AP50A - Improvements in pharmaceutially acceptable salts. - Google Patents
Improvements in pharmaceutially acceptable salts. Download PDFInfo
- Publication number
- AP50A AP50A APAP/P/1987/000060A AP8700060A AP50A AP 50 A AP50 A AP 50A AP 8700060 A AP8700060 A AP 8700060A AP 50 A AP50 A AP 50A
- Authority
- AP
- ARIPO
- Prior art keywords
- amlodipine
- salt
- solution
- besylate
- steps
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Classifications
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- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Abstract
Improved pharmaceutical salts of amlodipine, particularly the besylate salt, and pharmaceutical compositions thereof. These salts find utility as anti-ischaemic and anti-hypertensive agents.
Description
DESCRIPTION
Imcrovements in Pharmaceutics 11 Accacrable Salts
The present invention relates to improved pharmaceutical salts of amlodipine and pharmaceutical compositions thereof.
The compound amlodipine (3-ethyl 5-met.hyl 2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,-i-dihydro-b-methylpyridine-3,5-dicarboxylate) is a potent and long acting calcium channel blocker having utility as an anti-ischaemic and anti-hypertensive agent.
European patent application publication no. 39107 discloses several different pharmaceutically acceptable salt forms of amlodipine. In particular the pharmaceutically acceptable acid addition salts are said to be those formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions such as the hydrochloride, hydrobromide., sulphate, phosphate or acid phosphate,-acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate salts! Of these salts the maleate is disclosed as being particularly preferred.
It has now unexpectedly been found that the benzene sulphonate salt (hereinafter referred to as the besylats salt) has a number of advantages over the known salts of amlodipine and, additionally has unexpectedly been found to have a unique combination of good formulation properties which make it particularly suitable for the preparation of pharmaceutical formulations of amlodipine.
Thus according to the present invention there is s 0 0 0 0 dV provided the besylats salt of amlodipine.
In a further aspect the invention provides a pharmaceutical composition of the besyiate salt of amlodipine together with a pharmaceutically acceptable diluent or carrier.
The invention further provides a tablet formulation comprising the besyiate salt of amlodipine in admixture with excipients. A preferred formulation includes the bad original
besylate salt, a compression aid such as nicrccrystnlli r.e cellulose, an additive to provide sheen to the tablet such a? anhydrous dibasic calcium phosphate, a d:sinteyrant such as sodium starch glycollat<_ and: a lubricant such as magnesium stearate.
In addition the invention provides a capsule formulation comprising the besylate salt of amlodipine in admixture wjth excipients. A preferred formulation includes the besylate salt, an inert diluent, a dried disintegrant and a lubricant as described above.
The invention further provides the besylate salt of amlodipine in sterile aqueous solution for parenteral administration. Preferably such solution contains from 10 to 40% by volume of propylene glycol and preferably also sufficient sodium chloride to avoid haemolysis, e.e. about 19 w/v.
The invention also provides the besylate salt of amlodipine for use in treating ischaemic heart disease, especially angina, or hypertension, in a human being.
The invention also provides a process for preparing the besylate salt of amlodipine by reacting amiodipir > base with a solution of benzenesulphonic acid <. r its ammonium salt in an inert solvent and recovering the besylate salt of amlodipine.
The preferred inert solvent is industrial methylated spirit.
Although amlodipine is effective as the free base, in practice it is best administered in the form of a salt of a pharmaceutically acceptable acid. In erder to be suitable for this purpose the pharmaceutically acceptable salt must satisfy the following four phyri c-dvr i cc 1 criteria: (1) good solubility; (2) good stability;
(3) non-hygroscopicity; (4) processability for tablet formulation, etc.
