CA2095499A1 - Depot preparation - Google Patents
Depot preparationInfo
- Publication number
- CA2095499A1 CA2095499A1 CA002095499A CA2095499A CA2095499A1 CA 2095499 A1 CA2095499 A1 CA 2095499A1 CA 002095499 A CA002095499 A CA 002095499A CA 2095499 A CA2095499 A CA 2095499A CA 2095499 A1 CA2095499 A1 CA 2095499A1
- Authority
- CA
- Canada
- Prior art keywords
- chloro
- oxepino
- trans
- pyrrole
- dibenz
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
Abstract
Abstract of The Disclosure Disclosed are the hemipamoate and pamoate salt of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz-[2,3;6,7]oxepino-[4,5-c]pyrrole, very insoluble compounds having excellent properties for use as depot preparations. Also disclosed are pharmaceutical preparations which include the pamoate salts of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-z[dibenz[2,3;6,7]
oxepino-[4,5-c]pyrrole, especially in crystalline form.
Such preparations release therapeutically useful amounts of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino-[4,5-c]pyrrole for 2 to S weeks after administration.
The invention also includes process of manufacturing the pharmaceutical preparations which generally involves allowing the free base of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz-[2,3:6,7]oxepino[4,5-c]pyrrole to react with pamoic acid to form a pamoate or hemipamoate salt.
oxepino-[4,5-c]pyrrole, especially in crystalline form.
Such preparations release therapeutically useful amounts of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino-[4,5-c]pyrrole for 2 to S weeks after administration.
The invention also includes process of manufacturing the pharmaceutical preparations which generally involves allowing the free base of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz-[2,3:6,7]oxepino[4,5-c]pyrrole to react with pamoic acid to form a pamoate or hemipamoate salt.
Description
209S4~
DEPOT PR~PA~ATIO~
Technical Field. The invention relates to pharma-ceutical preparations generally, and mor~ specifically to a depot prepara~ion useful in the treatment of various mental illnesses.
~ackqround Art. The compound trans-5-chloro-2-methyl-2,3,3a,1~b-tetrahydro-lH-dibenz~2,3;6,7~oxepino-[4,5-c]pyrrole and its preparation are described in U.S~
Patent No. 4,145,434 to van den Burg, the contents of which are incorporated by this re~erence. The compound is de~cribed as having CNS-depressant activity ~nd excellent antihistaminic and antiserotonin activities.
Nu~erous acid addition salts of related compounds are described in this patent. However, the pamoate salt i~ not described.
':
Disclosure o~ the Invention Surprisingly it is found that the pamoate and hemipamoat~ salt~ of tranæ-5-chloro-2-m~thyl-2,3,3a,12b-tetrahydro-lH-dibenz-~2,3;6,7]oxepino-[4,5-G]pyrrole are very insoluble co~pounds having excellent properties for ; 25 use as depot preparations.
The invention thus includes a pharmaceutical prepa-ration comprising a depot preparation including trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1~-dibenz[2,3;6,7]
oxepino-t4,5-c~pyrrole pa~oate or hemipamoate. Such preparations will release therapeutically useful amounts of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH~
dibenz[2,3;6,7] oxepino-~4,5-c]pyrrole after administration by injection.
The invention also includes processes of manufac-turing the pharmaceutical preparations which generally involve~ allowing the free base of trans-5-chloro-2-met~yl-2,3,3a,12b-tetrahydro-lH-dibenz-[2,3 6,7]oxepino [4,5-c]pyrrole to react with pamoic acid to form the pamoate or hemipamoate.
. .
.
20~99 Once made, the compositions of the invention are useful in treating mammals, including humans, suffering from disease states which are susceptible to treatment by the free base generally. Such disease states include tension, excitation, anxiety, psychosis, schizophrenia.
~p The co~positions may also be used as antihistamines, and for their antiserotonin activities.
Best Mode of the Invention The free base trans-5-chloro-2-methyl-2,3,3a,12b-te~rahydro-lH-dibenz~2,3;~,7]oxepino-[4,5-c]pyrrol~ may be made as described in EXA~PLE IV of U. S. Patent No.
