Pregabalin immediate release tablets with increased API content

Abstract

The present invention provides an immediate release oral pharmaceutical composition, for example, a tablet, comprising 50.1% by weight or more of pregabalin, 8.0% by weight or more of polyvinylpyrrolidone, 3.0% by weight or more of croscarmellose sodium, and 0% to 38.9% by weight of additional pharmaceutical excipients.

Description

[Technical Field]

[0001] The present invention provides an immediate-release tablet composition comprising 50.1% by weight or more pregabalin (median particle size less than 200 μm), 8.0% by weight or more polyvinylpyrrolidone, 3.0% by weight or more croscarmellose sodium, and 0% to 38.9% by weight of additional pharmaceutical excipients. The pregabalin immediate-release tablet prepared with the composition of the present invention has the benefit of a higher API content while also having surprisingly high tablet hardness. The pregabalin may also include other pharmaceutically acceptable salts of pregabalin.

[0002] The present invention is in the field of pharmaceutical formulations, compositions of matter for compositions of pregabalin or its racemate, immediate release tablets. [Background technology]

[0003] Pregabalin is an anticonvulsant, analgesic and anti-anxiety medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless legs syndrome, opioid withdrawal and generalized anxiety disorder (GAD).

[0004] Pregabalin is typically administered in the form of immediate-release capsules, controlled-release tablets, and, rarely, immediate-release tablets. A typical commercially available pregabalin immediate-release tablet contains approximately 40% pregabalin by weight, and a typical immediate-release capsule contains approximately 60% pregabalin by weight. Standard doses range from 25 mg to 300 mg. Pregabalin dosage forms are typically and optionally packaged in PVC / ALU or ALU / ALU blisters to ensure product stability.

[0005] The environmental impact of pharmaceutical packaging is significant. This is because the aluminum and plastic used to form blister packs are difficult, or even impossible, to effectively recycle because the materials are sealed together. Separating the materials again requires a large amount of energy, and even then, the resulting aluminum is not of the same high quality as new aluminum. The larger the immediate-release oral pharmaceutical dosage form, the larger the primary packaging must be, and therefore, more waste is generated.

[0006] There is also an environmental burden caused by the extensive transportation steps required for the finished product, including transport from manufacturer to wholesaler and then to pharmacy. Each box of finished product in the pharmaceutical industry must be transported in several stages before reaching the customer, often even involving global shipping routes. This is particularly true for generic drugs, and even more so for products sold in large quantities, such as pregabalin. The volume of the final product determines how efficiently it can be transported and stored, as a large volume product requires more space and more transportation compared to the same product with a smaller volume.

[0007] Furthermore, if exposing patients to additives can be avoided, this should be done. Immediate-release tablets are administered to allow the drug, not the additive, to act on the human body. The use of additives in products where additives can be avoided, especially when used in large quantities, is a waste of resources for the pharmaceutical industry. Furthermore, global demand for additives continues to increase, and the chemical industry's supply capacity is lagging behind demand, making resource waste a more serious problem.

[0008] Previously patented combinations of pregabalin tablets with an API content increased by more than 50% are primarily controlled-release (sustained-release or extended-release) formulations, not immediate-release tablets. This is the case with AU2017300185 (65% by weight pregabalin content) and WO2016187718 (95% by weight pregabalin content). Pregabalin immediate-release tablets have been researched and patented, but under the condition that very specific excipients must be used for successful tableting. Such cases are those of WO2008128775, which requires the use of alkaline earth phosphates, pentite / hexite, polyacrylates, or surfactants, and WO2011107812A2, which requires the use of disaccharide or higher polyols as stabilizers. Furthermore, Patent CN103494796A discloses a formulation of immediate release tablets with a high content of pregabalin, but under the condition that pregabalin with a median particle size of more than 200 μm must be used.

