CN109922806B - Vortioxetine hydrobromide long-acting injection preparation - Google Patents
Vortioxetine hydrobromide long-acting injection preparation Download PDFInfo
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- CN109922806B CN109922806B CN201780066679.6A CN201780066679A CN109922806B CN 109922806 B CN109922806 B CN 109922806B CN 201780066679 A CN201780066679 A CN 201780066679A CN 109922806 B CN109922806 B CN 109922806B
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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
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- 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
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- 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
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- 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
Abstract
The invention relates to a vortioxetine hydrobromide long-acting injection preparation. The preparation comprises vortioxetine hydrobromide, a suspending agent, a stabilizer, a buffering agent, a pH regulator and a solvent, can be a ready-to-use liquid injection or a freeze-dried powder injection, has an obvious sustained-release effect after injection, can reduce administration times, prolong the action time of the medicine, improve the compliance of patients and improve the bioavailability. Meanwhile, the invention also provides a method for preparing the vortioxetine hydrobromide long-acting injection preparation, which is simple and economic and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of medicinal preparations, in particular to a vortioxetine hydrobromide long-acting injection preparation.
Background
Depression, also known as depressive disorder, is characterized clinically by a marked and persistent depression in the mood, the main type of mood disorder. Clinically, there are depressed mood, depression, and even pessimistic and boredom, suicide attempts or behaviors. In most cases, there is a tendency for recurrent episodes, with most of each episode remitting and some remaining symptoms or becoming chronic. Worldwide, the population affected by some form of depression accounts for 25% of all women, 10% of all men, and 5% of all teenagers. The cause of depression is not clear, at present, antidepressant has become the first treatment means for depression patients, and the selective serotonin (5-HT) reuptake inhibitor is mainly used clinically, so that the application is most extensive.
Vortioxetine is a new drug marketed in 2013, mainly used for the treatment of major depression (MDD), the mechanism of action of which is not completely clear, but is generally considered to be related to 5-HT re-extraction inhibition, and is the first antidepressant drug with dual mechanisms of action including 5-HT receptor activation and reabsorption inhibition. The composition has safety data that are not inferior or superior to SSRIs (5-hydroxytryptamine reuptake inhibitors) and SNRIs (5-hydroxytryptamine and norepinephrine reuptake inhibitors), and better body weight control data. Vortioxetine is superior to agomelatine for patients who do not respond fully to SSRI/SNRI. The effect of treating depression is similar to duloxetine, and is better than venlafaxine and agomelatine, the safety is good, the effect is better than vilazodone, the risk of juvenile suicide tendency is increased, but the effectiveness and safety of vortioxetine are better than those of traditional SSRIs on the whole. Currently, vortioxetine only has different specifications of vortioxetine hydrobromide tablets for oral administration, the blood concentration of the vortioxetine tablet is short in maintenance time, the vortioxetine tablet needs to be administered every day (once a day), the frequent administration is needed, the non-compliance of a patient is increased, and the self-administration is difficult due to the mood fluctuation of the patient and the influence of other symptoms, so that the treatment failure is often caused.
No long-acting injection of vortioxetine and salts thereof is currently on the market, and studies on parenteral administration preparations of vortioxetine and salts thereof are lacking in the prior art.
Disclosure of Invention
Summary of The Invention
The invention provides a vortioxetine hydrobromide long-acting injection preparation, which has higher concentration and controllable particle size, can obtain higher dosage of a drug in a limited injection volume, and achieves the effect of long-acting drug release by controlling particle size distribution.
The invention provides a preparation method of the vortioxetine hydrobromide long-acting injection preparation, which is simple and easy to implement, good in stability, high in safety and suitable for industrial production.
The invention provides an application of a vortioxetine hydrobromide long-acting injection preparation in preparation of a drug for treating major depression.
Definition of terms
The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. There may be differences below 10% in the value of each number or reasonably considered by those skilled in the art, such as differences of 1%, 2%, 3%, 4% or 5%.
The term "D [4,3 ]" refers to a volume weighted average as determined using a Malvern Mastersizer 2000 laser particle sizer.
The term "Dv 10" refers to the particle size corresponding to a cumulative percent particle size distribution for a sample of 10%, the term "Dv 50" refers to the particle size corresponding to a cumulative percent particle size distribution for a sample of 50%, and the term "Dv 90" refers to the particle size corresponding to a cumulative percent particle size distribution for a sample of 90%.
LC/MS/MS refers to liquid chromatography-mass spectrometry.
The term "sustained release" refers to the detection of the blood concentration of vortioxetine hydrobromide by using an LC/MS/MS analytical instrument to detect the sample according to the detection limit.
TPGS refers to polyethylene glycol 1000 vitamin E succinate, EL35 to polyoxyethylene (35) castor oil.
The concentration "mg/mL" refers to mg/mL, as weight/volume, which is the volume of the suspension.
μ m means micron, μ L means microliter, L means liter, mm means millimeter, mL means milliliter, nm means nanometer, ng means nanogram, kg means kilogram, min means minute, d means days, Hz means hertz, g means gram, qs. means add up to mbar, V means volt, deg.c means celsius.
