WO2006059217A1 - Stable solid dosage forms of amlodipine besylate and processes for their preparation - Google Patents
Stable solid dosage forms of amlodipine besylate and processes for their preparation Download PDFInfo
- Publication number
- WO2006059217A1 WO2006059217A1 PCT/IB2005/003632 IB2005003632W WO2006059217A1 WO 2006059217 A1 WO2006059217 A1 WO 2006059217A1 IB 2005003632 W IB2005003632 W IB 2005003632W WO 2006059217 A1 WO2006059217 A1 WO 2006059217A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dosage form
- microcrystalline cellulose
- amlodipine
- months
- concentration
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The technical field of the invention relates to stable solid dosage forms of amlodipine besylate and processes for their preparation. In particular, the solid dosage forms have reduced levels of 3-ethyl methyl [(2-aminoethoxy) methyl] (2-chlorophenyl) methylpyridine-3,5 dicarboxylate ('impurity D') and total impurities when free of dicalcium phosphate.
Description
STABLE SOLID DOSAGE FORMS OF AMLODIPINE BESYLATE AND PROCESSES FOR THEIR PREPARATION THEREOF
Technical Field of the Invention
The technical field of the invention relates to stable solid dosage forms of amlodipine besylate and processes for their preparation. In particular, the solid dosage forms have reduced levels of 3 -ethyl methyl [(2-aminoethoxy) methyl] (2-chlorophenyl) methylpyridine-3,5 dicarboxylate ("impurity D") and total impurities when free of dicalcium phosphate.
Background of the Invention Amlodipine is a long acting calcium channel blocker marketed by Pfizer as amlodipine besylate under the trade name Norvasc®. It is available as oral tablets in strengths of 2.5 mg, 5 mg, and 10 mg, and is indicated for the treatment of hypertension, chronic stable angina and vasospastic angina. The ina*§tive ingredients in the Norvasc® tablets include microcrystalline cellulose, dibasic calcium pnosphate anhydrous, sodium starch glycolate, and magnesium stearate.
The preparation of amlodipine base is described in U.S. Patent No. 4,572,909. Further, U.S. Patent No. 4,879,303 discloses that free base compositions that include microcrystalline cellulose and dicalcium phosphate as diluents excessively stick to the tablet punches during processing and are not suitable in making solid dosage forms for peroral administration. The patent teaches that the amlodipine besylate salt can be used to make solid dosage forms and those solid dosage forms can include microcrystalline cellulose and dibasic calcium phosphate. The microcrystalline cellulose is present at a concentration of between about 62% (w/w) and about 76% (w/w) of the total dosage form composition. U.S. Patent Application No. 2003/0022922 discloses that to reduce the stickiness of the tablet, amlodipine free base should be incorporated into the tablet composition in the form of particulates having an average particle size of 150 - 350 μm; and a preferred excipient is a combination of calcium phosphate and microcrystalline cellulose. A capsule dosage form also is disclosed in this patent application as containing amlodipine base,
microcrystalline cellulose, predried potato starch, and magnesium stearate. The microcrystalline cellulose makes up approximately 74% (w/w) of the capsule dosage form.
Amlodipine is highly hygroscopic and absorbs moisture, which leads to degradation. One of the major routes of degradation is via the catalytic oxidative process, which is pH dependent. The major related substances produced are 13 -ethyl 5 -methyl (4RS) 4-(2chlorophenyl) methyl [[2-[[2-(methylcarbamoyl) benzoyl]amino]ethoxy]methyl]-l,4dihydropyridine-3,5 dicarboxylate ("Impurity B"); 13- ethyl methyl [(2-aminoethoxy)methyl] (2-chlorophenyl) methylpyridine-3,5 dicarboxylatel ("Impurity D"); and 13-ethyl 5-methyl (4RS) 4-(2-chlorophenyl)-2[[2-(l,3-dioxo-dihydro- 2H-isoindolyl) ethoxyjmethyl] methyl- l,4-dihydropyridine-3,5 dicarboxylate ("Impurity A"), along with some unknown impurities. Being an unstable compound, amlodipine requires well-directed stability approaches to formulate pharmaceutical compositions with reasonable stability.
