect of the drug. 阿片样物质的等价效力(测定为“治疗等效比”)在文献中已经良好地建立,且将患者治疗方案从一种阿片样物质改变成另一种时经常使用。 Equivalent potency of opioids (measured as a "therapeutic equivalence ratio") have been well established in the literature, and the patient's treatment regimen from one opioid to change to another during regular use.

尽管存在这些差异,所有的阿片样物质都同样有可能导致极度痛觉丧失和因缺氧导致极度毒性,后者可能是致死的。 Despite these differences, all opioids are equally likely to cause extreme pain and loss due to hypoxia lead to extreme toxicity, which may be fatal. 由于有缺氧的危险,医师不愿使用适当剂量的阿片样物质治疗急性和慢性疼痛。 Because of the risk of hypoxia, physicians do not want to use the treatment of acute and chronic pain, the appropriate dose of opioid. 结果造成无数有可能被提供更好疼痛控制的患者接受了不足剂量的阿片样物质。 The result is likely to be provided countless patients better pain control received inadequate doses of opioids. 相反的,即使卫生保健组织采取了可理解的谨慎步骤处理疼痛,每年仍有许多患者死于阿片样物质诱发的通气减缓。 Conversely, even if health care organizations to take a cautious step understandable pain management, there are still many patients die from opioid-induced ventilatory year slowed.

疼痛是非常不确定和非常主观的。 Pain is very uncertain and very subjective. 不同的患者对阿片样物质的反应不同。 Different patients respond differently to opioids. 结果造成不同的患者需要不同量的止痛剂控制疼痛。 Resulting in different patients require different amounts of an analgesic to control pain. 因此需要允许患者改变他们所接受的止痛剂的量。 It is necessary to allow the patient to change the amount they receive analgesics.

一种更好的调节患者阿片样物质用量的尝试是引入“患者控制的止痛”(″PCA″)(Ballantyne JC,et al. Postoperative patient-controlled analgesia:Meta-analyses ofinitial randomized control trials.J Clin Anesth 1993:5:182-193.)。 A better attempt to adjust the amount of material introduced into a patient is opioid "patient controlled analgesia" ( "PCA") (Ballantyne JC, et al Postoperative patient-controlled analgesia:. Meta-analyses ofinitial randomized control trials.J Clin Anesth 1993: 5: 182-193). 利用PCA系统,在给药前患者必须是清醒的,且必须起动递送装置以接收更多的阿片样物质。 The PCA system, prior to administration to a patient must be awake, and must be activated delivery device to receive more opioid. 如果患者施用了过量阿片样物质,那时患者就会变得无意识且要求更多的药物。 If the patient is administered an excess opioid, then the patient will become unconscious and requires more drug. 以此方式,PCA系统利用了阿片样物质的副作用-镇静-来限制阿片样物质的给药量。 In this way, PCA system uses a side effect of opioid - sedation - to limit the amount of opioid administered. 使用PCA系统的一个问题是药物在患者请求后迅速注射(通常,药物的施用时间框在1分钟之内),且因为最频繁使用于PCA中的药物是吗啡,一种从血浆缓慢转移至作用位点的药物,这造成患者请求药物和药物止痛作用之间的延迟。 One problem with the PCA system is injected rapidly after the patient a pharmaceutical request (typically, the time frame of administration of drug within 1 minute), and because the most frequently used drugs in the PCA is morphine, a slow transfer from the plasma to the effect Drug site, which results in a delay between the patient request for drug and the analgesic effect of the drug. 这种延迟的结果是当第一次注射的阿片样物质的药效水平仍在上升时患者经常请求了第二次(或第三次)用药。 This delay results when the level of efficacy of the first injection is still rising opioid patients often request a second (or third) medication. PCA系统包括一个“锁定”期(通常是5分钟),帮助防止当阿片样物质药效仍在增加时患者施用更多的阿片样物质。 PCA systems include a "lock" period (usually 5 minutes), to help prevent patients from administering more opioid when opioid efficacy is still increasing. 锁定期通常是由卫生保健提供者控制、限定或编程,而已有许多案例由于使用者错误或不注意编程锁定期导致患者死亡。 Lock-up period is usually controlled by a health care provider, limit or programming, there are many cases just because the users pay no attention to programming errors or lock-up period leads to death. 患者也常常由于锁定而感到失望,因为它减少了患者对用药的控制。 Patients are often due to a lock disappointed, because it reduces the patient control of the administration. PCA的其它缺点包括侵入性非胃肠道施用(静脉注射)以及昂贵的灌流泵,由此PCA限制在由住院患者使用。 Other disadvantages of the PCA include the invasive parenteral administration (intravenous) infusion pump and expensive, thus limiting the use of the PCA in hospitalized patients.

第二种更好的调控患者对阿片样物质用药量的尝试是在分娩相关的阵痛期间自我施加氧化亚氮。 Self-imposed nitrous oxide during the attempt to the dosage of opioid second better regulation patient is in the throes of childbirth. 氧化亚氮面罩在宫缩期被戴到患者的脸上,而当达到适当止痛效果时再从脸上取下。 Nitrous oxide mask is worn to the contractions of the patient's face, and then removed from the face When the appropriate analgesic effect. 不过,这种装置是通过滴定到止痛效果而不被用作是保险装置,因为利用此施加系统过量施用氧化亚氮不是一个重要的问题。 However, this device is determined by titration to analgesic effect and not be used as a safety device, because with this system is applied to an excess of nitrous oxide administered is not an important issue. 此外,氧化亚氮是一种需要巨大钢桶贮存以及复杂递送系统进行施用的气体。 Furthermore, nitrous oxide is a complex and requires a large storage drums gas delivery system for administration. 因此,使用氧化亚氮主要局限于医院环境而不适于流动患者。 Therefore, the use of nitrous oxide is mainly confined to the hospital environment is not suitable for the flow of patients. 另外有关氧化亚氮的潜在问题涉及它的低效力由此必须施用氧气中的高浓度(超过50%)的氧化亚氮,从而可能造成缺氧。 Further potential problems associated nitrous oxide relates to its low potency thus must be administered in high oxygen concentrations (over 50%) of nitrous oxide, which may cause hypoxia.

本发明试图利用阿片样物质的两种生理反应:镇静和通气减缓,来限制患者接受阿片样物质的总剂量。 The present invention seeks to use two physiological opioid reaction: sedation and ventilatory depression, to limit the patient received a total dose of opioids. 以此方式,本发明试图提高阿片样物质药物递送的安全性,超过利用PCA或其它现存阿片样物质递送方法目前所达到的安全性,后者只利用单一副作用来限制患者接收危险的高水平阿片样物质药物作用。 In this embodiment, the present invention seeks to improve the safety of opioid drug delivery beyond the PCA or other existing opioid security delivery methods currently achieved, which is limited only by the single side-effects in patients receiving high levels of opioid dangerous drug-like substance. 本发明还通过排除对目前PCA系统中所需的“锁定期”的需要以及消除其中的挫折感和使用者错误的可能性改进了镇静的用途。 The invention further by eliminating the need for the current PCA system needed to "lock-up period" and eliminating the user frustration and the possibility of error which improves the use of sedation.

发明内容 SUMMARY

因此,本发明第一方面提供一种阿片样物质制剂,其用于向患者提供止痛而避免毒性的方法;所述方法包括用肺部药物递送装置连续吸入所述制剂产生止痛,并在获得满意的止痛效果或产生副作用时停止吸入;使所述肺部药物递送装置适合在肺部以有效速率沉积所述制剂颗粒;所述制剂包含有效量的至少一种快速起效的阿片样物质和至少一种持续作用的阿片样物质以及药用可接受载体,选择每种阿片样物质的浓度和类型使得在吸入期间在所述副作用发作之前达到止痛效果,并且所述副作用发作出现在毒性发作之前,并使得最大总阿片样物质血浆浓度不会达到中毒水平,由此可由患者利用所述副作用的发作而停止吸入以避免中毒。 Accordingly, a first aspect of the present invention to provide an opioid formulation to provide analgesia to a patient and a method for avoiding toxicity; the method comprises pulmonary drug delivery device to produce analgesia continuously sucked into the formulation, and satisfactory stopping the suction when the analgesic effect or side effects; the pulmonary drug delivery device suitable for deposition in the lungs at an effective rate of the particles of the formulation; said formulation comprising an effective amount of at least one rapid-onset opioid and at least one sustained-effect opioid and a pharmaceutically acceptable carrier, the concentration and type of each opioid is such that analgesia is achieved before the onset of said side effect during inhalation, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum total opioid plasma concentration does not reach toxic levels substance, whereby the onset of said side effect by the patient to terminate inhalation to avoid toxicity and.

在一个实施方案中,选择所述制剂中每种阿片样物质的浓度和类型,使得在副作用发作时最大总阿片样物质血浆浓度不低于66%或不低于80%的最大总阿片样物质血浆浓度。 In one embodiment, the selected type of formulation and the concentration of each opioid is such that the plasma concentration at the onset of side effects of the maximum total opioid is not less than 66%, or not less than 80% of the maximum total opioid plasma concentrations.

在另一实施方案中,所述制剂中至少一种快速起效的阿片样物质是芬太尼、阿芬太尼、舒芬太尼或瑞芬太尼。 In another embodiment, the formulation of at least one rapid-onset opioid is fentanyl, alfentanil, sufentanil and remifentanil.

在另一实施方案中,所述至少一种持续作用阿片样物质是吗啡、吗啡-6-葡糖酸苷、美沙酮、氢吗啡酮、度冷丁、包裹于生物相容载体中延迟药物在肺表面释放的阿片样物质、或脂质体包裹的阿片样物质。 In another embodiment, the at least one sustained-effect opioid is morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, an opioid encapsulated in a biocompatible carrier that delays drug lung surface releasable opioid, or a liposome encapsulated opioid. 所述脂质体包裹的阿片样物质可以是脂质体包裹的芬太尼。 The liposomally encapsulated opioid may be a liposome encapsulated fentanyl.

在一个实施方案中,阿片样物质制剂的总阿片样物质浓度是250-1500mcg/ml。 In one embodiment, the total opioid concentration opioid formulations are 250-1500mcg / ml.

在一个实施方案中,制剂中的阿片样物质由游离的芬太尼和脂质体包裹的芬太尼组成。 In one embodiment, the opioids in the formulation of free fentanyl and liposomally encapsulated fentanyl.

在一个实施方案中,游离芬太尼与脂质体包裹芬太尼的浓度比例是1∶5至2∶1。 In one embodiment, the free fentanyl and liposomally encapsulated fentanyl concentration ratio is 5 to 2:1.

在另一实施方案中,游离芬太尼与脂质体包裹芬太尼的浓度比例是大约2∶3。 In another embodiment, the ratio of concentration of free fentanyl to liposomally encapsulated fentanyl is about 2:3.

在另一实施方案中,阿片样物质制剂包含100-750mcg/ml浓度的游离芬太尼。 In another embodiment, the opioid formulation comprising 100-750mcg / ml concentration of free fentanyl.

在另一实施方案中,阿片样物质制剂包含250-1500mcg/ml浓度的脂质体包裹的芬太尼。 In another embodiment, the opioid formulation comprising encapsulated fentanyl 250-1500mcg / ml concentration of liposome.

在另一实施方案中,阿片样物质制剂的总阿片样物质浓度约为500mcg/ml,游离芬太尼的浓度约为200mcg/ml,而脂质体包裹的芬太尼浓度约为300mcg/ml。 In another embodiment, the total opioid concentration is about opioid formulation 500mcg / ml, the free fentanyl concentration is about 200mcg / ml, and the liposomally encapsulated fentanyl concentration is about 300mcg / ml .

在另一实施方案中,制剂包含两种或更多种不同的阿片样物质,不包括其中仅有两种阿片样物质是游离芬太尼和脂质体包裹芬太尼的制剂。 In another embodiment, the formulation comprises two or more different opioids, excluding a formulation wherein the only two opioids are free fentanyl and liposomally encapsulated fentanyl.

在另一实施方案中,制剂中的阿片样物质由阿芬太尼和吗啡组成。 In another embodiment, the opioids in the formulation consist of alfentanil and morphine composition.

在另一实施方案中,制剂包含浓度为300-6700mcg/ml的阿芬太尼。 In another embodiment, the formulation at a concentration of 300-6700mcg / ml alfentanil.

在另一实施方案中,制剂包含浓度为650-13350mcg/ml的吗啡。 In another embodiment, the formulation at a concentration of 650-13350mcg / ml of morphine.

本发明的另一方面是施用阿片样物质制剂使患者止痛同时避免中毒的方法,包括以下步骤:用适于以有效速率将制剂的气溶胶颗粒递送入肺的肺部药物递送装置连续吸入制剂以止痛;和在达到满意的止痛效果或副作用发作时停止吸入;其中制剂包含有效量的至少一种快速起效的阿片样物质和药用可接受载体;选择每种阿片样物质的浓度和类型以及颗粒的有效递送速率,使得在吸入期间在所述副作用发作之前达到止痛效果,且所述副作用发作出现在毒性发作之前,并使得最大总阿片样物质血浆浓度不会达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒。 Another aspect of the present invention is the administration of opioid formulation analgesia to a patient while avoiding toxicity, comprising the steps of: means for continuous delivery into the lungs by inhalation formulation suitable for the formulations at an effective rate of drug delivery to pulmonary aerosol particles pain; and stopping inhalation when satisfactory analgesia or onset of a side effect; wherein the formulation comprises an effective amount of at least one rapid-onset opioid and a pharmaceutically acceptable carrier; the concentration and type of each opioid, and the effective rate of delivery of particles, so that analgesia is achieved before the onset of said side effect during inhalation, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum total opioid plasma concentration does not reach toxic levels substance, whereby by the patient the onset of said side effect to terminate inhalation to avoid toxicity.

在一个实施方案中,制剂由肺部药物递送装置以1-5微米的质量中值空气动力学直径分配。 In one embodiment, the value of the air mass of the formulation to 1-5 microns kinetic diameters assigned by pulmonary drug delivery device.

在另一实施方案中,制剂通过肺部药物递送装置以1-3微米的质量中值空气动力学直径分配。 In another embodiment, the formulation delivery device to the air mass median aerodynamic diameter of 1-3 microns dispensed by the pulmonary drug.

在另一实施方案中,制剂通过肺部药物递送装置以1.5-2微米的质量中值空气动力学直径分配。 In another embodiment, the formulation delivery device to the air mass median aerodynamic diameter of 1.5 microns dispensed by the pulmonary drug.

本发明的另一实施方案是一种方法,其中选择每种阿片样物质的浓度和类型,使得副作用发作时的最大总阿片样物质血浆浓度不低于最大总阿片样物质血浆浓度的66%或80%。 Another embodiment of the present invention is a method, wherein the concentration and type of each opioid is such that the maximum total opioid plasma concentration at the onset of a side no less than 66% of the maximum total opioid plasma concentration or 80%.

本发明的另一实施方案是一种方法,其中所述至少一种快速起效的阿片样物质选自芬太尼、阿芬太尼、舒芬太尼和瑞芬太尼的方法。 Another embodiment of the present invention is a method, wherein said at least one rapid-onset opioid is chosen from fentanyl, alfentanil, sufentanil and remifentanil method.

本发明的另一实施方案是一种方法,进一步包含有效量的至少一种持续作用的阿片样物质以提供持续减轻痛苦,其中选择每种阿片样物质的浓度和类型,使得吸入期间在所述副作用发作之前达到止痛效果,且所述副作用发作出现在毒性发作之前,并使得最大总阿片样物质血浆浓度不会达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒。 Another embodiment of the present invention is a process, at least one sustained-effect further comprising an effective amount of the opioid to provide sustained relieve pain, wherein the concentration and type of each opioid is such that during inhalation of the prior to the onset of side effects to achieve the analgesic effect, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum total plasma concentration of opioid does not reach toxic levels, whereby the onset of said side effect by the patient to terminate inhalation to avoid toxicity.

另一实施方案是一种方法,其中所述至少一种持续作用的阿片样物质选自吗啡、吗啡-6-葡糖酸苷、美沙酮、氢吗啡酮、度冷丁、包裹于生物相容载体中延迟药物在肺表面释放的阿片样物质以及脂质体包裹的阿片样物质。 Another embodiment is a method, wherein the at least one sustained-effect opioid is chosen from morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, an opioid encapsulated in a biocompatible carrier delay drug release surface of the lung and the opioid is liposomally encapsulated opioid.

另一实施方案是其中脂质体包裹的阿片样物质是脂质体包裹芬太尼的方法。 Another embodiment is wherein the liposomally encapsulated opioid is liposomally encapsulated fentanyl method.

另一实施方案是其中至少一种持续作用的阿片样物质选自吗啡和脂质体包裹芬太尼的方法。 Another embodiment is wherein the at least opioid is chosen from morphine and liposomally encapsulated fentanyl method of sustained-effect.

另一实施方案是其中所述制剂中的阿片样物质由游离芬太尼和脂质体包裹芬太尼组成的方法。 Another embodiment is wherein the opioids in the formulation of free fentanyl and liposomally encapsulated fentanyl method.

另一实施方案是其中游离芬太尼与脂质体包裹芬太尼的浓度比例为1∶5-2∶1的方法。 Another embodiment is wherein the free fentanyl and liposomally encapsulated fentanyl concentration ratio of a method 1:5-2:1.

另一实施方案是其中游离态芬太尼和脂质体包裹芬太尼的浓度比例约为2∶3的方法。 Another embodiment is wherein the free fentanyl and liposomally encapsulated fentanyl concentration is about 2:3 ratio method.

另一实施方案是其中总阿片样物质浓度为250-1500mcg/ml的方法。 Another embodiment is wherein the total opioid concentration 250-1500mcg method / ml.

另一实施方案是其中制剂含有浓度为100-750mcg/ml游离芬太尼的方法。 Another embodiment wherein the formulation is a concentration of 100-750mcg / ml fentanyl free methods.

另一实施方案是其中制剂含有浓度为250-1500mcg/ml脂质体包裹芬太尼的方法。 Another embodiment is a method wherein the formulation contains 250-1500mcg / ml liposomally encapsulated fentanyl concentration.

另一实施方案是其中总阿片样物质浓度约为500mcg/ml、游离芬太尼浓度约为200mcg/ml和脂质体包裹芬太尼浓度约为300mcg/ml的方法。 Another embodiment is wherein the total opioid concentration is about 500mcg / ml, the free fentanyl concentration is about 200mcg / ml fentanyl and liposome method a concentration of about 300mcg / ml package.

另一实施方案是其中吸入期间游离芬太尼以4-50mcg/分钟的速度沉积于肺部的方法。 Another embodiment is wherein the free fentanyl 4-50mcg / min is deposited in the lungs during inhalation.

另一实施方案是其中吸入期间游离芬太尼以10-20mcg/分钟的速度沉积于肺部的方法。 Another embodiment is wherein the free fentanyl 10-20mcg / min is deposited in the lungs during inhalation.

另一实施方案是其中吸入期间游离芬太尼以约15mcg/分钟的速度沉积于肺部的方法。 Another embodiment in which the speed of fentanyl free during inhalation from about 15mcg / min deposition in the lungs.

另一实施方案是其中吸入期间脂质体包裹芬太尼以5-150mcg/分钟的速度沉积于肺部的方法。 Another embodiment of liposomally encapsulated fentanyl during inhalation at a rate 5-150mcg / min deposition in the lungs.

另一实施方案是其中吸入期间脂质体包裹芬太尼以10-90mcg/分钟的速度沉积于肺部的方法。 Another embodiment of liposomally encapsulated fentanyl during inhalation at a rate 10-90mcg / min deposition in the lungs.

另一实施方案是其中吸入期间脂质体包裹芬太尼以15-60mcg/分钟的速度沉积于肺部的方法。 Another embodiment of liposomally encapsulated fentanyl during inhalation at a rate 15-60mcg / min deposition in the lungs.

另一实施方案是其中吸入期间脂质体包裹芬太尼以20-45mcg/分钟的速度沉积于肺部的方法。 Another embodiment of liposomally encapsulated fentanyl during inhalation at a rate 20-45mcg / min deposition in the lungs.

另一实施方案是其中吸入期间总阿片样物质以5-200mcg/分钟的速度沉积于肺部的方法。 Another embodiment is a method wherein during inhalation of total opioid at a speed 5-200mcg / is deposited in the lungs.

另一实施方案是其中吸入期间总阿片样物质以10-40mcg/分钟的速度沉积于肺部的方法。 Another embodiment is a method wherein during inhalation of total opioid at a speed 10-40mcg / is deposited in the lungs.

另一实施方案是其中吸入期间总阿片样物质以30-35mcg/分钟的速度沉积于肺部的方法。 Another embodiment is a method wherein during inhalation of total opioid at a speed 30-35mcg / is deposited in the lungs.

另一实施方案是一种方法,其中制剂包含两种或更多种不同阿片样物质,不包括其中仅有的两种阿片样物质是游离芬太尼和脂质体包裹芬太尼的制剂,另一实施方案是其中经50-500次吸入进行施用的方法。 Another embodiment is a method, wherein the formulation comprises two or more different opioids, excluding a formulation wherein the only two opioids are free fentanyl and liposomally encapsulated fentanyl formulation, another embodiment is the method wherein administration by inhalation is 50-500 times.

另一实施方案是其中制剂中的阿片样物质由阿芬太尼和吗啡组成的方法。 Another embodiment is a method wherein the opioids in the formulation consist of alfentanil and morphine thereof.

另一实施方案是其中制剂含有浓度为300-6700mcg/ml阿芬太尼的方法。 Another embodiment is 300-6700mcg / ml alfentanil process wherein a concentration of the formulation.

另一实施方案是其中吸入期间阿芬太尼以100-500mcg/分钟的速度沉积于肺部的方法。 A further embodiment is a method wherein during inhalation at a rate of fentanyl 100-500mcg / is deposited in the lungs.

另一实施方案是其中吸入期间阿芬太尼以约250mcg/分钟的速度沉积于肺部的方法。 Another embodiment is a method wherein alfentanil during inhalation at a rate of about 250mcg / is deposited in the lungs.

另一实施方案是其中制剂含有浓度为650-13350mcg/ml吗啡的方法。 Another embodiment is a method 650-13350mcg / ml wherein the formulation contains morphine in a concentration of.

另一实施方案是其中吸入期间吗啡以100-2000mcg/分钟的速度沉积于肺部的方法。 Another embodiment is a method wherein a rate of morphine during inhalation 100-2000mcg / is deposited in the lungs.

另一实施方案是其中吸入期间吗啡以200-1000mcg/分钟的速度沉积于肺部的方法。 Another embodiment is a method wherein the rate of morphine during inhalation 200-1000mcg / is deposited in the lungs.

另一实施方案是其中吸入期间吗啡以约500mcg/分钟的速度沉积于肺部的方法。 Another embodiment is wherein morphine at about 500mcg / is deposited in the lungs during inhalation.

本发明的另一方面是阿片样物质的副作用用于预防阿片样物质中毒的用途。 Another aspect of the present invention is to opioid side effects for the prevention of opioid poisoning.

本发明的另一方面是含有使患者止痛的阿片样物质制剂的肺部药物递送装置,其包括:含有上述制剂的容器;与容器连接的出口;与容器相连的手段,用于通过有意识患者努力的动作并以有效速率将所述制剂的颗粒通过所述出口并分配入肺部,由此在吸入期间在阿片样物质副作用发作之前达到止痛的效果,且所述副作用发作出现在毒性发作之前,并使得最大总阿片样物质血浆浓度不会达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒。 Pulmonary drug another aspect of the present invention is a patient opioid analgesic formulation delivery device comprising: a container containing the above formulation; an outlet coupled to the container; means associated with the container, there is used by conscious patient effort and an effective rate of operation of the particles of the formulation through the dispensing outlet and into the lungs, so as to achieve analgesic effect prior to the onset of an opioid side effect during inhalation, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum total opioid plasma concentration does not reach toxic levels substance, whereby the onset of said side effect by the patient to terminate inhalation to avoid toxicity.

本发明的另一方面是含有使患者止痛的阿片样物质制剂的肺部药物递送装置,所述装置包括:含有制剂的容器,所述制剂包含有效量的至少一种快速起效的阿片样物质和药用可接受载体;与容器连接的出口;与容器相连的手段,用于将所述制剂通过所述出口并分配入肺部,所述手段需要有意识的患者用力驱动;其中选定每种阿片样物质的浓度和类型以及所述颗粒的有效递送速率,使得在吸入期间在阿片样物质副作用发作之前达到止痛的效果,且所述副作用发作出现在毒性发作之前,并使得最大总阿片样物质血浆浓度不会达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒。 Pulmonary drug another aspect of the present invention is a patient opioid analgesic formulation delivery device, said apparatus comprising: at least one rapid-onset opioid container containing a formulation comprising an effective amount of a formulation and a pharmaceutically acceptable carrier; and an outlet connected to the container; means associated with the container, said formulation for dispensing through the outlet and into the lungs, the means required driving force conscious patient; wherein each selected type and concentration of the effective rate of delivery of the particles and the opioid, such that achieve analgesic effect before the onset of an opioid side effect during inhalation, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum total opioid plasma concentration does not reach toxic levels, whereby the onset of said side effect by the patient to terminate inhalation to avoid toxicity.

另一实施方案是一种装置,进一步包含递送速率控制手段以限制制剂分配速率低于选定阈值。 Another embodiment is an apparatus further comprising delivery rate controlling means to limit the rate of dispensing the formulation is below a selected threshold.

另一实施方案是一种装置,其中出口包含开孔,为了分配制剂所述开孔必须被患者嘴唇密封。 Another embodiment is an apparatus, which comprises an outlet opening, said opening for dispensing the formulation must be sealed lip patient.

另一实施方案是其中分配器由呼吸驱动的装置。 Another embodiment is where a breath actuated dispenser means.

另一实施方案是其中颗粒具有1-5微米的质量中值空气动力学直径的装置。 Another embodiment is the device wherein the particles have a mass median aerodynamic diameter of air of 1 to 5 microns.

另一实施方案是其中所述颗粒具有1-3微米的质量中值空气动力学直径的装置。 Another embodiment is the device wherein the particles have a mass median aerodynamic diameter of 1-3 microns air of.

另一实施方案是其中所述颗粒具有1.5-2微米的质量中值空气动力学直径的装置。 Another embodiment is the device wherein the particles have a mass median aerodynamic diameter of the air of 1.5 microns.

另一实施方案是一种装置,其中选择每种阿片样物质的浓度和类型,使得副作用发作时的最大总阿片样物质血浆浓度不低于最大总阿片样物质血浆浓度的66%。 Another embodiment is a device in which the concentration and type of each opioid is such that the maximum total opioid plasma concentration at the onset of a side no less than 66% of the maximum total opioid plasma concentration.

另一实施方案是一种装置,其中选择每种阿片样物质的浓度和类型,使得副作用发作时的最大总阿片样物质血浆浓度不低于最大总阿片样物质血浆浓度的80%。 Another embodiment is a device in which the concentration and type of each opioid is such that the maximum total opioid plasma concentration at the onset of a side no less than 80% of the maximum total opioid plasma concentration.

另一实施方案是其中至少一种快速起效的阿片样物质选自芬太尼、阿芬太尼、舒芬太尼和瑞芬太尼的装置。 Another embodiment is wherein the at least one rapid-onset opioid is chosen from fentanyl, alfentanil, sufentanil and remifentanil apparatus.

另一实施方案是一种装置,进一步包含有效量的至少一种持续作用的阿片样物质以持续减轻痛苦,其中选择制剂中每种阿片样物质的浓度和类型,使得在吸入期间在阿片样物质副作用发作之前达到止痛的效果,且所述副作用发作出现在毒性发作之前,并使得最大总阿片样物质血浆浓度不会达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒。 Another embodiment is an apparatus, further comprising an effective amount of at least one sustained-effect opioid in a sustained relieve pain, wherein the concentration and type of each opioid in the formulation, so that during inhalation opioid to achieve the analgesic effect, and the onset of said side effect occurs before the onset of a side before the onset of toxicity, and so that the maximum total opioid plasma concentration does not reach toxic levels substance, whereby the onset of said side effect by the patient to terminate inhalation to avoid toxicity .

另一实施方案是一种装置,其中至少一种持续作用的阿片样物质选自吗啡、吗啡-6-葡糖酸苷、美沙酮、氢吗啡酮、度冷丁、包裹于生物相容载体中延迟药物在肺表面释放的阿片样物质或脂质体包裹的阿片样物质。 Another embodiment is an apparatus, wherein the at least one sustained-effect opioid is chosen from morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, an opioid encapsulated in a biocompatible carrier that delays medicament in the lung surface release opioid or liposomally encapsulated opioid.