Detailed Description
Based on the defects of the prior art, the invention prepares the long-acting injection containing the vortioxetine hydrobromide medicament through deep research and research, the preparation can be in the form of suspension, and also can be in the form of freeze-dried powder, the former can be directly used, and the latter can be mixed with matched sterile water for injection to prepare suspension for use, and the preparation adopts an intramuscular injection or subcutaneous injection mode, compared with an oral vortioxetine tablet, the invention has the advantages that:
(1) the vortioxetine hydrobromide exists in insoluble particles with low solubility, can slowly and continuously release the medicament after injection, can obviously reduce administration times, and avoid peak-valley fluctuation, thereby improving the treatment compliance and safety of patients;
(2) the preparation has high drug loading rate, and can achieve sustained release for at least 2 weeks or longer;
(3) the vortioxetine hydrobromide in the suspension has small particle size, uniform distribution and good injectability, and is beneficial to improving the bioavailability.
The suspension or the freeze-dried preparation obtained by the invention has good stability and is beneficial to storage and transportation.
The invention provides a vortioxetine hydrobromide injection preparation which is high in drug-loading rate, wherein the concentration range of the vortioxetine hydrobromide is 40.0mg/mL-400.0 mg/mL. In some embodiments, the concentration of vortioxetine hydrobromide is 60.0mg/mL to 350.0 mg/mL. In some embodiments, the concentration of vortioxetine hydrobromide is 50.0mg/mL to 200.0 mg/mL; in some embodiments, the concentration of vortioxetine hydrobromide is 60.0mg/mL to 150.0 mg/mL; in some embodiments, the concentration of vortioxetine hydrobromide is 150.0mg/mL to 200.0 mg/mL; in some embodiments, the concentration of vortioxetine hydrobromide is 150.0mg/mL to 300.0 mg/mL; in some embodiments, the concentration of vortioxetine hydrobromide is 200.0mg/mL to 300.0 mg/mL; in some embodiments, the concentration of vortioxetine hydrobromide is 50.0mg/mL to 300.0 mg/mL; in some embodiments, the concentration of vortioxetine hydrobromide is 300.0mg/mL to 350.0 mg/mL. In some embodiments, the concentration of vortioxetine hydrobromide is 63mg/mL, 150.0mg/mL, 190.2mg/mL, 300.0mg/mL, or 380.0 mg/mL.
The vortioxetine hydrobromide injection preparation comprises a stabilizer.
In some embodiments, an injectable formulation of vortioxetine hydrobromide comprises a stabilizer and a suspending agent.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises a stabilizer, and/or a suspending agent, and/or a buffer, and/or a pH adjusting agent.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises a stabilizer, a suspending agent, a buffer, and a pH adjusting agent.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises a stabilizer, a buffer, and a pH adjusting agent.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises a stabilizing agent, a suspending agent, and a pH adjusting agent.
In some embodiments, the vortioxetine hydrobromide injection formulation comprises a stabilizer, a buffer.
In some embodiments, the vortioxetine hydrobromide injection preparation comprises a stabilizer and a pH regulator.
In some embodiments, the vortioxetine hydrobromide injection formulation comprises a stabilizer, a suspending agent, and a buffer.
The concentration range of the stabilizer is 0.1mg/mL-60.0 mg/mL. In some embodiments, the stabilizer is present in a concentration range of 1.0mg/mL to 40.0mg/mL, or 0.01mg/mL to 20.0mg/mL, or 0.1mg/mL to 10.0mg/mL, or 5.0mg/mL to 55.0mg/mL, or 1.0mg/mL to 5.0mg/mL, or 5.0mg/mL to 10.0mg/mL, or 5.0mg/mL to 20.0mg/mL, or 5.0mg/mL to 40.0mg/mL, or 10.0mg/mL to 20.0mg/mL, or 10.0mg/mL to 40.0mg/mL, or 20.0mg/mL to 40.0mg/mL, or 40.0mg/mL to 50.0 mg/mL. In some embodiments, the concentration of the stabilizing agent ranges from 5.0mg/mL to 55.0 mg/mL. In some embodiments, the concentration of the stabilizing agent is 4.0mg/mL, 6.0mg/mL, 10.0mg/mL, 18.0mg/mL, 20.0mg/mL, 40.0mg/mL, or 50.0 mg/mL. In some embodiments, the concentration of the stabilizing agent is about 53.5 mg/mL.
The stabilizer comprises at least one selected from Tween 20, Tween 60, Tween 80, span 20, poloxamer 188, polyethylene glycol 1000 vitamin E succinate, polyoxyethylene hydrogenated castor oil RH40, EL35, lecithin, acid ester polyethylene glycol-15-hydroxystearate and polyethylene glycol. In some embodiments, the stabilizer is tween 20, tween 80, TPGS, EL35, or a combination of tween 20 and span 20.
