Pregabalin quick-release tablet with improved API content percentage

Abstract

The present invention provides an immediate release oral pharmaceutical composition, such as a tablet, comprising > = 50.1% by weight of pregabalin, > = 8.0% by weight of polyvinylpyrrolidone, > = 3.0% by weight of croscarmellose sodium and from 0% to 38.9% by weight of additional pharmaceutically acceptable excipients.

Description

[0001] Description of the Invention

[0002] The present invention provides a composition for an immediate-release tablet comprising, by weight, ≥50.1% pregabalin (median particle size less than 200 μm), ≥8.0% polyvinylpyrrolidone, ≥3.0% croscarmellose sodium, and 0% to 38.9% of an additional pharmaceutical excipient. The immediate-release pregabalin tablets prepared using the composition of the present invention have the advantage of a higher percentage of API content while also exhibiting surprisingly high tablet hardness. The pregabalin tablets may also contain other pharmaceutically acceptable salts of pregabalin. Technical Field

[0003] The present invention belongs to the field of pharmaceutical preparations and relates to a composition, for example, a composition of a rapid-release tablet of pregabalin or its racemate. Background Art

[0004] Pregabalin is an anticonvulsant, analgesic, and anxiolytic medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless legs syndrome, opioid withdrawal, and generalized anxiety disorder (GAD).

[0005] Pregabalin is typically administered as immediate-release capsules, controlled-release tablets, and, less commonly, immediate-release tablets. A typical commercially available immediate-release pregabalin tablet contains approximately 40% pregabalin by weight, and a typical immediate-release capsule contains approximately 60% pregabalin by weight. The standard dose ranges from 25 mg to 300 mg. Pregabalin dosage forms are typically (and must be) 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 these materials are sealed together. Separating these materials again requires a significant amount of energy, and even then, the resulting aluminum is not as high quality as new aluminum. The larger the immediate-release oral dosage form, the larger the packaging that comes into direct contact with the drug must be, generating more waste.

[0007] Furthermore, the numerous transportation steps required for finished products, such as from manufacturer to wholesaler to pharmacy, also place a burden on the environment. Each box of finished pharmaceutical product must travel through multiple stages before reaching the customer, often encompassing global shipping routes. This is particularly true for generic drugs, and even more so for products sold in high volumes like pregabalin. The volume of the finished product determines the efficiency of transportation and storage, as larger products require more space and require more frequent shipments than smaller equivalents.

[0008] Furthermore, if patient exposure to excipients can be avoided, it should be avoided. The purpose of administering an immediate-release tablet is drug absorption, not excipients. Using excipients in products where their use can be avoided, especially in high volumes, is a waste of pharmaceutical industry resources. This waste is exacerbated by the growing global demand for excipients, while the chemical industry's supply capacity lags behind demand.

[0009] Previously patented pregabalin tablet combinations with increased API content exceeding 50% are mostly controlled-release (sustained-release or extended-release) formulations, rather than immediate-release tablets. This applies to AU2017300185 (65% pregabalin content by weight) and WO2016187718 (95% pregabalin content by weight). While there are currently research and patents for immediate-release pregabalin tablets, these require the use of very specific excipients for successful tablet formulation. For example, WO2008128775 requires the use of alkaline earth metal phosphates, pentitols / hexitols, polyacrylates, or surfactants, while WO2011107812A2 requires the use of disaccharides or higher polyols as stabilizers. Furthermore, patent CN103494796A discloses the formulation of an immediate-release tablet with a high percentage of pregabalin, but requires the use of pregabalin with a median particle size >200µm.

[0010] Pregabalin particles <200 μm exhibited poor tablet compressibility due to insufficient tablet hardness after compression. This is likely the primary reason why pregabalin is typically manufactured in capsule form rather than tablet form. Adding binder excipients to pregabalin powder did not sufficiently improve tablet compressibility for further processing.

[0011] We unexpectedly discovered a very specific composition in which pregabalin can be processed into tablets with sufficient hardness for further handling and processing. This discovery allows the production of pregabalin tablets with higher active ingredient contents and particle sizes <200 microns, and the composition does not rely on excipients previously thought to be necessary for a stable composition.