另一实施方案是其中脂质体包裹的阿片样物质是脂质体包裹的芬太尼的装置。 Another embodiment is wherein the liposomally encapsulated opioid is fentanyl to liposomally encapsulated device.

另一实施方案是其中至少一种持续作用的阿片样物质选自吗啡和脂质体包裹的芬太尼的装置。 Another embodiment is wherein the opioid is chosen from fentanyl and liposomally encapsulated morphine means of at least one sustained-effect.

另一实施方案是其中所述制剂中的阿片样物质是由游离芬太尼和脂质体包裹芬太尼组成的装置。 Another embodiment is a formulation wherein the opioid is a free fentanyl and liposomally encapsulated fentanyl apparatus.

另一实施方案是其中游离芬太尼与脂质体包裹芬太尼浓度比例为1∶5-2∶1的装置。 Another embodiment is wherein the free fentanyl and liposomally encapsulated fentanyl concentration ratio means the 1:5-2:1.

另一实施方案是其中游离芬太尼和脂质体包裹芬太尼的浓度比例约为2∶3的装置。 Another embodiment is wherein the free fentanyl and liposomally encapsulated fentanyl concentration ratio means 2:3 about.

另一实施方案是其中总阿片样物质浓度为250-1500mcg/ml的装置。 Another embodiment is wherein the total opioid concentration is 250 to 1500 mcg / ml of the device.

另一实施方案是其中所述制剂含有浓度为100-750mcg/ml游离芬太尼的装置。 Another embodiment is wherein the formulation contains a concentration of 100-750mcg / ml fentanyl free device.

另一实施方案是其中所述制剂含有浓度为250-1500mcg/ml脂质体包裹芬太尼的装置。 Another embodiment is wherein the formulation comprises a concentration means 250-1500mcg / ml liposomally encapsulated fentanyl.

另一实施方案是其中总阿片样物质浓度约为500mcg/ml、游离芬太尼浓度约为200mcg/ml和脂质体包裹芬太尼浓度约为300mcg/ml的装置。 Another embodiment is wherein the total opioid concentration is about 500mcg / ml, the free fentanyl concentration is about 200mcg / ml fentanyl and liposome means a concentration of about 300mcg / ml package.

另一实施方案是其中吸入期间游离芬太尼以4-50mcg/分钟的速度沉积于肺部的装置。 Another embodiment in which the lungs during inhalation free fentanyl at a rate 4-50mcg / min deposited.

另一实施方案是其中吸入期间游离芬太尼以10-20mcg/分钟的速度沉积于肺部的装置。 Another embodiment in which the lungs during inhalation free fentanyl at a rate 10-20mcg / min deposited.

另一实施方案是其中吸入期间游离芬太尼以约15mcg/分钟的速度沉积于肺部的装置。 Another embodiment is the device wherein fentanyl from about 15mcg / min deposited in the lungs during inhalation free.

另一实施方案是其中吸入期间脂质体包裹的芬太尼以5-150mcg/分钟的速度沉积于肺部的装置。 Another embodiment is the device in which the liposomally encapsulated fentanyl during inhalation 5-150mcg / is deposited in the lungs.

另一实施方案是其中吸入期间脂质体包裹的芬太尼以10-90mcg/分钟的速度沉积于肺部的装置。 Another embodiment is the device in which the liposomally encapsulated fentanyl during inhalation 10-90mcg / is deposited in the lungs.

另一实施方案是其中吸入期间脂质体包裹的芬太尼以15-60mcg/分钟的速度沉积于肺部的装置。 Another embodiment is the device in which the liposomally encapsulated fentanyl during inhalation 15-60mcg / is deposited in the lungs.

另一实施方案是其中吸入期间脂质体包裹的芬太尼以20-45mcg/分钟的速度沉积于肺部的装置。 Another embodiment is the device in which the liposomally encapsulated fentanyl during inhalation 20-45mcg / is deposited in the lungs.

另一实施方案是其中吸入期间总阿片样物质以5-200mcg/分钟的速度沉积于肺部的装置。 Another embodiment is where the device during inhalation of total opioid at a speed 5-200mcg / is deposited in the lungs.

另一实施方案是其中吸入期间总阿片样物质以10-40mcg/分钟的速度沉积于肺部的装置。 Another embodiment is where the device during inhalation of total opioid at a speed 10-40mcg / is deposited in the lungs.

另一实施方案是其中吸入期间总阿片样物质以30-35mcg/分钟的速度沉积于肺部的装置。 Another embodiment is where the device during inhalation of total opioid at a speed 30-35mcg / is deposited in the lungs.

另一实施方案是一种装置,其中所述制剂含有两种或更多种不同阿片样物质,不包括其中仅有的两种阿片样物质是游离芬太尼和脂质体包裹的芬太尼的制剂。 Another embodiment is an apparatus, wherein the formulation contains two or more different opioids, excluding a formulation wherein the only two opioids are free fentanyl and liposomally encapsulated fentanyl preparations.

另一实施方案是其中所述制剂中的阿片样物质由阿芬太尼和吗啡组成的装置。 Another embodiment is the device wherein the opioids in the formulation consist of alfentanil and morphine thereof.

另一实施方案是其中所述制剂含有浓度为300-6700mcg/ml阿芬太尼的装置。 Another embodiment is wherein the formulation contains 300-6700mcg / ml concentration of alfentanil apparatus.

另一实施方案是其中吸入期间阿芬太尼以100-500mcg/分钟的速度沉积于肺部的装置。 Another embodiment is an apparatus wherein during inhalation alfentanil speed 100-500mcg / is deposited in the lungs.

另一实施方案是其中吸入期间阿芬太尼以约250mcg/分钟的速度沉积于肺部的装置。 Another embodiment is the device wherein alfentanil during inhalation at a rate of about 250mcg / is deposited in the lungs.

另一实施方案是其中制剂含有浓度为650-13350mcg/ml吗啡的装置。 Another embodiment is an apparatus 650-13350mcg / ml wherein the formulation contains morphine in a concentration of.

另一实施方案是其中吸入期间吗啡以100-2000mcg/分钟的速度沉积于肺部的装置。 Another embodiment is where the device during inhalation at a rate of morphine 100-2000mcg / is deposited in the lungs.

另一实施方案是其中吸入期间吗啡以200-1000mcg/分钟的速度沉积于肺部的装置。 Another embodiment is where the device during inhalation at a rate of morphine 200-1000mcg / is deposited in the lungs.

另一实施方案是其中吸入期间吗啡以约500mcg/分钟的速度沉积于肺部的装置。 Another embodiment is wherein morphine at about 500mcg / min is deposited in the lungs during inhalation.

另一实施方案是其中每次吸入分配器分配0.2%-1%制剂的装置。 Another embodiment is wherein the dispenser dispenses each inhalation formulation of 0.2% to 1% of the device.

本发明的另一方面是阿片样物质施用药盒,包含:上述肺部药物递送装置;和所述装置的使用说明,其包括使用所述装置连续吸入制剂并在达到满意的止痛效果或副作用发作时停止吸入的步骤。 Another aspect of the present invention is an opioid administration kit, comprising: a pulmonary drug delivery device described above; and instructions for use of the apparatus, which means comprising the use of the continuous inhalation formulation and to achieve a satisfactory analgesic effect or onset of a side stop step inhalation.

本发明的另一方面是阿片样物质施用药盒,包含:含有效量的至少一种快速起效的阿片样物质和药用可接受载体的制剂;肺部药物递送装置,其中包含容器、与容器连接的出口、与容器连接的由患者用力动作以有效速率将其中所含制剂颗粒通过所述出口分配并进入肺部的手段,使得在吸入期间在阿片样物质副作用发作之前达到止痛的效果,且所述副作用发作出现在毒性发作之前,并使得最大总阿片样物质血浆浓度不会达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒;和所述装置的使用说明,其包括步骤有:用制剂填充该容器,用所述装置连续吸入制剂,并在达到满意的止痛效果或副作用发作时停止吸入。 Another aspect of the present invention is an opioid administration kit comprising: a pharmaceutical carrier containing an effective amount of at least one rapid-onset opioid and a pharmaceutically acceptable; pulmonary drug delivery device, which comprises a container, and an outlet connected to the container, the container is connected by force action at an effective rate in patients with particles of the formulation contained therein through said outlet means for dispensing and into the lungs, so that to achieve the analgesic effect before the onset of an opioid side effect during inhalation, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum total opioid plasma concentration does not reach toxic levels substance, whereby the onset of said side effect by the patient to terminate inhalation to avoid toxicity; and instructions for use of the device comprising the steps of: filling the container with the formulation, by means of the continuous inhalation formulation, and stopping inhalation when satisfactory analgesia is achieved or the onset of side effects.

另一实施方案是阿片样物质施用药盒,其中所述制剂包含有效量的至少一种持续作用的阿片样物质。 Another embodiment is an opioid administration kit, wherein the formulation comprises an effective amount of at least one sustained-effect opioid.

本发明的另一方面是用于向患者提供止痛的方法中的阿片样物质制剂,包含:150-250mcg/ml游离芬太尼;200-400mcg/ml脂质体包裹的芬太尼;和药用可接受载体。 Another aspect of the present invention is an opioid analgesic formulation to a method for providing a patient, comprising: 150-250mcg / ml free fentanyl; 200-400mcg / ml liposomally encapsulated fentanyl; and a pharmaceutically acceptable carrier.

本发明的另一方面是用于通过肺部施用途径向患者提供止痛的方法中的阿片样物质制剂,其包含:两种或更多种不同的阿片样物质,不包括其中仅有的两种阿片样物质是芬太尼和脂质体包裹芬太尼的制剂;药用可接受载体。 Another aspect of the present invention is a method for opioid formulation to provide analgesia to a patient through a pulmonary route of administration, which comprises: two or more different opioids, excluding only two wherein opioid is fentanyl and liposomally encapsulated fentanyl; pharmaceutically acceptable carrier.

依照本发明进一步的方面,提供本发明制剂用于向患者提供止痛的用途以及用于制备提供止痛的药物的用途。 According to a further aspect of the invention, there is provided formulations of the present invention to provide analgesia to a patient for the purpose and for the manufacture of a medicament to provide analgesia.

依照本发明有用的药物制剂和施用参数可由本领域技术人员基于已知的药理学数据以及通过本文所述药动学和药效学模型确定。 Skilled in the art based on known pharmacological data as well as determined by the pharmacokinetic and pharmacodynamic modeling and pharmaceutical formulations described herein in accordance with the application parameters may be useful in the present invention. 这种模型意在确保在副作用发作之前达到止痛效果,以及副作用肯定在毒性发作前出现,并确保一旦患者停止吸入所述制剂,血浆中总阿片样物质浓度就不会继续升高至中毒水平。 This model is intended to ensure that analgesia is achieved before the onset of side effects, side effects and certainly before the onset of toxicity occur, and to ensure that once the patient stops inhalation formulations, the total plasma opioid concentration will not continue to rise to toxic levels.

附图说明 BRIEF DESCRIPTION

图1是代表计算机模拟镇静模型的流程图。 1 is a flowchart representative of a computer simulation model sedation.

图2是代表计算机模拟通气减缓(ventilatory depression)模型的流程图。 FIG 2 is a flowchart representative of a computer simulation Ventilatory Depression (ventilatory depression) model.

图3是代表计算机模拟吸入装置模型的流程图。 FIG 3 is a flowchart representative of a computer simulation model of a suction device.

图4是代表对通过肺部途径施用于患者的阿片样物质药物动力学特征所作的计算机模拟模型的流程图。 FIG 4 is a flowchart of a computer simulation model representing dynamic characteristics of opioid administered to a patient via the pulmonary route is made.

图5A和5B合起来是代表StellaTM计算机模拟施用单一阿片样物质的药动学的流程图。 5A and 5B together are a flowchart representative of StellaTM computer simulation of a single opioid is administered pharmacokinetics. 图5A显示模拟的装置模型和药物动力学模型方面,图5B显示模拟的通气减缓模型和镇静模型方面。 5A shows the simulation model and the pharmacodynamic model apparatus aspect, FIG. 5B shows the analog ventilatory depression and sedation models aspect model.

图6是显示图5A和5B的StellaTM计算机模拟输出值的曲线图(通气减缓和镇静模型禁用),表示为吸入装置内和患者肺中阿片样物质量的时间曲线。 FIG 6 is a graph showing StellaTM computer simulation of Figures 5A and 5B, the output value (ventilatory depression and sedation models disabled) expressed as a time curve of the suction means and the mass of opioids patient's lungs.

图7是显示图5A和5B中StellaTM计算机模拟通气减缓的时间进程的曲线图(通气减缓和镇静模型禁用)。 FIG 7 is a graph of FIGS. 5A and 5B StellaTM computer simulation of the time course of ventilatory depression (ventilatory depression and sedation models disabled).

图8是显示图5A和5B的StellaTM计算机模拟中吸入装置内和患者肺内阿片样物质量的时间进程曲线图(通气减缓模型启用,镇静模型禁用)。 FIG 8 is a graph showing the time course of computer simulation of FIGS. 5A and 5B StellaTM inhalation device and in the lung of the patient of substance opioid graph (ventilatory depression model enabled, sedation model disabled).

图9是显示图5A和5B的StellaTM计算机模拟中通气减缓的时间进程的曲线图(通气减缓模型启用,镇静模型禁用)。 FIG 9 is a graph showing the time course of FIGS. 5A and 5B StellaTM computer simulation of ventilatory depression (ventilatory depression model enabled, sedation model disabled).

图10是显示图5A和5B的StellaTM计算机模拟中吸入装置内和患者肺内阿片样物质量的时间进程的曲线图(通气减缓和镇静模型启用)。 FIG 10 is a graph showing the time course of the apparatus and the quality of the patient's lungs were opioid FIGS. 5A and 5B, computer simulation StellaTM inhalation (ventilatory depression and sedation models enabled).

图11是显示图5A和5B的StellaTM计算机模拟中通气减缓的时间进程的曲线图(通气减缓和镇静模型启用)。 FIG 11 is a graph showing the time course of FIGS. 5A and 5B StellaTM computer simulation of ventilatory depression (ventilatory depression and sedation models enabled).

图12是代表施加两种阿片样物质的计算机模拟模型的流程图。 12 is a flowchart representative of a computer simulation model is applied to the two opioids.

图13A、13B和13C合起来是代表施加两种阿片样物质的药物动力学的StellaTM计算机模拟的流程图。 13A, 13B, and 13C together are a flow chart StellaTM computer simulation of two opioids drug kinetics Representative applied.

图14是显示图13A、13B和13C的StellaTM计算机模拟输出值的曲线图,表示为吸入装置中和患者肺内的阿片样物质总量的时间曲线(通气减缓和镇静模型启用)。 FIG 14 is a graph showing FIGS. 13A, 13B and a computer simulation graph illustrating output values ​​StellaTM 13C, showing (ventilatory depression and sedation models enabled) as curve means the total amount of time the patient's lungs and opioid inhaled.

图15是显示图13A、13B和13C的StellaTM计算机模拟中作用位点处每种阿片样物质浓度和总阿片样物质浓度的时间进程的曲线图(通气减缓和镇静模型启用)。 FIG 15 is a graph showing FIGS. 13A, at a site StellaTM computer simulation 13B and 13C in a graph showing the time course effects of each opioid substance concentration and total opioid concentration (ventilatory depression and sedation models enabled).

图16是显示图13A、13B和13C的StellaTM计算机模拟中阿片样物质递送期间和之后通气减缓的时间进程曲线图(通气减缓和镇静模型启用)。 FIG 16 is a graph showing the period 13A, StellaTM 13B and 13C of the computer simulation of opioid delivery and after the time course of ventilatory depression graph (ventilatory depression and sedation models enabled).

图17A、17B和17C合起来是代表施加两种阿片样物质的药动学的StellaTM计算机模拟的流程图,其中被施加的两种阿片样物质是阿芬太尼和吗啡。 FIG. 17A, 17B and 17C together are a flow chart StellaTM computer simulation of two opioids representative pharmacokinetic applied, wherein the two opioids alfentanil and is applied morphine. 图17A和17B显示模拟的装置模型和药效学模型方面,而图17C显示模拟的通气减缓模型、镇静模型以及双药物模型方面。 17A and 17B show aspects of the simulation model and the pharmacodynamic model device, and FIG. 17C shows Ventilatory Depression simulation model, and sedation models aspects of dual drug model.

图18是显示图17A、17B和17C的StellaTM计算机模拟中作用位点处阿芬太尼、吗啡和组合阿片样物质的浓度的时间进程的曲线图(通气减缓和镇静模型启用)。 FIG 18 is a graph showing Figs. 17A, at a site StellaTM computer simulation 17B and 17C of action of alfentanil, a graph showing the time course of the concentration of morphine and opioid combinations (ventilatory depression and sedation models enabled).

图19是显示图17A、17B和17C的StellaTM计算机模拟中通气减缓的时间进程的曲线图(通气减缓和镇静模型启用)。 Figure 19 is a graph showing 17A, a graph of the time course of StellaTM computer simulation 17B and 17C of ventilatory depression (ventilatory depression and sedation models enabled).

图20是显示相对于施用阿片样物质的患者血浆内阿片样物质用药浓度最终值的血浆内阿片样物质最大浓度的曲线图。 FIG 20 is a graph showing the maximum concentration in plasma within a final value with respect to the plasma of patients administered opioid opioid drug concentration opioid display. 图20A显示通过肺部途径联合施用芬太尼和脂质体包裹芬太尼的患者。 20A shows the combined administration of fentanyl and liposomally encapsulated fentanyl through a pulmonary route patient. 图20B显示静脉注射芬太尼的患者。 FIG. 20B patients fentanyl display.

图21是显示通过肺部途径联合施用芬太尼和脂质体包裹芬太尼的患者中达到副/毒作用的时间相对于因为副作用和毒性作用终止用药的时间的曲线图。 FIG 21 is a combined administration of fentanyl and liposomally wrapping a patient via the pulmonary route in reach sub fentanyl / toxic effect versus time because of the side effects and toxic effects of drugs termination time.

图22是显示副作用对毒性作用统计学相关性的表。 FIG 22 is a side toxic effects on statistical correlation table.

具体实施方式 detailed description

在此申请中,以下术语具有下述含义:“止痛作用”或“痛觉丧失”意味着由于药物作用而造成疼痛减轻。 In this application, the following terms have the following meanings: "analgesic effect" or "analgesia" means that due to the effect of the drug caused by pain relief.

“药物递送谱”指药物作用位点处药物浓度随时间的变化,通过向患者施用药物的量和速率以及将吸入剂量与肺、血浆中和药物作用位点处浓度关联的药动学来测量。 "Drug delivery profile" means the change in drug concentration at the site of drug action over time, and the inhaled dose and the lungs, the concentration of the associated plasma and at the site of drug action pharmacokinetics measured by the amount and rate of administration of the drug to a patient .

“缺氧”是施用阿片样物质的毒性作用,在此申请中被定义为血氧浓度降低到低于90%的饱和度。 "Hypoxia" is a toxic effect of opioid administration, and is defined as reduced to less than 90% of the saturation concentration of oxygen in this application.

“通气减缓”指空气进入肺的速率、呼吸容量和/或流速降低。 "Ventilatory depression" means the rate of air into the lungs, respiratory volume and / or flow rate reduction. 通气减缓可能表现为晕眩、呼吸短促或呼吸速率减缓。 Ventilatory depression may manifest as dizziness, shortness of breath or breathing rate slowed. “阿片样物质诱发的通气减缓”指由于阿片样物质在药物作用位点的作用所引起的通气减缓。 "Opioid induced ventilatory depression" refers to ventilatory action of opioid drugs at the site of action due to slow down.

“镇静”指阿片样物质引起的专注度、精神知觉、注意力和意识状态的减弱,并表现为乏力(肌肉疲劳)、缺乏主动行为、无生气、嗜睡和睡眠。 "Sedation" refers to the degree of focus on opioid-induced mental perception, attention and weakened state of consciousness, and showed weakness (muscle fatigue), lack of proactive behavior, lethargy, drowsiness and sleep. “阿片样物质诱导的镇静“指由阿片样物质在药物作用位点的作用所引起的镇静表现。 "Opioid-induced sedation" refers to sedation expressed by opioid effect site of drug effect caused.

“快速起效”,当用于描述药物制剂时,意味着该制剂在血浆阿片样物质浓度升高后迅速具有止痛效果。 "Rapid onset", when used to describe a drug formulation, means that the formulation has an analgesic effect after rapid rise in plasma opioid concentration. “快速起效的阿片样物质”是在施用5分钟内具有止痛效果的阿片样物质。 "Rapid onset opioid" is an opioid administration with analgesic effect within 5 minutes.

“持续作用”意味着制剂的止痛效果能持续数小时以上。 Analgesic effect "sustained action" means preparations can last for several hours or more. “持续作用的阿片样物质”指止痛作用持续2小时以上的阿片样物质。 "Sustained effect opioid" means an analgesic effect lasts over 2 hours opioid.

“副作用”指阿片样物质不止痛或有毒的作用。 "Side effect" refers to the action of an opioid analgesic or not toxic. 例如,严重的通气减缓是阿片样物质中毒的一个例子,而轻度的通气减缓和镇静则不被认为是阿片样物质中毒的症状,而是阿片样物质的副作用。 For example, severe ventilatory depression is an example of opioid toxicity, while mild ventilatory depression and sedation are not considered to be symptoms of opioid poisoning, but the side effects of opioids.

“作用位点”指患者内实质的或假想的药物作用位点。 "The role of site" refers to the site of drug action within the patient substantial or imaginary. “作用位点”可以是身体的某一区隔,诸如脑、肝或脾,或者可以是基于相关性和药动学模型的理论和未知的位置。 "Site of action" may be a segment of the body, such as the brain, the liver or spleen, or may be based on a theoretical correlation and pharmacokinetic models and unknown location. 例如,已知阿片样物质部分在脊髓的胶状质内发挥其止痛作用,因此这是阿片样物质止痛作用的位点。 For example, it is known that opioids exert their analgesic effect in the portion of the spinal cord gelatinous mass, so this is a site of opioid analgesic effect. 阿片样物质在作用位点的浓度可以通过直接测量或通过使用药动学和药效学模型确定。 Opioid may be measured directly or pharmacokinetic and pharmacodynamic model is determined by using the concentration of drug action through the site of action.

“有效量”指达到止痛效果所需要的药物量。 "Effective amount" refers to the amount of the drug to achieve the desired analgesic effect.

“质量中值空气动力学直径”指气溶胶的空气动力学直径,使得所有颗粒累计质量的一半包含于具有更小(或更大)直径的颗粒中,且其中空气动力学直径被定义为与所测量颗粒具有相同重力沉降速度的单位密度球体的直径。 "Mass median aerodynamic diameter" means the aerodynamic diameter an aerosol such that half of the cumulative mass of all particles contained in a smaller (or larger) diameter particles, and wherein the aerodynamic diameter is defined as the particles have the same gravitational settling velocity measured unit density sphere diameter.

“呼吸速率”指每单位时间内呼吸的次数。 "Breathing rate" means the number of breaths per unit time.

“滴定至发挥作用”指施加阿片样物质直至患者感到满意的止痛效果,然后停止施加阿片样物质。 "Titration to play" refers to Shijia A opioid until the patient is satisfied with the analgesic effect, then stop Shijia A sheet-like substance.

“滴定至发挥副作用”指施加阿片样物质直至感受到副作用,然后停止施用。 "Titration to side play" refers to opioid Shijia A felt side up, then ceasing administration. 停止施用可能是主动的(例如,在感到瞌睡、晕眩或气促时指导患者停止施用阿片样物质)或被动的(例如,当由于通气减缓或镇静造成患者不再能呼吸有效剂量的阿片样物质时)。 Stop administration may be active (for example, feel sleepy, guiding patients to stop administration of opioid when dizziness or shortness of breath) or passive (for example, when, due to ventilatory depression or sedation caused the patient is no longer able to breathe effective dosages of opioid ) when substances.

术语“毒性”、“毒性作用”和“阿片样物质毒性”指导致患者有死亡危险的阿片样物质的作用。 The term "toxic", "toxic effect" and "opioid toxicity" refers to the lead role of risk of death in patients with opioids. 例如,阿片样物质通常产生对患者很少有危险的轻度通气减缓。 For example, opioids commonly produce very little risk to patients with mild ventilatory depression. 这不被认为是阿片样物质毒性的例子。 This is not considered an example of opioid toxicity. 不过,严重的通气减缓有引起缺氧、意识丧失和死亡的危险。 However, there is serious cause hypoxic ventilatory depression, loss of consciousness and risk of death. 因此,严重的通气减缓是阿片样物质毒性的一个例子,而轻微的通气减缓不被认为是阿片样物质毒性的标志。 Thus, severe ventilatory depression is an example of opioid toxicity, while mild ventilatory depression is not considered a sign of opioid toxicity.

本发明是关于患者自我施用阿片样物质的用途。 The present invention is about the use of patient self-administration of opioids. 本发明利用阿片样物质的副作用来自我调节给予患者的阿片样物质的量,从而调整剂量以满足患者的止痛需求,同时又避免中毒和死亡。 The present invention utilizes the opioid side effects from I adjust the amount of opioid given to a patient to adjust the dose of painkillers to meet the needs of patients, while avoiding poisoning and death.

在患者感觉疼痛的时候开始使用本发明。 The present invention is started when the patient feels pain. 对于轻度至中度疼痛而言有许多治疗方式是合适的,但阿片样物质是中度至重度疼痛的主要治疗方法。 For mild to moderate pain it has for many treatment is suitable, but opioids are the main treatment of moderate to severe pain. 在中度或重度疼痛的时候,患者或患者的护理提供人打开阿片样物质液体溶液或乳液的预填充管。 When moderate or severe pain, the patient or the patient's care provider open a prefilled tube opioid liquid solutions or emulsions. 将所述液体加入喷雾器中。 The added liquid sprayer.

然后将喷雾器放到口中,并用手保持于该处。 The nebulizer is then placed in the mouth, and held there by hand. 喷雾器不用带子附着在脸上,因为这妨碍了自我限制的工作机制。 Sprayer without straps attached to the face, because it prevents the working mechanism of self-limiting.

伴随着每一次呼吸,喷雾器释放小量的液态阿片样物质作为气溶胶。 Along with each breath, the nebulizer releases a small amount of the liquid opioid as an aerosol. 所述气溶胶经过患者的口腔进入气管和肺,在那里气溶胶化阿片样物质会沉积下来。 The aerosol through the mouth into the trachea and lungs of a patient, where the aerosolized opioid is deposited will.

在整篇专利申请中,喷雾器也被称为吸入器或气溶胶肺部药物递送装置。 Throughout this patent application, the nebulizer is also called an inhaler or an aerosol pulmonary drug delivery device. 吸入器可以指喷雾器或者指与压缩空气或氧气源组合的喷雾器,或者任何其它产生气溶胶的装置用于经肺部途径施用药物。 It may refer to a nebulizer inhaler or nebulizer or pressurized air source means in combination with oxygen, or any other aerosol generating device for administering a drug via the pulmonary route. 气溶胶肺部药物递送装置指允许使物质气溶胶化以递送入肺的任意装置。 Aerosol pulmonary drug delivery device refers to any device that allows a substance to aerosol delivery into the lungs. 多种喷雾器技术是本领域所已知的和可用的。 More sprayers techniques are known in the art and available.

阿片样物质药物作用起效的速率被认为是受阿片样物质进入肺的速度、吸收进入全身循环的速率和阿片样物质穿越血脑屏障的速率控制的。 Opioid rate of onset of action is considered to be affected by the speed of the opioid enters the lungs, the rate of absorption into the systemic circulation and cross the blood brain barrier of a rate of opioid substance control. 某些阿片样物质,诸如阿芬太尼和瑞芬太尼等,穿越血脑屏障非常迅速,并因此非常迅速的开始发挥药物作用。 Some opioid, alfentanil and remifentanil such as, across the blood-brain barrier very quickly, and therefore very quickly start to play a role in the drug. 其它的阿片样物质,诸如吗啡和吗啡-6-葡萄糖苷酸等,穿越血脑屏障非常缓慢,并因此产生缓慢起始但持久的作用。 Other opioids, such as morphine and other morphine-6-glucuronide, cross the blood brain barrier very slowly, and thus produce a slow start but lasting effect.

当阿片样物质穿越血脑屏障的时候,它开始在药物作用位点发挥作用。 When opioids across the blood-brain barrier, it starts to play a role in the site of drug effect. 尽管在某些情况下,患者可能感受到不同的效果,但是通常,当阿片样物质的浓度升高的时候,所感受到的效果依次是止痛作用、副作用和毒性作用。 Although in some cases, patients may experience different effects, but in general, when the concentration of opioid increases, the effects felt are analgesic effect successively, side effects and toxicity.

