WO2021180196A1 - 一种哌嗪基类药物的组合物 - Google Patents
一种哌嗪基类药物的组合物 Download PDFInfo
- Publication number
- WO2021180196A1 WO2021180196A1 PCT/CN2021/080384 CN2021080384W WO2021180196A1 WO 2021180196 A1 WO2021180196 A1 WO 2021180196A1 CN 2021080384 W CN2021080384 W CN 2021080384W WO 2021180196 A1 WO2021180196 A1 WO 2021180196A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- vothiaxetine
- injection
- concentration
- poloxamer
- carboxymethyl cellulose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Definitions
- the invention relates to the field of pharmaceutical preparations, in particular to a composition of piperazinyl drugs and a preparation method thereof.
- Depression also known as depressive disorder, is the main type of mood disorder with significant and lasting depression as its main clinical feature. Clinically, it can be seen that the mood is low, low self-esteem, depression, even pessimism, and suicidal attempts or behaviors. Most cases have a tendency to recur, most of them can be relieved each time, and some may have residual symptoms or become chronic. In the world, the number of people affected by some form of depression accounts for 25% of all women, 10% of all men, and 5% of all adolescents. The cause of depression is still unclear. At present, antidepressants have become the first choice for treatment of depressed patients. Clinically, selective serotonin reuptake inhibitors (SSRI) are the most widely used.
- SSRI selective serotonin reuptake inhibitors
- Vothiaxetine (English name vortioxetine), the chemical name is 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazinyl, and the chemical structure is as follows:
- Vothiaxetine is a selective serotonin reuptake inhibitor (SSRI). Its effect on depression is similar to that of duloxetine, and it is superior to venlafaxine and agomelatine. In addition, it has good safety It is also suitable for patients with liver and kidney injury. The effect is better than that of vilazodone, and it is better than traditional SSRI in terms of effectiveness and safety.
- SSRI serotonin reuptake inhibitor
- the first aspect of the present invention provides a vothiaxetine injection, in which the active ingredient has a high concentration and a controllable particle size, which can obtain a higher dose within a limited injection volume, and is controlled by the particle Diameter distribution, etc., to achieve the effect of long-acting drug release.
- the preparation will continue to release vothiaxetine for at least 2 weeks after injection. It is administered once a week or longer, which increases patient compliance.
- the vothiaxetine injection provided by the present invention has a simple prescription and only needs to add fewer types of excipients, which can reduce the cost of excipients. risks of.
- the vothiaxetine injection provided by the present invention can be a ready-to-use injection and can be used directly to avoid pollution and safety risks introduced by operational errors during reconstitution.
- the injection provided by the invention has good storage stability and is still stable after being placed for 6 months under accelerated conditions.
- the second aspect of the present invention provides a method for preparing the vothiaxetine injection, which is simple and easy to implement, has good stability and high safety, and is suitable for industrial production.
- the third aspect of the present invention provides the use of the vothiaxetine injection in the preparation of a medicament for the treatment of major depression.
- suspending agent means: a suspending agent may be included, or a suspending agent may not be included.
- D[4,3] refers to the volume-weighted average measured by the Malvern Mastersizer 2000 laser particle size analyzer.
- Dv10 refers to the particle size when the cumulative particle size volume distribution percentage of a sample reaches 10%
- Dv50 refers to the particle size when the cumulative particle size volume distribution percentage of a sample reaches 50%
- Dv90 refers to the particle size corresponding to the cumulative particle size volume distribution percentage of a sample reaching 90%
- Dv99 refers to the particle size corresponding to the cumulative particle size volume distribution percentage of a sample reaching 99%.
- LC/MS/MS refers to liquid-mass spectrometry.
- sustained release refers to the use of LC/MS/MS analytical equipment to detect samples, and the blood concentration of vothiaxetine can be detected according to its detection limit.
- TPGS refers to polyethylene glycol 1000 vitamin E succinate
- RH40 refers to polyoxyethylene hydrogenated (40) castor oil.
- concentration “mg/mL” refers to milligrams per milliliter, which is weight/volume, and the volume is the volume of the suspension.
- 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.
- ⁇ m refers to micrometers
- ⁇ L refers to microliters
- L refers to liters
- mm refers to millimeters
- mL refers to milliliters
- nm refers to nanometers
- ng refers to nanograms
- kg refers to kilograms
- min refers to minutes
- d refers to days
- Hz refers to hertz
- g refers to grams
- qs. refers to adding to
- mbar refers to millibar
- V refers to volts
- °C refers to degrees Celsius.
- the present invention provides an injection containing vothiaxetine after in-depth investigation and research.
- the preparation can be a suspension that can be used directly. It can be injected intramuscularly or subcutaneously.
- Thioxetine tablets, invention advantages include:
- the vothiaxetine in the suspension exists as insoluble particles with low solubility, which can slowly and continuously release the drug after injection, which can significantly reduce the number of administrations and avoid peak-to-valley fluctuations, thereby improving patient compliance and safety sex;
- the vothiaxetine in the suspension has a small particle size and a uniform distribution, and has good injectability, which is beneficial to improve its bioavailability.
- the vothiaxetine injection provided by the invention has good stability and is beneficial to storage and transportation.
- the present invention provides a vothiaxetine injection
- the active ingredient is vothiaxetine or its salt, calculated according to the ratio of the weight of vothiaxetine to the total volume of the injection, the concentration range of the active ingredient is 50.0mg/mL-400.0mg /mL(W/V)
- the vothiaxetine injection further includes a wetting agent.
- the concentration range of the active ingredient is 100.0mg/mL-300.0mg/mL; in some embodiments, the concentration range of the active ingredient is 50.0mg/mL-100.0mg/mL; in some In an embodiment, the concentration range of the active ingredient is 50.0mg/mL-200.0mg/mL; in some embodiments, the concentration range of the active ingredient is 50.0mg/mL-300.0mg/mL; in some embodiments, the concentration range of the active ingredient is 100.0 mg/mL-200.0 mg/mL; in some embodiments, the concentration range of the active ingredient is 100.0 mg/mL-400.0 mg/mL; in some embodiments, The concentration range of the active ingredient is 200.0mg/mL-300.0mg/mL; in some embodiments, the concentration range of the active ingredient is 200.0mg/mL-400.0mg/mL; in some embodiments, the The concentration range of the active ingredient is 300.0mg/mL-400.0mg/mL. In
- the active ingredient is vothiaxetine. In some embodiments, the active ingredient is vothiaxetine hydrobromide.
- the active ingredient of the vothiaxetine injection is vothiaxetine free base, and the injection is a ready-to-use suspension.
- the ready-to-use vothiaxetine suspension is injected intramuscularly or subcutaneously.
- the wetting agent may include poloxamer 188, poloxamer 338, poloxamer 407, Tween-20, Tween-60, Tween-80, polyethylene glycol 1000 vitamin E At least one of succinate TPGS, polyoxyethylene hydrogenated castor oil RH40, castor oil polyoxyl ester EL35, and 15-hydroxystearate polyethylene glycol ester.
- the wetting agent includes at least one selected from the group consisting of poloxamer 188, poloxamer 338, and poloxamer 407. Calculated according to the ratio of the weight of the wetting agent to the total volume of the injection, the concentration of the wetting agent ranges from 5.0 mg/mL to 80.0 mg/mL (W/V). In some embodiments, the concentration of the wetting agent ranges from 10.0 mg/mL to 80.0 mg/mL.
- the concentration range of the wetting agent is 10.0 mg/mL-60.0 mg/mL; in some embodiments, the concentration range of the wetting agent is 20.0 mg/mL-60.0 mg/mL; In some embodiments, the concentration range of the wetting agent is 20.0 mg/mL-30.0 mg/mL; in some embodiments, the concentration range of the wetting agent is 20.0 mg/mL-40.0 mg/mL; In some embodiments, the concentration range of the wetting agent is 20.0 mg/mL-50.0 mg/mL; in some embodiments, the concentration range of the wetting agent is 30.0 mg/mL-40.0 mg/mL; In some embodiments, the concentration range of the wetting agent is 30.0 mg/mL-50.0 mg/mL; in some embodiments, the concentration range of the wetting agent is 30.0 mg/mL-60.0 mg/mL; In some embodiments, the concentration range of the wetting agent is 40.0 mg/mL-50.0 mg/mL; in some embodiments, the concentration range of the wetting agent is 20.0
- the wetting agent includes at least one selected from Tween-20, Tween-60 and Tween-80. Calculated according to the ratio of the weight of the wetting agent to the total volume of the injection, the concentration of the wetting agent ranges from 2.0 mg/mL to 20.0 mg/mL (W/V).
- the concentration range of the wetting agent is 5.0 mg/mL-10.0 mg/mL; in some embodiments, the concentration range of the wetting agent is 2.0 mg/mL-5.0 mg/mL; In some embodiments, the concentration of the wetting agent ranges from 2.0 mg/mL to 10.0 mg/mL; in some embodiments, the concentration of the wetting agent ranges from 2.0 mg/mL to 15.0 mg/mL; In some embodiments, the concentration range of the wetting agent is 5.0 mg/mL-15.0 mg/mL; in some embodiments, the concentration range of the wetting agent is 5.0 mg/mL-20.0 mg/mL; In some embodiments, the concentration of the wetting agent ranges from 10.0 mg/mL to 15.0 mg/mL; in some embodiments, the concentration of the wetting agent ranges from 10.0 mg/mL to 20.0 mg/mL; In some embodiments, the concentration of the wetting agent ranges from 15.0 mg/mL to 20.0 mg/mL.
