Treatment methods and dosage forms

Abstract

To provide methods for treating pain with reduced adverse pharmacodynamic responses and dosage forms for treatment.SOLUTION: The invention provides an oral dosage form comprising (i) an amount of oxycodone and (ii) an amount of buprenorphine, where the weight ratio of the predetermined amount of buprenorphine to the predetermined amount of oxycodone is greater than 1:40 calculated with the amount of buprenorphine in the dosage form expressed as the equimolar amount of buprenorphine base (Mw=467.64 g / mol) in mg, and the amount of oxycodone in the dosage form expressed as the equimolar amount of oxycodone hydrochloride (Mw=351.82 g / mol) in mg. Combinations of an opioid agonist and buprenorphine for use to treat pain achieve a reduction of adverse pharmacodynamic responses (such as respiratory depression), compared with a corresponding stand-alone opioid medicine.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a method and dosage form for treating pain. Certain combinations of agonists and buprenorphine and such specific combinations In certain embodiments, the present invention relates to a method for treating pain using a dosage form containing the combination. Specific combinations include oxycodone and buprenorphine, and fentanyl and buprenorphine, or hydromorphone and buprenorphine In certain embodiments, a combination as used herein refers to, for example, a single Opioid agonist therapeutic agents (e.g., oxycodone, fentanyl, and hydromorphone) adverse pharmacodynamic reactions (e.g., respiratory depression, bowel dysfunction, sedation, and In particular, the combinations of the present invention provide improved characteristics, including suppression of drug addiction and the like. reduces the potential toxicity associated with certain opioid agonists and reduces adverse side effects (e.g., Respiratory depression), thereby improving the overall safety profile of a particular opioid treatment. Furthermore, the therapeutic methods and dosage forms of the present invention may be used with a single opioid therapeutic agent. It is believed to provide effective pain relief with less abuse potential compared to [Background technology]

[0002] Certain opioid medications (e.g., fentanyl, hydromorphone, and Opioid-induced adverse pharmacodynamic reactions in patients receiving opioids (oxycodone) These patients are already struggling with pain management and fear that harmful side effects could be added to their suffering. Potential opioid-induced adverse pharmacodynamic reactions Respiratory depression, one of the symptoms, can lead to respiratory arrest, which can be fatal in some cases. Unfortunately, overdose of certain opioids can lead to It has been observed that these drugs can cause respiratory depression when administered. Safety has become a major concern with opioid medications.

[0003] Therefore, opioid-induced adverse pharmacodynamic reactions (e.g., respiratory depression, excessive or unnecessary Opioids with low drug preference and euphoria, and low likelihood of illegal use by non-patients Improved methods and dosage forms for effective pain treatment with steroid drugs have long been desired. opioids with effective pain relief and a much improved overall safety profile. There remains a need in the art for therapeutic agents and methods. Summary of the Invention

[0004] It is an object of certain embodiments of the present invention to provide improved methods for treating pain. And so.

[0005] An object of certain embodiments of the present invention is to reduce adverse pharmacodynamic reactions (e.g., intoxication and drug less potential for abuse and improved safety), The present invention provides a method for treating

[0006] The objective of certain embodiments of the present invention is to provide a method for treating public health issues related to toxicity, respiratory depression, addiction, and substance abuse. The object of the present invention is to provide a method for treating pain that minimizes hygiene risks.

[0007] An object of certain embodiments of the present invention is to provide a pain-relieving agent with an improved overall safety profile. The object of the present invention is to provide a dosage form for effective treatment of

[0008] The objective of certain embodiments of the present invention is to provide a method for treating respiratory depression, addiction, and drug abuse. To provide a dosage form for treating pain that is less painful and has an improved safety profile is.

[0009] The objective of certain embodiments of the present invention is to provide a method for treating public health issues related to toxicity, respiratory depression, addiction, and substance abuse. The object of the present invention is to provide a dosage form for treating pain that reduces hygiene risks.

[0010] These objectives also apply to the limited use products and methods of treatment described herein. It should be understood that the term relates to the use of

[0011] The above objectives are to provide a therapeutically effective treatment for opioid agonists (e.g., hydromorphone, oxycodone, and administering a specific combination of buprenorphine and fentanyl to patients who need it This is achieved by certain embodiments of the present invention relating to methods for treating pain, including It is possible.

[0012] In certain embodiments, certain combinations of opioid agonists and buprenorphine are It is a combination of hydromorphone and buprenorphine. The combination of morphine with hydromorphone was associated with a significantly increased risk of death compared with the corresponding hydromorphone monotherapy. In one embodiment, hydromorphone and bupivacaine inhibit morphine-induced respiratory depression by at least about 20%. The combination of lenorphin and lenorphin reduces hydromorphone-induced respiratory depression by approximately one-third or more. .

[0013] In another embodiment, the method for treating pain comprises: (i) During Administration Period 1, the average infusion rate (mg / hour) of An effective dose of hydromorphone is administered at the average rate of administration. Dromorphone administered during Dosing Period 1 divided by the duration of Dosing Period 1 expressed as an equimolar amount of hydromorphone free base, (ii) During Administration Period 2, the average infusion rate (mg / hour) of Another effective dose of buprenorphine administered with buprenorphine and the average rate of administration. The dose of buprenorphine administered during Administration Period 2 divided by the duration of Administration Period 2 expressed as an equimolar amount of buprenorphine free base, administering it to a patient in need thereof; Administration Period 1 and Administration Period 2 overlap by at least 75% and are administered at the above average injection rate. The ratio of hydromorphone to the above average injection rate is approximately 1:8000 to approximately 1:100. be.

[0014] In another embodiment, the specific combination of the present invention is a combination of fentanyl and buprenorphine. The combination of fentanyl and buprenorphine is Compared with fentanyl monotherapy, it reduces fentanyl-induced respiratory depression by approximately 30% or more.

[0015] In one embodiment, the present invention provides (i) During Administration Period 1, the average infusion rate (mg / hour) of The effective dose of fentanyl administered with the average injection rate of fentanyl is is the equimolar amount of fluoxetine administered during Administration Period 1 above, divided by the duration of Administration Period 1 above. It is represented by the fentanyl free base, (ii) During Administration Period 2, the average infusion rate (mg / hour) of Another effective dose of buprenorphine administered with buprenorphine and the average rate of administration. The dose of buprenorphine administered during Administration Period 2 divided by the duration of Administration Period 2 expressed as an equimolar amount of buprenorphine free base, and a method for treating pain comprising administering to a patient in need thereof Administration Period 1 and Administration Period 2 overlap by at least 75% and are administered at the above average injection rate. The ratio of vin to fentanyl at the above average injection speed is about 1:80 to about 1:0.5.

[0016] In certain embodiments, the present invention provides a pain reliever comprising hydromorphone and buprenorphine. and a pharmaceutical composition suitable for treating (i) An effective amount of hydromorphone is administered during a dosing period, and the average dose during said dosing period is The average rate of hydromorphone administration was 1 mg / hour. The equivalent molar amount of fluoxetine administered during the administration period is divided by the duration of the administration period. It is represented by hydromorphone free base, (ii) Another effective dose of buprenorphine is administered during the same administration period. buprenorphine at an average infusion rate (mg / hour) of buprenorphine administered during the administration period divided by the duration of the administration period expressed as an equimolar amount of buprenorphine free base, The ratio of buprenorphine at the above average injection rate to hydromorphone at the above average injection rate is , approximately 1:8000 to approximately 1:100.

[0017] In another embodiment, the present invention provides a method for treating pain comprising administering fentanyl and buprenorphine. and a pharmaceutical composition suitable for administering (i) An effective amount of fentanyl is administered at an average rate of 100 mg / kg / day during the administration period. (mg / hour) of fentanyl, and at this time, the average injection rate of fentanyl is Equimolar amount of fentanyl administered during the administration period divided by the duration of the administration period Expressed as the free base, (ii) Another effective dose of buprenorphine is administered during the same administration period. buprenorphine at an average infusion rate (mg / hour) of buprenorphine administered during the administration period divided by the duration of the administration period expressed as an equimolar amount of buprenorphine free base, The ratio of buprenorphine at the above average injection rate to fentanyl at the above average injection rate is approximately It is 1:80 to approximately 1:0.5.

[0018] In certain embodiments, the present invention provides a method for producing a pharmaceutical composition comprising: (i) During Administration Period 1, the average input rate (mg / hour) during Administration Period 1 Fentanyl, oxycodone, oxymorphone, hydrocodone, hydromorphone an effective amount of an opioid selected from the group consisting of morphine and morphine, and The rate of opioid administration during Administration Period 1 is the dose of opioid administered during Administration Period 1 divided by the duration of Administration Period 1. expressed in terms of the equimolar amount of its free base added, (ii) During Administration Period 2, the average infusion rate (mg / hour) of Another effective dose of buprenorphine administered with buprenorphine and the average rate of administration. The dose of buprenorphine administered during Administration Period 2 divided by the duration of Administration Period 2 expressed as an equimolar amount of buprenorphine free base, and a method for treating pain comprising administering to a patient in need thereof Treatment Period 1 and Treatment Period 2 will overlap by at least 75%.

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

[0020] The present invention further achieves the above and other objects, but in particular implementations In one aspect, the present invention provides a method for manufacturing a semiconductor device comprising: (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; 20. An oral dosage form comprising: A weight ratio of a given amount of buprenorphine to a given amount of oxycodone is equivalent to an equimolar amount of buprenorphine. Constant in the dosage form expressed as rufin base (mg) (Mw = 467.64 g / mol) 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 , which is over 1:40.

[0021] While the present invention accomplishes these and other objects, certain embodiments So, the present invention is (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; 2. A method for treating pain, comprising administering to a patient in need thereof an oral dosage form comprising: Regarding the law, A weight ratio of a given amount of buprenorphine to a given amount of oxycodone is equivalent to an equimolar amount of buprenorphine. Constant in the dosage form expressed as rufin base (mg) (Mw = 467.64 g / mol) 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 , which is over 1:40.

[0022] While the present invention accomplishes these and other objects, certain embodiments So, the present invention is (i) a fixed dose of immediate-release oxycodone; (ii) a fixed dose of immediate-release buprenorphine; 20. An oral dosage form comprising: A weight ratio of a given amount of buprenorphine to a given amount of oxycodone is equivalent to an equimolar amount of buprenorphine. Constant in the dosage form expressed as rufin base (mg) (Mw = 467.64 g / mol) 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.

[0023] While the present invention accomplishes these and other objects, certain embodiments So, the present invention is (i) a fixed dose of immediate-release oxycodone; (ii) a fixed dose of immediate-release buprenorphine; 2. A method for treating pain, comprising administering to a patient in need thereof an oral dosage form comprising: Regarding the law, A weight ratio of a given amount of buprenorphine to a given amount of oxycodone is equivalent to an equimolar amount of buprenorphine. Constant in the dosage form expressed as rufin base (mg) (Mw = 467.64 g / mol) 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.

[0024] While the present invention accomplishes these and other objects, certain embodiments So, the present invention is (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; Regarding a dosage form comprising: After single dose administration, the dosage form provides at least about 1:280 of buprenorphine to one subject. Average C max and mean C of oxycodone max This results in a ratio of

[0025] While the present invention accomplishes these and other objects, certain embodiments So, the present invention is (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; and co-administering to a patient in need thereof, After a single dose, the co-administration provides at least about 1:280 of buprenorphine in one subject group. Norphine average C max and mean C of oxycodone max This results in a ratio of

[0026] While the present invention accomplishes these and other objects, certain embodiments Thus, the present invention provides at least two oral dosage forms containing oxycodone at different active ingredient concentrations. For 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); and an equimolar amount of oxycodone. (ii) a quantity of buprenorphine; Including, The weight ratio of a given amount of buprenorphine to a given amount of oxycodone is: - expressed as an equimolar amount of buprenorphine base (mg) (Mw = 467.64 g / mol) A fixed amount of buprenorphine and an equimolar amount of oxycodone hydrochloride in a dosage form A certain amount of oxycodone in a dosage form expressed in mg (Mw = 351.82 g / mol) When calculated using the ratio of 1:40, -having the same value in each dosage form of the set.

[0027] While the present invention accomplishes these and other objects, certain embodiments So, the present invention is (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; 2. A method for treating pain, comprising administering to a patient in need thereof an oral dosage form comprising: Regarding the law, Average E of "Emotion VAS" max is at least 15% when measured using a comparative test Decreased and / or Mean E of "Temporary Drug Preference VAS" max is less when measured using comparative tests. and / or Mean E of "Overall Drug Preference VAS" max is less when measured using comparative tests. and / or Mean E of "Drug Relapse VAS" maxis at least 1 when measured using a comparative test. 5% decrease, and / or The mean cold pain scores measured using the cold pressor test at 1, 2, 3, and 4 hours after administration were The VAS must not increase by more than 10% compared to the comparator treatment when measured using a controlled test. stomach.

[0028] While the present invention accomplishes these and other objects, certain embodiments So, the present invention is (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; and co-administering to a patient in need thereof, Average E of "Emotion VAS" max is at least 15% when measured using a comparative test Decreased and / or Mean E of "Temporary Drug Preference VAS" max is less when measured using comparative tests. and / or Mean E of "Overall Drug Preference VAS" max is less when measured using comparative tests. and / or Mean E of "Drug Relapse VAS" max is at least 1 when measured using a comparative test. 5% decrease, and / or The mean cold pain scores measured using the cold pressor test at 1, 2, 3, and 4 hours after administration were The VAS must not increase by more than 10% compared to the comparator treatment when measured using a controlled test. stomach.

[0029] According to certain embodiments of the present invention, the pharmaceutical combination is According to certain embodiments, the present invention is directed to a method for treating pain. The present invention relates to the use of a pharmaceutical combination as defined above in the manufacture of a medicament for the treatment of

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

[0031] As used herein, the singular forms "a," "an," and "the" are used unless the context clearly indicates otherwise. Unless specifically stated, plural referents are included.

[0032] As used herein, the term "therapeutically effective" refers to the amount of drug required to produce a desired therapeutic effect. It refers to the amount of something or the rate at which a drug is administered.

[0033] The term "pain" includes, but is not limited to, nociceptive pain, neuropathic pain, and visceral pain. acute and chronic pain of malignant and non-malignant origin, of moderate to severe origin, not treated with steroids, in particular It refers to acute and chronic pain of severe to extremely severe origin, both malignant and non-malignant. Examples include, but are not limited to, severe pain caused by diseases such as cancer, rheumatism and arthritis. Further examples include post-operative pain, cluster headache, toothache, surgical pain, and pain due to severe burns. pain due to third degree burns, back pain, lower back pain, herpes neuralgia, phantom limb pain, central These include nerve pain, bone injury pain, and pain during labor and delivery.

[0034] The term "patient" refers to a subject, particularly one who is experiencing a particular condition or multiple symptoms that indicate the need for treatment. Humans who are showing clinical signs of a condition, who are being treated preventatively or prophylactically for a disease, The term "subject" refers to a patient, or a human who has been diagnosed with the disease being treated. Includes a definition of the term "patient" to exclude individuals who are completely normal in all respects or with respect to a particular disease. It is not something to do.

[0035] The "pharmaceutically acceptable salt" includes inorganic acid salts, such as hydrochloride, hydrobromide, and sulfate. salts, phosphates, etc., organic acid salts, e.g., myristate, formate, acetate, trifluoro acetates, maleates, tartrates, etc.; sulfonates, e.g., methanesulfonates, benzyl toluenesulfonates, p-toluenesulfonates, etc.; amino acid salts, e.g., arginine salts, such as sodium salts, potassium salts, etc. alkaline earth metals, such as calcium salts and magnesium salts; and organic amine salts, such as triethylamine salts, pyridine salts, picoline salts, ethanol salts, diethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzo The preferred salt is the hydrochloride salt. is.

[0036] The term "buprenorphine" includes buprenorphine base and all its pharmaceutically acceptable forms. Suitable salts include, for example, buprenorphine hydrochloride. Buprenorphine base and its pharmaceutically acceptable salts may be present in the form of solvates (e.g., as solvent-free forms (e.g., anhydrous forms), as complexes, and mixtures thereof; It may be present in the form of

[0037] The term "fentanyl" refers to fentanyl base and all its pharmaceutically acceptable salts. Suitable salts include, for example, fentanyl citrate and fentanyl Fentanyl base and its pharmaceutically acceptable salts are also available as solvates. (e.g., hydrates), as complexes, and mixtures thereof; in solvent-free forms (e.g., For example, the anhydrous form may be present.

[0038] The term "hydromorphone" includes hydromorphone base and all its pharmaceutically acceptable salts. Suitable salts include, for example, hydromorphone hydrochloride. Hydromorphone base and its pharmaceutically acceptable salts may be present in the form of solvates (e.g., as solvent-free forms (e.g., anhydrous forms), as complexes, and mixtures thereof; It may be present in the form of

[0039] The term "oxycodone" refers to oxycodone base and all its pharmaceutically acceptable salts. Suitable salts include, for example, oxycodone hydrochloride and oxycodone tele Oxycodone base and its pharmaceutically acceptable salts are preferably used in the presence of a solvent. As solvates (e.g., hydrates), as complexes, and mixtures thereof, in solvent-free form ( For example, it may be in an anhydrous form.

[0040] When adding the molecular weight of Mw = 467.64 g / mol to the reference of buprenorphine base, Mw = 504.10 g / m Whenever the molecular weight of ol is added to a reference to buprenorphine hydrochloride, the solvent or complexing agent This means buprenorphine hydrochloride that does not contain methylprenorphine. Mw=351.82g / mol Whenever a molecular weight is added to a reference to oxycodone hydrochloride, it does not include solvents or complexing agents. When the term "free base" is used, it means oxycodone hydrochloride. means the base in solvent-free form.

[0041] PCT International Publication WO2005 / 097801A1, U.S. Patent No. 7,129,248B2 No. 2006 / 0173029A1, and U.S. Patent Application Publication No. 2006 / 0173029A1, all of which are incorporated by reference. and the like) is less than about 25 ppm, preferably less than about 15 ppm, Less than 10 ppm, or less than about 5 ppm, more preferably less than about 2 ppm, about 1 ppm less than about 0.5 ppm, or less than about 0.25 ppm of 14-hydroxycodemine This document describes a process for preparing oxycodone hydrochloride having a non-ionic surfactant. .

[0042] As used herein, the term "ppm" means "parts per million." With respect to hydroxycodeinone, "ppm" means the number of ppm in a particular sample product. It means parts per million of 4-hydroxycodeinone. The bell may be detected by any method known in the art, preferably using UV detection. It can be measured by HPLC analysis.

[0043] In certain embodiments of the present invention where the active agent is oxycodone hydrochloride, less than about 25 ppm Preferably, it is less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm, more preferably Or less than about 2 ppm, less than about 1 ppm, less than about 0.5 ppm, or less than about 0.25 ppm Oxycodone hydrochloride with 14-hydroxycodeinone levels below pm is used .

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

[0045] The term “C av " refers to the mean plasma concentration obtained during the dosing interval and / or dosing period. This means that "C av ” is the total under-curve plasma concentration versus 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 ) means the time until

[0047] The term “E max " means the maximum effect during the test period.

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

[0049] The term "oral bioavailability" refers, for purposes of the present invention, to a normalized intravenous dose. The rate of absorption of a drug (e.g., buprenorphine) from an oral unit dosage form compared to the administered dose Defined as (%).

[0050] The term "opioid-induced adverse pharmacodynamic reaction" refers to a reaction in which an opioid is not administered for its intended therapeutic effect. It refers to unintended side effects experienced by patients receiving a therapeutic drug. The intended effect is pain relief, and opioids are opioid analgesics. Associated unintended side effects include euphoria, euphoria, bowel dysfunction, nausea, and vomiting. , somnolence, dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, malaise minutes, delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance These include, among others, respiratory depression, euphoria, elation, and bowel dysfunction.

[0051] The term "toxicity" refers to the potential for fatal overdose, also known as "lethal." In certain embodiments of the invention, toxicity is not considered an adverse pharmacodynamic response, but rather is a It's a physical effect.

[0052] The term "opioid" or "opioid analgesic" refers to an opioid agonist, an opioid mixed opioid agonists and antagonists, partial opioid agonists Opioid analgesics include alphenazone, benzodiazepine, and benzodiazepine. Tanil, Allylprozin, Alphaprozin, Anileridine, Benzylmorphine, Veget Lamipramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine , dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine , dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, Dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptadine, ethylmethicone Luthianbutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine , fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, Somethadone, ketobemidone, levorphanol, levophenacylmorphan, Lofenta Nil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, milo Fin, Narceine, Nicomorphine, Norlevorphanol, Normethadone, Nalorfy nalbufen, normorphine, norpipanone, opium, oxycodone, oxymorph On, papaveretam, pentazocine, phenadoxone, phenomorphan, phenazocine , phenoperidine, piminodine, piritramide, propheptadine, promedol, pro These include peridine, propoxyphene, sufentanil, tilidine, and tramadol. The present invention relates to, among other things, certain opioid agonists, For example, adverse pharmacodynamics associated with the use of oxycodone, fentanyl, and hydromorphone Reactions and toxicity.

[0053] The term "co-administration" refers to administration of oxycodone before the end of the administration interval of oxycodone, e.g. A period beginning 6 hours before the start of the oxycodone dosing interval and ending 1 hour before the end of the oxycodone dosing interval. Within the oxycodone dosing interval, or within the oxycodone dosing interval, starting 3 hours before the start of the oxycodone dosing interval This means that the dose of buprenorphine is administered within a period ending one hour before the end of the interval. Oxycodone doses spaced 6 hours apart are given within 6 hours of oxycodone administration. In particular, buprenorphine may be administered simultaneously with the intravenously administered dose of buprenorphine. Doses should be taken within 60 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or If administered within one minute, it may be administered simultaneously with a dose of oxycodone. When administered in this form, buprenorphine should preferably be administered exactly the same amount as oxycodone. The above considerations are particularly relevant to the administration of oxycodone and buprenorphine. Both apply to orally administered embodiments.

[0054] The term "administration period" refers to the period during which a drug (e.g., buprenorphine, fentanyl, The term refers to the period during which a drug (such as dromorphone and oxycodone) is administered. The administration period of the transdermal therapeutic system begins when the system is applied and ends when it is removed. The administration period for subcutaneous implants begins when the subcutaneous implant is placed and ends at Ends upon removal of the subcutaneous implant or complete degradation of the subcutaneous implant. The administration period for an administration, e.g., an infusion, begins when the infusion begins and ends when the infusion ends. The administration period may be the same as the administration interval, which means repeated administration, or The duration of the administration may vary and may include periods of non-administration. For example, the dosing interval and duration are the same for transdermal systems and subcutaneous implants.

[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 of the two drugs is not indicated. i.e., have the same start and end time points), or if one of the treatment periods If one treatment period is 100% within the other treatment period (i.e., completely contained within), then there is a 100% overlap. Two drugs (e.g., one is buprenorphine and the other is hyphallic) are considered to be The duration of administration of the drug (dromorphone, fentanyl, or oxycodone) varies to some extent. However, such overlap may be limited to 75% or more, 90% or more, Or, 95% or more. The percentage of overlap is based on the opioid agonist (e.g., The calculation is based on the duration of administration of the following drugs: hydromorphone, fentanyl, and oxycodone. For example, a buprenorphine dose that begins at 8:00 AM and ends at 10:00 AM on the same day period and hydromorphone starting at 9:00 AM and ending at 2:00 PM on the same day. The dosing periods may be considered to overlap by 20%. The buprenorphine administration period started at 9:00 AM on Day 1 and ended at 8:00 AM on Day 1. The hydromorphone administration period ending at 10:00 AM on the first day is considered to overlap 100%. It can be done.

[0056] The amount of oxycodone is administered orally, and the amount of buprenorphine is administered transdermally. In certain embodiments, the dosing interval of buprenorphine is the same as the dosing interval of oxycodone. This is significantly longer than the usual (e.g., several times a day versus several days). Cycodone is administered orally and the dose of buprenorphine is administered subcutaneously (i.e., In embodiments, the buprenorphine administration interval may also be adjusted to accommodate the oxytocin-containing buprenorphine. The interval between codon administrations is significantly longer (e.g., weeks or months versus Therefore, the above-mentioned dose of oxycodone is administered orally (e.g., several times a day). (each having a dose interval of 100 μg / dose) and the above-mentioned fixed amount of buprenorphine is administered transdermally or In embodiments where the dose of oxycodone is administered subcutaneously, the term "co-administration" refers to the administration of oxycodone in combination with buprenoline. This means that it is administered within the dosing interval of Luphin. It is administered subcutaneously at a dosing interval of 6 months. The dose of buprenorphine administered is based on the amount of oxygen administered within 6 months of buprenorphine administration. It may be administered simultaneously with the dose of codon.

[0057] The term "subcutaneous / subcutaneously" refers to administration via a subcutaneous implant. The implant is placed subcutaneously (e.g., by insertion through a small subcutaneous incision) , for a long period of time, such as weeks or months, e.g., 1 to 6 months or even longer A dosage form that delivers an active agent.

[0058] The term "average injection rate" refers to the rate at which a drug (e.g., fentanyl, hydromorphone, oxycodone, This average is defined as the rate at which drugs (e.g., benzodiazepine and buprenorphine) are delivered to the blood system. The input rate is a measure of the rate of delivery into the blood system where first-pass effects do not play a significant role. This concept also applies to transdermal, subcutaneous, and all other routes of administration. It can be applied to sublingual and buccal administration as well as to various types of injections / infusions. In the case of transdermal therapeutic systems, the average dosage rate should be the same as the average release rate stated in the package insert. The same is true for subcutaneous implants. The ratio between the rates of buprenorphine and opioids (hydromorphone) can be calculated. (alcohol, fentanyl or oxycodone) are administered by the same route of administration, and the route of administration is Choose from any type of injection or infusion (e.g., subcutaneous, intravenous, or intramuscular injection / infusion, etc.) When the dose is selected, the administration period is the same and the ratio of the average administration rate varies depending on the amount of drug administered. This also applies to simultaneous subcutaneous injections, for example.

[0059] The term "immediate release" formulation or form refers to the In vitro dissolution was measured using a USP Apparatus 2 (paddle) at 50 rpm. "Dose form" refers to a dosage form that releases at least about 70% of the active agent within 45 minutes when measured.

[0060] C max Value and / or T max The term "in a group of subjects" in relation to values is the corresponding C max Value and / or T max The values ​​were obtained in the same clinical trial in the same subject group. This means that the measurement is performed in accordance with the

[0061] "High" and / or "drug preference" ("overall drug preference", "temporary drug preference" " and "drug relapse") and / or in the context of measuring differences in "cold pain scores" The term "comparative study" in this context preferably refers to a double-blind, placebo-controlled, positive-controlled, randomized In a crossover study, the dosage form of the present invention and / or the treatment method of the present invention and a comparative treatment Clinical trials are conducted and / or applied to a group of subjects (the results of which are compared with each other). The subjects are preferably healthy male and female recreational opioid users. It is preferable to select according to the selection criteria used in Example 1. Euphoria score and drug preference The evaluation of the sex and pain scores was performed using a visual analog scale (VAS). Make a judgment.

[0062] "High" and / or "drug preference" ("overall drug preference", "temporary drug preference" " and "drug relapse") and / or in the context of measuring differences in "cold pain scores" The term "comparison treatment method" in this context refers to a method for treating a subject in a dosage form of the present invention and / or a method for treating a subject in a treatment method of the present invention. Total combination of the same active agents (excluding buprenorphine) (compared to the administration of oxycodone) "Bioequivalent" refers to a treatment method involving the administration of a compound (biomedicine) that is bioequivalent to a compound used in a therapeutic agent.

[0063] the dosage form of the present invention is an oral dosage form comprising oxycodone and buprenorphine; and / or In one embodiment, the method of treatment of the present invention comprises administering an oral dosage form containing oxycodone and buprenorphine. In embodiments, the "high" and / or "drug preference" ("overall drug preference", "temporary drug preference") Measure differences in "drug preference" and "drug relapse" and / or "cold pain scores" The term "comparison treatment method" in this context may alternatively refer to the same as in the dosage form according to the present invention. Total combination of one active agent (except buprenorphine, especially equimolar amounts of oxycodone) Oral dosage forms containing oxycodone (the in vitro dissolution rate of the dosage forms of the present invention and / or substantially the same in vitro dissolution rate of oxycodone in the dosage form administered in the method of treatment of the invention; "oxycodone in vitro dissolution rate" refers to a method of treatment comprising administering a .

