WO2023128905A1 - Composition pharmaceutique comprenant du tolvaptan amorphe - Google Patents

Composition pharmaceutique comprenant du tolvaptan amorphe Download PDF

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Publication number
WO2023128905A1
WO2023128905A1 PCT/TR2021/051629 TR2021051629W WO2023128905A1 WO 2023128905 A1 WO2023128905 A1 WO 2023128905A1 TR 2021051629 W TR2021051629 W TR 2021051629W WO 2023128905 A1 WO2023128905 A1 WO 2023128905A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
tolvaptan
screened
pharmaceutically acceptable
Prior art date
Application number
PCT/TR2021/051629
Other languages
English (en)
Inventor
Erol KIRESEPI
Ersin Yildirim
Original Assignee
Santa Farma Ilac Sanayii A.S.
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 Sanayii A.S. filed Critical Santa Farma Ilac Sanayii A.S.
Priority to PCT/TR2021/051629 priority Critical patent/WO2023128905A1/fr
Publication of WO2023128905A1 publication Critical patent/WO2023128905A1/fr

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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
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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 pharmaceutical composition
  • a pharmaceutical composition comprising tolvaptan or one of its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient manufactured by using dry granulation with improved pharmaceutical characteristics to obtain proper release profiles in three different physiological media of gastrointestinal tract.
  • Arginine vasopressin is a neuropeptide synthesized in the para- ventricular and supraoptic nuclei of the hypothalamus, transported to the posterior pituitary gland and released into general circulation. It actively plays role to the regulation of water and solute excretion by the kidney, as well as blood pressure control and associated disorders such as congestive heart failure (CHF), liver cirrhosis, and syndrome of inappropriate antidiuretic hormone (SIADH) secretion.
  • CHF congestive heart failure
  • SIADH syndrome of inappropriate antidiuretic hormone
  • Tolvaptan is indicated for the treatment of hypervolemic and euvolemic hyponatremia and for the prevention of hyponatremia.
  • a selective vasopressin V2 receptor antagonist can be used for minimizing the effects of the increased AVP levels and reduce water retention without disturbing electrolytic balance.
  • Tolvaptan is a non-peptide, selective vasopressin V2-receptor antagonist with affinity for the V2 receptor that is 1.8 time that of native arginine vasopressin (AVP). It selectively inhibits AVP induced water reabsorption at the renal collecting ducts by blocking V2 receptors located therein, which increased water excretion without any change in electrolyte excretion is occurred.
  • AVP native arginine vasopressin
  • Tolvaptan molecule has a racemic nature and the chemical name is ( ⁇ )-4’-[(7-chloro-2, 3,4,5- tetrahydro-5-hydroxy-lH-l-benzazepin-l-yl) carbonyl] -o-tolu-m-toluidide.
  • the molecular formula is C26H25CIN2O3 and the compound has a molecular weight of 448.9 g/mol.
  • Tolvaptan appeal's as a white crystalline powder and non-hygroscopic and exhibits low and pH independent water solubility. Tolvaptan is classified as Biopharmaceutical Classification System (BCS) IV drug.
  • BCS Biopharmaceutical Classification System
  • Tolvaptan and its pharmaceutically acceptable salts thereof first have been described in EP1028111 numbered patent document by Otsuka Pharmaceutical Co. for treatment of hypertension, edema, ascites, heart failure, renal function disorder, vasopressin parasecretion syndrome (SIADH), hepatocirrhosis, hyponatremia, hypokaliemia, diabetic, and circulation disorder.
  • SIADH vasopressin parasecretion syndrome
  • Tolvaptan was firstly commercially authorized by U.S. Food&Drug Administration in August 2009. The medicinal product of it been launched in the immediate release tablet dosage form under the name of the SAMSCA® in the strength of 15 mg and 30 mg which is used for the treatment of clinically significant a (serum sodium ⁇ 125 niEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), in patients with heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).
  • a serum sodium ⁇ 125 niEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction
  • SIADH Syndrome of Inappropriate Antidiuretic Hormone
  • ADPKD autosomal dominant polycystic kidney disease
  • EP2167046 relates to solid pharmaceutical composition
  • solid pharmaceutical composition comprising tolvaptan or a pharmaceutically acceptable salt thereof, hydroxypropylcellulose containing a hydroxypropyl group in an amount of 50 wt% or greater; and at least one member selected from the group consisting of carmellose, sodium carboxy methyl starch, crospovidone, and low substituted hydroxypropylcellulose with an average particle diameter of 30 to 70 pm, and a 90% cumulative particle diameter of 100 to 200 pm manufactured by wet granulation method.
  • EP2961383 relates to a suspension for oral pharmaceutical composition comprising amorphous tolvaptan, hydroxypropyl methylcellulose (HPMC) and a water. This dosage form is a suspension.
  • JPH1121241 relates to a pharmaceutical composition
  • amorphous tolvaptan prepared by dissolving with hydroxypropyl cellulose in an organic solvent and spray-drying the mixture to obtain a powder. This pre-study is performed to keep the tolvaptan molecule in stable.
  • WO2014068586 relates to solid pharmaceutical composition
  • solid pharmaceutical composition comprising tolvaptan or a pharmaceutically acceptable salt thereof, a polymer selected from povidone; graft co-polymer of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate; and combinations thereof manufactured by fluid bed top spray granulation.
  • This pre-study is also a pre-treatment process for a possible unstable situation.
  • EP2586464 relates to solid pharmaceutical composition
  • solid pharmaceutical composition comprising amorphous tolvaptan dissolved in an organic solvent and crosslinked polyvinylpyrrolidone, wherein the ratio of the active ingredient tolvaptan and the cross-linked polyvinylpyrrolidone by weight is 1:0.1-10.
  • W02020122670 relates to pharmaceutical composition
  • pharmaceutical composition comprising tolvaptan or a pharmaceutically acceptable salt thereof, polyvinylpyrrolidone used as a water penetration enhancer and at least one from the group consisting of methylene chloride and ethanol used as an organic solvent for dissolving tolvaptan and polyvinylpyrrolidone.
