AP50A - Improvements in pharmaceutially acceptable salts. - Google Patents

Improvements in pharmaceutially acceptable salts. Download PDF

Info

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
Prior art date
Application number
APAP/P/1987/000060A
Other versions
AP8700060A0 (en
Inventor
Davison Edward Mr
Wells James Ingram Dr
Original Assignee
Pfizer Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=10595731&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=AP50(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Publication of AP8700060A0 publication Critical patent/AP8700060A0/en
Application filed by Pfizer Ltd filed Critical Pfizer Ltd
Application granted granted Critical
Publication of AP50A publication Critical patent/AP50A/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

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.
! , A capsule formulation as claimed in claim 5 wherein the excipients comprise an inert diluent, a dried disinteg rant . and a lubricant. 3 . A capsule formulation as claimed in claim 1 wherein the excipients comprise microcrystaliine
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.
APAP/P/1987/000060A 1986-04-04 1987-04-02 Improvements in pharmaceutially acceptable salts. AP50A (en)

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)

Country Link
US (1) US4879303A (en)
EP (1) EP0244944B1 (en)
JP (1) JPS62240660A (en)
KR (1) KR950006710B1 (en)
CN (1) CN1023800C (en)
AP (1) AP50A (en)
AR (1) AR242562A1 (en)
AT (1) ATE49752T1 (en)
BE (1) BE1000130A4 (en)
BG (1) BG60698B2 (en)
CA (1) CA1321393C (en)
CS (1) CS265237B2 (en)
CY (1) CY1669A (en)
CZ (1) CZ289095B6 (en)
DD (1) DD265142A5 (en)
DE (2) DE3710457A1 (en)
DK (1) DK171708B1 (en)
EC (1) ECSP941129A (en)
EG (1) EG18266A (en)
ES (2) ES2012803B3 (en)
FI (1) FI85017C (en)
FR (1) FR2596758B1 (en)
GB (2) GB8608335D0 (en)
GR (2) GR870525B (en)
HK (1) HK76092A (en)
HU (1) HU196962B (en)
IE (1) IE59457B1 (en)
IL (1) IL82101A (en)
IN (1) IN168414B (en)
IT (1) IT1203853B (en)
LU (1) LU86812A1 (en)
MA (1) MA20938A1 (en)
MX (1) MX5847A (en)
MY (1) MY101177A (en)
NL (1) NL8700791A (en)
NO (1) NO172181C (en)
NZ (1) NZ219868A (en)
PH (1) PH24348A (en)
PL (1) PL149532B1 (en)
PT (1) PT84611B (en)
SE (1) SE463457B (en)
SG (1) SG59692G (en)
SK (1) SK278435B6 (en)
SU (1) SU1498388A3 (en)
UA (1) UA6344A1 (en)
YU (1) YU44801B (en)
ZA (1) ZA872439B (en)

Families Citing this family (172)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5270323A (en) * 1990-05-31 1993-12-14 Pfizer Inc. Method of treating impotence
EP1013275A3 (en) * 1991-11-26 2001-01-10 Sepracor, Inc. Method and compositions for treating hypertension, angina and other disorders using optically pure (-) amlodipine
US6057344A (en) * 1991-11-26 2000-05-02 Sepracor, Inc. Methods for treating hypertension, and angina using optically pure (-) amlodipine
US6162802A (en) * 1992-03-10 2000-12-19 Papa; Joseph Synergistic combination therapy using benazepril and amlodipine for the treatment of cardiovascular disorders and compositions therefor
AT399718B (en) * 1992-04-16 1995-07-25 Lek Tovarna Farmacevtskih INCLUSION COMPLEXES OF OPTICALLY ACTIVE AND RACEMIC 1,4-DIHYDROPYRIDINES WITH METHYL-BETA-CYCLODEXTRIN OR OTHER CYCLODEXTRINE DERIVATIVES, A METHOD FOR THE PRODUCTION OF OPTICALLY ACTIVE DIHYDROPYRIDE-DOMETHYL-DOMETHYL-DOMETHYL-DOMETHYL POWERS
US5389654A (en) * 1992-11-26 1995-02-14 Lek, Tovarna, Farmacevtskih In Kemicnih . . . 3-ethyl 5-methyl(±)2-[2-(N-tritylamino)ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-6-methyl-3,5-pyridinedicarboxylate
SI9200344B (en) * 1992-11-26 1998-06-30 Lek, A process for the preparation of amlodipine benzenesulfonate
USRE39384E1 (en) 1993-09-01 2006-11-07 Smithkline Beecham P.L.C. Substituted thiazolidinedione derivatives
US6221335B1 (en) * 1994-03-25 2001-04-24 Isotechnika, Inc. Method of using deuterated calcium channel blockers
ATE235251T1 (en) 1995-03-16 2003-04-15 Pfizer USE OF AMLODIPINE, ONE OF ITS SALTS OR FELODIPINE IN COMBINATION WITH AN ACE INHIBITOR FOR THE PRODUCTION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF NON-ISCHEMIC CONGESTIVE HEART FAILURE
HU221810B1 (en) * 1997-08-12 2003-01-28 EGIS Gyógyszergyár Rt. Process for producing amlopidine besylate and the intermediates
GT199800127A (en) * 1997-08-29 2000-02-01 THERAPEUTIC COMBINATIONS.
