WO1999018957A1 - Stable pharmaceutical composition containing amlodipine besylate and atenolol - Google Patents
Stable pharmaceutical composition containing amlodipine besylate and atenolol Download PDFInfo
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- WO1999018957A1 WO1999018957A1 PCT/US1998/005564 US9805564W WO9918957A1 WO 1999018957 A1 WO1999018957 A1 WO 1999018957A1 US 9805564 W US9805564 W US 9805564W WO 9918957 A1 WO9918957 A1 WO 9918957A1
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- atenolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
Definitions
- the present invention relates to a stable pharmaceutical composition containing a combination of medicaments such as a dihydropyridine class calcium channel blocker drug Amlodipine besylate and a benzeneacetamide class ⁇ - adrenergic blocker drug Atenolol having utility in certain cardiovascular diseases like Angina pectoris, Myocardial infarction, Hypertension. It is also related to selection of pharmaceutical excipients to prepare stable composition of Amlodipine besylate in combination with Atenolol.
- medicaments such as a dihydropyridine class calcium channel blocker drug Amlodipine besylate and a benzeneacetamide class ⁇ - adrenergic blocker drug Atenolol having utility in certain cardiovascular diseases like Angina pectoris, Myocardial infarction, Hypertension. It is also related to selection of pharmaceutical excipients to prepare stable composition of Amlodipine besylate in combination with Atenolol.
- the present invention also relates to methods of preparing said stable pharmaceutical combination product.
- Nifedipine, Felodipine, Nicardipine, Amlodipine and Nisolidipine have a calcium channel blocking action and are useful for the treatment of various cardiovascular disorders such as Angina pectoris, Myocardial infarction, Hypertension etc. It is also known that ⁇ -adrenergic blocking agents such as Propranolol, Metaprolol, Atenolol, Timolol etc. are also useful for the treatment of such cardiovascular diseases.
- dihydropyridine derivative class calcium channel blocking agents are entirely different from that of ⁇ -adrenoceptor blocking agents in treating cardiovascular ailments. It has been reported that a combined administration of a calcium ion antagonist Verapamil and a ⁇ -blocker drug Propranolol can achieve maximal symptomatic improvement in clinical Angina pectoris. [ Bassan., et al., "Additive antianginal effect of Verapamil in patients receiving Propranolol"., Br. Med. J., 284, 1067 (1982)]. Further it has been reported that Plasma rerun activity of normo- tensive and hypertensive subjects is increased by calcium channel blocker - Nifedipine.
- Propranolol decreases plasma renin activity in both normotensive and hypertensive patients.
- the antihypertensive effect of Nifedipine is enhanced and prolonged by Propranolol.
- the observed increase in heart rate and plasma renin activity with Nifedipine is inhibited by Propranolol. That is, ⁇ -blocker inhibits the calcium antagonist induced reflex increase of heart rate; and also completely inhibits the calcium ion antagonist induced increase of plasma renin activity. Since the side effects of either drug are almost abolished or inhibited by the combination administration of both the drugs, combined administration of such two kinds of drug can be recommended for the satisfactory management of Hypertension with minimal adverse drug reactions.
- Indian patent 168414 or UK Patent application GB 2 188 630 discloses a process for preparing the besylate salt of Amlodipine i.e. by reacting Amlodipine base with a solution of benzene sulphonic acid or its ammonium salt in an inert solvent.
- This invention also describes the process of preparing - Tablets, Capsules and injectable compositions containing amlodipine besylate as a sole active ingredient in admixture with certain excipients.
- EP 0 795 327 Al discloses a method for reducing morbidity and / or mortality in a mammal with congestive heart failure due to non - ischemic etiology comprising administering amlodipine or a pharmaceutically acceptable amlodipine acid addition salt, and, optionally, a diuretic and / or digoxin. Further this invention relates to compositions comprising amlodipine or a pharmaceutically acceptable salt thereof and one or both of digoxin and / or a diuretic. This invention does not disclose the compositions of Amlodipine or its acceptable salts with any of calcium channel blocker drugs.
- WO 96/28185 discloses a composition comprising of a compound selected from Amlodipine or its pharmaceutically accepted salt or Felodipine and an ACE inhibitor selected from the group consisting of Benazepril, Captopril, Enalapril, Enalaprilat, Fosinopril Sodium, Lisinopril, Pentopril, Quinapril Hydrochloride, Quinaprilat, Ramipril, Ramiprilat, Trandolapril and Zofenopril calcium and optionally containing a Diuretic and/or Digoxin. Even though this Patent document disclosed various combinations of calcium channel blocker drugs with ACE inhibitors and Diuretics and/ or Digoxin, there is no mention about the combination products of calcium channel blocker drugs and ⁇ -blocker drugs.
- US Patent 4,794,111 (Bayer) discloses a composition comprising by weight a synergistically effective mixture of a Dihydropyridine selected from the group containing Nisolidipine, Nimodipine and Nitrenidipine and a ⁇ -blocker drug selected from the group containing Atenolol, Sotalol, Timolol and Nadolol. But this Patent document does not disclose anything about the combination of Amlodipine besylate and Atenolol.
- US Patent 4,814,175 discloses a combination preparation containing a dihydropyridine drug - Nifedipine with a ⁇ -blocking drug - Mepindolol, in which the Nifedipine component of the combination exhibits retarded release pattern of the active compound.
- the purpose of this invention is to identify the excipients which are compatible with both Amlodipine besylate and Atenolol in combination, to develop a stable composition and the process for manufacturing of such stable combination product of Amlodipine besylate and Atenolol.
- a stable pharmaceutical composition containing a calcium channel blocker drug - Amlodipine besylate in combination with a ⁇ -adrenergic blocker drug - Atenolol in the form of a solid dosage form for oral administration to the individuals suffering with certain cardiovascular ailments.
- the combination product of Amlodipine besylate and Atenolol according to the invention is preferably used as a solid formulation, for example, in the form of tablets, pills, dragees, granules, powder, capsule or sachets.
- the invention further provides a stable pharmaceutical combination product of Amlodipine besylate with Atenolol in admixture with carefully screened excipients compatible with both the drugs when taken in combination and are necessary for the processing.
- the present invention further provides different processes for preparing a stable pharmaceutical combination product of Amlodipine besylate with Atenolol and selected excipients.
- the dose range of Amlodipine besylate in the combination product according to the present invention is 3.0 - 20.0 mg and dose range for Atenolol is 25.0 - 125.0 mg. Most preferred dose range in the combination product is, for Amlodipine besylate 3.0-15.0 mg, and for Atenolol 25.0-100.0 mg.
