WO2023080854A1 - Compositions de chlorhydrate de lurasidone - Google Patents

Compositions de chlorhydrate de lurasidone Download PDF

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Publication number
WO2023080854A1
WO2023080854A1 PCT/TR2021/051124 TR2021051124W WO2023080854A1 WO 2023080854 A1 WO2023080854 A1 WO 2023080854A1 TR 2021051124 W TR2021051124 W TR 2021051124W WO 2023080854 A1 WO2023080854 A1 WO 2023080854A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
lurasidone
composition according
oral solid
solid pharmaceutical
Prior art date
Application number
PCT/TR2021/051124
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/TR2021/051124 priority Critical patent/WO2023080854A1/fr
Publication of WO2023080854A1 publication Critical patent/WO2023080854A1/fr

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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
    • A61K9/2013—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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising lurasidone or its pharmaceutically acceptable salt thereof and mannitol within specified range of ratio by total weight of the composition.
  • Schizophrenia is a psychosis, a type of mental illness characterized by distortions in thinking, perception, emotions, language, sense of self and behavior that severe and chronic mental illness is estimated approximately 1.0% of the population throughout the world. Besides that, it also reduces life expectancy by approximately 10 years, mostly as a consequence of suicide.
  • Antipsychotic medications are mainly standard treatment for patients with schizophrenia for being effective in treating symptoms and behaviours associated with the disorder. But the treatment should be continued for a long time due to being risk of reoccurring of schizophrenia in case the drug’s withdrawal. Thus, any possible side effects during administration may always be serious problems.
  • the second-generation or “atypical” antipsychotic drugs were desired to develop safe medicament which exhibits an excellent effect on various schizophrenia as an antipsychotic without causing side effects such as extrapyramidal symptoms for prolonged medication.
  • Lurasidone is a second-generation antipsychotic belonging to the chemical class of benzisothiazol derivatives. Also, it has also antagonist activity on the dopamine 2 (D2) and serotonin (5-HT)-2A receptors.
  • lurasidone is (3aR,4S,7R,7aS)-2- ⁇ (lR,2R)-2-[4-(l,2-benzisothiazol-3- yl)piperazin-l-ylmethyl]cyclohexylmethyl ⁇ hexahydro-4,7-methano-2H-isoindole- 1,3-dione.
  • the empirical formula of lurasidone is C28H36N4O2S and the compound has a molecular weight of 492.676 g/mol.
  • the structural formula of lurasidone is shown in the Formula I.
  • Lurasidone hydrochloride is a white to off-white powder and non-hygroscopic. It is very slightly soluble in water, practically insoluble or insoluble in 0.1 N HC1, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene and very slightly soluble in acetone.
  • Lurasidone base and its pharmaceutically acceptable acid addition salts first have been described in EP0464846 numbered patent document by Sumitomo Pharmaceuticals Company wherein the compound is described as antipsychotic-, neuroleptic- and anti-anxiety agents for the treatment of schizophrenia, senile insanity, manic-depressive psychosis and neurosis.
  • Example l-(a) discloses the preparation of lurasidone and its pharmaceutically acceptable salt thereof, with hydrochloride salt.
  • patent document numbered as EP1535616 was first disclosed a pharmaceutical composition comprising lurasidone or a pharmaceutically acceptable salt thereof in the preparation of an agent for improving the negative symptoms and/or cognitive dysfunction of schizophrenia.
  • EP1535616 numbered patent document has divisional patent applications as EP1944030 and EP2295061.
  • EP 1944030 relates to an oral preparation comprising lurasidone or a pharmaceutically acceptable salt thereof, for use in a method for improving the negative symptoms and/or cognitive dysfunction of schizophrenia.
  • EP2295061 patent document disclosed a novel oral method comprising lurasidone used for the treatment of schizophrenia. The said patent application was withdrawn.
  • a pharmaceutical final product comprising lurasidone as an active was firstly approved by the U.S. Food&Drug Administration on October 2010 and by European Medicines Agency on March 2014 and has been launched under the brand name of LATUDA®.
  • LATUDA® is a medicine that is indicated for treatment of adult and adolescent patients (13 to 17 years) with schizophrenia, monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression and adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar I disorder (bipolar depression).
  • the commercial product is presented as film-coated tablets available in strengths designated as, 20, 40, 60, 80 and 120 mg of lurasidone HC1.
  • EP 1884242 relates to an oral preparation comprising lurasidone, a pregelatinized starch, a water-soluble excipient and a water-soluble polymer binder; wherein a content of lurasidone in the preparation is 20 to 45% (wt/wt), and the pregelatinized starch is incorporated in an amount of 10 to 50% (wt/wt) based on the weight of the preparation.
  • EP1884242 numbered patent document has divisional patent application as EP2422783.
  • EP2422783 relates to an oral preparation comprising lurasidone, a pregelatinized starch, a water-soluble excipient, a water-soluble polymer binder and a disintegrant; wherein lurasidone in the preparation is 20 to 45% (wt/wt), pregelatinized starch in the preparation is 10 to 50% (wt/wt) based on the weight of the preparation; and wherein the disintegrant is selected from the group consisting of corn starch, crystalline cellulose, low substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl starch sodium and crospovidone.
  • EP1327440 relates to a pharmaceutical preparation in the form of a rapidly disintegrating oral preparation comprising granules comprising lurasidone, two disintegrating agents, a water- soluble excipient and a polymer binder.
  • EP1327440 numbered patent document has divisional patent application as EP1974724.
  • EP1891956 relates to a solution-type preparation comprising lurasidone or a pharmaceutically acceptable acid addition salt thereof, wherein the active ingredient is solubilized by incorporating at least one substance selected from benzyl alcohol, N,N-dimethylacetamide, lactic acid, anhydrous ethanol and propylene glycol.
  • EP3318279 relates to pharmaceutical compositions comprising lurasidone hydrochloride with at least one binder and one or more other pharmaceutically acceptable excipient.
  • WO2016012898 relates to an oral pharmaceutical composition
  • an oral pharmaceutical composition comprising lurasidone or pharmaceutically acceptable salts thereof, one or more water-soluble pharmaceutical excipients, a disintegrating agent consisting essentially of a single disintegrating agent, wherein the composition is free of starch.
  • WO2012156981 relates to an oral pharmaceutical composition comprising lurasidone or pharmaceutically acceptable salts thereof and one or more pharmaceutical excipients, wherein the composition is free of water-soluble excipients.
  • WO2019128991 relates to an oral pharmaceutical composition comprising lurasidone wherein the lurasidone is in a free base form.
  • WO2014076712 relates to pharmaceutical composition
