KR20030070594A - Pharmaceutical compositions comprising amlodipine maleate - Google Patents

Abstract

The present invention provides amlodipine maleate pharmaceutical compositions with good stability when formulated at a pH in the range of 5.5-7 when measured as a 20% by weight aqueous slurry. In addition, stability can be obtained by preparing the pharmaceutical composition from amlodipine maleate indenters having an average particle size of at least 20 microns, preferably at least 100 microns.

Description

Pharmaceutical composition containing amlodipine maleate {PHARMACEUTICAL COMPOSITIONS COMPRISING AMLODIPINE MALEATE}

Calcium channel blockers are useful for treating various heart conditions, mainly angina and high blood pressure. EP 089 167 and the corresponding US Pat. No. 4,572,909 disclose a class of substituted dihydropyridine derivatives as useful calcium channel blockers. In these patents one of the most preferred compounds is 2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl- It was confirmed to be 1,4-dihydropyridine. This compound, commonly known as amlodipine, has the formula:

Examples 8, 11, 12 and 22 of EP 089 167 show the synthesis of amlodipine in maleate form. Although various acid addition salts are taught to be suitable, maleate has been found to be the most preferred acid addition salt.

Subsequently, EP 244 944 and the corresponding US Pat. No. 4,879,303 relate to the besylate (or benzene sulfonate) salts of amlodipine. Besylate salts offer certain advantages over known salts, including good preparation properties. Indeed, amlodipine besylate, but not amlodipine maleate, was developed by Pitcher as a commercial prescription drug and is marketed in the United States under the trade name NORVASC.

A review of the valid portion of the NORVASC (Amlodipine Besylate) New Drug Application (NDA) filed by the company to the US Food and Drug Administration revealed that it was converted from the original amlodipine maleate to amlodipine besylate during development (under the Freedom of Information Act). See, “NDA's Review” on NDA # 19-787, filed October 10, 1990, available from FDA. The reasons for the conversion are obvious tableting and stability issues. However, the exact stability and tableting issues / issues / causes are not publicly disclosed in the information available from FDA. Interestingly, clinical studies of NDA include the use of maleate salt forms and besylate salt forms, both salt forms being therapeutically equivalent (bioequivalent). In this study, however, amlodipine maleate has always been used in capsule or solution formulations, and never in tablet formulations.

The present invention relates to a pharmaceutical composition comprising amlodipine maleate and a process for preparing the same.

The present invention relates to the discovery of stable amlodipine maleate pharmaceutical compositions. A first aspect of the invention relates to a pharmaceutical composition comprising an effective amount of amlodipine maleate and one or more pharmaceutically acceptable excipients, wherein the composition has a pH in the range of 5.5 to 7.0. The composition is preferably in a solid dosage form such as a tablet or capsule. The invention also relates to methods of making such compositions, as well as to the use of such compositions in the treatment or prevention of angina or hypertension.

Another aspect of the invention relates to a method comprising mixing solid particles of amlodipine maleate having an average particle size of at least 20 microns with at least one pharmaceutically acceptable excipient to form a mixture. The mixture preferably has a pH of 5.5 to 7.0. The mixture may be compressed into tablets or filled into capsules to form a solid dosage form.

Stability is an important aspect of pharmaceutical compositions. The present invention is based on the finding that the prior art stability problems associated with amlodipine maleate can be overcome primarily by adjusting the pH of the composition within the range of about 5.5 to 7.0, preferably about 6.0 to 7.0. In particular, the formation of the following degradation products, referred to herein as amlodipine aspartate, is minimized or prevented within this pH range:

Amlodipine Aspartate

Amlodipine aspartate is formed by the Michael addition reaction between amlodipine and maleic acid. Since amlodipine and maleic acid are in intimate contact with each other in the amlodipine maleate salt, the chance of addition reactions occurring increases over time, resulting in stability problems. By adjusting the pH, the addition is significantly slowed or completely prevented. Thus, it was found that pH levels above 7.0 tend to encourage the degradation of amlodipine maleate to amlodipine aspartate. Below pH of about 5.5, other degradation reactions tend to be encouraged, including pyridine analogs of amlodipine having the structure:

"Amlo-pyridine"

The pH of the stabilizing composition of the present invention is preferably in the range of about 6.0 to 7.0, more typically in the range of about 6.1 or 6.2 to 6.8. In the case of a solid composition, the pH is determined by forming a slurry of the material with water (demineralized water) and measuring the pH of the slurry, as will be appreciated by those skilled in the art regarding the pH of the solid composition. The concentration of the composition in the slurry is 20% by weight. pH is measured by any standard technique.

The pharmaceutical composition of the present invention comprises a pharmaceutically effective amount of amlodipine maleate and one or more pharmaceutically acceptable excipients. The stability of the composition is a loss of amlodipine of less than 10%, preferably less than 5%, more preferably less than 1% (or, therefore, after 3 months, more preferably 6 months, in an environmental control room at 40 ° C./75% RH). Increase in the impurity content). Alternatively, the amlodipine maleate pharmaceutical composition of the present invention exhibits the same or better storage stability as the amlodipine besylate composition. For example, the loss of the amlodipine to the degradation reaction during storage is equal to (+/− 10%) or less than the loss of amlodipine in the amlodipine besylate composition, especially the commercial product.

