Immediate release oral pharmaceutical forms of amlodipine with increased API content

Abstract

The present invention provides an immediate release oral pharmaceutical composition comprising from 25.1% to 99.5% by weight of amlodipine besylate, at least 0.5% by weight of a disintegrant and from 0% to 74.4% by weight of other pharmaceutical excipients.

Description

illustrate

[0001] The present invention provides a composition of an immediate release oral pharmaceutical form, which comprises 25.1% to 99.5% by weight of amlodipine besylate, at least 0.5% of a disintegrant and 0% to 74.4% of other pharmaceutical excipients. Using the composition of the present invention, the prepared amlodipine besylate immediate release oral pharmaceutical form has the advantages of a higher percentage of amlodipine besylate content and a lower percentage of excipient content, and meets the drug quality requirements. Technical Field

[0002] The invention belongs to the field of pharmaceutical preparations and relates to a material composition for an immediate-release oral pharmaceutical form of amlodipine besylate. Background Art

[0003] High blood pressure is a serious health problem in many countries. In the United States alone, about one-third of adults are thought to have high blood pressure, according to the National Heart Blood and Lung Institute. If left uncontrolled, high blood pressure is considered a significant risk factor for cardiovascular disease and other conditions, including coronary heart disease, myocardial infarction, congestive heart failure, stroke, and kidney failure. High blood pressure is classified as either primary (essential) hypertension or secondary hypertension. The cause of primary hypertension is unknown and may be related to several environmental, lifestyle, and genetic factors such as stress, obesity, smoking, lack of exercise, and sodium intake. Secondary hypertension can be caused by medication or surgical intervention or abnormalities of the renal, cardiovascular, or endocrine systems.

[0004] Amlodipine is a calcium channel blocker. It affects the movement of calcium into the cells of the heart and blood vessels. Thus, amlodipine relaxes blood vessels and increases the blood and oxygen supply to the heart while reducing its workload.

[0005] Amlodipine is currently administered in the form of oral tablets (e.g., Norvasc) or refrigerated liquid formulations. Typical tablet formulations of the immediate release oral drug form of amlodipine contain about 2% to 25% amlodipine besylate. The standard dose is 2.5 mg to 10 mg of amlodipine, and the typical dosage form is a tablet. Amlodipine is one of the most commonly prescribed drugs worldwide. Amlodipine tablets are usually and necessarily packaged in PVC / ALU or ALU / ALU blisters to ensure product stability.

[0006] The environmental burden of pharmaceutical packaging is enormous. This is because the aluminum and plastic used to form blister packs are difficult or even impossible to recycle effectively because the materials are sealed together. Separating the materials again requires a lot of energy, and even then, the quality of the aluminum obtained from them is not as good as new aluminum. The larger the immediate release oral dosage form, the larger the primary packaging must be, and therefore the more waste is generated.

[0007] In addition, there is the environmental burden caused by the numerous transport steps required for finished products, such as from manufacturer to wholesaler to pharmacy. Each box of finished product in the pharmaceutical industry needs to travel through several steps before it reaches the customer, often involving global shipping routes. This is especially true for generic drugs, and even more so for products that sell in the millions, such as amlodipine. The volume of the finished product determines the efficiency of transportation and storage, as a large product requires more space and more shipments than a smaller version of the same product.

[0008] Furthermore, when patient exposure to excipients can be avoided, this should be done. The purpose of administering an immediate-release oral drug form is to expose the body to the drug rather than the excipients. The use of excipients in products where excipients can be avoided is a waste of pharmaceutical industry resources, especially when used in large quantities. Furthermore, the global demand for excipients continues to increase, while the chemical industry’s ability to supply lags behind this demand, making this waste of resources even more problematic.

