ZA200309333B - Use of the opioid antagonist naltrexone to prevent and control side effects caused by opioids. - Google Patents
Use of the opioid antagonist naltrexone to prevent and control side effects caused by opioids. Download PDFInfo
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- ZA200309333B ZA200309333B ZA200309333A ZA200309333A ZA200309333B ZA 200309333 B ZA200309333 B ZA 200309333B ZA 200309333 A ZA200309333 A ZA 200309333A ZA 200309333 A ZA200309333 A ZA 200309333A ZA 200309333 B ZA200309333 B ZA 200309333B
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- South Africa
- Prior art keywords
- naltrexone
- morphine
- side effects
- administration
- opioids
- Prior art date
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- 229960003086 naltrexone Drugs 0.000 title claims description 41
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 title claims description 37
- 230000000694 effects Effects 0.000 title claims description 27
- 229940005483 opioid analgesics Drugs 0.000 title description 15
- 239000003401 opiate antagonist Substances 0.000 title description 5
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 58
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
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- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
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- 230000002980 postoperative effect Effects 0.000 description 2
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- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
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- 238000001033 granulometry Methods 0.000 description 1
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- 231100000869 headache Toxicity 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Description
“+ 2003/9333
USE OF OPIOID ANTAGONISTS TO PREVENT AND CONTROL SIDE
EFFECTS CAUSED BY OPIOIDS
USE OF THE OPIOID ANTAGONIST NALTREXONE TO PREVENT AND CONTROL SIDE EFFECTS
CAUSED BY OPIOIDS
S TECHNICAL FIELD
The present invention refers to the use of opioid antagonists to prepare compositions suitable to prevent and control the side effects caused by the administration of opioids
Opioids are drugs indispensable for the control of severe painful syndromes, but they cause many side effects that, sometimes, render their use by the patients impossible.
Many authors have documented that pain is one of the greatest problem of the public health.
For example, Valkenberg (Valkenberg H., Epidemiologic considerations of the geriatric population. Gerontology 1988; 34, suppl. 1, 2 - 10) refers that 33% of the population of more than 55 years old suffers from rheumatic pains.
In the USA it has been evaluated that the cost of the lumbar pains amounts to 50 - 100 billion dollars per year (Frymoyer J.W. and Casta-Baril W.L., “An overview of the incidences and costs of low back pain”. Orthop.Clin. N. Am. 1991, 22: 263 - 271).
From the official OMS publications it comes out that pain is present in the 30 - 40% of patients in the starting phase of cancer and in the 60 - 80% in the terminal phase.
Finally, pain is present in many other situations like, for example, in the operating and postoperative phase, in AIDS-affected people, etc.
As above stated, the use of opioids is indispensable in the management of severe pain forms.
Opioids are drugs that cause an intense analgesic reaction acting on specific receptors.
Drugs acting on the same receptors without causing any biological effect are defined as opioid antagonists, Among the opioids, for example, morphine, codeine and fentanyl can be cited.
Among the opioid antagonists, naloxone, naltrexone and cholecystokinin can be mentioned.
CONFIRMATION COPY
IE
“2003/9333 2
Unfortunately, the treatment with opioids causes many and severe side effects such as sleepiness, nausea, emesis, constipation, confusion, pruritus, headache, ritention of urine, dysphoric reactions, respiratory depression and myoclonus.
These effects negatively influence the quality of life, particularly in patients under long-term treatment.
Various methods have been proposed to control the side effects of opioids.
For example, for nausea and emesis the use of neuroleptics like haloperidol or droperidol at low doses has been proposed (Cohen S.E. et al., Anestesiology 1984,60:67-9).
Nevertheless these drugs have to be used with caution because of the adverse effects caused by themselves.
The use of opioid antagonists administered simultaneously with the opioids has been proposed with the aim of reducing the development of physical addiction.
For example, patent USP 5580876 A describes the use of morphine combined with the administration of low doses of naltrexone in mouse.
Patent application PCT - WO 96/02251 describes the simultaneous intake of morphine and of an opioid antagonist in a ratio antagonist - morphine of 1,0 mg of antagonist per 1 mg of morphine.