The form of amlodipine maleate is not particularly limited, and there are anhydrides, solvates, hydrates and partial hydrates, as well as crystalline and amorphous forms. In addition, the ratio of amlodipine to maleate may vary, in particular of the Applicant filed March 16, 2001, which is incorporated herein by reference in its entirety, as well as the more conventional prior art forms of 1: 1. There is a 2: 1 form described in pending US patent application Ser. No. 09 / 809,356, entitled “Amlodipine Hemimaleate”.

The amount of amlodipine maleate is not particularly limited and includes any amount that provides a pharmaceutical effect. In particular, amlodipine maleate may be used to treat or prevent hypertension or angina by administering an effective amount to a patient in need of treatment or prevention of hypertension or angina. The particular form of angina is not particularly limited, and in particular, chronic stable angina and vasoconvulsive angina (Prinzmetal Angina). The compound may be administered by any suitable route, including oral or parenteral routes, depending on the formulation. "Patients" intended for treatment include human and non-human animals, especially non-human mammals. Generally, the amount of amlodipine maleate in the unit dosage form is 1 to 100 mg, more typically 1 to 25 mg, preferably about 1, 1.25, 2.5, 5 or 10 mg (expressed in terms of free base).

Amlodipine maleate can be made by any of the known techniques described in the prior art, including those described in the aforementioned patent EP 089 167 and US Pat. No. 4,572,909. Preferably, the amlodipine maleate active material is substantially pure. For example, it is preferable that the content of impurities such as amlodipine aspartate, amlopypyridine, etc., which can be produced during synthesis should be limited to less than 2% by weight, but such purity is not required in the present invention. Useful methods for producing amlodipine maleate substantially free of amlodipine aspartate are generally described in the pending US patent application Ser. No. 09 / 809,343, filed March 16, 2001, entitled “Amlodipine Maleate”. Manufacturing method, the entire contents of which are incorporated herein by reference. Similarly, useful methods of making amlodipine free bases are generally described in the pending US patent application Ser. No. 09 / 809,351, filed March 16, 2001, entitled “Amlodipine, Derivatives thereof, and Precursors thereof. Manufacturing method, the entire contents of which are incorporated herein by reference.

In addition, the pharmaceutical compositions of the present invention comprise one or more excipients. As used herein, "excipient" means any pharmaceutically acceptable inert component of the composition. As is well known in the art, excipients include diluents, binders, lubricants, disintegrants, colorants, preservatives, pH adjusting agents and the like. Excipients are selected based on certain physical properties of the final form, such as obtaining a tablet with a predetermined hardness and friability, rapid dispersibility and easy to swallow. In addition, the predetermined release rate of the active substance from the composition after ingestion also plays a role in the selection of excipients. Preferred release rates are comparable to commercially available amlodipine besylate tablets.

Suitable excipients for use in the present invention include:

Diluents such as calcium hydrogen phosphate, lactose, mannitol and the like.

Binders such as microcrystalline cellulose or denatured cellulose, povidone and the like.

Disintegrants such as sodium starch glycolate, crospovidone.

Lubricants such as magnesium stearate, sodium stearyl fumarate, talc.

-Colorants, flavors and the like.

The pH of the composition can be adjusted or adjusted by appropriate choice of excipients. Keep in mind that amlodipine maleate is slightly acidic. For example, amlodipine maleate has a pH of about 4.8 as a saturated aqueous solution. Thus, the use of excipients that are pH inactive, i.e., which have little or no effect on pH, result in non-alkaline pharmaceutical compositions, since amlodipine maleate substantially acts as a regulator of itself. An example of a pH inert excipient is microcrystalline cellulose. Generally, compositions comprising amlodipine maleate and microcrystalline cellulose have a pH of about 6. In comparison, the amlodipine besylate generally has a pH of about 7 and the amlodipine free base composition generally has a pH of about 9. Commercially available tablets, including amlodipine besylate and sold under the trade name Norvasc, typically have a pH of 7.05 to 7.35 (measured again with a 20 wt% slurry).

Excipients with a pH effect can also be used. The pH of such excipients should be considered to develop a pharmaceutical composition such that the overall pH of the pharmaceutical composition is in the range of about 5.5 to 7.0.

For example, commercially available / pharmaceutically acceptable calcium phosphates are generally alkaline, i.e., having a pH of 7 or greater, as measured above, in a 20% slurry. For example, commercially available dibasic calcium phosphate dihydrate, DI-TAB, has been reported to have a pH of about 7.4. Nevertheless, some forms and grades of calcium phosphate are acidic or neutral pH. This low pH can be attributed to the species of calcium phosphate, as well as to the processing of materials such as impurities removal / washing. For example, dibasic calcium phosphate anhydride is generally considered to have a pH of about 7.3, while dibasic calcium phosphate anhydride, A-Tab ^™ (Rhodia), also has a pH of about 5.0. Another example of commercially available non-alkali calcium phosphate is DiCAFOS A (Buddenheim) having a pH of about 7 (10% slurry) and Fujicalin SG (Fuji) having a pH of 6.1 to 7.2 (5% slurry). By using non-alkaline calcium phosphate as an excipient, a pharmaceutical composition that satisfies a predetermined pH can be obtained. Alternatively, blends of calcium phosphate, some of which have a pH above 7 and some of which have a pH below 7, can be used to achieve the desired pH of the composition.

