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WO2025186785A1 - Composition pharmaceutique orale de pitavastatine, son procédé et ses utilisations - Google Patents

Composition pharmaceutique orale de pitavastatine, son procédé et ses utilisations

Info

Publication number
WO2025186785A1
WO2025186785A1 PCT/IB2025/052490 IB2025052490W WO2025186785A1 WO 2025186785 A1 WO2025186785 A1 WO 2025186785A1 IB 2025052490 W IB2025052490 W IB 2025052490W WO 2025186785 A1 WO2025186785 A1 WO 2025186785A1
Authority
WO
WIPO (PCT)
Prior art keywords
pitavastatin
previous
composition according
ezetimibe
silicon dioxide
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/IB2025/052490
Other languages
English (en)
Other versions
WO2025186785A8 (fr
Inventor
Augusto Eugénio PARDAL FILIPE
João Pedro SILVA SERRA
Ricardo José Camilo FERREIRA PEREIRA
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.)
Tecnimede Sociedade Tecnico Medicinal SA
Original Assignee
Tecnimede Sociedade Tecnico Medicinal SA
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
Application filed by Tecnimede Sociedade Tecnico Medicinal SA filed Critical Tecnimede Sociedade Tecnico Medicinal SA
Publication of WO2025186785A1 publication Critical patent/WO2025186785A1/fr
Publication of WO2025186785A8 publication Critical patent/WO2025186785A8/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present disclosure relates to compositions comprising pitavastatin with improved stability and which are appropriate to be manufactured at an industrial scale, as well as to obtain fixed-dose compositions comprising pitavastatin and ezetimibe.
  • the present disclosure further relates to the manufacturing process of those pharmaceutical compositions.
  • Pitavastatin is an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, also known as a HMG-CoA reductase inhibitor.
  • Pharmaceutical compositions of pitavastatin as its calcium salt form are registered and marketed under the trade names ALIPZA* and LIVAZO* for the treatment of high cholesterol in patients with primary hypercholesterolemia.
  • Ezetimibe is the INN for (3R,4S)-l-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]- 4-(4-hydroxyphenyl)-2-azetidinone which has the following chemical structure:
  • Ezetimibe is a selective cholesterol-absorption inhibitor.
  • Pharmaceutical compositions of ezetimibe are registered and marketed under the trade name EZETROL* for the treatment of high cholesterol in patients with primary hypercholesterolemia by itself or concomitantly with an HMG-CoA reductase inhibitor.
  • Ezetimibe and pitavastatin combined products are registered in Korea under the trade name LIVALOZET*, film coated tablets.
  • WO2020178878, JP2021008432 and JP6937195 disclose conventional tablets comprising ezetimibe and pitavastatin, housed in airtight package.
  • CN 102451161 (Liyan Wang) discloses orodispersible tablets comprising ezetimibe and statins (namely ezetimibe and pitavastatin) and is focused on the dispersibility of the compositions and is silent on stability issues.
  • CN 112999178 discloses tablets comprising ezetimibe and pitavastatin - bilayer tablets with inappropriate dissolution properties and compositions comprising mixed granulates of both Active Pharmaceutical Ingredients (APIs).
  • APIs Active Pharmaceutical Ingredients
  • US 20220047547A1 discloses a manually filled gelatin capsule composition comprising pitavastatin granules or tablets or pellets and, ezetimibe granules or tablets or pellets - the granules or tablets' composition were explicitly filled manually and not using any industrial equipment.
  • the finished capsule composition comprises an alkaline stabilizing agent selected from the group consisting of magnesium oxide, magnesium aluminometasilicate, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydroxide, calcium carbonate, ammonium hydroxide, diethanolamine and, an acidic stabilizing agent selected from the group consisting of citric acid, acetic acid, tartaric acid, lactic acid and sodium phosphate monobasic.
  • Ezetimibe is a labile molecule in water and alkali, whereas pitavastatin is stable under alkaline conditions.
