WO2018086534A1 - 氢溴酸沃替西汀长效注射制剂 - Google Patents

氢溴酸沃替西汀长效注射制剂 Download PDF

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Publication number
WO2018086534A1
WO2018086534A1 PCT/CN2017/109941 CN2017109941W WO2018086534A1 WO 2018086534 A1 WO2018086534 A1 WO 2018086534A1 CN 2017109941 W CN2017109941 W CN 2017109941W WO 2018086534 A1 WO2018086534 A1 WO 2018086534A1
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hydrobromide
suspension
formulation
preparation
concentration
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English (en)
French (fr)
Inventor
宋平
朱思琪
赵步文
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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    • 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
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to a long-acting injection preparation of vortioxet hydrobromide.
  • Depression also known as depressive disorder, is characterized by significant and persistent low mood and is the main type of mood disorder. Clinically, there are low moods, low self-esteem depression, and even pessimistic, suicidal attempts or behaviors. Most cases have a tendency to recurrent, most of which can be relieved, and some may have residual symptoms or become chronic. Worldwide, the number of people affected by some form of depression accounts for 25% of all women, 10% of all men, and 5% of all adolescents. The etiology of depression is still unclear. At present, antidepressants have become the first choice for treatment of depressed patients. Clinically, selective serotonin (5-HT) reuptake inhibitors are the most widely used.
  • 5-HT serotonin
  • Votilizine is a new drug marketed in 2013. It is mainly used for the treatment of major depressive disorder (MDD). Its mechanism of action is not fully understood, but it is generally considered to be related to 5-HT re-extraction inhibition. It is the first to include 5-HT. Receptor activation and reuptake inhibit the dual action mechanism of antidepressants. This drug has safety data that is not inferior or superior to SSRIs (serotonin reuptake inhibitors) and SNRIs (serotonin and norepinephrine reuptake inhibitors), and better weight control data. For patients who did not respond adequately to SSRI/SNRI, vortistatin was superior to agomelatine.
  • SSRIs serotonin reuptake inhibitors
  • SNRIs serotonin and norepinephrine reuptake inhibitors
  • vortioxetine is only available in different specifications of orally administered wortithine hydrobromide tablets, which have a short blood concentration and require daily dosing (once a day). Due to the need for frequent administration, Increased patient discomfort, and due to the patient's own mood swings and other symptoms, resulting in self-medication difficulties, often leading to treatment failure.
  • the first aspect of the invention provides a long-acting injection preparation of vortioxet hydrobromide, wherein the concentration of wortoxime hydrobromide is higher, the particle size is controllable, and the method can be obtained within a limited injection volume. Higher doses, and by controlling the particle size distribution, to achieve a long-acting release effect, the formulation continuously releases wortithine hydrobromide for at least 2 weeks after injection, the formulation is stable. Well, it is a new medication option for special populations that are not suitable for oral administration, and can be administered once every two weeks, increasing patient compliance.
  • the second aspect of the present invention provides the preparation method of the long-acting injection preparation of vortioxet hydrobromide according to the first aspect, which is simple and easy to perform, has good stability and high safety, and is suitable for industrial production. It is also possible to add a freeze-drying step to prepare vorticoxine hydrobromide lyophilized preparation.
  • a third aspect of the present invention provides a use of a long-acting injection formulation of vortioxet hydrobromide for the preparation of a medicament for the treatment of major depression.
  • D[4,3] refers to a volume-weighted average measured using a Malvern Mastersizer 2000 laser granulometer.
  • Dv10 refers to the particle size corresponding to a cumulative particle size distribution of a sample of 10%.
  • Dv50 refers to the particle size corresponding to a cumulative particle size distribution of a sample of 50%, the term “ Dv90” refers to the particle size corresponding to a cumulative particle size distribution of a sample of 90%.
  • LC/MS/MS refers to LC/MS.
  • sustained release refers to the detection of a sample using an LC/MS/MS analytical instrument, and the blood concentration of wortithine hydrobromide can be detected based on its detection limit.
  • TPGS refers to polyethylene glycol 1000 vitamin E succinate
  • EL 35 refers to polyoxyethylene (35) castor oil.
  • concentration “mg/mL” refers to mg/ml as weight/volume, which is the volume of the suspension.
  • Mm refers to micron
  • ⁇ L refers to microliter
  • L refers to liter
  • mm refers to millimeter
  • mL refers to milliliter
  • nm refers to nanometer
  • ng refers to nanogram
  • kg refers to kilogram
  • min refers to minute
  • d refers to number of days
  • Hz refers to hertz
  • g refers to gram
  • Qs. refers to the addition
  • mbar refers to mbar
  • V refers to volts
  • °C refers to degrees Celsius.
  • the present invention has intensively investigated and studied to prepare a long-acting injection containing fluoxetine hydrobromide, which
  • the preparation may be in the form of a suspension or a form of a lyophilized powder.
  • the former may be used as it is, and the latter may be used as a suspension in a mixture of sterile sterile water for injection, and may be administered by intramuscular or subcutaneous injection.
  • Oral vorticeptine tablets the advantages of the invention include:
  • vortioxet hydrobromide is present in the form of poorly soluble granules with low solubility.
  • the drug can be slowly and continuously released after injection, which can significantly reduce the number of administrations and avoid peak and valley fluctuations, thereby improving the patient's treatment compliance. Sex and safety;
  • the preparation has a higher drug loading amount and can obtain sustained release for at least 2 weeks or longer;
  • the wortidine hydrobromide in the suspension has a small particle size and uniform distribution, and has good injectability, which is favorable for improving the bioavailability.
  • the suspension or the lyophilized preparation obtained by the invention has good stability and is convenient for storage and transportation.
  • the invention provides a preparation preparation of vortioxet hydrobromide, wherein the preparation has a higher drug loading amount, wherein the concentration of wortoximin hydrobromide ranges from 40.0 mg/mL to 400.0 mg/mL. In some embodiments, the concentration of wortithine hydrobromide is from 60.0 mg/mL to 350.0 mg/mL.
  • the concentration of wortithine hydrobromide is from 50.0 mg/mL to 200.0 mg/mL; in some embodiments, the concentration of wortoximin hydrobromide is 60.0 mg/mL -150.0 mg/mL; in some embodiments, the concentration of vortioxet hydrobromide is from 150.0 mg/mL to 200.0 mg/mL; in some embodiments, the vortioxet hydrobromide The concentration is from 150.0 mg/mL to 300.0 mg/mL; in some embodiments, the concentration of the vortioxet hydrobromide is from 200.0 mg/mL to 300.0 mg/mL; in some embodiments, the hydrobromine The concentration of wortithine acid is from 50.0 mg/mL to 300.0 mg/mL; in some embodiments, the concentration of wortithine hydrobromide is from 300.0 mg/mL to 350.0 mg/mL. In some embodiments, the concentration of wortithine hydrobromide is
  • a formulation of vortioxet hydrobromide comprising a stabilizer and a suspending agent.
  • a formulation of vortioxet hydrobromide including a stabilizer, and/or a suspending agent, and/or a buffer, and/or a pH adjusting agent.
  • a formulation of vortioxet hydrobromide comprising a stabilizer, a suspending agent, a buffer, and a pH adjusting agent.
  • a formulation of vortioxet hydrobromide injection including a stabilizer, a buffer, and a pH adjuster.
  • a formulation of vortioxet hydrobromide injection including a stabilizer, a suspending agent, and a pH adjusting agent.
  • a formulation of vortioxet hydrobromide injection including a stabilizer, a buffer.
  • a formulation of vortioxet hydrobromide injection including a stabilizer, a pH adjuster.
  • a formulation of vortioxet hydrobromide comprising a stabilizer, a suspending agent, a buffer.
  • the concentration of the stabilizer ranges from 0.1 mg/mL to 60.0 mg/mL. In some embodiments, the concentration of the stabilizer ranges from 1.0 mg/mL to 40.0 mg/mL, or from 0.01 mg/mL to 20.0 mg/mL, or from 0.1 mg/mL to 10.0 mg/mL, or 5.0 mg/ mL-55.0 mg/mL, or 1.0 mg/mL-5.0 mg/mL, or 5.0 mg/mL-10.0 mg/mL, or 5.0 mg/mL-20.0 mg/mL, or 5.0 mg/mL-40.0 mg/mL , or 10.0mg/mL-20.0mg/mL, or 10.0mg/mL-40.0mg/mL, or 20.0 Mg/mL-40.0 mg/mL, or 40.0 mg/mL-50.0 mg/mL.