[0012] Currently, commercially available 25mg immediate-release pregabalin tablets weigh approximately 64mg, and 300mg pregabalin tablets weigh approximately 762mg. The excipient content per tablet is 39mg and 362mg, respectively. 25mg immediate-release pregabalin capsules weigh approximately 69mg, and 300mg immediate-release pregabalin capsules weigh approximately 489mg. The excipient content (including capsule weight) is 24mg and 189mg, respectively. The present invention reduces the excipient content to only 11% (in tablet form), or approximately 3mg of excipients for the 25mg tablet and approximately 37mg of excipients for the 300mg tablet.

[0013] Because the amount of excipients required is minimized, immediate-release tablets can also be shrunk, which in turn reduces the size of the blister and, consequently, the size of the finished product. Much smaller blisters can now be used, resulting in finished products that are only a fraction of the current volume. This, in turn, significantly improves shipping efficiency, reduces the product's carbon footprint, and generates minimal packaging waste.

[0014] It also reduces the amount of excipients administered to patients to the essential quantity and greatly relieves the pharmaceutical industry of the pressure to find and process unnecessary large quantities of excipients.

[0015] Because pregabalin is a highly prescribed drug, it is synthesized in many manufacturing plants and the finished product is produced worldwide. The facilities and equipment required to produce this combination are readily available. The following examples of compositions and preparations can be implemented in virtually any production site used for tableting. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 Shown are graphs representing exemplary results of the dissolution studies in the following examples. DETAILED DESCRIPTION

[0017] Example

[0018] Example 1 - Exemplary Preparation of Pregabalin Film-Coated Tablets

[0019] Step 1. Mix pregabalin, polyvinyl pyrrolidone, and croscarmellose sodium. Prior to mixing, pregabalin, polyvinyl pyrrolidone, and croscarmellose sodium may be passed through a suitable sieve. For the avoidance of doubt, the sieve herein refers to a sieve, preferably one with a pore size of 250 μm to 710 μm.

[0020] Step 2. Add and mix optional additional excipients. Prior to addition, the additional excipients may be passed through a suitable sieve (see above).

[0021] Step 3. Compress the final mixture into tablets.

[0022] Step 4. A film coating may be added to the tablets.

[0023] 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] . The pressure in direct compression is particularly 40 kg / mm 2 or higher, more particularly 45 kg / mm 2 or higher, more particularly 50 kg / mm 2 or higher, more particularly 55 kg / mm2 or higher, more particularly 60 kg / mm 2 or higher, more particularly 65 kg / mm 2 or higher, more particularly 70 kg / mm 2 or higher, and in any of the above embodiments, even more particularly up to 75 kg / mm 2 .

[0024] Exemplary compositions

[0025] Table 1 - Composition Example 1

[0026]

[0027] Table 2 - Composition Example 2

[0028]

[0029] Table 3 - Composition Example 3

[0030]

[0031] Table 4 - Composition Example 4

[0032]

[0033] Example 2 - Exemplary Tablet Weights of Different Compositions

[0034] Table 5 - Summary of Example Tablet Weights

[0035]

[0036] Example 3 - Analytical Results

[0037] Table 6 - Disintegration time and resistance to breakage

[0038]

[0039] Disintegration studies were conducted on pregabalin tablets according to Ph. Eur. 2.9.1, Apparatus A. The disintegration medium consisted of 1 L of buffer, pH 6.8, at 37°C. Resistance to crushing was tested according to Ph. Eur. 2.9.8 using a Dr. Schleuniger THP-4M tablet hardness tester.

[0040] The tablets of Example 3 were subjected to dissolution studies in 900 ml of pH 6.8 buffer at 37° C. using USP Apparatus No. 1 set at 100 rpm. The resulting dissolution profile indicated that the tablets dissolved rapidly and were completely dissolved within 30 minutes.