WO1999018957A1 (en) * 1998-03-26 1999-04-22 Reddy-Cheminor, Inc. Stable pharmaceutical composition containing amlodipine besylate and atenolol
RU2188636C2 (en) * 1998-03-26 2002-09-10 Др. Редди'С Лабораторис Лтд. Stable pharmaceutical preparation containing amlodipine benzylate and atenolol
PL189666B1 (en) * 1998-04-09 2005-09-30 Adamed Sp Z Oo Method of obtaining amlopidine benzenosulphonate
EP1870098A3 (en) 1998-07-10 2010-07-07 Novartis Ag Combined use of valsartan and calcium channel blockers for therapeutic purposes
US20070072828A1 (en) * 1998-07-24 2007-03-29 Yoo Seo H Bile preparations for colorectal disorders
US20050158408A1 (en) * 1998-07-24 2005-07-21 Yoo Seo H. Dried forms of aqueous solubilized bile acid dosage formulation: preparation and uses thereof
US7303768B2 (en) * 1998-07-24 2007-12-04 Seo Hong Yoo Preparation of aqueous clear solution dosage forms with bile acids
US7772220B2 (en) * 2004-10-15 2010-08-10 Seo Hong Yoo Methods and compositions for reducing toxicity of a pharmaceutical compound
UA33033A (en) * 1998-10-16 2001-02-15 Др.Редіс Леборетрис Лтд Method of making bezilate amlodipine
US7129265B2 (en) * 1999-04-23 2006-10-31 Mason R Preston Synergistic effects of amlodipine and atorvastatin metabolite as a basis for combination therapy
RU2142942C1 (en) * 1999-04-28 1999-12-20 Дж. Б.Кемикалс энд Фармасьютикалс Лтд. Method of preparing monobenzosulfonate of 2-[(2- aminoethoxy) methyl -4- (2-chlorophenyl)-1,4-dihydro-6- methyl]-3,5-pyridine dicarboxylic acid 3-ethyl-5-methyl ester
HN2000000050A (en) 1999-05-27 2001-02-02 Pfizer Prod Inc MUTUAL SALT OF AMLODIPINO AND ATORVASTATINA
AU3313900A (en) 1999-05-27 2000-12-18 Pfizer Products Inc. Mutual prodrugs of amlodipine and atorvastatin
RU2161156C1 (en) * 1999-06-01 2000-12-27 Джи.Б.Кемикалс Энд Фармасьютикалс Лтд Method of preparing 3-ethyl-5-methyl ester of 2-[2-n-(phthalimido)ethoxymethyl]- 4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid
UA72768C2 (en) 1999-07-05 2005-04-15 Richter Gedeon Vegyeszet A method for obtaining amilodipine benzenesulphonate
RU2146672C1 (en) * 1999-10-13 2000-03-20 Др.Редди'С Лабораторис Лтд. Method of synthesis of 3-ethyl-5-methyl(±)2-[(2-aminoethoxy)- -methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine- -dicarboxylate monobenzenesulfonate
US6521647B2 (en) 2000-04-04 2003-02-18 Pfizer Inc. Treatment of renal disorders
AU2001283085A1 (en) 2000-08-04 2002-02-18 R. Preston Mason Synergistic effect of amlodipine and atorvastatin
GB0027410D0 (en) * 2000-11-09 2000-12-27 Pfizer Ltd Mutual prodrug of amlodipine and atorvastatin
US6737430B2 (en) 2000-11-09 2004-05-18 Pfizer, Inc. Mutual prodrug of amlodipine and atorvastatin
WO2002054062A2 (en) 2000-12-29 2002-07-11 Pfizer Limited Reference standards and processes for determining the purity or stability of amlodipine maleate
EP1309558A1 (en) * 2000-12-29 2003-05-14 Synthon Licensing, Ltd. Aspartate derivative of amlodipine as calcium channel antagonist
MXPA03005882A (en) 2000-12-29 2005-04-19 Pfizer Ltd Amide derivative of amlodipine.
