HK1064601B - Pharmaceutical compositions comprising amlodipine maleate - Google Patents

Description

Pharmaceutical composition containing amlodipine maleate

The invention relates to a pharmaceutical composition containing amlodipine maleate and a preparation process thereof.

Calcium channel blockers are useful in the treatment of various heart conditions, primarily angina pectoris and hypertension. Patent EP 089167 and its corresponding US 4,572,909 disclose a group of substituted dihydropyridine derivatives as effective calcium channel blockers. One of the compounds considered to be preferred in these patents is 2- [ (2-aminoethoxy) methyl ] -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1, 4-dihydropyridine. The compound is amlodipine which is well known at present, and the structural formula of the compound is as follows:

examples 8, 11, 12 and 22 of EP 089167 show the synthesis of amlodipine in the maleate form. Of a series of suitable acid addition salts, the maleate salt is considered to be the most desirable one.

Subsequently, EP 244944 and its corresponding US 4,879,303 issued a route for the preparation of besylate salts of amlodipine. The benzenesulfonate salts are believed to have certain advantages over known salts, including good formulation characteristics. Indeed, amlodipine besylate, rather than amlodipine maleate, has been developed by Pfizer as a commercially prescribed drug by Pfizer and is sold in the united states under the trade name norvassc.

A Review of NOVACS (amlodipine besylate) New Drug Application (NDA) received by FDA in the United states shows that a shift from the Original amlodipine maleate to amlodipine besylate occurred during development [ see "Review of organic NDA" NDA #19-787, available from FDA under the < information free law > (FOIA) at 10 months and 10 days 1990 ]. The reason for the diversion is apparently due to problems with sheeting and stability. However, no information on the stability and the tableting is disclosed in the information available from the FDA. Interestingly, NDA clinical studies have included the maleate and besylate forms, both salts being therapeutically equivalent (bioequivalent). However, horse utilization in these studies was always used in capsule or solution dosage forms, not tablet dosage forms.

The present invention relates to the discovery of a stable amlodipine maleate pharmaceutical composition. A first aspect of the present invention relates to a pharmaceutical composition comprising an effective amount of amlodipine maleate and at least one pharmaceutically acceptable excipient, wherein the pH of the composition is 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 preparing such compositions, and to the use of said compositions for the treatment or prevention of angina pectoris or hypertension.

Another aspect of the present invention relates to a process which comprises mixing solid particles of amlodipine maleate having an average particle size of at least 20 microns with one or more pharmaceutically acceptable excipients to form a mixture. The pH of the mixture is preferably 5.5 to 7.0. The mixture may be compressed into tablets or filled into capsules to form solid dosage forms.

Stability is an important aspect of pharmaceutical compositions. The present invention is based on the discovery that the stability problems associated with the prior art amlodipine maleate can be overcome by controlling the composition pH in the range of about 5.5 to 7.0, and more preferably in the range of 6.0 to 7.0. The possibility of degradation reactions occurring within this range is minimized. In particular, the formation of the degradation products shown below (herein referred to as amlodipine aspartate) is reduced or avoided in this pH range.

Amlodipine aspartic acid:

amlodipine aspartate is produced by the Michael addition reaction that occurs between amlodipine and maleic acid. Since amlodipine and maleic acid are in close contact with each other in the amlodipine maleate molecule, the chance of occurrence of addition reaction will rise with the lapse of time, thus causing a stability problem. By controlling the pH, the addition reaction is greatly slowed or completely avoided. It has been found that a pH higher than 7.0 tends to exacerbate the degradation of amlodipine maleate to amlodipine aspartate. Below pH 5.5, other degradation reactions have a tendency to be exacerbated, including the pyridine analog of amlodipine having the structure:

"amlodipine-pyridine":

the stabilized compositions of the invention desirably have a pH in the range of about 6.0 to 7.0, more typically between about 6.1 or 6.2 to 6.8. For the determination of the pH of the solid composition, it is accomplished by slurrying the material with water (deionized water) and determining the pH of the slurry, as is known to those skilled in the art of such processes. The concentration of the composition in the slurry was 20 wt%. The pH is determined by any standard technique.

