JPH0225427A - Treatment of patient suffering from chronic pain and cough - Google Patents
Treatment of patient suffering from chronic pain and coughInfo
- Publication number
- JPH0225427A JPH0225427A JP17686688A JP17686688A JPH0225427A JP H0225427 A JPH0225427 A JP H0225427A JP 17686688 A JP17686688 A JP 17686688A JP 17686688 A JP17686688 A JP 17686688A JP H0225427 A JPH0225427 A JP H0225427A
- Authority
- JP
- Japan
- Prior art keywords
- antagonist
- opioid
- antitussive
- analgesic
- naloxone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 208000002193 Pain Diseases 0.000 title claims abstract description 32
- 208000000094 Chronic Pain Diseases 0.000 title claims abstract description 24
- 206010011224 Cough Diseases 0.000 title claims abstract description 20
- 208000013116 chronic cough Diseases 0.000 title claims abstract description 17
- 238000011282 treatment Methods 0.000 title claims abstract description 6
- 239000005557 antagonist Substances 0.000 claims abstract description 51
- 229960004127 naloxone Drugs 0.000 claims abstract description 28
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 claims abstract description 24
- 239000000014 opioid analgesic Substances 0.000 claims abstract description 24
- 230000000954 anitussive effect Effects 0.000 claims abstract description 23
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- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims abstract description 20
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 claims abstract description 18
- 230000000202 analgesic effect Effects 0.000 claims abstract description 16
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- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960001797 methadone Drugs 0.000 claims abstract description 14
- 239000003401 opiate antagonist Substances 0.000 claims abstract description 14
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims abstract description 13
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 claims abstract description 11
- 229960002085 oxycodone Drugs 0.000 claims abstract description 11
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims abstract description 10
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- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 claims abstract description 6
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- 208000018731 motor weakness Diseases 0.000 claims 1
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- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 description 3
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- XQXGQAPDQPAKRC-OHQBDVSPSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;(4r,4ar,7ar,12bs)-9-hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C XQXGQAPDQPAKRC-OHQBDVSPSA-N 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
- HLMSIZPQBSYUNL-IPOQPSJVSA-N Noroxymorphone Chemical group O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4 HLMSIZPQBSYUNL-IPOQPSJVSA-N 0.000 description 1
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Abstract
Description
【発明の詳細な説明】
本発明は腸の運動異常を誘発することなく慢性痛あるい
は慢性咳にかかった患者を治療する方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method of treating patients suffering from chronic pain or chronic cough without inducing intestinal dysmotility.
重症の慢性痛あるいは慢性咳にかかった患者の治療は多
くの重大な臨床的むずかしさを示す。モルヒネ、メタド
ン、コデイン、メペリジンおよびオキシコドンのような
麻薬あるいはオピオイド鎮痛剤は、例えば進行性癌、肺
疾患、変性関節疾患および慢性腹痛にかかっている患者
のような患者にしばしば投与される。しかしながら、長
期に及ぶオピオ“イド投与の望ましくない副作用のほか
に、長期作用のオピオイド鎮痛剤の慢性的使用は重症の
便秘や腸運動減弱の他の症状をもたらすことはよく知ら
れている。慢性的な麻薬投与の便秘作用に対する耐性が
いつかは発展することは信じられているけれども、これ
は極端にゆっくりと発展する。実際、耐性の発展は、限
定的な時間因子のだめあるいは鎮痛剤の量は耐性がその
鎮痛効果に対して発展するにつれて普通は増やさねばな
らないので、年取った患者あるいは末期患者の場合には
あまり重大ではない。Treatment of patients with severe chronic pain or chronic cough presents many significant clinical challenges. Narcotic or opioid painkillers such as morphine, methadone, codeine, meperidine, and oxycodone are often administered to patients, such as those suffering from advanced cancer, lung disease, degenerative joint disease, and chronic abdominal pain. However, in addition to the undesirable side effects of long-term opioid administration, it is well known that chronic use of long-acting opioid analgesics can result in severe constipation and other symptoms of decreased intestinal motility. Although it is believed that tolerance to the constipating effects of narcotic administration will eventually develop, this develops extremely slowly; It is less critical in older or terminally ill patients, as tolerance usually has to increase as tolerance develops to its analgesic effects.
慢性痛あるいは慢性咳に対するオピオイド鎮痛剤投与に
より引き起こされる便秘および腸運動減弱の他の症状は
患者にとって不快に覆るたりてなく、治療プログラムや
患者の根元にある症状を複雑にすることがある。実際に
、慢性便秘は心臓病患者や老人患者にとっては新たな健
康の危険を弓き起こすことがある。Constipation and other symptoms of reduced bowel motility caused by the administration of opioid analgesics for chronic pain or chronic cough can be uncomfortable for the patient and can complicate the treatment program and the patient's underlying symptoms. In fact, chronic constipation can pose new health risks for heart patients and elderly patients.
長期に及ぶオピオイド鎮痛療法を受けた患者の便秘を緩
解する従来の方法は各種の緩下剤、下剤。Traditional methods of relieving constipation in patients receiving long-term opioid pain therapy include various laxatives and laxatives.
便軟化剤および潤滑剤の投与、食事の調整等を含む。あ
る場合には、便秘によって引き起こされる不快感や腸破
裂の潜在的危険性は痛みの治療における制限因子となる
こともあり、また鎮痛剤の用量は与えられたレベルで一
定に保持されるかあるいは賜の固有運動性を改善するた
めには減量しな【プればならないこともある。Includes administration of stool softeners and lubricants, dietary adjustments, etc. In some cases, the discomfort caused by constipation and the potential risk of bowel rupture may be limiting factors in the treatment of pain, and the dose of analgesic may be held constant at a given level or You may have to lose weight to improve your proprioceptive mobility.
経口投与に対して重大な全身作用をもつある種のＡビオ
イド拮抗薬がオピオイド作用物質の長期投与によって誘
発される腸運動減弱に反作用づるために用いられる。勿
論、実用化づるためには、鎮痛剤あるいは鎮咳剤に対す
る補助薬として経口投与されるこのような拮抗薬は痛み
を軽減したりあるいは咳を減退させるために投与される
オピオイド作用物質の鎮痛あるいは鎮咳効果を実質的に
妨害してはならない。このように、米国特許第４１７６
．１８６号においては、ノルオキシモルホンの第四級誘
導体を構成する化合物族はその鎮痛活性を妨害Ｊること
なく麻薬性鎮痛剤の腸固有運動阻害性副作用を予防また
は軽減するのに有用であることが明らかにされている。Certain A bioid antagonists, which have significant systemic effects upon oral administration, are used to counteract the reduced intestinal motility induced by long-term administration of opioid agonists. Of course, for practical use, such antagonists, administered orally as adjuncts to analgesics or antitussives, would have to overcome the analgesic or antitussive effects of opioid agonists administered to reduce pain or reduce cough. shall not be substantially interfered with. Thus, U.S. Patent No. 4176
．． No. 186, a family of compounds comprising quaternary derivatives of noroxymorphone are useful for preventing or reducing the intestinal motility inhibiting side effects of narcotic analgesics without interfering with their analgesic activity. It has been made clear that
米国特許第４，１７６．１８６号に発表されている化合
物おＪ：び慢性痛患者の便秘の問題を軽減するために前
記のにうに示唆された同類の薬物は多くの欠点をもつ。Compound J, disclosed in US Pat. No. 4,176,186, and similar drugs suggested above for alleviating the problem of constipation in patients with chronic pain, have a number of drawbacks.
