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WO2025087351A1 - Formulation de chlorhydrate de lurasidone - Google Patents

Formulation de chlorhydrate de lurasidone Download PDF

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Publication number
WO2025087351A1
WO2025087351A1 PCT/CN2024/127194 CN2024127194W WO2025087351A1 WO 2025087351 A1 WO2025087351 A1 WO 2025087351A1 CN 2024127194 W CN2024127194 W CN 2024127194W WO 2025087351 A1 WO2025087351 A1 WO 2025087351A1
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WIPO (PCT)
Prior art keywords
weight
parts
hpmcas
lurasidone hydrochloride
optionally
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/CN2024/127194
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English (en)
Chinese (zh)
Inventor
汪志辉
冯双艳
黄心
游劲松
黄芳芳
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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Publication of WO2025087351A1 publication Critical patent/WO2025087351A1/fr
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Classifications

    • 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
    • A61K47/30—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
    • 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 belongs to the technical field of biopharmaceuticals. Specifically, the present invention relates to a lurasidone hydrochloride preparation, and more specifically, the present invention relates to a lurasidone hydrochloride composition and a preparation method thereof.
  • Lurasidone hydrochloride is an atypical antipsychotic drug.
  • lurasidone hydrochloride tablets were approved for marketing in the United States. The specifications are 20mg, 40mg, 60mg, 80mg, and 120mg per tablet, respectively, for the treatment of schizophrenia.
  • lurasidone was approved for two new indications, one as a monotherapy and the other as an adjunct to lithium or sodium valproate for major depressive episodes associated with type I bipolar disorder in adult patients.
  • lurasidone hydrochloride has the advantages of good efficacy, high safety, and good tolerability, and has been used as a first-line antipsychotic drug.
  • the currently available lurasidone tablets have low bioavailability and must be taken with food, and the calorie content of the food must be greater than 350 calories, otherwise the average peak blood concentration (Cmax) and area under the drug-time curve (AUC) of lurasidone will decrease by 3 times and 2 times, respectively.
  • Cmax average peak blood concentration
  • AUC area under the drug-time curve
  • lurasidone hydrochloride The solubility of lurasidone hydrochloride is highly pH-dependent, with solubilities of 5.24 ⁇ 10-2 mg/mL, ⁇ 3.00 ⁇ 10-2 mg/mL, and 0.224 mg/mL in 0.1 mol/L hydrochloric acid, pH 6.8 phosphate buffer, and water, respectively.
  • lurasidone hydrochloride belongs to BCS Class II drugs, which have the characteristics of low solubility and high permeability.
  • lurasidone hydrochloride dissolved or partially dissolved in the stomach may precipitate in large quantities after entering the neutral environment of the intestine, while only a very small part of the drug is dissolved and absorbed, which will affect the dissolution of the drug in specific parts and is a key factor leading to differences in clinical efficacy.
  • the increase in gastrointestinal surfactant caused by food may be magnified, resulting in an excessive food effect.
  • lurasidone hydrochloride can be solubilized to a greater extent, the dissolution rate and solubility of the drug in multiple media can be increased, while the precipitation of the drug in a neutral medium can be inhibited and the dissolution stability can be improved, the absorption of the drug can be improved to a greater extent.
  • the present invention aims to solve the technical problems existing in the prior art to at least a certain extent.
  • the present invention provides a lurasidone hydrochloride preparation, which can increase the dissolution rate and solubility of lurasidone hydrochloride, thereby improving the in vivo absorption and bioavailability of lurasidone hydrochloride.
  • the present invention provides a composition.
  • the composition comprises lurasidone hydrochloride and a carrier; wherein the carrier comprises: Soluplus, and at least one of HPMCAS HG and HPMCAS HF.
  • the composition of the present invention can improve the dissolution rate and solubility of lurasidone hydrochloride, ensure the increased dissolution of lurasidone hydrochloride in the small intestine, improve the bioavailability of lurasidone hydrochloride and improve the in vivo absorption, reduce excessive medication restrictions, avoid the reduction of efficacy or even ineffectiveness caused by improper medication, and ensure the normal performance of the drug effect.
  • the lurasidone hydrochloride composition of the present invention can also weaken or eliminate the food effect, thereby facilitating the improvement of the flexibility and compliance of patients in medication.
  • the above composition may further include at least one of the following technical features:
  • the mass ratio of lurasidone hydrochloride to the carrier is 1:(4-24), for example 1:4, 1: 5.