The pharmaceutical composition of the present invention comprises an effective pharmaceutical dose of amlodipine maleate and at least one pharmaceutically acceptable excipient. The composition stability is desirably such that after three months, more desirably after six months, in a controlled room environment at 40 ℃/75% RH (relative humidity), the composition exhibits a decrease in the amount of amlodipine (or a corresponding increase in the amount of impurities) of less than 10 wt%, more desirably less than 5 wt%, and still more desirably less than 1 wt%. In addition, the amlodipine maleate pharmaceutical composition of the present invention preferably exhibits storage stability comparable to or superior to that of amlodipine besylate composition. For example, the reduction in the amount of amlodipine during storage due to degradation reactions is equivalent to (+ -10%) or less than the reduction in amlodipine besylate compositions, especially in commercial products.

The form of amlodipine maleate is not particularly limited and may include anhydrate, solvate, hydrate and partial hydrate as well as crystalline and amorphous forms. In addition, the ratio between amlodipine and maleic acid can vary, and includes primarily the more general and prior art 1: 1 ratio, as well as the newly discovered 2: 1 ratio described in the United states public provisional patent application (common-owned co-pending US patent application) No. 09/809,356 (3/16 2001), entitled "amlodipine hemi-maleate", the entire contents of which are incorporated herein by reference.

The amount of amlodipine is not particularly limited and may include any amount having a pharmaceutical effect. In particular, amlodipine maleate can be used to treat or prevent hypertension or angina by administering an effective amount to a patient in need thereof. The type of angina pectoris is not particularly limited herein, and mainly includes chronic stable angina pectoris and vasospastic angina pectoris (Prinzmetal's angina). The compounds may be administered by any suitable route, including orally and parenterally, depending on the dosage form. A "patient" to be treated includes humans and animals, particularly humans and mammals. Typically, the effective amount of amlodipine maleate in a unit dose is in the range of 1 to 100mg, more typically 1 to 25mg, and more desirably about 1, 1.25, 2.5, 5 or 10mg (expressed as the free base).

Amlodipine maleate may be prepared by any of the known techniques established in the prior art, including those described in the above-mentioned patents EP 089167 and US 4,572,909. The amlodipine maleate active ingredient in the ideal has good purity. For example, the amount of impurities such as amlodipine aspartate, amlodipine-pyridine and the like which can be produced during the synthesis process is limited, preferably to less than 2 wt%, although such purity is not required in the present patent. An efficient method for preparing amlodipine maleate substantially free of amlodipine aspartate is described in the commonly-owned co-pending US patent application 09/809,343(2001, 3/16), entitled "Process for preparing amlodipine maleate", the entire contents of which are incorporated herein by reference. Similarly, an efficient method for preparing amlodipine free base is described in U.S. public-owned co-pending US patent application 09/809,351 (3/16/2001), entitled "Processes for preparing amlodipine, amlodipine derivatives and precursors", the entire contents of which are incorporated herein by reference.

The pharmaceutical composition of the present invention also contains at least one excipient. By "excipient" herein is meant any pharmaceutically acceptable inactive ingredient in the composition. As is well known, excipients include diluents, binders, lubricants, disintegrants, colorants, pH adjusters and the like. The choice of excipients depends on the desired physical properties of the final dosage form, e.g., achieving a tablet with the desired hardness and friability, rapid disintegration and easy swallowing, etc. The desired rate of release of the active from the composition after administration of the drug also plays an important role in excipient selection. The ideal release rate should be comparable to that of commercial amlodipine besylate.

Suitable excipients for use in the present invention include:

diluents such as calcium hydrogen phosphate, lactose, mannitol, etc.

Binders such as microcrystalline or modified cellulose, povidone, etc.

Disintegrants such as sodium starch glycolate, crospovidone, etc.

Lubricants such as magnesium stearate, sodium stearyl fumarate, talc

Colorants, taste-masking agents, etc.

The pH of the composition can be controlled and adjusted by selecting appropriate excipients. It should be remembered that amlodipine maleate is slightly acidic. For example, amlodipine maleate has a pH of about 4.8 when in a saturated aqueous solution. Thus, using a pH inert excipient (i.e., it has little or no effect on pH), a pharmaceutical composition is generally formed that is non-basic in that the amlodipine maleate therein essentially functions as a self-regulating agent. An example of a pH inert excipient is microcrystalline cellulose. A pharmaceutical composition comprising amlodipine maleate and microcrystalline cellulose substantially exhibits a pH of about 6. In contrast, the corresponding amlodipine besylate composition has a general pH of about 7, and the corresponding amlodipine free base composition has a general pH of about 9. Commercial tablets containing amlodipine besylate and sold under the trade name Norvasc exhibit a typical pH range of 7.05-7.35 (again measured in a 20 wt% slurry).

