WO2022135343A1 - 维拉佐酮药物组合物、其制备方法及应用 - Google Patents
维拉佐酮药物组合物、其制备方法及应用 Download PDFInfo
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- WO2022135343A1 WO2022135343A1 PCT/CN2021/139678 CN2021139678W WO2022135343A1 WO 2022135343 A1 WO2022135343 A1 WO 2022135343A1 CN 2021139678 W CN2021139678 W CN 2021139678W WO 2022135343 A1 WO2022135343 A1 WO 2022135343A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- vilazodone
- microns
- pharmaceutical composition
- limited
- sodium
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- 229960003740 vilazodone Drugs 0.000 title claims abstract description 143
- SGEGOXDYSFKCPT-UHFFFAOYSA-N vilazodone Chemical compound C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 SGEGOXDYSFKCPT-UHFFFAOYSA-N 0.000 title claims abstract description 143
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- 239000007787 solid Substances 0.000 claims abstract description 40
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 56
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 18
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 18
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 18
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 16
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
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- 230000001788 irregular Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 102220042174 rs141655687 Human genes 0.000 description 1
- 102220076495 rs200649587 Human genes 0.000 description 1
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- 238000002633 shock therapy Methods 0.000 description 1
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- 239000001488 sodium phosphate Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
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- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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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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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Definitions
- the invention relates to a vilazodone pharmaceutical composition, a preparation method and application thereof, and belongs to the field of pharmaceutical preparations.
- Depression is a common psychiatric disorder with signs and symptoms including: low mood, loss of interest in normal activities, significant changes in weight or appetite, insomnia or excessive sleepiness (somnia), restlessness/pacing (psychomotor agitation) ), increased fatigue, feelings of guilt or inferiority, slow thinking or inattention, and in severe cases, self-injury and suicidal impulses.
- the disease severely affects people's ability to work, sleep, study, eat and enjoy pleasurable activities.
- TCA tricyclic antidepressant
- the drug has a slow onset of action and is accompanied by serious adverse reactions, such as cardiotoxicity;
- the second class of antidepressants is a monoamine oxidase inhibitor (MAOI), which can delay the degradation of NE and 5-HT in the brain, To prolong the action time of these transmitters; in the 1980s, a new class of antidepressants, the selective serotonin reuptake inhibitor (SSRI), was developed, which can inhibit the presynaptic membrane on 5-HT.
- MAOI monoamine oxidase inhibitor
- SSRI selective serotonin reuptake inhibitor
- HT neurotransmitter receptor
- SSRIs are less effective than TCAs in the treatment of major depressive disorder, and because SSRIs non-selectively stimulate various subtypes of the 5-HT receptor, there are some associated adverse effects.
- buspirone has a high affinity for the 5-HT 1A receptor, a finding that has led to the development of selective 5-HT 1A receptor agonist antidepressants.
- vilazodone hydrochloride (trade name Viibryd) plain tablet for the treatment of major depressive disorder in adults. Viibryd is produced by PGxHealth, New Haven, Conn.
- Vilazodone hydrochloride is a dual-active drug that is a serotonin 1A (5-HT 1A) partial agonist and a selective serotonin (5-HT) reuptake inhibitor (SSRI) and is the first indolyl New amine antidepressants.
- the dosage forms of vilazodone hydrochloride listed abroad are 10mg, 20mg and 40mg respectively.
- such small-dose tablets have disadvantages such as frequent medication, difficulty in swallowing, and unpleasant odor of the drug that affects patient compliance. Therefore, finding a pharmaceutical composition of vilazodone with long-acting sustained release, reducing the frequency of administration and improving patient compliance is a technical problem that needs to be solved urgently at present.
- the present invention provides a vilazodone pharmaceutical composition, which comprises vilazodone solid particles, and the particle size of the vilazodone solid particles is that Dv(10) is not greater than 20 microns, Dv(50) is not greater than 50 microns and Dv(90) is not greater than 100 microns.
- the solid particles of vilazodone may be selected from solid particles of vilazodone, a pharmaceutically acceptable salt of vilazodone (eg, hydrochloride) or a solvate thereof.