The concentration range of the suspending agent is 0.1mg/mL-20.0mg/mL, or 0.1mg/mL-5.0mg/mL, or 0.2mg/mL-2.0mg/mL, or 0.5mg/mL-5.0mg/mL, or 1.0mg/mL-5.0mg/mL, or 2.0mg/mL-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 0.5mg/mL, 1.0mg/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 sodium carboxymethylcellulose, gelatin, polyvinylpyrrolidone, methylcellulose, and acacia. In some embodiments, the suspending agent is sodium carboxymethyl cellulose. The buffer comprises at least one selected from the group consisting of sodium dihydrogen phosphate 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 regulator is selected from an acidic pH regulator or an alkaline pH regulator, the acidic pH regulator is selected from at least one of hydrochloric acid, acetic acid and phosphoric acid, and the alkaline pH regulator is selected from at least one of sodium hydroxide, sodium hydrogen phosphate, calcium carbonate and magnesium hydroxide. In some embodiments, the pH adjusting agent is sodium hydroxide.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises:
(a) vortioxetine hydrobromide at a concentration range of 60.0mg/mL to 350.0mg/mL,
(b) the stabilizing agent Tween 80 is added into the mixture,
(c) the suspending agent is sodium carboxymethyl cellulose as a suspending agent,
(d) the buffering agent is sodium dihydrogen phosphate monohydrate, and the buffering agent is sodium dihydrogen phosphate monohydrate,
and optionally sodium hydroxide as a pH adjuster.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises:
(a) vortioxetine hydrobromide at a concentration of 190.2mg/mL,
(b) tween 80 as stabilizer in the concentration of 10.0mg/mL,
(c) sodium carboxymethylcellulose as suspending agent with concentration of 0.5mg/mL,
(d) buffering agent sodium dihydrogen phosphate monohydrate;
sodium hydroxide, a pH adjuster, is optionally included to adjust the pH to 6.0 to 7.0.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises:
(a) vortioxetine hydrobromide at a concentration of 190.2mg/mL,
(b) tween 80 as stabilizer in the concentration of 10.0mg/mL,
(c) sodium carboxymethylcellulose as suspending agent with concentration of 1.0mg/mL,
(d) buffering agent sodium dihydrogen phosphate monohydrate;
sodium hydroxide, a pH adjuster, is optionally included to adjust the pH to 6.0 to 7.0.
In one specific example, a vortioxetine hydrobromide injection formulation comprises:
(a) vortioxetine hydrobromide at a concentration of 150.0mg/mL,
(b) tween 80 as stabilizer in the concentration of 40.0mg/mL,
(c) sodium carboxymethylcellulose as suspending agent at a concentration of about 0.53mg/mL,
(d) the buffering agent is sodium dihydrogen phosphate monohydrate, and the buffering agent is sodium dihydrogen phosphate monohydrate,
sodium hydroxide, a pH adjuster, is optionally included to adjust the pH to 6.0 to 7.0.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises:
(a) vortioxetine hydrobromide at a concentration of 50mg/mL,
(b) tween 20 as stabilizer in the concentration of 50.0mg/mL,
(c) sodium carboxymethylcellulose as suspending agent with concentration of 2.0mg/mL,
(d) buffering agent sodium dihydrogen phosphate monohydrate;
sodium hydroxide, a pH adjuster, is optionally included to adjust the pH to 6.0 to 7.0.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises:
(a) vortioxetine hydrobromide at a concentration of 60mg/mL,
(b) stabilizer EL35, concentration 20.0mg/mL,
(c) sodium carboxymethylcellulose as suspending agent with concentration of 0.5mg/mL,
(d) buffering agent sodium dihydrogen phosphate monohydrate;
sodium hydroxide, a pH adjuster, is optionally included to adjust the pH to 6.0 to 7.0.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises:
(a) vortioxetine hydrobromide at a concentration of 300.0mg/mL,
(b) the concentration of the stabilizer TPGS is 5.0mg/mL,
(c) sodium carboxymethylcellulose as suspending agent with concentration of 5.0mg/mL,
(d) buffering agent sodium dihydrogen phosphate monohydrate;
sodium hydroxide, a pH adjuster, is optionally included to adjust the pH to 6.0 to 7.0.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises:
(a) vortioxetine hydrobromide at a concentration of 200.0mg/mL,
(b) tween 80 as stabilizer in the concentration of 10.0mg/mL,
(c) sodium carboxymethylcellulose as suspending agent with concentration of 0.5mg/mL,
(d) buffering agent sodium dihydrogen phosphate monohydrate;
sodium hydroxide, a pH adjuster, is optionally included to adjust the pH to 6.0 to 7.0.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises:
(a) vortioxetine hydrobromide at a concentration of 200.0mg/mL,
(b) tween 20 as stabilizer in the concentration of 10.0mg/mL,
(c) sodium carboxymethylcellulose as suspending agent with concentration of 0.5mg/mL,
(d) buffering agent sodium dihydrogen phosphate monohydrate;
sodium hydroxide, a pH adjuster, is optionally included to adjust the pH to 6.0 to 7.0.
In some embodiments, a vortioxetine hydrobromide injection formulation comprises:
(a) vortioxetine hydrobromide at a concentration of 200.0mg/mL,
(b) stabilizer EL35, concentration 10.0mg/mL,
(c) sodium carboxymethylcellulose as suspending agent with concentration of 0.5mg/mL,
(d) buffering agent sodium dihydrogen phosphate monohydrate;
sodium hydroxide, a pH adjuster, is optionally included to adjust the pH to 6.0 to 7.0.
The vortioxetine hydrobromide injection preparation, wherein the D [4,3] range of the vortioxetine hydrobromide is 0.05 micron to 20.0 micron, or 0.1 micron to 10.0 micron, or 1.0 micron to 10.0 micron, or 0.5 micron to 15 micron, or 0.1 micron to 1.0 micron, or 10.0 micron to 15.0 micron, or 15.0 micron to 20.0 micron. In some embodiments, said vortioxetine hydrobromide has a D [4,3] in the range of 1.0 micron to 10.0 microns.
The vortioxetine hydrobromide injection preparation disclosed by the invention can continuously release vortioxetine hydrobromide in a period of at least 2 weeks after injection.