- the vothiaxetine injection of the present invention may also include a suspending agent.
- the vothiaxetine injection includes an active ingredient and a wetting agent, and the active ingredient is vothiaxetine or a salt thereof, calculated according to the ratio of the weight of vothiaxetine to the total volume of the injection,
- the concentration range of the active ingredient is 50.0 mg/mL-400.0 mg/mL (W/V); optionally, a suspending agent is included.
- the suspending agent comprises at least one selected from the group consisting of sodium carboxymethyl cellulose, pectin, gelatin, polyvinylpyrrolidone, methyl cellulose, gum arabic, and polyethylene glycol. In some embodiments, the suspending agent is sodium carboxymethyl cellulose.
- the suspending agent includes sodium carboxymethyl cellulose; the sodium carboxymethyl cellulose includes sodium carboxymethyl cellulose 7L2P, sodium carboxymethyl cellulose 7MF, carboxymethyl cellulose At least one of sodium carboxymethyl cellulose 7LF and sodium carboxymethyl cellulose HF.
- the suspending agent is sodium carboxymethyl cellulose 7L2P; in some embodiments, the suspending agent is sodium carboxymethyl cellulose 7MF.
- the suspending agent is selected from povidone K12, povidone K17, povidone K25, povidone K30, povidone K90, hydroxypropyl cellulose, polyethylene glycol 300 , At least one of polyethylene glycol 400, polyethylene glycol 3350 and polyethylene glycol 4000.
- 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.
- the suspending agent is selected from the group consisting of sodium carboxymethyl cellulose 7L2P, sodium carboxymethyl cellulose 7MF, sodium carboxymethyl cellulose 7LF, sodium carboxymethyl cellulose 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 At least one of the suspending agent; 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 0-30.0 mg/mL.
- the concentration of the suspending agent is 0-30.0 mg/mL, calculated according to the ratio of its weight to the total volume of the injection. In some embodiments, the concentration of the suspending agent is 1.0 mg/mL-30.0 mg/mL. In some embodiments, the concentration of the suspending agent is 0-5.0 mg/mL; in some embodiments, the concentration of the suspending agent is 0-10.0 mg/mL; in some embodiments, the concentration of the suspending agent is 0-5.0 mg/mL; The concentration of the suspending agent is 0-20.0 mg/mL; in some embodiments, the concentration of the suspending agent is 1.0 mg/mL-20.0 mg/mL; in some embodiments, the concentration of the suspending agent is In some embodiments, the concentration of the suspending agent is 5.0 mg/mL-20.0 mg/mL; in some embodiments, the concentration of the suspending agent is 5.0 mg/mL-30.0mg/mL; in some embodiments, the concentration of the suspending agent is 10.0mg/mL-20.0
- the vothiaxetine injection of the present invention may also include an osmotic pressure regulator.
- the osmotic pressure adjusting agent is selected from at least one of sodium chloride, glucose, mannitol and sorbitol. In some embodiments, the osmotic pressure regulator is sodium chloride.
- the osmotic pressure regulator calculated according to the ratio of its weight to the total volume of the injection, has a concentration of 1.0 mg/mL to 30.0 mg/mL.
- the concentration of the osmotic pressure regulator is 1.0 mg/mL-20.0 mg/mL.
- the concentration of the osmotic pressure regulator is 1.0 mg/mL-5.0 mg/mL; in some embodiments, the concentration of the suspending agent is 1.0 mg/mL-10.0 mg/mL; In some embodiments, the concentration of the osmotic pressure regulator is 3.0 mg/mL-6.0 mg/mL.
- the vothiaxetine injection includes an active ingredient and a wetting agent, and the active ingredient is vothiaxetine or a salt thereof, calculated according to the ratio of the weight of vothiaxetine to the total volume of the injection,
- the concentration range of the active ingredient is 50.0 mg/mL-400.0 mg/mL (W/V); optionally, an osmotic pressure regulator is included.
- a vothiaxetine injection comprises:
- a vothiaxetine injection comprises:
- Wetting agent calculated according to the ratio of its weight to the total volume of the injection, its concentration range is 20.0mg/mL-60.0mg/mL.
- a vothiaxetine injection comprises:
- a vothiaxetine injection comprises:
- a vothiaxetine injection comprises:
- a vothiaxetine injection comprises:
- a vothiaxetine injection comprises:
- a vothiaxetine injection comprises:
- a vothiaxetine injection comprises:
- Wetting agent calculated according to the ratio of its weight to the total volume of the injection, its concentration is 10.0mg/mL-60.0mg/mL; optionally including
- Suspending agent calculated according to the ratio of its weight to the total volume of the injection, and its concentration is 0-20.0 mg/mL.
- a vothiaxetine injection comprises:
- Wetting agent calculated according to the ratio of its weight to the total volume of the injection, its concentration is 10.0mg/mL-60.0mg/mL; optionally including
- Suspending agent calculated according to the ratio of its weight to the total volume of the injection, its concentration is 0-20.0mg/mL; optionally including
- a vothiaxetine injection comprises:
- Poloxamer 188 or Poloxamer 338, or Poloxamer 407, at a concentration of 10.0 mg/mL-60.0 mg/mL; optionally including
- a vothiaxetine injection comprises:
- Poloxamer 188 or Poloxamer 338, or Poloxamer 407, at a concentration of 10.0 mg/mL-60.0 mg/mL; optionally including
- a vothiaxetine injection comprises:
- the D[4,3] range of the active ingredient is 0.05 ⁇ m-20.0 ⁇ m, or 0.1 ⁇ m-10.0 ⁇ m, or 1.0 ⁇ m-10.0 ⁇ m, or 0.5 ⁇ m- 15 microns, or 0.1 microns-1.0 microns, or 10.0 microns-15.0 microns, or 15.0 microns-20.0 microns.
- the D[4,3] range of the active ingredient is 1.0 ⁇ m to 10.0 ⁇ m.
- the vothiaxetine injection of the present invention continuously releases vothiaxetine for a period of at least 2 weeks after the injection.
- the vothiaxetine injection of the present invention is in the form of a suspension.
- the D[4,3] of the vothiaxetine present in the suspension ranges from 0.05 ⁇ m to 20.0 ⁇ m.
- the preparation will last for at least 2 weeks.
- the vothiaxetine is released continuously for a period of up to 4 weeks or longer, such as up to 6 weeks.
- the vothiaxetine injection of the present invention is in the form of a suspension.
- concentration of vothiaxetine in the suspension ranges from 50.0 mg/mL to 400.0 mg/mL.
- the continuous release of vothiaxetine For a period of up to 4 weeks or longer, such as up to 6 weeks, the continuous release of vothiaxetine.
- the present invention provides a method for preparing any of the above-mentioned vothiaxetine injections.
- a method for preparing the vothiaxetine injection including the following steps:
- a method for preparing vothiaxetine injection includes the following steps:
- the present invention also provides the use of the aforementioned vothiaxetine injection in the preparation of a medicament for the treatment of major depression.
- the medicament can be injected intramuscularly or subcutaneously.
- Figure 1 depicts the relationship between the average plasma concentration of vothiaxetine and time after injection of the preparation of Example 4 of the present invention (prescription No. 01-06 in Example 4) into a rat.
- Figure 2 depicts the relationship between the average plasma concentration of vothiaxetine and time after injection of the preparation of Example 5 of the present invention (prescription Nos. 01-05, 07, and 08 in Example 5) into rats.
- Figure 3 depicts the relationship between the average plasma concentration of vothiaxetine and time after injection of the preparation of Example 6 of the present invention (prescription No. 01-04 in Example 6) into a rat.
- Figure 4 depicts a graph of the relationship between the average plasma concentration of vothiaxetine and time after the preparation of Example 7 of the present invention (prescription No. 01-03 in Example 7) was injected into a rat.
- Figure 5 depicts a graph of the relationship between the average plasma concentration of vothiaxetine and time after injection of the preparation of Example 8 of the present invention (prescription No. 01-03 in Example 8) into a rat.
- Example 1 Preparation of vothiaxetine suspension with different wetting agents
- the vothiaxetine suspensions with a concentration of 300 mg/mL prepared by different types of wetting agents can obtain suspensions with D[4,3] between 1.0 and 10.0 microns, and the pH is all In the range of 4-9, the viscosity is within 30mPa ⁇ s.
- the suspension meets the injection requirements and has good injectability.
- the vothiaxetine suspension with a concentration of 300 mg/mL prepared by different types of wetting agents has dispersed particles without aggregation, and the potential is within 30 mV, indicating that the suspension is relatively stable.
- Sample 01 has uneven particle distribution, and sample 05 D[4,3] is relatively large, so it is not suitable for further research.
- the results of other samples are shown in Table 2-1 and Table 2-2.
- samples of 02, 03 and 04 can obtain suspensions with D[4,3] between 1.0 and 10 microns, the pH is in the range of 4-9, and the viscosity is within 30 mPa ⁇ s.
- the suspension meets the injection requirements and has good injectability.
- the particles of the samples in batches 02, 03 and 04 are uniformly dispersed without aggregation, and the potentials are all within 30mV, indicating that the suspension is relatively stable.
