CN115052601B - Composition of piperazine drugs - Google Patents
Composition of piperazine drugs Download PDFInfo
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- CN115052601B CN115052601B CN202180009518.XA CN202180009518A CN115052601B CN 115052601 B CN115052601 B CN 115052601B CN 202180009518 A CN202180009518 A CN 202180009518A CN 115052601 B CN115052601 B CN 115052601B
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- 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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Abstract
A composition of piperazine drugs is Vothiocetin or salts thereof, the composition contains active ingredients and wetting agent, and is a ready-to-use liquid injection.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a composition of piperazine drugs and a preparation method thereof.
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, antidepressants become the first treatment means for depression patients, and the selective 5-hydroxytryptamine reuptake inhibitor (SSRI) is mainly used clinically and is most widely applied.
Vortioxetine (Invitrostatin), chemically 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl ] -piperazinyl, having the following chemical formula:
vortioxetine is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), has similar effect on treating depression to duloxetine, is superior to venlafaxine and agomelatine, has good safety, is suitable for patients with liver and kidney injury, has superior effect to vilazodone, and is superior to the traditional SSRI in the aspects of effectiveness and safety. Currently, the vortioxetine is only orally administered hydrobromic acid vortioxetine tablets with different specifications to be marketed, the blood concentration of the dosage form is short in maintenance time, the dosage form needs to be administered every day (once a day), the non-compliance of a patient is increased due to frequent administration, 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.
Currently, no long-acting injection of vortioxetine and salts thereof is available on the market, and researches on parenteral administration preparations of vortioxetine and salts thereof are lacked in the prior art.
Disclosure of Invention
Summary of The Invention
The invention provides a vortioxetine injection, which has higher concentration of active ingredients and controllable particle size, can obtain higher dosage of the drug in a limited injection volume, and achieves the effect of long-acting drug release by controlling particle size distribution and the like, and after the injection, the preparation can continuously release vortioxetine in the time period of at least 2 weeks, thereby bringing new drug selection to special people who are not suitable for oral administration, and the vortioxetine injection can be administered once in two weeks or more, thereby increasing the compliance of patients. According to the known technical personnel in the field, the more types of auxiliary materials are added into the injection, the greater the introduced risk, but the valacitretin injection provided by the invention has a simple prescription, only needs to add fewer types of auxiliary materials, and can reduce the risk brought by the auxiliary materials. The vortioxetine injection provided by the invention can be a ready-to-use injection, can be directly used, and avoids pollution and safety risks caused by misoperation during redissolution. The injection provided by the invention has good storage stability and is stable after being placed for 6 months under an accelerated condition.
The second aspect of the invention provides a preparation method of the Vortictin injection, which is simple and easy to implement, good in stability, high in safety and suitable for industrial production.
The invention provides application of the vortioxetine injection in preparation of a medicine for treating major depressive disorder.
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 present invention, "optionally" or "optional" means that there may or may not be present, as "optionally comprising a suspending agent" means: a suspending agent may or may not be included.
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. The numerical value of each figure may vary by less than 10% or as reasonably understood by one skilled in the art, such as by 1%, 2%, 3%, 4%, or 5%.
The term "D [4,3] refers to the volume weighted average as determined using a Malvern Mastersizer 2000 laser particle sizer.
The term "Dv10" refers to the particle size corresponding to a cumulative percent particle size volume distribution for a sample of 10%, the term "Dv50" refers to the particle size corresponding to a cumulative percent particle size volume distribution for a sample of 50%, the term "Dv90" refers to the particle size corresponding to a cumulative percent particle size volume distribution for a sample of 90%, and the term "Dv99" refers to the particle size corresponding to a cumulative percent particle size volume distribution for a sample of 99%.
LC/MS/MS refers to liquid chromatography-mass spectrometry.
The term "sustained release" refers to the detection of a sample by an LC/MS/MS analytical instrument, and the blood concentration of vortioxetine can be detected according to the detection limit.
TPGS refers to polyethylene glycol 1000 vitamin E succinate and RH40 to polyoxyethylene hydrogenated (40) castor oil.
The concentration "mg/mL" refers to mg/mL, as weight/volume, which is the volume of the suspension. The concentration range of each component in the injection is calculated according to the ratio of the weight of the component to the total volume of the injection.
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 day, hz means hertz, g means gram, qs. means add up to, mbar means millibar, V means volt, and c means celsius.
Detailed Description
Based on the defects of the prior art, the invention provides the injection containing the vortioxetine medicament through deep research and research, the preparation can be suspension which can be directly used, 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 in the suspension exists in insoluble particles with low solubility, and can slowly and continuously release the medicine after injection, so that the administration frequency can be obviously reduced, and the fluctuation of peaks and valleys can be avoided, 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 in the suspension has small particle size, uniform distribution and good injectability, and is beneficial to improving the bioavailability.
The vortioxetine injection provided by the invention has good stability, and is beneficial to storage and transportation.
The invention provides a vortioxetine injection, wherein the active ingredient is vortioxetine or salt thereof, the concentration range of the active ingredient is 50.0mg/mL-400.0mg/mL (W/V) according to the ratio of the weight of Fu Liu sitein to the total volume of the injection, and the vortioxetine injection further comprises a wetting agent.