  • the pitavastatin pharmaceutical formulation and the ezetimibe pharmaceutical formulation that are on the market have different compositions and comprise different excipients. Both, individually, are under the form of tablets, but due to chemical incompatibilities between excipients and/or between active ingredients and/or active ingredient/excipient, their combination in a single oral dose results in unstability and inadequate dissolution.
  • the technical problem underlying the present disclosure was to develop an oral pharmaceutical composition comprising pitavastatin showing improved stability and adequate properties to be manufactured at an industrial scale; also, the pitavastatin composition of the present disclosure may be combined with ezetimibe.
  • An aspect of the present disclosure relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising a therapeutically effective amount of pitavastatin, an alkalizing agent and colloidal silicon dioxide.
  • a pharmaceutical composition comprising pitavastatin, an alkalizing agent and colloidal silicon dioxide allows an improved stability of the active ingredient pitavastatin in a pharmaceutical formulation, over various storage conditions and even in low doses.
  • the pitavastatin calcium composition of the present disclosure and the preparation method thereof can not only stabilize the pitavastatin in the pharmaceutical composition, in particular a tablet, but also improve the content uniformity/assay of the small dose of pitavastatin in the composition.
  • the pharmaceutical composition of the present disclosure comprising pitavastatin, an alkalizing agent and colloidal silicon dioxide, is stable, shows an improved content uniformity, a high dissolution rate, and present a good stability and shelf-life and is suitable for industrial production.
  • the present disclosure describes a process for the preparation of a composition which ensures a good recovery by assay of the small dose of pitavastatin present in the composition.
  • An aspect of the present disclosure relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising a therapeutically effective amount of pitavastatin or a pharmaceutically acceptable salt, an alkalizing agent and a colloidal silicon dioxide.
  • the stable solid oral pharmaceutical composition of the present disclosure may comprise 1-2 mg of pitavastatin or a pharmaceutically acceptable salt; preferably 1 mg.
  • the weight ratio between pitavastatin or a pharmaceutically acceptable salt: colloidal silicon dioxide ranges from 1:1 to 1:5; preferably 1:1 to 1:3; more preferably 1:2.2 to 1:2.4; even more preferably 1:2.3.
  • the alkalizing agent is selected from the list consisting of: sodium carbonate, dipotassium hydrogen orthophosphate, or mixtures thereof.
  • the alkalizing agent is sodium carbonate.
  • the weight ratio between pitavastatin or a pharmaceutically acceptable salt: alkaline agent is between 1:1 to 1:5.5; preferably between 1:1 to 1:3.4; more preferably 1:1.5 to 1:1.7.
  • the pitavastatin pharmaceutically acceptable salt is pitavastatin calcium.
  • the stable solid oral pharmaceutical composition of the present disclosure may comprise: a filler, preferably the weight ratio between pitavastatin calcium: filler ranges from 1:40 to 1:76; a disintegrant, preferably the weight ratio between pitavastatin calcium: disintegrant ranges from 1:0.3 to 1:1.5; more preferably 1:0.5 to 1:1.5; a lubricant, preferably the weight ratio between pitavastatin calcium: lubricant ranges from 1:0.2 to 1:1.5; more preferably 1:0.5 to 1:1.5.
  • the lubricant is selected from the list consisting of: sodium stearyl fumarate, magnesium stearate, stearic acid, talc, or mixtures thereof; preferably sodium stearyl fumarate.
  • the disintegrant is selected from the list consisting of sodium starch glycolate, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, croscarmellose sodium, crospovidone, or mixtures thereof; preferably sodium starch glycolate.
  • the filler is selected from the list consisting of microcrystalline cellulose, calcium phosphate, lactose, mannitol, starch, sorbitol, or mixtures thereof; preferably microcrystalline cellulose.
  • the composition is a compressed composition.
  • the stable solid oral pharmaceutical composition of the present disclosure may comprise comprising a therapeutically effective amount of Ezetimibe.
  • the therapeutically effective amount of Ezetimibe is in a form of solid dispersion granules of Ezetimibe.
