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WO2025144122A1 - Composition pharmaceutique comprenant de la dapagliflozine base sous forme amorphe - Google Patents

Composition pharmaceutique comprenant de la dapagliflozine base sous forme amorphe Download PDF

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Publication number
WO2025144122A1
WO2025144122A1 PCT/TR2023/051757 TR2023051757W WO2025144122A1 WO 2025144122 A1 WO2025144122 A1 WO 2025144122A1 TR 2023051757 W TR2023051757 W TR 2023051757W WO 2025144122 A1 WO2025144122 A1 WO 2025144122A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
dapagliflozin
stable pharmaceutical
composition according
pharmaceutically acceptable
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/TR2023/051757
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English (en)
Inventor
Erol KIRESEPI
Ersin Yildirim
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.)
Santa Farma Ilac Sanayi AS
Original Assignee
Santa Farma Ilac Sanayi 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
Application filed by Santa Farma Ilac Sanayi AS filed Critical Santa Farma Ilac Sanayi AS
Priority to PCT/TR2023/051757 priority Critical patent/WO2025144122A1/fr
Publication of WO2025144122A1 publication Critical patent/WO2025144122A1/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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • 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 stable pharmaceutical composition comprising amorphous form of dapagliflozin base presenting proper in vivo and in vitro dissolution profiles.
  • Background Of The Invention Diabetes is a group of metabolic disorder in which is related with high glucose in plasma.
  • type 1, type 2, and gestational diabetes there is three types of diabetes, such as type 1, type 2, and gestational diabetes.
  • type 2 diabetes is known to be the most common form of the diabetes in both of the developed and developing counties.
  • Type 2 diabetes non-insulin dependent diabetes, (NIDDM)
  • NIDDM non-insulin dependent diabetes,
  • Type 2 diabetes is a condition and is called as insulin resistance where the body produces insulin, but certain mechanisms prevent insulin from moving glucose into cells. Therefore, glucose level rises to the unsafe in the blood and which is called as hyperglycemia. Sustained hyperglycemia leads to worsen insulin resistance contributes to dysfunction in the beta cells of the pancreas. Diabetic microvascular complications and macro-vascular complications is the directly result of the degree of the sustained hyperglycemia.
  • Type 2 diabetes is characterized by hyperglycemia and an increased risk of microvascular and macro- vascular complications. In normal healthy individuals, glucose in plasma is filtered by glomerulus in the kidney and is actively reabsorbed in the proximal tube.
  • Dapagliflozin is a first-in class compound which is a highly selective and orally active inhibitor of the human sodium-dependent glucose co-transporter 2 (SGLT2), and also is the major transporter responsible for renal glucose reabsorption from the turbula lumen. It inhibits the renal reabsorption of glucose and promotes excretion of excess glucose in the urine, thus it improves glycemic control in patients with Type 2 diabetes and lower glucose level in plasma.
  • Dapagliflozin is (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol.
  • the empirical formula of Dapagliflozin is C21H25ClO6 and its relative molecular mass is 408.87 mg/mole as a free base and 502.98 mg/mole as propanediol monohydrate salt.
  • Propane diol salt is the form that reference product Forxiga consisting of. Dapagliflozin is a white to off-white powder, soluble in many polar organic solvents and non- hygroscopic.
  • Dapagliflozin in drug product marketed by Astra Zeneca is rapidly and well absorbed after oral administration.
  • Maximum dapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration in the fasted state.
  • Geometric mean steady-state dapagliflozin Cmax and AUC ⁇ values following once daily 10 mg doses of dapagliflozin were 158 ng/mL and 628 ng h/mL, respectively.
  • the absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%.
  • Administration with a high-fat meal decreased dapagliflozin Cmax by up to 50% and prolonged Tmax by approximately 1 hour, but did not alter AUC as compared with the fasted state.
  • AstraZeneca developed composition comprising Dapagliflozin for the treatment of the Type 2 diabetes, wherein Dapagliflozin is presented in the immediate release formulation. It is currently marketed under the trade name of Forxiga in the strengths of 5 mg and 10 mg per tablet.
  • EP3024442 relates to an amorphous solid dispersion of at least one polymer such as polyethyleneglycol, polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl cellulose, and dapagliflozin in its free form.
  • adsorbate comprising dapagliflozin adsorbed onto the surface of a substrate wherein dapagliflozin is substantially amorphous.