- Example 3 Preparation of vothiaxetine long-acting injections with different dosages of poloxamer 338
- the samples of 02, 03 and 06 can obtain suspensions with D[4,3] between 0.5-15 microns in the acceleration of 0, 1, 3, 6 months and long-term 9, 12 months.
- Samples 04 and 05 can obtain suspensions with D[4,3] between 1.0 and 10 microns at 0, 1, 3, and 6 months of acceleration.
- the pH of samples 02, 03, 04, 05 and 06 are all at In the range of 4-9, the viscosity is within 30mPa ⁇ s.
- the suspension meets the requirements of injections and has good injectability.
- Example 4 Pharmacokinetics study of vothiaxetine suspension prepared by different kinds of wetting agents in rats
- the vothiaxetine suspensions with a concentration of 300 mg/mL prepared by different types of wetting agents can obtain suspensions with D[4,3] between 1.0 and 10.0 microns, and the pH is all In the range of 4-9, the viscosity is within 30mPa ⁇ s.
- the suspension meets the injection requirements and has good injectability.
- the vothiaxetine suspension with a concentration of 300 mg/mL prepared by different types of wetting agents has dispersed particles without aggregation, and the potential is within 30 mV, indicating that the suspension is relatively stable.
- the samples of different prescriptions in Example 4 were selected to conduct a rat experiment.
- the experiment is as follows:
- the LC/MS/MS system used for analysis includes an LC-30 ultra-high performance liquid chromatograph and a Qtrap-5500 ion hydrazine mass spectrometer. Quantitative analysis is carried out in MRM mode, and the parameters of MRM conversion are shown in Table A:
- a Waters Xbridge C18, 2.1 ⁇ 50mm, 2.7 ⁇ M column was used for analysis, and 1 ⁇ L of sample was injected. Analysis conditions: the mobile phase is 2mM ammonium formate+0.1% formic acid (A) and methanol+2mM ammonium formate+0.1% formic acid (B). The flow rate is 0.7 mL/min.
- the mobile phase gradient is shown in Table B:
- the suspension of each group was diluted to a final concentration of 100 mg/mL and then administered to rats by intramuscular injection.
- the dosage of the suspension was 30 mg/kg and the dosage of the solution was 1.3 mg/kg.
- Table 4-4 lists the pharmacokinetic data of the five samples in Example 4 in rats.
- vothiaxetine suspensions prepared with different types of suspending agents can obtain suspensions with D[4,3] between 1.0 and 10.0 microns, and the pH is in the range of 4-9.
- the viscosity is within 30mPa ⁇ s, the suspension meets the injection requirements, and the injectability is good.
- the vothiaxetine suspensions with a concentration of 300 mg/mL prepared by different types of wetting agents have dispersed particles without aggregation, and the potentials are all within ⁇ 50 mV, indicating that the suspension is relatively stable.
- Example 4-01 and the samples of different prescriptions in Example 5 were selected to conduct rat experiments.
- the suspensions of each group were diluted to a final concentration of 100 mg/mL and then intramuscularly administered to rats.
- the dosage is 30 mg/kg, and the dosage of the solution is 1.3 mg/kg.
- the plasma was collected and stored at -20°C or -70°C until the LC/MS/MS analysis (analysis method is the same as in Example 4).
- Table 5-4 lists the pharmacokinetic data of the five samples in Example 2 in rats.
- Example 6 Pharmacokinetic study of vothiaxetine suspension prepared with different concentrations of sodium carboxymethyl cellulose 7L2P in rats
- the vothiaxetine suspensions prepared with different concentrations of sodium carboxymethyl cellulose 7L2P can obtain suspensions with D[4,3] between 1.0-10.0 microns, and the pH is all 4- Within the range of 9, the viscosity is within 30mPa ⁇ s.
- the suspension meets the injection requirements and has good injectability.
- the vothiaxetine suspension prepared with different concentrations of sodium carboxymethyl cellulose 7L2P has dispersed particles without aggregation, and the potential results show that the suspension is stable.
- Example 6 The samples of different prescriptions in Example 6 were selected for rat experiment, and the suspension of each group was diluted to a final concentration of 100 mg/mL, and the rats were injected intramuscularly at a dose of 30 mg/kg. Collect whole blood at 0.25h, 0.5h, 1h, 2h, 5h, 7h, 24h, 48h, 72h, 96h, 120h, 144h, 168h after administration, and freeze the plasma for testing after separation. And centrifuge at 12,000 rpm for 2 minutes at 4°C. The plasma was collected and stored at -20°C or -70°C until the LC/MS/MS analysis (analysis method is the same as in Example 4). Table 6-4 lists the pharmacokinetic data of the four samples in Example 6 in rats.
- Example 7 Pharmacokinetic study of vothiaxetine suspension prepared with different dosages of Poloxamer 338 in rats
- vothiaxetine suspensions prepared with different dosages of poloxamer 338 can obtain suspensions with D[4,3] between 1.0 and 10.0 microns, and the pH is in the range of 4-9.
- the viscosity is within 30mPa ⁇ s.
- the suspension meets the injection requirements and has good injectability.
- the vothiaxetine suspension prepared with different dosages of poloxamer 338 has dispersed particles without aggregation, and the potential is within 30 mV, indicating that the suspension is relatively stable.
- Example 7 The samples of different prescriptions in Example 7 were selected to conduct rat experiments, and the suspensions of each group were diluted to a final concentration of 100 mg/mL and then administered to rats by intramuscular injection at a dose of 30 mg/kg. Collect whole blood at 0.25h, 0.5h, 1h, 2h, 5h, 7h, 24h, 48h, 72h, 96h, 120h, 144h, 168h after administration, and freeze the plasma for testing after separation. And centrifuge at 12,000 rpm for 2 minutes at 4°C. The plasma was collected and stored at -20°C or -70°C until the LC/MS/MS analysis (analysis method is the same as in Example 4). Table 7-4 lists the pharmacokinetic data of the three samples in Example 7 in rats.
- samples 01-03 have good pharmacokinetic properties, including ideal peak time (Tmax), half-life (T1/2) and exposure (AUClast).
- Tmax peak time
- T1/2 half-life
- AUClast exposure
- the absorption and release curves are compared with those of the solution.
- T1/2 is between 70-103h, and the blood concentration of vothiaxetine at 480h can basically be maintained above the detection limit.
- the drug-time curve is shown in Figure 4.
- Example 8 Pharmacokinetic study of vothiaxetine suspension with different particle sizes in rats
- the pH of the vothiaxetine suspensions of different particle sizes is within the range of 4-9, and the viscosity is within 30mPa ⁇ s.
- the suspension meets the injection requirements and has good injectability.
- the vothiaxetine suspensions of different particle sizes have dispersed particles without aggregation, and the potentials are all within 30 mV, indicating that the suspension is relatively stable.
- Example 8 The samples of different prescriptions in Example 8 were selected to carry out the rat experiment, and the suspension of each group was diluted to a final concentration of 100 mg/mL, and the rats were injected intramuscularly at a dose of 30 mg/kg.