通气减缓是受阿片样物质(减缓通气)和二氧化碳(增加通气)的相反作用上下调节的。 Ventilatory depression is reversed by the opioid effect (slow ventilation) and carbon dioxide (increased ventilation) is vertically adjustable. 这一反馈循环过程如下:最初阿片样物质减缓通气。 This feedback loop as follows: initially slow venting opioids. 由于患者不再呼出同样多的二氧化碳,所以患者血液中的二氧化碳水平上升。 Since the patient is no longer the same amount of exhaled carbon dioxide, so the rise in carbon dioxide level in the patient's blood. 随着二氧化碳增加,它刺激通气,部分抵消了阿片样物质诱发的通气减缓。 With the increase in carbon dioxide, it stimulates ventilation, partly offsetting the opioid-induced ventilatory depression of. 阿片样物质诱发的通气减缓必须反应非常迅速,使得当患者吸入阿片样物质时它即可发生,从而限制所吸入的阿片样物质的量。 Opioid-induced ventilatory depression must respond very quickly, so that when the patient inhales the opioid it can occur, thereby limiting the amount of opioid inhaled. 不过,它又必须不是太迅速反应,以致于在二氧化碳有机会升高并抵消阿片样物质诱发的通气减缓之前使患者处于中毒作用的危险之中。 However, it must not be too quick response, so that the opportunity to rise and counteract the toxic effects before the patient is opioid-induced ventilatory depression risk in carbon dioxide.

每分钟患者吸入阿片样物质的量是与该分钟内的通气量成比例的。 The amount of opioid inhaled patient per minute is proportional to the amount of the minute ventilation. 随着呼吸被减缓,阿片样物质运送入肺的速率成比例的减慢。 With the breathing is slowed, opioid delivery into the lungs at a rate proportional to slow down. 以此方式,运送速率由于通气减缓而减慢,降低了患者自我施加有毒剂量阿片样物质的能力。 In this way, since the air delivery rate slowed and slowed, reducing the patient's ability to self-imposed toxic doses of opioids. 由于通气减缓引起的阿片样物质吸入减慢通过发生镇静作用创造了完全停止药物递送的机会。 Because of opioid-induced ventilatory depression slowed by inhalation sedation occurred has created the opportunity to completely stop drug delivery.

当阿片样物质发挥其止痛作用的时候,患者会变得安静,部分是由于他们的疼痛减轻了,部分是由于阿片样物质的副作用。 When opioids exert their analgesic effects, patients will become quiet, partly because they reduce the pain, in part due to the side effects of opioids. 随着镇静作用在患者身上发展,将装置保持在口腔、保持嘴唇密闭、和通过呼吸所述装置施加更多的阿片样物质就变得困难了。 With the development of sedation in the patient, to hold the device in the oral cavity, the lips remains closed, and the respiratory device by applying more opioid becomes difficult. 取而代之的是,患者开始通过鼻子呼吸,或者通过嘴但在喷雾器的喷口周围呼吸。 Instead, the patient begins to breathe through the nose, or the sprayer nozzle but around the breathing through the mouth. 随着镇静作用的增强,手臂从导气管落下,从而将装置从口腔除去。 With the enhancement of sedation, the arm drops from the airway, removing the device from the mouth thereby. 通过特意将装置制造的较沉重,或者通过在所述装置上添加重量,可以使手臂在较低水平的镇静作用时就落下。 By means intentionally made relatively heavy, or by adding the weight on the device, the arm can be made to fall at a lower level of sedation. 所述装置的重量可以随患者不同进行调节,由各个患者在镇静前的力量强度决定。 The weight of the device can be adjusted with the different patients, each patient is determined by the strength of the force before sedation.

由于阿片样物质的副作用通常发生在较低的阿片样物质浓度(较阿片样物质的毒性作用而言),通过以足够慢的速率经肺部施用阿片样物质(或者阿片样物质的组合)使得在发生副作用和发生毒性作用之间有一时间间隙,已建立了一种更安全的、患者自我限制的阿片样物质施用法。 Since the side effects of opioids typically occur at lower opioid concentrations (in terms of the more toxic effects of opioids), by a sufficiently slow rate through the pulmonary administration of an opioid (or a combination of opioids) such that between the incidence of side effects and toxic effects occur with a time gap, has established a more safe method in patients administered opioid self-limiting. 所述速率还必须足够慢(较阿片样物质起效的速率而言),以正在施药期间时产生副作用。 The rate must also be slow enough (in terms of more opioid onset rate), time to side effects during administration being.

在涉及本发明的临床研究中,健康对象被指导在10-25分钟时间吸入由快速作用的游离芬太尼和持续作用的脂质体包裹芬太尼组成的固定剂量的芬太尼制剂。 In clinical studies involving the present invention, healthy subjects were instructed 10-25 minutes by the suction liposomes rapidly acting free fentanyl and sustained acting wrapped fixed dose of fentanyl is fentanyl formulation. 在此研究中,数名对象尝试自我限制剂量且需要外部帮助来接受全部剂量。 In this study, the number of subjects to try to self-limit the dose and need outside help to accept the full dose. 随着通气速率的降低而减少了吸入药物的量,一些受试者由于阿片样物质诱发的通气减缓而自我限制了剂量。 As the aeration rate is reduced to reduce the amount of inhaled drug, some subjects because opioid-induced ventilatory depression and self-limiting dose. 另一些受试者因为镇静作用以及他们不能控制装置于嘴部以继续吸入芬太尼而自我限制了用药量。 Other subjects because they can not control and sedation device to the mouth to continue inhaled fentanyl and self-limiting the dosage. 一些患者呈现出这两种副作用。 Some patients showing both side effects. 该试验证明了患者实际上会在施加中毒水平的芬太尼之前自我限制经肺部途径施用芬太尼,当1)有意在过长时间期间吸入药物时(例如,长达25分钟),2)在给药期间(但在施加中毒剂量之前)出现阿片样物质诱发的通气减缓,和/或3)在给药期间(但在施加中毒剂量之前)产生镇静作用。 The tests showed the patient actually self-limiting by the pulmonary route of administration of fentanyl prior to application of fentanyl intoxication level, when 1) intentionally too long during inhalation drugs (for example, up to 25 minutes), 2 ) during the administration period (but appears opioid-induced ventilatory depression prior to the application of toxic dose), and / or 3) during the administration period (but before applying produce sedation toxic doses). 我们已发现这些因素可以通过设计向患者给予阿片样物质的速率从而加以控制。 We have found that these factors can give a rate of opioids to patients in order to be controlled by design.

优选的,在4-25分钟内施加阿片样物质制剂。 Preferably, in 4-25 min Neishijiaa opioid formulation. 在4-25分钟内所施加的阿片样物质的总量将取决于几种因素,包括所递送的阿片样物质或阿片样物质组合的类型,以及被吸入颗粒的质量中值空气动力学直径(MMAD)。 The total amount of opioid in the 4-25 minutes will depend on several factors applied, the type of opioid or combination of substances comprising the opioid delivery of respirable particles and a mass median aerodynamic diameter of air ( MMAD). 这一施加时段导致作用起效速率受施药速率的影响,并通过发生通气减缓和镇静作用使患者能被动地自我限制剂量。 This period is applied to cause the rate of onset of action is affected by the rate of administration, and by the occurrence of sedation and ventilatory depression patient doses can passively self-limiting. 我们已发现,对于阿芬太尼/吗啡组合药物而言,100-500mcg/分钟范围的阿芬太尼和200-1000mcg/分钟范围的吗啡是最适合的(当药物递送到患者肺部时测量(“系统性可用药物”))。 We have found for alfentanil / morphine combination of drugs, morphine and alfentanil 200-1000mcg / min range 100-500mcg / min range is the most suitable (measured when the drug is delivered to the patient's lungs ( "systemic available drug")).

至于游离的和脂质体包裹的芬太尼制剂,我们发现对于系统性可用药物而言最适合的水平是10-25mcg/分钟的游离芬太尼和10-50mcg/分钟的脂质体包裹的芬太尼。 As fentanyl formulation of free and liposome-encapsulated, we found that in terms of available drugs for systemic optimum level is 10-25mcg / min of free fentanyl and 10-50mcg / min of liposome-encapsulated fentanyl.

至于其它的阿片样物质制剂,我们预期治疗等效速率的系统性可用药物具有相似的优势。 For other opioid formulations, we expect that a therapeutically equivalent rate of systemic drugs can be used with similar advantages.

在具有至少一种快速起效阿片样物质和至少一种持续起效阿片样物质的复合阿片样物质制剂中,为了防止阿片样物质作用峰值高于患者停止摄入时的浓度,我们预期所施加的持续作用的阿片样物质与快速作用的阿片样物质的比例按治疗等效性而言小于1∶1。 Having at least one rapid-onset opioid and at least one sustained effect opioid from the opioid compound formulation, in order to prevent opioid concentration is higher than the peak of substance intake in patients stopped, we expect the applied the proportion of fast acting opioid and opioid sustained action by the therapeutic equivalence in terms of less than 1:1.

影响阿片样物质施用速率的另一因素是患者的呼吸速率。 Another factor affecting the rate of administration of opioid is the patient's respiration rate. 我们已发现每分钟10-15次呼吸的呼吸速率(即,“正常的”呼吸速率)是优选的。 We have found that a breathing rate of 10-15 breaths per minute (i.e., a "normal" breathing rate) is preferred.

阿片样物质的反应是高度个体化的。 The reaction opioid is highly individualized. 这部分反应了疼痛刺激的变化水平。 This part reflects the change in the level of painful stimuli. 在疼痛非常严重的情况下,可施加很高剂量的阿片样物质而不会有不适当的毒性。 In case of very severe pain, without undue toxicity can be applied to very high doses of opioids. 长期施用阿片样物质的患者需要更高的剂量才会产生预期的治疗效果和阿片样物质毒性。 Patients need long-term administration of higher doses of opioids will produce the desired therapeutic effects and opioid toxicity. 这也反应了发生对阿片样物质的耐受。 This reaction occurs tolerance of opioids. 医师已试图寻找施加阿片样物质的改进方法,部分是因为需要广泛的剂量范围来适当调整个体化患者对阿片样物质的需求。 Physicians have tried to find improved methods Shijia A sheet-like material, in part because of the need wide range of doses to be adjusted to the needs of opioid individual patient.

利用所描述的发明,需要大剂量阿片样物质来提供止痛的患者可选择施用更大量的药物(在更长的时间段内吸入),或者可提供在预期的4-25分钟内吸入更浓的药物溶液。 With the invention described herein, it requires large doses of opioids to provide analgesia to a patient selectable greater amount administered drug (inhaled over a longer period of time), or may provide suction within the expected 4-25 minutes more concentrated drug solution. 不管以任一种方式,在吸入中毒剂量之前,阿片样物质诱发的通气减缓和镇静作用都仍将削弱并最终停止药物施用。 Whether either way, before inhalation poisoning dose, opioid-induced ventilatory depression and sedation will still have to weaken and eventually stop drug administration. 优选的,患者在较长时间段内吸入药物。 Preferably, the patient inhaled the drug over a longer period. 相反的,只需要小剂量的患者在较短的吸入期后就会体验预期的疼痛缓解。 Conversely, patients only need a small dose will experience the desired pain relief after a relatively short period of inhalation. 患者可选择不吸入更多的药物。 Patients may choose not to inhale more medication. 尽管已获得预期的疼痛缓解效果但仍不明智地继续自我施用阿片样物质的患者将体验通气减缓和镇静,然后他们会主动的(依照给予患者的指导)或被动的(由于副作用本身造成的)在吸入中毒剂量阿片样物质之前减弱并随后终止施用药物。 Despite achieve the desired effect of pain relief but patients still unwisely continues to self-administer opioids will experience ventilatory depression and sedation, and then they will take the initiative (in accordance with the guidance given to the patient) or passive (due to side effects caused by itself) weakened before inhalation toxic dose of opioid and subsequently terminate drug administration. 因此患者能够自我滴定至达到止痛效果而无需锁定期且中毒的风险更低。 So patients can self-titrated to achieve analgesic effect without the lock-up period and lower risk of poisoning.

选择用于所述装置的阿片样物质和阿片样物质浓度(如前公开,或者如其它处公开)需要考虑到阿片样物质从肺吸收入血浆的时间进程、以及阿片样物质从血浆转移入药物作用位点(例如,脑或脊髓)的时间进程。 Selected for opioid and opioid concentration of said device (as previously disclosed, or as disclosed elsewhere) needs to take into account the opioid is transferred into the plasma from the time course of drug from the lungs into the bloodstream of the slurry, and the opioid site of action (eg, the brain or spinal cord) of the time course.

某些阿片样物质与从肺进入全身性循环的非常迅速的吸收相关。 Some opioids from the lungs into the systemic circulation associated with very rapid absorption. 例如,游离芬太尼从肺吸收进入血浆几乎是瞬间的。 For example, the absorption of free fentanyl from the lung into the plasma is nearly instantaneous. 这对于瑞芬太尼、阿芬太尼和舒芬太尼等都很可能是真实的。 This is remifentanil, alfentanil and sufentanil, etc. are likely to be true. 而从脂质体包裹芬太尼释放的游离芬太尼从肺吸收入血浆就要慢得多。 The release of liposome encapsulated fentanyl free fentanyl from going much more slowly absorbed into the bloodstream from the lungs pulp.

某些阿片样物质则与从血浆非常快速的转移至药物作用位点是相关的。 Some opioids is very fast and the transfer from the plasma to the site of drug effect is relevant. 例如,药物作用位点处的峰值阿芬太尼和瑞芬太尼浓度产生于静脉注射的两分钟内。 For example, peak alfentanil and remifentanil concentrations at the site of drug effect produced intravenous injection of two minutes. 另一些阿片样物质与非常缓慢的从血浆转移至药物作用位点相关。 Other opioid very slow transfer from the plasma to the site of drug effect correlation. 例如,静脉注射吗啡产生的峰值药物作用可能比注射时间延迟10-15分钟。 For example, the peak drug effect produced by intravenous morphine injection time can be delayed 10-15 minutes.

为了让自我限制阿片样物质递送系统工作,阿片样物质之一应兼具从肺快速转移至血浆和从血浆快速转移至阿片样物质药物作用位点的特性。 To make self-limiting opioid delivery system to work, one of opioids should be the characteristics of both rapid transfer from the lungs to the blood plasma and rapid transfer from the plasma to the opioid site of action. 芬太尼、阿芬太尼、舒芬太尼和瑞芬太尼都具有此特性(快速起效)。 Fentanyl, alfentanil, sufentanil and remifentanil all have this characteristic (rapid onset). 度冷丁和美沙酮可能也具有此效果,但目前尚不清楚。 Meperidine and methadone may also have this effect, but it is not clear. 尽管有可能用单一的阿片样物质获得本发明所需的参数,我们还是发现将快速起效的阿片样物质与作用较慢但持久的阿片样物质组合会得到优选的结果,因为利用这样的组合患者通常会感到止痛效果持续较长的时间。 Although it is possible to obtain the parameters required for the present invention with a single opioid, we found that rapid onset opioid with a slower acting, but sustained opioid in combination will be preferable results, because the use of such a combination patients typically feel analgesic effect lasts longer.

如果期望维持阿片样物质的止痛效果,那么可能有必要将快速起效的阿片样物质与起效较慢但持续作用的阿片样物质组合在一起。 If the analgesic effect of opioids to maintain desired, it may be necessary to rapid-onset opioid with a slower onset but sustained effect opioid together. 这种制剂的实例包括(1)芬太尼和脂质体包裹芬太尼的制剂,(2)与吗啡组合的瑞芬太尼、阿芬太尼、舒芬太尼或芬太尼的制剂,以及(3)与美沙酮组合的瑞芬太尼、阿芬太尼、舒芬太尼或芬太尼的制剂。 Examples of such formulations include (1) preparation of fentanyl and liposomally encapsulated fentanyl, (2) in combination with morphine remifentanil, alfentanil, sufentanil, or fentanyl , and remifentanil, alfentanil, sufentanil, or fentanyl formulation (3) in combination with methadone. 在持续作用的阿片样物质的最大作用时间点必须小心预防第二次作用“峰值”,它高于由快速起效的阿片样物质引起的峰值,使得患者在他或她施用药物期间感觉到有副作用。 Care must be taken at the maximum point of time opioid sustained action to prevent a second role in "peak", which is higher than the peak caused by the rapid-onset opioid, making the patient feel during his or her administration of drugs side effect.

当快速起效的阿片样物质与起效慢但持续作用的阿片样物质组合时,调节两种阿片样物质的浓度使得快速起效的阿片样物质的自我限制作用用于限制患者暴露于起效慢的阿片样物质。 When a rapid onset opioid with a slower onset but sustained effect opioid substance combination of two opioids adjusted such that the concentration of rapid onset opioid self-limiting effect for limiting patient exposure to onset slow opioid. 快速起效的的阿片样物质用作分拣的早期预警系统,在适当的时间框内触发副作用。 Rapid onset opioid serves as sort of early warning systems, at an appropriate time frame to trigger side effects.

我们已发现副作用是在中毒之前达到的。 We have found that the side effects are reached before the poisoning. 更具体地说,在用药末期或用药完成后短时间内经历副作用的对象不会发展到有毒副作用,而在用药期间经历副作用并继续或被辅助继续吸入药物的对象则会发展成中毒,具体地说,就是缺氧。 More specifically, the subject experienced side effects after the end of treatment or medication will not be completed within a short time to develop toxic side effects, but the side effects experienced during treatment and continue to assist the object or inhaled drugs will continue to develop into poisoning, specifically that is hypoxia.

正如通过上述描述可认识到的,本发明的建立需要(1)全面了解一种或多种阿片样物质的药动学和药效学,和(2)全面了解阿片样物质、二氧化碳产生和消除以及通气情况之间的关系,(3)仔细选择一种或多种阿片样物质,和(4)精确确定最终制剂中各种阿片样物质的最适浓度以实现药物的预期临床表现。 As can be appreciated from the above description, the requirement for (1) a comprehensive understanding of the present invention, one or more opioid pharmacokinetics and pharmacodynamics, and (2) a comprehensive understanding of opioids, carbon dioxide production and elimination and the relationship between the ventilation case, (3) careful selection of one or more opioids, and (4) precise determination of the optimal concentration in the final formulation of various opioids in order to achieve the desired clinical manifestations of drug. 通过系统参数的药动学和药效学模型,利用剂量优化寻找表现出最佳的患者安全特征且仍具有充分止痛效果的剂量,从而确定最终的制剂。 By pharmacokinetic and pharmacodynamic modeling of the system parameters, the use of dose optimization to find the best security performance characteristics of the patient and still having sufficient analgesic effect dose, to determine the final formulation.

附图说明图1是代表镇静作用的计算机模拟模型流程图。 Figure 1 is representative of a computer simulation model for sedation flowchart. 在所有的流程图中,正方形代表量,箭头代表速率(每单位时间的量),而圆圈代表计算值、速率或常数。 In all the flowcharts, squares represent amounts, arrows represent rates (amounts per unit time), and circles represent calculated values, or constant rate.

图2是描述针对通气减缓的计算机模拟模型流程图。 FIG 2 is a flowchart of a computer simulation model for ventilatory depression described.

图3是代表吸入装置的计算机模拟模型的流程图。 3 is a flowchart representative of a computer simulation model for the inhalation device.

图4是代表通过肺部途径施用于患者的阿片样物质的药动学特征谱的计算机模拟模型的流程图。 FIG 4 is a flowchart of a computer simulation model for the pharmacokinetic characteristics representative of a patient via the pulmonary route administered opioid spectrum.

图5A和5B合起来是代表StellaTM计算机模拟施用单一阿片样物质的药动学特征的流程图。 5A and 5B together are a flowchart representative of StellaTM computer simulation of the pharmacokinetics of a single opioid is administered. 图5A显示模拟的装置模型和药物动力学模型方面,图5B显示模拟的通气减缓模型和镇静模型方面。 5A shows the simulation model and the pharmacodynamic model apparatus aspect, FIG. 5B shows the analog ventilatory depression and sedation models aspect model.

图6是显示图5A和5B的StellaTM计算机模拟输出值的曲线图(通气减缓和镇静模型禁用),表示为吸入装置内阿片样物质的量和患者肺中阿片样物质的量的时间曲线。 FIG 6 is a graph showing StellaTM computer simulation of Figures 5A and 5B, the output value (ventilatory depression and sedation models disabled) expressed as a time curve of the intake means the amount of opioid the patient's lungs and the quantity of opioid. X轴是以分钟表示的时间。 X-axis is time in minutes. Y轴是以毫克表示的制剂的剂量单位。 Y-axis is formulation in milligrams per unit dosage. 在刺激的前10分钟内吸入器内的药物量稳定下降。 The amount of drug in the suction filter for 10 minutes before stimulation steady decline. 肺内的药物量反映了药物吸入肺和药物从肺吸收进入全身循环的净过程。 The amount of drug in the lungs reflects the net processes of drug inhaled into the lungs and absorption of the drug from the lungs into the systemic circulation.

图7是显示图5A和5B中StellaTM计算机模拟通气减缓的时间进程的曲线图(通气减缓和镇静模型禁用)。 FIG 7 is a graph of FIGS. 5A and 5B StellaTM computer simulation of the time course of ventilatory depression (ventilatory depression and sedation models disabled). 通气减缓(表示为基线通气量的分数)表示为随刺激时间(以分钟计)变化。 Ventilatory depression (expressed as a fraction of baseline ventilation) was expressed over time of simulation (in minutes) changes.

图8是显示图5A和5B的StellaTM计算机模拟中吸入装置内和患者肺内阿片样物质量的时间进程曲线图(通气减缓模型启用,镇静模型禁用)。 FIG 8 is a graph showing the time course of computer simulation of FIGS. 5A and 5B StellaTM inhalation device and in the lung of the patient of substance opioid graph (ventilatory depression model enabled, sedation model disabled). X轴是以分钟表示的时间。 X-axis is time in minutes. Y轴是以毫克表示的制剂的剂量单位。 Y-axis is formulation in milligrams per unit dosage. 患者通气量下降到基线通气量的大约25%,这样的减缓情况持续了大约5-10分钟。 Ventilation patients decreased to approximately 25% of baseline ventilation, thus slowing lasted about 5-10 minutes.

图9是显示图5A和5B的StellaTM计算机模拟中通气减缓的时间进程的曲线图(通气减缓模型启用,镇静模型禁用)。 FIG 9 is a graph showing the time course of FIGS. 5A and 5B StellaTM computer simulation of ventilatory depression (ventilatory depression model enabled, sedation model disabled). 通气减缓(表示为基线通气量的分数)表示为随刺激时间(以分钟计)变化。 Ventilatory depression (expressed as a fraction of baseline ventilation) was expressed over time of simulation (in minutes) changes. 由于自我限制阿片样物质摄取所引起的通气量改变为患者提供了相当的安全性(与图7比较)。 Since the amount of ventilation self-limiting opioid induced changes uptake offers considerable safety to the patient (compared to FIG. 7).

图10是显示图5A和5B的StellaTM计算机模拟中吸入装置内和患者肺内阿片样物质量的时间进程的曲线图(通气减缓和镇静作用模型启用)。 FIG 10 is a graph showing the time course of the apparatus and the quality of the patient's lungs were opioid FIGS. 5A and 5B, computer simulation StellaTM inhalation (ventilatory depression and sedation models enabled). X轴是以分钟表示的时间。 X-axis is time in minutes. Y轴是以毫克表示的制剂的剂量单位。 Y-axis is formulation in milligrams per unit dosage. 药物吸入在约8分钟时完全停止,这是由于达到了镇静状态并自我限制了药物摄取造成的。 Drug inhalation stopped completely at approximately 8 minutes, which is due to reach a state of calm and self-limitation of drug intake caused.

图11是显示图5A和5B的StellaTM计算机模拟中通气减缓的时间进程的的曲线图(通气减缓和镇静模型启用)。 FIG 11 is a graph showing the time course of computer simulation of FIGS. 5A and 5B in StellaTM ventilatory depression (ventilatory depression and sedation models enabled). 通气减缓(表示为基线通气量的分数)表示为随刺激时间(以分钟计)变化。 Ventilatory depression (expressed as a fraction of baseline ventilation) was expressed over time of simulation (in minutes) changes. 由于镇静作用自我限制阿片样物质摄取所引起的通气量改变为患者提供了相当的安全性(与图7或9比较)。 Since the amount of ventilation sedation self-limitation of opioid uptake induced changes offers considerable safety (cf. FIG. 7 or 9) for the patient.

图12是代表施用两种阿片样物质的计算机模拟模型的流程图。 12 is a flowchart representative of a computer simulation model for the administration of two opioids.

图13A、13B和13C合起来是代表施用两种阿片样物质的药物动力学的StellaTM计算机模拟流程图。 13A, 13B, and 13C together are a flow chart StellaTM dynamics computer simulation representative of drug administration of two opioids.

图14是显示图13A、13B和13C的StellaTM计算机模拟输出值的曲线图,表示为吸入装置中和患者肺内的阿片样物质总量的时间曲线(通气减缓和镇静模型启用)。 FIG 14 is a graph showing FIGS. 13A, 13B and a computer simulation graph illustrating output values ​​StellaTM 13C, showing (ventilatory depression and sedation models enabled) as curve means the total amount of time the patient's lungs and opioid inhaled. Y轴显示了吸入器内制剂(1)、肺内快速起效的阿片样物质(2)和肺内持续作用的阿片样物质(3)的芬太尼当量,表示为随时间变化(以分钟计)的药物的ng/ml(芬太尼当量)。 Y-axis shows the inhaler formulation (1), intrapulmonary rapid-onset opioid (2) and the sustained-effect opioid lungs (3) of fentanyl equivalents, expressed as a function of time (in minutes meter) drug ng / ml (fentanyl equivalents). 在大约12分钟后,患者停止吸入更多的阿片样物质,反映了阿片样物质诱发的镇静作用。 In about 12 minutes, the patient stopped inhale more opioid, reflecting the sedative effect of opioid-induced.

图15是显示图13A、13B和13C的StellaTM计算机模拟中作用位点处各种阿片样物质浓度和全部阿片样物质浓度的时间进程的曲线图(通气减缓和镇静模型启用)。 FIG 15 is a graph showing FIGS. 13A, at a site StellaTM computer simulation 13B and 13C in a graph showing the time course effects of various opioid concentrations and total opioid concentration of substances (ventilatory depression and sedation models enabled). 图中显示了作用位点处快速起效的阿片样物质(1)、持续作用的阿片样物质(2)和快速起效的阿片样物质与持续作用的阿片样物质联合作用(3)的量,以随时间变化(以分钟计)的ng/ml芬太尼当量表示。 The figure shows at the site of effect of rapid-onset opioid (1), the amount of sustained-effect opioid (2) and a rapid-onset opioid and the sustained-effect combined effect opioid (3) , in ng / ml of fentanyl equivalents over time (in minutes) of FIG.

图16是显示图13A、13B和13C的StellaTM计算机模拟中阿片样物质递送期间和之后通气减缓的时间进程的曲线图(通气减缓和镇静模型启用)。 FIG 16 is a graph showing the period 13A, StellaTM 13B and 13C of the computer simulation of opioid delivery and after the time course of ventilatory depression (ventilatory depression and sedation models enabled). 通气减缓(表示为基线通气量的分数)表示为随刺激时间(以分钟计)变化。 Ventilatory depression (expressed as a fraction of baseline ventilation) was expressed over time of simulation (in minutes) changes. 在施加第一种阿片样物质期间两种阿片样物质的组合达到了峰值。 In a first application of a combination of two opioid substance during opioid peaked.

图17A、17B和17C合起来是代表施加两种阿片样物质的药效学的StellaTM计算机模拟的流程图,其中被施加的两种阿片样物质是阿芬太尼和吗啡。 FIG. 17A, 17B and 17C together are a flow chart of a computer simulation StellaTM pharmacodynamics two opioids representative applied, wherein the two opioids alfentanil and is applied morphine. 图17A和17B显示模拟的装置模型和药效学模型方面,而图17C显示模拟的通气减缓模型、镇静模型以及双药物模型方面。 17A and 17B show aspects of the simulation model and the pharmacodynamic model device, and FIG. 17C shows Ventilatory Depression simulation model, and sedation models aspects of dual drug model.