Instead of or in addition to the non-alkaline calcium phosphate, other acidic excipients can be used on their own, or used to counterbalance the alkaline excipients. An example of such an acidic excipient is the disintegrant Explotab ^™ from Fenwest, which is a crosslinked low substituted sodium starch glycolate. In addition, pH adjusting agents can be used to obtain the desired pH. Such agents include pharmaceutically acceptable acids such as maleic acid, citric acid or ascorbic acid (the second two also have the use of acting as antioxidants) and pharmaceutically acceptable bases such as calcium oxide or magnesium oxide. Salts of weak acids and / or weak bases are also suitable pH regulators because they act as buffers to lower or raise the pH depending on the chemical nature of the components.

The pharmaceutical composition of the present invention is not particularly limited in terms of dosage form or route. In addition to oral formulations, parenteral formulations are included. The composition may be in the form of a liquid, a solid or a suspension. The pharmaceutical composition is preferably a solid dosage form such as a tablet, capsule or bag for oral administration.

Preferred solid dosage forms contain calcium phosphate, in particular calcium hydrogen phosphate or combinations thereof as the main excipient microcrystalline cellulose. If other excipients are present, the sum is generally less than 25%, more typically less than 10%, and in some cases less than 5% by weight of the total pharmaceutical composition. Other preferred excipients are disintegrants such as sodium starch glycolate and / or glidants such as magnesium stearate and / or talc.

For example, pharmaceutical compositions comprising amlodipine maleate and microcrystalline cellulose as the sole excipient have been shown to provide good stability against the formation of impurities.

The pharmaceutical compositions of the present invention may be prepared by techniques generally known in the art. In general, amlodipine maleate is mixed with one or more excipients to form a blend. Mixing can be performed wet or dry (ie with or without solvent or liquid diluent in the process) and can involve granulation, slugging or blending of powders. However, dry processes are preferred. After any further process, the blend may be compressed into tablets or filled into capsules, such as gelatin capsules. Typically, the amlodipine maleate to be mixed is in the form of particles. The storage stability of the pharmaceutical compositions of the present invention is generally improved by using larger particle sizes. The average particle size of amlodipine maleate is preferably at least 20 microns, more preferably at least 100 microns, and in some embodiments at least 300 microns. If adjustment of the pH of the composition is required, it is preferred to adjust it before processing into a final form such as a tablet or capsule.

For example, tablets of the present invention may comprise wet granulation of a mixture of amlodipine maleate with a solid carrier / diluent such as calcium phosphate of a suitable grade, for example with a granulation solvent such as water or ethanol; Drying of wet granules; Sieve treatment of granules; Blending with sodium starch glycolate and magnesium stearate; And by compression of the purification mixture.

For example, tablets of the present invention may comprise wet granulation of a mixture of amlodipine maleate with a solid carrier / diluent such as calcium phosphate of a suitable grade, for example with a granulation solvent such as water or ethanol; Drying of wet granules; Sieve treatment of granules; Blending with sodium starch glycolate and magnesium stearate; And compression of the purification mixture into tablets. The adjustment of pH and / or adjustment of pH value is advantageously to be included before mixing with magnesium stearate. In this example, the ablation step and the blending step are considered "mixing" steps because the amlodipine maleate and the excipient are mixed.

Another suitable process involves the direct compression of a blend of amlodipine maleate and excipient (s). In this process, the components are blended together to form a compressible blend and then compressed into tablets. Blends comprising amlodipine maleate, microcrystalline cellulose and / or calcium phosphate, and optionally sodium starch glycolate and / or magnesium stearate, may be useful for tablet formation by direct compression. For example, blends containing amlodipine maleate, calcium hydrogen phosphate, microcrystalline cellulose and sodium starch glycolate, pHs of 5.5 to 7.0, blend together, reblend with magnesium stearate, and press to form a stable tablet can do.

Tablets of the present invention comprising amlodipine maleate, microcrystalline cellulose, sodium starch glycolate and magnesium stearate, optionally with addition of calcium hydrogen phosphate, have been reported in the prior art for other amlodipine preparations (see EP 244 944 above). There is no problem of sticking to the tablet punch as shown. Thus, the compositions of the present invention can be produced on an industrial scale without technical problems.

Tablets may be coated with a suitable coating. For example, the coating can be a moisture barrier or sustained release or delayed release coating composition that has storage stability as is well known in the art.

Alternative formulations are capsules and may be soft and hard capsules. The stabilized amlodipine maleate compositions of the present invention as described above may be filled into capsules by techniques known in the art in an amount that includes the desired therapeutic dose of amlodipine.

Suitable package materials for packing pharmaceutical formulations include plastic or glass containers and blisters. In particular, blisters made of non-permeable material (high density polyethylene or aluminum) are advantageous because they can contribute to reducing the rate of formation of decomposing impurities, i.e., amlo-pyridine impurities, during storage.

The pharmaceutical composition of the present invention is used to treat or prevent angina or hypertension by administering an effective amount of the pharmaceutical composition to a patient in need of treatment or prevention of angina or hypertension as described above. Typically, the pharmaceutical composition is in unit dosage form. Generally, the individual unit dosage compositions contain 1 to 100 mg, more typically 1 to 25 mg of amlodipine maleate. Preferred is a unit dosage form comprising amlodipine maleate in an equivalent amount of amlodipine 1.25, 2.5 or 10 mg, such as a tablet or capsule for oral administration. The pharmaceutical composition is administered 1-3 times daily, preferably once daily. In addition, the composition is useful for reducing symptoms of heart failure, improving systolic left ventricular function, and increasing exercise capacity in patients with ischemic LVD and heart failure who are currently unfamiliar.