- Table 8-4 lists the pharmacokinetic data of the three samples in Example 8 in rats.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
一种哌嗪基类药物的组合物及制备方法，该哌嗪基类药物为伏硫西汀或其盐，组合物包含活性成分和润湿剂，为即用型液体注射剂。
Description
本发明涉及医药制剂领域，具体涉及一种哌嗪基类药物的组合物及其制备方法。
抑郁症又称抑郁障碍，以显著而持久的心境低落为主要临床特征，是心境障碍的主要类型。临床可见心境低落，自卑抑郁，甚至悲观厌世，有自杀企图或行为。多数病例有反复发作的倾向，每次发作大多数可以缓解，部分可有残留症状或转为慢性。在全世界，受某种形式的抑郁影响的人数占全部妇女的25％，全部男性的10％，以及全部青少年的5％。抑郁症的病因尚不清楚，目前，抗抑郁药已成为抑郁病人的首选治疗手段，临床上以选择性5-羟色胺再摄取抑制剂(SSRI)为主，应用最为广泛。
伏硫西汀(英文名vortioxetine)，化学名为1-[2-(2,4-二甲基-苯基硫烷基)-苯基]-哌嗪基，化学结构式如下：
伏硫西汀是一种选择性5-羟色胺再摄取抑制剂(SSRI)，其治疗抑郁症效果与度洛西汀相似，且优于文拉法辛和阿戈美拉汀，加之安全性良好，肝、肾损伤患者人群也适用，效果优于维拉佐酮，在有效性和安全性方面优于传统的SSRI。目前伏硫西汀只有不同规格的经口服给药的氢溴酸伏硫西汀片剂上市，该剂型血药浓度维持时间短，需要每日给药(每天一次)，由于需要频繁给药，增加了患者的不顺应性，且由于患者本身情绪波动及其他症状的影响，造成自行服药困难，常常导致治疗失败。
当前并没有伏硫西汀及其盐的长效注射剂上市，现有技术中缺乏对伏硫西汀及其盐的非肠道给药制剂的研究。
发明内容
发明概述
本发明第一方面提供了一种伏硫西汀注射剂，该制剂中活性成分的浓度较高、粒径可控，可在有限的注射体积内，获得较高的给药剂量，并通过控制粒径分布等，达到长效释药的作用，该制剂在注射后，在至少2周的时间期间持续释放伏硫西汀，给不宜口服给药的特殊人群带来新的用药选择，并且可两周或者 更长时间给药一次，增加了患者的顺应性。根据本领域技术人员公知，注射剂中加入的辅料种类越多，引入的风险越大，而本发明提供的伏硫西汀注射剂，处方简单，只需要加入较少种类的辅料，可降低辅料带来的风险。本发明提供的伏硫西汀注射剂可为即用型注射剂，可直接使用，避免复溶时操作失误引入的污染和安全风险。本发明提供的注射剂储存稳定性好，加速条件下放置6个月仍然稳定。
本发明第二方面提供了一种所述伏硫西汀注射剂的制备方法，该方法简单易行，稳定性好，安全性高，适于工业化生产。
本发明第三方面提供了所述伏硫西汀注射剂在制备用于治疗重度抑郁症药物中的用途。
术语定义
本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
本发明中，“任选地”或“任选的”表示可以有也可以没有，如“任选地包含助悬剂”表示：可以包含助悬剂，或者不包含助悬剂。
在本发明的上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现10％以下的差异或者本领域人员认为的合理的差异，如1％、2％、3％、4％或5％的差异。
术语“D[4,3]”是指采用Malvern Mastersizer 2000激光粒度测定仪测定得到的体积加权平均值。
术语“Dv10”是指一个样品的累计粒度体积分布百分数达到10％时所对应的粒径，术语“Dv50”是指一个样品的累计粒度体积分布百分数达到50％时所对应的粒径，术语“Dv90”是指一个样品的累计粒度体积分布百分数达到90％时所对应的粒径，术语“Dv99”是指一个样品的累计粒度体积分布百分数达到99％时所对应的粒径。
LC/MS/MS指液质联用。
“持续释放”是指采用LC/MS/MS分析仪器检测样品，根据其检测限，能检测到伏硫西汀的血药浓度。
TPGS是指聚乙二醇1000维生素E琥珀酸酯，RH40是指聚氧乙烯氢化(40)蓖麻油。
浓度“mg/mL”指毫克/毫升，为重量/体积，所述体积为混悬液体积。所述注射剂中各组分的浓度范围，按照组分的重量与注射剂总体积的比计算。
μm指微米，μL指微升，L指升，mm指毫米，mL指毫升，nm指纳米，ng指纳克，kg指千克，min指分钟，d指天数，Hz指赫兹，g指克，qs.指加至，mbar指毫巴，V指伏特，℃指摄氏度。
发明详述
基于现有技术的不足，本发明经过深入考察和研究，提供了含伏硫西汀药物的注射剂，该制剂可为可以直接使用的混悬液，采取肌肉注射或者皮下注射方式，相对于口服伏硫西汀片剂，发明优势包括：
(1)该混悬液中伏硫西汀以溶解度低的难溶性颗粒存在，注射后能够缓慢持续释放药物，可明显降低给药次数，避免峰谷波动，从而提高患者的治疗依从性和安全性；
(2)本制剂载药量较高，可获得至少2周或更长时间的持续释放；
(3)该混悬液中伏硫西汀粒度较小，且分布均匀，具有良好的可注射性，有利于提高其生物利用度。
本发明提供的伏硫西汀注射剂，具有良好的稳定性，利于储藏和运输。
本发明提供一种伏硫西汀注射剂，活性成分为伏硫西汀或其盐，按照伏硫西汀的重量与注射剂总体积的比计算，活性成分的浓度范围为50.0mg/mL-400.0mg/mL(W/V)，所述伏硫西汀注射剂进一步包括润湿剂。
在一些实施方式中，所述活性成分的浓度范围为100.0mg/mL-300.0mg/mL；在一些实施方式中，所述活性成分的浓度范围为50.0mg/mL-100.0mg/mL；在一些实施方式中，所述活性成分的浓度范围为50.0mg/mL-200.0mg/mL；在一些实施方式中，所述活性成分的浓度范围为50.0mg/mL-300.0mg/mL；在一些实施方式中，所述活性成分的浓度范围为100.0mg/mL-200.0mg/mL；在一些实施方式中，所述活性成分的浓度范围为100.0mg/mL-400.0mg/mL；在一些实施方式中，所述活性成分的浓度范围为200.0mg/mL-300.0mg/mL；在一些实施方式中，所述活性成分的浓度范围为200.0mg/mL-400.0mg/mL；在一些实施方式中，所述活性成分的浓度范围为300.0mg/mL-400.0mg/mL。在一些实施例中，所述活性成分的浓度为100.0mg/mL，200.0mg/mL，或者300.0mg/mL。
在一些实施方式中，所述活性成分为伏硫西汀。在一些实施方式中，所述活性成分为伏硫西汀氢溴酸盐。
在一些实施方式中，所述伏硫西汀注射剂，活性成分为伏硫西汀游离碱，所述注射剂为即用型混悬液。在一些实施例中，所述伏硫西汀即用型混悬液经肌肉注射或者皮下注射。
所述润湿剂，可包括选自泊洛沙姆188、泊洛沙姆338、泊洛沙姆407、吐温-20、吐温-60、吐温-80、聚乙二醇1000维生素E琥珀酸酯TPGS、聚氧乙烯氢化蓖麻油RH40、蓖麻油聚烃氧酯EL35和15-羟基硬脂酸聚乙二醇酯中的至少一种。
在一些实施方式中，所述润湿剂，包括选自泊洛沙姆188、泊洛沙姆338和泊洛沙姆407中的至少一种。按照润湿剂的重量与注射剂总体积的比计算，所述润湿剂的浓度范围为5.0mg/mL-80.0mg/mL(W/V)。在一些实施方式中，所述润湿剂的浓度范围为10.0mg/mL-80.0mg/mL。在一些实施方式中，所述润湿剂的浓度范围为10.0mg/mL-60.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为20.0mg/mL-60.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为20.0mg/mL-30.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为20.0mg/mL-40.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为20.0mg/mL-50.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为30.0mg/mL-40.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为30.0mg/mL-50.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为30.0mg/mL-60.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为40.0mg/mL-50.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为40.0mg/mL-60.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为50.0mg/mL-60.0mg/mL。在一些实施例中，所述润湿剂的浓度为20.0mg/mL，30.0mg/mL，40.0mg/mL，50.0mg/mL，或者60.0mg/mL。
在一些实施方式中，所述润湿剂，包括选自吐温-20、吐温-60和吐温-80中的至少一种。按照润湿剂的重量与注射剂总体积的比计算，所述润湿剂的浓度范围为2.0mg/mL-20.0mg/mL(W/V)。在一些实施方式中，所述润湿剂的浓度范围为5.0mg/mL-10.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为2.0mg/mL-5.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为2.0mg/mL-10.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为2.0mg/mL-15.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为5.0mg/mL-15.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为5.0mg/mL-20.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为10.0mg/mL-15.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为10.0mg/mL-20.0mg/mL；在一些实施方式中，所述润湿剂的浓度范围为15.0mg/mL-20.0mg/mL。