4,145,434 to van den Burg, the contents c,f the entire patent being incorporated by reference. The free base is also available from Organon International, bv of Oss, The Netherlands.
The chemical name of pamoic acid is 4,4'-methylenebis[3-~ydroxy-~-napthalenecarboxylic acidl. It i5 readily commercially available, ~nd i~ al80 known as "embonic acidn.
In order to make the pamoa~e salt, trans-5-chloro-2 ~ethyl-2,3,3a,l2b-tetrahydro~ dibænzt2,3:6,7]0xe-pino~4,5-c]pyrrole is allowed to react with pamoic acid in an polar solvent until the pamoate is fo~med. Half the amount of pamoic acid is reacted to make the hemipamoate salt.
The pamoate salt spontaneously crystallizes with time at increased te~peratur~ (e.g. 50" C)~ This crystalline form -- which ccntains equal parts of pamoate salt and free base of the co~pound -- is prefered for use in the invention.
Whatever form the resulting salt takes, it may then be mixed with, for example, water, in order to make a pharmaceutical preparation for intramuscular injection.
Other liquids which can be used with the pamoate compound to make depot preparations are vegetable oils, such as arachis or sesame oil.
.
DEPOT PR~PA~ATIO~
Technical Field. The invention relates to pharma-ceutical preparations generally, and mor~ specifically to a depot prepara~ion useful in the treatment of various mental illnesses.
~ackqround Art. The compound trans-5-chloro-2-methyl-2,3,3a,1~b-tetrahydro-lH-dibenz~2,3;6,7~oxepino-[4,5-c]pyrrole and its preparation are described in U.S~
Patent No. 4,145,434 to van den Burg, the contents of which are incorporated by this re~erence. The compound is de~cribed as having CNS-depressant activity ~nd excellent antihistaminic and antiserotonin activities.
Nu~erous acid addition salts of related compounds are described in this patent. However, the pamoate salt i~ not described.
':
Disclosure o~ the Invention Surprisingly it is found that the pamoate and hemipamoat~ salt~ of tranæ-5-chloro-2-m~thyl-2,3,3a,12b-tetrahydro-lH-dibenz-~2,3;6,7]oxepino-[4,5-G]pyrrole are very insoluble co~pounds having excellent properties for ; 25 use as depot preparations.
The invention thus includes a pharmaceutical prepa-ration comprising a depot preparation including trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1~-dibenz[2,3;6,7]
oxepino-t4,5-c~pyrrole pa~oate or hemipamoate. Such preparations will release therapeutically useful amounts of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH~
dibenz[2,3;6,7] oxepino-~4,5-c]pyrrole after administration by injection.
The invention also includes processes of manufac-turing the pharmaceutical preparations which generally involve~ allowing the free base of trans-5-chloro-2-met~yl-2,3,3a,12b-tetrahydro-lH-dibenz-[2,3 6,7]oxepino [4,5-c]pyrrole to react with pamoic acid to form the pamoate or hemipamoate.
. .
.
20~99 Once made, the compositions of the invention are useful in treating mammals, including humans, suffering from disease states which are susceptible to treatment by the free base generally. Such disease states include tension, excitation, anxiety, psychosis, schizophrenia.
~p The co~positions may also be used as antihistamines, and for their antiserotonin activities.
Best Mode of the Invention The free base trans-5-chloro-2-methyl-2,3,3a,12b-te~rahydro-lH-dibenz~2,3;~,7]oxepino-[4,5-c]pyrrol~ may be made as described in EXA~PLE IV of U. S. Patent No.
4,145,434 to van den Burg, the contents c,f the entire patent being incorporated by reference. The free base is also available from Organon International, bv of Oss, The Netherlands.
The chemical name of pamoic acid is 4,4'-methylenebis[3-~ydroxy-~-napthalenecarboxylic acidl. It i5 readily commercially available, ~nd i~ al80 known as "embonic acidn.