In some embodiments, the concentration of the active ingredient ranges from 100.0mg/mL to 300.0mg/mL; in some embodiments, the concentration of the active ingredient ranges from 50.0mg/mL to 100.0mg/mL; in some embodiments, the concentration of the active ingredient ranges from 50.0mg/mL to 200.0mg/mL; in some embodiments, the concentration of the active ingredient ranges from 50.0mg/mL to 300.0mg/mL; in some embodiments, the concentration of the active ingredient ranges from 100.0mg/mL to 200.0mg/mL; in some embodiments, the concentration of the active ingredient ranges from 100.0mg/mL to 400.0mg/mL; in some embodiments, the concentration of the active ingredient ranges from 200.0mg/mL to 300.0mg/mL; in some embodiments, the concentration of the active ingredient ranges from 200.0mg/mL to 400.0mg/mL; in some embodiments, the concentration of the active ingredient ranges from 300.0mg/mL to 400.0mg/mL. In some embodiments, the concentration of the active ingredient is 100.0mg/mL,200.0mg/mL, or 300.0mg/mL.
In some embodiments, the active ingredient is vortioxetine. In some embodiments, the active ingredient is vortioxetine hydrobromide.
In some embodiments, the vortioxetine injection has an active ingredient that is vortioxetine free base, and the injection is a ready-to-use suspension. In some embodiments, the vortioxetine ready-to-use suspension is injected intramuscularly or subcutaneously.
The wetting agent can comprise at least one selected from poloxamer 188, poloxamer 338, poloxamer 407, tween-20, tween-60, tween-80, polyethylene glycol 1000 vitamin E succinate TPGS, polyoxyethylene hydrogenated castor oil RH40, castor oil polyoxyl ester EL35 and 15-hydroxystearic acid polyethylene glycol ester.
In some embodiments, the wetting agent comprises at least one selected from poloxamer 188, poloxamer 338, and poloxamer 407. The concentration of the wetting agent ranges from 5.0mg/mL to 80.0mg/mL (W/V) calculated as the ratio of the weight of the wetting agent to the total volume of the injection. In some embodiments, the wetting agent is present in a concentration range of 10.0mg/mL to 80.0mg/mL. In some embodiments, the concentration of the wetting agent ranges from 10.0mg/mL to 60.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 20.0mg/mL to 60.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 20.0mg/mL to 30.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 20.0mg/mL to 40.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 20.0mg/mL to 50.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 30.0mg/mL to 40.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 30.0mg/mL to 50.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 30.0mg/mL to 60.0mg/mL; in some embodiments, the wetting agent is present in a concentration range of 40.0mg/mL
-50.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 40.0mg/mL to 60.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 50.0mg/mL to 60.0mg/mL. In some embodiments, the concentration of the wetting agent is 20.0mg/mL,30.0mg/mL,40.0mg/mL,50.0mg/mL, or 60.0mg/mL.
In some embodiments, the wetting agent comprises at least one selected from the group consisting of tween-20, tween-60 and tween-80. The concentration of the wetting agent ranges from 2.0mg/mL to 20.0mg/mL (W/V) calculated as the ratio of the weight of the wetting agent to the total volume of the injection. In some embodiments, the concentration of the wetting agent ranges from 5.0mg/mL to 10.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 2.0mg/mL to 5.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 2.0mg/mL to 10.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 2.0mg/mL to 15.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 5.0mg/mL to 15.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 5.0mg/mL to 20.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 10.0mg/mL to 15.0mg/mL; in some embodiments, the concentration of the wetting agent ranges from 10.0mg/mL to 20.0mg/mL; in some embodiments, the wetting agent is present in a concentration range of 15.0mg/mL
-20.0mg/mL。
The vortioxetine injection can also comprise a suspending agent.
In some embodiments, the vortioxetine injection comprises an active ingredient which is vortioxetine or a salt thereof, and a wetting agent, wherein the concentration of the active ingredient ranges from 50.0mg/mL to 400.0mg/mL (W/V) calculated as the ratio of the weight of Fu Liu sitagliptin to the total volume of the injection; optionally comprising a suspending agent.
In some embodiments, the suspending agent comprises at least one selected from the group consisting of sodium carboxymethylcellulose, pectin, gelatin, polyvinylpyrrolidone, methylcellulose, acacia, and polyethylene glycol. In some embodiments, the suspending agent is sodium carboxymethylcellulose.
In some embodiments, the suspending agent comprises sodium carboxymethyl cellulose; the sodium carboxymethylcellulose comprises at least one selected from sodium carboxymethylcellulose 7L2P, sodium carboxymethylcellulose 7MF, sodium carboxymethylcellulose 7LF and sodium carboxymethylcellulose HF. In some embodiments, the suspending agent is sodium carboxymethyl cellulose 7L2P; in some embodiments, the suspending agent is sodium carboxymethyl cellulose 7MF.
In some embodiments, the suspending agent comprises at least one selected from povidone K12, povidone K17, povidone K25, povidone K30, povidone K90, hydroxypropylcellulose, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 3350, and polyethylene glycol 4000. In some embodiments, the suspending agent is povidone K12; in some embodiments, the suspending agent is povidone K30; in some embodiments, the suspending agent is hydroxypropyl cellulose; in some embodiments, the suspending agent is polyethylene glycol 4000.