图18是显示图17A、17B和17C的StellaTM计算机模拟中作用位点处阿芬太尼、吗啡和组合阿片样物质的浓度的时间进程曲线图(通气减缓和镇静模型启用)。 FIG 18 is a graph showing Figs. 17A, at a site StellaTM computer simulation 17B and 17C of the role alfentanil, morphine, and combined opioid concentration time course graph (ventilatory depression and sedation models enabled). 线1显示阿芬太尼的浓度;线2显示吗啡的浓度,而线3显示组合浓度。 Line 1 shows concentration of alfentanil; line 2 shows concentration of morphine, and line 3 shows a combination of concentration. 所有药物水平均在作用位点处显示,并表示为随时间(以分钟计)变化的ng/ml芬太尼当量。 All drugs levels were displayed at the site of effect, and expressed as a function of time (in minutes) changes ng / ml of fentanyl equivalents. 在递送90%药物后由于患者的镇静作用而终止药物施用。 After 90% of the drug delivery due to the sedation of the patient to terminate drug administration. 如线3中所示,最高的阿片样物质暴露出现于吸入期间。 As shown in line, the highest opioid exposure occurs during inhalation 3.

图19是显示图17A、17B和17C的StellaTM计算机模拟中通气减缓的时间进程曲线图(通气减缓和镇静模型启用)。 Figure 19 is a graph showing 17A, the time course graph StellaTM computer simulation 17B and 17C of ventilatory depression (ventilatory depression and sedation models enabled). 通气减缓(表示为基线通气量的分数)表示为随刺激时间(以分钟计)变化。 Ventilatory depression (expressed as a fraction of baseline ventilation) was expressed over time of simulation (in minutes) changes. 在药物施用期间通气减少到基线的约65%。 During drug administration decrease in ventilation to approximately 65% ​​of baseline.

图20是显示相对于施用阿片样物质患者血浆中阿片样物质用药浓度最终值,血浆内阿片样物质最大浓度的曲线图。 FIG 20 is a graph showing with respect to the plasma of patients administered opioid concentration of drug substance material opioid final value, a graph of the maximum concentration of opioid in plasma. 图20A显示通过肺部途径联合施用芬太尼和脂质体包裹芬太尼的患者。 20A shows the combined administration of fentanyl and liposomally encapsulated fentanyl through a pulmonary route patient. 图20B显示静脉注射芬太尼的患者。 FIG. 20B patients fentanyl display. 阿片样物质的最大浓度并不显著高于用药终点浓度,表明如果“用药终点”的量是无毒的,受试者所摄取的阿片样物质的最大浓度也可能是无毒的。 The maximum concentration of opioid was not significantly higher than the concentration of drug endpoint, showed that if the amount "administration end" is non-toxic, the maximum concentration of the subject picked opioid may also be non-toxic.

图21是显示通过肺部途径联合施用芬太尼和脂质体包裹芬太尼的患者中达到副作用/毒性作用的时间相对于因副作用和毒性作用终止用药的时间的曲线图。 FIG 21 is a combined administration of fentanyl and liposomally encapsulated reach side / toxic effect versus time due to drug side effects and toxic effects of the time termination of fentanyl in the patient by the pulmonary route. 在所有的情况下,达到中毒的时间都等于或长于达到副作用的时间。 In all cases, time to reach toxic arrival time are equal to or longer than a side effect.

图22是显示副作用对毒性作用统计学相关性的表。 FIG 22 is a side toxic effects on statistical correlation table. 副作用与毒性作用的相关性是p<0.04。 Side effects associated with toxic effects is p <0.04.

实施例下面的实施例设计用于证明而非限制本发明的实施方案。 EXAMPLES The following Examples are designed to demonstrate and not to limit embodiments of the present invention.

实施例1:阿片样物质递送的理论模型实施例2-4以阿片样物质递送的理论模型为基础;为了具有更大的确定性,本文在实施例1中描述了此理论模型。 Example 1: Theoretical Model Example opioid delivery 2-4 theoretical model for opioid delivery basis; for greater certainty, in Example 1 herein this theoretical model is described.

将阿片样递送的理论模型编程入计算机模拟软件包“Stella”(High PerformanceSystems,Lebanon,NH)。 The theoretical model of programming opioid delivery into the computer simulation package "Stella" (High PerformanceSystems, Lebanon, NH). 此实施例中显示的要素,包括附图和正文,自Stella模型表现改编,并解释模拟的编程和模拟如何工作。 Elements of this embodiment in the embodiment shown, including the drawings and the body, adapted from the Stella model performance, and explains how the analog programming and simulation work.

在附图中,矩形代表指示物质积累的变量(以下注明的除外)。 In the figures, rectangles represent variables indicating the accumulation of the substance (other than noted below). 空心箭头代表积累物的流入或流出,而实心箭头代表控制流动的要素。 Hollow arrows represent flow into or accumulated effluents, while the solid arrows represent the flow control element. 为了简化表现,省略了有些实心箭头。 To simplify the performance, omitted some solid arrow. 椭圆代表模型参数(输入)和时间独立性计算。 Ovals represent model parameters (inputs) and time independent calculations. 许多模型参数和常数是由现有技术获得的(参阅Scott JC,Stanski DR.Decreased fentanyl and alfentanil doserequirements with age.A simultaneous pharmacokinetic and pharmacodynamicevaluation.J Pharmacol Exp Ther.1987 Jan;240(1):159-66)。 Many model parameters and constants were obtained from the prior art (see Scott JC, Stanski DR.Decreased fentanyl and alfentanil doserequirements with age.A simultaneous pharmacokinetic and pharmacodynamicevaluation.J Pharmacol Exp Ther.1987 Jan; 240 (1): 159-66 ).

(a)镇静模型设计阿片样物质诱导镇静的模型(图1-镇静模型)。 (A) Sedation Model Design opioid-induced sedation model (Figure 1 - Sedation Model). 作用位点的阿片样物质1010(Opioid in Effect Site 1010)用于表示药物作用位点处阿片样物质浓度的变量。 Opioid effect site 1010 (Opioid in Effect Site 1010) is used to indicate a variable concentration of opioid at the site of drug action. 若药物作用位点存在超过1种阿片样物质,则作用位点的阿片样物质1010用来代表存在的阿片样物质总和,其中每一种都根据其相对效力进行了标准化(例如在下文实施例3和4中)。 If the drug effect site is present more than one kinds of opioids, the site of action of opioid 1010 to represent the sum of the opioids present, each of which is standardized according to their relative potency (e.g. EXAMPLES Hereinafter 3 and 4).

镇静阈1020(Sedation Threshold 1020)定义为将使患者不能使用吸入器的阿片样物质浓度1010。 Sedation Threshold 1020 (Sedation Threshold 1020) is defined as the concentration of opioid in patients will not use the inhaler 1010. 镇静阈1020是通过实验或者通过阿片样物质的已知药动学而确定的。 Sedation Threshold 1020 was determined experimentally or by a known opioid pharmacokinetics.

镇静评价器1030(Sedation Evaluator 1030)是阿片样物质浓度1010是否超出镇静阈1020的测试。 Sedation evaluator 1030 (Sedation Evaluator 1030) opioid concentration is 1010 1020 exceeds a threshold test sedation. 若阿片样物质浓度1010超出镇静阈1020,则镇静评价器将镇静状态1040(Sedation State 1040)的值由0改成1。 If the opioid concentration exceeded Sedation Threshold 1010 1020, will evaluate the sedative sedation 1040 (Sedation State 1040) is changed to 0 by the value of 1. 镇静状态1040是矩形代表物质积累这一规则的例外:模型内镇静状态1040的角色改变为记忆阿片样物质曾经超出镇静阈的记忆组件。 Sedation 1040 is an exception to this rule represents the accumulation rectangular material: the role of sedation in the 1040 model change memory components as memory opioid had exceeded the sedation threshold. 在后续模型中,镇静状态1040的数据的功能是关闭继续施用阿片样物质、模拟患者镇静及因而从口中取出吸入器。 In subsequent models, data sedation function 1040 is closed to continue the administration of opioid, sedation and thus simulate the inhaler taken from the mouth.

(b)通气减缓模型编制通气减缓模拟的程序(图2)。 Procedure (b) Ventilatory Depression Model slow analog ventilatory preparation (FIG. 2). 在此模型中,CO2由身体的代谢活动以速率CO2生成2010(CO2 Production 2010)产生,流入血浆(血浆CO2 2020,Plasma CO22020)。 In this model, CO2 by the metabolic activities of the body at a rate CO2 Production 2010 (CO2 Production 2010) generated flows into the plasma (Plasma CO2 2020, Plasma CO22020). CO2生成2010或是通过实验测定的或是根据现有技术知道的(参阅例如Bouillon T,Schmidt C,Garstka G,Heimbach D,Stafforst D,Schwilden H,Hoeft A.Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect ofalfentanil. Anesthesiology. 1999 Jul;91(1):144-55;Bouillon T,Bruhn J,Radu-Radulescu L,Andresen C,Cohane C,Shafer SL. A model of the ventilatorydepressant potency of remifentanil in the non-steady state. Anesthesiology. 2003 Oct;99(4):779-87)。 CO2 Production 2010, or according to the prior art or known (see e.g. Bouillon T, Schmidt C, Garstka G, Heimbach D, Stafforst D, Schwilden H, Hoeft A.Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect experimentally determined . ofalfentanil Anesthesiology 1999 Jul; 91 (1):. 144-55; Bouillon T, Bruhn J, Radu-Radulescu L, Andresen C, Cohane C, Shafer SL A model of the ventilatorydepressant potency of remifentanil in the non-steady state. .. Anesthesiology 2003 Oct; 99 (4): 779-87). 血浆CO2 2020(Plasma CO2 2020)与脑中的CO2(脑CO2 2040,Brain CO2 2040)以比率(脑-血浆CO2平衡2030,Brain-Plasma CO2 Equilibrium2030)保持平衡。 Plasma CO2 2020 (Plasma CO2 2020) and CO2 in the brain (Brain CO2 2040, Brain CO2 2040) at a rate (Brain - equilibrium plasma CO2 2030, Brain-Plasma CO2 Equilibrium2030) balance. CO2以模拟由肺呼出空气的方式以由参数通气减缓2060(Ventilatory Depression 2060)介导的速率CO2清除2050(CO2 Elimination 2050)由血浆清除。 CO2 in an analog manner exhaled air from the lungs at a rate slow mediated by the parameter vent 2060 (Ventilatory Depression 2060) CO2 Clear 2050 (CO2 Elimination 2050) cleared by the plasma.

通气减缓2060随药物作用位点处阿片样物质浓度(作用位点的阿片样物质1010)增加而增加。 Ventilatory Depression 2060 opioid concentration at the site of drug action over (the site of action of opioid 1010) increases. 通气减缓降低由肺清除CO2(CO2清除2050),引起脑中CO2增加(脑CO2 2040)。 Ventilatory depression cleared from the lungs to reduce CO2 (CO2 purge 2050), causing the brain to increase CO2 (Brain CO2 2040). 随着脑CO2 2040增加,它通过对通气减缓2060的负作用而刺激通气,部分抵消作用位点的阿片样物质1010的减缓作用,其对通气减缓2060具有正作用。 With Brain CO2 2040 increased, by which a negative effect on Ventilatory Depression 2060 stimulate ventilation, alleviating the 1010 site of action partially offset opioid, which has a positive effect on Ventilatory Depression 2060.

其它参数设计用于影响通气减缓2060;这些参数的集合在此模型中表示为模型参数2070(Model Parameters 2070);包含模型参数2070的参数在图5A和5B中有更为详细的描述。 The other factors for influencing the Ventilatory Depression 2060; these parameters is represented as a set of model parameters 2070 (Model Parameters 2070) In this model; 2070 comprises a parameter model parameters are described in more detail in FIGS. 5A and 5B. 这些模型参数2070影响通气减缓2060,它继而影响CO2清除2050和脑CO2 2040。 The 2070 model parameters affect ventilatory depression 2060, which in turn affect the brain and CO2 removals 2050 CO2 2040.

尽管将此模拟在Stella中编程是新颖的,然而通气减缓模型是本领域已知的,且被称作“间接应答模型”。 Although the programming of this simulation in Stella is novel, the Ventilatory Depression Model is however known in the art, and is referred to as "indirect response model."

(c)装置模型吸入装置的模型显示于图3。 Model (c) Device Model inhalation device shown in Figure 3. 剂量3050(Dose 3050)代表加到吸入器中的阿片样物质的总量。 Dose 3050 (Dose 3050) representative of the total amount of added inhaler opioid. 将阿片样物质剂量3050以速率填充吸入器3010(Fill Inhaler 3010)加到吸入器中。 The opioid dose inhaler is filled at a rate of 3050 3010 (Fill Inhaler 3010) was added inhaler. 此速率对模拟工作是需要的,但是以瞬时速率计算。 This rate of simulation work is needed, but in order to calculate the instantaneous rate. 吸入器中的制剂3020(Formulation in Inhaler 3020)代表装在吸入器中的阿片样物质。 3020 inhaler formulation (Formulation in Inhaler 3020) mounted in the inhaler Representative opioid. 患者将制剂以吸入速率(吸入3030,Inhalation 3030)吸到肺中,(肺中的制剂3040,Formulationin Lung 3040)。 The formulation patient inhalation rate (inhalation 3030, Inhalation 3030) into the lungs, the (3040 formulation lung, Formulationin Lung 3040). 吸入3030受到通气减缓2060和镇静状态1040的影响。 Inhalation 3030 is affected ventilatory depression and sedation 2060 1040. 具体而言,吸入3030因通气减缓2060的增加而减慢。 Specifically, inhalation of 3030 due to increased ventilatory depression 2060 slowed down. 例如,若通气减缓2060是基线的50%,则药物以半值基线速率吸入(吸入3030达到基线一半)。 For example, if Ventilatory Depression 2060 was 50% of baseline, then drug half the baseline rate of inhalation (inhalation baseline half of 3030). 然而,若镇静状态1040=1,则将药物吸入肺停止,且不再吸入药物。 However, if sedation 1040 = 1, then stop the drug into the lungs and are not inhaled drug.

(d)药动学模型编制系统性阿片样物质的药动学模型的程序。 Pharmacokinetic models procedure (d) in the preparation of pharmacokinetic models of systemic opioid. 肺中的制剂3040以速率系统吸收4010(Systemic Absorption 4010)系统性吸收到血浆中(血浆中的阿片样物质4020,Opioid in Plasma 4020)。 Formulation at a rate of 3040 lung systemic absorption 4010 (Systemic Absorption 4010) systemic absorption into the blood plasma (Opioid in Plasma 4020, Opioid in Plasma 4020). 血浆中的阿片样物质4020与药物作用位点的阿片样物质(作用位点的阿片样物质1010)以速率血浆-作用位点药物平衡4030(Plasma-Effect SiteDrug Equilibrium 4030)保持平衡。 Opioid plasma opioid 4020 and the site of drug effect (the site of action of opioid 1010) at the rate of the plasma - the site of drug action equilibrium 4030 (Plasma-Effect SiteDrug Equilibrium 4030) balance. 阿片样物质还以速率阿片样物质重分配4050(Opioid Redistribution 4050)重新分配到组织中(组织中的阿片样物质4060,Opioidin Tissue 4060),或者以速率阿片样物质清除4070(Opioid Elimination 4070)由血浆清除。 Opioid further at a rate of opioid redistribution 4050 (Opioid Redistribution 4050) is reassigned to the tissue (tissue opioid 4060, Opioidin Tissue 4060), or at a rate of opioid Clear 4070 (Opioid Elimination 4070) from the plasma clearance. 将组织中的阿片样物质4060和阿片样物质重分配4050编程为根据所用具体阿片样物质的药动学模型而可以使用或不用的任选参数。 The organization of the opioid and the opioid 4060 4050 reallocation optionally programmed parameter may be used or not according to pharmacokinetic models specific opioid is used. 速率系统性吸收4010、血浆-作用位点药物平衡4030、阿片样物质清除4070、和阿片样物质重分配4050都是通过在模型中以阿片样物质药动学参数4080(Opioid Pharmacokinetic Parameters4080)代表的所施用具体阿片样物质的药动学参数的矢量来测定的,并通过药动学模型计算得到。 Systemic absorption rate of 4010, the plasma - the site of action drugs balance 4030 4070 clears opioids, opioid and 4050 are reallocated by opioid pharmacokinetic parameters in the model 4080 (Opioid Pharmacokinetic Parameters4080) represented vector of pharmacokinetic parameters of the particular opioid being administered is determined and pharmacokinetic models obtained by calculation.

尽管将此模拟在Stella中编制程序是新颖的,然而药动学模型是本领域已知的,且称作“具有作用位点的乳房药动学模型”。 While this analog programming in the Stella is novel, however Pharmacokinetic Model is known in the art, and is referred to as "breast pharmacokinetic model with the site of action." 以上代表的乳房模型通常具有0、1或2个组织区隔,产生的模型分别称作具有作用位点的1、2、或3区隔模型。 Breast model represented above typically have 0, 1 or 2 tissue segment, generated by the model are referred to as 1, 2 or 3 having a segment model of the site of action.

实施例2:单一阿片样物质的施用此实施例是实施例1:阿片样物质递送的理论模型的一种应用。 Example 2: administration of a single opioid This embodiment is described in Example 1: Theoretical Model an application of opioid delivery. 此实施例意图通过使用举例说明阿片样物质递送的理论模型;模型参数不反映任何特定阿片样物质。 Examples are intended to illustrate this embodiment by using a theoretical model of opioid delivery; model parameters do not reflect any specific opioid. 相反,此实施例中的模型参数已被设计用于清楚地证明所建议的阿片样物质递送系统的自我限制方面。 Instead, the model parameters in the embodiment of this embodiment has been designed to clearly demonstrate the self-limiting aspect of the proposed system of opioid delivery. 此实施例显示集成了实施例1中描述的四种模拟,以及当运行模拟时模型的输出。 This example shows four integrated analog described in Example 1, and when running a simulation model output.

(a)模型的集成图5A和5B显示了实施例1中描述的模型的要素,其中通过吸入施用单一阿片样物质。 Integrated 5A and 5B (a) shows a model of the elements of the model described in Example 1, wherein a single administration by inhalation of opioids. 图5分成两个部分:图5A和图5B。 FIG 5 is divided into two parts: FIGS. 5A and 5B. 图5A包括:与实施例1中作为整个图3显示和解释的装置模型等同的装置模型5010;与实施例1中作为整个图4显示和解释的药动学模型等同的药动学模型5020(排除了任选的参数:组织中的阿片样物质4060和阿片样物质重分配4050,而且还有例外:阿片样物质药动学参数4080构建为系统吸收4010、阿片样物质清除4070、和血浆作用位点平衡4030,且没有作为单独的参数显示-更多信息见源码);图5B包括:与实施例1中作为整个图2显示和解释的通气减缓模型等同的通气减缓模型5030(但是模型参数2070显示为“扩展”形式,具有多种包括模型参数2070的要素,即所示PACO2@0 2071、Kel CO2 2072、ke0CO2 2073、C50 2074、γ2075、和F2076;及与图1中显示的镇静模型等同的镇静模型5040。图5A和5B中显示的模型是同一模拟的一部分,但是为了容易参考显示在两个图中。图5A和5B中显示的四种模型的 FIG 5A comprising: Model 5010 device as described in Example 1 as a whole, Figure 3 shows and device model interpreter equivalent; described in Example 1 as a whole, Figure 4 shows and explains the pharmacokinetic models equivalent Pharmacokinetic Model 5020 ( excluding optional parameters: tissue opioid and opioid 4060 4050 weight distribution, but also exceptions: opioid pharmacokinetic parameters 4080 4010 constructed as systemic absorption, opioid clear 4070, and the role of plasma balance site 4030 and not shown as a separate parameter - see source code for more information); FIG. 5B comprising: a ventilatory Depression model 5030 and model equivalent to vent as in Example 1 and 2 show the entire FIG explained slow (but model parameters 2070 is shown as "extended" form, having a plurality of elements 2070 comprising model parameters, i.e. PACO2 FIG @ 0 2071, Kel CO2 2072, ke0CO2 2073, C50 2074, γ2075, and F2076; and shown in FIG. 1 sedation models sedation models equivalent model 5040. figures 5A and 5B show the part of the same simulation, but for ease of reference shown in the two figures. FIG. 5A and 5B four models of display 术细节已在实施例1中有深入描述,只是模型参数2070进行了扩展,其技术细节说明如下:基线CO2 2071(Baseline CO2 2071)是施用阿片样物质前在基线处的CO2。kelCO2 2072是联系血浆CO2 2020与CO2清除2050的清除速率,因此在基线处(即缺乏通气减缓时):CO2清除2050=kel CO2 2072 x血浆CO2 2020。 Technical details have been in-depth description of Example 1, except that the model parameters 2070 is extended, the technical details are described as follows: Baseline CO2 2071 (Baseline CO2 2071) is administered before opioid CO2.kelCO2 2072 is linked at baseline (i.e. absence of ventilatory depression) 2020 plasma CO2 2050 to CO2 removal rate of clearance, so at baseline: CO2 Clear 2050 = kel CO2 2072 x plasma CO2 2020.

由此得出结论,在基线处,身体中的二氧化碳处于稳定状态,因此CO2清除2050=CO2生成2010。 It follows that at baseline, carbon dioxide in the body in a stable state, and therefore remove CO2 generated 2010 2050 = CO2. 这允许参考基线CO2 2071和kel CO2 2072如下计算CO2的生成速率(它是常数):CO2生成2010=kel CO2 2072 x基线血浆CO2 2071。 This allows the reference baseline and kel CO2 2072 CO2 2071 CO2 generation rate is calculated as follows (which is constant): CO2 generated 2010 = kel CO2 2072 x baseline plasma CO2 2071.

脑血浆平衡2020的速率是由参数ke0 CO2 2073决定的,因此:脑血浆平衡2020=ke0 CO2 2073 x(血浆CO2 2020-脑CO2 2040)。 2020 equilibrium plasma brain is determined by the rate parameter ke0 CO2 2073, so that: Brain Plasma balanced by 2020 = ke0 CO2 2073 x (Plasma CO2 2020- Brain CO2 2040).

作为作用位点的阿片样物质1030、及参数C50 2074即与50%最大效果相关的阿片样物质浓度、和γ 2075即浓度比答关系的陡度的∑函数,阿片样物质减缓通气,且阿片样物质对通气减缓的贡献表达为: As the opioid effect site 1030, and the parameters C50 2074 i.e. opioid concentration associated with 50% of maximum effect, and γ 2075 i.e., the steepness of the concentration dependence of the ratio of A Σ function, opioids slow vent and opioid like material contribution to ventilatory depression expressed as: 相反,二氧化碳刺激通气。 Conversely, stimulation of carbon dioxide ventilation. 可以将通气增加建模为基线CO2 2071、脑CO2 2040和F2076即描述如下关系的陡度的参数的函数: Ventilation can be modeled as a baseline increase CO2 2071, Brain CO2 2040, and F2076 i.e. parameters describing the steepness of the function of the following relationship: 综合这些来看,通气减缓2060可描述为:通气减缓2060= The combination of these point of view, ventilation Depression 2060 can be described as: Ventilatory Depression 2060 = 根据现在定义的通气减缓2060,我们能够将存在阿片样物质诱导通气减缓时的CO2清除2050完全定义为:CO2清除2050=kel CO2 2072 x血浆CO2 2020 x通气减缓2060,从而完成模型的描述。 The slow vent 2060 now defined, we can be in the presence of CO2 during opioid-induced ventilatory depression 2050 is completely clear is defined as: CO2 Clear 2050 = kel CO2 2072 x Ventilatory Depression Plasma CO2 2020 x 2060, thereby completing the description of the model.

如此,将实施例1的模型组合成阿片样物质作用的一个模型。 Thus, the model of the embodiment of Example 1 are combined into one model of opioid effect. 图5A和5B中显示的此模型还可由如下数学模型来描述,用Stella编程语言(源码)表示: This model is shown in FIGS. 5A and 5B may also be described by the following mathematical model, represented by the Stella programming language (source code):

<pre id="pre0001" xml:space="preserve" listing-type="sequence">Brain_CO2_2040(t)=Brain_CO2_2040(t-dt)+(Brain_Plasma_CO2_Equilibration_2020)*dtINIT Brain_CO2_2040=Baseline_CO2_2071INFLOWS:Brain_Plasma_CO2_Equilibration_2020=ke0_CO2_2073*(Plasma_CO2_2020-Brain_CO2_2040)Formulation_in_Inhaler_3020(t)=Formulation_in_Inhaler_3020(t-dt)+(Fill_Inhaler_3010-Inhalation_3030)*dtINIT Formulation_in_Inhaler_3020=0INFLOWS:Fill_Inhaler_3010=if time=0 then Dose_3050/DT else 0OUTFLOWS:Inhalation_3030=If Sedation_State_1040=0 then.5*(Ventilatory_Depression_2060) else 0Formulation_in_Lung_3040(t)=Formulation_in_Lung_3040(t-dt)+(Inhalation_3030-Systemic_Absorption_4010)*dtINIT Formulation_in_Lung_3040=0INFLOWS:Inhalation_3030=If Sedation_State_1040=0 then.5*(Ventilatory_Depression_2060) else 0OUTFLOWS:Systemic_Absorption_4010=Formulation_in_Lung_3040*.693/1Opioid_in_Effect_Site_1010(t)=Opioid_in_Effect_Site_1010(t-dt)+(Plasma_Effect_Site_Equilibration_4030)*dtINIT <Pre id = "pre0001" xml: space = "preserve" listing-type = "sequence"> Brain_CO2_2040 (t) = Brain_CO2_2040 (t-dt) + (Brain_Plasma_CO2_Equilibration_2020) * dtINIT Brain_CO2_2040 = Baseline_CO2_2071INFLOWS: Brain_Plasma_CO2_Equilibration_2020 = ke0_CO2_2073 * (Plasma_CO2_2020- Brain_CO2_2040) Formulation_in_Inhaler_3020 (t) = Formulation_in_Inhaler_3020 (t-dt) + (Fill_Inhaler_3010-Inhalation_3030) * dtINIT Formulation_in_Inhaler_3020 = 0INFLOWS: Fill_Inhaler_3010 = if time = 0 then Dose_3050 / dT else 0OUTFLOWS: Inhalation_3030 = If Sedation_State_1040 = 0 then.5 * (Ventilatory_Depression_2060 ) else 0Formulation_in_Lung_3040 (t) = Formulation_in_Lung_3040 (t-dt) + (Inhalation_3030-Systemic_Absorption_4010) * dtINIT Formulation_in_Lung_3040 = 0INFLOWS: Inhalation_3030 = If Sedation_State_1040 = 0 then.5 * (Ventilatory_Depression_2060) else 0OUTFLOWS: Systemic_Absorption_4010 = Formulation_in_Lung_3040 * .693 / 1Opioid_in_Effect_Site_1010 ( t) = Opioid_in_Effect_Site_1010 (t-dt) + (Plasma_Effect_Site_Equilibration_4030) * dtINIT Opioid_in_Effect_Site_1010=0INFLOWS:</pre> Plasma_Effect_Site_Equilibration_4030= (Opioid_in_Plasma_4020_Opioid_in_Effect_Site_1010)*.693/1 Opioid_in_Plasma_4020(t)=Opioid_in_Plasma_4020(t-dt)+ (Systemic_Absorption_4010-Opioid_Elimination_4070- Plasma_Effect_Site_Equilibration_4030)*dt INIT Opioid_in_Plasma_4020=0 INFLOWS: Systemic_Absorption_4010=Formulation_in_Lung_3040*.693/1 OUTFLOWS: Opioid_Elimination_4070=Opioid_in_Plasma_4020*.693/10 Plasma_Effect_Site_Equilibration_4030= (Opioid_in_Plasma_4020-Opioid_in_Effect_Site_1010)*.693/1 Plasma_CO2_2020(t)=Plasma_CO2_2020(t-dt)+ (CO2_Production_2010-Brain_Plasma_CO2_Equilibration_2020 -CO2_Elimination_2050)*dt INIT Plasma_CO2_2020=Baseline_CO2_2071 INFLOWS: CO2_Production_2010=Baseline_CO2_2071*kelCO2_2072 OUTFLOWS: Brain_Plasma_CO2_Equilibration_2020= ke0_CO2_2073*(Plasma_CO2_2020-Brain_CO2_2040) CO2_Elimination_2050= Plasma_CO2_2020*kelCO2_2072*Ventilatory_Depression_2060 Sedation_State_1040(t)=Seda Opioid_in_Effect_Site_1010 = 0INFLOWS:. </ Pre> Plasma_Effect_Site_Equilibration_4030 = (Opioid_in_Plasma_4020_Opioid_in_Effect_Site_1010) * 693/1 Opioid_in_Plasma_4020 (t) = Opioid_in_Plasma_4020 (t-dt) + (Systemic_Absorption_4010-Opioid_Elimination_4070- Plasma_Effect_Site_Equilibration_4030) * dt INIT Opioid_in_Plasma_4020 = 0 INFLOWS: Systemic_Absorption_4010 = Formulation_in_Lung_3040 *. 693/1 OUTFLOWS:. Opioid_Elimination_4070 = Opioid_in_Plasma_4020 * .693 / 10 Plasma_Effect_Site_Equilibration_4030 = (Opioid_in_Plasma_4020-Opioid_in_Effect_Site_1010) * 693/1 Plasma_CO2_2020 (t) = Plasma_CO2_2020 (t-dt) + (CO2_Production_2010-Brain_Plasma_CO2_Equilibration_2020 -CO2_Elimination_2050) * dt INIT Plasma_CO2_2020 = Baseline_CO2_2071 INFLOWS: CO2_Production_2010 = Baseline_CO2_2071 * kelCO2_2072 OUTFLOWS: Brain_Plasma_CO2_Equilibration_2020 = ke0_CO2_2073 * (Plasma_CO2_2020-Brain_CO2_2040) CO2_Elimination_2050 = Plasma_CO2_2020 * kelCO2_2072 * Ventilatory_Depression_2060 Sedation_State_1040 (t) = Seda tion_State_1040(t-dt)+ (Sedation_Evaluator_1030)*dt INIT Sedation_State_1040=0 INFLOWS: Sedation_Evaluator_1030= if(Opioid_in_Effect_Site_1010>Sedation_Threshhold_1020) then 1 else 0 Baseline_CO2_2071=40 C50_2074=.3 Dose_3050=5 F_2076=4 Gamma_2075=1.2 ke0_CO2_2073=0.92 kelCO2_2072=0.082 Sedation_Threshhold_1020=1.5 Ventilatory_Depression_2060=(1- Opioid_in_Effect_Site_1010^Gamma_2075/(C50_2074^Gamma_2075+ Opioid_in_Effect_Site_1010^Gamma_2075))*(Brain_CO2_2040/Bas eline_CO2_2071)^F_2076(b)当通气减缓模型和镇静模型禁用时运行的模型输出使用如下初始参数运行(a)中设计和描述的模型作为阿片样物质作用的模拟:在时间=0时吸入器中的制剂3020=5毫升。 tion_State_1040 (t-dt) + (Sedation_Evaluator_1030) * dt INIT Sedation_State_1040 = 0 INFLOWS: Sedation_Evaluator_1030 = if (Opioid_in_Effect_Site_1010> Sedation_Threshhold_1020) then 1 else 0 Baseline_CO2_2071 = 40 C50_2074 = .3 Dose_3050 = 5 F_2076 = 4 Gamma_2075 = 1.2 ke0_CO2_2073 = 0.92 kelCO2_2072 = 0.082 Sedation_Threshhold_1020 = 1.5 Ventilatory_Depression_2060 = (1- Opioid_in_Effect_Site_1010 ^ Gamma_2075 / (C50_2074 ^ Gamma_2075 + Opioid_in_Effect_Site_1010 ^ Gamma_2075)) * (Brain_CO2_2040 / Bas eline_CO2_2071) ^ F_2076 (b) model output used when the ventilatory Depression model and sedation model disabled operation is as follows model and design parameters described initial operation (a) as a simulation of opioid effect: the formulation at time = 0 in the suction unit 3020 = 5 milliliters. 允许模型运行两小时的时间曲线。 Allow the model to two hours running time curve. 对此模拟,禁用对通气减缓模型的药物摄取方面的反馈环(即通气减缓2060对装置模型5010的作用的反馈)和镇静模型。 This simulation, the feedback loop is disabled on drug uptake aspects of the Ventilatory Depression Model (i.e. the feedback Ventilatory Depression Model 5010, 2060 pairs of means acting) and sedation models. 运行时模型的输出对各种参数绘图,表示于图6和7中。 Operation of various output parameters of the model drawing, shown in FIGS. 6 and 7.