- the particle size of the vilazodone solid particles may be Dv(10) not greater than 10 microns, or may be not greater than 8 microns, such as 0.1 to 8 microns, such as 0.1 microns, 0.2 microns , 0.5 microns, 1 microns, 2 microns, 3 microns, 4 microns, 5 microns, 6 microns, 7 microns or 8 microns, examples of which can be 7.187 microns, 147.16 nanometers, 4.813 microns, 5.522 microns, 0.808 microns, 187.63 nanometers, 0.873 microns, 4.517 microns, 6.708 microns, 7.483 microns, 4.737 microns, 4.759 microns, 2.105 microns, 8.4 microns.
- the particle size of the vilazodone solid particles may be Dv(50) not greater than 40 microns, or not greater than 30 microns, such as 0.1-30 microns, such as 0.1 microns, 0.2 microns , 0.5 microns, 1 microns, 2 microns, 3 microns, 4 microns, 5 microns, 6 microns, 7 microns, 8 microns, 9 microns, 10 microns, 11 microns, 12 microns, 13 microns, 14 microns, 15 microns, 16 microns microns, 17 microns, 18 microns, 19 microns, 20 microns, 21 microns, 22 microns, 23 microns, 24 microns, 25 microns, 26 microns, 27 microns, 28 microns, 29 microns, or 30 microns, examples of which may be 17.245 microns , 322.47 nm, 25.913 micron
- the particle size of the vilazodone solid particles may be Dv(90) not greater than 80 microns, or may be not greater than 50 microns, such as 0.1-50 microns, such as 0.1 microns, 0.2 microns , 0.5 microns, 1 microns, 2 microns, 3 microns, 4 microns, 5 microns, 6 microns, 7 microns, 8 microns, 9 microns, 10 microns, 11 microns, 12 microns, 13 microns, 14 microns, 15 microns, 16 microns microns, 17 microns, 18 microns, 19 microns, 20 microns, 21 microns, 22 microns, 23 microns, 24 microns, 25 microns, 26 microns, 27 microns, 28 microns, 29 microns, 30 microns, 31 microns, 32 microns, 33 microns, 34 microns, 35 microns,
- the vilazodone pharmaceutical composition may further comprise a carrier.
- the carrier can be a non-oily carrier or an oily carrier.
- the non-oil carrier includes but is not limited to water.
- the water can be conventional commercially available water for injection, preferably sterile water for injection.
- the oily carrier includes, but is not limited to, one or more of castor oil, triglycerides, cottonseed oil, and sesame oil.
- the vilazodone pharmaceutical composition may further comprise one or more selected from the group consisting of: suspending agent, wetting agent, osmotic pressure regulator, solvent, stabilizer, buffer , pH adjusters, surfactants, polymers, electrolytes and non-electrolytes.
- the polymer may be a cross-linked polymer and/or a non-cross-linked polymer.
- the suspending agent includes, but is not limited to, one or more of sodium carboxymethyl cellulose, polyethylene glycol and povidone.
- the wetting agent includes, but is not limited to, one or more of poloxamer, povidone, sodium docusate, sodium deoxycholate and Tween.
- the Tween can be a conventional commercially available Tween reagent, such as one or more of Tween 20 and Tween 80.
- the osmotic pressure regulator includes, but is not limited to, one or more of sodium chloride, mannitol and sucrose.
- the solvent includes, but is not limited to, water for injection.
- the stabilizers include, but are not limited to, antioxidants, metal ion chelating agents, polyethylene oxide (PEO), polyethylene oxide derivatives, polysorbates, deoxycholic acid Sodium, Docusate Sodium, Poloxamer, Polyethoxylated Vegetable Oil, Polyethoxylated Castor Oil, Sorbitan Palmitate, Lecithin, Polyvinyl Alcohol, Human Serum Albumin, Polyvinylpyrrolidone , one or more of povidone, polyethylene glycol, sodium chloride, calcium chloride, dextrose, glycerol, mannitol, and cross-linked polymers.