[0064] "High" and / or "drug preference" ("overall drug preference", "temporary drug preference" " and "drug relapse") and / or in the context of measuring differences in "cold pain scores" The term "substantially the same in vitro dissolution rate of oxycodone" means the rate at 37°C, 900m 1 of simulated gastric fluid (SGF) (enzyme-free) at 100 rpm, USP Approved At 1 hour of dissolution, as measured using ratus 1 (basket), preferably The ointment is released at 1 and 2 hours of dissolution, more preferably at 1, 2 and 3 hours of dissolution. The percentage amount of oxycodone is adjusted to the corresponding in vitro dissolution rate of oxycodone in the dosage form of the present invention. The deviation is about 20% points or less, preferably about 10% points or less, from the normal. The in vitro dissolution rate refers to the rate at which the

[0065] The term "bioequivalent / bioequivalence" as defined for the purposes of this invention means that the Agent C max , AUC t , and AUC inf It means a dosage form that provides the geometric mean value of The 90% confidence interval estimated from the ratio (test / reference) ranged from 80.00% to 125.00%. When measured in both fed and fasted states, C max , AUC t , and A UC inf The average value of is preferably within the range of 80.00% to 125.00%. .

[0066] Within the scope of the present invention, the term "cold pressor" in the context of measuring "cold pain score" is used. The CPT test involves holding an adult's hand up to the wrist in water maintained at a temperature of 0-2°C. This refers to a test using a circulating water bath that can measure the temperature within the range of 0 to 2°C. Ideally, it should be set at 1°. A range of motion greater than 2° may affect the pain experienced by the subject. The test involves the subject quickly dipping their hand into a bath of water. The subject is asked to relax their hand in an open position until the pain becomes unbearable. Instruct patients to keep their hands submerged for a maximum initial duration of 2 minutes. This can be extended to a maximum of 5 minutes. The subject is allowed to remove their hand from the water at any time. If you feel the pain is unbearable, you should keep your hand in the water. The duration of hand immersion was measured from the moment of complete immersion until the subject was satisfied that he or she The time from when her hand was removed from the water bath was measured. The onset time (seconds) and duration (seconds) were recorded. Recorded in the source document.

[0067] "Expressed as an equimolar amount of buprenorphine base (mg) (Mw = 467.64 g / mol) A fixed amount of buprenorphine and an equimolar amount of oxycodone hydrochloride ( A certain amount of oxycodone in a dosage form expressed as mg (Mw = 351.82 g / mol) The weight ratio of a given amount of buprenorphine to a given amount of oxycodone when calculated using "Rate" refers to the amount used in Example 1 below. - oxycodone HCl (Mw=351.82g / mol): 40mg, - buprenorphine HCl (Mw=504.10 g / mol): 5.39 mg, - Buprenorphine represented by an equimolar amount of buprenorphine base (Mw = 467.64 g / mol) Renorphin HCl: 5 mg; -Weight ratio=5mg:40mg=1:8; - A weight ratio of 1:8 is equal to 0.125, so for example, 1:40 is equal to 0.02 Equals 5 It is calculated as shown in the example below. [Brief explanation of the drawings]

[0068] [Figure 1] 1 is a graphical representation of the study design of Example 1. [Figure 2] FIG. 1 shows the results of Example 1 (mean plasma concentrations of oxycodone over time after oral administration of oxycodone alone and after combined oral administration of oxycodone and transdermal administration of buprenorphine). [Figure 3] FIG. 1 shows the combined results of Example 1 and Example 2 (mean plasma concentrations of buprenorphine over time after transdermal, intravenous, and oral administration (results after transdermal administration are from Example 1, and results after intravenous and oral administration are from Example 2)). [Figure 4] FIG. 1 shows the results of Example 1 (mean plasma concentrations of buprenorphine over time after transdermal administration of buprenorphine alone and after combined transdermal administration of buprenorphine and oral administration of oxycodone). [Figure 5] FIG. 1 shows the results of Example 1 (mean "temporary" drug preference, VAS), including results for both replicates and all six treatments. [Figure 6] FIG. 1 shows the results of Example 1 (mean "temporary" drug preference, VAS, Emax), including results for both replicates and all six treatments. [Figure 7]FIG. 1 shows the results of Example 1 (mean elation, VAS), including results for both replicates and all six treatments. [Figure 8] FIG. 1 shows the results of Example 1 (mean elation, VAS, Emax) including results for both replicates and all six treatments. [Figure 9] FIG. 1 shows the results of Example 1 (overall drug preference, VAS, Emax), including results for both replicates and all six treatments. [Figure 10] FIG. 1 shows the results of Example 1 (drug reuse, VAS, Emax), including results for both replicates and all six treatments. [Figure 11] FIG. 1 shows the results of Example 1 (replicate 2) and all six treatments (mean cold pain score over time: 0 hours - before oral administration). [Figure 12] FIG. 1 shows the results of Example 1 (replicate 2) and all six treatments (mean cold pain score over time: 1 hour). [Figure 13] FIG. 1 shows the results of Example 1 (replicate 2) and all six treatments (mean cold pain score over time: 2 hours). [Figure 14] FIG. 1 shows the results of Example 1 (replicate 2) and all six treatments (mean cold pain score over time: 3 hours). [Figure 15] FIG. 1 shows the results of Example 1 (replicate 2) and all six treatments (mean cold pain score over time: 4 hours). [Figure 16] FIG. 1 shows the combined results of Example 1 and Example 2 (mean plasma concentrations of buprenorphine over time after transdermal buprenorphine administration in Example 1, mean plasma concentrations of buprenorphine over time after oral IR buprenorphine administration in Example 2, and mean plasma concentrations of oxycodone over time after oral IR oxycodone administration in Example 1). [Figure 17] Figure 17A) shows the effect of buprenorphine alone on blood gas parameters in rats: A) pCO2. Figure 17B) shows the effect of buprenorphine alone on blood gas parameters in rats: B) sO2. [Figure 18]Figure 18A) shows the effect of oxycodone alone on blood gas parameters in rats: A) pCO2. Figure 18B) shows the effect of oxycodone alone on blood gas parameters in rats: B) sO2. [Figure 19] Figure 19A) shows the effect of hydromorphone alone on blood gas parameters in rats: A) pCO2. Figure 19B) shows the effect of hydromorphone alone on blood gas parameters in rats: B) sO2. [Figure 20] Figure 20A) shows the effect of fentanyl alone on blood gas parameters in rats: A) pCO2. Figure 20B) shows the effect of fentanyl alone on blood gas parameters in rats: B) sO2. [Figure 21] Figure 21A) shows the effect of buprenorphine on oxycodone-induced impairment of rat arterial blood gas (ABG) parameters: A) sO2%. Figure 21B) shows the effect of buprenorphine on oxycodone-induced impairment of rat arterial blood gas (ABG) parameters: B) pO2. Figure 21C) shows the effect of buprenorphine on oxycodone-induced impairment of rat arterial blood gas (ABG) parameters: C) pCO2. Figure 21D) shows the effect of buprenorphine on oxycodone-induced impairment of rat arterial blood gas (ABG) parameters: D) arterial blood pH. [Figure 22] Figure 22A) shows the effect of buprenorphine on oxycodone-induced impairment of arterial blood gas (ABG) parameters in rats 1 hour after administration: A) pCO2%. Figure 22B) shows the effect of buprenorphine on oxycodone-induced impairment of arterial blood gas (ABG) parameters in rats 1 hour after administration: B) sO2%. [Figure 23] FIG. 1 shows the analgesic effects of buprenorphine, oxycodone, and the combination of buprenorphine-oxycodone (8 mg / kg) in rats. [Figure 24]Figure 24A) Effect of buprenorphine on fentanyl-induced impairment of rat arterial blood gas (ABG) parameters: A) sO2%. Figure 24B) Effect of buprenorphine on fentanyl-induced impairment of rat arterial blood gas (ABG) parameters: B) pO2. Figure 24C) Effect of buprenorphine on fentanyl-induced impairment of rat arterial blood gas (ABG) parameters: C) pCO2. Figure 24D) Effect of buprenorphine on fentanyl-induced impairment of rat arterial blood gas (ABG) parameters: D) arterial blood pH. Figure 24E) Effect of buprenorphine on fentanyl-induced impairment of rat arterial blood gas (ABG) parameters: E) acid-base status. [Figure 25] Figure 25A) shows the effect of buprenorphine on fentanyl-induced impairment of arterial blood gas (ABG) parameters in rats 1 hour after administration: A) pCO2%. Figure 25B) shows the effect of buprenorphine on fentanyl-induced impairment of arterial blood gas (ABG) parameters in rats 1 hour after administration: B) sO2%. [Figure 26] FIG. 1 shows the analgesic effects of buprenorphine, fentanyl, and the combination of buprenorphine-fentanyl (0.5 mg / kg) in rats. [Figure 27] Figure 27A) Effect of buprenorphine on hydromorphone-induced impairment of rat arterial blood gas (ABG) parameters: A) sO2%. Figure 27B) Effect of buprenorphine on hydromorphone-induced impairment of rat arterial blood gas (ABG) parameters: B) pO2. Figure 27C) Effect of buprenorphine on hydromorphone-induced impairment of rat arterial blood gas (ABG) parameters: C) pCO2. Figure 27D) Effect of buprenorphine on hydromorphone-induced impairment of rat arterial blood gas (ABG) parameters: 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 1 hour after administration: A) pCO2%. Figure 28B) shows the effect of buprenorphine on hydromorphone-induced impairment of arterial blood gas (ABG) parameters in rats 1 hour after administration: B) sO2%. [Figure 29] FIG. 1 shows the analgesic effects of buprenorphine, hydromorphone, and the combination of buprenorphine-hydromorphone (10 mg / kg) 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) is a schematic diagram of three hydromorphone (HMP) infusions with a placebo patch (A) in Study Part 2a). Figure 33B) is a schematic diagram of three hydromorphone (HMP) infusions with buprenorphine (BUP, 20 mcg / hr, Butrans® patch) (B) in Study Part 2a). [Figure 34] FIG. 1 shows the mean HCVR slopes normalized to placebo following administration of IV hydromorphone (HMP), buprenorphine (BUP, Butrans® patch), and the HMP-BUP combination in study part 2a). [Figure 35] FIG. 1 shows hydromorphone concentrations during HCVR measurements in study part 2a). [Figure 36]FIG. 1 shows buprenorphine concentrations during HCVR measurements in study part 2a). [Figure 37] Part 2b) Schematic diagram of the study design. [Figure 38] FIG. 1 shows hydromorphone concentrations during HCVR measurements in study part 2b). [Figure 39] FIG. 1 shows buprenorphine concentrations during HCVR measurements in study part 2b). [Figure 40] FIG. 1 shows the mean HCVR slopes normalized to placebo following administration of HMP (3.0 mg IV), BTDS (doses of 2.5 mcg / hr, 5 mcg / hr, and 10 mcg / hr), and the HMP-BTDS combination in study part 2b). [Figure 41] FIG. 1 shows the analgesic effects of HMP (3.0 mg IV), BTDS (doses of 2.5 mcg / hr, 5 mcg / hr, and 10 mcg / hr), and the HMP-BTDS combination compared to placebo in study part 2b). DETAILED DESCRIPTION OF THE INVENTION

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

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

[0071] Hydromorphone is formulated, for example, as an intravenous infusion composition for treating pain. It has been done.

[0072] Oxycodone is formulated as an oral IR formulation to treat pain, e.g. Rapid release of oxycodone using IR formulations, among other things, promotes euphoria and drug preference. Oxycodone is known to promote abuse and cause addiction in certain situations. It is known that:

[0073] Buprenorphine is administered, for example, through transdermal patches (transdermal therapeutic systems) for the treatment of pain. Sublingual buprenorphine is also used to treat addiction-forming opioids, such as For example, sublingual buprenorphine is used in substitution therapy for oxycodone. A new subcutaneous depot product has been approved by the USFDA under the name Sublocade®. It was recently approved as a subcutaneous injection once a month, providing sustained release of buprenorphine. Opioid substitution therapy involves the use of alternative drugs, prescription medications, such as methadone or buprenorphine. Norphine (usually administered in a supervised clinical setting) is used by illicit drug users. Buprenorphine is an opioid partial agonist. Norphine may produce the usual opioid effects and side effects (e.g., euphoria) Although it is an opioid, its maximum effect is not as strong as that of a full agonist such as oxycodone. This means that buprenorphine, at low doses, has been shown to reduce the risk of opioid addiction. Sufficient to allow an individual to discontinue opioid misuse without experiencing withdrawal symptoms The agonist effect of buprenorphine is such that the effect plateaus. The effect increases linearly with increasing dose until it reaches . This is called the "ceiling effect." Therefore, buprenorphine Opioid agonists have a lower risk of abuse, addiction, and side effects compared to full opioid agonists. Although buprenorphine has a risk, the risk is limited by a ceiling effect. When administered to opioid-addicted individuals, full agonists act as full antagonists while present in the bloodstream. It effectively blocks the effects of all opioid agonists and can suddenly induce withdrawal symptoms. Buprenorphine is commonly administered transdermally, bucally, sublingually, and intravenously. Oral treatment is thought to be ineffective due to extensive first-pass metabolism.

[0074] Currently, opioid agonists (oxycodone, fentanyl, or hydrochloride) Certain combinations of buprenorphine and buprenorphine provide the same dose of orally active steroids as those administered alone. Virtually identical analgesic efficacy compared to xycodone, fentanyl, or hydromorphone results in an overall reduction in respiratory depression, euphoria, and drug addiction, as well as improved safety. It has been found that the results of the following examples and See Figures 5-10 and further figures.

[0075] Certain oral treatments and certain combinations of oxycodone and buprenorphine are used. The corresponding oral dosage form provides substantially the same efficacy as the same dose of oxycodone administered alone. It has been found that it produces a significant analgesic effect, but also produces a sense of euphoria and suppresses drug addiction. See Example 1 and FIGS. 11 to 15.

[0076] Oral administration of buprenorphine produces blood levels comparable to those achieved by transdermal administration. See Figure 3. Buprenorphine and Oxycodone Oral IR administration of the two drugs results in similar blood concentration curve shapes (the absolute amounts of the two drugs differ by approximately 100-fold). It has also been found that (see Figure 16).

[0077] Methods of administration and dosage forms of fentanyl, hydromorphone, and buprenorphine In certain embodiments, the present invention provides a specific combination of hydromorphone and buprenorphine. The combination of hydromorphone and buprenorphine provides a Reduces hydromorphone-induced respiratory depression by approximately 20% or more compared to hydromorphone monotherapy In one embodiment, the combination of hydromorphone and buprenorphine is It reduces steroid-induced respiratory depression by approximately one-third or more.

[0078] In certain embodiments, the method for treating pain of the present invention comprises: (i) During administration period 1, the average infusion rate (mg / hour) / hour) hydromorphone, and at this time, the average The average infusion rate of hydromorphone is calculated by dividing the duration of Infusion Period 1 by the duration of Infusion Period 1. expressed as an equimolar amount of hydromorphone free base administered during (ii) During Administration Period 2, the average infusion rate (mg / hour) of Another effective dose of buprenorphine administered with buprenorphine and the average rate of administration. The dose of buprenorphine administered during Administration Period 2 divided by the duration of Administration Period 2 expressed as an equimolar amount of buprenorphine free base, administering it to a patient in need thereof; Administration Period 1 and Administration Period 2 overlap by at least 75% and are administered at the above average injection rate. The ratio of hydromorphone to the above average injection rate is about 1:8000 to about 1:100. Or, about 1:8000 to about 1:200, or about 1:8000 to about 1:400, or is about 1:8000 to about 1:600, or about 1:8000 to about 1:800, or It is about 1:4000 to about 1:800, or about 1:3000 to about 1:1100.

[0079] In certain embodiments, the method for treating pain of the present invention comprises: (i) During Administration Period 1, the average infusion rate (mg / hour) of The effective dose of fentanyl administered with the average injection rate of fentanyl is is the equimolar amount of fluoxetine administered during Administration Period 1 above, divided by the duration of Administration Period 1 above. It is represented by the fentanyl free base, (ii) During Administration Period 2, the average infusion rate (mg / hour) of Another effective dose of buprenorphine administered with buprenorphine and the average rate of administration. The dose of buprenorphine administered during Administration Period 2 divided by the duration of Administration Period 2 expressed as an equimolar amount of buprenorphine free base, administering it to a patient in need thereof; Administration Period 1 and Administration Period 2 overlap by at least 75% and are administered at the above average injection rate. The ratio of vin to fentanyl at the above average injection speed is about 1:80 to about 1:0.5, or Approximately 1:80 to approximately 1:1, or approximately 1:80 to approximately 1:2, or approximately 1:80 to approximately 1:4 , or about 1:80 to about 1:6, or about 1:80 to about 1:8, or about 1:40 to about 1:8, or about 1:30 to about 1:11.

[0080] In a particular embodiment of the present invention, fentanyl or hydromorphone and buprenorphine In certain embodiments, hydromorphone is administered at a dose of about 1 mg. / hour to 10 mg / hour, or about 2 mg / hour to about 8 mg / hour, or is administered at a rate of about 3 mg / hour to about 7 mg / hour, or about 3 mg / hour to about 5 mg / hour or at a rate of about 1 mg / hour to about 3.5 mg / hour, or at a rate of about 3.5 mg / hour In certain embodiments, hydromorphone is administered at a rate of about 10 mg / hour to about 10 mg / hour. , about 1 mg / hour, about 3.5 mg / hour, about 4 mg / hour, about 4.5 mg / hour, or In certain embodiments, fentanyl is administered at a rate of about 12 mg / hour. .5μg / hour, 25μg / hour, 50μg / hour, 75μg / hour, 100μg / hour , 150 μg / hour, or 200 μg / hour.

[0081] In another embodiment of the present invention, fentanyl or hydromorphone and buprenorphine In certain embodiments, hydromorphone is administered by different routes of administration. / hour to 10 mg / hour, or at a rate of about 2 mg / hour to 8 mg / hour, or , at a rate of about 3 mg / hour to 7 mg / hour, or at a rate of about 3 mg / hour to 5 mg / hour In certain embodiments, hydromorphone is administered at a rate of about 1 mg / hour, about 3.5 m g / hour, about 4 mg / hour, about 4.5 mg / hour, or about 10 mg / hour In certain embodiments, fentanyl is administered at a dose of about 12.5 μg / hour, 25 μg / hour, 50μg / hour, 75μg / hour, 100μg / hour, 150μg / hour, or It is administered at a rate of 200 μg / hour.

[0082] In certain embodiments of the methods of the present invention, the route of administration is intravenous, intramuscular, subcutaneous, or , sublingual administration, buccal administration, subcutaneous administration, and transdermal administration. In one embodiment, the fentanyl is administered transdermally. In another embodiment, the hydromorphone is administered intravenously. In certain embodiments of the present invention, fentanyl and buprenorphine are administered transdermally. In certain other embodiments of the present invention, hydromorphone and buprenoline are administered. Luphin is administered intravenously.

[0083] In a particular embodiment of the present invention, fentanyl or hydromorphone and buprenorphine The compositions include intravenous compositions, intramuscular compositions, subcutaneous compositions, sublingual compositions, buccal compositions, and subcutaneous compositions. The drug is administered in a dosage form selected independently from a plant-based system or a transdermal therapeutic system. The preferred dosage form for fentanyl is a transdermal therapeutic system, whereas that for hydromorphone is A preferred dosage form is an intravenous composition. In a particular embodiment of the present invention, fentanyl and bromide are Prenorphine is a transdermal therapeutic system containing fentanyl and buprenorphine. The administration period is 1 day to 7 days, for example, 1 day, 3 days, 3.5 days, and In certain other embodiments of the present invention, hydromorphone and buprenorphine are administered for 7 days. Norphine is administered in one intravenous composition containing buprenorphine and hydromorphone. The administration period is about 5 minutes to 24 hours, or about 15 minutes to 24 hours, or about 1 5 minutes to 12 hours, or about 30 minutes to 6 hours, or about 30 minutes to 3 hours, or The time is about 30 minutes to 2 hours, particularly about 1 hour.

[0084] In certain embodiments of the present invention, only buprenorphine is administered transdermally and for a period of time. 2 is 1 day to 7 days, for example, 1 day, 3 days, 3.5 days, 7 days, etc.

[0085] In certain embodiments of the invention, buprenorphine is administered subcutaneously and the duration of administration is: Approximately 1 month to 1 year, or approximately 1 month to 4 months, or approximately 1 month to 3 months For example, the period may be selected from 1 month, 2 months, 3 months, 4 months, and 6 months.

[0086] Blood levels In certain embodiments, the method comprises administering hydromorphone and buprenorphine. The method of the invention provides an average of 100 mg of buprenorphine and 100 mg of hydromorphone after a single dose. C max Or average C av and the mean C of buprenorphine max Or average C a v and hydromorphone mean C max Or average C av The ratio is about 0.001 to about 0. It is characterized in that it is 006.

[0087] In certain embodiments, the present invention provides a method for administering fentanyl and buprenorphine. The method used to measure the mean C max Or average C av and the mean C of buprenorphine max Or average C av and Fe Average C of methylparaben max Or average C av The ratio is approximately 0.02 to 0.3. In certain embodiments, the mean C of buprenorphine max or C av and Fe Average C of methylparaben max or Cav The ratio is about 0.02 to about 0.2.

[0088] In certain embodiments, (i) an amount of oxycodone and (ii) an amount of buprenorphine The method of treatment of the present invention, which comprises co-administering to a patient in need thereof a compound selected from the group consisting of benzodiazepines, ... A single dose of oxycodone and buprenorphine administered simultaneously to one subject under fasting conditions After administration, the mean C of buprenorphine is at least approximately 1:280. max and mean C of oxycodone max In certain embodiments, the average buprenorphine Average C max and mean C of oxycodone max The ratio of is at least about 1:250, or At least about 1:230, or at least about 1:200, or at least about 1: 180. In certain embodiments, the mean C max and oxycodone average C max The ratio is preferably about 1:50 to about 1:280 under fasting conditions. or about 1:50 to about 1:250, or about 1:80 to about 1:230, or about 1: 100 to about 1:200, or about 1:100 to about 1:180.

[0089] According to certain such embodiments, the oxycodone is administered in the form of oxycodone hydrochloride. In other such embodiments, the oxycodone is oxycodone myristate. According to certain such embodiments, buprenorphine is administered in the form of According to certain embodiments, the amount of buprenorphine is administered in the form of buprenorphine hydrochloride. The oxycodone is administered in an immediate release form. is administered in immediate release form and the dose of buprenorphine is administered in immediate release form.

[0090] In certain such embodiments, the treatment method comprises administering to a group of subjects, preferably under fasting conditions. of about 1.5:1 or less after single-dose coadministration of oxycodone and buprenorphine; or Buprenorphine at about 1.3:1 or less, or about 1.1:1 or less, or about 1:1 or less Average T max and mean T of oxycodone max The ratio of In certain embodiments, the method of treatment comprises administering oxycodone to a group of subjects, preferably under fasting conditions. After co-administration of a single dose of oxycodone and buprenorphine, the co-administration Average T max Faster mean T of buprenorphine compared to max to bring about In certain embodiments, the method of treatment comprises administering to a group of subjects, preferably under fasting conditions. After single-dose co-administration of oxycodone and buprenorphine, the co-administration about 0.1:1 to about 1.5:1, or about 0.1:1 to about 1.3:1, or about 0 0.1:1 to about 1.1:1, or about 0.1:1 to about 1:1, or about 0.1:1 to about Mean T of buprenorphine of 0.9:1 max and mean T of oxycodone max The ratio of According to certain such embodiments, the oxycodone is In other such embodiments, oxycodone is administered in the form of oxycodone hydrochloride. According to certain such embodiments, the buprenorphine is administered in the form of buprenorphine myristate. The renorphine is administered in the form of buprenorphine hydrochloride. The dose of buprenorphine is administered in an immediate release form. The dose of oxycodone is administered in an immediate release form, and the dose of buprenorphine is administered in an immediate release form. It is administered in a release form.

[0091] In certain embodiments, (i) an amount of oxycodone and (ii) an amount of buprenorphine and co-administration of the same to a patient in need thereof. The method of treatment is characterized in that the co-administration is oral administration. In certain embodiments, the co-administration is a dose of both the buprenorphine and the oxycodone described herein. and administering an oral dosage form comprising:

[0092] In certain embodiments, (i) an amount of oxycodone and (ii) an amount of buprenorphine and co-administration of the same to a patient in need thereof. The treatment method comprises orally administering the predetermined amount of oxycodone (i.e., the amount of buprenorphine is administered transdermally (i.e., in an oral dosage form containing the above-mentioned a transdermal dosage form (e.g., a transdermal patch) containing a fixed amount of buprenorphine. An example of a transdermal dosage form containing buprenorphine is one that delivers buprenorphine for up to 7 days of administration. It delivers norphine and is commercially available in dose strengths of 5, 10, and 20 micrograms per hour. The Butrans® patch is

[0093] The fixed dose of oxycodone is orally administered and the fixed dose of buprenorphine is transdermally administered. In certain embodiments, the oral dosage form comprising a quantity of oxycodone is a liquid dosage form, e.g. The above-mentioned fixed amount of oxycodone is orally administered. In certain embodiments where the amount of buprenorphine is administered transdermally, the amount of oxalate is Oral dosage forms containing cycodone are solid dosage forms, such as tablets or capsules. In one embodiment, the oral dosage form comprises about 5 mg to about 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 In such embodiments, the oral dosage form comprises the above-mentioned amount of oxycodone in immediate release form.

[0094] In certain embodiments, (i) an amount of oxycodone and (ii) an amount of buprenorphine and co-administration of the same to a patient in need thereof. The treatment method comprises orally administering the predetermined amount of oxycodone (i.e., the dose of buprenorphine is administered subcutaneously (i.e., in an oral dosage form containing the A subcutaneous dosage form containing a fixed amount of buprenorphine (e.g., a subcutaneous dosage form containing the fixed amount of buprenorphine described above) In certain such embodiments, the buprenorphine is a subcutaneous implant. Renorphin mean C max and mean C of oxycodone max The ratio of buprenorphine Mean steady-state plasma concentrations of oxycodone and mean C max It is defined as the ratio of

[0095] An example of a subcutaneous dosage form for use in the treatment methods of the present invention is Probuphine ( It is a subcutaneous implant marketed under the brand name Pharmacokinetics (registered trademark). According to the 2018 edition of the Probuphine® drug, The Probuphine® implant is described as a long-term treatment. It contains buprenorphine hydrochloride as the active pharmaceutical ingredient. The (Registered Trademark) implant is a sterile, single, off-white, soft, elastic rod. Each stick is 26mm long and 2.5mm in diameter and contains 80mg of buprenorphine hydrochloride (equivalent to 74.2 mg of buprenorphine base) and ethyl Contains ethylene vinyl acetate. Probuphine® is not intended for use by trained medical professionals. It is implanted subcutaneously by the patient and provides sustained delivery of buprenorphine for up to six months. The prescribing information states that it is intended for the maintenance treatment of opioid addiction. Each dose is administered subcutaneously into the inner upper arm for 6 months of treatment and administered until the end of the 6-month period. It consists of four Probuphine® implants that are removed immediately. In pharmacokinetic studies, the median time to maximum plasma concentration of buprenorphine was Initial buprenorphine was present at 12 hours after buphine® insertion. After the peak, plasma buprenorphine concentrations declined slowly and reached a plateau by approximately week 4. The mean steady-state plasma buprenorphine concentrations were The values ​​were approximately 0.5 ng / mL to 1.0 ng / mL, and the values ​​were approximately 0.5 ng / mL to 1.0 ng / mL during the 24-week treatment period. The effect was maintained for 20 weeks (weeks 4 to 24) (prescribing information 02 / 2018, or Smith et al., Probuphine (Buprenorphine )Subdermal Implants for the Treatment Of Opioid-Dependent Patients,Pharmacy and See Therapeutics 2017 Aug;42(8):505-508 To achieve a plasma buprenorphine concentration suitable for the treatment method of the present invention, for example, , the number and / or size of the implants may be adjusted.

[0096] The fixed dose of oxycodone is administered orally and the fixed dose of buprenorphine is administered subcutaneously. In certain embodiments, the oral dosage form comprising a quantity of oxycodone is a liquid dosage form, e.g. The above-mentioned fixed amount of oxycodone is orally administered. In certain embodiments where the amount of buprenorphine is administered subcutaneously, the amount of oxalate is administered subcutaneously. Oral dosage forms containing cycodone are solid dosage forms, such as tablets or capsules. In one embodiment, the oral dosage form comprises about 5 mg to about 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 In such embodiments, the oral dosage form comprises the above-mentioned amount of oxycodone in immediate release form.