[0041] Example 4 - Comparative Example: Compositions that do not meet the quality threshold

[0042] Table 7 - Composition Example 5

[0043]

[0044] Table 8 - Composition Example 6

[0045]

[0046] Table 9 - Composition Example 7

[0047]

[0048] Table 10 - Composition Example 8

[0049]

[0050] Table 11 - Composition Example 9

[0051]

[0052] Table 12 - Composition Example 10

[0053]

[0054] Table 13 - Composition Example 11

[0055]

[0056] Table 14 - Composition Example 12

[0057]

[0058] Only with the specific compositions of the present invention can tablets with sufficient hardness be obtained for further handling and processing. The comparative compositions (see above) proved to be less hard than the compositions of the present invention, exhibiting a crushing resistance of ≤ 15 N in the tests described herein, making them less suitable for handling and processing.

[0059] Certain embodiments of the present invention are listed below:

[0060] 1. A pharmaceutical composition for an immediate-release tablet comprising ≥50.1% by weight of pregabalin, ≥8.0% of polyvinylpyrrolidone, ≥3.0% of croscarmellose sodium, and 0% to 38.9% of an additional pharmaceutically acceptable excipient. More preferably, the composition comprises ≥70.1% by weight of pregabalin, and even more preferably, comprises ≥80.1% by weight of pregabalin.

[0061] 2. The pregabalin of claim 1 further comprising a pharmaceutically acceptable salt of pregabalin.

[0062] 3. The pregabalin of claim 1 having a median particle size of less than 200 μm.

[0063] 4. The pharmaceutical excipient of claim 1 is composed of one or more disintegrants, lubricants, fillers and glidants, but is not limited thereto.

[0064] 5. The disintegrant of claim 4 is composed of, but not limited to, microcrystalline cellulose, sodium alginate, croscarmellose sodium, croscarmellose sodium, crospovidone, and any "super disintegrant."

[0065] 6. The filler according to claim 4 is composed of cellulose, lactose, mannitol, starch, sucrose and calcium phosphate, but is not limited thereto.

[0066] 7. The lubricant of claim 4 is composed of calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulfate and magnesium lauryl sulfate, but is not limited thereto.

[0067] 8. The glidant according to claim 4 is composed of a silicon dioxide derivative, talc and corn starch, but is not limited thereto.

[0068] 9. The immediate-release tablet of claim 1 comprises a tablet form and a film-coated tablet form. For the film-coated tablet form, the weight percentage of pregabalin refers to the proportion of the API to the entire dosage form (including the film coating).

[0069] 10. The composition of claim 1 having a dosage range of 12.5 mg to 600 mg of pregabalin.

[0070] The preparation method of the composition of claim 1 comprises direct tableting and wet granulation.

[0071] Further embodiments of the present invention are listed below:

[0072] 1. An immediate-release oral pharmaceutical composition comprising, by weight, ≥50.1% pregabalin, ≥8.0% polyvinylpyrrolidone, ≥3.0% croscarmellose sodium, and 0% to 38.9% of an additional pharmaceutical excipient.

[0073] In a preferred embodiment, the immediate release oral pharmaceutical composition contains no active agent other than pregabalin, which means that it contains, for example, ≥ 50.1% by weight (or another percentage or specific dose, etc., as described herein, mutatis mutandis) of the active agent, wherein the active agent is pregabalin.

[0074] 2. The immediate-release oral pharmaceutical composition according to item 1, comprising ≥70.1% pregabalin by weight, preferably ≥80.1% pregabalin.

[0075] In another embodiment, the amount of pregabalin in the immediate-release oral pharmaceutical composition is ≥ 87%, more preferably about 89%. In certain embodiments, the amount of pregabalin in the immediate-release oral pharmaceutical composition is between 50% or 50.1% and 89% or 90% pregabalin.

[0076] 3. The immediate-release oral pharmaceutical composition according to any one of items 1 or 2, wherein the pregabalin has a median particle size of less than 200 μm.

[0077] 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 consisting of a disintegrant, a lubricant, a filler, and a glidant.