  • the dissolution rate and solubility of lurasidone hydrochloride can be further improved, the dissolution of lurasidone hydrochloride in the small intestine can be increased, the bioavailability of lurasidone hydrochloride can be increased, and the absorption in the body can be improved.
  • drug-carrying ratio refers to the weight ratio of the active ingredient to the carrier, that is, the weight ratio of lurasidone hydrochloride to the carrier.
  • the weight of the carrier is the combined weight of the multiple carriers.
  • the carrier includes Soluplus and HPMCAS HG.
  • the carrier includes Soluplus and HPMCAS HF.
  • the mass ratio of Soluplus to HPMCAS HF is 1:(0.5-5), such as 1:0.5, 1:1, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5 or a range between the two ratios, such as 1:(0.5-1), 1:(0.5-2).
  • the dissolution rate and solubility of lurasidone hydrochloride can be further improved, the dissolution of lurasidone hydrochloride in the small intestine can be increased, the bioavailability of lurasidone hydrochloride can be increased, and the absorption in the body can be improved.
  • the composition further comprises a surfactant.
  • the surfactant includes at least one of TPGS, Kolliphor RH40, Tween 80 and SDS.
  • the surfactant is Kolliphor RH40.
  • the mass percentage of the surfactant is 5% to 15%, for example, 5%, 5.06%, 5.08%, 6%, 7%, 8%, 9%, 9.92%, 10%, 11%, 12%, 13%, 14%, 14.75%, 15% or a range value between two point values thereof, such as 5.06% to 14.75%, 5.08% to 14.75%.
  • the composition further comprises an inorganic salt.
  • the inorganic salt comprises K ions and/or Na ions.
  • the inorganic salt includes at least one of KCl, K 2 SO 4 and KH 2 PO 4 .
  • the weight ratio of lurasidone hydrochloride to the inorganic salt is 1:(0.1-2), for example 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.05 or a range value between two ratios thereof, such as 1:(0.5-1.5), 1:(0.5-1).
  • the composition is an oral solid preparation.
  • the oral solid preparation is a micropill, a capsule or a tablet.
  • composition when the composition is a different oral solid preparation, according to the type of the dosage form, it may further include other pharmaceutically acceptable ingredients contained in the dosage form, which are not specifically limited and are within the scope of protection of the present invention.
  • the composition when the composition is a micropill, it may further include a blank pellet core, such as a sucrose pellet core, etc.; when the composition is a capsule, it may further include a capsule layer; when the composition is a tablet, it may further include a coating material.
  • micropellets are spherical or quasi-spherical solid dosage forms with a diameter within a certain range, which can be taken alone, put into capsules, compressed into tablets, or made into other preparations.
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 40 to 260 parts by weight of Soluplus, and 80 to 200 parts by weight of HPMCAS HF or HPMCAS HG; wherein the mass ratio of lurasidone hydrochloride to the carrier is 1:(5 to 12).
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 40 to 260 parts by weight of Soluplus, 80 to 200 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of a surfactant; wherein the mass ratio of lurasidone hydrochloride to the carrier is 1:(5 to 12).
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 40 to 260 parts by weight of Soluplus, 80 to 200 parts by weight of HPMCAS HF or HPMCAS HG, 10 to 20 parts by weight of a surfactant, and 30 to 40 parts by weight of an inorganic salt; wherein the mass ratio of lurasidone hydrochloride to the carrier is 1:(5 to 12).
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 90 to 140 parts by weight of Soluplus, and 100 to 150 parts by weight of HPMCAS HF or HPMCAS HG.
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 60 to 90 parts by weight of Soluplus, and 150 to 180 parts by weight of HPMCAS HF or HPMCAS HG.
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 30 to 60 parts by weight of Soluplus, and 180 to 210 parts by weight of HPMCAS HF or HPMCAS HG.
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 220 to 240 parts by weight of Soluplus, and 220 to 240 parts by weight of HPMCAS HF or HPMCAS HG.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 100 to 140 parts by weight of Soluplus, and 100 to 140 parts by weight of HPMCAS HF or HPMCAS HG.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, and 120 parts by weight of HPMCAS HF or HPMCAS HG.
