Treatment methods and their dosage forms

Abstract

This document provides a method for treating pain and a dosage form thereof. [Solution] The present invention provides an oral dosage form comprising (i) a fixed amount of oxycodone and (ii) a fixed amount of buprenorphine, wherein the weight ratio of the fixed amount of buprenorphine to the fixed amount of oxycodone is greater than 1:40 when calculated using a fixed amount of buprenorphine in a dosage form represented by equimolar amounts of buprenorphine base (mg) (Mw = 467.64 g / mol) and a fixed amount of oxycodone in a dosage form represented by equimolar amounts of oxycodone hydrochloride (mg) (Mw = 351.82 g / mol). The present invention also provides a combination of an opioid agonist and buprenorphine for use in treating pain, the combination achieving suppression of adverse pharmacodynamic responses (such as respiratory depression) compared to the corresponding single opioid therapeutic agent.

Description

[Technical Field]

[0001] The present invention relates to a method and dosage form for treating pain. In particular, the present invention relates to opioid Certain combinations of doorgonist and buprenorphine and such particular combinations The present invention relates to a method for treating pain using a dosage form containing a combination. Certain combinations include oxycodone and buprenorphine, and fentanyl. The combination of and buprenorphine, or the combination of hydromorphone and buprenorphine It is a combination. In certain embodiments, the combinations used herein are, for example, a single combination. Opioid agonist therapeutics (e.g., oxycodone, fentanyl, and hydromorphone) Adverse drug dynamics (e.g., respiratory depression, bowel dysfunction, sedation and) related to the treatment of drugs (such as cereals) It provides improved characteristics, including the suppression of drug addiction, etc. In particular, the combination of the present invention This suppresses the potential toxicity associated with certain opioid agonists and harmful side effects (for example) This suppresses respiratory depression, thereby improving the overall safety profile of certain opioid medications. To improve the file. Furthermore, the therapeutic method and dosage form of the present invention are a single opioid therapeutic agent. It is thought to offer effective pain relief with a lower potential for abuse compared to other methods. [Background technology]

[0002] Certain opioid medications for pain management (e.g., fentanyl, hydromorphone and The opioid-induced adverse drug dynamics response in patients receiving oxycodone is as follows: When patients are already undergoing pain management, there is a risk that harmful side effects may be added to their suffering. Therefore, it can sometimes become a troublesome issue. Potential opioid-induced adverse drug dynamics One of these is respiratory depression, which can lead to respiratory arrest, which can be fatal in some cases. Therefore, it is a particularly dangerous drug-mediated reaction. Unfortunately, when certain opioids are consumed in excess... It has been observed that these drugs can cause respiratory depression upon administration. As a result, these Safety is a major concern with pioid medications.

[0003] Therefore, opioid-induced adverse drug reactions (e.g., respiratory depression, excessive or unnecessary) Opioids have low drug addiction potential (including euphoria) and are less likely to be illegally used by non-patients. Improved methods and dosage forms for effective pain treatment using drugs have long been desired. It has an analgesic effect and a much improved overall safety profile. There is still a need for therapeutic drugs and methods in this field. [Overview of the project]

[0004] The objective of certain embodiments of the present invention is to provide an improved method for treating pain. And so it is.

[0005] The objective of certain embodiments of the present invention is to suppress harmful drug dynamic reactions (e.g., poisoning and drug reactions). Less likely to cause abuse, and improved safety, etc., and treats pain. The objective is to provide a method for treatment.

[0006] The objective of certain embodiments of the present invention is to address the public's concerns regarding toxicity, respiratory depression, poisoning, and drug abuse. The objective is to provide a method for treating pain while minimizing sanitary risks.

[0007] The objective of certain embodiments of the present invention is to provide an improved overall safety profile and effective pain relief. The objective is to provide a dosage form that effectively treats the condition.

[0008] The objective of certain embodiments of the present invention is to address the potential for causing respiratory depression, poisoning, and drug abuse. To provide a dosage form for treating pain that is less invasive and has an improved safety profile. That is the case.

[0009] The objective of certain embodiments of the present invention is to address the public's concerns regarding toxicity, respiratory depression, poisoning, and drug abuse. The objective is to provide a dosage form for treating pain that minimizes hygiene risks.

[0010] These purposes also apply to products with limited uses and to the therapeutic methods described herein. It should be understood that this relates to the use of [the object].

[0011] The purpose of the above is to use opioid agonists (e.g., hydromorphone, oxycodone and It is administered to patients who require a specific combination of fentanyl and buprenorphine. A particular embodiment of the present invention, which includes a method for treating pain, achieves the following: It is possible.

[0012] In certain embodiments, a particular combination of an opioid agonist and buprenorphine is It is a combination of hydromorphone and buprenorphine, and hydromorphone and buprenorphine The combination of rufin, compared to the corresponding hydromorphone monotherapy, It suppresses ion-induced respiratory depression by approximately 20% or more. In one embodiment, hydromorphone and bup The combination of renorphines suppresses hydromorphone-induced respiratory depression by more than one-third. .

[0013] In another embodiment, a method for treating pain is: (i) During administration period 1, the average infusion rate (mg / hour) during administration period 1 The effective amount of hydromorphone is administered by lomorphone, and at this time the average injection rate is as described above. Dromorphone is administered during the above administration period 1, divided by the duration of the above administration period 1. It is expressed in equimolar amounts of hydromorphone free base, (ii) During administration period 2, the average infusion rate (mg / hour) during administration period 2 Another effective dose of buprenorphine is administered via prenorphine, and at this time, the average infusion rate is as described above. The amount of buprenorphine administered during the above administration period 2 is calculated by dividing the duration of the above administration period 2 by the duration of the above administration period 2. It is represented by equimolar amounts of free buprenorphine base, This includes administering it to patients who require it, Administration period 1 and administration period 2 overlap by at least 75%, and buprenorph is administered at the above average infusion rate. The ratio of hydromorphone to the above average input rate is approximately 1:8000 to 1:100. be.

[0014] In another embodiment, a particular combination of the present invention is a combination of fentanyl and buprenorphine. This is a combination, and the combination of fentanyl and buprenorphine is the corresponding fentanyl Compared to fentanyl monotherapy, it suppresses fentanyl-induced respiratory depression by more than 30%.

[0015] In one embodiment, the present invention is (i) During administration period 1, the average infusion rate (mg / hour) during administration period 1 An effective amount of fentanyl is administered with antanil, and at this time, the average infusion rate of fentanyl is as described above. The amount is calculated by dividing the duration of the above administration period 1 by the equimolar amount of the amount administered during the above administration period 1. It is represented by a free entanyl base, (ii) During administration period 2, the average infusion rate (mg / hour) during administration period 2 Another effective dose of buprenorphine is administered via prenorphine, and at this time, the average infusion rate is as described above. The amount of buprenorphine administered during the above administration period 2 is calculated by dividing the duration of the above administration period 2 by the duration of the above administration period 2. It is represented by equimolar amounts of free buprenorphine base, Regarding methods for treating pain, including administering it to patients who require it, Administration period 1 and administration period 2 overlap by at least 75%, and buprenorph is administered at the above average infusion rate. The ratio of fentanyl to fluoride at the above average injection rate is approximately 1:80 to 1:0.5.

[0016] In certain embodiments, the present invention relates to pain relief comprising hydromorphone and buprenorphine. Regarding pharmaceutical compositions suitable for treating the condition, (i) An effective amount of hydromorphone is administered on average during the administration period. Hydromorphone is administered at a rate (mg / hour), and at this time, the average administration rate of hydromorphone is as described above. Lufon is calculated by dividing the duration of the above administration period by the equimolar amount administered during the above administration period. It is represented by a free hydromorphone base, (ii) Another effective dose of buprenorphine during the same administration period, Buprenorphine is administered at an average infusion rate (mg / hour), and at this time, the above average infusion rate Buprenorphine is calculated by dividing the duration of the above administration period by the amount administered during the above administration period. It is expressed in equimolar amounts of free buprenorphine base, The ratio of buprenorphine at the above average injection rate to hydromorphone at the above average injection rate is The ratio is approximately 1:8000 to 1:100.

[0017] In another embodiment, the present invention provides a treatment for pain comprising fentanyl and buprenorphine. Regarding pharmaceutical compositions suitable for this purpose, (i) An effective amount of fentanyl is administered at an average rate during the administration period. Fentanyl is administered at (mg / hour) doses, and at this time, the average infusion rate of fentanyl is as follows: The equimolar amount of fentanyl administered during the above administration period, divided by the duration of the above administration period. It is represented by free bases, (ii) Another effective dose of buprenorphine during the same administration period, Buprenorphine is administered at an average infusion rate (mg / hour), and at this time, the above average infusion rate Buprenorphine is calculated by dividing the duration of the above administration period by the amount administered during the above administration period. It is expressed in equimolar amounts of free buprenorphine base, The ratio of buprenorphine at the above average infusion rate to fentanyl at the above average infusion rate is approximately It's approximately 1:80 to 1:0.5.

[0018] In certain embodiments, the present invention is (i) During administration period 1, administer at the average input rate (mg / hour) during the above administration period 1. Fentanyl, oxycodone, oxymorphone, hydrocodone, hydromorph An effective amount of opioid selected from the group consisting of ointment and morphine, and at this time the above average dose The input rate of opioid is divided by the duration of administration period 1, and the amount administered during administration period 1 is calculated as follows: It is expressed in equimolar amounts of that free base, (ii) During administration period 2, the average infusion rate (mg / hour) during administration period 2 Another effective dose of buprenorphine is administered via prenorphine, and at this time, the average infusion rate is as described above. The amount of buprenorphine administered during the above administration period 2 is calculated by dividing the duration of the above administration period 2 by the duration of the above administration period 2. It is represented by equimolar amounts of free buprenorphine base, Regarding methods for treating pain, including administering it to patients who require it, Treatment period 1 and treatment period 2 overlap by at least 75%.

[0019] In one embodiment, buprenorphine is administered subcutaneously. In another embodiment, buprenorphine is administered subcutaneously. Lenorphin is administered transdermally.

[0020] The present invention can further achieve the above-mentioned objectives and other objectives, but in a specific implementation In terms of form, the present invention is (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, Regarding oral dosage forms including, The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is equal to equimolar amounts of buprenorphine. A constant amount of ruphin base (mg) (Mw = 467.64 g / mol) in a dosage form A certain amount of buprenorphine and an equimolar amount of oxycodone hydrochloride (mg) (Mw=351). When calculating using a fixed amount of oxycodone in a dosage form expressed as 82 g / mol) The time is over 1:40.

[0021] The present invention can achieve the above-mentioned objectives and other objectives, but in certain embodiments So, the present invention is, (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, For the treatment of pain, including administering it to patients who require an oral dosage form that includes [this]. Regarding the law, The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is equal to equimolar amounts of buprenorphine. A constant amount of ruphin base (mg) (Mw = 467.64 g / mol) in a dosage form A certain amount of buprenorphine and an equimolar amount of oxycodone hydrochloride (mg) (Mw=351). When calculating using a fixed amount of oxycodone in a dosage form expressed as 82 g / mol) The time is over 1:40.

[0022] The present invention can achieve the above-mentioned objectives and other objectives, but in certain embodiments So, the present invention is, (i) A fixed amount of immediate-release oxycodone, (ii) A fixed amount of buprenorphine in an immediate-release form, Regarding oral dosage forms including, The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is equal to equimolar amounts of buprenorphine. A constant amount of ruphin base (mg) (Mw = 467.64 g / mol) in a dosage form A certain amount of buprenorphine and an equimolar amount of oxycodone hydrochloride (mg) (Mw=351). When calculating using a fixed amount of oxycodone in a dosage form expressed as 82 g / mol) The ratio is approximately 1:100 or higher.

[0023] The present invention can achieve the above-mentioned objectives and other objectives, but in certain embodiments So, the present invention is, (i) A fixed amount of immediate-release oxycodone, (ii) A fixed amount of buprenorphine in an immediate-release form, For the treatment of pain, including administering it to patients who require an oral dosage form that includes [this]. Regarding the law, The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is equal to equimolar amounts of buprenorphine. A constant amount of ruphin base (mg) (Mw = 467.64 g / mol) in a dosage form A certain amount of buprenorphine and an equimolar amount of oxycodone hydrochloride (mg) (Mw=351). When calculating using a fixed amount of oxycodone in a dosage form expressed as 82 g / mol) The ratio is approximately 1:100 or higher.

[0024] The present invention can achieve the above-mentioned objectives and other objectives, but in certain embodiments So, the present invention is, (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, Regarding dosage forms that include, After a single dose, the dosage form is administered to one control group at least approximately 1:280 buprenorphine. The average C max and the average C of oxycodone max This results in a ratio of .

[0025] The present invention can achieve the above-mentioned objectives and other objectives, but in certain embodiments So, the present invention is, (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, Regarding a method for treating pain, which includes administering it concurrently to patients who require it, After a single dose, the above-mentioned simultaneous administration involves at least approximately 1:280 bupresence in one control group. Norphin's average C max and the average C of oxycodone max This results in a ratio of .

[0026] The present invention can achieve the above-mentioned objectives and other objectives, but in certain embodiments Therefore, the present invention provides at least two oral dosage forms containing oxycodone with different active ingredient content. Regarding the set, each of the dosage forms is: (i) a. Approximately 10 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), b. Approximately 15 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), c. Approximately 20 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), d. Approximately 30 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), or e. Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), Against this, equimolar amounts of a fixed amount of oxycodone, (ii) A certain amount of buprenorphine, Includes, The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is, -The table is displayed using equimolar amounts of buprenorphine base (mg) (Mw = 467.64 g / mol). A certain amount of buprenorphine and an equimolar amount of oxycodone hydrochloride in the dosage form. A certain amount of oxyco in a dosage form expressed as (mg) (Mw=351.82g / mol) When calculating using "don," the ratio is greater than 1:40. - The same value is found in each dosage form of the set.

[0027] The present invention can achieve the above-mentioned objectives and other objectives, but in certain embodiments So, the present invention is, (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, For the treatment of pain, including administering it to patients who require an oral dosage form that includes [this]. Regarding the law, Average E of "Exhilaration VAS" max When measured using comparative tests, at least 15% to decrease, and / or, The average E of the "Temporary Drug Preference VAS" max When measuring using comparative tests, less Both decrease by 15%, and / or The average E of the "Overall Drug Preference VAS" max When measuring using comparative tests, less Both decrease by 15%, and / or Average E of "Drug Reuse VAS" maxis at least 1 when measured using a comparative test % decrease, and / or The average "cold pain score [[ID=�]]measured using the cold pressor test at 1, 2, 3, and 4 hours after administration is not more than 10% higher than the comparative treatment method when measured using a comparative test .

[0028] The above object and other objects can be achieved by the present invention. In a specific embodiment , the present invention relates to (i) a certain amount of oxycodone, and (ii) a certain amount of buprenorphine, and a method for treating pain, comprising co-administering the same to a patient who requires it The average E of the "euphoria VAS" max is at least 15% decrease, and / or The average E of the "temporary drug craving VAS" max is at least 15% decrease, and / or The average E of the "overall drug craving VAS" max is at least 15% decrease, and / or The average E of the "drug reuse VAS" max is at least 1 5% decrease, and / or The average "cold pain score measured using the cold pressor test at 1, 2, 3, and 4 hours after administration is not more than 10% higher than the comparative treatment method when measured using a comparative test .

[0029] According to a specific embodiment of the present invention, the above pharmaceutical combination is for use in a method for treating pain . According to a specific embodiment, the present invention treats pain Regarding the use of the above-mentioned drug combination in the manufacture of pharmaceuticals for the purpose of...

[0030] definition In describing the present invention, the following terms will be used as shown below.

[0031] As used herein, the singular forms "a," "an," and "the" are used only when the context is particularly clear. Unless otherwise specified, it includes multiple referents.

[0032] As used herein, the term “therapeutic effectiveness” means the amount of medicine required to produce the desired therapeutic effect. It refers to the quantity of a substance or the rate of drug administration.

[0033] The term "pain" includes, but is not limited to, nociceptive pain, neuropathic pain, and visceral pain. Acute and chronic pain of moderate to severe malignant and non-malignant origin, in particular, This refers to severe to profound acute and chronic pain of malignant and non-malignant origin. Examples include severe pain caused by diseases such as cancer, rheumatism, and arthritis, but these are not limited to these. It is not determined. Further examples include postoperative pain, cluster headaches, toothaches, surgical pain, and pain resulting from severe burns. Pain, pain resulting from third-degree burns, back pain, lower back pain, herpes neuralgia, phantom limb pain, central nervous system pain These include nerve pain, bone injury pain, and pain during childbirth and delivery.

[0034] The term "patient" refers to a subject, in particular, to specific symptoms or multiple symptoms that suggest the need for treatment. People showing clinical signs of symptoms, people being treated preventively or prophylactically for the disease. It refers to a person who has been diagnosed with the disease to be treated. The definition of the term "patient" includes excluding individuals who are completely normal in all respects or with respect to a particular illness. It's not something you should do.

[0035] Examples of "pharmaceutically acceptable salts" include inorganic salts, such as hydrochloride salts, hydrobromide salts, and sulfuric acid salts. Salts, phosphates, organic acid salts, such as myristic acid, formate, acetate, trifluorocarbons. Sulfonates such as acetates, maleates, tartrates, etc., for example, methanesulfonates, etc. Amino acid salts such as toluenesulfonate and p-toluenesulfonate, for example, arginine Salts such as aspartates, glutamates, and metal salts, for example, sodium salts, potassium salts Alkaline earth metals such as calcium salts, cesium salts, and magnesium salts, for example. , and organic amine salts, for example, triethylamine salt, pyridine salt, picoline salt, ethanol Alamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibene Examples include, but are not limited to, dilethylenediamine salts. Preferred salts are hydrochloride salts. That is the case.

[0036] The term "buprenorphine" refers to buprenorphine base and all of its pharmaceutically acceptable components. This refers to a salt that is derived from [a substance]. Suitable salts include, for example, buprenorphine hydrochloride. Buprenorphine bases and their pharmaceutically acceptable salts are solvates (e.g., As a hydrate, as a complex, and as a mixture thereof, in solvent-free form (e.g., an anhydride) It may be present in the form.

[0037] The term "fentanyl" refers to fentanyl base and all pharmaceutically acceptable salts thereof. This means that. Suitable salts include, for example, fentanyl citrate and fentanyl Examples include hydrochloride salts. Fentanyl bases and their pharmaceutically acceptable salts are solvates. (For example, as a hydrate), as a complex, and as a mixture thereof, in solvent-free form (e.g.) It may also exist in an anhydrous form.

[0038] The term "hydromorphone" refers to hydromorphone bases and all their pharmaceutically acceptable compounds. This refers to a salt that is derived from the salt. Suitable salts include, for example, hydromorphone hydrochloride. Hydromorphone bases and their pharmaceutically acceptable salts are solvates (e.g., As a hydrate, as a complex, and as a mixture thereof, in solvent-free form (e.g., an anhydride) It may be present in the form.

[0039] The term "oxycodone" refers to the oxycodone base and all pharmaceutically acceptable salts thereof. This means that. Suitable salts include, for example, oxycodone hydrochloride and oxycodone tereol. Phthalates are an example. Oxycodone base and its pharmaceutically acceptable salts are solvents. As a dihydrate (e.g., hydrate), as a complex, and as a mixture thereof, in solvent-free form ( For example, it may exist in an anhydrous form.

[0040] When adding the molecular weight Mw = 467.64 g / mol to the mention of buprenorphine base, In any case, it refers to a base that does not contain a solvent or complexing agent. Mw = 504.10 g / m Whenever the molecular weight of ol is added to the reference to buprenorphine hydrochloride, the solvent or complexing agent This refers to buprenorphine hydrochloride that does not contain [unclear]. Mw = 351.82 g / mol Whenever the molecular weight is added to the reference to oxycodone hydrochloride, it should not include any solvent or complexing agent. This refers to oxycodone hydrochloride. When using the term "free base," please note that "free base" and This refers to a base in a solvent-free form.

[0041] PCT International Publication WO2005 / 097801A1, U.S. 7,129,248B2 No., and U.S. Patent Application Publication No. 2006 / 0173029A1 (all of these are referenced below) (as incorporated herein) is less than about 25 ppm, preferably less than about 15 ppm, about Less than 10 ppm, or about less than 5 ppm, more preferably less than about 2 ppm, about 1 ppm 14-hydroxycordycete less than m, less than approximately 0.5 ppm, or less than approximately 0.25 ppm This document describes the process for preparing oxycodone hydrochloride with a non-level concentration. .

[0042] As used herein, the term "ppm" means "parts per million." 14- Regarding hydroxycodeinone, "ppm" means that 1% of a particular sample product contains This refers to parts per million of 4-hydroxycodeinone. 14-hydroxycodeinone Bell uses any method known in the art, preferably UV detection. It can be measured by HPLC analysis.

[0043] In a particular embodiment of the present invention in which the activator is oxycodone hydrochloride, the concentration is less than approximately 25 ppm. Preferably less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm, more preferably Alternatively, less than approximately 2 ppm, less than approximately 1 ppm, less than approximately 0.5 ppm, or approximately 0.25 ppm. Oxycodone hydrochloride with 14-hydroxycodeinone levels below p / m is used. .

[0044] The term “C max "The maximum plasma concentration obtained during the administration interval and / or during the administration period" refers to the maximum plasma concentration obtained during the administration interval and / or during the administration period. It means that.

[0045] The term “C av "The average plasma concentration obtained during the administration interval and / or during the administration period" This means "C av " is the total plasma curve against time, divided by the appropriate duration. It is calculated as an area.

[0046] The term “T max " refers to the maximum plasma concentration (C max It means the time until ).

[0047] The term “E max " " refers to the maximum effect during the testing period.

[0048] The mean pharmacokinetic and mean pharmacodynamic values ​​are arithmetic mean values.

[0049] The term "oral bioavailability" is, for the purposes of this invention, a normalized intravenous injection Absorption ratio of drugs (e.g., buprenorphine) from orally administered dosage forms compared to administered dose. It is defined as (%).

[0050] The term "opioid-induced adverse drug dynamics" refers to the adverse drug reactions that occur when opioids are used to achieve their intended therapeutic effect. This refers to unintended side effects experienced by patients receiving medication. Generally, The intended effect is pain relief, and opioids are opioid analgesics. Related unintended side effects include, for example, euphoria, elation, bowel dysfunction, nausea, and vomiting. drowsiness, dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria Diarrhea, delirium, miosis, pruritus, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance In particular, side effects include respiratory depression, euphoria, elation, and bowel dysfunction.

[0051] The term "toxicity" refers to the possibility of an overdose that could lead to death, and can also mean "lethal." This means that in certain embodiments of the present invention, toxicity is not considered a harmful pharmacodynamic reaction, and is itself It is a bodily effect.

[0052] The term "opioid" or "opioid analgesic" refers to opioid agonists, opioid A mixture of idagonists and antagonists, selected from partial opioidagonists. It refers to one or more types of compounds. As an opioid analgesic, alfene Tanyl, allylprozine, alphaprozine, anirelizine, benzylmorphine, vegito Lamid, buprenorphine, butorphanol, clonitazene, codeine, desomorphine Dextromoramide, Dezosine, Diampromide, Diamorphone, Dihydrocodeine , dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, Dioxafetyl butyrate, dipipanone, eptazocine, etoheptadine, ethylmeth Luthianbutene, ethylmorphine, etonitazene, etorphine, dihydroethorphine fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, i Somesadon, ketobemidone, levofenol, levofenacilmorphan, lofentan Nil, meperidine, meptazinol, metazosine, methadone, methopon, morphine, milo Finn, Narsein, Nicomorphine, Norlevolfanol, Normesadon, Narolfi N, nalbufen, normorphine, norpipanone, opium, oxycodone, oxymorph Papaveletam, pentazocine, phenadoxone, phenomorphan, phenazosine , fenoperidin, piminodin, pyritramide, propeptadine, promedol, pro Peridine, propoxyfen, sufentanil, tyridine, and tramadol are among the listed examples. The present invention is not limited to these, but is particularly important for certain opioid agonists. For example, the pharmacodynamics associated with the use of oxycodone, fentanyl, and hydromorphone. Regarding reactions and toxicity.

[0053] The term "simultaneous administration" refers to administering oxycodone before the end of the administration interval, for example, when administering oxycodone The interval begins 6 hours before the start of the administration interval and ends 1 hour before the end of the oxycodone administration interval. Within the interval, or starting 3 hours before the start of the oxycodone administration interval. The dose of buprenorphine is to be administered within a period that ends one hour before the end of the interval. It tastes good. The dose of oxycodone administered at a 6-hour interval is 6 hours after oxycodone administration. It can be administered concurrently with the dose of buprenorphine administered internally. In particular, buprenorphine The dosages are within 60 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or If administered within one minute, it can be administered simultaneously with the dose of oxycodone. For example, the same drug When administered in this form, buprenorphine is preferably exactly the same as oxycodone. It is preferable to administer it at a specific time. The above considerations are particularly relevant to oxycodone and buprenorphine. This applies to embodiments in which both are administered orally.

[0054] The term "administration period" refers to the period during which the drug (e.g., buprenorphine, fentanyl, hi) is administered. This refers to the period during which drugs (such as dromorphone and oxycodone) are administered. The administration period of the treatment system begins when the transdermal absorption treatment system is applied and ends when it is removed. The administration period for subcutaneous implants begins when the subcutaneous implant is placed. The procedure is terminated when the subcutaneous implant is removed or completely disassembled. Intravenous The duration of administration, such as infusion, begins when the infusion starts and ends when the infusion is finished. The treatment is terminated. The duration of administration may be the same as the dosing interval, which means repeated administration, or it may be different. This may be different and may include periods of non-administration. In most cases, even In the case of percutaneous systems and subcutaneous implants, the administration interval and administration period are the same.

[0055] Furthermore, the administration periods of the two drugs, referred to above as "administration period 1" and "administration period 2," are 2 The order of the administration periods is not indicated. The administration periods of the two drugs are the same ( That is, if they have the same start and end dates, or if one of the administration periods is If 100% is present (i.e., completely included) within the other administration period, then there is 100% overlap. It is considered that two drugs (for example, one is buprenorphine and the other is hi The duration of administration of dromorphone, fentanyl, or oxycodone is determined to a certain degree. Overlap is acceptable only in certain cases, but even then, such overlap is considered to be 75% or more, 90% or more, Or, it is 95% or more. The percentage of overlap is the opioid agonist (for example, It is calculated based on the duration of administration of hydromorphone, fentanyl, and oxycodone. For example, the administration of buprenorphine starting at 8:00 AM and ending at 10:00 AM on the same day. The period and the hydromorphone that will start at 9:00 a.m. on the same day and end at 2:00 p.m. on the same day The administration period can be considered to have a 20% overlap. Starting at 8:00 AM on day 1 and continuing until afternoon on day 2. The administration period of buprenorphine ends at 8:00 AM, and the administration period begins at 9:00 AM on day 1. The hydromorphone administration period ending at 10:00 AM on day [number] is considered to have 100% overlap. It is possible.

[0056] The above-mentioned fixed amount of oxycodone is administered orally, and the above-mentioned fixed amount of buprenorphine is administered transdermally. In certain embodiments, the administration interval for buprenorphine is the same as the administration interval for oxycodone. Compared to that, it becomes significantly longer (for example, several times a day compared to several days). The above-mentioned fixed amount of oxygen Cycodone is administered orally, and the above-mentioned fixed amount of buprenorphine is administered subcutaneously (i.e., In embodiments (via subcutaneous implants), the administration interval of buprenorphine is also oxidized. This is significantly longer compared to the codon dosing interval (for example, several weeks or months). (and several times a day). Therefore, the above-mentioned amount of oxycodone is administered orally (for example, over several hours) (Each dose has the following administration intervals) and the above-mentioned fixed amount of buprenorphine is administered transdermally or skin-wise. In embodiments where the dose is administered below, the term "simultaneous administration" means that the dose of oxycodone is equal to the dose of bupreno. This means it is administered within the dosing interval of Rufin. It is administered subcutaneously at a 6-month interval. The dosage of buprenorphine is administered within a 6-month period of buprenorphine treatment. It can be administered concurrently with the codon dose.

[0057] The term "subcutaneous / subcutaneously" refers to administration via a subcutaneous implant. The implant is embedded under the skin (for example, by insertion through a small subcutaneous incision). over a long period of time, such as several weeks or months, for example, 1 to 6 months or even longer. This is a dosage form that delivers the active ingredient.

[0058] The term "average input rate" refers to the drug (e.g., fentanyl, hydromorphone, oxyco). It is defined as the rate at which drugs such as buprenorphine are supplied to the blood system. Such an average The input rate means the rate of the administration route that can measure the supply rate to the blood system without the first-pass effect playing an important role. This concept can also be applied to sublingual administration and buccal administration in addition to transdermal, subcutaneous, and all kinds of injection / infusion. In the case of a patch / transdermal therapeutic system, the average input rate is defined to be the same as the average release rate described in the package insert. The same can be said for subcutaneous implants. Therefore, the ratio between average input rates can be calculated. When buprenorphine and an opioid (hydromorphone, fentanyl or oxycodone) are administered by the same administration route, and the administration route is selected from all kinds of injection and infusion (such as subcutaneous, intravenous or intramuscular injection / infusion, etc.), the administration period is the same, and the ratio of the average input rate can be calculated according to the amount of the drug to be administered. This is also the case for, for example, simultaneous subcutaneous injection. This is also the case for, for example, simultaneous subcutaneous injection. The term "immediate release" formulation or type means a dosage form that releases at least about 70% of the active agent within 45 minutes when measured by in vitro dissolution using USP Apparatus 2 (paddle) at 50 rpm in 500 ml of 0.1 N HCl at 37°C. When the administration period is the same, and the ratio of the average input rate can be calculated according to the amount of the drug to be administered. This is also the case for, for example, simultaneous subcutaneous injection.

[0059] The term "in one subject group" in relation to C values and / or T values means that the corresponding C

[0060] values and / or T max values are measured in the same clinical trial in the same subject group. max The term "in one subject group" in relation to C values and / or T max values means that the corresponding C max values and / or T values are measured in the same clinical trial in the same subject group.

[0061] "Euphoria" and / or "drug preference" ("overall drug preference", "temporary drug preference") In the context of measuring differences in "drug reuse" and / or "cold pain score" The term "comparative trial" preferably refers to a double-blind, placebo-controlled, positive-controlled, and randomized trial. In crossover trials, the dosage form and / or therapeutic method of the present invention and comparative treatment A clinical trial in which a treatment method is implemented and / or applied to a control group (with the results being compared between them) is a clinical trial. This means that the target audience is preferably healthy men and women who use recreational opioids. It is preferable to select according to the selection criteria used in Example 1. Euphoria score and drug preference For the evaluation of sex scores and pain scores, a visual analog scale (VAS) was used. Determine.

