GB1565447A - Pharmaceutical preparations for venotonic use - Google Patents
Pharmaceutical preparations for venotonic use Download PDFInfo
- Publication number
- GB1565447A GB1565447A GB20210/77A GB2021077A GB1565447A GB 1565447 A GB1565447 A GB 1565447A GB 20210/77 A GB20210/77 A GB 20210/77A GB 2021077 A GB2021077 A GB 2021077A GB 1565447 A GB1565447 A GB 1565447A
- Authority
- GB
- United Kingdom
- Prior art keywords
- pharmaceutical composition
- etilefrin
- formula
- compound
- dihydroergotamine
- 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.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/02—Ergot alkaloids of the cyclic peptide type
-
- 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
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
(54) PHARMACEUTICAL PREPARATIONS FOR
VENOTONIC USE
(71) We, SANDOZ LTD., of 35 Lichtstrasse, 4002 Basle, Switzerland, a Swiss Body
Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to new pharmaceutical compositions containing compounds of formula
I:
in which
R is hydrogen or alkyl having from 1 to
4 carbon atoms, other than t-butyl,
R, is methyl, ethyl or isopropyl, R3 is isopropyl, sec.-butyl, isobutyl or
benzyl, and
X is hydrogen or methoxy.
The invention provides a pharmaceutical composition comprising a mixture of a compound of formula I and etilefrin in association with a pharmacologically acceptable diluent or carrier.
By the terms "compounds of formula I" and "etilefrin" are included pharmacologically acceptable salts of these compounds. A pharmacologically acceptable salt is one which does not have substantially higher toxicity than the corresponding free base. Examples of such salts are the methanesulphonate, maleate and tartrate of compounds of formula I, and the hydrochloride and sulphate of etilefrin.
The preferred compound of formula I is dihydroergotamine (DHE), in which R= methyl, R1 = methyl, R2 = benzyl and X= hydrogen. Etilefrin is the generic name for the compound a - [(ethylamino)methyl] - 3 hydroxybenzenemethanol, of formula II
Pharmacologically acceptable diluents and carriers include binding agents for example polyvinylpyrrolidone and gelatine; tablet lubricants, for example stearic acid, magnesium stearate and talc; fillers, for example lactose and calcium carbonate; disintegrants, for example starches and alginic acid; flavourings and colourings.
The proportion of compound of formula
I to etilefrin is suitably from 1: 5 to 1:15 by weight, preferably 1:10 by weight.
The invention also provides a process for the preparation of a pharmaceutical composition according to the invention, characterised by mixing a compound of formula I and etilefrin together with a pharmacologically acceptable diluent or carrier.
One preferred process according to the invention comprises working up a compound of formula I with a pharmacologically acceptable polymer, preferably polyvinylpyrrolidone, to obtain a solid material which is then mixed with etilefrin. Preferably the etilefrin is in the form of a granulate containing one or more pharmacologically acceptable adjuvants, for example lactose, starch and gelatine.
A further preferred process according to the invention comprises forming a granulate of one of the active components together with one or more pharmacologically acceptable adjuvants, and mixing this granulate with the other component.
The first process is preferably carried out by mixing the compound of formula I together with polyvinylpyrrolidone in the form of an uncrosslinked poly(N - vinyl - 2 pyrrolidone) of average molecular weight from 10,000 to 100,000, preferably from 11,500 to
40,000, particularly 25,000, optionally to
gether with pharmacologically acceptable addi
tives. Such additives may include surfactants,
for example polyethylene glycol fatty acid
esters, particularly polyethylene glycol stearate,
as well as stabilizing additives for example
acids, particularly methanesulphonic acid,
maleic acid and tartaric acid, to maintain a
pH of less than 7, preferably 4-5. The pro
portion of compound of formula I to poly
vinylpyrrolidone is suitably from 1 to 30%, preferably from 5 to 15 Ojo by weight.
The mixture is then worked up so as to
obtain a dry homogeneous material, for
example by dissolving in a suitable solvent,
and evaporating the solution. Suitable solvents
include alcohols having from 1 to 4 carbon
atoms, for example methanol and ethanol.