Summary of the Invention hi one general aspect there is provided a stable solid dosage form that includes amlodipine besylate, microcrystalline cellulose, is substantially free of dicalcium phosphate, and has less than about 0.5% concentration (w/w) of Impurity D after three months at 40°C and 75%RH.
Embodiments of the dosage form may include one or more of the following features. For example, the dosage form may include more than about 80% (w/w) microcrystalline cellulose. The dosage form may include more than 60% (w/w) microcrystalline cellulose. The ratio of microcrystalline cellulose to amlodipine base may be at least 24: 1. The dosage form may include more than 20% (w/w) mannitol.
The dosage form may include less than about 0.75% concentration (w/w) of impurity D after three months at 400C and 75%RH. The dosage form may include less than about 2% concentration (w/w) of total impurities after three months at 40°C and 75%RH.
The dosage form may further include one or more pharmaceutically inert excipients. The one or more pharmaceutically inert excipients may be one or more of
diluents, binders, desiccants, disintegrants, coloring agents, flavoring agents, stabilizers, surfactants, lubricants/glidants, plasticizers and preservatives. The desiccant may be colloidal silicon dioxide. The dosage form may further include one or more of mannitol, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate. The dosage form is a tablet or a capsule.
In another general aspect there is provided a process for the preparation of a stable solid dosage form of amlodipine besylate substantially free of dicalcium phosphate. The process includes the steps of: (a) blending amlodipine besylate, microcrystalline cellulose and one or more pharmaceutically inert excipients to form a blend; (b) optionally granulating the blend; (c) optionally blending the granules with extragranular excipients; (d) lubricating the blend of step a) or granules of step b) or c); and (e) compressing or filling into a suitable size solid dosage form.
Embodiments may include one or more of the following features. For example, the blend may further include mannitol. The granulation may be carried out by wet granulation or dry granulation. The wet granulation may be carried out with a granulating fluid or solution/dispersion of one or more binders. The dry granulation may be carried out by roller compactor or slugging.
In another general aspect there is provided a method for the treatment of hypertension, chronic stable angina, or vasospastic angina in a mammal in need thereof. The method includes administering a stable solid dosage form comprising amlodipine besylate, microcrystalline cellulose, being substantially free of dicalcium phosphate, and having less than about 0.5% concentration (w/w) of Impurity D after three months at 40DC and 75%R.
Embodiments of the method may include one or more of the following features or those described above. For example, the dosage form may include less than about 0.75% concentration (w/w) of impurity D after three months at 40°C and 75%RH. The dosage form may include more than 60% (w/w) microcrystalline cellulose.
The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the invention will be apparent from the description and the claims.
Detailed Description of the Invention The prior art discloses the use of dicalcium phosphate as one of the preferred excipients for amlodipine formulations. The inventors have now discovered that the presence of dicalcium phosphate in the amlodipine formulation triggers the degradation of amlodipine, which is more pronounced at a pH below 6. Hence, removal of dicalcium phosphate from the composition increases the stability of the amlodipine. hi our attempts to stabilize amlodipine in solid dosage forms we discovered that stability may be improved by replacing dicalcium phosphate with microcrystalline cellulose and mannitol. This is evident from the stability data generated over a period of 3 months at 40°C and 75% relative humidity on the basis of percentage concentrations of related substances. This stability data is provided below in Table 2, in terms of the percent concentrations of related substances (w/w).
The inventors also have developed a stable solid dosage form that includes an effective amount of amlodipine besylate, microcrystalline cellulose and mannitol, but is substantially free of dicalcium phosphate, and has less than about 0.75% concentration (w/w) of Impurity D after three months at 40°C and 75% relative humidity and less than about 0.3% concentration (w/w) of Impurity D after one month at 40°C and 75% relative humidity. The stable solid dosage form has less than about 2% concentration (w/w) of total impurities after three months at 4O0C and 75% relative humidity and less than about 1% concentration (w/w) of total impurities after one month at 40°C and 75% relative humidity. The term "stable" as used herein refers to chemical stability of amlodipine in solid dosage forms and indicates presence of less than 2% w/w of related substances when stored at 4O0C and 75 % relative humidity for 1 month. The stability is measured using HPLC to measure the presence of related substances.
Amlodipine as used herein is the free base or besylate salt and can be of any form including one or more of crystalline form I, crystalline form II, amorphous form, and mixtures thereof.