It has been found that whilst many of the salts outlined above satisfy some of these criteria, none satisfy them all and even the preferred maleate, whilst exhibiting excellent solubility tends to break-down in
solution alter a few weeks. Consequently a range of yharmacevtica1ly acceptable salts of amlodipine has been made and evaluated using these criteria:
1. Generally, it is known in the art that a good aqueous solubility is necessary for good bioavailability.
Usually a solubility of greater than i mg ml~^ at pH 1-7.5 is sought although higher solubilities are required to formulate injections. In addition salts which provide solutions having a pH close to that of blood (7.4) ere preferred because they are readily biccompatible end can easily be buffered to the required pH range without altering their solubility. c
As can be seen from the following comparative data ir the besylate salt of amlodipine exhibits good solubility c oharacteristics, compared with other salts. C <Σ
C
TABLE 1 Q
Sait | solubility pH at mg ml saturation |
Benzene sulphonate (besylate) | 4.6 6.6 |
Toluene sulphonate (tosylate) | 0.9 5.9 |
.'•'ethane sulphonate (mesylate) | 25 3.1 |
Succinate | 4.4 4.9 |
Salicylate | _ ' 1.0 7.0 , |
Maleate | 4.5 4.8 |
Acetate | 50 6.6 |
Hydrochloride | 50 3.5 |
2. Good stability in | the solid state is very |
important for tablets and o | apsules, whilst good srscilc-v- |
m solution is required for | an aqueous infection. |
In order to screen for | chemical stability, each of |
the salts was blended in a | powder vehicle and formed into |
tablets or capsules. In. the case of tablets the vehicle | |
comprised microcrystalline | cellulose in 50:50 |
BAD ORIGINAL combination with anhydrous dibasic calcium phosphate. in the case of capsules the vehicle comprised mann_col.
4:1 combination with dried maize starch. These were oner, stored in sealed vials at 50 and 75°C for up to three weeks. The drug and any breakdown products were extracted with methanol: chloroform (50:50) and separated on silica tic plates using a variety of solvent systems.
• The results were compared and the salts ranked according to the number and amount of breakdown products produced .
By comparing the results the following rank order emerges with besylate being the most stable salt and hydrochloride the least stable.
Salt | Stability | |
3esylate .Mesylate Tosylate Succinate Salicylate Maleate | most | stable |
Acetate | > | s |
Hydrochloride | unstable |
3. In order to provide stable formulations it is desirable to have a non-hygroscopic salt. In the solid state where drug content is high, absorbed, films of moisture can act as a vector for hydrolysis and chemical breakdown. It is the hygroscopic nature of a true or ics salt which contributes to the free moisture which is normally responsible for instability.
Only the maleate, tosylate and besylate salts do not pick up any moisture when exposed to 75% relative
humidity at 37 °C for 24 hours. Even when exposed to 33 3 relative humidity at 30°C for 3 days ccth the oesylate and maleate remain anhydrous whilst the tcsyiate formed the dihydrate salt. Therefore the besylate salt can he considered to be non-hygroscopic and thus provides stable formulations while minimising the risk of intrinsic chemical breakdown.
4. The final characteristic of an acceptable salt to be considered is the processability, i.e. the compression properties and also the ability not to stick or adhere to the tablet making machinery.
For high dose formulations, good compressibility is very important to make elegant tablets. With. lower rose tablets the need for good compressibilicy can be eliminated to a certain extent by the use of suitable diluting excipients called compression aids.
Microcrystalline cellulose is a commonly used compression aid. However whatever the dose the adhesion of the drug to the punches of the tablet machine must be avoided.
When drug accumulates on the punch surfaces this causes the tablet surface to become pitted and therefore unacceptable. Also sticking of the drug in this way results in high ejection forces when removing the cablet from the machine. In practice it is possible to reduce sticking by wet-massing, careful selection of tucipients and the use of high levels of anti-adherents, e.g. magnesium stearate. However selection of a salt with good anti-adhesion properties minimises these problems.
In order to compare the stickiness of the various salts of amlcdipine the following procedure was carried cut using conventional tablet making machinery, fifty tablets containing calcium sulphate dihydrate, microcrystalline cellulose and amlodipi.oe besylate were made (47.5:47.5:5), the material sticking to the tablet punch was then extracted using methanol and the amount measured spectrometrically. This procedure was then repeated for runs of 100, 150, 200, 250 and 300 tablets. After each run the amount of material sticking to the i
bad ORIGINAL
AP 0 0 0 0 5 0
tablet punch was measured after extraction with meohmol. The values are plotted and an average value calculated from the sioce of the Line produced.
