Immediate release oral pharmaceutical forms of amlodipine with increased API content

Abstract

The present invention provides an immediate release oral pharmaceutical composition comprising 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 additional pharmaceutical excipients.

Description

[Technical Field]

[0001] The present invention provides a composition for an immediate-release oral pharmaceutical form comprising 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 additional pharmaceutical additives. Using the composition of the present invention, the immediate-release oral pharmaceutical form of amlodipine besylate prepared has the advantages of a high content of amlodipine besylate and a low content of additives, while maintaining the requirements for pharmaceutical quality.

[0002] The present invention relates to the field of pharmaceutical formulations and compositions for the composition of an immediate release oral pharmaceutical form of amlodipine besylate. [Background technology]

[0003] High blood pressure, or hypertension, is a serious health problem in many countries. According to the National Heart, Blood, and Lung Institute, approximately one in three adults in the United States alone is believed to have high blood pressure. If left unchecked, high blood pressure is considered a significant risk factor for cardiovascular and other diseases, including coronary heart disease, myocardial infarction, congestive heart failure, stroke, and renal failure. High blood pressure is classified as primary (essential) or secondary hypertension. Primary hypertension has an unknown cause 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 drugs or surgical intervention, or by abnormalities in the kidneys, cardiovascular system, or endocrine system.

[0004] Amlodipine is a calcium channel blocker. It affects the movement of calcium into the cells of the heart and blood vessels. As a result, amlodipine relaxes the blood vessels, increasing the supply of blood and oxygen to the heart while reducing the heart's workload.

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

[0006] The environmental burden of pharmaceutical packaging is enormous because the aluminum and plastic used to form blister packs are tightly packed together, making them difficult, even impossible, to recycle effectively. Reseparating these materials requires a large amount of energy, and even then, the resulting aluminum is not of the same high quality as virgin aluminum. As immediate-release oral pharmaceutical dosage forms become larger, the primary packaging must also become larger, resulting in a corresponding increase in the amount of waste material.

[0007] Additionally, there is an environmental impact caused by the extensive transportation steps required for the final product, from manufacturer to wholesaler to pharmacy. In the pharmaceutical industry, each box of final product must travel through several stages before reaching the customer, often involving international shipping routes. This is particularly true for generic drugs, and even for products sold in the millions, such as amlodipine. The volume of the final product determines the efficiency of transportation and storage, with products with high volume requiring more space and more frequent transportation than the same product with a smaller volume.

[0008] Furthermore, if exposing patients to additives can be avoided, it should be avoided. Immediate-release oral pharmaceutical forms are administered with the goal of exposing the human body to the drug, not the additive. The use of additives in products where additives can be avoided is a waste of resources in the pharmaceutical industry, especially when used in large quantities. Furthermore, the global demand for additives is constantly increasing, and the chemical industry's supply capacity cannot keep up with the demand, making this waste of resources even more problematic.

[0009] Patented formulations of amlodipine tablets, for example, achieve an amlodipine content of 20.0 wt% in European Patent No. 2359815(A1), 2.5 wt% in International Publication No. 2004075825(A2), and 2.0 wt% to 10.0 wt% in European Patent No. 1932528. The highest amlodipine content of 25.0% has been found to be possible in Chinese Patent No. 104739799(B). A 2004 paper by Abdoh et al. (A. Abdoh et al., Amlodipine Besylate-Excipient Interaction in Solid Dosage Form; Pharmaceutical Development and Technology, 2004, Vol. 9, No. 1, pp. 15-24) examined the compatibility of amlodipine besylate with various drug excipients in solid dosage forms. Binary (1:1 w / w) or multi-component (1:1:1 w / w) mixtures of amlodipine besylate and excipients were incubated under "stress stability" conditions (e.g., elevated temperature and / or relative humidity). However, this study focused on the stability of amlodipine besylate and excipient powders under such conditions. Because no immediate-release oral pharmaceutical compositions were prepared, the suitability of such mixtures for oral pharmaceutical compositions was not clear from this study. It is unclear from previous patents or studies whether higher levels of amlodipine content are possible.

[0010] The present inventors have discovered a method for producing an immediate-release oral pharmaceutical formulation of amlodipine with an increased amlodipine content, which can greatly help solve the above problems. Currently, 5 mg amlodipine tablets on the market weigh approximately 120 mg, and 10 mg amlodipine tablets weigh approximately 190 mg. The additive contents are 113 mg per tablet and 176 mg per tablet, respectively. According to the present invention, the additive contents can be reduced to 0.035 mg per 5 mg tablet and 0.070 mg per 10 mg tablet, eliminating up to 99.96% of the additives currently used in tablets.