The term "dicalcium phosphate" as used herein includes one or more of anhydrous calcium phosphate, anhydrous dicalcium phosphate, dibasic calcium phosphate as well as hydrates and solvates thereof. Dicalcium phosphate is normally used as a diluent. The term "substantially free" as used herein refers to the use of dicalcium phosphate in a concentration less than that used as a diluent.
Microcrystalline cellulose is a white, odorless, tasteless, free flowing powder, and is widely accepted in the pharmaceutical industry as a universal diluent. It is purified, partially depolymerized alpha cellulose, derived from purified specialty grades of wood pulp. There are various grades which differ in bulk density, particle size, and moisture content. Some of the commercially available grades of microcrystalline cellulose are Avicel®, Vivapur® and Tabulos®. When used without mannitol, the amount of microcrystalline cellulose is increased relative to the prior art, more particularly, greater than 90% (w/w). When used with mannitol, the amount of microcrystalline cellulose is greater than about 60% (w/w).
Mannitol is a naturally occurring sugar alcohol having a cool taste and 50% sweetness compared to sucrose. It is non-hygroscopic, chemically inert and does not undergo the Maillard reaction, and therefore does not discolor in the presence of free amines. Mannitol is available as a powder and free flowing granules, and is used widely in pharmaceutical preparations. The granular form is particularly useful in the direct compression technique of preparing tablets. Some of the commercial grades are Mannogem®, Pearlitol® and Partech M®. The concentration of mannitol may vary from about 5% to about 80%, in particular it may vary from 20% to 60% by weight of the total uncoated tablet weight.
The term "solid dosage form" as used herein includes conventionally used dosage forms such as tablets, capsules and the like.
The term "pharmaceutically inert excipient" as used herein includes one or more of diluents, binders, desiccants, disintegrants, coloring agents, flavoring agents, stabilizers,
surfactants, lubricants/glidants, plasticizers and preservatives for pharmaceutical compositions. The excipients are selected based on the desired physical aspects of the final tablets; e.g., obtaining a tablet with desired hardness and friability, being rapidly dispersible and easily swallowed, etc. Further, the inert excipients may be selected so as to provide slow and/or controlled release of the amlodipine from the tablets.
Suitable disintegrants may include one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and mixtures thereof.
Suitable binders may include one or more of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and mixtures thereof.
Suitable diluents may include one or more of cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and mixtures thereof.
Suitable lubricants and glidants may include one or more of magnesium stearate, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof.
Suitable desiccants may include one or both of colloidal silicon dioxide, silicon dioxide, and mixtures thereof.
Suitable surfactants may include both non-ionic and ionic (Cationic, Anionic and Zwitterionic) surfactants suitable for use in pharmaceutical compositions. These may include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate and polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides, for example glyceryl ricinoleate;
sterol and sterol derivatives, for example sitosterol; sorbitan fatty acid esters and their derivatives, for example polyethylene glycol - 20 sorbitan monooleate and sorbitan monolaurate; polyethylene glycol 8 alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether and polyethylene glycol 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl filmarate, propylene glycol alginate, octyl sulfosuccinate disodium and palmitoyl carnitine; and mixtures thereof.
Suitable plasticizers may include one or more of polyethylene glycol, triethyl citrate, triacetin, diethyl plithalate, dibutyl sebacate and mixtures thereof.
Suitable stabilizers may include antioxidants, buffers, alkalizers, chelating agents and the like.
Suitable coloring agents include any FDA approved colors for oral use. hi one embodiment, stable amlodipine besylate tablets are prepared by a process that includes the steps of: (a) blending an effective amount of amlodipine besylate, microcrystalline cellulose, one or more disintegrants and, optionally, mannitol; (b) mixing the blend with one or more lubricants/glidants; (c) directly compressing the blend in a suitable tableting machine; and, optionally, (d) coating with one or more film forming polymers. hi another embodiment, stable amlodipine besylate tablets are prepared by a process that includes the steps of (a) blending an effective amount of amlodipine besylate, microcrystalline cellulose, one or more disintegrants and, optionally, mannitol; (b) granulating the blend; (c) mixing the granules with lubricant/glidant; (d) compressing the blend in a suitable tabletting machine; and, optionally, (e) coating with one or more film forming polymers, if desired.