  • a pharmaceutical composition comprising amorphous dapagliflozin, is formed by mixing with pharmaceutically acceptable excipients.
  • WO2015104658 relates to a pharmaceutical composition comprising amorphous dapagliflozin, is formed by adding pharmaceutically acceptable excipients. In the manufacturing process, an amorphous solid dispersion is formed with a pre-treatment and other pharmaceutically acceptable excipients are mixed subsequently.
  • the object of this invention relates to pharmaceutical composition
  • pharmaceutical composition comprising dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipient. It is an object of the present invention is that dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipient present in the prepared pharmaceutical composition is used for the treatment of major depressive disorder (MDD) in adults.
  • MDD major depressive disorder
  • the active agent is dapagliflozin base in amorphous form, defined herein as not presenting any peaks in X-ray powder diffraction pattern.
  • the present invention also comprises at least one pharmaceutically acceptable excipient presented in the prepared pharmaceutical composition wherein the composition is manufactured by using direct compression process to get solid dosage forms containing the active ingredient, diluent, disintegrant, glidant and lubricant selected as to be the most suitable ones with respect to the intended form of administration.
  • at least two diluents selected from the group comprising compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, talc, and the like and mixtures thereof.
  • diluents are lactose and microcrystalline cellulose.
  • the glidant selected from the group comprising silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and other known glidant.
  • the glidant is silicon dioxide.
  • the disintegrant selected from the group comprising croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose, and the like and mixtures thereof.
  • the disintegrant is crospovidone.
  • prepared pharmaceutical composition by using direct compression process comprises dapagliflozin in amorphous form and at least one pharmaceutically acceptable excipient exhibit proper correlation between in vitro and in vivo release profiles.
  • the embodiment was designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using direct compression process.
  • Example 1 is given in Table 1 below.
  • the proposed embodiment provides an immediate release oral solid pharmaceutical composition wherein the amount ranges in w/w% by weight of the total composition are as stated in the table below.
  • Example 2 is given in Table 2 below.
  • the proposed embodiment provides an immediate release oral solid pharmaceutical composition wherein the amount ranges in w/w% by weight of the total composition are as stated in the table below.
  • Table 2: Unit Formula of Example 2 Ingredients w/w, % Dapagliflozin base in amorphous form 4-6 Lactose 20-25 Microcrystalline cellulose 65-70 Crospovidone 4-8 Silicone dioxide 0.1-1 Magnesium stearate 0.1-1 Core tablet 100.0 The detailed manufacturing steps are presented below: a.
  • Dapagliflozin base in amorphous form Lactose, Microcrystalline cellulose, Silicon dioxide and Crospovidone are screened through a proper sieve and stirred, b.
  • Magnesium stearate is screened through a proper sieve and added to the powder mixture prepared in Step (a) and stirred to obtain a uniform final blend, The obtained final blend does not present a uniform blend texture and not able to be compressed for tableting. Therefore, another embodiment was proposed to over this problem. Since the sticking problem was solved, type of excipients and their quantities were not changed. Instead, processability was re-designed. The embodiment, Example 3 is given in Table 3 below.
  • the proposed embodiment provides an immediate release pharmaceutical composition in accordance with the present invention wherein the amount ranges in w/w% by weight of the total composition are as stated in the table below.
  • Table 3 Unit Formula of Example 3 Ingredients w/w, % Dapagliflozin base in amorphous form 4-6 Lactose 20-25 Microcrystalline cellulose 65-70 Crospovidone 4-8 Silicone dioxide 0.1-1 Ingredients w/w, % Magnesium stearate 0.1-1 Core tablet 100.0
  • the detailed manufacturing steps are presented below: a. Dapagliflozin base in amorphous form, Lactose, half amount of Microcrystalline cellulose quantity, Silicon dioxide and Crospovidone are screened through a proper sieve and stirred, b.
  • Microcrystalline cellulose amount is added to the powder mixture obtained in Step (a).
  • Magnesium stearate is screened through a proper sieve and added to the powder mixture prepared in Step (b) and stirred to obtain a uniform final blend,
  • Tablets are compressed with the final blend presenting homogeneous texture in Step (c) and optionally coated.