このような物質は欠陥−脳障壁を交叉せず、従って、脳
を通じて調停されるオピオイド剤のこの鎮痛効果を実質
的に妨害しないけれども、前記で示唆された拮抗薬はを
髄、末梢知覚システム、 ＩＩ’！下垂体および基底視
床下部を通じて調停される鎮痛作用を十分に妨害づると
考えられ、これらの全てが重要なオピオイドリセプタを
含むと信じられる。ざらに、第四級拮抗薬は消化管リセ
ブタを含むオピオイドリセプタに対して親和力が弱く、
麻薬による腸運動性減弱に反作用するのには効果的では
ない。さらに、前記の第四級拮抗化合物は容認できない
ほどの高い毒性をもつことが認められており、そのため
に慢性痛患者に長期投与することは特に不適切とされて
いる。第四級化合物を用いる慢性の痛みあるいは咳をも
つ患者の可能性のあるあるいは満足すべき方法は今だに
発表されていない。Although such substances do not cross the defect-brain barrier and therefore do not substantially interfere with this analgesic effect of opioids mediated through the brain, the antagonists suggested above do not cross the medullary, peripheral sensory systems, II'! It is thought to be sufficient to interfere with analgesic effects mediated through the pituitary gland and basal hypothalamus, all of which are believed to contain important opioid receptors. In general, quaternary antagonists have a weak affinity for opioid receptors, including gastrointestinal receptors.
It is not effective in counteracting the decrease in intestinal motility caused by narcotics. Furthermore, the quaternary antagonist compounds described above have been found to have unacceptably high toxicity, making them particularly inappropriate for long-term administration to chronic pain patients. No potential or satisfactory methods for treating patients with chronic pain or cough using quaternary compounds have yet been published.
簡単に言うと、オピオイド療法を受【プている慢性痛あ
るいは慢性咳患者の腸運動性減弱の重症の合併症を軽減
する安全で、有効な、実用的方法は、このような方法が
長い間臨床的に必要とされてきだにもかかわらず、これ
まで開発されていない。In short, these methods have long been available as safe, effective, and practical ways to reduce the severe complications of reduced intestinal motility in patients with chronic pain or chronic cough receiving opioid therapy. Despite the clinical need, it has not been developed to date.
膜固有運動性の障害を誘発または悪化することなく慢性
痛あるいは慢性咳患者の症状を軽減づ゛る安全で、有効
な方法を提供づることが本発明の目的である。It is an object of the present invention to provide a safe and effective method for alleviating the symptoms of chronic pain or chronic cough without inducing or exacerbating disorders of membrane proper motility.
前記のように長期のオピオイド療法を必要とする患者に
適した方法を提供することが本発明の別の目的である。It is another object of the present invention to provide a method suitable for patients requiring long-term opioid therapy as described above.
便秘や他の賜運動減弱の症状を予防および軽減するため
にその痛みまたは咳のための投薬に付随して慢性痛また
は慢性咳患者に薬物を投与することから成る前記のよう
な方法を提供することが本発明のさらにその上の目的で
ある。A method as described above comprising administering a drug to a patient with chronic pain or chronic cough in conjunction with medication for the pain or cough to prevent and alleviate constipation and other symptoms of hypokinesia. It is a further object of the present invention.
本発明のなお別の目的は、鎮痛または鎮咳剤投薬に付随
して投与される薬物が後者の鎮痛Ｊ：たは鎮咳作用を重
大に減少または損なわないところの前記の方法を提供す
ることである。Yet another object of the invention is to provide such a method, wherein the drug administered concomitantly with an analgesic or antitussive medication does not significantly reduce or impair the analgesic or antitussive action of the latter.
本発明のなおその上の目的は、オピオイド鎮痛剤に対す
る補助薬どして投与される薬剤が軽［１的に投与するこ
とができ、低い毒性レベルと望ましくない副作用の低い
発現率を示すところの前記のような方法を提供すること
である。It is a still further object of the present invention to provide a drug that can be administered as an adjunct to opioid analgesics, be easily administered, and exhibit low toxicity levels and a low incidence of undesirable side effects. An object of the present invention is to provide a method as described above.
本発明のなお別の目的は、補助剤が経口的に投与された
場合全身的生物適合性が少ししがないかあるいは全くな
く、腸運動減弱を予防または軽減するのに有効なオピオ
イド拮抗剤から成るところの前記の方法を提供づること
である。Still another object of the invention is that the adjuvant comprises an opioid antagonist that has little or no systemic biocompatibility when administered orally and is effective in preventing or reducing intestinal motility impairment. An object of the present invention is to provide the aforementioned method.
前記の方法で使用するのに適した組成物を提供覆ること
が本発明のざらに進んだ目的である。It is a general object of the present invention to provide a composition suitable for use in the above method.
これらの目的およびその後に明らかになるであろう他の
目的と一致して、本発明は、簡単に言うと、慢性痛ある
いは慢性咳患者、例えば、進行性病、肺疾患あるいは進
行性、変性関節病態のある患者を便秘のような膜固有運
動性の疾患を誘発または悪化することなく治療づる方法
にある。主題の方法はオピオイド鎮痛剤あるいは鎮咳剤
の有効量と非経口的経路によって投与した場合に全身的
に生物適合的であるが、経口的に投与した場合には実質
的に非生物適合的であるオピオイド拮抗薬の組合ぼ投与
あるいは共投与から成る。適切なオピオイド鎮痛剤はモ
ルヒネ、メペリジン、オキシコドン、メタドン等を含む
。最も一般的に用いられるオピオイド鎮咳剤の中にはコ
デインとヒドロコドンがある。適当な拮抗薬の例はナロ
キソン。Consistent with these objects and others that may subsequently become apparent, the present invention briefly describes the use of chronic pain or chronic cough patients, such as those with progressive disease, pulmonary disease or progressive, degenerative joint pathology. There are ways to treat certain patients without inducing or exacerbating membrane propriomotion disorders such as constipation. The subject method provides an effective amount of an opioid analgesic or antitussive agent and an opioid that is systemically biocompatible when administered by a parenteral route, but substantially non-biocompatible when administered orally. It consists of combination administration or co-administration of antagonists. Suitable opioid analgesics include morphine, meperidine, oxycodone, methadone, and the like. Among the most commonly used opioid cough suppressants are codeine and hydrocodone. An example of a suitable antagonist is naloxone.