In order to make the pamoa~e salt, trans-5-chloro-2 ~ethyl-2,3,3a,l2b-tetrahydro~ dibænzt2,3:6,7]0xe-pino~4,5-c]pyrrole is allowed to react with pamoic acid in an polar solvent until the pamoate is fo~med. Half the amount of pamoic acid is reacted to make the hemipamoate salt.
The pamoate salt spontaneously crystallizes with time at increased te~peratur~ (e.g. 50" C)~ This crystalline form -- which ccntains equal parts of pamoate salt and free base of the co~pound -- is prefered for use in the invention.
Whatever form the resulting salt takes, it may then be mixed with, for example, water, in order to make a pharmaceutical preparation for intramuscular injection.
Other liquids which can be used with the pamoate compound to make depot preparations are vegetable oils, such as arachis or sesame oil.
.
3 2095~99 Other pharmaceutical preparations into which the pamoate can be incorporated are implants including microspheres and microcapsules.
Although not necessary for the practice of the invention, other compounds such as phosphate salts, citric acid, and acetic acid or salts thereof; parabens;
benzyl alcohol; an~ chlorobutanol may be included in the pharmaceutical preparations according to the invention to act as buffers, preservatives, and local anesthetics.
Su~pendi~g agent~ such as carboxy~ethylcelllulose or gelatin and ~urfactants such as Twean 20 or Tween 80 ean be added to i~prove the suspen~ion characteri~tics.
The dose of trans 5-chloro-2-methyl-2,3,3a,12b-tekrahydro-l~-dibenz~2,3:6,7]oxepino [~,5 clpyrrole pam-oate contained wi~hin the phar~aceutical preparations of the invention are pre~erably choaen wi~h a particular patient in mind. However, pharmaceutical preparations made according to the invention will typically contain : sufflcient trans-5-chloro-2-methyl-2,3,3a,12b-tetra~
hydro-lH-~ibenz[2~3:6~7]oxepino-~4~5-c]pyrrole pamoate to release, in a sustained or prolonged manner, ~ to 4 mg daily into a subject are extremely useful in the practice of the invention. The ultimate dosaqe to provide relief for the patient depends, apart from ; 25 individual characteristics, on the patient's weight, condition and age.
After intramuscular injec~ion, the compound will typically release into an animal's blood strea~ for about four ~froM 2 to 6) weeks.
A method of providing therapy u~ing the pharmaceut-ical preparation of the instant invention comprises ad-mini~tering it to a subject, such as a man, in need thereof. The treatment will generally be by intramusc-ular injection into the subject. The treat~ent may be continued for as long as necessary or desired.
The invention is further explained by the following illustrative EXAMPLES.
~0~99 EXAMPLE I
The free base of trans-5 chloro-2-methyl-2,3, 3a,12b-tetrahydro-lH-dibenz[2,3:6,7]oxepino-[4,5-c] pyr-role was obtained from Organon International, bv of Oss, The Netherlands. 2.91 grams of the free base was : dissolved in 50 ml o~ dimet~ylformamide kept at 20 C.
To this solution was added 3.95 g of pamoic acid ~Janssen Chimica). The mixture was stirred for 20 hours, and the pamoate salt was obtained by adding 80 ml of water, the resulting precipita~e was collect~d by filtratio~ and slurried once with a 100 ~1 portion of acetone-hexane (1:1). The yellow sclid was collected ~y : filtration and dried va~o at 50 C for 48 hours;
yield 5.52 g. The re~ul~ing pa~o~te ~al~ had a water solubility o~ less than 0.2 ~g/~l with a melting point o~ 224.3 to 254.1 C.
In a similar way were made tha ~umarate, l-hydrox~-2-naphtoic acid and palmitic acid ~alts of trans-5-chloro-2-me~hyl 2,3,3a,12b~tetrahydro-lH-dibenZ-: 20 t2~3;6~7]oxepino~4~5-a]pyrrole. The l-hydroxy-2-naphtoic aaid and palmitic acid salts were oils. The fumarate had a meltin~ point of 185.5-187.5 C and water solubility of 1 mg / ml, which is not that desirable for a depot preparation.