[0097] Weight ratio and amount of oral dosage form In certain embodiments, the method of treatment comprises: (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; administering to a patient in need thereof an oral dosage form comprising: A weight ratio of a given amount of buprenorphine to a given amount of oxycodone is equivalent to an equimolar amount of buprenorphine. Constant in the dosage form expressed as rufin base (mg) (Mw = 467.64 g / mol) 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 In certain embodiments, the ratio of buprenorphine to oxalate is greater than 1:40. The weight ratio of cycodone is about 1:3 to more than 1:40, or about 1:38 or more, or About 1:3 to about 1:38, or about 1:4 to over 1:40, or about 1:4 to about 1:38 , or about 1:5 to over 1:40, or about 1:5 to about 1:38, or about 1:5 or About 1:35, or about 1:5 to about 1:30, or about 1:6 to over 1:40, or Approximately 1:6 to approximately 1:38, or approximately 1:6 to approximately 1:35, or approximately 1:6 to approximately 1:30 , or about 1:6 to about 1:28, or about 1:6 to about 1:20, or about 1:8 to About 1:30, or about 1:8 to about 1:28, or about 1:8 to about 1:20, or Approximately 1:8 to approximately 1:15, or approximately 1:10 to approximately 1:20, or approximately 1:10 to approximately 1: 15. According to certain such embodiments, the oxycodone is oxycodone hydrochloride. In other such embodiments, oxycodone is present in the form of oxycodone mils. According to certain such embodiments, buprenorphine is present in the form of a buprenorphine salt. In certain embodiments, the dosage form is an immediate release form of prenorphine hydrochloride. According to certain embodiments, the dosage form comprises an immediate release dosage form of buprenorphine. and an immediate release form of said amount of buprenorphine.

[0098] In certain such embodiments, the treatment method comprises administering from about 5 mg to about 50 mg of an oxycodone salt. Equimolar amount of the acid salt (Mw=351.82g / mol) or about 5mg to about 40mg g of oxycodone hydrochloride (Mw=351.82 g / mol) or about 10 mg, about 15 mg, about 20 mg, about 30 mg, or about 40 mg of oxycodone salt A fixed amount of oxycodone was added to the dosage form in an equimolar amount to the oxycodone salt (Mw=351.82g / mol). According to certain such embodiments, the oxycodone is In other such embodiments, oxycodone is present in the form of oxycodone hydrochloride. According to certain such embodiments, buprenolol is present in the form of a buprenolol myristate salt. Buprenorphine is present in the form of buprenorphine hydrochloride. According to certain embodiments, the dosage form is In certain embodiments, the dosage form comprises the above-mentioned amount of buprenorphine in immediate release form. an immediate release dose of oxycodone and an immediate release dose of buprenorphine Includes

[0099] In certain such embodiments, the method of treatment comprises administering to a subject a dose of about 40 mg of oxycodone hydrochloride. A constant amount of oxycodone equimolar 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) 40 mg of buprenorphine or the dosage form contains approximately 40 mg of oxycodone. A fixed amount of oxycodone was added equimolarly to oxycodone hydrochloride (Mw=351.82g / mol), and and for approximately 2 mg to approximately 5 mg of buprenorphine base (Mw=467.64 g / mol), The invention is characterized by containing a fixed amount of buprenorphine equimolar to the amount of buprenorphine. According to an embodiment, the oxycodone is present in the form of oxycodone hydrochloride. In such embodiments, the oxycodone is present in the form of oxycodone myristate. According to such embodiments, the buprenorphine is present in the form of buprenorphine hydrochloride. According to certain embodiments, the dosage form contains the above-mentioned amount of buprenorphine in immediate release form. According to certain embodiments, the dosage form comprises the above-mentioned amount of oxycodone in immediate release form and It contains the above-mentioned amount of buprenorphine in immediate release form.

[0100] In certain embodiments, the method of treatment comprises: (i) a fixed dose of immediate-release oxycodone; (ii) a fixed dose of immediate-release buprenorphine; administering to a patient in need thereof an oral immediate release (IR) dosage form comprising: A weight ratio of a given amount of buprenorphine to a given amount of oxycodone is equivalent to an equimolar amount of buprenorphine. Constant in the dosage form expressed as rufin base (mg) (Mw = 467.64 g / mol) 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 In certain embodiments, the ratio of buprenorphine to buprenorphine is about 1:100 or greater. The weight ratio of oxycodone to acetaminophen is about 1:80 or more, or about 1:60 or more, or About 1:50 or more, or about 1:40 or more, or about 1:6 to about 1:100, or Approximately 1:6 to 1:80, or approximately 1:6 to 1:60, or approximately 1:6 to 1:50 , or about 1:6 to about 1:40, or about 1:8 to about 1:100, or about 1:8 up to about 1:80, or about 1:8 to about 1:60, or about 1:8 to about 1:50, or , 1:8 to about 1:40, or about 1:10 to about 1:100, or about 1:10 to about 1 :80, or about 1:10 to about 1:60, or about 1:10 to about 1:50, or Approximately 1:10 to approximately 1:40, or approximately 1:20 to approximately 1:100, or approximately 1:20 to approximately 1:80, or about 1:20 to about 1:60, or about 1:20 to about 1:50, or , about 1:20 to about 1:40, or about 1:20 to about 1:30. According to an embodiment, the oxycodone is present in the form of oxycodone hydrochloride. In such embodiments, the oxycodone is present in the form of oxycodone myristate. According to certain such embodiments, the buprenorphine is in the form of buprenorphine hydrochloride. exist.

[0101] In certain such embodiments, the treatment method comprises administering from about 5 mg to about 50 mg of an oxycodone salt. Equimolar amount of the acid salt (Mw=351.82g / mol) or about 5mg to about 40mg g of oxycodone hydrochloride (Mw=351.82 g / mol) or about 10 mg, about 15 mg, about 20 mg, about 30 mg, or about 40 mg of oxycodone salt A fixed amount of oxycodone was added to the dosage form in an equimolar amount to the oxycodone salt (Mw=351.82g / mol). According to certain such embodiments, the oxycodone is In other such embodiments, oxycodone is present in the form of oxycodone hydrochloride. According to certain such embodiments, buprenolol is present in the form of a buprenolol myristate salt. Buprenorphine exists in the form of buprenorphine hydrochloride.

[0102] In certain such embodiments, the method of treatment comprises administering to a subject a dose of about 40 mg of oxycodone hydrochloride. A constant amount of oxycodone equimolar 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) 40 mg of buprenorphine or the dosage form contains approximately 40 mg of oxycodone. A fixed amount of oxycodone was added equimolarly to oxycodone hydrochloride (Mw=351.82g / mol), and and for approximately 1 mg to approximately 4 mg of buprenorphine base (Mw=467.64 g / mol), The invention is characterized by containing a fixed amount of buprenorphine equimolar to the amount of buprenorphine. According to an embodiment, the oxycodone is present in the form of oxycodone hydrochloride. In such embodiments, the oxycodone is present in the form of oxycodone myristate. According to such embodiments, the buprenorphine is present in the form of buprenorphine hydrochloride. There is.

[0103] Dosage forms containing oxycodone and buprenorphine According to certain embodiments, the dosage form provides at least Buprenorphine average C of approximately 1:280 max and mean C of oxycodone max The ratio of In certain embodiments, the mean C of buprenorphine is obtained. max and O Average C of xycodone max The ratio of is at least about 1:250, or at least about 1 :230, or at least about 1:200, or at least about 1:180. In certain embodiments, the mean C of buprenorphine max and mean C of oxycodone max of The ratio is about 1:50 to about 1:280, or about 1:50 to about 1:250, or about 1 :80 to approx. 1:230, or approx. 1:100 to approx. 1:200, or approx. 1:100 According to certain such embodiments, the oxycodone is about 1:180. In other such embodiments, oxycodone is present in the form of the hydrochloride salt. According to certain such embodiments, buprenorphine is present in the form of buprenorphine myristate. In certain embodiments, the dosage form is According to certain embodiments, the dosage form comprises a time-release dose of buprenorphine. the amount of oxycodone in a time-release form and the amount of buprenorphine in an immediate-release form include.

[0104] According to certain embodiments, the dosage form contains an equimolar amount of buprenorphine base (mg) (Mw= 467.64 g / mol) and a certain amount of buprenorphine in the dosage form, Equimolar amounts of oxycodone hydrochloride (mg) (Mw = 351.82 g / mol) A certain amount of oxycodone in a dosage form that is greater than 1:40 when calculated using In certain embodiments, the buprenorphine and oxycodone are combined in a weight ratio of 0.01 to 0.01. The weight ratio of the fixed amount of buprenorphine to the fixed amount of oxycodone is about 1:3 to 1:1. :40 or more, or about 1:38 or more, or about 1:3 to about 1:38, or about 1:4 to more than 1:40, or from about 1:4 to about 1:38, or from about 1:5 to more than 1:40, or , about 1:5 to about 1:38, or about 1:5 to about 1:35, or about 1:5 to about 1:3 0, or about 1:6 to over 1:40, or about 1:6 to about 1:38, or about 1:6 to about 1:35, or about 1:6 to about 1:30, or about 1:6 to about 1:28, or , about 1:6 to about 1:20, or about 1:8 to about 1:30, or about 1:8 to about 1:2 8, or about 1:8 to about 1:20, or about 1:8 to about 1:15, or about 1:1 In certain such embodiments, the ratio is from about 0 to about 1:20, or from about 1:10 to about 1:15. According to the present invention, oxycodone is present in the form of oxycodone hydrochloride. In this formulation, oxycodone is present in the form of oxycodone myristate. According to such embodiments, the buprenorphine is present in the form of buprenorphine hydrochloride. According to certain embodiments, the dosage form comprises the above-mentioned amount of buprenorphine in immediate release form. According to certain embodiments, the dosage form comprises the above-mentioned amount of oxycodone in immediate release form and immediate release The dosage form contains the above-mentioned amount of buprenorphine.

[0105] According to certain such embodiments, the dosage form comprises about 40 mg of oxycodone hydrochloride. A constant amount of oxycodone equimolar 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) 40 mg of buprenorphine or the dosage form contains approximately 40 mg of oxycodone. A fixed amount of oxycodone was added equimolarly to oxycodone hydrochloride (Mw=351.82g / mol), and and for approximately 2 mg to approximately 5 mg of buprenorphine base (Mw=467.64 g / mol), The invention is characterized by containing a fixed amount of buprenorphine equimolar to the amount of buprenorphine. According to an embodiment, the oxycodone is present in the form of oxycodone hydrochloride. In such embodiments, the oxycodone is present in the form of oxycodone myristate. According to such embodiments, the buprenorphine is present in the form of buprenorphine hydrochloride. According to certain embodiments, the dosage form contains the above-mentioned amount of buprenorphine in immediate release form. According to certain embodiments, the dosage form comprises the above-mentioned amount of oxycodone in immediate release form and It contains the above-mentioned amount of buprenorphine in immediate release form.

[0106] According to certain embodiments, the dosage form comprises a fixed amount of buprenorphine and a fixed amount of oxycodone. is equivalent to the weight ratio of buprenorphine base (mg) (Mw=467.64g / mol l) A certain amount of buprenorphine and an equimolar amount of oxycodone in a dosage form represented by A certain amount of benzophenone hydrochloride in a dosage form expressed as (mg) (Mw = 351.82 g / mol) Oxycodone, in an immediate release (IR) dosage form that is greater than or equal to about 1:100 when calculated using In certain such embodiments, the amount of buprenorphine and The weight ratio of the oxycodone in the metered dose is about 1:80 or more, or about 1:60 or more, or is about 1:50 or more, or about 1:40 or more, or about 1:6 to about 1:100, or is about 1:6 to about 1:80, or about 1:6 to about 1:60, or about 1:6 to about 1: 50, or about 1:6 to about 1:40, or about 1:8 to about 1:100, or about 1 :8 to about 1:80, or about 1:8 to about 1:60, or about 1:8 to about 1:50, or Or 1:8 to about 1:40, or about 1:10 to about 1:100, or about 1:10 to Approximately 1:80, or approximately 1:10 to approximately 1:60, or approximately 1:10 to approximately 1:50, or is about 1:10 to about 1:40, or about 1:20 to about 1:100, or about 1:20 ~ about 1:80, or about 1:20 ~ about 1:60, or about 1:20 ~ about 1:50, or Alternatively, it is about 1:20 to about 1:40, or about 1:20 to about 1:30.

[0107] According to certain such embodiments, the oral immediate release dosage form contains from about 5 mg to about 50 mg of oral Equimolar or approximately 5mM of oxycodone hydrochloride (Mw=351.82g / mol) g to approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / mol) or about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 40 mg of A fixed amount of oxycodone was added equimolarly to xycodone hydrochloride (Mw=351.82g / mol). According to certain such embodiments, the oral immediate release dosage form comprises a codon. In other such embodiments, the oxycodone is present in the form of oxycodone hydrochloride. In certain such cases, oxycodone is present in the form of oxycodone myristate. According to an embodiment, the buprenorphine is present in the form of buprenorphine hydrochloride.

[0108] In certain such embodiments, the oral immediate release dosage form comprises a dosage form containing about 40 mg of oxycodone. a fixed amount of oxycodone equimolar to oxycodone hydrochloride (Mw=351.82g / mol); and about 1 mg to about 5 mg of buprenorphine base (Mw=467.64 g / mol). or the dosage form contains a fixed amount of buprenorphine equimolar to about 40 mg of buprenorphine. A fixed amount of oxycodone was added equimolar to oxycodone hydrochloride (Mw = 351.82 g / mol). and about 1 mg to about 4 mg of buprenorphine base (Mw=467.64 g / mol l) and contains a fixed amount of buprenorphine equimolar to the According to such embodiments, the oxycodone is present in the form of oxycodone hydrochloride. In such embodiments, the oxycodone is present in the form of oxycodone myristate. According to certain such embodiments, the buprenorphine is buprenorphine hydrochloride. It exists in the form

[0109] In the above embodiment, the dosage form is a liquid in the form of a solution, suspension, emulsion, e.g. For example, it may be in the form of a syrup.

[0110] In the above embodiment, the dosage form is in the form of a solid dosage form, for example, a tablet, multiparticulate or capsule. It may also be a capsule.

[0111] Pharmacodynamic response According to certain embodiments, the method and / or dosage form, particularly the amount of buprenorphine in the dosage form, Co-administration of norphine is not recommended as it will increase the dose of oxycodone and phenytoin in the dosage form when administered alone. Oxycodone, fentanyl, or hydromorphone This results in prevention or reduction of the adverse pharmacodynamic reactions of hydromorphone.

[0112] Adverse pharmacodynamic reactions include euphoria, elation, bowel dysfunction, nausea, vomiting, somnolence, dizziness, and respiratory depression. Sedation, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium, miosis, pruritus urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance. In certain embodiments, the adverse pharmacodynamic reactions include respiratory depression, euphoria, elation, and bowel dysfunction. In other embodiments, the adverse pharmacodynamic response is selected from the group consisting of euphoria and / or In other embodiments, the adverse pharmacodynamic response is euphoria. In one embodiment, the adverse pharmacodynamic reaction is bowel dysfunction. The response is respiratory depression.

[0113] In other embodiments, the pharmacodynamic response is toxic (or fatal).

[0114] According to certain embodiments, the method and / or dosage form has at least At least 15%, or at least 20%, or at least 25%, or less At least 30%, or at least 35%, or at least 40% decrease in "elevation" Average of "Feeling VAS" max See Figure 8.

[0115] According to certain embodiments, the method and / or dosage form, particularly the amount of buprenorphine in the dosage form, Co-administration of norphine will not affect the above-mentioned fixed amount of oxycodone in the dosage form when administered alone. This results in the prevention or suppression of the drug preference for oxycodone that is observed in

[0116] According to certain embodiments, the method and / or dosage form has at least At least 15%, or at least 20%, or at least 25%, or less A decrease of at least 30% in the mean E of the "Temporary Drug Preference VAS" max Figure 6 Please refer to.

[0117] According to certain embodiments, the method and / or dosage form has at least At least 15%, or at least 20%, or at least 25%, or less A mean reduction in the "Overall Drug Preference VAS" of at least 30% or at least 35% E max See Figure 9.

[0118] According to certain embodiments, the method and / or dosage form has at least At least 15%, or at least 20%, or at least 25%, or less A mean E of at least 30% or at least 35% reduction in the Medication Reuse VAS ma x See FIG. 10.

[0119] According to certain such embodiments, the analgesic effect is substantially According to certain such embodiments, the levels are not significantly reduced at 1, 2, 3, and 4 hours after administration. The average "cold pain score VAS" measured using the cold pressor test was The measurement of the serotonin concentration does not increase by more than 10% compared to the comparative treatment. See Figures 11 to 15. .

[0120] According to certain embodiments, the methods and / or dosage forms may be used to prevent the formation of addiction, the development of drug abuse, or Prevent or reduce the incidence of adult or recreational drug use.

[0121] According to certain other embodiments, the methods and / or dosage forms of the present invention comprise a single opioid. Reduces opioid-induced respiratory depression compared with the use of anti-opioid drugs.

[0122] In other embodiments, the methods and / or dosage forms of the present invention have a much improved safety profile. and provide a profile that may, for example, prevent or significantly reduce opioid-induced lethality due to overdose. Suppress to.

[0123] According to certain embodiments, a medicament containing both oxycodone and buprenorphine and containing equal amounts of oxycodone and buprenorphine is provided. Alternatively, an oral dosage form according to the present invention containing oxycodone may be administered to provide a constant amount of oxycodone. Prevents or prevents the adverse pharmacodynamic effects of oxycodone when used alone to treat pain. The present invention provides a method for suppressing pain using the above-mentioned amount of oxycodone alone. This includes suppressing the drug preference of oxycodone, which is used to treat

[0124] According to certain embodiments, by providing a dosage form according to the invention for treating pain and provide a method for reducing the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. do.

[0125] Buprenorphine mono-oral dosage form Buprenorphine is ineffective when administered orally due to extensive first-pass metabolism. However, in Example 2, 5 mg of buprenolol is currently A constant amount of IR-type buprenorphine base (Mw=467.64g / mol) was used in an equimolar amount. Dosage forms containing lenorphin HCl are administered with Butrans (registered trademark) for a period of at least 12 hours. (Registered Trademark) has been shown to produce pain-relieving blood levels above 20 mcg / hour. See Figure 3.

[0126] Therefore, according to certain embodiments, the present invention provides a method for treating rheumatoid arthritis with a certain amount of rheumatoid arthritis as the only opioid analgesic. and (iii) providing an oral dosage form containing buprenorphine, preferably buprenorphine HCl, in an amount sufficient to provide a therapeutically effective dose of buprenorphine. The present invention relates to a method for treating pain comprising administering the same to a patient suffering from pain.

[0127] According to certain embodiments, the present invention provides a method for administering a dose of buprenorphine as the only opioid analgesic. The present invention relates to oral dosage forms containing norphine, preferably buprenorphine HCl.

[0128] According to certain embodiments, the buprenorphine is 1 to 40 mg of buprenorphine base. (Mw=467.64g / mol) in an equimolar amount, or 2.5, 5, 1 0, 15, 20, 30, and 40 mg of buprenorphine base (Mw = 467.64 g / m ol) in the dosage form. Daily doses range from 1 to 40 mg of buprenorphine base (Mw=467.64 g / mol). In certain embodiments, the dosage form contains IR buprenorphine. In certain embodiments, the buprenorphine is in the form of buprenorphine HCl.

[0129] According to certain embodiments, the dosage form may be liquid or solid, e.g., a solution, suspension, emulsion, or the like. These may be in the form of a syrup, tablet, or capsule.

[0130] Further embodiments In view of the above, certain embodiments of the present invention relate to the following: Clause 1: (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; 1. An oral dosage form comprising: The weight ratio of the amount of buprenorphine to the amount of oxycodone is equimolar. In the above dosage form, expressed as buprenorphine base (mg) (Mw = 467.64 g / mol) the amount of buprenorphine and an equimolar amount of oxycodone hydrochloride (mg) (Mw=351.82 g / mol) Don, when calculated using the ratio, it is more than 1:40, The oral dosage form.

[0131] Clause 2. The weight ratio of said amount of buprenorphine to said amount of oxycodone is , about 1:38 or greater.

[0132] Clause 3. The weight ratio of the amount of buprenorphine to the amount of oxycodone is , about 1:3 to greater than 1:40, or about 1:3 to about 1:38. shape.

[0133] Clause 4. The weight ratio of said amount of buprenorphine to said amount of oxycodone is , about 1:4 to greater than 1:40, or about 1:4 to about 1:38. shape.

[0134] Clause 5. The weight ratio of said amount of buprenorphine to said amount of oxycodone is , about 1:5 to more than 1:40, or about 1:5 to about 1:38. shape.

[0135] Clause 6. The weight ratio of said amount of buprenorphine to said amount of oxycodone is , about 1:5 to about 1:35, preferably about 1:5 to about 1:30. Oral dosage form.

[0136] Clause 7. The weight ratio of said amount of buprenorphine to said amount of oxycodone is , about 1:6 to more than 1:40, or about 1:6 to about 1:38. shape.

[0137] Clause 8: The weight ratio of the amount of buprenorphine to the amount of oxycodone is , about 1:6 to about 1:35, preferably about 1:6 to about 1:30, more preferably about 1: 10. The oral dosage form of clause 1, wherein the ratio of hydroxybenzoates to hydroxybenzoates is from about 1:6 to about 1:28, or from about 1:6 to about 1:20.

[0138] Clause 9: The weight ratio of the amount of buprenorphine to the amount of oxycodone is , about 1:8 to about 1:30.

[0139] Clause 10: the weight ratio of said amount of buprenorphine to said amount of oxycodone. is about 1:8 to about 1:28.

[0140] Clause 11: the weight ratio of said amount of buprenorphine to said amount of oxycodone. 2. The oral dosage form of clause 1, wherein the ratio of hydroxybenzoates to hydroxybenzoates is about 1:8 to about 1:20.

[0141] Clause 12: the weight ratio of said amount of buprenorphine to said amount of oxycodone. 2. The oral dosage form of clause 1, wherein the ratio of hydroxybenzoates to hydroxybenzoates is about 1:8 to about 1:15.

[0142] Clause 13: the weight ratio of said amount of buprenorphine to said amount of oxycodone. 2. The oral dosage form of clause 1, wherein the ratio of hydroxybenzoates to hydroxybenzoates is about 1:10 to about 1:20.

[0143] Clause 14: the weight ratio of said amount of buprenorphine to said amount of oxycodone. 2. The oral dosage form of clause 1, wherein the ratio of hydroxybenzoates to hydroxybenzoates is about 1:10 to about 1:15.

[0144] Clause 15: The dosage form comprises about 5 mg to about 50 mg of oxycodone hydrochloride (Mw=351. 82 g / mol), preferably about 5 mg to about 40 mg of oxycodone hydrochloride (Mw=3 51.82 g / mol) and a fixed amount of oxycodone equivalent to the amount of oxycodone in Articles 1 to 51.82 g / mol. 15. The oral dosage form according to any one of claims 14.

[0145] Clause 16: The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) was treated with an equimolar 15. An oral dosage form according to any one of clauses 1 to 14, comprising a fixed amount of oxycodone.

[0146] Clause 17: The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) was treated with an equimolar 17. An oral dosage form according to clause 16, comprising a fixed amount of oxycodone hydrochloride.

[0147] Clause 18: The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) was treated with an equimolar 17. An oral dosage form according to clause 16, comprising a fixed amount of oxycodone myristate.

[0148] Clause 19: The dosage form comprises about 40 mg of oxycodone hydrochloride (Mw=351.82 g / m ol) and about 1 mg to about 6 mg of buprenorphine. A fixed amount of buprenorphine was used, equimolar to the buprenorphine base (Mw = 467.64 g / mol). 15. An oral dosage form according to any one of clauses 1 to 14, comprising

[0149] Clause 20: The dosage form comprises about 40 mg of oxycodone hydrochloride (Mw=351.82 g / m ol) and about 2 mg to about 5 mg of buprenorphine. A fixed amount of buprenorphine was used, equimolar to the buprenorphine base (Mw = 467.64 g / mol). 15. An oral dosage form according to any one of clauses 1 to 14, comprising

[0150] Clause 21: The oxycodone is oxycodone hydrochloride and the buprenorphine is buprenorphine. Any one of clauses 1 to 16, 19 and 20, which is prenorphine hydrochloride Item 1. An oral dosage form according to item 1.

[0151] Clause 22: The dosage form according to any one of clauses 1 to 10, wherein the dosage form comprises the amount of buprenorphine in immediate release form. 21. An oral dosage form according to any one of clauses 1 to 21.

[0152] Clause 23: The dosage form comprises the amount of oxycodone in immediate release form and 23. The oral administration method according to any one of clauses 1 to 22, comprising the amount of buprenorphine. Dosage form.

[0153] Clause 24: The method according to any one of clauses 1 to 23, wherein the dosage form is a liquid dosage form. Oral dosage form.

[0154] Clause 25: The dosage form is a solution, a suspension or an emulsion, preferably a solution. , an oral dosage form according to clause 24.

[0155] Clause 26: The method according to any one of clauses 1 to 23, wherein the dosage form is a solid dosage form. Oral dosage form.

[0156] Clause 27: The oral dosage form of clause 26, wherein said dosage form is a tablet or a capsule.

[0157] Clause 28: After single dose administration, the dosage form provides at least about 1:280 of Buprenorphine mean C max and mean C of oxycodone max The provision brings about a ratio of 28. An oral dosage form according to any one of clauses 1 to 27.

[0158] Article 29: Buprenorphine mean C max and mean C of oxycodone max The ratio of 29. The oral dosage form of clause 28, wherein the ratio of β-glucan to β-glucan is at least about 1:250.

[0159] Article 30: Buprenorphine mean C max and mean C of oxycodone max The ratio of 29. The oral dosage form of clause 28, wherein the ratio of β-glucan to ... is at least about 1:230.

[0160] Article 31: Buprenorphine mean C max and mean C of oxycodone max The ratio of 29. The oral dosage form of clause 28, wherein the ratio of α, β ...

[0161] Article 32: Buprenorphine mean C max and mean C of oxycodone max The ratio of 29. The oral dosage form of clause 28, wherein the ratio of α, β ...

[0162] Article 33: Buprenorphine mean C max and mean C of oxycodone max The ratio of 29. The oral dosage form of clause 28, wherein the ratio of hydroxybenzoates to hydroxybenzoates is from about 1:50 to about 1:280.

[0163] Article 34: Buprenorphine mean C max and mean C of oxycodone max The ratio of 29. The oral dosage form of clause 28, wherein the ratio of hydroxybenzoates to hydroxybenzoates is about 1:50 to about 1:250.

[0164] Article 35: Buprenorphine mean C max and mean C of oxycodone max The ratio of 29. The oral dosage form of clause 28, wherein the ratio of hydroxybenzoates to hydroxybenzoates is about 1:80 to about 1:230.

[0165] Article 36: Buprenorphine mean C max and mean C of oxycodone max The ratio of 29. The oral dosage form of clause 28, wherein the ratio of the total amount of hydroxybenzoates to the total amount of hydroxybenzoates is about 1:100 to about 1:200.

[0166] Article 37: Buprenorphine mean C max and mean C of oxycodone max The ratio of 29. The oral dosage form of clause 28, wherein the ratio of the total amount of hydroxybenzoates to the total amount of hydroxybenzoates is about 1:100 to about 1:180.

[0167] Clause 38: After single dose administration, said dosage form provides said subject population with a buprenoline to buprenoline ratio of about 1.5:1 or less. Rufin's average T max and mean T of oxycodone max Article 28 further provides for the ratio of 37. An oral dosage form according to any one of clauses 1 to 37.

[0168] Article 39: Mean T of Buprenorphine max and mean T of oxycodone max The ratio of 39. The oral dosage form of clause 38, wherein the ratio is about 1.3:1 or less.

[0169] Article 40: Mean T of Buprenorphine max and mean T of oxycodone max The ratio of 39. The oral dosage form of clause 38, wherein the ratio is about 1.1:1 or less.

[0170] Article 41: Mean T of Buprenorphine max and mean T of oxycodone max The ratio of 39. The oral dosage form of clause 38, wherein the ratio is about 1:1 or less.

[0171] Clause 42: After single dose administration, said dosage form provides said subject group with a mean T of oxycodone. max Faster mean T of buprenorphine compared to max Further, Articles 28 to 29 37. The oral dosage form of any one of claims 37.

[0172] Clause 43: After single dose administration, the dosage form provides the subject group with 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 from about 0.1:1 to about 1:1, or from about 0.1:1 to about 0.9:1 The mean T of buprenorphine max and mean T of oxycodone max further bringing the ratio of , an oral dosage form according to any one of clauses 28 to 42.

[0173] Article 44: (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; administering to a patient in need thereof an oral dosage form comprising The weight ratio of the amount of buprenorphine to the amount of oxycodone is equimolar. In the above dosage form, expressed as buprenorphine base (mg) (Mw = 467.64 g / mol) the amount of buprenorphine and an equimolar amount of oxycodone hydrochloride (mg) (Mw=351.82 g / mol) Don, when calculated using the ratio, it is more than 1:40, A method for treating pain.

[0174] Clause 45. The weight ratio of said amount of buprenorphine to said amount of oxycodone. is greater than or equal to about 1:38.

[0175] Clause 46. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio of the hydroxybenzoates to the hydroxybenzoates is about 1:3 to more than 1:40, or about 1:3 to about 1:38. Law.

[0176] Clause 47. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio of the hydroxybenzoates to the total hydroxybenzoates is about 1:4 to more than 1:40, or about 1:4 to about 1:38. Law.