图6显示模型在缺乏患者自我限制吸入阿片样物质(即禁用通气减缓模型和镇静模型)运行时的输出。 Figure 6 shows the model in the absence of patient self-limiting inhalation of opioid (ie disabled ventilatory depression and sedation models model) output operation. 图6显示在缺乏本发明的自我限制方面时药物在吸入器中(吸入器中的制剂3020-线1)和在肺中(肺中的制剂3040-线2)的时间曲线。 Figure 6 shows the drug in the absence of the self-limiting aspect of the present invention (Formulation 3020- inhaler 1 line) and the time curves in the inhaler in the lungs (lung formulation 3040- line 2) is. 吸入器中的药物量在模拟的前10分钟以速率吸入3030稳定下降。 Amount of drug in the inhaler simulated first 10 minutes of steady decline in the rate of inhalation of 3030. 肺中的药物量反映了药物吸入肺中和药物由肺吸收到系统循环中的净过程。 It reflects the amount of drug in the lungs and the medicament inhaled into the lungs during medicament net systemic circulation by absorption into the lungs.

图7显示同一模拟(禁用通气减缓模型和镇静模型)的通气减缓2060随时间变化。 Figure 7 shows the same simulation (Ventilatory Depression Model and Sedation disable model) Ventilatory Depression 2060 over time. 输出图指示在此模拟中患者的通气下降至基线通气的约25%。 FIG output indicating this simulation ventilation of the patient decreased to about 25% of baseline ventilation. 通气减缓持续约5-10分钟。 Ventilatory depression lasts about 5-10 minutes. 通气的下降随着二氧化碳在患者血浆中及以相同速率在患者肺中(未模拟)中的积累而逆转,抵消了阿片样物质对通气的减缓作用。 With the decrease ventilation and carbon dioxide in the patient's plasma at the same rate of accumulation in the patient's lungs (not simulated) reversed by the opioid offset mitigation ventilation induced by. 通气的这种下降使患者暴露于缺氧损伤的风险。 This ventilation decrease the risk of patients exposed to hypoxic injury.

(c)启用通气减缓模型运行时的模型输出通过启用通气减缓模型而修改(b)中使用的模拟,并以相同起始参数即时间0时吸入器中的制剂3020=5毫升再次运行。 Modified analog (b) is used in (c) Ventilatory Depression Model enabled runtime model output Depression Model enabled through the vent, and at the same time start parameters i.e. inhaler 3020 = 5 milliliters of the formulation to run again 0:00. 将各种参数的输出对时间作图。 The outputs various parameters plotted against time. 图8显示在存在通气减缓即本发明的两个自我限制方面之一(另一个是镇静)时代表吸入器中剩余药物量的吸入器中的制剂3020(线1)和代表肺中药物量的肺中的制剂(线2)。 Figure 8 shows Formulation 3020 (line 1) represents the presence of ventilatory depression i.e. two self-limiting aspects of the present invention, one (the other being sedation) the remaining amount of drug in the inhaler inhaler and representative of the amount of drug in the lung lung formulation (line 2). 与实施例2(b)相比,正如预期,在启用通气减缓模型运行模拟时,需要更长时间来吸入药物-图8的药物吸入花了约17分钟,而图6只用了10分钟。 Compared with Example 2 (b), as expected, the Ventilatory Depression Model enabled when running a simulation, it takes longer to inhale the medicine - 8 of FIG inhalation medicament took about 17 minutes, and FIG. 6 only 10 minutes. 这要归于由通气减缓引起的通气降低,它限制了患者暴露于阿片样物质。 This should be attributed to reduced ventilation caused by the ventilatory depression, which limited the patient is exposed to opioids. 这种通气降低在图9中有最好的图示,它绘制了同一模拟的随时间变化的通气减缓2060。 This has reduced the vent best illustrated in Figure 9, which plotted the same simulated time-varying ventilatory depression 2060. 在图9中通气减缓2060降低了50%。 In FIG. 9 Ventilatory Depression 2060 was reduced by 50%. 与图7所示模拟进行比较时,患者的呼吸(图9)是禁用通气减缓模型运行模拟时(图7)的一半。 When compared with the simulation shown in Figure 7, the breathing of the patient (FIG. 9) is disabled when the half Ventilatory Depression simulation model is run (FIG. 7). 此模拟显示了由自我限制阿片样物质摄取引起的通气变化为患者提供了相当高的安全性。 This simulation shows the change in the self-limiting ventilation opioid uptake offers considerable due to high safety to the patient.

(d)启用通气减缓模型和镇静模型运行时的模型输出此时启用通气减缓模型5030和镇静模型5040二者来运行相同模拟(时间=0时吸入器中的制剂3020=5毫升)。 (D) Ventilatory Depression Model enabled output model and sedation models enabled runtime case both the Ventilatory Depression Model 5030 and the Sedation Model 5040 running the same simulation (time = 0 inhaler formulation 3020 = 5 milliliters). 将各种参数的输出对时间作图。 The outputs various parameters plotted against time. 图10显示了在存在通气减缓和镇静时吸入器中的制剂3020(线1)和肺中的制剂3040(线2)的时间曲线。 Figure 10 shows the time profile of formulation inhaled 3020 (Line 1) and Formulation vessel 3040 (Line 2) in the lung in the presence of ventilatory depression and sedation. 如图所示,8分钟后药物吸入完全停止。 As shown, the drug inhalation stopped completely after 8 minutes. 原因是患者已经镇静了,而且不能再将吸入器保持在口中(此处模拟为镇静状态1040由0变为1)。 The reason is that the patient has been sedated, but can no longer keep the inhaler in the mouth (simulated here as Sedation 1040 state from 0 to 1). 此时,吸入器中的制剂3020剩余约2毫升,因此吸入器中剩余约40%的阿片样物质剂量而没有吸入。 At this time, the inhaler formulation remaining about 2 milliliters 3020, thus remaining in about 40% of the opioid dose inhalers without suction. 图11作图了此模拟时程期间的通气减缓2060。 FIG 11 is plotted ventilation mitigation process 2060 during this simulation. 在图11中最大通气减缓是约60%。 Maximum ventilatory depression in FIG. 11 is about 60%. 在与图9相比时,因阿片样物质诱导的镇静而提高安全性是明显的。 When compared to FIG. 9, because the material and the opioid-induced sedation is evident improve security.

如此,如图5至11所示,实施例2通过模拟证明了本文所述自我限制阿片样物质递送系统的效果和优点。 Thus, 5 to 11, Example 2 demonstrated herein through simulation the effects and advantages of the self-limiting opioid delivery system.

实施例3:两种阿片样物质的施用在此模拟中,模型参数不反映任何具体的阿片样物质,而是已被调整过以清楚证明所建议的阿片样物质递送体系的自我限制方面。 Example 3: Administration of two opioids In this simulation, the model parameters do not reflect any specific opioids, but have been adjusted in order to clearly demonstrate the self-limiting aspect of the proposed system of opioid delivery. 此模拟模仿并测量了相同的变量,这次是针对含有两种具不同药动学特征的不同阿片样物质的阿片样物质组合物。 This analog and mimic the same measured variables, this time for an opioid composition comprising of different opioids with different pharmacokinetics two kinds of characteristics.

(a)建立双阿片样物质模型图12说明了如何将将两种阿片样物质组合成单个阿片样物质浓度用于模型。 (A) establishing bis opioid model Figure 12 illustrates how two opioids combined into a single opioid concentration for the model. 在所述的两种阿片样物质模拟中,作用位点中的快阿片样物质12010(Rapid Opioid inEffect Site 12010)代表快速起效的阿片样物质的浓度;作用位点中的慢阿片样物质12020(Slow Opioid In Effect Site 12020)代表缓慢起效的阿片样物质。 In both the opioid simulation, the site of action is fast opioid 12010 (Rapid Opioid inEffect Site 12010) representative of the concentration of rapid-acting opioid; site of action in the slow opioid 12020 (slow opioid in effect Site 12020) representative of the slow onset opioid. 其中的每一个都是以与一种阿片样物质模型(实施例2)相同的方式平行测定的。 Each of which is in the one opioid model (Example 2) determined in the same manner as in parallel. 不过,每个是分开测定的,然后组合起来确定组合的阿片样物质作用位点浓度12030(CombinedOpioid Effect Site Concentration 12030)。 However, each is determined separately, then combined to determine the combined opioid effect site concentrations 12030 (CombinedOpioid Effect Site Concentration 12030). 组合的阿片样物质作用位点浓度12030是用每种阿片样物质的已知相对效力-相对效力12040(Relative Potency 12040)计算的。 Opioid effect site concentrations of 12030 in combination with each opioid known relative potency - relative efficacy 12040 (Relative Potency 12040) calculation. 组合的阿片样物质作用位点浓度12030等于且被描述为图13A、13B、13C和图17A、17B和17C中所示的两种阿片样物质模型中的作用位点的阿片样物质1010。 Opioid effect site concentration equal to the combined 12030 and described in FIG 13A, 13B, two opioids model 17A, as shown in FIGS. 17B and 17C and 13C in the site of action of opioid 1010.

图13A、13B和13C合起来描述两种阿片样物质模型模拟的算法。 FIG. 13A, 13B and 13C together material model simulating the two algorithmic descriptions of the opioid. 它包括:装置模型13010,相当于实施例1和2中所述的装置模型5010;药动学模型13020,包含药动学模型5020的两种情况(一种是对于快阿片样物质,一种是对于慢阿片样物质)的组合,每种情况如图4、5A和5B以及实施例1和2中所述,且各自平行运行,然后用双药物模型13050组合,如图12所示;通气减缓模型5030,如图2和图5A和5B所示,如实施例1和2所述;镇静模型5040,如图2、图5A和5B所示,如实施例1和2中所述。 Comprising: means Model 13010, equivalent to Examples and model 5010 apparatus according to Embodiment 12; Pharmacokinetic Model 13020 comprising both cases Pharmacokinetic Model 5020 (one is for fast opioid A compositions for the slow opioid), each case of FIG. 4,5A and 5B and in the embodiment 12 and embodiment, and each running in parallel, then the model 13050 with a dual drug combination, shown in Figure 12; vent Depression model 5030, as shown in FIGS. 2 and 5A and 5B, as described in Example 1 and 2 embodiment; sedation model 5040, as shown in FIG 2, FIGS. 5A and 5B, in the Examples 1 and 2 as described.

图13A、13B和13C中显示的模型还可由如下数学模型来描述,并以Stella编程语言(源码)表示。 FIGS. 13A, 13B and 13C shows the model may also be described by the following mathematical model, and is expressed in Stella programming language (source code).

<pre id="pre0002" xml:space="preserve" listing-type="sequence">Brain_CO2_2040(t)=Brain_CO2_2040(t-dt)+(Brain_Plasma_CO2_Equilibration_2020)*dtINIT Brain_CO2_2040=Baseline_CO2_2071INFLOWS:Brain_Plasma_CO2_Equilibration_2020=ke0_CO2_2073*(Plasma_CO2_2020-Brain_CO2_2040)Formulation_in_Inhaler_3020(t)=Formulation_in_Inhaler_3020(t-dt)+(Fill_Inhaler_3010-Inhalation_1_3031-Inhalation_2_3032)*dtINIT Formulation_in_Inhaler_3020=0INFLOWS:Fill_Inhaler_3010=if time=0 then Dose_3050/DT else 0OUTFLOWS:Inhalation_1_3031=if Sedation_State_1040=0 then0.25*Ventilatory_Depression else 0</pre> Inhalation_2_3032=if Sedation_State_1040=0 then 0.25*Ventilatory_Depression_2060 else 0 Opioid_in_Effect_Site_1010(t)= Opioid_in_Effect_Site_1010(t-dt) INIT Opioid_in_Effect_Site_1010=0 Plasma_CO2_2020(t)=Plasma_CO2_2020(t-dt)+ (CO2_Production_2010-Brain_Plasma_CO2_Equilibration_2020 -CO2_Elimination_2050)*dt INIT Plasma_CO2_2020=Baseline_CO2_2071 INFLOWS: CO2_Production_2010 <Pre id = "pre0002" xml: space = "preserve" listing-type = "sequence"> Brain_CO2_2040 (t) = Brain_CO2_2040 (t-dt) + (Brain_Plasma_CO2_Equilibration_2020) * dtINIT Brain_CO2_2040 = Baseline_CO2_2071INFLOWS: Brain_Plasma_CO2_Equilibration_2020 = ke0_CO2_2073 * (Plasma_CO2_2020- Brain_CO2_2040) Formulation_in_Inhaler_3020 (t) = Formulation_in_Inhaler_3020 (t-dt) + (Fill_Inhaler_3010-Inhalation_1_3031-Inhalation_2_3032) * dtINIT Formulation_in_Inhaler_3020 = 0INFLOWS: Fill_Inhaler_3010 = if time = 0 then Dose_3050 / dT else 0OUTFLOWS: Inhalation_1_3031 = if Sedation_State_1040 = 0 then0.25 * Ventilatory_Depression else 0 </ pre> Inhalation_2_3032 = if Sedation_State_1040 = 0 then 0.25 * Ventilatory_Depression_2060 else 0 Opioid_in_Effect_Site_1010 (t) = Opioid_in_Effect_Site_1010 (t-dt) INIT Opioid_in_Effect_Site_1010 = 0 Plasma_CO2_2020 (t) = Plasma_CO2_2020 (t-dt) + (CO2_Production_2010-Brain_Plasma_CO2_Equilibration_2020 -CO2_Elimination_2050) * dt INIT Plasma_CO2_2020 = Baseline_CO2_2071 INFLOWS: CO2_Production_2010 {Place right hand side of equation here...} OUTFLOWS: Brain_Plasma_CO2_Equilibration_2020= ke0_CO2_2073*(Plasma_CO2_2020-Brain_CO2_2040) CO2_Elimination_2050= Plasma_CO2_2020*kelCO2_2072*Ventilatory_Depression_2060 Rapid_Drug_Effect_Site(t)=Rapid_Drug_Effect_Site(t-dt) +(Rapid_Drug_Plasma_Effect_Site_Equilibration)*dt INIT Rapid_Drug_Effect_Site=0 INFLOWS: Rapid_Drug_Plasma_Effect_Site_Equilibration= (Rapid_Drug_In_Plasma-Rapid_Drug_Effect_Site)*.693/1 Rapid_Drug_In_Plasma(t)=Rapid_Drug_In_Plasma(t-dt)+ (Rapid_Drug_Absorption-Rapid_Drug_Clearance- Rapid_Drug_Plasma_Effect_Site_Equilibration)*dt INIT Rapid_Drug_In_Plasma=0 INFLOWS: Rapid_Drug_Absorption= Rapid_Formulation_in_Lung*.693/1*Rapid_Drug_Concentration OUTFLOWS: Rapid_Drug_Clearance=Rapid_Drug_In_Plagma*.693/10 Rapid_Drug_Plasma_Effect_Site_Equilibration= (Rapid_Drug_In_Plasma-Rapid_Drug_Effect_Site)*.693/1 Rapid_Formulation_in_Lung(t)=Rapid_Formulation_in_Lung(t -dt)+(Inhalation_1_3031-Rapid_Drug {Place right hand side of equation here ...} OUTFLOWS: Brain_Plasma_CO2_Equilibration_2020 = ke0_CO2_2073 * (Plasma_CO2_2020-Brain_CO2_2040) CO2_Elimination_2050 = Plasma_CO2_2020 * kelCO2_2072 * Ventilatory_Depression_2060 Rapid_Drug_Effect_Site (t) = Rapid_Drug_Effect_Site (t-dt) + (Rapid_Drug_Plasma_Effect_Site_Equilibration) * dt INIT Rapid_Drug_Effect_Site = 0 INFLOWS:. Rapid_Drug_Plasma_Effect_Site_Equilibration = (Rapid_Drug_In_Plasma-Rapid_Drug_Effect_Site) * 693/1 Rapid_Drug_In_Plasma (t) = Rapid_Drug_In_Plasma (t-dt) + (Rapid_Drug_Absorption-Rapid_Drug_Clearance- Rapid_Drug_Plasma_Effect_Site_Equilibration) * dt INIT Rapid_Drug_In_Plasma = 0 INFLOWS: Rapid_Drug_Absorption = Rapid_Formulation_in_Lung * .693 / 1 * Rapid_Drug_Concentration OUTFLOWS: Rapid_Drug_Clearance = Rapid_Drug_In_Plagma * .693 / 10 Rapid_Drug_Plasma_Effect_Site_Equilibration = (Rapid_Drug_In_Plasma-Rapid_Drug_Effect_Site) * 693/1 Rapid_Formulation_in_Lung (t) = Rapid_Formulation_in_Lung (t -dt) + (Inhalation_1_3031-Rapid_Drug. _Absorption)*dt INIT Rapid_Formulation_in_Lung=0 INFLOWS: Inhalation_1_3031=if Sedation_State_1040=0 then 0.25*Ventilatory_Depression else 0 OUTFLOWS: Rapid_Drug_Absorption= Rapid_Formulation_in_Lung*.693/1*Rapid_Drug_Concentration Sedation_State_1040(t)=Sedation_State_1040(t-dt)+ (Sedation_Evaluator_1030)*dt INIT Sedation_State_1040=0 INFLOWS: Sedation_Evaluator_1030= if(Opioid_in_Effect_Site_1010>Sedation_Threshhold_1020) then 1 else 0 Slow_Drug_Effect_Site(t)=Slow_Drug_Effect_Site(t-dt)+ (Slow_Drug_Plasma_Effect_Site_Equilibration)*dt INIT Slow_Drug_Effect_Site=0 INFLOWS: Slow_Drug_Plasma_Effect_Site_Equilibration= (Slow_Drug_In_Plasma-Slow_Drug_Effect_Site)*.693/10 Slow_Drug_In_Plasma(t)=Slow_Drug_In_Plasma(t-dt)+ (Slow_Drug_Absorption-Slow_Drug_Clearance- Slow_Drug_Plasma_Effect_Site_Equilibration)*dt INIT Slow_Drug_In_Plasma=0 INFLOWS: SloW_Drug_Absorption= Slow_Formulation_In_Lung*.693/12*Slow_Drug_Concentration OUTFLOWS: Slow_Drug_Clearan _Absorption) * dt INIT Rapid_Formulation_in_Lung = 0 INFLOWS: Inhalation_1_3031 = if Sedation_State_1040 = 0 then 0.25 * Ventilatory_Depression else 0 OUTFLOWS: Rapid_Drug_Absorption = Rapid_Formulation_in_Lung * .693 / 1 * Rapid_Drug_Concentration Sedation_State_1040 (t) = Sedation_State_1040 (t-dt) + (Sedation_Evaluator_1030) * dt INIT Sedation_State_1040 = 0 INFLOWS: Sedation_Evaluator_1030 = if (Opioid_in_Effect_Site_1010> Sedation_Threshhold_1020) then 1 else 0 Slow_Drug_Effect_Site (t) = Slow_Drug_Effect_Site (t-dt) + (Slow_Drug_Plasma_Effect_Site_Equilibration) * dt INIT Slow_Drug_Effect_Site = 0 INFLOWS: Slow_Drug_Plasma_Effect_Site_Equilibration = (Slow_Drug_In_Plasma-Slow_Drug_Effect_Site) * .693 / 10 Slow_Drug_In_Plasma (t) = Slow_Drug_In_Plasma (t-dt) + (Slow_Drug_Absorption-Slow_Drug_Clearance- Slow_Drug_Plasma_Effect_Site_Equilibration) * dt INIT Slow_Drug_In_Plasma = 0 INFLOWS: SloW_Drug_Absorption = Slow_Formulation_In_Lung * .693 / 12 * Slow_Drug_Concentration OUTFLOWS: Slow_Drug_Clearan ce=Slow_Drug_In_Plasma*.693/300 Slow_Drug_Plasma_Effect_Site_Equilibration= (Slow_Drug_In_Plasma-Slow_Drug_Effect_Site)*.693/10 Slow_Formulation_In_Lung(t)=Slow_Formulation_In_Lung(t- dt)+(Inhalation_2_3032-Slow_Drug_Absorption)*dt INIT Slow_Formulation_In_Lung=0 INFLOWS: Inhalation_2_3032=if Sedation_State_1040=0 then 0.25*Ventilatory_Depression_2060 else 0 OUTFLOWS: Slow_Drug_Absorption= Slow_Formulation_In_Lung*.693/12*Slow_Drug_Concentration Baseline_CO2_2071=40 C50_2074=.3 Dose_3050=5 F_2076=4 Gamma_2075=1.2 ke0_CO2_2073=0.92 kelCO2_2072=0.082 Opioid_in__Effect_Site_1010= Rapid_Drug_Effect_Site+Slow_Drug_Effect_Site Rapid_Drug_Concentration=1 Sedation_Threshhold_1020=1.5 Slow_Drug_Concentration=1 Ventilatory_Depression_2060=(1- Opioid_in_Effect_Site_1010^Gamma_2075/(C50_2074^Gamma_2075+ Opioid_in_Effect_Site_1010^Gamma_2075))*(Brain_CO2_2040/Bas eline_CO2_2071)^F_2076 ce = Slow_Drug_In_Plasma * .693 / 300 Slow_Drug_Plasma_Effect_Site_Equilibration = (Slow_Drug_In_Plasma-Slow_Drug_Effect_Site) * 693/10 Slow_Formulation_In_Lung (t) = Slow_Formulation_In_Lung (t- dt) + (Inhalation_2_3032-Slow_Drug_Absorption) * dt INIT Slow_Formulation_In_Lung = 0 INFLOWS:. Inhalation_2_3032 = if Sedation_State_1040 = 0 then 0.25 * Ventilatory_Depression_2060 else 0 OUTFLOWS: Slow_Drug_Absorption = Slow_Formulation_In_Lung * .693 / 12 * Slow_Drug_Concentration Baseline_CO2_2071 = 40 C50_2074 = .3 Dose_3050 = 5 F_2076 = 4 Gamma_2075 = 1.2 ke0_CO2_2073 = 0.92 kelCO2_2072 = 0.082 Opioid_in__Effect_Site_1010 = Rapid_Drug_Effect_Site + Slow_Drug_Effect_Site Rapid_Drug_Concentration = 1 Sedation_Threshhold_1020 = 1.5 Slow_Drug_Concentration = 1 Ventilatory_Depression_2060 = (1- Opioid_in_Effect_Site_1010 ^ Gamma_2075 / (C50_2074 ^ Gamma_2075 + Opioid_in_Effect_Site_1010 ^ Gamma_2075)) * (Brain_CO2_2040 / Bas eline_CO2_2071) ^ F_2076

(b)启用通气减缓模型和镇静模型运行时的模型输出如实施例3(a)和图13A、13B和13C中所述在两种阿片样物质模型中运行相同的模拟(当时间=0时吸入器中的制剂3020=5毫升)。 (B) Ventilatory Depression Model enabled output model and sedation models run as described in Example 3 (a) and 13A, 13B, 13C and the two opioids run the same simulation model (time = 0 when inhaler formulation 3020 = 5 milliliters). 图14显示通气减缓和镇静状态下吸入器中的制剂3020(线1)、肺中的制剂(快阿片样物质)3040(线2)和肺中的制剂(慢阿片样物质)3040(线3)的时间曲线。 3 Inhalable preparations 3020 (Line 1) is in the lungs formulation (rapid opioid) 3040 (Line 2) and lung formulation (Slow Opioid) 3040 (Line 14 shows the ventilation FIG depression and sedation state ) time curve. 模拟显示,在运行12分钟期间,所述药物被患者吸入。 Analog display, during operation 12 minutes, the medicament is inhaled by the patient. 吸入器内药物量的下降速率并非完全线性,反映了随着阿片样物质诱发的通气减缓呼吸减慢。 Suction rate is decreased the amount of drug is not perfectly linear, reflecting as opioid induced ventilatory slow respiratory rate. 在大约12分钟后,患者停止吸入更多的阿片样物质,反映了阿片样物质诱导的镇静作用。 In about 12 minutes, the patient stopped inhale more opioid, reflecting opioid-induced sedation. 快速作用的阿片样物质很快被吸收进入全身循环,这限制了在肺中的大量积累,并造成当患者停止吸入更多阿片样物质时肺内的浓度很快下降。 Fast-acting opioid was quickly absorbed into the systemic circulation, which limits the massive accumulation in the lungs and cause more when the patient stops inhalation opioid concentration in the lung decreases rapidly. 缓慢作用的阿片样物质则缓慢的被肺吸收,这使得在吸入期间有更多的药物集聚于肺中,在停止向患者递送阿片样物质后阿片样物质仍在超过2小时的时间内进入全身循环。 Slow-acting opioid is slowly absorbed by the lungs, which makes it more drug accumulation in the lung during inhalation, delivery to the patient after stopping the substance into the systemic opioid time is still more than 2 hours opioid cycle.