[0062] "Euphoria" and / or "drug preference" ("overall drug preference", "temporary drug preference") In the context of measuring differences in "drug reuse" and / or "cold pain score" The term "comparative treatment method" refers to the dosage form and / or treatment method of the present invention. The total combination of the same activators (excluding buprenorphine) (compared to the administration of oxycodone) This refers to a treatment method that involves administering a substance that is biologically equivalent to the original substance.

[0063] The dosage form of the present invention is an oral dosage form comprising oxycodone and buprenorphine, and / or The present invention's therapeutic method includes the administration of an oral dosage form containing oxycodone and buprenorphine. In terms of administration methods, "euphoria" and / or "drug preference" ("overall drug preference", "temporary") Measure differences in "drug preference" and "drug reuse" and / or "cold pain score". In this context, the term "comparative treatment method" can be substituted for the same as that in the dosage form according to the present invention. The total combination of one activator (excluding buprenorphine, in particular equimolar amounts of oxycod Oral dosage forms containing (the in vitro dissolution rate of oxycodone in the dosage form of the present invention and / or this The in vitro dissolution rate of oxycodone in the dosage form administered by the therapeutic method of the invention is substantially the same as that of the present invention. This refers to a treatment method that involves administering (which results in the in vitro lysis rate of oxycodone). .

[0064] "Euphoria" and / or "drug preference" ("overall drug preference", "temporary drug preference") In the context of measuring differences in "drug reuse" and / or "cold pain score" The term "substantially identical in vitro solubility rate of oxycodone" refers to a solubility rate of 37°C at 900 ml. In 1 liter of artificial gastric juice (SGF) (enzyme-free), the USP Appa was operated at 100 rpm. When measured using ratus 1 (basket), at 1 hour after dissolution, preferably, The o released at 1 and 2 hours after dissolution, more preferably at 1, 2 and 3 hours after dissolution The percentage amount of oxycodone corresponds to the in vitro dissolution rate of oxycodone in the dosage form of the present invention. It is characterized by being approximately 20 percentage points or less, preferably approximately 10 percentage points or less, from the degree. This refers to the in vitro dissolution rate.

[0065] For the purposes of this invention, the term "biological equivalence" means activity Agent C max AUC t , and AUC inf This refers to a dosage form that yields a geometric mean value. The 90% confidence interval estimated from the ratio (test / reference) is in the range of 80.00% to 125.00%. It is included within the enclosed area. When measuring in both the intake state and the fasting state, C max AUC t , and A UC inf The average value of .

[0066] Within the scope of the gist of the present invention, in the context of measuring the "cold pain score", the "cold pressor test (CPT)" means a test using a circulating water bath capable of containing an adult's hand immersed up to the wrist while maintaining the water temperature at 0 to 2°C. The temperature is within the range of 0 to 2°C, ideally set at 1°C. A movable range exceeding 2°C is avoided because the movable range may affect the pain experienced by the subject. The test is performed by the subject quickly immersing his or her hand into the water bath. The subject is instructed to keep his or her hand relaxed and immersed in the open state until the pain becomes unbearable. The initial maximum duration of hand immersion is 2 minutes, but can be extended up to 5 minutes at most. The subject is instructed that he or she may withdraw his or her hand from the water at any time and that he or she should not keep his or her hand in the water if he or she feels that the pain is unbearable. The duration of hand immersion is measured from the moment of complete immersion until the subject withdraws his or her hand from the water bath. The start time (seconds) and duration (seconds) are recorded in the source document.

[0067] The "weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone when calculated using a certain amount of buprenorphine (mg) (Mw = 467.64 g / mol) in a dosage form represented by and a certain amount of oxycodone hydrochloride ( mg) (Mw = 351.82 g / mol) in a dosage form represented by is the amount used in Example 1 below, -Oxycodone HCl (Mw=351.82g / mol): 40mg, - Buprenorphine HCl (Mw=504.10g / mol): 5.39mg, - Buprenorphine base expressed in equimolar amounts (Mw = 467.64 g / mol) Lenorphine HCl: 5 mg; -Weight ratio=5mg:40mg=1:8; A weight ratio of -1:8 is equal to 0.125, and therefore, for example, a ratio greater than 1:40 is equal to 0.02. Equal to 5 It is calculated as shown in the example. [Brief explanation of the drawing]

[0068] [Figure 1] The test design for Example 1 is shown in graph form. [Figure 2] This figure shows the results of Example 1 (mean plasma concentration of oxycodone over time, after oral administration of oxycodone alone, and after a combination of oral administration of oxycodone and transdermal administration of buprenorphine). [Figure 3] This figure shows the combined results of Example 1 and Example 2 (mean plasma concentration of buprenorphine as a function of time after transdermal, intravenous, and oral administration (the results after transdermal administration are from Example 1, and the results after intravenous and oral administration are from Example 2)). [Figure 4] This figure shows the results of Example 1 (mean plasma concentration of buprenorphine over time, after transdermal administration of buprenorphine alone, and after a combination of transdermal administration of buprenorphine and oral administration of oxycodone). [Figure 5] This figure shows the results of Example 1 (mean "temporary" drug preference, VAS), including the results of both repetitions and all six types of treatment. [Figure 6] This figure shows the results of Example 1 (mean "temporary" drug preference, VAS, Emax), including the results of both repetitions and all six types of treatment. [Figure 7]This figure shows the results of Example 1 (average euphoria, VAS), including the results of both repetitions and all six types of treatment. [Figure 8] This figure shows the results of Example 1 (average euphoria, VAS, Emax), including the results of both repetitions and all six types of treatment. [Figure 9] This figure shows the results of Example 1 (overall drug preference, VAS, Emax), including the results of both repeats and all six types of treatment. [Figure 10] This figure shows the results of Example 1 (drug reuse, VAS, Emax), including the results of both repeated treatments and all six types of treatment. [Figure 11] This figure shows the results of Example 1 (Repeat 2) and all 6 types of treatment (average cold pain score as time: 0 hours - before oral administration). [Figure 12] This figure shows the results of Example 1 (Repeat 2) and all 6 types of treatment (average cold pain score as a percentage of time: 1 hour). [Figure 13] This figure shows the results of Example 1 (Repeat 2) and all 6 types of treatment (average cold pain score as a percentage of time: 2 hours). [Figure 14] This figure shows the results of Example 1 (Repeat 2) and all 6 types of treatment (average cold pain score relative to time: 3 hours). [Figure 15] This figure shows the results of Example 1 (Repeat 2) and all 6 types of treatment (average cold pain score as a percentage of time: 4 hours). [Figure 16] This figure shows the combined results of Example 1 and Example 2 (mean plasma concentration of buprenorphine as a function of time after transdermal administration of buprenorphine in Example 1, mean plasma concentration of buprenorphine as a function of time after oral IR buprenorphine administration in Example 2, and mean plasma concentration of oxycodone as a function of time after oral IR oxycodone administration in Example 1). [Figure 17] Figure 17A) shows the effect of buprenorphine alone on rat blood gas parameters: A) pCO2. Figure 17B) shows the effect of buprenorphine alone on rat blood gas parameters: B) sO2. [Figure 18]Figure 18A) shows the effect of oxycodone alone on the rat blood gas parameter: A) pCO2. Figure 18B) shows the effect of oxycodone alone on the rat blood gas parameter: B) sO2. [Figure 19] Figure 19A) shows the effect of hydromorphone alone on the rat blood gas parameter: A) pCO2. Figure 19B) shows the effect of hydromorphone alone on the rat blood gas parameter: B) sO2. [Figure 20] Figure 20A) shows the effect of fentanyl alone on rat blood gas parameters: A) pCO2. Figure 20B) shows the effect of fentanyl alone on rat blood gas parameters: B) sO2. [Figure 21] Figure 21A) shows the effect of buprenorphine on oxycodone-induced damage to rat arterial blood gas (ABG) parameter: A) sO2%. Figure 21B) shows the effect of buprenorphine on oxycodone-induced damage to rat arterial blood gas (ABG) parameter: B) pO2. Figure 21C) shows the effect of buprenorphine on oxycodone-induced damage to rat arterial blood gas (ABG) parameter: C) pCO2. Figure 21D) shows the effect of buprenorphine on oxycodone-induced damage to rat arterial blood gas (ABG) parameter: D) arterial blood pH. [Figure 22] Figure 22A) shows the effect of buprenorphine on oxycodone-induced damage to arterial blood gas (ABG) parameters in rats one hour after administration: A) pCO2%. Figure 22B) shows the effect of buprenorphine on oxycodone-induced damage to arterial blood gas (ABG) parameters in rats one hour after administration: B) sO2%. [Figure 23] This figure shows the analgesic effects of buprenorphine, oxycodone, and the buprenorphine-oxycodone (8 mg / kg) combination in rats. [Figure 24]Figure 24A) shows the effect of buprenorphine on fentanyl-induced injury of rat arterial blood gas (ABG) parameter: A) sO2%. Figure 24B) shows the effect of buprenorphine on fentanyl-induced injury of rat arterial blood gas (ABG) parameter: B) pO2. Figure 24C) shows the effect of buprenorphine on fentanyl-induced injury of rat arterial blood gas (ABG) parameter: C) pCO2. Figure 24D) shows the effect of buprenorphine on fentanyl-induced injury of rat arterial blood gas (ABG) parameter: D) arterial blood pH. Figure 24E) shows the effect of buprenorphine on fentanyl-induced injury of rat arterial blood gas (ABG) parameter: E) acid-base state. [Figure 25] Figure 25A) shows the effect of buprenorphine on fentanyl-induced damage to arterial blood gas (ABG) parameters in rats one hour after administration: A) pCO2%. Figure 25B) shows the effect of buprenorphine on fentanyl-induced damage to arterial blood gas (ABG) parameters in rats one hour after administration: B) sO2%. [Figure 26] This figure shows the analgesic effects of buprenorphine, fentanyl, and the buprenorphine-fentanyl combination (0.5 mg / kg) in rats. [Figure 27] Figure 27A) shows the effect of buprenorphine on hydromorphone-induced damage to the rat arterial blood gas (ABG) parameter: A) sO2%. Figure 27B) shows the effect of buprenorphine on hydromorphone-induced damage to the rat arterial blood gas (ABG) parameter: B) pO2. Figure 27C) shows the effect of buprenorphine on hydromorphone-induced damage to the rat arterial blood gas (ABG) parameter: C) pCO2. Figure 27D) shows the effect of buprenorphine on hydromorphone-induced damage to the rat arterial blood gas (ABG) parameter: D) arterial blood pH. [Figure 28]Figure 28A) shows the effect of buprenorphine on hydromorphone-induced impairment of arterial blood gas (ABG) parameters in rats one hour after administration: A) pCO2%. Figure 28B) shows the effect of buprenorphine on hydromorphone-induced impairment of arterial blood gas (ABG) parameters in rats one hour after administration: B) sO2%. [Figure 29] This figure shows the analgesic effects of buprenorphine, hydromorphone, and the buprenorphine-hydromorphone (10 mg / kg) combination in rats. [Figure 30] Figure 30A) shows the effect of buprenorphine on oxycodone-induced lethality. Figure 30B) shows the effect of buprenorphine on oxycodone-induced lethality. [Figure 31] Figure 31A) shows the effect of buprenorphine on fentanyl-induced lethality. Figure 31B) shows the effect of buprenorphine on fentanyl-induced lethality. [Figure 32] Figure 32A) shows the effect of buprenorphine on hydromorphone-induced lethality. Figure 32B) shows the effect of buprenorphine on hydromorphone-induced lethality. [Figure 33] Figure 33A) shows a schematic diagram of three hydromorphone (HMP) injections with a placebo patch (A) in study part 2a). Figure 33B) shows a schematic diagram of three hydromorphone (HMP) injections with buprenorphine (BUP, 20 mcg / hour, Butrans® patch) (B) in study part 2a). [Figure 34] This figure shows the mean HCVR gradient, normalized to placebo, after administration of IV hydromorphone (HMP), buprenorphine (BUP, Butrans® patch), and the HMP-BUP combination in Study Part 2a). [Figure 35] This figure shows the hydromorphone concentration during HCVR measurement in test part 2a). [Figure 36]This figure shows the buprenorphine concentration during HCVR measurement in test part 2a). [Figure 37] Part 2b) This is a diagram illustrating the outline of the examination design. [Figure 38] This figure shows the hydromorphone concentration during HCVR measurement in Test Part 2b). [Figure 39] This figure shows the buprenorphine concentration during HCVR measurement in test part 2b). [Figure 40] This figure shows the mean HCVR gradient, normalized to placebo, after administration of HMP (3.0 mg, IV), BTDS (doses of 2.5 mcg / hour, 5 mcg / hour, and 10 mcg / hour), and the HMP-BTDS combination in Part 2b of the study. [Figure 41] This figure shows the analgesic effects of HMP (3.0 mg, IV), BTDS (doses of 2.5 mcg / hour, 5 mcg / hour, and 10 mcg / hour), and the HMP-BTDS combination compared to placebo in trial part 2b). [Modes for carrying out the invention]

[0069] Oxycodone, fentanyl, hydromorphone, and buprenorphine are all of the same. They are commonly used individually for their analgesic properties.

[0070] Fentanyl is formulated, for example, as a transdermal therapy system for treating pain. It is being done.

[0071] Hydromorphone can be formulated, for example, as an intravenous infusion composition for the treatment of pain. It is being done.

[0072] Oxycodone is formulated, for example, as an oral IR agent for treating pain. The rapid release of oxycodone using IR formulations particularly promotes euphoria and drug addiction. It is suitable for this purpose. Oxycodone promotes abuse and causes addiction in certain situations. It is known that...

[0073] Buprenorphine is used, for example, in transdermal patches (transdermal absorption therapy systems) to treat pain. It is formulated as (mu). Sublingual buprenorphine is also an toxic-forming opioid, for example It is used as an alternative therapy in which sublingual buprenorphine is administered instead of oxycodone. A new subcutaneous depot product has been approved by the USFDA under the name Sublocade®. It was recently approved. Subcutaneous injection once a month provides sustained release of buprenorphine. In opioid replacement therapy, alternative drugs, prescription medications, such as methadone or buprecede are used. Norphine (which is usually administered in controlled clinical settings) and other drugs are given to illegal drug users. It provides. Buprenorphine is an opioid partial agonist. This means that bupre Norphine can produce the usual opioid effects and side effects (e.g., euphoria). Although it is an opioid, its maximum effect is the same as that of a complete agonist such as oxycodone. This means it has less than the expected effect. Buprenorphine, at low doses, is used to treat opioid addiction. Sufficient to enable individuals to discontinue opioid misuse without experiencing withdrawal symptoms. It exerts an agonist effect. The agonist effect of buprenorphine is that its effect plateaus. The effect increases linearly as the drug dose is increased until it reaches a certain point, and even if the dose is increased further... It will no longer continue to increase. This is called the "ceiling effect." Therefore, buprenor Finn has a lower risk of abuse, addiction, and side effects compared to full opioid agonists. It has a risk, but that risk is limited by the ceiling effect. In fact, Buprenorfi When administered to individuals with opioid addiction, complete agonists remain in the bloodstream while complete agonists are present. It can actually block the effects of all opioid agonists, and withdrawal symptoms can be suddenly triggered. It is thought that buprenorphine is usually administered transdermally, buccally, sublingually, and intravenously. Oral treatment is thought to be ineffective due to widespread first-pass metabolism.

[0074] Currently, opioid agonists (oxycodone, fentanyl or hydrochloride) Certain combinations of buprenorphine and buprenorphine are equivalent to the same dose when administered alone. It has substantially the same analgesic effect as xicodone, fentanyl, or hydromorphone. It brings about respiratory depression, an overall suppression of euphoria and drug addiction, and improved safety. It has been found that this results in a profile. The following examples, as well as Please refer to Figures 5-10 and further figures.

[0075] Using specific oral therapies and specific combinations of oxycodone and buprenorphine The corresponding oral dosage form is substantially equivalent to the same dose of oxycodone administered alone. It has been found that while it provides an analgesic effect, it also induces euphoria and suppresses drug addiction. Please refer to Example 1 and Figures 11-15.

[0076] Oral administration of buprenorphine results in transdermal blood levels. It has also been found that... (See Figure 3.) Buprenorphine and oxycodone Oral IR administration yields similar blood curve shapes (the absolute amounts of the two drugs differ by approximately 100 times). It has also been found that this is the case. Please refer to Figure 16.

[0077] Methods of administration and dosage forms of fentanyl, hydromorphone, and buprenorphine. In certain embodiments, the present invention relates to a specific combination of hydromorphone and buprenorphine. The combination of hydromorphone and buprenorphine provides the corresponding hydromorphone. Compared to lufone monotherapy, it suppresses hydromorphone-induced respiratory depression by approximately 20% or more. In one embodiment, the combination of hydromorphone and buprenorphine is hydromorph It suppresses ointment-induced respiratory depression by more than one-third.

[0078] In a particular embodiment, the method for treating pain according to the present invention is (i) During administration period 1, the average infusion rate (mg / hour) during administration period 1 An effective amount of hydromorphone is administered at a rate of ( / hour), and at this time, the above-mentioned rate is used. The average injection rate of hydromorphone is obtained by dividing it by the duration of the above administration period 1. It is represented by equimolar amounts of free hydromorphone base administered inside, (ii) During administration period 2, the average infusion rate (mg / hour) during administration period 2 Another effective dose of buprenorphine is administered via prenorphine, and at this time, the average infusion rate is as described above. The amount of buprenorphine administered during the above administration period 2 is calculated by dividing the duration of the above administration period 2 by the duration of the above administration period 2. It is represented by equimolar amounts of free buprenorphine base, This includes administering it to patients who require it, Administration period 1 and administration period 2 overlap by at least 75%, and buprenorph is administered at the above average infusion rate. The ratio of ion to hydromorphone at the above average input rate is approximately 1:8000 to approximately 1:100. Alternatively, approximately 1:8000 to 1:200, or approximately 1:8000 to 1:400, This is approximately 1:8000 to 1:600, or approximately 1:8000 to 1:800, or It is approximately 1:4000 to 1:800, or approximately 1:3000 to 1:1100.

[0079] In a particular embodiment, the method for treating pain according to the present invention is (i) During administration period 1, the average infusion rate (mg / hour) during administration period 1 An effective amount of fentanyl is administered with antanil, and at this time, the average infusion rate of fentanyl is as described above. The amount is calculated by dividing the duration of the above administration period 1 by the equimolar amount of the amount administered during the above administration period 1. It is represented by a free entanyl base, (ii) During administration period 2, the average infusion rate (mg / hour) during administration period 2 Another effective dose of buprenorphine is administered via prenorphine, and at this time, the average infusion rate is as described above. The amount of buprenorphine administered during the above administration period 2 is calculated by dividing the duration of the above administration period 2 by the duration of the above administration period 2. It is represented by equimolar amounts of free buprenorphine base, This includes administering it to patients who require it, Administration period 1 and administration period 2 overlap by at least 75%, and buprenorph is administered at the above average infusion rate. The ratio of fentanyl to the above average injection rate is approximately 1:80 to approximately 1:0.5, or Approximately 1:80 to 1:1, or approximately 1:80 to 1:2, or approximately 1:80 to 1:4 , or approximately 1:80 to 1:6, or approximately 1:80 to 1:8, or approximately 1:40 The ratio is approximately 1:8, or approximately 1:30 to 1:11.

[0080] In certain embodiments of the present invention, fentanyl or hydromorphone and buprenorph The drug is administered via the same route of administration. In certain embodiments, hydromorphone is administered in approximately 1 mg dose. A rate of approximately 10 mg / hour, or approximately 2 mg / hour to approximately 8 mg / hour, This is at a rate of approximately 3 mg / hour to approximately 7 mg / hour, or approximately 3 mg / hour to approximately 5 mg / hour. The rate, or a rate of approximately 1 mg / hour to approximately 3.5 mg / hour, or approximately 3.5 mg / It is administered at a rate of approximately 10 mg / hour. In certain embodiments, hydromorphone is Approximately 1 mg / hour, approximately 3.5 mg / hour, approximately 4 mg / hour, approximately 4.5 mg / hour, or It is administered at a rate of approximately 10 mg / hour. In certain embodiments, fentanyl is administered at a rate of approximately 12 .5μg / hour, 25μg / hour, 50μg / hour, 75μg / hour, 100μg / hour It is administered at a rate of 150 μg / hour or 200 μg / hour.

[0081] In another embodiment of the present invention, fentanyl or hydromorphone and buprenorphine The drug is administered via different routes of administration. In certain embodiments, hydromorphone is administered in approximately 1 mg doses. A rate of approximately 10 mg / hour, or approximately 2 mg / hour to 8 mg / hour, At a rate of approximately 3 mg / hour to 7 mg / hour, or at a rate of approximately 3 mg / hour to 5 mg / hour. It is administered as follows: In certain embodiments, hydromorphone is administered at approximately 1 mg / hour, approximately 3.5 m Administer at a rate of g / hour, approximately 4 mg / hour, approximately 4.5 mg / hour, or approximately 10 mg / hour. In certain embodiments, fentanyl is administered at approximately 12.5 μg / hour and 25 μg / hour. Intervals, 50 μg / hour, 75 μg / hour, 100 μg / hour, 150 μg / hour, or It is administered at a rate of 200 μg / hour.

[0082] In certain embodiments of the method of the present invention, the route of administration is intravenous, intramuscular, or subcutaneous. The group is selected from sublingual administration, buccal administration, subcutaneous administration, and transdermal administration. In one embodiment, fentanyl is administered transdermally. In another embodiment, hydromorphone is administered intravenously. It is administered orally. In certain embodiments of the present invention, fentanyl and buprenorphine are administered transdermally. Administered by dose, and in certain other embodiments of the present invention, hydromorphone and bupreno Rufin is administered intravenously.

[0083] In certain embodiments of the present invention, fentanyl or hydromorphone and buprenorph The ingredients include intravenous composition, intramuscular composition, subcutaneous composition, sublingual composition, buccal composition, and subcutaneous ingredient. Administered in a dosage form independently selected from a plant-type system or a transdermal therapy system. The preferred dosage form of fentanyl is a transdermal therapeutic system, and hydromorphone The preferred dosage form is an intravenous composition. In certain embodiments of the present invention, fentanyl and b Prenorphine is a transdermal therapy system containing fentanyl and buprenorphine. It is administered as follows. The duration of administration is 1 to 7 days, for example, 1 day, 3 days, 3.5 days and For example, 7 days. In certain other embodiments of the present invention, hydromorphone and buppre Norphine is administered in a single intravenous composition containing buprenorphine and hydromorphone. The administration period is approximately 5 minutes to 24 hours, or approximately 15 minutes to 24 hours, or approximately 1 5 minutes to 12 hours, or approximately 30 minutes to 6 hours, or approximately 30 minutes to 3 hours, It takes approximately 30 minutes to 2 hours, and especially about 1 hour.

[0084] In certain embodiments of the present invention, buprenorphine alone is administered transdermally, and the duration of administration is 2 refers to periods ranging from 1 to 7 days, for example, 1 day, 3 days, 3.5 days, and 7 days.

[0085] In certain embodiments of the present invention, buprenorphine is administered subcutaneously, and the duration of administration is as follows: For approximately 1 month to 1 year, or approximately 1 month to 4 months, or approximately 1 month to 3 months. Yes, for example, you can choose from 1 month, 2 months, 3 months, 4 months, and 6 months.

[0086] blood level In certain embodiments, this includes administering hydromorphone and buprenorphine. The method of the invention involves administering a single dose, after which buprenorphine and hydromorphone are each average C max or average C av This results in an average C of buprenorphine. max or average C a v and the average C of hydromorphone max or average C av The ratio is approximately 0.001 to approximately 0. It is characterized by being 006.

[0087] In certain embodiments, the present invention includes administering fentanyl and buprenorphine. The method involves administering a single dose, after which buprenorphine and fentanyl are each measured by average C. max or average C av This results in an average C of buprenorphine. max or average C av and The average C of antanyl max or average C av The ratio is approximately 0.02 to 0.3. Features include: In certain embodiments, the average C of buprenorphine max or C av and The average C of antanyl max or Cav The ratio is approximately 0.02 to 0.2.

[0088] In a particular embodiment, (i) a certain amount of oxycodone and (ii) a certain amount of buprenorph The therapeutic method of the present invention, which includes administering to a patient who requires a certain treatment, is preferred. Alternatively, a single dose of oxycodone and buprenorphine may be administered simultaneously to one control group under fasting conditions. Furthermore, the average C of buprenorphine was at least approximately 1:280. max and the average C of oxycodone max A characteristic feature is that the ratio of buprenorphine is obtained. In a particular embodiment, the ratio of buprenorphine Average C max and the average C of oxycodone max The ratio is at least about 1:250, or At least approximately 1:230, or at least approximately 1:200, or at least approximately 1: It is 180. In certain embodiments, the average C of buprenorphine max and oxycodone average C max The ratio is preferably about 1:50 to about 1:280 under fasting conditions. Or, approximately 1:50 to 1:250, or approximately 1:80 to 1:230, or approximately 1: The ratio is approximately 1:200 to 1:100 to 1:180.

[0089] According to certain such embodiments, oxycodone is administered in the form of oxycodone hydrochloride. In other such embodiments, oxycodone is oxycodone myristate. It is administered in the form of buprenorphine. According to certain such embodiments, buprenorphine is administered in the form of buprenorphine It is administered in the form of rufine hydrochloride. According to a particular embodiment, a certain amount of buprenor is administered. Fin is administered in an immediate-release form. According to a particular embodiment, a certain amount of oxycodone is administered. The above-mentioned fixed amount of buprenorphine is administered in an immediate-release form.

[0090] In certain such embodiments, the treatment method preferably involves a group of subjects under fasting conditions. After simultaneous administration of a single dose of oxycodone and buprenorphine, the ratio was approximately 1.5:1 or less, or Buprenorphine at approximately 1.3:1 or less, or approximately 1.1:1 or less, or approximately 1:1 or less The average T max and the average T of oxycodone max It is characterized by obtaining the ratio of [specific value]. In a specific embodiment, the treatment method preferably involves administering oxycodone to one control group under fasting conditions. After simultaneous administration of a single dose of buprenorphine, the above simultaneous administration was performed on the above control group, oxycod The average T max Compared to the average T of buprenorphine, it is faster. max to bring about Features include: In certain embodiments, the treatment method preferably involves a single group of subjects under fasting conditions. After the simultaneous administration of a single dose of oxycodone and buprenorphine, the above simultaneous administration was performed on the above control group. to approximately 0.1:1 to approximately 1.5:1, or approximately 0.1:1 to approximately 1.3:1, or approximately 0 0.1:1 to approximately 1.1:1, or approximately 0.1:1 to approximately 1:1, or approximately 0.1:1 to approximately 0.9:1 mean T of buprenorphine max and the average T of oxycodone max The ratio of It is characterized by being dripped. According to a particular such embodiment, oxycodone is oxyco It is administered in the form of oxycodone hydrochloride. In other such embodiments, oxycodone is administered as oxycodone. It is administered in the form of cycodone myristate. According to certain such embodiments, Renorphine is administered in the form of buprenorphine hydrochloride. According to certain embodiments, The above-mentioned fixed amount of buprenorphine is administered in an immediate-release form. According to a particular embodiment, The specified amount of oxycodone is administered in an immediate-release form, and the specified amount of buprenorphine is administered immediately It is administered as a release type.

[0091] In a particular embodiment, (i) a certain amount of oxycodone and (ii) a certain amount of buprenorph The therapeutic treatment of the present invention as described herein, which includes administering it simultaneously to patients who require it. The treatment method is characterized by simultaneous administration being oral administration. In a specific embodiment, simultaneous administration This refers to both the above-mentioned constant amount of buprenorphine and the above-mentioned constant amount of oxycodone as specified herein. This is an oral dosage form administration that includes [the substance].

[0092] In a particular embodiment, (i) a certain amount of oxycodone and (ii) a certain amount of buprenorph The therapeutic treatment of the present invention as described herein, which includes administering it simultaneously to patients who require it. The treatment method involves orally administering the above-mentioned fixed amount of oxycodone (i.e., the above-mentioned fixed amount of oxycodone (In the form of an oral dosage containing n), administer a certain amount of buprenorphine transdermally (i.e., the above It is characterized by being in a transdermal dosage form (e.g., a transdermal patch) containing a certain amount of buprenorphine. One example of a transdermal dosage form containing buprenorphine is administered for a maximum duration of 7 days. Norphine is commercially available in dose intensities of 5, 10, and 20 micrograms / hour. This is a Butrans (registered trademark) patch.

[0093] The above-mentioned fixed amount of oxycodone is administered orally, and the above-mentioned fixed dose of buprenorphine is administered transdermally. In a particular embodiment, the oral dosage form containing the above-mentioned fixed amount of oxycodone is a liquid dosage form, for example These are liquid formulations, suspensions, or emulsions. A certain amount of oxycodone is administered orally. In a specific embodiment in which a certain amount of buprenorphine is administered transdermally, the certain amount of ox Oral dosage forms containing cycodone include solid dosage forms, such as tablets or capsules. In this embodiment, the oral dosage form is approximately 5 mg to approximately 50 mg of oxycodone hydrochloride (Mw=35 1.82 g / mol), preferably about 5 mg to about 40 mg of oxycodone hydrochloride (Mw This particular product contains a fixed equimolar amount of oxycodone (351.82 g / mol). In such embodiments, the oral dosage form contains a fixed amount of immediate-release oxycodone.

[0094] In a particular embodiment, (i) a certain amount of oxycodone and (ii) a certain amount of buprenorph The therapeutic treatment of the present invention as described herein, which includes administering it simultaneously to patients who require it. The treatment method involves orally administering the above-mentioned fixed amount of oxycodone (i.e., the above-mentioned fixed amount of oxycodone (In the form of an oral dosage form containing n), administer a certain amount of buprenorphine subcutaneously (i.e., the above Subcutaneous formulations containing a certain amount of buprenorphine (for example, containing the above-mentioned certain amount of buprenorphine) It is characterized by (such as subcutaneous implants). In certain such embodiments, the bup Lenorphine average tone max and the average C of oxycodone max The ratio is buprenorphine The mean steady-state plasma concentration of oxycodone and the mean C max It is defined as the ratio of [the two proportions].

