WO2024052498A1 - An immediate-release oral pharmaceutical form of amlodipine with increased api content - Google Patents
An immediate-release oral pharmaceutical form of amlodipine with increased api content Download PDFInfo
- Publication number
- WO2024052498A1 WO2024052498A1 PCT/EP2023/074658 EP2023074658W WO2024052498A1 WO 2024052498 A1 WO2024052498 A1 WO 2024052498A1 EP 2023074658 W EP2023074658 W EP 2023074658W WO 2024052498 A1 WO2024052498 A1 WO 2024052498A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- immediate
- release oral
- oral pharmaceutical
- pharmaceutical composition
- amlodipine
- Prior art date
Links
- 229960000528 amlodipine Drugs 0.000 title claims abstract description 48
- 239000012729 immediate-release (IR) formulation Substances 0.000 title claims abstract description 34
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 title claims abstract 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 30
- 239000007884 disintegrant Substances 0.000 claims abstract description 26
- 239000008203 oral pharmaceutical composition Substances 0.000 claims abstract description 22
- 229940124531 pharmaceutical excipient Drugs 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims description 36
- 239000003826 tablet Substances 0.000 claims description 31
- 239000000314 lubricant Substances 0.000 claims description 14
- 229920002472 Starch Polymers 0.000 claims description 10
- 229940032147 starch Drugs 0.000 claims description 10
- 239000008107 starch Substances 0.000 claims description 10
- 235000019698 starch Nutrition 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 9
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- 229930006000 Sucrose Natural products 0.000 claims description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 6
- 229920002678 cellulose Polymers 0.000 claims description 6
- 239000001913 cellulose Substances 0.000 claims description 6
- 235000010980 cellulose Nutrition 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 5
- 239000007941 film coated tablet Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- -1 Ac Di Sol® Chemical compound 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 239000000783 alginic acid Substances 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 229960001126 alginic acid Drugs 0.000 claims description 4
- 150000004781 alginic acids Chemical class 0.000 claims description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 239000001506 calcium phosphate Substances 0.000 claims description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 3
- 235000011010 calcium phosphates Nutrition 0.000 claims description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
- 235000013539 calcium stearate Nutrition 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 235000010413 sodium alginate Nutrition 0.000 claims description 3
- 239000000661 sodium alginate Substances 0.000 claims description 3
- 229940005550 sodium alginate Drugs 0.000 claims description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 3
- 239000008109 sodium starch glycolate Substances 0.000 claims description 3
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 3
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 3
- 229910052623 talc Inorganic materials 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 239000005913 Maltodextrin Substances 0.000 claims description 2
- 229920002774 Maltodextrin Polymers 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 229940035034 maltodextrin Drugs 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims 1
- 238000000576 coating method Methods 0.000 claims 1
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 44
- 206010020772 Hypertension Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 239000004411 aluminium Substances 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 201000004239 Secondary hypertension Diseases 0.000 description 2
- 229960004005 amlodipine besylate Drugs 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 229940066469 amlodipine 5 mg Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229940036132 norvasc Drugs 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000010816 packaging waste Substances 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- 238000009512 pharmaceutical packaging Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000009516 primary packaging Methods 0.000 description 1
- 210000005227 renal system Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000021023 sodium intake Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
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
- A61K9/20—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
- 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
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
-
- 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
Definitions
- the invention provides the composition of an immediate-release oral pharmaceutical form which comprises by weight of 25.1% to 99.5% Amlodipine Besilate, at least 0.5% of disintegrant and from 0% to 74.4% additional pharmaceutical excipient.
- the prepared Amlodipine Besilate immediate-release oral pharmaceutical form has the benefit of a higher percentage Amlodipine Besilate content and a lowered percentage excipient content, while keeping with the requirements to the pharmaceutical quality.
- the invention belongs to the field of pharmaceutical preparations, a composition of matter, for the composition of an Amlodipine Besilate immediate-release oral pharmaceutical form.