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 220 to 260 parts by weight of Soluplus, and 100 to 140 parts by weight of HPMCAS HF or HPMCAS HG.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 240 parts by weight of Soluplus, and 120 parts by weight of HPMCAS HF or HPMCAS HG.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 140 to 170 parts by weight of Soluplus, 70 to 100 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of Kolliphor RH40.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 160 parts by weight of Soluplus, 80 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Kolliphor RH40.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 90 to 140 parts by weight of Soluplus, 100 to 150 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of Kolliphor RH40.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 80 to 140 parts by weight of Soluplus, 80 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of Kolliphor RH40.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Kolliphor RH40.
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 100 parts by weight of Soluplus, 100 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Kolliphor RH40.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 80 parts by weight of Soluplus, 80 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Kolliphor RH40.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 60 to 100 parts by weight of Soluplus, 140 to 180 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of Kolliphor RH40.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 80 parts by weight of Soluplus, 160 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Kolliphor RH40.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 30 to 60 parts by weight of Soluplus, 180 to 210 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of Kolliphor RH40.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 40 parts by weight of Soluplus, 200 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Kolliphor RH40.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 80 to 140 parts by weight of Soluplus, 80 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of TPGS.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 100 to 140 parts by weight of Soluplus, 100 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of TPGS.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of TPGS.
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 80 to 140 parts by weight of Soluplus, 80 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of Tween 80.
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 100 to 140 parts by weight of Soluplus, 100 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of Tween 80.
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Tween 80.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 80 to 140 parts by weight of Soluplus, 80 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of SDS.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 100 to 140 parts by weight of Soluplus, 100 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of SDS.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of SDS.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 80 to 140 parts by weight of Soluplus, 80 to 140 parts by weight of HPMCAS HF or HPMCAS HG, 10 to 20 parts by weight of Kolliphor RH40, and 30 to 40 parts by weight of KCl.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 100 to 140 parts by weight of Soluplus, 100 to 140 parts by weight of HPMCAS HF or HPMCAS HG, 10 to 20 parts by weight of Kolliphor RH40, and 30 to 40 parts by weight of KCl.
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF, and optionally, 15 parts by weight of Kolliphor RH40.
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 240 parts by weight of Soluplus, and 120 parts by weight of HPMCAS HF.
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, 10 to 20 parts by weight of Kolliphor RH40, and 33 parts by weight of KCl.
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 80-140 parts by weight of Soluplus, 80-140 parts by weight of HPMCAS HF or HPMCAS HG, 10-20 parts by weight of Kolliphor RH40, and 30-40 parts by weight of K 2 SO 4 .
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, 15 parts by weight of Kolliphor RH40, and 33 parts by weight of K 2 SO 4 .
  • the composition comprises: 40 parts by weight of lurasidone hydrochloride, 80-140 parts by weight of Soluplus, 80-140 parts by weight of HPMCAS HF or HPMCAS HG, 10-20 parts by weight of Kolliphor RH40, and 30-40 parts by weight of KH 2 PO 4 .
  • the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, 10-20 parts by weight of Kolliphor RH40, and 33 parts by weight of KH 2 PO 4 .
  • the present invention proposes a method for preparing the composition described in the first aspect.
  • the method comprises: mixing a carrier and lurasidone hydrochloride to obtain the composition.
  • the preparation method of the present invention is simple, and the prepared compositions have high solubility, which can increase the dissolution rate and solubility of lurasidone hydrochloride, thereby improving the in vivo absorption and bioavailability of lurasidone hydrochloride. Therefore, the lurasidone hydrochloride composition of the present invention can also weaken or eliminate the food effect, thereby helping to improve the flexibility and compliance of patients.
  • the above method may further include at least one of the following technical features:
  • the composition may be in the form of particles or micropellets (or micropellets).
  • the composition is a granule
  • the method further comprises: mixing a surfactant and/or an inorganic salt with lurasidone hydrochloride and a carrier.
  • the method further comprises: subjecting the mixed treatment product to fluidized bed-level drug treatment.
  • the spraying is performed by fluidized bed layer coating.
  • the atomization pressure of the fluidized bed layer loading is 2.0 bar-3.0 bar.
  • the temperature of the fluidized bed layer for applying medicine is 30°C-50°C.
  • the composition is a micropellet, and the composition further includes a blank pellet core.
  • the blank pill core is selected from at least one of a sucrose blank pill core and a microcrystalline cellulose blank pill core.
  • FIG1 is an XRD pattern of the lurasidone hydrochloride bulk drug in Example 14 of the present invention.
  • FIG2 is an XRD pattern of prescription F1 in Example 14 of the present invention.