[0095] An example of a subcutaneous dosage form used in the therapeutic method of the present invention is Probuphine ( This is a subcutaneous implant marketed under the trademark name (registered trademark). Prescription information (02 According to the 2018 edition, Probuphine (registered trademark) is used to treat opioid addiction. It is stated that it is for therapeutic use. Probuphine® implants are It contains buprenorphine hydrochloride as the active ingredient. (Registered Trademark) The implant is a sterile, single, off-white, soft, and flexible rod. This is a pharmaceutical product. Each stick is 26mm long, 2.5mm in diameter, and contains 80mg. Buprenorphine hydrochloride (equivalent to 74.2 mg of buprenorphine base) and eth Contains vinyl acetate. Probuphine® is a registered trademark of skilled medical professionals. It is implanted subcutaneously by a doctor and provides sustained delivery of buprenorphine for up to 6 months. It is designed to be applied by dripping. According to the prescription information, it is used for maintenance therapy of opioid dependence. Each dose is administered subcutaneously to the inner side of the upper arm for 6 months of treatment, until the end of the 6-month period. It consists of four Probuphine® implants that are removed. In pharmacokinetic studies, the median time to buprenorphine's maximum plasma concentration was, Pro The first buprenorphine was present 12 hours after buphine® insertion. After the peak, plasma buprenorphine concentrations slowly decrease, reaching a steady state by approximately 4 weeks. The plasma buprenorphine concentration reached the current state. The mean steady-state plasma buprenorphine concentration was The level is approximately 0.5 ng / mL to 1.0 ng / mL, and over a 24-week treatment period. This was maintained for 20 weeks (from week 4 to week 24) (prescription information from 02 / 2018, Smith et al., Probuphine (Buprenorphine) )Subdermal Implants for the Treatment Of Opioid-Dependent Patients,Pharmacy and See Therapeutics 2017 Aug;42(8):505-508. (and). In order to achieve a plasma buprenorphine concentration suitable for the therapeutic method of the present invention, for example, The number and / or size of the implants may be adjusted.

[0096] The above-mentioned fixed amount of oxycodone is administered orally, and the above-mentioned fixed dose of buprenorphine is administered subcutaneously. In a particular embodiment, the oral dosage form containing the above-mentioned fixed amount of oxycodone is a liquid dosage form, for example These are liquid formulations, suspensions, or emulsions. A certain amount of oxycodone is administered orally. In a specific embodiment in which a certain amount of buprenorphine is administered subcutaneously, the certain amount of ox Oral dosage forms containing cycodone include solid dosage forms, such as tablets or capsules. In this embodiment, the oral dosage form is approximately 5 mg to approximately 50 mg of oxycodone hydrochloride (Mw=35 1.82 g / mol), preferably about 5 mg to about 40 mg of oxycodone hydrochloride (Mw This particular product contains a fixed equimolar amount of oxycodone (351.82 g / mol). In such embodiments, the oral dosage form contains a fixed amount of immediate-release oxycodone.

[0097] Weight ratio and quantity of oral dosage forms In certain embodiments, the treatment method is (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, It is characterized by administering it to patients who require an oral dosage form that includes it. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is equal to equimolar amounts of buprenorphine. A constant amount of ruphin base (mg) (Mw = 467.64 g / mol) in a dosage form A certain amount of buprenorphine and an equimolar amount of oxycodone hydrochloride (mg) (Mw=351). When calculating using a fixed amount of oxycodone in a dosage form expressed as 82 g / mol) The ratio is greater than 1:40. In a particular embodiment, a certain amount of buprenorphine and a certain amount of oxy The weight ratio of sycodon mentioned above is approximately 1:3 to over 1:40, or approximately 1:38 or higher, or Approximately 1:3 to 1:38, or approximately 1:4 to over 1:40, or approximately 1:4 to 1:38 , or approximately 1:5 to over 1:40, or approximately 1:5 to approximately 1:38, or approximately 1:5 Approximately 1:35, or approximately 1:5 to 1:30, or approximately 1:6 to over 1:40, or Approximately 1:6 to 1:38, or approximately 1:6 to 1:35, or approximately 1:6 to 1:30 , or approximately 1:6 to 1:28, or approximately 1:6 to 1:20, or approximately 1:8 Approximately 1:30, or approximately 1:8 to 1:28, or approximately 1:8 to 1:20, or Approximately 1:8 to 1:15, or approximately 1:10 to 1:20, or approximately 1:10 to 1: 15. According to certain such embodiments, oxycodone is oxycodone hydrochloride It exists in a form. In other such embodiments, oxycodone is oxycodone myris It exists in the form of a tinate. According to certain such embodiments, buprenorphine is bu It exists in the form of prenorphine hydrochloride. According to certain embodiments, the dosage form is immediate-release. It contains the above-mentioned certain amount of buprenorphine. According to a particular embodiment, the dosage form is immediate-release. It contains the above-mentioned fixed amount of oxycodone and the above-mentioned fixed amount of immediate-release buprenorphine.

[0098] In certain such embodiments, the treatment method involves approximately 5 mg to approximately 50 mg of oxycodone salt. Equimolar amounts, or approximately 5 mg to approximately 40 mg, relative to the salt acid (Mw = 351.82 g / mol). Equimolar amounts of oxycodone hydrochloride (Mw = 351.82 g / mol) relative to g, or Approximately 10 mg, 15 mg, 20 mg, 30 mg, or 40 mg of oxycodone salt A fixed amount of oxycodone in equimolar form relative to the salt (Mw = 351.82 g / mol) It is characterized by containing. According to certain such embodiments, oxycodone is oxyco It exists in the form of oxycodone hydrochloride. In other such embodiments, oxycodone is oxycodone It exists in the form of codone myristate salt. According to certain such embodiments, bupreno Rufine exists in the form of buprenorphine hydrochloride. According to certain embodiments, the dosage form is , containing a fixed amount of buprenorphine in an immediate-release form. According to a particular embodiment, the dosage form is , an immediate-release type of a certain amount of oxycodone and an immediate-release type of a certain amount of buprenorphine It includes n.

[0099] In certain such embodiments, the treatment method is a dosage form of about 40 mg of oxycodone hydrochloride. A fixed amount of equimolar oxycodone is added to the salt (Mw = 351.82 g / mol), and approximately Equivalent to 1 mg to approximately 6 mg of buprenorphine base (Mw = 467.64 g / mol) It contains a certain molar amount of buprenorphine, or the dosage form is approximately 40 mg of oxycod Equimolar amounts of a fixed amount of oxycodone and hydroxylase are added to hydroxylase hydrochloride (Mw = 351.82 g / mol). Furthermore, approximately 2 mg to 5 mg of buprenorphine base (Mw = 467.64 g / mol) It is characterized by containing an equimolar constant amount of buprenorphine. Depending on the application form, oxycodone exists in the form of oxycodone hydrochloride. In this embodiment, oxycodone exists in the form of oxycodone myristate salt. According to such embodiments, buprenorphine exists in the form of buprenorphine hydrochloride. It exists. According to a particular embodiment, the dosage form is an immediate-release type of a certain amount of buprenorphine. Includes. According to a particular embodiment, the dosage form is an immediate-release type containing a certain amount of oxycodone and Contains a fixed amount of buprenorphine in an immediate-release form.

[0100] In certain embodiments, the treatment method is (i) A fixed amount of immediate-release oxycodone, (ii) A fixed amount of buprenorphine in an immediate-release form, It is characterized by administering it to patients who require an oral immediate-release (IR) dosage form, The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is equal to equimolar amounts of buprenorphine. A constant amount of ruphin base (mg) (Mw = 467.64 g / mol) in a dosage form A certain amount of buprenorphine and an equimolar amount of oxycodone hydrochloride (mg) (Mw=351). When calculating using a fixed amount of oxycodone in a dosage form expressed as 82 g / mol) The ratio is approximately 1:100 or more. In a particular embodiment, a certain amount of buprenorphine and a certain amount The above weight ratio of oxycodone is approximately 1:80 or higher, or approximately 1:60 or higher, or Approximately 1:50 or longer, or approximately 1:40 or longer, or approximately 1:6 to approximately 1:100, or Approximately 1:6 to 1:80, or approximately 1:6 to 1:60, or approximately 1:6 to 1:50 , or approximately 1:6 to 1:40, or approximately 1:8 to 1:100, or approximately 1:8 ~approximately 1:80, or approximately 1:8~1:60, or approximately 1:8~1:50, or , 1:8 to approximately 1:40, or approximately 1:10 to approximately 1:100, or approximately 1:10 to approximately 1 :80, or approximately 1:10 to 1:60, or approximately 1:10 to 1:50, or Approximately 1:10 to 1:40, or approximately 1:20 to 1:100, or approximately 1:20 to 1:40 1:80, or approximately 1:20 to 1:60, or approximately 1:20 to 1:50, or It is approximately 1:20 to 1:40, or approximately 1:20 to 1:30. According to one embodiment, oxycodone exists in the form of oxycodone hydrochloride. In such embodiments, oxycodone exists in the form of oxycodone myristate salt. According to such a specific embodiment, buprenorphine is in the form of buprenorphine hydrochloride. exist.

[0101] In certain such embodiments, the treatment method involves approximately 5 mg to approximately 50 mg of oxycodone salt. Equimolar amounts, or approximately 5 mg to approximately 40 mg, relative to the salt acid (Mw = 351.82 g / mol). Equimolar amounts of oxycodone hydrochloride (Mw = 351.82 g / mol) relative to g, or Approximately 10 mg, 15 mg, 20 mg, 30 mg, or 40 mg of oxycodone salt A fixed amount of oxycodone in equimolar form relative to the salt (Mw = 351.82 g / mol) It is characterized by containing. According to certain such embodiments, oxycodone is oxyco It exists in the form of oxycodone hydrochloride. In other such embodiments, oxycodone is oxycodone It exists in the form of codone myristate salt. According to certain such embodiments, bupreno Rufine exists in the form of buprenorphine hydrochloride.

[0102] In certain such embodiments, the treatment method is a dosage form of about 40 mg of oxycodone hydrochloride. A fixed amount of equimolar oxycodone is added to the salt (Mw = 351.82 g / mol), and approximately Equivalent to 1 mg to approximately 5 mg of buprenorphine base (Mw = 467.64 g / mol) It contains a certain molar amount of buprenorphine, or the dosage form is approximately 40 mg of oxycod Equimolar amounts of a fixed amount of oxycodone and hydroxylase are added to hydroxylase hydrochloride (Mw = 351.82 g / mol). Furthermore, approximately 1 mg to 4 mg of buprenorphine base (Mw = 467.64 g / mol) It is characterized by containing an equimolar constant amount of buprenorphine. Depending on the application form, oxycodone exists in the form of oxycodone hydrochloride. In this embodiment, oxycodone exists in the form of oxycodone myristate salt. According to such embodiments, buprenorphine exists in the form of buprenorphine hydrochloride. To exist.

[0103] Dosage form containing oxycodone and buprenorphine According to a particular embodiment, the dosage form provides at least one dose after administration in one control group. The average C of buprenorphine is approximately 1:280. max and the average C of oxycodone max The ratio It is characterized by being obtained. In a particular embodiment, the average C of buprenorphine max and The average C of xycodone max The ratio is at least about 1:250, or at least about 1 :230, or at least approximately 1:200, or at least approximately 1:180. In certain embodiments, the average C of buprenorphine max and the average C of oxycodone max of The ratio is approximately 1:50 to 1:280, or approximately 1:50 to 1:250, or approximately 1 :80~approximately 1:230, or approximately 1:100~approximately 1:200, or approximately 1:100~ It is approximately 1:180. According to certain such embodiments, oxycodone is oxycodone It exists in the form of a hydrochloride salt. In other such embodiments, oxycodone is oxycod It exists in the form of myristate salt. According to certain such embodiments, buprenorph The fin exists in the form of buprenorphine hydrochloride. According to a particular embodiment, the dosage form is immediately It contains the above-mentioned fixed amount of buprenorphine in an instant release form. According to a particular embodiment, the dosage form is immediate A fixed amount of oxycodone released at intervals and a fixed amount of buprenorphine released immediately are used. include.

[0104] According to a particular embodiment, the dosage form is an equimolar amount of buprenorphine base (mg) (Mw = A certain amount of buprenorphine in a dosage form expressed as 467.64 g / mol, A drug expressed in equimolar amounts of oxycodone hydrochloride (mg) (Mw = 351.82 g / mol) When calculating using a certain amount of oxycodone in the form, a certain amount greater than 1:40 It is characterized by a weight ratio of buprenorphine to a certain amount of oxycodone. In certain embodiments The above weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is approximately 1:3~1 :40 or more, or approximately 1:38 or more, or approximately 1:3 to approximately 1:38, or approximately 1:4 ~1:40+, or approximately 1:40~1:38, or approximately 1:5~1:40+, Approximately 1:5 to 1:38, or approximately 1:5 to 1:35, or approximately 1:5 to 1:3 0, or approximately 1:6 to over 1:40, or approximately 1:6 to approximately 1:38, or approximately 1:6 ~approximately 1:35, or approximately 1:6~1:30, or approximately 1:6~1:28, or Approximately 1:6 to 1:20, or approximately 1:8 to 1:30, or approximately 1:8 to 1:20 8, or approximately 1:8 to 1:20, or approximately 1:8 to 1:15, or approximately 1:1 0 to approximately 1:20, or approximately 1:10 to approximately 1:15. According to this, oxycodone exists in the form of oxycodone hydrochloride. Other such implementations Morphologically, oxycodone exists in the form of oxycodone myristate. According to one embodiment, buprenorphine exists in the form of buprenorphine hydrochloride. According to a particular embodiment, the dosage form comprises a fixed amount of buprenorphine in an immediate-release form. According to a particular embodiment, the dosage form is an immediate-release type containing a fixed amount of oxycodone and an immediate-release type. Contains a certain amount of buprenorphine of the above type.

[0105] According to certain such embodiments, the dosage form is approximately 40 mg of oxycodone hydrochloride. A fixed amount of equimolar oxycodone is added to the salt (Mw = 351.82 g / mol), and approximately Equivalent to 1 mg to approximately 6 mg of buprenorphine base (Mw = 467.64 g / mol) It contains a certain molar amount of buprenorphine, or the dosage form is approximately 40 mg of oxycod Equimolar amounts of a fixed amount of oxycodone and hydroxylase are added to hydroxylase hydrochloride (Mw = 351.82 g / mol). Furthermore, approximately 2 mg to 5 mg of buprenorphine base (Mw = 467.64 g / mol) It is characterized by containing an equimolar constant amount of buprenorphine. Depending on the application form, oxycodone exists in the form of oxycodone hydrochloride. In this embodiment, oxycodone exists in the form of oxycodone myristate salt. According to such embodiments, buprenorphine exists in the form of buprenorphine hydrochloride. It exists. According to a particular embodiment, the dosage form is an immediate-release type of a certain amount of buprenorphine. Includes. According to a particular embodiment, the dosage form is an immediate-release type containing a certain amount of oxycodone and Contains a fixed amount of buprenorphine in an immediate-release form.

[0106] According to a particular embodiment, the dosage form is a certain amount of buprenorphine and a certain amount of oxycodone. The weight ratio is equal to equimolar amounts of buprenorphine base (mg) (Mw = 467.64 g / mo A certain amount of buprenorphine and an equimolar amount of oxycodone in the dosage form represented by (l). A certain amount in a dosage form expressed as nitrate hydrochloride (mg) (Mw=351.82 g / mol) When calculating using oxycodone, the immediate-release (IR) dosage form is approximately 1:100 or higher. It is characterized by having a certain amount of buprenorphine and The above weight ratio of quantitative oxycodone is approximately 1:80 or higher, or approximately 1:60 or higher. This includes approximately 1:50 or longer, or approximately 1:40 or longer, or approximately 1:6 to approximately 1:100, and This is approximately 1:6 to 1:80, or approximately 1:6 to 1:60, or approximately 1:6 to 1: 50, or approximately 1:6 to 1:40, or approximately 1:8 to 1:100, or approximately 1 :8 to approximately 1:80, or approximately 1:8 to approximately 1:60, or approximately 1:8 to approximately 1:50, Alternatively, 1:8 to approximately 1:40, or approximately 1:10 to approximately 1:100, or approximately 1:10 to Approximately 1:80, or approximately 1:10 to 1:60, or approximately 1:10 to 1:50, This is approximately 1:10 to 1:40, or approximately 1:20 to 1:100, or approximately 1:20 ~approximately 1:80, or approximately 1:20~1:60, or approximately 1:20~1:50, The timeframe is approximately 1:20 to 1:40, or approximately 1:20 to 1:30.

[0107] According to certain embodiments of this type, the oral immediate-release dosage form is approximately 5 mg to approximately 50 mg. Equimolar, or approximately 5 m, relative to xicodone hydrochloride (Mw = 351.82 g / mol) g is equivalent to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) in equimolar form. or approximately 10mg, 15mg, 20mg, 30mg, or 40mg of Equimolar amounts of a fixed amount of oxycodone hydrochloride (Mw = 351.82 g / mol) The oral immediate-release dosage form is characterized by containing a codon. According to certain such embodiments, Oxycodone exists in the form of oxycodone hydrochloride. In other such embodiments Oxycodone exists in the form of oxycodone myristate salt. Depending on the application method, buprenorphine exists in the form of buprenorphine hydrochloride.

[0108] In certain such embodiments, the oral immediate-release dosage form is a dosage form of approximately 40 mg of oxyco A constant equimolar amount of oxycodone is added to dovone hydrochloride (Mw = 351.82 g / mol). In addition, approximately 1 mg to 5 mg of buprenorphine base (Mw = 467.64 g / mol) In contrast, it contains an equimolar amount of buprenorphine, or the dosage form is approximately 40 mg. A constant amount of equimolar oxycodone hydrochloride (Mw = 351.82 g / mol) is added to xicodone hydrochloride (Mw = 351.82 g / mol). Don, and approximately 1 mg to 4 mg of buprenorphine base (Mw = 467.64 g / mol). It is characterized by containing a constant equimolar amount of buprenorphine per l. According to such embodiments, oxycodone exists in the form of oxycodone hydrochloride. In such embodiments, oxycodone exists in the form of oxycodone myristate salt. According to certain such embodiments, buprenorphine is buprenorphine hydrochloride. It exists in form.

[0109] In the above embodiment, the dosage form is a liquid in the form of a solution, suspension, or emulsion, for example. Alternatively, a syrup or similar preparation may be used.

[0110] In the above embodiment, the dosage form is in the form of a solid dosage form, for example, a tablet, a multi-particle preparation or Please refrain from using capsules or similar products.

[0111] Pharmacodynamic reactions According to a particular embodiment, a method and / or dosage form, in particular a certain amount of bupre in the dosage form When norphin is administered simultaneously, the above-mentioned fixed amount of oxycodone and fe in the dosage form should be used when it is administered alone. Oxycodone, fentanyl, or hydromorphone are found in fentanyl or hydromorphone. It provides prevention or suppression of the toxic pharmacokinetic reactions of hydromorphone.

[0112] The pharmacokinetic reactions to adverse drug reactions include euphoria, euphoria, bowel dysfunction, nausea, vomiting, drowsiness, dizziness, and respiratory depression. Symptoms include: dysregulation, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium, miosis, and itching. A group consisting of urticaria, urinary retention, hyperalgesia, allodynia, physical dependence, and tolerance is selected. In certain embodiments, the adverse drug dynamics response includes respiratory depression, euphoria, euphoria, and bowel dysfunction. Selected from the group consisting of harmful substances. In other embodiments, the toxic drug dynamic response is euphoria and / or In other embodiments, the toxic drug dynamic response is euphoria. In one embodiment, the toxic drug mechanical response is intestinal dysfunction. In other embodiments, the toxic drug mechanical response is The response is respiratory depression.

[0113] In other embodiments, the pharmacodynamic reaction is toxic (or lethal).

[0114] According to certain embodiments, the method and / or dosage form is less when measured using comparative tests. At least 15%, or at least 20%, or at least 25%, or less "Exhilaration" decreases by at least 30%, or at least 35%, or at least 40%. The average E of "Sensitivity VAS" max This results in [the following]. See Figure 8.

[0115] According to a particular embodiment, a method and / or dosage form, in particular a certain amount of bupre in the dosage form The simultaneous administration of norphine is necessary because, when administered alone, the aforementioned certain amount of oxycodone in the dosage form... This results in the prevention or suppression of oxycodone drug addiction, which is recognized by the drug.

[0116] According to certain embodiments, the method and / or dosage form is less when measured using comparative tests. At least 15%, or at least 20%, or at least 25%, or less The average E of the "temporary drug preference VAS" decreases by at least 30%. max This brings about Figure 6. Please refer to this.

[0117] According to certain embodiments, the method and / or dosage form is less when measured using comparative tests. At least 15%, or at least 20%, or at least 25%, or less The average "overall drug preference VAS" will decrease by at least 30%, or at least 35%. E max This brings about [the desired outcome]. See Figure 9.

[0118] According to certain embodiments, the method and / or dosage form is less when measured using comparative tests. At least 15%, or at least 20%, or at least 25%, or less The mean E of the "drug reuse VAS" decreases by at least 30%, or at least 35%. ma x This brings about [the desired outcome]. See Figure 10.

[0119] According to certain such embodiments, the analgesic effect is substantial when measured using comparative tests. It does not decrease significantly. According to certain embodiments of this type, at 1, 2, 3 and 4 hours after administration The average "cold pain score (VAS)" measured using the cold-induced blood pressure test is measured using a comparative test. When determining the treatment method, the increase should not exceed 10% compared to the comparative treatment method. Please refer to Figures 11-15. .

[0120] According to certain embodiments, the method and / or dosage form may prevent the formation of poisoning, the occurrence of drug abuse, and or prevent or suppress the occurrence of recreational drug use.

[0121] According to certain other embodiments, the method and / or dosage form of the present invention is a single opioid It suppresses opioid-induced respiratory depression compared to the use of anticoagulants.

[0122] In other embodiments, the method and / or dosage form of the present invention provides a much improved safety profile. This can lead to, for example, the prevention or significant reduction of opioid-induced death due to overdose. To suppress.

[0123] According to a particular embodiment, the body contains both oxycodone and buprenorphine, in equal amounts of oxycodone. By administering an oral dosage form containing cycodone according to the present invention instead, a certain amount of oxycodone can be administered. To prevent or avoid the adverse drug reaction of oxycodone observed in the treatment of pain using don alone A method for suppressing pain is provided. The method involves using a fixed amount of oxycodone alone. This includes suppressing the drug dependence of oxycodone observed in the treatment of [condition].

[0124] According to certain embodiments, the present invention provides a dosage form for treating pain. This provides methods for preventing the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. do.

[0125] Buprenorphine monooral dosage form Buprenorphine is ineffective when administered orally due to its extensive first-pass metabolism. It is thought that... However, in Example 2, at present, 5 mg of bupreno A constant equimolar amount of IR-type bubu is added to ruphine base (Mw = 467.64 g / mol). Dosage forms containing lenorphine HCl are used for a period of at least 12 hours before Butrans(introduction) It has been found that it produces analgesic blood levels of 20 mcg / hour or higher (registered trademark). Please refer to Figure 3.

[0126] Therefore, according to certain embodiments, the present invention provides a certain opioid analgesic as the only opioid analgesic. An oral dosage form containing a certain amount of buprenorphine, preferably buprenorphine HCl, is required. The present invention relates to methods for treating pain, including administering it to patients.

[0127] According to a particular embodiment, the present invention provides a certain amount of bupre as the sole opioid analgesic. This invention relates to an oral dosage form containing norphine, preferably buprenorphine HCl.

[0128] According to a particular embodiment, buprenorphine is 1 to 40 mg of buprenorphine base (Mw = 467.64 g / mol) in equimolar amounts, or 2.5, 5, 1 Buprenorphine base (Mw = 467.64 g / m²) in 0, 15, 20, 30, and 40 mg doses. It is present in the dosage form in an equimolar constant amount relative to ol. According to such embodiments, 1 The daily dose is 1-40 mg of buprenorphine base (Mw = 467.64 g / mol) It is an equimolar constant amount. In certain embodiments, the dosage form contains IR-type buprenorphine. In certain embodiments, buprenorphine is in the form of buprenorphine HCl.

[0129] According to a particular embodiment, the dosage form may be a liquid or a solid, for example, a liquid, a suspension, or an emulsion. These include syrups, tablets, or capsules.

[0130] Further Embodiments Taking the above into consideration, a particular embodiment of the present invention relates to the following. Clause 1: (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, An oral dosage form containing, The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is equal to an equimolar amount In the dosage form represented by buprenorphine base (mg) (Mw = 467.64 g / mol) The aforementioned fixed amount of buprenorphine and equimolar amount of oxycodone hydrochloride (mg) The certain amount of oxyco in the dosage form (Mw = 351.82 g / mol) When calculating using "don," if the ratio is greater than 1:40, The aforementioned oral dosage form.

[0131] Clause 2. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is The oral dosage form described in Clause 1, with a ratio of approximately 1:38 or higher.

[0132] Clause 3. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is Oral preparations as described in Clause 1, with a ratio of approximately 1:3 to over 1:40, or approximately 1:3 to approximately 1:38. shape.

[0133] Clause 4. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is Oral preparations as described in Clause 1, which have a ratio of approximately 1:4 to over 1:40, or approximately 1:4 to approximately 1:38. shape.

[0134] Clause 5. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is Oral preparations as described in Clause 1, with a ratio of approximately 1:5 to over 1:40, or approximately 1:5 to approximately 1:38. shape.

[0135] Clause 6. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is The ratio is approximately 1:5 to 1:35, preferably approximately 1:5 to 1:30, as described in Clause 1. Oral dosage form.

[0136] Article 7. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is Oral preparations as described in Clause 1, with a ratio of approximately 1:6 to over 1:40, or approximately 1:6 to approximately 1:38. shape.

[0137] Clause 8: The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is , approximately 1:6 to approximately 1:35, preferably approximately 1:6 to approximately 1:30, more preferably approximately 1: The oral dosage forms described in Clause 1, which are 6 to approximately 1:28, or approximately 1:6 to approximately 1:20.

[0138] Clause 9: The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is The oral dosage form described in Clause 1 is approximately 1:8 to 1:30.

[0139] Clause 10: The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The oral dosage form is approximately 1:8 to approximately 1:28, as described in Clause 1.

[0140] Clause 11: The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The oral dosage form is as described in Clause 1, with a ratio of approximately 1:8 to approximately 1:20.

[0141] Clause 12: The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The oral dosage form is approximately 1:8 to approximately 1:15, as described in Clause 1.

[0142] Clause 13: The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The oral dosage form is as described in Clause 1, with a ratio of approximately 1:10 to approximately 1:20.

[0143] Clause 14: The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The oral dosage form is approximately 1:10 to 1:15, as described in Clause 1.

[0144] Clause 15: The dosage form shall be approximately 5 mg to approximately 50 mg of oxycodone hydrochloride (Mw=351). 82 g / mol), preferably about 5 mg to about 40 mg of oxycodone hydrochloride (Mw=3 A fixed amount of equimolar oxycodone per 51.82 g / mol) is included in clauses 1 to 1. The oral dosage form described in any one of item 14.

[0145] Clause 16: The dosage form is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) is equivalent to one equimolar unit An oral dosage form according to any one of clauses 1 to 14, containing a quantitative amount of oxycodone.

[0146] Clause 17: The dosage form is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) is equivalent to one equimolar unit The oral dosage form according to Clause 16, comprising a fixed amount of oxycodone hydrochloride.

[0147] Clause 18: The dosage form may be approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) is equivalent to one equimolar unit The oral dosage form according to Clause 16, comprising a fixed amount of oxycodone myristate.

[0148] Clause 19: The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / m²). A fixed amount of oxycodone in equimolar proportions to (ol), and approximately 1 mg to 6 mg of buprenor. A constant equimolar amount of buprenorphine is used for each fin base (Mw = 467.64 g / mol). An oral dosage form, including n, as described in any one of clauses 1 to 14.

[0149] Clause 20: The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / m²). A fixed amount of oxycodone in equimolar proportions to (ol), and approximately 2 mg to 5 mg of buprenor. A constant equimolar amount of buprenorphine is used for each fin base (Mw = 467.64 g / mol). An oral dosage form, including n, as described in any one of clauses 1 to 14.

[0150] Clause 21: The oxycodone is oxycodone hydrochloride, and the buprenorphine is bu Prenorphine hydrochloride, one of the following: Clauses 1 through 16, 19 and 20 The oral dosage form as described in the section.

[0151] Clause 22: The dosage form contains the same fixed amount of buprenorphine as described in Clause 1, which is an immediate-release form. The oral dosage form described in any one of the clauses of Article 21.

[0152] Clause 23: The dosage form is an immediate-release form of a certain amount of oxycodone, and an immediate-release form Oral oral in any one of Clauses 1 to 22, comprising the aforementioned fixed amount of buprenorphine. Dosage form.

[0153] Clause 24: The dosage form is a liquid dosage form as described in any one of Clauses 1 to 23. Oral dosage form.

[0154] Clause 25: The dosage form is a liquid, a suspension, or an emulsion, preferably a liquid. , the oral dosage form as specified in Article 24.

[0155] Clause 26: The dosage form is a solid dosage form, as described in any one of Clauses 1 to 23. Oral dosage form.

[0156] Clause 27: The oral dosage form according to Clause 26, wherein the dosage form is a tablet or a capsule.

[0157] Clause 28: After a single dose is administered, the dosage form shall be administered to one control group at a ratio of at least approximately 1:280 Average C of buprenorphine max and the average C of oxycodone max The clause that brings about the ratio An oral dosage form as specified in any one of clauses 1 to 27.

[0158] Clause 29: Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The oral dosage form described in Clause 28 is at least about 1:250.

[0159] Clause 30: Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The oral dosage form described in Clause 28 is at least about 1:230.

[0160] Clause 31: Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The oral dosage form described in Clause 28 is at least about 1:200.

[0161] Clause 32: Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The oral dosage form described in Clause 28 is at least about 1:180.

[0162] Clause 33: Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The oral dosage form described in Clause 28 is approximately 1:50 to approximately 1:280.

[0163] Clause 34: Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The oral dosage form described in Clause 28 is approximately 1:50 to approximately 1:250.

[0164] Clause 35: Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The oral dosage form described in Clause 28 is approximately 1:80 to approximately 1:230.

[0165] Clause 36: Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The oral dosage form described in Clause 28 is approximately 1:100 to approximately 1:200.

[0166] Clause 37: The average C of buprenorphine max and the average C of oxycodone max for the said ratio is from about 1:100 to about 1:180, for the oral dosage form described in Clause 28.