- Hypertension or high blood pressure, is a serious health issue in many countries. According to the National Heart Blood and Lung Institute, it is thought that about 1 in 3 adults in the United States alone have hypertension. Left unchecked, hypertension is considered a substantial risk factor for cardiovascular and other diseases including coronary heart disease, myocardial infarction, congestive heart failure, stroke, and kidney failure. Hypertension is classified as primary (essential) hypertension or secondary hypertension. Primary hypertension has no known cause and may be related to several environmental, lifestyle and genetic factors such as stress, obesity, smoking, inactivity, and sodium intake. Secondary hypertension can be caused by drug or surgical interventions or by abnormalities in the renal, cardiovascular, or endocrine system.
- Amlodipine is a calcium channel blocker. It affects the movement of calcium into the cells of the heart and blood vessels. As a result, Amlodipine relaxes blood vessels and increases the supply of blood and oxygen to the heart while reducing its workload.
- Amlodipine is currently administered in the form of oral tablets, (e.g., Norvasc) or in the form of a refrigerated liquid formulation.
- a typical tablet formulation of Amlodipine immediate-release oral pharmaceutical form contains around 2 to 25% Amlodipine Besilate. The standard dosages being from 2.5mg to lOmg Amlodipine, and the typical dosage form being tablet.
- Amlodipine is one of the most often prescribed medicines in the world. Amlodipine tablets are usually and out of necessity packaged in PVC/ALU or ALU/ALU blisters, to ensure the stability of the product.
- the volume of the finished product determines how efficiently transportation and storage can be conducted, as a product with a high volume will require more space and more shipments as the same product at a smaller volume.
- Patented combinations of Amlodipine tablets such as EP2359815A1 reach an Amlodipine content of 20.0% by weight
- W02004075825A2 reaches 2.5% by weight
- EP1932528 manages to reach 2.0% to 10.0% by weight.
- the highest Amlodipine content of 25.0% has been found possible in the patent CN104739799B.
- Abdoh et al. A. Abdoh et al., Amlodipine Besylate- Excipients Interaction in Solid Dosage Form; Pharmaceutical Development and Technology, 2004, Vol. 9, No. 1. pp.
- the immediate-release oral pharmaceutical form shrinks, which in turn shrinks the size of the blister and shrinks the size of the entire finished product.
- a previously impossibly small sized blister can be used, and this enables the finished product to have a fraction of the current volume. This in turn allows for much more efficient transportation, lowering the carbon footprint of the product, and only a fraction of the packaging waste is created.
- Figure 1 shows a graph representing exemplary results of the dissolution study in the below examples.
- Example 1 Example preparation of Amlodipine Tablets
- Step 1 All excipients of either Table 1 to 6 (the amounts being scaled according to the desired batch size), are passed through an appropriate screen.
- a screen in this context refers to a sieve. Preferably sieves with a pore size of 250pm - 710pm.
- Step 2 All excipients other than any optional lubricant, are first blended for 5 minutes at lOrpm in an appropriate blender.
- Step 3 Any optional lubricant is then added to the blend, and again blended for 3 minutes at lOrpm.
- Step 4 The final blend is compressed into tablets.
- Step 5 A film coating can be added to the tablets.
- a pharmaceutical composition of an immediate-release oral pharmaceutical form which comprises by weight of 25.1% to 99.5% Amlodipine Besilate, at least 0.5% of disintegrant and from 0% to 74.4% additional pharmaceutical excipient.
- the preferred amount of Amlodipine Besilate being 30.1% to 81.5% by weight.
- the pharmaceutical excipient of embodiment 1 consists of, but is not limited to, one or more disintegrant, lubricant, fdler and glidant.
- the disintegrant of embodiment 1 and embodiment 2 consists of, but is not limited to microcrystalline cellulose, sodium alginate, sodium starch glycolate, croscarmellose sodium, crospovidone and any “super-disintegrants”.
- the filler of embodiment 2 consists of, but is not limited to cellulose, lactose, mannitol, starch, sucrose, and calcium phosphate.