Excipients having a pH effect may also be employed. The pH of these excipients must be considered in the development of pharmaceutical compositions so that the overall pH of the pharmaceutical composition is in the range of 5.5-7.0. For example, commercially/pharmaceutically acceptable calcium phosphates are generally alkaline, i.e., have a pH of greater than 7 when measured in the above 20% slurry. For example, DI-TAB, a commercial dibasic calcium phosphate dihydrate, is reported to have a pH of about 7.4. Of course, there are some forms or grades of calcium phosphate that may be at an acidic or neutral pH. This lower pH may result from treatment processes like impurity removal/washing in the processing of the calcium phosphate species or materials. For example, dibasic calcium phosphate anhydrate is generally considered to have a pH of about 7.3, whereas A-Tab^TM(product of Rhodia), which is also a dibasic calcium phosphate anhydrate, has a pH of about 5.0. As a further example, commercial non-alkaline calcium phosphates include DiCAFOS (available from Budenheim) at a pH of about 7 (10% slurry), Fujicalin SG (available from Fuji)) The pH of (1) is 6.1-7.2 (5% slurry). Pharmaceutical compositions meeting the desired pH can be achieved using non-basic calcium phosphate as an excipient. Alternatively, mixing a portion of calcium phosphate with a pH above 7 and a portion below 7 can also be used to bring the composition to the desired pH.

Other acidic excipients may be used alone or to counteract the basic excipient as a replacement for or in addition to the non-basic calcium phosphate. An example of such an acidic excipient is Penwest's disintegrant Explotab (TM), which is a cross-linked, low-substituted sodium starch glycolate. In addition, pH adjusters can also be used to achieve the desired pH. These include pharmaceutically acceptable acids such as maleic acid, citric acid or ascorbic acid (the latter two may also act as antioxidants), and pharmaceutically acceptable bases such as calcium oxide or magnesium oxide. The weak acid and/or base salts are also suitable pH modifiers because they act as buffers by raising or lowering the pH depending on the chemical nature of the ingredients.

The pharmaceutical composition of the present invention is not particularly limited to the dosage form or the administration route. Both oral and parenteral dosage forms are included. The compositions may be in liquid, solid, or suspension dosage forms. The preferred dosage form of the composition is a solid dosage form such as a tablet, capsule or oral powder.

The preferred oral dosage form contains as the main excipients microcrystalline cellulose, a calcium phosphate, especially calcium hydrogen phosphate, or a combination thereof. If there are other excipients, their total amount is generally less than 25 wt%, more usually less than 10 wt%, and in some cases less than 5 wt% of the total composition. Preferred further excipients are disintegrants such as sodium starch glycolate and/or lubricants such as magnesium stearate and/or talc.

For example, a pharmaceutical composition containing only amlodipine maleate and the only excipient microcrystalline cellulose shows good stability in terms of impurity formation.

The pharmaceutical compositions of the present invention may be prepared by techniques generally understood in the art. Generally, amlodipine maleate is mixed with one or more excipients to form a mixture. Mixing may be done wet or dry (i.e., with or without a solvent or liquid diluent in the process), and may involve granulation, fluidization, or powder mixing. But is more amenable to dry processes. The mixture may be compressed into tablets or filled into capsules, such as gelatin capsules, with or without further processing steps. Amlodipine maleate, which is typically blended, is in the form of granules. By using larger particles, the storage stability of the pharmaceutical composition of the invention is generally enhanced. The amlodipine maleate granules preferably have a particle size of at least 20 microns, more preferably at least 100 microns, and in certain embodiments up to at least 300 microns. If it is desired to adjust the pH of the composition, it is preferably adjusted before it is processed into a final dosage form such as a tablet or capsule.

For example, tablets may be prepared by the process of the invention by procedures such as: a mixture of amlodipine maleate and a solid carrier/diluent (like calcium phosphate of appropriate grade) is subjected to wet granulation with the aid of a granulating solvent (like water or ethanol); drying the wet granules; sieving the granules; mixing with sodium starch glycolate and magnesium stearate and compressing the mixture into tablets. The pH control and/or adjustment should advantageously be carried out before mixing with the magnesium stearate. In this example, both the granulation step and the mixing step are considered as "mixing" steps, as amlodipine maleate and excipients are mixed together here.

Yet another suitable process comprises direct compression of a mixture of amlodipine maleate and excipients. In this process, all ingredients are mixed together to form a pressable mixed composition, which is then compressed into tablets. A mixture of amlodipine maleate with microcrystalline cellulose and/or calcium phosphate, or sodium starch glycolate and/or magnesium stearate is useful in a direct compression tableting process. For example, a formulation consisting of amlodipine maleate, dibasic calcium phosphate, microcrystalline cellulose and sodium starch glycolate, at a pH of 5.5-7.0, can be blended together, blended with magnesium stearate, and compressed into a stable tablet.