  • CN 109646391 relates to a sustained release pharmaceutical composition
  • a sustained release pharmaceutical composition comprising tolvaptan, hypromellose and at least one excipient, wherein the amount of hypromellose is between 30% and 45% of the total amount of the preparation with having viscosity ranges from 50 mPas to 10,000 mPas.
  • Tolvaptan active substance is a BCS IV drug and due to this it is poorly soluble in water and the solubility is poor across all pH ranges. Thus, it is expected to have low absorption due to poor solubility.
  • following single dose of 30 to 480 mg it is rapidly absorbed in healthy volunteers with a median time to peak plasma concentrations of about 2 hours.
  • the absolute bioavailability is about 56% with close relative bioavailability between different dose strength.
  • the mean elimination half-life is 7.8 hour.
  • plasma protein is extensive (99%) and it bound mainly to serum albumin and al-acid glycoprotein.
  • the inventors of the present invention have developed a pharmaceutical composition comprising amorphous tolvaptan and at least one pharmaceutically acceptable excipient in the immediate release dosage form manufactured by using dry granulation to obtain suitable release profiles in three different physiological media of gastrointestinal tract with improved pharmaceutical characteristics of solubility and flowability.
  • the object of this invention is to develop a pharmaceutical composition comprising a therapeutically effective amount of amorphous tolvaptan in the immediate release dosage form, with a dedicated manufacturing process.
  • amorphous tolvaptan is known to be poorly soluble in physiological pH range.
  • it is the objective of the present invention is to provide a pharmaceutical composition comprising amorphous tolvaptan with improved solubility.
  • the utilization of the amorphous form can increase the solubility of tolvaptan in physiological pH range.
  • the amorphous tolvaptan is unstable and the flowability is very challenging to overcome.
  • Another object of the present invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising amorphous tolvaptan and at least one pharmaceutically acceptable excipient manufactured by using dry granulation where obtained granules are manufactured without using moisture, solvents and heat and a pre-treatment to get a solid dispersion or composite.
  • Another object of the present invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising the active ingredient, diluents, binder, disintegrant, lubricant and glidant with respect to the intended form of administration.
  • Amorphous tolvaptan has another restriction during development pharmaceutical such as having quite poor flowability property.
  • colloidal silicon dioxide is used as glidant and the composition is manufactured by using the dry granulation process.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising amorphous tolvaptan and at least one pharmaceutically acceptable excipient manufactured by using dry granulation to release more than 85% of the amorphous tolvaptan in 15 minutes in 0.22% sodium lauryl sulphate (SLS) in pH 1.2, pH 4.5, pH 6.8 buffer solutions simulating GI tract conditions at 37 ⁇ 0.5°C using USP type II (paddle) apparatus rotating at 50 rpm.
  • SLS sodium lauryl sulphate
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising amorphous tolvaptan and at least one pharmaceutically acceptable excipients developed in the immediate release dosage form wherein the prepared composition is manufactured with the most proper manufacturing process with critical parameters.
  • Direct compression refers to being a relatively quick process where the powdered materials are compressed are mixed well and performed the tablet compression without requiring further granulation steps. Thus, it is preferred to use over wet or dry granulation because of quick processing time. However, it has some challenges when the drug has poor solubility and flowability characteristics during proceeding steps. Therefore, characterisation of tolvaptan active substance was investigated.
  • Tolvaptan active substance is known to be practically insolubility in water and exhibit poor solubility (approximately 0.01 mg/250 mL) across all pH ranges stated in Table 1.
  • tolvaptan is poorly soluble and in addition, permeability is low as to be expected due to BCS IV drug characterisation.
  • tolvaptan is preferred to be used in amorphous form.
  • the amorphous form is one of the promising strategy to overcome the poor oral bioavailability associated with BCS Class IV compounds due to having a higher free energy than its crystalline counterpart, and that will increase the apparent solubility and dissolution rate. However, it tends to crystallize over time due to being thermodynamically unstable and this crystallization effect is evaluated with in-vitro dissolution study.
  • wet granulation is preferred to be experienced that refers to converting a powder blend into granules having suitable flow and being cohesive properties for tableting to achieve the desired properties for subsequent processes.
  • the granulating solution can be a solvent or a solution comprising a binder or granulating agent to used to ensure particle adhesion once the granule is dried.
  • a pharmaceutical composition comprising amorphous tolvaptan and at least one pharmaceutically acceptable excipient was designed to be able use wet granulation manufacturing process.
  • a pharmaceutical composition for oral administration is a pharmaceutical composition for oral administration.
  • Suitable solid oral dosage forms are selected from the group comprising tablets, capsules, granules, powders, and pellet or unit dose packets, preferably the solid oral dosage form is tablet.
  • a pharmaceutical composition containing amorphous tolvaptan manufactured by using wet granulation process in tablet dosage form to comprise pharmaceutically acceptable excipients in function of binder, disintegrant, surfactant, lubricants and granulation solvent selected as to be the most suitable ones with respect to the intended form of administration.
  • the diluent may include, but are not limited to dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof.
  • diluents are lactose and microcrystalline cellulose.