- the lubricant of embodiment 2 consists of, but is not limited to calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulphate, and magnesium lauryl sulphate.
- the glidant of embodiment 2 consists of, but is not limited to silica derivatives, talc, and com starch.
- the immediate -release oral pharmaceutical form of embodiment 1 entails the tablet form or the fdm -coated tablet form. In the case of film-coated tablet form, the percentage weight refers to the weight of the tablet core.
- the Amlodipine Besilate of embodiment 1 entails also the other pharmaceutically acceptable salts of Amlodipine.
- composition of embodiment 1 is for the dosage range of 2.5mg Amlodipine to 20mg Amlodipine.
- the preferred dosage range is from of 5mg Amlodipine to lOmg Amlodipine.
- An immediate-release oral pharmaceutical composition comprising by weight of 25.1% to 99.5% Amlodipine Besilate, at least 0.5% of disintegrant and from 0% to 74.4% additional pharmaceutical excipient.
- the amount of Amlodipine Besilate in the immediate-release oral pharmaceutical composition is more than 50% to 99.5% by weight, preferably 75% to 99.5% by weight, more preferably 80% to 99.5% by weight, more preferably 81.5% to 99.5% by weight.
- the disintegrant is one or more disintegrants selected from the group comprising microcrystalline cellulose, sodium croscarmellose, carboxymethyl cellulose, alginic acid, sodium alginate and their derivatives, sodium starch glycolate (such as Glycolys®, Explotab®, Vivastar® P), croscarmellose sodium (such as Ac Di Sol®, Solutab®, Vivasol®), crospovidone (such as Kollidon®, Kollicoat®) and other super-disintegrants, as well as cellulose, lactose, mannitol, starch and sucrose.
- disintegrants selected from the group comprising microcrystalline cellulose, sodium croscarmellose, carboxymethyl cellulose, alginic acid, sodium alginate and their derivatives, sodium starch glycolate (such as Glycolys®, Explotab®, Vivastar® P), croscarmellose sodium (such as Ac Di Sol®, Solutab®, Vivasol®), crospovid
- Super disintegrants are disintegrants that typically can be used in small concentrations, such as 0.5 to 5% in typical pharmaceutical formulations, while still achieving suitable disintegrant effect.
- examples of other super-disintegrants according the present invention are disintegrants, such as L- hydroxy propyl cellulose, Sodium carboxymethyl starch (such as Primogel®), magnesium aluminum silicate (such as Veegum® HV), calcium silicate, cross-linked alginic acid (also known as alginic acid National Formulary (NF), such as Satialgine®), Soy derivatives / polysaccharides (such as Emcosoy®).
- the filler is one or more fillers selected from the group comprising cellulose, lactose, mannitol, starch, sucrose, and calcium phosphate, calcium carbonate, maltodextrin, sorbitol and dextrin.
- the lubricant is one or more lubricants selected from the group comprising calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulphate, and magnesium lauryl sulphate.
- the immediate-release oral pharmaceutical composition according to any one of embodiments 3 to
- glidant is one or more glidants selected from the group comprising silica derivatives, such as silicone dioxide, talc, and com starch.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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Abstract
The invention provides an immediate-release oral pharmaceutical composition which comprises by weight of 25.1% to 99.5% Amlodipine Besilate, at least 0.5% of disintegrant and from 0% to 74.4% additional pharmaceutical excipient.
Description
AN IMMEDIATE-RELEASE ORAL PHARMACEUTICAL FORM OF AMLODIPINE WITH INCREASED API CONTENT
Description
[001] The invention provides the composition of an immediate-release oral pharmaceutical form which comprises by weight of 25.1% to 99.5% Amlodipine Besilate, at least 0.5% of disintegrant and from 0% to 74.4% additional pharmaceutical excipient. With the composition invented, the prepared Amlodipine Besilate immediate-release oral pharmaceutical form has the benefit of a higher percentage Amlodipine Besilate content and a lowered percentage excipient content, while keeping with the requirements to the pharmaceutical quality.