In addition, the amlodipine maleate of the present invention may be used in the medical field in combination with other antihypertensive and / or anti-anginases such as ACE-inhibitors such as benazepril. This combination may be realized in the form of a capsule containing a single combination preparation, such as amlodipine maleate and benazepril hydrochloride, or by separate administration of a drug containing the preparation. Similarly, amlodipine maleate may be combined with HMG-CoA reductase inhibitors, in particular statins such as lovastin, simvastatin, atorvastatin and the like.

Accordingly, the present invention is directed to administering a pharmaceutical composition of the present invention comprising an effective amount and / or prophylactic amount of amlodipine maleate to a patient in need of treatment and / or prevention of any one or more of angina, hypertension and heart failure (disorder). Further provided are methods of treating and / or preventing a disorder.

The present invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment and / or prophylaxis of any one or more of the above disorders.

Example 1 Amlodipine Maleate Tablet Based on Calcium Phosphate Excipients

a) tablet compositions comprising calcium phosphate at different pH

Batch number (A) (B) (C) (D) (E) (F) Amlodipine equivalent 2.5 mg 10 mg 2.5 mg 10 mg 2.5 mg 10 mg Amlodipine Maleate 3.21 mg 12.8 mg 3.21 mg 12.8 mg 3.21 mg 12.8 mg Calcium hydrogen phosphate anhydride: -Di CAFOS A-A-TAB-Fujicalin 31.5 mg 126.0 mg 31.5 mg 126.0 mg 31.5 mg 126.0 mg Microcrystalline cellulose 62.05 mg 248.1 mg 62.05 mg 248.1 mg 62.05 mg 248.1 mg Sodium starch glycolate 2.0 mg 8.0 mg 2.0 mg 8.0 mg 2.0 mg 8.0 mg Magnesium stearate 1.0 mg 4.0 mg 1.0 mg 4.0 mg 1.0 mg 4.0 mg gun 99.76 mg 398.9 mg 99.76 mg 398.9 mg 99.76 mg 398.9 mg

Types of Anhydrous Calcium Hydrogen Phosphate Used

Batch number Final pH of 20% (m / V) slurry of tap Types of CaHPO ₄ Source of CaHPO ₄ PH of 5% (m / V) slurry of CaHPO ₄ PH of 20% (m / V) slurry of CaHPO ₄ (A), (B) 6.13, 6.19 Di CAFOS A Buddenheim 7.29 6.69 (E), (F) 5.74, 5.74 Fujicalin Fuji 6.12 5.62 (C), (D) 5.53, 5.54 A-TAB Ron-Follen 6.03 5.25

b) tablet compositions comprising amlodipine maleates of different particle sizes

Batch number (G) (H) (I) Equivalent of Amlodipine Base 2.5 mg 10 mg 2.5 mg Amlodipine Maleate, milled 3.21 mg 12.8 mg - Amlodipine Maleate - - 3.21 mg Calcium hydrogen phosphate anhydride (pH 6.7) 31.5 mg 126.0 mg 31.5 mg Microcrystalline cellulose 62.05 mg 248.1 mg 62.05 mg Sodium starch glycolate 2.0 mg 8.0 mg 2.0 mg Magnesium stearate 1.0 mg 4.0 mg 1.0 mg gun 99.76 mg 398.9 mg 99.76 mg

The particle size of the amlodipine maleate material used in the preparation of batches A to F was measured by laser diffraction, demonstrating that less than 90% of the particles were smaller than 204 microns and 50% of the particles were smaller than 80 microns.

This amlodipine maleate was milled to a particle size of 10 to 20 microns and used to prepare batches (G) and (H). Alternatively, another batch of amlodipine maleate having a particle size of 90% less than 11 microns and 50% less than 6 microns was used to make batch (I).

c) manufacturing procedure

Batches (A) to (F) and (I) were prepared as follows:

Amlodipine maleate was sieved through a 500 μm screen.

Other excipients were sieved through a 850 μm screen.

All excipients except magnesium stearate were mixed in a free-fall mixer at about 25 rpm for 15 minutes. pH values were checked in 20% aqueous slurry.

Magnesium stearate was added and the powder blend was mixed at about 25 rpm for 5 minutes.

2.5 mg and / or 10 mg tablets were compressed using a Korsch EK0 Excenter Press.

Batch (G) and (H) were prepared as follows:

Amlodipine maleate was milled.

Other excipients were sieved through a 850 μm screen.

All excipients except magnesium stearate were mixed in a free-fall mixer at about 25 rpm for 15 minutes. pH values were checked in 20% aqueous slurry.

Magnesium stearate was added and the powder blend was mixed at about 25 rpm for 5 minutes.

2.5 mg and / or 10 mg tablets were compressed with Korsch EK0 Excenter Press.

Example 2 Tablet Composition Comprising Microcrystalline Cellulose

a) composition

Batch number (J) (K) Equivalent of Amlodipine Base 2.5 mg 10 mg Amlodipine Maleate 3.21 mg 12.8 mg Microcrystalline cellulose 75.55 mg 302.1 mg Pre-dried potato starch 20.0 mg 80.0 mg Magnesium stearate 0.5 mg 2.0 mg Talc 0.5 mg 2.0 mg gun 99.76 mg 398.9 mg

Manufacture process

Amlodipine maleate was sieved through a 500 μm screen.

Other excipients were sieved through a 850 μm screen.

All excipients except magnesium stearate and talc were mixed in a free fall mixer at about 25 rpm for 15 minutes. pH values were checked in 20% aqueous slurry.

Magnesium stearate was added and the powder blend was mixed at about 25 rpm for 5 minutes.