US7335380B2 (en) 2000-12-29 2008-02-26 Synthon Ip Inc. Amlodipine free base
US6653481B2 (en) 2000-12-29 2003-11-25 Synthon Bv Process for making amlodipine
AT5874U1 (en) 2000-12-29 2003-01-27 Bioorg Bv PHARMACEUTICAL PREPARATIONS CONTAINING AMLODIPINMALEAT
ATE315026T1 (en) 2000-12-29 2006-02-15 Pfizer Ltd AMLODIPINE HEMIMALEATE
RS53403A (en) * 2000-12-29 2006-10-27 Pfizer Limited Process for making amlodipine maleate
WO2002053541A1 (en) 2000-12-29 2002-07-11 Pfizer Limited Amide derivative of amlodipine
EP1309556B1 (en) 2000-12-29 2004-11-24 Pfizer Limited Amlodipine fumarate
DE50112189D1 (en) * 2001-01-09 2007-04-26 Siegfried Generics Int Ag Salts of amlodipine mesylate
GB0103046D0 (en) 2001-02-07 2001-03-21 Novartis Ag Organic Compounds
KR100452491B1 (en) * 2001-03-29 2004-10-12 한미약품 주식회사 A novel crystalline amlodipine camsylate and a preparing method thereof
US20030027848A1 (en) * 2001-06-15 2003-02-06 Anne Billotte Stabilized formulations
DE60235101D1 (en) 2001-07-06 2010-03-04 Lek Pharmaceuticals PROCESS FOR PREPARING HIGH-PURITY AMLODIPINBENZENESULFONATE
US20030220310A1 (en) * 2001-07-27 2003-11-27 Schuh Joseph R. Epoxy-steroidal aldosterone antagonist and calcium channel blocker combination therapy for treatment of congestive heart failure
US6680334B2 (en) 2001-08-28 2004-01-20 Pfizer Inc Crystalline material
US7544681B2 (en) 2001-09-27 2009-06-09 Ramot At Tel Aviv University Ltd. Conjugated psychotropic drugs and uses thereof
US20040001886A1 (en) * 2001-10-17 2004-01-01 Dr. Reddy's Laboratories Limited Stabilized pharmaceutical formulations containing amlodipine maleate
AR037565A1 (en) * 2001-11-21 2004-11-17 Synthon Bv FORMS OF AMLODIPINE SALTS AND PROCEDURES TO PREPARE THEM.
HU226642B1 (en) * 2001-12-17 2009-05-28 Egis Gyogyszergyar Nyilvanosan Amlodipine bezylate tablets having extended stability and process for producing the same
NL1019882C2 (en) * 2002-02-01 2003-08-04 Synthon Licensing Pharmaceutical tablet composition useful for treating or preventing hypertension, angina or congestive heart failure comprises amlodipine free base
CN1649614A (en) 2002-02-22 2005-08-03 新河药品股份有限公司 Active agent delivery systems and methods for protecting and administering active agents
EP1499592A4 (en) * 2002-04-13 2010-01-13 Hanlim Pharmaceutical Co Ltd Amlodipine nicotinate and process for the preparation thereof
PT2151250E (en) 2002-05-06 2013-12-09 Endocyte Inc Vitamin-targeted imaging agents
EG24716A (en) 2002-05-17 2010-06-07 Novartis Ag Combination of organic compounds
SI21233A (en) * 2002-05-31 2003-12-31 LEK, tovarna farmacevtskih in kemičnih izdelkov, d.d. High purity crystalline hydrate forms of amlodipine benzensulphonate, methods of their preparation and usage
US6699892B2 (en) 2002-06-04 2004-03-02 Yung Shin Pharmaceutical Industrial Co., Ltd. Pharmaceutically acceptable salt of amlodipine and method of preparing the same
RU2221784C1 (en) * 2002-07-05 2004-01-20 Марвел Лайфсайнсез Прайвит Лимитед Amlodipin benzolsulfonate preparation method
KR100496436B1 (en) * 2002-07-30 2005-06-20 씨제이 주식회사 An organic acid salt of amlodipine
KR100538641B1 (en) * 2002-07-30 2005-12-22 씨제이 주식회사 An organic acid salt of amlodipine
KR20040011751A (en) * 2002-07-30 2004-02-11 씨제이 주식회사 An organic acid salt of amlodipine
KR100462304B1 (en) * 2002-07-30 2004-12-17 씨제이 주식회사 An organic acid salt of amlodipine
KR100467669B1 (en) * 2002-08-21 2005-01-24 씨제이 주식회사 An organic acid salt of amlodipine
AU2003261748B2 (en) 2002-08-29 2006-11-23 Taisho Pharmaceutical Co., Ltd. Benzenesulfonate of 4-fluoro-2-cyanopyrrolidine derivative
US6784297B2 (en) * 2002-09-04 2004-08-31 Kopran Limited Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate
EP1537083A4 (en) * 2002-09-11 2006-11-22 Hanlim Pharmaceutical Co Ltd S-(-)-amlodipine nicotinate and process for the preparation thereof
WO2004026834A1 (en) * 2002-09-19 2004-04-01 Cj Corporation Crystalline organic acid salt of amlodipine
US7166641B2 (en) * 2002-10-02 2007-01-23 Yung Shin Pharmaceutical Industrial Co., Ltd. Pharmaceutically acceptable salts containing local anesthetic and anti-inflammatory activities and methods for preparing the same
EP1407773A1 (en) * 2002-10-08 2004-04-14 Council of Scientific and Industrial Research A process for the preparation of s (-) amlodipine salts
US20040072879A1 (en) * 2002-10-10 2004-04-15 Dr. Reddy's Laboratories Limited Crystalline 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine maleate salt (Amlodipine)
AU2002368531A1 (en) * 2002-12-30 2004-07-22 Eos Eczacibasi Ozgun Kimyasal Urunler Sanayi Ve Ticaret A.S. Isolation of dihydropyridine derivative and preparation salts thereof
US20060128763A1 (en) 2003-01-27 2006-06-15 Moon Young H Stable amorphous amlodipine camsylate, process for preparing same and composition for oral administration thereof
MXPA05008142A (en) * 2003-01-31 2005-09-30 Sankyo Co Medicine for prevention of and treatment for arteriosclerosis and hypertension.
KR20040072363A (en) * 2003-02-12 2004-08-18 주식회사 대웅 Novel amlodipine cyclamate salt and a preparation method thereof
US20060270715A1 (en) * 2003-02-28 2006-11-30 Singh Romi B Dosage forms of amlodipine and processes for their preparation
EP2113506A3 (en) 2003-04-25 2010-02-24 Cadila Healthcare Limited Salts of clopidogrel and process for preparation
GB2415696B (en) * 2003-04-25 2007-06-20 Cipla Ltd Process for preparing amlodipine mesylate monohydrate
US20050182125A1 (en) * 2003-05-16 2005-08-18 Ambit Biosciences Corporation Pyrrole compounds and uses thereof
WO2004103959A2 (en) * 2003-05-16 2004-12-02 Ambit Biosciences Corporation Heterocyclic compounds and uses thereof
AU2004242777B2 (en) 2003-05-30 2011-05-12 Ranbaxy Laboratories Limited Substituted pyrrole derivatives and their use as HMG-Co inhibitors
RU2239433C1 (en) * 2003-06-09 2004-11-10 Закрытое акционерное общество "Фармацевтическое предприятие "Оболенское" Medicinal formulation eliciting vasodilating, anti-anginal, hypotensive and spasmolytic effect and method for its preparing
US7145125B2 (en) 2003-06-23 2006-12-05 Advanced Optical Technologies, Llc Integrating chamber cone light using LED sources
US20050048118A1 (en) * 2003-07-25 2005-03-03 Joan Cucala Escoi Modified release venlafaxine hydrochloride tablets
WO2005042485A1 (en) * 2003-10-30 2005-05-12 Sk Chemicals, Co., Ltd. Acid added salts of amlodipine
KR100841409B1 (en) * 2003-12-16 2008-06-25 에스케이케미칼주식회사 Amlodipine gentisate salt and preparation method thereof
US7262318B2 (en) * 2004-03-10 2007-08-28 Pfizer, Inc. Substituted heteroaryl- and phenylsulfamoyl compounds
US20060030602A1 (en) * 2004-03-16 2006-02-09 Sepracor Inc. (S)-amlodipine malate
ATE493973T1 (en) 2004-06-04 2011-01-15 Teva Pharma PHARMACEUTICAL COMPOSITION CONTAINING IRBESARTAN
US20050288340A1 (en) * 2004-06-29 2005-12-29 Pfizer Inc Substituted heteroaryl- and phenylsulfamoyl compounds
BRPI0514725A (en) * 2004-08-30 2008-06-24 Seo Hong Yoo neuroprotective effect of solubilized udca in the focal ischemic model
CA2584184A1 (en) * 2004-10-15 2006-04-27 Seo Hong Yoo Methods and compositions for reducing toxicity of a pharmaceutical compound
WO2006050165A2 (en) * 2004-11-01 2006-05-11 Seo Hong Yoo Methods and compositions for reducing neurodegeneration in amyotrophic lateral sclerosis
ATE439347T1 (en) * 2004-11-23 2009-08-15 Warner Lambert Co 7-(2H-PYRAZOLE-3-YL)-3,5-DIHYDROXY-HEPTANIC ACID DERIVATIVES AS HMG-CO-A-REDUCTASE INHIBITORS FOR THE TREATMENT OF LIPIDEMIA
