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WO2025018960A1 - Comprimé pelliculé de brivaracétam - Google Patents

Comprimé pelliculé de brivaracétam Download PDF

Info

Publication number
WO2025018960A1
WO2025018960A1 PCT/TR2024/050705 TR2024050705W WO2025018960A1 WO 2025018960 A1 WO2025018960 A1 WO 2025018960A1 TR 2024050705 W TR2024050705 W TR 2024050705W WO 2025018960 A1 WO2025018960 A1 WO 2025018960A1
Authority
WO
WIPO (PCT)
Prior art keywords
film coated
coated tablet
brivaracetam
tablet according
cellulose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/TR2024/050705
Other languages
English (en)
Inventor
Fatih Sunel
Fadime Bilgehan ATAK
Seval Ataman
Selin DERELI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from TR2023/008262 external-priority patent/TR2023008262A2/tr
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of WO2025018960A1 publication Critical patent/WO2025018960A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a film coated tablet comprising brivaracetam and at least one pharmaceutically acceptable excipient wherein brivaracetam has a d (0.9) particle size between 40 pm to 450 pm and lactose monohydrate and lactose anhydrous is present as diluent. Furthermore, the tablet is also obtained by using an effective process which is simple, rapid, cost effective, time-saving and industrially convenient process.
  • brivaracetam (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl]butanamide and its chemical structure is shown in the Formula I.
  • brivaracetam as an adjunctive therapy drug for the treatment of partial seizures with or without secondary generalized seizures of epilepsy patients of 16-year-old and older, under the trade name Briviact®.
  • the drug is a derivative of levetiracetam and belongs to the 3rd generation of antiepileptic drug.
  • Clinical trials evaluated the efficacy and safety of Brivaracetam (5, 20, 50 and 150 mg per day) in the adjunctive treatment of adult patients (16-65 years).
  • Brivaracetam is highly soluble and is Class I according to the Biopharmaceutical Classification System (BCS).
  • the active substance is a white to off-white non-hygroscopic crystalline solid. Additionally, brivaracetam is an extremely viscous compound (adhesive capacity).
  • Patent CN102292071 A discloses that the excipient "cyclodextrin" is used as a compacting agent to produce brivaracetam tablets, but since brivaracetam is an extremely viscous compound (adhesion ability), cyclodextrin can reduce the compaction and especially the bonding during the rolling process alleviates the risk of tablet sticking to a certain extent.
  • PCT Patent Publications No. WO 2010/086315 and WO 2010/094535 disclose immediate release oral pharmaceutical formulation of Brivaracetam. These patent publications discloses dissolution, sticking problem associated with Brivaracetam, which is a major challenge during the formulation development.
  • brivaracetam is an active ingredient that has flowability, compressibility and stability problems in formulation, focusing only on its tablet sticking to will not yield successful results.
  • the film coated tablet is created to overcome the above problems and provides additional advantages to the relevant field of art.
  • Other advantages and embodiments of the present invention will be clarified in the following description.
  • the main object of the present invention is to provide a film coated tablet comprising brivaracetam with excellent properties, such as compressibility, flowability, homogeneity, and content uniformity which overcomes the above-described problems in the prior art and have additive advantages over them.
  • Another object of the present invention is to provide a desired stability of the film coated tablet comprising brivaracetam.
  • Another object of the present invention is to provide a film coated tablet comprising brivaracetam with the desired dissolution profile.
  • Another object of the present invention is to provide a process for preparing a film coated tablet comprising brivaracetam.
  • the process is free of solvent, for example dry granulation or direct compression. It is a simple, rapid, cost effective, time-saving, and industrially convenient method.