The mixture may suitably be dissolved at an
elevated temperature, preferably from 300 to 800C, more preferably from 400 to 700C.
After complete solution, the solvent may be
evaporated under the above conditions of
temperature; preferably initially under atmos
pheric pressure and finally under vacuum.
Optionally, only a part of the polyvinyl
pyrrolidone and/or the further additives may
be added to the compound of formula I
before the solution is prepared, and the addi
tion of the remainder may take place during
the evaporation stage. The solid residue ob
tained by complete removal of the solvent
and cooling to room temperature (150--250C) may be ground to a fine powder in conven
tional manner and dried for example in vacuo
for 12 hours at 300C.
The dried product is then mixed with the
corresponding quantity of etilefrin, preferably
in the form of a granulate with conventional
pharmacologically acceptable adjuvants.
The second process is preferably carried out
by forming a granulate of one component in
conventional manner, and mixing this with
the other component optionally together with
other pharmacologically acceptable adjuvants,
so as to give a solid mixture suitable for filling
capsules or for pressing into tablets. If desired,
both components may be converted to
granulates before being mixed.
The pharmaceutical compositions according
to the invention give a surprisingly high increase in venous tone as indicated by the measurement of the volume elasticity coefficient E'1 in human subjects as described by M. Echt and L. Lange in "Das Orthostatesyndrom" (5th Rothenburg Conference, page 109, F. K. Schattauer Verlag, Stuttgart
New York, 1973). For these measurements, the left hand of the subject was isolated from the circulation in the left lower arm by a wrist cuff inflated to a high pressure (200 mm
Hg), and a cuff around the upper arm was slowly inflated at a rate of 0.25 mm Hg/ second. The venous pressure in the lower arm was measured by means of a catheter running from the back of the left hand to the distal third of the lower arm, and the change in the circumference of the left lower arm was measured by means of mercury-filled strip of silicone rubber tubing. These two measurements were recorded continuously on an x-y plotter during inflation of the upper arm cuff, and the slope of the curve at a venous pressure of 15 mm Hg was measured.
This slope corresponds to the volume elasticity coefficient of the veins in the corresponding part of the body, E'15, which may be expressed in units of
mm Hg my. 100 g tissue and which is a measure of venous tone. An increase in venous tone is shown directly by an increase in the F.'l, value. In this way venous tone may be measured independently of the blood flow.
It is found that administration of etilefrin alone (0.5 mg/min. for 20 min. by intravenous infusion) gives an increase of E', to 145% of the initial level before medication.
Administration of DHE alone (0.5 mg intravenously) raises the E'1s level to 256% of the initial level. However, it has been found that administration of DHE (0.5 mg intravenously) followed by etilefrin (0.5 mg/min.
for 20 min. by intravenous infusion) caused the E'1 level to rise to a peak of 562% of the initial value. This increase is considerably greater than could be accounted for by a purely additive effect of the two agents, and is attributed to a synergistic effect.
The compositions according to the invention are therefore indicated for venotonic use, particularly in the treatment of orthostatic and hypotonic circulatory disorders in mammals. A suitable indicated daily dosage is from 0.5 to 5 mg of compound of formula I and from 5 to 50 mg etilefrin. This daily dosage may suitably be administered in divided dosages of from 0.125 to 2.5 mg of compound of formula I and from 1.25 to 25 mg etilefrin 2 to 4 times daily, or in retard form. Particularly preferred is a mixture of 2 mg dihydroergotamine methanesulphonate and 20 mg etilefrin hydrochloride, for administration twice daily.
The active ingredients may also be administered separately, and may be supplied for this purpose in separate containers in the same package (twin-pack) with instructions for concomitant administration.
The compositions may be made up into galenic forms such as capsules, tablets, or solutions for oral administration by conventional methods. The compositions themselves, or galenic preparations thereof, may suitably be packaged in unit dosage forms, for example capsules, tablets or ampoules of solution each containing a unit dosage of the active ingredients.