图15显示了同一模拟的不同变量。 Figure 15 shows the same simulation of different variables. 在图15中,线1表示随时间变化的作用位点处快速作用的阿片样物质浓度(快速药物作用位点),并证明由于快速吸收和快速的血浆作用位点平衡造成迅速升高,而由于快速的代谢造成快速下降。 In Figure 15, line 1 represents the concentration of opioid over time fast acting at the site of action (the fast site of drug effect), and because of the rapid absorption and demonstrate rapid equilibrium plasma site of action caused by the rapid increase, and due to the rapid metabolism resulting in rapid decline. 线2是随时间变化的作用位点处缓慢作用的阿片样物质的浓度(慢药物作用位点),并证明由于缓慢吸收和缓慢的血浆作用位点平衡造成浓度缓慢升高,而由于缓慢的代谢造成缓慢降低。 Concentration at the site of action lines 2 are time varying slow acting opioid (slow site of drug effect), and since proved slow absorption and slow plasma site of action resulting equilibrium concentrations slowly raised, and due to the slow Metabolism in slowly reduced. 线3显示快速和缓慢起效的药物的组合浓度(组合的阿片样物质作用位点浓度)。 Line 3 shows the combined concentration of (opioid effect site concentrations combined) fast and slow acting drugs. 正如可观察到的,所述组合在施加第一种阿片样物质期间达到峰值。 As can be seen, the combination reaches a peak is applied during a first opioid.

图15和图14显示在同一X轴(时间)上运行的同一模拟的不同变量。 Figures 15 and 14 show the same simulation run on different variables (time) the same X-axis. 因此可回去参照图14认识患者在大约12分钟时停止自我施药。 Referring back to FIG. 14 can thus recognize that the patient stopped self-administration at about 12 minutes. 当将图15插入图14时,我们可观察到这反映了患者对快速作用的阿片样物质的反应,因为缓慢作用的阿片样物质的浓度在12分钟时是可以忽略不计的。 When the insert 15 of FIG. 14, we can observe the patient's response which reflects the rapid acting opioid, as the concentration of the slowly acting opioid in 12 minutes is negligible. 不过,在整个时间内总阿片样物质浓度保持相当的稳定。 However, during the entire time the total opioid concentration remained fairly stable. 这反映了当快速作用的阿片样物质通过快速药物清除机制被从系统中除去时,作用位点内阿片样物质中缓慢作用的阿片样物质逐渐取代了快速作用的阿片样物质。 This reflects the time when the fast-acting opioid is removed from the system by rapid drug clearance mechanisms, sites of action of opioid slowly acting opioid gradually replacing the rapid acting opioid.

图16显示了在同一模拟运行中,利用双阿片样物质递送体系递送阿片样物质期间和之后通气减缓2060的时间曲线。 Figure 16 shows the same simulation run, using two-opioid delivery system during delivery of the opioid and time profiles after ventilatory depression 2060. 图16说明最初的通气降低至基线的60%左右。 Figure 16 illustrates an initial decrease ventilation to about 60% of baseline. 正如前文所提及的(图11的描述中),这是被患者良好耐受的。 As mentioned previously (in the description of FIG. 11), which is well tolerated by the patient. 随着CO2累积,就刺激了通气。 With the accumulation of CO2, it stimulates ventilation. 值得注意的是在此最初的下降之后只有很少的通气降低。 It is noteworthy that only a few ventilation decreased after this initial drop. 其原因是此时患者体内有足够的CO2积累以继续驱动通气。 The reason is that this time the patient has enough CO2 to accumulate in order to continue driving ventilation.

正如图13A、13B、13C、14和15所证实的,在所述装置的两药物实施方案中,第一种药物用作患者对阿片样物质灵敏度的“探针”,并限制了第一种和第二种阿片样物质二者的剂量。 As 13A, 13B, 13C, demonstrated 14 and 15, two embodiments of the device the drug in the first drug to a patient as opioid sensitivity "probe", and the first limit and both doses of opioids second. 以此方式,患者可接受缓慢作用的阿片样物质而不会接受过多的剂量。 In this way, the patient may receive slow-acting opioid without receiving excessive doses. 因此两种阿片样物质的组合,其中一种是快速作用的,可用于增加单独任一种阿片样物质的安全特性谱,或者,更具体而言,增加缓慢作用的阿片样物质的安全特性谱。 Thus a combination of two opioids, one of which is fast acting, either alone may be used to increase the security features opioid spectrum, or, more specifically, to increase the safety characteristics of the slow acting opioid spectrum .

实施例4:作为双药物模型中阿片样物质实例的阿芬太尼和吗啡本实施例显示了实施例3在两种具体药物上的应用,即,阿芬太尼和吗啡,其中阿芬太尼是快速作用的阿片样物质,而吗啡是缓慢作用的阿片样物质。 Example 4: Alfentanil and Morphine as examples of opioid substances dual drug model This example shows an application of Example 3 on two specific drugs embodiment, i.e., alfentanil and morphine, wherein Affen too Nepal is a fast-acting opioid, morphine and is slow-acting opioid.

图17A、17B和17C合起来包括:装置模型17010,包含两个装置模型5010,如图5A和5B中所描述以及实施例1中所说明的,各自平行运行,但针对阿片样物质阿芬太尼和吗啡的具体已知参数分别进行了修正和再标注(图17A和17B中所示);通气减缓模型5030,如图2所述;镇静模型5040,如图1所述,以及双药物模型17050,如图12所述但进行了重新标注以反映具体药物阿芬太尼和吗啡(图17C所示)。 FIG. 17A, 17B and 17C together, comprising: a Device Model 17010, comprising two Model 5010 devices, 5A and 5B and described in Example 1 below, each running in parallel, but for too opioid Affen DETAILED Nepal known parameters and morphine were modified and re-labeled (FIGS. 17A and 17B); ventilatory Depression model 5030, as described in Figure 2; sedation model 5040, 1, and FIG dual drug model 17050, but the 12 were re-labeled to reflect the specific drugs alfentanil and morphine (FIG. 17C). 图17A、17B和17C揭示了通气减缓模型17030的所有参数2070。 Figures 17A, 17B and 17C reveal all of the parameters 2070 of the ventilatory depression model 17030. 有关吗啡和阿芬太尼的药动学模型17020的参数4080此时也被完全揭示了。 Parameters Pharmacokinetic Model 17020 morphine and alfentanil about 4080 at this time is also completely revealed. 阿芬太尼和吗啡的每个用具有作用位点的3区隔乳房模型代表。 Each has a site of action with a 3 segment breasts model represents alfentanil and morphine.

图17A、17B和17C中显示的模型还可由如下数学模型来描述,用Stella编程语言代表。 17A, 17B, and 17C display model may also be described by the following mathematical model, represented by a Stella programming language. 阿芬太尼和吗啡的有关常数是以现存的关于这些药物的文献为基础的。 About the constant alfentanil and morphine is based on the existing literature on the basis of these drugs.

<pre id="pre0003" xml:space="preserve" listing-type="sequence">Alfentanil_in_Inhaler(t)=Alfentanil_in_Inhaler(t-dt)+(-Inhale_Alfentanil)*dtINIT Alfentanil_in_Inhaler=Alfentanil_Dose_ugOUTFLOWS:Inhale_Alfentanil=If Sedation_State=0 thenAlfentanil_Dose_ug/Dose_Duration*Ventilatory_Depressionelse 0Alfentanil_in_Lung(t)=Alfentanil_in_Lung(t-dt)+(Inhale_Alfentanil-Alfentanil_Uptake)*dtINIT Alfentanil_in_Lung=0INFLOWS:Inhale_Alfentanil=If Sedation_State=0 thenAlfentanil_Dose_ug/Dose_Duration*Ventilatory_Depressionelse 0OUTFLOWS:Alfentanil_Uptake=Alfentanil_in_Lung*.693/Alfentanil_Absorption_Half_LifeAlfentanil_X1(t)=Alfentanil_X1(t-dt)+(Alfentanil_C12+Alfentanil_C13+Alfentanil_CLe+Alfentanil_Uptake-Alfentanil_C11)*dtINIT Alfentanil_X1=0</pre> INFLOWS: Alfentanil_C12=Alfentanil_X2*Alfentanil_K21- Alfentanil_X1*Alfentanil_K12 Alfentanil_C13=Alfentanil_X3*Alfentanil_K31- Alfentanil_X1*Alfentanil_K13 Alfentanil_CLe=Alfentanil_Xeffect*Alfentanil_Ke0- Alfentanil <Pre id = "pre0003" xml: space = "preserve" listing-type = "sequence"> Alfentanil_in_Inhaler (t) = Alfentanil_in_Inhaler (t-dt) + (- Inhale_Alfentanil) * dtINIT Alfentanil_in_Inhaler = Alfentanil_Dose_ugOUTFLOWS: Inhale_Alfentanil = If Sedation_State = 0 thenAlfentanil_Dose_ug / Dose_Duration * Ventilatory_Depressionelse 0Alfentanil_in_Lung (t) = Alfentanil_in_Lung (t-dt) + (Inhale_Alfentanil-Alfentanil_Uptake) * dtINIT Alfentanil_in_Lung = 0INFLOWS: Inhale_Alfentanil = If Sedation_State = 0 thenAlfentanil_Dose_ug / Dose_Duration * Ventilatory_Depressionelse 0OUTFLOWS: Alfentanil_Uptake = Alfentanil_in_Lung * .693 / Alfentanil_Absorption_Half_LifeAlfentanil_X1 ( t) = Alfentanil_X1 (t-dt) + (Alfentanil_C12 + Alfentanil_C13 + Alfentanil_CLe + Alfentanil_Uptake-Alfentanil_C11) * dtINIT Alfentanil_X1 = 0 </ pre> INFLOWS: Alfentanil_C12 = Alfentanil_X2 * Alfentanil_K21- Alfentanil_X1 * Alfentanil_K12 Alfentanil_C13 = Alfentanil_X3 * Alfentanil_K31- Alfentanil_X1 * Alfentanil_K13 Alfentanil_CLe = Alfentanil_Xeffect * Alfentanil_Ke0- Alfentanil _X1*Alfentanil_Ke0*.001/Alfentanil_V1 Alfentanil_Uptake= Alfentanil_in_Lung*.693/Alfentanil_Absorption_Half_Life OUTFLOWS: Alfentanil_C11=Alfentanil_X1*Alfentanil_K10 Alfentanil_X2(t)=Alfentanil_X2(t-dt)+(- Alfentanil_C12)*dt INIT Alfentanil_X2=0 OUTFLOWS: Alfentanil_C12=Alfentanil_X2*Alfentanil_K21- Alfentanil_X1*Alfentanil_K12 Alfentanil_X3(t)=Alfentanil_X3(t-dt)+(- Alfentanil_C13)*dt INIT Alfentanil_X3=0 OUTFLOWS: Alfentanil_C13=Alfentanil_X3*Alfentanil_K31- Alfentanil_X1*Alfentanil_K13 Alfentanil_Xeffect(t)=Alfentanil_Xeffect(t-dt)+(- Alfentanil_CLe)*dt INIT Alfentanil_Xeffect=0 OUTFLOWS: Alfentanil_CLe=Alfentanil_Xeffect*Alfentanil_Ke0- Alfentanil_X1*Alfentanil_Ke0*.001/Alfentanil_V1 Morphine_in_Inhaler(t)=Morphine_in_Inhaler(t-dt)+(- Inhale_Morphine)*dt INIT Morphine_in_Inhaler=Morphine_Dose_mg*1000 OUTFLOWS: Inhale_Morphine=If sedation_state=0 then Morphine_Dose_mg*1000/Dose_Duration*Ventilatory_Depression else 0 Morphine_in_Lung(t)=Morp _X1 * Alfentanil_Ke0 * .001 / Alfentanil_V1 Alfentanil_Uptake = Alfentanil_in_Lung * .693 / Alfentanil_Absorption_Half_Life OUTFLOWS: Alfentanil_C11 = Alfentanil_X1 * Alfentanil_K10 Alfentanil_X2 (t) = Alfentanil_X2 (t-dt) + (- Alfentanil_C12) * dt INIT Alfentanil_X2 = 0 OUTFLOWS: Alfentanil_C12 = Alfentanil_X2 * Alfentanil_K21- Alfentanil_X1 * Alfentanil_K12 Alfentanil_X3 (t) = Alfentanil_X3 (t-dt) + (- Alfentanil_C13) * dt INIT Alfentanil_X3 = 0 OUTFLOWS: Alfentanil_C13 = Alfentanil_X3 * Alfentanil_K31- Alfentanil_X1 * Alfentanil_K13 Alfentanil_Xeffect (t) = Alfentanil_Xeffect (t-dt) + (- Alfentanil_CLe) * dt INIT Alfentanil_Xeffect = 0 OUTFLOWS: Alfentanil_CLe = Alfentanil_Xeffect * Alfentanil_Ke0- Alfentanil_X1 * Alfentanil_Ke0 * .001 / Alfentanil_V1 Morphine_in_Inhaler (t) = Morphine_in_Inhaler (t-dt) + (- Inhale_Morphine) * dt INIT Morphine_in_Inhaler = Morphine_Dose_mg * 1000 OUTFLOWS: Inhale_Morphine = If sedation_state = 0 then Morphine_Dose_mg * 1000 / Dose_Duration * Ventilatory_Depression else 0 Morphine_in_Lung (t) = Morp hine_in_Lung(t-dt)+ (Inhale_Morphine-Morphine_Uptake)*dt INIT Morphine_in_Lung=0 INFLOWS: Inhale_Morphine=If sedation_state=0 then Morphine_Dose_mg*1000/Dose_Duration*Ventilatory_Depression else 0 OUTFLOWS: Morphine_Uptake= Morphine_in_Lung*.693/Morphine_Absorption_Half_Life Morphine_X1(t)=Morphine_X1(t-dt)+(Morphine_C12+ Morphine_C13+Morphine_CLe+Morphine_Uptake- Morphine_C11)*dt INIT Morphine_X1=0 INFLOWS: Morphine_C12=Morphine_X2*Morphine_K21- Morphine_X1*Morphine_K12 Morphine_C13=Morphine_X3*Morphine_K31- Morphine_X1*Morphine_K13 Morphine_CLe=Morphine_Xeffect*Morphine_Ke0- Morphine_X1*Morphine_Ke0*.001/Morphine_V1 Morphine_Uptake= Morphine_in_Lung*.693/Morphine_Absorption_Half_Life OUTFLOWS: Morphine_C11=Morphine_X1*Morphine_K10 Morphine_X2(t)=Morphine_X2(t-dt)+(-Morphine_C12)* dt INIT Morphine_X2=0 OUTFLOWS: Morphine_C12=Morphine_X2*Morphine_K21- Morphine_X1*Morphine_K12 Morphine_X3(t)=Morphine_X3(t-dt)+(-Morphine_C13)* dt INIT Morphine_X3 hine_in_Lung (t-dt) + (Inhale_Morphine-Morphine_Uptake) * dt INIT Morphine_in_Lung = 0 INFLOWS: Inhale_Morphine = If sedation_state = 0 then Morphine_Dose_mg * 1000 / Dose_Duration * Ventilatory_Depression else 0 OUTFLOWS: Morphine_Uptake = Morphine_in_Lung * .693 / Morphine_Absorption_Half_Life Morphine_X1 (t) = Morphine_X1 (t-dt) + (Morphine_C12 + Morphine_C13 + Morphine_CLe + Morphine_Uptake- Morphine_C11) * dt INIT Morphine_X1 = 0 INFLOWS: Morphine_C12 = Morphine_X2 * Morphine_K21- Morphine_X1 * Morphine_K12 Morphine_C13 = Morphine_X3 * Morphine_K31- Morphine_X1 * Morphine_K13 Morphine_CLe = Morphine_Xeffect * Morphine_Ke0- Morphine_X1 * Morphine_Ke0 * .001 / Morphine_V1 Morphine_Uptake = Morphine_in_Lung * .693 / Morphine_Absorption_Half_Life OUTFLOWS: Morphine_C11 = Morphine_X1 * Morphine_K10 Morphine_X2 (t) = Morphine_X2 (t-dt) + (- Morphine_C12) * dt INIT Morphine_X2 = 0 OUTFLOWS: Morphine_C12 = Morphine_X2 * Morphine_K21- Morphine_X1 * Morphine_K12 Morphine_X3 (t) = Morphine_X3 (t-dt) + (- Morphine_C13) * dt INIT Morphine_X3 0 OUTFLOWS: Morphine_C13=Morphine_X3*Morphine_K31- Morphine_X1*Morphine_K13 Morphine_Xeffect(t)=Morphine_Xeffect(t-dt)+(- Morphine_CLe)*dt INIT Morphine_Xeffect=0 OUTFLOWS: Morphine_CLe=Morphine_Xeffect*Morphine_Ke0- Morphine_X1*Morphine_Ke0*.001/Morphine_V1 PaCO2(t)=PaCO2(t-dt)+(CO2_Accumulation-CO2Equilb)* dt INIT PaCO2=PaCO2@0 INFLOWS: CO2_Accumulation=KelCO2*PaCO2@0- KelCO2*Ventilatory_Depression*PaCO2 OUTFLOWS: CO2Equilb=ke0CO2*(PaCO2-PeCO2) PeCO2(t)=PeCO2(t-dt)+(CO2Equilb)*dt INIT PeCO2=PaCO2@0 INFLOWS: CO2Equilb=ke0CO2*(PaCO2-PeCO2) Sedation_State(t)=sedation_State(t-dt)+ (Sedation_Evaluator)*dt INIT Sedation_State=0 INFLOWS: Sedation_Evaluator=if Combined_Opioid_Effeci_Site_Concentration<Sedation_Threshol d then 0 else 1 Alfentanil_Absorption_Half_Life=1 Alfentanil_Ce=Alfentanil_Xeffect/.001 Alfentanil_Cp=Alfentanil_X1/Alfentanil_V1 Alfentanil_Dose_ug=1500 Alfentanil_K10=0.090957 Alfentanil_K12=0.655935 Alfentanil_K13=0.1 0 OUTFLOWS: Morphine_C13 = Morphine_X3 * Morphine_K31- Morphine_X1 * Morphine_K13 Morphine_Xeffect (t) = Morphine_Xeffect (t-dt) + (- Morphine_CLe) * dt INIT Morphine_Xeffect = 0 OUTFLOWS: Morphine_CLe = Morphine_Xeffect * Morphine_Ke0- Morphine_X1 * Morphine_Ke0 * .001 / Morphine_V1 PaCO2 (t) = PaCO2 (t-dt) + (CO2_Accumulation-CO2Equilb) * dt INIT PaCO2 = PaCO2 @ 0 INFLOWS: CO2_Accumulation = KelCO2 * PaCO2 @ 0- KelCO2 * Ventilatory_Depression * PaCO2 OUTFLOWS: CO2Equilb = ke0CO2 * (PaCO2-PeCO2 ) PeCO2 (t) = PeCO2 (t-dt) + (CO2Equilb) * dt INIT PeCO2 = PaCO2 @ 0 INFLOWS: CO2Equilb = ke0CO2 * (PaCO2-PeCO2) Sedation_State (t) = sedation_State (t-dt) + (Sedation_Evaluator) * dt INIT Sedation_State = 0 INFLOWS: Sedation_Evaluator = if Combined_Opioid_Effeci_Site_Concentration <Sedation_Threshol d then 0 else 1 Alfentanil_Absorption_Half_Life = 1 Alfentanil_Ce = Alfentanil_Xeffect / .001 Alfentanil_Cp = Alfentanil_X1 / Alfentanil_V1 Alfentanil_Dose_ug = 1500 Alfentanil_K10 = 0.090957 Alfentanil_K12 = 0.655935 Alfentanil_K13 = 0.1 12828 Alfentanil_K21=0.214 Alfentanil_K31=0.017 Alfentanil_Ke0=0.77 Alfentanil_V1=2.18 C50=1.1 Combined_Opioid_Effeci_Site_Concentration= Alfentanil_Ce/60+Morphine_Ce/70 Dose_Duration=12 F=4 Gamma=1.2 ke0CO2=0.92 KelCO2=0.082 Morphine_Absorption_Half_Life=2 Morphine_Ce=Morphine_Xeffect/.001 Morphine_Cp=Morphine_X1/Morphine_V1 Morphine_Dose_mg=20 Morphine_K10=0.070505618 Morphine_K12=0.127340824 Morphine_K13=0.018258427 Morphine_K21=0.025964108 Morphine_K31=0.001633166 Morphine_Ke0=0.005 Morphine_V1=17.8 PaCO2@0=40 Sedation_Threshold=1.5 Ventilatory_Depression=(1- Combined_Opioid_Effeci_Site_Concentration^Gamma/(C50^Gamma+ Combined_Opioid_Effeci_Site_Concentration^Gamma))*(PeCO2/Pa CO2@0)^F在时间0处以吸入器中700mcg生物可用的阿芬太尼和67mcg生物可用的吗啡为起始参数进行模拟(在时间=0时,吸入器中的阿芬太尼=700mcg;在时间=0时,吸入器中的吗啡=67mcg)。 12828 Alfentanil_K21 = 0.214 Alfentanil_K31 = 0.017 Alfentanil_Ke0 = 0.77 Alfentanil_V1 = 2.18 C50 = 1.1 Combined_Opioid_Effeci_Site_Concentration = Alfentanil_Ce / 60 + Morphine_Ce / 70 Dose_Duration = 12 F = 4 Gamma = 1.2 ke0CO2 = 0.92 KelCO2 = 0.082 Morphine_Absorption_Half_Life = 2 Morphine_Ce = Morphine_Xeffect / .001 Morphine_Cp = Morphine_X1 / Morphine_V1 Morphine_Dose_mg = 20 Morphine_K10 = 0.070505618 Morphine_K12 = 0.127340824 Morphine_K13 = 0.018258427 Morphine_K21 = 0.025964108 Morphine_K31 = 0.001633166 Morphine_Ke0 = 0.005 Morphine_V1 = 17.8 PaCO2 @ 0 = 40 Sedation_Threshold = 1.5 Ventilatory_Depression = (1- Combined_Opioid_Effeci_Site_Concentration ^ Gamma / (C50 ^ Gamma + Combined_Opioid_Effeci_Site_Concentration ^ Gamma)) * (PeCO2 / Pa CO2 @ 0) ^ F impose morphine inhaler 700mcg bioavailable alfentanil and 67mcg bioavailable at time 0 as a starting simulation parameters (at time = 0, the suction alfentanil reactor = 700 meg; at time = 0, morphine inhaler = 67mcg). 图18和19显示了进行模拟时各种参数的浓度。 Figures 18 and 19 show the concentrations of various parameters when the simulation. 图18显示吸入组合产物后作用位点处阿芬太尼(ng/ml,线1)、吗啡(ng/ml,线2)和组合阿片样物质(ng/ml阿芬太尼当量,线3)浓度随时间(以分钟计)的变化。 After inhalation of the product composition at the site of action Figure 18 shows alfentanil (ng / ml, line 1), morphine (ng / ml, line 2) and combinations of an opioid (ng / ml alfentanil equivalents, line 3 ) changes in the concentration over time (in minutes) of. 在此实施例中,在90%的吸入药物运送后由于患者的镇静作用而终止了施药。 In this embodiment, the 90% of the inhaled drug transport due to the patient's sedation administration terminated. 正如可观察到的,阿芬太尼的浓度在作用位点处迅速升高(线1)而产生快速药物作用。 As can be seen, the alfentanil concentration rises quickly in the effect site (line 1) to produce rapid drug effect. 吗啡的药物作用则在作用位点处提高的相当慢(线2),造成缓慢升高的药物作用。 Morphine drug effect is enhanced at the site of action is rather slow (line 2), resulting in a slow rise of the drug. 线3显示组合阿片样物质的作用位点浓度,其中每种药物都已经调整为相对于芬太尼的效力。 Site of action lines 3 shows a combination of the concentration of the opioid, wherein each drug have already been adjusted with respect to the effectiveness of fentanyl. 正如在Y轴上可观察到的,所有三条线都具有不同的Y刻度,以便针对相对效力标准化作用位点浓度。 As can be observed in the Y-axis, all three lines have different Y scales, normalized to the relative potency of action for the sites of concentration. 在线3中可观察到,最高的阿片样物质暴露发生在吸入时,而且几乎完全归功于阿芬太尼。 3 online can be observed, the highest opioid exposure occurs during inhalation, and is almost entirely due to the alfentanil. 不过,随着阿芬太尼从作用位点被洗除,它几乎恰好被流入作用位点的吗啡所取代。 However, with the site of action of alfentanil from being washed away, it almost happens to be the site of action of morphine inflow replaced. 阿芬太尼刻度上低于25ng/ml的作用位点浓度(由于它们的相对效力,这在吗啡刻度上相当于37.5ng/ml和在芬太尼刻度上的0.5ng/ml)被认为是亚治疗剂量;患者通常在50ng/ml至100ng/ml(在阿芬太尼刻度上)之间感受到止痛效果,在75至125ng/ml(在阿芬太尼刻度上)之间感受到副作用,而在125ng/ml以上(在阿芬太尼刻度上)感受到中毒效果。 Below the site of action in a concentration of 25ng / ml on the alfentanil scale (due to their relative potency, which is equivalent to 37.5ng / ml and 0.5ng / ml on the fentanyl scale on the morphine scale) it is considered to be subtherapeutic dose; patients generally at 50ng / ml to 100ng / ml (on the alfentanil scale) feel analgesic effects between, between the felt side (on the alfentanil scale) at 75 to 125ng / ml and in more than 125ng / ml (on the alfentanil scale) feel the effects of poisoning.

图19显示了由于阿芬太尼吗啡组合阿片样物质递送体系的吸入造成的通气减缓。 Figure 19 shows the ventilation caused by inhalation of alfentanil morphine combination opioid delivery system caused by slowed. 如图19所示,在施药期间通气降低到基线的65%左右,然后由于CO2积累恢复到基线的80%左右。 As shown in FIG. 19, the ventilation decreases to about 65% of baseline during administration, since the accumulation of CO2 and then restored to 80% of baseline. 由于吗啡作用持续,在随后的4小时内通气都维持在基线的80%处。 Since the duration of action of morphine, in the next 4 hours aeration are maintained at 80% of baseline.

如图17A、17B、17C、18和19中所证实的,在阿芬太尼吗啡组合阿片样物质递送体系中,基于利用来自文献的参数值进行模拟,患者自我限制的阿片样物质递送体系防止施用中毒剂量阿片样物质,并通过将慢效阿片样物质与快速起效的阿片样物质组合,并利用快速作用的阿片样物质限制总阿片样物质暴露的作用,来提供安全递送慢效阿片样物质。 FIG. 17A, 17B, 17C, 18 and 19 demonstrated, in the alfentanil morphine combination opioid delivery system, based on the simulation using the parameter values ​​from the literature, the patient self-limiting opioid delivery system prevents administration of toxic doses of opioids, and by limiting the total opioid exposure of slow effect opioid and rapid-onset composition of matter opioid, and using fast-acting opioid, to provide secure delivery slow acting opioid-like substance.

实施例5:芬太尼制剂在人对象上的临床试验(a)游离的和脂质体包裹的芬太尼制剂的制备方法通过混合乙醇相和水相制备含有游离态和脂质体包裹的芬太尼的混合物的制剂。 Example 5: Preparation of fentanyl preparations in human subjects in clinical trials (a) free and liposomally encapsulated fentanyl formulation phase containing free and prepared Fen liposomally encapsulated by mixing ethanol and water formulation of the mixture of fentanyl. 乙醇相包含乙醇、芬太尼柠檬酸盐、磷脂酰胆碱和胆固醇。 Ethanol phase comprises ethanol, fentanyl citrate, phosphatidylcholine and cholesterol. 水相包含注射用水。 The aqueous phase comprises water for injection. 在混合前,两相均被加热至温度为56-60摄氏度左右。 Before mixing, the two phases are heated to a temperature of about 56-60 degrees Celsius. 将两相混合并在56-60摄氏度进一步搅拌10分钟。 The two were mixed and further stirred at 56-60 ° C for 10 minutes. 然后将混合物经约两小时冷却至室温。 The mixture was then cooled to room temperature over two hours. 通常,在注射用水的溶液中,每ml的最终水性制剂含有500mcg芬太尼(相当于800mcg芬太尼柠檬酸盐)、40mg磷脂酰胆碱、4mg胆固醇和100mg乙醇。 Typically, in a solution of water for injection, each ml of the final aqueous formulation containing 500mcg of fentanyl (corresponding 800mcg of fentanyl citrate), 40mg phosphatidylcholine, cholesterol and 100mg 4mg ethanol. 填充以后,将制剂进行高压灭菌。 After filling, the formulation is autoclaved. 最终制剂含有35-45%的芬太尼作为游离的药物,其余的是脂质体包裹部分。 The final formulation containing 35-45% of the fentanyl as free drug, the liposome remaining portion.