WO2006059217A1 (en) * 2004-12-01 2006-06-08 Ranbaxy Laboratories Limited Stable solid dosage forms of amlodipine besylate and processes for their preparation
EP1833466A1 (en) * 2004-12-28 2007-09-19 Ranbaxy Laboratories Limited Methods for the preparation of stable pharmaceutical solid dosage forms of atorvastatin and amlodipine
WO2006085208A2 (en) * 2005-02-11 2006-08-17 Ranbaxy Laboratories Limited Stable solid dosage forms of amlodipine and benazepril
US20090298814A1 (en) * 2005-06-07 2009-12-03 Ramot At Tel Aviv Univeristy Ltd Novel salts of conjugated psychotropic drugs and processes of preparing same
KR20130135994A (en) * 2005-06-27 2013-12-11 다이이찌 산쿄 가부시키가이샤 Pharmaceutical preparation containing an angiotensin ii receptor antagonist and a calcium channel blocker
US8158146B2 (en) 2005-09-28 2012-04-17 Teva Pharmaceutical Industries Ltd. Stable combinations of amlodipine besylate and benazepril hydrochloride
EP1930008A1 (en) * 2005-09-28 2008-06-11 Teva Pharmaceutical Industries Ltd Sable composition of benazepril hydrochloride
US7741317B2 (en) 2005-10-21 2010-06-22 Bristol-Myers Squibb Company LXR modulators
CA2627599A1 (en) 2005-11-08 2007-05-18 Ranbaxy Laboratories Limited Process for (3r,5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt
US7888376B2 (en) 2005-11-23 2011-02-15 Bristol-Myers Squibb Company Heterocyclic CETP inhibitors
FR2894826B1 (en) * 2005-12-21 2010-10-22 Servier Lab NOVEL ASSOCIATION OF SINUSAL IF CURRENT INHIBITOR AND CALCIUM INHIBITOR AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
WO2008010223A2 (en) 2006-07-17 2008-01-24 Ramot At Tel Aviv University Ltd. Conjugates comprising a psychotropic drug or a gaba agonist and an organic acid and their use in treating pain and other cns disorders
KR100795313B1 (en) 2006-09-05 2008-01-21 현대약품 주식회사 Pharmaceutical composition comprising amlodipine besylate
TWI399223B (en) * 2006-09-15 2013-06-21 Daiichi Sankyo Co Ltd Solid dosage form of olmesartan and amlodipine
US20080096863A1 (en) * 2006-10-19 2008-04-24 Torrent Pharmaceuticals Limited Stable pharmaceutical compositions of calcium channel blocker and an ACE inhibitor
CN101167724B (en) * 2006-10-25 2012-08-22 北京华安佛医药研究中心有限公司 Application of medicinal composition containing amlodipine in preparing medicine for treating lower urinary tract disease
JP5498168B2 (en) 2006-12-01 2014-05-21 ブリストル−マイヤーズ スクイブ カンパニー N-((3-Benzyl) -2,2- (bis-phenyl) -propan-1-amine derivatives as CETP inhibitors for the treatment of atherosclerosis and cardiovascular disease
TW200843732A (en) * 2006-12-21 2008-11-16 Xenoport Inc Levodopa dimethyl-substituted diester prodrugs, compositions, and methods of use
US8058312B2 (en) * 2007-01-29 2011-11-15 Hanall Biopharma Co., Ltd. N, N-dimethyl imidodicarbonimidic diamide acetate, method for producing the same and pharmaceutical compositions comprising the same
WO2008124121A1 (en) * 2007-04-06 2008-10-16 Scidose, Llc Co-therapy with and combinations of statins and 1,4-dihydropyridine-3,5-dicarboxydiesters
WO2009032286A2 (en) 2007-09-06 2009-03-12 Nektar Therapeutics Al, Corporation Oligomer-calcium channel blocker conjugates
US8143314B1 (en) * 2007-09-13 2012-03-27 Robert Carl Stover Methods and formulations for treating ineffective or decreased esophageal motility
WO2009038396A2 (en) * 2007-09-21 2009-03-26 Hanall Pharmaceutical Company. Ltd N,n-dimethyl imidodicarbonimidic diamide dicarboxylate, method for producing the same and pharmaceutical compositions comprising the same
MX2010007281A (en) 2007-12-31 2010-10-05 Lupin Ltd Pharmaceutical compositions of amlodipine and valsartan.