  • the binder may include, but are not limited to lactose monohydrate, starch, pregelatinized starch, cellulose or cellulose derivatives, povidone, sucrose, polyethylene glycol, or mixtures thereof.
  • the binder is pregelatinized starch.
  • the disintegrant may include, but is not limited to calcium, croscarmellose sodium, sodium starch glycolate, crospovidone, com starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose.
  • the disintegrants are croscarmellose sodium.
  • the surfactant may include, but is not limited to betain, quaternary ammonium salts, polysorbates, poloxamer.
  • the surfactant is a poloxamer.
  • the lubricants may include, but are not limited to sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof.
  • the lubricants are talc and magnesium stearate.
  • the granulation solvent may include, but are not limited to methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dichloromethane, dichloroethane, chloroform, or carbon tetrachloride; and mixed solvents of those.
  • the granulation solvents are ethanol and dichloromethane.
  • a mixed solvent comprising dichloromethane and ethanol is in the ratio of 4:1.
  • Another object of the present invention is to provide a pharmaceutical compositions containing tolvaptan wherein the total weight of the tolvaptan is less than 20% w/w by total tablet weight.
  • the proposed embodiment based on the invention provides an immediate release pharmaceutical composition wherein the amounts in w/w% by weight of the total composition are as stated in the Table 2 below:
  • Example 1 for immediate release pharmaceutical
  • Amorphous tolvaptan, croscarmellose sodium, microcrystalline cellulose, lactose and pregelatinized starch were screened through a proper sieve and transferred into cubic mixer and stirred,
  • Poloxamer was dissolved in sufficient quantity of dichloromethane and ethanol mixture
  • Step (3) The preparation in Step (1) was added to solution in Step (2) to perform high-shear granulation process
  • the dissolution test is carried out in 0.22% sodium lauryl sulphate (SLS) aqueous solution.
  • SLS sodium lauryl sulphate
  • Other conditions are defined as; volume of dissolution media is 900 ml, temperature is 37°C ⁇ 0.5°C, rotation speed is 50 rpm, apparatus is paddle and the duration of dissolution study is 60-minute.
  • the amount of dissolved active ingredient over time was determined by HPLC.
  • Example 1 It is observed that the release pattern of Example 1 was remarkably slower than the reference drug product.
  • the similarity factor f2 value is a tool to measure similarity of two products. This value should be between 50-100 to be defined as similar and closer this value to 100 means scale of similarity is high.
  • the similarity factor f2 of Example 1 and the reference drug product was calculated as 17 since less than 50, the products compared were not similar.
  • the desired concentration was not achieved and the dissolved amorphous tolvaptan was less than 40% within 60 minutes.
  • the physicochemical properties of amorphous tolvaptan such as solubility properties were considered to formulate by optimizing critical parameters to obtain successful drug composition which could reach the required therapeutic amount in a specified time.
  • the manufacturing process of the pharmaceutical composition comprising amorphous tolvaptan and at least one pharmaceutically acceptable excipient was altered as using dry granulation. This process was not preferred considering disadvantages of tolvaptan in solubility and processability points of view. To improve these physicochemical properties, formulation design and details of manufacturing process should be proposed carefully.
  • Dry granulation refers to obtaining granules without wetting and subsequent drying processes to be avoided some issues related to wet granulation where the powdered materials comprising active substance with or without at least one pharmaceutically acceptable excipient are mixed and aggregated under high pressure which are then sieved before the addition of other ingredients to obtain final compression.
  • Example 2 the percentage of therapeutically effective dose of amorphous tolvaptan and the amount of pharmaceutically acceptable excipients were adjusted.
  • tolvaptan active substance bulk density and tapped density were found as 0.19 g/ml and 0.34 g/ml, respectively and compressibility index and Hausner ratio were 44.00 and 1.738, respectively.
  • the glidant may include, but is not limited to colloidal silicon dioxide, talc, magnesium stearate or the like.
  • the glidant is a colloidal silicon dioxide.
  • the tablet composition of the present invention comprising the following ingredients, based on the total weight of the composition:
  • a therapeutically effective dose of amorphous tolvaptan was adjusted in an amount of from 5% to 8% w/w by total weight of composition.
  • Microcrystalline cellulose and lactose used as diluent in a mixture thereof were adjusted in an amount of from 70% to 78% w/w by total weight of composition.
  • Pregelatinized starch used as binder and croscarmellose sodium used as disintegrant were adjusted in an amount of from 8% to 10% w/w by total weight of composition.
  • Colloidal silicon dioxide used as glidant was added in an amount of from 0.0% to 1.0% w/w by total weight of composition.
  • Poloxamer used as surfactant was removed from the composition.
  • Example 2 The formulation of proposed embodiment identified as Example 2 is given in the Table 5.
  • Example 2 The release pattern of Example 2 was similar to the reference drug product, in which the similarity factor f2 were calculated as 62.
  • SLS sodium lauryl sulphate
  • Example 2 Based on the results presented in Table 6 above, the release patterns of Example 2 in 0.22% sodium lauryl sulphate (SLS) in pH 1.2, pH 4.5 acetate buffer and pH 6.8 phosphate buffer were similar to the reference drug product, in which the similarity factor f2 were calculated for all buffer solutions as 64.1, 72.2 and 84 respectively.
  • SLS sodium lauryl sulphate
  • the developed pharmaceutical composition comprising amorphous tolvaptan and at least one pharmaceutically acceptable excipient in the immediate release dosage form manufactured by using dry granulation method where the composition was compressed into tablets between 150 kP to 200 kP to get similar dissolution profile in 0.22% sodium lauryl sulphate (SLS) in pH 1.2, pH 4.5 acetate buffer and pH 6.8 phosphate buffer to the reference drug product.
  • SLS sodium lauryl sulphate