[0167] Clause 38: After single-dose administration, the said dosage form provides to the said subject group a ratio of the average T of buprenorphine to the average T of oxycodone max as further described in Clause 28 max for the oral dosage form described in any one of Clauses 28 to Clause 37.

[0168] Clause 39: The said ratio of the average T of buprenorphine max to the average T of oxycodone max is about 1.3: I or less, for the oral dosage form described in Clause 38.

[0169] Clause 40: The said ratio of the average T of buprenorphine max to the average T of oxycodone max is about 1.1:1 or less, for the oral dosage form described in Clause 38.

[0170] Clause 41: The said ratio of the average T of buprenorphine to the average T of oxycodone max is about 1:1 or less, for the oral dosage form described in Clause 38. max

[0171] is about 1:1 or less, for the oral dosage form described in Clause 38.

[0171] Clause 42: After single-dose administration, the said dosage form provides to the said subject group an average T of buprenorphine max earlier than the average T of oxycodone max for the oral dosage form described in any one of Clauses 28 to Clause 37.

[0172] Clause 43: After single-dose administration, the said dosage form provides to the said subject group a ratio of about 0.1:1 to about 1.5:1 Preferably about 0.1:1 to about 1.3:1, more preferably about 0.1:1 to about 1.1 :1, most preferably about 0.1:1 to about 1:1, or about 0.1:1 to about 0.9:1 The average T of buprenorphine max and the average T of oxycodone max This will bring about an even greater ratio. or any one of the oral dosage forms specified in any one of clauses 28 to 42.

[0173] Clause 44: (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, This includes administering it to patients who require an oral dosage form that includes it. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is equal to an equimolar amount In the dosage form represented by buprenorphine base (mg) (Mw = 467.64 g / mol) The aforementioned fixed amount of buprenorphine and equimolar amount of oxycodone hydrochloride (mg) The certain amount of oxyco in the dosage form (Mw = 351.82 g / mol) When calculating using "don," if the ratio is greater than 1:40, Methods for treating pain.

[0174] Clause 45. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The method described in Clause 44, which is approximately 1:38 or greater.

[0175] Article 46. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone This refers to the ratio greater than approximately 1:3 to 1:40, or approximately 1:3 to approximately 1:38, as described in Article 44. Law.

[0176] Clause 47. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone This refers to the ratio greater than approximately 1:4 to 1:40, or approximately 1:4 to approximately 1:38, as described in Article 44. Law.

[0177] Clause 48. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone This refers to the person described in Article 44, whose ratio is approximately 1:5 to over 1:40, or approximately 1:5 to approximately 1:38. Law.

[0178] Article 49. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:5 to approximately 1:35, preferably approximately 1:5 to approximately 1:30, as stated in Clause 44. The method.

[0179] Clause 50. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone This refers to the ratio greater than approximately 1:6 to 1:40, or approximately 1:6 to approximately 1:38, as described in Article 44. Law.

[0180] Clause 51. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:6 to approximately 1:35, preferably approximately 1:6 to approximately 1:30, more preferably approximately 1 The method described in Clause 44, where the ratio is 6 to approximately 1:28, or approximately 1:6 to approximately 1:20.

[0181] Article 52. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The method described in Clause 44, which is approximately 1:8 to approximately 1:30.

[0182] Article 53. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The method described in Clause 44, which is approximately 1:8 to approximately 1:28.

[0183] Clause 54. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The method described in Clause 44, which is approximately 1:8 to approximately 1:20.

[0184] Clause 55. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The method described in Clause 44, which is approximately 1:8 to approximately 1:15.

[0185] Article 56. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The method described in Clause 44, which is approximately 1:10 to approximately 1:20.

[0186] Article 57. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The method described in Clause 44, which is approximately 1:10 to approximately 1:15.

[0187] Article 58. The dosage form shall be approximately 5 mg to approximately 50 mg of oxycodone hydrochloride (Mw=351). 82 g / mol), preferably about 5 mg to about 40 mg of oxycodone hydrochloride (Mw=3 Clauses 44 to 44 contain a fixed amount of equimolar oxycodone per 51.82 g / mol. The method described in any one of paragraphs 57.

[0188] Article 59. The dosage form may be approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) is equivalent to one equimolar unit The method described in any one of the clauses 44 to 57, comprising a quantitative amount of oxycodone.

[0189] Clause 60. The dosage form is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) is equivalent to one equimolar unit The method according to Clause 59, comprising a quantitative amount of oxycodone hydrochloride.

[0190] Clause 61. The dosage form may be approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) is equivalent to one equimolar unit The method according to Clause 59, comprising a quantitative amount of oxycodone myristate.

[0191] Clause 62. The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / m²). A fixed amount of oxycodone in equimolar proportions to (ol), and approximately 1 mg to 6 mg of buprenor. A constant equimolar amount of buprenorphine is used for each fin base (Mw = 467.64 g / mol). The method described in any one of the clauses 44 to 57, including n.

[0192] Article 63. The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / m²). A fixed amount of oxycodone in equimolar proportions to (ol), and approximately 2 mg to 5 mg of buprenor. A constant equimolar amount of buprenorphine is used for each fin base (Mw = 467.64 g / mol). The method described in any one of the clauses 44 to 57, including n.

[0193] Clause 64. The oxycodone is oxycodone hydrochloride, and the buprenorphine is bu Prenorphine hydrochloride, as specified in any of clauses 44 to 59, 62 and 63. The method described in item 1.

[0194] Clause 65. The dosage form comprises the same fixed amount of buprenorphine in an immediate-release form, Clause 44 The method described in any one of the paragraphs of Article 64.

[0195] Article 66. The dosage form is an immediate-release form of a certain amount of oxycodone, and an immediate-release form The person described in any one of paragraphs 44 to 65, comprising the aforementioned certain amount of buprenorphine. Law.

[0196] Clause 67. The dosage form is a liquid dosage form as described in any one of Clauses 44 to 66. method.

[0197] Clause 68. The dosage form is a liquid, a suspension, or an emulsion, preferably a liquid. , the method described in Article 67.

[0198] Clause 69. The dosage form is a solid dosage form as described in any one of Clauses 44 to 66. method.

[0199] Clause 70. The method according to Clause 69, wherein the dosage form is a tablet or a capsule.

[0200] Clause 71. After a single dose is administered, the dosage form shall be administered to at least approximately 1:280 of one control group. Average C of buprenorphine max and the average C of oxycodone max The clause that brings about the ratio The method described in any one of the clauses 44 to 70.

[0201] Article 72. Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The method described in Clause 71, which is at least about 1:250.

[0202] Article 73. Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The method described in Clause 71, which is at least about 1:230.

[0203] Article 74. Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The method described in Clause 71, which is at least about 1:200.

[0204] Article 75. Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The method described in Clause 71, which is at least about 1:180.

[0205] Article 76. Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The method described in Clause 71, which is approximately 1:50 to approximately 1:280.

[0206] Article 77. Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The method described in Clause 71, which is approximately 1:50 to approximately 1:250.

[0207] Article 78. Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The method described in Clause 71, which is approximately 1:80 to approximately 1:230.

[0208] Article 79. Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The method described in Clause 71, which is approximately 1:100 to approximately 1:200.

[0209] Clause 80. Mean C of buprenorphine max and the average C of oxycodone max the aforementioned ratio The method described in Clause 71, which is approximately 1:100 to approximately 1:180.

[0210] Clause 81. After a single dose administration, the dosage form shall be administered to the control group in a ratio of approximately 1.5:1 or less of bupreno. Rufin's average T max and the average T of oxycodone max Article 71 further brings about the ratio The method described in any one of the paragraphs of Article 80.

[0211] Article 82. Mean T of buprenorphine max and the average T of oxycodone max the aforementioned ratio The method described in Clause 81, wherein the ratio is approximately 1.3:1 or less.

[0212] Article 83. Mean T of buprenorphine max and the average T of oxycodone max the aforementioned ratio The method described in Clause 81, wherein the ratio is approximately 1.1:1 or less.

[0213] Article 84. Mean T of buprenorphine max and the average T of oxycodone max the aforementioned ratio The method described in Clause 81, where the ratio is approximately 1:1 or less.

[0214] Article 85. After a single dose administration, the dosage form is used to provide the control group with an average dose of oxycodone T max Compared to the average T of buprenorphine, it is faster. max This further brings about, from Clause 71 to Clause 71 The method described in any one of item 80.

[0215] Clause 86. After a single dose is administered, the dosage form shall be administered to the target group in a ratio of approximately 0.1:1 to approximately 1.5:1. Preferably about 0.1:1 to about 1.3:1, more preferably about 0.1:1 to about 1.1 :1, most preferably about 0.1:1 to about 1:1, or about 0.1:1 to about 0.9:1 The average T of buprenorphine max and the average T of oxycodone max This will bring about an even greater ratio. , the method described in any one of the paragraphs 71 to 85.

[0216] Article 87. The method described above results in the prevention or suppression of the adverse drug dynamics reaction of oxycodone. The method described in any one of the clauses 44 to 86.

[0217] Clause 88. The simultaneous administration of the certain amount of buprenorphine in the dosage form is equivalent to the administration of buprenorphine alone. When performing the above dosage form, the harmful pharmacodynamic reaction observed with the above-mentioned fixed amount of oxycodone is anticipated. The method described in any one of the clauses 44 to 86 to prevent or suppress.

[0218] Article 89. The adverse drug reactions include euphoria, euphoria, bowel dysfunction, nausea, vomiting, somnolence, Dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium These symptoms include miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence, and tolerance. Selected from the group, preferably the adverse drug dynamic response is respiratory depression, euphoria, euphoria, and The method described in Clause 87 or Clause 88, selected from the group consisting of intestinal dysfunction.

[0219] Clause 90. The adverse drug reaction is euphoria, as described in Clause 87 or Clause 88. .

[0220] Clause 91. The adverse drug reaction is euphoria, as described in Clause 87 or Clause 88. .

[0221] Clause 92. Average E of "Euphoria VAS" max When measuring using comparative tests, less The method described in Clause 91 reduces both by 15%.

[0222] Clause 93. Average E of "Euphoria VAS" max is at least 20%, preferably less 25% each, more preferably at least 30%, most preferably at least 35%, and This is reduced by a further 40%, as described in Clause 92.

[0223] Clause 94. The method results in the prevention or suppression of drug addiction to oxycodone, The method described in any one of clauses 44 to 93.

[0224] Clause 95. The simultaneous administration of the certain amount of buprenorphine in the dosage form is equivalent to the administration of buprenorphine alone. When doing so, compare with the drug preference observed at a certain amount of oxycodone in the aforementioned dosage form. to prevent or suppress drug addiction to oxycodone, any of the provisions from 44 to 93. The method described in item 1.

[0225] Article 96. Average E of "Temporary Drug Preference VAS" max This is measured using comparative tests. The method described in Clause 94 or Clause 95, which reduces the amount by at least 15% in the event of a reduction.

[0226] Article 97. Average E of "Temporary Drug Preference VAS" max At least 20% preferred The amount is reduced by at least 25%, more preferably at least 30%, as described in Clause 96. Law.

[0227] Article 98. Average E of "Overall Drug Preference VAS" max This is measured using comparative tests. The method described in Clause 94 or Clause 95, which reduces the amount by at least 15% in the event of a reduction.

[0228] Article 99. Average E of "Overall Drug Preference VAS" max At least 20% preferred The amount should be at least 25%, more preferably at least 30%, and most preferably at least 3 The method described in Clause 98 reduces the amount by 5%.

[0229] Article 100. Average E of "Drug Reuse VAS" max When measuring using comparative tests The method described in Clause 94 or Clause 95, which reduces the amount by at least 15%.

[0230] Article 101. Average E of "Drug Reuse VAS" max at least 20%, preferably At least 25%, more preferably at least 30%, most preferably at least 35% The method described in clause 100, which reduces.

[0231] Clause 102. The method provides an analgesic effect that is not substantially reduced when measured using comparative tests. The method described in any one of the clauses 44 to 101, which brings about the results of the following:

[0232] Clause 103. Mean measured using the cold pressurization test at 1, 2, 3, and 4 hours after administration. The "Cold Pain Score (VAS)" is measured using comparative trials, and when compared to the comparative treatment method, it is 10 The method described in Clause 102 shall not increase by more than %.

[0233] Article 104. The method shall not cause the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. The method described in any one of the clauses 44 to 103 to prevent or suppress.

[0234] Clause 105. Any one of Clauses 1 through 43 used for methods of treating pain. The oral dosage form as described in the section.

[0235] Article 106. The method described herein results in the prevention or suppression of the adverse pharmacokinetic reaction of oxycodone. , the oral dosage form described in Clause 105 for use in methods for treating pain.

[0236] Clause 107. The simultaneous administration of the certain amount of buprenorphine in the dosage form is administered alone. When administering, the adverse drug dynamics reaction observed with the certain amount of oxycodone in the dosage form Oral dosage forms described in Clause 105 for use in methods of preventing or suppressing pain, or for treating pain. .

[0237] Article 108. The adverse drug reactions include euphoria, euphoria, bowel dysfunction, nausea, vomiting, and drowsiness. dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dyspnea, delirium Delirium, miosis, pruritus, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance Selected from the group, preferably the adverse drug dynamic response is respiratory depression, euphoria, euphoria, and Clause 10 for use in methods for treating pain, selected from the group consisting of bowel dysfunction and bowel dysfunction. Oral dosage forms as described in Article 6 or Article 107.

[0238] Clause 109. The aforementioned adverse drug reaction is euphoria, and is used in methods to treat pain. The oral dosage form as described in clause 106 or clause 107.

[0239] Clause 110. The adverse drug reaction is euphoria, and the drug is used in a method to treat pain. The oral dosage form as described in clause 106 or clause 107.

[0240] Clause 111. Average E of "Euphoria VAS" max When measuring using comparative tests, the amount is small. Oral medications used in methods for treating pain, as described in Clause 110, which reduce pain by at least 15% shape.

[0241] Clause 112. Average E of "Euphoria VAS" max is at least 20%, preferably less At least 25%, more preferably at least 30%, most preferably at least 35%, Or, the oral method used for treating pain, as described in Clause 111, is reduced by a further 40%. Dosage form.

[0242] Article 113. The method described above results in the prevention or suppression of drug dependence of oxycodone, pain The method used to treat pain as described in any one of the clauses 105 to 112 Oral dosage form.

[0243] Clause 114. The simultaneous administration of the certain amount of buprenorphine in the dosage form is administered alone. When administering, compare with the drug preference observed at the aforementioned fixed amount of oxycodone in the aforementioned dosage form. It is used in methods to treat pain, to prevent or suppress drug dependence on oxycodone. The oral dosage form used as described in any one of clauses 105 to 112.

[0244] Clause 115. Mean E of "Temporary Drug Preference VAS" max This is measured using comparative tests. Clause 113, which is used for methods of treating pain that reduce it by at least 15% when doing so. This is the oral dosage form as described in Article 114.

[0245] Clause 116. Mean E of "Temporary Drug Preference VAS" max At least 20% prefer To treat pain, it reduces it by at least 25%, more preferably at least 30%. The oral dosage form used in the method of administration as described in Clause 115.

[0246] Article 117. Average E of "Overall Drug Preference VAS" max This is measured using comparative tests. Clause 113, which is used for methods of treating pain that reduce it by at least 15% when doing so. This is the oral dosage form as described in Article 114.

[0247] Clause 118. Average E of "Overall Drug Preference VAS" max At least 20% prefer or at least 25%, more preferably at least 30%, most preferably at least An oral dosage form described in Clause 117 for use in methods of treating pain, which reduces pain by 35%.

[0248] Article 119. Average E of "Drug Reuse VAS" max When measuring using comparative tests A method used to treat pain that reduces it by at least 15%, as per clause 113 or clause The oral dosage form described in 114.

[0249] Article 120. Average E of "Drug Reuse VAS" max at least 20%, preferably At least 25%, more preferably at least 30%, most preferably at least 35% Oral dosage forms as described in Clause 119 for use in methods of treating pain that reduces it.

[0250] Clause 121. The method provides an analgesic effect that is not substantially reduced when measured using comparative tests. Any of the clauses 105 to 120 used for methods of treating pain that results from The oral dosage form described in item 1.

[0251] Clause 122. Mean measured using the cold pressurization test at 1, 2, 3, and 4 hours after administration. The "Cold Pain Score (VAS)" is measured using comparative trials, and when compared to the comparative treatment method, it is 10 Oral dosage forms as described in Clause 121 for use in methods of treating pain, which do not increase by more than %.

[0252] Article 123. The method described herein shall not preempt the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. The methods used to prevent or suppress pain, as described in Clauses 105 to 122. Either of the oral dosage forms described in item 1.

[0253] Clause 124. The same amount of oxycodone as described in any one of Clauses 1 to 43. By administering an oral formulation instead, the treatment of pain using a fixed amount of oxycodone alone can be achieved. A method for preventing or suppressing the adverse drug dynamics reactions of oxycodone observed in [unspecified].

[0254] Clause 125. The adverse drug reactions include euphoria, euphoria, bowel dysfunction, nausea, vomiting, and drowsiness. dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dyspnea, delirium Delirium, miosis, pruritus, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance Selected from the group, preferably the adverse drug dynamic response is respiratory depression, euphoria, euphoria, and The method described in Clause 124, selected from the group consisting of bowel dysfunction and bowel dysfunction.

[0255] Clause 126. The method described in Clause 124, wherein the toxic drug-mediated response is euphoria.

[0256] Clause 127. The method according to Clause 124, wherein the toxic drug's mechanical response is euphoria.

[0257] Clause 128. The same amount of oxycodone as described in any one of Clauses 1 to 43. By administering an oral formulation instead, the treatment of pain using a fixed amount of oxycodone alone can be achieved. A method for preventing or suppressing the drug addiction associated with oxycodone.

[0258] Clause 129. By providing the dosage form described in any one of Clauses 1 to 43, Methods for preventing or suppressing the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. .

[0259] Article 130. To prevent or suppress the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. The use of any one of the dosage forms specified in any one of the clauses 1 through 43 in relation to the use of any one of the dosage forms specified in the clauses 1 through 43.

[0260] Article 131. (i) A fixed amount of immediate-release oxycodone, (ii) A fixed amount of buprenorphine in an immediate-release form, An oral dosage form containing, The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is equal to an equimolar amount In the dosage form represented by buprenorphine base (mg) (Mw = 467.64 g / mol) The aforementioned fixed amount of buprenorphine and equimolar amount of oxycodone hydrochloride (mg) The certain amount of oxyco in the dosage form (Mw = 351.82 g / mol) When calculating using "don," the ratio is approximately 1:100 or higher. The aforementioned oral dosage form.

[0261] Clause 132. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The oral dosage form described in Clause 131 has a ratio of approximately 1:80 or higher.

[0262] Clause 133. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The oral dosage form described in Clause 131 has a ratio of approximately 1:60 or higher.

[0263] Clause 134. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The oral dosage form described in Clause 131 has a ratio of approximately 1:50 or higher.

[0264] Clause 135. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The oral dosage form described in Clause 131 has a ratio of approximately 1:40 or higher.

[0265] Clause 136. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:6 to approximately 1:100, preferably approximately 1:6 to approximately 1:80, more preferably, Oral administration as described in Clause 131, approximately 1:6 to approximately 1:60, or approximately 1:6 to approximately 1:50. Dosage form.

[0266] Clause 137. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The oral dosage form described in Clause 131 has a ratio of approximately 1:6 to approximately 1:40.

[0267] Clause 138. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:8 to approximately 1:100, preferably approximately 1:8 to approximately 1:80, more preferably, Oral administration as described in Clause 131, which is approximately 1:8 to approximately 1:60, or approximately 1:8 to approximately 1:50. Dosage form.

[0268] Clause 139. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The oral dosage form described in Clause 131 has a ratio of approximately 1:8 to approximately 1:40.

[0269] Clause 140. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:10 to approximately 1:100, preferably approximately 1:10 to approximately 1:80, and more preferably This is approximately 1:10 to 1:60, or approximately 1:10 to 1:50, as stated in Article 131. The oral dosage form listed.

[0270] Clause 141. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:10 to approximately 1:40 for the oral dosage form as described in Clause 131.

[0271] Clause 142. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:20 to approximately 1:100, preferably approximately 1:20 to approximately 1:80, more preferably This is approximately 1:20 to 1:60, or approximately 1:20 to 1:50, as stated in Article 131. The oral dosage form listed.

[0272] Clause 143. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:20 to approximately 1:40 for the oral dosage form as described in Clause 131.

[0273] Clause 144. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:20 to approximately 1:30 for the oral dosage form as described in Clause 131.

[0274] Article 145. The dosage form is approximately 5 mg to approximately 50 mg of oxycodone hydrochloride (Mw=351 0.82 g / mol), preferably about 5 mg to about 40 mg of oxycodone hydrochloride (Mw= (351.82 g / mol) containing a fixed equimolar amount of oxycodone, as per clause 131. The oral dosage form as specified in any one of paragraphs 144 of Article 144.

[0275] Clause 146. The dosage form is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Equimolar amounts to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) An oral agent containing a certain amount of oxycodone, as described in any one of paragraphs 131 to 144. shape.

[0276] Clause 147. The dosage form is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Equimolar amounts to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) An oral dosage form as described in Clause 146, containing a certain amount of oxycodone hydrochloride.

[0277] Clause 148. The dosage form is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Equimolar amounts to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) An oral dosage form as described in Clause 146, containing a certain amount of oxycodone myristate.

[0278] Clause 149. The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / A fixed amount of oxycodone in equimolar proportions (per mole), and approximately 1 mg to 5 mg of buprenococcone. Equimolar amounts of buprenorphate (buprenorphate) relative to ruphine base (Mw = 467.64 g / mol) An oral dosage form, including one of the provisions of any one of the provisions of paragraphs 131 to 144.

[0279] Clause 150. The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / A fixed amount of oxycodone in equimolar proportions (per mole), and approximately 1 mg to 4 mg of buprenococcone. Equimolar amounts of buprenorphate (buprenorphate) relative to ruphine base (Mw = 467.64 g / mol) An oral dosage form, including one of the provisions of any one of the provisions of paragraphs 131 to 144.

[0280] Clause 151. The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / A fixed amount of oxycodone in equimolar proportions (per mole), and approximately 2 mg to 4 mg of buprenococcone. Equimolar amounts of buprenorphate (buprenorphate) relative to ruphine base (Mw = 467.64 g / mol) An oral dosage form, including one of the provisions of any one of the provisions of paragraphs 131 to 144.

[0281] Clause 152. The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / A fixed amount of oxycodone in equimolar proportions (per mole), and approximately 1 mg to 2 mg of buprenococcone. Equimolar amounts of buprenorphate (buprenorphate) relative to ruphine base (Mw = 467.64 g / mol) An oral dosage form, including one of the provisions of any one of the provisions of paragraphs 131 to 144.

[0282] Article 153. The oxycodone is oxycodone hydrochloride, and the buprenorphine is Buprenorphine hydrochloride, as stated in clauses 131 to 146, and clauses 149 to 152. The oral dosage form described in any one of the items.

[0283] Clause 154. The dosage form is a liquid dosage form, as specified in any one of Clauses 131 to 153. The oral dosage form as described.

[0284] Clause 155. The dosage form is a liquid, a suspension, or an emulsion, preferably a liquid. The oral dosage form as described in Article 154.

[0285] Clause 156. The dosage form is a solid dosage form, as specified in any one of Clauses 131 to 153. The oral dosage form as described.

[0286] Clause 157. The oral dosage form described in Clause 156, wherein the dosage form is a tablet or a capsule.

[0287] Clause 158. After a single dose, the dosage form shall be administered to one control group at a ratio of at least approximately 1:280 The average C of buprenorphine max and the average C of oxycodone max The ratio that results in An oral dosage form as described in any one of paragraphs 131 to 157.

[0288] Article 159. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:250 for the oral dosage form as described in Clause 158.

[0289] Clause 160. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:230 for the oral dosage form as described in Clause 158.

[0290] Clause 161. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:200 for the oral dosage form as described in Clause 158.

[0291] Clause 162. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:180 for the oral dosage form as described in Clause 158.

[0292] Clause 163. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is approximately 1:50 to approximately 1:280 for the oral dosage form as described in Clause 158.

[0293] Clause 164. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is approximately 1:50 to approximately 1:250 for the oral dosage form as described in Clause 158.

[0294] Clause 165. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is approximately 1:80 to approximately 1:230 for the oral dosage form as described in Clause 158.

[0295] Clause 166. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is approximately 1:100 to approximately 1:200 for the oral dosage form as described in Clause 158.

[0296] Clause 167. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is approximately 1:100 to approximately 1:180 for the oral dosage form as described in Clause 158.

[0297] Clause 168. After a single dose administration, the dosage form shall be administered to the control group in a ratio of approximately 1.5:1 or less of bupleurum. Norfin's average T max and the average T of oxycodone max Clause 1 further brings about the ratio An oral dosage form as specified in any one of paragraphs 58 to 167.

[0298] Article 169. Mean T of buprenorphine max and the average T of oxycodone max The ratio The oral dosage form described in Clause 168 has a ratio of approximately 1.3:1 or less.

[0299] Clause 170. Mean T of buprenorphine max and the average T of oxycodone max The ratio The oral dosage form described in Clause 168 has a ratio of approximately 1.1:1 or less.

[0300] Clause 171. Mean T of buprenorphine max and the average T of oxycodone max The ratio The oral dosage form described in Clause 168 has a ratio of approximately 1:1 or less.

[0301] Article 172. After a single dose administration, the dosage form is used to provide the control group with an average dose of oxycodone T ma x Compared to the average T of buprenorphine, it is faster. max Article 158 further brings about the following: The oral dosage form specified in any one of paragraphs 167.

[0302] Clause 173. After a single dose administration, the dosage form shall be distributed to the target group at a ratio of approximately 0.1:1 to approximately 1.5: 1. Preferably, about 0.1:1 to about 1.3:1, more preferably about 0.1:1 to about 1. 1:1, most preferably about 0.1:1 to about 1:1, or about 0.1:1 to about 0.9: The average T of buprenorphine 1 max and the average T of oxycodone max This will bring the ratio even further The oral dosage form as described in any one of clauses 158 to 172.

[0303] Article 174. (i) A fixed amount of immediate-release oxycodone, (ii) A fixed amount of buprenorphine in an immediate-release form, This includes administering it to patients who require an oral dosage form that includes it. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is equal to an equimolar amount In the dosage form represented by buprenorphine base (mg) (Mw = 467.64 g / mol) The aforementioned fixed amount of buprenorphine and equimolar amount of oxycodone hydrochloride (mg) The certain amount of oxyco in the dosage form (Mw = 351.82 g / mol) When calculating using "don," the ratio is approximately 1:100 or higher. Methods for treating pain.

[0304] Clause 175. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:80 or greater, as described in Clause 174.

[0305] Article 176. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:60 or greater, as described in Clause 174.

[0306] Clause 177. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:50 or greater, as described in Clause 174.

[0307] Clause 178. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:40 or greater, as described in Clause 174.

[0308] Article 179. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone. The ratio is approximately 1:6 to approximately 1:100, preferably approximately 1:6 to approximately 1:80, more preferably, The method described in Clause 174, which is approximately 1:6 to approximately 1:60, or approximately 1:6 to approximately 1:50. .

[0309] Clause 180. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:6 to approximately 1:40, as described in Clause 174.

[0310] Clause 181. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:8 to approximately 1:100, preferably approximately 1:8 to approximately 1:80, more preferably, The method described in Clause 174, which is approximately 1:8 to approximately 1:60, or approximately 1:8 to approximately 1:50. .

[0311] Clause 182. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:8 to approximately 1:40, as described in Clause 174.

[0312] Clause 183. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:10 to approximately 1:100, preferably approximately 1:10 to approximately 1:80, and more preferably This is approximately 1:10 to 1:60, or approximately 1:10 to 1:50, as stated in Article 174. Method of loading.

[0313] Clause 184. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The rate is approximately 1:10 to approximately 1:40, as described in Clause 174.

[0314] Clause 185. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:20 to approximately 1:100, preferably approximately 1:20 to approximately 1:80, more preferably This is approximately 1:20 to 1:60, or approximately 1:20 to 1:50, as stated in Article 174. Method of loading.

[0315] Clause 186. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The rate is approximately 1:20 to approximately 1:40, as described in Clause 174.

[0316] Clause 187. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The rate is approximately 1:20 to 1:30, as described in Clause 174.

[0317] Article 188. The dosage form is approximately 5 mg to approximately 50 mg of oxycodone hydrochloride (Mw=351 0.82 g / mol), preferably about 5 mg to about 40 mg of oxycodone hydrochloride (Mw= (351.82 g / mol) containing a fixed equimolar amount of oxycodone, clause 174 The method described in any one of the paragraphs of Article 187.

[0318] Clause 189. The dosage form is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Equimolar amounts to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) The method described in any one of the clauses 174 to 187, comprising a certain amount of oxycodone.

[0319] Clause 190. The dosage form is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Equimolar amounts to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) The method according to Clause 189, comprising a certain amount of oxycodone hydrochloride.

[0320] Clause 191. The dosage form is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Equimolar amounts to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) The method according to Clause 189, comprising a certain amount of oxycodone myristate.

[0321] Clause 192. The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / A fixed amount of oxycodone in equimolar proportions (per mole), and approximately 1 mg to 5 mg of buprenococcone. Equimolar amounts of buprenorphate (buprenorphate) relative to ruphine base (Mw = 467.64 g / mol) The method described in any one of Clauses 174 to 187, including the method described in the article.

[0322] Article 193. The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / A fixed amount of oxycodone in equimolar proportions (per mole), and approximately 1 mg to 4 mg of buprenococcone. Equimolar amounts of buprenorphate (buprenorphate) relative to ruphine base (Mw = 467.64 g / mol) The method described in any one of Clauses 174 to 187, including the method described in the article.

[0323] Article 194. The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / A fixed amount of oxycodone in equimolar proportions (per mole), and approximately 2 mg to 4 mg of buprenococcone. Equimolar amounts of buprenorphate (buprenorphate) relative to ruphine base (Mw = 467.64 g / mol) The method described in any one of Clauses 174 to 187, including the method described in the article.

[0324] Article 195. The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / A fixed amount of oxycodone in equimolar proportions (per mole), and approximately 1 mg to 2 mg of buprenococcone. Equimolar amounts of buprenorphate (buprenorphate) relative to ruphine base (Mw = 467.64 g / mol) The method described in any one of Clauses 174 to 187, including the method described in the article.