  • Flowability is an important parameter in tablet formulation. Especially the high sticky behavior of the active substance caused flowability problems in formulations. The problem with flowability negatively affects the content uniformity and manufacturing process success, and the problem with the content uniformity negatively affects the dissolution profile. We have found that these problems are overcome when using brivaracetam in the particle sizes specified below. In addition, the compressibility problem was overcome with the use of lactose monohydrate and lactose anhydrous. So, both the content uniformity was ensured and the dissolution profile was brought to the desired level.
  • particle size means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (i.e. Malvern analysis).
  • d (0.1 ) means, the size at which 10% by volume of the particles are finer and d (0.5) means the size at which 50% by volume of the particles are finer and d (0.9) means the size at which %90 by volume of the particles is finer.
  • a film coated tablet comprising brivaracetam and at least one pharmaceutically acceptable excipient wherein brivaracetam has a d (0.9) particle size between 40 pm to 450 pm and lactose monohydrate and lactose anhydrous is present as diluent.
  • the weight ratio of lactose anhydrous to lactose monohydrate is between 1 .0 and 2.0, preferably between 1 .1 and 1 .6, preferably between 1 .1 and 1 .4.
  • the tablet comprises one more diluent.
  • Suitable diluents are selected from the group comprising microcrystalline cellulose, corn starch, starch, mannitol, calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate anhydrate, calcium phosphate trihydrate, neutral pellets, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides or mixtures thereof.
  • diluent is microcrystalline cellulose.
  • the amount of diluents is 50.0% to 85.0% by weight in the total composition.
  • the amount of diluents is 65.0% to 85.0% by weight in the total composition.
  • brivaracetam has a d (0.9) particle size between 55 pm to 94 pm or between 75 pm to 96 pm or between 104 pm to 125 pm or between 126 pm to 138 pm or between 139 pm to 152 pm or between 153 pm to 167 pm or between 168 pm to 183 pm or between 184 pm to 198 pm or between 203 pm to 218 pm or between 219 pm to 234 pm or between 237 pm to 253 pm or between 257 pm to 268 pm or between 269 pm to 278 pm or between 283 pm to 298 pm or between 304 pm to 345 pm or between 348 pm to 390 pm or between 395 pm to 445 pm Brivaracetam having above-described particle size provides the flowability and compressibility, mass uniformity also provides the improved dissolution profile.
  • brivaracetam has a d (0.1 ) particle size between 1 pm to 40 pm or between 4 pm to 34 pm or between 6 pm to 25 pm.
  • brivaracetam has a d (0.5) particle size between 8 pm to 85 pm or between 13 pm to 76 pm or between 22 pm to 65 pm or between 27 pm to 58 pm.
  • the tablet is free of betadex (p-cyclodextrin).
  • p-cyclodextrin p-cyclodextrin
  • Adding p-cyclodextrin will bring in the formulation, the preparation and finished product in storage process has many problems.
  • the finished product comprising cyclodextrin during storing process will result increasing drug exposure in the body, causing adverse drug reactions, such as gastrointestinal tract reaction, toxic and side effect of the medicine.
  • At least one pharmaceutically acceptable excipient is selected from the group comprising disintegrant, binders, lubricants, glidant or mixtures thereof.
  • the composition comprises a disintegrant, and the inventors have found that the use of the specified amount ranges of disintegrant in the pharmaceutical composition of the present invention has an unexpected anti-sticking effect, and used disintegrant is unexpectedly used as an anti-sticking agent for powder direct compression or dry granulation, It is beneficial to reduce the high sticky behavior of the active ingredient and avoid sticking and punching when tableting.
  • Suitable disintegrants are selected from the group comprising crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, hydroxymethyl starch or mixtures thereof.
  • the disintegrant is croscarmellose sodium.
  • binder can be used in the film coated tablet.
  • Suitable binders are selected from the group comprising hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyethylene glycol, starch, pregelatinized starch, sodium alginate, hydroxypropyl methyl cellulose, carboxy methyl cellulose, methyl cellulose, guar gum, polymethacrylates, methacrylate polymers, polysaccharides, poloxamer, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