Technical Field
[002] The invention belongs to the field of pharmaceutical preparations, a composition of matter, for the composition of an Amlodipine Besilate immediate-release oral pharmaceutical form.
Background
[003] Hypertension, or high blood pressure, is a serious health issue in many countries. According to the National Heart Blood and Lung Institute, it is thought that about 1 in 3 adults in the United States alone have hypertension. Left unchecked, hypertension is considered a substantial risk factor for cardiovascular and other diseases including coronary heart disease, myocardial infarction, congestive heart failure, stroke, and kidney failure. Hypertension is classified as primary (essential) hypertension or secondary hypertension. Primary hypertension has no known cause and may be related to several environmental, lifestyle and genetic factors such as stress, obesity, smoking, inactivity, and sodium intake. Secondary hypertension can be caused by drug or surgical interventions or by abnormalities in the renal, cardiovascular, or endocrine system.
[004] Amlodipine is a calcium channel blocker. It affects the movement of calcium into the cells of the heart and blood vessels. As a result, Amlodipine relaxes blood vessels and increases the supply of blood and oxygen to the heart while reducing its workload.
[005] Amlodipine is currently administered in the form of oral tablets, (e.g., Norvasc) or in the form of a refrigerated liquid formulation. A typical tablet formulation of Amlodipine immediate-release oral pharmaceutical form contains around 2 to 25% Amlodipine Besilate. The standard dosages being from 2.5mg to lOmg Amlodipine, and the typical dosage form being tablet. Amlodipine is one of the most often prescribed medicines in the world. Amlodipine tablets are usually and out of necessity packaged in PVC/ALU or ALU/ALU blisters, to ensure the stability of the product.
[006] The environmental burden of pharmaceutical packaging is immense. This is because the aluminium and plastics used to form the blister packaging are difficult and even impossible to recycle effectively as the materials are sealed together. Separating the materials again requires high amounts of energy and even then, the aluminium received from this is not of the same high quality as new aluminium. The larger the immediate-release oral pharmaceutical dosage form is, the larger the primary packaging must be and therefore also the more waste material is created.
[007] Additionally, there is the environmental burden caused through the extensive transportation steps required of the finished product, such as the transportation from the manufacturer to the wholesaler and then to the pharmacy. Each box of finished product in the pharmaceutical industry needs to be transported several steps until it reaches the customer, often even global transportation routes are involved. This is especially the case for generic medicines, and further relevant for products which are sold in the millions, like with Amlodipine. The volume of the finished product determines how efficiently transportation and storage can be conducted, as a product with a high volume will require more space and more shipments as the same product at a smaller volume.
[008] Furthermore, when it is avoidable to expose the patient to excipients, it should be done. An immediate-release oral pharmaceutical form is administered with the goal of subjecting the human body to the drug and not the excipients. It is a waste of resources of the pharma industry to use excipients in products where they can be avoided, especially when used in high quantities. Also, the global demand of excipients is ever increasing, and the supply capabilities of the chemical industry is falling behind the demand which makes this waste of recourses even more problematic.
[009] Patented combinations of Amlodipine tablets, such as EP2359815A1 reach an Amlodipine content of 20.0% by weight, W02004075825A2 reaches 2.5% by weight and EP1932528 manages to reach 2.0% to 10.0% by weight. The highest Amlodipine content of 25.0% has been found possible in the patent CN104739799B. In a 2004 Paper from Abdoh et al. (A. Abdoh et al., Amlodipine Besylate- Excipients Interaction in Solid Dosage Form; Pharmaceutical Development and Technology, 2004, Vol. 9, No. 1. pp. 15-24), the compatibility of amlodipine besylate in its solid formulations with various drug excipients was tested. Binary (1: 1. w/w) mixtures or multicomponent mixtures (1: 1: 1, w/w) of amlodipine besilate and excipients were incubated under "stress stability” conditions (e.g. elevated temperature and/or relative humidity). However, the studies were focused on studying the stability of powders of amlodipine besylate and excipients under such conditions. Immediate-release oral pharmaceutical compositions were not prepared and the suitability of such mixtures for oral pharmaceutical compositions was therefore not apparent from this study. It is not evident from previous patents or studies that the Amlodipine content could be brought to any higher levels.