WO2009101616A1 (en) 2008-02-11 2009-08-20 Ramot At Tel Aviv University Ltd. Novel conjugates for treating neurodegenerative diseases and disorders
RU2359672C1 (en) * 2008-02-18 2009-06-27 Зао "Биоком" Solid medicinal form intended for treatment of arterial hypertensia and stenocardia, and way of its reception
CN101564536B (en) * 2008-04-21 2010-12-15 鲁南制药集团股份有限公司 Sustained and controlled release preparation for pharmaceutical composition for curing hypertension
EP2361248B1 (en) 2008-06-27 2018-09-19 Celgene CAR LLC Heteroaryl compounds and uses thereof
US8338439B2 (en) 2008-06-27 2012-12-25 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidines useful as kinase inhibitors
US11351168B1 (en) 2008-06-27 2022-06-07 Celgene Car Llc 2,4-disubstituted pyrimidines useful as kinase inhibitors
US8399513B2 (en) * 2008-10-20 2013-03-19 Xenoport, Inc. Levodopa prodrug mesylate hydrate
JP2012505885A (en) * 2008-10-20 2012-03-08 ゼノポート，インコーポレーテッド Methods for synthesizing levodopa ester prodrugs
CN102256604A (en) * 2008-12-17 2011-11-23 株式会社医药处方 Aqueous oral preparation of stable amlodipine
ES2580777T3 (en) 2009-01-23 2016-08-26 Hanmi Holdings Co., Ltd. Solid pharmaceutical composition comprising amlodipine and losartan and method for producing it
NZ601747A (en) * 2009-11-09 2014-08-29 Xenoport Inc Pharmaceutical compositions and oral dosage forms of a levodopa prodrug and methods of use
CN102762211A (en) 2009-12-09 2012-10-31 拜欧利纳斯有限公司 Methods of improving cognitive functions
SG10201406805RA (en) 2010-02-12 2014-11-27 Pfizer Salts and polymorphs of 8-fluoro-2-{4-[(methylamino}methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd]indol-6-one
CN102858345A (en) 2010-02-24 2013-01-02 雷蒙特亚特特拉维夫大学有限公司 Crystalline forms of the tri-mesylate salt of perphenazine-GABA and process of producing the same
WO2011117876A1 (en) 2010-03-26 2011-09-29 Fdc Limited An improved process for the preparation of amlodipine free base and acid addition salts thereof
IT1400309B1 (en) 2010-05-10 2013-05-24 Menarini Int Operations Lu Sa ASSOCIATION OF XANTHIN INHIBITORS OXIDASE AND CALCIUM ANTAGONISTS AND THEIR USE.
EP2425859A1 (en) 2010-08-08 2012-03-07 Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi Olmesartan formulations
MX336875B (en) * 2010-08-10 2016-02-04 Celgene Avilomics Res Inc BESYLATE SALT OF A BRUTON TYPEOSIN CINASA INHIBITOR (BTK).