In yet another embodiment, stable amlodipine besylate capsules are prepared by a process that includes the steps of: (a) blending an effective amount of amlodipine besylate, microcrystalline cellulose, and, optionally, mannitol; (b) optionally granulating the blend; (c) mixing the granules/blend with one or more lubricants/glidants; and (d) filling the blend into suitable sized capsules.
Granulation may be carried out by wet granulation or dry granulation techniques. Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/suspension using any conventional coating technique known in the art, such as spray coating in a conventional coating pan, fluidized bed processor or dip coating.
The following examples illustrate the invention but should not be construed as limiting the scope of the invention.
EXAMPLES 1-3
Amlodipine tablets were prepared according to the composition listed in Table 1 using the following steps.
1. Appropriate amounts of amlodipine and all other ingredients were separately passed through suitable sized sieves.
2. Amlodipine, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and dicalcium phosphate (only for Example 1) or mannitol (only for Example 3) were mixed together to form a uniform blend.
3. The blend of step 2 was lubricated by mixing with magnesium stearate.
4. The compression machine was adjusted to a fill weight of 400 mg.
5. The final lubricated blend of step 3 was directly compressed using suitable size punches to obtain compressed tablets. Table 1. Composition of amlodipine tablets (Examples 1- 3)
These results indicate the clear role that dicalcium phosphate plays in the degradative reactions of amlodipine and the advantageous use of microcrystalline cellulose and mannitol in stabilization of amlodipine.
Table 2. Results of stability evaluation of amlodipine tablets (Examples 1 - 3) as percentage (w/w) related substances, over a period of 3 months at 4O0C and 75% relative humidity.
* Month
As can be seen from Table 2, Example 2 has less than about 0.5 % concentration (w/w) of Impurity D after three months at 4O0C and 75% relative humidity and less than about 0.2% concentration (w/w) of Impurity D after one month at 4O0C and 75% relative humidity. Example 2 also has less than about 2% concentration (w/w) of total impurities after three months at 400C and 75% relative humidity and less than about 0.6%
concentration (w/w) of total impurities after one month at 40°C and 75% relative humidity. Example 3 has less than about 0.75 % concentration (w/w) of Impurity D after three months at 40°C and 75% relative humidity and less than about 0.3% concentration (w/w) of Impurity D after one month at 4O0C and 75% relative humidity. Example 3 also has less than about 2% concentration (w/w) of total impurities after three months at 40°C and 75% relative humidity and less than about 1% concentration (w/w) of total impurities after one month at 40°C and 75% relative humidity.
Based on the results presented in Table 2, there appears to be a correlation between the formation of impurities and the amount of microcrystalline cellulose in the formulation, and the presence or absence of dicalcium phosphate in the formulation. The formulation of Example 1 had a ratio of microcrystalline cellulose to amlodipine of 25.4:1 with the presence of dicalcium phosphate in the tablet. This formulation, however, had significantly higher levels of impurity D and total impurities initially, after one month, and after three months. In contrast, the formulation of Example 2 had a ratio of microcrystalline cellulose to amlodipine of 37: 1 without the presence of dicalcium phosphate in the tablet. Relative to the formulation of Example 1, this formulation had significantly lower levels of impurity D and total impurities initially, after one month, and after three months. Similarly, the formulation of Example 3 had a ratio of microcrystalline cellulose to amlodipine of 24.4:1 without the presence of dicalcium phosphate in the tablet. Relative to the formulation of Example 1, this formulation had significantly lower levels of impurity D and total impurities initially, after one month, and after three months. Thus, the data in Table 2 indicates that the stability of dosage forms of amlodipine base can be improved based on the amount and ratio of microcrystalline cellulose to amlodipine base in the formulation and the presence or absence of dicalcium phosphate in the formulation.
EXAMPLES 4-6
Similarly, using the disclosure contained herein, dosage forms of amlodipine can be made that are one or more of bioequivalent to the reference listed drug product or have suitable in vitro dissolution profiles. For example, the following dosage forms have been made and tested.
Table 3. Compositions of amlodipine tablets (Examples 4-6)
*This quantity is calculated based on 100% w/w assay on anhydrous base and no water content.