  • the concentration of the stabilizer ranges from 5.0 mg/mL to 55.0 mg/mL. In some embodiments, the concentration of the stabilizer is 4.0 mg/mL, 6.0 mg/mL, 10.0 mg/mL, 18.0 mg/mL, 20.0 mg/mL, 40.0 mg/mL, or 50.0 mg/mL. In some embodiments, the concentration of the stabilizer is about 53.5 mg/mL.
  • the stabilizer comprises a selected from the group consisting of Tween 20, Tween 60, Tween 80, Span 20, Poloxamer 188, polyethylene glycol 1000 vitamin E succinate, polyoxyethylene hydrogenated castor oil RH40, EL 35 At least one of lecithin, acid ester polyethylene glycol-15-hydroxystearate, and polyethylene glycol.
  • the stabilizer is Tween 20, Tween 80, TPGS, EL 35, or a combination of Tween 20 and Span 20.
  • the concentration of the suspending agent ranges from 0.1 mg/mL to 20.0 mg/mL, or from 0.1 mg/mL to 5.0 mg/mL, or from 0.2 mg/mL to 2.0 mg/mL, or from 0.5 mg/mL to 5.0 mg/mL, or 1.0 mg/mL to 5.0 mg/mL, or 2.0 mg/mL to 5.0 mg/mL. In some embodiments, the concentration of the suspending agent ranges from 0.2 to 2.0 mg/mL. In some embodiments, the concentration of the suspending agent is 0.5 mg/mL, 1.0 mg/mL, or about 0.53 mg/mL. In some embodiments, the concentration of the suspending agent is 0.5 mg/mL. In some embodiments, the concentration of the suspending agent is 1.0 mg/mL. In some embodiments, the concentration of the suspending agent is about 0.53 mg/mL. In some embodiments, the concentration of the suspending agent is about 5.0 mg/mL.
  • the suspending agent comprises at least one selected from the group consisting of sodium carboxymethylcellulose, gelatin, polyvinylpyrrolidone, methylcellulose, and gum arabic. In some embodiments, the suspending agent is sodium carboxymethylcellulose.
  • the buffering agent comprises at least one selected from the group consisting of sodium dihydrogen monohydrate monohydrate, disodium hydrogen phosphate, acetic acid, citric acid, sodium citrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid, and malic acid. In some examples, the buffer is sodium dihydrogen phosphate monohydrate.
  • the pH adjusting agent is selected from an acidic pH adjusting agent selected from at least one of hydrochloric acid, acetic acid, and phosphoric acid, or an alkaline pH adjusting agent selected from the group consisting of sodium hydroxide and phosphoric acid. At least one of sodium hydrogenate, calcium carbonate, and magnesium hydroxide. In some embodiments, the pH adjusting agent is sodium hydroxide.
  • a formulation of vortioxet hydrobromide injection comprises:
  • a formulation of vortioxet hydrobromide injection comprises:
  • a pH adjuster sodium hydroxide is optionally included to adjust the pH to 6.0 to 7.0.
  • a formulation of vortioxet hydrobromide injection comprises:
  • a pH adjuster sodium hydroxide is optionally included to adjust the pH to 6.0 to 7.0.
  • a spray formulation of vortioxet hydrobromide comprises:
  • a pH adjuster sodium hydroxide is optionally included to adjust the pH to 6.0 to 7.0.
  • a formulation of vortioxet hydrobromide injection comprises:
  • a pH adjuster sodium hydroxide is optionally included to adjust the pH to 6.0 to 7.0.
  • a formulation of vortioxet hydrobromide injection comprises:
  • a pH adjuster sodium hydroxide is optionally included to adjust the pH to 6.0 to 7.0.
  • a formulation of vortioxet hydrobromide injection comprises:
  • a pH adjuster sodium hydroxide is optionally included to adjust the pH to 6.0 to 7.0.
  • a formulation of vortioxet hydrobromide injection comprises:
  • a pH adjuster sodium hydroxide is optionally included to adjust the pH to 6.0 to 7.0.
  • a formulation of vortioxet hydrobromide injection comprises:
  • a pH adjuster sodium hydroxide is optionally included to adjust the pH to 6.0 to 7.0.
  • a formulation of vortioxet hydrobromide injection comprises:
  • a pH adjuster sodium hydroxide is optionally included to adjust the pH to 6.0 to 7.0.
  • the preparation preparation of vortioxet hydrobromide wherein the D[4,3] of the wortoxime hydrobromide has a range of 0.05 ⁇ m to 20.0 ⁇ m, or 0.1 ⁇ m to 10.0 ⁇ m, or 1.0 ⁇ m- 10.0 microns, or 0.5 microns to 15 microns, or 0.1 microns to 1.0 microns, or 10.0 microns to 15.0 microns, or 15.0 microns to 20.0 microns.
  • the D[4,3] of wortithine hydrobromide ranges from 1.0 micron to 10.0 micron.
  • the fluoxetine hydrobromide injection preparation of the present invention continuously releases vortioxet hydrobromide for a period of at least 2 weeks after the injection.
  • the preparation preparation of vortioxet hydrobromide according to the present invention may be in the form of a suspension, and the D[4,3] of wortidine hydrobromide present in the suspension may range from 0.05 ⁇ m to 20.0 ⁇ m.
  • the formulation is sustained to release wortoxicillin hydrobromide for a period of at least 2 weeks, for a period of up to 4 weeks or for a longer period of time, for example up to 6 weeks.
  • the preparation preparation of vortioxet hydrobromide according to the present invention may be in the form of a suspension, and the concentration of wortidine hydrobromide present in the suspension ranges from 40.0 mg/mL to 400.0 mg/mL.
  • the formulation continuously releases wortoxicillin hydrobromide for a period of at least 2 weeks, for a period of up to 4 weeks or for a longer period of time, for example up to 6 weeks.
  • the injection preparation of vortioxet hydrobromide according to the present invention may be a ready-to-use liquid injection or a lyophilized preparation. In some embodiments it is ready to use A liquid injection, in some embodiments, is a lyophilized powder injection.
  • the vortexetine hydrobromide injection formulation is a lyophilized formulation, the lyophilized formulation being in the form of a cake.
  • the present invention provides a method of preparing any of the above-described injection preparations of vortioxet hydrobromide.
  • a method of preparing a formulation of vortioxetine hydrobromide comprising the steps of:
  • a method of preparing a formulation of vortioxetine hydrobromide comprising the steps of:
  • the method for preparing the injection preparation of wortite hydrochloride hydrobromide according to the present invention adopts a wet grinding technique, and the grinding beads are made of zirconia with good compatibility.
  • a method of preparing a formulation of fluoxetine hydrobromide injection which may further comprise the step of preparing a lyophilized formulation, the step of preparing the lyophilized formulation comprising: lyophilizing the final suspension.
  • the freeze drying comprises drying the final suspension by cooling the final suspension to below -30 ° C; and drying the cooled final suspension below 0 ° C; in some embodiments, the final The freeze-drying of the suspension is carried out in three stages:
  • the lyophilized preparation of wortite hydrobromide after being mixed with water, forms an injection in the form of a suspension, wherein D[4,3 of wortithine hydrobromide is present in the suspension.
  • the range is from 0.05 microns to 20.0 microns, and after the formulation is injected, the release of wortoxifene hydrobromide is continued for a period of at least 2 weeks, for a period of up to 4 weeks or for a longer period of time, for example up to 6 weeks.
  • the lyophilized preparation of wortite hydrobromide after mixing with water, forms an injection in the form of a suspension, wherein the concentration of wortoxifene hydrobromide present in the suspension ranges from 40.0 mg. /mL-400.0 mg/mL, after the formulation is injected, sustained release of wortoxicillin hydrobromide for a period of at least 2 weeks, for a period of up to 4 weeks or longer, for example up to 6 weeks.
  • the present invention also provides the use of the aforementioned fluoxetine bromide injection preparation for the preparation of a medicament for the treatment of major depression.