: EXAMPLE II
A he~ipa~oata salt o~ the compound was made by the process of EXAMPLE I, but using only half (2 g) of the pa~oic acidO
EXAMPLE III
The pamoate salt of EXAMPLE I was stored for two weeks at 50 C, and crystals spontaneously formed.
These crystals were less soluble ana more stable than the amorphous yellow solid. Furthermore they were easier to segregate for micronization, and easier to form a suspension with.
:
5 2095~9 EXAMPLE V
A preparation for intramuscular injection includes:
10 mg/ml tr~ns-5-chloro-2-methyl-2,3,3a,12b-tetrahydro lH-dibenz[2,3:6,7]oxepino[~,5-c]pyrrole pamoat-e 10 mg/ml citric acid monohydrate 18 mg~ml disodium biphoæphate A dihydrate 0.5 mg/ml polysorbata 80 5 mg/ml sodium carboxymethylcellulose qsad 1 ml water EXAMPLE VT
A preparation for intramugcular iniection includes:
50 mg/ml trans-5-chloro-2 met~yl-2,3~3a,12b-tetrahydro lH-dibenz[2,3:6,7]oxepino~4,5-c]pyrrole pamoate 10 mg/ml citric acid ~onohydrate 18 mg/ml disodium biphosphate-dihydrate 0.5 mg/ml polysorbate 80 5 mgJml sodium carboxymethylcellulo~e qsad 1 ml water EX~PLE VII
A preparation for intramuscular injection includes:
100 ~g~ml trans-5-chloro-2-methyl 2,3,3a,l2b-tetrahydro lH-dibenz[2,3:6,7]oxepino~4,5-c]pyrrole ~crystal of EXAMPLE III) 10 mg/ml citric acid monohydrate 1~ mg/ml disodium biphosphate-dihydrate 0.5 mg~ml polysorbate 80 5 mg/ml sodiu~ carboxymethylcellulose qsad 1 ml water Reference her~in to specific embodiments or exam-ples should not be interpre~ed a~ li~ita~ions to the scope of the invention, which is defined by the appended claims.
Although not necessary for the practice of the invention, other compounds such as phosphate salts, citric acid, and acetic acid or salts thereof; parabens;
benzyl alcohol; an~ chlorobutanol may be included in the pharmaceutical preparations according to the invention to act as buffers, preservatives, and local anesthetics.
Su~pendi~g agent~ such as carboxy~ethylcelllulose or gelatin and ~urfactants such as Twean 20 or Tween 80 ean be added to i~prove the suspen~ion characteri~tics.
The dose of trans 5-chloro-2-methyl-2,3,3a,12b-tekrahydro-l~-dibenz~2,3:6,7]oxepino [~,5 clpyrrole pam-oate contained wi~hin the phar~aceutical preparations of the invention are pre~erably choaen wi~h a particular patient in mind. However, pharmaceutical preparations made according to the invention will typically contain : sufflcient trans-5-chloro-2-methyl-2,3,3a,12b-tetra~
hydro-lH-~ibenz[2~3:6~7]oxepino-~4~5-c]pyrrole pamoate to release, in a sustained or prolonged manner, ~ to 4 mg daily into a subject are extremely useful in the practice of the invention. The ultimate dosaqe to provide relief for the patient depends, apart from ; 25 individual characteristics, on the patient's weight, condition and age.
After intramuscular injec~ion, the compound will typically release into an animal's blood strea~ for about four ~froM 2 to 6) weeks.
A method of providing therapy u~ing the pharmaceut-ical preparation of the instant invention comprises ad-mini~tering it to a subject, such as a man, in need thereof. The treatment will generally be by intramusc-ular injection into the subject. The treat~ent may be continued for as long as necessary or desired.
The invention is further explained by the following illustrative EXAMPLES.
~0~99 EXAMPLE I
The free base of trans-5 chloro-2-methyl-2,3, 3a,12b-tetrahydro-lH-dibenz[2,3:6,7]oxepino-[4,5-c] pyr-role was obtained from Organon International, bv of Oss, The Netherlands. 2.91 grams of the free base was : dissolved in 50 ml o~ dimet~ylformamide kept at 20 C.