ナロキソン・グルクロニドおよびナルメフェン・グルク
ロニドを含む。Contains naloxone glucuronide and nalmefene glucuronide.
本発明によると、慢性痛あるいは慢性咳の患者はオピオ
イド鎮痛剤または鎮咳剤約１．５〜約１００■および適
当なオピオイド拮抗薬（下にさらに詳しく定義）約１１
ｎ９〜約１８■から成る１〜２用量ユッ］−を１日１〜
５回経口投経口受ける。この２つの薬物は錠剤、カプセ
ル剤、カプレット剤あるいは調製された経口溶液の形で
組成物中に組み合わせて投与されるか、あるいは水、ジ
コースまたは他の飲料のような適当な液体賦形薬中に投
与の時に一緒に溶かすか、懸濁される。この２つの薬物
はまた非同時的方法で共投与されるすなわち薬物の１つ
が投与され、そのｉｎ ｖｉｖｏ活性のある間に他の
薬物が投与される。According to the present invention, patients with chronic pain or chronic cough may be treated with an opioid analgesic or antitussive agent of about 1.5 to about 100 mg and a suitable opioid antagonist (defined in more detail below) about 11
1 to 2 doses consisting of 9 to about 18 ml per day
Received oral administration 5 times. The two drugs may be administered in combination in a composition in the form of a tablet, capsule, caplet or prepared oral solution, or in a suitable liquid vehicle such as water, dicose or other beverage. be dissolved or suspended together at the time of administration. The two drugs may also be co-administered in a non-simultaneous manner, ie, one of the drugs is administered and the other drug is administered during its in vivo activity.
本発明は麻薬単独の使用からくる腸運動減弱の開始を同
時に予防し、あるいは運動減弱を同時に軽減しながら、
慢性痛の患者あるいは慢性咳のある患者を長期にわたっ
て治療する方法に関する。The present invention simultaneously prevents the onset of decreased intestinal motility caused by the use of narcotics alone, or simultaneously alleviates decreased intestinal motility, and
Concerning a method for long-term treatment of patients with chronic pain or chronic cough.
これらの方法はオピオイド鎮痛剤または鎮咳剤の薬学的
に有効な量と活性型で全身的な生物適合性が少ししかな
いかまたは全くないオピオイド拮抗薬を組み合わせて経
口投与することから成り、従って、経口投与した時に実
質的に全身的な拮抗薬作用がない。These methods consist of the oral administration of a pharmaceutically effective amount of an opioid analgesic or antitussive in combination with an active form of an opioid antagonist with little or no systemic biocompatibility; There is virtually no systemic antagonistic effect when administered.
本発明の方法で使用されるオ゛ビオイド作用物質は全て
の既知の安全で、有効なオピオイド鎮痛剤、短期および
長期作用のオピオイド鎮痛剤、例えばモルヒネ、メペリ
ジン、オキシコドン、メタドン。Obioid agents used in the method of the invention include all known safe and effective opioid analgesics, both short- and long-acting opioid analgesics, such as morphine, meperidine, oxycodone, methadone.
ヒドロモルホン、コデイン、ヒドロコドンおよびプロポ
キシフェンを含む。主題の方法は単に作用物質と拮抗薬
の経口投与に関づるものであるから、選ばれたオピオイ
ド鎮咳剤または鎮咳剤は高度の経***性をもたねばなら
ず、経口投与に対して安全でな【プればならない。Contains hydromorphone, codeine, hydrocodone and propoxyphene. Since the subject method simply involves oral administration of agonist and antagonist, the opioid antitussive or antitussive agent chosen must have a high degree of oral activity and must not be safe for oral administration. Must be.
本発明の方法で使用づるのに適したオピオイド拮抗薬は
、下で時には゛適切なオピオイド拮抗薬″として考えら
れるが、経口的に投与した場合、全身的な拮抗薬作用が
わずかしかないか全くあってはならない。拮抗薬はここ
で指示されているようにオ゛ビオイド作用物質と組み合
わせて与えられる場合オピオイド作用物質の鎮痛作用を
中和あるいは実質的に打ち消すならばそれは余り価値は
ないので、低度の経口的全身作用が本発明で用いられる
オピオイド拮抗薬の必要な特性である。Opioid antagonists suitable for use in the methods of the invention, which are sometimes considered below as "suitable opioid antagonists," have little or no systemic antagonistic effect when administered orally. There should be no, since it is of little value if the antagonist neutralizes or substantially negates the analgesic effects of the opioid agonist when given in combination with the opioid agonist as directed herein. Low oral systemic effects are necessary properties of the opioid antagonists used in the present invention.
適当なオピオイド拮抗薬は一般に２つのタイプをもって
いる：
１、非経口的に投与した場合高度の拮抗作用を表づが、
経口投与された場合には実質的に代謝され（少なくとも
９５％）、全身的な拮抗作用を失う薬物。このような拮
抗薬は、例えばナロギソン（Ｎ−アリル−１４−ヒドロ
キシジヒドロノルモルフィノン）を含む。Suitable opioid antagonists are generally of two types: 1. exhibit a high degree of antagonistic action when administered parenterally;
Drugs that are substantially metabolized (at least 95%) and lose systemic antagonism when administered orally. Such antagonists include, for example, nalogison (N-allyl-14-hydroxydihydronormorphinone).
２、拮抗薬代謝産物、例えばナロギソン・グルクロニド
およびナルメフェン（６−メチレン６−デスオキシ−Ｎ
−シクロプロピルメチル−１４−ヒドロキシ・ジヒドロ
ノルモルフイン）グルクロニド、これらは不活性な代謝
産物あるいは非経口的に活性な拮抗薬である、の形であ
る薬物。2. Antagonist metabolites, such as nalogison glucuronide and nalmefene (6-methylene 6-desoxy-N
-cyclopropylmethyl-14-hydroxy dihydronormorphine) glucuronide, which are inactive metabolites or parenterally active antagonists.
経口投与した場合には生物適合性が乏しいある種のオピ
オイド拮抗薬は実質的に未変化の形で賜に達し、腸壁を
通じて門脈循環に吸収されるが、次いで速やかに代謝さ
れ、肝臓で不活性化されることが発見されている・・・
例えばナロキソンは肝臓でナロキソン・グルクロニドに
代謝され、これは全身的な拮抗薬活性は少ししかないか
全くない。Certain opioid antagonists, which have poor biocompatibility when administered orally, arrive essentially unchanged and are absorbed into the portal circulation through the intestinal wall, but are then rapidly metabolized and metabolized by the liver. It has been discovered that inactivation...