  • the therapeutically effective amount of Ezetimibe is in a form of a compressed composition.
  • the amount pf Ezetimibe ranges from 5 to 10 mg.
  • the solid dispersion granules of Ezetimibe comprises Hypromellose and Lactose monohydrate-croscarmellose sodium.
  • the amount of colloidal silicon dioxide ranges from 1.2 to 5% w/w (w colloidal silicon dioxide /w total); preferably from 1.2 to 3 %w/w (w colloidal silicon dioxide /w total); more preferably the amount is 1.3 % w/w (w colloidal silicon dioxide /w total).
  • the amount of alkalizing agent ranges from 0.5 to 6.6 %w/w (w alkalizing agent /w total); preferably from 0.8 to 2 % (w alkalizing agent /w total); more preferably from 0.9 to 1.9 % (w alkalizing agent /w total)-
  • Another aspect of the present disclosure relates to a method for obtaining the composition of the present disclosure comprising the following steps: weighing and sieving the pitavastatin, the colloidal silicon dioxide, the alkalinizing agent, the diluent, the disintegrant and the lubricant; mixing a first part of the diluent, a first part of the disintegrant, a first part of the lubricant and a first part of the colloidal silicon dioxide to obtain a pre-mixture; adding the pitavastatin, the alkalinizing agent, a second part of the diluent, a second part of the disintegrant, a second part of the lubricant;
  • the first part of the colloidal silicon dioxide is 20% to 60% of the total mass of the colloidal silicon dioxide; the first part of the diluent is 25 to 50 % of the total mass of the diluent; the first part of the disintegrant is 25 to 50 % of the total mass of the disintegrant; the first part of the lubricant is 25 to 50 % of the total mass of the lubricant.
  • the second part of the colloidal silicon dioxide is 40% to 80% of the total mass of the colloidal silicon dioxide; the second part of the diluent is 50 to 75 % of the total mass of the diluent; the second part of the disintegrant is 50 to 75 % of the total mass of the disintegrant; the second part of the lubricant is 50 to 75 % of the total mass of the lubricant;
  • Another aspect of the present disclosure relates to a fixed-dose composition of the present disclosure comprising at least one pitavastatin calcium compressed composition of the present disclosure and an ezetimibe compressed composition, preferably the fixed-dose composition is a capsule dosage form. It was surprisingly found a synergistic effect between pitavastatin (in particular, pitavastatin calcium) and ezetimibe. When combined in a fixed-dose composition, it was observed a significant improvement in the dissolution profile of ezetimibe.
  • At least around 80 % of the amount of each ezetimibe and pitavastatin are released in 15 min; preferably at least around 85% of the amount of each ezetimibe and pitavastatin are released in 15 min.
  • Another aspect of the present disclosure relates to a method for obtaining the solid dispersion granules of Ezetimibe of the present disclosure comprising the following steps: providing a suspension comprising an ethanolic solution of ezetimibe and an aqueous solution of hypromellose; adding the previous suspension to lactose monohydrate-croscarmellose sodium and mixing to obtain a uniform mixture; mixing and granulating the uniform mixture to obtain solid dispersion granules of Ezetimibe.
  • the therapeutically effective amount of Ezetimibe is in a form of solid dispersion granules of Ezetimibe.
  • the solid dispersion granules of Ezetimibe comprise Hypromellose and Lactose monohydrate-croscarmellose sodium.
  • composition of the present disclosure may be used in the prevention or treatment of hypercholesterolemia.
  • the composition may be use for the manufacture of a medicament for the treatment of hypercholesterolemia.
  • the disclosure is also related to a method for treating or preventing hypercholesterolemia in a subject, the method comprising administering the composition of the present disclosure.
  • Another aspect of the present disclosure relates to the manufacturing process of those pharmaceutical compositions.
  • Another aspect of the present disclosure relates to a stable solid oral pharmaceutical composition that further comprises a therapeutically effective amount of ezetimibe.