  • a use of a wound preparation of vortioxetine bromide for the preparation of a medicament for the treatment of major depression which may be administered intramuscularly or subcutaneously.
  • Figure 1 depicts a graph of mean plasma concentration versus time for vortioxetine after injection of a formulation of Example 10 of the invention (prescription No. 01, 02, 03 in Example 10) in a rat.
  • Example 1 Preparation of different concentrations of wortidine hydrochloride hydrobromide suspension
  • Table 1-1 Granite content of wortite hydrobromide in the suspension after grinding (unit: ⁇ m)
  • the suspensions having a concentration of 63 mg/mL and 380 mg/mL can obtain D[4,3] between 1.0 and 10.0 micrometers after grinding, and the suspension has good injectability.
  • the suspensions with concentrations of 63 mg/mL and 380 mg/mL were not introduced with process impurities after grinding; and after 30 (or 35) days of accelerated conditions, the content and related substances did not change significantly.
  • the gradient elution conditions for the substance are as follows, the run time is 70 min, and the injection volume is 20 ⁇ l:
  • the content gradient elution conditions were as follows, the run time was 40 min, and the injection volume was 10 ⁇ l:
  • Example 3 Preparation of lyophilized formulation of different prescriptions of wortite hydrobromide
  • TPGS and sodium dihydrogen phosphate monohydrate are sequentially dissolved in about 60% of the total amount of purified water;
  • Table 4-1 Granule size of wortite hydrobromide in each batch of suspension after grinding (unit: ⁇ m)
  • the same prescription suspension can be prepared by controlling the grinding parameters (grinding bead ratio and grinding time), and the content of the D[4,3] suspension can meet the requirements.
  • Example 5 Preparation of different Tween-20 dosages of wortidine hydrochloride hydrobromide suspension
  • Table 5-1 Granule size of wortite hydrobromide in each batch of suspension after grinding (unit: ⁇ m)
  • the dosage of Tween-20 in the prescription is in the range of 6mg/mL to 40mg/mL. After the grinding, the suspension of D[4,3] between 1.0-10.0 microns can be obtained, and after accelerating conditions for 30 days, There was no significant change in particle size.
  • Table 6-1 Granule size of fluoxetine hydrobromide in each batch of suspension after grinding (unit: ⁇ m)
  • the dosage of Tween-80 in the prescription is in the range of 4mg/mL to 40mg/mL. After the grinding, the suspension of D[4,3] between 1.0-10.0 microns can be obtained, and after accelerating conditions for 30 days, There was no significant change in particle size.
  • the dosage of Tween-80 in the prescription is in the range of 4mg/mL to 40mg/mL.
  • the prepared suspension has good stability and accelerated conditions. After 30 days, there was no significant change in the content and related substances. When the amount of Tween 80 is 2 mg/ml or less, a stable suspension cannot be prepared.
  • Example 7 Preparation of different EL 35 dosages of wortidine hydrochloride hydrobromide suspension
  • Table 7-1 Granule size of wortite hydrobromide in each batch of suspension after grinding (unit: ⁇ m)
  • the dosage of EL-35 in the prescription is in the range of 4mg/mL to 40mg/mL. After the grinding, the suspension of D[4,3] between 1.0-10.0 microns can be obtained, and after 30 days of accelerated conditions, the particles are obtained. There is no significant change in the diameter. When the amount of EL-35 is 2 mg/ml or less, a stable suspension cannot be prepared.
  • Example 8 Preparation of different TPGS dosages of wortidine hydrochloride hydrobromide suspension
  • TPGS and sodium dihydrogen phosphate monohydrate are sequentially dissolved in about 60% of the total amount of purified water, and dissolved by heating;
  • Table 8-1 Particle size of fluoxetine hydrobromide in each batch of suspension after grinding (unit: ⁇ m)
  • the dosage of TPGS in the prescription is in the range of 10mg/mL to 40mg/mL. After the grinding, the suspension of D[4,3] between 1.0-10.0 microns can be obtained, and after 30 days of accelerated conditions, the particle size is not obvious change.
  • Tween 20, TPGS, Span 20 monohydrate sodium dihydrogen phosphate were sequentially dissolved and dispersed in about 60% of the total amount of purified water;
  • Example 9 The different concentrations and prescription samples in Example 9 were selected for the rat experiment. The experiment was as follows:
  • the LC/MS/MS system for analysis includes the Agilent 1200 Series vacuum degassing furnace, binary syringe pump, orifice autosampler, column incubator, and charged spray ionization (ESI) source for the Agilent G6430 three-stage quadrupole mass spectrometer . Quantitative analysis is performed in MRM mode, MRM The parameters of the conversion are shown in Table A:
  • the present invention evaluated the pharmacokinetic study of samples Nos. 01, 02, and 03 of Example 9 in rats. After administration by intramuscular injection, the animals were given a suspension preparation of wortite (30 mg/kg or 47.2 mg/kg). Whole blood was collected before and after administration at 0.25h, 1h, 2h, 5h, 7h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 216h, 288h, 336h, 408h and 504h. Save for testing. It was centrifuged at 12,000 rpm for 2 minutes. Plasma was collected and stored at -20 ° C or -70 ° C until the above LC/MS/MS analysis was performed.
  • Table 9-2 lists the pharmacokinetic data of the three samples in Example 9 in rats.
  • the compounds of the present invention have good pharmacokinetic properties and exhibit different sustained release trends compared to solutions. Including the ideal peak time (T max ), half-life (T 1/2 ) and exposure (AUC last ), the absorption and release curves are relatively flat compared to the solution, T 1/2 is between 95-134h, The plasma concentration of 504h vortioxine can be maintained above the detection limit.
  • the average drug time curve of the preparation of the embodiment 9 of the present invention after intramuscular injection in rats is shown in Figure 1 of the specification.
  • Example 10 Preparation of different carboxymethylcellulose sodium suspensions of wortite hydrochloride hydrobromide
  • the dosage of carboxymethylcellulose in the prescription is in the range of 0.5 mg/mL to 5 mg/mL, and a suspension of D[4,3] between 1.0-10.0 micron can be obtained after grinding.
  • the amount of carboxymethylcellulose exceeds 10.0 mg/mL, an injectable suspension cannot be prepared.
  • the particle size distribution of the milled suspension was measured using a Malvern Mastersizer 2000 particle size analyzer.