[0009] Pregabalin with a particle size of less than 200 μm has been shown to lack tablet hardness after compression, resulting in poor tabletability. This may be the main reason why pregabalin is typically manufactured in capsule form, not tablet form. Adding binder additives to pregabalin powder did not improve tabletability enough for further processing. Summary of the Invention

[0010] The present inventors have surprisingly discovered a highly specific composition that allows pregabalin to be processed into tablets with sufficient hardness to allow further handling and processing. This discovery allows pregabalin tablets to be produced with higher API content and particle sizes less than 200 μm, and the composition does not rely on previously thought-out necessary additives required to form a stable composition.

[0011] Currently, commercially available 25 mg immediate-release pregabalin tablets weigh approximately 64 mg, and 300 mg immediate-release pregabalin tablets weigh approximately 762 mg. The additive contents are 39 mg and 362 mg per tablet, respectively. 25 mg immediate-release pregabalin capsules weigh approximately 69 mg, and 300 mg immediate-release pregabalin capsules weigh approximately 489 mg. The additive contents (including capsule weight) are 24 mg and 189 mg, respectively. According to the present invention, the additive content can be reduced to as little as 11% in tablet formulation, or to approximately 3 mg for 25 mg tablets and 37 mg for 300 mg tablets.

[0012] With the amount of additives required reduced to a minimum, immediate release tablets shrink, which in turn reduces the size of the blister and the overall size of the finished product. Much smaller blisters can now be used, allowing the finished product to be a fraction of its current volume. This results in much more efficient transportation, a reduced carbon footprint of the product, and a fraction of the packaging waste generated.

[0013] It also reduces the amount of excipients administered to patients to only the essential amount, dramatically reducing the burden on the pharmaceutical industry of procuring and disposing of unnecessarily large amounts of excipients.

[0014] Because pregabalin is a high-volume prescription drug, it is synthesized in numerous manufacturing plants and the finished product is produced worldwide. The facilities and equipment required to carry out the manufacturing of a given combination are readily available. The following composition and preparation examples can be practically implemented at any manufacturing site intended for tableting. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows a graph depicting exemplary results of the dissolution tests in the examples below. [Example]

[0016] Example 1 - Preparation of pregabalin film-coated tablets Step 1. Mix pregabalin, polyvinylpyrrolidone, and croscarmellose sodium. Pregabalin, polyvinylpyrrolidone, and croscarmellose sodium can be passed through a suitable sieve before mixing. For the avoidance of doubt, sieve in this context preferably refers to a sieve with a pore size of 250 μm to 710 μm.

[0017] Step 2. Add any additional additives and mix. Additional additives may be passed through a suitable sieve (see above) before addition.

[0018] Step 3. Compress the final mixture into tablets.

[0019] Step 4. The tablets can be film coated.

[0020] Preparation methods may include, but are not limited to, direct compression and wet granulation. Direct compression is preferred, and exemplary compression methods are outlined in

[16] . In particular, the compression force in direct compression is 40 kg / mm 2 More specifically, 45 kg / mm 2 More specifically, 50 kg / mm 2 More specifically, 55 kg / mm 2 More specifically, 60 kg / mm 2 More specifically, 65 kg / mm 2 More specifically, 70 kg / mm 2 In any of the above embodiments, more specifically, the maximum load is 75 kg / mm 2 is.

[0021] Composition example [Table 1]

[0022] [Table 2]

[0023] [Table 3]

[0024] [Table 4]

[0025] Example 2 - Examples of tablet weights with different compositions [Table 5]

[0026] Example 3 - Analytical Results [Table 6]

[0027] Disintegration tests were performed on pregabalin tablets according to Apparatus A of the European Pharmacopoeia 2.9.1. The disintegration test medium was 1 L of buffer solution at pH 6.8 and 37°C. Crushing resistance was tested according to Pharmacopoeia 2.9.8 using a Schleuniger THP-4M 4M tablet hardness tester.

[0028] The tablets of Example 3 were subjected to dissolution testing in 900 mL of pH 6.8 buffer at 37° C. using USP Apparatus 1 at 100 rpm. The resulting dissolution curves show that the tablets dissolved rapidly and completely within 30 minutes.