Tablets of the invention containing amlodipine maleate, microcrystalline cellulose, sodium starch glycolate and magnesium stearate, or alternatively calcium hydrogen phosphate, do not suffer from the problem of sticking to the tablet die as reported in the prior art for other amlodipine formulations (see EP 244944, cited above). Thus, the composition of the present invention can be produced on an industrial scale without technical problems.

The tablets may be covered by a suitable coating. For example, as is well known, the coating may serve as a moisture barrier to aid storage stability, or to retain or delay release of the components.

The other optional dosage forms can be capsule, soft capsule and hard capsule. The stabilized amlodipine maleate composition of the present invention as described above is filled into capsules by known techniques in the desired therapeutic dose of amlodipine.

Suitable packaging materials for packaging pharmaceutical dosage forms are plastic or glass containers and blister packs. Blister packs, particularly those made of non-permeable materials (high density polyethylene or aluminum), are advantageous because they help to reduce the rate of formation of degradative impurities (known as amlodipine-pyridine) during storage.

As defined previously, 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 thereof. Typically the pharmaceutical composition is a unit dose. Individual unit dosage compositions contain from 1 to 100mg, more typically 1 to 25mg, of amlodipine maleate. Desirably, the unit dose, such as in an oral tablet or capsule, contains about 1.25, 2.5, 5 or 10mg of amlodipine maleate. The pharmaceutical composition is administered 1 to 3 times per day, preferably once a day. The composition can also be used for relieving heart failure symptoms, improving left ventricular contraction function, improving exercise endurance of patients with ischemic left ventricular dysfunction, and treating heart failure without angina pectoris.

The amlodipine maleate composition of the present invention may also be used in combination therapy with other antihypertensive and/or antianginal drugs, for example with ACE (angiotensin converting enzyme) inhibitors such as benazepril. The combination can be achieved in a single mixed formulation (e.g., a capsule containing both amlodipine maleate and benazepril hydrochloride) or in a form in which the above-mentioned drugs are administered separately. Similarly, amlodipine maleate can also be used in combination with HMG-CoA reductase inhibitors, particularly statins such as lovastatin, simvastatin, atorvastatin, and the like.

Accordingly, the present invention further provides a method for treating and/or preventing any one or more symptoms of angina pectoris, hypertension, heart failure by administering the pharmaceutical composition of the present invention containing an effective and/or preventive dose of amlodipine maleate to a patient in need thereof.

The invention also provides the use of a composition of the invention in the manufacture of a medicament for the treatment and/or prevention of any one or more of the specified conditions.

Example 1 amlodipine maleate tablet with calcium phosphate as excipient

a) Tablet composition containing calcium phosphates of different pH

Batch number	(A)	(B)	(C)	(D)	(E)	(F)
							Corresponding to the amount of amlodipine	2.5mg	10mg	2.5mg	10mg	2.5mg	10mg
Amlodipine maleate	3.21mg	12.8mg	3.21mg	12.8mg	3.21mg	12.8mg
							Anhydrous calcium hydrogen phosphate: di CAFOS A-A-TAB-Fujicalin	31.5mg	126.0mg	31.5mg	126.0mg	31.5mg	126.0mg
Microcrystalline cellulose	62.05mg	248.1mg	62.05mg	248.1mg	62.05mg	248.1mg
							Sodium starch glycolate	2.0mg	8.0mg	2.0mg	8.0mg	2.0mg	8.0mg
Stearic acid magnesium salt	1.0mg	4.0mg	1.0mg	4.0mg	1.0mg	4.0mg
							Total amount of	99.76mg	398.9mg	99.76mg	398.9mg	99.76mg	398.9mg