This same procedure was then repeared for each of the salts of amlodipine. The amount of amlodipine measured as sticking to the tablet punch is shown in Table 2 for each salt and relative to the maleate salt.
TABLE 2
Salt | Stickiness | |
zug Amlodipine tablet | cm relative to maleate | |
x'-iesvlate | 1.16 | 53¾ |
Besylate | 1.17 | 59 |
Tosylate | 1.95 | 98 |
Maleate | 1.98 | 100 |
Free base | 2.02 | 102 |
Succinate | 2.39 | 121 |
Hydrochloride | 2.51 | 127 |
Salicylate | 2.85 | 144 ·« |
Clearly the besylate has superior anti-adhesion properties to the maleate. Whilst the mesylate also snows good processability it tends to be isolated as the anhydride but this equilibrates to the monohydrate leading to variable composition after manufacture which makes it unacceptable for use in tablets.
Thus the besylate salt of amlodipine shows a unique combination of good solubility, good stability, ncn-nygroscopicity and good processabiliry which makes ir .outstandingly suitable for the preparation of pharmaceutical formulations of amlodipine.
In order that the present invention be more readily understood, reference is now made to the following 1
Examples. a
Example 1 ?:ecer2‘.;on of Besvlate salt of Amlcdioine
Amiodipine base (65.6g, 0.161 mcisj was slurried i: industrial methylated spirit (326.4 mi) and cooled to 5’C. Benzenesulphonic acid (26.2g, 0.163 mols) was dissolved in industrial methylated spirit (65.6 ml) at 5’C and added to the slurry of the base. The resulting slurry was then granulated, filtered and washed with 2 volumes of industrial methylated spirit (65.6 ml). The damp solid was slurried at 5°C for Ihr in industrial methylated spirit (327.6 ml), filtered, washed with 2 volumes of industrial methylated spirit (65.6 ml) and dried under vacuum at 55’C for 24 hours.
.eld of
76.5g (83.8%) was obtained with the following analysis.
AP 0 0 0 0 5 0
Melting Point Analysis % | 201.0°C. C | H | N |
Calc . | 55.07 | 5.51 | 4.94 |
Found | 54.91 | 5.46 | 4.93 |
Formulation of | Tablets | Example 2 Containing | Besyla |
Amlcdioine
Amiodipine besylate was blended with sodium starch giycoiiate and anhydrous dibasic calcium phosphate for 5 minutes. This mixture was then sieved, reblended and sieved again followed by blending with microcrystal1ine cellulose. The resultant mixture was then sieved again and blended for a further 10 minutes. Finally magnesium stearate was added and the whole mixture blended for 5 minutes. The blend was then pressed into tablets using conventional tablet making machinery.
This method was used_to make tablets containing different concentrations of the amiodipine besylate salt as shown in Table 3. ·
BAD ORIGINAL
TABLE 3 : TABLET COMPOSITIONS
1/ ‘Γϊ <—I Z ΐ £C 'Λ
<0 | σ·» | ||
m | P* | 00 | |
r** | σ> | X | |
• | • | • | • |
r*H | m | LO | m «Μ |
BAD ORIGINAL
Example 3
Formulation of Capsules Containing Besylate Salt of
Amlodioine
Microcrystalline cellulose and dried maize starch were pre blended. The besylate salt of amlodipine was then mixed with some of this preblend and then sieved.
The remainder of the preblend was then added and mixed for 10 minutes. This was then sieved again and mixed for a further 5 minutes.
This method was used to make mixtures containing different concentrations of the amlodipine cesylata salt as shown in Table 4 and the mixtures were then filled into capsules of appropriate size.
Example 4
Formulation of Sterile Aqueous Solution of Besylate Salt of Amlodipine -..Sodium chloride was dissolved in water for injection and propylene glycol was mixed with this solution. The besylate salt of amlodipine was added and, when in had dissolved, further water for injection was added to adjust the volume to give the desired concentration cf amlodipine (1 mg/ml). The solution was then filtered through a sterilising filter and filled into suitable sterile containers, e.g. ampoules, for use in parenteral, e.g. intravenous, administration.