2.5 mg and / or 10 mg tablets were compressed using a Korsch EK0 Excenter Press.

Properties of Tablet Composition:

PH of 20% (w / V) slurry:-Batch (J) = 5.92

-Batch (K) = 5.96

Example 3 Amlodipine Maleate Tablet Containing Mannitol

Furtherance

Batch number (L) Equivalent of Amlodipine Base 10 mg Amlodipine Maleate 12.8 mg Mannitol 370.1 mg Sodium starch glycolate 8.0 mg Magnesium stearate 6.0 mg Talc 2.0 mg gun 398.9 mg

Manufacturing procedure

Amlodipine maleate was sieved through a 500 μm screen.

Other excipients were sieved through a 850 μm screen.

All excipients except magnesium stearate were mixed in a free fall mixer at about 25 rpm for 15 minutes. pH values were checked in 20% aqueous slurry.

Magnesium stearate was added and the powder blend was mixed at about 25 rpm for 5 minutes.

10 mg tablets were compressed using a Korsch EK0 Excenter Press.

Example 4 Amlodipine Maleate Tablets having a pH of 7 or Above (Comparative Example)

Composition (pH of 20% w / v slurry: 8.68)

Batch number (X) Equivalent of Amlodipine Base 2.5 mg Amlodipine Maleate Calcium Hydrogen Phosphate Anhydride (pH 6.69) 3.21 mg31.5 mg Magnesium Oxide Ponderosum 0.5 mg Microcrystalline cellulose 62.05 mg Sodium starch glycolate 2.0 mg Magnesium stearate 1.0 mg gun 100.26 mg

Manufacture process

Amlodipine maleate was sieved through a 500 μm screen.

Other excipients were sieved through a 850 μm screen.

About 30% of the amount of amlodipine maleate, magnesium oxide and microcrystalline cellulose (MCC) was mixed in a free fall mixer at about 25 rpm for 10 minutes.

The remaining amount of MCC, calcium hydrogen phosphate anhydride and sodium starch glycolate were added and the blend was mixed in a free fall mixer at about 25 rpm for 15 minutes. pH values were checked in 20% aqueous slurry.

Magnesium stearate was added and the powder blend was mixed for another 5 minutes at 25 rpm.

2.5 mg tablets and proportionally larger 10 mg tablets were compressed using a Korsch EK0 Excenter Press.

Example 5 Stability Studies for Amlodipine Maleate Tablets

Stability studies on the batches prepared in Examples 1-4 were performed in various package materials (HDPE bottles, PVC / PVDC / PE blisters) in a temperature controlled chamber adjusted to 40 ± 2 ° C. and 75 ± 5% relative humidity. Or on an open dish. Analysis of the active substance and analysis of the impurity content was carried out by HPLC method using the reference substance of amlodipine maleate and the main decomposition impurities:

Amlodipine Aspartate (Z # 204)

Amlo-pyridine (Z # 202)

Two other negative impurities Z # 203 and Z # 205 were detected and confirmed.

The content of other detected impurities / degradation products was calculated by internal normalization.

In the table below, the analysis of the active substance is expressed in milligrams, and the content of impurities is expressed in percentage.

A) Stability studies were performed in 40 ° C./75% RH, open dishes (pH influence).

T = 0 months (A) (B) (E) (F) (C) (D) Assay (mg / tablet) 2.45 9.85 2.38 10.01 2.38 9.88 Z # 202 (%) 0.15 0.15 0.08 0.08 0.05 0.08 Z # 203 (%) 0.00 0.03 0.03 0.03 0.03 0.03 Z # 204 (%) 0.16 0.15 0.13 0.12 0.13 0.12 Z # 205 (%) 0.01 0.01 0.00 0.00 0.00 0.00 Total Unknown (%) 0.31 0.28 0.27 0.28 0.27 0.27 T = 1 month Assay (mg / tablet) 2.48 9.82 2.31 9.55 2.23 9.29 Z # 202 (%) 0.15 0.15 0.21 0.23 1.27 1.25 Z # 203 (%) 0.00 0.03 0.04 0.04 0.04 0.04 Z # 204 (%) 0.24 0.23 0.41 0.30 0.27 0.22 Z # 205 (%) 0.01 0.01 0.03 0.02 0.04 0.03 Total Unknown (%) 0.35 0.31 0.58 0.56 0.83 0.72 T = 3 months Assay (mg / tablet) 2.40 9.69 2.30 9.57 2.16 8.94 Z # 202 (%) 0.20 0.18 0.37 0.39 1.85 1.85 Z # 203 (%) 0.03 0.03 0.04 0.05 0.04 0.04 Z # 204 (%) 0.31 0.29 0.77 0.63 0.33 0.27 Z # 205 (%) 0.01 0.01 0.05 0.04 0.03 0.02 Total Unknown (%) 0.42 0.35 1.11 1.10 1.37 1.10

Stability studies were performed in PVC / PE / PVDC blisters at 40 ° C./75%RH.