To this solution was added 3.95 g of pamoic acid ~Janssen Chimica). The mixture was stirred for 20 hours, and the pamoate salt was obtained by adding 80 ml of water, the resulting precipita~e was collect~d by filtratio~ and slurried once with a 100 ~1 portion of acetone-hexane (1:1). The yellow sclid was collected ~y : filtration and dried va~o at 50 C for 48 hours;
yield 5.52 g. The re~ul~ing pa~o~te ~al~ had a water solubility o~ less than 0.2 ~g/~l with a melting point o~ 224.3 to 254.1 C.
In a similar way were made tha ~umarate, l-hydrox~-2-naphtoic acid and palmitic acid ~alts of trans-5-chloro-2-me~hyl 2,3,3a,12b~tetrahydro-lH-dibenZ-: 20 t2~3;6~7]oxepino~4~5-a]pyrrole. The l-hydroxy-2-naphtoic aaid and palmitic acid salts were oils. The fumarate had a meltin~ point of 185.5-187.5 C and water solubility of 1 mg / ml, which is not that desirable for a depot preparation.
: EXAMPLE II
A he~ipa~oata salt o~ the compound was made by the process of EXAMPLE I, but using only half (2 g) of the pa~oic acidO
EXAMPLE III
The pamoate salt of EXAMPLE I was stored for two weeks at 50 C, and crystals spontaneously formed.
These crystals were less soluble ana more stable than the amorphous yellow solid. Furthermore they were easier to segregate for micronization, and easier to form a suspension with.
:
5 2095~9 EXAMPLE V
A preparation for intramuscular injection includes:
10 mg/ml tr~ns-5-chloro-2-methyl-2,3,3a,12b-tetrahydro lH-dibenz[2,3:6,7]oxepino[~,5-c]pyrrole pamoat-e 10 mg/ml citric acid monohydrate 18 mg~ml disodium biphoæphate A dihydrate 0.5 mg/ml polysorbata 80 5 mg/ml sodium carboxymethylcellulose qsad 1 ml water EXAMPLE VT
A preparation for intramugcular iniection includes:
50 mg/ml trans-5-chloro-2 met~yl-2,3~3a,12b-tetrahydro lH-dibenz[2,3:6,7]oxepino~4,5-c]pyrrole pamoate 10 mg/ml citric acid ~onohydrate 18 mg/ml disodium biphosphate-dihydrate 0.5 mg/ml polysorbate 80 5 mgJml sodium carboxymethylcellulo~e qsad 1 ml water EX~PLE VII
A preparation for intramuscular injection includes:
100 ~g~ml trans-5-chloro-2-methyl 2,3,3a,l2b-tetrahydro lH-dibenz[2,3:6,7]oxepino~4,5-c]pyrrole ~crystal of EXAMPLE III) 10 mg/ml citric acid monohydrate 1~ mg/ml disodium biphosphate-dihydrate 0.5 mg~ml polysorbate 80 5 mg/ml sodiu~ carboxymethylcellulose qsad 1 ml water Reference her~in to specific embodiments or exam-ples should not be interpre~ed a~ li~ita~ions to the scope of the invention, which is defined by the appended claims.
Claims (9)
1. A pamoate or hemipamoate salt of trans-5-chloro-2 methyl-2,3,3a,12b-tetrahydro-12-dibenz[2,3:6,7]
oxepino[4,5-c]pyrrole.
oxepino[4,5-c]pyrrole.
2. Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzt2,3:6,7]oxepino[4,5-c]pyrrole pamoate or hemipamoate for use in therapy.
3. Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro lH-dibenz[2,3:6,7[oxepino[4,5-c]pyrrole pamoate for use in the manufacture of a depot pharmaceutical preparation.
4. A depot pharmaceutical preparation comprising trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole pamoate.
5. The depot preparation of claim 4 wherein the trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole pamoate is present in crystalline form.