  • the binder is hydroxypropyl methyl cellulose.
  • the amount of binders is 1.5% to 30.0% by weight in the total composition.
  • the amount of binders is 1.5% to 15.0% by weight, more preferably it is 1 .5% to 6.0% by weight in the total composition.
  • Suitable lubricant is selected from the group comprising talc, sodium stearyl fumarate, magnesium stearate, potassium stearate, stearic acid, sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols or mixtures thereof.
  • the lubricant is magnesium stearate.
  • the amount of lubricant is between 0.3% and 2.0% by weight in the total formulation.
  • Brivaracetam is stable to heat exposure but degrades and picks up water when exposed to both high temperature and humidity however, this problem is minimized by using film coating with appropriate content. Thus, stability is ensured.
  • the film coated is based on Polyvinyl Alcohol or Hydroxypropylmethyl cellulose.
  • the amount of film coated is between 2.0% and 5.0% by weight in the total formulation. This help to affect positively the distribution time.
  • the film coated comprises;
  • the film coated comprises;
  • the film coated tablet comprises;
  • the film coated tablet comprises;
  • Example 1 The film coated tablet
  • a process for example 1 a) Mixing Brivaracetam, Lactose monohydrate, Lactose anhydrous, croscarmellose sodium for 15 minutes, b) Adding weighed and 0.6 mm sieved Magnesium stearate to dry mixture and mixing for 3 minutes, c) Compressing the mixture into tablets at appropriate specifications, d) Coating the tablets with film coating.
  • Example 2 The film coated tablet A process for example 2; a) Mixing Brivaracetam, lactose monohydrate, HPMC, and the half of the amount of croscarmellose sodium for 15 minutes, b) Adding weighed and 0.6 mm sieved 1/2 Magnesium stearate to dry mixture and mixing for 3 minutes, c) Performing slug granulation in compactor, d) Sieving dry granules 1 .2 mm, e) Adding 0.6mm sieved half of the amount of croscarmellose sodium, Lactose anhydrous and mixing for 5 minutes, f) Adding 0.6mm sieved 1/2 Mg-stearate and mixing for 3 minutes, g) Compressing the mixture into tablets at appropriate specifications, h) Coating the tablets with film coating.
  • a process for example 3 a) Mixing Brivaracetam, Lactose monohydrate, Lactose anhydrous, croscarmellose sodium for 15 minutes, b) Adding weighed and 0.6 mm sieved Magnesium stearate to dry mixture and mixing for 3 minutes, c) Compressing the mixture into tablets at appropriate specifications, d) Coating the tablets with film coating. e) The coated tablets are filled into the capsules.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un comprimé pelliculé comprenant du brivaracétam et au moins un excipient pharmaceutiquement acceptable, le brivaracétam ayant une taille de particule d(0,9) comprise entre 40 µm et 450 µm et du lactose monohydraté et du lactose anhydre étant présent en tant que diluant. En outre, le comprimé est également obtenu en utilisant un procédé efficace qui est simple, rapide, économique, économe en temps et industriellement pratique.
PCT/TR2024/050705 2023-07-14 2024-06-25 Comprimé pelliculé de brivaracétam Pending WO2025018960A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
TR2023008262 2023-07-14
TR2023/008262 TR2023008262A2 (tr) 2023-07-14 Fi̇lm kapli bri̇varasetam tabletleri̇
TR2023/011827 TR2023011827A1 (tr) 2023-09-22 Bri̇varasetamin bi̇r fi̇lm kapli tableti̇
TR2023011827 2023-09-22

Publications (1)

Publication Number Publication Date
WO2025018960A1 true WO2025018960A1 (fr) 2025-01-23

Family

ID=94282424

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2024/050705 Pending WO2025018960A1 (fr) 2023-07-14 2024-06-25 Comprimé pelliculé de brivaracétam

Country Status (1)

Country Link
WO (1) WO2025018960A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111374956A (zh) * 2018-12-28 2020-07-07 上海迪赛诺生物医药有限公司 改进的布瓦西坦速释制剂
CN112569198A (zh) * 2020-12-29 2021-03-30 浙江和泽医药科技股份有限公司 一种含布立西坦的药物组合物及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111374956A (zh) * 2018-12-28 2020-07-07 上海迪赛诺生物医药有限公司 改进的布瓦西坦速释制剂
CN112569198A (zh) * 2020-12-29 2021-03-30 浙江和泽医药科技股份有限公司 一种含布立西坦的药物组合物及其制备方法

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