The vortioxetine hydrobromide injection formulation of the present invention, which may be in the form of a suspension, has a D [4,3] of vortioxetine hydrobromide present in the suspension in the range of 0.05 microns to 20.0 microns, and releases vortioxetine hydrobromide continuously over a period of at least 2 weeks, up to 4 weeks, or longer, e.g. up to 6 weeks.
The vortioxetine hydrobromide injection formulation of the present invention, which can be in the form of a suspension, is present in the suspension at a concentration ranging from 40.0mg/mL to 400.0mg/mL, and releases vortioxetine hydrobromide continuously over a period of at least 2 weeks, up to 4 weeks, or longer, e.g. up to 6 weeks.
The vortioxetine hydrobromide injection preparation can be a ready-to-use liquid injection or a freeze-dried preparation. In some embodiments, a ready-to-use liquid injection, and in some embodiments, a lyophilized powder injection.
In some embodiments, the vortioxetine hydrobromide injection formulation is a lyophilized formulation, which is in the form of a cake.
In another aspect, the present invention provides a method for preparing any one of the vortioxetine hydrobromide injectable formulations described above. A method for preparing vortioxetine hydrobromide injection preparation, comprising the following steps:
(a) respectively dissolving the stabilizer, the optional stabilizer and the buffering agent in water in turn,
(b) optionally, adding suspending agent into the above solution, stirring to dissolve completely,
(c) adding vortioxetine hydrobromide to obtain suspension, optionally adjusting pH to 6.0-7.0 with pH regulator, metering volume,
(d) and grinding the suspension by using a ball mill to obtain the final suspension.
In some embodiments, a method of preparing an injectable formulation of vortioxetine hydrobromide comprises the steps of:
(a) dissolving Tween 20 and sodium dihydrogen phosphate monohydrate in water in turn,
(b) adding sodium carboxymethylcellulose in the prescribed amount into the solution, stirring until the sodium carboxymethylcellulose is completely dissolved,
(c) adding vortioxetine hydrobromide to obtain suspension, adjusting pH to 6.0-7.0 with sodium hydroxide, diluting to constant volume,
(d) and (3) grinding the suspension by using a planetary ball mill to obtain the final suspension.
The invention relates to a method for preparing vortioxetine hydrobromide injection, which adopts a wet grinding technology, wherein the grinding beads are made of zirconium oxide with good compatibility.
A method for preparing vortioxetine hydrobromide injection preparation can further comprise a step of preparing into a lyophilized preparation, wherein the step of preparing into the lyophilized preparation comprises the following steps: the final suspension was freeze dried. In some embodiments, the freeze-drying comprises freeze-drying the final suspension by cooling the final suspension to below-30 ℃ and drying the cooled final suspension below 0 ℃; in some embodiments, the final suspension freeze-drying is performed in three stages:
(l) A prefreezing stage comprising cooling the final suspension at-45 ℃,
(2) a preliminary drying stage of drying the cooled final suspension at a temperature below 0 ℃, and
(3) and a secondary drying stage, drying the cooled final suspension at a temperature higher than 0 ℃, thereby obtaining the vortioxetine hydrobromide freeze-dried preparation.
The lyophilized vortioxetine hydrobromide formulation, upon mixing with water, forms an injection in the form of a suspension, wherein the D [4,3] of vortioxetine hydrobromide present in the suspension ranges from 0.05 microns to 20.0 microns, said formulation upon injection releasing vortioxetine hydrobromide continuously over a period of at least 2 weeks, up to 4 weeks, or longer, e.g. up to 6 weeks.
The lyophilized vortioxetine hydrobromide formulation, when mixed with water, forms an injection in the form of a suspension, wherein the vortioxetine hydrobromide concentration present in the suspension ranges from 40.0mg/mL to 400.0mg/mL, and wherein the release of vortioxetine hydrobromide is sustained for a period of at least 2 weeks, up to 4 weeks, or longer, e.g. up to 6 weeks, after injection.
The invention also provides application of the vortioxetine bromide injection preparation in preparation of a medicine for treating major depression.
Use of vortioxetine bromide injection preparation for the preparation of a medicament for the treatment of major depression, which can be injected intramuscularly or subcutaneously.
Drawings
Figure 1 is a graph depicting mean plasma concentrations of vortioxetine versus time following injection of the formulation of example 9 of the present invention (prescription nos. 01, 02, 03 of example 9) in rats.
Detailed Description
Example 1: preparation of vortioxetine hydrobromide suspensions of different concentrations
A prescription table:
the preparation process comprises the following steps:
(1) dissolving Tween 20 and sodium dihydrogen phosphate monohydrate in purified water of 60% of the total preparation amount in sequence;
(2) adding the sodium carboxymethylcellulose with the prescription amount into the solution, and stirring until the sodium carboxymethylcellulose is completely dissolved;
(3) slowly adding vortioxetine hydrobromide in a prescribed amount while stirring to obtain vortioxetine suspension, adjusting the pH value to 6.0-7.0 by using sodium hydroxide, and fixing the volume;
(4) grinding the suspension by using a ball mill;
(5) and (3) measuring the particle size distribution of the ground suspension by using a Malvern Mastersizer 2000 particle size tester, detecting the content and related substances, placing under an accelerating condition, and inspecting the stability.
The experimental results are as follows: 04 sample was substantially free flowing, relatively viscous and non-syringeable, so the formulation was not investigated further. The remaining prescription samples are shown in tables 1-1 and 1-2.