  • the pharmaceutical composition of the present disclosure comprising pitavastatin also showed to be suitable to obtain pharmaceutical compositions combining pitavastatin and ezetimibe.
  • Ezetimibe powder was very unstable when mixed with pitavastatin powder and filled in capsules.
  • the same instability of ezetimibe was observed when pitavastatin powder was filled in capsules with ezetimibe granules. Nonetheless, surprisingly such instability was not observed in the pharmaceutical composition of the present disclosure comprising a therapeutically effective amount of pitavastatin and ezetimibe, wherein the results obtained showed adequate stability of both the active ingredients, as well as adequate dissolution rates.
  • the therapeutically effective amount of ezetimibe is in the form of a compressed composition.
  • the compressed composition comprises a solid dispersion of ezetimibe and from 0.0001 to 5 mg of a solubilizing agent.
  • the ezetimibe compressed composition further comprises a hydrophilic agent, which is, preferably, hypromellose.
  • the ezetimibe compressed composition does not contain an alkalinizing excipient, an acidifying excipient nor a buffer.
  • the stable solid oral pharmaceutical composition of the present disclosure surprisingly exhibits suitable stability, cost effectiveness, and process robustness (good uniformity, good flowability, good compact ability/compressibility, mass uniformity, and adequate hardness). At the same time, such composition exhibits dissolution and pharmacokinetics comparable to the respective marketed product (reference composition) containing one of the active substances (pitavastatin or ezetimibe) (in the present disclosure, the composition may be a stable solid oral pharmaceutical composition comprising pitavastatin, or the combination of two stable solid oral pharmaceutical compositions, each one comprising separately ezetimibe and pitavastatin).
  • Figure 1 Dissolution profile of pitavastatin on composition XIII (Fixed dose composition of pitavastatin lmg and ezetimibe 10 mg).
  • Figure 2 Dissolution profile of ezetimibe on composition XIII (Fixed dose composition of pitavastatin 1 mg and ezetimibe 10 mg).
  • the present disclosure relates to improved stability and dissolution rate compositions of pitavastatin comprising colloidal silicon dioxide as glidant.
  • the present disclosure relates to the manufacturing process of the improved stability and dissolution rate compositions of pitavastatin comprising Colloidal Silicon Dioxide as glidant.
  • colloidal silicon dioxide is particularly used as an excipient in the pitavastatin composition. It was surprisingly found that when colloidal silicon dioxide is used, the pitavastatin calcium is prevented from degrading with time (formation of a related substance), so that a pitavastatin -containing composition, preferably a pitavastatin calcium-containing composition, having excellent stability can be produced.
  • the compounding amount of colloidal silicon dioxide can be selected, for example, in the range of 1 to 5 parts by weight with respect to 1 part by weight of pitavastatin calcium, preferably, in the range of 1 to 3 parts; more preferably, in the range of 2.2 to 2.3 parts.
  • Sodium Carbonate Anhydrous or Dipotassium Hydrogen-orthophosphate in the range of 1 to 5 parts by weight with respect to 1 part by weight of pitavastatin calcium, preferably in the range of 1 to 3.3 parts and, more preferably, in the range of 1.5 to 1.7 parts by weight with respect to 1 part by weight of pitavastatin calcium.
  • the pitavastatin containing composition of the present invention may further comprise other excipients, such as, diluents, binders, lubricants and/or disintegrants.
  • the filler may be selected from microcrystalline cellulose, calcium phosphate, lactose, mannitol, starch, and sorbitol, and may be used singly or in combination; preferably the diluent is microcrystalline cellulose.
  • the binder may be selected from microcrystalline cellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, starch slurry, water, various concentrations of ethanol solution, and may be used singly or in combination; preferably the binder is microcrystalline cellulose.
  • the lubricant may be selected from sodium stearyl fumarate, magnesium stearate, stearic acid and talc, and they may be used singly or in combination; preferably the lubricant is sodium stearyl fumarate.
  • the disintegrant may be selected from sodium starch glycolate, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, croscarmellose sodium and crospovidone, and they may be used singly or in combination; preferably the disintegrant is sodium starch glycolate.