[0177] Clause 48. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio of the hydroxybenzoates to the total hydroxybenzoates is about 1:5 to more than 1:40, or about 1:5 to about 1:38. Law.

[0178] Clause 49. The weight ratio of said amount of buprenorphine to said amount of oxycodone. is about 1:5 to about 1:35, preferably about 1:5 to about 1:30, as described in Clause 44. How to do it.

[0179] Clause 50. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio of the hydroxybenzoates to the total hydroxybenzoates is about 1:6 to more than 1:40, or about 1:6 to about 1:38. Law.

[0180] Clause 51. The weight ratio of said amount of buprenorphine to said amount of oxycodone. is about 1:6 to about 1:35, preferably about 1:6 to about 1:30, more preferably about 1: 45. The method of claim 44, wherein the ratio of the hydroxybenzoate to the hydroxybenzoate is from about 1:6 to about 1:28, or from about 1:6 to about 1:20.

[0181] Clause 52. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 45. The method according to clause 44, wherein the ratio of the hydroxyl group to the hydroxyl group is from about 1:8 to about 1:30.

[0182] Clause 53. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 45. The method of clause 44, wherein the ratio of the saturation of the saturation agent to the total saturation agent is about 1:8 to about 1:28.

[0183] Clause 54. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 45. The method according to clause 44, wherein the ratio of the hydroxyl group to the hydroxyl group is from about 1:8 to about 1:20.

[0184] Clause 55. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 45. The method of clause 44, wherein the ratio of the hydroxyl group to the hydroxyl group is about 1:8 to about 1:15.

[0185] Clause 56. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 45. The method according to clause 44, wherein the ratio of the hydroxyl group to the total hydroxyl group is about 1:10 to about 1:20.

[0186] Clause 57. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 45. The method of clause 44, wherein the ratio of the hydroxyl group to the hydroxyl group is about 1:10 to about 1:15.

[0187] Clause 58. The dosage form comprises about 5 mg to about 50 mg of oxycodone hydrochloride (Mw=351. 82 g / mol), preferably about 5 mg to about 40 mg of oxycodone hydrochloride (Mw=3 Articles 44 to 51.82 g / mol) containing a fixed amount of oxycodone equivalent to the Item 58. The method of any one of items 57.

[0188] Clause 59. The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) was treated with an equimolar 58. The method of any one of clauses 44 to 57, comprising a fixed amount of oxycodone.

[0189] Clause 60. The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) was treated with an equimolar 60. The method of clause 59, comprising administering a fixed amount of oxycodone hydrochloride.

[0190] Clause 61. The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or Approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) was treated with an equimolar 60. The method of clause 59, comprising administering a fixed amount of oxycodone myristate.

[0191] Clause 62. The dosage form comprises approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / m ol) and about 1 mg to about 6 mg of buprenorphine. A fixed amount of buprenorphine was used, equimolar to the buprenorphine base (Mw = 467.64 g / mol). 57. The method of any one of clauses 44 to 57, including

[0192] Clause 63. The dosage form comprises approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / m ol) and about 2 mg to about 5 mg of buprenorphine. A fixed amount of buprenorphine was used, equimolar to the buprenorphine base (Mw = 467.64 g / mol). 57. The method of any one of clauses 44 to 57, including

[0193] Article 64. The oxycodone is oxycodone hydrochloride and the buprenorphine is buprenorphine. Any of Articles 44 to 59, 62 and 63, which is prenorphine hydrochloride 1. The method according to claim 1.

[0194] Clause 65. The dosage form comprises the amount of buprenorphine in immediate release form. 64. A method according to any one of clauses 1 to 64.

[0195] Article 66. The dosage form comprises the amount of oxycodone in immediate release form and A method according to any one of clauses 44 to 65, comprising said amount of buprenorphine. Law.

[0196] Clause 67. The method according to any one of clauses 44 to 66, wherein the dosage form is a liquid dosage form. method.

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

[0198] Clause 69. The method according to any one of clauses 44 to 66, wherein the dosage form is a solid dosage form. method.

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

[0200] Clause 71. After administration of a single dose, the dosage form provides a subject population of at least about 1:280 Buprenorphine mean C max and mean C of oxycodone max The provision brings about a ratio of 44 to 70.

[0201] Article 72. Buprenorphine Average C max and mean C of oxycodone max The ratio of 72. The method of clause 71, wherein the ratio of the β-amino acid to the β-amino acid is at least about 1:250.

[0202] Article 73. Buprenorphine Average C max and mean C of oxycodone max The ratio of 72. The method of clause 71, wherein the ratio of the β-amino acid to the β-amino acid is at least about 1:230.

[0203] Article 74. Buprenorphine Average C max and mean C of oxycodone max The ratio of 72. The method of clause 71, wherein the ratio of the β-amino acid to the β-amino acid is at least about 1:200.

[0204] Article 75. Buprenorphine Average C max and mean C of oxycodone max The ratio of 72. The method of clause 71, wherein the ratio of the β-amino acid to the β-amino acid is at least about 1:180.

[0205] Article 76. Buprenorphine Average C max and mean C of oxycodone max The ratio of 72. The method of claim 71, wherein the ratio of the hydroxyl group to the total hydroxyl group is from about 1:50 to about 1:280.

[0206] Article 77. Buprenorphine Average C max and mean C of oxycodone max The ratio of 72. The method of clause 71, wherein the ratio of the hydroxyl group to the total hydroxyl group is from about 1:50 to about 1:250.

[0207] Article 78. Buprenorphine Average C max and mean C of oxycodone max The ratio of 72. The method of claim 71, wherein the ratio of the hydroxyl group to the total hydroxyl group is about 1:80 to about 1:230.

[0208] Article 79. Buprenorphine Average C max and mean C of oxycodone max The ratio of 72. The method of claim 71, wherein the ratio of the hydroxybenzoate to the hydroxybenzoate is about 1:100 to about 1:200.

[0209] Article 80. Buprenorphine Average C max and mean C of oxycodone max The ratio of 72. The method of claim 71, wherein the concentration of HCl is about 1:100 to about 1:180.

[0210] Clause 81. After single dose administration, the dosage form provides a buprenoline to the subject group with a ratio of about 1.5:1 or less. Rufin's average T max and mean T of oxycodone max Article 71 further provides for the ratio of 80. A method according to any one of clauses 1 to 80.

[0211] Article 82. Buprenorphine mean T max and mean T of oxycodone max The ratio of 82. The method of claim 81, wherein the ratio of the ratio of the

[0212] Article 83. Buprenorphine mean T max and mean T of oxycodone max The ratio of 82. The method of claim 81, wherein the ratio is about 1.1:1 or less.

[0213] Article 84. Buprenorphine mean T max and mean T of oxycodone max The ratio of 82. The method of claim 81, wherein the ratio is about 1:1 or less.

[0214] Clause 85. After administration of a single dose, the dosage form provides the subject group with a mean T of oxycodone. max Faster mean T of buprenorphine compared to max Further, Articles 71 to 78 80. The method of any one of claims 80 to 80.

[0215] Clause 86. After single dose administration, the dosage form provides a dose of about 0.1:1 to about 1.5:1 to the subject group. , preferably about 0.1:1 to about 1.3:1, more preferably about 0.1:1 to about 1.1 :1, most preferably from about 0.1:1 to about 1:1, or from about 0.1:1 to about 0.9:1 The mean T of buprenorphine max and mean T of oxycodone max further bringing the ratio of , a method according to any one of clauses 71 to 85.

[0216] Article 87. The method results in prevention or suppression of adverse pharmacodynamic reactions of oxycodone. 8. A method according to any one of clauses 44 to 86.

[0217] Article 88. The co-administration of the amount of buprenorphine in the dosage form is not limited to administration alone. In this case, adverse pharmacodynamic reactions observed at said fixed amount of oxycodone in said dosage form are predicted. 86. A method according to any one of clauses 44 to 86 for preventing or inhibiting

[0218] Article 89. The adverse pharmacodynamic reactions include euphoria, elation, bowel dysfunction, nausea, vomiting, somnolence, Dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium , miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance Preferably, the adverse pharmacodynamic reaction is selected from the group consisting of respiratory depression, euphoria, elation, and 89. The method of clause 87 or clause 88, wherein the condition is selected from the group consisting of functional bowel disorders.

[0219] Clause 90. The method of clause 87 or clause 88, wherein the adverse pharmacodynamic reaction is euphoria. .

[0220] Clause 91. The method of clause 87 or clause 88, wherein the adverse pharmacodynamic reaction is euphoria. .

[0221] Article 92. Mean E of "Emotion VAS" max is less when measured using comparative tests. The method of clause 91, wherein both the

[0222] Article 93. Mean E of "Emotion VAS" max should be at least 20%, preferably less at least 25%, more preferably at least 30%, and most preferably at least 35%, is further reduced by 40%.

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

[0224] Clause 95. The co-administration of the amount of buprenorphine in the dosage form is not limited to administration alone. and comparing the drug palatability observed with the fixed amount of oxycodone in the dosage form when Articles 44 to 93 of the Act, which prevent or reduce drug addiction to oxycodone 1. The method according to claim 1.

[0225] Article 96. Mean E of "Temporary Drug Preference VAS" max is measured using comparative tests 96. The method of claim 94 or 95, wherein the concentration of hydroxybenzoates in the blood is reduced by at least 15% upon administration.

[0226] Article 97. Mean E of "Temporary Drug Preference VAS" max At least 20%, preferably or at least 25%, more preferably at least 30%, Law.

[0227] Article 98. Mean E of "Overall Drug Preference VAS" max is measured using comparative tests 96. The method of claim 94 or 95, wherein the concentration of hydroxybenzoates in the blood is reduced by at least 15% upon administration.

[0228] Article 99. Mean E of "Overall Drug Preference VAS" max At least 20%, preferably At least 25%, more preferably at least 30%, and most preferably at least 3 5% reduction, as described in clause 98.

[0229] Article 100. Mean E of "Drug Re-use VAS" max When measuring using a comparative test, 96. The method of clause 94 or clause 95, wherein the concentration of hydroxybenzoates in the blood is reduced by at least 15%.

[0230] Article 101. Mean E of "Drug Re-use VAS" max is at least 20%, preferably At least 25%, more preferably at least 30%, and most preferably at least 35% The method of claim 100, wherein the decrease

[0231] Clause 102. The method provides a method for producing an analgesic effect that is not substantially reduced when measured using a comparative test. 102. The method of any one of clauses 44 to 101,

[0232] Article 103. Mean values ​​measured using the cold pressor test at 1, 2, 3, and 4 hours after administration The "cold pain score VAS" was 10 times lower than the comparative treatment method when measured using a comparative test. 103. The method of claim 102, wherein the concentration of hydroxybenzoates does not increase by more than 10%.

[0233] Article 104. The method prevents the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. 103. A method according to any one of clauses 44 to 103 for preventing or inhibiting

[0234] Article 105. Any one of Articles 1 to 43 for use in a method for treating pain Item 1. An oral dosage form according to item 1.

[0235] Article 106. The method results in prevention or suppression of adverse pharmacodynamic reactions of oxycodone. 106. An oral dosage form according to clause 105 for use in a method for treating pain.

[0236] Article 107. The co-administration of the amount of buprenorphine in the dosage form is not limited to administration alone. and (c) determining whether or not an adverse pharmacodynamic reaction occurs when administering oxycodone at a given dose in the dosage form. An oral dosage form according to clause 105 for use in a method for treating pain, preventing or suppressing pain. .

[0237] Article 108. The adverse pharmacodynamic reactions include euphoria, elation, bowel dysfunction, nausea, vomiting, somnolence. , dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium Symptoms include delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance. Preferably, the adverse pharmacodynamic reactions are selected from the group consisting of respiratory depression, euphoria, elation, and and bowel dysfunction. 6 or an oral dosage form as defined in Clause 107.

[0238] Article 109. A method for treating pain, wherein the adverse pharmacodynamic reaction is euphoria. 106 or 107. An oral dosage form according to clause 106 or clause 107.

[0239] Article 110. The method for treating pain, wherein the adverse pharmacodynamic reaction is euphoria. 106 or 107. An oral dosage form according to clause 106 or clause 107.

[0240] Article 111. Mean E of "Emotion VAS" max is a small amount when measured using comparative tests. 110. An oral preparation according to clause 110 for use in a method for treating pain, wherein the pain is reduced by at least 15%. shape.

[0241] Article 112. Mean E of "Emotion VAS" max At least 20%, preferably less at least 25%, more preferably at least 30%, most preferably at least 35%, or 111. Oral administration of a compound according to claim 111 for use in a method for treating pain, wherein the pain is reduced by 40% or even 40%. Dosage form.

[0242] Article 113. The method provides a pain reliever that prevents or suppresses drug addiction to oxycodone. A method for treating pain according to any one of clauses 105 to 112. Oral dosage form.

[0243] Article 114. The simultaneous administration of the amount of buprenorphine in the dosage form is not limited to administration alone. and comparing the drug palatability observed with the fixed amount of oxycodone in the dosage form when administered. and used in a method for treating pain, which prevents or suppresses drug addiction to oxycodone. 112. An oral dosage form according to any one of clauses 105 to 112 for use in

[0244] Article 115. Mean E of "Temporary Drug Preference VAS" max is measured using comparative tests Article 113 or is an oral dosage form as described in clause 114.

[0245] Article 116. Mean E of "Temporary Drug Preference VAS" max At least 20% are preferred or at least 25%, more preferably at least 30% reduction in pain. 115. An oral dosage form as defined in Clause 115 for use in a method for

[0246] Article 117. Mean E of "Overall Drug Preference VAS" max is measured using comparative tests Article 113 or is an oral dosage form as described in clause 114.

[0247] Article 118. Mean E of "Overall Drug Preference VAS" max At least 20% are preferred or at least 25%, more preferably at least 30%, and most preferably at least 118. An oral dosage form according to clause 117 for use in a method for treating pain, wherein the pain is reduced by 35%.

[0248] Article 119. Mean E of "Drug Re-use VAS" max When measuring using a comparative test, Article 113 or Article 114 used in a method for treating pain, which reduces pain by at least 15% 114. An oral dosage form as set forth in claim 114.

[0249] Article 120. Mean E of "Drug Re-use VAS" max is at least 20%, preferably At least 25%, more preferably at least 30%, and most preferably at least 35% 119. An oral dosage form according to clause 119 for use in a method for treating pain, wherein the pain is reduced.

[0250] Article 121. The method provides an analgesic effect that is not substantially reduced when measured using a comparative test. any of clauses 105 to 120 for use in a method for treating pain, 1. The oral dosage form of claim 1.

[0251] Article 122. Mean values ​​measured using the cold pressor test at 1, 2, 3, and 4 hours after administration The "cold pain score VAS" was 10 times lower than the comparative treatment method when measured using a comparative test. 122. An oral dosage form according to clause 121 for use in a method for treating pain, wherein the oral dosage form does not increase by more than 1%.

[0252] Article 123. The method is for preventing the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. Any of the substances listed in Articles 105 to 122 used in methods for preventing or suppressing pain, or for treating pain 10. The oral dosage form according to any one of claims 1 to 9.

[0253] Article 124. A pharmaceutical composition according to any one of Articles 1 to 43 containing the same amount of oxycodone. Treatment of pain with a fixed dose of oxycodone alone by administering the oral form instead A method for preventing or inhibiting the adverse pharmacodynamic reactions of oxycodone observed in

[0254] Article 125. The adverse pharmacodynamic reactions include euphoria, elation, bowel dysfunction, nausea, vomiting, somnolence. , dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium Symptoms include delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance. Preferably, the adverse pharmacodynamic reactions are selected from the group consisting of respiratory depression, euphoria, elation, and and functional bowel disorders.

[0255] Clause 126. The method of clause 124, wherein said adverse pharmacodynamic reaction is euphoria.

[0256] Clause 127. The method of clause 124, wherein said adverse pharmacodynamic reaction is euphoria.

[0257] Article 128. A pharmaceutical composition according to any one of Articles 1 to 43 containing the same amount of oxycodone. Treatment of pain with a fixed dose of oxycodone alone by administering the oral form instead A method for preventing or suppressing drug addiction to oxycodone as seen in

[0258] Article 129. By providing a dosage form according to any one of Articles 1 to 43, Methods for preventing or inhibiting the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use .

[0259] Article 130. Preventing or suppressing the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. 44. Use of a dosage form according to any one of clauses 1 to 43 in administering to a patient

[0260] Article 131. (i) a fixed dose of immediate-release oxycodone; (ii) a fixed dose of immediate-release buprenorphine; 1. An oral dosage form comprising: The weight ratio of the amount of buprenorphine to the amount of oxycodone is equimolar. In the above dosage form, expressed as buprenorphine base (mg) (Mw = 467.64 g / mol) the amount of buprenorphine and an equimolar amount of oxycodone hydrochloride (mg) (Mw=351.82 g / mol) When calculated using the ratio of 1:100, The oral dosage form.

[0261] Clause 132. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 132. The oral dosage form of clause 131, wherein the ratio is about 1:80 or greater.

[0262] Clause 133. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 132. The oral dosage form of clause 131, wherein the ratio is about 1:60 or greater.

[0263] Clause 134. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 132. The oral dosage form of clause 131, wherein the ratio is about 1:50 or greater.

[0264] Clause 135. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 132. The oral dosage form of clause 131, wherein the ratio is about 1:40 or greater.

[0265] Clause 136. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is about 1:6 to about 1:100, preferably about 1:6 to about 1:80, more preferably 132. The oral administration method according to claim 131, wherein the oral administration ratio is about 1:6 to about 1:60, or about 1:6 to about 1:50. Dosage form.

[0266] Clause 137. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 132. The oral dosage form of clause 131, wherein the ratio is from about 1:6 to about 1:40.

[0267] Clause 138. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is about 1:8 to about 1:100, preferably about 1:8 to about 1:80, more preferably 132. The oral administration of claim 131, wherein the oral administration is from about 1:8 to about 1:60, or from about 1:8 to about 1:50. Dosage form.

[0268] Clause 139. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 132. The oral dosage form of clause 131, wherein the ratio is from about 1:8 to about 1:40.

[0269] Clause 140. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is about 1:10 to about 1:100, preferably about 1:10 to about 1:80, more preferably about 1:10 to about 1:80. is about 1:10 to about 1:60, or about 1:10 to about 1:50, as set forth in Article 131. Oral dosage form of the above.

[0270] Clause 141. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 132. The oral dosage form of clause 131, wherein the ratio is from about 1:10 to about 1:40.

[0271] Clause 142. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is about 1:20 to about 1:100, preferably about 1:20 to about 1:80, more preferably is about 1:20 to about 1:60, or about 1:20 to about 1:50, as set forth in Article 131. Oral dosage form of the above.

[0272] Clause 143. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 132. The oral dosage form of clause 131, wherein the ratio is from about 1:20 to about 1:40.

[0273] Clause 144. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 132. The oral dosage form of clause 131, wherein the ratio is from about 1:20 to about 1:30.

[0274] Clause 145. The dosage form comprises about 5 mg to about 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 amount of oxycodone equivalent to Article 131 144 to 144.

[0275] Clause 146. The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or , equimolar to approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / mol) Oral preparations according to any one of clauses 131 to 144, containing a certain amount of oxycodone shape.

[0276] Clause 147. The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or , equimolar to approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / mol) 147. An oral dosage form according to clause 146, comprising an amount of oxycodone hydrochloride.

[0277] Clause 148. The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or , equimolar to approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / mol) 147. An oral dosage form according to clause 146, comprising an amount of oxycodone myristate.

[0278] Clause 149. The dosage form contains approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / oxycodone in an equimolar amount relative to the oxycodone and about 1 mg to about 5 mg of buprenolol A fixed amount of buprenorphine was added to the equimolar amount of buprenorphine base (Mw=467.64g / mol). 144. An oral dosage form according to any one of clauses 131 to 144, comprising

[0279] Clause 150. The dosage form comprises approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / oxycodone in an equimolar amount relative to the oxycodone (mol) and about 1 mg to about 4 mg of buprenoline. A fixed amount of buprenorphine was added to the equimolar amount of buprenorphine base (Mw=467.64g / mol). 144. An oral dosage form according to any one of clauses 131 to 144, comprising

[0280] Clause 151. The dosage form contains approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / oxycodone in an equimolar amount relative to the oxycodone (mol) and about 2 mg to about 4 mg of buprenoline. A fixed amount of buprenorphine was added to the equimolar amount of buprenorphine base (Mw=467.64g / mol). 144. An oral dosage form according to any one of clauses 131 to 144, comprising

[0281] Clause 152. The dosage form contains approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / oxycodone in an equimolar amount relative to the oxycodone (mol) and about 1 mg to about 2 mg of buprenoline. A fixed amount of buprenorphine was added to the equimolar amount of buprenorphine base (Mw=467.64g / mol). 144. An oral dosage form according to any one of clauses 131 to 144, comprising

[0282] Article 153. The oxycodone is oxycodone hydrochloride, and the buprenorphine is Buprenorphine hydrochloride, Articles 131 to 146, Articles 149 to 152 The oral dosage form according to any one of claims 1 to 10.

[0283] Clause 154. The dosage form is a liquid dosage form. The oral dosage form as described.

[0284] Article 155. The dosage form is a solution, a suspension or an emulsion, preferably a solution. 154. An oral dosage form according to claim 154,

[0285] Clause 156. The dosage form is a solid dosage form, The oral dosage form as described.

[0286] Clause 157. An oral dosage form according to clause 156, wherein said dosage form is a tablet or a capsule.

[0287] Article 158. After single dose administration, the dosage form provides a dose of at least about 1:280 to a group of subjects. The mean C of buprenorphine max and mean C of oxycodone max The ratio of 157. An oral dosage form according to any one of clauses 131 to 157.

[0288] Article 159. Buprenorphine Average C max and mean C of oxycodone max The ratio of 159. The oral dosage form of clause 158, wherein the ratio is at least about 1:250.

[0289] Article 160. Buprenorphine Average C max and mean C of oxycodone max The ratio of 159. The oral dosage form of clause 158, wherein the ratio is at least about 1:230.

[0290] Article 161. Average C of Buprenorphine max and mean C of oxycodone max The ratio of 159. The oral dosage form of clause 158, wherein the ratio is at least about 1:200.

[0291] Article 162. Buprenorphine Average C max and mean C of oxycodone max The ratio of 159. The oral dosage form of clause 158, wherein the ratio is at least about 1:180.

[0292] Article 163. Buprenorphine Average C max and mean C of oxycodone max The ratio of 159. The oral dosage form of clause 158, wherein the ratio is from about 1:50 to about 1:280.

[0293] Article 164. Buprenorphine Average C max and mean C of oxycodone max The ratio of 159. The oral dosage form of clause 158, wherein the ratio is from about 1:50 to about 1:250.

[0294] Article 165. Buprenorphine Average C max and mean C of oxycodone max The ratio of 159. The oral dosage form of clause 158, wherein the ratio is from about 1:80 to about 1:230.

[0295] Article 166. Buprenorphine Average C max and mean C of oxycodone max The ratio of 159. The oral dosage form of clause 158, wherein the ratio is from about 1:100 to about 1:200.

[0296] Article 167. Buprenorphine Average C max and mean C of oxycodone max The ratio of 159. The oral dosage form of clause 158, wherein the ratio is from about 1:100 to about 1:180.

[0297] Clause 168. After single dose administration, said dosage form provides said subject group with a bupivacaine ratio of about 1.5:1 or less. Norphine's average T max and mean T of oxycodone max Clause 1 further provides for a ratio of 58 to 167. An oral dosage form according to any one of clauses 58 to 167.

[0298] Article 169. Buprenorphine mean T max and mean T of oxycodone max The ratio of 169. The oral dosage form of clause 168, wherein the ratio is about 1.3:1 or less.

[0299] Article 170. Buprenorphine mean T max and mean T of oxycodone max The ratio of 169. The oral dosage form of clause 168, wherein the ratio is about 1.1:1 or less.

[0300] Article 171. Buprenorphine mean T max and mean T of oxycodone max The ratio of 169. The oral dosage form of clause 168, wherein the ratio is about 1:1 or less.

[0301] Clause 172. After administration of a single dose, the dosage form provides a mean T of oxycodone to the subject group. ma x Faster mean T of buprenorphine compared to max Further, Article 158 167. An oral dosage form according to any one of clauses 167.

[0302] Article 173. After single dose administration, the dosage form provides the subject group with a dose 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 from about 0.1:1 to about 1:1, or from about 0.1:1 to about 0.9: Average T of buprenorphine in 1 max and mean T of oxycodone max further increasing the ratio of 172. An oral dosage form according to any one of clauses 158 to 172.

[0303] Article 174. (i) a fixed dose of immediate-release oxycodone; (ii) a fixed dose of immediate-release buprenorphine; administering to a patient in need thereof an oral dosage form comprising The weight ratio of the amount of buprenorphine to the amount of oxycodone is equimolar. In the above dosage form, expressed as buprenorphine base (mg) (Mw = 467.64 g / mol) the amount of buprenorphine and an equimolar amount of oxycodone hydrochloride (mg) (Mw=351.82 g / mol) When calculated using the ratio of 1:100, A method for treating pain.

[0304] Clause 175. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 175. The method of claim 174, wherein the ratio is about 1:80 or greater.

[0305] Clause 176. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 175. The method of claim 174, wherein the ratio is about 1:60 or greater.

[0306] Clause 177. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 175. The method of claim 174, wherein the ratio is about 1:50 or greater.

[0307] Clause 178. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 175. The method of claim 174, wherein the ratio is about 1:40 or greater.

[0308] Clause 179. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is about 1:6 to about 1:100, preferably about 1:6 to about 1:80, more preferably 175. The method of claim 174, wherein the ratio is from about 1:6 to about 1:60, or from about 1:6 to about 1:50. .

[0309] Clause 180. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 175. The method of clause 174, wherein the ratio is from about 1:6 to about 1:40.

[0310] Clause 181. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is about 1:8 to about 1:100, preferably about 1:8 to about 1:80, more preferably 175. The method of claim 174, wherein the ratio is from about 1:8 to about 1:60, or from about 1:8 to about 1:50. .

[0311] Clause 182. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 175. The method of clause 174, wherein the ratio is from about 1:8 to about 1:40.

[0312] Clause 183. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is about 1:10 to about 1:100, preferably about 1:10 to about 1:80, more preferably about 1:10 to about 1:80. is about 1:10 to about 1:60, or about 1:10 to about 1:50, as set forth in Article 174 How to post.

[0313] Clause 184. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 175. The method of clause 174, wherein the ratio is from about 1:10 to about 1:40.

[0314] Clause 185. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is about 1:20 to about 1:100, preferably about 1:20 to about 1:80, more preferably is about 1:20 to about 1:60, or about 1:20 to about 1:50, as set forth in Article 174 How to post.

[0315] Clause 186. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 175. The method of clause 174, wherein the ratio is from about 1:20 to about 1:40.

[0316] Clause 187. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 175. The method of clause 174, wherein the ratio is about 1:20 to about 1:30.

[0317] Article 188. The dosage form comprises about 5 mg to about 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 amount of oxycodone equivalent to Article 174 187 et seq.

[0318] Article 189. The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or , equimolar to approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / mol) 188. The method of any one of clauses 174 to 187, comprising a quantity of oxycodone.

[0319] Clause 190. The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or , equimolar to approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / mol) 189. The method of claim 189, comprising an amount of oxycodone hydrochloride.

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

[0321] Clause 192. The dosage form contains approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / oxycodone in an equimolar amount relative to the oxycodone and about 1 mg to about 5 mg of buprenolol A fixed amount of buprenorphine was added to the equimolar amount of buprenorphine base (Mw=467.64g / mol). 187. The method of any one of clauses 174 to 187, including

[0322] Clause 193. The dosage form contains approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / oxycodone in an equimolar amount relative to the oxycodone (mol) and about 1 mg to about 4 mg of buprenoline. A fixed amount of buprenorphine was added to the equimolar amount of buprenorphine base (Mw=467.64g / mol). 187. The method of any one of clauses 174 to 187, including

[0323] Clause 194. The dosage form contains approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / oxycodone in an equimolar amount relative to the oxycodone (mol) and about 2 mg to about 4 mg of buprenoline. A fixed amount of buprenorphine was added to the equimolar amount of buprenorphine base (Mw=467.64g / mol). 187. The method of any one of clauses 174 to 187, including

[0324] Clause 195. The dosage form contains approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / oxycodone in an equimolar amount relative to the oxycodone (mol) and about 1 mg to about 2 mg of buprenoline. A fixed amount of buprenorphine was added to the equimolar amount of buprenorphine base (Mw=467.64g / mol). 187. The method of any one of clauses 174 to 187, including

[0325] Article 196. The oxycodone is oxycodone hydrochloride, and the buprenorphine is Buprenorphine hydrochloride, Articles 174 to 189, Articles 192 to 195 10. The method according to any one of claims 1 to 9.

[0326] Clause 197. The dosage form is a liquid dosage form. The method described.