[010] We have found a way to create an immediate-release oral pharmaceutical form of Amlodipine with an increased percentage amlodipine content that can help immensely with the listed problems. Currently, on the market Amlodipine 5mg Tablets weigh roughly 120mg, and Amlodipine lOmg Tablets weigh roughly 190mg. The excipient content is 113mg per tablet and 176mg per tablet respectively. Through this invention the excipient content can be brough down to 0,035mg per 5mg tablet and down to 0,070mg per lOmg tablet, making up to 99.96% of the excipient in the current tablets obsolete.
[OH] As the amount of excipient needed is reduced to a minimum, the immediate-release oral pharmaceutical form shrinks, which in turn shrinks the size of the blister and shrinks the size of the entire finished product. Now a previously impossibly small sized blister can be used, and this enables the finished product to have a fraction of the current volume. This in turn allows for much more efficient transportation, lowering the carbon footprint of the product, and only a fraction of the packaging waste is created.
[012] It also reduces the amount of excipient administered to the patient down to the indispensable and drastically alleviates the pressure on the pharmaceutical industry to seek out and process an unnecessarily high quantity of excipient.
[013] As Amlodipine is one of the most prescribed medicines in the world, it is synthesized in many production plants and the finished product is manufactured globally. The facilities and equipment needed to implement production of the given combination is readily available. The following examples of composition and preparation can realistically be realized at any production site intended for tabletting.
Brief Description of the Figures
[014] Figure 1 shows a graph representing exemplary results of the dissolution study in the below examples.
Examples
Example 1 - Example preparation of Amlodipine Tablets
[015] Step 1. All excipients of either Table 1 to 6 (the amounts being scaled according to the desired batch size), are passed through an appropriate screen. For the avoidance of doubt, a screen in this context refers to a sieve. Preferably sieves with a pore size of 250pm - 710pm.
Step 2. All excipients other than any optional lubricant, are first blended for 5 minutes at lOrpm in an appropriate blender.
For the avoidance of doubt, in view of the below tables it is apparent that Amlodipine Besilate is added; it can be added in Step 1 or 2.
Step 3. Any optional lubricant is then added to the blend, and again blended for 3 minutes at lOrpm.
Step 4. The final blend is compressed into tablets.
Step 5. A film coating can be added to the tablets.
Example Compositions
[016] Table 1 - Composition Example 1
[017] Table 2 - Composition Example 2
[018] Table 3 - Composition Example 3
[019] Table 4 - Composition Example 4
[020] Table 5 - Composition Example 5
[021] Table 6 - Composition Example 6
[022] Table 7 - Composition Example 7
[023] Table 8 - Composition Example 8
[024] Table 9 - Composition Example 9
[025] Table 10 - Composition Example 10
[026] Table 11- Composition Example 11
[027] Table 12 - Composition Example 12
[028] Table 13 - Composition Example 13
[029] Table 14 - Composition Example 14
Example 2 - Example Tablet Weights form Different Compositions
[030] Table 15 - Overview of example tablet weights
Example 3 - Analytical Results [031] Table 16 - Disintegration Time & Resistance to Crushing
[032] A dissolution study was conducted on a tablet of Example 3 in 900ml of pH 6.8 buffer at 37°C, USP Apparatus 1 set to lOOrpm. The resultant dissolution curve demonstrates that the tablet rapidly dissolved with complete dissolution within 30 minutes. The results are shown in Table 7 and Fig. 1.
[033] Table 17 - Data of the dissolution study in tabulated form
[034] The suitability of the quality of the immediate -release oral pharmaceutical form made under the invention is met, as it fullfills the requirements of the USP monograph for Amlodipine Tablets.