[0011] Minimizing the amount of excipients required reduces the size of immediate release oral pharmaceutical forms, which in turn reduces blister size and the overall size of the final product. This allows for the use of smaller blister sizes than previously possible, allowing the final product to be a fraction of its current volume. This results in more efficient transportation, a reduced carbon footprint for the product, and negligible packaging waste.

[0012] It also reduces the amount of excipients administered to patients to the bare minimum, dramatically reducing the burden on the pharmaceutical industry from sourcing and processing unnecessarily large amounts of excipients.

[0013] Since amlodipine is one of the most prescribed drugs in the world, it is synthesized in many production plants and the final product is manufactured globally. The facilities and equipment required to carry out the production of a given formulation are readily available. The following composition and preparation examples can be realistically realized at any production site intended for tablet manufacturing. [Brief explanation of the drawings]

[0014] [Figure 1] 1 shows graphs depicting exemplary results of dissolution testing in the following examples. [Example]

[0015] Example 1 - Preparation of Amlodipine Tablets Step 1. Pass all additives from any of Tables 1-6 (amounts adjusted according to the desired batch size) through a suitable screen. For the avoidance of doubt, screen in this context refers to a sieve. Preferably, the sieve has a pore size of 250 μm to 710 μm. Step 2. All excipients except for the optional lubricant are first blended in a suitable blender at 10 rpm for 5 minutes. For the avoidance of doubt, it is clear from the table below that amlodipine besylate is added; it can be added in step 1 or step 2. Step 3. An optional lubricant is then added to the blend and blended again for 3 minutes at 10 rpm. Step 4. Compress the final blend into tablets. Step 5. A film coating can be added to the tablets.

[0016] Composition example [Table 1]

[0017] [Table 2]

[0018] [Table 3]

[0019] [Table 4]

[0020] [Table 5]

[0021] [Table 6]

[0022] [Table 7]

[0023] [Table 8]

[0024] [Table 9]

[0025] [Table 10]

[0026] [Table 11]

[0027] [Table 12]

[0028] [Table 13]

[0029] [Table 14]

[0030] Example 2 - Exemplary tablet weights forming different compositions [Table 15]

[0031] Example 3 - Analytical Results [Table 16]

[0032] Dissolution tests were performed on the tablets of Example 3 in 900 ml of pH 6.8 buffer at 37°C using USP Apparatus 1 set at 100 rpm. The resulting dissolution curves show that the tablets rapidly dissolved, with complete dissolution occurring within 30 minutes. The results are shown in Table 7 and Figure 1.

[0033] [Table 17]

[0034] The immediate release oral pharmaceutical form prepared under the present invention meets the requirements of the USP monograph for amlodipine tablets, thus ensuring its quality conformity.