6. Use of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole pamoate or hemipamoate for the manufacture of a medicament having antipsychotic activity.
7. A process of manufacturing a pharmaceutical product comprising a pamoate or hemipamoate salt of trans-5-chloro-2-methyl-2,3,3a,12b-tetra-hydro-1H-dibenz-[2,3:6,7]oxepino[4,5-c]pyrrole, said process characterized in that the free base trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz-[2,3:6,7]oxepino[4,5-c]pyrrole is reacted with pamoic acid.
8. Trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1-dibenz[2,3:6,7[oxepino[4,5-c]pyrrole hemipamoate for use in the manufacture of a depot pharmaceutical preparation.
9. A depot pharmaceutical preparation comprising trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole hemipamoate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP92201319.8 | 1992-05-08 | ||
| EP92201319 | 1992-05-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2095499A1 true CA2095499A1 (en) | 1993-11-09 |
Family
ID=8210598
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002095499A Abandoned CA2095499A1 (en) | 1992-05-08 | 1993-05-04 | Depot preparation |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPH0656840A (en) |
| KR (1) | KR930023338A (en) |
| AU (1) | AU3846293A (en) |
| CA (1) | CA2095499A1 (en) |
| FI (1) | FI932088A (en) |
| MX (1) | MX9302711A (en) |
| NO (1) | NO931671L (en) |
| ZA (1) | ZA933134B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ284633B6 (en) * | 1994-03-02 | 1999-01-13 | Akzo Nobel N. V. | PHARMACEUTICAL PREPARATION AND USE OF TRANS-5-CHLORO-2-METHYL-2,3,3a,12b-TETRAHYDRO-1H-DIBENZ[2,3:6,7]OXEPINO [4,5-c]PYRROLE FOR PREPARING THE PHARMACEUTICAL PREPARATION |
| DK1119359T3 (en) * | 1998-09-30 | 2004-08-16 | Lilly Co Eli | 2-methyl-thieno-benzodiazepine formulation |
| DE10041479A1 (en) * | 2000-08-24 | 2002-03-14 | Sanol Arznei Schwarz Gmbh | New pharmaceutical composition for the administration of N-0923 |
| GB0216416D0 (en) * | 2002-07-15 | 2002-08-21 | Novartis Ag | Organic compounds |
| US6987111B2 (en) * | 2003-08-06 | 2006-01-17 | Alkermes Controlled Therapeutics, Ii | Aripiprazole, olanzapine and haloperidol pamoate salts |
| AU2010264670A1 (en) * | 2009-06-24 | 2012-01-19 | Merck Sharp & Dohme B.V. | Injectable formulations containing asenapine and method of treatment using same |
| JP2021014404A (en) * | 2017-10-13 | 2021-02-12 | アステラス製薬株式会社 | Triazolopyrazine derivative salt and crystal |
-
1993
- 1993-05-04 CA CA002095499A patent/CA2095499A1/en not_active Abandoned
- 1993-05-04 ZA ZA933134A patent/ZA933134B/en unknown
- 1993-05-06 KR KR1019930007736A patent/KR930023338A/en not_active Application Discontinuation
- 1993-05-07 MX MX9302711A patent/MX9302711A/en unknown
- 1993-05-07 AU AU38462/93A patent/AU3846293A/en not_active Abandoned
- 1993-05-07 FI FI932088A patent/FI932088A/en unknown
- 1993-05-07 NO NO93931671A patent/NO931671L/en unknown
- 1993-05-07 JP JP5106969A patent/JPH0656840A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| FI932088A (en) | 1993-11-09 |
| JPH0656840A (en) | 1994-03-01 |
| FI932088A0 (en) | 1993-05-07 |
| KR930023338A (en) | 1993-12-18 |
| NO931671D0 (en) | 1993-05-07 |
| ZA933134B (en) | 1993-11-30 |
| MX9302711A (en) | 1994-05-31 |
| AU3846293A (en) | 1993-11-11 |
| NO931671L (en) | 1993-11-09 |
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