  • WO2018130943 relates to pharmaceutical composition
  • pharmaceutical composition comprising lurasidone or its pharmaceutically acceptable salt(s) or solvate(s) thereof, microcrystalline cellulose and, one or more other pharmaceutical excipient(s); wherein the ratio of lurasidone to microcrystalline cellulose is in the range from about 2: 1 to about 10: 1.
  • Absorbed lurasidone in approximately 1-3 hours can reach peak serum concentrations. Its absorption rate is quite low that is estimated as 9-19% after dosing in suspension from after food. Also when lurasidone is administered with food, mean Cmax and AUC were about 3-times and 2-times, respectively, compared to the levels observed under fasting conditions. Thus, it has been recommended to be administered with food.
  • a solid oral pharmaceutical composition comprising lurasidone or one of its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient was developed to obtain suitable dissolution profile with making improvements on friability, disintegration and easy tableting processes by using lurasidone and mannitol with specified range ratio 4:1 to 5.5:1 by total weight of the composition.
  • the object of this invention is to develop an oral pharmaceutical composition
  • an oral pharmaceutical composition comprising a therapeutically effective amount of lurasidone or one of its pharmaceutically acceptable salts, mannitol and at least one pharmaceutically acceptable excipient with improved physicochemical characteristics.
  • the active agent is lurasidone hydrochloride for the preparation of an oral dosage form.
  • mannitol is also present as an excipient with the active agent lurasidone hydrochloride for the preparation of an oral dosage form.
  • the present invention relates to an oral pharmaceutical composition
  • an oral pharmaceutical composition comprising lurasidone hydrochloride, mannitol and a pharmaceutically acceptable excipient manufactured by using wet granulation method.
  • Another object of the present invention is related to an oral pharmaceutical composition comprising lurasidone or one of its pharmaceutically acceptable salt thereof, mannitol and at least one pharmaceutically acceptable excipient wherein the weight ratio of lurasidone and mannitol is in the range of 4:1 to 5.5:1.
  • the present invention provides an oral pharmaceutical composition
  • an oral pharmaceutical composition comprising therapeutically effective amount of lurasidone or one of its pharmaceutically acceptable salts, mannitol and at least one pharmaceutically acceptable excipient presenting improved flowability and dissolution characteristics.
  • lurasidone used in the prepared oral pharmaceutical composition is in hydrochloride salt.
  • lurasidone is known to have very low aqueous solubility such as 0.224 mg/mL in water and its estimated bioavailability value in the range about 9% to 19%.
  • wet granulation (high- shear granulation or fluid-bed granulation) could be more proper to use as a manufacturing method to get desired dissolution profile of Lurasidone.
  • wet granulation refers to converting a powder blend into granules having suitable flow and being cohesive properties for tableting. The procedure consists of mixing the powders in a suitable blender followed by adding the granulating solution under shear to the mixed powders to obtain a granulation.
  • compositions comprising lurasidone hydrochloride, mannitol and other excipients such as diluents, disintegrant, binders, lubricant and solvent.
  • At least one diluent may include, but are not limited to mannitol, lactose, saccharose, sorbitol, D-sorbitol, erythritol, xylitol, dibasic calcium phosphate dihydrate, polysaccharides, primarily microcrystalline cellulose and the like and mixtures thereof.
  • diluents are mannitol and lactose.
  • At least one disintegrant may include, but are not limited to corn starch, pregelatinized starch, microcrystalline cellulose, low substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone and the like and mixtures thereof.
  • disintegrants are pregelatinized starch and croscarmellose sodium.
  • At least one binder may include, but are not limited to hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, gelatin, starch, pregelatinized starch and the like and mixtures thereof.
  • binder is hydroxypropyl methylcellulose.
  • lubricant may include, but is not limited to magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulphate and magnesium lauryl sulphate and the like and mixtures thereof.
  • the lubricant is magnesium stearate.
  • solvent may include, but is not limited to can be selected from deionized water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, ethyl acetate, dimethylsulfoxide and their mixtures thereof.
  • the solvent is ethanol.
  • Example 1 The embodiment in accordance with the present invention was designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using wet granulation process.
  • the embodiment, Example 1 is given in the below.
  • the embodiment Example 1 based on the invention provides an oral pharmaceutical composition in the amounts of w/w% by weight of the total composition.
  • Step (b) Lurasidone, mannitol, pregelatinized starch and specified amount of croscarmellose Sodium are screened through a proper sieve and stirred
  • c. The solution in Step (b) is added into the powder blend prepared in Step (a) to perform granulation process, d.
  • the granule prepared in Step (c) were dried in fluid bed dryer and shifted through a proper sieve, e.
  • the remaining amounts of the croscarmellose sodium, lactose are screened through a proper sieve and added to the granules prepared in Step (d) and stirred
  • Magnesium stearate is screened through a proper sieve and added to the granules prepared in Step (e) and stirred to obtain a uniform final blend, g. Tablet compression is performed with the final blend in Step (f).
  • the prepared tablets were subjected to friability study in order to measure the resistance of tablets to fractures according to USP ⁇ 1216 > Tablet Friability test.
  • in vitro dissolution study The conditions of in vitro dissolution study are set by USFDA, based on the information available dissolution medium is McIIvaine buffer. Other conditions are defined as; volume of dissolution medium is 900 ml, temperature of study is 37°C ⁇ 0.5, rotation speed is 50 rpm, apparatus is paddle and the duration of dissolution study is 60 minutes.
  • Example 2 Based on the results presented in Table 2, the release pattern of Example 1 was remarkably slower than the reference drug product.
  • the amount of croscarmellose sodium is increased in the pharmaceutical composition.
  • Other ingredients are also adjusted to improve ability to process.
  • the manufacturing process is the same with the Example 1.
  • the compressibility index and Hausner ratio were calculated as 17.00 and 1,250, respectively and the results of bulk and tapped densities were 0.580 g/ml and 0.699 g/ml.
  • Example 2 The formulation design of Example 2 is modified quantitatively to overcome the problems due to lurasidone hydrochloride. As being diluent, mannitol in the Example 2 has the highest impact on powder blend. Thus, the correlation in amount between lurasidone hydrochloride and mannitol is investigated to get successful tablet compression process and dissolution characteristics.
  • an oral pharmaceutical composition was developed with improved friability, disintegration time and dissolution profile by keeping constant