- a preferred combination product according to the present invention includes the besylate salt of Amlodipine and Atenolol in admixture with commonly known but carefully screened pharmaceutical excipients belonging to the categories: diluents, binders, disintegrating agents, film formers, plasticizers, lubricants and/or glidants.
- excipients commonly known in the pharmaceutical art are: Diluents such as Lactose, anhydrous Lactose, spray dried Lactose, starch, Directly compressible starches, Hydrolyzed starches, Microcrystalline cellulose, other cellulose derivatives, Mannitol, Sorbitol, Sucrose and sucrose based materials, Dextrose, dibasic calcium phosphate dihydrate, Calcium sulfate dihydrate; Binders, such as cellulose derivatives, acacia, Gelatin, Tragacanth, Sorbitol, Glucose, Starch paste, Pregelatinised starch, Polyvinylpyrrolidone, Sodium alginate and alginate derivatives; Lubricants, such as Stearic acid, Stearic acid salts, Talc, Polyethylene glycols, and Waxes; and Glidants, such as Silica derivatives, Talc and corn starch.; Examples of Disintegration promoters which may be mentioned are: Starch, modified Starch,
- each of the excipients in the composition shall have good physical and chemical compatibility with the active substances in the product and with other excipients independently and when taken in combination.
- thermal methods such as Differential Scanning Calorimetric technique or studying the physical and chemical stability of the Drug substance when present in uniform mixture form with excipients in different combinations, exposed to variety of accelerated or long term conditions, are the methods used to study the Drug substance - Excipient compatibility.
- Amlodipine besylate is compatible with Anhydrous Lactose, Directly compressible Lactose, Microcrystalline cellulose, Maize Starch, Anhydrous Dicalcium phosphate, Dicalcium phosphate engranules, Polyvinyl- pyrrolidone, Hydroxy propyl methyl cellulose, Magnesium stearate, Colloidal Silicon dioxide, Talc and Croscarmellose Sodium.
- Amlodipine besylate was found to be incompatible with Polyvinylpolypyrrolidone, Sodium alginate, Gelatin and Hydroxypropyl Cellulose.
- a similar study by HPLC was carried out and Atenolol was found to be compatible with Anhydrous Lactose, Directly compressible Lactose, Microcrystalline Cellulose, Maize starch, Anhydrous Dicalcium phosphate, Dicalcium phosphate engranules, Sodium alginate, Hydroxypropyl Cellulose, Magnesium stearate, Pregelatinised starch, Polyvinylpyrrolidone, Hydroxy propyl methyl cellulose; and Atenolol was found to be incompatible with Polyvinylpolypyrrolidone.
- the invention is unique because, the said combination product is physically and chemically stable over its shelf life period, only when the said drug substances - Amlodipine besylate and Atenolol are in admixture with certain carefully screened and selected excipients.
- the present invention provides a stable pharmaceutical composition containing a dihydropyridine derivative and a benzeneacetamide derivative together with selected excipients which include, diluents preferably selected from the group containing Directly compressible Lactose, anhydrous Lactose, microcrystalline cellulose, Starch, Pregelatinised starch, dibasic calcium phosphate or its modified form; disintegrants selected preferably from the group containing Starch, modified starch, Croscarmellose Sodium; Binders selected preferably from the group containing Starch, Poly vinyl pyrrolidone and cellulose derivatives; Lubricants selected preferably from the group containing Magnesium stearate, Talc and colloidal Silicon dioxide; and other miscellaneous auxiliaries required for the processing and stability of the product.
- selected excipients which include, diluents preferably selected from the group containing Directly compressible Lactose, anhydrous Lactose, microcrystalline cellulose, Starch, Pregelatinised starch
- a process for preparing a stable pharmaceutical composition containing a dihydropyridine derivative and a benzeneacetamide derivative which comprises (i) Granulating the ⁇ -blocker drug - Atenolol together with carefully screened excipients using a moist granulation process, (ii) preparing the blend of such granules together with calcium channel blocker drug - Besylate salt of Amlodipine and compatible excipients, (iii) Such prepared blend can be compressed into tablets using standard compression tooling known in the art or can be filled into capsules or sachets for human oral administration.
- a process for preparing a stable pharmaceutical composition containing a dihydropyridine derivative and a benzeneacetamide derivative which comprises (i) granulating the ⁇ -blocker drug - Atenolol together with carefully screened excipients using a moist granulation process or dry compaction process; (ii)
- a process for preparing a stable pharmaceutical composition containing a dihydropyridine derivative and a benzeneacetamide derivative which comprises (i) Granulating the ⁇ -blocker drug - Atenolol together with selected excipients using a dry compaction process, (ii) preparing the blend of such granules together with the selected calcium channel blocker drug - Besylate salt of Amlodipine and carefully screened excipients, (iii) Such prepared blend can be compressed into tablets using standard compression tooling known in the art or can be filled into capsules or sachets for human oral administration.
- a process for preparing a stable pharmaceutical composition containing a dihydropyridine derivative and a benzeneacetamide derivative which comprises Direct compression process of ⁇ -blocker drug - Atenolol together with the calcium channel blocker drug -Amlodipine besylate and with carefully screened and selected excipients, using standard compression tooling known in the art.
- a process for preparing a stable pharmaceutical composition containing a dihydropyridine derivative and a benzeneacetamide derivative which comprises (i) Granulating the ⁇ -blocker drug - Atenolol together with carefully screened excipients using a moist granulation process or dry compaction process, (ii) preparing the blend of calcium channel blocker drug - Amlodipine besylate with compatible excipients, and (iii) Such prepared granules from (i) and blend from (ii) can be compressed into two layer tablets characterized by the presence of the two drug substances in two different layers, using standard compression tooling known in the art.
- Purified Water q.s. q.s. q.s. (i) Components 1 through 3 are sifted, blended and wet granulated with starch paste formed with components 4 and 13. The granulate is passed through a mill and mesh screen to obtain suitable granules. The granules are dried in a tray or fluid bed dryer, (ii) The dried granules are blended with previously sifted components 5 through 10 in a suitable blender for 5-10 minutes and the components 11 and 12 are added to the blender and blending continued for another 15 minutes, (iii) Then the final blend was passed through Rotary tablet press to obtain tablets of suitable strength or filled into Hard gelatin capsules on a semiautomatic capsulation machine.
- Components 1 and 2 are sifted, blended in a Planetary mixer and granulated using starch paste prepared by components 3 and 13. The granulate was passed through a mill and mesh screen to obtain suitable granules. The granules are dried in a Tray or fluid bed dryer, (ii) Components 4 through 6 are sifted, blended and this blend was coated with component 7 solution. The coated granules are passed through a mesh screen to get suitable coated granules, (iii) Atenolol granules obtained from step (i) and Amlodipine besylate coated granules obtained from step (ii) are blended along with sifted component 9 for 10-15 minutes in a Blender.