  • Table 11-1 Particle size of fluoxetine hydrobromide in the suspension after grinding (unit: ⁇ m)

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Abstract

本发明涉及一种氢溴酸沃替西汀长效注射制剂。所述制剂包含氢溴酸沃替西汀、助悬剂、稳定剂、缓冲剂、pH调节剂、溶剂，所述制剂可以为即用型液体注射剂，也可以为冻干粉针剂，所述制剂注射后具有明显缓释效果，可减少给药次数，延长药物作用时间，提高患者依从性，提高生物利用度。同时，本发明还提供了制备上述氢溴酸沃替西汀长效注射制剂的方法，该方法简单经济，适用于工业化生产。

Description

氢溴酸沃替西汀长效注射制剂 技术领域
本发明涉及医药制剂领域，具体涉及一种氢溴酸沃替西汀长效注射制剂。
背景技术
抑郁症又称抑郁障碍，以显著而持久的心境低落为主要临床特征，是心境障碍的主要类型。临床可见心境低落，自卑抑郁，甚至悲观厌世，有自杀企图或行为。多数病例有反复发作的倾向，每次发作大多数可以缓解，部分可有残留症状或转为慢性。在全世界，受某种形式的抑郁影响的人数占全部妇女的25％，全部男性的10％，以及全部青少年的5％。抑郁症的病因尚不清楚，目前，抗抑郁药已成为抑郁病人的首选治疗手段，临床上以选择性五羟色胺(5-HT)再摄取抑剂为主，应用最为广泛。
沃替西汀是2013年上市的新药，主要用于重度抑郁症(MDD)的治疗，其作用机制尚未完全明确，但通常认为与5-HT再提取抑制有关，是第一个包括5-HT受体激活和重吸收抑制双重作用机制的抗抑郁药。该药具有非劣或优于SSRIs(5-羟色胺再摄取抑制剂)和SNRIs(5-羟色胺与去甲肾上腺素再摄取抑制剂)的安全性数据，更好的体重控制数据。对于对SSRI/SNRI不能完全响应的患者沃替西汀优效于阿戈美拉汀。治疗抑郁症效果与度洛西汀相似，且优于文拉法辛和阿戈美拉汀，加之安全性良好，肝、肾损伤患者人群也适用，效果优于维拉佐酮，需注意的是其增加青少年自杀倾向的危险性，但总体来说沃替西汀在有效性和安全性方面优于传统的SSRIs。目前沃替西汀只有不同规格的经口服给药的氢溴酸沃替西汀片剂上市，该剂型血药浓度维持时间短，需要每日给药(每天一次)，由于需要频繁给药，增加了患者的不顺应性，且由于患者本身情绪波动及其他症状的影响，造成自行服药困难，常常导致治疗失败。
当前并没有沃替西汀及其盐的长效注射剂上市，现有技术中缺乏对沃替西汀及其盐的非肠道给药制剂的研究。
发明内容
发明概述
本发明第一方面提供了一种氢溴酸沃替西汀长效注射制剂，该制剂中氢溴酸沃替西汀的浓度较高、粒径可控，可在有限的注射体积内，获得较高的给药剂量，并通过控制粒径分布，达到长效释药的作用，该制剂在注射后，在至少2周的时间期间持续释放氢溴酸沃替西汀，该制剂储存稳定性好，给不宜口服给药的特殊人群带来新的用药选择，并且可两周给药一次，增加了患者的顺应性。
本发明第二方面提供了一种第一方面所述氢溴酸沃替西汀长效注射制剂的制备方法，该方法简单易行，稳定性好，安全性高，适于工业化生产，该方法还可增加冷冻干燥步骤，制备得氢溴酸沃替西汀冻干 制剂。
本发明第三方面提供了一种氢溴酸沃替西汀长效注射制剂在制备用于治疗重度抑郁症药物中的用途。
术语定义
本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
在本发明的上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现10％以下的差异或者本领域人员认为的合理的差异，如1％、2％、3％、4％或5％的差异。
术语“D[4,3]”是指采用Malvern Mastersizer 2000激光粒度测定仪测定得到的体积加权平均值。
术语“Dv10”是指一个样品的累计粒度体积分布百分数达到10％时所对应的粒径，术语“Dv50”是指一个样品的累计粒度体积分布百分数达到50％时所对应的粒径，术语“Dv90”是指一个样品的累计粒度体积分布百分数达到90％时所对应的粒径。
LC/MS/MS指液质联用。
“持续释放”是指采用LC/MS/MS分析仪器检测样品，根据其检测限，能检测到氢溴酸沃替西汀的血药浓度。
TPGS是指聚乙二醇1000维生素E琥珀酸酯，EL 35是指聚氧乙烯(35)蓖麻油。
浓度“mg/mL”指毫克/毫升，为重量/体积，所述体积为混悬液体积。
μm指微米,μL指微升，L指升，mm指毫米，mL指毫升，nm指纳米，ng指纳克，kg指千克，min指分钟，d指天数，Hz指赫兹，g指克，qs.指加至，mbar指毫巴，V指伏特，℃指摄氏度。
发明详述
基于现有技术的不足，本发明经过深入考察和研究，制备了含氢溴酸沃替西汀药物的长效注射剂，该 制剂可以是混悬液的形式，也可以是冻干粉的形式，前者可以直接使用，后者以配套的无菌注射用水混合调配成混悬液使用，采取肌肉注射或者皮下注射方式，相对于口服沃替西汀片剂，发明优势包括：
(1)该混悬液中氢溴酸沃替西汀以溶解度低的难溶性颗粒存在，注射后能够缓慢持续释放药物，可明显降低给药次数，避免峰谷波动，从而提高患者的治疗依从性和安全性；
(2)本制剂载药量较高，可获得至少2周或更长时间的持续释放；
(3)该混悬液中氢溴酸沃替西汀粒度较小，且分布均匀，具有良好的可注射性，有利于提高其生物利用度。
本发明得到的混悬液或者经冻干制剂，均具有良好的稳定性，利于储藏和运输。
本发明提供一种氢溴酸沃替西汀注射制剂，所述制剂载药量较高，其中氢溴酸沃替西汀的浓度范围为40.0mg/mL-400.0mg/mL。在一些实施例中，所述氢溴酸沃替西汀的浓度为60.0mg/mL-350.0mg/mL。在一些实施例中，所述氢溴酸沃替西汀的浓度为50.0mg/mL-200.0mg/mL；在一些实施例中，所述氢溴酸沃替西汀的浓度为60.0mg/mL-150.0mg/mL；在一些实施例中，所述氢溴酸沃替西汀的浓度为150.0mg/mL-200.0mg/mL；在一些实施例中，所述氢溴酸沃替西汀的浓度为150.0mg/mL-300.0mg/mL；在一些实施例中，所述氢溴酸沃替西汀的浓度为200.0mg/mL-300.0mg/mL；在一些实施例中，所述氢溴酸沃替西汀的浓度为50.0mg/mL-300.0mg/mL；在一些实施例中，所述氢溴酸沃替西汀的浓度为300.0mg/mL-350.0mg/mL。在一些实施例中，所述氢溴酸沃替西汀的浓度为63mg/mL，150.0mg/mL，190.2mg/mL，300.0mg/mL，或380.0mg/mL。
所述氢溴酸沃替西汀注射制剂，包括稳定剂。
在一些实施方式中，一种氢溴酸沃替西汀注射制剂，包括稳定剂和助悬剂。
在一些实施方式中，一种氢溴酸沃替西汀注射制剂，包括稳定剂，和/或助悬剂，和/或缓冲剂，和/或pH调节剂。
在一些实施方式中，一种氢溴酸沃替西汀注射制剂，包括稳定剂、助悬剂、缓冲剂和pH调节剂。
在一些实施方式中，一种氢溴酸沃替西汀注射制剂，包括稳定剂、缓冲剂和pH调节剂。
在一些实施方式中，一种氢溴酸沃替西汀注射制剂，包括稳定剂、助悬剂和pH调节剂。
在一些实施方式中，一种氢溴酸沃替西汀注射制剂，包括稳定剂、缓冲剂。
在一些实施方式中，一种氢溴酸沃替西汀注射制剂，包括稳定剂、pH调节剂。
在一些实施方式中，一种氢溴酸沃替西汀注射制剂，包括稳定剂、助悬剂、缓冲剂。