The following Examples illustrate the invention:
EXAMPLE 1 a) Preparation of solid solution of dihydro
ergotamine in polyvinyl pyrrolidone
To a 4 1 round bottomed flask were added 34.6 g dihydroergotamine methanesulphonate, 195.4 g polyvinyl pyrrolidone (average M.W.
25,000) and 500 ml methanol. The flask was connected to a rotary evaporator and rotated in a water bath maintained at 600C until a clear solution was obtained.
The solution was then evaporated at reduced pressure (-250 Torr) at a bath temperature of 600C until the residue had a syrupy consistency. This liquid was transferred to an evaporating basin and left approximately 2 hours at room temperature to solidify. The resulting solid was dried in a vacuum oven for 12 hours at 300C, approximately 1 Torr, then ground to a powder and dried further.
b) Preparation of etilefrin granulate
Etilefrin hydrochloride (346.0 g) was mixed with 650.8 g lactose and 110.4 g corn starch in a planetary mixer. The mixture was evenly dampened with a solution of 17.3 g gelatin in 70 g water, granulated through a sieve of mesh size 1.3 mm, and dried in a drying cup board at 500C for 12 hours. The dried granulate was then separated from fines by means of a sieve of mesh size 1.0 mm.
c) Mixing and Tabletting
230 g of the solid solution prepared as in a) and 1124.5 g of the granulate prepared according to b) were mixed homogeneously in a free fall mixer together with 895.0 g lactose, 86.5 g corn starch, 467.0 g cellulose powder, 294.0 g talc and 17.0 g silicic acid.
The mixture was then worked into tablets of 180 mg nominal weight in a conventional tabletting press.
The tablets consisted of the following in gredients: Etilefrin hydrochloride 20.0 mg
Dihydroergotamine methane
sulphonate 2.0 mg
silicic acid 1.0 mg
gelatine 1.0 mg
corn starch 11.3 mg polyvinylpyrrolidoiie 11.3 mg
talc 17.0 mg
cellulose powder 27.0 mg
lactose 89.4 mg
180.0 mg
EXAMPLE 2
1124.5 g of the granulate prepared as in
Example 1 b) was mixed to a homogeneous state with 34.6 g dihydroergotamine methanesulphate, 895.0 g lactose, 86.5 g corn starch,
662.4 g cellulose powder, 294.0 g talc and
17.0 g silicic acid. The mixture so prepared was worked into tablets of 180 mg nominal weight on a conventional tabletting press, to give tablets of the following composition; Etikfrin hydrochloride 20.0 mg
Dihydroergotamine methane
sulphonate 2.0 mg
silicic acid 1.0 mg
gelatine 1.0 mg
corn starch 11.3 mg
talc 17.0 mg
cellulose powder 38.8 mg
lactose 89.4 mg
180.0 mg
WHAT WE CLAIM IS:
1. A pharmaceutical composition comprising a mixture of a compound of formula I
in which
R is hydrogen or alkyl having from 1 to 4
carbon atoms, other than t-butyl,
R1 is methyl, ethyl or isopropyl,
R2 is isopropyl, sec.-butyl, isobutyl or
benzyl, and
X is hydrogen or methoxy, and etilefrin, in association with a pharmaceutically acceptable diluent or carrier.
2. A pharmaceutical composition as claimed in Claim 1, in which the compound of formula
I is dihydroergotamine.
3. A pharmaceutical composition as claimed in Claim 1 or Claim 2 in which the proportion of compound of formula I to etilefrin is from 1:5 to 1:15 by weight.
4. A pharmaceutical composition as claimed in Claim 3 in which the proportion of compound of formula I to etilefrin is 1:10 by weight.
5. A pharmaceutical composition as claimed in any one of the preceding claims in which the pharmacologically acceptable diluent or carrier comprises uncrosslinked poly - N vinyl - 2 - pyrrolidone of average molecular weight from 10,000 to 100,000.
6. A pharmaceutical composition as claimed in Claim 5 in which the polyvinylpyrrolidone has an average molecular weight of from 11,500 to 40,000.