Type of anhydrous calcium phosphate used

Batch number	Final pH of 20% (m/V) tablet slurry	Calcium hydrogen phosphate type	Calcium Hydrogen phosphate supplier	pH of 5% (m/V) calcium Hydrogen phosphate slurry	pH of 20% (m/V) calcium Hydrogen phosphate slurry
						(A)，(B)	6.13，6.19	Di CAFOS A	Budenheim	7.29	6.69
(E)，(F)	5.74，5.74	Fujicalin	Fuji	6.12	5.62
						(C)，(D)	5.53，5.54	A-TAB	Rhone-Poulenc	6.03	5.25

b) Amlodipine containing different particle sizesTablet composition of maleate

Batch number	(G)	(H)	(I)
				Corresponding to the amount of amlodipine base	2.5mg	10mg	2.5mg
Amlodipine maleate, by grinding	3.21mg	12.8mg	-
				Amlodipine maleate	-	-	3.21mg
Anhydrous calcium hydrogen phosphate (pH6.7)	31.5mg	126.0mg	31.5mg
				Microcrystalline cellulose	62.05mg	248.1mg	62.05mg
Sodium starch glycolate	2.0mg	8.0mg	2.0mg
				Stearic acid magnesium salt	1.0mg	4.0mg	1.0mg
Total amount of	99.76mg	398.9mg	99.76mg

The particle size of the amlodipine maleate material used in production lots A-F was determined by laser diffraction and demonstrated that less than 90% of the particles were smaller than 204 microns and 50% were smaller than 80 microns.

The amlodipine maleate is ground to a particle size of 10-20 microns and used to produce lots (G) and (H). In addition, another batch of amlodipine maleate, 90% of which had granules smaller than 11 microns and 50% of which had granules smaller than 6 microns, was used to produce batch (I).

c) Production procedure

Batches (A) - (F) and (I) were produced as follows:

amlodipine maleate is sieved through a 500 μm sieve.

Other excipients are sieved through 850 μm sieve.

All excipients except magnesium stearate were mixed in a free fall blender with agitation at about 25rpm for 15 minutes. The pH was checked in a 20% aqueous slurry.

-adding magnesium stearate and mixing the powder blend for a further 5 minutes at about 25 rpm.

Pressing into 2.5mg and/or 10mg tablets with a Korsch EKO eccentric press (eccentric press).

Batch numbers (G) and (H) were produced as follows:

ground amlodipine maleate

Other excipients are sieved through 850 μm sieve.

All excipients except magnesium stearate were mixed in a free fall blender with agitation at about 25rpm for 15 minutes. The pH was checked in a 20% aqueous slurry.

-adding magnesium stearate and mixing the powder blend for a further 5 minutes at about 25 rpm.

Pressing into 2.5mg/10mg tablets with a Korsch EKO eccentric press.

EXAMPLE 2 tablet composition containing microcrystalline cellulose

a) Components

Batch number	(J)	(K)
			Corresponding to the amount of amlodipine base	2.5mg	10mg
Amlodipine maleate	3.21mg	12.8mg
			Microcrystalline cellulose	75.55mg	302.1mg
Predried potato starch	20.0mg	80.0mg
			Stearic acid magnesium salt	0.5mg	2.0mg
Talcum powder	0.5mg	2.0mg
			Total amount of	99.76mg	398.9mg

Production process flow

Amlodipine maleate is sieved through a 500 μm sieve.

Other excipients are sieved through 850 μm sieve.

All excipients except magnesium stearate and talc were mixed in a free fall blender with stirring at about 25rpm for 15 minutes. The pH was checked in a 20% aqueous slurry.

-adding magnesium stearate and talc and mixing the mixed powder for a further 5 minutes at a speed of about 25 rpm.

Pressing into 2.5mg and 10mg tablets with a Korsch EKO eccentric press.

Properties of the tablet composition:

pH of 20% (w/V) slurry: batch number (J) 5.92

Batch number (K) 5.96

EXAMPLE 3 mannitol-containing amlodipine maleate tablet composition

Components

Batch number	(L)
		Corresponding to the amount of amlodipine base	10mg
Amlodipine maleate	12.8mg
		Mannitol	370.1mg
Sodium starch glycolate	8.0mg
		Stearic acid magnesium salt	6.0mg
Talcum powder	2.0mg
		Total amount of	398.9mg

Example 5 stability study of amlodipine maleate tablets

The batch numbers produced in examples 1 to 4 were tested for stability in various packaging forms (HDPE bottles, PVC/PVDC/PE blister packs) or placed in open dishes in an incubator environment adjusted to a temperature of 40. + -. 2 ℃ and a Relative Humidity (RH) of 75. + -. 5%. The contents of active substances and impurities in the extract are analyzed by an HPLC method, and the adopted amlodipine maleate and a reference substance of main degradation impurities are as follows:

amlodipine aspartic acid (Z #204)

Amlodipine-pyridine (Z #202)

In addition to this, two trace impurities Z #203 and Z #205 were examined and identified.

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

In the following tablets, the active substance content is expressed in milligrams and the impurity content in percentages.