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

[0328] Clause 199. The dosage form is a solid dosage form. The method described.

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

[0330] Clause 201. After single dose administration, the dosage form provides a dose of at least about 1:280 to a group of subjects. The mean C of buprenorphine max and mean C of oxycodone max The ratio of 20. A method according to any one of clauses 174 to 200.

[0331] Article 202. Buprenorphine Average C max and mean C of oxycodone max The ratio of 202. The method of claim 201, wherein the ratio is at least about 1:250.

[0332] Article 203. Buprenorphine Average C max and mean C of oxycodone max The ratio of 202. The method of claim 201, wherein the ratio is at least about 1:230.

[0333] Article 204. Buprenorphine Average C max and mean C of oxycodone max The ratio of 202. The method of claim 201, wherein the ratio is at least about 1:200.

[0334] Article 205. Buprenorphine Average C max and mean C of oxycodone max The ratio of 202. The method of claim 201, wherein the ratio is at least about 1:180.

[0335] Article 206. Buprenorphine Average C max and mean C of oxycodone max The ratio of 202. The method of claim 201, wherein the ratio is from about 1:50 to about 1:280.

[0336] Article 207. Buprenorphine Average C max and mean C of oxycodone max The ratio of 202. The method of clause 201, wherein the ratio is from about 1:50 to about 1:250.

[0337] Article 208. Buprenorphine Average C max and mean C of oxycodone max The ratio of 202. The method of clause 201, wherein the ratio is from about 1:80 to about 1:230.

[0338] Article 209. Buprenorphine Average C max and mean C of oxycodone max The ratio of 202. The method of clause 201, wherein the ratio is about 1:100 to about 1:200.

[0339] Article 210. Buprenorphine Average C max and mean C of oxycodone max The ratio of 202. The method of clause 201, wherein the ratio is from about 1:100 to about 1:180.

[0340] Clause 211. After single dose administration, said dosage form provides said subject group with a bupivacaine ratio of about 1.5:1 or less. Norphine's average T max and mean T of oxycodone max Clause 2 further provides for a ratio of 21. A method according to any one of clauses 01 to 210.

[0341] Article 212. Buprenorphine mean T max and mean T of oxycodone max The ratio of 212. The method of claim 211, wherein the ratio is about 1.3:1 or less.

[0342] Article 213. Buprenorphine mean T max and mean T of oxycodone max The ratio of 212. The method of claim 211, wherein the ratio is about 1.1:1 or less.

[0343] Article 214. Buprenorphine mean T max and mean T of oxycodone max The ratio of 212. The method of claim 211, wherein the ratio is about 1:1 or less.

[0344] Clause 215. After administration of a single dose, the dosage form provides the subject group with a mean T of oxycodone. ma x Faster mean T of buprenorphine compared to maxFurther, Article 201 211. The method according to any one of clauses 210.

[0345] Article 216. After single dose administration, the dosage form provides the subject group with a dose 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 from about 0.1:1 to about 1:1, or from about 0.1:1 to about 0.9: Average T of buprenorphine in 1 max and mean T of oxycodone max further increasing the ratio of A method according to any one of clauses 201 to 215.

[0346] Article 217. The method results in prevention or suppression of adverse pharmacodynamic reactions of oxycodone. , a method according to any one of clauses 174 to 216.

[0347] Article 218. The simultaneous administration of the amount of buprenorphine in the dosage form is not limited to administration alone. and (c) determining whether or not an adverse pharmacodynamic reaction occurs when administering oxycodone at a given dose in the dosage form. 216. A method according to any one of clauses 174 to 216 for preventing or inhibiting

[0348] Article 219. The adverse pharmacodynamic reactions are euphoria, elation, bowel dysfunction, nausea, vomiting, somnolence. , dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium Symptoms include delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance. Preferably, the adverse pharmacodynamic reactions are selected from the group consisting of respiratory depression, euphoria, elation, and and functional bowel disorders.

[0349] Article 220. The adverse pharmacodynamic reaction is euphoria, as described in Article 217 or Article 218. How to do it.

[0350] Article 221. The adverse pharmacodynamic reaction is euphoria, as described in Article 217 or Article 218. How to do it.

[0351] Article 222. Mean E of "Emotion VAS" max is a small amount when measured using comparative tests. 221. The method of claim 221, wherein the temperature is reduced by at least 15%.

[0352] Article 223. Mean E of "Emotion VAS" max At least 20%, preferably less at least 25%, more preferably at least 30%, most preferably at least 35%, or or a further 40% reduction.

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

[0354] Article 225. The simultaneous administration of the amount of buprenorphine in the dosage form is not limited to administration alone. and comparing the drug palatability observed with the fixed amount of oxycodone in the dosage form when administered. Articles 174 to 223 of the Act, which are intended to prevent or reduce the drug addiction of oxycodone, 1. The method according to any one of claims 1 to 9.

[0355] Article 226. Mean E of "Temporary Drug Preference VAS" max is measured using comparative tests 226. The method of claim 224 or 225, wherein the concentration of hydroxybenzoates is reduced by at least 15% upon application of the compound.

[0356] Article 227. Mean E of "Temporal Drug Preference VAS" maxAt least 20% are preferred or at least 25%, more preferably at least 30%, as set forth in Article 226 How to do it.

[0357] Article 228. Mean E of "Overall Drug Preference VAS" max is measured using comparative tests 226. The method of claim 224 or 225, wherein the concentration of hydroxybenzoates is reduced by at least 15% upon application of the compound.

[0358] Article 229. Mean E of "Overall Drug Preference VAS" max At least 20% are preferred or at least 25%, more preferably at least 30%, and most preferably at least 35% reduction, as described in clause 228.

[0359] Article 230. Mean E of "Drug Re-use VAS" max When measuring using a comparative test, The method of clause 224 or clause 225, wherein the concentration of hydroxybenzoates is reduced by at least 15%.

[0360] Article 231. Mean E of "Drug Re-use VAS" max is at least 20%, preferably At least 25%, more preferably at least 30%, and most preferably at least 35% The method of clause 230, wherein the decrease

[0361] Article 232. The method provides a method for producing an analgesic effect that is not substantially reduced when measured using a comparative test. 231. A method according to any one of clauses 174 to 231,

[0362] Article 233. Mean values ​​measured using the cold pressor test at 1, 2, 3, and 4 hours after administration The "cold pain score VAS" was 10 times lower than the comparative treatment method when measured using a comparative test. 232. The method of claim 232, wherein the increase in the concentration of hydroxybenzoates does not exceed 100%.

[0363] Article 234. The method is for preventing the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. 233. A method according to any one of clauses 174 to 233 for preventing or inhibiting

[0364] Article 235. Any of Articles 131 to 173 for use in a method for treating pain. 1. The oral dosage form according to claim 1.

[0365] Article 236. The method results in prevention or suppression of adverse pharmacodynamic reactions of oxycodone. 235. An oral dosage form according to clause 235 for use in a method for treating pain.

[0366] Article 237. The co-administration of the amount of buprenorphine in the dosage form is not limited to administration alone. and (c) determining whether or not an adverse pharmacodynamic reaction occurs when administering oxycodone at a given dose in the dosage form. An oral dosage form as defined in clause 235 for use in a method for treating pain, preventing or suppressing pain. .

[0367] Article 238. The adverse pharmacodynamic reactions are euphoria, elation, bowel dysfunction, nausea, vomiting, somnolence. , dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium Symptoms include delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance. Preferably, the adverse pharmacodynamic reactions are selected from the group consisting of respiratory depression, euphoria, elation, and and bowel dysfunction. 6 or an oral dosage form as described in Clause 237.

[0368] Article 239. The method for treating pain, wherein the adverse pharmacodynamic reaction is euphoria. 236 or 237. An oral dosage form according to clause 236 or 237.

[0369] Article 240. The method for treating pain, wherein the adverse pharmacodynamic reaction is euphoria. 236 or 237. An oral dosage form according to clause 236 or 237.

[0370] Article 241. Mean E of "Emotion VAS" max is a small amount when measured using comparative tests. an oral preparation according to clause 240 for use in a method for treating pain, the oral preparation reducing the pain level by at least 15% shape.

[0371] Article 242. Mean E of "Emotion VAS" max At least 20%, preferably less at least 25%, more preferably at least 30%, most preferably at least 35%, or 241 for use in a method for treating pain, wherein the pain is reduced by 40% or even 40%. Dosage form.

[0372] Article 243. The method provides a pain-relieving agent that prevents or suppresses drug addiction to oxycodone. A method for treating pain according to any one of clauses 235 to 242. Oral dosage form.

[0373] Article 244. The co-administration of the amount of buprenorphine in the dosage form is not limited to administration alone. and comparing the drug palatability observed with the fixed amount of oxycodone in the dosage form when administered. and used in a method for treating pain, which prevents or suppresses drug addiction to oxycodone. 242. An oral dosage form according to any one of clauses 235 to 242 for use in

[0374] Article 245. Mean E of "Temporary Drug Preference VAS" max is measured using comparative tests Article 243 or is an oral dosage form as described in clause 244.

[0375] Article 246. Mean E of "Temporary Drug Preference VAS" max At least 20% are preferred or at least 25%, more preferably at least 30% reduction in pain. 245. An oral dosage form as defined in Clause 245 for use in a method for

[0376] Article 247. Mean E of "Overall Drug Preference VAS" max is measured using comparative tests Article 243 or is an oral dosage form as described in clause 244.

[0377] Article 248. Mean E of "Overall Drug Preference VAS" max At least 20% are preferred or at least 25%, more preferably at least 30%, and most preferably at least 247. An oral dosage form according to clause 247 for use in a method for treating pain, wherein the pain is reduced by 35%.

[0378] Article 249. Mean E of "Drug Re-use VAS" max When measuring using a comparative test, Article 243 or Article 244 for use in a method for treating pain, which reduces pain by at least 15% 244. An oral dosage form as set forth in claim 244.

[0379] Article 250. Mean E of "Drug Re-use VAS" max is at least 20%, preferably At least 25%, more preferably at least 30%, and most preferably at least 35% 249. The oral dosage form of claim 249 for use in a method for treating pain, wherein the pain is reduced.

[0380] Article 251. The method provides an analgesic effect that is not substantially reduced when measured using a comparative test. any of clauses 235 to 250 for use in a method for treating pain, 1. The oral dosage form of claim 1.

[0381] Article 252. Mean values ​​measured using the cold pressor test at 1, 2, 3, and 4 hours after administration The "cold pain score VAS" was 10 times lower than the comparative treatment method when measured using a comparative test. 251. An oral dosage form as defined in clause 251 for use in a method for treating pain, wherein the oral dosage form does not increase by more than 50%.

[0382] Article 253. The method is for preventing the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. Any of the substances listed in Articles 235 to 252 used in methods for preventing or suppressing pain, or for treating pain 10. The oral dosage form according to any one of claims 1 to 9.

[0383] Article 254. Any of the items from Article 131 to Article 173 containing the same amount of oxycodone By administering the oral dosage form listed above instead, a fixed dose of oxycodone alone can be used to treat pain. A method for preventing or inhibiting adverse pharmacodynamic reactions of oxycodone approved for the treatment of

[0384] Article 255. The adverse pharmacodynamic reactions include euphoria, elation, bowel dysfunction, nausea, vomiting, somnolence. , dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium Symptoms include delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance. Preferably, the adverse pharmacodynamic reactions are selected from the group consisting of respiratory depression, euphoria, elation, and and functional bowel disorders.

[0385] Clause 256. The method of clause 254, wherein said adverse pharmacodynamic reaction is euphoria.

[0386] Clause 257. The method of clause 254, wherein said adverse pharmacodynamic reaction is euphoria.

[0387] Article 258. Any of the items from Article 131 to Article 173 containing the same amount of oxycodone By administering the oral dosage form listed above instead, a fixed dose of oxycodone alone can be used to treat pain. A method for preventing or suppressing drug addiction to oxycodone, which is approved for the treatment of

[0388] Article 259. Providing a dosage form according to any one of Articles 131 to 173 to prevent or reduce the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use; How to do it.

[0389] Article 260. Preventing or suppressing the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. 173. Use of a dosage form according to any one of clauses 131 to 173 in

[0390] Article 261. (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; A dosage form comprising: After single dose administration, the dosage form provides at least about 1:280 of buprenorphine to one subject. Fin average C max and mean C of oxycodone max yielding a ratio of The dosage form.

[0391] Article 262. Buprenorphine Average C max and mean C of oxycodone max The ratio of 262. The dosage form of clause 261, wherein the ratio is at least about 1:250.

[0392] Article 263. Buprenorphine Average C max and mean C of oxycodone max The ratio of 262. The dosage form of clause 261, wherein the ratio is at least about 1:230.

[0393] Article 264. Buprenorphine Average C max and mean C of oxycodone max The ratio of 262. The dosage form of clause 261, wherein the ratio is at least about 1:200.

[0394] Article 265. Buprenorphine Average C max and mean C of oxycodone max The ratio of 262. The dosage form of clause 261, wherein the ratio is at least about 1:180.

[0395] Article 266. Buprenorphine Average C max and mean C of oxycodone max The ratio of 262. The dosage form of clause 261, wherein the ratio is from about 1:50 to about 1:280.

[0396] Article 267. Buprenorphine Average C max and mean C of oxycodone max The ratio of 262. The dosage form of clause 261, wherein the ratio is from about 1:50 to about 1:250.

[0397] Article 268. Buprenorphine Average C max and mean C of oxycodone max The ratio of 262. The dosage form of clause 261, wherein the ratio is from about 1:80 to about 1:230.

[0398] Article 269. Buprenorphine Average C max and mean C of oxycodone max The ratio of 262. The dosage form of clause 261, wherein the ratio is from about 1:100 to about 1:200.

[0399] Article 270. Buprenorphine Average C max and mean C of oxycodone max The ratio of 262. The dosage form of clause 261, wherein the ratio is from about 1:100 to about 1:180.

[0400] Clause 271. After single dose administration, said dosage form provides said subject group with a bupivacaine ratio of about 1.5:1 or less. Norphine's average T max and mean T of oxycodone max Clause 2 further provides for a ratio of 61 to 270. A dosage form according to any one of clauses 61 to 270.

[0401] Article 272. Buprenorphine mean T max and mean T of oxycodone max The ratio of 272. The dosage form of claim 271, wherein the ratio is about 1.3:1 or less.

[0402] Article 273. Buprenorphine mean T max and mean T of oxycodone max The ratio of 272. The dosage form of claim 271, wherein the ratio is about 1.1:1 or less.

[0403] Article 274. Buprenorphine mean T max and mean T of oxycodone max The ratio of 272. The dosage form of claim 271, wherein the ratio is about 1:1 or less.

[0404] Clause 275. After administration of a single dose, the dosage form provides the subject group with a mean T of oxycodone. ma x Faster mean T of buprenorphine compared to max Further, Article 261 270. A dosage form according to any one of clauses 270.

[0405] Article 276. After single dose administration, the dosage form provides the subject group with a dose 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 from about 0.1:1 to about 1:1, or from about 0.1:1 to about 0.9: Average T of buprenorphine in 1 max and mean T of oxycodone max further increasing the ratio of 2. A dosage form according to any one of clauses 261 to 275.

[0406] Article 277. The dosage form is an oral dosage form. The dosage form described.

[0407] Clause 278. The dosage form comprises about 5 mg to about 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) and contains a fixed amount of oxycodone equivalent to Article 277 The oral dosage form as described.

[0408] Article 279. The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or , equimolar to approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / mol) 277. An oral dosage form according to claim 277, comprising a quantity of oxycodone.

[0409] Clause 280. The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or , equimolar to approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / mol) 279. An oral dosage form according to claim 279, comprising an amount of oxycodone hydrochloride.

[0410] Article 281. The dosage form is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or , equimolar to approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / mol) 279. An oral dosage form according to claim 279, comprising an amount of oxycodone myristate.

[0411] Article 282. The dosage form contains approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / oxycodone in an equimolar amount relative to the oxycodone (mol) and about 1 mg to about 6 mg of buprenoline. A fixed amount of buprenorphine was added to the equimolar amount of buprenorphine base (Mw=467.64g / mol). 277. An oral dosage form according to Clause 277, comprising

[0412] Article 283. The dosage form contains approximately 40 mg of oxycodone hydrochloride (Mw=351.82 g / mol) and about 2 mg to about 5 mg of buprenoline. Sulfin base (Mw=467.64 g / mol) or about 2 mg to about 4 mg of buprenorphine A fixed amount of buprenorphine was used, equimolar to the buprenorphine base (Mw = 467.64 g / mol). 277. An oral dosage form according to Clause 277, comprising

[0413] Article 284. The oxycodone is oxycodone hydrochloride, and the buprenorphine is Buprenorphine hydrochloride, Articles 261 to 279, 282 and 283 The dosage form according to any one of the preceding claims.

[0414] Clause 285. The dosage form comprises the amount of buprenorphine in immediate release form. 61 to 284. A dosage form according to any one of clauses 61 to 284.

[0415] Article 286. The dosage form comprises the amount of oxycodone in immediate release form and the amount of oxycodone in immediate release form. 285, containing the amount of buprenorphine. The dosage form listed.

[0416] Article 287. The dosage form is a liquid dosage form. The dosage form described.

[0417] Article 288. The dosage form is a solution, a suspension or an emulsion, preferably a solution. 287.

[0418] Article 289. The dosage form is a solid dosage form. The dosage form described.

[0419] Clause 290. The dosage form according to clause 289, wherein said dosage form is a tablet or a capsule.

[0420] Article 291. (i) a quantity of oxycodone; (ii) a fixed dose of buprenorphine; administering to a patient in need thereof After a single dose, the co-administration provides at least about 1:280 of buprenorphine to one subject. Norphine average C max and mean C of oxycodone max yielding a ratio of A method for treating pain.

[0421] Article 292. Buprenorphine Average C max and mean C of oxycodone max The ratio of 292. The method of claim 291, wherein the ratio is at least about 1:250.

[0422] Article 293. Buprenorphine Average C max and mean C of oxycodone max The ratio of 292. The method of claim 291, wherein the ratio is at least about 1:230.

[0423] Article 294. Buprenorphine Average C max and mean C of oxycodone max The ratio of 292. The method of claim 291, wherein the ratio is at least about 1:200.

[0424] Article 295. Buprenorphine Average C max and mean C of oxycodone max The ratio of 292. The method of claim 291, wherein the ratio is at least about 1:180.

[0425] Article 296. Buprenorphine Average C max and mean C of oxycodone max The ratio of 292. The method of claim 291, wherein the ratio is from about 1:50 to about 1:280.

[0426] Article 297. Buprenorphine Average C max and mean C of oxycodone max The ratio of 292. The method of claim 291, wherein the ratio is from about 1:50 to about 1:250.

[0427] Article 298. Buprenorphine Average C max and mean C of oxycodone max The ratio of 292. The method of claim 291, wherein the ratio is from about 1:80 to about 1:230.

[0428] Article 299. Buprenorphine Average C max and mean C of oxycodone max The ratio of 292. The method of claim 291, wherein the ratio is about 1:100 to about 1:200.

[0429] Article 300. Buprenorphine Average C max and mean C of oxycodone max The ratio of 292. The method of claim 291, wherein the ratio is about 1:100 to about 1:180.

[0430] Clause 301. After single dose administration, said co-administration provides said subject group with a bromide ratio of about 1.5:1 or less. Prenorphine mean T max and mean T of oxycodone max Further bringing about a ratio of 3. A method according to any one of clauses 291 to 300.

[0431] Article 302. Buprenorphine mean T max and mean T of oxycodone max The ratio of 302. The method of claim 301, wherein the ratio is about 1.3:1 or less.

[0432] Article 303. Buprenorphine mean T max and mean T of oxycodone max The ratio of 302. The method of claim 301, wherein the ratio is about 1.1:1 or less.

[0433] Article 304. Buprenorphine mean T max and mean T of oxycodone max The ratio of 302. The method of claim 301, wherein the ratio is about 1:1 or less.

[0434] Clause 305. After administration of a single dose, the co-administration provides the subject group with a mean T of oxycodone. max Faster mean T of buprenorphine compared to max Article 291 further 300. The method according to any one of clauses 1 to 300.

[0435] Clause 306. After single dose administration, said co-administration is performed in a ratio of about 0.1:1 to about 1 to said subject group. 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 from about 0.1:1 to about 1:1, or from about 0.1:1 to about 0. 9:1 ​​buprenorphine mean T max and mean T of oxycodone max Further increase the ratio of 3. The method according to any one of clauses 291 to 305.

[0436] Clause 307. Any one of clauses 291 to 306, wherein the simultaneous administration is oral administration. The method described in paragraph .

[0437] Article 308. The amount of buprenorphine and the amount of oxycodone are 3 times greater than or equal to 100 mg of buprenorphine. Administered within 0, 20, 10, 5, or 1 minute Preferably, the buprenorphine is administered prior to the oxycodone. 307. A method according to any one of clauses 1 to 307.

[0438] Article 309. The co-administration comprises the amount of buprenorphine and the amount of oxycodone. Any one of clauses 291 to 307, wherein the administration of an oral dosage form containing both The method described below.

[0439] Clause 310. The amount of oxycodone is about 5 mg to about 50 mg of oxycodone hydrochloride. salt (Mw=351.82 g / mol), preferably about 5 mg to about 40 mg of oxycodone The molar ratio of benzophenone hydrochloride (Mw=351.82g / mol) is equimolar to that of benzophenone hydrochloride (Mw=351.82g / mol), as shown in Article 307 to Article 308. 309. The method of any one of claims 309 to 309.

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

[0441] Clause 312. The amount of oxycodone is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or approximately 40 mg, of oxycodone hydrochloride (Mw=351.82 g / mol) 312. The method of claim 311, wherein the amount of oxycodone hydrochloride is equimolar to the amount of oxycodone hydrochloride.

[0442] Clause 313. The amount of oxycodone is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or approximately 40 mg, of oxycodone hydrochloride (Mw=351.82 g / mol) 312. The method of claim 311, wherein the amount of oxycodone myristate is equimolar to .

[0443] Clause 314. The amount of oxycodone is about 40 mg of oxycodone hydrochloride (Mw= 351.82 g / mol), and the amount of buprenorphine is about Equivalent to 1 mg to approximately 6 mg of buprenorphine base (Mw = 467.64 g / mol) 309. The method of any one of clauses 307 to 309, wherein the compound is a molar.

[0444] Clause 315. The amount of oxycodone is about 40 mg of oxycodone hydrochloride (Mw= 351.82 g / mol), and the amount of buprenorphine is about 2 mg to approximately 5 mg of buprenorphine base (Mw=467.64 g / mol) or approximately 2 Equimolar to approximately 4 mg of buprenorphine base (Mw=467.64 g / mol) 309. The method of claim 307, wherein the

[0445] Article 316. The oxycodone is oxycodone hydrochloride, and the buprenorphine is Buprenorphine hydrochloride, Articles 291 to 311, 314 and 315 10. The method according to any one of claims 1 to 9.

[0446] Article 317. The amount of buprenorphine is immediate release. 316. The method of any one of claims 316 to 316.

[0447] Article 318. The amount of oxycodone is immediate release, and the amount of buprenorphine The method of any one of clauses 291 to 317, wherein the fin is immediate release.

[0448] Article 319. The dosage form is a liquid dosage form. The method described.

[0449] Article 320. The dosage form is a solution, a suspension or an emulsion, preferably a solution. 319.

[0450] Clause 321. The dosage form is a solid dosage form. The method described.

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

[0452] Article 323. The method results in prevention or suppression of adverse pharmacodynamic reactions of oxycodone. , a method according to any one of clauses 291 to 322.

[0453] Article 324. The simultaneous administration of the amount of buprenorphine in the dosage form is not limited to administration alone. and (c) determining whether or not an adverse pharmacodynamic reaction occurs when administering oxycodone at a given dose in the dosage form. 3. A method according to any one of clauses 291 to 322 for preventing or inhibiting

[0454] Article 325. The adverse pharmacodynamic reactions are euphoria, elation, bowel dysfunction, nausea, vomiting, somnolence. , dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium Symptoms include delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance. Preferably, the adverse pharmacodynamic reactions are selected from the group consisting of respiratory depression, euphoria, elation, and and functional bowel disorders.

[0455] Article 326. The adverse pharmacodynamic reaction is euphoria, as described in Article 323 or Article 324. How to do it.

[0456] Article 327. The adverse pharmacodynamic reaction is euphoria, as described in Article 323 or Article 324. How to do it.

[0457] Article 328. Mean E of "Emotion VAS" max is a small amount when measured using comparative tests. 327. The method of claim 327, wherein the temperature is reduced by at least 15%.

[0458] Article 329. Mean E of "Emotion VAS" max At least 20%, preferably less at least 25%, more preferably at least 30%, most preferably at least 35%, or or a further 40% reduction, as set forth in Clause 328.

[0459] Article 330. The method results in the prevention or suppression of drug addiction to oxycodone. 3. A method according to any one of clauses 291 to 329.

[0460] Article 331. The simultaneous administration of the amount of buprenorphine in the dosage form is not limited to administration alone. and comparing the drug palatability observed with the fixed amount of oxycodone in the dosage form when administered. Articles 291 to 329 of the Act, which are intended to prevent or reduce the addiction to oxycodone, 1. The method according to any one of claims 1 to 9.

[0461] Article 332. Mean E of "Temporal Drug Preference VAS" max is measured using comparative tests 332. The method of claim 330 or 331, wherein the concentration of hydroxybenzoates is reduced by at least 15% upon application of the hydroxybenzoates.

[0462] Article 333. Mean E of "Temporary Drug Preference VAS" max At least 20% are preferred or at least 25%, more preferably at least 30%, as set forth in Article 332 How to do it.

[0463] Article 334. Mean E of "Overall Drug Preference VAS" max is measured using comparative tests 332. The method of claim 330 or 331, wherein the concentration of hydroxybenzoates is reduced by at least 15% upon application of the hydroxybenzoates.

[0464] Article 335. Mean E of "Overall Drug Preference VAS" max At least 20% are preferred or at least 25%, more preferably at least 30%, and most preferably at least 35% reduction, as set forth in clause 334.

[0465] Article 336. Mean E of "Drug Reuse VAS" max When measuring using a comparative test, The method of clause 330 or clause 331, wherein the decrease is at least 15%.

[0466] Article 337. Mean E of "Drug Re-use VAS" max is at least 20%, preferably At least 25%, more preferably at least 30%, and most preferably at least 35% The method described in clause 336 is reduced.

[0467] Article 338. The method provides an analgesic effect that is not substantially reduced when measured using a comparative test. 337. A method according to any one of clauses 291 to 337,

[0468] Article 339. Mean values ​​measured using the cold pressor test at 1, 2, 3, and 4 hours after administration The "cold pain score VAS" was 10 times lower than the comparative treatment method when measured using a comparative test. 338. The method of claim 338, wherein the increase is not more than %.

[0469] Article 340. The method prevents the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. 339. A method according to any one of clauses 291 to 339 for preventing or inhibiting

[0470] Article 341. Any of Articles 261 to 290 for use in a method for treating pain. 1. The oral dosage form according to claim 1.

[0471] Article 342. The method results in prevention or suppression of adverse pharmacodynamic reactions of oxycodone. 341. An oral dosage form according to clause 341 for use in a method for treating pain.

[0472] Article 343. The simultaneous administration of the amount of buprenorphine in the dosage form is not limited to administration alone. and (c) determining whether or not an adverse pharmacodynamic reaction occurs when administering oxycodone at a given dose in the dosage form. An oral dosage form as described in Article 341 for use in a method for treating pain, preventing or suppressing pain. .

[0473] Article 344. The adverse pharmacodynamic reactions are euphoria, elation, bowel dysfunction, nausea, vomiting, somnolence. , dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium Symptoms include delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance. Preferably, the adverse pharmacodynamic reactions are selected from the group consisting of respiratory depression, euphoria, elation, and and bowel dysfunction. 2 or an oral dosage form as described in Clause 343.

[0474] Article 345. The method for treating pain, wherein the adverse pharmacodynamic reaction is euphoria. 342. An oral dosage form according to claim 342 or 343.

[0475] Article 346. The method for treating pain, wherein the adverse pharmacodynamic reaction is euphoria. 342. An oral dosage form according to claim 342 or 343.

[0476] Article 347. Mean E of "Emotion VAS" max is a small amount when measured using comparative tests. an oral preparation according to Clause 346 for use in a method for treating pain, the oral preparation reducing the pain level by at least 15% shape.

[0477] Article 348. Mean E of "Emotion VAS" max At least 20%, preferably less at least 25%, more preferably at least 30%, most preferably at least 35%, or 347. Oral administration of a compound according to claim 347 for use in a method for treating pain, wherein the pain is reduced by 40% or even 40%. Dosage form.

[0478] Article 349. The method provides a pain-relieving agent that prevents or suppresses drug addiction to oxycodone. A method for treating pain according to any one of clauses 341 to 348. Oral dosage form.

