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WO2022042646A1 - Composition de chlorhydrate de lurasidone et son procédé de préparation - Google Patents

Composition de chlorhydrate de lurasidone et son procédé de préparation Download PDF

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Publication number
WO2022042646A1
WO2022042646A1 PCT/CN2021/114761 CN2021114761W WO2022042646A1 WO 2022042646 A1 WO2022042646 A1 WO 2022042646A1 CN 2021114761 W CN2021114761 W CN 2021114761W WO 2022042646 A1 WO2022042646 A1 WO 2022042646A1
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WO
WIPO (PCT)
Prior art keywords
lurasidone hydrochloride
lurasidone
granular composition
composition according
filler
Prior art date
Application number
PCT/CN2021/114761
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English (en)
Chinese (zh)
Inventor
张津州
郭达
牛光强
章正赞
滕哲翊
赵周明
Original Assignee
浙江华海药业股份有限公司
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Publication date
Application filed by 浙江华海药业股份有限公司 filed Critical 浙江华海药业股份有限公司
Priority to CN202180050280.5A priority Critical patent/CN115843243A/zh
Publication of WO2022042646A1 publication Critical patent/WO2022042646A1/fr

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    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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
    • 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 invention belongs to the technical field of medicine, and relates to a lurasidone hydrochloride composition and a preparation method thereof.
  • Lurasidone is an atypical antipsychotic. Its structural formula is as follows:
  • Chinese patent CN201010564784.2 discloses a lurasidone instant tablet and a preparation method thereof. The method achieves the effect of improving the dissolution rate by making the content of pregelatinized starch by weight 10-50% of the weight of the preparation.
  • Chinese patent CN201410602319.1 discloses the use of a mixture of low-substituted hydroxypropyl cellulose and croscarmellose sodium, the low-substituted hydroxypropyl cellulose is 5-20% of the weight of the preparation, and the The mixture is 1-5% of the weight of the preparation, the weight ratio of low-substituted hydroxypropyl cellulose and croscarmellose sodium is 4-6:1, and the effect of improving the dissolution rate is achieved by using two disintegrants .
  • Bioavailability is the rate at which a drug enters a target organ or tissue and the extent to which it is utilized by the target organ.
  • Lurasidone is a poorly soluble drug and has bioavailability problems when administered orally. Because the drug bioavailability test is more complicated than the in vitro dissolution test, in practice, the in vivo bioavailability of poorly soluble drugs can generally be predicted by measuring the in vitro dissolution rate, but there is also the possibility of poor in vitro and in vivo correlation.
  • the present invention provides a lurasidone hydrochloride composition and a preparation method thereof.
  • the lurasidone hydrochloride composition can comprehensively improve the dissolution effect of lurasidone hydrochloride and simultaneously improve the bioavailability.
  • the present invention provides a lurasidone hydrochloride granular composition, the granular composition comprising the following components: lurasidone hydrochloride, croscarmellose sodium, silicon dioxide, pregelatinized starch , fillers and adhesives.
  • the granular composition of the present invention refers to the product after granulation.
  • Granulation is the operation of processing powder and other materials into granules with a certain shape and size.
  • Granulation as a processing process of particles, is related to almost all solid preparations.
  • the granulate may be the final product or an intermediate, eg in capsules the granules are the product and in the production of tablets the granules are the intermediate.
  • the present invention provides a lurasidone hydrochloride granular composition
  • the lurasidone hydrochloride granular composition comprising the following components: by weight, 20-45wt% lurasidone hydrochloride, 0.5-5.0 wt% croscarmellose sodium, 0.25-4.0 wt% silicon dioxide, greater than 0 wt% and less than 10 wt% pregelatinized starch, fillers and binders.
  • the lurasidone hydrochloride granule composition of the present invention comprises 0.5-3.0wt% of croscarmellose sodium, particularly preferably 1.5-2.5wt% of croscarmellose sodium, preferably 0.5-1.5 wt % silica, particularly preferably 0.5-1 wt % silica, and/or preferably greater than 0 wt % and less than or equal to 9.0 wt % pregelatinized starch.
  • the lurasidone hydrochloride granular composition of the present invention comprises 30-80wt% filler, preferably 40-70wt% filler, more preferably 55-60wt% filler, particularly preferably 56-60wt% filler .