  • FIG3 is an XRD pattern of prescription F4 in Example 14 of the present invention.
  • FIG4 is an XRD pattern of prescription F10 in Example 14 of the present invention.
  • FIG5 is an XRD pattern of prescription F11 in Example 14 of the present invention.
  • FIG6 is an XRD pattern of prescription F12 in Example 14 of the present invention.
  • FIG7 is an XRD pattern of prescription F15 in Example 14 of the present invention.
  • FIG8 is an XRD pattern of prescription F20 in Example 14 of the present invention.
  • FIG9 is an XRD pattern of prescription F30 in Example 14 of the present invention.
  • FIG10 is an XRD pattern of prescription F31 in Example 14 of the present invention.
  • FIG11 is an XRD pattern of prescription F32 in Example 14 of the present invention.
  • FIG12 is an XRD pattern of prescription F37 in Example 14 of the present invention.
  • FIG13 is an XRD pattern of prescription F38 in Example 14 of the present invention.
  • FIG14 is an XRD pattern of prescription F40 in Example 14 of the present invention.
  • FIG15 is an XRD pattern of prescription F52 in Example 14 of the present invention.
  • FIG17 is an XRD pattern of prescription F55 in Example 14 of the present invention.
  • FIG18 is an XRD pattern of prescription F60 in Example 14 of the present invention.
  • FIG19 is an XRD pattern of prescription F76 in Example 14 of the present invention.
  • FIG. 20 shows the pharmacokinetic results of the prescriptions F78, F79 and the reference preparation (trade name: Latuda) in Example 16 of the present invention in beagle dogs.
  • first and second are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Therefore, features defined as “first” and “second” may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise stated, it is noted that “plurality” means two or more.
  • HPMCAS refers to hydroxypropyl methylcellulose acetate succinate
  • HPMCAS HF, HPMCAS HG, HPMCAS LF, and HPMCAS MF are different types of hydroxypropyl methylcellulose acetate succinate
  • HPMC refers to Hydroxypropyl Methylcellulose
  • HPC refers to Hydroxypropyl Cellulose
  • PVP refers to Povidone
  • KCl refers to potassium chloride
  • K 2 SO 4 refers to potassium sulfate
  • KH 2 PO 4 refers to potassium dihydrogen phosphate
  • TPGS refers to vitamin E polyethylene glycol succinate
  • Kolliphor RH40 refers to polyoxyl 40 hydrogenated castor oil
  • 44/14 refers to laurate macrogol glyceride
  • SDS refers to sodium dodecyl sulfate.
  • composition of the present invention includes an optional binder, which means that the composition may include the binder or may not include the binder.
  • compositions or preparations provided by the present invention can be administered to the patient alone, or can be administered together or in combination with other active agents.
  • administered together and “combined” include administering two or more therapeutic agents simultaneously or sequentially without a specific time limit.
  • the therapeutic agents are present in cells or in the individual body at the same time, or exert biological or therapeutic effects simultaneously.
  • each therapeutic agent is in the same composition or unit dosage form. In other embodiments, each therapeutic agent is in different compositions or unit dosage forms.
  • the second therapeutic agent is administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before).
  • the first agent is administered after 1 week, 8 weeks or 12 weeks.
  • parts by weight refers to the mass fraction obtained by comparing the mass of a component of a composition with the mass of other components.
  • the detection method of dissolution under the condition of pH 6.8 in the comparative examples and embodiments of the present invention is as follows: according to the United States Pharmacopoeia II method (USP II), with 900mL ⁇ 9ml medium, 50rpm/min rotation speed as the conditions, medium temperature 37.0 ⁇ 0.5°C, slurry method, respectively determine its dissolution in pH 6.8 medium (phosphate buffer). After the test starts, 10ml of samples are taken at 5min, 30min, 45min, 60min, 90min and 120min time points, and 10ml of fresh dissolution medium is immediately added to continue the test. The sample is filtered through a 0.45 ⁇ m filter membrane, and an appropriate amount of filtrate is taken. The drug content in the sample is determined by HPLC method, and the cumulative dissolution rate at each time point is calculated.