In some embodiments, the suspending agent comprises at least one selected from the group consisting of sodium carboxymethylcellulose 7L2P, sodium carboxymethylcellulose 7MF, sodium carboxymethylcellulose 7LF, sodium carboxymethylcellulose HF, povidone K12, povidone K17, povidone K25, povidone K30, povidone K90, hydroxypropyl cellulose, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 3350, and polyethylene glycol 4000; the concentration of the suspending agent is 0-30.0mg/mL calculated according to the ratio of the weight of the suspending agent to the total volume of the injection.
The concentration of the suspending agent is 0-30.0mg/mL calculated according to the ratio of the weight of the suspending agent to the total volume of the injection. In some embodiments, the concentration of the suspending agent is from 1.0mg/mL to 30.0mg/mL. In some embodiments, the concentration of the suspending agent is 0-5.0mg/mL; in some embodiments, the concentration of the suspending agent is 0-10.0mg/mL; in some embodiments, the concentration of the suspending agent is 0-20.0mg/mL; in some embodiments, the concentration of the suspending agent is from 1.0mg/mL to 20.0mg/mL; in some embodiments, the concentration of the suspending agent is 5.0mg/mL to 10.0mg/mL; in some embodiments, the concentration of the suspending agent is 5.0mg/mL to 20.0mg/mL; in some embodiments, the concentration of the suspending agent is 5.0mg/mL to 30.0mg/mL; in some embodiments, the concentration of the suspending agent is from 10.0mg/mL to 20.0mg/mL; in some embodiments, the concentration of the suspending agent is from 10.0mg/mL to 30.0mg/mL; in some embodiments, the concentration of the suspending agent is 20.0mg/mL to 30.0mg/mL. In some embodiments, the concentration of the suspending agent is 2.0mg/mL,4.0mg/mL, or 10.0mg/mL.
The vortioxetine injection can also comprise an osmotic pressure regulator.
In some embodiments, the tonicity modifier is selected from at least one of the group consisting of sodium chloride, dextrose, mannitol, and sorbitol. In some embodiments, the osmolality adjusting agent is sodium chloride.
The concentration of the osmotic pressure regulator is 1.0mg/mL-30.0mg/mL calculated according to the ratio of the weight of the osmotic pressure regulator to the total volume of the injection. In some embodiments, the concentration of the osmolality adjusting agent is between 1.0mg/mL and 20.0mg/mL. In some embodiments, the concentration of the osmolality adjusting agent is from 1.0mg/mL to 5.0mg/mL; in some embodiments, the concentration of the suspending agent is from 1.0mg/mL to 10.0mg/mL; in some embodiments, the concentration of the osmolality adjusting agent is between 3.0mg/mL and 6.0mg/mL.
In some embodiments, the vortioxetine injection comprises an active ingredient which is vortioxetine or a salt thereof, and a wetting agent, wherein the concentration of the active ingredient ranges from 50.0mg/mL to 400.0mg/mL (W/V) calculated as the ratio of the weight of Fu Liu sitein to the total volume of the injection; optionally comprising an osmotic pressure regulator.
In some embodiments, a vortioxetine injection comprises:
(a) Vortioxetine or a salt thereof at a concentration in the range of 50.0mg/mL to 400.0mg/mL (W/V), and
(b) Wetting agent, the concentration of which is in the range of 10.0mg/mL to 80.0mg/mL (W/V) calculated as the ratio of the weight of wetting agent to the total volume of the injection. In some embodiments, a vortioxetine injection comprises:
(a) The active ingredient vortioxetine, at a concentration range of 100.0mg/mL to 300.0mg/mL, and
(b) The wetting agent is in a concentration range of 20.0mg/mL to 60.0mg/mL calculated as the ratio of the weight of the wetting agent to the total volume of the injection.
In some embodiments, a vortioxetine injection comprises:
(a) Vortioxetine at a concentration in the range of 100.0mg/mL to 300.0mg/mL, and
(b) Poloxamer 338, at a concentration range of 20.0mg/mL to 60.0mg/mL.
In some embodiments, a vortioxetine injection comprises:
(a) Vothioxetine, the concentration range is 100.0mg/mL-300.0mg/mL,
(b) Poloxamer 338 at a concentration range of 20.0mg/mL to 60.0mg/mL, an
(c) Sodium chloride.
In some embodiments, a vortioxetine injection comprises:
(a) Vortioxetine, the concentration range is 100.0mg/mL-300.0mg/mL,
(b) Poloxamer 338, at a concentration range of 20.0mg/mL-60.0mg/mL,
(c) Sodium chloride, and
(d) And (5) purifying the water.
In some embodiments, a vortioxetine injection comprises:
(a) Vortioxetine, concentration 100.0mg/mL, and
(b) Poloxamer 338, at a concentration of 20.0mg/mL.
In some embodiments, a vortioxetine injection comprises:
(a) Vortioxetine at a concentration of 300.0mg/mL, and
(b) Poloxamer 338, at a concentration of 50.0mg/mL.
In some embodiments, a vortioxetine injection comprises:
(a) Vortioxetine at a concentration in the range of 100.0mg/mL to 300.0mg/mL, and
(b) Tween-80 with concentration range of 2.0mg/mL-20.0mg/mL.