所述稳定剂的浓度范围为0.1mg/mL-60.0mg/mL。在一些实施例中，所述稳定剂的浓度范围为1.0mg/mL-40.0mg/mL，或者0.01mg/mL-20.0mg/mL，或者0.1mg/mL-10.0mg/mL，或者5.0mg/mL-55.0mg/mL，或者1.0mg/mL-5.0mg/mL，或者5.0mg/mL-10.0mg/mL，或者5.0mg/mL-20.0mg/mL，或者5.0mg/mL-40.0mg/mL，或者10.0mg/mL-20.0mg/mL，或者10.0mg/mL-40.0mg/mL，或者20.0 mg/mL-40.0mg/mL，或者40.0mg/mL-50.0mg/mL。在一些实施例中，所述稳定剂的浓度范围为5.0mg/mL-55.0mg/mL。在一些实施例中，所述稳定剂的浓度为4.0mg/mL，6.0mg/mL，10.0mg/mL，18.0mg/mL，20.0mg/mL，40.0mg/mL，或50.0mg/mL。在一些实施例中，所述稳定剂的浓度为约53.5mg/mL。
所述稳定剂包含选自吐温20、吐温60、吐温80、司盘20、泊洛沙姆188、聚乙二醇1000维生素E琥珀酸酯、聚氧乙烯氢化蓖麻油RH40、EL 35、卵磷脂、酸酯聚乙二醇-15-羟基硬脂酸酯、聚乙二醇的至少一种。在一些实施例中，所述稳定剂为吐温20，吐温80，TPGS，EL 35，或者吐温20和司盘20的组合。
所述助悬剂的浓度范围为0.1mg/mL-20.0mg/mL，或者0.1mg/mL-5.0mg/mL，或者0.2mg/mL-2.0mg/mL，或者0.5mg/mL-5.0mg/mL，或者1.0mg/mL-5.0mg/mL，或者2.0mg/mL-5.0mg/mL。在一些实施例中，所述助悬剂的浓度范围为0.2-2.0mg/mL。在一些实施例中，所述助悬剂的浓度为0.5mg/mL，1.0mg/mL，或者约0.53mg/mL。在一些实施例中，所述助悬剂的浓度为0.5mg/mL。在一些实施例中，所述助悬剂的浓度为1.0mg/mL。在一些实施例中，所述助悬剂的浓度为约0.53mg/mL。在一些实施例中，所述助悬剂的浓度为约5.0mg/mL。
所述助悬剂包含选自羧甲基纤维素钠、明胶、聚乙烯吡咯烷酮、甲基纤维素、阿拉伯胶的至少一种。在一些实施例中，所述助悬剂为羧甲基纤维素钠。所述缓冲剂包含选自一水磷酸二氢钠、磷酸氢二钠、乙酸、柠檬酸、柠檬酸钠、琥珀酸、己二酸、酒石酸、抗坏血酸、苯甲酸、苹果酸的至少一种。在一些示例中，所述缓冲剂为一水磷酸二氢钠。
所述pH调节剂选自酸性pH调节剂或者碱性pH调节剂，所述酸性pH调节剂选自盐酸、乙酸、磷酸的至少一种，所述碱性pH调节剂选自氢氧化钠、磷酸氢钠、碳酸钙、氢氧化镁的至少一种。在一些实施例中，所述pH调节剂为氢氧化钠。
在一些实施方式中，一种氢溴酸沃替西汀注射制剂，包括：
(a)氢溴酸沃替西汀，浓度范围为60.0mg/mL-350.0mg/mL，
(b)稳定剂吐温80，
(c)助悬剂羧甲基纤维素钠，
(d)缓冲剂一水磷酸二氢钠，
并任选地包含pH调节剂氢氧化钠。
在一些实施例中，一种氢溴酸沃替西汀注射制剂，包括：
(a)氢溴酸沃替西汀，浓度为190.2mg/mL，
(b)稳定剂吐温80，浓度为10.0mg/mL，
(c)助悬剂羧甲基纤维素钠，浓度为0.5mg/mL，
(d)缓冲剂一水磷酸二氢钠；
任选地包含pH调节剂氢氧化钠，以调节pH值为6.0至7.0。
在一些实施例中，一种氢溴酸沃替西汀注射制剂，包括：
(a)氢溴酸沃替西汀，浓度为190.2mg/mL，
(b)稳定剂吐温80，浓度为10.0mg/mL，
(c)助悬剂羧甲基纤维素钠，浓度为1.0mg/mL，
(d)缓冲剂一水磷酸二氢钠；
任选地包含pH调节剂氢氧化钠，以调节pH值为6.0至7.0。
在一个具体示例中，一种氢溴酸沃替西汀注射制剂，包括：
(a)氢溴酸沃替西汀，浓度为150.0mg/mL，
(b)稳定剂吐温80，浓度为40.0mg/mL，
(c)助悬剂羧甲基纤维素钠，浓度为约0.53mg/mL，
(d)缓冲剂一水磷酸二氢钠，
任选地包含pH调节剂氢氧化钠，以调节pH值为6.0至7.0。
在一些实施例中，一种氢溴酸沃替西汀注射制剂，包括：
(a)氢溴酸沃替西汀，浓度为50mg/mL，
(b)稳定剂吐温20，浓度为50.0mg/mL，
(c)助悬剂羧甲基纤维素钠，浓度为2.0mg/mL，
(d)缓冲剂一水磷酸二氢钠；
任选地包含pH调节剂氢氧化钠，以调节pH值为6.0至7.0。
在一些实施例中，一种氢溴酸沃替西汀注射制剂，包括：
(a)氢溴酸沃替西汀，浓度为60mg/mL，
(b)稳定剂EL35，浓度为20.0mg/mL，
(c)助悬剂羧甲基纤维素钠，浓度为0.5mg/mL，
(d)缓冲剂一水磷酸二氢钠；
任选地包含pH调节剂氢氧化钠，以调节pH值为6.0至7.0。
在一些实施例中，一种氢溴酸沃替西汀注射制剂，包括：
(a)氢溴酸沃替西汀，浓度为300.0mg/mL，
(b)稳定剂TPGS，浓度为5.0mg/mL，
(c)助悬剂羧甲基纤维素钠，浓度为5.0mg/mL，
(d)缓冲剂一水磷酸二氢钠；
任选地包含pH调节剂氢氧化钠，以调节pH值为6.0至7.0。
在一些实施例中，一种氢溴酸沃替西汀注射制剂，包括：
(a)氢溴酸沃替西汀，浓度为200.0mg/mL，
(b)稳定剂吐温80，浓度为10.0mg/mL，
(c)助悬剂羧甲基纤维素钠，浓度为0.5mg/mL，
(d)缓冲剂一水磷酸二氢钠；
任选地包含pH调节剂氢氧化钠，以调节pH值为6.0至7.0。
在一些实施例中，一种氢溴酸沃替西汀注射制剂，包括：
(a)氢溴酸沃替西汀，浓度为200.0mg/mL，
(b)稳定剂吐温20，浓度为10.0mg/mL，
(c)助悬剂羧甲基纤维素钠，浓度为0.5mg/mL，
(d)缓冲剂一水磷酸二氢钠；
任选地包含pH调节剂氢氧化钠，以调节pH值为6.0至7.0。
在一些实施例中，一种氢溴酸沃替西汀注射制剂，包括：
(a)氢溴酸沃替西汀，浓度为200.0mg/mL，
(b)稳定剂EL35，浓度为10.0mg/mL，
(c)助悬剂羧甲基纤维素钠，浓度为0.5mg/mL，
(d)缓冲剂一水磷酸二氢钠；
任选地包含pH调节剂氢氧化钠，以调节pH值为6.0至7.0。
所述的氢溴酸沃替西汀注射制剂，其中所述的氢溴酸沃替西汀的D[4,3]范围为0.05微米-20.0微米，或者0.1微米-10.0微米，或者1.0微米-10.0微米，或者0.5微米-15微米，或者0.1微米-1.0微米，或者10.0微米-15.0微米，或者15.0微米-20.0微米。在一些实施方式中，其中所述的氢溴酸沃替西汀的D[4,3]范围为1.0微米-10.0微米。
本发明所述的氢溴酸沃替西汀注射制剂，其在注射后，在至少2周的时间期间持续释放氢溴酸沃替西汀。
本发明所述的氢溴酸沃替西汀注射制剂，可为混悬液形式，存在于混悬液中的氢溴酸沃替西汀的D[4,3]范围为0.05微米-20.0微米，所述制剂在至少2周的时间，多达4周的时间或者更长时间例如多达6周的时间期间持续释放氢溴酸沃替西汀。
本发明所述的氢溴酸沃替西汀注射制剂，可为混悬液形式，存在于混悬液中的氢溴酸沃替西汀的浓度范围为40.0mg/mL-400.0mg/mL，所述制剂在至少2周的时间，多达4周的时间或者更长时间例如多达6周的时间期间持续释放氢溴酸沃替西汀。
本发明所述的氢溴酸沃替西汀注射制剂，可为即用型液体注射剂或冻干制剂。在一些实施例中为即用 型液体注射剂，在一些实施例中为冻干粉针剂。
在一些实施方式中，所述的氢溴酸沃替西汀注射制剂为冻干制剂，所述冻干制剂是饼块的形式。
另一方面，本发明提供一种制备上述任一氢溴酸沃替西汀注射制剂的方法。一种制备氢溴酸沃替西汀注射制剂的方法，包括下列步骤：
(a)分别将稳定剂、任选的，和缓冲剂依次溶解于水中，
(b)任选地，加入助悬剂至上述溶液中，搅拌至完全溶解，
(c)加入氢溴酸沃替西汀，得混悬液，任选地，用pH调节剂调节pH值为6.0至7.0，定容，
(d)将上述混悬液用球磨机研磨，得最终混悬液。