  • USP II United States Pharmacopoeia II method
  • Acid-resistant conditions i.e., the sample is first dissolved under 0.1M HCl conditions, and then dissolved under pH 6.8 phosphate buffer medium conditions
  • test According to the United States Pharmacopoeia II method (USP II), first use 500mL 0.1M HCl as the medium, 50rpm/min as the rotation speed, and the medium temperature of 37.0 ⁇ 0.5°C. At 30min, sample 10ml and immediately add 10ml of fresh dissolution medium to measure its dissolution in the medium. After the 0.1M HCl medium sampling is completed, the rotation speed remains unchanged, and pH 6.8 phosphate buffer is added to 900mL, and 10M NaOH is used to quickly adjust the pH to 6.8.
  • USP II United States Pharmacopoeia II method
  • the sample was filtered through a 0.45 ⁇ m filter membrane, and an appropriate amount of the filtrate was taken.
  • the drug content in the sample was determined by HPLC, and the cumulative dissolution rate at each time point was calculated.
  • lurasidone hydrochloride-polyethylene glycol 4000 solid dispersion The specific preparation method is: add lurasidone hydrochloride to molten polyethylene glycol 4000, control the temperature at 40-50°C, add methanol dropwise while stirring until the solid is completely dissolved, keep the temperature and stir for 15 minutes, evaporate the methanol under reduced pressure at 50-60°C, solidify the solid at below -15°C for 2 hours, crush, and pass through a 100-mesh sieve to obtain lurasidone hydrochloride solid dispersion.
  • Lurasidone hydrochloride tablets were prepared according to the following prescription.
  • Preparation method Potassium citrate and sorbitol are heated and melted in a hot melt extruder, and then lurasidone hydrochloride is added and melted, the molten liquid is extruded and granulated, and then directly tableted with calcium hydrogen phosphate, micro-powder silica gel and magnesium stearate.
  • Lurasidone hydrochloride capsules were prepared according to the following prescription.
  • Preparation method Weigh lurasidone hydrochloride and copovidone according to the prescribed amount, dissolve them in a mixed solvent of methanol and dichloromethane in a volume ratio of 1:1 (200 mL in total) to fully dissolve the drug and the carrier, and then spray dry at 60-65°C, add magnesium stearate to the obtained spray-dried powder, mix, and fill capsules.
  • Lurasidone hydrochloride capsules were prepared according to the following prescription.
  • Lurasidone hydrochloride capsules were prepared according to the following prescription.
  • Preparation method Weigh the hot melt added components according to the prescription, mix them thoroughly and add them to the powder feeder of the hot melt extruder, set the temperatures of the feeding port to the extrusion die barrel to 110°C, 130°C, 165°C, 165°C, 165°C, 165°C and 160°C respectively, set the screw speed to 50rpm, hot melt extrusion, crush the extrudate after cooling, pass the crushed material through a 60-mesh sieve, add microcrystalline cellulose to the obtained spray-dried powder, mix, and fill capsules.
  • Lurasidone hydrochloride capsules were prepared according to the following prescription.
  • Preparation method Weigh the hot-melt added components according to the prescription, add them to the powder feeder of the hot-melt extruder after thorough mixing, set the temperatures of the feeding port to the extrusion die barrel to 110°C, 130°C, 165°C, 165°C, 165°C, 165°C, 165°C, and 160°C respectively, set the screw speed to 50rpm, hot-melt extrusion, crush the extrudate after cooling, pass the crushed material through a 60-mesh sieve, add external components according to the components, mix, and press into tablets.
  • Table 1-1 Drug release results of comparative examples 1-6 and reference preparations (%)
  • Table 1-2 Drug release results of comparative examples 1-6 and reference preparations (%)
  • Comparative Examples 1, 2, 3, 4, 5 and 6 when a single pH 6.8 medium is used to simulate human absorption after eating, the dissolution amount of Comparative Examples 1, 2, 3, 4, 5 and 6 is only 1%-49%. Further, when the pH 6.8 medium is transferred after acid resistance for half an hour, Comparative Examples 1, 2, 3 and 4 show obvious precipitation effect, which cannot reduce the risk of precipitation of the drug dissolved in the stomach in the small intestine, and the final dissolution amount is extremely low, only 1%-15%; the final dissolution amount of Comparative Examples 5 and 6 is only 18%-48%.
  • prescriptions F1, F2, F3, F4, F5, and F6 did not eliminate the pH dependence of lurasidone hydrochloride and could not improve the absorption of the drug in vivo.
  • prescriptions F7, F8, F9, F10, F11, and F12 did not eliminate the pH dependence of lurasidone hydrochloride and could not improve the drug's absorption in vivo.
