CN1329590A - Therapeutic product and its use - Google Patents
Therapeutic product and its use Download PDFInfo
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- CN1329590A CN1329590A CN99813934A CN99813934A CN1329590A CN 1329590 A CN1329590 A CN 1329590A CN 99813934 A CN99813934 A CN 99813934A CN 99813934 A CN99813934 A CN 99813934A CN 1329590 A CN1329590 A CN 1329590A
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- 230000001225 therapeutic effect Effects 0.000 title 1
- 230000000694 effects Effects 0.000 claims abstract description 25
- 206010047700 Vomiting Diseases 0.000 claims abstract description 13
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000008673 vomiting Effects 0.000 claims abstract description 8
- 206010010774 Constipation Diseases 0.000 claims abstract description 3
- 208000002173 dizziness Diseases 0.000 claims abstract 2
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical class Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 20
- 208000002193 Pain Diseases 0.000 claims description 18
- 230000036407 pain Effects 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 238000013270 controlled release Methods 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 5
- 230000007794 irritation Effects 0.000 claims description 5
- 108010001237 Cytochrome P-450 CYP2D6 Proteins 0.000 claims description 4
- 206010041349 Somnolence Diseases 0.000 claims description 4
- 208000019695 Migraine disease Diseases 0.000 claims description 3
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 3
- 206010027599 migraine Diseases 0.000 claims description 3
- 208000032140 Sleepiness Diseases 0.000 claims description 2
- 206010047513 Vision blurred Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- 230000000202 analgesic effect Effects 0.000 abstract description 3
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 abstract 1
- 206010028813 Nausea Diseases 0.000 abstract 1
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- 230000036280 sedation Effects 0.000 abstract 1
- 231100001274 therapeutic index Toxicity 0.000 abstract 1
- 229960004380 tramadol Drugs 0.000 abstract 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 abstract 1
- 238000012986 modification Methods 0.000 description 6
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- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
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- 230000001939 inductive effect Effects 0.000 description 2
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- 238000011369 optimal treatment Methods 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
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- 229930008564 C01BA04 - Sparteine Natural products 0.000 description 1
- 101150010738 CYP2D6 gene Proteins 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 108090000417 Oxygenases Proteins 0.000 description 1
- 102000004020 Oxygenases Human genes 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- SLRCCWJSBJZJBV-UHFFFAOYSA-N alpha-isosparteine Natural products C1N2CCCCC2C2CN3CCCCC3C1C2 SLRCCWJSBJZJBV-UHFFFAOYSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003502 anti-nociceptive effect Effects 0.000 description 1
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- 239000007943 implant Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 230000000966 norepinephrine reuptake Effects 0.000 description 1
- 230000037325 pain tolerance Effects 0.000 description 1
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- 210000000664 rectum Anatomy 0.000 description 1
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- 230000000697 serotonin reuptake Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- SLRCCWJSBJZJBV-AJNGGQMLSA-N sparteine Chemical compound C1N2CCCC[C@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 SLRCCWJSBJZJBV-AJNGGQMLSA-N 0.000 description 1
- 229960001945 sparteine Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
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- 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
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention is based on the discovery that, by employing certain, non-racemic, proportions of the respective enantiomers of tramadol, the most beneficial therapeutic index, in terms of analgesic efficacy and reduction of side effects (e.g. nausea, vomiting, dizziness, constipation, sedation and others) associated with administration of the racemate, may be achieved.
Description
Invention field
The present invention relates to U-26225A new, non-racemic form, and the application in pain relieving.
Background of invention
U-26225A (cis-2,6-dimethyl aminomethyl-1,2-(3-p-methoxy-phenyl)-1-hexalin) is the chiral drug as efficient pain killer.Though U-26225A is only sold as racemic modification on market at present, but people's pair enantiomer independent with it, be 1S, 2S-(-)-U-26225A and 1R, the relevant physiological property of 2R-(+)-U-26225A has shown keen interest, and the structure of back one mapping isomer is shown in following (1).