[0325] Article 196. The oxycodone is oxycodone hydrochloride, and the buprenorphine is Buprenorphine hydrochloride, clauses 174 to 189, clauses 192 to 195 The method described in any one of the items.

[0326] Article 197. The dosage form is a liquid dosage form, as specified in any one of Articles 174 to 196. Method of description.

[0327] Clause 198. The dosage form is a liquid, a suspension, or an emulsion, preferably a liquid. The method described in Article 197.

[0328] Clause 199. The dosage form is a solid dosage form, as specified in any one of Clauses 174 to 196. Method of description.

[0329] Clause 200. The method according to Clause 199, wherein the dosage form is a tablet or a capsule.

[0330] Clause 201. After a single dose, the dosage form shall be administered to one control group at a ratio of at least approximately 1:280 The average C of buprenorphine max and the average C of oxycodone max The ratio that results in The method described in any one of paragraphs 174 to 200.

[0331] Clause 202. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:250, as described in Clause 201.

[0332] Clause 203. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:230, as described in Clause 201.

[0333] Clause 204. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:200, as described in Clause 201.

[0334] Clause 205. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:180, as described in Clause 201.

[0335] Clause 206. Mean C of buprenorphine max and the average C of oxycodone max The ratio The rate is approximately 1:50 to approximately 1:280, as described in Clause 201.

[0336] Clause 207. Mean C of buprenorphine max and the average C of oxycodone max The ratio The rate is approximately 1:50 to approximately 1:250, as described in Clause 201.

[0337] Clause 208. Mean C of buprenorphine max and the average C of oxycodone max The ratio The rate is approximately 1:80 to approximately 1:230, as described in Clause 201.

[0338] Clause 209. Mean C of buprenorphine max and the average C of oxycodone max The ratio The rate is approximately 1:100 to approximately 1:200, as described in Clause 201.

[0339] Clause 210. Mean C of buprenorphine max and the average C of oxycodone max The ratio The rate is approximately 1:100 to approximately 1:180, as described in Clause 201.

[0340] Clause 211. After a single dose administration, the dosage form shall be administered to the control group in a ratio of approximately 1.5:1 or less of bupleurum. Norfin's average T max and the average T of oxycodone max Clause 2 further brings about the ratio The method described in any one of the clauses from 01 to 210.

[0341] Clause 212. Mean T of buprenorphine max and the average T of oxycodone max The ratio The ratio is approximately 1.3:1 or less, as described in Clause 211.

[0342] Clause 213. Mean T of buprenorphine max and the average T of oxycodone max The ratio The ratio is approximately 1.1:1 or less, as described in Clause 211.

[0343] Clause 214. Mean T of buprenorphine max and the average T of oxycodone max The ratio The ratio is approximately 1:1 or less, as described in Clause 211.

[0344] Clause 215. After a single dose administration, the dosage form is used to provide the control group with an average dose of oxycodone T ma x Compared to the average T of buprenorphine, it is faster. maxThis further brings about, from Article 201 The method described in any one of the paragraphs of Article 210.

[0345] Clause 216. After a single dose, the dosage form shall be distributed to the target group at a ratio of approximately 0.1:1 to approximately 1.5: 1. Preferably, about 0.1:1 to about 1.3:1, more preferably about 0.1:1 to about 1. 1:1, most preferably about 0.1:1 to about 1:1, or about 0.1:1 to about 0.9: The average T of buprenorphine 1 max and the average T of oxycodone max This will bring the ratio even further The method described in any one of the clauses 201 to 215.

[0346] Article 217. The method described herein results in the prevention or suppression of the adverse drug mechanical reaction of oxycodone. , the method described in any one of the clauses 174 to 216.

[0347] Clause 218. The simultaneous administration of the certain amount of buprenorphine in the dosage form is administered alone. When administering, the adverse drug dynamics reaction observed with the certain amount of oxycodone in the dosage form The method described in any one of the clauses 174 to 216 for preventing or suppressing.

[0348] Clause 219. The adverse drug reactions include euphoria, euphoria, bowel dysfunction, nausea, vomiting, and drowsiness. dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dyspnea, delirium Delirium, miosis, pruritus, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance Selected from the group, preferably the adverse drug dynamic response is respiratory depression, euphoria, euphoria, and The method described in Clause 217 or Clause 218, selected from the group consisting of bowel dysfunction.

[0349] Clause 220. The toxic drug-mediated response is euphoria, as described in Clause 217 or Clause 218. The method.

[0350] Clause 221. The adverse drug mechanical response is euphoria, as described in Clause 217 or Clause 218. The method.

[0351] Clause 222. Average E of "Euphoria VAS" max When measuring using comparative tests, the amount is small. The method described in Clause 221 reduces the amount by at least 15%.

[0352] Clause 223. Average E of "Euphoria VAS" max is at least 20%, preferably less At least 25%, more preferably at least 30%, most preferably at least 35%, Or it is reduced by a further 40%, as described in Clause 222.

[0353] Article 224. The method described herein results in the prevention or suppression of drug addiction to oxycodone. The method described in any one of paragraphs 174 to 223.

[0354] Clause 225. The simultaneous administration of the certain amount of buprenorphine in the dosage form is administered alone. When administering, compare with the drug preference observed at the aforementioned fixed amount of oxycodone in the aforementioned dosage form. And to prevent or suppress drug addiction to oxycodone, as per Articles 174 to 223 Either the method described in item 1.

[0355] Clause 226. Mean E of "Temporary Drug Preference VAS" max This is measured using comparative tests. The method described in Clause 224 or Clause 225, which reduces the amount by at least 15% when doing so.

[0356] Clause 227. Mean E of "Temporary Drug Preference VAS" maxAt least 20% prefer Or a reduction of at least 25%, more preferably at least 30%, as stated in Clause 226. The method.

[0357] Clause 228. Average E of "Overall Drug Preference VAS" max This is measured using comparative tests. The method described in Clause 224 or Clause 225, which reduces the amount by at least 15% when doing so.

[0358] Clause 229. Average E of "Overall Drug Preference VAS" max At least 20% prefer or at least 25%, more preferably at least 30%, most preferably at least The method described in Clause 228 reduces the amount by 35%.

[0359] Article 230. Average E of "Drug Reuse VAS" max When measuring using comparative tests A reduction of at least 15% as described in Clause 224 or Clause 225.

[0360] Article 231. Average E of "Drug Reuse VAS" max at least 20%, preferably At least 25%, more preferably at least 30%, most preferably at least 35% The method described in Clause 230 to reduce.

[0361] Clause 232. The method provides an analgesic effect that is not substantially reduced when measured using comparative tests. The method described in any one of the clauses 174 to 231, which brings about the results of the following:

[0362] Clause 233. Mean measured using cold pressurization tests at 1, 2, 3, and 4 hours post-administration. The "Cold Pain Score (VAS)" is measured using comparative trials, and when compared to the comparative treatment method, it is 10 The method described in Clause 232 shall not increase by more than %.

[0363] Article 234. The method described herein shall not cause the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. The method described in any one of the clauses 174 to 233 to prevent or suppress.

[0364] Article 235. Any of the methods used to treat pain, as described in Articles 131 to 173. The oral dosage form described in item 1.

[0365] Article 236. The method described herein results in the prevention or suppression of the adverse pharmacodynamic reaction of oxycodone. , the oral dosage form described in Clause 235 for use in methods for treating pain.

[0366] Clause 237. The simultaneous administration of the certain amount of buprenorphine in the dosage form is administered alone. When administering, the adverse drug dynamics reaction observed with the certain amount of oxycodone in the dosage form Oral dosage forms described in Clause 235 for use in methods of preventing or suppressing pain, or for treating pain. .

[0367] Clause 238. The adverse drug reactions include euphoria, euphoria, bowel dysfunction, nausea, vomiting, and drowsiness. dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dyspnea, delirium Delirium, miosis, pruritus, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance Selected from the group, preferably the adverse drug dynamic response is respiratory depression, euphoria, euphoria, and Clause 23, used for methods of treating pain, selected from the group consisting of bowel dysfunction and bowel dysfunction. Oral dosage forms as described in Article 6 or Article 237.

[0368] Clause 239. The aforementioned adverse drug reaction is euphoria, and is used in methods to treat pain. The oral dosage form as described in Clause 236 or Clause 237.

[0369] Clause 240. The adverse drug reaction is euphoria, and the drug is used in a method to treat pain. The oral dosage form as described in Clause 236 or Clause 237.

[0370] Clause 241. Average E of "Euphoria VAS" max When measuring using comparative tests, the amount is small. Oral medications described in Clause 240 for use in methods of treating pain, which reduce pain by at least 15% shape.

[0371] Clause 242. Average E of "Euphoria VAS" max is at least 20%, preferably less At least 25%, more preferably at least 30%, most preferably at least 35%, Or, the oral method used for treating pain, as described in Clause 241, is reduced by a further 40%. Dosage form.

[0372] Article 243. The method described above results in the prevention or suppression of drug dependence of oxycodone, pain The method used to treat pain as described in any one of the clauses 235 to 242 Oral dosage form.

[0373] Clause 244. The simultaneous administration of the certain amount of buprenorphine in the dosage form is administered alone. When administering, compare with the drug preference observed at the aforementioned fixed amount of oxycodone in the aforementioned dosage form. It is used in methods to treat pain, to prevent or suppress drug dependence on oxycodone. The oral dosage form used as described in any one of clauses 235 to 242.

[0374] Clause 245. Mean E of "Temporary Drug Preference VAS" max This is measured using comparative tests. Clause 243, which is used for methods of treating pain that reduce the pain by at least 15% when used. This is the oral dosage form as described in Article 244.

[0375] Clause 246. Mean E of "Temporary Drug Preference VAS" max At least 20% prefer To treat pain, it reduces it by at least 25%, more preferably at least 30%. The oral dosage form used in the method of administration as described in Clause 245.

[0376] Clause 247. Average E of "Overall Drug Preference VAS" max This is measured using comparative tests. Clause 243, which is used for methods of treating pain that reduce the pain by at least 15% when used. This is the oral dosage form as described in Article 244.

[0377] Clause 248. Average E of "Overall Drug Preference VAS" max At least 20% prefer or at least 25%, more preferably at least 30%, most preferably at least An oral dosage form described in Clause 247 for use in methods of treating pain, which reduces pain by 35%.

[0378] Article 249. Average E of "Drug Reuse VAS" max When measuring using comparative tests A method used to treat pain that reduces it by at least 15%, as per clause 243 or clause The oral dosage form described in section 244.

[0379] Article 250. Average E of "Drug Reuse VAS" max at least 20%, preferably At least 25%, more preferably at least 30%, most preferably at least 35% Oral dosage forms as described in Clause 249 for use in methods of treating pain that reduces it.

[0380] Clause 251. The method provides an analgesic effect that is not substantially reduced when measured using comparative tests. Any of the clauses 235 to 250 used for methods of treating pain that results from The oral dosage form described in item 1.

[0381] Clause 252. Mean measured using the cold vasopressor test at 1, 2, 3, and 4 hours after administration. The "Cold Pain Score (VAS)" is measured using comparative trials, and when compared to the comparative treatment method, it is 10 Oral dosage forms as described in Clause 251 for use in methods of treating pain, which do not increase by more than %.

[0382] Article 253. The method shall not preempt the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. The methods used to prevent or suppress pain, as described in Clauses 235 to 252. Either of the oral dosage forms described in item 1.

[0383] Article 254. The same amount of oxycodone as described in any one of Articles 131 to 173. By administering the oral dosage form listed above instead, pain relief can be achieved using a certain amount of oxycodone alone. A method for preventing or suppressing the adverse drug-mechanical reactions of oxycodone observed in the treatment of [condition].

[0384] Clause 255. The adverse drug reactions include euphoria, euphoria, bowel dysfunction, nausea, vomiting, and drowsiness. dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dyspnea, delirium Delirium, miosis, pruritus, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance Selected from the group, preferably the adverse drug dynamic response is respiratory depression, euphoria, euphoria, and The method described in Clause 254, selected from the group consisting of bowel dysfunction and bowel dysfunction.

[0385] Clause 256. The method described in Clause 254, wherein the toxic drug-mediated response is euphoria.

[0386] Clause 257. The adverse drug mechanical response is euphoria, as described in Clause 254.

[0387] Article 258. The same amount of oxycodone as described in any one of Articles 131 to 173. By administering the oral dosage form listed above instead, pain relief can be achieved using a certain amount of oxycodone alone. A method for preventing or suppressing oxycodone drug dependence observed in the treatment of [condition].

[0388] Clause 259. To provide the dosage form described in any one of Clauses 131 to 173. To prevent or suppress the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. The method.

[0389] Article 260. To prevent or suppress the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. The use of any one of the dosage forms specified in any one of the clauses 131 to 173 in relation to the use of any one of the dosage forms specified in the clauses 131 to 173.

[0390] Article 261. (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, A dosage form containing, After a single dose administration, the dosage form provides at least approximately 1:280 buprenor to one control group. Finn's average C max and the average C of oxycodone max This results in the ratio The aforementioned dosage form.

[0391] Clause 262. Mean C of buprenorphine max and the average C of oxycodone max The ratio The dosage form as described in Clause 261, with a ratio of at least approximately 1:250.

[0392] Clause 263. Mean C of buprenorphine max and the average C of oxycodone max The ratio The dosage form as described in Clause 261, with a ratio of at least approximately 1:230.

[0393] Clause 264. Mean C of buprenorphine max and the average C of oxycodone max The ratio The dosage form as described in Clause 261, with a ratio of at least approximately 1:200.

[0394] Article 265. Mean C of buprenorphine max and the average C of oxycodone max The ratio The dosage form as described in Clause 261, with a ratio of at least approximately 1:180.

[0395] Article 266. Mean C of buprenorphine max and the average C of oxycodone max The ratio The dosage form as described in Clause 261, with a ratio of approximately 1:50 to approximately 1:280.

[0396] Article 267. Mean C of buprenorphine max and the average C of oxycodone max The ratio The dosage form as described in Clause 261, with a ratio of approximately 1:50 to approximately 1:250.

[0397] Article 268. Mean C of buprenorphine max and the average C of oxycodone max The ratio The dosage form as described in Clause 261, with a ratio of approximately 1:80 to approximately 1:230.

[0398] Clause 269. Mean C of buprenorphine max and the average C of oxycodone max The ratio The dosage form as described in Clause 261, with a ratio of approximately 1:100 to approximately 1:200.

[0399] Clause 270. Mean C of buprenorphine max and the average C of oxycodone max The ratio The dosage form as described in Clause 261, with a ratio of approximately 1:100 to approximately 1:180.

[0400] Clause 271. After a single dose administration, the dosage form shall be administered to the control group in a ratio of approximately 1.5:1 or less of bupleurum. Norfin's average T max and the average T of oxycodone max Clause 2 further brings about the ratio The dosage form specified in any one of paragraphs 61 to 270.

[0401] Article 272. Mean T of buprenorphine max and the average T of oxycodone max The ratio The dosage form described in Clause 271, with a ratio of approximately 1.3:1 or less.

[0402] Article 273. Mean T of buprenorphine max and the average T of oxycodone max The ratio The dosage form described in Clause 271, with a ratio of approximately 1.1:1 or less.

[0403] Article 274. Mean T of buprenorphine max and the average T of oxycodone max The ratio The dosage form described in Clause 271, with a ratio of approximately 1:1 or less.

[0404] Article 275. After a single dose administration, the dosage form provides the control group with an average T dose of oxycodone. ma x Compared to the average T of buprenorphine, it is faster. max Article 261 further brings about the following: The dosage form specified in any one of paragraphs of Article 270.

[0405] Clause 276. After a single dose administration, the dosage form shall be distributed to the target group at a ratio of approximately 0.1:1 to approximately 1.5: 1. Preferably, about 0.1:1 to about 1.3:1, more preferably about 0.1:1 to about 1. 1:1, most preferably about 0.1:1 to about 1:1, or about 0.1:1 to about 0.9: The average T of buprenorphine 1 max and the average T of oxycodone max This will bring the ratio even further The dosage form as specified in any one of clauses 261 to 275.

[0406] Clause 277. The dosage form is an oral dosage form, as specified in any one of Clauses 261 to 276. The dosage form as described.

[0407] Article 278. The dosage form is approximately 5 mg to approximately 50 mg of oxycodone hydrochloride (Mw=351 0.82 g / mol), preferably about 5 mg to about 40 mg of oxycodone hydrochloride (Mw= Clause 277 contains a fixed amount of oxycodone in equimolar amounts per 351.82 g / mol. The oral dosage form as described.

[0408] Clause 279. The dosage form is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Equimolar amounts to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) An oral dosage form as described in Clause 277, containing a certain amount of oxycodone.

[0409] Clause 280. The dosage form is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Equimolar amounts to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) An oral dosage form as described in Clause 279, containing a certain amount of oxycodone hydrochloride.

[0410] Clause 281. The dosage form is approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or Equimolar amounts to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) An oral dosage form as described in Clause 279, containing a certain amount of oxycodone myristate.

[0411] Clause 282. The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / A fixed amount of oxycodone in equimolar proportions (per mole), and approximately 1 mg to 6 mg of buprenococcone. Equimolar amounts of buprenorphate (buprenorphate) relative to ruphine base (Mw = 467.64 g / mol) Oral dosage forms as described in Clause 277, including fin.

[0412] Clause 283. The dosage form is approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / A fixed amount of oxycodone in equimolar proportions (per mole), and approximately 2 mg to 5 mg of buprenococcone. Ruphine base (Mw = 467.64 g / mol) or approximately 2 mg to 4 mg of buprenor A constant equimolar amount of buprenorphine is used for each fin base (Mw = 467.64 g / mol). Oral dosage forms as described in Clause 277, including n.

[0413] Clause 284. The oxycodone is oxycodone hydrochloride, and the buprenorphine is Buprenorphine hydrochloride, as stated in Clauses 261 to 279, 282 and 283. The dosage form described in any one of the items.

[0414] Clause 285. The dosage form comprises the same fixed amount of buprenorphine in an immediate-release form, Clause 2 The dosage form specified in any one of paragraphs 61 to 284.

[0415] Article 286. The dosage form is a fixed amount of oxycodone in an immediate-release form, and an immediate-release form The following provisions include a certain amount of buprenorphine as described in any one of paragraphs 261 to 285. The dosage form listed.

[0416] Clause 287. The dosage form is a liquid dosage form, as specified in any one of Clauses 261 to 286. The dosage form as described.

[0417] Clause 288. The dosage form is a liquid, a suspension, or an emulsion, preferably a liquid. The dosage form as described in Article 287.

[0418] Clause 289. The dosage form is a solid dosage form, as specified in any one of Clauses 261 to 286. The dosage form as described.

[0419] Clause 290. The dosage form described in Clause 289, wherein the dosage form is a tablet or a capsule.

[0420] Article 291. (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, This includes performing this procedure for patients who require simultaneous administration of the drug, After a single dose, the aforementioned co-administration involves at least approximately 1:280 bupresence in one control group. Norphin's average C max and the average C of oxycodone max This results in the ratio Methods for treating pain.

[0421] Clause 292. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:250, as described in Clause 291.

[0422] Article 293. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:230, as described in Clause 291.

[0423] Article 294. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:200, as described in Clause 291.

[0424] Article 295. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:180, as described in Clause 291.

[0425] Article 296. Mean C of buprenorphine max and the average C of oxycodone max The ratio The rate is approximately 1:50 to approximately 1:280, as described in Clause 291.

[0426] Article 297. Mean C of buprenorphine max and the average C of oxycodone max The ratio The rate is approximately 1:50 to approximately 1:250, as described in Clause 291.

[0427] Article 298. Mean C of buprenorphine max and the average C of oxycodone max The ratio The rate is approximately 1:80 to approximately 1:230, as described in Clause 291.

[0428] Article 299. Mean C of buprenorphine max and the average C of oxycodone max The ratio The rate is approximately 1:100 to approximately 1:200, as described in Clause 291.

[0429] Clause 300. Mean C of buprenorphine max and the average C of oxycodone max The ratio The rate is approximately 1:100 to approximately 1:180, as described in Clause 291.

[0430] Clause 301. After a single dose is administered, the simultaneous administration shall be to the control group at a ratio of approximately 1.5:1 or less. Average T of prenorphines max and the average T of oxycodone max The ratio further brings about The method described in any one of paragraphs 291 to 300.

[0431] Clause 302. Mean T of buprenorphine max and the average T of oxycodone max The ratio The ratio is approximately 1.3:1 or less, as described in Clause 301.

[0432] Clause 303. Mean T of buprenorphine max and the average T of oxycodone max The ratio The method described in Clause 301, wherein the ratio is approximately 1.1:1 or less.

[0433] Clause 304. Mean T of buprenorphine max and the average T of oxycodone max The ratio The method described in Clause 301, wherein the ratio is approximately 1:1 or less.

[0434] Clause 305. After a single dose administration, the aforementioned simultaneous administration of oxycodone to the control group shall be as follows: max Compared to the average T of buprenorphine, it is faster. max Article 291 further brings about The method described in any one of the paragraphs of Article 300.

[0435] Clause 306. After a single dose, the aforementioned simultaneous administration shall be administered to the control group in a ratio of approximately 0.1:1 to approximately 1. 5:1, preferably about 0.1:1 to about 1.3:1, more preferably about 0.1:1 to about 1.1:1, most preferably about 0.1:1 to about 1:1, or about 0.1:1 to about 0. 9:1 ​​average T of buprenorphine max and the average T of oxycodone max The ratio of The method described in any one of Clauses 291 to 305.

[0436] Clause 307. The aforementioned concurrent administration is administered orally, any one of Clauses 291 to 306 The method described in section [section number].

[0437] Article 308. The certain amount of buprenorphine and the certain amount of oxycodone shall be 3 Administered within 0 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute. Preferably, the buprenorphine is administered up to the time of the oxycodone, Clause 291 The method described in any one of the paragraphs of Article 307.

[0438] Clause 309. The simultaneous administration of the above-mentioned fixed amount of buprenorphine and the above-mentioned fixed amount of oxyco The aforementioned administration is an oral dosage form containing both Don, any one of Clauses 291 to 307. Methods used.

[0439] Article 310. The aforementioned certain amount of oxycodone is approximately 5 mg to approximately 50 mg of oxycodone hydrochloride. Salt (Mw = 351.82 g / mol), preferably about 5 mg to about 40 mg of oxycod It is equimolar to the hydrochloride (Mw = 351.82 g / mol), as per clause 307. The method described in any one of item 309.

[0440] Clause 311. The aforementioned certain amounts of oxycodone are approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or approximately 40 mg, of oxycodone hydrochloride (Mw = 351.82 g / mol) The method according to any one of the clauses 307 to 309, wherein the amount is equimolar.

[0441] Clause 312. The aforementioned certain amounts of oxycodone are approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or approximately 40 mg, of oxycodone hydrochloride (Mw = 351.82 g / mol) The method according to Clause 311, wherein the amount is a constant equimolar amount of oxycodone hydrochloride.

[0442] Clause 313. The aforementioned certain amounts of oxycodone are approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or approximately 40 mg, of oxycodone hydrochloride (Mw = 351.82 g / mol) The method according to Clause 311, wherein the amount is a constant equimolar amount of oxycodone myristate salt relative to the given amount. .

[0443] Article 314. The aforementioned certain amount of oxycodone is approximately 40 mg of oxycodone hydrochloride (Mw= It is equimolar to 351.82 g / mol, and the aforementioned fixed amount of buprenorphine is approximately Equivalent to 1 mg to approximately 6 mg of buprenorphine base (Mw = 467.64 g / mol) The method described in any one of the clauses 307 to 309, wherein the amount is a mole.

[0444] Article 315. The aforementioned certain amount of oxycodone is approximately 40 mg of oxycodone hydrochloride (Mw= It is equimolar to 351.82 g / mol, and the aforementioned fixed amount of buprenorphine is approximately 2 mg to approximately 5 mg of buprenorphine base (Mw = 467.64 g / mol) or approximately 2 For approximately 4 mg of buprenorphine base (Mw = 467.64 g / mol), the equivalent amount is... The method described in any one of clauses 307 to 309.

[0445] Clause 316. The oxycodone is oxycodone hydrochloride, and the buprenorphine is Buprenorphine hydrochloride, as specified in Clauses 291 to 311, 314 and 315. The method described in any one of the items.

[0446] Clause 317. The certain amount of buprenorphine is immediate-release, Clauses 291 to Clause 317. The method described in any one of paragraphs 316.

[0447] Clause 318. The certain amount of oxycodone is immediate-release, and the certain amount of buprenor The fins are of the immediate release type, as described in any one of Clauses 291 to 317.

[0448] Clause 319. The dosage form is a liquid dosage form, as specified in any one of Clauses 291 to 318. Method of description.

[0449] Clause 320. The dosage form is a liquid, a suspension, or an emulsion, preferably a liquid. The method described in Article 319.

[0450] Clause 321. The dosage form is a solid dosage form, as specified in any one of Clauses 291 to 318. Method of description.

[0451] Clause 322. The method according to Clause 321, wherein the dosage form is a tablet or a capsule.

[0452] Article 323. The method described herein results in the prevention or suppression of the adverse pharmacokinetic reaction of oxycodone. , the method described in any one of Clauses 291 to 322.

[0453] Clause 324. The simultaneous administration of the certain amount of buprenorphine in the dosage form is administered alone. When administering, the adverse drug dynamics reaction observed with the certain amount of oxycodone in the dosage form The method described in any one of the clauses 291 to 322 to prevent or suppress.

[0454] Clause 325. The adverse drug reactions include euphoria, euphoria, bowel dysfunction, nausea, vomiting, and drowsiness. dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dyspnea, delirium Delirium, miosis, pruritus, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance Selected from the group, preferably the adverse drug dynamic response is respiratory depression, euphoria, euphoria, and The method according to Clause 323 or Clause 324, selected from the group consisting of bowel dysfunction.

[0455] Clause 326. The toxic drug-mediated response is euphoria, as described in Clause 323 or Clause 324. The method.

[0456] Clause 327. The toxic drug-mechanical response is euphoria, as described in Clause 323 or Clause 324. The method.

[0457] Clause 328. Average E of "Euphoria VAS" max When measuring using comparative tests, the amount is small. The method described in Clause 327 reduces the amount by at least 15%.

[0458] Clause 329. Average E of "Euphoria VAS" max is at least 20%, preferably less At least 25%, more preferably at least 30%, most preferably at least 35%, Or it is reduced by a further 40%, as described in Clause 328.

[0459] Article 330. The method described above results in the prevention or suppression of drug addiction to oxycodone. The method described in any one of paragraphs 291 to 329.

[0460] Clause 331. The simultaneous administration of the certain amount of buprenorphine in the dosage form is administered alone. When administering, compare with the drug preference observed at the aforementioned fixed amount of oxycodone in the aforementioned dosage form. And to prevent or suppress drug addiction to oxycodone, as stipulated in Articles 291 to 329. Either the method described in item 1.

[0461] Clause 332. Mean E of "Temporary Drug Preference VAS" max This is measured using comparative tests. The method described in Clause 330 or Clause 331, which reduces the amount by at least 15% when doing so.

[0462] Clause 333. Average E of "Temporary Drug Preference VAS" max At least 20% prefer Or a reduction of at least 25%, more preferably at least 30%, as stated in Clause 332. The method.

[0463] Clause 334. Average E of "Overall Drug Preference VAS" max This is measured using comparative tests. The method described in Clause 330 or Clause 331, which reduces the amount by at least 15% when doing so.

[0464] Clause 335. Average E of "Overall Drug Preference VAS" max At least 20% prefer or at least 25%, more preferably at least 30%, most preferably at least The method described in Clause 334 reduces the amount by 35%.

[0465] Article 336. Average E of "Drug Reuse VAS" max When measuring using comparative tests The method described in Clause 330 or Clause 331, which reduces the amount by at least 15%.

[0466] Article 337. Average E of "Drug Reuse VAS" max at least 20%, preferably At least 25%, more preferably at least 30%, most preferably at least 35% The method described in Clause 336, which reduces the amount of damage.

[0467] Article 338. The method provides an analgesic effect that is not substantially reduced when measured using comparative tests. The method described in any one of the clauses 291 to 337, which brings about the results of the following:

[0468] Clause 339. Mean measured using the cold pressurization test at 1, 2, 3, and 4 hours after administration. The "Cold Pain Score (VAS)" is measured using comparative trials, and when compared to the comparative treatment method, it is 10 The method described in Clause 338 shall not increase by more than %.

[0469] Article 340. The method shall not cause the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. The method described in any one of the clauses 291 to 339 to prevent or suppress.

[0470] Article 341. Any of the methods used to treat pain, as described in Articles 261 to 290. The oral dosage form described in item 1.

[0471] Clause 342. The method described above results in the prevention or suppression of the adverse pharmacodynamic reaction of oxycodone. , an oral dosage form as described in Clause 341 for use in methods for treating pain.

[0472] Clause 343. The simultaneous administration of the certain amount of buprenorphine in the dosage form is administered alone. When administering, the adverse drug dynamics reaction observed with the certain amount of oxycodone in the dosage form Oral dosage forms described in Clause 341 for use in methods of preventing or suppressing pain or treating pain .

[0473] Clause 344. The adverse drug reactions include euphoria, euphoria, bowel dysfunction, nausea, vomiting, and somnolence. dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dyspnea, delirium Delirium, miosis, pruritus, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance Selected from the group, preferably the adverse drug dynamic response is respiratory depression, euphoria, euphoria, and Clause 34, used for methods of treating pain, selected from the group consisting of bowel dysfunction and bowel dysfunction. The oral dosage form as described in Article 2 or Article 343.

[0474] Clause 345. The aforementioned adverse drug reaction is euphoria, and is used in methods to treat pain. The oral dosage form as described in Clause 342 or Clause 343.

[0475] Clause 346. The adverse drug reaction is euphoria, and the drug is used in a method to treat pain. The oral dosage form as described in Clause 342 or Clause 343.

[0476] Clause 347. Average E of "Euphoria VAS" max When measuring using comparative tests, the amount is small. Oral agents used in methods for treating pain, as described in Clause 346, which reduce pain by at least 15% shape.

[0477] Clause 348. Average E of "Euphoria VAS" max is at least 20%, preferably less At least 25%, more preferably at least 30%, most preferably at least 35%, Or, the oral method used for treating pain, as described in Clause 347, is reduced by a further 40%. Dosage form.

[0478] Article 349. The method described above results in the prevention or suppression of drug preference for oxycodone, pain The method used to treat pain as described in any one of the clauses 341 to 348 Oral dosage form.