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique comprenant du tolvaptan ou l'un de ses sels pharmaceutiquement acceptables et au moins un excipient pharmaceutiquement acceptable fabriqué en utilisant une granulation sèche avec des caractéristiques pharmaceutiques améliorées pour obtenir des profils de libération appropriés dans trois milieux physiologiques différents du tractus gastro-intestinal.
PCT/TR2021/051629 2021-12-30 2021-12-30 Composition pharmaceutique comprenant du tolvaptan amorphe WO2023128905A1 (fr)

Priority Applications (1)

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PCT/TR2021/051629 WO2023128905A1 (fr) 2021-12-30 2021-12-30 Composition pharmaceutique comprenant du tolvaptan amorphe

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2021/051629 WO2023128905A1 (fr) 2021-12-30 2021-12-30 Composition pharmaceutique comprenant du tolvaptan amorphe

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110165249A1 (en) * 2008-09-05 2011-07-07 Otsuka Pharmaceutical Co., Ltd. Pharmaceutical solid preparation
CN102512393A (zh) * 2011-12-19 2012-06-27 浙江华海药业股份有限公司 一种托伐普坦的口腔崩解片
CN111888335A (zh) * 2020-08-21 2020-11-06 福安药业集团重庆礼邦药物开发有限公司 一种托伐普坦的药物固体制剂及制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110165249A1 (en) * 2008-09-05 2011-07-07 Otsuka Pharmaceutical Co., Ltd. Pharmaceutical solid preparation
CN102512393A (zh) * 2011-12-19 2012-06-27 浙江华海药业股份有限公司 一种托伐普坦的口腔崩解片
CN111888335A (zh) * 2020-08-21 2020-11-06 福安药业集团重庆礼邦药物开发有限公司 一种托伐普坦的药物固体制剂及制备方法

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