本发明所述伏硫西汀注射剂，还可以包括助悬剂。
在一些实施方式中，所述伏硫西汀注射剂，包括活性成分和润湿剂，所述活性成分为伏硫西汀或其盐，按照伏硫西汀的重量与注射剂总体积的比计算，活性成分的浓度范围为50.0mg/mL-400.0mg/mL(W/V)；任选地包含助悬剂。
在一些实施方式中，所述助悬剂包含选自羧甲基纤维素钠、果胶、明胶、聚乙烯吡咯烷酮、甲基纤维素、阿拉伯胶和聚乙二醇中的至少一种。在一些实施例中，所述助悬剂为羧甲基纤维素钠。
在一些实施方式中，所述助悬剂包括羧甲基纤维素钠；所述羧甲基纤维素钠包括选自羧甲基纤维素钠7L2P，羧甲基纤维素钠7MF，羧甲基纤维素钠7LF和羧甲基纤维素钠HF中的至少一种。在一些实施例中，所述助悬剂为羧甲基纤维素钠7L2P；在一些实施例中，所述助悬剂为羧甲基纤维素钠7MF。
在一些实施方式中，所述助悬剂包括选自聚维酮K12，聚维酮K17，聚维酮K25，聚维酮K30，聚维酮K90，羟丙基纤维素，聚乙二醇300，聚乙二醇400，聚乙二醇3350和聚乙二醇4000中的至少一种。在一些实施例中，所述助悬剂为聚维酮K12；在一些实施例中，所述助悬剂为聚维酮K30；在一些实施例中，所述助悬剂为羟丙基纤维素；在一些实施例中，所述助悬剂为聚乙二醇4000。
在一些实施方式中，所述助悬剂包括选自羧甲基纤维素钠7L2P，羧甲基纤维素钠7MF，羧甲基纤维素钠7LF，羧甲基纤维素钠HF，聚维酮K12，聚维酮K17，聚维酮K25，聚维酮K30，聚维酮K90，羟丙基纤维素，聚乙二醇300，聚乙二醇400，聚乙二醇3350和聚乙二醇4000中的至少一种；按照助悬剂的重量与注射剂总体积的比计算，所述助悬剂的浓度为0-30.0mg/mL。
所述助悬剂，按照其重量与注射剂总体积的比计算，其浓度为0-30.0mg/mL。在一些实施例中，所述助悬剂的浓度为1.0mg/mL-30.0mg/mL。在一些实施例中，所述助悬剂的浓度为0-5.0mg/mL；在一些实施例中，所述助悬剂的浓度为0-10.0mg/mL；在一些实施例中，所述助悬剂的浓度为0-20.0mg/mL；在一些实施例中，所述助悬剂的浓度为1.0mg/mL-20.0mg/mL；在一些实施例中，所述助悬剂的浓度为5.0mg/mL-10.0mg/mL；在一些实施例中，所述助悬剂的浓度为5.0mg/mL-20.0mg/mL；在一些实施例中，所述助悬剂的浓度为5.0mg/mL-30.0mg/mL；在一些实施例中，所述助悬剂的浓度为10.0mg/mL-20.0mg/mL；在一些实施例中，所述助悬剂的浓度为10.0mg/mL-30.0mg/mL；在一些实施例中，所述助悬剂的浓度为20.0mg/mL-30.0mg/mL。在一些实施例中，所述助悬剂的浓度为2.0mg/mL，4.0mg/mL，或者10.0mg/mL。
本发明所述伏硫西汀注射剂，还可以包括渗透压调节剂。
在一些实施方式中，所述渗透压调节剂选自包括氯化钠，葡萄糖，甘露醇和山梨醇的至少一种。在一些实施例中，所述渗透压调节剂为氯化钠。
所述渗透压调节剂，按照其重量与注射剂总体积的比计算，其浓度为1.0mg/mL-30.0mg/mL。在一些实施方式中，所述渗透压调节剂的浓度为1.0mg/mL-20.0mg/mL。在一些实施例中，所述渗透压调节剂的浓度为1.0mg/mL-5.0mg/mL；在一些实施例中，所述助悬剂的浓度为1.0mg/mL-10.0mg/mL；在一些实施例中，所述渗透压调节剂的浓度为3.0mg/mL-6.0mg/mL。
在一些实施方式中，所述伏硫西汀注射剂，包括活性成分和润湿剂，所述活性成分为伏硫西汀或其盐，按照伏硫西汀的重量与注射剂总体积的比计算，活性成分的浓度范围为50.0mg/mL-400.0mg/mL(W/V)；任选地包含渗透压调节剂。
在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)伏硫西汀或其盐，浓度范围为50.0mg/mL-400.0mg/mL(W/V)，和
(b)润湿剂，按照其重量与注射剂总体积的比计算，其浓度范围为10.0mg/mL-80.0mg/mL(W/V)。在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)活性成分伏硫西汀，浓度范围为100.0mg/mL-300.0mg/mL，和
(b)润湿剂，按照其重量与注射剂总体积的比计算，其浓度范围为20.0mg/mL-60.0mg/mL。
在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)伏硫西汀，浓度范围为100.0mg/mL-300.0mg/mL，和
(b)泊洛沙姆338，浓度范围为20.0mg/mL-60.0mg/mL。
在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)伏硫西汀，浓度范围为100.0mg/mL-300.0mg/mL，
(b)泊洛沙姆338，浓度范围为20.0mg/mL-60.0mg/mL，和
(c)氯化钠。
在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)伏硫西汀，浓度范围为100.0mg/mL-300.0mg/mL，
(b)泊洛沙姆338，浓度范围为20.0mg/mL-60.0mg/mL，
(c)氯化钠，和
(d)纯化水。
在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)伏硫西汀，浓度为100.0mg/mL，和
(b)泊洛沙姆338，浓度为20.0mg/mL。
在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)伏硫西汀，浓度为300.0mg/mL，和
(b)泊洛沙姆338，浓度为50.0mg/mL。
在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)伏硫西汀，浓度范围为100.0mg/mL-300.0mg/mL，和
(b)吐温-80，浓度范围为2.0mg/mL-20.0mg/mL。
在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)伏硫西汀，浓度为100.0mg/mL-300.0mg/mL；
(b)润湿剂，按照其重量与注射剂总体积的比计算，其浓度为10.0mg/mL-60.0mg/mL；任选地包含
(c)助悬剂，按照其重量与注射剂总体积的比计算，其浓度为0-20.0mg/mL。
在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)伏硫西汀，浓度为100.0mg/mL-300.0mg/mL；
(b)润湿剂，按照其重量与注射剂总体积的比计算，其浓度为10.0mg/mL-60.0mg/mL；任选地包含
(c)助悬剂，按照其重量与注射剂总体积的比计算，其浓度为0-20.0mg/mL；任选地包含
(d)渗透压调节剂。
在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)伏硫西汀，浓度为100.0mg/mL-300.0mg/mL；
(b)泊洛沙姆188，或者泊洛沙姆338，或者泊洛沙姆407，浓度为10.0mg/mL-60.0mg/mL；任选地包含
(c)羧甲基纤维素钠7L2P，或者羧甲基纤维素钠7MF，浓度为0-20.0mg/mL。
在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)伏硫西汀，浓度为100.0mg/mL-300.0mg/mL；
(b)泊洛沙姆188，或者泊洛沙姆338，或者泊洛沙姆407，浓度为10.0mg/mL-60.0mg/mL；任选地包含
(c)羧甲基纤维素钠7L2P或者羧甲基纤维素钠7MF，浓度为0-20.0mg/mL；任选地包含
(c)氯化钠。
在一些实施方式中，一种伏硫西汀注射剂，包含：
(a)伏硫西汀，浓度为300.0mg/mL；
(b)泊洛沙姆188，或者泊洛沙姆338，或者泊洛沙姆407，浓度为50.0mg/mL；和/或
(c)羧甲基纤维素钠7L2P或者羧甲基纤维素钠7MF，浓度为10.0mg/mL。
本发明所述的伏硫西汀注射剂，其中所述的活性成分的D[4,3]范围为0.05微米-20.0微米，或者0.1微米-10.0微米，或者1.0微米-10.0微米，或者0.5微米-15微米，或者0.1微米-1.0微米，或者10.0微米-15.0微米，或者15.0微米-20.0微米。在一些实施方式中，其中所述的活性成分的D[4,3]范围为1.0微米-10.0微米。
本发明所述的伏硫西汀注射剂，其在注射后，在至少2周的时间期间持续释放伏硫西汀。
本发明所述的伏硫西汀注射剂，为混悬液形式，存在于混悬液中的伏硫西汀的D[4,3]范围为0.05微米-20.0微米，所述制剂在至少2周的时间，多达4周的时间或者更长时间例如多达6周的时间期间持续释放伏硫西汀。
本发明所述的伏硫西汀注射剂，为混悬液形式，存在于混悬液中的伏硫西汀的浓度范围为50.0mg/mL-400.0mg/mL，所述制剂在至少2周的时间，多达4周的时间或者更长时间例如多达6周的时间期间持续释放伏硫西汀。
另一方面，本发明提供一种制备上述任一伏硫西汀注射剂的方法。一种制备所述伏硫西汀注射剂的方法，包括下列步骤：
(1)将润湿剂和/或其他辅料加入水中，完全溶解，再加入活性成分，搅拌分散均匀，得伏硫西汀混悬液；
(2)研磨(1)所得伏硫西汀混悬液。