(b)治疗方案以下实例的操作显示施用游离的和脂质体包裹的芬太尼混合物如何通过患者的肺递送治疗有效浓度至血流中,且施药期间嗜睡、晕眩或镇静通常(但不是总是)先于缺氧的副作用。 The following example of the operation (b) show the administration regimen of free fentanyl and liposomally encapsulated mixture of how the patient's lungs to deliver a therapeutically effective concentration in the blood stream, administration period and somnolence, dizziness or sedation generally (but not always) prior to the hypoxic side effects.

用单剂量或多剂量的游离和脂质体包裹的芬太尼处理健康志愿者对象,其中使用AeroEclipseTM喷雾器呼吸促动设备,压缩空气设定为8升/分钟。 With a single or multiple doses of free and liposome encapsulated fentanyl healthy volunteers treated objects, wherein AeroEclipseTM actuated nebulizer breathing apparatus, the compressed air is set to 8 l / min. 在每次用药期间,用3ml游离的(40%)和脂质体包裹的(60%)的芬太尼填充喷雾器并指导受试者吸入喷雾状药物直至该装置不再产生用于吸入的气溶胶。 During each treatment, with 3ml free wrapping (40%) and liposomes (60%) fentanyl and the subjects were instructed to fill the sprayer medicament inhalation spray until the device no longer produces gas for inhalation sol. 在吸入期间变得嗜睡、困倦或晕眩的对象被鼓励继续自我施药直至喷雾器不再产生气溶胶。 Become sleepiness, drowsiness or dizziness object is to encourage self-administration during inhalation continue until no longer produces an aerosol sprayer. 在整个施药期间以及开始施药后12小时内收集血浆样品以监测血浆芬太尼浓度。 Throughout the administration, and plasma fentanyl concentration in plasma samples were collected within 12 hours after the initiation of administration to monitor. 监测对象的任何不良反应,包括呼吸速率的改变和缺氧。 The object of any adverse reactions, including changes in respiratory rate and hypoxia.

对照对象被静脉给予芬太尼。 Control subjects were intravenously administered fentanyl.

(c)最大血浆浓度和施药终点血浆浓度的检测为了确定在中毒效果呈现之前,对象是否能通过自我限制用药防止药物达到有毒水平,将最大血浆浓度(Cmax)对用药终点处的血浆浓度(Ceod)作图(图20A)。 (C) detecting the maximum plasma concentration and plasma concentration prior to administration in order to determine the end of the poisoning effect of rendering, whether the object is to prevent drug by self-limiting the drug reaches toxic levels, the maximum plasma concentration (Cmax) of the drug plasma concentration at the end point ( Ceod) plotted (FIG. 20A). 发现在大部分情况下Ceod在Cmax的80%以内,表明阿片样物质的最大浓度并未显著高于受试者停止摄入阿片样物质时的浓度。 Ceod found in most cases less than 80% Cmax, indicating that the maximum concentration of opioid was not significantly higher than the concentration of subjects stop the intake of opioids. 这与对照对象(图20B)形成了鲜明的对比,其中被施加静脉芬太尼的对象呈现出Cmax浓度显著高于Ceod。 This is in stark contrast to the control subjects (FIG. 20B), where the object is applied intravenous fentanyl exhibited Cmax concentrations significantly higher than Ceod. 这表明由对象滴定施药提高了安全性,因为阿片样物质的浓度(以及产生的毒性作用)在对象停止摄入阿片样物质后不会显著增加。 This indicates that improves security by the object titration spraying, because the concentration of the opioid (as well as toxic effects produced) will not stop the intake of the target substance after a significant increase in opioid. 这表明,在相对长的时间(2-20分钟)内吸入所公布浓度的阿片样物质制剂,如果“用药终点”量是无毒的,则对象所摄取的阿片样物质最大浓度也可能是无毒的。 This indicates that a relatively long time (2-20 minutes) the suction of the opioid released formulation concentration, the maximum concentration of the opioid substance if the "end drug" amount is non-toxic, the object may also be ingested without toxic.

(d)测定副作用和毒性作用的时间点为了对象有效的进行自我滴定,诸如嗜睡、晕眩、或通气减缓等副作用应在毒性作用发作之前出现。 (D) determining side effects and toxicity of the object points in time to effectively self-titrate, such as drowsiness, dizziness or ventilatory depression should occur before the side effects such as the onset of toxic effects. 在此实验中毒性作用定义为对象的血氧不足导致血液氧饱和度低于正常值的90%。 In this experiment lack toxic effects is defined as an object leading to blood oxygen saturation of oxygen below 90% of normal. 为了确定副作用是否在毒性作用之前出现,将达到副作用的时间和达到毒性作用的时间对停止用药的时间作图(图21)。 In order to determine whether side effects occur before toxic effects, time to reach the side effects and toxic effects of time reaches plotted against time of stopping the treatment (Fig. 21). 对于任何用药时间终点,达到副作用的时间都等于或短于达到毒性作用的时间,表明嗜睡、晕眩或通气减缓总是发生在毒性作用之前或之时。 For any medication the end of time, to the side effects of time equal to or shorter than the reach of the toxic effects of time, shows that drowsiness, dizziness or ventilatory depression always occurs prior to or upon the toxic effects.

(e)确定毒性作用和副作用之间的相关性为了对象进行有效的自我滴定,引起(或指示)停止施药的副作用应几乎总是早于毒性作用。 (E) determining a correlation between toxic effect and side effects to objects effectively self-titrate, causing (or instruction) to stop spraying of side effects should almost always be earlier than toxicity. 图22显示,就试验的总体而言,副作用与毒性作用密切相关,表明非常有可能呈现毒性作用的对象也会呈现副作用。 Figure 22 shows that, on the whole test, the closely-related side effects and toxic effects, indicate target is very likely to exhibit toxic effects will be presented side effects.

本实施例显示,在人对象的对照试验中,(1)副作用几乎总是早于毒性作用,且(2)在本实施例所给出的剂量特征谱中,吸入阿片样物质的Cmax近似于Ceod。 Cmax embodiment shows the embodiment, in controlled trials in human subject, (1) a toxic side effect is almost always earlier, and (2) at a dose profiles of the present embodiment is given, similar to the suction opioid Ceod. 因此,在感受到副作用时停止施用阿片样物质的对象将可能不会达到毒性作用所需的阿片样物质浓度水平。 Thus, stop administering the opioid side effects will feel when the substances may not reach opioid concentration levels required for toxic effect.

实施例6:测试最适于药物递送的喷雾器技术图3、5、13和17包括取决于吸入速率的装置模型和一定时间内递送入肺的药物量的说明。 Test most suitable nebulizer drug delivery technology described FIGS. 3,5,13 and 17 comprises a suction means dependent on the rate of the model within a certain time and the amount of drug delivered into the lungs: Example 6. 图5、13和17中的通气减缓模型预示了副作用将如何限制吸入速率。 Figure 5, 13 and 17 ventilatory depression model predicts how the side effects will limit the inhalation rate. 此外,阿片样物质在肺内沉积的速率与在作用位点处起效的速率之间需要有个平衡。 In addition, opioids between lung deposition rate at the onset of the site of action need to have a balanced rate. 每次吸入所分配的药物量必须控制在低于阈值,使得所述药物制剂在4-20分钟期间方便、安全和有效的施用。 Per inhalation assigned amount of drug to be controlled to below a threshold value, such that the pharmaceutical preparations conveniently, safely and effectively administered during 4-20 min. 为了帮助优化制剂和装置选择,具有特定制剂的装置的性能可以在体外表征。 To help optimize the formulation and selection means, the apparatus having a performance of a particular formulation can be characterized in vitro. 以下实施例举例说明了用于最适合的向肺递送药物的喷雾器技术的测试。 The following examples illustrate the most appropriate test for a nebulizer drug delivery technology to the lungs.

用实施例5所述的方法制备含游离态和脂质体包裹芬太尼的混合物的制剂。 Using the method described in Example 5 is prepared containing the free and liposomally encapsulated fentanyl formulation mixture. 最终的制剂包含35-45%之间的游离态芬太尼,剩余的是脂质体包裹的部分。 The final formulation comprises free fentanyl of between 35-45%, the remainder being liposome-encapsulated portion.

Andersen Cascade Impactor(ACI)技术是用于表征喷雾器中所发出气溶胶的公认方法。 Andersen Cascade Impactor (ACI) technique is a recognized method used to characterize the emitted aerosol sprayer. (USP 26-NF21-2003,Chapter 601:Physical tests and determinations:aerosols. United States Pharmacopoeia,Rockville,MD,2105-2123. United StatesFederal Drug Administration,1998. Draft guidance:metered dose inhaler(MDI)anddry powder inhaler(DPI)drug products chemistry,manufacturing and controlsdocumentation,Docket 98D-0997. United States Federal Drug Administration,Rockville,MD.Mitchell,JP;PA Costa;S Waters. 1987. An assessment of an AndersenMark-lI Cascade Impactor. J. Aerosol Sci.19:213-221)。 (USP 26-NF21-2003, Chapter 601: Physical tests and determinations:.. Aerosols United States Pharmacopoeia, Rockville, MD, 2105-2123 United StatesFederal Drug Administration, 1998 Draft guidance:. Metered dose inhaler (MDI) anddry powder inhaler ( DPI) drug products chemistry, manufacturing and controlsdocumentation, Docket 98D-0997 United States Federal Drug Administration, Rockville, MD.Mitchell, JP;. PA Costa; S Waters 1987. An assessment of an AndersenMark-lI Cascade Impactor J. Aerosol.. Sci.19: 213-221). 用此技术可测定多种参数,包括阿片样物质输出速率、MMAD和精细颗粒分数。 This technique can be determined using a variety of parameters, including opioid output rate, and MMAD of the fine particle fraction. 在实验室环境条件下以28.3升/分钟的速率操作ACI来检测含所述制剂的商品喷雾器。 Under laboratory conditions at a rate of 28.3 l / min detecting operation ACI nebulizer containing the product formulation. 按照美国食品和药物管理局方案601(USP 26-NF21-2003,Chapter 601:Physical Tests and Determinations:Aerosols. United States Pharmacopoeia,Rockville,MD,2105-2123. United StatesFederal Drug Administration(FDA).)计算MMAD,精细颗粒剂量确定为ACI中收集的总气溶胶输出的、沉积在截留参数小于4.7微米的板上的分数。 According to the US Food and Drug Administration program 601 (USP 26-NF21-2003, Chapter 601: Physical Tests and Determinations:... Aerosols United States Pharmacopoeia, Rockville, MD, 2105-2123 United StatesFederal Drug Administration (FDA)) calculated MMAD , determined as the total fine particle dose collected in the aerosol output of ACI, the retentate fractional deposition parameter of less than 4.7 microns on the plate. 通过HPLC分析测定沉积在ACI不同阶段的总阿片样物质药物和脂质载体的量。 By HPLC analysis the total amount of opioid lipid carrier and deposited at different stages of ACI measurement.

用ACI技术检测了多种商品化的小体积喷雾器,呼吸促动AeroEclipse(TrudellMedical,London,Ontario)、呼吸加强的Pari-LC Plus(PARI GmbH,Starnberg,Germany)以及两种传统的小体积喷雾器:MistyNeb(Allegiance Healthcare Corp.,McGraw Park,IL)和OptiMist(Maersk Medical Inc.,McAllen,Texas)。 ACI detection technique using a plurality of small commercial nebulizers, breath actuated AeroEclipse (TrudellMedical, London, Ontario), enhanced respiratory Pari-LC Plus (PARI GmbH, Starnberg, Germany) and two conventional small sprayer: MistyNeb (Allegiance Healthcare Corp., McGraw Park, IL) and OptiMist (Maersk Medical Inc., McAllen, Texas). 对于每个装置而言,芬太尼在肺内的理论沉积速率计算方式为:用实验测定的阿片样物质输出速率(mcg/秒)乘以在一分钟内发生吸入的平均时间(20秒),并用实验测定的精细颗粒分数进行修正。 For each device, the deposition rate of fentanyl calculated theoretical lungs way: opioids experimentally determined output rate (mcg / sec) the average time of inhalation (20 seconds) by multiplying occurred in one minute and corrected with the experimentally determined fine particle fraction.

采用多种喷雾器(如上所述)以单一剂量的游离态和脂质体包裹的芬太尼混合物(如上所述)处理健康志愿者对象,来确定理论上沉积于肺部深处的芬太尼是否可能与体内总芬太尼的递送平均速率相关。 Fentanyl using a variety of nebulizers (as described above) in a single dose of free and liposome encapsulated fentanyl mixture (as described above) of healthy volunteers treated objects, theoretically to determine whether the deposited deep lung It may be related to the average rate of the total fentanyl delivery in vivo. 结果概述如下: The results are summarized as follows:

本实验显示特定芬太尼组合物(如实施例5中所述)的吸入速率产生一定范围的芬太尼向肺部深处沉积的速率。 This experiment shows that the specific composition of fentanyl (as described in Example 5) in a range of the suction rate at which the rate of fentanyl is deposited to the deep lung. 利用呼吸促动AeroEclipse喷雾器和呼吸增强Pari-LC Plus喷雾器可以实现理论和实际沉积速率之间非常好的相关性。 Using a nebulizer and breath actuated AeroEclipse respiratory enhanced Pari-LC Plus nebulizer can achieve a very good correlation between the theoretical and the practical deposition rate. 而用传统的小体积喷射喷雾器MistyNeb和OptiMist则观察到理论值和实际值之间相关性较差,体内沉积的实际值低于体外研究的预测值。 A small volume and conventional jet nebulizers and OptiMist MistyNeb poor correlation is observed between the theoretical and actual values, the actual value is below the predicted value of the deposited vivo in vitro studies. 本实验还显示可以开发其它组合的组合物(具有不同浓度的阿片样物质或不同的阿片样物质比率),与不同喷雾器的联合,可以产生阿片样物质的期望沉积速率,而且还描述了用常规实验法确定最佳组合的方法。 This experiment is also shown to develop compositions other combinations (opioids or different opioid ratios with different concentrations), in combination with different nebulizer may produce the desired deposition rate of the opioid, but also describes a conventional the method of determining the best combination of experimentation.

实施例7:芬太尼制备物在人类受试者中的定性效果的临床试验下面的实施例显示了患者可如何使用适当吸入的药物制剂的止痛作用和副作用来递送治疗有效量的止痛剂。 Example 7: Clinical Trial The following examples were prepared qualitative effect of fentanyl in human subjects show how the patient can use the pharmaceutical formulation suitable for inhalation analgesic effect and side effects to deliver a therapeutically effective amount of the analgesic.

含有游离芬太尼和脂质体包裹的芬太尼混合物的制剂是用实施例5中描述的方法制备的。 Formulation containing free fentanyl and liposomally encapsulated fentanyl mixtures are prepared by the method described in Example 5 of the embodiment. 最终制剂含有35-45%游离药物形式的芬太尼,其余为包裹形式。 The final formulation containing 35-45% free drug form of fentanyl, the remainder being in the form of parcels.

研究了接受关节镜前交叉韧带修复的术后患者。 Patients were studied after cruciate ligament arthroscopic repair before accepting. 用静脉内芬太尼作为术中阿片样物质止痛剂,施用标准全身麻醉剂。 As with intraoperative intravenous fentanyl opioid analgesics, general anesthetics administered standard. 手术后,患者在麻醉后看护病房(PACU)中恢复,当他们首次表示他们遭受中度或重度疼痛时,使用AeroEclipseTM喷雾器呼吸促动装置用游离的和脂质体包裹的芬太尼混合物处理患者,其中压缩空气设为8升/分钟。 After surgery, the patient anesthesia care unit (the PACU) to recover, when they for the first time that they suffer from moderate or severe pain, the use of a nebulizer breathing AeroEclipseTM actuating device with a free and liposomally encapsulated fentanyl mixture was treated patients wherein the compressed air is set to 8 l / min. 患者通过由装有3ml游离的和脂质体包裹的芬太尼混合物的AeroEclipse喷雾器的输出端主动吸入而自我调节他们的用药。 AeroEclipse output of the nebulizer by a patient through with 3ml of free and liposome encapsulated fentanyl mixture of active self-regulating their inhalation medication. 指导患者报告首次可察觉的止痛作用出现的时间并在有效疼痛发作或副作用发作时停止自我施药。 Time reporting guide patients first perceptible analgesic effect occurs and stop self-administration in the effective seizure onset of pain or side effects. 在喷雾器不再产生气溶胶时未达到有效止痛效果的受试者被提供第二个装载另外3ml游离态和脂质体包裹芬太尼混合物的喷雾器。 When no longer produce an aerosol nebulizer does not reach the subject an effective analgesic effect is further provided a second loading 3ml free and liposomally encapsulated fentanyl mixture nebulizer. 以此方式,有效的为患者提供了“无限制”治疗。 In this way, effectively providing "unlimited" treatment for patients. 患者自我施加喷雾状药物包括:患者用单手或双手握住喷雾器,将喷雾器的喷口放进嘴里并紧闭嘴,在呼吸循环的吸气期间启动喷雾器。 Patient self-applied spray medicament comprising: a patient with one hand grip or hand sprayer, a nebulizer nozzle into the mouth tightly shut and, during inhalation nebulizer starts breathing cycle. 在整个疗程中患者都被指导进行“正常呼吸”直至它们达到止痛的效果。 Throughout the course of the patients were instructed to carry out "normal breath" until they achieve analgesic effect.

监测患者的任何不良反应,包括呼吸速率的改变和缺氧。 Monitoring the patient for any adverse reactions, including changes in respiratory rate and hypoxia. 患者还被要求在自我施加喷雾状药物之前和之后将他们的疼痛水平描述为“无”、“轻微”、“中等”或“严重”,以及初次经历突破性疼痛的时间。 Patients were also asked to describe their pain levels before the self-imposed and after nebulized drugs to "none", "mild", "moderate" or "severe", and the first time experiencing breakthrough pain.

在此“单剂量”或“单治疗期”研究期间,所有患者都可在他们经历突破性疼痛的任何时候获取常规的止痛药物(静脉注射吗啡)。 During this period the "single dose" "single treatment period" or study, all patients can get routine pain medication (morphine intravenously) at any time they experienced breakthrough pain.

PACU中大部分术后患者(80%)适合用喷雾状药物进行治疗并报告“中等”(46%)至“严重”(34%)的术后疼痛。 Most postoperative patients (80%) PACU suitable for treatment with the medicament and sprayed report "moderate" (46%) to "severe" (34%) of postoperative pain.

95%的适合治疗患者在喷雾开始后不久就成功利用本研究药物迅速获得了明显止痛效果,并且能够经停止喷雾而自我滴定用药至达到足够/有效的止痛效果。 95% of patients suitable for treatment after spraying began shortly successfully exploited this study, the drug quickly gained a significant analgesic effect, and can stop spraying by self-medication titrated to achieve adequate / effective analgesic effect. 达到最初可察觉的止痛作用的平均时间是5.2分钟。 Achieve analgesic effect initially perceived the average time was 5.2 minutes. 达到有效止痛作用的时间是自我施药22.8分钟。 Achieve an effective analgesic effect of time of self-administration is 22.8 minutes. 在充分/有效的止痛时,5%报告无疼痛,78%报告“轻微”疼痛,而12%报告他们的疼痛从“严重”降低至“中等”。 When the full / effective analgesic, 5% reported no pain and 78% reported "mild" pain, while 12% reported that their pain was reduced from "severe" to "moderate." 监测实现足够/有效止痛的患者的突破性疼痛。 Monitoring the achievement of breakthrough pain enough / effective pain patients. 在12小时研究期间17%的患者不再要求更多的阿片样物质。 During the 12 hours of study 17% of patients no longer requires more opioid. 83%的患者在完成吸入后平均超过2小时体验到突破性疼痛并要求静脉注射吗啡。 83% of patients experienced an average of more than 2 hours and breakthrough pain in claim intravenous morphine after the completion of inhalation.

在治疗的患者中,有95%在自我施加喷雾状药物后报告有效的止痛,无人经历毒性作用。 In treated patients, 95 percent reported after application of nebulized medicament effective self pain, experienced no toxicity. 84%的患者在达到满意的止痛时停止自我施药。 84% of patients stop spraying when the self-satisfactory pain. 11%的患者在感受到(并报告)副作用(困倦或恶心)后不久(3分钟)停止自我施药。 11% of patients experience (and report) shortly after side effects (drowsiness or nausea) (3 minutes) stop self-administration.

这些结果表明患者可利用适当的吸入药物制剂的止痛作用和副作用在避免毒性作用的同时递送治疗有效量的止痛剂。 These results indicate that patients may inhaled drug formulations with an appropriate analgesic effect and side effects while avoiding the toxic effects of delivery of a therapeutically effective amount of the analgesic.

实施例8:测试多种制剂的最佳药物递送下面的实施例显示了适用于本发明的多种阿片样物质制剂。 Example 8: Testing more optimal pharmaceutical formulation delivered following examples show various opioid formulations suitable for use in the present invention. 这些制剂是以药物成分的已知药动学和药效学特性、它们与芬太尼相比的已知等价效力、及上文描述的临床研究结果为基础的。 These formulations are known pharmacokinetic and pharmacodynamic properties of the pharmaceutical composition, which compared to the known potency of fentanyl equivalents, and clinical findings described above based.

含有阿片样物质混合物的制剂是依照下文显示的配方表制备的: Opioid formulation contained in the mixture is prepared according to the following table shows the formulation:

以上描述仅仅作为实例,而不应当理解为限制由所附权利要求定义的发明范围。 The above description of example only, and should not be construed as limiting the appended claims is defined by the scope of the invention.

Claims (106)