In some embodiments, a vortioxetine injection comprises:
(a) Vortioxetine, the concentration of Vortioxetine is 100.0mg/mL-300.0mg/mL;
(b) The wetting agent is calculated according to the ratio of the weight of the wetting agent to the total volume of the injection, and the concentration of the wetting agent is 10.0mg/mL-60.0mg/mL; optionally (c) a suspending agent in a concentration of 0 to 20.0mg/mL, calculated as the ratio of its weight to the total volume of the injection.
In some embodiments, a vortioxetine injection comprises:
(a) Vortioxetine, the concentration of Vortioxetine is 100.0mg/mL-300.0mg/mL;
(b) Wetting agent, its concentration is calculated according to the ratio of its weight and total volume of injection, its concentration is 10.0mg/mL-60.0mg/mL; optionally comprising
(c) The suspending agent, the concentration of which is 0-20.0mg/mL calculated according to the ratio of the weight of the suspending agent to the total volume of the injection; optionally comprising
(d) An osmotic pressure regulator.
In some embodiments, a vortioxetine injection comprises:
(a) Vortioxetine, the concentration of Vortioxetine is 100.0mg/mL-300.0mg/mL;
(b) Poloxamer 188, or poloxamer 338, or poloxamer 407, at a concentration of 10.0mg/mL to 60.0mg/mL; optionally comprising
(c) Sodium carboxymethyl cellulose 7L2P, or sodium carboxymethyl cellulose 7MF, the concentration is 0-20.0mg/mL.
In some embodiments, a vortioxetine injection comprises:
(a) Vortioxetine, the concentration of Vortioxetine is 100.0mg/mL-300.0mg/mL;
(b) Poloxamer 188, or poloxamer 338, or poloxamer 407, at a concentration of 10.0mg/mL to 60.0mg/mL; optionally comprising
(c) Sodium carboxymethylcellulose 7L2P or sodium carboxymethylcellulose 7MF with a concentration of 0-20.0mg/mL; optionally comprising
(c) Sodium chloride.
In some embodiments, a vortioxetine injection comprises:
(a) Vortioxetine, the concentration of which is 300.0mg/mL;
(b) Poloxamer 188, or poloxamer 338, or poloxamer 407, at a concentration of 50.0mg/mL; and/or
(c) Sodium carboxymethyl cellulose 7L2P or sodium carboxymethyl cellulose 7MF, the concentration is 10.0mg/mL.
The vortioxetine injection provided by the invention has the D [4,3] range of 0.05-20.0 micrometers, or 0.1-10.0 micrometers, or 1.0-10.0 micrometers, or 0.5-15 micrometers, or 0.1-1.0 micrometers, or 10.0-15.0 micrometers, or 15.0-20.0 micrometers. In some embodiments, wherein the active ingredient has a D [4,3] in the range of 1.0 microns to 10.0 microns.
The vortioxetine injection disclosed by the invention can continuously release vortioxetine in a period of at least 2 weeks after injection.
The vortioxetine injection of the present invention is in the form of a suspension, the D of the vortioxetine present in the suspension [4,3] ranges from 0.05 microns to 20.0 microns, and the formulation releases vortioxetine continuously over a period of at least 2 weeks, up to 4 weeks, or longer, e.g. up to 6 weeks.
The vortioxetine injection according to the present invention is in the form of a suspension, wherein the concentration of vortioxetine present in the suspension ranges from 50.0mg/mL to 400.0mg/mL, and wherein the formulation releases vortioxetine continuously over a period of at least 2 weeks, up to 4 weeks, or longer, e.g. up to 6 weeks.
In another aspect, the present invention provides a method for preparing any one of the foregoing vortioxetine injections. A method for preparing the vortioxetine injection, comprising the following steps:
(1) Adding a wetting agent and/or other auxiliary materials into water, completely dissolving, adding the active ingredients, and uniformly stirring and dispersing to obtain a vortioxetine suspension;
(2) And (2) grinding the vortioxetine suspension obtained in the step (1).
In some embodiments, a method of preparing a vortioxetine injection comprises the steps of:
(1) Adding poloxamer 338 into water, completely dissolving, adding vortioxetine, and uniformly stirring and dispersing to obtain vortioxetine suspension;
(2) And (2) grinding the vortioxetine suspension obtained in the step (1).
The invention also provides application of the vortioxetine injection in preparation of a medicine for treating major depressive disorder.
The use of vortioxetine injection for the preparation of a medicament for the treatment of major depressive disorder, said medicament being administered intramuscularly or subcutaneously.
Drawings
FIG. 1 is a graph depicting mean plasma concentrations of vortioxetine versus time following injection of the formulation of example 4 of the present invention (prescription Nos. 01-06 in example 4) in rats.
Figure 2 is a graph depicting mean plasma concentrations of vortioxetine versus time following injection of the formulation of example 5 of the present invention (formula nos. 01-05, 07, 08 in example 5) in rats.
FIG. 3 is a graph depicting mean plasma concentrations of vortioxetine versus time following injection of the formulation of example 6 of the present invention (prescription Nos. 01-04 in example 6) in rats.
FIG. 4 is a graph depicting mean plasma concentrations of vortioxetine versus time following injection of the formulation of example 7 of the present invention (prescription Nos. 01-03 of example 7) in rats.
Figure 5 is a graph depicting mean plasma concentrations of vortioxetine versus time following injection of the formulation of example 8 of the present invention (prescription nos. 01-03 of example 8) in rats.