[0479] Article 350. The co-administration of the amount of buprenorphine in the dosage form is not limited to administration alone. and comparing the drug palatability observed with the fixed amount of oxycodone in the dosage form when administered. and used in a method for treating pain, which prevents or suppresses drug addiction to oxycodone. 348. An oral dosage form according to any one of clauses 341 to 348 for use in

[0480] Article 351. Mean E of "Temporary Drug Preference VAS" max is measured using comparative tests Article 349 or is an oral dosage form as described in clause 350.

[0481] Article 352. Mean E of "Temporary Drug Preference VAS" max At least 20% are preferred or at least 25%, more preferably at least 30% reduction in pain. 351. An oral dosage form as described in Clause 351 for use in a method for

[0482] Article 353. Mean E of "Overall Drug Preference VAS" max is measured using comparative tests Article 349 or is an oral dosage form as described in clause 350.

[0483] Article 354. Mean E of "Overall Drug Preference VAS" max At least 20% are preferred or at least 25%, more preferably at least 30%, and most preferably at least 35% reduction in pain.

[0484] Article 355. Mean E of "Drug Re-use VAS" max When measuring using a comparative test, Article 349 or Article 349 used in a method for treating pain, which reduces pain by at least 15% 350. An oral dosage form as set forth in claim 350.

[0485] Article 356. Mean E of "Drug Re-use VAS" max is at least 20%, preferably At least 25%, more preferably at least 30%, and most preferably at least 35% 355. The oral dosage form of claim 355 for use in a method for treating pain, wherein the pain is reduced.

[0486] Article 357. The method provides an analgesic effect that is not substantially reduced when measured using a comparative test. any of clauses 341 to 356 for use in a method for treating pain, 1. The oral dosage form of claim 1.

[0487] Article 358. Mean values ​​measured using the cold pressor test at 1, 2, 3, and 4 hours after administration The "cold pain score VAS" was 10 times lower than the comparative treatment method when measured using a comparative test. %. An oral dosage form as defined in clause 357 for use in a method for treating pain.

[0488] Article 359. The method is to prevent the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. Any of the substances listed in Articles 341 to 358 used in methods for preventing or suppressing pain, or for treating pain 10. The oral dosage form according to any one of claims 1 to 9.

[0489] Article 360. Any of the drugs listed in any one of Articles 203 to 232 containing the same amount of oxycodone. By administering the oral dosage form listed above instead, a fixed dose of oxycodone alone can be used to treat pain. A method for preventing or inhibiting adverse pharmacodynamic reactions of oxycodone approved for the treatment of

[0490] Article 361. The adverse pharmacodynamic reactions are euphoria, elation, bowel dysfunction, nausea, vomiting, somnolence. , dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium Symptoms include delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance. Preferably, the adverse pharmacodynamic reactions are selected from the group consisting of respiratory depression, euphoria, elation, and and functional bowel disorders.

[0491] Clause 362. The method of clause 360, wherein said adverse pharmacodynamic reaction is euphoria.

[0492] Clause 363. The method of clause 360, wherein said adverse pharmacodynamic reaction is euphoria.

[0493] Article 364. Any of the items listed in Articles 261 to 290 containing the same amount of oxycodone. By administering the oral dosage form listed above instead, a fixed dose of oxycodone alone can be used to treat pain. A method for preventing or suppressing drug addiction to oxycodone, which is approved for the treatment of

[0494] Article 365. Providing a dosage form according to any one of Articles 261 to 290 to prevent or reduce the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use; How to do it.

[0495] Article 366. Preventing or suppressing the formation of addiction, the occurrence of drug abuse, or the occurrence of recreational drug use. 290. Use of a dosage form according to any one of clauses 261 to 290 in

[0496] Article 367. At least two oral dosage forms containing oxycodone with different active ingredient concentrations a set, each of said dosage forms comprising: (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); and an equimolar amount of oxycodone. (ii) a quantity of buprenorphine; Including, The weight ratio of the amount of buprenorphine to the amount of oxycodone is - expressed as an equimolar amount of buprenorphine base (mg) (Mw = 467.64 g / mol) The amount of buprenorphine and an equimolar amount of oxycodone in the dosage form The amount of the compound in the dosage form expressed as 1,2,3-trimethylsilyl methylpropional (mg) (Mw=351.82 g / mol) A fixed dose of oxycodone, calculated using a ratio greater than 1:40, -having the same value in each dosage form of the set, The set.

[0497] Article 368. The weight ratio of said amount of buprenorphine to said amount of oxycodone. 368. The set of at least two oral dosage forms according to Clause 367, wherein the ratio is about 1:38 or greater.

[0498] Article 369. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is from about 1:3 to over 1:40, or from about 1:3 to about 1:38, as described in Article 367 A set of at least two oral dosage forms of:

[0499] Clause 370. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is from about 1:4 to over 1:40, or from about 1:4 to about 1:38, as described in Article 367 A set of at least two oral dosage forms of:

[0500] Clause 371. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is from about 1:5 to over 1:40, or from about 1:5 to about 1:38, as described in Article 367 A set of at least two oral dosage forms of:

[0501] Clause 372. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is about 1:5 to about 1:35, preferably about 1:5 to about 1:30. A set of at least two oral dosage forms as described.

[0502] Clause 373. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is from about 1:6 to over 1:40, or from about 1:6 to about 1:38, as described in Article 367 A set of at least two oral dosage forms of:

[0503] Clause 374. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio is about 1:6 to about 1:35, preferably about 1:6 to about 1:30, more preferably about 1:6 to about 1:28, or about 1:6 to about 1:20. Both are sets of two oral dosage forms.

[0504] Clause 375. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio of at least two oral dosage forms according to Clause 367 is about 1:8 to about 1:30. tt.

[0505] Clause 376. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio of the at least two oral dosage forms described in Clause 367 is about 1:8 to about 1:28. tt.

[0506] Clause 377. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio of the at least two oral dosage forms described in Clause 367 is about 1:8 to about 1:20. tt.

[0507] Clause 378. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio of the at least two oral dosage forms described in Clause 367 is about 1:8 to about 1:15. tt.

[0508] Article 379. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio of the at least two oral dosage forms according to Clause 367 is about 1:10 to about 1:20. set.

[0509] Clause 380. The weight ratio of said amount of buprenorphine to said amount of oxycodone. The ratio of the at least two oral dosage forms according to Clause 367 is about 1:10 to about 1:15. set.

[0510] Article 381. Each of the dosage forms contains the following amounts: 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); oxycodone hydrochloride in an equimolar amount to one of the following: 1. A set of at least two oral dosage forms according to any one of claims 1 to 0.

[0511] Article 382. Each of the dosage forms contains the following amounts: 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); oxycodone myristate in an equimolar amount to one of the following: A set of at least two oral dosage forms according to any one of clauses 380.

[0512] Article 383. The said set (1) Equivalent to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) A molar amount of oxycodone and about 1 mg to about 6 mg of buprenorphine base (Mw A first solution containing an equimolar amount of buprenorphine (467.64 g / mol) A dosage form; (2) Approximately 10 mg, approximately 15 mg, approximately 20 mg, or approximately 30 mg of oxycodone hydrochloride A small amount of oxycodone was added to the salt (Mw=351.82 g / mol) in an equimolar amount. at least one further dosage form; at least two oral dosage forms according to any one of clauses 367 to 382, set.

[0513] Article 384. The said set (1) Equivalent to approximately 40 mg of oxycodone hydrochloride (Mw = 351.82 g / mol) A molar amount of oxycodone and about 2 mg to about 5 mg of buprenorphine base (Mw A first solution containing an equimolar amount of buprenorphine (467.64 g / mol) A dosage form; (2) Approximately 10 mg, approximately 15 mg, approximately 20 mg, or approximately 30 mg of oxycodone hydrochloride A small amount of oxycodone was added to the salt (Mw=351.82 g / mol) in an equimolar amount. at least one further dosage form; at least two oral dosage forms according to any one of clauses 367 to 382, set.

[0514] Article 385. The oxycodone is oxycodone hydrochloride, and the buprenorphine is Buprenorphine hydrochloride, Articles 367 to 380, 383 and 384 A set of at least two oral dosage forms according to any one of claims 1 to 4.

[0515] Article 386. Each of said dosage forms contains said amount of buprenorphine in immediate release form. A set of at least two oral dosage forms according to any one of clauses 367 to 385, to.

[0516] Article 387. Each of said dosage forms comprises said amount of oxycodone in immediate release form, and Any of Articles 367 to 386 containing said amount of buprenorphine in immediate release form. A set of at least two oral dosage forms according to claim 1.

[0517] Clause 388. Any of clauses 367 to 387, wherein each of said dosage forms is a liquid dosage form. A set of at least two oral dosage forms according to any one of claims 1 to 4.

[0518] Article 389. Each of the above dosage forms is a solution, suspension or emulsion, preferably , and liquid formulations, A set of oral dosage forms.

[0519] Clause 390. Any of clauses 367 to 387, wherein each of said dosage forms is a solid dosage form. A set of at least two oral dosage forms according to any one of claims 1 to 4.

[0520] Article 391. Each of the dosage forms is of the same form selected from tablets or capsules. A set of at least two oral dosage forms according to Clause 390.

[0521] Article 392. After single dose administration, each of said dosage forms provides at least about Average C of buprenorphine at 1:280 max and mean C of oxycodone max The ratio of at least two oral dosage forms according to any one of clauses 367 to 391; set.

[0522] Article 393. Buprenorphine Average C max and mean C of oxycodone max The ratio of the ratio of the at least two oral dosage forms according to Clause 392 is at least about 1:250. set.

[0523] Article 394. Buprenorphine Average C max and mean C of oxycodone max The ratio of the ratio of the at least two oral dosage forms according to Clause 392 is at least about 1:230. set.

[0524] Article 395. Buprenorphine Average C max and mean C of oxycodone max The ratio of the ratio of the at least two oral dosage forms according to Clause 392 is at least about 1:200. set.

[0525] Article 396. Buprenorphine Average C max and mean C of oxycodone max The ratio of the ratio of the at least two oral dosage forms according to Clause 392 is at least about 1:180. set.

[0526] Article 397. Buprenorphine Average C max and mean C of oxycodone max The ratio of the ratio of the at least two oral dosage forms according to Clause 392 is from about 1:50 to about 1:280. Set of.

[0527] Article 398. Buprenorphine Average C max and mean C of oxycodone max The ratio of the ratio of the at least two oral dosage forms according to Clause 392 is from about 1:50 to about 1:250. Set of.

[0528] Article 399. Buprenorphine Average C max and mean C of oxycodone max The ratio of the ratio of the at least two oral dosage forms according to Clause 392 is from about 1:80 to about 1:230. Set of.

[0529] Article 400. Buprenorphine Average C max and mean C of oxycodone max The ratio of The ratio of the at least two oral agents according to Clause 392 is about 1:100 to about 1:200. Set of shapes.

[0530] Article 401. Buprenorphine Average C max and mean C of oxycodone max The ratio of The ratio of the at least two oral agents according to Clause 392 is about 1:100 to about 1:180. Set of shapes.

[0531] Clause 402. After single dose administration, each of said dosage forms provides a 1.5:1 or greater ratio to said subject population. Lower Buprenorphine Mean T max and mean T of oxycodone max further increasing the ratio of A set of at least two oral dosage forms according to any one of clauses 392 to 401. to.

[0532] Article 403. Buprenorphine Average T max and mean T of oxycodone max The ratio of 403. The set of at least two oral dosage forms of clause 402, wherein the ratio is about 1.3:1 or less.

[0533] Article 404. Buprenorphine Average T max and mean T of oxycodone max The ratio of 403. The set of at least two oral dosage forms of clause 402, wherein the ratio is about 1.1:1 or less.

[0534] Article 405. Buprenorphine Average T max and mean T of oxycodone max The ratio of 403. The set of at least two oral dosage forms of clause 402, wherein the ratio is about 1:1 or less.

[0535] Article 406. After administration of a single dose, each of said dosage forms provides said subject group with oxycodone average T max Faster mean T of buprenorphine compared to max Further, the clause A set of at least two oral dosage forms according to any one of clauses 392 to 401.

[0536] Clause 407. After single dose administration, each of said dosage forms is administered to said subject group in 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 The mean T of buprenorphine is approximately 0.9:1. max and mean T of oxycodone max The ratio of and further comprising at least two oral preparations according to any one of clauses 392 to 406. A set of dosage forms.

[0537] Article 408. The set comprises at least three tablets containing oxycodone in different active ingredient strengths. any one of clauses 367 to 407, which preferably comprises at least four dosage forms; A set of at least two oral dosage forms according to claim 1.

[0538] Article 409. (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; administering to a patient in need thereof an oral dosage form comprising Average E of "Emotion VAS" max is at least 15% when measured using a comparative test Decreased and / or Mean E of "Temporary Drug Preference VAS" max is less when measured using comparative tests. and / or Mean E of "Overall Drug Preference VAS" max is less when measured using comparative tests. and / or Mean E of "Drug Relapse VAS" max is at least 1 when measured using a comparative test. 5% decrease, and / or The mean cold pain scores measured using the cold pressor test at 1, 2, 3, and 4 hours after administration were The VAS must not increase by more than 10% compared to the comparator treatment when measured using a controlled test. stomach, A method for treating pain.

[0539] Article 410. (i) a quantity of oxycodone; (ii) a fixed dose of buprenorphine; administering to a patient in need thereof Average E of "Emotion VAS" max is at least 15% when measured using a comparative test Decreased and / or Mean E of "Temporary Drug Preference VAS" max is less when measured using comparative tests. and / or Mean E of "Overall Drug Preference VAS" max is less when measured using comparative tests. and / or Mean E of "Drug Relapse VAS" max is at least 1 when measured using a comparative test. 5% decrease, and / or The mean cold pain scores measured using the cold pressor test at 1, 2, 3, and 4 hours after administration were The VAS must not increase by more than 10% compared to the comparator treatment when measured using a controlled test. stomach, A method for treating pain.

[0540] Article 411. (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; administering to a patient in need thereof an oral dosage form comprising Average E of "Emotion VAS" max is at least 35% when measured using a comparative test Decreased and / or Mean E of "Temporary Drug Preference VAS" max is less when measured using comparative tests. and / or Mean E of "Overall Drug Preference VAS" max is less when measured using comparative tests. and / or Mean E of "Drug Relapse VAS" maxis at least 3 when measured using a comparative test. 0% decrease and / or The mean cold pain scores measured using the cold pressor test at 1, 2, 3, and 4 hours after administration were The VAS must not increase by more than 10% compared to the comparator treatment when measured using a controlled test. stomach, A method for treating pain.

[0541] Article 412. (i) a quantity of oxycodone; (ii) a fixed dose of buprenorphine; administering to a patient in need thereof Average E of "Emotion VAS" max is at least 35% when measured using a comparative test Decreased and / or Mean E of "Temporary Drug Preference VAS" max is less when measured using comparative tests. and / or Mean E of "Overall Drug Preference VAS" max is less when measured using comparative tests. and / or Mean E of "Drug Relapse VAS" max is at least 3 when measured using a comparative test. 0% decrease and / or The mean cold pain scores measured using the cold pressor test at 1, 2, 3, and 4 hours after administration were The VAS must not increase by more than 10% compared to the comparator treatment when measured using a controlled test. stomach, A method for treating pain.

[0542] Article 413. A fixed dose of buprenorphine, preferably as the only opioid analgesic and administering to a patient in need thereof an oral dosage form containing buprenorphine HCl. , a method for treating pain.

[0543] Clause 414. The amount of buprenorphine present in the dosage form is between about 1 mg and about 4 mg. Equimolar to 0 mg of buprenorphine base (Mw=467.64 g / mol) , the method described in Article 413.

[0544] Article 415. The daily dose is from about 1 mg to about 40 mg of buprenorphine base (Mw=467 The method of claim 413, wherein the amount is a constant amount equimolar to the amount of the compound (0.64 g / mol).

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

[0546] Article 417. A fixed dose of buprenorphine, preferably as the only opioid analgesic , an oral dosage form containing buprenorphine HCl.

[0547] Article 418. Buprenorphine is prepared by administering from about 1 to about 40 mg of buprenorphine base (Mw = 467.64 g / mol) in said dosage form in a constant amount equimolar to The dosage form described in

[0548] Article 419. Buprenorphine is administered at doses of approximately 2.5, approximately 5, approximately 10, approximately 15, approximately 20, and approximately 30 , and for approximately 40 mg of buprenorphine base (Mw=467.64 g / mol) 419. The dosage form of clause 418, wherein the isomers are present in the dosage form in equimolar amounts.

[0549] Clause 420. The dosage form comprises the amount of buprenorphine in immediate release form. 17 to 419. A dosage form according to any one of clauses 17 to 419.

[0550] Article 421. The dosage form is a liquid, such as a solution, suspension or emulsion. 420. A dosage form according to Clause 420.

[0551] Clause 422. The dosage form is a solid, such as a tablet or capsule. Clause 42 The dosage form described in 0.

[0552] Article 423. The amount of oxycodone is administered orally, and the amount of buprenorphine is administered orally. The drug is administered transdermally, Articles 291 to 306, Articles 323 to 340, Article 41 0 and the method according to any one of clauses 412.

[0553] Article 424. The amount of oxycodone is administered orally, and the amount of buprenorphine is administered orally. The drug is administered subcutaneously, Articles 291 to 306, Articles 323 to 340, Article 41 0 and the method according to any one of clauses 412.

[0554] Article 425. The amount of oxycodone is about 5 mg to about 50 mg of oxycodone hydrochloride. salt (Mw=351.82 g / mol), preferably about 5 mg to about 40 mg of oxycodone Article 423 or Article 424 Item 424. The method according to item 424.

[0555] Article 426. The amount of oxycodone is about 10 mg, about 15 mg, about 20 mg, about 30 mg, or approximately 40 mg, of oxycodone hydrochloride (Mw=351.82 g / mol) The method of claim 423 or 424, wherein the molar ratio is equimolar to

[0556] Article 427. The oxycodone is oxycodone hydrochloride and the buprenorphine is The method according to any one of clauses 423 to 426, wherein the compound is buprenorphine hydrochloride. .

[0557] The invention will now be described with reference to the accompanying examples. are illustrative only and should not be construed as limiting the invention in any manner. It should be understood that. [Example]

[0558] Example 1 Example 1 describes the effects of oxycodone hydrochloride on abuse potential, pain management, and co-administered and 32 healthy male and female recreational subjects to evaluate the pharmacokinetics of buprenorphine. A single-center, double-blind, placebo-controlled, positive-controlled, randomized, cross-sectional study in opioid users. The study was a randomized, double-blind, crossover study. During each period, 16 subjects received oral and transdermal treatments. The study was conducted in two replicates, replicate 1 and replicate 2, including the elephant, but replicate 1 included only 15 subjects. One subject discontinued for reasons unrelated to study drug. , abuse potential, and the effects of co-administered oxycodone hydrochloride and buprenorphine Pharmacokinetics was assessed, and in Replicate 2, pain management was additionally assessed. Pharmacokinetic results of oxycodone hydrochloride and buprenorphine administered at the same time The results of Replicate 1 and Replicate 2 were combined to give N=32, whereas for pain management, The N=16 consisted of only group 2.

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

[0560] Each buprenorphine dose was compared with three oxycodone doses administered in random order. Administered. Oxycodone HCl (351.82 g / mol) IR (0 mg), (lactose powder) Capsule, oral Oxycodone HCl (351.82 g / mol) IR (20 mg), ZyGene Blind-coated oral tablets manufactured by rics Oxycodone HCl (351.82 g / mol) IR (2 x 20 mg), ZyGe Blinded, coated oral tablets manufactured by nerics A total of six treatments. ·placebo OxyIR-20 OxyIR-40 Butrans-20 Butrans-20 / OxyIR-20 Butrans-20 / OxyIR-40

[0561] During each period, buprenorphine (Butrans 20 mcg / hour) transdermal patches were administered. Subjects were randomized to receive either a placebo or a placebo transdermal patch for 108 hours, after which they were removed. During each design period, oxycodone was administered at 48, 72, and 96 hours after patch application. Patients were given either donor IR or placebo orally. The administration scheme is summarized in Figure 1. There are.

[0562] Selecting a target Patients with a history of oral use who were deemed appropriate by the investigator to participate in this clinical trial were 18 Healthy men aged 18 to 55 years (including 18 and 55 years) with no clinically significant medical history and Female recreational opioid users were selected.

[0563] After the screening phase, appropriate measures are taken to exclude subjects who are physically dependent on opioids. Subjects underwent a naloxone challenge test.

[0564] To be eligible for the treatment phase, subjects with self-reported recreational opioid experience were required to receive controlled In addition to reporting clear subjective effects of drugs in controlled testing environments, It was confirmed that IR and placebo could be tolerated and distinguished. For "placebo responders," i.e., subjects who report a subjective effect of the placebo, Excluded.

[0565] Subjects who met all inclusion criteria and no exclusion criteria were randomized into the study.

[0566] Inclusion criteria 1.Submit written informed consent. 2. Subjects must be male or female between the ages of 18 and 55 (inclusive). and. 3. 18.0 to 34.0 kg / m at screening 2 Range (18.0k g / m 2 and 34.0 kg / m 2 Body Mass Index (BMI) within 5 years (including Have a minimum weight of 0.0kg. 4. The following criteria were met: 1) at least 10 non-therapeutic (i.e., psychotropic) 1) use of opioids for the treatment of rheumatoid arthritis; and 2) use of opioids for the treatment of rheumatoid arthritis in the 12 weeks prior to screening. have used opioids at least three times in a single day, and have moderate experience with opioids. Being an ID user. 5. Opioid equivalent to 30 mg or more of oxycodone IR at least once in the previous year Doses must be reported. 6. Women of heterosexual sexual reproductive potential are not permitted to take the study drug during or at the end of the study. Adequate and reliable contraception must be used for at least 30 days after treatment. Heterosexual women who are postmenopausal and not using approved contraception The sex was defined as being postmenopausal for ≥1 year and having high serum follicle-stimulating hormone (FSH) levels (i.e. , ≥ 50mIU / mL). 7. Female subjects must have a negative pregnancy test at screening and / or admission. be. 8. Understand the contents of the study, provide written informed consent, and participate in all studies. Be able to speak, read, and understand English sufficiently to complete the assessment. 9. Must be willing and able to comply with all testing requirements and regulations. do.

[0567] Exclusion criteria 1. Physical examination, medical history, as determined by the investigator or designee at screening Clinically significant abnormalities in 12-lead electrocardiogram (ECG), vital signs, or laboratory values . 2.The Diagnostic and Statistical Manual as defined in the Division of Mental Disorders (DSM-IV) self-reported history of drug or alcohol dependence (in the past 2 years), ever having used a drug registrable drug Subjects who have been in a habilitation program (smoking cessation treatment or case On a case-by-case basis, for example, to reduce incarceration or for marijuana use only (with the exception of alternative conditions to incarceration), or current drug or alcohol dependence. Current medical conditions (within the last 12 months, excluding nicotine or caffeine). 3. Any activity that, in the opinion of the investigator, jeopardizes the safety of the subject or the validity of the study results. Any clinically significant disease (e.g., cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, glandular, immune, cutaneous, neurological, oncological, musculoskeletal, or psychiatric) or any other medical condition History or presence of 4. Any personal or family history of QT interval prolongation or cardiac rhythm disorder. 5. Below, QTcF interval >450 msec at screening QTcF interval >48 recorded during any ECG at check-in or during treatment 0 milliseconds An abnormal heart condition, including any of the following: 6. Clinically significant as determined by the investigator or designee, History or presence of hypotension. 7. Prohibited drugs (i.e., non-prescription drugs, prescription drugs, herbal products, or natural health products) ) use. 8.Currently pregnant or nursing during the study or within 30 days after the last dose of study drug Intended for women who are pregnant or planning to become pregnant. 9. Alanine aminotransferase (ALT) or aspartate aminotransferase AST >1.5x the upper limit of normal (ULN) or serum total Evidence of clinically significant liver or kidney impairment, including >10% above the ULN. 10. Severe allergic reaction (anaphylaxis) to any food, drug, or bee sting history of asthma (including asthma) or previous status asthmaticus. 11. Oxycodone, buprenorphine, naloxone or related drugs (e.g., other opioids or opioid antagonists), or pharmaceutical excipients or History of allergy or hypersensitivity to any of the other ingredients of this medicine. 12. History of allergy to lactose. 13. Positive for Hepatitis B and Hepatitis C. 14. Except as required by this Protocol, within 56 days prior to entering the Qualification Phase, or or donated whole blood up to the EOS visit and within 30 days after the completion of the EOS visit thing. 15. Except as required by this Protocol, within 14 days prior to entering the Qualification Phase, or or have donated plasma by the end of study (EOS) visit. 16. Difficult venous access or catheterization is inappropriate or undesirable If it is not desirable. 17. Have had any study drug treatment within 30 days prior to the first drug administration of naloxone provocation The patient is receiving treatment. 18. Consumed an average of more than 20 cigarettes per day in the month prior to screening and / or refrain from smoking (or using any nicotine-containing substance) for at least 18 hours. The inability to do so. 19. Positive urine drug screen at screening and / or admission Positive results may be repeated and / or discontinued at the investigator's discretion. Subjects may reschedule, although this is at the discretion of the investigator on a case-by-case basis. For tetrahydrocannabinol (THC) positive results, a licensed physician must be present to conduct the test. After a thorough physical examination (either a detailed or brief physical examination) and interview, the subject is diagnosed with cannabinoid-related If it is confirmed that the equipment is not under influence, it may be permitted. 20. Any activity that, in the opinion of the investigator, may interfere with study procedures or data integrity; and has any medical condition that may jeopardize the subject's safety. 21. In the opinion of the investigator or designee, for any other reason, Subjects deemed suitable or unlikely to comply with the study protocol The target. 22. Have an allergy or other contraindication to transdermal systems or patch adhesives The subject. 23. Clinically relevant information regarding allergic reactions to wound dressings or Elastoplast Significant medical history. 24. Any skin condition that prevents proper placement and / or rotation of the patch. The object to be attached at the site of application. 25. Taking antihistamines within 72 hours prior to administration or taking antihistamines within 3 hours prior to administration Treatment with systemic or topical corticosteroids within the past week. 26. Shave any hair at the recommended patch application site that may interfere with proper placement of the patch. Subjects who cannot. 27. Subjects with a history of frostbite or any current injury or abnormality to the non-dominant hand ( Subjects with skin, circulatory, or nervous system abnormalities, if applicable. 28. Any reason not listed above (e.g., safety concerns in the subject, or The investigator may consider the study to be inappropriate due to concerns about the scientific integrity of the study. elephant.

[0568] Naloxone provocation criteria For clinical evaluation of withdrawal signs and symptoms during naloxone provocation testing, 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). If the elephant's OOWS score is ≥ 3, the symptoms in question are not related to opioid withdrawal. The subject was excluded from further participation in the study.

[0569] Eligibility Criteria Pharmacodynamic evaluation confirmed appropriate placebo and baseline effects, and oxycodone I Subjects who did not consistently discriminate between R and placebo were screened out. The subject must be comfortable with and complete the procedure, follow instructions, and be cooperative. It showed that it was possible.

[0570] Subjects had to pass the following eligibility criteria to be eligible to enter the treatment phase: "Temporary" Drug Preference VAS (at least 15 points on this bipolar scale) difference between the two), drug relapse VAS (a difference of at least 15 points on this bipolar scale) Difference), and Overall Drug Preference VAS (at least 10 points on this bipolar scale) The peak score (E) of the placebo max ) higher, adjusted Oki Peak score for Cycodon IR (E max ) for oxycodone IR, A peak score of ≥ 65 on the Drug Preference VAS and an overall Drug Preference VAS and must demonstrate a peak score of ≥65 on the medication reuse VAS. Drug Preference VAS, Overall Drug Preference VAS and Drug Reuse VAS (i.e., 4 Scores ranged from 0 to 60 (including 40 and 60) and euphoria VAS (peak score ranged from 0 to 10) Acceptable placebo effect in scores (defined as 0 and 10 inclusive). - Determined by the principal investigator or designated sub-investigator based on available safety data and ability to tolerate oxycodone. A general indication, as judged by clinical staff, that the subject successfully completed the study behavior.

[0571] Difficulty distinguishing between bipolar and unipolar scales (e.g., The eligible subjects (who make mistakes such as choosing 50 as the middle) are actually They received additional practice training on the differences between the different types of lenses.

[0572] Cold pressor tests (repeat 2) were performed five times on each day of administration, and the efficacy of the active drug was compared with placebo. Subjects who did not demonstrate adequate pain control after the procedure were excluded from the treatment phase.

[0573] Exclusion of subjects from study participation The subjects were informed that they had the freedom to discontinue the study at any time and for any reason. If, in the opinion of the attending physician, it is not in the subject's best interest to continue the trial, the investigator Subjects were excluded from the study if there was clinical significance to the subject's safety and efficacy. Changes in inclusion / exclusion criteria that affect the occurrence of adverse events (AEs) or safety of the subject Concomitant medications prohibited by the protocol that may affect the sex or evaluation / objectives of the study Notification of the discontinuation was given to the sponsor (or its designee). Ta.