According to this application the ratio antagonist - morphine is fixed while in the clinical practice variable ratios are required in function of the individual reactions of the various patients. Furthermore the aim of said application is restricted to the prevention of addiction.
From the study of the prior art it is evident that the various methods so far proposed to solve the problem of the side effects of the opioid therapy are not satisfactory as they deal only with some of said side effects, or they propose the treatment with drugs that, in their turn, require caution in their administration.
Therefore, the problem of a pharmacological control of the side effects of opioids, maintaining their analgesic efficacy, remains open.
Now we have found that the treatment with very low doses of an opioid antagonist like naltrexone in patients under opioid treatment allows to obtain a significant global reduction of the opioid side effects, by maintaining the analgesic efficacy of opioids themselves.
The naltrexone administration according to this invention ranges between 0,01 and 0,9 mg per mg of morphine. Naltrexone is administered by mouth.
This invention, therefore, refers to the use of naltrexone in the preparation of pharmaceutical compositions to be administered by mouth suitable to prevent and control the side effects caused by the opioid therapy.
The invention, furthermore, refers to a therapeutic method to prevent and control the side effects caused by the treatment with opioids consisting in the administration by mouth of said compositions in quantity equal to 0,01 - 0,9 mg of naltrexone per mg of morphine.
The main object of the present invention is to propose a fast, reliable and economic method for the production of tiles with irregular edges having a handcrafted look, starting from plates, consisting of tiles or natural or synthetic slabs.
Another object is to propose a method allowing to produce tiles having at least a rectilinear regular edge fit for the joining with other coverings or for carrying out the end portions of covering and having irregular remaining edges.
The above-mentioned object are achieved according with the content of the claims.
The characteristics and the advantages of the use of opioid antagonists to prevent and control the side effects caused by opioids will be better explained in the following detailed description.
The preferred opioid antagonist is naltrexone, for which the clinical experience has demonstrated a great reliability of use also for long periods of administration.
Moreover naltrexone has the advantage that it can be administered by mouth.
We have found that the administration of a dose ranging from 0,01 to 0,9 mg of naltrexone per mg of morphine allows to significatively reduce the side effects of morphine maintaining 5S unchanged the analgesic activity of morphine.
Preferably naltrexone is prepared in form of a multiparticulate pharmaceutical composition constituted by pellets of saccharose and starch coated with a polyvinylpyrrolidone and naltrexone layer. Preferably said composition has a potency of naltrexone ranging from 0,005 to 0,1 mg per mg.
Preferably said composition is prepared in form of hard gelatine capsules having a content of naltrexone ranging from 0,25 to 0,5 mg per single capsule. Preferably the composition containing naltrexone is administered half an hour before morphine.
The invention is explained by the following clinical experimentation.
CLINICAL EXAMPLES
1) Five patients with persistent nausea and emesis non-reacting to metoclopramide, caused by the administration of morphine to control the postoperative pain, were treated with a composition of naltrexone prepared according to example 1.
The treatment with naltrexone began after 2 days of treatment with morphine.
The treatment with naltrexone was carried out by administering 0,5 mg by mouth half an hour before the administration of morphine.
The treatment with morphine was carried out by administering 10 mg intramuscularly every 12 hours.
The side effect incidence and the analgesic efficacy were evaluated by means of internationally accepted and validated questionnaires, utilized to evaluate the variation degrees of the single symptoms.
After the first administration of naltrexone, a 60% reduction of the nausea subjective sensation and a 50% reduction of the emesis episodes was noted, while no variation of the analgesic efficacy of the morphine therapy was noted. 5 2) 10 mg of morphine every 12 hours were intramuscularly administered to five patients in postoperative phase with analgesic aim. To the same patients a dose of 0,5 mg of naltrexone was administered half an hour before every administration of morphine.
With this treatment the onset of the side effects of morphine was prevented in three patients and, in the other two patients, the intensity and the frequency of such effects turned out to be of moderate degree. 3) Fifteen patients affected by pain of osteogenic origin, secondary to multiple vertebral collapses from primary osteoporosis, who showed side effects (ritention of urine, pruritus, nausea, emesis, inappetence and constipation) due to the administration of 2 mg of morphine every 12 hours per epidural way, were treated with naltrexone.