TABLE 1-1 Woltixiding hydrobromide particle size in suspension after milling (unit: μm)
Vortioxetine hydrobromide suspension particle size detection instrument parameters (example general):
the measurements were repeated three times and an average value was created.
According to the experimental results, the D4, 3 of the suspension with the concentration of 63mg/mL and 380mg/mL can be obtained between 1.0 and 10.0 microns after grinding, and the injectability of the suspension is good.
TABLE 1-2 suspension 40 ℃ stability Studies
According to the experimental result, suspension with the concentration of 63mg/mL and 380mg/mL does not introduce process impurities after grinding; and after the mixture is placed under the accelerated condition for 30 (or 35) days, the content and related substances are not obviously changed.
Vortioxetine hydrobromide content and related substance methods (general examples)
Chromatographic conditions are as follows:
high performance liquid chromatograph (Agilent HPLC-DAD)
A chromatographic column: symmethyyseld RPC18, 150 mm. times.4.6 mm, 3.5 μm
A detector: UV detector, detecting flow rate at wavelength 230 nm: 1.0ml/min
Mobile phase A: 0.05% trifluoroacetic acid mobile phase B: acetonitrile
Diluent agent: water acetonitrile 80:20 column temperature: 35 deg.C
The relevant substance gradient elution conditions were as follows, with a run time of 70min and a sample size of 20. mu.l:
the content gradient elution conditions were as follows, run time 40min, sample size 10. mu.l:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 30 | 60 | 40 |
| 30.1 | 80 | 20 |
| 40 | 80 | 20 |
Example 2: preparation of vortioxetine hydrobromide suspension with different formulations
A prescription table:
the preparation process comprises the following steps:
(1) sequentially dissolving or dispersing Tween 20, Tween 80, EL35, TPGS and span 80 and sodium dihydrogen phosphate monohydrate into purified water with the total preparation amount of about 60%;
(2) adding the sodium carboxymethylcellulose with the prescription amount into the solution, and stirring until the sodium carboxymethylcellulose is completely dissolved;
(3) slowly adding vortioxetine hydrobromide in a prescribed amount while stirring to obtain vortioxetine suspension, adjusting the pH value to 6.0-7.0 by using sodium hydroxide, and fixing the volume;
(4) grinding the suspension by using a ball mill;
(5) and (3) measuring the particle size distribution of the ground suspension by using a Malvern Mastersizer 2000 particle size tester, detecting the content and related substances, placing under an accelerating condition, and inspecting the stability.
The experimental results are as follows: when span 80 is used as a stabilizer, a large amount of API is precipitated after grinding, and stable suspension cannot be obtained, so that the formula is not suitable for further research. The results for the remaining samples are shown in tables 2-1 and 2-2.
TABLE 2-1 Vortioxetine hydrobromide particle size (unit: μm) in batches of suspension after milling
And (4) conclusion: the suspension with concentration of 190.2mg/mL, after grinding, different prescription (stabilizer) samples can obtain the suspension with D4, 3 between 1.0-10.0 microns, and after the suspension is placed under the accelerated condition for 20 days, the particle size has no obvious change.
TABLE 2-2 suspension 40 ℃ stability study
And (4) conclusion: the suspension with the concentration of 190.2mg/mL has stable content after being ground for samples of different formulas (stabilizing agents), and no process impurity is introduced, and the suspension has no obvious change after being placed at 40 ℃ for 35 days.
Example 3: preparation of vortioxetine hydrobromide freeze-dried preparations with different prescriptions
A prescription table:
the preparation process comprises the following steps:
(1) sequentially dissolving Tween 20, Tween 80, EL35, TPGS and sodium dihydrogen phosphate monohydrate into purified water with the total preparation amount of about 60 percent respectively;
(2) adding the sodium carboxymethylcellulose with the prescription amount into the solution, and stirring until the sodium carboxymethylcellulose is completely dissolved;
(3) slowly adding vortioxetine hydrobromide in a prescribed amount while stirring to obtain vortioxetine suspension, adjusting the pH value to 6.0-7.0 by using sodium hydroxide, and fixing the volume;
(4) grinding the suspension by using a ball mill;
(5) measuring the particle size distribution of the ground suspension by using a Malvern Mastersizer 2000 particle size tester, and detecting the content and related substances;
(6) filling the ground suspension into a 7ml penicillin bottle, wherein the filling amount is 2ml, performing freeze drying, measuring the particle size, content and related substances after freeze drying, placing under accelerated conditions, and investigating stability, wherein the freeze drying process is as shown in a table 3-1:
TABLE 3-1 Freeze drying Process
The experimental results are as follows: see tables 3-2 and 3-3.
TABLE 3-2 Vortioxetine hydrobromide particle size (unit: μm) in each suspension batch before and after lyophilization
And (4) conclusion: the suspension with concentration of 190.2mg/mL can obtain suspensions with D4, 3 of 1.0-10.0 microns in different prescription (stabilizer) samples after grinding, and the particle size does not change obviously before and after freeze-drying.
Table 3-3 change in content and related substances before and after lyophilization of suspensions
And (4) conclusion: the concentration of the suspension is 190.2mg/mL, and samples of different prescriptions (stabilizing agents) have no obvious change in content and related substances after freeze-drying.