- PEO polyethylene oxide
- polyethylene oxide derivatives polysorbates
- deoxycholic acid Sodium Docusate Sodium
- Poloxamer Polyethoxylated Vegetable Oil
- Polyethoxylated Castor Oil Sorbitan Palmitate
- Lecithin Polyvinyl Alcohol
- Human Serum Albumin Polyvinylpyrrolidone
- the antioxidants include, but are not limited to, one or more of citric acid, vitamin C and vitamin E.
- the metal ion chelating agent includes but is not limited to ethylenediaminetetraacetic acid (EDTA).
- the poloxamers include but are not limited to one or more of poloxamer 188, poloxamer 124 and poloxamer 407.
- the polysorbate includes, but is not limited to, one or more of polysorbate 80 and polysorbate 20. Described povidone includes but is not limited to: one or more of povidone K12, povidone K17, PLASDONETM C-12 povidone, PLASDONETM C-17 povidone and PLASDONETM C-30 povidone. kind.
- the polyethylene glycols include but are not limited to polyethylene glycol 3350.
- the cross-linked polymer includes but is not limited to sodium carboxymethyl cellulose.
- the buffering agent includes, but is not limited to: phosphoric acid, phosphate, citric acid (citric acid), sodium citrate (sodium citrate), tris (Tris), Buffers of sodium hydroxide, hydrochloric acid (HCl) or mixtures thereof.
- the pH adjusting agent includes, but is not limited to, phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide.
- the phosphates include, but are not limited to, sodium dihydrogen phosphate, disodium hydrogen phosphate, anhydrous or hydrate of sodium dihydrogen phosphate, and anhydrous or hydrate of disodium hydrogen phosphate
- disodium hydrogen phosphate monohydrate Na 2 HPO 4 ⁇ H 2 O
- disodium hydrogen phosphate dihydrate Na 2 HPO 4 ⁇ 2H 2 O
- disodium hydrogen phosphate anhydrous no water Na 2 HPO 4
- sodium dihydrogen phosphate monohydrate NaH 2 PO 4 ⁇ H 2 O
- sodium dihydrogen phosphate dihydrate NaH 2 PO 4 ⁇ 2H 2 O
- anhydrous sodium dihydrogen phosphate anhydrous sodium dihydrogen phosphate (anhydrous one or more of NaH 2 PO 4 ).
- the co-solvent includes, but is not limited to, one or more of ethanol and propylene glycol.
- the weight fraction of the vilazodone solid particles can be 1.00% to 50.00%, or 2.00% to 45.00%, such as 2.00%, 3.00%, 4.00%, 5.00% , 6.00%, 7.00%, 8.00%, 9.00%, 10.00%, 11.00%, 12.00%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 19.00%, 20.00%, 21.00%, 22.00 %, 23.00%, 24.00%, 25.00%, 30.00%, 35.00%, 40.00% or 45.00%, examples of which may be 5.00% or 30.00%; the weight fraction refers to the weight of the vilazodone solid particles. Percentage of the total weight of the lazodone pharmaceutical composition.
- the weight fraction of the wetting agent can be 0-5.00%, such as 1.00%, 2.00%, 3.00%, 4.00%, 5.00%, such as 1.00%; the The weight fraction refers to the percentage of the weight of the surfactant to the total weight of the vilazodone pharmaceutical composition.
- the weight fraction of the osmotic pressure regulator can be 0-5.00%, such as 0, 1.00%, 2.00%, 3.00%, 4.00%, 5.00%, such as 2.15% ;
- the weight fraction refers to the percentage of the weight of the osmotic pressure regulator to the total weight of the vilazodone pharmaceutical composition.
- the weight fraction of the buffer may be 0-1.00%, such as 0, 0.10%, 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.70% , 0.80%, 0.90%, 1.00%; the weight fraction refers to the percentage of the weight of the buffer in the total weight of the vilazodone pharmaceutical composition.
- the weight fraction of the stabilizer may be 0-1.00%, such as 0, 0.10%, 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.70% , 0.80%, 0.90%, 1.00%, such as 0.60%; the weight fraction refers to the percentage of the weight of the stabilizer in the total weight of the vilazodone pharmaceutical composition.
- the pH adjusting agent can be used in an amount ranging from 6.5 to 8.0 to adjust the pH of the composition solution, such as 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4 , 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0, such as 7.4.