Naltrexone was administered by mouth half an hour before the administration of morphine, in the dose of 0,25 mg every 12 hours.
Five patients showed a total remission of the side effects, except for constipation. The other ten patients showed a 60% reduction of the side effects. 4) Twelve patients with pain of metastasized cancer showed nausea, emesis, pruritus and constipation caused by the intake of morphine in the dose of 30 mg every 12 hours.
To said patients a dose of 0,5 mg of naltrexone was administered every 12 hours, by mouth, half an hour before the administration of morphine. A 50% reduction of said side effects was observed, except for constipation.
EXAMPLES OF COMPOSITIONS CONTAINING NALTREXONE
Some examples of multiparticulate preparations are described, suitable for the administration of microdosages of naltrexone.
Example 1 1 Kg of pellets constituted by saccharose and starch in a weight ratio of 75/25, having granulometry ranging from 0,7 to 1,1 mm, was put in fluid bed UNIGLATT produced by the company Glatt GmbH.
The fluidization of the pellets was realized by means of an airflow having a temperature of 40°
C. On the fluidized pellets the following solution was sprayed: - naltrexone HCI 0,100 g - water 100 g - ethanol 100 g - PVP at 20% in ethanol 50g
The so obtained pellets were analyzed as for the naltrexone HCI content, which came out to be 0,01 mg / mg. Moreover, the pellets were tested to check the dissolution pattern in water, utilizing the apparatus described in the European Pharmacopoeia - Par. 2.9.3. - Dissolution test for solid dosage forms - “Paddle Apparatus”. The value observed was 100% after 10 minutes.
The pellets obtained according to this example were encapsulated in hard gelatine capsules.
Capsules containing S0 mg of pellets equivalent to 0,5 mg of naltrexone HCI and capsules containing 25 mg of pellets, equivalent to 0,25 mg of naltrexone HCI, were prepared.
Example 2 2 Kg of pellets constituted by saccharose and starch, like in example 1, were put in a rotating pan and onto said pellets the following solution was sprayed: - naltrexone HCI 0,200 g - water 200g - ethanol 200g - PVP at 20% in ethanol 50g
The above described pellets were analyzed as per example 1 obtaining results similar to those of example 1.
Example 3
A preparation according to the technique of example | was carried out, using the following solution: - naltrexone HCI 0,100 g - water 200g - PVPat20% in ethanol lg
The obtained pellets were analyzed obtaining results similar to those of Example 1.
Example 4
A test as per example 3 was carried out, replacing water with ethanol, thus obtaining the same results.
Ina VIANI granulator model ST25 the following components were mixed: : - lactose 2,0Kg - microcrystalline cellulose 3,0 Kg .
The above-indicated mixture was wet with 0,6 Kg of a solution compounded as follows: - naltrexone HCI 0,500 g - PVP at 20% in water 599,5 g
About 2 Kg of the above indicated granulate were put in desiccator; then, the granules were mixed with 0,5% of magnesium stearate and tableted to obtain microtablets with a diameter of 2 mm. "The so obtained microtablets were dosed in hard gelatine capsules to obtain the dosages of 2,5 and 1,25 mg of naltrexone HCI / capsule.
The remaining part of granulate of example 5 was extruded by means of an extruder FUJI
PAUDAL DG-L! having a perforated disc of 0,8 mm and spheronized by means of a spheronizer FUJI PAUDAL Q-230T. The so obtained pellets were desiccated in desiccator at a temperature of 50°C, thus obtaining results similar to those of example 1.
Claims (6)
1) Use of naltrexone to prepare pharmaceutical compositions suitable to prevent and control the side effects caused by the treatment with morphine, to be administered by mouth in the dose ranging between 0,01 and 0,9 mg / mg of administered morphine.
2) Pharmaceutical compositions in multiparticulate form suitable to control the side effects caused by the treatment with morphine characterized by the fact of being constituted by pellets of saccharose and starch coated with a polyvinylpyrrolidone and naltrexone layer.