Example 4: preparation of vortioxetine hydrobromide suspension with different particle sizes
A prescription table:
the preparation process comprises the following steps:
(1) respectively dissolving TPGS and sodium dihydrogen phosphate monohydrate in purified water with the total preparation amount of about 60 percent;
(2) adding the sodium carboxymethylcellulose with the prescription amount into the solution, and stirring until the sodium carboxymethylcellulose is completely dissolved;
(3) slowly adding vortioxetine hydrobromide in a prescribed amount while stirring to obtain vortioxetine suspension, adjusting the pH value to 6.0-7.0 by using sodium hydroxide, and fixing the volume;
(4) grinding the suspension by using a ball mill; (ii) a
(5) The particle size distribution of the suspension after grinding was determined using a Malvern Mastersizer 2000 particle size analyzer and the stability was investigated by placing under accelerated conditions.
The experimental results are as follows: see tables 4-1 and 4-2.
TABLE 4-1 Vortioxetine hydrobromide particle size (unit: μm) in batches of suspension after milling
TABLE 4-2 suspension day 0 content and related materials results
And (4) conclusion: the suspensions with the same prescription can be prepared into suspensions with different D4, 3 contents and related substances according with requirements by controlling grinding parameters (grinding bead proportion and grinding time).
Example 5: preparation of vortioxetine hydrobromide suspensions with different amounts of tween-20
A prescription table:
the preparation process comprises the following steps:
(1) dissolving Tween 20 and sodium dihydrogen phosphate monohydrate in purified water of 60% in sequence;
(2) adding the sodium carboxymethylcellulose with the prescription amount into the solution, and stirring until the sodium carboxymethylcellulose is completely dissolved;
(3) slowly adding vortioxetine hydrobromide in a prescribed amount while stirring to obtain vortioxetine suspension, adjusting the pH value to 6.0-7.0 by using sodium hydroxide, and fixing the volume;
(4) grinding the suspension by using a ball mill;
(5) the particle size distribution of the suspension after grinding was determined using a Malvern Mastersizer 2000 particle size analyzer and the stability was investigated by placing under accelerated conditions.
The experimental results are as follows: see Table 5-1.
TABLE 5-1 Vortioxetine hydrobromide particle size (unit: μm) in batches of suspension after milling
And (4) conclusion: the dosage of Tween-20 in the prescription is 6 mg/mL-40 mg/mL, after grinding, a suspension with D4, 3 of 1.0-10.0 microns can be obtained, and after the suspension is placed under an accelerated condition for 30 days, the particle size is not obviously changed.
Example 6: preparation of vortioxetine hydrobromide suspensions with different amounts of tween-80
A prescription table:
the preparation process comprises the following steps:
(1) dissolving Tween 80 and sodium dihydrogen phosphate monohydrate in purified water of 60% in sequence;
(2) adding the sodium carboxymethylcellulose with the prescription amount into the solution, and stirring until the sodium carboxymethylcellulose is completely dissolved;
(3) slowly adding vortioxetine hydrobromide in a prescribed amount while stirring to obtain vortioxetine suspension, adjusting the pH value to 6.0-7.0 by using sodium hydroxide, and fixing the volume;
(4) grinding the suspension by using a ball mill;
(5) the particle size distribution of the suspension after grinding was determined using a Malvern Mastersizer 2000 particle size analyzer and the stability was investigated by placing under accelerated conditions.
The experimental results are as follows: when the amount of Tween 80 is 2mg/ml, more AP is separated out after grinding, and stable suspension is difficult to prepare, so that the prescription is not subjected to further research, and the results of other batches are shown in tables 6-1 and 6-2.
TABLE 6-1 Vortioxetine hydrobromide particle size (unit: μm) in batches of suspension after milling
And (4) conclusion: the dosage of Tween-80 in the prescription is in the range of 4 mg/mL-40 mg/mL, and after grinding, a suspension with D4, 3 of 1.0-10.0 microns can be obtained, and after the suspension is placed under an accelerated condition for 30 days, the particle size is not obviously changed.
TABLE 6-2 Vortioxetine hydrobromide content and related substances in the suspensions of the respective batches after grinding
And (4) conclusion: the dosage of the Tween-80 in the prescription is in the range of 4mg/mL to 40mg/mL, the prepared suspension has good stability, and the content and related substances do not change obviously after the suspension is placed under the accelerated condition for 30 days. When tween 80 is used in an amount of 2mg/ml or even less, a stable suspension cannot be prepared.
Example 7: vortioxetine hydrobromide suspension preparation with different EL35 dosage
A prescription table:
the preparation process comprises the following steps:
(1) respectively dissolving EL35 and sodium dihydrogen phosphate monohydrate in purified water with the total preparation amount of about 60 percent;
(2) adding the sodium carboxymethylcellulose with the prescription amount into the solution, and stirring until the sodium carboxymethylcellulose is completely dissolved;
(3) slowly adding vortioxetine hydrobromide in a prescribed amount while stirring to obtain vortioxetine suspension, adjusting the pH value to 6.0-7.0 by using sodium hydroxide, and fixing the volume;
(4) grinding the suspension by using a ball mill;
(5) the particle size distribution of the suspension after grinding was determined using a Malvern Mastersizer 2000 particle size analyzer and the stability was investigated by placing under accelerated conditions.
The experimental results are as follows: at an EL35 dose of 2mg/ml, more API precipitated out after milling and it was difficult to prepare a stable suspension, so the formulation was not investigated further and the results for the remaining batches are shown in Table 7-1.