7. A pharmaceutical composition as claimed
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (24)
- **WARNING** start of CLMS field may overlap end of DESC **.solution each containing a unit dosage of the active ingredients.The following Examples illustrate the invention: EXAMPLE 1 a) Preparation of solid solution of dihydro ergotamine in polyvinyl pyrrolidone To a 4 1 round bottomed flask were added 34.6 g dihydroergotamine methanesulphonate, 195.4 g polyvinyl pyrrolidone (average M.W.25,000) and 500 ml methanol. The flask was connected to a rotary evaporator and rotated in a water bath maintained at 600C until a clear solution was obtained.The solution was then evaporated at reduced pressure (-250 Torr) at a bath temperature of 600C until the residue had a syrupy consistency. This liquid was transferred to an evaporating basin and left approximately 2 hours at room temperature to solidify. The resulting solid was dried in a vacuum oven for 12 hours at 300C, approximately 1 Torr, then ground to a powder and dried further.b) Preparation of etilefrin granulate Etilefrin hydrochloride (346.0 g) was mixed with 650.8 g lactose and 110.4 g corn starch in a planetary mixer. The mixture was evenly dampened with a solution of 17.3 g gelatin in 70 g water, granulated through a sieve of mesh size 1.3 mm, and dried in a drying cup board at 500C for 12 hours. The dried granulate was then separated from fines by means of a sieve of mesh size 1.0 mm.c) Mixing and Tabletting 230 g of the solid solution prepared as in a) and 1124.5 g of the granulate prepared according to b) were mixed homogeneously in a free fall mixer together with 895.0 g lactose, 86.5 g corn starch, 467.0 g cellulose powder, 294.0 g talc and 17.0 g silicic acid.The mixture was then worked into tablets of 180 mg nominal weight in a conventional tabletting press.The tablets consisted of the following in gredients: Etilefrin hydrochloride 20.0 mg Dihydroergotamine methane sulphonate 2.0 mg silicic acid 1.0 mg gelatine 1.0 mg corn starch 11.3 mg polyvinylpyrrolidoiie 11.3 mg talc 17.0 mg cellulose powder 27.0 mg lactose 89.4 mg 180.0 mg EXAMPLE 2 1124.5 g of the granulate prepared as in Example 1 b) was mixed to a homogeneous state with 34.6 g dihydroergotamine methanesulphate, 895.0 g lactose, 86.5 g corn starch, 662.4 g cellulose powder, 294.0 g talc and 17.0 g silicic acid. The mixture so prepared was worked into tablets of 180 mg nominal weight on a conventional tabletting press, to give tablets of the following composition; Etikfrin hydrochloride 20.0 mg Dihydroergotamine methane sulphonate 2.0 mg silicic acid 1.0 mg gelatine 1.0 mg corn starch 11.3 mg talc 17.0 mg cellulose powder 38.8 mg lactose 89.4 mg 180.0 mg WHAT WE CLAIM IS: 1. A pharmaceutical composition comprising a mixture of a compound of formula Iin which R is hydrogen or alkyl having from 1 to 4 carbon atoms, other than t-butyl, R1 is methyl, ethyl or isopropyl, R2 is isopropyl, sec.-butyl, isobutyl or benzyl, and X is hydrogen or methoxy, and etilefrin, in association with a pharmaceutically acceptable diluent or carrier.
- 2. A pharmaceutical composition as claimed in Claim 1, in which the compound of formula I is dihydroergotamine.
- 3. A pharmaceutical composition as claimed in Claim 1 or Claim 2 in which the proportion of compound of formula I to etilefrin is from 1:5 to 1:15 by weight.
- 4. A pharmaceutical composition as claimed in Claim 3 in which the proportion of compound of formula I to etilefrin is 1:10 by weight.
- 5. A pharmaceutical composition as claimed in any one of the preceding claims in which the pharmacologically acceptable diluent or carrier comprises uncrosslinked poly - N vinyl - 2 - pyrrolidone of average molecular weight from 10,000 to 100,000.
- 6. A pharmaceutical composition as claimed in Claim 5 in which the polyvinylpyrrolidone has an average molecular weight of from 11,500 to 40,000.