Particularly, people have studied the pain relieving effectiveness and the security of this racemic modification and each enantiomer with the pain relieving of intravenously patient control in the randomized, double-blind experiment that is participated in by the gynecopathy patient; Referring to people such as S.Grond, Pain (1995) 62 (3): 313-320.Though look (+)-U-26225A producing aspect the analgesia more effective force, and it also produces more serious nausea and vomiting.Because the effectiveness of racemic modification is stronger than (-)-U-26225A, and side effect is serious unlike (+)-U-26225A, so the author infers that racemic modification has better clinical practice.
In another research, between the independent enantiomer of U-26225A, there is complementary and collaborative anti-nociception to interact according to showing; Referring to people such as R.B.Raffa, JPharmacol.Exp.Ther. (1993) 267 (1): 331-340.The enantiomer of U-26225A is having different effectiveness aspect opiate receptor, inhibition serotonin reuptake and the norepinephrine reuptake.Therefore look that these two kinds of enantiomers of U-26225A all have contribution to analgesic effect.
The invention summary
The present invention is based on that following discovery finishes: by adopting each U-26225A enantiomer of some non-racemize ratios, can obtain to render a service and the optimal treatment index that reduces the side effect relevant with using racemic modification (for example nauseating, vomiting, giddy, constipation, calmness etc.) about pain relieving.
According to first aspect of the present invention, the invention provides as being used for simultaneously, separately or use in order and treat or the product of the non-racemic mixture that comprises each U-26225A enantiomer of the combined preparation (medicine box) of prevent irritation.
According to second aspect of the present invention, the non-racemic mixture that the invention provides each U-26225A enantiomer is used for the treatment of or prevent irritation, tends to show the application in patient's the medicine of side effect when using the racemize U-26225A especially for treatment in preparation.Yet described medicine also can be used for treatment other type patient as discussed below.
According to third aspect of the present invention, the invention provides the non-racemic mixture that comprises each U-26225A enantiomer and the product of pharmaceutically acceptable carrier.
Detailed Description Of The Invention
In the application's context, when mentioning the non-racemic mixture of U-26225A, it comprises (-)-U-26225A of enantiomer-pure, perhaps the excessive mixture near enantiomer-pure of enantiomerism with regard to (-)-U-26225A.
Be used for (-)-U-26225A that non-racemic mixture of the present invention generally comprises at least 60% (weight).Though (-) of enantiomer-pure-U-26225A can be used for realizing pain relieving, but it is preferred that (+)-U-26225A and at least some (+)-U-26225A is formulated together, because when having two kinds of enantiomers, can be implemented in the optimum balance between pain relieving effectiveness and the security.The particularly preferred weight ratio of these two kinds of enantiomers is between 10-40: 90-60 (+)-U-26225A: (-)-U-26225A (+:-), preferred weight ratio be between 20-40: 80-60 (+:-), and most preferred weight ratio is between 30-40: 70-60 (+:-).
These preferred non-racemic mixtures can be used in particular for treating the patient who tends to show side effect when using the racemize U-26225A.Several examples of these side effects have above been provided.When using the racemize U-26225A, generally can observed other side effect comprise that blurred vision, drowsiness, somnolence, illusion, breathing are prevented and excitement.Yet the present invention can be used in particular for treating the patient of nausea and vomiting tendency.This is because the explanation in the following examples, it is believed that (-)-U-26225A can modulate the emetic characteristic of (+)-U-26225A, so reduced the overall emetic ability of racemize U-26225A.As described below, use the different release profile of different enantiomers, can utilize this effect to obtain greatest benefit.
It is believed that the present invention also is particularly suitable for treating the patient who shows unusual CYP2D6 enzyme activity of liver.The CYP2D6 gene of coding sparteine oxygenase is the height polymorph, and is identifying the ever-increasing sudden change of quantity.Wild type gene is CYP2D6*1A.Anyone of this wild type gene can not classify as the individuality that shows unusual enzymic activity.The definite character of any specific sudden change has determined the patient to show the degree of unusual enzymic activity.Therefore,, can determine the roughly speed of particular patient metabolism (+)-U-26225A, and therefore will reach how soon and how effective analgesic effect by adopting simple laboratory genetic analysis technology.