  • the lurasidone hydrochloride granule composition of the present invention comprises 0.5-20wt% binder, preferably 0.5-8wt% binder, particularly preferably 4.0-5.0wt% binder.
  • Fillers suitable for the lurasidone hydrochloride granular composition of the present invention include, but are not limited to: mannitol, lactose, microcrystalline cellulose, xylitol, silicified microcrystalline cellulose, starch, sucrose, glucose, maltitol, One or any combination of fructose, sorbitol, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium silicate, etc., preferably mannitol and microcrystalline cellulose, more preferably mannitol.
  • Adhesives suitable for the lurasidone hydrochloride granule composition of the present invention include but are not limited to: hypromellose, hypromellose, methylcellulose, copovidone, povidone, polyvinyl alcohol, etc. , preferably hypromellose and polyvinyl alcohol, more preferably hypromellose.
  • the silicon dioxide described in the present invention is colloidal silicon dioxide.
  • the present invention provides a lurasidone hydrochloride pharmaceutical composition, the pharmaceutical composition comprising the above-mentioned lurasidone hydrochloride granular composition and a lubricant, and the pharmaceutical composition is preferably a tablet agent.
  • Lubricants suitable for the lurasidone hydrochloride pharmaceutical composition of the present invention include but are not limited to: stearic acid, magnesium stearate, sodium stearyl fumarate, talc, etc., preferably magnesium stearate, stearic acid Sodium fumarate; more preferably sodium stearyl fumarate.
  • the lurasidone hydrochloride pharmaceutical composition of the present invention contains 0.1-5wt% lubricant, preferably 0.5%-2wt%, more preferably 0.75-2wt%, particularly preferably 0.75-1wt%.
  • the particle size of lurasidone hydrochloride in the lurasidone hydrochloride granular composition or pharmaceutical composition of the present invention is preferably D90 of 1-25 ⁇ m, more preferably D90 of 6-25 ⁇ m, particularly preferably D90 of 6-16 ⁇ m.
  • the particle size D50 of lurasidone hydrochloride in the lurasidone hydrochloride granule composition or pharmaceutical composition of the present invention is 2-9 ⁇ m, particularly preferably D50 is 2.5-8 ⁇ m.
  • the present invention also provides a preparation method of lurasidone hydrochloride granule composition, the method comprises the following steps:
  • the present invention also provides a method for preparing a lurasidone hydrochloride pharmaceutical composition, the method comprising adding a lubricant to the lurasidone hydrochloride granule composition, selectively adding an external disintegrant, etc.
  • the pharmaceutical composition is obtained by processing, such as tableting to obtain tablets, and encapsulation to obtain capsules.
  • the lurasidone hydrochloride pharmaceutical composition obtained above may optionally be film-coated, if desired.
  • the lurasidone hydrochloride pharmaceutical composition provided by the present invention may further comprise a dosage form such as a granule, a tablet or a capsule after being mixed with external adjuvants.
  • additional excipients include additional disintegrants and the like.
  • the added disintegrant includes but is not limited to: crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, etc., preferably crospovidone.
  • the percentage of the additional disintegrant in the weight of the preparation is 1-4 wt %, preferably 1.5-3 wt %.
  • additives can be optionally added, and the additives include colorants, coating agents, flavoring agents, surfactants, plasticizers, fragrances or polishing agents Wait.
  • the lurasidone hydrochloride composition provided by the present invention improves the dissolution rate and/or bioavailability of lurasidone hydrochloride. In some cases, there may be an incomplete correlation between the in vivo bioavailability test and the in vitro dissolution test. At the same time, the preparation method of the lurasidone hydrochloride composition of the present invention is easy to operate, has good reproducibility, and is suitable for large-scale industrial production.
  • Figure 1 shows the results of intra-batch differences in cumulative dissolution of lurasidone hydrochloride tablets prepared according to Example 1 and Comparative Examples 1-2 of the present invention
  • Figure 2 shows the comparative results of cumulative dissolution of lurasidone hydrochloride tablets prepared according to Examples 1-4 of the present invention
  • Figure 3 shows the comparative results of cumulative dissolution of lurasidone hydrochloride tablets prepared according to Examples 1 to 5-7 of the present invention.