- 7. A pharmaceutical composition as claimedin Claim 5 or Claim 6 in which the proportion of compound of formula I to polyvinyl pyrrolidone is from 1% O/o to 30% by weight.
- 8. A pharmaceutical composition as claimed in Claim 7 in which the said proportion is from 5 ';, to 15t", by weight.
- 9. A pharmaceutical composition as claimed in any one of the preceding claims, in which the compound of formula I is dihydroergotamine in the methanesulphonate salt form.
- 10. A pharmaceutical composition as claimed in any one of the preceding claims, in which the etilefrin is in the hydrochloride salt form.
- 11. A pharmaceutical composition as claimed in any one of the preceding claims, in unit dosage form, containing from 0.125 to 2.5 mg of the compound of formula I and 1.25 to 25 mg etilefrin per unit dosage.
- 12. A pharmaceutical composition as claimed in Claim 11 containing 2 mg dihydroergotamine methanesulphonate and 20 mg etilefrin hydrochloride per unit dosage.
- 13. A pharmaceutical composition as claimed in Claim 11 or Claim 12, in capsule form.
- 14. A pharmaceutical composition as claimed in Claim 11 or Claim 12, in capsule form.
- 15. A twin-pack preparation comprising separate containers of compound of formula I and of etilefrin together with instructions for their concomitant administration.
- 16. A twin-pack preparation as claimed in Claim 15 in which the containers contain unit dosages of dihydroergotamine and of etilefrin.
- 17. A method for the preparation of a pharmaceutical composition as claimed in Claim 5, characterised by working up a compound of formula I with polyvinylpyrrolidone to obtain a solid material which is then mixed with etilefrin.
- 18. A method as claimed in Claim 17 in which the compound of formula I, together with polyvinylpyrrolidone, is dissolved in a solvent which is then evaporated, and the dried residue is mixed with etilefrin.
- 19. A method as claimed in Claim 18 in which the solvent is methanol.
- 20. A method as claimed in any one of Claims 17-19 in which the etilefrin is in the form of a granulate containing one or more pharmacologically acceptable adjuvants.
- 21. A method for the preparation of a pharmaceutical composition as claimed in Claim 1 characterised by forming a granulate of one of the active components together with one or more pharmacologically acceptable adjuvants, and mixing the granulate with the other component.
- 22. A method as claimed in any one of Claims 17-21, in which the compound of formula I is dihydroergotamine.
- 23. A method for the preparation of a pharmaceutical composition as claimed in Claim 1, substantially as herein described with reference to Example 1 or Example 2.
- 24. A pharmaceutical composition as claimed in Claim 1 whenever prepared by a method as claimed in any one of Claims 1723.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19762621906 DE2621906A1 (en) | 1976-05-17 | 1976-05-17 | NEW THERAPEUTIC MIXTURE AND METHOD FOR PRODUCING IT |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1565447A true GB1565447A (en) | 1980-04-23 |
Family
ID=5978199
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB20210/77A Expired GB1565447A (en) | 1976-05-17 | 1977-05-13 | Pharmaceutical preparations for venotonic use |
Country Status (22)
Country | Link |
---|---|
JP (1) | JPS52139730A (en) |
AT (1) | AT366574B (en) |