A) Stability test at 40 ℃/75% RH open dish (influence of pH)

The time is 0 month	(A)	(B)	(C)	(D)	(E)	(F)
							Content (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 amount of unknown (%)	0.31	0.28	0.27	0.28	0.27	0.27
							1 month later
Content (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 amount of unknown (%)	0.35	0.31	0.58	0.56	0.83	0.72
The time is 3 months
							Content (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 amount of unknown (%)	0.42	0.35	1.11	1.10	1.37	1.10

Stability test under 40 ℃/75% RH conditions, PVC/PE/PVDC blister pack

The time is 0 month	(A)	(B)	(J)	(K)
					Content (mg/tablet)	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 amount of unknown (%)	0.31	0.31	0.46	0.49
					The time is 3 months
Content (mg/tablet)	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 amount of unknown (%)	0.36	0.34	0.45	0.38
The time is 6 months
					Content (mg/tablet)	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 amount of unknown (%)	0.57	0.54	0.64	0.51

Stability study at 40 ℃/75% RH in open dish

The time is 0 month	(J)	(K)
			Content (mg/tablet)	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 amount of unknown (%)	0.42	0.36
			1 month later
Content (mg/tablet)	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 amount of unknown (%)	0.45	0.42
The time is 3 months
			Content (mg/tablet)	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 amount of unknown (%)	0.63	0.56

Stability at 0 deg.C/75% RH in HDPE containers

The time is 0 month	(A)	(B)	(J)	(K)	(L)
						Content (mg/tablet)	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 amount of unknown (%)	0.31	0.31	0.46	0.49	0.40
						The time is 3 months
Content (mg/tablet)	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 amount of unknown (%)	0.33	0.32	0.41	0.49	0.66
The time is 6 months
						Content (mg/tablet)	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 amount of unknown (%)	0.46	0.44	0.44	0.37

^*Amount of Z #202 and Z #204 added together

Stability data for comparison, the composition was at alkaline pH (open dish, 40 ℃/75% RH)

The time is 0 month	(X)
		Content (mg/tablet)	2.52
Z#202(％)	0.04
		Z#203(％)	0.03
Z#204(％)	0.13
		Z#205(％)	0.00
Total amount of unknown (%)	0.30
		1 month later
Content (mg/tablet)	2.43
		Z#202(％)	0.06
Z#203(％)	0.03
		Z#204(％)	1.73
Z#205(％)	0.00
		Total amount of unknown (%)	0.51

Stability test at 40 ℃/75% RH open dish (influence of particle size)

The time is 0 month	(A)	(B)	(G)	(H)	(I)
						Content (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 amount of unknown (%)	0.31	0.28	0.17	0.11	0.26
						1 month later
Content (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 amount of unknown (%)	0.35	0.31	0.22	0.19	-
The time is 2 months
						Content (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 amount of unknown (%)	0.47	0.43	0.63	0.52	0.60
						The time is 3 months
Content (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 amount of unknown (%)	0.42	0.35	0.90	0.74	0.64

The increase in total amounts of known and unknown impurities compared to the stabilizer for t-0 months gave the following results:

the total amount of impurities is increased%	(A)	(B)	(G)	(H)	(I)
						After 3 months at 40 ℃/75% RH	+0.33	+0.24	+1.82	+1.43

Comparative study on stability with Norvasc (commercial amlodipine besylate tablet)

Stability study at 40 ℃/75% RH in the original blister pack

	Norvasc * 5mg batch No. 81040100(DE)		Norvasc * 10mg batch No. 901 05941(NL)
					The time is 0 month
Content (mg/tablet)		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 amount of unknown (%)		0.12		0.12
The time is 3 months
					Content (mg/tablet)		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 amount of unknown (%)		0.38		0.62
					The time is 6 months
Content (mg/tablet)		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 amount of unknown (%)		0.49		0.78

Stability study at 40 ℃/75% RH in open dish

		Norvasc * 2.5.5 mg batch No. 8QP115A (US)	Norvasc * 10mg batch number N-09(ES)
				The time is 0 month	Content (mg/tablet)	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 amount of unknown (%)	0.02	0.34
			1 month later		Content (mg/tablet)	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 amount of unknown (%)	0.10	1.21
				The time is 2 months	Content (mg/tablet)	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 amount of unknown (%)	0.33	2.51
			The time is 3 months		Content (mg/tablet)	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 amount of unknown (%)	0.27	2.76