- the vilazodone pharmaceutical composition may include the following components by weight percentage: 1.00%-50.00% vilazodone solid particles, 0-5.00% wetting agent, 0-5.00% stabilizer, 0-5.00% ⁇ 5.00% osmotic pressure regulator, 0-1.00% buffer salt and solvent.
- the weight/volume (g/mL) percentage of the vilazodone solid particles may be 1.00% to 50.00%, or 2.00% to 45.00%. , such as 2.00%, 3.00%, 4.00%, 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, 10.00%, 11.00%, 12.00%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 19.00%, 20.00%, 21.00%, 22.00%, 23.00%, 24.00%, 25.00%, 30.00%, 35.00%, 40.00% or 45.00%, examples of which may be 5.00% or 30.00%.
- the weight/volume (g/mL) percentage of the wetting agent may be 0 to 5.00%, such as 1.00%, 2.00%, 3.00%, 4.00%, 5.00%, such as 1.00%; the said percentage refers to the mass/volume percentage (g/mL) of the weight of the component in the volume of the vilazodone pharmaceutical composition.
- the weight/volume (g/mL) percentage content of the osmotic pressure regulator may be 0 to 5.00%, such as 0, 1.00%, 2.00%, 3.00%, 4.00%, 5.00%, such as 2.15%; the said percentage refers to the mass/volume percentage (g/mL) of the weight of the component in the volume of the vilazodone pharmaceutical composition.
- the weight/volume (g/mL) percentage content of the buffer may be 0-1.00%, such as 0, 0.10%, 0.20%, 0.30%, 0.40% , 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%; wherein the percentages refer to the mass/volume percentage (g/mL) of the weight of the component in the volume of the vilazodone pharmaceutical composition .
- the weight/volume (g/mL) percentage of the stabilizer can be 0-1.00%, such as 0, 0.10%, 0.20%, 0.30%, 0.40% , 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%, such as 0.60%; wherein the percentage refers to the weight of the component in the volume of the vilazodone pharmaceutical composition by mass/volume percentage ( g/mL).
- the pH adjusting agent can be used in an amount ranging from 6.5 to 8.0 to adjust the pH of the composition solution, such as 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4 , 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0, such as 7.4.
- the vilazodone pharmaceutical composition may include the following components in terms of weight/volume (g/mL) percentage: 1.00%-50.00% vilazodone solid particles, 0-5.00% wetting agent , 0-5.00% stabilizer, 0-5.00% osmotic pressure regulator, 0-1.00% buffer salt and solvent; wherein the percentages refer to the weight of each component accounting for the mass/volume of the vilazodone pharmaceutical composition Volume percent (g/mL).
- the vilazodone pharmaceutical composition can be selected from one of the following prescriptions:
- Recipe b 5% vilazodone hydrochloride, 1% Tween 20, 0.3% PVPK12, 0.3% sodium deoxycholate, preferably the balance is water, wherein the percentage refers to the weight of each component in the vilazodone Percentage of the total weight of the ketone pharmaceutical composition;
- Formulation c 20% vilazodone hydrochloride, 1% Tween 20, 0.3% PVPk12, 0.3% sodium deoxycholate, 0.45% disodium hydrogen phosphate, 0.09% sodium dihydrogen phosphate, 2.5% mannitol, 0.18% carboxylate Methylcellulose sodium, preferably the balance is water, wherein the percentage refers to the percentage of the weight of each component in the total weight of the vilazodone pharmaceutical composition;
- Prescription d 36.3% vilazodone hydrochloride, 0.91% Tween 20, 0.34% disodium hydrogen phosphate, 0.07% sodium dihydrogen phosphate, 2.0% mannitol, 0.21% sodium carboxymethyl cellulose, preferably the balance is water, wherein said percentage refers to the percentage of the weight of each component accounting for the total weight of the vilazodone pharmaceutical composition;
- Prescription f 30% ⁇ 40% vilazodone hydrochloride, 1% Tween 20, 0% ⁇ 0.3% PVP K12, 0.33% ⁇ 0.39% disodium hydrogen phosphate, 0.07% ⁇ 0.08% sodium dihydrogen phosphate, 1.6% ⁇ 2.2% mannitol, 0% ⁇ 1.0% sodium carboxymethyl cellulose, preferably the balance is water, wherein the percentage refers to the percentage of the weight of each component to the total weight of the vilazodone pharmaceutical composition.