3) Compositions according claim 2, wherein the naltrexone content ranges between 0,005 and 0,1 mg/ mg of composition.
4) Compositions according to claim 2, prepared in form of hard gelatine capsules having a naltrexone content ranging from 0,25 to 0,9 mg per single dose of composition.
5) Therapeutic method to control the side effects caused by the treatment with morphine consisting in the administration by mouth of a composition according to claim 2 in a quantity ranging from 0,01 to 0,9 mg of naltrexone per mg of morphine.
6) Method according to claim 5, wherein said administration of naltrexone is carried out half an hour before the administration of morphine.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2001MI000907A ITMI20010907A1 (en) | 2001-05-02 | 2001-05-02 | USE OF OPIOID ANTAGONISTS FOR THE PREVENTION AND CONTROL OF THE SIDE EFFECTS PRODUCED BY THE OPIOIDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200309333B true ZA200309333B (en) | 2004-02-17 |
Family
ID=11447580
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200309333A ZA200309333B (en) | 2001-05-02 | 2003-12-01 | Use of the opioid antagonist naltrexone to prevent and control side effects caused by opioids. |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1395260A1 (en) |
| IT (1) | ITMI20010907A1 (en) |
| RU (1) | RU2003135201A (en) |
| WO (1) | WO2002087582A1 (en) |
| ZA (1) | ZA200309333B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY135852A (en) * | 2003-04-21 | 2008-07-31 | Euro Celtique Sa | Pharmaceutical products |
| US20060063792A1 (en) * | 2004-09-17 | 2006-03-23 | Adolor Corporation | Substituted morphinans and methods of their use |
| US9056054B2 (en) * | 2009-06-25 | 2015-06-16 | Elite Laboratories, Inc. | Abuse resistant oral dosage forms |
| US20140179727A1 (en) | 2012-12-14 | 2014-06-26 | Trevi Therapeutics, Inc. | Methods for treating pruritus |
| US8987289B2 (en) | 2012-12-14 | 2015-03-24 | Trevi Therapeutics, Inc. | Methods for treating pruritus |
| US8637538B1 (en) | 2012-12-14 | 2014-01-28 | Trevi Therapeutics, Inc. | Methods for treatment of pruritis |
| CN112703000A (en) | 2018-07-23 | 2021-04-23 | 特雷维治疗股份有限公司 | Treatment of chronic cough, shortness of breath and dyspnea |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5512578A (en) * | 1992-09-21 | 1996-04-30 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists |
| US6096756A (en) * | 1992-09-21 | 2000-08-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
| US5580876A (en) * | 1992-09-21 | 1996-12-03 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
| US20010006967A1 (en) * | 1992-09-21 | 2001-07-05 | Stanley M. Crain | Method of simultaneously enhancing analgesic potency and attenuating adverse side effects caused by tramadol and other bimodally-acting opioid agonists |
| SI2266564T1 (en) * | 1997-12-22 | 2013-07-31 | Euro-Celtique S.A. | Pharmaceutical oral dosage form comprising a combination of an opioid agonist and an opioid antagonist |
| AU2001268353A1 (en) * | 2000-06-09 | 2001-12-17 | The Regents Of The University Of California | Method of treating pain using nalbuphine and opioid antagonists |
-
2001
- 2001-05-02 IT IT2001MI000907A patent/ITMI20010907A1/en unknown
-
2002
- 2002-05-02 RU RU2003135201/15A patent/RU2003135201A/en not_active Application Discontinuation
- 2002-05-02 WO PCT/IB2002/001473 patent/WO2002087582A1/en not_active Application Discontinuation
- 2002-05-02 EP EP02726358A patent/EP1395260A1/en not_active Withdrawn
-
2003
- 2003-12-01 ZA ZA200309333A patent/ZA200309333B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| RU2003135201A (en) | 2005-03-27 |
| EP1395260A1 (en) | 2004-03-10 |
| WO2002087582A1 (en) | 2002-11-07 |
| ITMI20010907A1 (en) | 2002-11-02 |
| ITMI20010907A0 (en) | 2001-05-02 |
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