[0479] Clause 350. The simultaneous administration of the certain amount of buprenorphine in the dosage form is administered alone. When administering, compare with the drug preference observed at the aforementioned fixed amount of oxycodone in the aforementioned dosage form. It is used in methods to treat pain, to prevent or suppress drug dependence on oxycodone. The oral dosage form used as specified in any one of clauses 341 to 348.

[0480] Clause 351. Mean E of "Temporary Drug Preference VAS" max This is measured using comparative tests. Clause 349, which is used for methods of treating pain that reduce the pain by at least 15% when used. This is the oral dosage form as described in Clause 350.

[0481] Clause 352. Mean E of "Temporary Drug Preference VAS" max At least 20% prefer To treat pain, it reduces it by at least 25%, more preferably at least 30%. The oral dosage form used in the method described in Clause 351.

[0482] Clause 353. Average E of "Overall Drug Preference VAS" max This is measured using comparative tests. Clause 349, which is used for methods of treating pain that reduce the pain by at least 15% when used. This is the oral dosage form as described in Clause 350.

[0483] Clause 354. Average E of "Overall Drug Preference VAS" max At least 20% prefer or at least 25%, more preferably at least 30%, most preferably at least An oral dosage form described in Clause 353 for use in methods of treating pain, which reduces pain by 35%.

[0484] Article 355. Average E of "Drug Reuse VAS" max When measuring using comparative tests A method used to treat pain that reduces it by at least 15%, as per clause 349 or clause The oral dosage form described in 350.

[0485] Article 356. Average E of "Drug Reuse VAS" max at least 20%, preferably At least 25%, more preferably at least 30%, most preferably at least 35% Oral dosage forms as described in Clause 355 for use in methods of treating pain that reduces it.

[0486] Article 357. The method provides an analgesic effect that is not substantially reduced when measured using comparative tests. Any of the clauses 341 to 356 used for methods of treating pain that results from The oral dosage form described in item 1.

[0487] Clause 358. Mean measured using the cold pressurization test at 1, 2, 3, and 4 hours after administration. The "Cold Pain Score (VAS)" is measured using comparative trials, and when compared to the comparative treatment method, it is 10 Oral dosage forms as described in Clause 357 for use in methods of treating pain, which do not increase by more than %.

[0488] Article 359. The method described herein shall not cause the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. The provisions of Clauses 341 to 358, used for methods to prevent or suppress pain, or to treat pain. Either of the oral dosage forms described in item 1.

[0489] Clause 360. The same amount of oxycodone as described in any one of Clauses 203 to 232. By administering the oral dosage form listed above instead, pain relief can be achieved using a certain amount of oxycodone alone. A method for preventing or suppressing the adverse drug-mechanical reactions of oxycodone observed in the treatment of [condition].

[0490] Clause 361. The adverse drug reactions include euphoria, euphoria, bowel dysfunction, nausea, vomiting, and drowsiness. dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dyspnea, delirium Delirium, miosis, pruritus, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance Selected from the group, preferably the adverse drug dynamic response is respiratory depression, euphoria, euphoria, and The method according to Clause 360, selected from the group consisting of bowel dysfunction.

[0491] Clause 362. The method according to Clause 360, wherein the toxic drug's mechanical response is euphoria.

[0492] Clause 363. The method according to Clause 360, wherein the toxic drug's mechanical response is euphoria.

[0493] Article 364. The same amount of oxycodone as described in any one of Articles 261 to 290. By administering the oral dosage form listed above instead, pain relief can be achieved using a certain amount of oxycodone alone. A method for preventing or suppressing oxycodone drug dependence observed in the treatment of [condition].

[0494] Clause 365. To provide the dosage form described in any one of Clauses 261 to 290. To prevent or suppress the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. The method.

[0495] Article 366. To prevent or suppress the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. The use of any one of the dosage forms specified in paragraphs 261 to 290 in relation to the use of any one of the dosage forms specified in paragraphs 261 to 290.

[0496] Clause 367. At least two oral dosage forms containing oxycodone with different active ingredient content. The set is such that each of the aforementioned dosage forms is (i) a. Approximately 10 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), b. Approximately 15 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), c. Approximately 20 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), d. Approximately 30 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), or e. Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), Against this, equimolar amounts of a fixed amount of oxycodone, (ii) A certain amount of buprenorphine, Includes, The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is, -The table is displayed using equimolar amounts of buprenorphine base (mg) (Mw = 467.64 g / mol). The dosage form contains a certain amount of buprenorphine and an equimolar amount of oxycod The dosage form expressed as n hydrochloride (mg) (Mw=351.82 g / mol) When calculating using a fixed amount of oxycodone, the ratio is greater than 1:40. - Having the same value in each dosage form of the set, The aforementioned set.

[0497] Clause 368. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone A set of at least two oral dosage forms as described in Clause 367, with a ratio of approximately 1:38 or higher.

[0498] Article 369. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:3 to over 1:40, or approximately 1:3 to approximately 1:38, as stated in Clause 367. A set of at least two oral dosage forms.

[0499] Clause 370. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:4 to over 1:40, or approximately 1:4 to approximately 1:38, as stated in Clause 367. A set of at least two oral dosage forms.

[0500] Clause 371. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:5 to over 1:40, or approximately 1:5 to approximately 1:38, as stated in Clause 367. A set of at least two oral dosage forms.

[0501] Clause 372. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:5 to approximately 1:35, preferably approximately 1:5 to approximately 1:30, as per clause 367. A set of at least two of the oral dosage forms listed.

[0502] Clause 373. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone. The ratio is approximately 1:6 to over 1:40, or approximately 1:6 to approximately 1:38, as stated in Clause 367. A set of at least two oral dosage forms.

[0503] Clause 374. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:6 to approximately 1:35, preferably approximately 1:6 to approximately 1:30, more preferably approximately The ratio is 1:6 to approximately 1:28, or approximately 1:6 to approximately 1:20, as specified in Article 367. Each set contains two different oral dosage forms.

[0504] Clause 375. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:8 to approximately 1:30, for at least two oral dosage forms as described in Clause 367. .

[0505] Article 376. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:8 to approximately 1:28, for at least two oral dosage forms as described in Clause 367. .

[0506] Clause 377. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:8 to approximately 1:20, for at least two oral dosage forms as described in Clause 367. .

[0507] Clause 378. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:8 to approximately 1:15, for at least two oral dosage forms as described in Clause 367. .

[0508] Clause 379. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:10 to approximately 1:20 for at least two oral dosage forms as described in Clause 367. set.

[0509] Clause 380. The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone The ratio is approximately 1:10 to approximately 1:15 for at least two oral dosage forms as described in Clause 367. set.

[0510] Clause 381. Each of the above dosage forms shall be in the following quantities: a. Approximately 10 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), b. Approximately 15 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), c. Approximately 20 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), d. Approximately 30 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), or e. Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), One of them contains oxycodone hydrochloride in equimolar amounts, as per Articles 367 to 38 A set of at least two oral dosage forms as described in any one of item 0.

[0511] Clause 382. Each of the above dosage forms shall be in the following quantities: a. Approximately 10 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), b. Approximately 15 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), c. Approximately 20 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), d. Approximately 30 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), or e. Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol), One of them contains oxycodone myristate in equimolar amounts, according to Clause 367 A set of at least two oral dosage forms as described in any one of clauses 380.

[0512] Clause 383. The set is, (1) Equivalent to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) A fixed amount of oxycodone in moles, and approximately 1 mg to 6 mg of buprenorphine base (Mw The first compound contains a fixed amount of buprenorphine in equimolar amounts (467.64 g / mol) Dosage form and, (2) Approximately 10 mg, 15 mg, 20 mg, or 30 mg of oxycodone hydrochloride A small amount of oxycodone, equimolar to a salt (Mw = 351.82 g / mol), is contained in the salt. At the very least, one further dosage form, including at least two oral dosage forms as described in any one of paragraphs 367 to 382 set.

[0513] Clause 384. The set is, (1) Equivalent to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) A fixed amount of oxycodone in moles, and approximately 2 mg to 5 mg of buprenorphine base (Mw The first compound contains a fixed amount of buprenorphine in equimolar amounts (467.64 g / mol) Dosage form and, (2) Approximately 10 mg, 15 mg, 20 mg, or 30 mg of oxycodone hydrochloride A small amount of oxycodone, equimolar to a salt (Mw = 351.82 g / mol), is contained in the salt. At the very least, one further dosage form, including at least two oral dosage forms as described in any one of paragraphs 367 to 382 set.

[0514] Clause 385. The oxycodone is oxycodone hydrochloride, and the buprenorphine is Buprenorphine hydrochloride, as stated in Clauses 367 to 380, 383 and 384. A set of at least two oral dosage forms as described in any one of the items.

[0515] Clause 386. Each of the above dosage forms contains the above-mentioned fixed amount of buprenorphine in an immediate-release form. a set of at least two oral dosage forms as described in any one of clauses 367 to 385 to.

[0516] Article 387. Each of the above dosage forms contains the above-mentioned fixed amount of oxycodone in an immediate-release form, Any of the provisions of Clauses 367 to 386, comprising a fixed amount of buprenorphine in an immediate-release form. A set of at least two oral dosage forms as described in item 1.

[0517] Article 388. Each of the aforementioned dosage forms is a liquid dosage form, as per Articles 367 to 387 A set of at least two oral dosage forms as described in item 1.

[0518] Clause 389. Each of the above dosage forms is a liquid, a suspension, or an emulsion, preferably At least two types of the same form selected from the group consisting of liquid preparations, as described in Clause 388 A set of oral dosage forms.

[0519] Article 390. Each of the aforementioned dosage forms is a solid dosage form, as per Articles 367 to 387 A set of at least two oral dosage forms as described in item 1.

[0520] Clause 391. Each of the above dosage forms shall be in the same form selected from tablets or capsules. A set of at least two oral dosage forms as described in Article 390.

[0521] Clause 392. After a single dose, each of the dosage forms shall provide at least approximately one control group. Average C of buprenorphine at 1:280 max and the average C of oxycodone max The ratio of To include at least two oral dosage forms as described in any one of paragraphs 367 to 391. set.

[0522] Clause 393. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:250, for at least two oral dosage forms as described in Clause 392. set.

[0523] Clause 394. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:230 for at least two oral dosage forms as described in Clause 392. set.

[0524] Article 395. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:200, for at least two oral dosage forms as described in Clause 392. set.

[0525] Clause 396. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is at least about 1:180 for at least two oral dosage forms as described in Clause 392. set.

[0526] Article 397. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is approximately 1:50 to approximately 1:280, for at least two oral dosage forms as described in Clause 392. A set.

[0527] Article 398. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is approximately 1:50 to approximately 1:250, for at least two oral dosage forms as described in Clause 392. A set.

[0528] Clause 399. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is approximately 1:80 to approximately 1:230, for at least two oral dosage forms as described in Clause 392. A set.

[0529] Clause 400. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is approximately 1:100 to approximately 1:200, for at least two oral agents as described in Clause 392. A set of shapes.

[0530] Clause 401. Mean C of buprenorphine max and the average C of oxycodone max The ratio The ratio is approximately 1:100 to approximately 1:180, for at least two oral agents as described in Clause 392. A set of shapes.

[0531] Clause 402. After a single dose administration, each of the dosage forms shall be administered to the control group in a ratio of approximately 1.5:1 or The average T of buprenorphine below max and the average T of oxycodone max This will bring the ratio even further The set of at least two oral dosage forms as described in any one of clauses 392 to 401. to.

[0532] Clause 403. Mean T of buprenorphine max and the average T of oxycodone max The ratio A set of at least two oral dosage forms as described in Clause 402, with a ratio of approximately 1.3:1 or less.

[0533] Clause 404. Mean T of buprenorphine max and the average T of oxycodone max The ratio A set of at least two oral dosage forms as described in Clause 402, with a ratio of approximately 1.1:1 or less.

[0534] Clause 405. Mean T of buprenorphine max and the average T of oxycodone max The ratio A set of at least two oral dosage forms as described in Clause 402, with a ratio of approximately 1:1 or less.

[0535] Article 406. After a single dose, each of the dosage forms shall provide the subject group with oxycodone average T max Compared to the average T of buprenorphine, it is faster. max A clause that further brings about A set of at least two oral dosage forms as described in any one of paragraphs 392 to 401.

[0536] Clause 407. After a single dose administration, each of the dosage forms shall be administered to the control group in a ratio of approximately 0.1:1. Approximately 1.5:1, preferably approximately 0.1:1 to approximately 1.3:1, more preferably approximately 0.1: 1 to approximately 1.1:1, most preferably approximately 0.1:1 to approximately 1:1, or approximately 0.1:1 to The average T of buprenorphine is approximately 0.9:1. max and the average T of oxycodone max The ratio Furthermore, it brings about at least two oral substances as described in any one of clauses 392 to 406. A set of dosage forms.

[0537] Clause 408. The set comprises at least three oxycodones with different active ingredient content. Preferably, one of clauses 367 to 407, comprising at least four dosage forms. A set of at least two oral dosage forms as described above.

[0538] Article 409. (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, This includes administering it to patients who require an oral dosage form that includes it. Average E of "Exhilaration VAS" max When measured using comparative tests, at least 15% to decrease, and / or, The average E of the "Temporary Drug Preference VAS" max When measuring using comparative tests, less Both decrease by 15%, and / or The average E of the "Overall Drug Preference VAS" max When measuring using comparative tests, less Both decrease by 15%, and / or Average E of "Drug Reuse VAS" max When measuring using comparative tests, at least 1 It will decrease by 5%, and / or The average "cold pain score" measured using the cold vasopressor test at 1, 2, 3, and 4 hours after administration. "AVAS" is defined as a score that does not increase by more than 10% compared to a comparative treatment method when measured using comparative trials. stomach, Methods for treating pain.

[0539] Article 410. (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, This includes performing this procedure for patients who require simultaneous administration of the drug, Average E of "Exhilaration VAS" max When measured using comparative tests, at least 15% to decrease, and / or, The average E of the "Temporary Drug Preference VAS" max When measuring using comparative tests, less Both decrease by 15%, and / or The average E of the "Overall Drug Preference VAS" max When measuring using comparative tests, less Both decrease by 15%, and / or Average E of "Drug Reuse VAS" max When measuring using comparative tests, at least 1 It will decrease by 5%, and / or The average "cold pain score" measured using the cold vasopressor test at 1, 2, 3, and 4 hours after administration. "AVAS" is defined as a score that does not increase by more than 10% compared to a comparative treatment method when measured using comparative trials. stomach, Methods for treating pain.

[0540] Article 411. (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, This includes administering it to patients who require an oral dosage form that includes it. Average E of "Exhilaration VAS" max When measured using comparative tests, at least 35% to decrease, and / or, The average E of the "Temporary Drug Preference VAS" max When measuring using comparative tests, less Both decrease by 30%, and / or The average E of the "Overall Drug Preference VAS" max When measuring using comparative tests, less Both decrease by 30%, and / or Average E of "Drug Reuse VAS" maxWhen measuring using comparative tests, at least 3 It decreases by 0%, and / or, The average "cold pain score" measured using the cold vasopressor test at 1, 2, 3, and 4 hours after administration. "AVAS" is defined as a score that does not increase by more than 10% compared to a comparative treatment method when measured using comparative trials. stomach, Methods for treating pain.

[0541] Article 412. (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, This includes performing this procedure for patients who require simultaneous administration of the drug, Average E of "Exhilaration VAS" max When measured using comparative tests, at least 35% to decrease, and / or, The average E of the "Temporary Drug Preference VAS" max When measuring using comparative tests, less Both decrease by 30%, and / or The average E of the "Overall Drug Preference VAS" max When measuring using comparative tests, less Both decrease by 30%, and / or Average E of "Drug Reuse VAS" max When measuring using comparative tests, at least 3 It decreases by 0%, and / or, The average "cold pain score" measured using the cold vasopressor test at 1, 2, 3, and 4 hours after administration. "AVAS" is defined as a score that does not increase by more than 10% compared to a comparative treatment method when measured using comparative trials. stomach, Methods for treating pain.

[0542] Clause 413. As the sole opioid analgesic, a certain amount of buprenorphine, preferably This includes administering it to patients who require an oral dosage form containing buprenorphine HCl. Methods for treating pain.

[0543] Clause 414. The certain amount of buprenorphine present in the dosage form shall be approximately 1 mg to approximately 4 mg. It is equimolar to 0 mg of buprenorphine base (Mw = 467.64 g / mol). , the method described in Article 413.

[0544] Clause 415.1 The daily dose is approximately 1 mg to approximately 40 mg of buprenorphine base (Mw=467 The method according to Clause 413, wherein the amount is a constant equimolar amount relative to 0.64 g / mol.

[0545] Clause 416. The certain amount of buprenorphine present in the dosage form is approximately 2.5 mg. Approximately 5mg, 10mg, 15mg, 20mg, 30mg, or 40mg of It is equimolar to prenorphine base (Mw = 467.64 g / mol), Clause 41 The method described in 4.

[0546] Clause 417. As the sole opioid analgesic, a certain amount of buprenorphine, preferably An oral dosage form containing buprenorphine HCl.

[0547] Clause 418. Buprenorphine is approximately 1 to 40 mg of buprenorphine base (Mw= (467.64 g / mol) present in the dosage form in an equimolar constant amount, Clause 417 The dosage form as described above.

[0548] Article 419. Buprenorphine is approximately 2.5, approximately 5, approximately 10, approximately 15, approximately 20, approximately 30 And, for approximately 40 mg of buprenorphine base (Mw = 467.64 g / mol) The dosage form described in Clause 418, which is present in the dosage form in an equimolar amount.

[0549] Clause 420. The dosage form comprises the same fixed amount of buprenorphine in an immediate-release form, Clause 4 The dosage form specified in any one of paragraphs 17 to 419.

[0550] Clause 421. The dosage form is a liquid, for example, a liquid, suspension or emulsion. The dosage form as described in Article 420.

[0551] Clause 422. The dosage form is a solid, for example, a tablet or a capsule. The dosage form described in 0.

[0552] Clause 423. The certain amount of oxycodone is administered orally, and the certain amount of buprenorphine is administered orally. The drug is administered transdermally, in clauses 291 to 306, 323 to 340, and 41. The method described in either paragraph 0 or paragraph 412.

[0553] Clause 424. The certain amount of oxycodone is administered orally, and the certain amount of buprenorphine is administered orally. The drug is administered subcutaneously, as per clauses 291 to 306, 323 to 340, and 41. The method described in either paragraph 0 or paragraph 412.

[0554] Clause 425. The aforementioned certain amount of oxycodone is approximately 5 mg to approximately 50 mg of oxycodone hydrochloride. Salt (Mw = 351.82 g / mol), preferably about 5 mg to about 40 mg of oxycod It is equimolar to n hydrochloride (Mw = 351.82 g / mol), clause 423 or clause 423. The method described in item 424.

[0555] Clause 426. The aforementioned certain amounts of oxycodone are approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 30 mg, or approximately 40 mg, of oxycodone hydrochloride (Mw = 351.82 g / mol) The method according to clause 423 or clause 424, wherein the result is equimolar with respect to the given amount.

[0556] Clause 427. The oxycodone is oxycodone hydrochloride, and the buprenorphine is Buprenorphine hydrochloride, as described in any one of Clauses 423 to 426 .

[0557] The present invention will now be described with reference to the attached examples. However, the following description This is merely an example and should not be interpreted as limiting the invention in any way. You should understand that. [Examples]

[0558] Example 1 Example 1 concerns the potential for abuse, pain management, and the co-administration of oxycodone hydrochloride. and to evaluate the pharmacokinetics of buprenorphine, 32 healthy men and women participated in recreational activities. A single-center, double-blind, placebo-controlled, positive-controlled, randomized, cross-sectional study of opioid users. It was a crossover trial. The subjects were randomized, double-blind, and in a crossover design. During each of the following periods, oral and transdermal medications were administered. Each period involved 16 patients. The test was conducted in two replicates, 1 and 2, including elephants, but only 15 subjects participated in replicate 1. The study was completed, and one participant was discontinued for reasons unrelated to the study drug. In Repetitions 1 and 2... , the potential for abuse, and the co-administration of oxycodone hydrochloride and buprenorphine Pharmacokinetics were evaluated, and pain management was additionally assessed in repeat 2. The potential for abuse, as well as the same Results regarding the pharmacokinetics of oxycodone hydrochloride and buprenorphine administered at specific times. The results of repetitions 1 and 2 were combined to make N=32, and in contrast to that, for pain management, We set N=16 to consist only of pairs 2.

[0559] The experimental treatment drugs were as follows: Buprenorphine dosage: Butrans (registered trademark), 20 mcg / hour, 20 mg (buprenorphine base (Mw=467.64g / mol), patch, transdermal Butrans®, 0 mcg / hour, 0 mg (placebo patch), transdermal

[0560] The buprenorphine dose was determined by administering three different oxycodone doses in a randomized order. It was administered. • Oxycodone HCl (351.82 g / mol) IR (0 mg), (lactose powder) capsules, oral Oxycodone HCl (351.82 g / mol) IR (20 mg), ZyGene Oral tablets manufactured by RICS and coated for blinding purposes. • Oxycodone HCl (351.82 g / mol) IR (2 x 20 mg), ZyGe Oral tablets manufactured by Nerics and coated for blinding purposes. A total of six types of medication. ·placebo · OxyIR-20 · OxyIR-40 Butrans-20 • Butrans-20 / OxyIR-20 • Butrans-20 / OxyIR-40

[0561] During each period, buprenorphine (Butrans 20mcg / hour) transdermal patch was administered. A transdermal patch containing either chloride or placebo was applied to the target skin for 108 hours and then removed. This was a randomized controlled trial. During each of the Zain periods, at 48, 72, and 96 hours after patch application, oxyco Don IR or placebo was administered orally. The administration scheme is summarized in Figure 1. Yes, they are.

[0562] Selection of target The principal investigator deemed it appropriate for participants in this clinical trial to have a history of oral use and be 18 years of age or older. Healthy men aged up to 55 years (including those aged 18 and 55) with no clinically significant medical history and We selected female recreational opioid users.

[0563] After the screening stage, in order to exclude individuals who are physically dependent on opioids, The subjects underwent a naloxone induction test.

[0564] To be eligible for treatment, subjects with self-reported recreational opioid use history are managed In addition to reporting the clear and subjective effects of the drug in the specified testing environment, oxycodone We confirmed that IR and placebo could be tolerated and distinguished. Regarding "placebo responders," that is, those who report the subjective effects of the placebo: Excluded.

[0565] Participants who met all inclusion criteria and did not meet exclusion criteria were randomized to the trial.

[0566] Inclusion criteria 1. Written informed consent has been submitted. 2. The target audience must be male or female between the ages of 18 and 55 (including those aged 18 and 55). and. 3. At the time of screening, 18.0-34.0 kg / m² 2 Range (18.0k) g / m 2 and 34.0 kg / m 2 Body Mass Index (BMI) and at least 5 (including) The animal must have a minimum body weight of 0.0 kg. 4. The following criteria: 1) At least 10 times in the previous year for non-therapeutic purposes (i.e., psychotropic effects) 1) Using opioids for the following reasons, and 2) In the 12 weeks prior to screening Having used opioids at least three times, and having moderate experience with opioids. Being an ID user. 5. At least once in the previous year, an opioid equivalent to oxycodone IR at a dose of 30 mg or more. You need to report the dosage you took. 6. Women who have sexual relations with the opposite sex and are capable of becoming pregnant should not take the test drug during the study and the last test drug. You must use an appropriate and reliable method of contraception for at least 30 days after administration. There are women who are postmenopausal and not using approved contraception, and who have sexual relations with men. Sex is defined as being ≥1 year postmenopausal and having high serum follicle-stimulating hormone (FSH) levels (i.e.) It must have a concentration of ≥50 mIU / mL. 7. Female patients are required to provide a negative pregnancy test result upon screening and / or admission. be. 8. Understand the content of the exam, submit written informed consent, and take all exams. You must be able to speak, read, and understand English sufficiently to complete the assessment. 9. You must be prepared and able to comply with all test requirements and test regulations. ru.

[0567] Exclusion criteria 1. Physical examination and medical history as determined by the principal investigator or nominee at the time of screening. Clinically significant abnormalities in 12-lead electrocardiogram (ECG), vital signs, or laboratory values. . 2.The Diagnostic and Statistical Manual Defined in the Medical Specific Disorders (DSM-IV) Self-reported history of drug or alcohol dependence (in the past two years), past drug use Individuals who have participated in a rehabilitation program (treatment for smoking cessation, or cases) It depends on the case, but for example, for the purpose of reducing the sentence or for the sole use of marijuana. Conditions that replace detention, with the exception of, or the current drug or alcohol dependence Existing symptoms (within the last 12 months, excluding nicotine or caffeine). 3. In the opinion of the principal investigator, if the safety of the subject or the efficacy of the trial results is jeopardized To obtain any clinically significant disease (e.g., cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, internal). (of urinary, immunological, cutaneous, neurological, tumor, musculoskeletal, or psychiatric) or any other medical condition A medical history or presence of the following. 4. Any personal or family history of QT interval prolongation or cardiac rhythm disorder. 5. The following, • QTcF interval during screening > 450 milliseconds • QTcF interval > 48 recorded at check-in or during any ECG during treatment 0 milliseconds An abnormal cardiac condition including any of the following. 6. Based on the judgment of the principal investigator or the nominated investigator, it is determined to be clinically significant. A history or presence of hypotension. 7. Prohibited substances (i.e., non-prescription drugs, prescription drugs, herbal products, or natural health products) Use of ) 8. During the study or within 30 days after the last administration of the study drug, the patient is currently pregnant or breastfeeding. This is for women who are pregnant or planning to become pregnant. 9. Alanine aminotransferase (ALT) or aminotransferase of aspartate AST >1.5x above the upper limit of normal (ULN), or total serum bisphosphonate Evidence of clinically significant liver or kidney impairment, including >10% of patients with ULN (Ultra-Low Nucleation). 10. Severe allergic reaction (anaphylaxis) to any food, drug, or bee sting. A history of (including xi) or a previous status asthmaticus. 11. Oxycodone, buprenorphine, naloxone, or related drugs (for example, Other opioids or opioid antagonists, or pharmaceutical excipients or other A history of allergies or hypersensitivity to any of the other medicinal ingredients. 12. A medical history of lactose allergy. 13. Positive for Hepatitis B and Hepatitis C. 14. Unless otherwise required by this protocol, within 56 days prior to entering the qualification stage, Alternatively, if you have donated whole blood on the day of your EOS visit and for 30 days after the completion of your EOS visit, thing. 15. Unless otherwise required by this protocol, within 14 days prior to entering the qualification stage, Alternatively, the patient must have donated plasma by the end of the trial (EOS) visit date. 16. When venous access is difficult, or when catheter insertion is inappropriate or undesirable. If it's not good. 17. Within 30 days prior to the first drug administration for naloxone induction, any test drug The treatment is being performed. 18. In the month prior to screening, you consumed an average of more than 20 cigarettes per day. Or, refrain from smoking (or using any nicotine-containing substance) for at least 18 hours. The inability to obtain something. 19. If the urine drug screening during screening and / or admission is positive. Possible occurrences include repeated positive results and / or, at the discretion of the principal investigator. The participant may change the schedule. This is at the discretion of the principal investigator and is handled on a case-by-case basis. Regarding positive results for tetrahydrocannabinol (THC), testing is conducted by licensed physicians. Based on the examination (detailed or brief physical examination) and interview, the subject was found to have the influence of cannabinoids. If it is confirmed that there is no resonance, it may be permitted. 20. In the opinion of the principal investigator, any substance that could interfere with the study procedure or data integrity, This refers to the presence of any medical condition that could threaten the safety of the subject. 21. In the opinion of the principal investigator or the nominated investigator, for any other reason, Subjects deemed suitable, or those deemed unlikely to conform to the test protocol. The target. 22. Allergies or other contraindications to transdermal systems or patch adhesives. The target of the action. 23. Clinically relevant information regarding allergic reactions to wound dressings or elastoplasts. Significant medical history. 24. Proper placement and / or rotation of the patch will not interfere with any appropriate patch. The object located at the application site. 25. Having taken an antihistamine within 72 hours prior to administration, or 3 hours prior to administration The patient has received systemic or topical corticosteroid treatment within the past week. 26. Shave any hair that may interfere with the proper placement of the patch in the recommended patch application area. An object that cannot be used. 27. Subjects with a history of frostbite, or any current injury or abnormality in the non-dominant hand. Subjects with any of the following conditions (including, where applicable, abnormalities of the skin, blood circulation, or nervous system). 28. Any other reason not listed above (e.g., safety concerns regarding the subject, (This refers to a situation where the principal investigator deems a patient unsuitable due to concerns about the scientific integrity of the trial.) elephant.

[0568] Naloxone induction criteria For the clinical evaluation of withdrawal signs and symptoms during naloxone provocation studies, see Obje Based on the Active Opioid Withdrawal Scale (OOWS) (Handelsman, L., Cochrane, KJ, Aronson, M. J. et al. (1987) Two New Rating Scales for Opiate Withdrawal,American Journal of Al Cohol Abuse, 13, 293-308). Except for the opinion of the principal investigator, If the elephant's OOWS score is ≥3, and the symptoms in question are not related to opioid withdrawal, They were excluded from further participation in this examination.

[0569] Eligibility Criteria In pharmacodynamic evaluation, appropriate placebo and baseline effects were confirmed, and oxycodone I We screened for subjects that did not show consistent discrimination between R and placebo. In addition, the evaluation was actually Furthermore, the subject must feel comfortable with the procedure, complete it, follow instructions, and be cooperative. It demonstrated that it was possible.

[0570] To qualify for the treatment stage, the subjects had to pass the following eligibility criteria. • "Temporary" drug preference VAS (at least 15 points on this bipolar scale) (Differences in the score), Drug Reuse VAS (at least 15 points on this bipolar scale) (difference), and overall drug preference VAS (at least 10 points on this bipolar scale) In terms of differences in intensity, the peak score of the placebo group (E max ) higher, adjusted Oki Peak score for thycodone IR (E max ). "Temporary" for oxycodone IR "Peak scores of ≥65 in the drug preference VAS, and overall drug preference VAS Furthermore, a peak score of ≥65 on the drug reuse VAS must be demonstrated. • Drug preference VAS, overall drug preference VAS and drug reuse VAS (i.e., 4 A score of 0-60 (including 40 and 60), as well as a VAS score for exhilaration (peak score of 0-10). The acceptable placebo effect in a score (defined as including 0 and 10). • The principal investigator or designated co-investigator will make the decision based on the available safety data. The ability to tolerate oxycodone. • General indications made by clinical staff that the subject successfully completed the trial. behavior.