T = 0 months (A) (B) (J) (K) analysis 2.51 9.99 2.52 10.33 Z # 202 0.11 0.11 0.20 0.20 Z # 203 0.00 0.00 0.00 0.00 Z # 204 0.15 0.14 0.00 0.00 Z # 205 0.01 0.01 0.00 0.00 Total unknowns 0.31 0.31 0.46 0.49 T = 3 months analysis 2.49 9.49 2.49 9.99 Z # 202 0.15 0.15 0.07 0.05 Z # 203 0.00 0.00 0.00 0.03 Z # 204 0.26 0.29 0.46 0.40 Z # 205 0.01 0.01 0.02 0.02 Total unknowns 0.36 0.34 0.45 0.38 T = 6 months analysis 2.45 9.49 2.45 9.94 Z # 202 0.23 0.21 0.17 0.11 Z # 203 0.04 0.04 0.04 0.04 Z # 204 0.46 0.39 0.64 0.54 Z # 205 0.01 0.00 0.02 Total unknowns 0.57 0.54 0.64 0.51

Stability studies were performed in open dishes at 40 ° C./75% RH.

t = 0 months (J) (K) analysis 2.49 10.18 Z # 202 0.04 0.04 Z # 203 0.02 0.03 Z # 204 0.19 0.17 Z # 205 0.01 0.01 Total unknowns 0.42 0.36 t = 1 month analysis 2.44 10.14 Z # 202 0.08 0.07 Z # 203 0.02 0.03 Z # 204 0.34 0.36 Z # 205 0.01 0.01 Total unknowns 0.45 0.42 t = 3 months analysis 2.41 9.72 Z # 202 0.22 0.21 Z # 203 0.04 0.04 Z # 204 0.50 0.54 Z # 205 0.03 0.03 Total unknowns 0.63 0.56

Stability studies were performed in HDPE vessels at 40 ° C./75% RH.

T = 0 months (A) (B) (J) (K) (L) analysis 2.51 9.99 2.52 10.33 10.11 Z # 202 0.11 0.11 0.20 * 0.20 0.19 * Z # 203 0.00 0.00 0.00 0.00 * 0.00 Z # 204 0.15 0.14 0.00 * 0.00 0.00 * Z # 205 0.01 0.01 0.00 0.00 0.00 Total unknowns 0.31 0.31 0.46 0.49 0.40 T = 3 months analysis 2.52 9.84 2.51 10.26 8.69 Z # 202 0.13 0.15 0.41 * 0.37 * 0.45 * Z # 203 0.00 0.00 0.03 0.00 0.05 Z # 204 0.27 0.23 0.00 * 0.00 * 0.00 * Z # 205 0.03 0.03 0.07 0.05 0.01 Total unknowns 0.33 0.32 0.41 0.49 0.66 T = 6 months analysis 2.49 9.83 2.47 10.26 Z # 202 0.15 0.15 0.08 0.05 Z # 203 0.00 0.00 0.00 0.03 Z # 204 0.44 0.41 0.44 0.38 Z # 205 0.02 0.01 0.10 0.08 Total unknowns 0.46 0.44 0.44 0.37

* Values for Z # 202 and Z # 204 together

Comparative stability studies were performed with a composition with an alkaline pH (open dish, 40 ° C./75% RH).

t = 0 months (X) analysis 2.52 Z # 202 0.04 Z # 203 0.03 Z # 204 0.13 Z # 205 0.00 Total unknowns 0.30 t = 1 month analysis 2.43 Z # 202 0.06 Z # 203 0.03 Z # 204 1.73 Z # 205 0.00 Total unknowns 0.51

Stability studies were performed in 40 ° C./75% RH, open dishes (effect of particle size).

t = 0 months (A) (B) (G) (H) (I) Assay (mg / tablet) 2.45 9.85 2.38 10.12 2.54 Z # 202 (%) 0.15 0.15 0.05 0.05 0.10 Z # 203 (%) 0.00 0.03 0.00 0.01 0.04 Z # 204 (%) 0.16 0.15 0.03 0.03 0.01 Z # 205 (%) 0.01 0.01 0.00 0.00 0.02 Total unknowns 0.31 0.28 0.17 0.11 0.26 t = 1 month Assay (mg / tablet) 2.48 9.82 2.29 9.88 - Z # 202 (%) 0.15 0.15 0.17 0.14 - Z # 203 (%) 0.00 0.03 0.01 0.01 - Z # 204 (%) 0.24 0.23 0.52 0.48 - Z # 205 (%) 0.01 0.01 0.02 0.02 - Total unknowns 0.35 0.31 0.22 0.19 - t = 2 months Assay (mg / tablet) 2.46 9.87 2.22 9.64 2.35 Z # 202 (%) 0.17 0.16 0.28 0.25 0.34 Z # 203 (%) 0.00 0.00 0.01 0.01 0.03 Z # 204 (%) 0.28 0.28 1.02 1.01 0.41 Z # 205 (%) 0.01 0.01 0.03 0.03 0.04 Total unknowns 0.47 0.43 0.63 0.52 0.60 t = 3 months Assay (mg / tablet) 2.40 9.69 2.24 9.36 2.36 Z # 202 (%) 0.20 0.18 0.18 0.16 0.39 Z # 203 (%) 0.03 0.03 0.01 0.01 0.11 Z # 204 (%) 0.31 0.29 1.26 1.34 0.53 Z # 205 (%) 0.01 0.01 0.05 0.04 0.04 Total unknowns 0.42 0.35 0.90 0.74 0.64

For comparison of stability, we considered an increase in the total impurities identified or unidentified, relative to the t = 0 month level:

Total Impurity Growth (%) (A) (B) (G) (H) (I) After 3 months at 40 ℃ / 75% RH +0.33 +0.24 +1.82 +1.43

Comparative stability studies with Norvasc (commercial amlodipine besylate tablets)

Stability studies were performed in the original blisters at 40 ° C./75% RH.