It is contemplated that according to the present invention, by phenotype or genotype means be diagnosed as can produce racemize U-26225A metabotic change widely the patient with special benefit in using non-racemize U-26225A, because they especially are easy to show side effect such as nausea and vomiting.In addition, in case arbitrary patient's CYP2D6 genotype is known, can draft dosage regimen to be applicable to this patient at him or she.
According to the cause of disease of pain and/or the patient of desire treatment, also can use this two kinds of U-26225A enantiomer treatments or prevent irritation of other non-racemize ratio.For example, for the patient who shows the side effect relevant with the racemize U-26225A especially easily, can use to comprise the mixture of (-)-U-26225A very at high proportion, for example weight ratio is between 0-10: 100-90 (+:-).Another selection is to adopt these two kinds of enantiomers of isostatic more, allows to render a service stronger (+)-enantiomer excessive, for example weight ratio between 60-80: 40-20 (+:-), typically be 60-70: 40-30 (+:-).Such ratio can be used for treating the patient who is not to show especially easily the side effect relevant with the racemize U-26225A, and perhaps pain relieving is renderd a service and answered the patient of overriding concern.Yet, use (-)-U-26225A before (+)-U-26225A, perhaps to use (-)-U-26225A and also can advantageously reduce side effect than using the fast speed of (+)-U-26225A.
In the application's context, all weight ratios of mentioning all should be understood to comprise ± permissible error of 5wt.%.
It is believed that the present invention also can be used in particular for treating the pain relevant with migraine and/or other influence.The further aspect of the present invention is that the non-racemic mixture of each U-26225A enantiomer is used for preventing or treating the application of migrainous medicine in preparation.
Depending on the patient for the amount of the non-racemize U-26225A that any particular patient uses and using illness and the used non-racemize U-26225A that non-racemize U-26225A treats is that prophylactic applications or treatment are used.Those skilled in the art can easily determine suitable dosage.
Different U-26225A enantiomers can be simultaneously, separately or the order administration.They can be mixed with and promptly release or controlled release form, the perhaps combination of these two is perhaps prepared their so that discharge with different rates or at different time.Preferred administering mode is that (-)-U-26225A discharged before (+)-U-26225A, perhaps discharges with (-)-U-26225A speed faster than (+)-U-26225A, so that (-)-U-26225A reaches best to the effect of the emetic characteristic of (+)-U-26225A.But it is contemplated that such situation, promptly may need opposite situation and be desirably in to use before (-)-U-26225A or to use (+)-U-26225A than using the fast speed of (-)-U-26225A.
Particularly preferred administering mode is, by adopting as the described combination of promptly releasing with controlled-release technology of W0-A-9840053 (content introducing the present invention of the document is with for referencial use), (-)-U-26225A is formulated in the immediate release dosage form and with (+)-U-26225A and is formulated in the controlled release form.Can imagine that this formulation may be particularly conducive to and realize rapid pain relieving, the not side effect followed relevant with using the racemize U-26225A simultaneously.
For non-racemic mixture of the present invention, can adopt multiple different dosage form, with by for example oral, the rectum of number of ways, transdermal, intranasal, through eye, through lung and injection (subcutaneous injection or intravenous injection) administration.Suitable formulation comprises for example tablet, suppository, capsule, for example contains a plurality of particulate capsules, patch, polymeric implant, aerosol, Injectable liposomal or particulate and other any regular dosage form.
Particularly preferred formulation has been described among the WO-A-9840053.In the middle of the formulation that the document is described, comprise (-)-bilayer tablet that U-26225A is promptly released layer and (+)-U-26225A controlled release layer is particularly preferred.
Report in the following embodiments the present invention based on the result.