[0574] If study participation is terminated early, every effort will be made to conduct all end-of-study evaluations. All subjects who discontinued early were included in ongoing and ongoing studies as described in Section 10. Newly occurring AEs were followed up.

[0575] Subjects who discontinued the study early due to an AE were included in the United States, if feasible. Food and Drug Administration's (FDA) 's)Guidance for Industry-Premarketing Ri Per the SK Assessment (March 2005), appropriate information related to the event Eight copies of relevant hospital records, autopsy reports, biopsy reports, and radiology reports were obtained.

[0576] The reasons for failing the screening are as follows: The subject does not meet all inclusion criteria or meets any exclusion criteria. (criteria are recorded), or Subject selection (subjects choosing to withdraw from the study for personal reasons, e.g., A family emergency that prevents the subject from continuing the study, the subject's relocation, or the subject's new work schedules that prevent further study participation); Lost to trace (study facility personnel lose contact with the subject), or Subject withdrawal from the study due to an adverse event or serious adverse event (AE or SAE) (if applicable), or Administrative reasons (any logistics related to either the clinical site or the sponsor) Subjects discontinue the study early for ethical, non-medical reasons, e.g., when the sponsor or the clinical site is no longer able to conduct the study or or approval to conduct the test), It consists of:

[0577] The reasons for cancelling the test are as follows: Adverse events (subjects withdrawing from the study due to adverse events), or Subject selection (subjects choosing to withdraw from the study for personal reasons, e.g., A family emergency that prevents the subject from continuing the study, the subject's relocation, or the subject's a new work schedule that prevents further study participation), or Loss of traceability (study facility personnel lose contact with subject). If loss of contact with subject is suspected, The testing facility must conduct at least three recordings (separated by at least one week). For this purpose, an attempt should be made to contact the subject by telephone. In addition, a copy should be kept on file. The test facility must keep this information (e.g., telephone service) and send a registered copy. The service has been terminated or there is other evidence that communication is not feasible. 30 days after the first call recording, unless circumstances preclude After this time, the subject can only be considered untraceable, or - Confirmed or suspected diversion, or Administrative reasons (any logistics related to either the clinical site or the sponsor) Subjects discontinue the study early for ethical, non-medical reasons, e.g., when the sponsor or the clinical site is no longer able to conduct the study or or approval to conduct the test), It consists of:

[0578] If a subject is discontinued due to subject selection, administrative reasons, or loss to follow-up, the discontinuation will be The specific circumstances involved needed to be recorded.

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

[0580] For oral treatment, administer with 240 mL of water after an overnight fast (i.e., at least 10 hours). The subjects were administered the test drug at 10:00 AM, followed by a 4-hour fast (excluding water). An oral check was performed to ensure the dose was swallowed.

[0581] For transdermal treatment, the following approved areas of interest: ·Upper outer arm ·Upper chest ·Upper back Side of the chest The transdermal patch was attached to one of these four sites (located on both sides of the body). ) provides eight possible application sites. For specific instructions, see the Dispensing Manual and Site Operations Manual. It was stipulated in the anual.

[0582] Blood sample collection and analysis At the following time points, the baseline was set to -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 period, plasma concentrations of oxycodone and buprenorphine were measured. A blood sample for determination was obtained from each subject.

[0583] Buprenorphine-d4 and oxycodone-d3 were used as internal standards, and 200 The buprenorphine and oxycodone concentrations were determined from 1 μL of human plasma. The samples were extracted using the LLE (Likely abbreviation for LLE) method. A gradient system of 0.1% formic acid in acid and acetonitrile was used to measure Luna ( The extract was chromatographed under normal phase conditions on a 2 × 50 mm, 3 μm silica HPLC column (Trademark). Buprenorphine and oxycodone were detected and analyzed by Turbo Io MDS Sciex API 5000 (trademark) equipped with an nspray interface ) in positive ion mode and quantified by tandem mass spectrometry. The linear ranges of quantification for xycodone were 25–12,500 pg / mL and 100–50,000 pg / mL, respectively. 000pg / mL.

[0584] Abuse Potential Testing The first scale was "0 = strong dislike", "50 = neither like nor dislike", and "100 = strong dislike". A "temporary" drug preference visual analog scale (VAS, bipolar) anchored at "high preference" and "low preference" = strong dislike,” “50 = neither like nor dislike,” and “100 = strong preference.” Overall Drug Preference VAS and a scale of 0 = not at all, 50 = moderate, and 100 = completely The second scale was a drug reuse VAS anchored at 0 = not at all and 1 = no. The subjective scales were all rated on a 100 scale. The conclusions regarding relative abuse potential were indeed based on the following points in all The effects of the first and second measures were taken into account. Balance of Effects: "Temporary" Drug Preference VAS (E max ) Overall Drug Preference VAS (Emax ) Drug relapse VAS (E max ) Positive / euphoric subjective effects ·Average feeling of elation VAS (E max )

[0585] Pain control test, cold pressor test The water temperature is maintained at 0-2°C and the circulatory system can accommodate an adult's hand immersed up to the wrist. The cold pressor test (CPT) was performed using a water bath. The temperature was kept within the range of 0-2°C, ideally The range of motion was set at 1°. A range of motion greater than 2° was considered to be inappropriate for the range of motion to affect the pain experienced by the subject. Avoided in order to get.

[0586] The non-dominant hand is preferred, but the dominant hand may be used if necessary. Using a similar pen, a staff member drew a line on the subject's wrist distal to the radius and ulna. During the test, the subject was seated or standing and wore a tether up to the line on their wrist. Subjects were instructed to quickly submerge their hands in the water bath until the pain became unbearable. Participants were instructed to keep their hands open and relaxed while immersed. The maximum duration of the experiment was 2 minutes. Subjects were allowed to remove their hands from the water at any time. If you feel the pain is unbearable, you should not keep your hand in the water. The duration of hand immersion was measured from the moment of complete immersion until the subject was able to hold his or her hands in the water. The starting time (seconds) and duration (seconds) were recorded in the source document. It was recorded in the ment.

[0587] Subjects were asked to rate their response on a scale of "0 = pain" until they removed their hand from the bath or reached the maximum duration of immersion. A 100 mm visual analog scale (VAS) was used, anchored at 100 = no pain and 100 = worst pain. Pain levels were graded every 15 seconds using a visual analog scale (VAS).

[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 Relapse" max Comparisons were also based on VAS. ,The results are shown in Figures 9 and 10, respectively.

[0590] Example 2 A non-randomized, oral study in eight healthy male or female subjects under naltrexone blockade. Example 2 was conducted in a single-label, crossover, single-dose study to evaluate oral buprenorphine The pharmacokinetics of the hydrochloride salt was evaluated. Treatment consisted of oral and intravenous buprenorphine hydrochloride. There will be a 6-day washout period between study drug administrations.

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

[0592] Each treatment requires 1 minute of pre-administration monitoring to minimize opioid-related adverse events (AEs). Naltrexone HCl tablets (50 mg) for 12 hours between 2 hours and 36 hours after administration At the investigator's discretion, subjects who report intolerance to the 50 mg dose will be excluded. was administered a 25 mg naltrexone HCl dose with 240 mL of water. The subjects were administered acetaminophen HCl.

[0593] Selecting a target Healthy men aged 18-55 years (inclusive) with no clinically significant medical history and female subjects were deemed appropriate by the investigator to participate in this clinical trial.

[0594] Subjects who met all inclusion criteria and no exclusion criteria were randomized into the study.

[0595] Inclusion criteria 1.Submit written informed consent. 2. Subjects must be male or female between the ages of 18 and 55 (inclusive). and. 3. 18.0 to 34.0 kg / m at screening 2 Range (18.0k g / m 2 and 34.0 kg / m 2 Body Mass Index (BMI) within 5 years (including Have a minimum weight of 0.0kg. 4. Women of heterosexual sexual reproductive potential are not permitted to take the study drug during or at the end of the study. Adequate and reliable contraception must be used for at least 30 days after treatment. Heterosexual women who are postmenopausal and not using approved contraception The sex was defined as being postmenopausal for ≥1 year and having high serum follicle-stimulating hormone (FSH) levels (i.e. , ≥ 50mIU / mL). 5. Female subjects must have a negative pregnancy test at screening and / or admission. be. 6. Understand the contents of the study, provide written informed consent, and participate in all studies Be able to speak, read, and understand English sufficiently to complete the assessment. 7. Must be willing and able to comply with all testing requirements and regulations. do.

[0596] Exclusion criteria 1. Physical examination, medical history, as determined by the investigator or designee at screening Clinically significant abnormalities in 12-lead electrocardiogram (ECG), vital signs, or laboratory values . 2. Any activity that, in the opinion of the investigator, jeopardizes the safety of the subject or the validity of the study results. Any clinically significant disease (e.g., cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, glandular, immune, cutaneous, neurological, oncological, musculoskeletal, or psychiatric) or any other medical condition History or presence of 3. Any personal or family history of QT interval prolongation or cardiac rhythm disorder. 4. Below, QTcF interval >450 msec at screening QTcF interval >48 recorded during any ECG at check-in or during treatment 0 milliseconds An abnormal heart condition, including any of the following: 5. Clinically significant as determined by the investigator or designee, History or presence of hypotension. 6. Prohibited drugs (i.e., non-prescription drugs, prescription drugs, herbal products, or natural health products) ) use. 7.Currently pregnant or nursing during the study or within 30 days after the last dose of study drug Intended for women who are pregnant or planning to become pregnant. 8. Alanine aminotransferase (ALT) or aspartate aminotransferase AST >1.5x the upper limit of normal (ULN) or serum total Evidence of clinically significant liver or kidney impairment, including >10% above the ULN. 9. Severe allergic reaction (anaphylaxis) to any food, drug, or bee sting history of asthma (including asthma) or previous status asthmaticus. 10. Oxycodone, buprenorphine, naloxone or related drugs (e.g., other opioids or opioid antagonists), or pharmaceutical excipients or History of allergy or hypersensitivity to any of the other ingredients of this medicine. 11. History of allergy to lactose. 12. Positive for Hepatitis B and Hepatitis C. 13. Except as required by this Protocol, within 56 days prior to entering the Qualification Phase, or or donated whole blood up to the EOS visit and within 30 days after the completion of the EOS visit thing. 14. Except as required by this Protocol, within 14 days prior to entering the Qualification Phase, or or have donated plasma by the end of study (EOS) visit. 15. Difficult venous access or catheterization is inappropriate or undesirable. If it is not desirable. 16. Have had any study drug treatment within 30 days prior to the first drug administration of naloxone provocation The patient is receiving treatment. 17. Positive urinary cotinine result, frequent (>1x per week) smoking, or study drug administration Use of nicotine products within the last 45 days. 18. Positive urine drug screen at screening and / or admission Positive results may be repeated and / or discontinued at the investigator's discretion. The recipient may change the date. 19. Any activity that, in the opinion of the investigator, may interfere with study procedures or data integrity; and has any medical condition that may jeopardize the subject's safety. 20. In the opinion of the investigator or designee, for any other reason, Subjects deemed suitable or unlikely to comply with the study protocol The target. 21. Any reason not listed above (e.g., safety concerns in the subject, or The investigator may consider the study to be inappropriate due to concerns about the scientific integrity of the study. elephant.

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

[0598] For oral treatment, subjects received a liquid dose of the test drug, followed by four 35 mL rinses with water. The total volume of water consumed was 240 mL (including the water in the dose solution plus 4 rinses). It was.

[0599] Oral solution treatment was administered after an overnight fast (i.e., at least 10 hours), followed by 4 p.m. Fasting (excluding water) was performed between the two days.

[0600] Blood sample collection and analysis At the following time: IR oral solution: Pre-administration and 0.25, 0.5, 1, 1.5, 2 after administration of the study drug , 2.5, 3, 4, 5, 6, 8 and 12 hours, IV: Pre-dose, 2, 5, 10, and 15 minutes (infusion stopped at 15 minutes), and infusion 2, 5, 10, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8 and 12 hours after stopping During each period, blood samples were taken to measure the plasma concentration of buprenorphine. Fees were obtained from each subject.

[0601] Buprenorphine-d4 was used as an internal standard and buprenorphine was extracted from 150 μL of human plasma. Renorphin concentrations were quantified. Samples were extracted using the protein precipitation extraction (PPE) method. Gradient system with 0.1% formic acid in water and 0.1% formic acid in acetonitrile on an Xbridge C18 HPLC column (4.6 x 50 mm, 3.5 μm). The extract was chromatographed under reversed-phase conditions. Buprenorphine was detected and Turbo MDS Sciex API 5000 equipped with an Ionspray interface Quantification was performed by tandem mass spectrometry using buprenorphine (trademark) in positive ion mode. The linear range of quantification was 25 to 2,500 pg / mL.

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

[0603] Example 3 Experimental design After the animals' arrival, they were kept in a dark room (12 hours on / 12 hours dark) for at least 6 days before testing. The animals are acclimatized to an environment with controlled lighting, humidity, and temperature. Rats are housed in a cage of 2-3 animals. Before starting any behavioral testing, house the animals at 5 / cage for mice. Food and water should be available ad libitum. For administration of test compounds, animals were allowed to have food overnight (maximum 16-24 hours). do not have.

[0604] Experiments included 8-12 animals per experimental group, each with a stenosis on its tail. Each study contains 4-6 experimental groups, so the potential Dose-response and / or time course analyses for potential therapeutic agents can be performed. Design also allows for the inclusion of both negative and positive controls in each experiment. Individual experiments may vary with respect to test doses and evaluation times, but should be consistent with the known properties of the test drug. It can be adjusted to.

[0605] For most studies, a single dose of test compound is administered 0.5–1 h before behavioral assessment. Typically, behavior is assessed over a PK-specified time course for up to 24 hours after administration.

[0606] The recommended "good practice" dose volumes for these studies in rats 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 is.

[0607] The dose volume in mice was: PO (oral) = 10 ml / kg, SC (subcutaneous) = 10ml / kg, IP (intraperitoneal) = 10 ml / kg, and IV (intravenous) = 5 ml / kg Examples include:

[0608] Vehicles included sterile water, 0.9% saline, and 2% Tween / 0.5% methylcellulose. , and 25% 2-hydroxypropyl-β-cyclodextrin (HPBCD) In all routine assays, a vehicle control group is run concurrently with the drug-treated groups. A positive control compound was also included in every assay.

[0609] All studies were conducted in a manner that ensured that all experiments included in the study were blinded to the group assignment of any animals tested. The study will be conducted in a blinded, unbiased manner. The baseline effect thresholds will be used to ensure that group means are approximately equal. Animals are assigned to treatment groups using a blinded method after a pre-treatment baseline assessment. It is administered under laboratory conditions.

[0610] animal species Animals used in the assay were provided by Sage (Boyertown, PA), Jac kson (Bar Harbor, Maine) or Harlan Labs (Ind or alternatively, mating pairs (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, and Transgenic / knockout mice (129 / C57BL / 6 background) Do), They are bred in the laboratory using

[0611] Interpreting the results To reveal the statistical significance of compounds compared to vehicle treatment, use Graph Pad Prism™ was used to analyze raw data (i.e., latency, distance traveled, temperature) One-way or two-way ANOVA was performed. The criterion for significance was P < . Set to 0.05.

[0612] Example 3A Respiratory Depression To assess respiratory depression, analysis of arterial PCO2 and PO2 levels was performed. Rats with indwelling arterial catheters were purchased from Harlan.

[0613] Rats were co-administered SC with opioids and buprenorphine in the dorsal tail, or SC Rats were given doses of C opioids or buprenorphine alone. This involves injecting the compound into an alternative site but in a conservative manner.

[0614] After compound administration, baseline (time 0), then 1, 3, and 5 hours after SC administration were measured. At intervals, arterial blood samples (successively) were collected from an indwelling catheter (Harlan Labs, IN). A total of 180-200 microliters of blood was collected. Samples were collected using a syringe pump (Innovative Med Tech). offman et al.(Effects of NMDA receptor a ntagonists on opioid-induced depression and acute antinociception in rats.Pharma col Biochem Behav 74:933-941, 2003) Blood gas analyzer (ABL805, Radiometer America, Westl make, OH) to measure pH, pCO2, pO2, and sO2 (i.e., oxygen saturation) The samples were immediately analyzed for levels of .

[0615] To assess pH, pCO2, pO2, and sO2 in animals, a subset of rats were Carotid artery catheterization was performed.

[0616] result Rat blood gas parameters: A) pCO2 and B) sO2 (i.e., oxygen saturation) Buprenorphine, oxycodone, hydromorphone, and fentanyl alone The effects of each are shown in Figures 17 to 20. As shown in the figures, buprenorphine The effect of acetaminophen (0.05-3 mg / kg, sc) on arterial pCO2 and oxygen saturation in rats was Oxycodone (3 and 8 mg / kg), hydrochloride (10 mg / kg), and hydroxybenzoates (10 mg / kg) had a small but significant effect on Lupone (1-10 mg / kg) and fentanyl (0.5-1.5 mg / kg) It has significant effects on arterial pCO2 and oxygen saturation in rats.

[0617] Figures 21A) to 21D) show rats (male Sprague-Dawley rats, body Arterial blood gas (ABG) parameters in rats (weight = 192-262 g, n = 6-13 / group): A) Oxycodone-induced disturbances in A) sO2%, B) pO2, C) pCO2, and D) arterial pH Figure 22A-B shows the effect of buprenorphine on rats 1 hour after administration. Arterial blood gas (ABG) parameters: A) pCO2% and B) sO2% The figure shows the effect of buprenorphine on steroid-induced impairment. kg sc oxycodone was standardized to 0.5–3 mg / kg sc buprenorphine. Regarding the pCO2 and sO2%, there was a significant increase in pCO2 and a significant decrease in sO2%. This caused.

[0618] Furthermore, Figure 23 shows that 8 mg / kg sc oxycodone rescued the respiratory dysfunction. This produced sufficient analgesia in rats that was not reduced by buprenorphine at this dose. This shows that:

[0619] Figures 24A) to 24E) show rats (male, Sprague-Dawley operated rats), respectively. , body weight = 217-270g, n = 8-18 / group, Harlan Surgery) Blood gas (ABG) parameters: A) sO2%, B) pO2, C) pCO2, and D) kinematic Buprenorphine on fentanyl-induced impairment of pulse blood pH and acid-base status Figure 25A) and B) show the effect of fin on the arterial blood flow in rats 1 hour after administration. Absorbed Blood Graft (ABG) parameters: A) pCO2% and B) sO2% in response to fentanyl-induced impairment As shown in the figure, the effect of buprenorphine on Fentanyl is standardized to 0.5 mg / kg sc buprenorphine. 2 and sO2%, which caused a significant increase in pCO2 and a significant decrease in sO2%. Furthermore, Figure 26 shows that 0.5 mg / kg sc fentanyl rescues the respiratory dysfunction. produced sufficient analgesia in rats that was not reduced by the same dose of buprenorphine. This shows that

[0620] Figures 27A) to 27D) show rats (male, Sprague-Dawley operated rats), respectively. , body weight = 217-270g, n = 8-18 / group, Harlan Surgery) Blood gas (ABG) parameters: A) sO2%, B) pO2, C) pCO2, and D) kinematic 1 shows the effect of buprenorphine on hydromorphone-induced disturbances in pulse blood pH. Figure 28A) and B) show the arterial blood gas (ABG) parameters of rats 1 hour after administration: Buprenorphine on hydromorphone-induced impairment of B)pCO2% and C)sO2% As shown in the figure, 10 mg / kg sc hydromorphone has a 0. 5mg / kg sc buprenorphine was used for standardized pCO2 and sO2%. This resulted in a significant increase in pCO2 and a significant decrease in sO2%. 0 mg / kg sc hydromorphone rescued respiratory dysfunction at the same dose as buprenoline. This indicates that acetaminophen produced sufficient analgesia in rats that was not reduced by acetaminophen. .

[0621] Effects of various opioids in a model on arterial blood gas parameters in rats (Br The list of treatments (with and without prenorphine) is given in Tables 21 and 22, respectively. It is shown. [Table 21] [Table 22]

[0622] Example 3B Lethality Test The purpose of this test is to assess lethality. It is expected that animals will appear moribund. Such animals are expected to die shortly after they appear moribund. No pain or distress is associated with this, which is consistent with rapid loss of consciousness, respiratory and ventilatory depression. The mechanism of opioid-induced lethality is due to the gradual deepening of sedation associated with be.

[0623] Obvious side effects, including rigidity, sedation, and unresponsiveness to touch and / or startle, were reported. Male Sprague-Dawley or Hans Wistar rats (H (supplied by Arlan Labs, Indianapolis, IN) Death occurs due to lack of response to tail pinch, lack of breathing, and / or post-mortem Confirm by the onset of rigor.

[0624] In most studies, a single dose of the test compound or combination is administered. The recommended "good practice" dose volumes for these studies are hereafter referred to as IV (intravenous) = It is 1-2ml / kg.

[0625] Opioid agonists (oxycodone, fentanyl, and hydromorphone) and buprenorphine The results of lethality tests in rats using the norphine combination are shown in Figures 30-31. 32. Of note, the values ​​of 0.46875 mg / kg and 0.9375 mg / kg, and buprenorphine at an IV dose of 1.875 mg / kg was compared with oxycodone (30 0.56 mg / kg, IV) resulted in a complete reversal of induced lethality (Figures 30A and B). Buprenorphine at a 25 mg / kg IV dose was significantly lower than fentanyl (2.25 mg / kg, IV) It resulted in a complete reversal of induced lethality (Figures 31A and B).

[0626] Similarly, for IV doses of 0.5 mg / kg, 3.125 mg / kg, and 12.5 mg / kg Buprenorphine in this amount also reduced hydromorphone (100 mg / kg, IV)-induced mortality. significantly reduced development (Fig. 32A and B).

[0627] Example 4 A two-part, single-center study of healthy subjects and / or healthy recreational opioid users; Design a randomized, double-blind, multi-stage study, with each part having several replications. The replication consists of up to six periods. Cohorts can include only healthy subjects or both healthy and unhealthy subjects. Only healthy recreational opioid users were included.

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

[0629] Each part should be tailored to the target (e.g., adequate tolerability, HCVR, PK or other performance The study may include a qualification step to screen for subjects who do not exhibit the above-mentioned parameters. If the subject has already been qualified in a previous part / iteration, the qualification (if applicable) Each qualification cohort will consist of up to four periods. Cohorts are administered in parallel. Cohorts may include only healthy subjects or only healthy subjects. Only recreational opioid users with significant risk of respiratory depression were included. Up to two opioids, each of up to two dose strengths, will be administered to determine the appropriate dose. There will be a minimum washout of approximately 24 hours between doses.

[0630] Study design Part 1 is a study of opioid-induced respiratory depression (OIRD)-producing drugs that produce easily quantifiable opioid-induced respiratory depression (OIRD). The purpose of each repetition is to clarify the complete opioid administration regimen. It will consist of up to four cohorts of 20 subjects each. Each cohort will have a maximum The study consists of four periods. Cohorts are administered in parallel. In each cohort: up to two dose strengths of each to determine a safe and tolerable dose that induces respiratory depression Up to two opioids (IV fentanyl, IV hydromorphone, IV morphine) In the cohort, each opioid was administered The dose is titrated from low to high, with a minimum washout period of approximately 24 hours between doses. An outlet will be provided.

[0631] In part 2, the opioids transdermal buprenorphine co-administered with hydromorphone The effect on induced respiratory depression was evaluated.

[0632] Part 2a) was a single-blind, non-randomized, two-period crossover study of 16 patients. Healthy recreational opioid users receiving transdermal buprenorphine (Butrans® 20 mcg / hour) or placebo patches (applied for approximately 4.5 days). During the study, three separate hydromorphones were administered at 48, 72, and 96 hours after patch application. dosage, Hydromorphone 1.5 mg IV infusion (divided into 2 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 infusion (divided into 2 infusions) Hydromorphone 1.25 mg (loading dose) administered over 10 minutes Hydromorphone 1.75 mg (maintenance dose) given over 30 minutes Hydromorphone 3 mg repeated as above was administered.

[0633] There was a minimum washout of approximately 24 hours between IV hydromorphone doses A minimum washout period of approximately 36 hours was allowed between patch applications. The team is summarized in Figures 33A)-B).

[0634] Part 2b was a single-blind, non-randomized study of 16 healthy recreational opioid users. Idol users received transdermal buprenorphine or placebo patches. Planned transdermal patch nominal dose escalation was performed at 10 and 15 mcg / hour. The patch was applied for two days, and the buprenorphine patch was applied for four days. This order was changed for the final dose of 100 mg / kg. Based on the evaluation of the data from previous doses, the lower dose During each patch application, two IV hydrochloride doses were administered. Each IV hydromorphone was administered in 3 mg doses at 24-hour intervals. The dose was increased to two injections totaling 3 mg. Hydromorphone 1.25 mg (loading dose) administered over 10 minutes Hydromorphone 1.75 mg (maintenance dose) given over 30 minutes was divided into

[0635] The dosing scheme is summarized in FIG.

[0636] Inclusion / Exclusion Criteria Patients aged 18 to 55 years were deemed appropriate to participate in this clinical trial. (including steroids) in healthy men and women with a history of oral use and no clinically significant medical history. The study participants were selected from opioid users or other healthy subjects.

[0637] Study treatment, dose, and administration method Fentanyl citrate (up to 150 mcg), intravenous Hydromorphone hydrochloride (up to 3 mg), intravenous Oxycodone IR (up to 40 mg), oral Morphine sulfate (up to 20 mg) intravenously Butrans® (up to 20 mcg / hour), transdermal

[0638] Reference Therapeutic Agents, Doses, and Administration Methods Placebo, intravenous Placebo patch, transdermal Placebo, oral

[0639] Concomitant medications Naloxone HCl provocation test (at least approximately 12 hours before the first study drug administration) Use of other concomitant medications during this study may require treatment for adverse events (AEs). Unless you do, it's best to avoid it.

[0640] Duration of treatment and duration of study Subjects screened 28 days or less prior to check-in in Period 1 or prior to the eligibility phase do.

[0641] Qualification Stage Administer the study drug during each period according to the study randomization schedule (if applicable). From the day before the first study drug administration to approximately 24 hours after the last dose of study drug or at the time of early discontinuation of the study. Subjects may be discharged after the eligibility phase, or Subjects may remain confined to the facility until the treatment phase. Subjects discharged after the eligibility phase will be considered for eligibility confirmation. Subjects who did not proceed to treatment will undergo the final approval process 7-10 days after the completion of eligibility confirmation. Follow-up phone calls were made to each subject at each point of the study or after early discontinuation (or Subjects were followed up by a follow-up call to determine adverse events (AEs) and concomitant medications from the last study visit. Drugs are evaluated.

[0642] Treatment Phase The study drug will be administered in each period according to the study randomization schedule. Subjects were followed from the start of the day before drug administration (check-in) until EOS (or early discontinuation). Subjects may be discharged between periods, but will be restricted to the facility upon their return. Repeat the check-in procedure.

[0643] Any significant pharmacological effect, in the opinion of the PI or designee, is at a clinically acceptable level. Upon change or decline to the lowest level, or upon early discontinuation of the study, the subject will be removed from the study. undergo an EOS procedure performed before discharge from the hospital.

[0644] A follow-up call will be conducted with each subject 7-10 days after EOS or after early discontinuation of the study. (or receive a follow-up call from each subject) to assess AEs and Evaluate the patient's condition and any concomitant medications they are taking.

[0645] Total study duration: Part 1 - approximately 48 days maximum. Part 2 - approximately 54 days maximum.

[0646] Test Procedure Test procedures and time points will be recorded in the work schedule. Any AEs and concomitant medications will be recorded.

[0647] Screening stage Subjects will be screened within 28 days of check-in, including hypercapnic ventilation. This training session included a training session with a response (HCVR). as part of screening or admission procedures in It may be performed as both of these.

[0648] Qualification stage (if applicable) If the subject has already been qualified in a previous part / iteration, qualification (if applicable) (if applicable) is not required.

[0649] Check-in: Subjects will check into the site the day before Period 1 dosing.

[0650] To ensure that subjects are not opioid dependent, subjects were asked to undergo a short course of the first study drug administration. Have undergone a naloxone HCl provocation test and evaluation using OOWS at least approximately 12 hours prior do.

[0651] Subjects will receive study medication at specific time points according to the randomization schedule. In this case, monitor for respiratory depression with supplemental oxygen (transcutaneous CO2 and HCVR). .