  • the lubricant includes sodium stearyl fumarate, magnesium stearate, stearic acid and talc, and they may be used singly or in combination; preferably the lubricant is sodium stearyl fumarate.
  • excipients such as coloring agents, sweeteners, flavoring agents, may also be added if desired.
  • the pitavastatin composition is a oral solid dosage form.
  • the tablet may be coated.
  • the weight of the film coating material is from 1 to 3%.
  • the pitavastatin calcium tablet core components are as follows: 1.0 to 2.0 mg of pitavastatin calcium; 40.0 to 76.0 parts by weight of filler (in relation to the amount of pitavastatin calcium); 0.5 to 1.5 parts of disintegrant; 0.5 to 1.5 parts of lubricant; 1.5 to 5.5 parts of alkalizing agent;
  • the pharmaceutical composition comprising pitavastatin calcium tablets may be prepared through a process comprising the following steps:
  • a first part of the diluent, a first part of the disintegrant and a first part of the lubricant are mixed with a first part of the colloidal silicon dioxide to obtain a pre-mixture;
  • the pitavastatin calcium, the alkalinizing agent, the second part of the diluent, the second part of the disintegrant, the second part of the lubricant and the second part of the colloidal silicon dioxide are added to the pre-mix and the mixture is uniformly mixed;
  • the first part of the colloidal silicon dioxide is 20% to 60% of the total mass of the colloidal silicon dioxide, and the remaining colloidal silicon dioxide is 40% to 80% of the total mass of the colloidal silicon dioxide.
  • the first part of diluent, the first part of the disintegrant and the first part of the lubricant is 25 to 50% of the total mass of the diluent, of the total mass of the disintegrant or of the total mass of the lubricant, respectively, and the remaining diluent, disintegrant or lubricant is 50 to 75% of the total mass of the diluent, disintegrant or lubricant, respectively.
  • Example 1 Tablets comprising pitavastatin
  • Table 1 Qualitative and quantitative composition of compositions l-IV.
  • Table 2 Qualitative and quantitative composition of compositions V-VIL
  • composition I to VII was analysed for Assay and Related Substances using a High Performance Liquid Chromatography system with a UV detector at 244 nm.
  • a validated and stability indicating methodology was used for the samples analysis, and the quantification was performed using a characterized working standard to quantify lactone impurity, which is the prevalent impurity of pitavastatin and the total of impurities.
  • Example 2 Tablets comprising Pitavastatin and different amounts of Colloidal Silicon Dioxide
  • composition VIII to Composition X were prepared, using different amounts of colloidal silicon dioxide.
  • compositions VIII to X follow the process described in Example 1. Furthermore, Composition XI is film coated according to the methods described in the art.
  • compositions VIII and IX comprising an amount of colloidal silicon dioxide above 2.5 % (w/w) (preferably around 2.8 - 2.9 (w/w)), showed a significantly improved assay result comparing with composition I comprising an amount of colloidal silicon dioxide of 1.974% w/w (inferior to 2 % (w/w)).
  • Composition VIII comprises a weight ratio between pitavastatin calcium: colloidal silicon dioxide of 1:2.2 and composition IX comprises a weight ratio between pitavastatin calcium: colloidal silicon dioxide of 1:3.7.
  • Example 3 fixed-dose composition of Pitavastatin and Ezetimibe
  • An aspect of the present disclosure relates to a fixed-dose composition comprising pitavastatin and Ezetimibe, having improved stability and improved dissolution rates.
  • Said fixed dose composition preferably comprises one to four pitavastatin tablets and one ezetimibe tablet.
  • the present disclosure also relates to the manufacturing process of said fixed-dose composition.
  • Ezetimibe powder was very unstable when mixed with pitavastatin powder and filled in capsules. The same instability of Ezetimibe was observed when pitavastatin powder was filled in capsules with Ezetimibe granules. Nonetheless, surprisingly such instability was not observed in the pharmaceutical composition of the present disclosure comprising a therapeutically effective amount of pitavastatin, an alkalizing agent and colloidal silicon dioxide, and a therapeutically effective amount of ezetimibe.