  • the binder/silicon dioxide suspension Dissolve the binder (the amount of the binder is 0.5-20 wt %, preferably 0.5-8 wt %, particularly preferably 4.0-5.0 wt % based on the weight of the oral preparation) pure water, and then adding silicon dioxide (the amount of silicon dioxide is 0.25-4.0 wt % of the weight of the oral preparation, preferably 0.5-1.5 wt %, particularly preferably 1.5-2.5 wt %) to prepare the prepared adhesive/di Silicon oxide suspension, wherein the binder can be used such as hypromellose or polyvinyl alcohol, the concentration of the binder aqueous solution is preferably 1-15wt%, preferably 2-8wt%, more preferably 5wt%.
  • Drying The granules obtained above are dried in a fluidized bed.
  • the criterion for drying is loss on drying, eg, within 3 wt%, preferably 1-2 wt%.
  • a lubricant is added to the dried granules in (4) above, and mixed to obtain a mixture.
  • Agitators for example of the diffusion mixer type, can be used. In particular, a V mixer, a double cone mixer, a hopper mixer, or the like is used.
  • the coating material is a film coating premix.
  • the equipment used for coating may be a coating pan type equipment or the like.
  • the coating weight gain is selected to be about 1-5 wt%, preferably 2-4 wt%.
  • Example 1 (g) Comparative Example 1 (g) Comparative Example 2 (g) lurasidone hydrochloride 40 40 40 Mannitol 90.4 72 132 pregelatinized starch 14.4 14.4 14.4 Croscarmellose sodium 4 4 4 low substituted hydroxypropyl cellulose - 20 - Hydroxypropylmethylcellulose 8 8 8 silica 1.6 - - Magnesium stearate 1.6 1.6 1.6
  • Dissolution test The formulation prepared by the present invention is subjected to a dissolution test. Measurement conditions include: test solution; pH 1.2 hydrochloric acid solution; method: slurry method; rotational speed: 50 rpm; volume of dissolution medium: 900 mL.
  • the similarity factor f 2 is used here as an indicator for evaluating the similarity of the dissolution properties.
  • the f 2 value was calculated by the following formula. It was determined that each formulation prepared in the present invention had similar dissolution characteristics if f2 calculated from the dissolution rate of each formulation was 50 ⁇ f2 ⁇ 100 . After the start of the experiment, the dissolution rates at three time points, such as at 10 minutes, 15 minutes and 20 minutes, were used to calculate f2 values.
  • the calculation formula of the similarity factor f2 is as follows:
  • Ti and Ri are the dissolution percentages at each time point, and n is the number of points to be compared. The results are shown in Table 2 and Figure 1.
  • Example 1 As shown in Table 2 and Figure 1, the dissolution of Example 1 reaches more than 85% in 15 minutes, and can be rapidly dissolved, and basically completely dissolves and reaches more than 99% in 20 minutes.
  • Comparative Example 2 when croscarmellose sodium is used alone, the dissolution of the sample in a pH 1.2 hydrochloric acid solution is too slow, and it is not similar to Example 1.
  • the disintegrant of Comparative Example 1 was used in combination with L-HPC and croscarmellose sodium, the dissolution rate was improved, but the dissolution characteristics were not similar to those of Example 1. In Example 1, the dissolution reached more than 85% in 15 minutes, and the dissolution was rapid, and the dissolution was basically complete and reached more than 99% in 20 minutes.
  • the f2 values in Examples 2-4 show similarities to Example 1. That is, as shown in Table 4 and FIG. 2 , in Examples 1-4, the f 2 value representing the similarity of the dissolution characteristics was in the range of 50 ⁇ f 2 ⁇ 100, and preparations having similar dissolution characteristics were obtained.
  • Example 7 shows similarities to Example 1. That is, formulations prepared by using lurasidone hydrochloride powder exhibit similar dissolution characteristics, preferably wherein the powder has a 50% particle size distribution D50 of 2-9 ⁇ m and a 90% particle size distribution D90 of 24 ⁇ m or less.
  • Example 1, 8-10 raw materials and proportions are as shown in Table 8:
  • Embodiment 8-10 adopts the same production batch of lurasidone hydrochloride raw material to test, and the particle size distribution of described lurasidone hydrochloride is as follows in Table 9:
  • Embodiment 1, 8-10, comparative example 3 (trade name: Specification: 40mg)
  • the dissolution results are shown in Table 10.
  • Example 10 The purpose of this test is to study the pharmacokinetic characteristics of Example 10 after a single oral dose, and compare it with Comparative Example 3 (trade name: Specification: 40 mg) as a comparison, the pharmacokinetic parameters of the two preparations were compared, and the differences in the absorption rate and extent of Example 10 and Comparative Example 3 in healthy subjects were preliminarily evaluated.
  • Comparative Example 3 trade name: Specification: 40 mg