US8916610B2 (en) 2010-09-22 2014-12-23 Ramot At Tel-Aviv University Ltd. Acid addition salt of a nortriptyline-GABA conjugate and a process of preparing same
EP2635285B1 (en) 2010-11-01 2017-05-03 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
PH12013500870A1 (en) 2010-11-01 2013-06-03 Celgene Car Llc Heterocyclic compounds and uses thereof
EP2637502B1 (en) 2010-11-10 2018-01-10 Celgene CAR LLC Mutant-selective egfr inhibitors and uses thereof
WO2012071524A1 (en) * 2010-11-24 2012-05-31 Ratiopharm Gmbh Arylsulfonate salts of fingolimod and processes for preparation thereof
WO2013063401A1 (en) 2011-10-28 2013-05-02 Celgene Avilomics Research, Inc. Methods of treating a bruton's tyrosine kinase disease or disorder
PL2825042T3 (en) 2012-03-15 2019-02-28 Celgene Car Llc Salts of an epidermal growth factor receptor kinase inhibitor
US9056839B2 (en) 2012-03-15 2015-06-16 Celgene Avilomics Research, Inc. Solid forms of an epidermal growth factor receptor kinase inhibitor
US9126950B2 (en) 2012-12-21 2015-09-08 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
PL236001B1 (en) 2012-12-21 2020-11-30 Adamed Spolka Z Ograniczona Odpowiedzialnoscia Complex pharmaceutical composition comprising candesartan cilexetil and amlodipine, its preparation method and the unit dosage form comprising said composition,
ES2805359T3 (en) 2013-02-08 2021-02-11 Celgene Car Llc ERK inhibitors and their uses
US20150374713A1 (en) 2013-02-08 2015-12-31 Wockhardt Limited Stable pharmeceutical composition of amlodipine and benazepril or salts thereof
JP2016516804A (en) 2013-04-17 2016-06-09 ファイザー・インク N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases
US9492471B2 (en) 2013-08-27 2016-11-15 Celgene Avilomics Research, Inc. Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase
US9415049B2 (en) 2013-12-20 2016-08-16 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
ES2741785T3 (en) 2014-08-13 2020-02-12 Celgene Car Llc Forms and compositions of an ERK inhibitor
WO2016055901A1 (en) 2014-10-08 2016-04-14 Pfizer Inc. Substituted amide compounds
CN104610130A (en) * 2015-01-22 2015-05-13 华东理工常熟研究院有限公司 Amlodipine-palmic acid ionic liquid as well as preparation method and application thereof
CN104529877A (en) * 2015-01-22 2015-04-22 华东理工常熟研究院有限公司 Amlodipine-decylic acid ion liquid as well as preparation method and application thereof
CN104523588A (en) * 2015-01-22 2015-04-22 华东理工常熟研究院有限公司 Amlodipine-stearic acid ionic liquid as well as preparation method and application thereof
US10420850B2 (en) 2015-08-14 2019-09-24 Endocyte, Inc. Method of imaging with a chelating agent
US20180303811A1 (en) 2015-10-23 2018-10-25 Ftf Pharma Private Limited Oral solution of dihydropyridine derivatives
CN105395495A (en) * 2015-11-30 2016-03-16 宜昌东阳光长江药业股份有限公司 Composition containing amlodipine besylate and preparation method of composition
EP3219309A1 (en) 2016-03-17 2017-09-20 K.H.S. Pharma Holding GmbH Fixed dosed pharmaceutical composition comprising amlodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension
WO2017207375A1 (en) 2016-05-30 2017-12-07 Boehringer Ingelheim International Gmbh Fixed dose combination of telmisartan, hydrochlorothiazide and amlodipine
US10695329B2 (en) 2016-10-07 2020-06-30 Silvergate Pharmaceuticals, Inc. Amlodipine formulations
US10350171B2 (en) 2017-07-06 2019-07-16 Dexcel Ltd. Celecoxib and amlodipine formulation and method of making the same
EP3501502A1 (en) 2017-12-20 2019-06-26 Midas Pharma GmbH Fixed dosed pharmaceutical compositions comprising amlodipine, ramipril and atorvastatin
US10799453B2 (en) 2018-04-11 2020-10-13 Silvergate Pharmaceuticals, Inc. Amlodipine formulations
JP7470647B2 (en) 2018-06-14 2024-04-18 アストラゼネカ・ユーケイ・リミテッド Methods for lowering blood pressure using dihydropyridine calcium channel blocker pharmaceutical compositions
MA54261B1 (en) 2019-01-18 2025-03-28 Astrazeneca Ab PCSK9 INHIBITORS AND METHODS OF USE THEREOF
US11253474B1 (en) 2021-02-01 2022-02-22 Liqmeds Worldwide Limited Pharmaceutical solution of amlodipine
EP4052695A1 (en) 2021-03-05 2022-09-07 Midas Pharma GmbH Stable oral fixed-dose immediate release pharmaceutical compositions comprising amlodipine, atorvastatin and candesartan cilexetil