  • prescriptions F13, F14, F15, F16, and F17 did not eliminate the pH dependence of lurasidone hydrochloride and could not improve the absorption of the drug in vivo.
  • Example F32 can eliminate the pH dependence of lurasidone hydrochloride and improve the absorption of the drug in vivo.
  • Table 8-1 and Table 8-2 show that when a single pH 6.8 medium is used to simulate human absorption after eating, the dissolution rates of prescriptions F38, F40, F41 and F42 are significantly improved compared with prescription F32.
  • the pH 6.8 medium is transferred after half an hour of acid resistance to simulate human absorption after fasting, only prescription F40 (with Kolliphor RH40 added) has a significant improvement in dissolution rate compared with prescription F32.
  • prescription F40 can further significantly improve absorption in the body.
  • Table 9-1 and Table 9-2 show that the dissolution of prescriptions F40 and F47 is similar, whether the pH 6.8 medium alone simulates human absorption after eating, or the pH 6.8 medium is transferred to simulate human absorption after fasting after acid resistance for half an hour. Therefore, the results of this example can show that the dissolution of different particle sizes of HPMC succinate HF and HPMC succinate HG is not much different, and the two can be replaced in equal amounts.
  • the dissolution of prescriptions F47-50 was significantly improved, whether using pH 6.8 medium alone to simulate human absorption after eating, or transferring to pH 6.8 medium after acid resistance for half an hour to simulate human absorption after fasting.
  • Example 9 Study on Lurasidone Hydrochloride Solid Dispersion Using Soluplus and HPMCAS HF as Carriers
  • Table 10-1 Drug release results of prescriptions F32, F40, F51 ⁇ F60 and reference preparations (%)
  • Table 10-2 Drug release results of prescriptions F32, F40, F51 ⁇ F60 and reference preparations (%)
  • Table 10-1 and Table 10-2 show that compared with prescriptions F51, F58-F60, the dissolution of prescriptions F52-F57 was significantly improved, whether it was a single pH 6.8 medium to simulate human absorption after eating, or a half-hour acid resistance and then a transfer to a pH 6.8 medium to simulate human absorption after fasting. Therefore, when the mass ratio of lurasidone hydrochloride to the carrier is 1:4-1:24, and the mass ratio of Soluplus: HPMCAS HF is 1:(0.5-5), the absorption in the body can be significantly improved.
  • Example 10 Study on Lurasidone Hydrochloride Solid Dispersion Using Soluplus and HPMCAS HF as Carriers
  • Table 11-1 Drug release results of prescriptions F61 to F75 and reference preparations (%)
  • Preparation method Weigh the hot melt added components according to the prescription, mix them thoroughly and add them to the powder feeder of the hot melt extruder, set the temperatures of the feeding port to the extrusion die barrel to 110°C, 130°C, 165°C, 165°C, 165°C, 165°C and 160°C respectively, set the screw speed to 50rpm, hot melt extrusion, crush the extrudate after cooling, pass the crushed material through a 60-mesh sieve, add microcrystalline cellulose to the obtained spray-dried powder, mix, and fill capsules.
  • Example F75 and Example F76 in pH 6.8 medium and acid resistance were measured. The results are shown in Table 12-1 and Table 12-2.
  • Table 12-1 Drug release results of prescriptions F40, F76, F77 and reference preparations (%)
  • the final dissolution amount of Example F79 in a single pH 6.8 medium is 18% higher than that of Example F78; the final dissolution amount in a pH 6.8 medium after acid resistance for half an hour is equivalent.
  • the addition of the surfactant polyoxyethylene 40 hydrogenated castor oil can improve the absorption of drugs in vivo.
  • Example 13 Study on the preparation process of lurasidone hydrochloride solid dispersion micropellets
  • Example F84, Example F85, Example F86 or Example F87 Preparation of Lurasidone Hydrochloride Solid Dispersion by Layered Drug Delivery:
  • pellets sucrose pellets or microcrystalline cellulose pellets
  • the atomization pressure is set to: 2.0 bar-3.0 bar; the material temperature is set to 30°C-50°C.
  • XRD X-ray powder diffraction.
  • Tables 15-1, 15-2 and 15-3 show that the related substances of the lurasidone hydrochloride preparation F40 prepared by the present invention are stable from 0 day to 6 months of accelerated treatment, and there is no increase; the dissolution stability of F40 in a single pH 6.8 medium and an acid-resistant medium converted to pH 6.8 for half an hour is good, and the dissolution stability of F58 in a single pH 6.8 medium and an acid-resistant medium converted to pH 6.8 for half an hour is poor.