[035] Certain embodiments of the invention are enumerated in the following:
1. A pharmaceutical composition of an immediate-release oral pharmaceutical form which comprises by weight of 25.1% to 99.5% Amlodipine Besilate, at least 0.5% of disintegrant and from 0% to 74.4% additional pharmaceutical excipient. The preferred amount of Amlodipine Besilate being 30.1% to 81.5% by weight.
2. The pharmaceutical excipient of embodiment 1 consists of, but is not limited to, one or more disintegrant, lubricant, fdler and glidant.
3. The disintegrant of embodiment 1 and embodiment 2 consists of, but is not limited to microcrystalline cellulose, sodium alginate, sodium starch glycolate, croscarmellose sodium, crospovidone and any “super-disintegrants”.
4. The filler of embodiment 2 consists of, but is not limited to cellulose, lactose, mannitol, starch, sucrose, and calcium phosphate.
5. The lubricant of embodiment 2 consists of, but is not limited to calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulphate, and magnesium lauryl sulphate.
6. The glidant of embodiment 2 consists of, but is not limited to silica derivatives, talc, and com starch.
7. The immediate -release oral pharmaceutical form of embodiment 1 entails the tablet form or the fdm -coated tablet form. In the case of film-coated tablet form, the percentage weight refers to the weight of the tablet core.
8. The Amlodipine Besilate of embodiment 1 entails also the other pharmaceutically acceptable salts of Amlodipine.
9. The composition of embodiment 1 is for the dosage range of 2.5mg Amlodipine to 20mg Amlodipine. The preferred dosage range is from of 5mg Amlodipine to lOmg Amlodipine.
[036] Further embodiments of the invention are enumerated in the following:
1. An immediate-release oral pharmaceutical composition comprising by weight of 25.1% to 99.5% Amlodipine Besilate, at least 0.5% of disintegrant and from 0% to 74.4% additional pharmaceutical excipient.
2. Immediate-release oral pharmaceutical composition according to embodiment 1, wherein the amount of Amlodipine Besilate is 30. 1% to 81.5% by weight.
In another embodiment, the amount of Amlodipine Besilate in the immediate-release oral pharmaceutical composition is more than 50% to 99.5% by weight, preferably 75% to 99.5% by weight, more preferably 80% to 99.5% by weight, more preferably 81.5% to 99.5% by weight.
3. The immediate-release oral pharmaceutical composition according to embodiment 1 or 2, wherein the additional pharmaceutical excipient comprises one or more components selected from the group comprising disintegrant, lubricant, fdler and glidant.
4. The immediate-release oral pharmaceutical composition according to any one of embodiments 1 to
3, wherein the disintegrant is one or more disintegrants selected from the group comprising microcrystalline cellulose, sodium croscarmellose, carboxymethyl cellulose, alginic acid, sodium alginate and their derivatives, sodium starch glycolate (such as Glycolys®, Explotab®, Vivastar® P), croscarmellose sodium (such as Ac Di Sol®, Solutab®, Vivasol®), crospovidone (such as Kollidon®, Kollicoat®) and other super-disintegrants, as well as cellulose, lactose, mannitol, starch and sucrose.
Super disintegrants are disintegrants that typically can be used in small concentrations, such as 0.5 to 5% in typical pharmaceutical formulations, while still achieving suitable disintegrant effect. Examples of other super-disintegrants according the present invention are disintegrants, such as L- hydroxy propyl cellulose, Sodium carboxymethyl starch (such as Primogel®), magnesium aluminum silicate (such as Veegum® HV), calcium silicate, cross-linked alginic acid (also known as alginic acid National Formulary (NF), such as Satialgine®), Soy derivatives / polysaccharides (such as Emcosoy®).
5. The immediate-release oral pharmaceutical composition according to any one of embodiment 3 or
4, wherein the filler is one or more fillers selected from the group comprising cellulose, lactose, mannitol, starch, sucrose, and calcium phosphate, calcium carbonate, maltodextrin, sorbitol and dextrin.