[0035] Specific embodiments of the present invention are listed below. 1. A pharmaceutical composition in an immediate release oral pharmaceutical form, comprising 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 additional pharmaceutical additives. The preferred amount of amlodipine besylate is 30.1% to 81.5% by weight. 2. The pharmaceutical excipients described in embodiment 1 consist of, but are not limited to, one or more of disintegrants, lubricants, fillers, and glidants. 3. Disintegrants according to embodiments 1 and 2 include, but are not limited to, microcrystalline cellulose, sodium alginate, sodium starch glycolate, croscarmellose sodium, crospovidone, and any "super disintegrant." 4. The fillers described in embodiment 2 consist of, but are not limited to, cellulose, lactose, mannitol, starch, sucrose, and calcium phosphate. 5. Lubricants described in embodiment 2 include, but are not limited to, calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulfate, and magnesium lauryl sulfate. 6. Glidants according to embodiment 2 consist of, but are not limited to, silica derivatives, talc, and corn starch. 7. The immediate release oral pharmaceutical form according to embodiment 1 includes a tablet form or a film-coated tablet form. In the case of a film-coated tablet form, the weight percentage refers to the weight of the tablet core. 8. The amlodipine besylate salt described in embodiment 1 also encompasses other pharmaceutically acceptable salts of amlodipine. 9. The composition of embodiment 1 has a dose range of 2.5 mg to 20 mg of amlodipine. A preferred dose range is 5 mg to 10 mg of 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% by weight of a disintegrant, and 0% to 74.4% by weight of additional 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 more than 50% to 99.5% by weight, preferably 75% to 99.5% by weight, more preferably 80% to 99.5% by weight, more preferably 81.5% to 99.5% by weight. 3. An immediate release oral pharmaceutical composition according to embodiment 1 or 2, wherein the additional pharmaceutical excipients comprise one or more components selected from the group comprising disintegrants, lubricants, fillers and glidants. 4. The immediate release oral pharmaceutical composition according to any one of embodiments 1 to 3, wherein the disintegrant is one or more disintegrants selected from the group comprising microcrystalline cellulose, sodium croscarmellose, carboxymethylcellulose, alginic acid, sodium alginate and derivatives thereof, sodium starch glycolate (e.g., Glycolys®, Explotab®, Vivastar® P), croscarmellose sodium (e.g., Ac Di Sol®, Solutab®, Vivasol®), crospovidone (e.g., Kollidon®, Kollicoat®) and other superdisintegrants, as well as cellulose, lactose, mannitol, starch and sucrose. A superdisintegrant is a disintegrant that can still achieve an adequate disintegrating effect even when used at a low concentration, such as 0.5 to 5%, in a typical pharmaceutical formulation. Other examples of superdisintegrants according to the present invention include disintegrants such as L-hydroxypropylcellulose, sodium carboxymethyl starch (e.g., Primogel®), magnesium aluminum silicate (e.g., Veegum® HV), calcium silicate, cross-linked alginic acid (such as Satiargine®, also known as alginic acid National Formulary (NF)), and soybean derivatives / polysaccharides (e.g., Emcosoy®). 5. An immediate release oral pharmaceutical composition according to embodiment 3 or 4, wherein the filler is one or more fillers selected from the group comprising cellulose, lactose, mannitol, starch, sucrose, and calcium phosphate, calcium carbonate, maltodextrin, sorbitol and dextrin. Those skilled in the art know that certain additives used as fillers, such as cellulose, lactose, mannitol, starch and sucrose, can also act as disintegrants.In the embodiment in which one of them is included as a disintegrant, they are not additionally used as a filler.In other words, in the embodiment of the present invention, their inclusion as "disintegrant" or "filler" is mutually exclusive. 6. The immediate release oral pharmaceutical composition of any one of embodiments 3 to 5, wherein the lubricant is one or more lubricants selected from the group comprising calcium stearate, magnesium stearate, stearic acid, sodium lauryl 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 the group comprising silica derivatives such as silicon dioxide, talc, and corn starch. 8. An immediate release oral pharmaceutical composition according to any one of embodiments 1 to 7, in tablet form or film-coated tablet form, in which in 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 dose range of 2.5 mg to 20 mg, preferably 5 mg to 10 mg. 10. A method for preparing a tablet comprising the composition of any one of embodiments 1-9, comprising: a) passing 25.1 wt% to 99.5 wt% of amlodipine besylate, at least 0.5 wt% of a disintegrant, and 0 wt% to 74.4 wt% of additional pharmaceutical excipients through a screen; b) blending all excipients except the lubricant; c) optionally adding a lubricant to the blend of c) and blending; d) compressing the blend obtained from c) into tablets; e) optionally applying a film coating to the tablets; Including, The method wherein amlodipine besylate is added in either 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% by weight of a disintegrant, and 0% to 74.4% by weight of additional pharmaceutical excipients.

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

3. 3. The immediate release oral pharmaceutical composition of claim 1, wherein the additional pharmaceutical excipients comprise one or more components selected from the group comprising disintegrants, lubricants, fillers and glidants.

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

5. 5. The immediate release oral pharmaceutical composition of claim 3, wherein the filler is one or more fillers selected from the group comprising cellulose, lactose, mannitol, starch, sucrose, and calcium phosphate, calcium carbonate, maltodextrin, sorbitol, and dextrin.

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

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

8. 8. The immediate release oral pharmaceutical composition according to any one of claims 1 to 7, which is in tablet form or film-coated tablet form, and in said film-coated tablet form, the weight percentages refer to the weight of the tablet core.

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

10. A method for preparing a tablet comprising the composition of any one of claims 1 to 9, comprising the steps of: 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 additional pharmaceutical excipients through a screen; b) blending all excipients except the lubricant; c) optionally adding a lubricant to the blend of c) and blending; d) compressing the blend obtained from c) into tablets; e) optionally applying a film coating to said tablets; Including, The method wherein amlodipine besylate is added in either step a) or b).

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