  • total amount of microcrystalline cellulose was used in two equal amounts to carry out dilution process in two steps. Tablets are subjected into in-vitro dissolution study.
  • the conditions of dissolution study are described in international guidelines and identified as 900 mL of dissolution medium, 50 rpm at temperature of 37°C ⁇ 0.5°C with USP apparatus is II (Paddle) in three different physiological media to stimulate the behavior of drug product during gastrointestinal tract.
  • the physiological media are 0.1N HCI, pH 4.5 acetate buffer and pH 6.8 phosphate buffer.
  • Table 4 The results of dissolution study for Example 3 in 0.1N HCI Results, % Time, min Example 1 Reference drug product (FORXIGA ® ) 10 101 100 15 101 100 20 101 100 30 101 99 45 101 99 60 100 98
  • Table 5 The results of dissolution study for Example 3 in pH 4.5 acetate buffer Results, % Time, min Example 1 Reference drug product (FORXIGA ® ) 10 101 101 15 101 101 20 101 101 30 101 100 45 100 100 60 100 99
  • Table 6 The results of dissolution study of Example 3 in pH 6.8 phosphate buffer Results, % Time, min Example 1 Reference drug product (FORXIGA ® ) 10 104 102 15 104 102 20 104 101 30 104 101 45 103 100 60 103 100
  • the similarity is clearly observed for the product bioequivalency between example and reference drug product due to differences in formulation design, manufacturing process and the polymorphic form of active substance.
  • Example-3 the similarity between Example-3 and the reference product in each medium is obviously very high. It is understood that dapagliflozin base in amorphous form presented in the prepared pharmaceutical composition exhibits proper in vitro dissolution characteristics. After the evaluation of the in-vitro dissolution results, the prepared tablets were subjected to bioequivalence study. According to “Guideline on the Investigation on Bioequivalence” published by EMA, to establish bioequivalence of the test product with that of reference product. The assessment of bioequivalence is based upon 90% Confidence Intervals (CI) for the ratio of Test/Reference products and that, CI should be contained within the acceptance interval of 80.00-125.00%.
  • CI Confidence Intervals
  • the most adversely effective condition is the accelerated stability condition with 40°C ⁇ 0.5°C, 75% ⁇ 5% RH for 6-month period.
  • the examination for related substances and genotoxic impurities was performed by using validated analytical methods based on the international guidelines with the Example-3 samples stored under accelerated stability conditions.
  • Table 8 Impurity profile of the Example-3 under accelerated stability conditions at 6 th month period N itrosamine impurity, % *Total Related substances, % Example-3 Not detected 0.18 *specified limit is 1.0%
  • amorphous dapagliflozin was demonstrated to be polymorphically stable by having no polymorphic conversion in the amorphous state despite being subjected to several stress factors during manufacturing process including excipients compatibility or during storage.
  • a stable composition comprising dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipient, wherein - the manufacturing method is direct compression process, - the composition comprises microcrystalline cellulose as diluent, - the total amount of microcrystalline cellulose is processed in ratio of 1:1 through two steps in direct compression process.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique stable comprenant une forme amorphe de dapagliflozine base présentant des profils de dissolution in vivo et in vitro appropriés.
PCT/TR2023/051757 2023-12-27 2023-12-27 Composition pharmaceutique comprenant de la dapagliflozine base sous forme amorphe Pending WO2025144122A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2023/051757 WO2025144122A1 (fr) 2023-12-27 2023-12-27 Composition pharmaceutique comprenant de la dapagliflozine base sous forme amorphe

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2023/051757 WO2025144122A1 (fr) 2023-12-27 2023-12-27 Composition pharmaceutique comprenant de la dapagliflozine base sous forme amorphe

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WO2025144122A1 true WO2025144122A1 (fr) 2025-07-03

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017208136A1 (fr) * 2016-05-30 2017-12-07 Sun Pharmaceutical Industries Limited Composition pharmaceutique de co-cristal de dapagliflozine
WO2021101482A1 (fr) * 2019-11-20 2021-05-27 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Composition pharmaceutique solide comprenant de la dapagliflozine amorphe isolée à partir d'un solvant polaire

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017208136A1 (fr) * 2016-05-30 2017-12-07 Sun Pharmaceutical Industries Limited Composition pharmaceutique de co-cristal de dapagliflozine
WO2021101482A1 (fr) * 2019-11-20 2021-05-27 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Composition pharmaceutique solide comprenant de la dapagliflozine amorphe isolée à partir d'un solvant polaire

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