Embodiment
Target is that the suitableeest enantiomer proportional range of optimal treatment exponential that can provide about pain relieving effectiveness and the reduction nausea and vomiting relevant with the racemize U-26225A is provided.
Carry out two experiments with determine U-26225A and enantiomer thereof respectively the pain relieving in rat and ferret render a service and cause the vomiting effect.By the data that relatively in these experiments, obtain, can determine scope for the best enantiomer ratio of animal of these kinds.Pharmacokinetics/pharmacodynamics model makes these data can be extrapolated to the people.
The evaluation pain relieving is renderd a service
The pain relieving of using Randall Selitto test (Arch.Int.Pharmacodyn. (1957) 111:409-419) to measure U-26225A and pure enantiomer thereof in rat is renderd a service.This test is that design is used for measuring the effect to the yeast inductive pain sensation of U-26225A and enantiomer thereof, and evaluates the pain sensation with the odynometer measuring device by the pressure that raising is applied on the claw.In order to compare, also measured the effect of the active metabolite-O-demethyl U-26225A of U-26225A enantiomer.
Each tester of difference amount to the rat oral administration, is used the constant dosage volume of 10ml/kg.After the administration, immediately the suspension of 0.1ml 20%w/v yeast saccharomyces cerevisiae in salt solution is subcutaneously injected in the plantar surface of every right front pawl of rat, to induce the height pain sensation.Inject 0.1ml salt solution in the rear solid end left in a similar manner, in contrast.
After the tester administration 30 minutes, measure the tolerance of left pawl (not inflammation) and right pawl (inflammation) and press.
The result who is observed is shown in accompanying drawing 1 (claw of inflammation) and accompanying drawing 2 (the not claw of inflammation), and the result represents with the per-cent of the pain tolerance raising of the tester correspondence of various dose.In these two accompanying drawings, T=U-26225A, M1=O-demethyl U-26225A.
The evaluation of feeling sick
In ferret, measured the effect of feeling sick that causes of U-26225A and pure enantiomer thereof.In order to compare, also measured active metabolite-(+)-O-demethyl U-26225A (effect of (+)-M1) of (+)-U-26225A.Observe retch and the vomiting symptom of 4 hours oral administration ferrets.Any ferret that retch or vomiting took place during 4 hours is regarded as the respondent, promptly shows nauseating animal.
The gained result as shown in Figure 3; As in attached Fig. 1 and 2, T and M1 represent U-26225A and O-demethyl U-26225A.Just as expected, (+)-M1 is the height emetic.(-)-U-26225A does not cause vomiting under the dosage up to 200mg/kg.By contrast, (+) of 50mg/kg dosage-U-26225A has caused in 75% ferret feels sick, and the racemize U-26225A of 100mg/kg has caused in 25% animal and feels sick.Though racemic modification is 50: 50 mixtures of these two kinds of enantiomers, its inductive is felt sick beguine according to wanting gently that its (+)-enantiomerism body burden is estimated.This difference can be regulated and control the vomiting relevant with (+)-enantiomer by (-)-enantiomer and explain.
The bioanalysis of plasma sample and liver microsomes analysis have shown U-26225A metabolism in a similar manner in rat, ferret and human body.So the data that can relatively in these experiments, obtain, to obtain the suitableeest enantiomer proportional range for these kind animals.In addition,, can be extrapolated to the people to the gained data, to obtain to be used for the suitableeest enantiomer proportional range of the present invention by pharmacokinetics/pharmacodynamics model technology.
Claims (20)
1. as being used for simultaneously, separately or use in order and treat or the product of the non-racemic mixture that comprises each U-26225A enantiomer of the combined preparation (medicine box) of prevent irritation, described mixture comprises at least some (-)-U-26225A.
2. the product of claim 1 wherein comprises (-)-U-26225A of at least 60% (weight).
3. the product of claim 2, wherein the weight ratio of each enantiomer is 10-40: 90-60 (+:-).