Detailed Description
Example 1: preparation of different wetting agents Vortioxetine suspension
A prescription table:
the preparation process comprises the following steps:
(1) Weighing poloxamer 188, poloxamer 338, poloxamer 407, TPGS, RH40, EL35, HS15, lecithin, tween 20, tween 80 and sodium chloride in the prescribed amount, sequentially adding into the purified water in the prescribed amount of the different groups, and stirring until the purified water is completely dissolved;
(2) Slowly adding the vortioxetine with the formula amount into the auxiliary material solution under the stirring state, and uniformly stirring and dispersing to obtain a vortioxetine suspension;
(3) Grinding the suspension by using a ball mill;
(4) Observing microscopic results, detecting pH, particle size distribution, zeta potential and viscosity, and investigating stability and injectability.
The experimental results are as follows: 08 samples become sticky with the addition of vortioxetine free base and delaminate significantly after a period of time, so they are not suitable for further studies. The remaining samples are shown in tables 1-1 and 1-2.
TABLE 1-1 suspension particle size, pH and viscosity data
According to the experimental result, the vortioxetine suspension with the concentration of 300mg/mL, which is prepared by different wetting agents, can obtain the suspension with the D [4,3] of 1.0-10.0 micrometers, the pH value is in the range of 4-9, the viscosity is within 30mPa & s, and the suspension meets the injection requirement and has good injectability.
TABLE 1-2 suspension microscopy and Zeta potential results
According to the experimental results, the vortioxetine suspension with the concentration of 300mg/mL prepared by different wetting agents has the advantages of dispersed particles, no aggregation phenomenon and potential within 30mV, and shows that the suspension is relatively stable.
Example 2: preparation of different-concentration Voluscitine long-acting injection
A prescription table:
the preparation process comprises the following steps:
(1) Weighing poloxamer 338 and sodium chloride in the prescription amount, sequentially adding into the purified water in the prescription amount of the different groups, and stirring until the purified water is completely dissolved;
(2) Slowly adding the vortioxetine with the formula amount into the auxiliary material solution under the stirring state, and uniformly stirring and dispersing to obtain a vortioxetine suspension;
(3) Grinding the suspension by using a ball mill;
(4) Observing microscopic results, detecting pH, particle size distribution, zeta potential and viscosity, and investigating stability and injectability.
The experimental results are as follows: the 01 sample has non-uniform particle distribution, and the 05 sample D [4,3] is larger, so that the sample is not suitable for further research. The results for the remaining samples are shown in tables 2-1 and 2-2.
TABLE 2-1 suspension particle size, pH and viscosity data
According to the experimental results, the 02, 03 and 04 samples can obtain the suspension with the D [4,3] of 1.0-10 micrometers, the pH value is in the range of 4-9, the viscosity is within 30mPa s, and the suspension meets the injection requirement and has good injectability.
TABLE 2-2 suspension microscopy and Zeta potential results
According to the experimental results, the sample particles of the samples of the batches 02, 03 and 04 are uniformly dispersed without aggregation, the potential is within 30mV, and the suspension is relatively stable.
Example 3: preparation of Vothiocetin long-acting injection with different poloxamer 338 dosage
A prescription table:
the preparation process comprises the following steps:
(1) Weighing poloxamer 338 and sodium chloride according to the prescription amount, sequentially adding into the purified water according to the prescription amount of the different groups, and stirring until the poloxamer 338 and the sodium chloride are completely dissolved;
(2) Slowly adding the vortioxetine with the formula amount into the auxiliary material solution under the stirring state, and uniformly stirring and dispersing to obtain a vortioxetine suspension;
(3) Grinding the suspension by using a ball mill;
(4) The microscopic results were observed, pH, particle size distribution, zeta potential and viscosity were examined and placed under accelerated conditions (40 ℃, RH 75%) and long term conditions (25 ℃, RH 60%) for stability and injectability.
The experimental results are as follows: when poloxamer 338 is adopted in batch 01, the concentration of the poloxamer is 2.5mg/mL, a large amount of API is separated out after grinding, and stable suspension cannot be obtained; when poloxamer 338 was used in lot 07 at a concentration of 100mg/mL, it was substantially non-flowable, viscous and non-syringable before grinding, and both formulations did not meet the requirements and were not studied further. The remaining formulations are shown in tables 3-1 and 3-2.
TABLE 3-1 suspension particle size, pH and viscosity data
According to the experimental results, the 02, 03 and 06 samples can obtain the suspension with the D [4,3] between 0.5 and 15 micrometers in 0, 1, 3 and 6 months of acceleration and 9 and 12 months of long time, the 04 and 05 samples can obtain the suspension with the D [4,3] between 1.0 and 10 micrometers in 0, 1, 3 and 6 months of acceleration, the pH values of the 02, 03, 04, 05 and 06 samples are all in the range of 4 to 9, the viscosity is within 30 mPas, and the suspension meets the requirements of injection and has good injectability.
TABLE 3-2 suspension microscopy and Zeta potential results
The result shows that the 02-06 sample particles are dispersed, no aggregation phenomenon exists, the potential is within 30mV, and the suspension has good stability.