[0009] Patent combinations of amlodipine tablets such as EP2359815A1 reach an amlodipine content of 20.0 wt %, WO2004075825A2 reaches 2.5 wt %, and EP1932528 successfully reaches 2.0 wt % to 10.0 wt %. In patent CN104739799B, a maximum amlodipine content of 25.0% may be found. In Abdoh et al.'s 2004 paper (A.Abdoh et al., Amlodipine Besylate-Excipients Interaction in Solid Dosage Form, Pharmaceutical Development and Technology, 2004, Vol. 9, No. 1. pp. 15-24), the compatibility of amlodipine besylate with various pharmaceutical excipients in its solid formulation was tested. A binary (1:1, w / w) mixture or a multi-component mixture (1:1:1, w / w) of amlodipine besylate and excipients was incubated under "harsh stability" conditions (e.g., high temperature and / or relative humidity). However, the focus of the study was to investigate the stability of powders of amlodipine besylate and excipients under such conditions. No immediate release oral pharmaceutical composition was prepared, so the suitability of such mixtures for oral pharmaceutical compositions could not be significantly seen from this study. There was no evidence from previous patents or studies that the amlodipine content could be achieved at any higher level.

[0010] We have discovered a way to produce an immediate release oral pharmaceutical form of amlodipine with an increased percentage of amlodipine content, which can greatly help solve the problems listed. Currently, the amlodipine 5 mg tablet on the market weighs about 120 mg, and the amlodipine 10 mg tablet weighs about 190 mg. The excipient content is 113 mg per tablet and 176 mg per tablet, respectively. Through the present invention, the excipient content can be reduced to 0.035 mg per 5 mg tablet and 0.070 mg per 10 mg tablet, making up to 99.96% of the excipients in the current tablets discarded.

[0011] With the amount of excipients required reduced to a minimum, the immediate release oral drug form shrinks, which in turn shrinks the size of the blister and shrinks the size of the entire finished product. Smaller blisters that were previously impossible can now be used, allowing the finished product to be a fraction of the current volume. This in turn allows for more efficient shipping, reduces the carbon footprint of the product, and generates only a fraction of the packaging waste.

[0012] It also reduces the amount of excipients administered to patients to essential levels and greatly relieves the pharmaceutical industry from the pressure to find and process unnecessary large quantities of excipients.

[0013] Since amlodipine is one of the most commonly prescribed drugs in the world, it is synthesized in many production plants and the finished product is produced worldwide. The facilities and equipment required for the production of the given combination are easily available. The following embodiments of the compositions and preparations can be actually implemented at any production site intended for tableting. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Shown are graphs representing exemplary results of the dissolution studies described below in the Examples. Example Example 1 - Exemplary Preparation of Amlodipine Tablets

[0015] Step 1. Pass all excipients from any of Tables 1 to 6 (amounts scaled according to the desired batch size) through a suitable sieve. For the avoidance of doubt, sieves in this context refer to screens. Preferably, the screen has a pore size of 250µm – 710µm. Step 2. First blend all excipients except any optional lubricant in a suitable blender at 10 rpm for 5 minutes. For the avoidance of doubt, based on the table below, it is clear that amlodipine besylate was added; it could have been added in step 1 or 2. Step 3. Any optional lubricant was then added to the blend and blended again at 10 rpm for 3 minutes. Step 4. Compress the final blend into tablets. Step 5. A film coating may be added to the tablets. Exemplary compositions

[0016] Table 1 - Composition Example 1

[0017] Table 2 - Composition Example 2

[0018] Table 3 - Composition Example 3

[0019] Table 4 - Composition Example 4

[0020] Table 5 - Composition Example 5

[0021] Table 6 - Composition Example 6

[0022] Table 7 - Composition Example 7

[0023] Table 8 - Composition Example 8

[0024] Table 9 - Composition Example 9

[0025] Table 10 - Composition Example 10

[0026] Table 11 - Composition Example 11

[0027] Table 12 - Composition Example 12

[0028] Table 13 - Composition Example 13

[0029] Table 14 - Composition Example 14 Example 2 - Exemplary Tablet Weights from Different Compositions

[0030] Table 15 - Summary of Exemplary Tablet Weights Example 3 - Analysis Results

[0031] Table 16 - Disintegration time and resistance to crushing

[0032] The tablets of Example 3 were subjected to dissolution studies in 900 ml of pH 6.8 buffer at 37°C in USP Apparatus 1 set to 100 rpm. The resulting dissolution profile demonstrated that the tablets dissolved rapidly and were completely dissolved within 30 minutes. The results are shown in Tables 7 and Figure 1 middle.