- vilazodone hydrochloride 30% vilazodone hydrochloride, 1% Tween 20, 2.15% mannitol, 0.08% anhydrous sodium dihydrogen phosphate, 0.4% anhydrous disodium hydrogen phosphate, preferably the balance is water, wherein the Percentage refers to the mass/volume percentage (g/mL) of the weight of each component in the volume of the vilazodone pharmaceutical composition;
- Prescription bv 5% vilazodone hydrochloride, 1% Tween 20, 0.3% PVPK12, 0.3% sodium deoxycholate, preferably the balance is water, wherein the percentages refer to the weight of each component in the vilazodone The mass/volume percent (g/mL) of the volume of the ketone pharmaceutical composition;
- Prescription cv 20% vilazodone hydrochloride, 1% Tween 20, 0.3% PVPk12, 0.3% sodium deoxycholate, 0.45% disodium hydrogen phosphate, 0.09% sodium dihydrogen phosphate, 2.5% mannitol, 0.18% carboxylate Methylcellulose sodium, preferably the balance is water, wherein the percentage refers to the mass/volume percentage (g/mL) of the weight of each component in the volume of the vilazodone pharmaceutical composition;
- Prescription dv 36.3% vilazodone hydrochloride, 0.91% Tween 20, 0.34% disodium hydrogen phosphate, 0.07% sodium dihydrogen phosphate, 2.0% mannitol, 0.21% sodium carboxymethyl cellulose, preferably the balance is water, wherein said percentage refers to the mass/volume percentage (g/mL) of the weight of each component in the volume of the vilazodone pharmaceutical composition;
- Prescription ev 30% vilazodone hydrochloride, 1% Tween 20, 0.38% disodium hydrogen phosphate, 0.08% sodium dihydrogen phosphate, 2.20% mannitol, 0.23% sodium carboxymethylcellulose, preferably the balance is water, wherein said percentage refers to the mass/volume percentage (g/mL) of the weight of each component in the volume of the vilazodone pharmaceutical composition;
- Prescription fv 30% ⁇ 40% vilazodone hydrochloride, 1% Tween 20, 0% ⁇ 0.3% PVP K12, 0.33% ⁇ 0.39% disodium hydrogen phosphate, 0.07% ⁇ 0.08% sodium dihydrogen phosphate, 1.6% ⁇ 2.2% mannitol, 0% ⁇ 1.0% sodium carboxymethyl cellulose, preferably the balance is water, wherein the percentage refers to the weight of each component accounts for the mass/volume percentage of the volume of the vilazodone pharmaceutical composition ( g/mL).
- the sedimentation volume ratio (H/H 0 ) of the vilazodone pharmaceutical composition is above 0.8, such as 0.8-1.0, such as 0.81-0.99, preferably greater than 0.8.
- the present invention also provides the preparation method of the described vilazodone pharmaceutical composition, which comprises the following steps:
- Step 1 Mix the vilazodone solid particles with other components in the formula to obtain a premix
- Step 2 The premix obtained in Step 1 is co-milled with zirconium beads to obtain the vilazodone pharmaceutical composition.
- step 1 the mixing is preferably stirring and mixing.
- the particle size of the zirconium beads may be 0.01 mm ⁇ 2 mm, such as 0.1 mm, 0.3 mm, 0.6 mm or 1 mm, such as 0.3 mm.
- the volume ratio of the zirconium beads to the premix is preferably 1 to 5, such as 1, 1.5, 2 or 3, such as 1.5.
- the grinding time may be 1 minute to 24 hours, or 5 minutes to 20 hours, for example, 5 to 15 hours, such as 10 hours.
- the zirconium beads refer to conventional commercially available zirconia beads.
- the present invention also provides a pharmaceutical preparation, comprising the vilazodone pharmaceutical composition.