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
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  • Molecular Biology (AREA)
  • Physiology (AREA)
  • Nutrition Science (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique comprenant de la lurasidone ou un sel pharmaceutiquement acceptable de celui-ci et du mannitol compris dans une plage spécifiée de rapport par poids total de la composition.
PCT/TR2021/051124 2021-11-03 2021-11-03 Compositions de chlorhydrate de lurasidone WO2023080854A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2021/051124 WO2023080854A1 (fr) 2021-11-03 2021-11-03 Compositions de chlorhydrate de lurasidone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2021/051124 WO2023080854A1 (fr) 2021-11-03 2021-11-03 Compositions de chlorhydrate de lurasidone

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140348909A1 (en) * 2011-05-13 2014-11-27 Cadila Healthcare Limited Pharmaceutical compositions of lurasidone
CN106539768A (zh) * 2015-09-18 2017-03-29 成都康弘药业集团股份有限公司 一种盐酸鲁拉西酮口腔崩解片及其制备方法
CN107854446A (zh) * 2017-12-19 2018-03-30 佛山市弘泰药物研发有限公司 一种盐酸鲁拉西酮口崩片及其制备方法
CN110833532A (zh) * 2019-12-19 2020-02-25 赵洁 一种快速释药的盐酸鲁拉西酮片及其制备工艺
CN113081983A (zh) * 2021-04-19 2021-07-09 北京阳光诺和药物研究股份有限公司 一种鲁拉西酮舌下片及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140348909A1 (en) * 2011-05-13 2014-11-27 Cadila Healthcare Limited Pharmaceutical compositions of lurasidone
CN106539768A (zh) * 2015-09-18 2017-03-29 成都康弘药业集团股份有限公司 一种盐酸鲁拉西酮口腔崩解片及其制备方法
CN107854446A (zh) * 2017-12-19 2018-03-30 佛山市弘泰药物研发有限公司 一种盐酸鲁拉西酮口崩片及其制备方法
CN110833532A (zh) * 2019-12-19 2020-02-25 赵洁 一种快速释药的盐酸鲁拉西酮片及其制备工艺
CN113081983A (zh) * 2021-04-19 2021-07-09 北京阳光诺和药物研究股份有限公司 一种鲁拉西酮舌下片及其制备方法

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