Norvasc (registered trademark) 5 mg batch 81040100 (DE) Norvasc® 10 mg batch 901-05941 (NL) t = 0 months analysis 5.19 9.99 Z # 202 0.04 0.02 Z # 203 0.01 0.00 Z # 204 0.00 0.00 Z # 205 0.00 0.00 Total unknowns 0.12 0.12 t = 3 months analysis 5.13 9.70 Z # 202 0.16 0.17 Z # 203 0.03 0.00 Z # 204 0.00 0.00 Z # 205 0.00 0.00 Total unknowns 0.38 0.62 t = 6 months analysis 4.97 9.58 Z # 202 0.28 0.27 Z # 203 0.00 0.00 Z # 204 0.00 0.00 Z # 205 0.00 0.00 Total unknowns 0.49 0.78

Stability studies were performed on open dishes at 40 ° C./75% RH.

Norvasc® 5 mg batch 8QP115A (US) Norvasc® 10 mg batch N-09 (ES) t = 0 months analysis 2.44 9.91 Z # 202 0.08 0.82 Z # 203 0.00 0.00 Z # 204 0.00 0.00 Z # 205 0.00 0.00 Total unknowns 0.02 0.34 t = 1 month analysis 2.44 8.90 Z # 202 0.18 2.17 Z # 203 0.04 0.19 Z # 204 0.00 0.01 Z # 205 0.00 0.00 Total unknowns 0.10 1.21 t = 2 months analysis 2.39 7.98 Z # 202 0.27 3.24 Z # 203 0.00 0.00 Z # 204 0.00 0.00 Z # 205 0.00 0.03 Total unknowns 0.33 2.51 t = 3 months analysis 2.34 7.68 Z # 202 0.37 3.98 Z # 203 0.00 0.00 Z # 204 0.00 0.00 Z # 205 0.00 0.03 Total unknowns 0.27 2.76

Example 6 Amlodipine Maleate Capsule

Furtherance

Batch number (CA), (CB) Equivalent to amlodipine 5.0 mg Amlodipine Maleate 6.42 mg Microcrystalline cellulose 72.6 mg Pre-dried potato starch 20.0 mg Magnesium stearate 0.5 mg gun 99.52 mg

Batch number (CC) (CX) Equivalent to amlodipine 5.0 mg 5.0 mg Amlodipine Maleate 6.42 mg 6.42 mg Calcium hydrogen phosphate anhydride 31.5 mg 31.5 mg Magnesium oxide - 1.5 mg Microcrystalline cellulose 62.0 mg 62.0 mg Sodium starch glycolate 2.0 mg 2.0 mg Magnesium stearate 1.0 mg 1.0 mg gun 102.92 mg 104.43 mg

pH of capsule at t = 0

Batch number density Types of calcium hydrogen phosphate anhydride PH of 20% (m / V) slurry of capsule contents (CC) 5.0 mg DiCAFOS A 6.10 (CX) 5.0 mg DiCAFOS A 9.59

Batch (CA) was prepared as follows:

Amlodipine maleate was sieved through a 500 μm screen.

Other excipients were sieved through a 850 μm screen.

All excipients except magnesium stearate were mixed in a free-fall mixer at about 25 rpm for 15 minutes. pH values were checked in 20% aqueous slurry.

Magnesium stearate was added and the powder blend was mixed at about 25 rpm for 5 minutes.

This powder blend is filled into gelatin capsules.

Batch (CB) was prepared as follows:

Amlodipine maleate was sieved through a 500 μm screen.

Other excipients were sieved through a 850 μm screen.

All excipients except magnesium stearate were mixed in a free-fall mixer at about 25 rpm for 15 minutes. pH values were checked in 20% aqueous slurry.

Magnesium stearate was added and the powder blend was mixed at about 25 rpm for 5 minutes.

This powder blend was filled into an HPMC capsule.

Batch (CC) was prepared as follows:

Amlodipine maleate was sieved through a 500 μm screen.

Other excipients were sieved through a 850 μm screen.

All excipients except magnesium stearate were mixed in a free-fall mixer at about 25 rpm for 15 minutes. pH values were checked in 20% aqueous slurry.

Magnesium stearate was added and the powder blend was mixed for another 5 minutes at 25 rpm.

This powder blend is filled into gelatin capsules.

Batch (CX) was prepared as follows:

Amlodipine maleate was sieved through a 500 μm screen.

Other excipients were sieved through a 850 μm screen.

About 30% of the amount of amlodipine maleate, magnesium oxide and microcrystalline cellulose (MCC) was mixed in a free fall mixer at about 25 rpm for 10 minutes.

The remaining amount of MCC, calcium hydrogen phosphate anhydride and sodium starch glycolate were added and the blend was mixed in a free fall mixer at about 25 rpm for 15 minutes. pH values were checked in 20% aqueous slurry.

Magnesium stearate was added and the powder blend was mixed at about 25 rpm for 5 minutes.

This powder blend was filled into gelatin capsules using an automatic capsule filling machine.

Example 7 Stability Studies for Amlodipine Maleate Capsules

Stability studies on the batches prepared in Example 6 were performed essentially as described in Example 5.