For example, naloxone is metabolized in the liver to naloxone glucuronide, which has little or no systemic antagonist activity.
なお、腸のあへん剤リセプタに達することによって、こ
れらの拮抗薬はオピオイド作用物質の胃腸管に対する運
動減弱誘発作用を遮断することがでさ、こうして長期の
麻酔性鎮痛薬療法を受りた患者の便秘の初まりを予防ま
たは症状を軽減することができ、オピオイド作用物質の
鎮痛作用を妨害または除去しない。Additionally, by reaching opiate receptors in the intestine, these antagonists are able to block the hypomotility-inducing effects of opioid agonists on the gastrointestinal tract, thus preventing patients receiving long-term narcotic analgesic therapy. can prevent the onset or alleviate the symptoms of constipation and do not interfere with or eliminate the analgesic effects of opioid agonists.
上で詳述されたグルクロニド代謝産物はまたオピオイド
鎮痛剤を投与された慢性痛患者の便秘の初まりを予防し
、そのひどさを減少させるが、それは腸壁の細菌活性ま
たは酵素の活性によって脱グルク］コニデー１〜され、
拮抗薬塩基、すなわちナロキソンおよびナルメフェン、
の形である程度まで腸壁に達づるからと考えられる。こ
のように、これらの代謝産物は経口投与された場合前薬
物として作用づると信じられる。ここで用いられている
ように、パ前薬物″というタームは１ｎｖｉｔｒｏ不活
性であるが、ｉｎ ｖｉｖｏでは少なくともある程度
までは薬学的に活性な形に変換される物質を表している
。The glucuronide metabolites detailed above also prevent the onset and reduce the severity of constipation in chronic pain patients receiving opioid analgesics, but it is not possible to deglucose it by bacterial or enzymatic activity in the intestinal wall. ] Coniday 1~,
antagonist bases, namely naloxone and nalmefene,
This is thought to be due to the fact that it reaches the intestinal wall to some extent in the form of It is thus believed that these metabolites act as pro-drugs when administered orally. As used herein, the term "predrug" refers to a substance that is inactive in vitro, but which is converted, at least to some extent, to a pharmaceutically active form in vivo.
我々の共同出願の米国特許第８２８．５３３号、 １９
８６年１２月１５日出願で、１９８４年１２月１０日出
願の米国特許第６８０．２３０号の継続であり、これは
１９８３年２月４日出願の米国特許第４６４．１１０号
の継続である、において我々はイディオパシーまたは自
然の便秘、すなわち、例えば麻薬作用物質の慢性投与に
よって起らない便秘、を緩解する場合のナロキソンおよ
び他の拮抗薬の利用性を発表した。我々はその特許の３
ページに、ここに発表された発明は麻薬のようなオピオ
イド作用物質の作用を中和するためにオピオイド拮抗薬
を使用することに関してはいないことを強調した。本発
明はオピオイド鎮痛剤のような麻薬作用物質の全身効果
を中和しないが、全身的な作用物質活性を遮断または妨
害しないで胃腸運動性に対する作用物質の腸レベルの作
用に反作用するために特定のオピオイド拮抗薬を使用す
ることに関する。さらに、本発明の方法は、ひどい便秘
の合併症により患者の不快感を増さず、あるいは根元的
な疾病を悪化させることなく、適当な鎮痛および鎮咳作
用を確保する痛みまたは咳のある患者の急性または慢性
治療の首尾一貫した方法を提供Ｊるためにオピオイド鎮
痛剤と鎮咳剤および適当な拮抗薬の詳細な用量範囲と割
合を提供する。Our joint application U.S. Pat. No. 828.533, 19
Filed Dec. 15, 1986, it is a continuation of U.S. Pat. No. 680.230, filed Dec. 10, 1984, which is a continuation of U.S. Pat. In , we published the utility of naloxone and other antagonists in relieving idiopathic or natural constipation, that is, constipation that is not caused, for example, by chronic administration of narcotic agents. We own the patent 3
Page emphasized that the invention announced herein is not directed to the use of opioid antagonists to counteract the effects of opioid agonists, such as narcotics. The present invention does not neutralize the systemic effects of narcotic agents such as opioid analgesics, but is specifically designed to counteract the intestinal-level effects of agents on gastrointestinal motility without blocking or interfering with systemic agent activity. Concerning the use of opioid antagonists. Furthermore, the method of the present invention provides a method for treating patients with pain or cough that ensures adequate analgesia and antitussive action without increasing the patient's discomfort due to complications of severe constipation or worsening the underlying disease. Detailed dose ranges and proportions of opioid analgesics and antitussives and appropriate antagonists are provided to provide a consistent method of acute or chronic treatment.
本発明の新しい方法に従って、慢性痛または慢性咳にか
かっている患者、例えば、進行性病、肺疾患、変性関節
疾患９重症の外傷からの回復中にある患者などはオピオ
イド作用物質を適当な拮抗薬の１あるいは２用量ユニツ
トを１日に１〜５回投与される。本発明に従って用いら
れるオピオイド鎮痛剤または鎮咳剤は、例としてモルヒ
ネ、メペリジン、オキシコドン、ヒドロモルホン、メタ
ドン、］デイン、ヒドロコドンおよびプロポキシフェン
のような長期間使用で安全かつ有効であることが認めら
れている短期および長期作用薬物が考えられる。In accordance with the new method of the present invention, patients suffering from chronic pain or chronic cough, such as patients with advanced disease, pulmonary disease, degenerative joint disease, or those recovering from severe trauma, can replace opioid agonists with a suitable antagonist. 1 or 2 dose units of 1 to 5 times per day. Opioid analgesics or antitussives used in accordance with the present invention include short-term drugs that have been found to be safe and effective for long-term use, such as, for example, morphine, meperidine, oxycodone, hydromorphone, methadone,]deine, hydrocodone, and propoxyphene. and long-acting drugs are considered.