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  • General Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne une composition de chlorhydrate de lurasidone et son procédé de préparation. La composition de chlorhydrate de lurasidone comprend une composition de particules de chlorhydrate de lurasidone et un lubrifiant. La composition de particules de chlorhydrate de lurasidone comprend : du chlorhydrate de lurasidone, de la croscarmellose sodique, de la silice, de l'amidon prégélatinisé, une charge et un liant.
PCT/CN2021/114761 2020-08-26 2021-08-26 Composition de chlorhydrate de lurasidone et son procédé de préparation WO2022042646A1 (fr)

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Application Number Priority Date Filing Date Title
CN202180050280.5A CN115843243A (zh) 2020-08-26 2021-08-26 盐酸鲁拉西酮组合物及其制备方法

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CN202010867062 2020-08-26
CN202010867062.8 2020-08-26

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WO2022042646A1 true WO2022042646A1 (fr) 2022-03-03

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102048734A (zh) * 2005-05-26 2011-05-11 大日本住友制药株式会社 药物组合物
CN102688210A (zh) * 2012-06-21 2012-09-26 李兴惠 鲁拉西酮的药物组合物和制备方法
CN103536568A (zh) * 2012-07-12 2014-01-29 成都康弘药业集团股份有限公司 一种含有鲁拉西酮的口腔崩解片及其制备方法
CN104337790A (zh) * 2014-11-02 2015-02-11 石家庄四药有限公司 盐酸鲁拉西酮口服制剂及其制备方法
US20200046695A1 (en) * 2017-01-11 2020-02-13 Piramal Enterprises Limited Oral pharmaceutical composition of lurasidone and preparation thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102048734A (zh) * 2005-05-26 2011-05-11 大日本住友制药株式会社 药物组合物
CN102688210A (zh) * 2012-06-21 2012-09-26 李兴惠 鲁拉西酮的药物组合物和制备方法
CN103536568A (zh) * 2012-07-12 2014-01-29 成都康弘药业集团股份有限公司 一种含有鲁拉西酮的口腔崩解片及其制备方法
CN104337790A (zh) * 2014-11-02 2015-02-11 石家庄四药有限公司 盐酸鲁拉西酮口服制剂及其制备方法
US20200046695A1 (en) * 2017-01-11 2020-02-13 Piramal Enterprises Limited Oral pharmaceutical composition of lurasidone and preparation thereof

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