Example 4: pharmacokinetics research of Vortioxetine suspension prepared from different wetting agents in rat body
A prescription table:
the preparation process comprises the following steps:
(1) Weighing poloxamer 188, poloxamer 338, poloxamer 407, EL35, HS15 and sodium chloride according to the prescription amount, sequentially adding into the water for injection according to the prescription amount of the different groups, and stirring until the materials are completely dissolved;
(2) Slowly adding the vortioxetine with the formula amount into the auxiliary material solution under the stirring state, and uniformly stirring and dispersing to obtain a vortioxetine suspension;
(3) Grinding the suspension by using a ball mill;
(4) Observing a microscopic result, detecting pH, particle size distribution, zeta potential and viscosity, and investigating stability and injectability; in vivo pharmacokinetic experiments were performed to evaluate the sustained release effect.
The results of the experiments are shown in tables 4-1 to 4-4.
TABLE 4-1 suspension particle size, pH and viscosity data
According to the experimental result, the vortioxetine suspension with the concentration of 300mg/mL, which is prepared by different wetting agents, can obtain the suspension with the D [4,3] of 1.0-10.0 micrometers, the pH value is in the range of 4-9, the viscosity is within 30mPa & s, and the suspension meets the injection requirement and has good injectability.
TABLE 4-2 suspension microscopic results and Zeta potential data
According to the experimental results, the vortioxetine suspension with the concentration of 300mg/mL prepared by different wetting agents has the advantages of dispersed particles, no aggregation phenomenon and potential within 30mV, and shows that the suspension is relatively stable.
TABLE 4-3 suspension content and related substances
The rat experiments were performed by selecting the different prescription samples of example 4, as follows: the LC/MS/MS system for analysis comprises an LC-30 ultra-high performance liquid chromatograph and a Qtrap-5500 ion hydrazine mass spectrometer. 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→150 |
| Fragmentation voltage | 33V |
| Capillary voltage | 4000V |
| Dryer temperature | 350℃ |
| Atomizer | 40psi |
| Flow rate of dryer | 9L/min |
TABLE B
Each group of suspensions was diluted to a final concentration of 100mg/mL and then administered to rats by intramuscular injection, wherein the amount of the suspension administered was 30mg/kg and the amount of the solution administered was 1.3mg/kg. Whole blood was collected at 0.25h, 0.5h, 1h, 2h, 5h, 7h, 24h, 48h, 72h, 96h, 120h, 144h, 168h after administration, plasma was separated and frozen for testing. And centrifuged at 12,000 rpm for 2 minutes at 4 ℃. Plasma was collected and stored at-20 ℃ or-70 ℃ until LC/MS/MS analysis. Tables 4-4 present the pharmacokinetic data in rats for 5 samples from example 4.
Tables 4 to 4: pharmacokinetic data of Compounds in rats
The results show that the 01-05 sample has good pharmacokinetic properties and shows different slow release trends compared with the solution. The preparation comprises ideal peak time (Tmax), half life (T1/2) and exposure (AUClast), the absorption and release curve is smoother compared with the solution, the T1/2 is between 52 and 73h, and the blood concentration of the thiocetin can be basically maintained above the detection limit at 168 h. The time course of the drug is shown in FIG. 1.
Example 5: pharmacokinetics research of different types of suspension adjuvant vortioxetine suspension in rat body
A prescription table:
the preparation process of the suspension comprises the following steps:
(1) Weighing poloxamer 188, sodium carboxymethyl cellulose 7L2P/7MF, polyvidone K12/K30, polyethylene glycol 4000, hydroxypropyl methyl cellulose, hydroxypropyl cellulose and sodium chloride according to the prescription amount, sequentially adding into the purified water according to the prescription amount of the different groups, and stirring until the purified water is completely dissolved;
(2) Slowly adding the vortioxetine with the formula amount into the auxiliary material solution under the stirring state, and uniformly stirring and dispersing to obtain a vortioxetine suspension;
(3) Grinding the suspension by using a ball mill;
(4) The microscopic results were observed, pH, particle size distribution, zeta potential and viscosity were examined, and stability (acceleration conditions: 40 ℃ C., RH 75%) and injectability were examined.
The preparation process of the solution comprises the following steps:
(1) Weighing the vortioxetine free alkali with the prescription amount in a 50mL volumetric flask;
(2) Weighing hydroxypropyl beta-cyclodextrin with the prescription amount in injection water with the half prescription amount, stirring to fully dissolve the hydroxypropyl beta-cyclodextrin, and transferring the hydroxypropyl beta-cyclodextrin into a volumetric flask;
(3) Adding water to constant volume to scale after ultrasonic treatment for 20 min.
The experimental results are as follows: 06 after grinding, the air bubbles are full, the suspension has no fluidity and can not meet the prescription requirement, so the next step of research is not carried out. The remaining prescription samples are shown in tables 5-1 to 5-2.
TABLE 5-1 suspension particle size, pH and viscosity data
According to the experimental result, the vortioxetine suspension prepared by different suspending agents can obtain the suspension with the D [4,3] of 1.0-10.0 microns, the pH value is in the range of 4-9, the viscosity is within 30mPa & s, and the suspension meets the injection requirement and has good injectability.
TABLE 5-2 suspension microscopy and Zeta potential results
According to the experimental results, the vortioxetine suspension with the concentration of 300mg/mL prepared by different wetting agents has the advantages of dispersed particles, no aggregation phenomenon, and stable potential within +/-50 mV.