オピオイド薬物の用量範囲は用量ユニット当り約１．５
から約１００ ｍｇであり、１または２ユニツトが１日
５回投与され、オピオイド作用物質の１日の用量範囲は
約１．５〜約ｉ、ｏｏｏｑとなる。次の表は特定のオピ
オイド鎮痛剤に対づ“る実証的な範囲であるニ
ア
−」−二丸−
ユニット当りの
オビオイ゛ 徂ノ男 ■モルヒネ
１０〜３０メペリジン ５
０へ・１５０オキシコドン ５〜１５ヒ
ドロモルホン １．５〜３
メタドン ５〜１５コデイン
４０〜８０プロポキシフエン ４
０〜８０本発明で使用される適当なオピオイド拮抗薬は
、前に考察したように、経口投与しても腸あへん剤リセ
プタに対してオピオイド作用物質の運動減弱誘発作用を
遮断するように作用することのできる全身的拮抗作用が
少ししかないか全くないものである。このような適切な
拮抗薬はナロキソンのような５％以下の程度が非代謝型
で胃腸管から吸収されるものを含む。さらに、全身作用
が少ししかないか全くない麻薬拮抗薬の代謝産物、例え
ばすロキソン・グルクロニドおよびナルメフエン・フル
クロニド、はまた前薬物として作用することから、本発
明の目的に適していると認められた。本発明で使用する
のに適したオピオイド拮抗薬に対する主な資格は、共投
与されたオピオイド作用物質の鎮痛効果を大きく減少す
ることなく腸運動性に対する不利なオピオイド作用に拮
抗することである。Dosage range for opioid drugs is approximately 1.5 per dose unit
to about 100 mg, administered in 1 or 2 units five times a day, resulting in a daily dose range of opioid agonist from about 1.5 to about i,oooq. The following table shows the empirical range for certain opioid analgesics.
10-30 meperidine 5
0 to 150 Oxycodone 5-15 Hydromorphone 1.5-3 Methadone 5-15 Codeine
40-80 propoxyphen 4
0-80 Suitable opioid antagonists for use in the present invention, as previously discussed, act to block the hypomotility-inducing effects of opioid agonists on intestinal opiate receptors even when administered orally. There is little or no systemic antagonism that can occur. Suitable such antagonists include those such as naloxone, which is non-metabolized to an extent less than 5% and is absorbed from the gastrointestinal tract. Additionally, metabolites of narcotic antagonists that have little or no systemic effect, such as loxone glucuronide and nalmefene flucuronide, have also been found suitable for the purposes of the present invention since they also act as pre-drugs. . The primary qualification for opioid antagonists suitable for use in the present invention is to antagonize the adverse opioid effects on intestinal motility without significantly reducing the analgesic effects of co-administered opioid agonists.
本発明に従って、慢性痛または慢性咳患者はオピオイド
鎮痛剤の各用量と一緒にナロキソンまたは他の適当な拮
抗薬の用量を１日１〜５回投与される。各用量は両薬物
から成る１以上の用量ユニットを含む。この２種の薬物
は、例として、従来の担体、結合剤、賦形剤、崩壊剤、
潤滑剤、甘味剤および他の薬学的に受容できる添加剤を
添加したカプセル剤１錠剤、カプレット剤、シロップ剤
。In accordance with the present invention, chronic pain or chronic cough patients are administered doses of naloxone or other suitable antagonist 1 to 5 times per day along with each dose of an opioid analgesic. Each dose contains one or more dose units of both drugs. These two drugs may include, for example, conventional carriers, binders, excipients, disintegrants,
Capsules 1 tablet, caplets, syrups with added lubricants, sweeteners and other pharmaceutically acceptable additives.
■リキシル剤などを含む薬学的に受容できる経口用量型
で固定した割合で組み合わせることができる。代りに、
オピオイド作用物質と拮抗物質の用量はより患者に受は
入れられやすくするために果汁のような両立できる飲料
に粉末の形で添加することができる。オピオイド作用物
質おＪ：び適切な拮抗薬はまた作用物質と拮抗物質の１
〜５用爪ユニツトを用いて患者に別々に投与する非同時
的なやり方で患者に共投与してもよい。■Can be combined in fixed proportions in pharmaceutically acceptable oral dosage forms, including Lixil. Instead,
Doses of the opioid agonist and antagonist can be added in powder form to a compatible beverage, such as fruit juice, to make it more acceptable to patients. Opioid agonists and suitable antagonists also refer to one of the agonists and antagonists.
It may be co-administered to the patient in a non-simultaneous manner using ~5 nail units to administer the patient separately.
本発明の方法で使用するのに適した麻薬拮抗物質の勧め
られる用量範囲は相聞ユニツ］〜当り約１〜約１８ｍｇ
である。１２〜１８ｍｇのようなより大量の拮抗物質が
コデインやプロポキシフェンのような比較的弱い薬物に
は必要とされ、ユニット当り１〜５■のようなより少量
の拮抗物質はモルヒネやメペリジンのようなより強い作
用物質に必要とされる。数表は作用物質と拮抗物質の代
表的ユニツＩ〜と１日の用量である。The recommended dosage range of opiate antagonists suitable for use in the methods of the invention is from about 1 to about 18 mg per drug unit.
It is. Higher amounts of antagonist, such as 12-18 mg per unit, are required for relatively weak drugs such as codeine and propoxyphene, and lower amounts of antagonist, such as 1-5 mg per unit, are required for drugs such as morphine and meperidine. Required for stronger active substances. The tables are representative units and daily doses of agonists and antagonists.
オピオイド
組−血一剤
モルフイネ
メタドン
メペリジン
Ａキシコドン
ヒドロモルホン
コデイン
プロポキシフェン
２表
代表的な
代表的な ユニット用量
ユニット用量 拮抗物質
一一一工を上 （ナロキソン）
２．５ ３
作用物質：
拮抗物質の
典型的な
総１日用量
１〜２ユニット１日４回
２ユニット１日４回
便秘や他の腸運動減弱の他の症状を誘発または悪化する
ことなく有効な鎮痛や中枢的鎮咳作用を与えることによ
って慢性痛または慢性咳患者を治療する本方法の新規性
は、オピオイド作用物質および拮抗物質（第１にナロキ
ソン）の組み合わせはここで明らかにされている目的の
ためには組み合わせで、あるいは腸レベルのオピオイド
効果の局所的拮抗が望まれる場合には別の治療方法で前
記のオピオイド作用物質と経口的には効果のない拮抗物
質で明らかであるという事実によって減少はしない。Opioid Combination - Blood One Drug Morphine Methadone Meperidine A Oxycodone Hydromorphone Codeine Propoxyphene 2 Table Representative Representative Unit Dose Unit Dose Antagonist 111 (Naloxone) 2.5 3 Agent : Typical total daily dose of antagonist: 1-2 units 4 times a day 2 units 4 times a day Effective analgesia and central antitussive without inducing or worsening constipation or other symptoms of reduced intestinal motility The novelty of the present method of treating patients with chronic pain or chronic cough by providing a combination of opioid agonists and antagonists (primarily naloxone) is that the combination of an opioid agonist and an antagonist (primarily naloxone) is Alternatively, if local antagonism of the opioid effects at the intestinal level is desired, this is not diminished by the fact that other therapeutic methods are evident with the opioid agonist and an orally ineffective antagonist.