- Components 1 through 4 are blended in a planetary mixer for 15 minutes and the mix is compacted on a Roll compactor. The compacted flakes are milled and screened to obtain suitable granules, (ii) The granules are blended with sifted components 5 through 8 in a Blender for few minutes. Sifted components 9, 10 and 11 are added to the material in the Blender and blending continued for 10-15 minutes, (iii) The final blend was compressed into tablets on a Rotary tablet press or filled into Hard gelatin capsules on a semiautomatic capsulation machine. Examples - VIII. IX and X
- Components 1 through 7 are sifted and mixed in a Planetary mixer till uniform mix was obtained, (ii) Then the mix was transferred to a Blender along with the sifted components 8 through 10 and blended for 15 minutes, (iii) The final blend was compressed into tablets on a Rotary tablet press to obtain tablets of suitable strength.
- Components 1 through 3 are sifted, blended and wet granulated with starch paste formed with components 4 and 8. he granulate is passed through a mill and mesh screen to obtain suitable granules. The granules are dried in a tray or fluid bed dryer, (ii) The dried granules are blended with previously sifted components 5 through 7 in a suitable blender for 5-10 minutes, (iii) the components 9 through 11 are sifted, blended in a suitable blender. To this blend sifted components 12 and 13 are added and reblended.
- step (iv) The granules obtained from step (ii) and blend obtained from step (iii) are passed through layer press to obtain bilaminate tablets such that the granules from step (ii) forms the first layer and blend from step (iii) forms the second layer.
- Components 1 through 4 are sifted and mixed in a Planetary mixer to get uniform mix.
- Sifted components 5 through 7 are added to the above mix in a blender and blended for 10 - 15 minutes
- Components 8 through 10 are sifted and mixed well
- Sifted components 11 and 12 are added to the step (iii) and blended in a Blender for 10 minutes
- the blend obtained from step (ii) and blend obtained from step (iv) are passed through layer press to obtain bilaminate tablets such that the blend from step (ii) forms the first layer and blend from step (iv) forms the second layer.
Abstract
Pharmaceutical combination product of a benzeneacetamide category β-blocker drug-Atenolol with a dihydropyridine category calcium channel blocker drug-Amlodipine besylate having utility in certain cardiovascular diseases like Angina pectoris, Myocardial infarction, Hypertension is described. Different processes for preparing such combination product are also disclosed.
Description
STABLE PHARMACEUTICAL COMPOSITION CONTAINING AMLODIP INE BESYLATE AND ATENOLOL
FIELD OF THE INVENTION The present invention relates to a stable pharmaceutical composition containing a combination of medicaments such as a dihydropyridine class calcium channel blocker drug Amlodipine besylate and a benzeneacetamide class β- adrenergic blocker drug Atenolol having utility in certain cardiovascular diseases like Angina pectoris, Myocardial infarction, Hypertension. It is also related to selection of pharmaceutical excipients to prepare stable composition of Amlodipine besylate in combination with Atenolol.
The present invention also relates to methods of preparing said stable pharmaceutical combination product.
BACKGROUND OF THE INVENTION It is known that certain dihydropyridine derivatives such as
Nifedipine, Felodipine, Nicardipine, Amlodipine and Nisolidipine have a calcium channel blocking action and are useful for the treatment of various cardiovascular disorders such as Angina pectoris, Myocardial infarction, Hypertension etc. It is also known that β-adrenergic blocking agents such as Propranolol, Metaprolol, Atenolol, Timolol etc. are also useful for the treatment of such cardiovascular diseases.
However, the mechanism of action of dihydropyridine derivative class calcium channel blocking agents is entirely different from that of β-adrenoceptor blocking agents in treating cardiovascular ailments. It has been reported that a combined administration of a calcium ion antagonist Verapamil and a β-blocker drug Propranolol can achieve maximal symptomatic improvement in clinical Angina pectoris. [ Bassan., et al., "Additive antianginal effect of Verapamil in patients receiving Propranolol"., Br. Med. J., 284, 1067 (1982)]. Further it has been reported that Plasma rerun activity of normo- tensive and hypertensive subjects is increased by calcium channel blocker - Nifedipine. Combined administration of Nifedipine and β-blocker drug Propranolol
decreases plasma renin activity in both normotensive and hypertensive patients. The antihypertensive effect of Nifedipine is enhanced and prolonged by Propranolol. The observed increase in heart rate and plasma renin activity with Nifedipine is inhibited by Propranolol. That is, β-blocker inhibits the calcium antagonist induced reflex increase of heart rate; and also completely inhibits the calcium ion antagonist induced increase of plasma renin activity. Since the side effects of either drug are almost abolished or inhibited by the combination administration of both the drugs, combined administration of such two kinds of drug can be recommended for the satisfactory management of Hypertension with minimal adverse drug reactions. [ Aoki., et al "Antihypertensive effect of Cardiovascular calcium ion antagonist in hypertensive patients in the absence and presence of beta adrenergic blockade"., Am. Heart J., 96, 218 (1978) ].
Indian patent 168414 or UK Patent application GB 2 188 630 (Pfizer) discloses a process for preparing the besylate salt of Amlodipine i.e. by reacting Amlodipine base with a solution of benzene sulphonic acid or its ammonium salt in an inert solvent. This invention also describes the process of preparing - Tablets, Capsules and injectable compositions containing amlodipine besylate as a sole active ingredient in admixture with certain excipients.
The invention EP 0 795 327 Al (Pfizer Inc.) discloses a method for reducing morbidity and / or mortality in a mammal with congestive heart failure due to non - ischemic etiology comprising administering amlodipine or a pharmaceutically acceptable amlodipine acid addition salt, and, optionally, a diuretic and / or digoxin. Further this invention relates to compositions comprising amlodipine or a pharmaceutically acceptable salt thereof and one or both of digoxin and / or a diuretic. This invention does not disclose the compositions of Amlodipine or its acceptable salts with any of calcium channel blocker drugs.
WO 96/28185 (Pfizer Inc.) discloses a composition comprising of a compound selected from Amlodipine or its pharmaceutically accepted salt or Felodipine and an ACE inhibitor selected from the group consisting of Benazepril, Captopril, Enalapril, Enalaprilat, Fosinopril Sodium, Lisinopril, Pentopril, Quinapril Hydrochloride, Quinaprilat, Ramipril, Ramiprilat, Trandolapril and Zofenopril calcium and optionally containing a Diuretic and/or Digoxin. Even though this
Patent document disclosed various combinations of calcium channel blocker drugs with ACE inhibitors and Diuretics and/ or Digoxin, there is no mention about the combination products of calcium channel blocker drugs and β-blocker drugs.