AU (1) | AU513718B2 (en) |
BE (1) | BE854694A (en) |
CA (1) | CA1088865A (en) |
CS (1) | CS207455B2 (en) |
DE (1) | DE2621906A1 (en) |
ES (1) | ES458819A1 (en) |
FR (1) | FR2351657A1 (en) |
GB (1) | GB1565447A (en) |
GR (1) | GR72995B (en) |
HK (1) | HK3283A (en) |
HU (1) | HU175167B (en) |
IE (1) | IE45197B1 (en) |
IL (1) | IL52101A (en) |
MY (1) | MY8400062A (en) |
NL (1) | NL177981C (en) |
NZ (1) | NZ184111A (en) |
PH (1) | PH20257A (en) |
PT (1) | PT66552B (en) |
SE (1) | SE425545B (en) |
ZA (1) | ZA772935B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2935515A1 (en) * | 1979-09-03 | 1981-03-19 | Fa. Dr. Willmar Schwabe, 7500 Karlsruhe | MEDICINAL PRODUCT |
JPH0227013U (en) * | 1988-08-10 | 1990-02-22 | ||
HUP0200641A3 (en) | 1999-03-26 | 2002-09-30 | Pozen Inc | High potency dihydroergotamine compositions |
-
1976
- 1976-05-17 DE DE19762621906 patent/DE2621906A1/en active Granted
-
1977
- 1977-05-09 SE SE7705340A patent/SE425545B/en not_active IP Right Cessation
- 1977-05-12 FR FR7714507A patent/FR2351657A1/en active Granted
- 1977-05-13 PH PH19768A patent/PH20257A/en unknown
- 1977-05-13 GB GB20210/77A patent/GB1565447A/en not_active Expired
- 1977-05-13 NL NLAANVRAGE7705306,A patent/NL177981C/en not_active IP Right Cessation
- 1977-05-16 CS CS773204A patent/CS207455B2/en unknown
- 1977-05-16 NZ NZ184111A patent/NZ184111A/en unknown
- 1977-05-16 PT PT66552A patent/PT66552B/en unknown
- 1977-05-16 HU HU77SA3035A patent/HU175167B/en not_active IP Right Cessation
- 1977-05-16 AT AT0347677A patent/AT366574B/en not_active IP Right Cessation
- 1977-05-16 IE IE1001/77A patent/IE45197B1/en unknown
- 1977-05-16 ES ES458819A patent/ES458819A1/en not_active Expired
- 1977-05-16 IL IL52101A patent/IL52101A/en unknown
- 1977-05-16 JP JP5624877A patent/JPS52139730A/en active Granted
- 1977-05-16 CA CA278,488A patent/CA1088865A/en not_active Expired
- 1977-05-16 AU AU25169/77A patent/AU513718B2/en not_active Expired
- 1977-05-16 BE BE177623A patent/BE854694A/en not_active IP Right Cessation
- 1977-05-17 ZA ZA00772935A patent/ZA772935B/en unknown
- 1977-05-17 GR GR53485A patent/GR72995B/el unknown
-
1983
- 1983-01-20 HK HK32/83A patent/HK3283A/en unknown
-
1984
- 1984-12-30 MY MY62/84A patent/MY8400062A/en unknown
Also Published As
Publication number | Publication date |
---|---|
SE7705340L (en) | 1977-11-18 |
IL52101A (en) | 1980-01-31 |
BE854694A (en) | 1977-11-16 |
IL52101A0 (en) | 1977-07-31 |
NZ184111A (en) | 1980-02-21 |
CS207455B2 (en) | 1981-07-31 |
AU2516977A (en) | 1978-11-23 |
ZA772935B (en) | 1979-01-31 |
NL177981C (en) | 1986-01-02 |
IE45197L (en) | 1977-11-17 |
ATA347677A (en) | 1981-09-15 |
NL177981B (en) | 1985-08-01 |
PH20257A (en) | 1986-11-14 |
ES458819A1 (en) | 1978-08-01 |
GR72995B (en) | 1984-01-24 |
HU175167B (en) | 1980-05-28 |
NL7705306A (en) | 1977-11-21 |
SE425545B (en) | 1982-10-11 |
JPS628413B2 (en) | 1987-02-23 |
DE2621906C2 (en) | 1988-04-21 |
JPS52139730A (en) | 1977-11-21 |
HK3283A (en) | 1983-01-20 |
CA1088865A (en) | 1980-11-04 |
PT66552A (en) | 1977-06-01 |
AT366574B (en) | 1982-04-26 |
FR2351657A1 (en) | 1977-12-16 |
PT66552B (en) | 1979-09-03 |
FR2351657B1 (en) | 1980-01-18 |
IE45197B1 (en) | 1982-07-14 |
MY8400062A (en) | 1984-12-31 |
AU513718B2 (en) | 1980-12-18 |
DE2621906A1 (en) | 1977-12-01 |
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