The samples of examples 4-01 and the samples of example 5 were selected for rat experiments, and each group of suspensions was diluted to a final concentration of 100mg/mL and then administered to rats by intramuscular injection, wherein the amount of the suspension administered was 30mg/kg and the amount of the solution administered was 1.3mg/kg. Collecting whole blood at 0.25h, 0.5h, 1h, 2h, 5h, 7h, 24h, 48h, 72h, 96h, 120h, 144h and 168h after administration, separating plasma, and freezing and storing for testing. And centrifuged at 12,000 rpm for 2 minutes at 4 ℃. Plasma was collected and stored at-20 ℃ or-70 ℃ until LC/MS/MS analysis (same analysis as in example 4) was performed. Tables 5-4 present the pharmacokinetic data in rats for 5 samples from example 2.
Tables 5 to 4: pharmacokinetic data of Compounds in rats
The results show that the 01-07 samples have good pharmacokinetic properties and show different slow release trends compared with the 08 solution. The preparation comprises ideal peak reaching time (Tmax), half life (T1/2) and exposure (AUClast), the absorption and release curve is smoother compared with a solution, the T1/2 is between 35 and 97h, and the blood concentration of the thiocetin can be basically maintained above the detection limit at 168 h. The time course is shown in FIG. 2.
Example 6: pharmacokinetics research of Vortioxetine suspension prepared from sodium carboxymethylcellulose 7L2P with different concentrations in rat body
A prescription table:
the preparation process comprises the following steps:
(1) Weighing poloxamer 188, sodium carboxymethyl cellulose 7L2P and sodium chloride according to the prescription amount, sequentially adding into the purified water according to the prescription amount of different groups, and stirring until the purified water is completely dissolved;
(2) Slowly adding the vortioxetine with the formula amount into the auxiliary material solution under the stirring state, and uniformly stirring and dispersing to obtain a vortioxetine suspension;
(3) Grinding the suspension by using a ball mill;
(4) Observing microscopic results, detecting pH, particle size distribution, zeta potential and viscosity, and investigating stability and injectability; in vivo pharmacokinetic experiments were performed to evaluate the sustained release effect.
The experimental results are as follows: the prescription samples are shown in tables 6-1 to 6-4.
TABLE 6-1 suspension particle size, pH and viscosity data
According to the experimental results, the vortioxetine suspension prepared by the sodium carboxymethylcellulose 7L2P with different concentrations can obtain the suspension with the D [4,3] of 1.0-10.0 micrometers, the pH value is in the range of 4-9, the viscosity is within 30mPa & s, and the suspension meets the injection requirement and has good injectability.
TABLE 6-2 suspension microscopy and Zeta potential results
According to the experimental results, the Vortioxetine suspension prepared from the sodium carboxymethylcellulose 7L2P with different concentrations has dispersed particles and no aggregation phenomenon, and the potential results show that the suspension is stable.
TABLE 6-3 suspension content and related substances
The different prescribed samples of example 6 were selected and rat experiments were carried out, and rats were given an intramuscular injection at a dose of 30mg/kg after dilution of each group suspension to a final concentration of 100 mg/mL. Collecting whole blood at 0.25h, 0.5h, 1h, 2h, 5h, 7h, 24h, 48h, 72h, 96h, 120h, 144h and 168h after administration, separating plasma, and freezing and storing for testing. And centrifuged at 12,000 rpm for 2 minutes at 4 ℃. Plasma was collected and stored at-20 ℃ or-70 ℃ until LC/MS/MS analysis (same analysis as in example 4) was performed. Tables 6-4 present the pharmacokinetic data in rats for 4 samples from example 6.
Tables 6 to 4: pharmacokinetic data of Compounds in rats
The results show that the suspensions prepared from 4mg/mL and 10mg/mL sodium carboxymethyl cellulose 7L2P suspending agent have higher exposure and peak concentration than the suspension prepared without the suspending agent, and the blood exposure and peak concentration of rats prepared from the 2-10mg/mL range of sodium carboxymethyl cellulose 7L2P are increased along with the increase of the dosage of sodium carboxymethyl cellulose 7L 2P. The time course of the drug is shown in FIG. 3.
Example 7: pharmacokinetics study of Vothiocetin suspension prepared by using different dosages of poloxamer 338 in rat body
A prescription table:
the preparation process comprises the following steps:
(1) Weighing poloxamer 338 and sodium chloride in the prescription amount, sequentially adding into the sterilized water for injection in the prescription amount of different groups, and stirring until the poloxamer 338 and the sodium chloride are completely dissolved;
(2) Slowly adding the vortioxetine with the formula amount into the auxiliary material solution under the stirring state, and uniformly stirring and dispersing to obtain a vortioxetine suspension;
(3) Grinding the suspension by using a ball mill;
(4) Observing microscopic results, detecting pH, particle size distribution, osmotic pressure, zeta potential and viscosity, and investigating stability and injectability; in vivo pharmacokinetic experiments were performed to evaluate the sustained release effect.
The experimental results are as follows: prescription samples are shown in tables 7-1 to 7-4.
TABLE 7-1 suspension particle size, pH and viscosity data
According to the experimental result, the vortioxetine suspension prepared by different dosages of poloxamer 338 can obtain the suspension with D [4,3] between 1.0 and 10.0 micrometers, the pH value is in the range of 4 to 9, the viscosity is within 30mPa & s, and the suspension meets the injection requirement and has good injectability.