US Patent 4,794,111 (Bayer) discloses a composition comprising by weight a synergistically effective mixture of a Dihydropyridine selected from the group containing Nisolidipine, Nimodipine and Nitrenidipine and a β-blocker drug selected from the group containing Atenolol, Sotalol, Timolol and Nadolol. But this Patent document does not disclose anything about the combination of Amlodipine besylate and Atenolol. US Patent 4,814,175 (Schering) discloses a combination preparation containing a dihydropyridine drug - Nifedipine with a β-blocking drug - Mepindolol, in which the Nifedipine component of the combination exhibits retarded release pattern of the active compound.
Likewise combinations of various β-blockers with various calcium antagonists and/or with an ACE inhibitor are described in the literature, which can be used in the treatment of circulatory diseases. Even though a combination product of Amlodipine besylate and Atenolol makes a good combination for the treatment of Hypertension, angina pectoris and Myocardial infarction, no research work has been taken up previously, evidenced by no mention in the literature regarding pharmaceutical compositions containing Amlodipine besylate and Atenolol and manufacturing processes for preparing such compositions, probably due to difficulty in selecting excipients which are compatible with both the drug substances in combination, to yield a stable composition and probably also due to difficulties involved in preparing such stable composition. The purpose of this invention is to identify the excipients which are compatible with both Amlodipine besylate and Atenolol in combination, to develop a stable composition and the process for manufacturing of such stable combination product of Amlodipine besylate and Atenolol.
SUMMARY OF THE INVENTION In accordance with the present invention, a stable pharmaceutical composition is provided containing a calcium channel blocker drug - Amlodipine besylate in combination with a β-adrenergic blocker drug - Atenolol in the form of
a solid dosage form for oral administration to the individuals suffering with certain cardiovascular ailments.
The combination product of Amlodipine besylate and Atenolol according to the invention is preferably used as a solid formulation, for example, in the form of tablets, pills, dragees, granules, powder, capsule or sachets.
The invention further provides a stable pharmaceutical combination product of Amlodipine besylate with Atenolol in admixture with carefully screened excipients compatible with both the drugs when taken in combination and are necessary for the processing. The present invention further provides different processes for preparing a stable pharmaceutical combination product of Amlodipine besylate with Atenolol and selected excipients.
DETAILED DESCRIPTION OF THE INVENTION The dose range of Amlodipine besylate in the combination product according to the present invention is 3.0 - 20.0 mg and dose range for Atenolol is 25.0 - 125.0 mg. Most preferred dose range in the combination product is, for Amlodipine besylate 3.0-15.0 mg, and for Atenolol 25.0-100.0 mg.
A preferred combination product according to the present invention includes the besylate salt of Amlodipine and Atenolol in admixture with commonly known but carefully screened pharmaceutical excipients belonging to the categories: diluents, binders, disintegrating agents, film formers, plasticizers, lubricants and/or glidants.
Examples of excipients commonly known in the pharmaceutical art are: Diluents such as Lactose, anhydrous Lactose, spray dried Lactose, starch, Directly compressible starches, Hydrolyzed starches, Microcrystalline cellulose, other cellulose derivatives, Mannitol, Sorbitol, Sucrose and sucrose based materials, Dextrose, dibasic calcium phosphate dihydrate, Calcium sulfate dihydrate; Binders, such as cellulose derivatives, acacia, Gelatin, Tragacanth, Sorbitol, Glucose, Starch paste, Pregelatinised starch, Polyvinylpyrrolidone, Sodium alginate and alginate derivatives; Lubricants, such as Stearic acid, Stearic acid salts, Talc, Polyethylene glycols, and Waxes; and Glidants, such as Silica derivatives, Talc and corn starch.; Examples of Disintegration promoters which may be mentioned are: Starch,
modified Starch, Cellulose and cellulose derivatives, crosslinked polyvinyl- pyrrolidone and Sodium alginate.
It is apparent to those versed in the art that for good physical and chemical stability of a pharmaceutical product, it is necessary that each of the excipients in the composition shall have good physical and chemical compatibility with the active substances in the product and with other excipients independently and when taken in combination. And, it is also apparent that either thermal methods such as Differential Scanning Calorimetric technique or studying the physical and chemical stability of the Drug substance when present in uniform mixture form with excipients in different combinations, exposed to variety of accelerated or long term conditions, are the methods used to study the Drug substance - Excipient compatibility.
In the course of studying the drug substance - Excipient compatibility for the said pharmaceutical combination product of Amlodipine besylate with Atenolol, it has been found unexpectedly that whilst many of the excipients are physically and chemically compatible with Amlodipine besylate and Atenolol when studied independently, only few of these excipients are compatible with the combination of the said two drug substances and some of the excipients compatible independently with Amlodipine besylate are found to be incompatible with Atenolol and vice-versa.
This interesting outcome of the studies led to the careful screening of the excipients which are compatible with both Amlodipine besylate and Atenolol for preparing their combination product.
When the Drug substance - Excipient compatibility study of Amlodipine besylate was carried out by Differential Scanning calorimetric technique by using DSC-25 equipped with TC-11 TA Processor (Mettler, Switzerland), Maize Starch, Lactose, Anhydrous Lactose, Directly compressible Lactose, Pregelatinised Starch, Talc, Anhydrous Dicalcium Phosphate, Dicalcium Phosphate engranules, Microcrystalline cellulose and Croscarmellose Sodium are found to be compatible. Sodium starch Glycolate and Magnesium stearate are found to be incompatible.
In similar fashion Drug substance - Excipient compatibility study for Atenolol was carried out by DSC, and Maize Starch, Lactose, Anhydrous Lactose,
Directly compressible Lactose, Talc, Anhydrous Dicalcium Phosphate, Dicalcium Phosphate engranules, Microcrystalline cellulose, Magnesium stearate, Sodium starch glycolate, Colloidal silicon dioxide and Croscarmellose Sodium are found to be compatible. Pregelatinised Starch was found to be incompatible. When the Drug substance - Excipient compatibility study was carried out by High Performance Liquid Chromatographic analysis of Drug-Excipient mixture samples exposed to accelerated temperature and Humidity conditions over a period of time, it is found that Amlodipine besylate is compatible with Anhydrous Lactose, Directly compressible Lactose, Microcrystalline cellulose, Maize Starch, Anhydrous Dicalcium phosphate, Dicalcium phosphate engranules, Polyvinyl- pyrrolidone, Hydroxy propyl methyl cellulose, Magnesium stearate, Colloidal Silicon dioxide, Talc and Croscarmellose Sodium. Amlodipine besylate was found to be incompatible with Polyvinylpolypyrrolidone, Sodium alginate, Gelatin and Hydroxypropyl Cellulose. A similar study by HPLC was carried out and Atenolol was found to be compatible with Anhydrous Lactose, Directly compressible Lactose, Microcrystalline Cellulose, Maize starch, Anhydrous Dicalcium phosphate, Dicalcium phosphate engranules, Sodium alginate, Hydroxypropyl Cellulose, Magnesium stearate, Pregelatinised starch, Polyvinylpyrrolidone, Hydroxy propyl methyl cellulose; and Atenolol was found to be incompatible with Polyvinylpolypyrrolidone.