This method was used to prepare the formulations shewn in Table 5.
AP 0 0 0 0 5 0
Table 5; Sterile Aqueous Solutions
Besylate salt of amlodipine Sodium chloride Propylene glycol Water for injection
1.339 g
1.339 g
9.000 g 200.000 g
9.000 g 400.000 g to 1 litre to 1 litre
BAD ORIGINAL
TABLE 4 : CAPSULE COMPOSITIONS
—1 | •-C | ΛΙ | <τ» | |
> -J — | r*· | ’T | 05 | |
Λ — T> | σ» | CO | ||
υ t Ξ | • | • | • | |
Λ 'Λ | cn | m |
bad original $
Example 5
Alternative preparation of Besylate salt of Amlocipj
Ammonium benzenesulphonate (0.943g) was £ dded io a slurry of amlodipine base (2g) in industrial methylated spirit (lOmi) and the resulting solution was heated at reflux for 10 minutes. The reaction mixture was coded and granulated at 5°C for 1 hour. The amlodipine benzenesulphonate was filtered, washed with industrial methylated spirit (2x2 ml) and dried in vacuum.
Yield 1.9g (70% of theory).
Met.: 201.0 °C.
Analysis %:Found :
Calculated for
C,54.98; U,5.46; N,4.?0; C,55.07; H,5.51; N,4.95.
S 0 0 0 0 dV bad original
Claims (16)
1. The besylate salt of amicdipi.ne.
2. A pharmaceutical composition comprising the besylate salt of amlodipine as claimed i^ claim 1 together with a pharmaceutically acceptable diluent or carrier .
3. A tablet formulation comprising the besylate salt cf amlodipine as claimed in claim 1 in admixture with excipients.
4. A tablet formulation as claimed in claim 3 wherein the excipients comprise a compression aid, an additive to provide sheen to the tablet, a disinfectant and a lubricant.
5. A tablet formulation as claimed in claim 4 wherein the excipients comprise microcrystaliine cellulose, anhydrous dibasic calcium phosphate, sodium starch glycollate and magnesium stearate.
6. A capsule formulation comprising the besylate salt of amlodipine as claimed in claim 1 in admixture with excipients.
cellulose, dried maize starch and magnesium stearate.
9. A sterile aqueous solution comprising the besylate salt of amlodipine for parenteral administration.
11. A sterile aqueous solution as claimed in claim 9 comprising from 10 to 40% w/v cf propylene glycol.
11. A sterile aqueous solution as claimed in claim 9 or claim 10 comprising about 1% w/v sodium chloride.
12. The besylate salt of amlodipine for use in treating heart disease or hypertension.
BAD ORIGINAL
13. A process for preparing the bosylat.e salt ci amlodipine characterised by the steps of reacting amlodipine base with a solution of benzenesulohenic acid or its ammonium salt in an inert solvent and recoverina the besyiate salt of amlodipine.
14. A process as claimed in claim ‘3 wherein the inert solvent is industrial methylated spirit.
15. A process for preparing a pharmaceutics 1 composition characterised by the step of mixing the besyiate salt of amlodipine with a pharmaceutica1]y acceptable diluent or carrier.
If. A process as claimed in claim 1 3 for preparinc a tablet formulation characterised by the steps ;f mixinc the besyiate salt of amlodipine with excipients and pressing into tablets.
17. A process as claimed in claim If characterised by the steps of (a) blending the besyiate salt of amlodipine with sodium starch glycollate and anhydrous dibasic calcium phosphate;
(b) sieving, reblending and sieving;
(c) blending with microcrystalline cellulose;
(d) sieving and reblending;
(e) blending with magnesium stearate; and (f) pressing into tablets.
18. A process as claimed in claim 15 for preparinc a capsule formulation characterised by the steps of niixinc the besyiate salt of amlodipine with excipient; and filling into capsules.
19. A process as claimed in claim 13 characteri s·- ’ by the steps of preblending microcrystalline cellulose and dried maize starch;
mixing the besyiate salt of amlodipine with some of the preblend and sieving; mixing in the remainder of the preblend, sieving and re-mixing; and filling the mixture into capsules.