[0029] Example 4 - Comparative Example: Composition that did not meet the quality requirement threshold [Table 7]

[0030] [Table 8]

[0031] [Table 9]

[0032] [Table 10]

[0033] [Table 11]

[0034] [Table 12]

[0035] [Table 13]

[0036] [Table 14]

[0037] The ability to obtain tablets of suitable hardness for further handling and processing is only made possible by the specific compositions of the present invention: the comparative compositions (see above) have proven to have a lower hardness than the compositions of the present invention, all of which exhibit a crush resistance of 15 N or less in the test described herein above, making them less suitable for handling and processing. DETAILED DESCRIPTION OF THE INVENTION

[0038] Specific embodiments of the present invention are listed below: 1. A pharmaceutical composition for immediate release tablets comprising 50.1% by weight or more of pregabalin, 8.0% by weight or more of polyvinylpyrrolidone, 3.0% by weight or more of croscarmellose sodium, and 0% to 38.9% by weight of additional pharmaceutical excipients, more preferably 70.1% by weight or more of pregabalin, and even more preferably 80.1% by weight or more of pregabalin. 2. The pregabalin described in claim 1 also includes pharmaceutically acceptable salts of pregabalin. 3. The median particle size of the pregabalin according to claim 1 is less than 200 μm. 4. The pharmaceutical excipients of claim 1 consist of, but are not limited to, one or more of disintegrants, lubricants, fillers and glidants. 5. The disintegrants in claim 4 consist of, but are not limited to, microcrystalline cellulose, sodium alginate, croscarmellose sodium, croscarmellose sodium, crospovidone and any "super disintegrant." 6. The filler according to claim 4 consists of, but is not limited to, cellulose, lactose, mannitol, starch, sucrose, and calcium phosphate. 7. The lubricant according to claim 4 comprises, but is not limited to, calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulfate, and magnesium lauryl sulfate. 8. The lubricant according to claim 4 comprises, but is not limited to, silica derivatives, talc, and corn starch. 9. The immediate-release tablet according to claim 1 includes tablet form and film-coated tablet form. In the case of film-coated tablet form, the weight percentage of pregabalin refers to the weight of API in the entire dosage form (including the film coating). 10. The composition of claim 1 is for a dose range of 12.5 mg to 600 mg of pregabalin. Methods for preparing the composition of claim 1 include direct compression and wet granulation.

[0039] Further embodiments of the present invention are listed below: 1. An immediate release oral pharmaceutical composition comprising 50.1% by weight or more of pregabalin, 8.0% by weight or more of polyvinylpyrrolidone, 3.0% by weight or more of croscarmellose sodium, and 0% to 38.9% by weight of additional pharmaceutical excipients. In a preferred embodiment, the immediate release oral pharmaceutical composition does not contain any further active ingredients other than pregabalin, which means, for example, that it contains 50.1% by weight or more (or another percentage or specific dose described herein, mutatis mutandis) of the active ingredient, wherein said active ingredient is pregabalin. 2. The immediate release oral pharmaceutical composition according to item 1, comprising 70.1% by weight or more of pregabalin, preferably 80.1% by weight or more of pregabalin. In another embodiment, the amount of pregabalin in the immediate release oral pharmaceutical composition is 87% or more, more preferably about 89%. In certain embodiments, the amount of pregabalin in the immediate release oral pharmaceutical composition is 50% or 50.1% to 89% or 90% pregabalin. 3. The immediate release oral pharmaceutical composition according to item 1 or 2, wherein the median particle size of the pregabalin is less than 200 μm. 4. The immediate release oral pharmaceutical composition according to any one of items 1 to 3, wherein the additional pharmaceutical excipients comprise one or more components selected from the group comprising disintegrants, lubricants, fillers and glidants. 5. The immediate release oral pharmaceutical composition according to item 4, wherein the disintegrant is one or more disintegrants selected from the group comprising microcrystalline cellulose, carboxymethylcellulose, alginic acid, sodium alginate and derivatives thereof, sodium starch glycolate (such as Glycolys®, Explotab®, Vivastar® P), crospovidone (such as Kollidon®, Kollicoat®) and other superdisintegrants, as well as cellulose, lactose, mannitol, starch and sucrose. 6. The immediate release oral pharmaceutical composition according to item 4 or 5, 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 will appreciate that certain additives used as fillers may also act as disintegrants, such as cellulose, lactose, mannitol, starch, and sucrose. In embodiments in which one of these is included as a disintegrant, it is not additionally used as a filler; in other words, their inclusion as a "disintegrant" or a "filler" in embodiments of the present invention is mutually exclusive. 7. The immediate release oral pharmaceutical composition according to any one of items 4 to 6, 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. 8. The immediate release oral pharmaceutical composition according to any one of items 4 to 7, wherein the lubricant is one or more lubricants selected from the group comprising silica derivatives, e.g., silicon dioxide, talc, and corn starch. 9. The immediate release oral pharmaceutical composition according to any one of items 1 to 8, which is in tablet form or film-coated tablet form, wherein in said film-coated tablet form, the weight percentage refers to the entire pharmaceutical composition including the film coating weight of the tablet core. 10. The immediate release oral pharmaceutical composition according to any one of items 1 to 9, wherein pregabalin is contained in a dose range of 12.5 mg to 600 mg, in particular 25 mg to 300 mg. 11. A method for preparing a tablet comprising the composition according to any one of items 1 to 10, comprising: - mixing pregabalin, polyvinylpyrrolidone, and croscarmellose sodium in the ratios described in any one of items 1 to 9; - if necessary, adding and mixing additional additives in the ratios according to any one of items 1 to 9, - compressing the mixture into tablets; - optionally applying a film coating to said tablets; A method comprising:

Claims

1. 1. An immediate release oral pharmaceutical composition comprising 50.1% by weight or more of pregabalin, 8.0% by weight or more of polyvinylpyrrolidone, 3.0% by weight or more of croscarmellose sodium, and 0% to 38.9% by weight of additional pharmaceutical excipients.

2. 2. The immediate release oral pharmaceutical composition of claim 1, comprising 70.1% by weight or more of pregabalin, preferably 80.1% by weight or more of pregabalin.

3. 3. The immediate release oral pharmaceutical composition of claim 1, wherein the median particle size of the pregabalin is less than 200 μm.

4. 4. The immediate release oral pharmaceutical composition according to any one of claims 1 to 3, wherein the additional pharmaceutical excipients comprise one or more ingredients selected from the group comprising disintegrants, lubricants, fillers and glidants.

5. 5. The immediate release oral pharmaceutical composition of claim 4, wherein the disintegrant is one or more disintegrants selected from the group comprising microcrystalline cellulose, carboxymethylcellulose, alginic acid, sodium alginate and derivatives thereof, sodium starch glycolate (such as Glycolys®, Explotab®, Vivastar® P), crospovidone (such as Kollidon®, Kollicoat®) and other superdisintegrants, as well as cellulose, lactose, mannitol, starch and sucrose.

6. 6. The immediate release oral pharmaceutical composition of claim 4 or 5, 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.

7. 7. The immediate release oral pharmaceutical composition according to any one of claims 4 to 6, 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.

8. 8. The immediate release oral pharmaceutical composition according to any one of claims 4 to 7, wherein the lubricant is one or more lubricants selected from the group comprising silica derivatives, e.g., silicon dioxide, talc, and corn starch.

9. 9. The immediate release oral pharmaceutical composition according to any one of claims 1 to 8, in tablet form or film-coated tablet form, wherein in said film-coated tablet form the weight percentages refer to the entire pharmaceutical composition including the film coating weight of the tablet core.

10. 10. The immediate release oral pharmaceutical composition according to any one of claims 1 to 9, wherein pregabalin is contained in a dose range of 12.5 mg to 600 mg, in particular 25 mg to 300 mg.

11. A method for preparing a tablet comprising the composition of any one of claims 1 to 10, comprising: - mixing pregabalin, polyvinylpyrrolidone and croscarmellose sodium in the ratios according to any one of claims 1 to 9; - adding and mixing additional additives, if necessary, in the proportions according to any one of claims 1 to 9; - compressing the mixture into tablets; - optionally applying a film coating to the tablets; A method comprising:

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