In similar fashion Drug substance - Excipient compatibility study was carried out by HPLC for combination of Amlodipine besylate and Atenolol with different excipients, and found Maize starch, Anhydrous Dicalcium phosphate, Dicalcium phosphate engranules, Anhydrous Lactose, Directly compressible Lactose, Colloidal Silicon dioxide, Magnesium stearate, Pregelatinised Starch, Croscarmellose Sodium, Microcrystalline cellulose, Polyethyleneglycol, Hydroxypropyl methyl cellulose, Polyvinylpyrrolidone, Talc to be compatible and Sodium starch Glycolate, Polyvinylpolypyrrolidone, Hydroxypropyl Cellulose, Sodium alginate and Gelatin to be incompatible with the said drug substances taken in combination.
The invention is unique because, the said combination product is physically and chemically stable over its shelf life period, only when the said drug
substances - Amlodipine besylate and Atenolol are in admixture with certain carefully screened and selected excipients.
Accordingly, the present invention provides a stable pharmaceutical composition containing a dihydropyridine derivative and a benzeneacetamide derivative together with selected excipients which include, diluents preferably selected from the group containing Directly compressible Lactose, anhydrous Lactose, microcrystalline cellulose, Starch, Pregelatinised starch, dibasic calcium phosphate or its modified form; disintegrants selected preferably from the group containing Starch, modified starch, Croscarmellose Sodium; Binders selected preferably from the group containing Starch, Poly vinyl pyrrolidone and cellulose derivatives; Lubricants selected preferably from the group containing Magnesium stearate, Talc and colloidal Silicon dioxide; and other miscellaneous auxiliaries required for the processing and stability of the product.
It is apparent to those versed in the art that for good physical and chemical stability of a pharmaceutical product, the manufacturing process selected and used to prepare the product with the selected excipients shall not affect the drug substances present in the product physically or chemically during the process stage or during the shelf life period of the product. Apart from this character, it is generally desirable that the process selected should be simple, rugged and shall be possible with the equipment known to the art without much of processing difficulty. It is also apparent to those versed in the pharmaceutical art that stability studies of the finished formulations shall be carried out at least on three batches at 40° ± 2°C of temperature and 75 ± 5% RH for a minimum of six months period, and at 25° ± 2°C of temperature and 60 ± 5% RH for a sufficient period of time beyond 12 months. Stability studies on all the developed pharmaceutical combination products of Amlodipine besylate and Atenolol are carried out as per the ICH Harmonized Tripartite Guidelines on "Stability testing of New drug substances and Products".
According to an embodiment of the present invention there is provided a process for preparing a stable pharmaceutical composition containing a dihydropyridine derivative and a benzeneacetamide derivative which comprises (i) Granulating the β-blocker drug - Atenolol together with carefully screened
excipients using a moist granulation process, (ii) preparing the blend of such granules together with calcium channel blocker drug - Besylate salt of Amlodipine and compatible excipients, (iii) Such prepared blend can be compressed into tablets using standard compression tooling known in the art or can be filled into capsules or sachets for human oral administration.
According to another embodiment of the present invention there is provided a process for preparing a stable pharmaceutical composition containing a dihydropyridine derivative and a benzeneacetamide derivative which comprises (i) granulating the β-blocker drug - Atenolol together with carefully screened excipients using a moist granulation process or dry compaction process; (ii)
Preparing the blend of calcium channel blocker drug - Amlodipine besylate with few selected excipients and coating this blend material with a compatible protective polymer; and (iii) such prepared granules from (i) and coated blend material from (ii) can be lubricated and compressed into tablets using standard compression tooling known in the art or can be filled into capsules or sachets for human oral administration.
According to yet another embodiment of the present invention there is provided a process for preparing a stable pharmaceutical composition containing a dihydropyridine derivative and a benzeneacetamide derivative which comprises (i) Granulating the β-blocker drug - Atenolol together with selected excipients using a dry compaction process, (ii) preparing the blend of such granules together with the selected calcium channel blocker drug - Besylate salt of Amlodipine and carefully screened excipients, (iii) Such prepared blend can be compressed into tablets using standard compression tooling known in the art or can be filled into capsules or sachets for human oral administration.
According to still another embodiment of the present invention there is provided a process for preparing a stable pharmaceutical composition containing a dihydropyridine derivative and a benzeneacetamide derivative which comprises Direct compression process of β-blocker drug - Atenolol together with the calcium channel blocker drug -Amlodipine besylate and with carefully screened and selected excipients, using standard compression tooling known in the art.
According to still another embodiment of the present invention there
is provided a process for preparing a stable pharmaceutical composition containing a dihydropyridine derivative and a benzeneacetamide derivative which comprises (i) Granulating the β-blocker drug - Atenolol together with carefully screened excipients using a moist granulation process or dry compaction process, (ii) preparing the blend of calcium channel blocker drug - Amlodipine besylate with compatible excipients, and (iii) Such prepared granules from (i) and blend from (ii) can be compressed into two layer tablets characterized by the presence of the two drug substances in two different layers, using standard compression tooling known in the art. The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way, as these examples and other equivalents thereof will become more apparent to those versed in the Pharmaceutical art in the light of the present invention disclosure and the accompanying claims. Examples - I. II and III