  • Beagle PK study The prescriptions F78, F79 and the reference preparation (trade name: Latuda) were subjected to a three-preparation crossover pharmacokinetic experiment in beagles (18 healthy beagles, half male and half female, divided into 3 groups, 6 in each group, fed and fasted, once a day) to investigate the effect of food on their pharmacokinetic.
  • pentagastrin used to promote gastric acid secretion, gastric pH 4-6 under fasting conditions for beagles, gastric pH 1.3 under fasting conditions for humans was used for pretreatment.
  • the review report reported that food can significantly increase the bioavailability of lurasidone hydrochloride.
  • the exposure after feeding is 2.50 times that of fasting, and the Cmax after feeding is 3.25 times that of fasting.
  • the food effect is more significant.
  • the exposure of prescription F79 after feeding is 1.02 times that of fasting, and the Cmax after feeding is 1.07 times that of fasting, and the bioavailability is improved compared with the reference preparation.
  • the exposure of prescription F78 after feeding is 1.07 times that of fasting, and the Cmax after feeding is 1.21 times that of fasting, and the bioavailability is improved compared with the reference preparation.

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Abstract

L'invention concerne une formulation de chlorhydrate de lurasidone, comprenant du chlorhydrate de lurasidone et un excipient, l'excipient comprenant : du Soluplus, et au moins un parmi HPMCAS HG et HPMCAS HF. La formulation peut augmenter le taux de dissolution et la solubilité du chlorhydrate de lurasidone et assurer une dissolution accrue du chlorhydrate de lurasidone dans l'intestin grêle, de telle sorte que la biodisponibilité et l'absorption in vivo du chlorhydrate de lurasidone sont améliorées, réduisant les restrictions excessives de médicament, évitant des effets thérapeutiques réduits ou même inefficaces provoqués par un médicament incorrect, et assurant ainsi un effort normal de l'efficacité du médicament. De plus, la formulation de chlorhydrate de lurasidone peut également affaiblir ou éliminer l'effet de la nourriture, ce qui facilite une plus grande flexibilité et une plus grande observance dans le médicament du patient.
PCT/CN2024/127194 2023-10-26 2024-10-25 Formulation de chlorhydrate de lurasidone Pending WO2025087351A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110114063A (zh) * 2017-01-06 2019-08-09 广东东阳光药业有限公司 鲁拉西酮固体分散体及其制备方法
CN111818911A (zh) * 2017-12-26 2020-10-23 广东东阳光药业有限公司 一种鲁拉西酮固体分散体及其制备方法
WO2023179774A1 (fr) * 2022-03-25 2023-09-28 Shenzhen Pharmacin Co., Ltd. Dispersions solides amorphes et compositions pharmaceutiques les comprenant

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Publication number Priority date Publication date Assignee Title
CN110114063A (zh) * 2017-01-06 2019-08-09 广东东阳光药业有限公司 鲁拉西酮固体分散体及其制备方法
CN111818911A (zh) * 2017-12-26 2020-10-23 广东东阳光药业有限公司 一种鲁拉西酮固体分散体及其制备方法
WO2023179774A1 (fr) * 2022-03-25 2023-09-28 Shenzhen Pharmacin Co., Ltd. Dispersions solides amorphes et compositions pharmaceutiques les comprenant

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MIAO YANFEI, CHEN GUO-GUANG; REN LI-LI: "Preparation and Determination of Dissolution Rate of Ziprasidone Hydrochloride Solid Dispersion", CHINESE JOURNAL OF HOSPITAL PHARMACY, ZHONGGUO YAO XUEHUI WUHAN FENHUI, WUHAN, CN, vol. 34, no. 1, 28 November 2013 (2013-11-28), CN , pages 38 - 41, XP093309256, ISSN: 1001-5213, DOI: 10.13286/j.cnki.chinhosppharmacyj.2014.01.12 *
YU, PANPAN ET AL.: "Enhanced Oral Bioavailability and Diminished Food Effect of Lurasidone Hydrochloride Nanosuspensions Prepared by Facile Nanoprecipitation Based on Dilution", POWDER TECHNOLOGY, vol. 312, 20 February 2017 (2017-02-20), pages 11 - 20, XP029952197, DOI: 10.1016/j.powtec.2017.02.038 *

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