例えば、米国特許第３．４９３．６５７号では、ナロキ
ソンはオピオイドによって引き起される呼吸抑制を除去
するためにあへん剤アルカロイドと組み合わせて有効で
あることが明らかにされている。しかしながら、ナロキ
ソンの有益な胃腸作用はこの特許では明らかにされてい
ないだけなく、そこに指示されている組合せ処方は非経
口的使用についてのみである。非経口的に投与された作
用物質拮抗物質組み合せ剤は、経口投与された製剤と同
じ位有効に腸固有運動性を改善しないで、拮抗物質は作
用物質の鎮痛効果を非常に減少させるので本発明の方法
では有用ではないだろう。For example, in US Pat. No. 3,493,657, naloxone has been shown to be effective in combination with opiate alkaloids to eliminate respiratory depression caused by opioids. However, the beneficial gastrointestinal effects of naloxone are not disclosed in this patent, and the combination formulation indicated therein is only for parenteral use. Parenterally administered agonist-antagonist combinations do not improve intestinal intrinsic motility as effectively as orally administered formulations, and the antagonist greatly reduces the analgesic effect of the agonist. method would not be useful.
米国特許第３，９６６．９４０号においては、オピオイ
ド鎮痛剤とナロキソンの組み合わせから成る経口的に有
効な組成物が発表されている。しかしながら、これらの
組み合せ処方は、非経口投与に対して無痛覚、多幸症あ
るいは肉体的従属症を引き起さないために、主に薬物濫
用の予防に有用であると発表されている。ヘロインやモ
ルヒネ耽溺者によるような非軽口的濫用を防ぐために経
口投与された麻薬に′混ぜ物をする″目的でナロキソン
を用いることは以前の方法でよく知られている。しかし
ながら、麻薬誘導性の便秘を予防するのにナロキソンが
経口的に有効であるために、このような組み合わせ薬が
慢性痛患者の治療に有用であるとする発表はこれまで特
許にもあるいは医学文献にもない。さらに、患者による
非経口的濫用の可能性が重大な問題ではない慢性痛患者
を治療するために前記のＪ：うな作用物質−拮抗物質軽
口製剤を用いることはその分野の専門医ではなかったこ
とである。No. 3,966,940 discloses an orally effective composition consisting of a combination of an opioid analgesic and naloxone. However, these combination formulations have been shown to be useful primarily in the prevention of drug abuse because they do not cause analgesia, euphoria, or physical dependence upon parenteral administration. The use of naloxone to 'adulterate' orally administered opiates to prevent casual abuse, such as by heroin or morphine addicts, is well known in the past. Because naloxone is orally effective in preventing constipation, there are no prior publications in the patent or medical literature that such a drug combination would be useful in treating chronic pain patients.Furthermore, It would be unprofessional in the field to use the aforementioned J: agonist-antagonist delicacy formulations to treat chronic pain patients where the potential for parenteral abuse by the patient is not a significant problem.
オピオイド鎮痛剤を非経口的濫用の予防に適したナロキ
ソンの別の組み合わせは米国特許第４．５８２，８３５
号に発表されている次の実施例は本発明の方法と組
成物を説明するが、どの点においてももっばら技法、薬
剤、用量型あるいは本発明の範囲内になるように使用し
なければならない用量を指示するにうには考えられてい
ない。Another combination of naloxone suitable for the prevention of parenteral abuse of opioid analgesics is disclosed in U.S. Pat. No. 4,582,835.
The following examples, published in this issue, illustrate the methods and compositions of the present invention, but should be used in such a way as to fall within the scope of the present invention in terms of techniques, agents, dosage forms, etc. It is not designed to dictate dosage.
次の実施例は主題の患者について実施された力価測定研
究を示す。オピオイド鎮痛剤と拮抗物質は患者に経口的
に共投与され、その用量範囲は便通の重大な増加が便の
正味重量の増加と麻薬禁断症状または痛みの再発の徴候
により認められる点まで調節される。前記の結果を１ｑ
るために最適であることが力価測定により明らかにされ
た用量法は゛最適用組法″として実施例で紹介されてい
る。The following example presents a titration study performed on the subject patient. The opioid analgesic and the antagonist are co-administered orally to the patient, and the dose range is adjusted to the point where a significant increase in bowel movements is noted by an increase in net stool weight and signs of opiate withdrawal or pain recurrence. . 1q of the above results
The dosing method that was found to be optimal for the purpose of optimizing the drug by titer measurement is introduced in the Examples as the "optimal dosage method."
支匹狙ニュ 患者Ｎα１は９年間の左下腹部四分−区分の腹痛。Aiming for a branch animal Patient Nα1 has had abdominal pain in the left lower quadrant for 9 years.
鼓腸および直腸出血と５年間の発作のある４２才の女性
であった。彼女の最適用量法はプロポキシフェン６５ｍ
１とナロキソン１８ｍｇを経口的にｂｉｄ （４日２回
）投与であることがわかった。A 42-year-old woman presented with a 5-year history of bloating and rectal bleeding. Her optimal dosage regimen is propoxyphene 65m.
1 and 18 mg of naloxone were administered orally bid (twice 4 days).
Ｘ展叢二λ
患者Ｎｏ、 ２は１５年間の麻薬中毒と５年間の麻薬メ
タドン維持療法を受けた３３才の男性であった。Patient No. 2 was a 33-year-old man with a 15-year history of drug addiction and 5 years of maintenance therapy with the drug methadone.
入院の２年前に、患者は３０フイートの梯子から転落し
、脳出血、左大腿骨と鎖骨の骨折と２次的疼痛を受（プ
た。この患者の最適用量法はメタドン１００ｍｇ、オキ
シコドン５Ｉｎｇおよびナロキソン８ｒｎｇをａｄ （
１日１回）投与することであることがわかった。Two years prior to admission, the patient had fallen from a 30-foot ladder and suffered a cerebral hemorrhage, a fracture of the left femur and clavicle, and secondary pain. The optimal dosing regimen for this patient was methadone 100 mg, oxycodone 5 Ing and Naloxone 8rng ad (
It was found that the drug was administered once a day).
火１」（１旦
患者Ｎα３は１３年間の自動車衝突後の２次的を髄損傷
、対麻痺、慢性痛および便秘がある５９才の女性であっ
た。彼女の最適用量法はメタドン１０■。Patient Nα3 was a 59-year-old woman with paraplegia, chronic pain, and constipation secondary to a 13-year-old motor vehicle crash. Her optimal dosing regimen was methadone 10.
オキシコドン５ ｍ９ ｄ３よびナロキソン８Ｉｒｔｇ
をｔｉｄ（１日３回）であることが分った。Oxycodone 5 m9 d3 and naloxone 8 Irtg
was found to be tid (three times a day).