  • composition XII Ezetimibe tablet
  • the compressed ezetimibe composition XII is prepared according to the following process: a) Lactose monohydrate and Croscarmellose sodium powders were added into a fluid granulator, mixed and preheated at 45 °C. b) Then the mixture was granulated with a granulation suspension prepared by the combination of an ethanolic solution of Ezetimibe and an aqueous polymer solution. c) The obtained granules were dried at 45 °C inlet air with suitable volumetric flow rate and calibrated by a 0.7 mm sieve aperture. d) The granules were mixed with microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulphate and, then lubricated with sodium stearyl fumarate and thereafter compressed.
  • a tablet according to Composition XI was analysed for Assay and Related substances using a High- Performance Liquid Chromatography system with a UV detector at 244 nm for pitavastatin quantification.
  • For the samples analysis was used a validated and stability indicating methodology, and the quantification was performed using a characterized working standards to quantify specified impurities and the total impurities.
  • a Dissolution test was also performed. In the dissolution test of the disclosed examples the dissolutions were performed in 900 mL of dissolution medium at 37 °C ⁇ 0.5°C, using USP Apparatus 1 (baskets) method at a rotation speed of 75 rpm for pitavastatin.
  • compositions in the form of hard gelatine capsules filled with one Ezetimibe tablet of composition XII and one, two or four pitavastatin tablets of composition XI were prepared.
  • Fixed-dose composition XIII relates to a fixed-dose compositions in the form of hard gelatine capsules filled with one Ezetimibe tablet of composition XII and one pitavastatin tablet of composition XI.
  • Fixed-dose composition XIV relates to a fixed-dose compositions in the form of hard gelatine capsules filled with one Ezetimibe tablet of composition XII and four pitavastatin tablets of composition XI.
  • Each capsule according to the Fixed-dose Compositions XIII and XIV was analysed for Assay and Related substances using a High-Performance Liquid Chromatography system with a UV detector at 244 nm for pitavastatin quantification and 235 nm for ezetimibe quantification. For the samples analysis was used a validated and stability indicating methodology, and the quantification was performed using a characterized working standards to quantify specified impurities and the total impurities.
  • a Dissolution test was also performed.
  • the dissolutions were performed in 900 mL of dissolution medium at 37 °C ⁇ 0.5°C, using USP Apparatus 1 (baskets) method at a rotation speed of 100 rpm for ezetimibe and 75 rpm for pitavastatin. Samples are removed after 15 minutes from test initiation and analysed for dissolved Ezetimibe and pitavastatin using a suitable HPLC method at 242 nm.
  • Figure 1 and Figure 2 shows the dissolution profile of pitavastatin and ezetimibe, respectively, on composition XIII (fixed dose composition of pitavastatin 1 mg and ezetimibe 10 mg).
  • Table 15 In the table it is provided the dissolution profile of pitavastatin and ezetimibe on composition XIII (fixed dose composition of pitavastatin 1 mg and ezetimibe 10 mg).
  • Example 4 Ezetimibe compressed compositions
  • the Ezetimibe compressed composition of the present invention may comprise excipients, such as, diluents, binders, disintegrants, lubricants, solubilizing agents and/or wetting agents.
  • excipients such as, diluents, binders, disintegrants, lubricants, solubilizing agents and/or wetting agents.
  • the Ezetimibe composition optionally comprises one or more diluents, preferably selected from a list consisting of lactose (anhydrous or monohydrate) and microcrystalline cellulose, or mixtures thereof.
  • the Ezetimibe composition optionally comprises one or more binders, preferably selected from the list consisting of Hypromellose and povidone, or mixtures thereof.
  • the Ezetimibe composition optionally comprises one or more disintegrants, preferably selected from the list consisting of croscarmellose sodium, crospovidone, povidone and hydroxipropylcellulose, or mixtures thereof.