[0078] 5. The rapid-release oral pharmaceutical composition according to item 4, wherein the disintegrant is one or more disintegrants selected from the group consisting of microcrystalline cellulose, carboxymethyl cellulose, alginic acid, sodium alginate and its derivatives, sodium starch glycolate (e.g., Glycolysine), ® Explotab ® 、Vivastar ® P), crospovidone (e.g. Kollidon ® 、Kollicoat ® ) and other super disintegrants, as well as cellulose, lactose, mannitol, starch and sucrose.

[0079] 6. The immediate-release oral pharmaceutical composition according to any one of items 4 or 5, wherein the filler is one or more fillers selected from the group consisting of cellulose, lactose, mannitol, starch, sucrose, calcium phosphate, calcium carbonate, maltodextrin, sorbitol, and dextrin.

[0080] It is known to those skilled in the art 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 as a disintegrant, they are not additionally used as fillers. In other words, in embodiments of the present invention, their inclusion as "disintegrants" or "fillers" is mutually exclusive.

[0081] 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 consisting of calcium stearate, magnesium stearate, stearic acid, sodium lauryl sulfate, and magnesium lauryl sulfate.

[0082] 8. The immediate-release oral pharmaceutical composition according to any one of items 4 to 7, wherein the glidant is one or more glidants selected from the group consisting of silicon dioxide derivatives, such as silicon dioxide, talc and corn starch.

[0083] 9. The immediate-release oral pharmaceutical composition according to any one of items 1 to 8, 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 entire pharmaceutical composition including the weight of the film coating of the tablet core.

[0084] 10. The immediate-release oral pharmaceutical composition according to any one of items 1 to 9, wherein the dose of pregabalin ranges from 12.5 mg to 600 mg, in particular from 25 mg to 300 mg.

[0085] 11. A method for preparing a tablet comprising the composition according to any one of items 1 to 10, the method comprising

[0086] - pregabalin, polyvinylpyrrolidone and croscarmellose sodium are mixed together in the ratios described in any one of the preceding items,

[0087] - optionally adding additional excipients in the proportions described in any of the preceding items and mixing,

[0088] - compress the mixture into tablets,

[0089] - Optionally adding a film coating to the tablet.

Claims

1. An immediate-release oral pharmaceutical composition comprising, by weight, ≥50.1% pregabalin, ≥8.0% polyvinylpyrrolidone, ≥3.0% croscarmellose sodium, and 0% to 38.9% of an additional pharmaceutical excipient.

2. The immediate release oral pharmaceutical composition according to claim 1, comprising ≥70.1% pregabalin by weight, preferably ≥80.1% pregabalin.

3. The immediate-release oral pharmaceutical composition according to any one of claims 1 or 2, wherein the pregabalin has a median particle size of less than 200 μm.

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 components selected from the group consisting of a disintegrant, a lubricant, a filler, and a glidant.

5. The rapid-release oral pharmaceutical composition according to claim 4, wherein the disintegrant is one or more disintegrants selected from the group consisting of microcrystalline cellulose, carboxymethyl cellulose, alginic acid, sodium alginate and its derivatives, sodium starch glycolate (e.g., Glycolysine), ® Explotab ® 、Vivastar ® P), crospovidone (e.g. Kollidon ® 、Kollicoat ® ) and other super disintegrants, as well as cellulose, lactose, mannitol, starch and sucrose.

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

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 consisting of 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 claims 4 to 7, wherein the glidant is one or more glidants selected from the group consisting of silicon dioxide derivatives, such as silicon dioxide, talc and corn starch.

9. The immediate-release oral pharmaceutical composition according to any one of claims 1 to 8, 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 entire pharmaceutical composition including the weight of the film coating of the tablet core.

10. The immediate-release oral pharmaceutical composition according to any one of claims 1 to 9, wherein the dosage of pregabalin ranges from 12.5 mg to 600 mg, in particular from 25 mg to 300 mg.

11. A method for preparing a tablet comprising the composition according to any one of claims 1 to 10, the method comprising - pregabalin, polyvinylpyrrolidone and croscarmellose sodium are mixed together in the proportions described in any one of the preceding claims, - optionally adding additional excipients in the proportions according to any one of the preceding claims and mixing, - compress the mixture into tablets, - Optionally adding a film coating to the tablet.

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