在一些实施例中，一种制备氢溴酸沃替西汀注射制剂的方法，包括下列步骤：
(a)分别将吐温20、一水磷酸二氢钠依次溶解于水中，
(b)加入处方量的羧甲基纤维素钠至上述溶液中，搅拌至完全溶解，
(c)加入氢溴酸沃替西汀，得混悬液，用氢氧化钠调节pH值为6.0至7.0，定容，
(d)将上述混悬液用行星式球磨机研磨，得最终混悬液。
本发明所述的一种制备氢溴酸沃替西汀注射制剂的方法，采用的是湿磨技术，研磨珠材质为相容性良好的氧化锆。
一种制备氢溴酸沃替西汀注射制剂的方法，还可包括制备成冻干制剂的步骤，所述制备成冻干制剂的步骤包括：将所述最终混悬液冷冻干燥。在一些实施例中，所述冷冻干燥包括通过冷却所述最终混悬液至-30℃以下，并在低于0℃干燥所述冷却的最终混悬液；在一些实施例中，所述最终混悬液冷冻干燥是以三个阶段实施的：
(l)预冻阶段，包括在-45℃冷却最终混悬液，
(2)初步干燥阶段，在低于0℃干燥冷却的最终混悬液，和
(3)二次干燥阶段，在高于0℃干燥冷却的最终混悬液，从而得到氢溴酸沃替西汀冻干制剂。
所述的氢溴酸沃替西汀冻干制剂，在与水混合后，形成混悬液形式的注射剂，其中，存在于混悬液中的氢溴酸沃替西汀的D[4,3]范围为0.05微米-20.0微米，所述制剂注射后，在至少2周的时间，多达4周的时间或者更长时间例如多达6周的时间期间持续释放氢溴酸沃替西汀。
所述的氢溴酸沃替西汀冻干制剂，在与水混合后，形成混悬液形式的注射剂，其中，存在于混悬液中的氢溴酸沃替西汀的浓度范围为40.0mg/mL-400.0mg/mL，所述制剂注射后，在至少2周的时间，多达4周的时间或者更长时间例如多达6周的时间期间持续释放氢溴酸沃替西汀。
本发明还提供了前述的溴酸沃替西汀注射制剂在制备用于治疗重度抑郁症药物中的用途。
一种溴酸沃替西汀注射制剂在制备用于治疗重度抑郁症药物中的用途，所述药物可经肌肉内注射或者皮下注射。
附图说明
图1描述在大鼠体中注射本发明实施例10制剂(实施例10中的01、02、03号处方)后，沃替西汀的平均血浆浓度与时间关系的图。
具体实施方式
实施例1：不同浓度氢溴酸沃替西汀混悬液制备
处方表：
Figure PCTCN2017109941-appb-000001
制备过程：
(1)将吐温20、一水磷酸二氢钠依次溶解于约60％配制总量的纯化水中；
(2)加入处方量的羧甲基纤维素钠至上述溶液中，搅拌至完全溶解；
(3)一边搅拌，一边缓慢加入处方量的氢溴酸沃替西汀，搅拌得沃替西汀混悬液，用氢氧化钠调节pH值为6.0至7.0，定容；
(4)将上述混悬液用球磨机进行研磨；
(5)采用Malvern Mastersizer 2000粒度测定仪测定研磨后混悬液粒度分布，检测含量和有关物质，并放置加速条件，考察稳定性。
实验结果：04样品研磨之后，基本无流动性，较粘稠，不具备可注射性，故该处方不进行下一步研究。其余处方样品见表1-1和表1-2。
表1-1 研磨后混悬液中氢溴酸沃替西汀颗粒粒度(单位：μm)
Figure PCTCN2017109941-appb-000002
氢溴酸沃替西汀混悬液粒度检测仪器参数(实施例通用)：
Figure PCTCN2017109941-appb-000003
根据实验结果可知，浓度为63mg/mL及380mg/mL的混悬液，研磨后可获得D[4,3]在1.0-10.0微米之间，该混悬液可注射性良好。
表1-2 混悬液40℃稳定性考察
Figure PCTCN2017109941-appb-000004
根据实验结果可知，浓度为63mg/mL及380mg/mL的混悬液，研磨后均未引入工艺杂质；且加速条件放置30(或35)天后，含量及有关物质未有明显变化。
氢溴酸沃替西汀含量和有关物质方法(实施例通用)
色谱条件：
高效液相色谱仪(Agilent HPLC-DAD)
色谱柱：Symmetryshield RPC18，150mm×4.6mm，3.5μm
检测器：UV检测器，检测波长230nm     流速：1.0ml/min
流动相A：0.05％三氟乙酸             流动相B：乙腈
稀释剂：水:乙腈＝80:20              柱温：35℃
有关物质梯度洗脱条件如下，运行时间为70min，进样量为20μl：
时间(min) 流动相A(％) 流动相B(％)
0 80 20
30 60 40
50 20 80
60 20 80
60.1 80 20
70 80 20
含量梯度洗脱条件如下，运行时间为40min，进样量为10μl：
时间(min) 流动相A(％) 流动相B(％)
0 80 20
30 60 40
30.1 80 20
40 80 20
实施例2：不同处方氢溴酸沃替西汀混悬液制备
处方表：
Figure PCTCN2017109941-appb-000005
制备过程：
(1)将吐温20、吐温80、EL 35、TPGS、司盘80分别与一水磷酸二氢钠依次溶解或分散于约60％配制总量的纯化水中；
(2)加入处方量的羧甲基纤维素钠至上述溶液中，搅拌至完全溶解；
(3)一边搅拌，一边缓慢加入处方量的氢溴酸沃替西汀，搅拌得沃替西汀混悬液，用氢氧化钠调节pH值为6.0至7.0，定容；
(4)将上述混悬液用球磨机进行研磨；
(5)采用Malvern Mastersizer 2000粒度测定仪测定研磨后混悬液粒度分布，检测含量和有关物质，并放置加速条件，考察稳定性。
实验结果：采用司盘80为稳定剂时，研磨后大量API析出，无法获得稳定的混悬液，故该处方不适合进行下一步研究。其余样品结果见表2-1和表2-2。
表2-1 研磨后各批次混悬液中氢溴酸沃替西汀颗粒粒度(单位：μm)
Figure PCTCN2017109941-appb-000006
结论：浓度为190.2mg/mL的混悬液，研磨后不同处方(稳定剂)样品，均可获得D[4,3]在1.0-10.0微米之间的混悬液，加速条件放置20天后，粒径无明显变化。
表2-2 混悬液40℃稳定性考察
Figure PCTCN2017109941-appb-000007
结论：浓度为190.2mg/mL的混悬液，研磨后不同处方(稳定剂)样品，含量稳定，且均未引入工艺杂质，40℃放置35天后，未有明显变化。
实施例3：不同处方氢溴酸沃替西汀冻干制剂制备
处方表：
Figure PCTCN2017109941-appb-000008
Figure PCTCN2017109941-appb-000009
制备过程：
(1)分别将吐温20、吐温80、EL 35、TPGS、一水磷酸二氢钠依次溶解于约60％配制总量的纯化水中；
(2)加入处方量的羧甲基纤维素钠至上述溶液中，搅拌至完全溶解；
(3)一边搅拌，一边缓慢加入处方量的氢溴酸沃替西汀，搅拌得沃替西汀混悬液，用氢氧化钠调节pH值为6.0至7.0，定容；
(4)将上述混悬液用球磨机进行研磨；
(5)采用Malvern Mastersizer 2000粒度测定仪测定研磨后混悬液粒度分布，检测含量和有关物质；
(6)将研磨后的混悬液灌装于7ml西林瓶中，灌装量为2ml，进行冷冻干燥，测定冻干后粒径、含量、有关物质，放置加速条件，考察稳定性，冻干工艺如表3-1：
表3-1 冻干工艺
Figure PCTCN2017109941-appb-000010
实验结果：见表3-2和表3-3。
表3-2 冻干前后各批次混悬液中氢溴酸沃替西汀颗粒粒度(单位：μm)
Figure PCTCN2017109941-appb-000011
Figure PCTCN2017109941-appb-000012
结论：浓度为190.2mg/mL的混悬液，研磨后不同处方(稳定剂)样品，均可获得D[4,3]在1.0-10.0微米之间的混悬液，且冻干前后粒度无明显变化。