4. the product of claim 2, wherein the weight ratio of each enantiomer is 20-40: 80-60 (+:-).
5. the product of claim 2, wherein the weight ratio of each enantiomer is 0-20: 100-80 (+:-).
6. each product of aforementioned claim, wherein (-)-enantiomer discharged before (+)-enantiomer.
7. each product of claim 1-5, wherein (-)-enantiomer discharges sooner than (+)-enantiomer.
8. each product of claim 1-5, wherein (-)-enantiomer in immediate release dosage form and (+)-enantiomer in controlled release form.
As each defined non-racemic mixture of claim 1-5 preparation be used for the treatment of or the medicine of prevent irritation in application.
10. the application of claim 9, wherein said pain are the pain relevant with migraine.
11. the application of claim 9, wherein said medicine are to be used for the treatment of the patient who tends to show side effect when using the racemize U-26225A.
12. that the application of claim 11, wherein said side effect are selected from is nauseating, vomiting, dizziness, constipation, calmness, blurred vision, drowsiness, somnolence, illusion, breathing is prevented and excited, especially nausea and vomiting.
13. the application of claim 9, wherein said medicine are to be used for the treatment of the patient who shows unusual CYP2D6 enzyme activity of liver.
14. as each defined non-racemic mixture of claim 1-5 preparation be used for the treatment of or the medicine of prevention of migraine in application.
15. comprise product as each described non-racemic mixture of claim 1-5 and pharmaceutically acceptable carrier.
16. the product of claim 15, wherein (-)-enantiomer discharged before (+)-enantiomer.
17. the product of claim 15, wherein (-)-enantiomer discharge sooner than (+)-enantiomer.
18. the product of claim 15, wherein (-)-enantiomer in immediate release dosage form and (+)-enantiomer in controlled release form.
19. each product of claim 15-18, described product comprises this two kinds of enantiomers in its divided portion.
20. the product of claim 19, described product are the bilayer tablets that comprises (-)-U-26225A in an one part, comprise (+)-U-26225A in its another divided portion.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9826536.6 | 1998-12-02 | ||
| GB9826535.8 | 1998-12-02 | ||
| GBGB9826536.6A GB9826536D0 (en) | 1998-12-02 | 1998-12-02 | Therapeutic product and its use |
| GB9826537.4 | 1998-12-02 | ||
| GBGB9826535.8A GB9826535D0 (en) | 1998-12-02 | 1998-12-02 | Therapeutic product and its use |
| GBGB9826537.4A GB9826537D0 (en) | 1998-12-02 | 1998-12-02 | Therapeutic product and its use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1329590A true CN1329590A (en) | 2002-01-02 |
Family
ID=27269570
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99813934A Pending CN1329590A (en) | 1998-12-02 | 1999-12-02 | Therapeutic product and its use |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP1135361A1 (en) |
| JP (1) | JP2002531431A (en) |
| KR (1) | KR20010080364A (en) |
| CN (1) | CN1329590A (en) |
| AU (1) | AU1400100A (en) |
| BR (1) | BR9915873A (en) |
| CA (1) | CA2350635A1 (en) |
| HU (1) | HUP0104420A2 (en) |
| IL (1) | IL142778A0 (en) |
| NO (1) | NO20012738D0 (en) |
| PL (1) | PL347542A1 (en) |
| WO (1) | WO2000032558A1 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1313460A2 (en) * | 1999-11-09 | 2003-05-28 | Darwin Discovery Limited | Therapeutic use and formulation of (-)-tramadol |