Similarly, although a direct compression method has been used in preparing tablets of Examples 1 through 3, other conventional methods can also be used. For example, appropriately sieved amlodipine may be blended with other ingredients and a part of magnesium stearate, and compacted in a roller compacter to produce granules. The granules may then be sieved and lubricated with the remaining amount of magnesium stearate and compressed into suitable sized tablets. Alternatively, appropriately sieved amlodipine and other ingredients (except magnesium stearate) may be blended into a wet mass using a granulating fluid. Suitable sized granules can then be prepared in granulator. The granules may be dried, lubricated by mixing with magnesium stearate, and compressed into suitable sized tablets.
EXAMPLES 7-8 Similarly, although amlodipine base has been used in preparing the tablets of
Examples 1 through 3, tablets may be prepared using compositions similar to those described for amlodipine base for pharmaceutically acceptable salts of amlodipine, such as amlodipine besylate and amlodipine mesylate, as well as any and all pharmaceutically acceptable salts of amlodipine that are incompatible with dicalcium phosphate. The following examples in Table 4 describe tablets comprising amlodipine besylate as the active ingredient.
Table 4. Compositions of amlodipine besylate tablets (Examples 7-8)
Amlodipine besylate tablets according to the composition listed in Table 4, were prepared by using the following steps.
1. Appropriate amounts of amlodipine besylate and all other ingredients were separately passed through suitable sized sieves.
2. Amlodipine besylate, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and mannitol were mixed together to form a uniform blend.
3. The blend of step 2 was lubricated by mixing with magnesium stearate.
4. The compression machine was adjusted to a fill weight of 400 mg.
5. The final lubricated blend of step 3 was directly compressed using suitable size punches to obtain compressed tablets.
The tablets obtained above were subjected to stability evaluation at 400C and 75% relative humidity. Initially, after one month, and after the three months of aging, the tablets were evaluated for the presence of impurities using HPLC. The results of this measurement are listed as percentage (w/w) related substances in Table 5.
Table 5. Results of stability evaluation of amlodipine besylate tablets (Examples 7-8) as percentage (w/w) related substances, at 4O0C and 75% relative humidity.
• Month, ** Not Detected
While several particular formulations have been described above, it will be apparent that various modifications and combinations of the formulations detailed in the text can be made without departing from the spirit and scope of the invention. For example, although the tablet dosage form has been prepared, other conventional solid dosage forms, such as capsules, can also be prepared using compositions similar to those disclosed herein.
Claims
We Claim: 1. A stable solid dosage form comprising amlodipine besylate, microcrystalline cellulose, being substantially free of dicalcium phosphate, and having less than about 0.5% concentration (w/w) of Impurity D after three months at 40°C and 75%RH. 2. The dosage form according to claim 1, wherein the dosage form comprises more than about 80% (w/w) microcrystalline cellulose. 3. The dosage form according to claim 1, wherein the dosage form comprises more than 60% (w/w) microcrystalline cellulose. 4. The dosage form according to claim 1, comprising less than about 0.75 % concentration (w/w) of impurity D after three months at 40°C and 75%RH. 5. The dosage form according to claim 1, wherein the dosage form comprises more than 20% (w/w) mannitol. 6. The dosage form according to claim 1, wherein the dosage form comprises less than about 2% concentration (w/w) of total impurities after three months at 4O0C and 75%RH. 7. The dosage form according to claim 1, wherein the solid dosage form further comprises one or more pharmaceutically inert excipients. 8. The dosage form according to claim 7, wherein the one or more pharmaceutically inert excipients comprise diluents, binders, desiccants, disintegrants, coloring agents, flavoring agents, stabilizers, surfactants, lubricants/glidants, plasticizers and preservatives. 9. The dosage form according to claim 8, wherein the desiccant comprises colloidal silicon dioxide. 10. The dosage form according to claim 1, wherein the ratio of microcrystalline cellulose to amlodipine base is at least 24: 1. 11. The dosage form according to claim 10, further comprising mannitol, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate. 12. The dosage form according to claim 1, wherein the dosage form is a tablet or a capsule.