[0033] Table 17 - Dissolution Study Data in Tabular Format

[0034] The quality suitability of the immediate release oral pharmaceutical form prepared under the present invention is satisfied as it meets the requirements of the USP monograph for amlodipine tablets.

[0035] Some embodiments of the present invention are listed below: 1. A pharmaceutical composition in the form of an immediate release oral drug comprising 25.1% to 99.5% by weight of amlodipine besylate, at least 0.5% of a disintegrant and 0% to 74.4% of other pharmaceutical excipients. The preferred amount of amlodipine besylate is 30.1% to 81.5% by weight. 2. The pharmaceutical excipient described in embodiment 1 is composed of one or more disintegrants, lubricants, fillers and glidants, but is not limited thereto. 3. The disintegrant according to embodiment 1 and embodiment 2 consists of microcrystalline cellulose, sodium alginate, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, crospovidone and any "super disintegrant", but is not limited thereto. 4. The filler described in embodiment 2 is composed of cellulose, lactose, mannitol, starch, sucrose and calcium phosphate, but is not limited thereto. 5. The lubricant according to embodiment 2, which consists of calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulfate and magnesium lauryl sulfate, but is not limited thereto. 6. The glidant described in embodiment 2 consists of a silicon dioxide derivative, talc and corn starch, but is not limited thereto. 7. The immediate release oral pharmaceutical form of embodiment 1, which is in tablet form or film-coated tablet form. In the case of film-coated tablet form, the weight percentage refers to the weight of the tablet core. 8. The amlodipine besylate according to embodiment 1, which further requires other pharmaceutically acceptable salts of amlodipine. 9. The composition of embodiment 1, which is used in a dosage range of 2.5 mg amlodipine to 20 mg amlodipine. The preferred dosage range is 5 mg amlodipine to 10 mg amlodipine.

[0036] Further embodiments of the present invention are listed below: 1. An immediate release oral pharmaceutical composition comprising 25.1% to 99.5% by weight of amlodipine besylate, at least 0.5% of a disintegrant and 0% to 74.4% of other pharmaceutical excipients. 2. The immediate release oral pharmaceutical composition according to embodiment 1, wherein the amount of amlodipine besylate is 30.1% to 81.5% by weight. In another embodiment, the amount of amlodipine besylate in the immediate release oral pharmaceutical composition is greater than 50% to 99.5% by weight, preferably 75% to 99.5% by weight, more preferably 80% to 99.5% by weight, more preferably 81.5% to 99.5% by weight. 3. The immediate release oral pharmaceutical composition according to embodiment 1 or 2, wherein the other pharmaceutical excipients include one or more components selected from disintegrants, lubricants, fillers and glidants. 4. An immediate release oral pharmaceutical composition according to any one of embodiments 1 to 3, wherein the disintegrant is one or more disintegrants selected from microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, carboxymethyl cellulose, alginic acid, sodium alginate and its derivatives, sodium starch glycolate (e.g., Glycolys®, Explotab®, Vivastar® P), cross-linked sodium carboxymethyl cellulose (e.g., Ac Di Sol®, Solutab®, Vivasol®), crospovidone (e.g., Kollidon®, Kollicoat®) and other super disintegrants, as well as cellulose, lactose, mannitol, starch and sucrose. Superdisintegrants are disintegrants that can usually be used in small concentrations, for example 0.5 to 5% in a typical pharmaceutical formulation, while still achieving a suitable disintegration effect. Examples of other superdisintegrants according to the invention are disintegrants such as L-hydroxypropylcellulose, sodium carboxymethyl starch (e.g. Primogel®), magnesium aluminum silicate (e.g. Veegum® HV), calcium silicate, cross-linked alginic acid (also known as National Formulary of Alginate (NF), e.g. Satialgine®), soy derivatives / polysaccharides (e.g. Emcosoy®). 5. The immediate release oral pharmaceutical composition according to any one of embodiments 3 or 4, wherein the filler is one or more fillers selected from cellulose, lactose, mannitol, starch, sucrose, and calcium phosphate, calcium carbonate, maltodextrin, sorbitol and dextrin. It is known to the skilled person that certain excipients used as fillers can also act as disintegrants, such as cellulose, lactose, mannitol, starch and sucrose. In embodiments comprising one of these excipients as a disintegrant, they are not additionally used as fillers, in other words, their inclusion as "disintegrants" or "fillers" in embodiments of the present invention is mutually exclusive. 6. The immediate release oral pharmaceutical composition according to any one of embodiments 3 to 5, wherein the lubricant is one or more lubricants selected from calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulfate and magnesium lauryl sulfate. 7. An immediate release oral pharmaceutical composition according to any one of embodiments 3 to 6, wherein the glidant is one or more glidants selected from silicon dioxide derivatives such as silicon dioxide, talc and corn starch. 8. The immediate release oral pharmaceutical composition according to any one of embodiments 1 to 7, which is in the form of a tablet or a film-coated tablet, wherein in the film-coated tablet form, the weight percentage refers to the weight of the tablet core. 9. An immediate release oral pharmaceutical composition according to any one of embodiments 1 to 8, wherein amlodipine besylate is contained in a dosage range of 2.5 mg to 20 mg, preferably 5 mg to 10 mg. 10. A method for preparing a tablet comprising the composition according to any one of embodiments 1 to 9, the method comprising: a) passing 25.1% to 99.5% by weight of amlodipine besylate, at least 0.5% by weight of a disintegrant and 0% to 74.4% by weight of other pharmaceutical excipients through a sieve, b) Blend all excipients except lubricant, c) optionally adding a lubricant to the blend of c) and blending, d) compressing the blend obtained from c) into tablets, and e) optionally adding a film coating to the tablet, Wherein amlodipine besylate is added in step a) or b).