| JP2004513091A (en) * | 2000-10-03 | 2004-04-30 | ペンウェスト ファーマシューティカルズ カンパニー | Delivery systems for multiple pharmaceutically active ingredients at different rates |
| DE10108122A1 (en) * | 2001-02-21 | 2002-10-02 | Gruenenthal Gmbh | Medicines based on tramadol |
| AU2002364517A1 (en) | 2001-11-30 | 2003-06-17 | Sepracor Inc. | Tramadol analogs and uses thereof |
| CA2616204C (en) | 2005-09-09 | 2015-12-01 | Labopharm Inc. | Sustained drug release composition |
| CA2677691C (en) | 2007-02-12 | 2012-07-31 | David Bar-Or | Reducing side effects of tramadol |
| MX2009012685A (en) * | 2007-05-31 | 2009-12-14 | Sepracor Inc | Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors. |
| JOP20190251A1 (en) * | 2017-05-31 | 2019-10-21 | Metys Pharmaceuticals AG | Synergistic compositions comprising (r)-dimiracetam (1) and (s)-dimiracetam (2) in a non-racemic ratio |
| SG11202005016SA (en) | 2017-12-05 | 2020-06-29 | Sunovion Pharmaceuticals Inc | Nonracemic mixtures and uses thereof |
| JP2021505595A (en) | 2017-12-05 | 2021-02-18 | サノビオン ファーマシューティカルズ インクＳｕｎｏｖｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． | Crystal form and its manufacturing method |
| AU2019394706A1 (en) * | 2018-12-04 | 2021-05-20 | Metys Pharmaceuticals AG | Synergistic compositions comprising R-2-(substituted-sulfonyl)-hexahydro-pyrrolo[1,2-a]pyrazin-6(2H)-ones and S-2-(substituted-sulfonyl)-hexahydro-pyrrolo[1,2-a]pyrazin-6(2H)-ones in a non-racemic ratio |
| CN114401717A (en) | 2019-06-04 | 2022-04-26 | 赛诺维信制药公司 | Modified release formulations and uses thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5204116A (en) * | 1991-05-01 | 1993-04-20 | Alza Corporation | Dosage form providing immediate therapy followed by prolonged therapy |
| PL335619A1 (en) * | 1997-03-11 | 2000-05-08 | Darwin Discovery Ltd | Dosage forms including separate parts containing r and s enantiomers |
| DE19807535A1 (en) * | 1998-02-21 | 1999-08-26 | Asta Medica Ag | Drug combination for treating migraine, migraine-type headaches or pain accompanied by nausea, vomiting or delayed gastric emptying |
-
1999
- 1999-12-02 JP JP2000585200A patent/JP2002531431A/en active Pending
- 1999-12-02 EP EP99973016A patent/EP1135361A1/en not_active Withdrawn
- 1999-12-02 WO PCT/GB1999/004021 patent/WO2000032558A1/en not_active Application Discontinuation
- 1999-12-02 CN CN99813934A patent/CN1329590A/en active Pending
- 1999-12-02 CA CA002350635A patent/CA2350635A1/en not_active Abandoned
- 1999-12-02 KR KR1020017005443A patent/KR20010080364A/en not_active Application Discontinuation
- 1999-12-02 IL IL14277899A patent/IL142778A0/en unknown
- 1999-12-02 HU HU0104420A patent/HUP0104420A2/en unknown
- 1999-12-02 AU AU14001/00A patent/AU1400100A/en not_active Abandoned
- 1999-12-02 BR BR9915873-6A patent/BR9915873A/en not_active IP Right Cessation
- 1999-12-02 PL PL99347542A patent/PL347542A1/en not_active Application Discontinuation
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2001
- 2001-06-01 NO NO20012738A patent/NO20012738D0/en not_active Application Discontinuation
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| CA2350635A1 (en) | 2000-06-08 |
| AU1400100A (en) | 2000-06-19 |
| IL142778A0 (en) | 2002-03-10 |
| WO2000032558A1 (en) | 2000-06-08 |
| HUP0104420A2 (en) | 2002-08-28 |
| NO20012738L (en) | 2001-06-01 |
| NO20012738D0 (en) | 2001-06-01 |
| PL347542A1 (en) | 2002-04-08 |
| KR20010080364A (en) | 2001-08-22 |
| BR9915873A (en) | 2001-08-21 |
| JP2002531431A (en) | 2002-09-24 |
| EP1135361A1 (en) | 2001-09-26 |
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