在一些实施例中，一种制备伏硫西汀注射剂的方法，包括下列步骤：
(1)将泊洛沙姆338加入水中，完全溶解，再加入伏硫西汀，搅拌分散均匀，得伏硫西汀混悬液；
(2)研磨(1)所得伏硫西汀混悬液。
本发明还提供了前述的伏硫西汀注射剂在制备用于治疗重度抑郁症药物中的用途。
一种伏硫西汀注射剂在制备用于治疗重度抑郁症药物中的用途，所述药物可经肌肉内注射或者皮下注射。
图1描述在大鼠体中注射本发明实施例4制剂(实施例4中的01-06号处方)后，伏硫西汀的平均血浆浓度与时间关系的图。
图2描述在大鼠体中注射本发明实施例5制剂(实施例5中的01-05、07、08号处方)后，伏硫西汀的平均血浆浓度与时间关系的图。
图3描述在大鼠体中注射本发明实施例6制剂(实施例6中的01-04号处方)后，伏硫西汀的平均血浆浓度与时间关系的图。
图4描述在大鼠体中注射本发明实施例7制剂(实施例7中的01-03号处方)后，伏硫西汀的平均血浆浓度与时间关系的图。
图5描述在大鼠体中注射本发明实施例8制剂(实施例8中的01-03号处方)后，伏硫西汀的平均血浆浓度与时间关系的图。
实施例1：不同润湿剂伏硫西汀混悬液制备
处方表：
制备过程：
(1)称取处方量的泊洛沙姆188、泊洛沙姆338、泊洛沙姆407、TPGS、RH40、EL35、HS15、卵磷脂、吐温20、吐温80和氯化钠依次加入上述不同组别的处方量纯化水中，搅拌至完全溶解；
(2)将处方量的伏硫西汀在搅拌的状态下缓慢加入上述辅料溶液中，搅拌分散均匀，得伏硫西汀混悬液；
(3)将上述混悬液用球磨机进行研磨；
(4)观察显微结果，检测pH、粒度分布、Zeta电位和黏度，考察稳定性和可注射性。
实验结果：08样品加入伏硫西汀游离碱后变粘稠，并且一段时间后明显分层，故不适合进行下一步研究。其余样品见表1-1和表1-2。
表1-1混悬液粒径、pH和黏度数据
根据实验结果可知，不同润湿剂种类制备的浓度为300mg/mL的伏硫西汀混悬液，均可获得D[4,3]在1.0-10.0微米之间的混悬液，pH均在4-9范围内，黏度均在30mPa·s以内，该混悬液满足注射要求，可注射性良好。
表1-2混悬液显微和Zeta电位结果
根据实验结果可知，不同润湿剂种类制备的浓度为300mg/mL的伏硫西汀混悬液，颗粒分散，无聚集现象，电位均在30mV以内，显示该混悬液较为稳定。
实施例2：不同浓度伏硫西汀长效注射剂制备
处方表：
制备过程：
(1)称取处方量的泊洛沙姆338和氯化钠依次加入上述不同组别的处方量纯化水中，搅拌至完全溶解；
(2)将处方量的伏硫西汀在搅拌的状态下缓慢加入上述辅料溶液中，搅拌分散均匀，得伏硫西汀混悬液；
(3)将上述混悬液用球磨机进行研磨；
(4)观察显微结果，检测pH、粒度分布、Zeta电位和黏度，考察稳定性和可注射性。
实验结果：01样品颗粒分布不均一，05样品D[4,3]较大，故不适合进行下一步研究。其余样品结果见表2-1和表2-2。
表2-1混悬液粒径、pH和黏度数据
根据实验结果可知，02、03和04样品均可获得D[4,3]在1.0-10微米之间的混悬液，pH均在4-9范围内，黏度均在30mPa·s以内，该混悬液满足注射要求，可注射性良好。
表2-2混悬液显微和Zeta电位结果
根据实验结果可知，02、03和04批样品样品颗粒均分散均匀，无聚集现象，电位均在30mV以内，显示该混悬液较为稳定。
实施例3：不同泊洛沙姆338用量伏硫西汀长效注射剂制备
处方表：
制备过程：
(1)称取处方量的泊洛沙姆338和氯化钠依次加入上述不同组别的处方量纯化水中，搅拌至完全溶解；
(2)将处方量的伏硫西汀在搅拌的状态下缓慢加入上述辅料溶液中，搅拌分散均匀，得伏硫西汀混悬液；
(3)将上述混悬液用球磨机进行研磨；
(4)观察显微结果，检测pH、粒度分布、Zeta电位和黏度，并在加速条件(40℃，RH75％)和长期条件(25℃，RH60％)下放置，考察稳定性和可注射性。
实验结果：01批采用泊洛沙姆338浓度为2.5mg/mL时，研磨后有大量API析出，无法获得稳定的混悬液；07批采用泊洛沙姆338浓度为100mg/mL时，研磨前基本无流动性，较粘稠，不具备可注射性，这两个处方不满足要求，不进行下一步研究。其余处方见表3-1和表3-2。
表3-1混悬液粒径、pH和黏度数据
根据实验结果可知，02、03和06样品在加速0、1、3、6个月和长期9、12个月均可获得D[4,3]在0.5-15微米之间的混悬液，04和05样品在加速0、1、3、6个月均可获得D[4,3]在1.0-10微米之间的混悬液，02、03、04、05和06样品的pH均在4-9范围内，黏度均在30mPa·s以内，该混悬液满足注射剂要求，可注射性良好。
表3-2混悬液显微和Zeta电位结果
结果显示，02-06样品颗粒分散，无聚集现象，电位均在30mV以内，显示该混悬液稳定性好。
实施例4：不同种类润湿剂制备的伏硫西汀混悬液在大鼠体内的药物动力学研究
处方表：
制备过程：
(1)称取处方量的泊洛沙姆188、泊洛沙姆338、泊洛沙姆407、EL35、HS15和氯化钠依次加入上述不同组别的处方量注射用水中，搅拌至完全溶解；
(2)将处方量的伏硫西汀在搅拌的状态下缓慢加入上述辅料溶液中，搅拌分散均匀，得伏硫西汀混悬液；
(3)将上述混悬液用球磨机进行研磨；
(4)观察显微结果，检测pH、粒度分布、Zeta电位和黏度，考察稳定性和可注射性；进行体内药动学试验评价其缓释效果。
实验结果见表4-1至表4-4。
表4-1混悬液粒径、pH和黏度数据
根据实验结果可知，不同润湿剂种类制备的浓度为300mg/mL的伏硫西汀混悬液，均可获得D[4,3]在1.0-10.0微米之间的混悬液，pH均在4-9范围内，黏度均在30mPa·s以内，该混悬液满足注射要求，可注射性良好。
表4-2混悬液显微结果和Zeta电位数据
根据实验结果可知，不同润湿剂种类制备的浓度为300mg/mL的伏硫西汀混悬液，颗粒分散，无聚集现象，电位均在30mV以内，显示该混悬液较为稳定。
表4-3混悬液含量及有关物质
选择实施例4中不同处方样品，进行大鼠实验，实验如下：分析用的LC/MS/MS系统包括LC-30超高效液相色谱仪和Qtrap-5500离子肼质谱仪。定量分析在MRM模式下进行，MRM转换的参数如表A所示：
表A
| 多反应检测扫描 | 299→150 |
| 碎裂电压 | 33V |
| 毛细管电压 | 4000V |
| 干燥器温度 | 350℃ |
| 雾化器 | 40psi |
| 干燥器流速 | 9L/min |
分析使用Waters Xbridge C18，2.1×50mm，2.7μM柱，注入1μL样品。分析条件：流动相为2mM甲酸铵+0.1％甲酸(A)和甲醇+2mM甲酸铵+0.1％甲酸(B)。流速为0.7mL/min。流动相梯度如表B所示：
表B
| 时间 | 流动相B的梯度 |
| 0.3min | 20％ |
| 0.6min | 95％ |
| 1.8min | 95％ |
| 1.81min | 20％ |
| 2.8min | stop |
将各组别混悬液稀释至终浓度100mg/mL后对大鼠进行肌肉注射给药，其中混悬液的给药量是30mg/kg，溶液剂的给药量是1.3mg/kg。在给药后0.25h、0.5h、1h、2h、5h、7h、24h、48h、72h、96h、120h、144h、168h采集全血，分离血浆后冻存待测。并在4℃条件下12,000转/分钟下离心2分钟。收集血浆，于-20℃或-70℃下保存直到进行LC/MS/MS分析。表4-4列出了实施例4中5个样品在大鼠体内的药代动力学数据。
表4-4：化合物在大鼠体内的药代动力学数据
结果显示，01-05样品具有良好的药代动力学性质，与溶液剂相比体现出不同的缓释趋势。包括理想的达峰时间(Tmax)、半衰期(T1/2)和暴露量(AUClast)，吸收及释放曲线与溶液剂相比较为平缓，T1/2在52-73h之间，在168h伏硫西汀血药浓度基本可以维持在检测限以上。药时曲线见图1。
实施例5：不同类型助悬剂伏硫西汀混悬液在大鼠体内的药物动力学研究
处方表：
混悬液制备过程：
(1)称取处方量的泊洛沙姆188、羧甲基纤维钠7L2P/7MF、聚维酮K12/K30、聚乙二醇4000、羟丙甲基纤维素、羟丙基纤维素和氯化钠依次加入上述不同组别的处方量纯化水中，搅拌至完全溶解；
(2)将处方量的伏硫西汀在搅拌的状态下缓慢加入上述辅料溶液中，搅拌分散均匀，得伏硫西汀混悬液；
(3)将上述混悬液用球磨机进行研磨；
(4)观察显微结果，检测pH、粒度分布、Zeta电位和黏度，考察稳定性(加速条件：40℃，RH75％)和可注射性。
溶液制备过程：
(1)称取处方量的伏硫西汀游离碱于50mL容量瓶中；
(2)称取处方量的羟丙基β-环糊精于半处方量的注射用水中，搅拌充分溶解后转移至容量瓶中；
(3)超声20min后加水定容至刻度。
实验结果：06样品研磨后气泡满杯，混悬液无流动性，不满足处方要求，故不进行下一步研究。其 余处方样品见表5-1至表5-2。
表5-1混悬液粒径、pH和黏度数据
根据实验结果可知，不同助悬剂种类制备的伏硫西汀混悬液，均可获得D[4,3]在1.0-10.0微米之间的混悬液，pH均在4-9范围内，黏度均在30mPa·s以内，该混悬液满足注射要求，可注射性良好。
表5-2混悬液显微和Zeta电位结果
根据实验结果可知，不同润湿剂种类制备的浓度为300mg/mL的伏硫西汀混悬液，颗粒分散，无聚集现象，电位均在±50mV以内，显示该混悬液较为稳定。
选择实施例4-01样品和实施例5中不同处方样品，进行大鼠实验，将各组别混悬液稀释至终浓度100mg/mL后对大鼠进行肌肉注射给药，其中混悬液的给药量是30mg/kg，溶液剂的给药量是1.3mg/kg。在给药后0.25h、0.5h、1h、2h、5h、7h、24h、48h、72h、96h、120h、144h、168h采集全血，分离血浆后冻存待测。并在4℃条件下12,000转/分钟下离心2分钟。收集血浆，于-20℃或-70℃下保存直到进行LC/MS/MS分析(分析方法同实施例4)。表5-4列出了实施例2中5个样品在大鼠体内的药代动力学数据。
表5-4：化合物在大鼠体内的药代动力学数据