It is known to the skilled person that certain excipients used as fillers can also act as disintegrant, such as cellulose, lactose, mannitol, starch and sucrose. In embodiments where one of these is
included as disintegrant, they are not additionally used as fillers, in other words, their inclusion as “disintegrant” or “filler” in the embodiments of the present invention is mutually exclusive. The immediate-release oral pharmaceutical composition according to any one of embodiments 3 to
5, wherein the lubricant is one or more lubricants selected from the group comprising calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulphate, and magnesium lauryl sulphate. The immediate-release oral pharmaceutical composition according to any one of embodiments 3 to
6, wherein the glidant is one or more glidants selected from the group comprising silica derivatives, such as silicone dioxide, talc, and com starch. The immediate-release oral pharmaceutical composition of any one of embodiments 1 to 7, which is in tablet form or in a film-coated tablet form, wherein in said film-coated tablet form the percentage weight refers to the weight of the tablet core. The immediate-release oral pharmaceutical composition of any one of embodiments 1 to 8, wherein Amlodipine Besilate is comprised in a dosage range of 2.5mg to 20mg, preferably 5mg to lOmg. A method of preparing a tablet comprising a composition according to any one of embodiments 1 to 9, the method comprising a) passing comprises by weight of 25.1% to 99.5% Amlodipine Besilate, at least 0.5% of disintegrant and from 0% to 74.4% additional pharmaceutical excipient through a screen, b) blending all excipients other than lubricant, c) optionally adding lubricant to the blend of c), and blend, d) compressing the blend obtained from c) into tablets, and e) optionally adding a film coating to the tablets, wherein Amlodipine Besilate is added either in step a) or b).
Claims
1. An immediate-release oral pharmaceutical composition comprising by weight of 25.1% to 99.5% Amlodipine Besilate, at least 0.5% of disintegrant and from 0% to 74.4% additional pharmaceutical excipient.
2. Immediate-release oral pharmaceutical composition according to claim 1, wherein the amount of Amlodipine Besilate is 30. 1% to 81.5% by weight.
3. The immediate-release oral pharmaceutical composition according to claim 1 or 2, wherein the additional pharmaceutical excipient comprises one or more components selected from the group comprising disintegrant, lubricant, filler and glidant.
4. The immediate-release oral pharmaceutical composition according to any one of claims 1 to 3, wherein the disintegrant is one or more disintegrants selected from the group comprising microcrystalline cellulose, sodium croscarmellose, carboxymethyl cellulose, alginic acid, sodium alginate and their derivatives, sodium starch glycolate (such as Glycolys®, Explotab®, Vivastar® P), croscarmellose sodium (such as Ac Di Sol®, Solutab®, Vivasol®), crospovidone (such as Kollidon®, Kollicoat®) and other super-disintegrants, as well as cellulose, lactose, mannitol, starch and sucrose.
5. The immediate-release oral pharmaceutical composition according to any one of claim 3 or 4, wherein the filler is one or more fillers selected from the group comprising cellulose, lactose, mannitol, starch, sucrose, and calcium phosphate, calcium carbonate, maltodextrin, sorbitol and dextrin.
6. The immediate-release oral pharmaceutical composition according to any one of claims 3 to 5, wherein the lubricant is one or more lubricants selected from the group comprising calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulphate, and magnesium lauryl sulphate.
7. The immediate-release oral pharmaceutical composition according to any one of claims 3 to 6, wherein the glidant is one or more glidants selected from the group comprising silica derivatives, such as silicone dioxide, talc, and com starch.
8. The immediate-release oral pharmaceutical composition of any one of claims 1 to 7, which is in tablet form or in a film-coated tablet form, wherein in said film-coated tablet form the percentage weight refers to the weight of the tablet core.
9. The immediate-release oral pharmaceutical composition of any one of claims 1 to 8, wherein Amlodipine Besilate is comprised in a dosage range of 2.5mg to 20mg, preferably 5mg to lOmg.