Example 6 amlodipine maleate capsules

Components

Batch number	(CA)，(CB)
		Corresponding to the amount of amlodipine	5.0mg
Amlodipine maleate	6.42mg
		Microcrystalline cellulose	72.6mg
Predried potato starch	20.0mg
		Stearic acid magnesium salt	0.5mg
Total amount of	99.52mg

Batch number	(CC)	(CX)
			Corresponding to the amount of amlodipine	5.0mg	5.0mg
Amlodipine maleate	6.42mg	6.42mg
			Anhydrous calcium hydrogen phosphate	31.5mg	31.5mg
Magnesium oxide	-	1.5mg
			Microcrystalline cellulose	62.0mg	62.0mg
Sodium starch glycolate	2.0mg	2.0mg
			Stearic acid magnesium salt	1.0mg	1.0mg
Total amount of	102.92mg	104.43mg

Capsule pH at time 0

Batch number	Dosage form	Calcium hydrogen phosphate type	pH of capsule content in 20% (m/V) slurry
				(CC)	5.0mg	Di CAFOS A	6.10
(CX)	5.0mg	Di CAFOS A	9.59

Batch number (CA) was produced according to the following steps:

amlodipine maleate is sieved through a 500 μm sieve.

Other excipients are sieved through 850 μm sieve.

All excipients except magnesium stearate were mixed in a free fall blender with agitation at about 25rpm for 15 minutes. The pH was checked in a 20% aqueous slurry.

-adding magnesium stearate and mixing the powder blend for a further 5 minutes at about 25 rpm.

-filling the mixed powder into gelatin capsules.

Batch number (CB) was produced according to the following steps:

amlodipine maleate is sieved through a 500 μm sieve.

Other excipients are sieved through 850 μm sieve.

All excipients except magnesium stearate were mixed in a free fall blender with agitation at about 25rpm for 15 minutes. The pH was checked in a 20% aqueous slurry.

-adding magnesium stearate and mixing the powder blend for a further 5 minutes at about 25 rpm.

-filling the mixed powder into HPMC capsules.

Batch number (CC) was produced according to the following steps:

amlodipine maleate is sieved through a 500 μm sieve.

Other excipients are sieved through 850 μm sieve.

All excipients except magnesium stearate were mixed in a free fall blender with agitation at about 25rpm for 15 minutes. The pH was checked in a 20% aqueous slurry.

-adding magnesium stearate and mixing the powder blend for a further 5 minutes at about 25 rpm.

-filling the mixed powder into gelatin capsules.

Lot number (CX) was produced by the following procedure:

amlodipine maleate is sieved through a 500 μm sieve.

Other excipients are sieved through 850 μm sieve.

The remaining microcrystalline cellulose, anhydrous dibasic calcium phosphate and sodium starch glycolate are added and the mixture is mixed in a free fall mixer at about 25rpm for 15 minutes. The pH was checked in a 20% aqueous slurry.

-adding magnesium stearate and mixing the powder blend for a further 5 minutes at about 25 rpm.

Filling the mixed powder into gelatin capsules by an automatic filling machine.

Example 7 stability study of amlodipine maleate capsules

The batch prepared in example 6 was examined for stability essentially as described in example 5.

Production procedure

Amlodipine maleate is sieved through a 500 μm sieve.

Other excipients are sieved through 850 μm sieve.

All excipients except magnesium stearate and talc were mixed in a free fall blender with stirring at about 25rpm for 15 minutes. The pH was checked in a 20% aqueous slurry.

-adding magnesium stearate and talc and mixing the mixed powder for a further 5 minutes at a speed of about 25 rpm.

Pressing into 10mg tablets with a Korsch EKO eccentric press.

Example 4 amlodipine maleate tablets with pH higher than 7 (example for comparison)

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

Batch number	(X)
		Corresponding to the amount of amlodipine base	2.5mg
Amlodipine maleate anhydrous calcium hydrogen phosphate (pH6.69)	3.21mg31.5mg
		ponderosum magnesium oxide	0.5mg
Microcrystalline cellulose	62.05mg
		Sodium starch glycolate	2.0mg
Stearic acid magnesium salt	1.0mg
		Total amount of	100.26mg

Production process flow

Amlodipine maleate is sieved through a 500 μm sieve.

Other excipients are sieved through 850 μm sieve.

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

The remaining microcrystalline cellulose, anhydrous dibasic calcium phosphate and sodium starch glycolate are added and the mixture is mixed in a free fall mixer at about 25rpm for 15 minutes. The pH was checked in a 20% aqueous slurry.

-adding magnesium stearate and mixing the powder blend for a further 5 minutes at about 25 rpm.