Stability studies were performed in PVC / PE / PVDC blisters at 40 ° C./75%RH.

t = 0 months (CA) (CB) analysis 5.13 4.98 Z # 202 0.04 0.04 Z # 203 0.03 0.03 Z # 204 0.12 0.12 Z # 205 0.00 0.00 Total unknowns 0.32 0.31 t = 3 months analysis 4.82 4.76 Z # 202 0.08 0.06 Z # 203 0.02 0.02 Z # 204 0.15 0.14 Z # 205 0.01 0.00 Total unknowns 0.39 0.38 t = 6 months analysis 4.67 4.81 Z # 202 0.14 0.10 Z # 203 0.04 0.02 Z # 204 0.23 0.18 Z # 205 0.02 0.01 Total unknowns 0.45 0.42

Two 1 month stability studies were performed in open dishes.

t = 0 months (CC) (CX) analysis 4.91 4.72 Z # 202 0.04 0.04 Z # 203 0.03 0.04 Z # 204 0.12 0.13 Z # 205 0.00 0.00 Total unknowns 0.28 0.29 T = 1 month at 25 ℃ / 60% RH analysis 4.85 4.70 Z # 202 0.05 0.05 Z # 203 0.04 0.04 Z # 204 0.13 0.14 Z # 205 0.00 0.00 Total unknowns 0.28 0.28 T = 1 month at 40 ℃ / 75% RH analysis 4.76 4.16 Z # 202 0.06 0.08 Z # 203 0.04 0.03 Z # 204 0.15 11.36 Z # 205 0.00 0.00 Total unknowns 0.28 0.62

Stability studies were performed in HDPE containers.

t = 0 months (CA) (CB) analysis 4.99 5.01 Z # 202 0.05 0.04 Z # 203 0.03 0.03 Z # 204 0.12 0.11 Z # 205 0.00 0.00 Total unknowns 0.31 0.30 T = 3 months at 25 ℃ / 60% RH analysis 5.07 4.77 Z # 202 0.04 0.04 Z # 203 0.03 0.04 Z # 204 0.12 0.12 Z # 205 0.00 0.00 Total unknowns 0.30 0.32 T = 3 months at 40 ℃ / 75% RH analysis 5.01 4.65 Z # 202 0.05 0.05 Z # 203 0.03 0.04 Z # 204 0.12 0.13 Z # 205 0.00 0.00 Total unknowns 0.29 0.32

Stability Study on Commercial Amlor® (Amlodipine Besylate) Capsules

Stability studies were performed with the original blisters.

Amlor 5 mg capsule batch 9037002 t = 0 months t = 3 months40 ℃ / 75% RH analysis 4.59 4.44 Z # 202 0.01 0.20 Z # 203 0.00 0.00 Z # 204 0.00 0.00 Z # 205 0.00 0.00 Total unknowns 0.06 0.37

Having described the invention, those skilled in the art will recognize that further modifications and variations in the actual implementation of the concepts and embodiments described herein may be made without departing from the spirit and scope of the invention as defined by the appended claims. It will be readily appreciated that the implementation can be easily understood.

Claims (28)

A pharmaceutical composition comprising an effective amount of amlodipine maleate and one or more pharmaceutically acceptable excipients and having a pH of 5.5 to 7.0. The composition of claim 1, wherein the composition has a pH of about 6.0 to 7.0. The composition of claim 1 or 2, wherein said composition is solid. The composition of claim 1, wherein the excipient is calcium phosphate or microcrystalline cellulose. The composition of claim 4, wherein the composition comprises calcium phosphate and microcrystalline cellulose. The composition of claim 4 wherein the excipient is calcium hydrogen phosphate. The composition of claim 4, wherein the excipient is microcrystalline cellulose. 8. The composition of any one of the preceding claims, further comprising an acidic pH adjusting agent. The composition of claim 1, wherein the composition is in the form of a tablet. 10. The composition of claim 9, further comprising an external moisture and / or light blocking layer surrounding the tablet. The composition of claim 1, wherein the composition is in the form of a capsule. 12. The composition of any one of the preceding claims, wherein the amount of amlodipine maleate corresponds to 1.0 to 25 mg of amlodipine free base. The composition of claim 12, wherein the amount of amlodipine maleate corresponds to 1.25, 2.5, 5, or 10 mg of amlodipine free base. A method of treating or preventing angina or hypertension or heart failure, comprising administering an effective amount of the composition of any one of claims 1 to 13 to a patient in need thereof for treating or preventing angina or hypertension or heart failure. 14. The method of claim 1, comprising mixing amlodipine malate with one or more pharmaceutically acceptable excipients to form a mixture having a pH of 5.5 to 7 or 6.0 to 7.0, respectively. A process for the preparation of the composition of any one of claims 2-13. Mixing amlodipine maleate with at least one pharmaceutically acceptable excipient to form a mixture having a pH of 5.5 to 7.0. The method of claim 16 further comprising compressing the mixture into tablets. The method of claim 16 further comprising filling the mixture into a capsule to form a pharmaceutical formulation. The method of claim 16, wherein said mixing step is performed by wet granulation. The method of claim 16, wherein said mixing step is performed by a dry method. The method of claim 20, wherein said amlodipine maleate is mixed with said excipient as solid particles having an average particle size of at least 100 microns. A tablet made according to the method of claim 16, 17, 19, 20, 21. Mixing solid particles of amlodipine maleate having an average particle size of at least 20 microns with a pharmaceutically acceptable excipient to form a mixture. The method of claim 23, further comprising filling the mixture into a capsule to form a pharmaceutical formulation. The method of claim 23, further comprising compressing the mixture to form a tablet. The method of claim 23, wherein the average particle size is at least 100 microns. The method of claim 23, wherein the mixture is blended with one or more suitable excipients so that the pH is in the range of 5.5-7. Use of the composition of any one of claims 1 to 13 for the manufacture of a medicament for treating angina, hypertension or heart failure.