[0652] Treatment Phase Check-in: Subjects will check-in to the site the day before Period 1 dosing. If not already done in the study, to ensure that the subject is not opioid dependent, At least approximately 12 hours before the first study drug administration, a naloxone HCl provocation test and OOW Evaluation will be carried out using S. Treatment: Subjects receive study medication at specific times according to a randomization schedule. Treatment Phase At specific times during the study, respiratory depression was monitored with supplemental oxygen (transcutaneous CO2 and and HCVR). End of Study (EOS): Any significant pharmacological effect in the opinion of the PI or designee Upon change or decline to a clinically acceptable level or upon early discontinuation of the study At that point, subjects will undergo an EOS procedure which will be performed before they are discharged from the study. Follow-up: Each subject will be followed up 7-10 days after EOS or after early discontinuation of the study. By telephone (or by a follow-up call from each subject), the number of subjects from the last study visit to AEs and concomitant medications will be evaluated.

[0653] Criteria and methods for evaluation Pharmacodynamics Hypercapnic ventilatory response (HCVR) The minute ventilation per 1 mmHg increase in PCO2 (respiratory volume per breath x respiratory frequency, HCVR is calculated as the change in baseline status (per program basis). During normal conditions (no increase in CO2, subject breathing normally) and during increased CO2 breathing These values ​​are measured during the respiratory stimuli. HCVR is a direct response to respiratory stimuli involving central chemoreceptors. This is an indicator.

[0654] respiratory stimulation Before and after treatment with the test drug, minute ventilation and end-tidal CO2 (ET CO2) were used to measure high Respiratory stimulation was assessed by comparing the ventilatory response to carbon dioxide. -P ET HCVR is calculated by the slope of the CO2 correlation (LPM / mmHg CO2). The HCVR is linear over the range of CO2 tested in this protocol, allowing for standard assays. The approach involves measuring two steady-state CO2 levels (one at room air or baseline CO2) The ventilation volume at the time of the suction is measured, and the other is supplemental CO2, and the base HCVR is calculated. The key is to get it out.

[0655] Transcutaneous CO2 (PCO2) Transcutaneous CO2 is an important indicator of respiratory stimulation and an index of opioid-induced respiratory depression. Transcutaneous PCO2 monitoring after drug administration significantly predicts blunting of HCVR. is expected.

[0656] Subjective sedative effect ·Somnolence / Wakefulness VAS(E min )

[0657] Subjective breathlessness effect ·Difficulty breathing VAS (E max )

[0658] Drug concentration measurement As specified in the work schedule, opioids and Blood samples (if available) for measuring buprenorphine plasma concentrations should be collected from the Obtained from each target.

[0659] Adjust timing of PK collection if indicated.

[0660] Analysis population Enrollment population: All subjects who provide informed consent. Randomized Safety Population: All subjects who are randomized to receive study medication. Full analysis population: randomized, administered study drug, and had at least one effective pharmacodynamic (PD) All subjects with measurements.

[0661] bioanalytical method Plasma concentrations of opioids and buprenorphine are determined by approved bioanalytical methods.

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

[0663] Respiratory depression: CO2 provocation (part 2a) test Hydromorphone (IV HMP), and buprenorphine TDS (transdermal delivery system) Part 2a) was conducted using IV HMP in combination with Part 2a) is outlined in Figure 33A)-B), which shows the constant HMP and Bup. concentrations are shown.

[0664] of sample per mmHg increase in pCO2 in opioid-naive subjects Minute ventilation (respiratory volume per breath × respiratory frequency, per kilogram basis) was measured. The HCVR slope was calculated as follows:

number

[0665] pCO2 in subjects receiving 3.0 mg IV hydromorphone (HMP) The minute ventilation of the sample per 1 mmHg increase (respiratory volume per breath x respiratory frequency, kg) The HCVR slope was calculated as follows:

number

[0666] Figure 34 shows the opioid response in the positive control treatment (1.5 mg and 3.0 mg HMP injections). Idol-induced respiratory depression (OIRD) was significantly reduced compared with placebo. 37% (1.5 mg IV HMP only) and 49% (3.0 mg IV HMP only) This shows that it has been made clear that

[0667] Figure 34 also shows the effect of BUP (Butrans®, 20 mcg / hour) alone. The OIRD for 1.5 mg and 3.0 mg IV HMPs was specified. The effect of OIRD after adding BUP (20 mcg / hour) is shown in Figure 34. .

[0668] Figures 35 and 36 show the hydromorphone concentrations during HCVR measurements in Study Part 2a). (ng / mL) and buprenorphine concentrations (pg / mL) are shown.

[0669] Exam Part 2b) HMP infusion (3.0 mg, IV), and escalating BUP doses (BTDS, 0, 5, 10 and Part 2b) of the study was conducted using IV steroids (15 mcg / hour) and HMP (3.0 mg, IV). Part 2b) Overview of study design (HCVR measurements were performed before and during IV infusion, CPT was performed after HCVR measurement) is shown in Figure 37.

[0670] Figures 38 and 39 show the mean HMP concentration (ng / mL) and mean BUP concentration (pg / mL). Each of these was shown to remain constant during the HCVR assessment in study part 2b).

[0671] Figure 40 shows the results of HMP (3.0 mg, IV), BTDS (2. 5mcg / hour, 5mcg / hour, and 10mcg / hour doses), and HMP-BTD Shown are the mean HCVR slopes normalized to placebo after administration of the combination of S The results showed that BUP 2.5 mcg / hour significantly improved the OIRD effect of HMP (3.0 mg, IV) by approximately This indicates that the rotation has been reversed by 1 / 3.

[0672] The analgesic effects of HMP (3.0 mg, IV), BTDS (doses of 2.5 mcg / hr, 5 mcg / hr, and 10 mcg / hr), and the HMP-BTDS combination compared with placebo in Study Part 2b) are shown in Figure 41. Pain (quantified as pain VAS with AUC) was measured every 15 seconds over a 2-minute period using the cold pressor test. Figure 41 shows that HMP (3.0 mg, IV) suppressed cold pressor pain, and that coadministration of BUP (doses of 2.5, 5, and 10 mcg / hr) did not reduce (or increase) the HMP analgesic effect. The present invention also includes the following aspects. <1> (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; A dosage form comprising: After single dose administration, the dosage form provides a mean Cmax of prenorphine of at least about 1:280 in a group of subjects. max and mean C of oxycodone max yielding a ratio of The dosage form. <2> Buprenorphine mean C max and mean C of oxycodone max 2. The dosage form according to claim 1, wherein the ratio is about 1:50 to about 1:250. <3> Buprenorphine mean C max and mean C of oxycodone max 2. The dosage form according to claim 1, wherein the ratio is about 1:100 to about 1:200. <4> After single dose administration, the dosage form provides a mean T of buprenorphine of about 1.5:1 or less in the subject group. max and mean T of oxycodone max 4. A dosage form according to any one of claims 1 to 3, further providing a ratio of: <5> Buprenorphine mean T max and mean T of oxycodone max 5. The dosage form according to claim 4, wherein the ratio is about 1:1 or less. <6> After single dose administration, the dosage form provided the subject group with a mean T max Faster mean T of buprenorphine compared to max A dosage form according to any one of claims 1 to 3, further providing: <7> After single dose administration, the dosage form provides a mean T of buprenorphine in the subject group that is about 0.1:1 to about 1:1, or about 0.1:1 to about 0.9:1. max and mean T of oxycodone max 7. A dosage form according to any one of claims 1 to 6, further providing a ratio of: <8> 8. A dosage form according to any one of claims 1 to 7, wherein the dosage form is an oral dosage form. <9> 9. The oral dosage form according to 8 above, wherein the dosage form contains a fixed amount of oxycodone equimolar to about 5 mg to about 50 mg of oxycodone hydrochloride (Mw=351.82 g / mol). <10> 9. The oral dosage form according to claim 8, comprising a fixed amount of oxycodone equimolar to about 40 mg of oxycodone hydrochloride (Mw=351.82 g / mol) and a fixed amount of buprenorphine equimolar to about 1 mg to about 6 mg of buprenorphine base (Mw=467.64 g / mol). <11> 11. A dosage form described in any one of claims 1 to 10, wherein the oxycodone is oxycodone hydrochloride and the buprenorphine is buprenorphine hydrochloride. <12> 12. A dosage form according to any one of claims 1 to 11, wherein the dosage form comprises the fixed amount of buprenorphine in immediate release form. <13> 13. A dosage form according to any one of claims 1 to 12, wherein the dosage form comprises a fixed amount of oxycodone in immediate release form and a fixed amount of buprenorphine in immediate release form. <14> (i) a quantity of oxycodone; (ii) a fixed dose of buprenorphine; administering to a patient in need thereof After single dose administration, the co-administration provides a mean C of buprenorphine of at least about 1:280 in one subject group. max and mean C of oxycodone max yielding a ratio of A method for treating pain. <15> Buprenorphine mean C max and mean C of oxycodone max 15. The method according to claim 14, wherein the ratio is about 1:50 to about 1:250. <16> Buprenorphine mean C max and mean C of oxycodone max 15. The method according to claim 14, wherein the ratio is about 1:100 to about 1:200. <17> After single dose administration, the co-administration provides a mean T of buprenorphine of about 1.5:1 or less in the subject group. max and mean T of oxycodone max 17. The method of any one of claims 14 to 16, further resulting in a ratio of: <18> Buprenorphine mean T max and mean T of oxycodone max 18. The method of claim 17, wherein the ratio is about 1:1 or less. <19> After a single dose, the co-administration resulted in a mean T of oxycodone in the subject group. max Faster mean T of buprenorphine compared to max 17. The method according to any one of claims 14 to 16, further comprising: <20> After single dose administration, the co-administration provides a mean T of buprenorphine of about 0.1:1 to about 1:1, or about 0.1:1 to about 0.9:1 in the subject group. max and mean T of oxycodone max 20. The method of any one of claims 14 to 19, further resulting in a ratio of: <21> 21. The method according to any one of claims 14 to 20, wherein the method results in prevention or suppression of adverse pharmacodynamic reactions of oxycodone. <22> 22. The method of claim 21, wherein the adverse pharmacodynamic reaction is selected from the group consisting of euphoria, euphoria, bowel dysfunction, nausea, vomiting, somnolence, dizziness, headache, xerostomia, sedation, sweating, asthenia, hypotension, dysphoria, delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence and tolerance, preferably, the adverse pharmacodynamic reaction is selected from the group consisting of euphoria, euphoria, and bowel dysfunction. <23> 22. The method of claim 21, wherein the adverse pharmacodynamic reaction is euphoria. <24> Average E of "Emotion VAS" max 24. The method of claim 23, wherein the amount of hydroxybenzoates is reduced by at least 15% as measured using a comparative test. <25> 25. A method according to any one of claims 14 to 24, wherein the method results in the prevention or suppression of drug preference for oxycodone. <26> Mean E of "Temporary Drug Preference VAS" max 26. The method of claim 25, wherein the amount of hydroxybenzoates is reduced by at least 15% as measured using a comparative test. <27> Mean E of "Overall Drug Preference VAS" max 26. The method of claim 25, wherein the amount of hydroxybenzoates is reduced by at least 15% as measured using a comparative test. <28> Mean E of "Drug Relapse VAS" max 26. The method of claim 25, wherein the amount of hydroxybenzoates is reduced by at least 15% as measured using a comparative test. <29> 29. A method according to any one of claims 14 to 28, wherein the method results in an analgesic effect that is not substantially reduced as measured using a comparative test. <30> 29. The method of claim 29, wherein the mean "cold pain score VAS" measured using the cold pressor test at 1, 2, 3 and 4 hours after administration does not increase by more than 10% compared to the comparative treatment method when measured using a comparative test. <31> 31. A method according to any one of claims 14 to 30, wherein the method prevents or inhibits the formation of addiction, the development of drug abuse, or the development of recreational drug use. <32> (i) a quantity of oxycodone; (ii) a fixed dose of buprenorphine; administering to a patient in need thereof Average E of "Emotion VAS" max is reduced by at least 15% as measured using a comparative test, and / or Mean E of "Temporary Drug Preference VAS" max is reduced by at least 15% as measured using a comparative test, and / or Mean E of "Overall Drug Preference VAS" max is reduced by at least 15% as measured using a comparative test, and / or Mean E of "Drug Relapse VAS" max is reduced by at least 15% as measured using a comparative test, and / or The mean "cold pain score VAS" measured using the cold pressor test at 1, 2, 3, and 4 hours after administration does not increase by more than 10% compared to the comparator treatment when measured using a comparator test. A method for treating pain. <33> (i) a quantity of oxycodone; (ii) a fixed dose of buprenorphine; administering to a patient in need thereof Average E of "Emotion VAS" max is reduced by at least 35% as measured using a controlled test, and / or Mean E of "Temporary Drug Preference VAS" max is reduced by at least 30% as measured using a comparative test, and / or Mean E of "Overall Drug Preference VAS" max is reduced by at least 30% as measured using a comparative test, and / or Mean E of "Drug Relapse VAS" max is reduced by at least 30% as measured using a comparative test, and / or The mean "cold pain score VAS" measured using the cold pressor test at 1, 2, 3, and 4 hours after administration does not increase by more than 10% compared to the comparator treatment when measured using a comparator test. A method for treating pain. <34> (i) a quantity of oxycodone; (ii) a quantity of buprenorphine; 1. An oral dosage form comprising: the weight ratio of the aliquot amount of buprenorphine to the aliquot amount of oxycodone is greater than 1:40 when calculated using the aliquot amount of buprenorphine in the dosage form expressed in equimolar amounts of buprenorphine base (mg) (Mw=467.64 g / mol) and the aliquot amount of oxycodone in the dosage form expressed in equimolar amounts of oxycodone hydrochloride (mg) (Mw=351.82 g / mol); The oral dosage form. <35> (i) an effective amount of hydromorphone administered during administration period 1 at an average dose rate (mg / hr) of hydromorphone during said administration period 1, wherein said average dose rate of hydromorphone is expressed as the equimolar amount of hydromorphone free base administered during said administration period 1 divided by the duration of said administration period 1; (ii) during administration period 2, another effective amount of buprenorphine administered at an average dose rate (mg / hour) of buprenorphine during said administration period 2, wherein said average dose rate of buprenorphine is expressed as the equimolar amount of buprenorphine free base administered during said administration period 2 divided by the duration of said administration period 2; administering it to a patient in need thereof; the administration period 1 and the administration period 2 overlap by at least 75%, and the ratio of the average infusion rate of buprenorphine to the average infusion rate of hydromorphone is about 1:8000 to about 1:100. A method for treating pain. <36> 36. The method of claim 35, wherein said administration period 1 and said administration period 2 overlap by at least 90%. <37> 36. The method according to claim 35, wherein the administration period 1 and the administration period 2 overlap by 95% to 100%. <38> 38. A method according to any one of claims 35 to 37, wherein hydromorphone and buprenorphine are administered by the same route of administration. <39> 38. A method according to any one of claims 35 to 37, wherein hydromorphone and buprenorphine are administered by different routes of administration. <40> 40. The method according to claim 38 or 39, wherein the route of administration is selected from the group consisting of intravenous administration, intramuscular administration, subcutaneous administration, sublingual administration, buccal administration, subcutaneous administration, and transdermal administration. <41> 41. The method of any of claims 35 to 40, wherein hydromorphone and buprenorphine are administered in dosage forms independently selected from an intravenous composition, an intramuscular composition, a subcutaneous composition, a sublingual composition, a buccal composition, a subcutaneous implant, or a transdermal therapeutic system. <42> 39. A method according to any one of claims 35 to 38, wherein hydromorphone and buprenorphine are administered by the same administration route selected from the group consisting of intravenous administration, intramuscular administration, and subcutaneous administration. <43> 39. The method of any of claims 35 to 38, wherein hydromorphone and buprenorphine are administered in a single dosage form containing hydromorphone and buprenorphine, said dosage form being selected from an intravenous composition, an intramuscular composition, and a subcutaneous composition. <44> 42. The method according to any one of claims 35 to 41, wherein buprenorphine is administered transdermally, and said administration period 2 is 1 to 7 days. <45> 45. The method according to claim 44, wherein said administration period 2 is selected from 1 day, 3 days, 3.5 days, and 7 days. <46> 42. The method according to any one of claims 35 to 41, wherein buprenorphine is administered subcutaneously, and the administration period 2 is from 1 month to 1 year, or from 1 month to 4 months, or from 1 month to 3 months. <47> 47. The method according to claim 46, wherein the administration period 2 is selected from 1 month, 2 months, 3 months, 4 months, and 6 months. <48> 43. The method according to claim 42, wherein the hydromorphone and buprenorphine are administered by intravenous infusion. <49> 44. The method of claim 42 or 43, wherein the hydromorphone and buprenorphine are administered by intravenous infusion of an intravenous composition comprising both hydromorphone and buprenorphine. <50> 49. The method according to claim 48 or 49, wherein the administration period 1 and the administration period 2 are selected from about 15 minutes to about 24 hours, about 15 minutes to about 12 hours, about 30 minutes to about 6 hours, or about 30 minutes to about 3 hours. <51> 51. The method according to claim 50, wherein the administration period 1 and the administration period 2 are selected from about 30 minutes to about 2 hours, or about 1 hour. <52> 52. The method according to any one of claims 35 to 51, wherein hydromorphone is administered at a rate of about 1 mg / hour to about 10 mg / hour. <53> After single-dose administration, buprenorphine and hydromorphone each had a mean C max Or average C av and the mean C of buprenorphine max Or average C av and hydromorphone mean C max Or average C av 53. The method according to any one of claims 35 to 52, wherein said ratio is from about 0.001 to about 0.006. <54> 54. A method according to any one of claims 35 to 53, wherein toxicity is suppressed. <55> 55. A method according to any one of claims 35 to 54, wherein at least one side effect selected from the group consisting of respiratory depression, drug preference, sedation, and bowel dysfunction is suppressed. <56> 56. A method according to any one of claims 35 to 55, wherein respiratory depression is suppressed. <57> A method according to any one of claims 35 to 56, wherein drug preference is suppressed. <58> A method according to any one of claims 35 to 57, wherein sedation is suppressed. <59> 59. A method according to any one of claims 35 to 58, wherein bowel dysfunction is inhibited. <60> (i) an effective amount of hydromorphone is administered during a dosing period at an average dose rate (mg / hr) of hydromorphone during said dosing period, wherein said average dose rate of hydromorphone is expressed as the equimolar amount of hydromorphone free base administered during said dosing period divided by the duration of said dosing period; (ii) another effective amount of buprenorphine is administered during the same administration period at an average dose rate (mg / hour) of buprenorphine during said administration period, wherein said average dose rate of buprenorphine is expressed as the equimolar amount of buprenorphine free base administered during said administration period divided by the duration of said administration period; the ratio of the average injection rate of buprenorphine to the average injection rate of hydromorphone is about 1:8000 to about 1:100; A pharmaceutical composition suitable for treating pain comprising hydromorphone and buprenorphine. <61> 61. The pharmaceutical composition according to claim 60, in the form of an intravenous composition, an intramuscular composition, or a subcutaneous composition. <62> 61. The pharmaceutical composition according to claim 60, which is in the form of an intravenous composition. <63> 61. The pharmaceutical composition according to claim 60, wherein hydromorphone is administered at an average dosage rate of about 1 mg / hour to about 10 mg / hour. <64> 64. A pharmaceutical composition according to any one of claims 60 to 63, for use in a method for treating pain. <65> 64. Use of a pharmaceutical composition according to any one of claims 60 to 63 in the manufacture of a medicament for treating pain. <66> (i) an effective amount of fentanyl administered during administration period 1 at an average input rate (mg / hour) of fentanyl during said administration period 1, wherein said average input rate of fentanyl is expressed as the equimolar amount of fentanyl free base administered during said administration period 1 divided by the duration of said administration period 1; (ii) during administration period 2, another effective amount of buprenorphine administered at an average dose rate (mg / hour) of buprenorphine during said administration period 2, wherein said average dose rate of buprenorphine is expressed as the equimolar amount of buprenorphine free base administered during said administration period 2 divided by the duration of said administration period 2; administering it to a patient in need thereof; the administration period 1 and the administration period 2 overlap by at least 75%, and the ratio of the average injection rate of buprenorphine to the average injection rate of fentanyl is about 1:80 to about 1:0.5. A method for treating pain. <67> 67. The method of claim 66, wherein administration period 1 and administration period 2 overlap by at least 90%. <68> 67. The method according to claim 66, wherein said administration period 1 and said administration period 2 overlap by 95% to 100%. <69> 69. A method according to any one of claims 66 to 68, wherein fentanyl and buprenorphine are administered by the same route of administration. <70> 69. A method according to any one of claims 66 to 68, wherein fentanyl and buprenorphine are administered by different routes of administration. <71> 71. The method according to claim 69 or 70, wherein the route of administration is selected from the group consisting of intravenous administration, intramuscular administration, subcutaneous administration, sublingual administration, buccal administration, subcutaneous administration, and transdermal administration. <72> 72. The method of any of claims 66 to 71, wherein fentanyl and buprenorphine are administered in dosage forms independently selected from an intravenous composition, an intramuscular composition, a subcutaneous composition, a sublingual composition, a buccal composition, a subcutaneous implant, or a transdermal therapeutic system. <73> 69. A method according to any one of claims 66 to 69, wherein fentanyl and buprenorphine are administered by the same administration route selected from the group consisting of intravenous administration, subcutaneous administration, and transdermal administration. <74> 69. A method according to any one of claims 66 to 69, wherein fentanyl and buprenorphine are administered in a single dosage form containing fentanyl and buprenorphine, said dosage form being selected from an intravenous composition, a subcutaneously implantable system, or a transdermal therapeutic system. <75> 73. The method according to any one of claims 66 to 72, wherein buprenorphine is administered transdermally and said administration period 2 is 1 to 7 days. <76> 76. The method of claim 75, wherein the administration period 2 is selected from 1 day, 3 days, 3.5 days, and 7 days. <77> 73. The method according to any one of claims 66 to 72, wherein buprenorphine is administered subcutaneously, and the administration period 2 is from about 1 month to about 1 year, or from about 1 month to about 4 months, or from about 1 month to about 3 months. <78> 78. The method according to claim 77, wherein the administration period 2 is selected from 1 month, 2 months, 3 months, 4 months, and 6 months. <79> 74. The method according to claim 73, wherein the fentanyl and buprenorphine are administered transdermally. <80> 75. The method according to claim 73 or 74, wherein the fentanyl and buprenorphine are administered by transdermal administration of a transdermal therapeutic system containing both fentanyl and buprenorphine. <81> 81. The method according to claim 79 or 80, wherein the administration period 1 and the administration period 2 are selected from about 1 day to about 7 days, or about 1 day to about 3 days. <82> 82. The method according to claim 81, wherein the administration period 1 and the administration period 2 are selected from 1 day, 3 days, 3.5 days, and 7 days. <83> 83. A method according to any one of claims 66 to 82, wherein fentanyl is administered at a rate of about 12.5 μg / hour, 25 μg / hour, 50 μg / hour, 75 μg / hour, 100 μg / hour, 150 μg / hour, or 200 μg / hour. <84> After single-dose administration, buprenorphine and fentanyl each had a mean C max Or average C av and the mean C of buprenorphine max Or average C av and fentanyl mean C max Or average C av 84. The method according to any one of claims 66 to 83, wherein the ratio is from about 0.02 to about 0.3, or from 0.02 to about 0.2. <85> 85. A method according to any one of claims 66 to 84, wherein toxicity is suppressed. <86> 86. A method according to any one of claims 66 to 85, wherein at least one side effect selected from the group consisting of respiratory depression, drug addiction, sedation, and bowel dysfunction is suppressed. <87> A method according to any one of claims 66 to 86, wherein respiratory depression is suppressed. <88> A method according to any one of claims 66 to 87, wherein drug preference is suppressed. <89> A method according to any one of claims 66 to 88, wherein sedation is suppressed. <90> 89. A method according to any one of claims 66 to 89, wherein bowel dysfunction is inhibited. <91> (i) an effective amount of fentanyl is administered during an administration period at an average input rate (mg / hr) of fentanyl during said administration period, wherein said average input rate of fentanyl is expressed as the equimolar amount of fentanyl free base administered during said administration period divided by the duration of said administration period; (ii) another effective amount of buprenorphine is administered during the same administration period at an average dose rate (mg / hour) of buprenorphine during said administration period, wherein said average dose rate of buprenorphine is expressed as the equimolar amount of buprenorphine free base administered during said administration period divided by the duration of said administration period; the ratio of the average injection rate of buprenorphine to the average injection rate of fentanyl is about 1:80 to about 1:0.5; A pharmaceutical composition suitable for treating pain comprising fentanyl and buprenorphine. <92> 92. The pharmaceutical composition according to claim 91, which is in the form of an intravenous composition, an intramuscular composition, a subcutaneous composition, a sublingual composition, a subcutaneously implanted system, or a transdermal therapeutic system. <93> 92. The pharmaceutical composition according to claim 91, which is in the form of a transdermal therapeutic system. <94> 92. The pharmaceutical composition of claim 91, wherein fentanyl is administered at an average dose rate of about 12.5 μg / hour, 25 μg / hour, 50 μg / hour, 75 μg / hour, 100 μg / hour, 150 μg / hour, or 200 μg / hour. <95> 95. A pharmaceutical composition according to any one of claims 91 to 94, for use in a method for treating pain. <96> 95. Use of a pharmaceutical composition according to any one of claims 91 to 94 in the manufacture of a medicament for treating pain. <97> (i) during administration period 1, an effective amount of an opioid selected from the group consisting of fentanyl, oxycodone, oxymorphone, hydrocodone, hydromorphone, and morphine administered at an average input rate (mg / hr) during said administration period 1, wherein said average input rate of said opioid is expressed as an equimolar amount of its free base administered during said administration period 1 divided by the duration of said administration period 1; (ii) during administration period 2, another effective amount of buprenorphine administered at an average dose rate (mg / hour) of buprenorphine during said administration period 2, wherein said average dose rate of buprenorphine is expressed as the equimolar amount of buprenorphine free base administered during said administration period 2 divided by the duration of said administration period 2; administering it to a patient in need thereof; said administration period 1 and said administration period 2 overlap by at least 75%; A method for treating pain. <98> 98. The method according to claim 97, wherein buprenorphine is administered subcutaneously or transdermally.

Claims

1. (i) an effective amount of hydromorphone administered during administration period 1 at an average dose rate (mg / hr) of hydromorphone during said administration period 1, wherein said average dose rate of hydromorphone is expressed as an equimolar amount of hydromorphone free base administered during said administration period 1 divided by the duration of said administration period 1; (ii) during administration period 2, another effective amount of buprenorphine administered at an average dose rate (mg / hr) of buprenorphine during said administration period 2, wherein said average dose rate of buprenorphine is expressed as an equimolar amount of buprenorphine free base administered during said administration period 2 divided by the duration of said administration period 2; 1. A pharmaceutical composition comprising hydromorphone and buprenorphine for treating pain by administering to a patient the administration period 1 and the administration period 2 overlap by at least 75%, and the ratio of the average administration rate of buprenorphine to the average administration rate of hydromorphone is 1:3000 to 1:200; Hydromorphone is formulated into an intravenous infusion composition for treating pain, and buprenorphine is formulated into a transdermal patch or intravenous infusion composition for treating pain, Hydromorphone is administered at an average infusion rate of 1 mg / hour to 10 mg / hour; The pharmaceutical composition, wherein after administration of a single dose, buprenorphine and hydromorphone each provide a mean C max or mean C av , and the ratio of the mean C max or mean C av of buprenorphine to the mean C max or mean C av of hydromorphone is 0.001 to 0.

006.

2. 10. The pharmaceutical composition of claim 1, wherein the hydromorphone is formulated in an intravenous infusion composition for treating pain and the buprenorphine is formulated in a transdermal patch for treating pain.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein administration period 1 and administration period 2 overlap by at least 90%.

4. The pharmaceutical composition according to claim 1 or 2, wherein the administration period 1 and the administration period 2 overlap by 95 to 100%.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein buprenorphine is administered transdermally and the administration period 2 is 1 to 7 days.

6. The pharmaceutical composition of claim 5 , wherein the administration period 2 is selected from 1 day, 3 days, 3.5 days, and 7 days.

7. 10. The pharmaceutical composition of claim 1, wherein the hydromorphone and buprenorphine are administered by intravenous infusion of an intravenous composition comprising both hydromorphone and buprenorphine.

8. The pharmaceutical composition according to claim 7, wherein the administration period 1 and the administration period 2 are selected from 15 minutes to 24 hours, or 15 minutes to 12 hours, or 30 minutes to 6 hours, or 30 minutes to 3 hours.

9. The pharmaceutical composition according to claim 8, wherein the administration period 1 and the administration period 2 are selected from 30 minutes to 2 hours, or 1 hour.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein hydromorphone is administered at an average dose rate of 3 mg / hour to 8 mg / hour.

11. 11. The pharmaceutical composition of claim 10, wherein the hydromorphone is administered at an average dose rate of 3 mg / hour to 5 mg / hour.

12. 12. The pharmaceutical composition of claim 1, wherein the toxicity is reduced.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein at least one side effect selected from the group consisting of respiratory depression, drug preference, sedation, and bowel dysfunction is suppressed.

Images