Pressing into 2.5mg tablets and scaled up 10mg tablets with a Korsch EKO eccentric press.

Stability test under 40 ℃/75% RH conditions, PVC/PE/PVDC blister pack

The time is 0 month	(CA)	(CB)
			Content (wt.)	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 amount of unknown substance	0.32	0.31
			The time is 3 months
Content (wt.)	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 amount of unknown substance	0.39	0.38
The time is 6 months
			Content (wt.)	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 amount of unknown substance	0.45	0.42

Two sets of 1 month stability survey data in open dishes

The time is 0 month	(CC)	(CX)
			Content (wt.)	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 amount of unknown substance	0.28	0.29
			The time is 1 month under the condition of 25 ℃/60 percent RH
Content (wt.)	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 amount of unknown substance	0.28	0.28
The time is 1 month under the condition of 40 ℃/75 percent RH
			Content (wt.)	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 amount of unknown substance	0.28	0.62

Stability investigation in HDPE containers

The time is 0 month	(CA)	(CB)
			Content (wt.)	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 amount of unknown substance	0.31	0.30
			The time is 3 months under the condition of 25 ℃/60 percent RH
Content (wt.)	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 amount of unknown substance	0.30	0.32
The time is 3 months under the condition of 40 ℃/75 percent
			Content (wt.)	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 amount of unknown substance	0.29	0.32

Stability study of commercial Amlor * (amlodipine besylate) capsules

Stability considerations in the original blister pack

Amlor * 5mg Capsule batch No. 9037002	The time is 0 month	The time is 3 months, 40 ℃/75 percent
			Content (wt.)	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 amount of unknown substance	0.06	0.37

It will be apparent to those skilled in the art from this disclosure that various further changes and modifications can be made, or equivalents employed, in the practice of the concepts and embodiments thereof without departing from the spirit and scope of the invention as defined in the following claims.

Claims (23)

1. A pharmaceutical composition comprising an effective amount of amlodipine maleate and at least one pharmaceutically acceptable excipient, wherein the pH of said composition is in the range of 5.5 to 7.0 when the concentration of the composition in a slurry with deionized water is 20% wt, said composition being in solid form.

2. The composition of claim 1, wherein the pH of the composition is 6.0-7.0.

3. The composition of claim 1 or 2, wherein said excipient is calcium phosphate or microcrystalline cellulose.

4. The composition of claim 1 or 2, wherein the excipient comprises calcium phosphate and microcrystalline cellulose.

5. The composition of claim 3, wherein the excipient is calcium phosphate.

6. The composition of claim 3, wherein the excipient is microcrystalline cellulose.

7. The composition of claim 1, further comprising an acidic pH adjusting agent.

8. The composition of claim 1, wherein the composition is in the form of a tablet.

9. The composition of claim 8 further comprising an outer moisture and/or light barrier layer surrounding said tablet.

10. The composition of claim 1, wherein said composition is in the form of a capsule.

11. The composition according to claim 1, wherein said amlodipine maleate is in an amount corresponding to 1.0 to 25mg of amlodipine free base.

12. The composition of claim 11, wherein the amount of amlodipine maleate in the composition is equivalent to 1.25, 2.5, 5 or 10mg of amlodipine free base.

13. A process for the manufacture of the composition according to claim 1, comprising mixing amlodipine maleate and at least one pharmaceutically acceptable excipient to obtain a mixture having a pH in the range of 5.5 to 7.0, respectively.

14. The process of claim 13, wherein the pH of the mixture is in the range of 6.0 to 7.0.

15. The process of claim 13, further comprising compressing the mixture into a tablet.

16. The process of claim 13, further comprising filling a capsule with the mixture to form a pharmaceutical dosage form.

17. The process of claim 13, wherein the mixing is performed by wet granulation.

18. The process of claim 13, wherein the mixing is performed by a dry process.

19. The process according to claim 18, wherein said amlodipine maleate is in the form of solid particles having an average particle size of at least 100 microns, mixed with excipients.

20. The process of claim 13, wherein said amlodipine maleate is in the form of solid particles having an average particle size of at least 20 microns, and further comprising the step of mixing said mixture with one or more suitable excipients to provide a pH in the range of 5.5 to 7.0.

21. The process of claim 20, wherein the average particle size is at least 100 microns.

22. A tablet made by the process of any one of claims 14, 15, 17, 18, 19.

23. Use of a composition according to any one of claims 1 to 12 in the manufacture of a medicament for the treatment of angina pectoris, hypertension or heart failure.