结果显示，01-07样品具有良好的药代动力学性质，与08的溶液剂相比体现出不同的缓释趋势。包括理想的达峰时间(Tmax)、半衰期(T1/2)和暴露量(AUClast)，吸收及释放曲线与溶液剂相比较为平缓，T1/2在35-97h之间，在168h伏硫西汀血药浓度基本可以维持在检测限以上。药时曲线见图2。
实施例6：不同浓度羧甲基纤维素钠7L2P制备的伏硫西汀混悬液在大鼠体内的药物动力学研究
处方表：
制备过程：
(1)称取处方量的泊洛沙姆188、羧甲基纤维钠7L2P和氯化钠依次加入上述不同组别的处方量纯化水中，搅拌至完全溶解；
(2)将处方量的伏硫西汀在搅拌的状态下缓慢加入上述辅料溶液中，搅拌分散均匀，得伏硫西汀混悬液；
(3)将上述混悬液用球磨机进行研磨；
(4)观察显微结果，检测pH、粒度分布、Zeta电位和黏度，考察稳定性和可注射性；进行体内药动学试验评价其缓释效果。
实验结果：处方样品见表6-1至表6-4。
表6-1混悬液粒径、pH和黏度数据
根据实验结果可知，不同浓度羧甲基纤维素钠7L2P制备的伏硫西汀混悬液，均可获得D[4,3]在1.0-10.0微米之间的混悬液，pH均在4-9范围内，黏度均在30mPa·s以内，该混悬液满足注射要求，可注射性良好。
表6-2混悬液显微和Zeta电位结果
根据实验结果可知，不同浓度羧甲基纤维素钠7L2P制备的伏硫西汀混悬液，颗粒分散，无聚集现象，同时电位结果显示该混悬液稳定。
表6-3混悬液含量及有关物质
选择实施例6中不同处方样品，进行大鼠实验，将各组别混悬液稀释至终浓度100mg/mL后对大鼠进行肌肉注射给药，给药剂量30mg/kg。在给药后0.25h、0.5h、1h、2h、5h、7h、24h、48h、72h、96h、120h、144h、168h采集全血，分离血浆后冻存待测。并在4℃条件下12,000转/分钟下离心2分钟。收集血浆，于-20℃或-70℃下保存直到进行LC/MS/MS分析(分析方法同实施例4)。表6-4列出了实施例6中4个样品在大鼠体内的药代动力学数据。
表6-4：化合物在大鼠体内的药代动力学数据
结果显示，4mg/mL和10mg/mL羧甲基纤维素钠7L2P助悬剂制备的混悬液，其暴露量和峰浓度均高于不采用助悬剂制备的混悬液，同时2-10mg/mL范围羧甲基纤维素钠7L2P制备的混悬液大鼠血药暴露量和峰浓度随羧甲基纤维素钠7L2P用量的增大而增大。药时曲线见图3。
实施例7：不同用量泊洛沙姆338制备的伏硫西汀混悬液在大鼠体内的药物动力学研究
制备过程：
(1)称取处方量的泊洛沙姆338和氯化钠依次加入上述不同组别的处方量灭菌注射用水中，搅拌至完全溶解；
(2)将处方量的伏硫西汀在搅拌的状态下缓慢加入上述辅料溶液中，搅拌分散均匀，得伏硫西汀混悬液；
(3)将上述混悬液用球磨机进行研磨；
(4)观察显微结果，检测pH、粒度分布、渗透压、Zeta电位和黏度，考察稳定性和可注射性；进行体内药动学试验评价其缓释效果。
实验结果：处方样品见表7-1至表7-4。
表7-1混悬液粒径、pH和黏度数据
根据实验结果可知，不同泊洛沙姆338用量制备的伏硫西汀混悬液，均可获得D[4,3]在1.0-10.0微米之间的混悬液，pH均在4-9范围内，黏度均在30mPa·s以内，该混悬液满足注射要求，可注射性良好。
表7-2混悬液显微和Zeta电位结果
根据实验结果可知，不同泊洛沙姆338用量制备的伏硫西汀混悬液，颗粒分散，无聚集现象，电位均在30mV以内，显示该混悬液较为稳定。
表7-3混悬液含量及有关物质
选择实施例7中不同处方样品，进行大鼠实验，将各组别混悬液稀释至终浓度100mg/mL后对大鼠进行肌肉注射给药，给药剂量30mg/kg。在给药后0.25h、0.5h、1h、2h、5h、7h、24h、48h、72h、96h、120h、144h、168h采集全血，分离血浆后冻存待测。并在4℃条件下12,000转/分钟下离心2分钟。收集血浆，于-20℃或-70℃下保存直到进行LC/MS/MS分析(分析方法同实施例4)。表7-4列出了实施例7中3个样品在大鼠体内的药代动力学数据。
表7-4：化合物在大鼠体内的药代动力学数据
结果显示，01-03号样品均具有良好的药代动力学性质，包括理想的达峰时间(Tmax)、半衰期(T1/2)和暴露量(AUClast)，吸收及释放曲线与溶液剂相比较为平缓，T1/2在70-103h之间，在480h伏硫西汀血药浓度基本可以维持在检测限以上。药时曲线见图4。
实施例8：不同粒径伏硫西汀混悬液在大鼠体内的药物动力学研究
处方表：
制备过程：
(1)称取处方量的泊洛沙姆338和氯化钠依次加入上述不同组别的处方量纯化水中，搅拌至完全溶解；
(2)将处方量的伏硫西汀在搅拌的状态下缓慢加入上述辅料溶液中，搅拌分散均匀，得伏硫西汀混悬液；
(3)将上述混悬液用球磨机进行研磨；
(4)观察显微结果，检测pH、粒度分布、渗透压、Zeta电位和黏度，考察稳定性和可注射性；进行体内药动学试验评价其缓释效果。
实验结果：处方样品见表8-1至表8-4。
表8-1混悬液粒径、pH和黏度数据
根据实验结果可知，不同粒径大小的伏硫西汀混悬液，pH均在4-9范围内，黏度均在30mPa·s以内，该混悬液满足注射要求，可注射性良好。
表8-2混悬液显微和Zeta电位结果
根据实验结果可知，不同粒径大小的伏硫西汀混悬液，颗粒分散，无聚集现象，电位均在30mV以内，显示该混悬液较为稳定。
表8-3混悬液含量结果
选择实施例8中不同处方样品，进行大鼠实验，将各组别混悬液稀释至终浓度100mg/mL后对大鼠进行肌肉注射给药，给药剂量30mg/kg。在给药后0.25h、0.5h、1h、2h、5h、7h、24h、48h、72h、96h、120h、140h、170h、220h、290h、340h、410h、500h采集全血，分离血浆后冻存待测。并在4℃条件下12,000转/分钟下离心2分钟。收集血浆，于-20℃或-70℃下保存直到进行LC/MS/MS分析(分析方法同实施例4)。表8-4列出了实施例8中3个样品在大鼠体内的药代动力学数据。
表8-4：化合物在大鼠体内的药代动力学数据
结果显示，D[4,3]在1.0-15.0微米之间的混悬液，均具有良好的药代动力学性质，包括理想的达峰时间(Tmax)、半衰期(T1/2)和暴露量(AUClast)，在290h伏硫西汀血药浓度基本可以维持在检测限以上；药时曲线见图5。
本发明说明书的描述中，参考术语“一些实施例”、“一些实施方式”、“一个具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (20)
- 一种伏硫西汀注射剂，包括：润湿剂和活性成分伏硫西汀或其盐，按照伏硫西汀的重量与注射剂总体积的比计算，活性成分的浓度为50.0mg/mL-400.0mg/mL。
- 根据权利要求1所述的伏硫西汀注射剂，所述活性成分为伏硫西汀，所述注射剂为即用型混悬液。
- 根据权利要求1或2所述的伏硫西汀注射剂，所述润湿剂包括选自泊洛沙姆188、泊洛沙姆338、泊洛沙姆407、吐温-20、吐温-60、吐温-80、聚乙二醇1000维生素E琥珀酸酯TPGS、聚氧乙烯氢化蓖麻油RH40、蓖麻油聚烃氧酯EL35和15-羟基硬脂酸聚乙二醇酯中的至少一种。
- 根据权利要求1或2所述的伏硫西汀注射剂，所述润湿剂包括选自泊洛沙姆188、泊洛沙姆338和泊洛沙姆407中的至少一种；按照润湿剂的重量与注射剂总体积的比计算，所述润湿剂的浓度为10.0mg/mL-80.0mg/mL。
- 根据权利要求1或2所述的伏硫西汀注射剂，所述润湿剂包括选自吐温-20、吐温-60和吐温-80中的至少一种；按照润湿剂的重量与注射剂总体积的比计算，所述润湿剂的浓度为2.0mg/mL-20.0mg/mL。
- 根据权利要求1-5任一所述的伏硫西汀注射剂，其进一步包含助悬剂。
- 根据权利要求6所述的伏硫西汀注射剂，所述助悬剂包括选自羧甲基纤维素钠、果胶、明胶、聚乙烯吡咯烷酮、甲基纤维素、阿拉伯胶和聚乙二醇中的至少一种。
- 根据权利要求6所述的伏硫西汀注射剂，所述助悬剂包括羧甲基纤维素钠；所述羧甲基纤维素钠包括选自羧甲基纤维素钠7L2P，羧甲基纤维素钠7MF，羧甲基纤维素钠7LF和羧甲基纤维素钠HF中的至少一种。
- 根据权利要求6所述的伏硫西汀注射剂，所述助悬剂包括选自聚维酮K12，聚维酮K17，聚维酮K25，聚维酮K30，聚维酮K90，羟丙基纤维素，聚乙二醇300，聚乙二醇400和聚乙二醇3350中的至少一种。
- 根据权利要求6所述的伏硫西汀注射剂，所述助悬剂包括选自羧甲基纤维素钠7L2P，羧甲基纤维素钠7MF，羧甲基纤维素钠7LF，羧甲基纤维素钠HF，聚维酮K12，聚维酮K17，聚维酮K25，聚维酮K30，聚维酮K90，羟丙基纤维素，聚乙二醇300，聚乙二醇400，聚乙二醇3350和聚乙二醇4000中的至少一种；按照助悬剂的重量与注射剂总体积的比计算，所述助悬剂的浓度为0-30.0mg/mL。
- 根据权利要求1-10任一所述的伏硫西汀注射剂，其进一步包含渗透压调节剂。
- 根据权利要求11所述的伏硫西汀注射剂，所述渗透压调节剂包括选自氯化钠和葡萄糖中的至少一种。
- 根据权利要求1或2所述的伏硫西汀注射剂，包含：(a)活性成分伏硫西汀，浓度为100.0mg/mL-300.0mg/mL，和(b)润湿剂，按照其重量与注射剂总体积的比计算，其浓度为20.0mg/mL-60.0mg/mL。
- 根据权利要求1或2所述的伏硫西汀注射剂，包含：(a)活性成分伏硫西汀，浓度为100.0mg/mL-300.0mg/mL；(b)润湿剂，按照其重量与注射剂总体积的比计算，其浓度为10.0mg/mL-60.0mg/mL；任选地包含(c)助悬剂，按照其重量与注射剂总体积的比计算，其浓度为0-20.0mg/mL。
- 根据权利要求1或2所述的伏硫西汀注射剂，包含：(a)活性成分伏硫西汀，浓度为100.0mg/mL-300.0mg/mL；(b)泊洛沙姆188，或者泊洛沙姆338，或者泊洛沙姆407，按照其重量与注射剂总体积的比计算，其浓度为10.0mg/mL-60.0mg/mL；任选地包含(c)羧甲基纤维素钠7L2P，或者羧甲基纤维素钠7MF，按照其重量与注射剂总体积的比计算，其浓度为0-20.0mg/mL。