TABLE 7-1 Vortioxetine hydrobromide particle size (unit: μm) in batches of suspension after milling
And (4) conclusion: the dosage of EL-35 in the prescription is in the range of 4mg/mL to 40mg/mL, after grinding, a suspension with D4, 3 of 1.0-10.0 microns can be obtained, and after the suspension is placed under an accelerated condition for 30 days, the particle size is not obviously changed. When EL-35 was used at 2mg/ml or less, a stable suspension could not be prepared.
Example 8: preparation of vortioxetine hydrobromide suspensions at different TPGS dosages
A prescription table:
the preparation process comprises the following steps:
(1) respectively dissolving TPGS and sodium dihydrogen phosphate monohydrate in purified water with the total preparation amount of about 60%, and heating to dissolve;
(2) after cooling to room temperature, adding the sodium carboxymethylcellulose in the formula amount into the solution, and stirring until the sodium carboxymethylcellulose is completely dissolved;
(3) slowly adding vortioxetine hydrobromide in a prescribed amount while stirring to obtain vortioxetine suspension, adjusting the pH value to 6.0-7.0 by using sodium hydroxide, and fixing the volume;
(4) grinding the suspension by using a ball mill; (5) the particle size distribution of the suspension after grinding was determined using a Malvern Mastersizer 2000 particle size analyzer and the stability was investigated by placing under accelerated conditions.
The experimental results are as follows: see Table 8-1.
TABLE 8-1 Vortioxetine hydrobromide particle size (unit: μm) in batches of suspension after milling
And (4) conclusion: the TPGS dosage in the prescription is in the range of 10mg/mL to 40mg/mL, suspension with D4, 3 of 1.0-10.0 microns can be obtained after grinding, and the particle size is not obviously changed after the TPGS is placed under accelerated conditions for 30 days.
Example 9: pharmacokinetics research of vortioxetine hydrobromide long-acting injection in rat body
A prescription table:
the preparation process comprises the following steps:
(1) sequentially dissolving and dispersing Tween 20, TPGS and span 20-sodium dihydrogen phosphate monohydrate into purified water with the total preparation amount of about 60 percent respectively;
(2) adding the sodium carboxymethylcellulose with the prescription amount into the solution, and stirring until the sodium carboxymethylcellulose is completely dissolved;
(3) slowly adding vortioxetine hydrobromide in a prescribed amount while stirring to obtain vortioxetine suspension, adjusting the pH value to 6.0-7.0 by using sodium hydroxide, and fixing the volume;
(4) grinding the suspension by using a ball mill; (5) the particle size distribution of the suspension after grinding was determined using a Malvern Mastersizer 2000 particle size analyzer.
The experimental results are as follows: see Table 9-1.
TABLE 9-1 Vortioxetine hydrobromide particle size (unit: μm) in batches of suspension after milling
And (4) conclusion: the API concentration is 190.2mg/mL and 300mg/mL, and after grinding, different prescription (stabilizer) samples can obtain the suspension with D4, 3 being between 1.0 and 10.0 microns.
The rat experiments were performed with the different concentrations and prescriptions of example 9, as follows:
the LC/MS/MS system for analysis included an Agilent 1200 series vacuum degassing furnace, a binary injection pump, an orifice plate autosampler, a column oven, an Agilent G6430 three-stage quadrupole mass spectrometer with an electrospray ionization (ESI) source. The quantitative analysis was performed in MRM mode, with the parameters of the MRM transition as shown in table a:
TABLE A
| Multiple reaction detection scan | 299.1→150 |
| Fragmentation voltage | 25V |
| Capillary voltage | 4000V |
| Dryer temperature | 350℃ |
| Atomizer | 40psi |
| Flow rate of dryer | 9L/min |
Analysis 15. mu.L of sample was injected using a Waters Xbridge C18, 2.1X 50mm, 2.7. mu.M column. Analysis conditions were as follows: the mobile phase was 2mM ammonium formate + 0.1% formic acid (a) and methanol +2mM ammonium formate + 0.1% formic acid (B). The flow rate was 0.3 mL/min. Mobile phase gradients are shown in table B:
TABLE B
The present inventors evaluated the pharmacokinetic studies of samples No. 01, 02 and 03 of example 9 in rats. The vortioxetine suspension formulation (30mg/kg or 47.2mg/kg) was administered to animals by intramuscular injection. Whole blood was collected at 0.25h, 1h, 2h, 5h, 7h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 216h, 288h, 336h, 408h and 504h before and after administration, and plasma was separated and frozen for testing. And centrifuged at 12,000 rpm for 2 minutes. Plasma was collected and stored at-20 ℃ or-70 ℃ until the LC/MS/MS analysis described above was performed. Table 9-2 lists the pharmacokinetic data in rats for 3 samples from example 9. The compound has good pharmacokinetic property and shows different slow release trends compared with a solution. Including an ideal time to peak (T)max) Half life (T)1/2) And exposure (AUC)last) The absorption and release curve is more gentle compared with the solution, T1/2Between 95 h and 134h, the blood concentration of vortioxetine can be basically maintained above the detection limit at 504 h. The in vivo average drug delivery profile of the formulation of example 9 of the present invention following intramuscular injection in rats is shown in figure 1 of the specification.