  1. 1.阿片样物质制剂,用于向患者提供止痛并避免中毒的方法;所述方法包括用肺部药物递送装置连续吸入该制剂用来止痛,并在达到满意的止痛效果或副作用发作时停止吸入药物;所述肺部药物递送装置适于以有效速率在肺内沉积制剂颗粒;所述制剂包含有效量的至少一种快速起效的阿片样物质和至少一种持续作用的阿片样物质,以及药用可接受载体,选择每种阿片样物质的浓度和类型,使得在吸入期间在副作用发作之前实现止痛,且所述副作用发作出现在毒性发作之前,并使得最大阿片样物质血浆浓度不达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒。 1. The opioid formulation to provide analgesia to a patient and to avoid poisoning of the method; the method comprises pulmonary drug delivery device of the inhalation formulation for continuous pain, and stopping inhalation when satisfactory analgesia is achieved or the onset of side effects drugs; the pulmonary drug delivery device adapted for deposition in the lungs at an effective rate of particles of the formulation; said formulation comprising an effective amount of at least one rapid-onset opioid and at least one sustained-effect opioid, and a pharmaceutically acceptable carrier, the concentration and type of each opioid, so as to achieve analgesia prior to the onset of side effects during inhalation, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum opioid plasma concentration does not reach toxic level, thereby to stop by inhalation to avoid toxicity in patients with the onset of said side effect.
  2. 2.权利要求1的制剂,其中选择每种阿片样物质的浓度和类型,使得副作用发作时的最大阿片样物质血浆浓度不低于最大阿片样物质血浆浓度的66%。 2. The formulation of claim 1, wherein the concentration and type of each opioid, so that the maximum opioid plasma concentration at the onset of a side of not less than 66% of the maximum plasma concentration of opioid.
  3. 3.权利要求2的制剂,其中选择每种阿片样物质的浓度和类型,使得副作用发作时的最大阿片样物质血浆浓度不低于最大阿片样物质血浆浓度的80%。 3. A formulation as claimed in claim 2, wherein the concentration and type of each opioid, so that the maximum opioid plasma concentration at the onset of a side no less than 80% of the maximum plasma concentration of opioid.
  4. 4.权利要求1至3中任一项的制剂,其中至少一种快速起效阿片样物质选自芬太尼、阿芬太尼、舒芬太尼和瑞芬太尼。 The formulation according to claim 3, wherein the at least one rapid-onset opioid is chosen from fentanyl, alfentanil, sufentanil and remifentanil.
  5. 5.权利要求4的制剂,其中至少一种快速起效的阿片样物质选自芬太尼和阿芬太尼。 5. The formulation of claim 4, wherein the at least one rapid-onset opioid is chosen from fentanyl and alfentanil.
  6. 6.权利要求1至5中任一项的制剂,其中的至少一种持续作用的阿片样物质选自吗啡、吗啡-6-葡糖酸苷、美沙酮、氢吗啡酮、度冷丁、包裹于生物相容载体中延迟药物在肺表面释放的阿片样物质以及脂质体包裹的阿片样物质。 1-5 formulation according to any one of claim 1, wherein the at least one sustained-effect opioid is chosen from morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, an opioid encapsulated in biological pulmonary drug released from the surface of the opioid and the liposomally encapsulated opioid compatible carrier delay.
  7. 7.权利要求6的制剂,其中脂质体包裹的阿片样物质是脂质体包裹的芬太尼。 7. The formulation of claim 6, wherein the liposomally encapsulated opioid is liposomally encapsulated fentanyl.
  8. 8.权利要求7的制剂,其中至少一种持续作用的阿片样物质选自吗啡和脂质体包裹的芬太尼。 Formulation 7, wherein the opioid is chosen from morphine and liposomally encapsulated fentanyl at least one sustained-effect claim.
  9. 9.权利要求1至8中任一项的制剂,其中制剂中的阿片样物质由游离的芬太尼和脂质体包裹的芬太尼组成。 9. The formulation according to claim 8, wherein the opioid from the formulation of free fentanyl and liposomally encapsulated fentanyl.
  10. 10.权利要求9的阿片样物质制剂,其中总阿片样物质浓度为250-1500mcg/ml。 10. The opioid formulation of claim 9, wherein the total opioid concentration 250-1500mcg / ml.
  11. 11.权利要求10的制剂,其中游离的芬太尼与脂质体包裹的芬太尼的浓度比例大约为2∶3。 11. The formulation of claim 10, wherein the ratio of concentration of free fentanyl to liposomally encapsulated fentanyl is from 2 approximately.
  12. 12.权利要求10或11的阿片样物质制剂,其含有浓度为100-400mcg/ml的游离芬太尼。 12. The opioid formulation of claim 10 or 11, which contains a concentration of 100 to 400 mcg / ml of free fentanyl.
  13. 13.权利要求10、11或12的阿片样物质制剂,其含有浓度为250-750mcg/ml的脂质体包裹的芬太尼。 13. The opioid formulation of claim 10, 11 or 12, which contains a concentration of liposomes 250-750mcg / ml of encapsulated fentanyl.
  14. 14.权利要求10至13中任一项的阿片样物质制剂,其中总阿片样物质浓度大约为500mcg/ml,游离的芬太尼浓度大约为200mcg/ml,而脂质体包裹的芬太尼浓度大约为300mcg/ml。 The opioid formulation of any one of 10 to 13 and the liposomally encapsulated fentanyl to claim 14, wherein the total opioid concentration is about 500mcg / ml, the free fentanyl concentration is about 200mcg / ml, a concentration of about 300mcg / ml.
  15. 15.权利要求1至9中任一项的制剂,其含有两种或更多种不同的阿片样物质,不包括其中仅有的两种阿片样物质是游离的芬太尼和脂质体包裹的芬太尼的制剂。 15. A formulation according to claim 9, which contains two or more different opioids, excluding a formulation wherein the only two opioids are free fentanyl and liposomally encapsulated in fentanyl preparations.
  16. 16.权利要求1至15中任一项的制剂,其中所述制剂中的阿片样物质由阿芬太尼和吗啡组成。 16. A formulation according to claim 15, wherein the opioids in the formulation consist of alfentanil and morphine composition.
  17. 17.权利要求16的制剂,其含有浓度为300-6700mcg/ml的阿芬太尼。 17. The formulation as claimed in claim 16, which contains a concentration of 300-6700mcg / ml alfentanil.
  18. 18.权利要求16或17的制剂,其含有浓度为650-13350mcg/ml的吗啡。 18. The formulation of claim 16 or claim 17, which contains a concentration of morphine 650-13350mcg / ml.
  19. 19.施用阿片样物质制剂使患者止痛同时避免中毒的方法,包括以下步骤:用适于以有效速率将制剂颗粒递送入肺的肺部药物递送装置连续吸入制剂以止痛;和在达到满意的止痛效果或副作用发作时停止吸入;其中制剂包含有效量的至少一种快速起效的阿片样物质和药用可接受载体;选择每种阿片样物质的浓度和类型以及递送颗粒的有效速率,使得在吸入期间在所述副作用发作之前达到止痛效果,且所述副作用发作出现在毒性发作之前,并使得最大阿片样物质血浆浓度不达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒。 19. The opioid formulation is administered analgesia to a patient while avoiding toxicity, comprising the steps of: at an effective rate with the formulation is adapted to deliver the particles into the lungs of pulmonary drug delivery device to continuously inhalation formulation pain; pain and a satisfactory or side effect the onset of inhalation stopped; wherein the formulation comprises an effective amount of at least one rapid-onset opioid and a pharmaceutically acceptable carrier; the concentration and type of each opioid and effective rate of delivery of particles, so that during inhalation, prior to the onset of a side analgesic effect, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum opioid plasma concentration does not reach toxic levels, whereby the onset of said side effect by the patient to terminate inhalation to avoid poisoning.
  20. 20.权利要求19的方法,其中通过肺部药物递送装置以1-5微米的质量中值空气动力学直径分配制剂。 20. The method of claim 19, wherein the air mass median aerodynamic diameter of 1-5 micrometers formulation is dispensed by the pulmonary drug delivery device.
  21. 21.权利要求20的方法,其中通过肺部药物递送装置以1-3微米的质量中值空气动力学直径分配制剂。 21. The method of claim 20, wherein the air mass median aerodynamic diameter of 1-3 microns formulation is dispensed by the pulmonary drug delivery device.
  22. 22.权利要求21的方法,其中通过肺部药物递送装置以1.5-2微米的质量中值空气动力学直径分配制剂。 22. The method of claim 21, wherein the air mass median aerodynamic diameter of 1.5 microns formulation is dispensed by the pulmonary drug delivery device.
  23. 23.权利要求19至22中任一项的方法,其中选择每种阿片样物质的浓度和类型,使得副作用发作时的最大阿片样物质血浆浓度不低于最大阿片样物质血浆浓度的66%。 19 to 22 The method of any one of claims 23, wherein the concentration and type of each opioid, so that the maximum opioid plasma concentration at the onset of a side of not less than 66% of the maximum plasma concentration of opioid.
  24. 24.权利要求19至23中任一项的方法,其中选择每种阿片样物质的浓度和类型,使得副作用发作时的最大阿片样物质血浆浓度不低于最大阿片样物质血浆浓度的80%。 19 to 23 The method of any one of claims 24, wherein the concentration and type of each opioid, so that the maximum opioid plasma concentration at the onset of a side no less than 80% of the maximum plasma concentration of opioid.
  25. 25.权利要求19至24中任一项的方法,其中至少一种快速起效的阿片样物质选自芬太尼、阿芬太尼、舒芬太尼和瑞芬太尼。 19 to 24 The method of any one of claims 25, wherein the at least one rapid-onset opioid is chosen from fentanyl, alfentanil, sufentanil and remifentanil.
  26. 26.权利要求25的方法,其中至少一种快速起效的阿片样物质选自芬太尼和阿芬太尼。 26. The method of claim 25, wherein the at least one rapid-onset opioid is chosen from fentanyl and alfentanil.
  27. 27.权利要求19至26中任一项的方法,进一步包含有效量的至少一种持续作用的阿片样物质以持续缓解,其中选择每种阿片样物质的浓度和类型,使得在吸入期间在阿片样物质副作用发作之前达到止痛效果,且所述副作用发作出现在毒性发作之前,并使得最大总阿片样物质血浆浓度不达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒。 19-26 The method of any one of claims 27, further comprising an effective amount of at least one sustained-effect opioid sustained relief, wherein the concentration and type of each opioid is such that during inhalation of opioid like substance before the onset of side effects to achieve the analgesic effect, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum total opioid plasma concentration does not reach toxic levels, whereby the onset of said side effect by the patient to terminate inhalation to avoid toxicity .
  28. 28.权利要求27的方法,其中至少一种持续作用的阿片样物质选自吗啡、吗啡-6-葡糖酸苷、美沙酮、氢吗啡酮、度冷丁、包裹于生物相容载体中延迟药物在肺表面释放的阿片样物质以及脂质体包裹的阿片样物质。 28. The method of claim 27, wherein the at least one sustained-effect opioid is chosen from morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, an opioid encapsulated in a biocompatible carrier that delays drug lung surface release opioid and liposomally encapsulated opioid.
  29. 29.权利要求28的方法,其中脂质体包裹的阿片样物质是脂质体包裹的芬太尼。 29. The method of claim 28, wherein the liposomally encapsulated opioid is liposomally encapsulated fentanyl.
  30. 30.权利要求27、28或29的方法,其中至少一种持续作用的阿片样物质选自吗啡和脂质体包裹的芬太尼。 The method of 27, 28 or 29 wherein the opioid is chosen from morphine and liposomally encapsulated fentanyl at least one sustained-effect as claimed in claim 30.,.
  31. 31.权利要求27至30中任一项的方法,其中制剂中的阿片样物质由游离的芬太尼和脂质体包裹的芬太尼组成。 27 to 30 The method of any one of claims 31, wherein the opioids in the formulation of free fentanyl and liposomally encapsulated fentanyl.
  32. 32.权利要求31的方法,其中游离的芬太尼与脂质体包裹的芬太尼浓度比例为1∶5-2∶1。 32. The method of claim 31, wherein the ratio of concentration of free fentanyl to liposomally encapsulated fentanyl is 1:5-2:1.
  33. 33.权利要求32的方法,其中游离的芬太尼和脂质体包裹的芬太尼的浓度比例约为2∶3。 33. The method of claim 32, wherein the ratio of concentration of free fentanyl and liposomally encapsulated fentanyl is about 2:3.
  34. 34.权利要求31至33中任一项的方法,其中总阿片样物质浓度为250-1500mcg/ml。 The method of any one of claims 31 to 33 34., wherein the total opioid concentration 250-1500mcg / ml.
  35. 35.权利要求19至33中任一项的方法,其中制剂含有浓度为100-400mcg/ml的游离的芬太尼。 19-33 The method of any one of claims 35, wherein the formulation contains a concentration of free 100-400mcg / ml fentanyl.
  36. 36.权利要求19至33中任一项的方法,其中制剂含有浓度为250-750mcg/ml脂质体包裹的芬太尼。 19-33 The method of any one of claims 36, wherein the formulation contains a concentration of 250-750mcg / ml liposomally encapsulated fentanyl.
  37. 37.权利要求19至36中任一项的方法,其中总阿片样物质浓度约为500mcg/ml,游离芬太尼浓度约为200mcg/ml而脂质体包裹的芬太尼浓度约为300mcg/ml。 The method of any one of 19 to claim 36, wherein the total opioid concentration is about 500mcg / ml, the free fentanyl concentration is about 200mcg / ml and the liposomally encapsulated fentanyl concentration is about 300mcg / ml.
  38. 38.权利要求31至37中任一项的方法,其中吸入期间游离态芬太尼以4-50mcg/分钟的速度沉积于肺部。 31 to 37 The method of any one of claims 38, wherein the rate of free fentanyl 4-50mcg / min deposited in the lungs during inhalation.
  39. 39.权利要求38的方法,其中吸入期间游离态芬太尼以10-20mcg/分钟的速度沉积于肺部。 39. The method of claim 38, wherein during inhalation of free fentanyl 10-20mcg / min deposited in the lungs.
  40. 40.权利要求39的方法,其中吸入期间游离态芬太尼以约15mcg/分钟的速度沉积于肺部。 40. The method of claim 39, wherein during inhalation. Of free fentanyl from about 15mcg / min deposited in the lungs.
  41. 41.权利要求31至37中任一项的方法,其中吸入期间脂质体包裹的芬太尼以5-150mcg/分钟的速度沉积于肺部。 31 to 37 The method of any one of claims 41, wherein the liposomally encapsulated fentanyl during inhalation 5-150mcg / min deposited in the lungs.
  42. 42.权利要求41的方法,其中吸入期间脂质体包裹的芬太尼以10-90mcg/分钟的速度沉积于肺部。 42. The method of claim 41, wherein the liposomally encapsulated fentanyl during inhalation 10-90mcg / min deposited in the lungs.
  43. 43.权利要求42的方法,其中吸入期间脂质体包裹的芬太尼以15-60mcg/分钟的速度沉积于肺部。 43. The method of claim 42, wherein the liposomally encapsulated fentanyl during inhalation 15-60mcg / min deposited in the lungs.
  44. 44.权利要求43的方法,其中吸入期间脂质体包裹的芬太尼以20-45mcg/分钟的速度沉积于肺部。 44. The method of claim 43, wherein the liposomally encapsulated fentanyl during inhalation 20-45mcg / min deposited in the lungs.
  45. 45.权利要求19至44中任一项的方法,其中吸入期间总阿片样物质以5-100mcg/分钟的速度沉积于肺部。 19-44 The method of any one of claims 45, wherein during inhalation of total opioid at a speed 5-100mcg / min deposited in the lungs.
  46. 46.权利要求45的方法,其中吸入期间总阿片样物质以10-40mcg/分钟的速度沉积于肺部。 46. ​​The method of claim 45, wherein during inhalation of total opioid at a speed 10-40mcg / min deposited in the lungs.
  47. 47.权利要求46的方法,其中吸入期间总阿片样物质以30-35mcg/分钟的速度沉积于肺部。 47. The method of claim 46, wherein during inhalation of total opioid at a speed 30-35mcg / min deposited in the lungs.
  48. 48.权利要求19至30中任一项的方法,其中制剂包含两种或更多种不同的阿片样物质,不包括其中仅有的两种阿片样物质是游离的芬太尼和脂质体包裹的芬太尼的制剂。 19-30 The method of any one of claims 48, wherein the formulation comprises two or more different opioids, excluding a formulation wherein the only two opioids are free fentanyl and liposomally fentanyl formulation package.
  49. 49.权利要求48的方法,其中制剂中的阿片样物质由阿芬太尼和吗啡组成。 49. The method of claim 48, wherein the opioids in the formulation consist of alfentanil and morphine composition.
  50. 50.权利要求49的方法,其中制剂含有浓度为300-6700mcg/ml的阿芬太尼。 50. The method of claim 49, wherein the formulation contains a concentration of 300-6700mcg / ml alfentanil.
  51. 51.权利要求49或50的方法,其中吸入期间阿芬太尼以100-500mcg/分钟的速度沉积于肺部。 51. The method of claim 49 or claim 50, wherein during inhalation alfentanil speed 100-500mcg / min deposited in the lungs.
  52. 52.权利要求51的方法,其中吸入期间阿芬太尼以约250mcg/分钟的速度沉积于肺部。 52. The method of claim 51, wherein alfentanil during inhalation at a rate of about 250mcg / min deposited in the lungs.
  53. 53.权利要求49至52中任一项的方法,其中制剂含有浓度为650-13350mcg/ml的吗啡。 49-52 The method of any one of claims 53, wherein the formulation contains morphine concentration 650-13350mcg / ml.
  54. 54.权利要求49至53中任一项的方法,其中吸入期间吗啡以100-2000mcg/分钟的速度沉积于肺部。 The method of any one of 49 to 53 as claimed in claim 54., wherein a rate of morphine during inhalation 100-2000mcg / min deposited in the lungs.
  55. 55.权利要求54的方法,其中吸入期间吗啡以200-1000mcg/分钟的速度沉积于肺部。 55. The method of claim 54, wherein a rate of morphine during inhalation 200-1000mcg / min deposited in the lungs.
  56. 56.权利要求55的方法,其中吸入期间吗啡以约500mcg/分钟的速度沉积于肺部。 56. The method of claim 55, wherein during inhalation morphine at about 500mcg / min deposited in the lungs.
  57. 57.权利要求19至56中任一项的方法,其中经50至500次吸入进行施用。 19-56 The method of any one of claims 57, wherein 50 to 500 times by inhalation administered.
  58. 58.阿片样物质的副作用在防止阿片样物质中毒中的用途。 58. opioid side effects of opioid use in preventing the poisoning.
  59. 59.含有阿片样物质制剂用于使患者止痛的肺部药物递送装置,所述装置包括:含有根据权利要求1至18中任一项的制剂的容器;与容器连接的出口;与容器相连的手段,用于由有意识的患者努力驱动并以有效速率将所述制剂的颗粒通过所述出口分配入肺部,由此在吸入期间在阿片样物质副作用发作之前达到止痛效果,且所述副作用发作出现在毒性发作之前,并使得最大阿片样物质血浆浓度不达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒。 59. opioid analgesic formulation containing a patient for pulmonary drug delivery device, said apparatus comprising: a vessel containing 1 to 18 in the preparation of any one of claim; outlet coupled to the container; connected to the container means for a conscious patient effort and at an effective rate to drive the particles of the formulation dispensed into the lungs through the outlet, whereby during inhalation, analgesia is achieved before the onset of an opioid side effects, side effects and the hair before the onset of toxicity is now made, and so that the maximum opioid plasma concentration does not reach toxic levels, whereby the onset of said side effect by the patient to terminate inhalation to avoid toxicity.
  60. 60.含有阿片样物质制剂用于使患者止痛的肺部药物递送装置,所述装置包括:含有包括有效量的至少一种快速起效的阿片样物质和药用可接受载体的制剂的容器;与容器连接的出口;与容器相连的手段,用于将所述制剂的颗粒通过所述出口分配入肺部,所述手段需要有意识的患者努力驱动;其中选择每种阿片样物质的浓度和类型以及递送颗粒的有效速率,使得在吸入期间在阿片样物质副作用发作之前达到止痛效果,且所述副作用发作出现在毒性发作之前,并使得最大阿片样物质血浆浓度不达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒。 60. A formulation comprising an opioid analgesic for a patient's pulmonary drug delivery device, said apparatus comprising: a container containing a formulation acceptable carrier comprises an effective amount of at least one rapid-onset opioid and a pharmaceutically acceptable; an outlet coupled to the container; means associated with the container for the formulation particles into the lungs through the dispensing outlet, means a patient in need of a conscious effort driver; wherein the concentration and type of each opioid and a delivery rate of active particles, so that analgesia is achieved before the onset of an opioid side effect during inhalation, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum opioid plasma concentration does not reach toxic levels, whereby by the patient the onset of said side effect to terminate inhalation to avoid toxicity.
  61. 61.权利要求59或60的装置,其进一步包含递送速率控制手段,用于将制剂的分配速率限制在选定阈值之下。 61. The apparatus of claim 59 or 60, further comprising delivery rate controlling means for limiting the dispense rate below a selected threshold formulation.
  62. 62.权利要求59至61中任一项的装置,其中所述出口含有缝隙,患者必须紧闭嘴唇将其封住以分配制剂。 Device according 59 to claim 61, wherein said outlet comprising a slit, the patient must be closed lip seal to dispense the formulation.
  63. 63.权利要求59至61中任一项的装置,其中所述分配手段经是呼吸驱动的。 The device according to claim 63. 59-61, wherein said dispensing means is breath actuated through.
  64. 64.权利要求59至63中任一项的装置,其中所述颗粒具有1-5微米的质量中值空气动力学直径。 The device of any one of claims 59 to 63 64., wherein said particles have a value of the air mass aerodynamic diameter of 1-5 microns.
  65. 65.权利要求64的装置,其中所述颗粒具有1-3微米的质量中值空气动力学直径。 65. The apparatus of claim 64, wherein said particles have a value of the air mass aerodynamic diameter of 1-3 microns.
  66. 66.权利要求65的装置,其中所述颗粒具有1.5-2微米的质量中值空气动力学直径。 66. The apparatus as claimed in claim 65, wherein said particles have a value of the air mass aerodynamic diameter of 1.5 microns.
  67. 67.权利要求61至63中任一项的装置,其中所述用于分配颗粒的手段每次吸入分配0.2%-1%的制剂。 The device of any one of claims 61 to 63 67., wherein said means for dispensing particles per inhalation formulation of 0.2% to 1% distribution.
  68. 68.权利要求60至67中任一项的装置,其中选择每种阿片样物质的浓度和类型,使得副作用发作时的最大阿片样物质血浆浓度不低于最大阿片样物质血浆浓度的66%。 The device according to claim 68. 60-67, wherein the concentration and type of each opioid, so that the maximum opioid plasma concentration at the onset of a side of not less than 66% of the maximum plasma concentration of opioid.
  69. 69.权利要求68的装置,其中选择每种阿片样物质的浓度和类型,使得副作用发作时的最大阿片样物质血浆浓度不低于最大阿片样物质血浆浓度的80%。 69. The apparatus as claimed in claim 68, wherein the concentration and type of each opioid, so that the maximum opioid plasma concentration at the onset of a side no less than 80% of the maximum plasma concentration of opioid.
  70. 70.权利要求60至69中任一项的装置,其中至少一种快速起效的阿片样物质选自芬太尼、阿芬太尼、舒芬太尼和瑞芬太尼。 The device according to claim 70. 60-69, wherein the at least one rapid-onset opioid is chosen from fentanyl, alfentanil, sufentanil and remifentanil.
  71. 71.权利要求70的装置,其中至少一种快速起效的阿片样物质选自芬太尼和阿芬太尼。 71. The apparatus as claimed in claim 70, wherein the at least one rapid-onset opioid is chosen from fentanyl and alfentanil.
  72. 72.权利要求60至71中任一项的装置,其进一步包含有效量的至少一种持续作用的阿片样物质以提供持续缓解,其中选择制剂中的每种阿片样物质的浓度和类型,使得在吸入期间在阿片样物质副作用发作之前达到止痛效果,且所述副作用发作出现在毒性发作之前,并使得最大总阿片样物质血浆浓度不达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒。 The device according to claim 72. 60-71, which further comprises an effective amount of at least one sustained-effect opioid to provide sustained relief, wherein the concentration and type of each opioid in the formulation of the material, such that during inhalation, analgesia is achieved before the onset of an opioid side effect, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum total opioid plasma concentration does not reach toxic levels, whereby by the patient to the onset of said side effect stop inhalation to avoid toxicity.
  73. 73.权利要求72的装置,其中至少一种持续作用的阿片样物质选自吗啡、吗啡-6-葡糖酸苷、美沙酮、氢吗啡酮、度冷丁、包裹于生物相容载体中延迟药物在肺表面释放的阿片样物质以及脂质体包裹的阿片样物质。 73. The apparatus of claim 72, wherein the at least one sustained-effect opioid is chosen from morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, an opioid encapsulated in a biocompatible carrier that delays drug lung surface release opioid and liposomally encapsulated opioid.
  74. 74.权利要求73的装置,其中脂质体包裹的阿片样物质是脂质体包裹的芬太尼。 74. The apparatus as claimed in claim 73, wherein the liposomally encapsulated opioid is liposomally encapsulated fentanyl.
  75. 75.权利要求72、73或74的装置,其中至少一种持续作用的阿片样物质选自吗啡和脂质体包裹的芬太尼。 It means 72, 73 or 74 wherein the opioid is chosen from morphine and liposomally encapsulated fentanyl at least one sustained-effect as claimed in claim 75.,.
  76. 76.权利要求72至75中任一项的装置,其中制剂中的阿片样物质由游离的芬太尼和脂质体包裹的芬太尼组成。 75 in apparatus 72 to any one of claims 76, wherein the opioids in the formulation of free fentanyl and liposomally encapsulated fentanyl.
  77. 77.权利要求76的装置,其中游离的芬太尼与脂质体包裹的芬太尼浓度比例为1∶5-2∶1。 77. The apparatus of claim 76, wherein the ratio of concentration of free fentanyl to liposomally encapsulated fentanyl is 1:5-2:1.
  78. 78.权利要求77的装置,其中游离的芬太尼和脂质体包裹的芬太尼的浓度比例约为2∶3。 78. The apparatus of claim 77, wherein the ratio of concentration of free fentanyl and liposomally encapsulated fentanyl is about 2:3.
  79. 79.权利要求59至78中任一项的装置,其中总阿片样物质浓度为250-1500mcg/ml。 78 in apparatus 59 to any one of claims 79, wherein the total opioid concentration 250-1500mcg / ml.
  80. 80.权利要求59至79中任一项的装置,其中制剂含有浓度为100-400mcg/ml的游离芬太尼。 The device according to claim 80. 59-79, wherein the formulation contains a concentration of 100 to 400 mcg / ml of free fentanyl.
  81. 81.权利要求59至80中任一项的装置,其中制剂含有浓度为250-1500mcg/ml的脂质体包裹的芬太尼。 80 in apparatus 59 to any one of claim 81., wherein the liposome formulation having a concentration of 250-1500mcg / ml of encapsulated fentanyl.
  82. 82.权利要求59至81中任一项的装置,其中总阿片样物质浓度约为500mcg/ml,游离的芬太尼浓度约为200mcg/ml,并且脂质体包裹的芬太尼浓度约为300mcg/ml。 Fentanyl concentration apparatus according to any one of claims 59 to 81 82., wherein the total opioid concentration is about 500mcg / ml, the free fentanyl concentration is about 200mcg / ml, and the liposome is about 300mcg / ml.
  83. 83.权利要求76至82中任一项的装置,其中吸入期间游离芬太尼以4-50mcg/分钟的速度沉积于肺部。 82 in apparatus 76 to any one of claims 83, wherein the free fentanyl 4-50mcg / min deposited in the lungs during inhalation.
  84. 84.权利要求83的装置,其中吸入期间游离芬太尼以10-20mcg/分钟的速度沉积于肺部。 84. The apparatus of claim 83, wherein the free fentanyl 10-20mcg / min deposited in the lungs during inhalation.
  85. 85.权利要求84的装置,其中吸入期间游离芬太尼以约15mcg/分钟的速度沉积于肺部。 85. The apparatus as claimed in claim 84, wherein during inhalation. Of free fentanyl from about 15mcg / min deposited in the lungs.
  86. 86.权利要求76至85中任一项的装置,其中吸入期间脂质体包裹的芬太尼以5-150mcg/分钟的速度沉积于肺部。 76 to 85 apparatus according to claim 86., wherein the liposomally encapsulated fentanyl during inhalation 5-150mcg / min deposited in the lungs.
  87. 87.权利要求86的装置,其中吸入期间脂质体包裹的芬太尼以10-90mcg/分钟的速度沉积于肺部。 87. The apparatus of claim 86, wherein the liposomally encapsulated fentanyl during inhalation 10-90mcg / min deposited in the lungs.
  88. 88.权利要求87的装置,其中吸入期间脂质体包裹的芬太尼以15-60mcg/分钟的速度沉积于肺部。 88. The apparatus of claim 87, wherein the liposomally encapsulated fentanyl during inhalation 15-60mcg / min deposited in the lungs.
  89. 89.权利要求88的装置,其中吸入期间脂质体包裹的芬太尼以20-45mcg/分钟的速度沉积于肺部。 89. The apparatus of claim 88, wherein the liposomally encapsulated fentanyl during inhalation 20-45mcg / min deposited in the lungs.
  90. 90.权利要求59至89中任一项的装置,其中吸入期间总阿片样物质以5-100mcg/分钟的速度沉积于肺部。 59 90. The apparatus according to claim 89, wherein during inhalation of total opioid at a speed 5-100mcg / min deposited in the lungs.
  91. 91.权利要求90的装置,其中吸入期间总阿片样物质以10-40mcg/分钟的速度沉积于肺部。 91. The apparatus of claim 90, wherein during inhalation of total opioid at a speed 10-40mcg / min deposited in the lungs.
  92. 92.权利要求91的装置,其中吸入期间总阿片样物质以30-35mcg/分钟的速度沉积于肺部。 92. The apparatus of claim 91, wherein during inhalation of total opioid at a speed 30-35mcg / min deposited in the lungs.
  93. 93.权利要求59至75中任一项的装置,其中制剂包含两种或更多种不同的阿片样物质,不包括其中仅有的两种阿片样物质是游离的芬太尼和脂质体包裹的芬太尼的制剂。 93. The apparatus of any one of claims 59-75, wherein the formulation comprises two or more different opioids, excluding a formulation wherein the only two opioids are free fentanyl and liposomally fentanyl formulation package.
  94. 94.权利要求93的装置,其中制剂中的阿片样物质由阿芬太尼和吗啡组成。 94.93 apparatus as claimed in claim, wherein the opioids in the formulation consist of alfentanil and morphine composition.
  95. 95.权利要求94的装置,其中所述制剂含有浓度为300-6700mcg/ml阿芬太尼。 95. The apparatus of claim 94, wherein the formulation contains a concentration of 300-6700mcg / ml alfentanil.
  96. 96.权利要求94或95的装置,其中吸入期间阿芬太尼以100-500mcg/分钟的速度沉积于肺部。 96. The apparatus as claimed in claim 94 or 95, wherein during inhalation alfentanil speed 100-500mcg / min deposited in the lungs.
  97. 97.权利要求96的装置,其中吸入期间阿芬太尼以约250mcg/分钟的速度沉积于肺部。 97. The apparatus of claim 96, wherein alfentanil during inhalation at a rate of about 250mcg / min deposited in the lungs.
  98. 98.权利要求93至97中任一项的装置,其中制剂含有浓度为650-13350mcg/ml的吗啡。 93 98. The apparatus according to claim 97, wherein the formulation contains morphine concentration 650-13350mcg / ml.
  99. 99.权利要求93至98中任一项的装置,其中吸入期间吗啡以100-2000mcg/分钟的速度沉积于肺部。 93 99. The apparatus according to claim 98, wherein during inhalation at a rate of morphine 100-2000mcg / min deposited in the lungs.
  100. 100.权利要求99的装置,其中吸入期间吗啡以200-1000mcg/分钟的速度沉积于肺部。 100. The apparatus of claim 99, wherein a rate of morphine during inhalation 200-1000mcg / min deposited in the lungs.
  101. 101.权利要求100的装置,其中吸入期间吗啡以约500mcg/分钟的速度沉积于肺部。 101. The apparatus of claim 100, wherein morphine during inhalation rate of about 500mcg / min deposited in the lungs.
  102. 102.阿片样物质施用药盒,其包括:根据权利要求59至101中任一项的肺部药物递送装置;所述装置的使用说明,包括以下步骤:用所述装置连续吸入制剂,并在达到满意的止痛效果或副作用发作时停止吸入。 102. opioid administration kit, comprising: a pulmonary drug according to claim any one of 59 to 101 delivery means; instructions for use of the device, comprising the steps of: by means of the continuous inhalation formulation, and achieve satisfactory analgesia is achieved or side effects to stop the onset of inhalation.
  103. 103.阿片样物质施用药盒,其包括:包含有效量的至少一种快速起效的阿片样物质和药用可接受载体的制剂;肺部药物递送装置,其包含容器、与容器连接的出口、与容器连接的手段,其由有意识的患者努力驱动并以有效速率将其中所含制剂的颗粒通过所述出口分配入肺部,由此在吸入期间在阿片样物质副作用发作之前达到止痛效果,且所述副作用发作出现在毒性发作之前,并使得最大阿片样物质血浆浓度不达到中毒水平,由此可由患者利用所述副作用的发作来停止吸入以避免中毒;和所述装置的使用说明,包括以下步骤:用制剂填充该容器,用所述装置连续吸入制剂,并在达到满意的止痛效果或副作用发作时停止吸入。 103. opioid administration kit comprising: a pharmaceutical carrier comprising an effective amount of at least one rapid-onset opioid and a pharmaceutically acceptable; pulmonary drug delivery device comprising a container, an outlet connected to the vessel , and means connected to the container, which is driven by conscious patient effort and at an effective rate of particle formulation contained therein through the dispensing outlet into the lungs, thereby analgesia is achieved before the onset of an opioid side effect during inhalation, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum opioid plasma concentration does not reach toxic levels, whereby the onset of said side effect by the patient to terminate inhalation to avoid toxicity; and instructions for use of the device, comprising the steps of: filling the container with the formulation, by means of the continuous inhalation formulation, and stopping inhalation when satisfactory analgesia is achieved or the onset of side effects.
  104. 104.根据权利要求103的阿片样物质施用药盒,其中所述制剂包含有效量的至少一种持续作用的阿片样物质。 104. 103 opioid administration kit according to claim, wherein the formulation comprises an effective amount of at least one sustained-effect opioid.
  105. 105.用于使患者止痛的方法的阿片样物质制剂,包含:150-250mcg/ml游离的芬太尼;200-400mcg/ml脂质体包裹的芬太尼;和药用可接受载体。 105. The formulation opioid analgesic for a patient in a method comprising: 150-250mcg / ml of free fentanyl; 200-400mcg / ml liposomally encapsulated fentanyl; and a pharmaceutically acceptable carrier.
  106. 106.用于通过肺部施用途径使患者止痛的方法的阿片样物质制剂,包含:两种或更多种不同的阿片样物质,不包括其中仅有的两种阿片样物质是游离的芬太尼和脂质体包裹的芬太尼的制剂;药用可接受载体。 106. formulations for opioid analgesia to a patient by the pulmonary route of administration method, comprising: two or more different opioids, excluding a formulation wherein the only two opioids are free fentanyl Nigeria and liposomally encapsulated fentanyl formulation; pharmaceutically acceptable carrier.
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