  • the Ezetimibe composition optionally comprises one or more lubricants, preferably selected from the list consisting of sodium stearyl fumarate and magnesium stearate, or mixture thereof.
  • the Ezetimibe composition optionally comprises a wetting agent, preferably the wetting agent is sodium lauryl sulphate.
  • the Ezetimibe composition optionally comprises one or more solubilizing agents, preferably selected from the list consisting of purified water and ethanol, or mixtures thereof.
  • the method of preparing the Ezetimibe compressed composition comprises the following steps:
  • Lactose monohydrate and croscarmellose sodium are mixed in a fluid bed granulator
  • a suspension formed by the ethanolic solution of ezetimibe and the aqueous solution of hypromellose are added to the Lactose monohydrate-croscarmellose sodium mixture and the mixture is granulated;
  • Sodium lauryl sulfate, croscarmellose sodium, microcrystalline cellulose and a lubricant are added to the granules.
  • the granules and powders are mixed and compressed into tablets.
  • Comparative compositions El to E3 are alternative ezetimibe compressed compositions wherein the active ingredient is not in solid dispersion form.
  • Comparative composition El was prepared by mixing in a fluid bed granulator ezetimibe, croscarmellose sodium, lactose monohydrate, sodium lauryl sulfate and microcrystalline cellulose. The previous mixture was then granulated with water. The granulate that was formed was dried, lubricated with magnesium stearate and compressed.
  • Comparative composition E2 was prepared by mixing croscarmellose sodium, lactose monohydrate, sodium lauryl sulfate and microcrystalline cellulose in a fluid bed granulator. The previous mixture was then granulated with ezetimibe dissolved in ethanol. The granules that were formed were dried, lubricated with magnesium stearate and compressed.
  • Comparative composition E3 was prepared by mixing croscarmellose sodium, lactose monohydrate, sodium lauryl sulfate and microcrystalline cellulose in a fluid bed granulator. The previous mixture was then granulated with a granulation suspension of ezetimibe and hypromellose in ethanol. The granules that were formed were dried, lubricated with magnesium stearate and compressed.
  • Table 17 shows the breakdown of the quantity of each component forming comparative compositions El, E2 and E3.
  • the dissolution test was performed comparing the ezetimibe compressed compositions El -E2 and the comparative compositions El to E3.
  • the dissolution test was performed in 1000 mL of dissolution medium at 37 °C ⁇ 0.5 °C, using USP Apparatus 2 (paddles) method at a rotation speed of 50 rpm. Samples are removed after 5, 10, 15, 30, 45 and 60 minutes from test initiation and analyzed for dissolved ezetimibe using a suitable HPLC method at 240 nm. 0.1N HCI + 0.15% SDS was used as dissolution medium, with adequate discrimination ability. The reported dissolution results are the average values of six tablets.
  • the similarity factor (f2) is a measurement of the similarity in percentage of dissolution between two curves. Two dissolution profiles are considered similar when the f2 value is > 50. The results are summarized in Table 18.
  • Table 18 Data related to the dissolution profiles of disclosed compositions El and E2 (table 15) and comparative (comp.) compositions El to E3 (table 16) and Ezetrol® tablets. [00117] As depicted in Table 18, comparative compositions El to E3 do not constitute compositions with dissolution behaviour similar to the ezetimibe reference product Ezetrol’. On the other side, it was surprisingly found that compositions El and E2 show a dissolution profile compatible with the ezetimibe reference product Ezetrol®.
  • the oral fixed-dose combination pharmaceutical composition has a pharmacokinetic profile for Pitavastatin which gives rise to a 90% confidence interval (90% Cl) for the ratio of the geometric means of AUCo-t for test product (present disclosure) and Livazo’ (reference product), from 80.00 to 125.00%.
  • the oral fixed-dose combination pharmaceutical composition has a pharmacokinetic profile for Pitavastatin which gives rise to a 90% Cl for the ratio of the geometric means of Cmax for test product (present disclosure) and Livazo’ (reference product), from 80.00 to 125.00%.