Table 9-2: pharmacokinetic data of Compounds in rats
Example 10: preparation of vortioxetine hydrobromide suspensions with different amounts of sodium carboxymethyl cellulose
A prescription table:
the preparation process comprises the following steps:
(1) dissolving Tween 80 and sodium dihydrogen phosphate monohydrate in purified water of 60% in sequence;
(2) adding the sodium carboxymethylcellulose with the prescription amount into the solution, and stirring until the sodium carboxymethylcellulose is completely dissolved;
(3) slowly adding vortioxetine hydrobromide in a prescribed amount while stirring to obtain vortioxetine suspension, adjusting the pH value to 6.0-7.0 by using sodium hydroxide, and fixing the volume;
(4) grinding the suspension by using a ball mill; (5) the particle size distribution of the suspension after grinding was determined using a Malvern Mastersizer 2000 particle size analyzer and the stability was investigated by placing under accelerated conditions.
The experimental results are as follows: when the amount of the sodium carboxymethylcellulose is 10mg/ml, after grinding, the sample generates obvious bubbles and is viscous, and the suspension has no injectability, so that the prescription is not subjected to further research. The results of the remaining formulations are shown in Table 10-1.
TABLE 10-1 Vortioxetine hydrobromide particle size (unit: μm) in batches of suspension after milling
And (4) conclusion: the carboxymethyl cellulose dosage in the prescription is in the range of 0.5mg/mL to 5mg/mL, and after grinding, a suspension with D4, 3 of 1.0-10.0 microns can be obtained. When the amount of carboxymethylcellulose exceeds 10.0mg/mL, injectable suspensions cannot be prepared.
Example 11: preparation of vortioxetine hydrobromide suspensions with different suspending agents
A prescription table:
the preparation process comprises the following steps:
(1) dissolving Tween 80 and sodium dihydrogen phosphate monohydrate in purified water of 60% in sequence;
(2) adding the sodium carboxymethylcellulose and the hydroxypropyl methylcellulose in the formula amount into the solution, and stirring until the sodium carboxymethylcellulose and the hydroxypropyl methylcellulose are completely dissolved;
(3) slowly adding vortioxetine hydrobromide in a prescribed amount while stirring to obtain vortioxetine suspension, adjusting the pH value to 6.0-7.0 by using sodium hydroxide, and fixing the volume;
(4) grinding the suspension by using a ball mill;
(5) the particle size distribution of the suspension after grinding was determined using a Malvern Mastersizer 2000 particle size analyzer.
The experimental results are as follows: when hypromellose is used as a suspending agent, after grinding, the sample generates obvious bubbles and has no fluidity, and the suspension has no injectability, so the prescription is not subjected to further research. The results of the remaining formulations are shown in Table 11-1.
TABLE 11-1 Woltixiding hydrobromide particle size in suspension after milling (unit: μm)
And (4) conclusion: sodium carboxymethylcellulose is selected as suspending agent, and after grinding, a suspension with D4, 3 of 1.0-10.0 microns can be obtained. Hydroxypropyl methylcellulose is used as a suspending agent, and injectable suspensions cannot be prepared.
In the description of the present specification, reference to the terms "some embodiments," "one specific example," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. The vortioxetine hydrobromide injection preparation is characterized in that the concentration range of the vortioxetine hydrobromide is 150.0mg/mL-300.0 mg/mL; the particle size D [4,3] of the vortioxetine hydrobromide is 1.0-10.0 microns; the formulation further comprises a stabilizer in a concentration range of 5.0mg/mL to 20.0mg/mL, the stabilizer selected from tween 20, tween 80, macrogol 1000 vitamin E succinate, or polyoxyethylene (35) castor oil; the preparation further comprises a suspending agent, wherein the concentration range of the suspending agent is 0.2mg/mL-2.0mg/mL, and the suspending agent is sodium carboxymethylcellulose.
2. The formulation of claim 1, wherein the buffering agent is selected from at least one of monobasic sodium phosphate monohydrate, dibasic sodium phosphate, citric acid, sodium citrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid, malic acid.
3. The formulation of claim 1, wherein the pH adjusting agent is selected from at least one of an acidic pH adjusting agent selected from at least one of hydrochloric acid, acetic acid, phosphoric acid, or a basic pH adjusting agent selected from at least one of sodium hydroxide, sodium hydrogen phosphate, calcium carbonate, magnesium hydroxide.
4. The formulation of claim 1, comprising:
(a) the stabilizing agent Tween 80 is added into the mixture,
(b) the suspending agent is sodium carboxymethyl cellulose as a suspending agent,
(c) the buffering agent is sodium dihydrogen phosphate monohydrate, and the buffering agent is sodium dihydrogen phosphate monohydrate,
and optionally sodium hydroxide as a pH adjuster.
5. The formulation of claim 1, which upon injection, releases vortioxetine hydrobromide continuously over a period of at least 2 weeks.
6. The formulation of claim 1, which is a ready-to-use liquid injection or a lyophilized formulation.
7. The formulation of claim 6, wherein the lyophilized formulation is in the form of a cake.
8. A process for preparing a formulation as claimed in any one of claims 1 to 7, comprising the steps of:
(a) the stabilizer, optionally, and the buffering agent are dissolved in water in sequence,
(b) adding suspending agent into the above solution, stirring to dissolve completely,
(c) adding vortioxetine hydrobromide to obtain suspension, optionally adjusting pH to 6.0-7.0 with pH regulator, metering volume,
(d) and grinding the suspension by using a ball mill to obtain the final suspension.
9. The method of claim 8, further comprising the step of preparing a lyophilized formulation comprising: the final suspension was freeze dried.
10. Use of a formulation according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of major depressive disorder.
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