Parts bv weight
S.No. Component I II Ill
1. Atenolol 50.00 50.00 50.00
2. Maize starch 124.57 123.21 201.21
3. DCP anhydrous 128.00 128.00 —
4. Maize starch 18.63 18.50 18.50
5. Maize starch 38.50 — —
6. Directly compressible DCP — 50.00 —
7. Pregelatinised Starch — — 32.00
8. Amlodipine besylate 7.29 7.29 7.29
9. DCP Anhydrous 10.00 — —
10. Colloidal Silicon Dioxide 5.00 5.00 10.00
11. Talc 4.00 4.00 4.00
12. Magnesium Stearate 7.00 7.00 7.00
13. Purified Water q.s. q.s. q.s.
(i) Components 1 through 3 are sifted, blended and wet granulated with starch paste formed with components 4 and 13. The granulate is passed through a mill and mesh screen to obtain suitable granules. The granules are dried in a tray or fluid bed dryer, (ii) The dried granules are blended with previously sifted components 5 through 10 in a suitable blender for 5-10 minutes and the components 11 and 12 are added to the blender and blending continued for another 15 minutes, (iii) Then the final blend was passed through Rotary tablet press to obtain tablets of suitable strength or filled into Hard gelatin capsules on a semiautomatic capsulation machine. Example - IV
Parts by weight
S.No. Component IV
I. Atenolol 50.00 2. Maize starch 201.21
3. Maize starch 18.50
4. Amlodipine besylate 7.29
5. Microcrystalline Cellulose 35.00
6. Lactose anhydrous 35.00 7. Hydroxy proply methyl cellulose 8.00
9. Croscarmellose sodium 9.00
10. Talc 6.00
II. Magnesium stearate 8.00 12. Colloidal silicon dioxide 8.00 13. Purified water q.s.
(i) Components 1 and 2 are sifted, blended in a Planetary mixer and granulated using starch paste prepared by components 3 and 13. The granulate was passed through a mill and mesh screen to obtain suitable granules. The granules are dried in a Tray or fluid bed dryer, (ii) Components 4 through 6 are sifted, blended and this blend was coated with component 7 solution. The coated granules are passed
through a mesh screen to get suitable coated granules, (iii) Atenolol granules obtained from step (i) and Amlodipine besylate coated granules obtained from step (ii) are blended along with sifted component 9 for 10-15 minutes in a Blender. Sifted components 10 through 12 are added to the above blend in the Blender and blending continued for another 10-15 minutes, (iv) The above final blend was passed through Rotary tablet press to obtain tablets of suitable strength or filled into Hard gelatin capsules on a semiautomatic capsulation machine.
Examples V, VI and VII
Parts by weight
S.No. Component V VI VII
1. Atenolol 50.00 50.00 50.00
2. Maize starch 150.00 150.00 75.00
3. DCP anhydrous 70.00 — —
4. Microcrystalline cellulose — 70.00 70.00
5. Directly compressible DCP 250.00 — —
6. Pregelatinised Starch 152.70 152.70 207.70
7. Amlodipine besylate 7.29 7.29 7.29
8. Microcrystalline cellulose — 150.00 150.00
9. Colloidal Silicon Dioxide 15.00 15.00 15.00
10. Talc 10.00 8.00 10.00
11. Magnesium Stearate 17.00 15.00 15.00
(i) Components 1 through 4 are blended in a planetary mixer for 15 minutes and the mix is compacted on a Roll compactor. The compacted flakes are milled and screened to obtain suitable granules, (ii) The granules are blended with sifted components 5 through 8 in a Blender for few minutes. Sifted components 9, 10 and 11 are added to the material in the Blender and blending continued for 10-15 minutes, (iii) The final blend was compressed into tablets on a Rotary tablet press or filled into Hard gelatin capsules on a semiautomatic capsulation machine.
Examples - VIII. IX and X
Parts by weight
S.No. Component I II III 1. Atenolol 50.00 50.00 50.00
2. Maize starch 20.00 — 20.00
3. Directly compressibe DCP 262.71 352.70 —
4. Microcrystalline cellulose 250.00 — 242.71
5. Pregelatinised Starch --- 250.00 — 6. Amlodipine besylate 7.29 7.29 7.29
7. Directly compressible Lactose — — 250.00
8. Colloidal Silicon Dioxide 15.00 15.00 15.00
9. Talc 10.00 8.00 10.00
10. Magnesium Stearate 15.00 17.00 15.00
(i) Components 1 through 7 are sifted and mixed in a Planetary mixer till uniform mix was obtained, (ii) Then the mix was transferred to a Blender along with the sifted components 8 through 10 and blended for 15 minutes, (iii) The final blend was compressed into tablets on a Rotary tablet press to obtain tablets of suitable strength.
Examples - XI and XII
Parts bv weight
S.No. Component XI XII
LAYER - 1
1. Atenolol 50.00 50.00
2. Maize starch 123.21 201.21
3. DCP anhydrous 128.00 —
4. Maize starch 18.50 18.50
5. Croscarmellose sodium 5.00 8.00
6. Talc 3.00 3.00
7. Magnesium stearate 4.00 3.00
8. Purified water q.s. q.s.
LAYER - 2
9. Amlodipine besylate 7.29 7.29
10. Pregelatinised starch 151.00 —
11. Directly compressible DCP — 122.00
12. Talc 2.00 2.00
13. Colloidal silicon dioxide 5.00 5.00
(i) Components 1 through 3 are sifted, blended and wet granulated with starch paste formed with components 4 and 8. he granulate is passed through a mill and mesh screen to obtain suitable granules. The granules are dried in a tray or fluid bed dryer, (ii) The dried granules are blended with previously sifted components 5 through 7 in a suitable blender for 5-10 minutes, (iii) the components 9 through 11 are sifted, blended in a suitable blender. To this blend sifted components 12 and 13 are added and reblended. (iv) The granules obtained from step (ii) and blend obtained from step (iii) are passed through layer press to obtain bilaminate tablets such that the granules from step (ii) forms the first layer and blend from step (iii) forms the second layer.
Examples - XIII and XIV
Parts by weight
S.No. Component XIII XIV
LAYER - 1
1. Atenolol 50.00 50.00
2. Pregelatinised starch 128.00 40.00
3. Directly compressible DCP — 110.00
4. Microcrystalline cellulose 128.00 120.00
5. Colloidal silicon dioxide 8.00 8.00
6. Talc 4.00 4.00
7. Magnesium stearate 3.00 4.00
LAYER - 2
8. Amlodipine besylate 7.29 7.29
9. Pregelatinised starch 142.00 —
10. Directly compressible DCP — 148.00
11. Talc 2.00 2.00
12. Colloidal silicon dioxide 5.00 10.00
(i) Components 1 through 4 are sifted and mixed in a Planetary mixer to get uniform mix. (ii) Sifted components 5 through 7 are added to the above mix in a blender and blended for 10 - 15 minutes, (iii) Components 8 through 10 are sifted and mixed well, (iv) Sifted components 11 and 12 are added to the step (iii) and blended in a Blender for 10 minutes, (v) The blend obtained from step (ii) and blend obtained from step (iv) are passed through layer press to obtain bilaminate tablets such that the blend from step (ii) forms the first layer and blend from step (iv) forms the second layer.