- 根据权利要求1或2所述的伏硫西汀注射剂，包含：(a)活性成分伏硫西汀，浓度为100.0mg/mL-300.0mg/mL；(b)泊洛沙姆188，或者泊洛沙姆338，或者泊洛沙姆407，按照其重量与注射剂总体积的比计算，其浓度为10.0mg/mL-60.0mg/mL；任选地包含(c)羧甲基纤维素钠7L2P，或者羧甲基纤维素钠7MF，按照其重量与注射剂总体积的比计算，其浓度为0-20.0mg/mL；任选地包含(d)氯化钠。
- 根据权利要求1-16任一所述的伏硫西汀注射剂，所述活性成分的D[4,3]为0.05微米-20.0微米或0.1微米-10.0微米。
- 根据权利要求1-17任一所述的伏硫西汀注射剂，其在注射后，在至少2周的时间期间持续释放活性成分。
- 制备如权利要求1-18任一所述伏硫西汀注射剂的方法，包括下列步骤：(1)将润湿剂，任选的其他辅料加入水中，完全溶解，再加入活性成分，搅拌分散均匀，得伏硫西汀混悬液；和(2)研磨(1)所得伏硫西汀混悬液。
- 一种权利要求1-19任一所述的伏硫西汀注射剂在制备用于治疗重度抑郁症药物中的用途。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202180009518.XA CN115052601B (zh) | 2020-03-13 | 2021-03-12 | 一种哌嗪基类药物的组合物 |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010175561 | 2020-03-13 | ||
| CN202010175561.0 | 2020-03-13 | ||
| CN202010633150.1 | 2020-07-02 | ||
| CN202010633150 | 2020-07-02 | ||
| CN202010675258.7 | 2020-07-14 | ||
| CN202010675258 | 2020-07-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2021180196A1 true WO2021180196A1 (zh) | 2021-09-16 |
Family
ID=77672126
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2021/080384 Ceased WO2021180196A1 (zh) | 2020-03-13 | 2021-03-12 | 一种哌嗪基类药物的组合物 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN115052601B (zh) |
| WO (1) | WO2021180196A1 (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114681434A (zh) * | 2022-03-08 | 2022-07-01 | 福建瑞泰来医药科技有限公司 | 一种氢溴酸伏硫西汀口溶膜剂及其制备方法 |
| WO2023083212A1 (zh) * | 2021-11-10 | 2023-05-19 | 广东东阳光药业有限公司 | 一种喹啉类药物的组合物 |
| CN120037190A (zh) * | 2025-03-04 | 2025-05-27 | 珠海市丽珠微球科技有限公司 | 氢溴酸伏硫西汀缓释微球、其制剂、其制备方法及应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018086534A1 (zh) * | 2016-11-09 | 2018-05-17 | 广东东阳光药业有限公司 | 氢溴酸沃替西汀长效注射制剂 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110433131B (zh) * | 2018-05-03 | 2024-09-03 | 广东东阳光药业股份有限公司 | 一种药物组合物 |
-
2021
- 2021-03-12 CN CN202180009518.XA patent/CN115052601B/zh active Active
- 2021-03-12 WO PCT/CN2021/080384 patent/WO2021180196A1/zh not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018086534A1 (zh) * | 2016-11-09 | 2018-05-17 | 广东东阳光药业有限公司 | 氢溴酸沃替西汀长效注射制剂 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023083212A1 (zh) * | 2021-11-10 | 2023-05-19 | 广东东阳光药业有限公司 | 一种喹啉类药物的组合物 |
| CN114681434A (zh) * | 2022-03-08 | 2022-07-01 | 福建瑞泰来医药科技有限公司 | 一种氢溴酸伏硫西汀口溶膜剂及其制备方法 |
| CN114681434B (zh) * | 2022-03-08 | 2023-10-31 | 福建瑞泰来医药科技有限公司 | 一种氢溴酸伏硫西汀口溶膜剂及其制备方法 |
| CN120037190A (zh) * | 2025-03-04 | 2025-05-27 | 珠海市丽珠微球科技有限公司 | 氢溴酸伏硫西汀缓释微球、其制剂、其制备方法及应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115052601B (zh) | 2023-03-24 |
| CN115052601A (zh) | 2022-09-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wang et al. | Facile nose-to-brain delivery of rotigotine-loaded polymer micelles thermosensitive hydrogels: In vitro characterization and in vivo behavior study | |
| EP1660037B1 (en) | Aripiprazole injectable suspension | |
| EP3513809B1 (en) | Medicinal composition comprising tivozanib | |
| JP6072121B2 (ja) | リスペリドン徐放性ミクロスフェア組成物 | |
| WO2021180196A1 (zh) | 一种哌嗪基类药物的组合物 | |
| WO2018086534A1 (zh) | 氢溴酸沃替西汀长效注射制剂 | |
| CN112545995A (zh) | 一种阿立哌唑缓释微球及其制备方法 | |
| CN108261394A (zh) | 一种盐酸卡利拉嗪注射制剂及其制备方法和用途 | |
| CN103417492A (zh) | 含有奥氮平的生物降解微球制剂及其制备方法 | |
| CN116251186A (zh) | 一种酪氨酸激酶抑制剂眼用制剂及其制备方法和用途 | |
| Dhyani et al. | A new vision to eye: Novel ocular drug delivery system | |
| CN114681406B (zh) | 一种卡利拉嗪长效缓释微球及其制备方法 | |
| WO2023083212A1 (zh) | 一种喹啉类药物的组合物 | |
| CN113952298B (zh) | 硫酸头孢喹肟纳米混悬液及其制备方法 | |
| CN115671057A (zh) | 一种卢美哌隆药物组合物、长效微球缓释制剂及其制备方法 | |
| US20250319020A1 (en) | Dual chamber syringe for administering a hormone encapsulated by a hydrogel | |
| CN107510648A (zh) | 一种普拉克索纳米晶体透皮凝胶及其制备方法 | |
| CN109998991A (zh) | 一种盐酸鲁拉西酮长效肌肉注射纳米混悬液及其制备方法 | |
| WO2022135343A1 (zh) | 维拉佐酮药物组合物、其制备方法及应用 | |
| El-Ela et al. | Nose to brain delivery of dapoxetine-loaded PLGA nanoparticle for treatment of premature ejaculation distress in normal and diabetic rats with in silico targeting brain FOX and serotonin proteins | |
| CN103191059A (zh) | 溴新斯的明多囊脂质体及其制备方法 | |
| JP7837861B2 (ja) | 薬物組成物 | |
| CN104546774B (zh) | 一种格列美脲片 | |
| CN118787642A (zh) | 一种布瑞哌唑药物组合物及其制备方法和用途 | |
| CN120284882A (zh) | 氟维司群药物组合物、其制备方法及应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21767849 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 21767849 Country of ref document: EP Kind code of ref document: A1 |