13. A process for preparation of a stable solid dosage form of amlodipine besylate substantially free of dicalcium phosphate, the process comprising the steps of: a) blending amlodipine besylate, microcrystalline cellulose and one or more pharmaceutically inert excipients to form a blend; b) optionally granulating the blend; c) optionally blending the granules with extragranular excipients; d) lubricating the blend of step a) or granules of step b) or c); and e) compressing or filling into a suitable size solid dosage form. 14. The process according to claim 13, wherein the blend further comprises mannitol. 15. The process according to claim 13, wherein the granulation is carried out by wet granulation or dry granulation. 16. The process according to claim 15, wherein wet granulation is carried out with a granulating fluid or solution/dispersion of one or more binders. 17. The process according to claim 15, wherein dry granulation is carried out by roller compactor or slugging. 18. A method for the treatment of hypertension, chronic stable angina, or vasospastic angina in a mammal in need thereof, the method comprising administering a stable solid dosage form comprising amlodipine besylate, microcrystalline cellulose, being substantially free of dicalcium phosphate, and having less than about 0.5% concentration (w/w) of Impurity D after three months at 4O0C and 75%R. 19. The method according to claim 18, wherein the dosage form comprises less than about 0.75 % concentration (w/w) of impurity D after three months at 40°C and 75%RH. 20. The method according to claim 18, wherein the dosage form comprises more than 60% (w/w) microcrystalline cellulose.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2403DE2004 | 2004-12-01 | ||
| IN2403/DEL/2004 | 2004-12-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006059217A1 true WO2006059217A1 (en) | 2006-06-08 |
Family
ID=36000999
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2005/003632 WO2006059217A1 (en) | 2004-12-01 | 2005-12-01 | Stable solid dosage forms of amlodipine besylate and processes for their preparation |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2006059217A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008032107A1 (en) * | 2006-09-15 | 2008-03-20 | Daiichi Sankyo Company Limited | Solid dosage form of olmesartan medoxomil and amlodipine |
| EP1978956A1 (en) * | 2005-12-27 | 2008-10-15 | Hanmi Pharm. Co., Ltd. | Complex formulation comprising amlodipine camsylate and simvastatin and method for preparation thereof |
| WO2010033954A2 (en) * | 2008-09-22 | 2010-03-25 | Novartis Ag | Galenical formulations of organic compounds |
| GB2471970A (en) * | 2006-09-15 | 2011-01-19 | Daiichi Sankyo Co Ltd | Composition comprising olmesartan medoxomil, amlodipine and hydrochlorothiazide |
| AT14769U1 (en) * | 2008-09-30 | 2016-05-15 | Egis Gyogyszergyar Nyilvánosan Müködö Részvénytársaság | Stable pharmaceutical combination preparation |
| WO2018067959A1 (en) * | 2016-10-07 | 2018-04-12 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| US10350171B2 (en) | 2017-07-06 | 2019-07-16 | Dexcel Ltd. | Celecoxib and amlodipine formulation and method of making the same |
| US10799453B2 (en) | 2018-04-11 | 2020-10-13 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| CN113440490A (en) * | 2021-07-07 | 2021-09-28 | 海南锦瑞制药有限公司 | Levamlodipine besylate tablet and preparation method thereof |
| KR20230000506A (en) | 2021-06-24 | 2023-01-03 | 주식회사 종근당 | Pharmaceutical combination preparation comprising candesartan, amlodipine and atorvastatin |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4879303A (en) * | 1986-04-04 | 1989-11-07 | Pfizer Inc. | Pharmaceutically acceptable salts |
| WO1999018957A1 (en) * | 1998-03-26 | 1999-04-22 | Reddy-Cheminor, Inc. | Stable pharmaceutical composition containing amlodipine besylate and atenolol |
| WO2003011283A1 (en) * | 2001-07-31 | 2003-02-13 | Warner-Lambert Company Llc | Pharmaceutical compositions of amlodipine and atorvastatin |