火簾Ｍ二Ａ
患者Ｎｏ、 ４は１３年間の左***切除と右肺切除後の
２次的疼痛をもった５３才の女性であった。彼女の最適
用量法は１日１〜４回ナロキソン１０〜１２ｒＲｇと同
様に１日５回オキシコドン１０ｑを投与することである
ことがわかった。Karen M2A Patient No. 4 was a 53-year-old woman with secondary pain after left mastectomy and right lung resection for 13 years. Her optimal dosing regimen was found to be oxycodone 10q 5 times a day as well as naloxone 10-12 rRg 1-4 times a day.
実施例−５
患者Ｎα５は１３年間の偽閉鎖と診断された間欠性の小
腸閉鎖と慢性的麻薬従属症とメタドン維持療法を来たす
２次的慢性痛をもつ２１才の女性であった。彼女の最適
用量法はメタドン１００ｑをナロキソン４ｍ９と一緒に
ａｄ （１日１回）投与することであることがわかった
。Example-5 Patient Nα5 was a 21-year-old woman with intermittent small bowel atresia diagnosed as pseudo-atresia for 13 years and chronic pain secondary to chronic drug dependence and methadone maintenance therapy. Her optimal dosing regimen was found to be methadone 100q ad (once daily) with naloxone 4m9.
このように、発明の各種の目的を満たし、実用の条件に
合うように調整された新規の方法と組成物が提供される
ことが分るであろう。It will thus be seen that novel methods and compositions are provided that meet the various objectives of the invention and are tailored to meet practical requirements.
いろいろな考えられる具体例が前記発明についてつくら
れ、また各種の変化が前記で説明される具体例で認めら
れたので、ここに述べられている全ての事柄は実証的で
あって、限られた意味ではないと理解することができる
。Since various possible embodiments have been made of the invention, and various variations have been observed in the embodiments described above, all matters set forth herein are demonstrative and in a limited sense. I can understand that it doesn't mean anything.
新規であるとして特許請求され、専売特許証により保護
されることが望まれるものは添付の特許請求の範囲で説
明される。What is claimed as novel and desired protected by proprietary patent claims is set forth in the appended claims.
昭和６３年１０月 ６日October 1986 6th
Claims (1)
およびオピオイド拮抗薬または経口投与した時に実質的
に全身的拮抗作用のない拮抗物質前薬物を１日１〜５回
患者に経口投与することからなる、腸運動性減弱の発症
を同時に避けながら全身的鎮痛または中枢的鎮咳作用を
与えるために長期にわたって慢性痛患者または慢性咳の
ある患者を治療する方法。 ２）５％以下まで非代謝型で胃腸管を通じて血流に吸収
されるオピオイド拮抗薬の使用からなる特許請求の範囲
第１項による方法。 ３）前記オピオイド拮抗薬がナロキソンである特許請求
の範囲第２項による方法。 ４）非経口的に活性な拮抗薬の代謝産物の形の拮抗物質
前薬物の使用からなる特許請求の範囲第１項による方法
。 ５）前記拮抗物質前薬物がナロキソン・グルクロニドと
ナルメフェン・グルクロニドから成るグループから選ば
れる特許請求の範囲第４項による方法。 ６）前記オピオイド鎮痛剤または鎮咳剤がモルヒネ、メ
ペリジン、オキシコドン、ヒドロモルホン、メタドン、
コデイン、ヒドロコドンおよびプロポキシフェンから成
るグループから選ばれる特許請求の範囲第１項による方
法。 ７）前記の鎮痛剤または鎮咳剤および拮抗物質または拮
抗物質前薬物の各々の少なくとも１つの用量ユニットが
薬学的に受容できる経口用量型で組み合わせて患者に投
与される特許請求の範囲第１項による方法。 ８）前記経口用量型がカプセル剤、カプレット剤、錠剤
、シロップ剤およびエリキシル剤から成るグループから
選ばれる特許請求の範囲第７項による方法。 ９）鎮痛剤または鎮咳剤および拮抗物質または拮抗物質
前薬物の各々の少なくとも１つの用量ユニットから成る
用量が患者に投与する時に液体飲料中に溶解するか懸濁
させる特許請求の範囲第１項による方法。 １０）拮抗物質の前記用量ユニットがナロキソン約１ｍ
ｇから約１８ｍｇを含む特許請求の範囲第７項または第
９項による方法。 １１）鎮痛剤または鎮咳剤の前記用量ユニットが少なく
とも１種のオピオイド鎮痛剤または鎮咳剤約１．５ｍｇ
から約１００ｍｇを含む特許請求の範囲第７項または第
９項による方法。 １２）オピオイド鎮痛剤または鎮咳剤の薬学的に有効な
量、および 経口投与した場合実質的に全身的な拮抗作用のないオピ
オイド拮抗物質または拮抗物質前薬物の薬学的に有効な
量、 からなる、腸運動減弱の発生を同時に回避しながら全身
的な鎮痛または中枢的鎮咳作用を与えるために長期にわ
たって慢性痛や咳のある患者を治療するのに有効な経口
用組成物。１３）オピオイド鎮痛剤または鎮咳剤の薬学
的に有効な量が用量ユニット当り約１．５ｍｇから約１
００ｍｇであり、また オピオイド拮抗物質または拮抗物質前薬物の薬学的に有
効な量が用量ユニット当り約１ｍｇから１８ｍｇである
、 特許請求の範囲第１２項の組成物。 １４）用いられたオピオイド拮抗物質が５％以下の程度
まで非代謝型で胃腸管を通じて血流に吸収されるオピオ
イド拮抗物質である特許請求の範囲第１２項の組成物。 １５）前記オピオイド拮抗物質がナロキソンである特許
請求の範囲第１５項の組成物。 １６）拮抗物質前薬物が非経口的に活性な拮抗物質の代
謝産物の形となっている特許請求の範囲第１２項の組成
物。 １７）拮抗物質前薬物がナロキソン・グルクロニドおよ
びナルメフェン・グルクロニドから成るグループから選
ばれる特許請求の範囲第１６項の組成物。 １８）オピオイド鎮痛剤または鎮咳剤がモルヒネ、メペ
リジン、オキシコドン、ヒドロモルホン、メタドン、コ
デイン、ヒドロコドンおよびプロポキシフェンから成る
グループから選ばれる特許請求の範囲第１２項の組成物
。 １９）前記経口用量型がカプセル剤、カプレット剤、錠
剤、シロップ剤およびエリキシル剤から成るグループか
ら選ばれる特許請求の範囲第１２項の組成物。[Scope of Claims] 1) Pharmaceutically effective amounts of an opioid analgesic or antitussive and an opioid antagonist or pre-antagonist drug with no substantial systemic antagonism when administered orally to the patient 1 to 5 times per day. A method for the treatment of chronic pain patients or patients with chronic cough over a long period of time to provide systemic analgesia or central antitussive action while simultaneously avoiding the development of reduced intestinal motility. 2) A method according to claim 1 comprising the use of an opioid antagonist that is non-metabolized and absorbed into the bloodstream through the gastrointestinal tract by up to 5%. 3) The method according to claim 2, wherein said opioid antagonist is naloxone. 4) A method according to claim 1, consisting in the use of an antagonist predrug in the form of a metabolite of a parenterally active antagonist. 5) A method according to claim 4, wherein said pre-antagonist drug is selected from the group consisting of naloxone glucuronide and nalmefene glucuronide. 6) the opioid analgesic or antitussive is morphine, meperidine, oxycodone, hydromorphone, methadone,
A method according to claim 1 selected from the group consisting of codeine, hydrocodone and propoxyphene. 7) A method according to claim 1, wherein at least one dosage unit of each of said analgesic or antitussive and antagonist or pre-antagonist drug is administered to the patient in combination in a pharmaceutically acceptable oral dosage form. . 8) A method according to claim 7, wherein said oral dosage form is selected from the group consisting of capsules, caplets, tablets, syrups and elixirs. 9) A method according to claim 1, wherein a dose consisting of at least one dosage unit each of an analgesic or antitussive and an antagonist or pre-antagonist drug is dissolved or suspended in a liquid beverage when administered to a patient. . 10) said dose unit of antagonist is approximately 1 m of naloxone;
10. A method according to claim 7 or 9, comprising about 18 mg from g. 11) said dosage unit of analgesic or antitussive agent is about 1.5 mg of at least one opioid analgesic or antitussive agent;