表3-3 混悬液冻干前后含量、有关物质变化
Figure PCTCN2017109941-appb-000013
结论：浓度为190.2mg/mL的混悬液，冻干后不同处方(稳定剂)样品，含量及有关物质无明显变化。
实施例4：不同粒径氢溴酸沃替西汀混悬液制备
处方表：
Figure PCTCN2017109941-appb-000014
制备过程：
(1)分别将TPGS、一水磷酸二氢钠依次溶解于约60％配制总量的纯化水中；
(2)加入处方量的羧甲基纤维素钠至上述溶液中，搅拌至完全溶解；
(3)一边搅拌，一边缓慢加入处方量的氢溴酸沃替西汀，搅拌得沃替西汀混悬液，用氢氧化钠调节pH值为6.0至7.0，定容；
(4)将上述混悬液用球磨机进行研磨；；
(5)采用Malvern Mastersizer 2000粒度测定仪测定研磨后混悬液粒度分布，并放置加速条件，考察稳定性。
实验结果：见表4-1和表4-2。
表4-1 研磨后各批次混悬液中氢溴酸沃替西汀颗粒粒度(单位：μm)
Figure PCTCN2017109941-appb-000015
表4-2 混悬液0天含量和有关物质结果
Figure PCTCN2017109941-appb-000016
结论：同样处方的混悬液，通过控制研磨参数(研磨珠配比和研磨时间)，可以制备出不同D[4,3]的混悬液，且含量、有关物质符合要求。
实施例5：不同吐温-20用量氢溴酸沃替西汀混悬液制备
处方表：
Figure PCTCN2017109941-appb-000017
Figure PCTCN2017109941-appb-000018
制备过程：
(1)分别将吐温20、一水磷酸二氢钠依次溶解于约60％配制总量的纯化水中；
(2)加入处方量的羧甲基纤维素钠至上述溶液中，搅拌至完全溶解；
(3)一边搅拌，一边缓慢加入处方量的氢溴酸沃替西汀，搅拌得沃替西汀混悬液，用氢氧化钠调节pH值为6.0至7.0，定容；
(4)将上述混悬液用球磨机进行研磨；
(5)采用Malvern Mastersizer 2000粒度测定仪测定研磨后混悬液粒度分布，并放置加速条件，考察稳定性。
实验结果：见表5-1。
表5-1 研磨后各批次混悬液中氢溴酸沃替西汀颗粒粒度(单位：μm)
Figure PCTCN2017109941-appb-000019
结论：处方中吐温-20用量为6mg/mL至40mg/mL范围内，研磨后均可获得D[4,3]在1.0-10.0微米之间的混悬液，且加速条件放置30天后，粒径无明显变化。
实施例6：不同吐温-80用量氢溴酸沃替西汀混悬液制备
处方表：
Figure PCTCN2017109941-appb-000020
制备过程：
(1)分别将吐温80、一水磷酸二氢钠依次溶解于约60％配制总量的纯化水中；
(2)加入处方量的羧甲基纤维素钠至上述溶液中，搅拌至完全溶解；
(3)一边搅拌，一边缓慢加入处方量的氢溴酸沃替西汀，搅拌得沃替西汀混悬液，用氢氧化钠调节pH值为6.0至7.0，定容；
(4)将上述混悬液用球磨机进行研磨；
(5)采用Malvern Mastersizer 2000粒度测定仪测定研磨后混悬液粒度分布，并放置加速条件，考察稳定性。
实验结果：吐温80用量为2mg/ml时，研磨后，有较多AP析出，难以制备成稳定的混悬液，故该处方不进行下一步研究，其余批次结果见表6-1和表6-2。
表6-1 研磨后各批次混悬液中氢溴酸沃替西汀颗粒粒度(单位：μm)
Figure PCTCN2017109941-appb-000021
结论：处方中吐温-80用量为4mg/mL至40mg/mL范围内，研磨后均可获得D[4,3]在1.0-10.0微米之间的混悬液，且加速条件放置30天后，粒径无明显变化。
表6-2 研磨后各批次混悬液中氢溴酸沃替西汀含量及有关物质
Figure PCTCN2017109941-appb-000022
结论：处方中吐温-80用量为4mg/mL至40mg/mL范围内，制备的混悬液稳定性良好，加速条件放 置30天后，含量和有关物质没有明显变化。当吐温80用量为2mg/ml甚至更低时，则无法制备成稳定的混悬液。
实施例7：不同EL 35用量氢溴酸沃替西汀混悬液制备
处方表：
Figure PCTCN2017109941-appb-000023
制备过程：
(1)分别将EL 35、一水磷酸二氢钠依次溶解于约60％配制总量的纯化水中；
(2)加入处方量的羧甲基纤维素钠至上述溶液中，搅拌至完全溶解；
(3)一边搅拌，一边缓慢加入处方量的氢溴酸沃替西汀，搅拌得沃替西汀混悬液，用氢氧化钠调节pH值为6.0至7.0，定容；
(4)将上述混悬液用球磨机进行研磨；
(5)采用Malvern Mastersizer 2000粒度测定仪测定研磨后混悬液粒度分布，并放置加速条件，考察稳定性。
实验结果：EL 35用量为2mg/ml时，研磨后，有较多API析出，难以制备成稳定的混悬液，故该处方不进行下一步研究，其余批次结果见表7-1。
表7-1 研磨后各批次混悬液中氢溴酸沃替西汀颗粒粒度(单位：μm)
Figure PCTCN2017109941-appb-000024
Figure PCTCN2017109941-appb-000025
结论：处方中EL-35用量为4mg/mL至40mg/mL范围内，研磨后均可获得D[4,3]在1.0-10.0微米之间的混悬液，且加速条件放置30天后，粒径无明显变化。当EL-35用量为2mg/ml甚至更低时，则无法制备稳定的混悬液。
实施例8：不同TPGS用量氢溴酸沃替西汀混悬液制备
处方表：
Figure PCTCN2017109941-appb-000026
制备过程：
(1)分别将TPGS、一水磷酸二氢钠依次溶解于约60％配制总量的纯化水中，加热溶解；
(2)待冷却至室温后，加入处方量的羧甲基纤维素钠至上述溶液中，搅拌至完全溶解；
(3)一边搅拌，一边缓慢加入处方量的氢溴酸沃替西汀，搅拌得沃替西汀混悬液，用氢氧化钠调节pH值为6.0至7.0，定容；
(4)将上述混悬液用球磨机进行研磨；(5)采用Malvern Mastersizer 2000粒度测定仪测定研磨后混悬液粒度分布，并放置加速条件，考察稳定性。
实验结果：见表8-1。
表8-1 研磨后各批次混悬液中氢溴酸沃替西汀颗粒粒度(单位：μm)
Figure PCTCN2017109941-appb-000027
结论：处方中TPGS用量为10mg/mL至40mg/mL范围内，研磨后均可获得D[4,3]在1.0-10.0微米之间的混悬液，且加速条件放置30天后，粒径无明显变化。
实施例9：氢溴酸沃替西汀长效注射剂在大鼠体内的药物动力学研究
处方表：
Figure PCTCN2017109941-appb-000028
制备过程：
(1)分别将吐温20、TPGS、司盘20一水磷酸二氢钠依次溶解、分散于约60％配制总量的纯化水中；
(2)加入处方量的羧甲基纤维素钠至上述溶液中，搅拌至完全溶解；
(3)一边搅拌，一边缓慢加入处方量的氢溴酸沃替西汀，搅拌得沃替西汀混悬液，用氢氧化钠调节pH值为6.0至7.0，定容；
(4)将上述混悬液用球磨机进行研磨；(5)采用Malvern Mastersizer 2000粒度测定仪测定研磨后混悬液粒度分布。
实验结果：见表9-1。
表9-1 研磨后各批次混悬液中氢溴酸沃替西汀颗粒粒度(单位：μm)
Figure PCTCN2017109941-appb-000029
结论：API浓度为190.2mg/mL和300mg/mL的混悬液，研磨后不同处方(稳定剂)样品，均可获得D[4,3]在1.0-10.0微米之间的混悬液。
选择实施例9中不同浓度及处方样品，进行大鼠实验，实验如下：