| WO2003043635A1 (en) * | 2001-11-21 | 2003-05-30 | Synthon B.V. | Amlodipine salt forms and processes for preparing them |
| WO2003051364A1 (en) * | 2001-12-17 | 2003-06-26 | EGIS Gyógyszergyár Rt. | Amlopidine bezylate tablets with improved stability |
| WO2004075825A2 (en) * | 2003-02-28 | 2004-09-10 | Ranbaxy Laboratories Limited | Dosage forms of amlodipine and processes for their preparation |
-
2005
- 2005-12-01 WO PCT/IB2005/003632 patent/WO2006059217A1/en active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4879303A (en) * | 1986-04-04 | 1989-11-07 | Pfizer Inc. | Pharmaceutically acceptable salts |
| WO1999018957A1 (en) * | 1998-03-26 | 1999-04-22 | Reddy-Cheminor, Inc. | Stable pharmaceutical composition containing amlodipine besylate and atenolol |
| WO2003011283A1 (en) * | 2001-07-31 | 2003-02-13 | Warner-Lambert Company Llc | Pharmaceutical compositions of amlodipine and atorvastatin |
| WO2003043635A1 (en) * | 2001-11-21 | 2003-05-30 | Synthon B.V. | Amlodipine salt forms and processes for preparing them |
| WO2003051364A1 (en) * | 2001-12-17 | 2003-06-26 | EGIS Gyógyszergyár Rt. | Amlopidine bezylate tablets with improved stability |
| WO2004075825A2 (en) * | 2003-02-28 | 2004-09-10 | Ranbaxy Laboratories Limited | Dosage forms of amlodipine and processes for their preparation |
Non-Patent Citations (1)
| Title |
|---|
| ABDOH A ET AL: "AMLODIPINE BESYLATE-EXCIPIENTS INTERACTION IN SOLID DOSAGE FORM", PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY, NEW YORK, NY, US, vol. 9, no. 1, 2004, pages 15 - 24, XP008034356, ISSN: 1083-7450 * |
Cited By (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1978956A1 (en) * | 2005-12-27 | 2008-10-15 | Hanmi Pharm. Co., Ltd. | Complex formulation comprising amlodipine camsylate and simvastatin and method for preparation thereof |
| EP1978956A4 (en) * | 2005-12-27 | 2009-08-19 | Hanmi Pharm Ind Co Ltd | Complex formulation comprising amlodipine camsylate and simvastatin and method for preparation thereof |
| GB2454620B (en) * | 2006-09-15 | 2011-08-17 | Daiichi Sankyo Co Ltd | Solid dosage form of olmesartan medoxomil and amlodipine |
| GB2454620A (en) * | 2006-09-15 | 2009-05-13 | Daiichi Sankyo Co Ltd | Solid dosage form of olmesartan medoxomil and amlodipine |
| DE212007000063U1 (en) | 2006-09-15 | 2009-05-14 | Daiichi Sankyo Co., Ltd. | Solid dosage form of olmesartan medoxomil and amlodipine |
| WO2008032107A1 (en) * | 2006-09-15 | 2008-03-20 | Daiichi Sankyo Company Limited | Solid dosage form of olmesartan medoxomil and amlodipine |
| TWI399223B (en) * | 2006-09-15 | 2013-06-21 | Daiichi Sankyo Co Ltd | Solid dosage form of olmesartan medoxomil and amlodipine |
| AU2007297333B2 (en) * | 2006-09-15 | 2010-10-28 | Daiichi Sankyo Company, Limited | Solid dosage form of olmesartan medoxomil and amlodipine |
| JP2011500505A (en) * | 2006-09-15 | 2011-01-06 | 第一三共株式会社 | Solid formulation of olmesartan medoxomil and amlodipine |
| GB2471970A (en) * | 2006-09-15 | 2011-01-19 | Daiichi Sankyo Co Ltd | Composition comprising olmesartan medoxomil, amlodipine and hydrochlorothiazide |
| JP2015091830A (en) * | 2008-09-22 | 2015-05-14 | ノバルティス アーゲー | Galenical formulations of organic compounds |
| WO2010033954A3 (en) * | 2008-09-22 | 2010-10-21 | Novartis Ag | Fixed dose combination in form of a bilayered or monolayered tablet of aliskiren and amlodipine |
| US8613949B2 (en) | 2008-09-22 | 2013-12-24 | Novartis Ag | Galenical formulations of organic compounds |
| WO2010033954A2 (en) * | 2008-09-22 | 2010-03-25 | Novartis Ag | Galenical formulations of organic compounds |
| JP2012503020A (en) * | 2008-09-22 | 2012-02-02 | ノバルティス アーゲー | Organic galenic formulation |
| AT14769U1 (en) * | 2008-09-30 | 2016-05-15 | Egis Gyogyszergyar Nyilvánosan Müködö Részvénytársaság | Stable pharmaceutical combination preparation |
| US11364230B2 (en) | 2016-10-07 | 2022-06-21 | Azurity Pharmaceuticals, Inc. | Amlodipine formulations |