WO2023285646A1 (en) 2021-07-15 2023-01-19 Adamed Pharma S.A A pharmaceutical composition comprising amlodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension

Citations (2)

* Cited by examiner, † Cited by third party
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

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3816612A (en) * 1967-03-23 1974-06-11 Degussa Process for the production of basically reacting pharmaceuticals
US4032637A (en) * 1972-09-26 1977-06-28 Sandoz Ltd. Method of promoting sleep
US4177278A (en) * 1977-04-05 1979-12-04 Bayer Aktiengesellschaft 2-Alkyleneaminodihydropyridines compounds, their production and their medicinal use
JPS5547656A (en) * 1978-09-29 1980-04-04 Dainippon Pharmaceut Co Ltd 2-(2-substituted aminoethyl)-1,4-dihydropyridine derivative and its derivative
ZA839187B (en) * 1982-12-10 1984-07-25 Ciba Geigy Ag Amide compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
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

Also Published As

Publication number Publication date
SK278435B6 (en) 1997-05-07
FR2596758A1 (en) 1987-10-09
GB8608335D0 (en) 1986-05-08
AP8700060A0 (en) 1987-02-01
CS353991A3 (en) 1992-04-15
AR242562A1 (en) 1993-04-30
CS236387A2 (en) 1989-01-12
KR950006710B1 (en) 1995-06-21
CY1669A (en) 1993-05-14
MX5847A (en) 1993-08-01
GB2188630B (en) 1990-04-04
NO172181B (en) 1993-03-08
PH24348A (en) 1990-06-13
NO871408D0 (en) 1987-04-03
SE8701348D0 (en) 1987-03-31
DK170187A (en) 1987-10-05
ATE49752T1 (en) 1990-02-15
JPH037668B2 (en) 1991-02-04
DD265142A5 (en) 1989-02-22
NO871408L (en) 1987-10-05
CN1023800C (en) 1994-02-16
DK171708B1 (en) 1997-04-01
EP0244944B1 (en) 1990-01-24
NL8700791A (en) 1987-11-02
ZA872439B (en) 1988-11-30
PL264982A1 (en) 1988-05-26
IN168414B (en) 1991-03-30
EG18266A (en) 1992-12-30
DE3761485D1 (en) 1990-03-01
NO172181C (en) 1993-06-16
US4879303A (en) 1989-11-07
ES2002599A6 (en) 1988-08-16
SU1498388A3 (en) 1989-07-30
SG59692G (en) 1992-12-04
CN87102493A (en) 1987-10-14
PL149532B1 (en) 1990-02-28
YU44801B (en) 1991-02-28
NZ219868A (en) 1989-02-24
FI85017C (en) 1992-02-25
SE8701348L (en) 1987-10-05
CS265237B2 (en) 1989-10-13
GB2188630A (en) 1987-10-07
EP0244944A2 (en) 1987-11-11
SE463457B (en) 1990-11-26
AU7103087A (en) 1987-10-08
HK76092A (en) 1992-10-09
MA20938A1 (en) 1987-12-31
CA1321393C (en) 1993-08-17
KR870009998A (en) 1987-11-30
BE1000130A4 (en) 1988-04-12
LU86812A1 (en) 1987-08-12
PT84611A (en) 1987-05-01
HU196962B (en) 1989-02-28
IT1203853B (en) 1989-02-23
IL82101A0 (en) 1987-10-30
BG60698B2 (en) 1995-12-29
HUT43821A (en) 1987-12-28
JPS62240660A (en) 1987-10-21
IE59457B1 (en) 1994-02-23
FI85017B (en) 1991-11-15
YU58087A (en) 1988-08-31
CZ289095B6 (en) 2001-10-17
UA6344A1 (en) 1994-12-29
PT84611B (en) 1989-11-30
GB8707653D0 (en) 1987-05-07
MY101177A (en) 1991-07-31
AU573123B2 (en) 1988-05-26
FR2596758B1 (en) 1988-12-02
ES2012803B3 (en) 1990-04-16
FI871470L (en) 1987-10-05
FI871470A0 (en) 1987-04-03
GR870525B (en) 1987-08-12
GR3000394T3 (en) 1991-06-07
ECSP941129A (en) 1994-12-15
IT8719977A0 (en) 1987-04-03
DE3710457A1 (en) 1987-10-08
EP0244944A3 (en) 1988-01-07
IL82101A (en) 1991-01-31
DK170187D0 (en) 1987-04-03
IE870869L (en) 1987-10-04

Similar Documents

Publication Publication Date Title
AP50A (en) Improvements in pharmaceutially acceptable salts.
RU2241701C1 (en) Amlodipine camsylate, method for its preparing and pharmaceutical composition based on thereof
US20060014795A1 (en) S-(-) -amlodipine nicotinate and process for the preparation thereof
JP4287752B2 (en) Amlodipine nicotinate and method for producing the same
MXPA06006922A (en) Amlodipine gentisate and a method of its preparation.
KR950007228B1 (en) Besylate salt of amlodipine
EP1391453A1 (en) Pyroglutamic acid salt of amlodipine
JP2006500334A (en) Amlodipine organic acid salt
SI8710580A8 (en) Process for the preparation of benzenesulphonate salt of 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydr o-6-methyl-pyridine-3,5-dicarboxylate
US20040029923A1 (en) Organic acid salt of amlodipine
KR100496436B1 (en) An organic acid salt of amlodipine
WO2004072036A1 (en) Novel amlodipine cyclamate salt and a preparation method thereof