分析用的LC/MS/MS系统包括Agilent 1200系列真空脱气炉，二元注射泵，孔板自动采样器，柱恒温箱，带电喷雾电离(ESI)源的Agilent G6430三级四级杆质谱仪。定量分析在MRM模式下进行，MRM 转换的参数如表A所示：
表A
多反应检测扫描 299.1→150
碎裂电压 25V
毛细管电压 4000V
干燥器温度 350℃
雾化器 40psi
干燥器流速 9L/min
分析使用Waters Xbridge C18，2.1×50mm，2.7μM柱，注入15μL样品。分析条件：流动相为2mM甲酸铵+0.1％甲酸(A)和甲醇+2mM甲酸铵+0.1％甲酸(B)。流速为0.3mL/min。流动相梯度如表B所示：
表B
Figure PCTCN2017109941-appb-000030
本发明对实施例9的01、02、03号样品在大鼠体内的药代动力学研究进行了评估。采用肌肉注射给药，动物给予沃替西汀混悬制剂(30mg/kg或47.2mg/kg)后。在给药前和给药后0.25h、1h、2h、5h、7h、24h、48h、72h、96h、120h、144h、168h、216h、288h、336h、408h和504h采集全血，分离血浆后冻存待测。并在12,000转/分钟下离心2分钟。收集血浆，于-20℃或-70℃下保存直到进行上述的LC/MS/MS分析。表9-2列出了实施例9中3个样品在大鼠体内的药代动力学数据。本发明化合物具有良好的药代动力学性质，与溶液剂相比体现出不同的缓释趋势。包括理想的达峰时间(Tmax)、半衰期(T1/2)和暴露量(AUClast)，吸收及释放曲线与溶液剂相比较为平缓，T1/2在95-134h之间，在504h沃替西汀血药浓度基本可以维持在检测限以上。本发明实施例9制剂在大鼠肌肉注射后体内平均药时曲线见说明书附图1。
表9-2：化合物在大鼠体内的药代动力学数据
Figure PCTCN2017109941-appb-000031
Figure PCTCN2017109941-appb-000032
实施例10：不同羧甲基纤维素钠用量氢溴酸沃替西汀混悬液制备
处方表：
Figure PCTCN2017109941-appb-000033
制备过程：
(1)分别将吐温80、一水磷酸二氢钠依次溶解于约60％配制总量的纯化水中；
(2)加入处方量的羧甲基纤维素钠至上述溶液中，搅拌至完全溶解；
(3)一边搅拌，一边缓慢加入处方量的氢溴酸沃替西汀，搅拌得沃替西汀混悬液，用氢氧化钠调节pH值为6.0至7.0，定容；
(4)将上述混悬液用球磨机进行研磨；(5)采用Malvern Mastersizer 2000粒度测定仪测定研磨后混悬液粒度分布，并放置加速条件，考察稳定性。
实验结果：当羧甲基纤维素钠用量为10mg/ml时，研磨后，样品产生气泡明显，且较为粘稠，该混悬液不具备可注射性，故该处方不进行下一步研究。其余处方结果见表10-1。
表10-1 研磨后各批次混悬液中氢溴酸沃替西汀颗粒粒度(单位：μm)
Figure PCTCN2017109941-appb-000034
结论：处方中羧甲基纤维素用量为0.5mg/mL至5mg/mL范围内，研磨后均可获得D[4,3]在1.0-10.0微米之间的混悬液。当羧甲基纤维素用量超过10.0mg/mL时，则无法制备可注射的混悬液。
实施例11：不同助悬剂氢溴酸沃替西汀混悬液制备
处方表：
Figure PCTCN2017109941-appb-000035
Figure PCTCN2017109941-appb-000036
制备过程：
(1)分别将吐温80、一水磷酸二氢钠依次溶解于约60％配制总量的纯化水中；
(2)加入处方量的羧甲基纤维素钠、羟丙甲纤维素至上述溶液中，搅拌至完全溶解；
(3)一边搅拌，一边缓慢加入处方量的氢溴酸沃替西汀，搅拌得沃替西汀混悬液，用氢氧化钠调节pH值为6.0至7.0，定容；
(4)将上述混悬液用球磨机进行研磨；
(5)采用Malvern Mastersizer 2000粒度测定仪测定研磨后混悬液粒度分布。
实验结果：当采用羟丙甲纤维素为助悬剂时，研磨后，样品产生气泡明显，且无流动性，该混悬液不具备可注射性，故该处方不进行下一步研究。其余处方结果见表11-1。
表11-1 研磨后混悬液中氢溴酸沃替西汀颗粒粒度(单位：μm)
Figure PCTCN2017109941-appb-000037
结论：选择羧甲基纤维素钠为助悬剂，研磨后均可获得D[4,3]在1.0-10.0微米之间的混悬液。以羟丙甲纤维素为助悬剂，则无法制备可注射的混悬液。
本发明说明书的描述中，参考术语“一些实施例”、“一些实施方式”、“一个具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (17)

  1. 一种氢溴酸沃替西汀注射制剂，其特征在于，所述氢溴酸沃替西汀的浓度范围为40.0mg/mL-400.0mg/mL。
  2. 根据权利要求1所述的制剂，其进一步包括稳定剂。
  3. 根据权利要求2所述的制剂，任选地，其进一步包括助悬剂和/或缓冲剂，和/或pH调节剂。
  4. 根据权利要求3所述的制剂，所述助悬剂的浓度范围为0.1mg/mL-5mg/mL。
  5. 根据权利要求3所述的制剂，其中所述助悬剂包含选自羧甲基纤维素钠、明胶、聚乙烯吡咯烷酮、甲基纤维素、阿拉伯胶的至少一种。
  6. 根据权利要求2所述的制剂，所述稳定剂的浓度范围为5.0mg/mL-55.0mg/mL。
  7. 根据权利要求2所述的制剂，其中所述稳定剂包含选自吐温20、吐温60、吐温80、司盘20、泊洛沙姆188、聚乙二醇1000维生素E琥珀酸酯、聚氧乙烯氢化蓖麻油RH40、EL 35、卵磷脂、酸酯聚乙二醇-15-羟基硬脂酸酯、聚乙二醇的至少一种。
  8. 根据权利要求3所述的制剂，其中所述缓冲剂包含选自一水磷酸二氢钠、磷酸氢二钠、乙酸、柠檬酸、柠檬酸钠、琥珀酸、己二酸、酒石酸、抗坏血酸、苯甲酸、苹果酸的至少一种。
  9. 根据权利要求3所述的制剂，其中所述pH调节剂选自酸性pH调节剂或者碱性pH调节剂，所述酸性pH调节剂包含选自盐酸、乙酸、磷酸的至少一种，所述碱性pH调节剂选自包含氢氧化钠、磷酸氢钠、碳酸钙、氢氧化镁的至少一种。
  10. 根据权利要求1所述的制剂，其包括：
    (a)氢溴酸沃替西汀，浓度范围为60.0mg/mL-350.0mg/mL，
    (b)稳定剂吐温80，
    (c)助悬剂羧甲基纤维素钠，
    (d)缓冲剂一水磷酸二氢钠，
    并任选地包含pH调节剂氢氧化钠。
  11. 根据权利要求1所述的制剂，所述氢溴酸沃替西汀的D[4,3]为0.05微米-20.0微米，或者0.1微米-10.0微米。
  12. 根据权利要求1所述的制剂，其在注射后，在至少2周的时间期间持续释放氢溴酸沃替西汀。
  13. 根据权利要求1所述的制剂，其为即用型液体注射剂或冻干制剂。
  14. 根据权利要求13所述的制剂，其中所述冻干制剂是饼块的形式。
  15. 制备如权利要求3-10任一所述制剂的方法，包括下列步骤：
    (a)将稳定剂，任选的，和缓冲剂依次溶解于水中，
    (b)任选地，加入助悬剂至上述溶液中，搅拌至完全溶解，
    (c)加入氢溴酸沃替西汀，得混悬液，任选地，用pH调节剂调节pH值为6.0至7.0，定容，
    (d)将上述混悬液用球磨机研磨，得最终混悬液。
  16. 根据权利要求15所述的方法，其还包括制备成冻干制剂的步骤，所述步骤包括：将所述最终混悬液冷冻干燥。
  17. 一种权利要求1-14任一所述的制剂在制备用于治疗重度抑郁症药物中的用途。
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