TABLE 7-2 suspension microscopy and Zeta potential results
According to the experimental result, the vortioxetine suspension prepared by different dosages of poloxamer 338 has the advantages of dispersed particles, no aggregation phenomenon and potential within 30mV, and shows that the suspension is relatively stable.
TABLE 7-3 suspension content and related substances
The different prescribed samples of example 7 were selected and rat experiments were carried out, and rats were given an intramuscular injection at a dose of 30mg/kg after dilution of each group suspension to a final concentration of 100 mg/mL. Collecting whole blood at 0.25h, 0.5h, 1h, 2h, 5h, 7h, 24h, 48h, 72h, 96h, 120h, 144h and 168h after administration, separating plasma, and freezing and storing for testing. And centrifuged at 12,000 rpm for 2 minutes at 4 ℃. Plasma was collected and stored at-20 ℃ or-70 ℃ until LC/MS/MS analysis (same analysis as in example 4) was performed. The pharmacokinetic data in rats for 3 samples of example 7 are presented in tables 7-4.
Tables 7 to 4: pharmacokinetic data of Compounds in rats
The results show that the samples No. 01-03 all have good pharmacokinetic properties, including ideal peak time (Tmax), half-life (T1/2) and exposure (AUClast), the absorption and release curves are relatively flat compared with the solution, T1/2 is between 70 and 103h, and the blood concentration of thiocetin at 480h can be basically maintained above the detection limit. The time course of the drug is shown in FIG. 4.
Example 8: pharmacokinetics research of Vortioxetine suspension with different particle sizes in rat body
A prescription table:
the preparation process comprises the following steps:
(1) Weighing poloxamer 338 and sodium chloride in the prescription amount, sequentially adding into the purified water in the prescription amount of the different groups, and stirring until the purified water is completely dissolved;
(2) Slowly adding the vortioxetine with the formula amount into the auxiliary material solution under the stirring state, and uniformly stirring and dispersing to obtain a vortioxetine suspension; (3) grinding the suspension by using a ball mill;
(4) Observing microscopic results, detecting pH, particle size distribution, osmotic pressure, zeta potential and viscosity, and investigating stability and injectability; in vivo pharmacokinetic experiments were performed to evaluate the sustained release effect.
The experimental results are as follows: the prescription samples are shown in tables 8-1 to 8-4.
TABLE 8-1 suspension particle size, pH and viscosity data
According to the experimental results, the Vortioxetine suspension with different particle sizes has pH value within 4-9 and viscosity within 30mPa s, meets the injection requirement, and has good injectability.
TABLE 8-2 suspension microscopy and Zeta potential results
According to the experimental results, the Vortictin suspension with different particle sizes has the advantages of dispersed particles, no aggregation phenomenon, and potential within 30mV, and shows that the suspension is relatively stable.
TABLE 8-3 suspension content results
The different prescribed samples of example 8 were selected and rat experiments were carried out, and rats were given an intramuscular injection at a dose of 30mg/kg after dilution of each group suspension to a final concentration of 100 mg/mL. Collecting whole blood at 0.25h, 0.5h, 1h, 2h, 5h, 7h, 24h, 48h, 72h, 96h, 120h, 140h, 170h, 220h, 290h, 340h, 410h and 500h after administration, separating plasma, and freezing and storing to be tested. And centrifuged at 12,000 rpm for 2 minutes at 4 ℃. Plasma was collected and stored at-20 ℃ or-70 ℃ until LC/MS/MS analysis (same analysis as in example 4) was performed. The pharmacokinetic data in rats for 3 samples of example 8 are presented in tables 8-4.
Tables 8 to 4: pharmacokinetic data of Compounds in rats
The results show that the suspension of D [4,3] between 1.0 and 15.0 microns has good pharmacokinetic properties including ideal peak reaching time (Tmax), half-life (T1/2) and exposure (AUClast), and the blood concentration of the thiocetidine can be basically maintained above the detection limit at 290h volt; the time course is shown in FIG. 5.
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 (3)
1. The valacitretin injection is prepared from the following components:
(a) The active ingredient vortioxetine is calculated according to the ratio of Fu Liu sitein weight to the total volume of the injection, the concentration of the vortioxetine is 300.0mg/mL, and the D [4,3] of the active ingredient is 0.1 micrometer-10.0 micrometers;
(b) Poloxamer 338 or poloxamer 407, wherein the concentration of poloxamer 338 or poloxamer 407 is 20.0mg/mL-30.0mg/mL calculated as the ratio of the weight of poloxamer 338 or poloxamer 407 to the total volume of the injection;
(c) Sodium chloride, the concentration of which is 5.0mg/mL calculated according to the ratio of the weight of the sodium chloride to the total volume of the injection; and
(d) The balance of water for injection.
2. A method of preparing the vortioxetine injection of claim 1 comprising the steps of:
(1) Adding poloxamer 338 and sodium chloride or poloxamer 407 and sodium chloride into water, dissolving completely, adding active ingredients, stirring and dispersing uniformly to obtain vortioxetine suspension; and
(2) And (2) grinding the vortioxetine suspension obtained in the step (1).
3. Use of the vortioxetine injection of claim 1 for the preparation of a medicament for the treatment of major depressive disorder.
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