| WO2018067959A1 (en) * | 2016-10-07 | 2018-04-12 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| US10695329B2 (en) | 2016-10-07 | 2020-06-30 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| US10894039B2 (en) | 2016-10-07 | 2021-01-19 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| US10952998B2 (en) | 2016-10-07 | 2021-03-23 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| US10959991B2 (en) | 2016-10-07 | 2021-03-30 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| US10350171B2 (en) | 2017-07-06 | 2019-07-16 | Dexcel Ltd. | Celecoxib and amlodipine formulation and method of making the same |
| US10799453B2 (en) | 2018-04-11 | 2020-10-13 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| US11471409B2 (en) | 2018-04-11 | 2022-10-18 | Azurity Pharmaceuticals, Inc. | Amlodipine formulations |
| US11484498B2 (en) | 2018-04-11 | 2022-11-01 | Azurity Pharmaceuticals, Inc. | Amlodipine formulations |
| US11701326B2 (en) | 2018-04-11 | 2023-07-18 | Azurity Pharmaceuticals, Inc. | Amlodipine formulations |
| US11918685B2 (en) | 2018-04-11 | 2024-03-05 | Azurity Pharmaceuticals, Inc. | Amlodipine formulations |
| KR20230000506A (en) | 2021-06-24 | 2023-01-03 | 주식회사 종근당 | Pharmaceutical combination preparation comprising candesartan, amlodipine and atorvastatin |
| CN113440490A (en) * | 2021-07-07 | 2021-09-28 | 海南锦瑞制药有限公司 | Levamlodipine besylate tablet and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20080305158A1 (en) | Methods For the Preparation of Stable Pharmaceutical Solid Dosage Forms of Atorvastatin and Amlodipine | |
| WO2006059217A1 (en) | Stable solid dosage forms of amlodipine besylate and processes for their preparation | |
| RU2401125C2 (en) | Method of antidementia drug stabilisation | |
| JP4509118B2 (en) | PHARMACEUTICAL COMPOSITION AND METHOD FOR PRODUCING THE SAME, AND METHOD FOR STABILIZING DIHYDROPYRIDINE COMPOUNDS | |
| EP3067043B1 (en) | Pharmaceutical compositions based on superstructures of angiotensin receptor antagonist/blocker (arb) and neutral endopeptidase (nep) inhibitor | |
| US20080268049A1 (en) | Stable Solid Dosage Forms of Amlodipine and Benazepril | |
| AU2008280106B9 (en) | Improved pharmaceutical composition containing dihydropyridine calcium channel antagonist and method for the preparation thereof | |
| JP5763063B2 (en) | Solid pharmaceutical fixed dose compositions comprising irbesartan and amlodipine, their preparation and their therapeutic use | |
| US20040037880A1 (en) | Extended release formulation of divalproex sodium | |
| US20060270715A1 (en) | Dosage forms of amlodipine and processes for their preparation | |
| EA030704B1 (en) | Pharmaceutical composition containing candesartan cilexetil and amlodipine | |
| JP6737060B2 (en) | Method for producing pharmaceutical composition containing irbesartan | |
| EP3219309A1 (en) | Fixed dosed pharmaceutical composition comprising amlodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension | |
| MX2012009689A (en) | Solid pharmaceutical formulations of ramipril and amlodipine besylate, and their preparation. | |
| HU200924B (en) | Process for producing pharmaceutical compositions comprising terfenadine | |
| WO2003032954A1 (en) | Stabilized pharmaceutical formulations containing amlodipine maleate | |
| CA2450001A1 (en) | Stable pharmaceutical compositions containing pravastatin | |
| US20040001886A1 (en) | Stabilized pharmaceutical formulations containing amlodipine maleate | |
| EP2471520B1 (en) | Pharmaceutical compositions of levetiracetam | |
| JP7101464B2 (en) | A method for improving the quality of azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof, and azilsartan or a salt thereof and amlodipine or a salt-containing tablet thereof and a method for producing the same. | |
| WO2009110010A2 (en) | Stable oral dosage form | |
| US20030180354A1 (en) | Amlodipine maleate formulations | |
| WO2008152598A1 (en) | Stabilized pharmaceutical compositions comprising atorvastatin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 05804703 Country of ref document: EP Kind code of ref document: A1 |