[0571] It is difficult to distinguish between bipolar and unipolar scales (for example, the unipolar scale The eligible candidates who are likely to make mistakes such as selecting 50 in the center are actually two types of scale We received additional training on the differences between different types.

[0572] A cold vasopressor test (repeat 2) was performed five times on each administration day, and the active drug was compared to the placebo. Subjects who did not demonstrate adequate pain suppression after treatment were excluded from the treatment stage.

[0573] Exclusion from participation in the study The clinical trial director communicated that they have the freedom to discontinue the trial at any time and for any reason. If, in the opinion of the physician in charge, continuing the trial is not in the best interests of the subject, the principal investigator The instructor was able to exclude the subject from the trial. The subject had clinical significance and safety, and Changes made in accordance with inclusion / exclusion criteria that affect the occurrence of adverse events (AEs), or changes to the safety of the subject. Ingestion of concomitant medications prohibited by the protocol that may affect sex or the evaluation / purpose of the test. In some cases, the trial may be discontinued. Notification of discontinuation will be sent to the clinical trial sponsor (or nominated participant). Ta.

[0574] If you decide to withdraw from the exam early, we will go to great lengths to conduct all post-exam evaluations. Yes. For all items that were terminated early, the ongoing and We tracked down the newly occurring AE (Exposure Event).

[0575] For subjects whose trials were terminated early due to AE, United S will, if feasible, Food and Drug Administration's (FDA) 's)Guidance for Industry-Premarketing Ri Appropriate information related to the event, as seen in the SK Assessment (March 2005). I obtained copies of eight documents: hospital records, autopsy reports, biopsy reports, and radiology reports.

[0576] The reasons for failing the screening are as follows: • The subject does not meet all inclusion criteria, or meets any of the exclusion criteria. (The criteria will be recorded), or • Selection of subjects (for example, subjects who choose to withdraw from the test for personal reasons,) Family emergencies that prevent the subject from continuing the examination, the subject's relocation, or the subject's (New work schedule that would prevent further participation in the exam), • Untraceable (test facility staff lose contact with the subject), or • Adverse events or serious adverse events (AEs or SAEs) that cause a participant to withdraw from the study. (in the case of), or, • Administrative reasons (any logistics related to either the clinical site or the clinical trial sponsor) For non-medical reasons, such as a participant discontinuing the trial early, the sponsor of the clinical trial may decide to discontinue the trial. To discontinue the trial, or if the clinical site is no longer able to conduct the trial, or (or inability to obtain approval to conduct the test), It is composed of.

[0577] The reasons for the cancellation of the exam are as follows: • Adverse events (when a participant withdraws from the study due to an adverse event), or • Selection of subjects (for example, subjects who choose to withdraw from the test for personal reasons,) Family emergencies that prevent the subject from continuing the examination, the subject's relocation, or the subject's A new work schedule that would prevent further participation in the exam, or • Untraceable (test facility staff lose contact with the subject). If loss of contact with the subject is suspected... The testing facility must record at least three times (each with at least one week between each). The objective is to attempt to contact the subject by telephone. In addition, copies should be saved to a file. It is necessary to keep it and send one registered letter. The testing facility must do this (for example, by phone service) Other evidence indicating that the service has been terminated or that contact cannot be made is required. Unless the existence of such a person is excluded from the situation, for about 30 days after the initial call recording is made. After a certain amount of time has passed, the subject can only be considered untraceable. Or, • Confirmation or suspicion of misuse, or • Administrative reasons (any logistics related to either the clinical site or the clinical trial sponsor) For non-medical reasons, such as a participant discontinuing the trial early, the sponsor of the clinical trial may decide to discontinue the trial. To discontinue the trial, or if the clinical site is no longer able to conduct the trial, or (or inability to obtain approval to conduct the test), It is composed of.

[0578] If a subject is discontinued due to selection of subjects, administrative reasons, or inability to track them, the discontinuation will be... It was necessary to document the specific circumstances involved.

[0579] Administration During each treatment period, the subjects received both oral and transdermal treatment.

[0580] Oral treatment involves taking 240 mL of water after fasting overnight (i.e., at least 10 hours). The test drug was administered to the target group, followed by a 4-hour fast (without water). An oral examination was performed to confirm that the amount had been swallowed.

[0581] In percutaneous treatment, the following approved sites in the target area: ·Upper outer arm ·Upper chest ·Upper back • Side of the chest A transdermal patch was applied to one of these areas (located on both sides of the body). ) provides eight possible application sites. Regarding patch preparation, application, and removal. For specific instructions, please refer to the dispensing manual and Site Operations Manual. It was specified in the annual.

[0582] Collection and analysis of blood samples At the following points in time, based on the administration of each oral test drug, -1.0 and 0 (administration) (10 minutes before), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 o'clock During each of the following periods, the plasma concentrations of oxycodone and buprenorphine were measured. Blood samples were obtained from each subject for determination.

[0583] Buprenorphine-d4 and oxycodone-d3 were used as internal standards, and 200 Buprenorphine and oxycodone concentrations were quantified from μL of human plasma. Liquid-liquid extraction ( The sample was extracted using the LLE method. 0.2% ammonium formate in a 20 mM aqueous solution. Using a gradient system with acid and 0.1% formic acid in acetonitrile, Luna( (Registered Trademark) Extracts are collected under normal phase conditions on a silica HPLC column (2 × 50 mm, 3 μm). The sample was processed using chromatography. Buprenorphine and oxycodone were detected, and Turbo Io MDS Sciex API 5000 (trademark) equipped with an nspray interface The ions were quantified by tandem mass spectrometry using the cation mode. Buprenorphine and o The quantitative linear ranges for xicodone are 25-12,500 pg / mL and 100-50, respectively. The level was 000 pg / mL.

[0584] Abuse potential test The first scale is: "0 = strong aversion", "50 = neither like nor dislike", and "100 = strong A "temporary" drug preference visual analog scale (VAS, bipolar) fixed to "preference", "0 The scale was fixed as follows: "= strong aversion", "50 = neither like nor dislike", and "100 = strong preference". Overall drug preference VAS, with "0 = not at all", "50 = intermediate", and "100 = not at all". The drug reuse VAS was fixed at "That's right." The second scale was "0 = Not at all." The VAS scale for feeling exhilarated was fixed at "100 = very much so". All subjective scales were set to 100. The data was processed using a point-based VAS. The conclusion regarding relative abuse potential is, in fact, all of the following: The effects on the first and second scales were taken into consideration. Balance of effects: • "Temporary" drug preference VAS (E max ) • Overall drug preference VAS (Emax ) • Drug reuse VAS (E max ) • Subjective effects of positivity / euphoria ·Average feeling of elation VAS (E max )

[0585] Pain management test, cold vasoconstriction test A circulating system that can maintain a water temperature of 0-2°C and accommodate an adult's hand immersed up to the wrist. A cold pressurization test (CPT) was performed using a water bath. The temperature was kept within the ideal range of 0-2°C. It was set to 1°. A range of motion exceeding 2° affects the pain experienced by the subject. I avoided it in order to avoid it.

[0586] The non-dominant hand is preferred, but the dominant hand may be used if necessary. Skin marker or similar Using a similar pen, a staff member drew lines on the distal ends of the radius and ulna of the wrist. During the test, participants were required to remain seated or standing, and to reach the line drawn on their wrist. He instructed them to quickly immerse their hands in the water bath. The subjects were instructed to continue until the pain became unbearable. He instructed them to keep their hands open, relaxed, and immersed in the water. The maximum duration was 2 minutes. The subject could remove their hand from the water at any time. If you feel the pain is unbearable, you should not keep your hands in the water. Instructions were given. The duration of hand immersion is from the moment of complete immersion until the subject's hands are submerged in water. Measurements were taken from the time of withdrawal from the bath. Start time (seconds) and duration (seconds) were recorded in the source document. I recorded it in my comments.

[0587] The subject is "0 = pain" until the hand is withdrawn from the bath or until the maximum immersion period is reached. A 100mm visual analog scale (VAS) fixed to "none" and "100 = maximum pain". Pain levels were graded every 15 seconds. A Visual Analog Scale (VAS) was used at all time points.

[0588] result [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0589] E for "Overall drug preference" and "drug reuse" max The comparison is also based on VAS. The results are shown in Figures 9 and 10, respectively.

[0590] Example 2 In a non-randomized study involving 8 healthy men or women under naltrexone blocker, Example 2 was conducted using a punlabel, crossover, single-dose study, and oral buprenorphine. The pharmacokinetics of the hydrochloride were evaluated. Treatment involved oral and intravenous buprenorphine hydrochloride. A 6-day washout period is observed between administrations of the test drug.

[0591] The experimental treatment drugs were as follows: Buprenorphine HCl oral solution (5 mg of buprenorphine base (467.64) (Equimolar amount relative to g / mol) Buprenorphine HCl injection (0.3 mg) administered intravenously over 15 minutes. (Equimolar amount relative to buprenorphine base (467.64 g / mol)).

[0592] In each treatment, to minimize opioid-related adverse events (AEs), 1 Between 2 hours and 36 hours after administration, take naltrexone HCl tablets (50 mg) for 12 hours. It was administered at each dose. At the discretion of the principal investigator, subjects who reported intolerance to the 50 mg dose were selected. A dose of 25 mg of naltrexone HCl was administered. Naltrexone was administered with 240 mL of water. HCl was administered to the target patient.

[0593] Selection of target Healthy men aged 18-55 years (including 18- and 55-year-olds) with no clinically significant medical history. Female participants were deemed appropriate by the principal investigator to participate in this clinical trial.

[0594] Participants who met all inclusion criteria and did not meet exclusion criteria were randomized to the trial.

[0595] Inclusion criteria 1. Written informed consent has been submitted. 2. The target audience must be male or female between the ages of 18 and 55 (including those aged 18 and 55). and. 3. At the time of screening, 18.0-34.0 kg / m² 2 Range (18.0k) g / m 2 and 34.0 kg / m 2 Body Mass Index (BMI) and at least 5 (including) The animal must have a minimum body weight of 0.0 kg. 4. Women who have sexual relations with the opposite sex and are capable of becoming pregnant should not take the test drug during the study and the last test drug. You must use an appropriate and reliable method of contraception for at least 30 days after administration. There are women who are postmenopausal and not using approved contraception, and who have sexual relations with men. Sex is defined as being ≥1 year postmenopausal and having high serum follicle-stimulating hormone (FSH) levels (i.e.) It must have a concentration of ≥50 mIU / mL. 5. Female patients are required to provide a negative pregnancy test result upon screening and / or admission. be. 6. Understand the content of the exam, submit written informed consent, and take all exams. You must be able to speak, read, and understand English sufficiently to complete the assessment. 7. You must be prepared and able to comply with all test requirements and test regulations. ru.

[0596] Exclusion criteria 1. Physical examination and medical history as determined by the principal investigator or nominee at the time of screening. Clinically significant abnormalities in 12-lead electrocardiogram (ECG), vital signs, or laboratory values. . 2. In the opinion of the principal investigator, if the safety of the subject or the efficacy of the trial results is jeopardized To obtain any clinically significant disease (e.g., cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, internal). (of urinary, immunological, cutaneous, neurological, tumor, musculoskeletal, or psychiatric) or any other medical condition A medical history or presence of the following. 3. Any personal or family history of QT interval prolongation or cardiac rhythm disorder. 4. The following, • QTcF interval during screening > 450 milliseconds • QTcF interval > 48 recorded at check-in or during any ECG during treatment 0 milliseconds An abnormal cardiac condition including any of the following. 5. Based on the judgment of the principal investigator or the nominated investigator, it is determined to be clinically significant. A history or presence of hypotension. 6. Prohibited substances (i.e., non-prescription drugs, prescription drugs, herbal products, or natural health products) Use of ) 7. During the study or within 30 days after the last administration of the study drug, the patient is currently pregnant or breastfeeding. This is for women who are pregnant or planning to become pregnant. 8. Alanine aminotransferase (ALT) or aminotransferase of aspartate AST >1.5x above the upper limit of normal (ULN), or total serum bisphosphonate Evidence of clinically significant liver or kidney impairment, including >10% of patients with ULN (Ultra-Low Nucleation). 9. Severe allergic reaction (anaphylaxis) to any food, drug, or bee sting. A history of (including C) or a previous status asthmaticus. 10. Oxycodone, buprenorphine, naloxone, or related drugs (for example, Other opioids or opioid antagonists, or pharmaceutical excipients or other A history of allergies or hypersensitivity to any of the other medicinal ingredients. 11. A medical history of lactose allergy. 12. Positive for Hepatitis B and Hepatitis C. 13. Unless otherwise required by this protocol, within 56 days prior to entering the qualification stage, Alternatively, if you have donated whole blood on the day of your EOS visit and for 30 days after the completion of your EOS visit, thing. 14. Unless otherwise required by this protocol, within 14 days prior to entering the qualification stage, Alternatively, the patient must have donated plasma by the end of the trial (EOS) visit date. 15. When venous access is difficult, or when catheter insertion is inappropriate or undesirable. If it's not good. 16. Within 30 days prior to the first drug administration for naloxone induction, any study drug The treatment is being performed. 17. Positive urinary cotinine test result, frequent (>1x per week) smoking, or administration of the test drug. Use of nicotine products within the past 45 days. 18. If the urine drug screening during screening and / or admission is positive. Possible occurrences include repeated positive results and / or, at the discretion of the principal investigator. The target group may change the date. 19. In the opinion of the principal investigator, any substance that could impede the integrity of the study procedure or data, This refers to the presence of any medical condition that could threaten the safety of the subject. 20. In the opinion of the principal investigator or the nominated investigator, for any other reason, Subjects deemed suitable, or those deemed unlikely to conform to the test protocol. The target. 21. Any other reason not listed above (e.g., safety concerns regarding the subject, (This refers to a situation where the principal investigator deems a patient unsuitable due to concerns about the scientific integrity of the trial.) elephant.

[0597] Administration Each patient received both oral and intravenous treatment.

[0598] In oral treatment, subjects were administered the test drug solution. Subsequently, they rinsed four times with 35 mL of water. The total volume of water consumed was 240 mL (including the water in the dosage solution + 4 rinses of rinse solution). That's it.

[0599] After an overnight fast (i.e., at least 10 hours), administer oral liquid medication, followed by 4 hours I fasted (without water) during that time.

[0600] Collection and analysis of blood samples At the following point, IR oral solution: Before administration and after administration of the test drug: 0.25, 0.5, 1, 1.5, 2 , 2.5, 3, 4, 5, 6, 8 and 12 hours, IV: Before administration, at 2, 5, 10, and 15 minutes (stop infusion at 15 minutes), and during infusion. After stopping, at 2, 5, 10, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, and 12 hours, In each of these periods, blood samples were used to measure the plasma concentration of buprenorphine. The fees were obtained from each subject.

[0601] Buprenorphine-d4 was used as the internal standard, and buprenorphine was extracted from 150 μL of human plasma. The lenorphine concentration was quantified. The sample was extracted using protein precipitation extraction (PPE). A gradient system using 0.1% formic acid in water and 0.1% formic acid in acetonitrile. Using this, on an Xbridge C18 HPLC column (4.6 × 50 mm, 3.5 μm) The extracts were chromatographically treated under reversed-phase conditions. Buprenorphine was detected, and Turbo MDS Sciex API 5000 with Ionspray interface (Trademark) was quantified by tandem mass spectrometry using the cation mode. Buprenorphine The quantitative linear range for n was 25–2,500 pg / mL.

[0602] result [Table 17] [Table 18] [Table 19] [Table 20]

[0603] Example 3 Experimental Design After the animals arrive, they should be exposed to light (12 hours on / 12 hours off) for at least 6 days before the test is conducted. Animals are acclimatized to an environment with controlled lighting, humidity, and temperature. For rats, 2-3 rats / case For mice, house 5 animals per cage before starting any behavioral tests. Food and water should be freely available. Administered via oral route (PO). For the administration of the test compound, the animals were given food for only one night (up to 16-24 hours). do not have.

[0604] The experiment included 8 to 12 animals per experimental group, and each animal had its tail above They are distinguished by the number. Each trial contains 4 to 6 experimental groups, so the potential This allows for dose-response correlation and / or time-course analysis of therapeutic drugs. Zein also allows each experiment to include both negative and positive controls. Each experiment may vary in terms of test dose and evaluation time, but the known characteristics of the test drug It can be adjusted to suit.

[0605] In most studies, a single dose of the test compound is administered 0.5 to 1 hour before the behavioral assessment. Typically, behavior is evaluated according to the PK-specified time course for up to 24 hours after administration.

[0606] The recommended “good practice” dose volume in rats or these studies are as follows: PO (oral) = 2 ml / kg SC (subcutaneous) = 2ml / kg, IP (intraperitoneal) = 2ml / kg, IV (intravenous) = 1 ml / kg, and, IT (intradural) = 50μl That is the case.

[0607] In mice, the dose volume is as follows: PO (oral) = 10 ml / kg SC (subcutaneous) = 10ml / kg, IP (intraperitoneal) = 10 ml / kg, and, IV (intravenous) = 5 ml / kg These are some examples.

[0608] The solvents used were sterile water, 0.9% physiological saline, and 2% tween / 0.5% methylcellulose. , and 25% 2-hydroxypropyl-β-cyclodextrin (HPBCD) are included. In all specified assays, the solvent control group is performed simultaneously with the drug treatment group. Similarly, A positive control compound was also included in all assays.

[0609] All tests are conducted without knowing the group assignment of any animals being tested in any experiment included in the test. The study will be conducted under blind conditions. Based on the baseline effect threshold, the group means will be approximately equal. The animals are then assigned to the treatment group, but for this purpose, the animals are blinded after the baseline assessment before treatment. It is administered under medical supervision.

[0610] animal species Regarding the animals used in the assay, see Sage (Boyertown, PA), Jac kson (Bar Harbor, Maine) or Harlan Labs (Ind supplied from ianapolis, IN), or instead, a mating pair (i.e., Ba (rrestin2 rats and GRK5KO rats), Rats: Male or female Sprague-Dawley or Hans Wistar , Mice: Male, CD-I, ICR or C57BL / 6, Transgenic / Knockout Mouse (129 / C57BL / 6 Background) D), They will breed them within the research facility using this method.

[0611] Analysis of results To clarify the statistical significance of compounds compared to solvent therapy, Graph Pad Using Prism™, raw data (i.e., latency, distance traveled, temperature) is processed. One-way or two-way ANOVA was performed. The significance criterion was P< Set it to 0.05.

[0612] Example 3A: Respiratory depression To evaluate respiratory depression, arterial PCO2 and PO2 levels were analyzed. We purchased rats with indwelling arterial catheters from Harlan.

[0613] Simultaneous administration of opioid and buprenorphine via SC to the dorsal tail of rats, or S Rats were administered either a C dose of opioid or buprenorphine alone. Concurrent administration was alternative. This includes injecting the compound into a specific area using a conservative method.

[0614] After administering the compound, data was collected at baseline (time 0), and then at 1, 3, and 5 hours after SC administration. At the time interval, an arterial blood sample (from the indwelling catheter (Harlan Labs, IN)) was taken. In other words, 180-200 microliters were collected. Heparin was fixed to the ABL device. Samples were collected using an injector (Innovative Med Tech). offman et al.(Effects of NMDA receptor a ntagonists on opioid-induced depression and acute antinociception in rats.Pharma Following the method described in col Biochem Behav 74:933-941,2003) Blood gas analyzer (ABL805, Radiometer America, Westl Using ake,OH, pH, pCO2, pO2, and sO2 (i.e., oxygen saturation) The sample was immediately analyzed to determine the level of ( ).

[0615] To evaluate pH, pCO2, pO2, and sO2 in animals, some rats were used. A carotid artery catheterization procedure was performed.

[0616] result Rat blood gas parameters: A) pCO2 and B) sO2 (i.e., oxygen saturation) Buprenorphine, oxycodone, hydromorphone, and fentanyl alone are used against the following conditions. The effects of each are shown in Figures 17 to 20. As shown in the figures, Buprenorphine (0.05~3 mg / kg, sc) is a factor in the arterial blood pCO2 and oxygen saturation of rats. It has a slight but significant effect, and contains oxycodone (3 and 8 mg / kg), hydromolecule. Lufone (1-10 mg / kg) and fentanyl (0.5-1.5 mg / kg) It has a significant effect on arterial blood pCO2 and oxygen saturation in rats.

[0617] Figures 21A) to D) show, respectively, rats (male, Sprague-Dawley rat, body Arterial blood gas (ABG) parameters for individuals weighing 192-262g (n=6-13 / group): A) Oxycodone-induced disorders of sO2%, B) pO2, C) pCO2, and D) arterial blood pH The effect of buprenorphine is shown in the following figures. Figures 22A) and 22B) show the results 1 hour after administration. Arterial blood gas (ABG) parameters: A) pCO2% and B) sO2% oxycodone This shows the effect of buprenorphine on benzodiazepine-induced disorders. As shown in the figure, 8 mg / kg sc oxycodone is standardized to 0.5-3 mg / kg sc buprenorphine. Regarding the pCO2 and sO2%, a significant increase in pCO2 and a significant decrease in sO2% were observed. This caused it.

[0618] Furthermore, Figure 23 shows that 8 mg / kg sc oxycodone is the same as that which relieves respiratory function abnormalities. The dose of buprenorphine did not reduce the pain level in rats, but it did produce sufficient analgesia. This indicates that.

[0619] Figures 24A) to E) show, respectively, male rats (Sprague-Dawley surgical rats). Arteries (body weight = 217-270g, n = 8-18 / group, Harlan Surgery) Blood gas (ABG) parameters: A) sO2%, B) pO2, C) pCO2, and D) kinetics Buprenor for pulsate blood pH and, also, E) fentanyl-induced impairment of acid-base conditions. The effect of fin is shown. Figures 25A) and B) show arterial blood glucose levels in rats 1 hour after administration. ABG parameters: A) pCO2% and B) sO2% in fentanyl-induced disorders This shows the effect of buprenorphine on the opposite side. As shown in the figure, 0.5 mg / kg sc Fentanyl is standardized at 0.5 mg / kg sc buprenorphine pCO2. Regarding 2 and sO2%, this resulted in a significant increase in pCO2 and a significant decrease in sO2%. Furthermore, Figure 26 shows that 0.5 mg / kg sc-fentanyl relieves respiratory dysfunction. Sufficient analgesia was not reduced with the same dose of buprenorphine in rats. It's interesting.

[0620] Figures 27A) to D) show, respectively, male rats (Sprague-Dawley surgical rats). Arteries (body weight = 217-270g, n = 8-18 / group, Harlan Surgery) Blood gas (ABG) parameters: A) sO2%, B) pO2, C) pCO2, and D) kinetics This study demonstrates the effect of buprenorphine on hydromorphone-induced disorders of vascular blood pH. Figures 28A) and B) show arterial blood gas (ABG) parameters of rats 1 hour after administration: A Buprenorphine for hydromorphone-induced disorders of pCO2% and sO2% This shows the effect. As shown in the figure, 10 mg / kg sc hydromorphone is 0. For 5 mg / kg sc buprenorphine, the standardized pCO2 and sO2% are as follows: This resulted in a significant increase in pCO2 and a significant decrease in sO2%. Furthermore, Figure 29 shows that 1 0 mg / kg sc hydromorphone is the same dose as bupreno to relieve respiratory dysfunction. This indicates that it produced sufficient analgesia in rats, unlike ruphine. .

[0621] The effects of various opioids on rat arterial blood gas parameters in a model ( Tables 21 and 22 list the methods (with or without prenorphine), respectively. It is shown. [Table 21] [Table 22]

[0622] Example 3B Lethal Test The purpose of this study is to evaluate lethality. The animals are expected to be near death. Such animals are expected to die shortly after appearing to be on the verge of death. Furthermore, the state of being on the verge of death It is painless or distressing. This is accompanied by rapid loss of consciousness, respiratory failure, and ventilator failure. This is due to the opioid-induced lethal mechanism, which includes a gradual deepening of sedation. be.

[0623] Obvious side effects, including rigidity, sedation, and unresponsiveness to touch and / or startle. And male Sprague-Dawley rats or Hans Wistar rats (H Observe the data (supplied from Arlan Labs, Indianapolis, IN). Death occurs due to a lack of response to tail pinching, lack of respiration, and / or postmortem symptoms. Confirmation is made by the onset of rigidity.

[0624] In most studies, a single dose of the test compound or combination is administered to rats. The recommended “good implementation” dose volume or these tests are as follows: IV (intravenous) = The concentration is 1-2 ml / kg.

[0625] Opioid agonists (oxycodone, fentanyl, and hydromorphone) and bupre The results of lethal tests in rats using the norphine combination are shown in Figures 30-30. As shown in 32, note that 0.46875 mg / kg and 0.9375 mg / Buprenorphine at IV doses of 1.875 mg / kg and 1.875 mg / kg is oxycodone (30 mg / kg, IV) resulted in a complete reversal of induced lethality (Figures 30A and B). 0.56 Buprenorphine at an IV dose of 25 mg / kg is fentanyl (2.25 mg / kg, IV) This resulted in a complete reversal of induced lethality (Figures 31A and B).

[0626] Similarly, IV-administered doses of 0.5 mg / kg, 3.125 mg / kg, and 12.5 mg / kg are also available. Buprenorphine in large quantities also contributes to hydromorphone (100 mg / kg, IV)-induced death. The incidence was significantly reduced (Figures 32A and B).

[0627] Example 4 A two-part, single-center study for healthy subjects and / or healthy recreational opioid users. Design a randomized, double-blind, staged trial. Each part will have several iterations. The study consists of up to six periods. The cohort may include only healthy subjects, or healthy subjects. This includes only those who use opioids for healthy recreational purposes.

[0628] Each part consists of three stages: screening, treatment, and follow-up.

[0629] Each part is about the subject (e.g., appropriate tolerability, HCVR, PK or other aspects) It may include an eligibility screening stage to screen subjects that do not show a lameter. i. If the subject has already been verified for eligibility in the previous part / repetition, eligibility verification (applicable (If applicable) this is not required. Each eligibility cohort consists of a maximum of four periods. The cohort will be administered concurrently. The cohort will consist of healthy subjects only, or healthy subjects. This study includes only those who use opioids for recreational purposes. In each cohort, respiratory depression is induced. To determine the appropriate dose, up to two opioids, each with a maximum dose strength of 2, are administered. A minimum washout period of approximately 24 hours is provided between doses.

[0630] Test design Part 1 is a safe method that produces easily quantifiable opioid-induced respiratory depression (OIRD). This is to clarify all opioid administration regimens. Each repeat is the maximum It consists of up to four cohorts, each containing 20 participants. It consists of four periods. The cohorts receive administration in parallel. In each cohort, To determine a safe and tolerable dose that induces respiratory depression, each dose is administered at a maximum of two dose intensities. Up to two types of opioids (IV fentanyl, IV hydromorphone, IV morphine) Or oral oxycodone is administered. In the cohort, each opioid The dosage is gradually increased from low to high doses. A minimum of approximately 24 hours of washing is required between doses. An outhouse is set up.

[0631] Part 2 discusses the opioid buprenorphine administered transdermally along with hydromorphone. The effect on induced respiratory depression was evaluated.

[0632] In Part 2a), a single-blind, non-randomized, two-period crossover study was conducted involving 16 participants. Healthy recreational opioid users are taking transdermal buprenorphine (Butrans(registered trademark)20 Each patient received either mcg (per hour) or a placebo patch (applied for approximately 4.5 days). During the period, three different hydromorphs were detected at 48, 72, and 96 hours after patch application. Dosage, Hydromorphone 1.5 mg IV infusion (divided into two infusions) • Hydromorphone 0.625 mg (loading dose) administered over 10 minutes. Hydromorphone 0.875 mg (maintenance dose) administered over 30 minutes. Hydromorphone 3 mg IV injection (divided into two injections) Hydromorphone 1.25 mg (loading dose) administered over 10 minutes. Hydromorphone 1.75 mg (maintenance dose) administered over 30 minutes. As described above, repeated hydromorphone 3 mg They administered it.

[0633] A minimum washout period of approximately 24 hours was provided between hydromorphone IV doses. A minimum washout period of approximately 36 hours was allowed between patch applications. The details are summarized in Figures 33A) and 33B).

[0634] In Part 2b, a single-blind, non-randomized design was used to study 16 healthy recreational opioids. Id users received either a transdermal buprenorphine or placebo patch. 0 (placebo), 5 A planned dose escalation of the nominal transdermal patch was performed at 10 and 15 mcg / hour. Placebopa I applied the patch for two days and the buprenorphine patch for four days. This order was changed for the final dose. Based on the evaluation of data from previous doses, the lower dose 2.5 mcg / hour was administered. During each patch application, two IV hydrochloric acid injections were given. Lufon 3 mg was administered by infusion at 24-hour intervals. Each IV hydromorphic The dose is administered in two infusions totaling 3 mg. Hydromorphone 1.25 mg (loading dose) administered over 10 minutes. Hydromorphone 1.75 mg (maintenance dose) administered over 30 minutes. It was divided into parts.

[0635] The administration scheme is summarized in Figure 37.

[0636] Inclusion / Exclusion Criteria Those deemed suitable to participate in this clinical trial were between 18 and 55 years of age (18 and 55 years old). (including) healthy men and women with a history of oral use who have no clinically significant medical history. We selected either a bioid user or another healthy subject.

[0637] Investigational drug, dosage, and method of administration • Fentanyl citrate (maximum 150 mcg), intravenously • Hydromorphone hydrochloride (maximum 3 mg), intravenously • Oxycodone IR (up to 40 mg), orally Morphine sulfate (maximum 20 mg), intravenously • Butrans (registered trademark) (maximum 20 mcg / hour), transdermal

[0638] Reference therapeutic drugs, dosages, and methods of administration Placebo, intravenous • Placebo patch, transdermal Placebo, oral

[0639] Concomitant drugs • Naloxone HCl induction test (at least approximately 12 hours before the first administration of the test drug) • The use of other concomitant medications during this study may be necessary to treat adverse events (AEs). You should stop unless you have a reason to.

[0640] Duration of treatment and duration of trial Screening for eligible individuals within 28 days prior to check-in in Period 1 or before the eligibility verification stage. do.

[0641] Eligibility verification stage The study drug will be administered during each period according to the trial randomization schedule (if applicable). The date of the first investigational drug administration is approximately 24 hours after the last dose of the investigational drug, or the date of early termination of the study. The subject will be confined to the facility until a certain point is reached. The subject may be discharged after the eligibility assessment stage, or, Patients may remain confined to the facility until the treatment stage. Patients discharged after the eligibility assessment stage will be considered eligible. The certification completion procedure will be followed. For those who did not proceed to treatment, the procedure will be completed 7-10 days after the eligibility confirmation is finished. To each point, or after the early termination of the test, follow up with each subject by phone (or each (Following up with a follow-up call from the subject), adverse events (AEs) and concomitant medications since the last trial visit. We will evaluate the drugs.