Claims
C L A I M S 1. A stable solid pharmaceutical preparation for oral administration comprising a combination of a. Dihydropyridine category Calcium channel blocker drug besylate salt of Amlodipine and, b. Benzeneacetamide class ╬▓-adrenergic blocker drug Atenolol, in admixture with excipients compatible with both the drug substances in combination, comprising of Pharmaceutical Diluents, Binders, Disintegrants, Lubricants and Glidents.
2. A pharmaceutical combination product according to claim 1, wherein the amount of Amlodipine besylate ranges from 3.0 to 15.0 mg and the amount of ╬▓-blocker drug Atenolol ranges from 25.0 to 100.0 mg.
3. A pharmaceutical combination product according to claim 1 and 2, wherein the amount of Amlodipine besylate is 7.29 mg and the amount of ╬▓- blocker drug Atenolol is 50.0 mg.
4. A pharmaceutical combination product according to claims 1 and 3, wherein the stable solid preparation is a Tablet.
5. A pharmaceutical combination product according to claims 1 and 3, wherein the stable solid preparation is a Capsule.
6. A pharmaceutical combination product according to claims 1 and 3, wherein the stable solid preparation is a two layer tablet characterized by the presence of two drug substances in two different layers.
7. A pharmaceutical combination product according to any of claims 1 to 6, wherein the Pharmaceutical Diluents are selected from the group containing Anhydrous Lactose, Directly compressible Lactose, Microcrystalline cellulose, Maize starch, Pregelatinised starch, Dibasic calcium phosphate or its Directly compressible form.
8. A pharmaceutical combination product according to any of claims 1 to 7, wherein the Binders are selected from the group containing Maize starch, Polyvinylpyrrolidone and Cellulose derivatives.
9. A pharmaceutical combination product according to any of claims 1 to 8, wherein the Disintegrants are selected from the group containing Starch, Modified starch and Croscarmellose Sodium.
10. A pharmaceutical combination product according to any of claims 1 to 9, wherein the Lubricants and Glidents are selected from the group containing Magnesium stearate, Talc, Stearic acid and Colloidal Silicon dioxide.
11. A process for the preparation of the pharmaceutical combination product according to any of claims 1 to 5 or 7 to 10 characterized in that (i) Atenolol together with selected excipients is granulated using moist granulation process, (ii) blend of such granules together with Amlodipine besylate and selected excipients was prepared and, (iii) such prepared blend was compressed into tablets or filled into Hard gelatin capsules.
12. A pharmaceutical combination product according to any of claims 1 to 5 or 7 to 11, wherein the drug substance and the excipients are present in the given range:
Atenolol 25 - 100 mg Amlodipine besylate 3 - 15 mg
Maize starch 100 - 250 mg
Anhydrous dicalcium phosphate 80 - 210 mg
Directly compressible Dicalcium phosphate 30 - 250 mg Pregelatinised Starch 25 - 150 mg Colloidal silicon dioxide 3 - 20 mg
Talc 3 - 10 mg
Magnesium stearate 5 - 15 mg
13. A process for the preparation of the pharmaceutical combination product according to any of claims 1 to 5 or 7 to 10, characterized in that (i) Atenolol together with selected excipients was granulated by moist granulation or dry compaction process, (ii) the blend of Amlodipine besylate with selected excipients was prepared and coated with a compatible protective polymer, (iii) the granules from step (i) and coated blend from step (ii) was lubricated to form final blend and compressed into tablets or filled into Hard gelatin capsules.
14. A pharmaceutical combination product according to any of claims 1 to 5, 7 to 10 or 13, wherein the drug substance and the excipients are present in the given range: Atenolol 25 - 100 mg
Amlodipine besylate 3 - 15 mg
Maize starch 120 - 250 mg
Pregelatinised Starch 25 - 150 mg Lactose anhydrous 20 - 100 mg
Microcrystalline cellulose 20 - 125 mg
Hydroxy propyl methyl cellulose 5 - 25 mg
Croscarmellose sodium 5 - 20 mg
Colloidal silicon dioxide 3 - 15 mg Talc 5 - 10 mg
Magnesium stearate 5 - 15 mg
15. A process for the preparation of the pharmaceutical combination product according to any of claims 1 to 5 or 7 to 10, characterized in that (i) Atenolol together with selected excipients was granulated by Dry compaction process, (ii) the blend of such granules with amlodipine besylate and selected excipients was prepared and, (iii) such prepared blend was compressed into tablets or filled into Hard gelatin capsules.
16. A pharmaceutical combination product according to any of claims 1 to 5, 7 to 10 or 15 wherein the drug substance and the excipients are present in the given range:
Atenolol 25 - lOOmg Amlodipine besylate 3 - 15 mg
Maize starch 50 - 200 mg
Pregelatinised Starch 100 - 250 mg Anhydrous Dicalcium phosphate 20 - 100 mg
Microcrystalline cellulose 50 - 200 mg Directly compressible dicalcium phosphate 150 - 300 mg Croscarmellose sodium 5 - 20 mg
Colloidal silicon dioxide 5 - 20 mg Talc 5 - 15 mg
Magnesium stearate 8 - 18 mg
17. A process for the preparation of the pharmaceutical combination product according to any of claims 1 to 4 or 7 to 10 characterized in that Atenolol and Amlodipine besylate along with necessary compatible excipients are sifted, blended and such prepared blend was directly compressed into tablets.
18. A pharmaceutical combination product according to any of claims 1 to 5, 7 to 10 or 17 wherein the drug substance and the excipients are present in the given range:
Atenolol 25 - 100 mg
Amlodipine besylate 3 - 15 mg
Maize starch 20 - 100 mg Pregelatinised Starch 100 - 300 mg
Microcrystalline cellulose 100 - 300 mg Directly compressible dicalcium phosphate 150 - 380 mg
Croscarmellose sodium 5 - 20 mg
Directly compressible Lactose 100-300 mg Colloidal silicon dioxide 5 - 20 mg
Talc 5 - 15 mg
Magnesium stearate 8 - 20 mg
19. A process for the manufacture of the pharmaceutical combination product according to any of claims 1 to 3 or 6 to 10, characterized in that (i) Atenolol along with selected compatible excipients necessary for processing was granulated by wet granulation or dry compaction, (ii) the granules obtained are lubricated, (iii) Amlodipine besylate and selected excipients are sifted, mixed and lubricated, (iv) the lubricated granules obtained from step (ii) and the blend obtained from step (iii) are formed into two layer tablet on a layer press such that the granules from step (ii) forms the first layer and blend from step (iii) forms the other layer of the two layer tablet.