AP 0 0 0 0 5 0 (a) (b) (c) (d)
BAD ORIGINAL ft
Σ'?. A process as claimed in claim 1' for preparim sterile aqueous solution of the besylate salt of amlodipine for parenteral administration characterised : · the steps of forming a solution of the besylate salt of amlodipine in a sterile aqueous carrier.
21 . A process as claimed in claim 2ri cha.acterisec by the steps of (a) dissolving the besylate salt of amlodipine in a sterile solution of sodium chloride in a mixture of water for injection and propylene glycol;
(b) adjusting the volume of the solution with further water for injection;
(c) filtering the solution through a sterilising filter; and (d) filling the solution into sterile containers.
. A process as claimed in claim ?0 or claim 21 in which the solution contains from 20 to 40% w/v propylene glycol and about 1% w/.v sodium chloride.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB868608335A GB8608335D0 (en) | 1986-04-04 | 1986-04-04 | Pharmaceutically acceptable salts |
Publications (2)
Publication Number | Publication Date |
---|---|
AP8700060A0 AP8700060A0 (en) | 1987-02-01 |
AP50A true AP50A (en) | 1989-09-16 |
Family
ID=10595731
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
APAP/P/1987/000060A AP50A (en) | 1986-04-04 | 1987-04-02 | Improvements in pharmaceutially acceptable salts. |
Country Status (47)
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- 1987-04-03 ZA ZA872439A patent/ZA872439B/en unknown
- 1987-04-03 ES ES8700965A patent/ES2002599A6/en not_active Expired
- 1987-04-03 FR FR8704705A patent/FR2596758B1/en not_active Expired
- 1987-04-03 DD DD87301485A patent/DD265142A5/en unknown
- 1987-04-03 MA MA21175A patent/MA20938A1/en unknown
- 1987-04-03 IE IE86987A patent/IE59457B1/en not_active IP Right Cessation
- 1987-04-03 NZ NZ219868A patent/NZ219868A/en unknown
- 1987-04-03 BE BE8700349A patent/BE1000130A4/en not_active IP Right Cessation
- 1987-04-03 UA UA4202353A patent/UA6344A1/en unknown
- 1987-04-03 SU SU874202353A patent/SU1498388A3/en active
- 1987-04-03 IT IT19977/87A patent/IT1203853B/en active
- 1987-04-03 DK DK170187A patent/DK171708B1/en active IP Right Grant
- 1987-04-03 NO NO871408A patent/NO172181C/en unknown
- 1987-04-03 IL IL82101A patent/IL82101A/en not_active IP Right Cessation
- 1987-04-04 KR KR1019870003209A patent/KR950006710B1/en not_active IP Right Cessation
-
1988
- 1988-10-13 US US07/256,938 patent/US4879303A/en not_active Expired - Lifetime
-
1990
- 1990-03-21 GR GR90400158T patent/GR3000394T3/en unknown
-
1991
- 1991-11-22 SK SK3539-91A patent/SK278435B6/en unknown
- 1991-11-22 CZ CS19913539A patent/CZ289095B6/en not_active IP Right Cessation
-
1992
- 1992-03-16 BG BG96073A patent/BG60698B2/en unknown
- 1992-06-04 SG SG596/92A patent/SG59692G/en unknown
- 1992-10-01 HK HK760/92A patent/HK76092A/en not_active IP Right Cessation
-
1993
- 1993-05-14 CY CY1669A patent/CY1669A/en unknown
-
1994
- 1994-07-26 EC EC1994001129A patent/ECSP941129A/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0060674A1 (en) * | 1981-03-14 | 1982-09-22 | Pfizer Limited | Dihydropyridine anti-ischaemic and antihypertensive agents, processes for their production, and pharmaceutical compositions containing them |
EP0089167A2 (en) * | 1982-03-11 | 1983-09-21 | Pfizer Limited | Dihydropyridine anti-ischaemic and antihypertensive agents, processes for their production, and pharmaceutical compositions containing them |
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