Claims

1. An immediate release oral pharmaceutical composition comprising 25.1% to 99.5% by weight of amlodipine besylate, at least 0.5% of a disintegrant and 0% to 74.4% of other pharmaceutical excipients.

2. An immediate release oral pharmaceutical composition according to claim 1, wherein the amount of amlodipine besylate is 30.1% to 81.5% by weight.

3. An immediate release oral pharmaceutical composition according to claim 1 or 2, wherein the other pharmaceutical excipients include one or more components selected from disintegrants, lubricants, fillers and glidants.

4. An immediate release oral pharmaceutical composition according to any one of claims 1 to 3, wherein the disintegrant is one or more disintegrants selected from microcrystalline cellulose, croscarmellose sodium, carboxymethyl cellulose, alginic acid, sodium alginate and its derivatives, sodium starch glycolate (e.g. Glycolys®, Explotab®, Vivastar® P), croscarmellose sodium (e.g. Ac DiSol®, Solutab®, Vivasol®), crospovidone (e.g. Kollidon®, Kollicoat®) and other superdisintegrants, and cellulose, lactose, mannitol, starch and sucrose.

5. An immediate release oral pharmaceutical composition according to any one of claims 3 or 4, wherein the filler is one or more fillers selected from cellulose, lactose, mannitol, starch, sucrose, and calcium phosphate, calcium carbonate, maltodextrin, sorbitol and dextrin.

6. The immediate release oral pharmaceutical composition according to any one of claims 3 to 5, wherein the lubricant is one or more lubricants selected from calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulfate and magnesium lauryl sulfate.

7. An immediate release oral pharmaceutical composition according to any one of claims 3 to 6, wherein the glidant is one or more glidants selected from silicon dioxide derivatives such as silicon dioxide, talc and corn starch.

8. An immediate release oral pharmaceutical composition according to any one of claims 1 to 7, which is in the form of a tablet or a film-coated tablet, wherein in the film-coated tablet form, the weight percentage refers to the weight of the tablet core.

9. An immediate release oral pharmaceutical composition according to any one of claims 1 to 8, wherein amlodipine besylate is contained in a dosage range of 2.5 mg to 20 mg, preferably 5 mg to 10 mg.

10. A method for preparing a tablet comprising the composition according to any one of claims 1 to 9, the method comprising: a) passing 25.1% to 99.5% by weight of amlodipine besylate, at least 0.5% by weight of a disintegrant and 0% to 74.4% by weight of other pharmaceutical excipients through a sieve, b) Blend all excipients except lubricant, c) optionally adding a lubricant to the blend of c) and blending, d) compressing the blend obtained from c) into tablets, and e) optionally adding a film coating to the tablet, Wherein amlodipine besylate is added in step a) or b).

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