10. A method according to claim 7 or 9, comprising about 100 mg from . 12) a pharmaceutically effective amount of an opioid analgesic or antitussive, and a pharmaceutically effective amount of an opioid antagonist or pre-antagonist drug without substantial systemic antagonism when administered orally; An oral composition effective for treating patients with chronic pain and cough over a long period of time to provide systemic analgesia or central antitussive action while simultaneously avoiding the development of motor weakness. 13) a pharmaceutically effective amount of the opioid analgesic or antitussive from about 1.5 mg to about 1 mg per dosage unit;
13. The composition of claim 12, wherein the pharmaceutically effective amount of the opioid antagonist or pre-antagonist drug is about 1 mg to 18 mg per dosage unit. 14) The composition of claim 12, wherein the opioid antagonist used is an opioid antagonist that is non-metabolized and absorbed into the bloodstream through the gastrointestinal tract to an extent of up to 5%. 15) The composition of claim 15, wherein said opioid antagonist is naloxone. 16) The composition of claim 12, wherein the antagonist pre-drug is in the form of a parenterally active metabolite of the antagonist. 17) The composition of claim 16, wherein the pre-antagonist drug is selected from the group consisting of naloxone glucuronide and nalmefene glucuronide. 18) The composition of claim 12, wherein the opioid analgesic or antitussive is selected from the group consisting of morphine, meperidine, oxycodone, hydromorphone, methadone, codeine, hydrocodone, and propoxyphene. 19) The composition of claim 12, wherein said oral dosage form is selected from the group consisting of capsules, caplets, tablets, syrups and elixirs.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17686688A JPH0653683B2 (en) | 1988-07-14 | 1988-07-14 | Oral composition for treating chronic pain or cough |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17686688A JPH0653683B2 (en) | 1988-07-14 | 1988-07-14 | Oral composition for treating chronic pain or cough |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0225427A true JPH0225427A (en) | 1990-01-26 |
| JPH0653683B2 JPH0653683B2 (en) | 1994-07-20 |
Family
ID=16021176
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17686688A Expired - Fee Related JPH0653683B2 (en) | 1988-07-14 | 1988-07-14 | Oral composition for treating chronic pain or cough |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0653683B2 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001506640A (en) * | 1996-12-16 | 2001-05-22 | エルティエス ローマン テラピー−ズュステーメ アーゲー | Flat formulation for oral administration and release of buprenorphine or a pharmacologically equivalent substance in the oral cavity, and method for producing the same |
| WO2003007802A3 (en) * | 2001-07-18 | 2003-11-27 | Euro Celtique Sa | Pharmaceutical combinations of oxycodone and naloxone |
| JP2006151990A (en) * | 1993-10-07 | 2006-06-15 | Euro Celtique Sa | Sustained release orally administrable opioid formulation |
| JP2007210995A (en) * | 1994-05-24 | 2007-08-23 | Paolo Minoia | Pharmaceutical composition containing opiate antagonist and calcium salt and their use for treatment of endorphin-mediated pathology |
| JP2009062376A (en) * | 1994-07-19 | 2009-03-26 | Yeshiva Univ | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists |
| US9102680B2 (en) | 2007-03-29 | 2015-08-11 | Wyeth Llc | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
| US9669096B2 (en) | 2003-04-08 | 2017-06-06 | Progenics Pharmaceuticals, Inc. | Stable pharmaceutical formulations of methylnaltrexone |
| US9724343B2 (en) | 2008-09-30 | 2017-08-08 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
-
1988
- 1988-07-14 JP JP17686688A patent/JPH0653683B2/en not_active Expired - Fee Related
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006151990A (en) * | 1993-10-07 | 2006-06-15 | Euro Celtique Sa | Sustained release orally administrable opioid formulation |
| JP2007210995A (en) * | 1994-05-24 | 2007-08-23 | Paolo Minoia | Pharmaceutical composition containing opiate antagonist and calcium salt and their use for treatment of endorphin-mediated pathology |
| JP2009062376A (en) * | 1994-07-19 | 2009-03-26 | Yeshiva Univ | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists |
| JP2001506640A (en) * | 1996-12-16 | 2001-05-22 | エルティエス ローマン テラピー−ズュステーメ アーゲー | Flat formulation for oral administration and release of buprenorphine or a pharmacologically equivalent substance in the oral cavity, and method for producing the same |
| WO2003007802A3 (en) * | 2001-07-18 | 2003-11-27 | Euro Celtique Sa | Pharmaceutical combinations of oxycodone and naloxone |
| US9669096B2 (en) | 2003-04-08 | 2017-06-06 | Progenics Pharmaceuticals, Inc. | Stable pharmaceutical formulations of methylnaltrexone |
| US10376584B2 (en) | 2003-04-08 | 2019-08-13 | Progenics Pharmaceuticals, Inc. | Stable pharmaceutical formulations of methylnaltrexone |
| US9102680B2 (en) | 2007-03-29 | 2015-08-11 | Wyeth Llc | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
| US9879024B2 (en) | 2007-03-29 | 2018-01-30 | Progenics Pharmaceuticals., Inc. | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
| US9724343B2 (en) | 2008-09-30 | 2017-08-08 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0653683B2 (en) | 1994-07-20 |
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