[0642] Treatment stage The study drug will be administered during each period according to the trial randomization schedule. Period 1 of the trial. From the start of the day before drug administration (check-in) until the end of service (EOS) (or the point of early discontinuation), the target group is treated. The subject will be confined to the facility. The subject may be discharged between periods, but when the subject returns to the facility, Repeat the check-in procedure.

[0643] In the opinion of the PI or the designated person, any significant pharmacological effect is clinically acceptable. At the point when the test changes or drops to the bell, or at the point of early termination of the test, the subject is the test or They will undergo the EOS procedure, which is performed before discharge.

[0644] Follow-up calls will be made to each participant 7-10 days after the End of Study (EOS), or after the trial is terminated early. By calling (or receiving a follow-up call from each individual), the AEs from the last trial visit date and We will evaluate the use of concomitant medications.

[0645] Total trial duration: Part 1 - up to approximately 48 days. Part 2 - up to approximately 54 days.

[0646] Test Procedure Record the test procedures and timings in the work schedule. Record their adverse events (AEs) and concomitant medications.

[0647] Screening stage Screening will be conducted within 28 days of check-in, and this includes high carbon dioxide ventilation. This training session includes a response (HCVR). This training session is on day 1. As part of the screening process, or as part of the hospitalization procedure, or It may be implemented as both of the above.

[0648] Eligibility verification stage (if applicable) If the subject has already been verified for eligibility in the previous part / repetition, eligibility verification (applicable) (In the case of) it is not required.

[0649] Check-in: Participants must check in to the facility the day before the first dose of treatment.

[0650] To confirm that the subjects are not opioid-dependent, the subjects were given a small dose of the initial study drug. At the very least, undergo a naloxone HCl induction test and evaluation using OOWS approximately 12 hours prior to the test. ru.

[0651] Participants will receive the investigational drug at specific time points according to a randomization schedule. In this case, monitoring of respiratory depression due to oxygen supplementation (transcutaneous CO2 and HCVR) is performed. .

[0652] Treatment stage Check-in: Participants will check in to the facility the day before the administration of Period 1. If this has not yet been done, in order to confirm that the subject is not opioid-dependent, At least approximately 12 hours before the first administration of the test drug, perform a naloxone HCl induction test and an OOW (Out of Worth) test. An evaluation using S will be conducted. Treatment: Participants will receive the investigational drug at specific time points according to a randomization schedule. Treatment period Monitoring of respiratory depression due to oxygen supplementation at specific points in time (transcutaneous CO2 and We will implement HCVR. End of Study (EOS): Any significant pharmacological effect in the opinion of the PI or designated person. At the point when the level changes or decreases to a clinically acceptable level, or when the trial is terminated early. In this case, the subjects undergo the End-of-Services (EOS) procedure, which is performed before they are discharged from the hospital after the trial. Tracking: Tracking will be conducted for each participant 7-10 days after End of Study (EOS), or after early termination of the trial. By phone (or by receiving a follow-up call from each individual), from the date of the last trial visit We will evaluate adverse events (AEs) and concomitant medications.

[0653] Criteria and methods for evaluation Pharmacodynamics High Carbon Dioxide Ventilation Response (HCVR) Minute ventilation per 1 mmHg increase in PCO2 (respiratory volume per breath × respiratory rate, ki HCVR is calculated as the change per program base. Under normal conditions (no increase in CO2, subject is breathing normally), and during an increase in CO2 respiration. These values ​​are measured during the process. HCVR is a direct response to respiratory stimulation involving central chemoreceptors. It is a useful indicator.

[0654] respiratory stimulation Minute ventilation and end-tidal CO2 (ET CO2) were used before administration and after treatment with the study drug to determine the high level of performance. Respiratory stimulation was evaluated by comparing the ventilatory response to carbon dioxide. Minute ventilation -P ET HCVR is calculated using the CO2 correlation gradient (LPM / mmHg CO2). Because HCVR is linear over the range of CO2 tested in this protocol, a standard The approach involves two steady-state CO2 levels (one being indoor air, i.e., baseline CO2). The ventilation rate is measured (one of which is supplemented CO2), and the base HCVR is calculated. It is about releasing.

[0655] Transcutaneous CO2 (PCO2) Transcutaneous CO2 is an important indicator of respiratory stimulation and an indicator of opioid-induced respiratory depression. Monitoring transcutaneous PCO2 after drug administration strongly predicts a slowdown in HCVR. This is expected.

[0656] Subjective sedative effect • Slumber / Arousal VAS (E) min )

[0657] Subjective shortness of breath effect ·Difficulty breathing VAS (E max )

[0658] Drug concentration measurement As specified in the work schedule, during each administration of the investigational drug, opioids and A blood sample (if available) to measure the plasma concentration of buprenorphine. Obtain from each of those objects.

[0659] If instructed, adjust the timing of PK collection.

[0660] Analysis group Registered group: All individuals who submit informed consent. Randomized safety population: All subjects who are randomized and receive the investigational drug. Full analysis population: Randomized and administered the investigational drug, with at least one effective pharmacodynamic (PD) All objects for which a measurement value is available.

[0661] bioanalytical method The plasma concentrations of opioids and buprenorphine will be quantified using approved bioanalytical methods.

[0662] safety Recorded AE, clinical laboratory test results, vital signs, SpO2, physical examination, and conventional Safety will be evaluated using a 12-lead ECG.

[0663] Respiratory depression: CO2 induction (part 2a) test Hydromorphone (IV HMP) and buprenorphine TDS (transdermal delivery system) The Part 2a) trial was conducted using IV HMP in combination with ). An overview of Part 2a) is shown in Figures 33A) and 33B), but a certain amount of time is required during HCVR measurement. This shows the HMP and Bup concentrations.

[0664] In subjects not using opioids, the amount of pCO2 increase per 1 mmHg of sample Minute ventilation (respiratory volume per breath × respiratory rate, per kilogram) was measured. The HCVR gradient was calculated as follows.

number

[0665] In subjects administered 3.0 mg of IV hydromorphone (HMP), pCO2 Per 1 mmHg increase in sample minute ventilation (respiratory volume per breath × respiratory rate, kilograms) The HCVR gradient was measured (per base). The HCVR gradient was calculated as follows.

number

[0666] Figure 34 shows the opioidity in positive control therapy (1.5 mg and 3.0 mg HMP infusion). Idiopathic respiratory depression (OIRD) was more pronounced compared to placebo. 37% (1.5 mg IV HMP only) and 49% (3.0mg IV HMP only) This indicates that it has been explicitly stated that...

[0667] Figure 34 also shows the results for BUP (Butrans®, 20 mcg / hour) alone. This indicates that the OIRD has been clearly stated. 1.5 mg and 3.0 mg IV HMP Figure 34 shows the OIRD effect after adding BUP (20 mcg / hour). .

[0668] Figures 35 and 36 show the hydromorphone concentrations during HCVR measurement in test part 2a). The values ​​shown are (ng / mL) and buprenorphine concentration (pg / mL).

[0669] Exam Part 2b) HMP infusion (3.0 mg, IV), and escalating BUP dose (BTDS, 0, 5, 10 and Part 2b of the study was conducted using 15 mcg / hour and HMP (3.0 mg, IV). Part 2b) Outline of the study design (HCVR measurement before and during IV injection) Figure 37 shows the results (CPT performed after HCVR measurement).

[0670] Figures 38 and 39 show the average HMP concentration (ng / mL) and the average BUP concentration (pg / mL). Each of these indicates that the values ​​were maintained at a constant level during the HCVR assessment in Part 2b of the study.

[0671] Figure 40 shows the results for part 2b) of the study, with HMP (3.0 mg, IV) and BTDS (2. (Doses of 5mcg / hour, 5mcg / hour, and 10mcg / hour), and HMP-BTD This shows the mean HCVR gradient, normalized to placebo, after administration of the S combination. The results showed that BUP 2.5mcg / hour had approximately the same effect as HMP (3.0mg, IV) OIRD. This indicates that they reversed the situation by 1 / 3.

[0672] In trial part 2b), HMP (3.0 mg, IV), BT compared to placebo. DS (doses of 2.5 mcg / hour, 5 mcg / hour, and 10 mcg / hour), and HM The analgesic effect of the P-BTDS combination is shown in Figure 41. Using a cold pressurization test, the analgesic effect was observed over 2 minutes. Pain (quantified as pain VAS AUC) was measured every 15 seconds. Figure 41 shows HMP. (3.0 mg, IV) suppresses cold-induced hypertensive pain, and BUP (2.5, 5 and 10 mcg / hour) The study showed that co-administration of (intermediate doses) did not reduce (or increase) the analgesic effect of HMP. Yes, they are.

Claims

1. (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, A dosage form containing, After a single dose administration, the dosage form is administered to one control group in a ratio of at least approximately 1:

280. Norphin's average C ｍａｘ and the average C of oxycodone ｍａｘ This results in the ratio of The aforementioned dosage form.

2. Average C of buprenorphine ｍａｘ and the average C of oxycodone ｍａｘ The aforementioned ratio is approximately 1 The dosage form according to claim 1, wherein the ratio is 50 to approximately 1.

250.

3. Average C of buprenorphine ｍａｘ and the average C of oxycodone ｍａｘ The aforementioned ratio is approximately 1 The dosage form according to claim 1, wherein the ratio is 100 to approximately 1:

200.

4. After a single dose administration, the dosage form is used in the control group in a ratio of approximately 1.5:1 or less, and buprenorph The average T of the ｍａｘ and the average T of oxycodone ｍａｘ Claim 1 further provides a ratio with The dosage form according to any one of claims 3.

5. The average T of buprenorphine ｍａｘ and the average T of oxycodone ｍａｘ and the said ratio is about 1: The dosage form according to claim 4, wherein the dosage is 1 or less.

6. After a single dose administration, the dosage form was used to provide the control group with an average T150% oxycodone dose. ｍａｘ Compared Faster average T of buprenorphine ｍａｘ Any of claims 1 to 3 further brings about The dosage form described in item 1.

7. After a single dose administration, the dosage form is administered to the control group in a ratio of approximately 0.1:1 to approximately 1:1, or approximately 0. The average T of buprenorphine is 1:1 to approximately 0.9:

1. ｍａｘ and the average T of oxycodone ｍａｘ A dosage form according to any one of claims 1 to 6, which further provides the ratio of the above.

8. The dosage form according to any one of claims 1 to 7, wherein the dosage form is an oral dosage form.

9. The aforementioned dosage form contains approximately 5 mg to approximately 50 mg of oxycodone hydrochloride (Mw = 351.82 g / m²). The oral dosage form according to claim 8, comprising an equimolar amount of a fixed amount of oxycodone per ol.

10. The aforementioned dosage form is equivalent to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) Then, equimolar amounts of a fixed amount of oxycodone and approximately 1 mg to 6 mg of buprenorphine base. (Mw = 467.64 g / mol) contains a constant equimolar amount of buprenorphine. The oral dosage form according to claim 8.

11. The oxycodone is oxycodone hydrochloride, and the buprenorphine is buprenorphine The dosage form according to any one of claims 1 to 10, wherein the dosage form is phosphate hydrochloride.

12. The dosage form comprises a fixed amount of buprenorphine in an immediate-release form, as described in claims 1 to 1. The dosage form described in any one of item 11.

13. The dosage form is a fixed amount of oxycodone in an immediate-release form, and a fixed amount of oxycodone in an immediate-release form. A dosage form according to any one of claims 1 to 12, comprising buprenorphine.

14. (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, This includes performing this procedure for patients who require simultaneous administration of the drug, After a single dose, the aforementioned simultaneous administration was performed in one control group at a ratio of at least approximately 1:

280. Average C of prenorphines ｍａｘ and the average C of oxycodone ｍａｘ This results in the ratio of Methods for treating pain.

15. Average C of buprenorphine ｍａｘ and the average C of oxycodone ｍａｘ The aforementioned ratio is approximately 1 The method according to claim 14, wherein the ratio is 50 to approximately 1.

250.

16. Average C of buprenorphine ｍａｘ and the average C of oxycodone ｍａｘ The aforementioned ratio is approximately 1 The method according to claim 14, wherein the ratio is 100 to approximately 1.

200.

17. After a single dose, the aforementioned simultaneous administration was to the control group in a ratio of approximately 1.5:1 or less, bupreno Average T of rufin ｍａｘ and the average T of oxycodone ｍａｘ Claims that further bring about a ratio with The method according to any one of claims 14 to 16.

18. Average T of buprenorphine ｍａｘ and the average T of oxycodone ｍａｘ The aforementioned ratio is approximately 1: The method according to claim 17, wherein the value is 1 or less.

19. After a single dose administration, the aforementioned simultaneous administration involved the average T150 dose of oxycodone in the control group. ｍａｘ Compare And the average T of buprenorphine is faster ｍａｘ Claims 14 to 1 further bring about The method described in any one of item 6.

20. After a single dose administration, the aforementioned simultaneous administration is performed in the control group at a ratio of approximately 0.1:1 to approximately 1:1, or approximately The average T of buprenorphine is 0.1:1 to approximately 0.9:

1. ｍａｘ and oxycodone Average T ｍａｘ The ratio further brings about the ratio according to any one of claims 14 to 19 method.

21. Claim 14: The method results in the prevention or suppression of the harmful pharmacodynamic reaction of oxycodone. The method according to any one of claims 20.

22. The aforementioned adverse drug dynamics include euphoria, euphoria, bowel dysfunction, nausea, vomiting, somnolence, dizziness, and headache. Pain, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium, miosis, itching, urinary tract The group consists of rash, urinary retention, hyperalgesia, allodynia, physical dependence, and tolerance, and is preferred. Alternatively, the aforementioned adverse drug dynamics response is selected from the group consisting of euphoria, euphoria, and intestinal dysfunction. The method according to claim 21.

23. The method according to claim 21, wherein the aforementioned toxic drug mechanical response is euphoria.

24. Average E of "Exhilaration VAS" ｍａｘ When measured using comparative tests, at least 15% The method according to claim 23, which reduces

25. The method described above results in the prevention or suppression of oxycodone drug addiction, as described in claim 14. The method according to any one of claims 24.

26. Average E of "Temporary Drug Preference VAS" ｍａｘ When measuring using comparative tests, less The method according to claim 25, wherein both are reduced by 15%.

27. The average E of the "Overall Drug Preference VAS" ｍａｘ When measuring using comparative tests, less The method according to claim 25, wherein both are reduced by 15%.

28. Average E of "Drug Reuse VAS" ｍａｘ When measuring using comparative tests, at least 1 The method according to claim 25, which reduces by 5%.

29. The above method provides an analgesic effect that is not substantially reduced when measured using comparative tests. The method according to any one of claims 14 to 28.

30. The average "cold pain score" measured using the cold vasoconstrictor test at 1, 2, 3, and 4 hours after administration. "AVAS" is defined as a value that does not increase by more than 10% compared to a comparative treatment method when measured using comparative trials. i. The method according to claim 29.

31. The aforementioned method prevents or suppresses the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. The method according to any one of claims 14 to 30.

32. (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, This includes performing this procedure for patients who require simultaneous administration of the drug, Average E of "Exhilaration VAS" ｍａｘ When measured using comparative tests, at least 15% to decrease, and / or, Average E of "Temporary Drug Preference VAS" ｍａｘ When measuring using comparative tests, less Both will decrease by 15%, and / or The average E of the "Overall Drug Preference VAS" ｍａｘ When measuring using comparative tests, less Both will decrease by 15%, and / or Average E of "Drug Reuse VAS" ｍａｘ When measuring using comparative tests, at least 1 It will decrease by 5%, and / or, The average "cold pain score" measured using the cold vasoconstrictor test at 1, 2, 3, and 4 hours after administration. "AVAS" is defined as a value that does not increase by more than 10% compared to a comparative treatment method when measured using comparative trials. stomach, Methods for treating pain.

33. (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, This includes performing this procedure for patients who require simultaneous administration of the drug, Average E of "Exhilaration VAS" ｍａｘ When measured using comparative tests, at least 35% to decrease, and / or, Average E of "Temporary Drug Preference VAS" ｍａｘ When measuring using comparative tests, less Both will decrease by 30%, and / or The average E of the "Overall Drug Preference VAS" ｍａｘ When measuring using comparative tests, less Both will decrease by 30%, and / or Average E of "Drug Reuse VAS" ｍａｘ When measuring using comparative tests, at least 3 It decreases by 0%, and / or, The average "cold pain score" measured using the cold vasoconstrictor test at 1, 2, 3, and 4 hours after administration. "AVAS" is defined as a value that does not increase by more than 10% compared to a comparative treatment method when measured using comparative trials. stomach, Methods for treating pain.

34. (i) A certain amount of oxycodone, (ii) A certain amount of buprenorphine, An oral dosage form containing, The weight ratio of a certain amount of buprenorphine to a certain amount of oxycodone is equal to an equimolar amount In the dosage form represented by buprenorphine base (mg) (Mw = 467.64 g / mol) The aforementioned fixed amount of buprenorphine and equimolar amount of oxycodone hydrochloride (mg) The certain amount of oxyco in the dosage form (Mw = 351.82 g / mol) When calculating using "don," if the ratio is greater than 1:40, The aforementioned oral dosage form.

35. (i) During administration period 1, the average infusion rate (mg / hour) during administration period 1 An effective amount of hydromorphone is administered using lomorphone, and at this time the average injection rate is Dromorphone is the amount administered during the administration period 1, divided by the duration of the administration period 1. It is expressed in equimolar amounts of hydromorphone free base, (ii) During administration period 2, the average infusion rate (mg / hour) during administration period 2 Another effective dose of buprenorphine is administered via prenorphine, and at this time the average infusion rate The amount of buprenorphine administered during the administration period 2 is calculated by dividing the total amount by the duration of the administration period 2. It is represented by equimolar amounts of free buprenorphine base, This includes administering it to patients who require it, The administration period 1 and the administration period 2 overlap by at least 75%, and the average injection rate... The ratio of lenorphine to hydromorphone at the average injection rate is approximately 1:8000 to approximately The ratio is 1:

100. Methods for treating pain.

36. The method according to claim 35, wherein the administration period 1 and the administration period 2 overlap by at least 90%. Law.

37. The method according to claim 35, wherein the administration period 1 and the administration period 2 overlap by 95% to 100%. Law.

38. Hydromorphone and buprenorphine are administered via the same route of administration, claim 35 The method according to any one of claims 37.

39. Hydromorphone and buprenorphine are administered via different routes of administration, claim 35. The method according to any one of claims 37.

40. The aforementioned administration routes are intravenous administration, intramuscular administration, subcutaneous administration, sublingual administration, buccal administration, and subcutaneous administration. The method according to claim 38 or claim 39, selected from the group consisting of, and transdermal administration.

41. Hydromorphone and buprenorphine are used in intravenous, intramuscular, and subcutaneous compositions. Independent of sublingual compositions, buccal compositions, subcutaneous implants, or transdermal absorption therapy systems. The method according to any one of claims 35 to 40, administered in a dosage form selected by the method. 。

42. Hydromorphone and buprenorphine can be administered intravenously, intramuscularly, and subcutaneously. Administered via the same route of administration selected from the following groups, any one of claims 35 to 38 The method described in item 1.

43. Hydromorphone and buprenorphine contain hydromorphone and buprenorphine. It is administered in a single dosage form, and the dosage form may be an intravenous composition, an intramuscular composition, or a subcutaneous composition. The method according to any one of claims 35 to 38, selected from among them.

44. Buprenorphine is administered transdermally, and the administration period 2 is 1 to 7 days. The method according to any one of claims 35 to 41.

45. The administration period 2 is selected from 1 day, 3 days, 3.5 days, and 7 days, according to the claim. Method 44.

46. Buprenorphine is administered subcutaneously, and the administration period 2 is from one month to one year, The period is one to four months, or one to three months, as per claims 35 to 4. The method described in any one of item 1.

47. The administration period 2 is selected from 1 month, 2 months, 3 months, 4 months, and 6 months. The method according to claim 46.

48. Hydromorphone and buprenorphine are administered by intravenous infusion, as described in claim 42. The method.

49. Hydromorphone and buprenorphine are both hydromorphone and buprenorphine The method described in claim 42 or claim 43, which is administered by intravenous infusion of an intravenous composition containing the method. method.

50. The administration period 1 and the administration period 2 are approximately 15 minutes to approximately 24 hours, or approximately 15 minutes. Choose from approximately 12 hours, 30 minutes to 6 hours, or 30 minutes to 3 hours. The method according to claim 48 or claim 49.

51. The administration period 1 and the administration period 2 are approximately 30 minutes to approximately 2 hours, or approximately 1 hour to The method according to claim 50, which is selected.

52. Hydromorphone is administered at a rate of approximately 1 mg / hour to approximately 10 mg / hour, claim. The method according to any one of claims 35 to 51.

53. After a single dose, buprenorphine and hydromorphone, respectively, showed the following mean C levels. ｍａｘ Also The average is C ａｖ This results in an average C of buprenorphine. ｍａｘ or average C ａｖ and hydromo Lefon's average C ｍａｘ or average C ａｖ The aforementioned ratio is approximately 0.001 to approximately 0.

006. A method according to any one of claims 35 to 52.

54. The method according to any one of claims 35 to 53, wherein toxicity is suppressed.

55. At least one selected from the group consisting of respiratory depression, drug preference, sedation, and bowel dysfunction. The method according to any one of claims 35 to 54, wherein the side effects of the species are suppressed.

56. Respiratory depression is suppressed, the method according to any one of claims 35 to 55.

57. The method according to any one of claims 35 to 56, wherein drug preference is suppressed.

58. The method according to any one of claims 35 to 57, wherein sedation is suppressed.

59. The method according to any one of claims 35 to 58, wherein bowel dysfunction is suppressed.

60. (i) An effective amount of hydromorphone is administered on average during the administration period. Hydromorphone is administered at a rate (mg / hour), and at this time, the average administration rate of hydromorphone is as described above. Lufon is calculated by dividing the amount of equimolars administered during the administration period by the duration of the administration period. It is represented by a free hydromorphone base, (ii) Another effective dose of buprenorphine during the same administration period Buprenorphine is administered at an average infusion rate (mg / hour), and at this time the average infusion rate Buprenorphine is calculated by dividing the duration of the administration period by the amount administered during the administration period. It is expressed in equimolar amounts of free buprenorphine base, The ratio of buprenorphine at the average injection rate to hydromorphone at the average injection rate The ratio is approximately 1:8000 to 1:

100. A pharmaceutical composition containing hydromorphone and buprenorphine suitable for treating pain.

61. The pharmaceutical composition according to claim 60, which is in the form of an intravenous composition, an intramuscular composition, and a subcutaneous composition. composition.

62. The pharmaceutical composition according to claim 60, in the form of an intravenous composition.

63. Hydromorphone is administered at an average rate of approximately 1 mg / hour to approximately 10 mg / hour. The pharmaceutical composition according to claim 60.

64. A method for treating pain, as described in any one of claims 60 to 63 A listed pharmaceutical composition.

65. In the manufacture of a pharmaceutical product for treating pain, any one of claims 60 to 63 Use of the pharmaceutical compositions described in the section.

66. (i) During administration period 1, the average infusion rate (mg / hour) during administration period 1 An effective amount of fentanyl is administered with antanil, and at this time the average infusion rate of fentanyl The amount is calculated by dividing the duration of the administration period 1 by the equimolar amount of fluid administered during the administration period 1. It is represented by a free entanyl base, (ii) During administration period 2, the average infusion rate (mg / hour) during administration period 2 Another effective dose of buprenorphine is administered via prenorphine, and at this time the average infusion rate The amount of buprenorphine administered during the administration period 2 is calculated by dividing the total amount by the duration of the administration period 2. It is represented by equimolar amounts of free buprenorphine base, This includes administering it to patients who require it, The administration period 1 and the administration period 2 overlap by at least 75%, and the average injection rate... The ratio of lenorphine to fentanyl at the average injection rate is approximately 1:80 to approximately 1:

0. It is 5. Methods for treating pain.

67. The method according to claim 66, wherein the administration period 1 and the administration period 2 overlap by at least 90%. Law.

68. The method according to claim 66, wherein the administration period 1 and the administration period 2 overlap by 95% to 100%. Law.

69. Fentanyl and buprenorphine are administered via the same route of administration, as claimed in claim 66. The method described in any one of paragraphs 68.

70. Fentanyl and buprenorphine are administered via different routes of administration, as per claim 66. The method described in any one of the claims in claim 68.

71. The aforementioned administration routes are intravenous administration, intramuscular administration, subcutaneous administration, sublingual administration, buccal administration, and subcutaneous administration. The method according to claim 69 or claim 70, selected from the group consisting of, and transdermal administration.

72. Fentanyl and buprenorphine are used in intravenous, intramuscular, subcutaneous, and tongue compositions. Independently selected from the underside composition, buccal composition, subcutaneous implant, or transdermal absorption therapy system. The method according to any one of claims 66 to 71, administered in a selected dosage form.

73. Fentanyl and buprenorphine are administered intravenously, subcutaneously, and transdermally. Administered via the same route of administration selected from the group, any one of claims 66 to 69 Methods used.

74. Fentanyl and buprenorphine are one product containing fentanyl and buprenorphine. The drug is administered in a dosage form, which may be an intravenous composition, a subcutaneous implantable system, or a transdermal absorption system. A method according to any one of claims 66 to 69, selected from a treatment system.

75. Buprenorphine is administered transdermally, and the administration period 2 is 1 to 7 days. The method according to any one of claims 66 to 72.

76. The administration period 2 is selected from 1 day, 3 days, 3.5 days, and 7 days, according to the claim. Method 75.

77. Buprenorphine is administered subcutaneously, and the administration period 2 is approximately 1 month to approximately 1 year. Alternatively, the period is approximately one month to approximately four months, or approximately one month to approximately three months, as per claim 66. The method according to any one of claims 72.

78. The administration period 2 is selected from 1 month, 2 months, 3 months, 4 months, and 6 months. The method according to claim 77.

79. The method according to claim 73, wherein fentanyl and buprenorphine are administered transdermally. 。

80. Fentanyl and buprenorphine contain both fentanyl and buprenorphine. The person according to claim 73 or claim 74, administered by transdermal administration of a transdermal absorption therapy system. Law.

81. The administration period 1 and the administration period 2 are approximately 1 to 7 days, or approximately 1 to 3 days. The method according to claim 79 or claim 80, selected from days.

82. The aforementioned administration period 1 and administration period 2 are 1 day, 3 days, 3.5 days, and 7 days. The method according to claim 81, which is selected.

83. Fentanyl is administered at approximately 12.5 μg / hour, 25 μg / hour, 50 μg / hour, and 75 μg / hour. Administer at a rate of 100 μg / hour, 150 μg / hour, or 200 μg / hour. The method according to any one of claims 66 to 82.

84. After a single dose, buprenorphine and fentanyl, respectively, showed the following mean C1 levels. ｍａｘ or flat Average C ａｖ This results in an average C of buprenorphine. ｍａｘ or average C ａｖ and fentanyl Average C ｍａｘ or average C ａｖ The aforementioned ratio is approximately 0.02 to approximately 0.3, or 0.0 The method according to any one of claims 66 to 83, wherein the ratio is 2 to approximately 0.

2.

85. The method according to any one of claims 66 to 84, wherein toxicity is suppressed.

86. At least one selected from the group consisting of respiratory depression, drug preference, sedation, and bowel dysfunction. The method according to any one of claims 66 to 85, wherein the side effects of the species are suppressed.

87. Respiratory depression is suppressed, according to any one of claims 66 to 86.

88. The method according to any one of claims 66 to 87, wherein drug preference is suppressed.

89. The method according to any one of claims 66 to 88, wherein sedation is suppressed.

90. The method according to any one of claims 66 to 89, wherein bowel dysfunction is suppressed.

91. (i) An effective amount of fentanyl is administered at an average rate during the administration period. Fentanyl is administered at a dose of (mg / hour), and at this time, the average rate of fentanyl administration is as follows: The equimolar amount of fentanyl administered during the aforementioned administration period, divided by the duration of the aforementioned administration period. It is represented by a free base, (ii) Another effective dose of buprenorphine during the same administration period Buprenorphine is administered at an average infusion rate (mg / hour), and at this time the average infusion rate Buprenorphine is calculated by dividing the duration of the administration period by the amount administered during the administration period. It is expressed in equimolar amounts of free buprenorphine base, The ratio of buprenorphine at the average injection rate to fentanyl at the average injection rate is The ratio is approximately 1:80 to 1:0.

5. A pharmaceutical composition containing fentanyl and buprenorphine suitable for treating pain.

92. Intravenous composition, intramuscular composition, subcutaneous composition, sublingual composition, subcutaneous implantable system, The pharmaceutical composition according to claim 91, or in the form of a transdermal absorption therapy system.

93. The pharmaceutical composition according to claim 91, in the form of a transdermal absorption therapy system.

94. Fentanyl is administered at approximately 12.5 μg / hour, 25 μg / hour, 50 μg / hour, and 75 μg / hour. Average input rate per hour, 100 μg / hour, 150 μg / hour, or 200 μg / hour The pharmaceutical composition according to claim 91, which is administered in a certain amount.

95. A method for treating pain, as described in any one of claims 91 to 94 A listed pharmaceutical composition.

96. In the manufacture of a pharmaceutical product for treating pain, any one of claims 91 to 94 Use of the pharmaceutical compositions described in the section.

97. (i) During administration period 1, the average input rate (mg / hour) during administration period 1 is used for administration. Fentanyl, oxycodone, oxymorphone, hydrocodone, hydromorph An effective amount of opioid selected from the group consisting of ion and morphine, and at this time the average amount The force velocity of the opioid is divided by the duration of the administration period 1, and the amount administered during the administration period 1. It is expressed in terms of the equimolar amounts of the free base that are given, (ii) During administration period 2, the average infusion rate (mg / hour) during administration period 2 Another effective dose of buprenorphine is administered via prenorphine, and at this time the average infusion rate The amount of buprenorphine administered during the administration period 2 is calculated by dividing the total amount by the duration of the administration period 2. It is represented by equimolar amounts of free buprenorphine base, This includes administering it to patients who require it, The administration period 1 and the administration period 2 overlap by at least 75%. Methods for treating pain.

98. The method according to claim 97, wherein buprenorphine is administered subcutaneously or transdermally.

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