  • the oral fixed-dose combination pharmaceutical composition has a pharmacokinetic profile for total Ezetimibe which gives rise to a 90% Cl for the ratio of the geometric means of AUC for test product (present disclosure) and Ezetrol’ (reference product), from 80.00 to 125.00%.
  • the oral fixed-dose combination pharmaceutical composition has a pharmacokinetic profile for total Ezetimibe which gives rise to a 90% confidence interval (90% Cl) for the ratio of the geometric means of Cmax for test product (present disclosure) and Ezetrol’ (reference product).

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Abstract

La présente divulgation concerne une composition pharmaceutique orale solide comprenant une quantité thérapeutiquement efficace de pitavastatine ou d'un sel pharmaceutiquement acceptable, un agent alcalinisant et du dioxyde de silicium colloïdal. En outre, la présente invention concerne également ladite composition comprenant en outre une quantité thérapeutiquement efficace d'Ezétimibe.
PCT/IB2025/052490 2024-03-08 2025-03-07 Composition pharmaceutique orale de pitavastatine, son procédé et ses utilisations Pending WO2025186785A1 (fr)

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102451161A (zh) 2010-10-18 2012-05-16 王丽燕 包含胆固醇吸收抑制剂和调脂药物的分散片及其应用
WO2012153181A1 (fr) * 2011-05-11 2012-11-15 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Composition pharmaceutique comprenant de la pitavastatine ou ses sels pharmaceutiquement acceptables
WO2013037838A1 (fr) * 2011-09-12 2013-03-21 Farma Grs, D.O.O. Forme polymorphique de calcium de pitavastatine
WO2017079748A1 (fr) * 2015-11-06 2017-05-11 Gemphire Therapeutics, Inc. Traitement de la dyslipidémie mixte
US20190070167A1 (en) * 2017-09-07 2019-03-07 Imtiyaz Naikwadi Pitavastatin containing preparation and method for producing same
WO2020178878A1 (fr) 2019-03-01 2020-09-10 興和株式会社 Composition pharmaceutique
JP2021008432A (ja) 2019-07-01 2021-01-28 興和株式会社 医薬組成物
CN112999178A (zh) 2021-03-01 2021-06-22 乐普制药科技有限公司 一种依折麦布匹伐他汀钙复方双层片剂
JP6937195B2 (ja) 2017-09-01 2021-09-22 興和株式会社 医薬組成物
US20220047547A1 (en) 2020-08-13 2022-02-17 Orient Pharma Co., Ltd. Solid oral pharmaceutical composition

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102451161A (zh) 2010-10-18 2012-05-16 王丽燕 包含胆固醇吸收抑制剂和调脂药物的分散片及其应用
WO2012153181A1 (fr) * 2011-05-11 2012-11-15 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Composition pharmaceutique comprenant de la pitavastatine ou ses sels pharmaceutiquement acceptables
WO2013037838A1 (fr) * 2011-09-12 2013-03-21 Farma Grs, D.O.O. Forme polymorphique de calcium de pitavastatine
WO2017079748A1 (fr) * 2015-11-06 2017-05-11 Gemphire Therapeutics, Inc. Traitement de la dyslipidémie mixte
JP6937195B2 (ja) 2017-09-01 2021-09-22 興和株式会社 医薬組成物
US20190070167A1 (en) * 2017-09-07 2019-03-07 Imtiyaz Naikwadi Pitavastatin containing preparation and method for producing same
WO2020178878A1 (fr) 2019-03-01 2020-09-10 興和株式会社 Composition pharmaceutique
JP2021008432A (ja) 2019-07-01 2021-01-28 興和株式会社 医薬組成物
US20220047547A1 (en) 2020-08-13 2022-02-17 Orient Pharma Co., Ltd. Solid oral pharmaceutical composition
CN112999178A (zh) 2021-03-01 2021-06-22 乐普制药科技有限公司 一种依折麦布匹伐他汀钙复方双层片剂

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