20. A pharmaceutical combination product according to any of claims 1 to 3, 6 to 10 or 19, wherein the drug substance and the excipients are present in the given range: Atenolol 25 - 100 mg
Amlodipine besylate 3 - 15 mg
Maize starch 50 - 250 mg Pregelatinised Starch 20 - 200 mg
Microcrystalline cellulose 50 - 180 mg
Directly compressible dicalcium phosphate 30 - 180 mg Croscarmellose sodium 5 - 20 mg Colloidal silicon dioxide 5 - 20 mg
Talc 5 - 15 mg
Magnesium stearate 8 - 20 mg
21. A pharmaceutical combination product according to any of claims 1 to 20, is physically and chemically stable for a minimum period of 18 months when stored between 15 - 25┬░C.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1998/005564 WO1999018957A1 (en) | 1998-03-26 | 1998-03-26 | Stable pharmaceutical composition containing amlodipine besylate and atenolol |
| ROA200000407A RO121084B1 (en) | 1997-10-16 | 1998-03-26 | Stable solid pharmaceutical composition for oral administration and process for preparing the same |
| AU67671/98A AU6767198A (en) | 1998-03-26 | 1998-03-26 | Stable pharmaceutical composition containing amlodipine besylate and atenol ol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1998/005564 WO1999018957A1 (en) | 1998-03-26 | 1998-03-26 | Stable pharmaceutical composition containing amlodipine besylate and atenolol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999018957A1 true WO1999018957A1 (en) | 1999-04-22 |
Family
ID=22266649
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1998/005564 WO1999018957A1 (en) | 1997-10-16 | 1998-03-26 | Stable pharmaceutical composition containing amlodipine besylate and atenolol |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU6767198A (en) |
| WO (1) | WO1999018957A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005099699A1 (en) * | 2004-04-07 | 2005-10-27 | Sepracor Inc. | Combination of (s)-amlodipine and a beta-blocker, and methods for reducing hypertension |
| WO2006059217A1 (en) * | 2004-12-01 | 2006-06-08 | Ranbaxy Laboratories Limited | Stable solid dosage forms of amlodipine besylate and processes for their preparation |
| EP1932528A1 (en) * | 2005-09-28 | 2008-06-18 | Teva Pharmaceutical Industries Ltd | Stable composition of amlodipine besylate |
| US8158146B2 (en) | 2005-09-28 | 2012-04-17 | Teva Pharmaceutical Industries Ltd. | Stable combinations of amlodipine besylate and benazepril hydrochloride |
| WO2013030725A1 (en) | 2011-08-26 | 2013-03-07 | Wockhardt Limited | Methods for treating cardiovascular disorders |
| US11197848B2 (en) * | 2018-06-01 | 2021-12-14 | Tavanta Therapeutics Hungary Incorporated | Topical amlodipine salts for the treatment of anorectal diseases |
| CN114712319A (en) * | 2022-03-25 | 2022-07-08 | 北京诺康达医药科技股份有限公司 | Felodipine propranolol hydrochloride compound preparation and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2188630A (en) * | 1986-04-04 | 1987-10-07 | Pfizer Ltd | Improvements in pharmaceutically acceptable salts |
-
1998
- 1998-03-26 AU AU67671/98A patent/AU6767198A/en not_active Abandoned
- 1998-03-26 WO PCT/US1998/005564 patent/WO1999018957A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2188630A (en) * | 1986-04-04 | 1987-10-07 | Pfizer Ltd | Improvements in pharmaceutically acceptable salts |
Non-Patent Citations (7)
| Title |
|---|
| "AMLODIPIN - ANTIHYPERTENSIVUM MIT NEUER EXPERTISE", FORTSCHR. MED., 1994, 112/34 (60), Germany, XP002089968 * |
| BIOLOGICAL ABSTRACTS, vol. 1995, Philadelphia, PA, US; abstract no. 98224819, DAVIES RICHARD F_(A) PIERRE SANKARANARAYANAN JENNIFER A: "Effect of Amlodipine, Atenolol and Their Combination on Myocardial Ischemia During Treadmill Exercise and Ambulatory Monitoring." XP002089970 * |
| CLINICAL DRUG INVESTIGATION, 1997, 13/SUPPL. 1 (22-28), New Zealand * |
| DATABASE EMBASE ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; SILVA P. ET AL: "Amlodipine improves the anti-ischaemic effect of atenolol in postinfarction patients with effort-induced ischaemia. An echostress study", XP002089971 * |
| DEANFIELD J.: "Treatment effects on the total ischaemic burden and prognostic implications", EUROPEAN HEART JOURNAL, 1996, 17/SUPPL. G (64-68), United Kingdom, XP002089969 * |
| DUNSELMAN, PETER H. J. M. ET AL: "Value of the addition of amlodipine to atenolol in patients with angina pectoris despite adequate beta blockade", AM. J. CARDIOL., 81, 128-132, 15 January 1998 (1998-01-15), XP002089967 * |
| JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1995 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005099699A1 (en) * | 2004-04-07 | 2005-10-27 | Sepracor Inc. | Combination of (s)-amlodipine and a beta-blocker, and methods for reducing hypertension |
| WO2006059217A1 (en) * | 2004-12-01 | 2006-06-08 | Ranbaxy Laboratories Limited | Stable solid dosage forms of amlodipine besylate and processes for their preparation |
| EP1932528A1 (en) * | 2005-09-28 | 2008-06-18 | Teva Pharmaceutical Industries Ltd | Stable composition of amlodipine besylate |
| US8158146B2 (en) | 2005-09-28 | 2012-04-17 | Teva Pharmaceutical Industries Ltd. | Stable combinations of amlodipine besylate and benazepril hydrochloride |
| WO2013030725A1 (en) | 2011-08-26 | 2013-03-07 | Wockhardt Limited | Methods for treating cardiovascular disorders |
| US11197848B2 (en) * | 2018-06-01 | 2021-12-14 | Tavanta Therapeutics Hungary Incorporated | Topical amlodipine salts for the treatment of anorectal diseases |
| US11766428B2 (en) | 2018-06-01 | 2023-09-26 | Tavanta Therapeutics Hungary Incorporated | Topical amlodipine salts for the treatment of anorectal diseases |
| CN114712319A (en) * | 2022-03-25 | 2022-07-08 | 北京诺康达医药科技股份有限公司 | Felodipine propranolol hydrochloride compound preparation and preparation method thereof |
| CN114712319B (en) * | 2022-03-25 | 2024-01-09 | 北京诺康达医药科技股份有限公司 | Felodipine and propranolol hydrochloride compound preparation and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| AU6767198A (en) | 1999-05-03 |
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