10. A method of preparing a tablet comprising a composition according to any one of claims 1 to 9, the method comprising a) passing comprises by weight of 25.1% to 99.5% Amlodipine Besilate, at least 0.5% of disintegrant and from 0% to 74.4% additional pharmaceutical excipient through a screen,
b) blending all excipients other than lubricant, c) optionally adding lubricant to the blend of c), and blend, d) compressing the blend obtained from c) into tablets, and e) optionally adding a fdm coating to the tablets, wherein Amlodipine Besilate is added either in step a) or b).
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| Application Number | Priority Date | Filing Date | Title |
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| DE102022003339.9 | 2022-09-07 | ||
| DE102022003339 | 2022-09-07 |
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| WO2024052498A1 true WO2024052498A1 (en) | 2024-03-14 |
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| PCT/EP2023/074658 WO2024052498A1 (en) | 2022-09-07 | 2023-09-07 | An immediate-release oral pharmaceutical form of amlodipine with increased api content |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004075825A2 (en) | 2003-02-28 | 2004-09-10 | Ranbaxy Laboratories Limited | Dosage forms of amlodipine and processes for their preparation |
| WO2005120502A1 (en) * | 2004-06-10 | 2005-12-22 | Richter Gedeon Vegyészeti Gyár Rt. | New pharmaceutical composition and process for the preparation thereof |
| EP1932528A1 (en) | 2005-09-28 | 2008-06-18 | Teva Pharmaceutical Industries Ltd | Stable composition of amlodipine besylate |
| EP2359815A1 (en) | 2008-09-30 | 2011-08-24 | Egis Gyógyszergyár Nyilvánosan Müködö Részvénytársaság | Compositions comprising amlodipine and bisoprolol |
| CN104739799A (en) | 2013-12-27 | 2015-07-01 | 辰欣药业股份有限公司 | An amlodipine besylate composition used for direct tabletting and a preparing method of tablets of the composition |
| CN105380915A (en) * | 2015-12-14 | 2016-03-09 | 西南药业股份有限公司 | Amlodipine besylate composition, preparation method thereof, and amlodipine besylate tablet |
-
2023
- 2023-09-07 WO PCT/EP2023/074658 patent/WO2024052498A1/en unknown
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004075825A2 (en) | 2003-02-28 | 2004-09-10 | Ranbaxy Laboratories Limited | Dosage forms of amlodipine and processes for their preparation |
| WO2005120502A1 (en) * | 2004-06-10 | 2005-12-22 | Richter Gedeon Vegyészeti Gyár Rt. | New pharmaceutical composition and process for the preparation thereof |
| EP1932528A1 (en) | 2005-09-28 | 2008-06-18 | Teva Pharmaceutical Industries Ltd | Stable composition of amlodipine besylate |
| EP2359815A1 (en) | 2008-09-30 | 2011-08-24 | Egis Gyógyszergyár Nyilvánosan Müködö Részvénytársaság | Compositions comprising amlodipine and bisoprolol |
| CN104739799A (en) | 2013-12-27 | 2015-07-01 | 辰欣药业股份有限公司 | An amlodipine besylate composition used for direct tabletting and a preparing method of tablets of the composition |
| CN105380915A (en) * | 2015-12-14 | 2016-03-09 | 西南药业股份有限公司 | Amlodipine besylate composition, preparation method thereof, and amlodipine besylate tablet |
Non-Patent Citations (2)
| Title |
|---|
| A. ABDOH ET AL.: "Amlodipine Besylate-Excipients Interaction in Solid Dosage Form", PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY, vol. 9, no. 1, 2004, pages 15 - 24, XP008034356, DOI: 10.1081/PDT-120027414 |
| ABDOH A ET AL: "AMLODIPINE BESYLATE-EXCIPIENTS INTERACTION IN SOLID DOSAGE FORM", PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY, NEW YORK, NY, US, vol. 9, no. 1, 1 January 2004 (2004-01-01), pages 15 - 24, XP008034356, ISSN: 1083-7450, DOI: 10.1081/PDT-120027414 * |
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