- the present invention also provides the application of the vilazodone pharmaceutical composition in the preparation of medicine, for example, the application in the preparation of the vilazodone pharmaceutical preparation.
- the medicament acts as a serotonin 1A (5-HT 1A ) partial agonist and/or a selective serotonin (5-HT) reuptake inhibitor (SSRI); more preferably, the The medicaments are used to prevent and/or treat depression, such as major depressive disorder in adults.
- SSRI selective serotonin 1A reuptake inhibitor
- the vilazodone pharmaceutical preparations include, but are not limited to, one or more of tablets, granules, capsules, pellets, oral liquids, and injections.
- the tablet includes, but is not limited to, one or more of sustained release tablet, osmotic pump tablet and orally disintegrating tablet.
- the injection can be a liquid injection, a powder for injection or a tablet for injection; for example, the liquid injection can be a suspension, such as an aqueous suspension or a powder for suspension; for example, the suspension The powder can be lyophilized for injection.
- the injection can be a long-acting injection;
- the long-acting injection can be a water suspension, or a powder for suspension, and a specific diluent is used to disperse it into a suspension for temporary use. .
- the concentration of the vilazodone in the long-acting injection is not less than 50 mg/ml.
- the present invention also provides a vilazodone pharmaceutical preparation, which contains the above-mentioned vilazodone pharmaceutical composition.
- the vilazodone pharmaceutical formulation has the dosage form selection and/or vilazodone concentration as described above.
- the present invention also provides the above-mentioned vilazodone pharmaceutical composition, drug and/or vilazodone pharmaceutical preparation as serotonin 1A (5-HT 1A) partial agonist and/or selective serotonin (5-HT) Use of reuptake inhibitors (SSRIs).
- serotonin 1A serotonin 1A
- SSRIs reuptake inhibitors
- the present invention also provides the use of the above-mentioned vilazodone pharmaceutical composition, medicine and/or vilazodone pharmaceutical preparation in preventing and/or treating depression, such as adult major depression.
- the present invention also provides a method of preventing and/or treating depression, such as major depressive disorder in adults, comprising administering the above-mentioned vilazodone pharmaceutical composition, drug and/or vilazodone pharmaceutical preparation to a patient in need, such as a human .
- the present invention also provides a method for partially agonizing serotonin 1A (5-HT 1A ) and/or selectively inhibiting the reuptake of serotonin (5-HT), comprising combining the above-mentioned vilazodone pharmaceutical composition, medicament and A pharmaceutical formulation of vilazodone is administered to a patient, eg, a human, in need thereof.
- the active ingredient in the pharmaceutical composition of the present invention is vilazodone, a pharmaceutically acceptable salt or a solvate thereof known in the prior art
- the pharmaceutical composition can be applied in the prior art Known diseases or conditions to which vilazodone, a pharmaceutically acceptable salt or solvate thereof is applicable.
- the "Dv(10)”, “Dv(25)”, “Dv(50)”, “Dv(75)” and “Dv(90)” are Refers to the volume-weighted particle diameter where cumulative 10 v/v%, 25 v/v%, 50 v/v%, 75 v/v% or 90 v/v% of particles respectively have equal or smaller diameters when measured. For example, if the Dv(50) of a population of particles is about 25 microns, then 50% of the particles by volume have a diameter of less than or equal to about 25 microns.
- Particle diameter parameters in the context of this application such as “D(10)”, “D(25)”, “D(50)”, “D(75)” and “D(90)", unless otherwise specified, are Refers to the volume-weighted particle diameter, which has the same meaning as “Dv(10)”, “Dv(25)”, “Dv(50)”, “Dv(75)” and “Dv(90)", respectively.
- the reagents and raw materials used in the present invention are all commercially available.
- the room temperature refers to an ambient temperature ranging from 10°C to 35°C.
- the positive progress effect of the present invention is that: the vilazodone pharmaceutical composition of the present invention improves the defects of the existing vilazodone hydrochloride tablets, such as frequent medication, difficulty in swallowing, and bad smell of the drug affecting the compliance of patients, and has a long-term effect. It has obvious advantages such as sustained release, reduced dosing frequency, and improved patient compliance, and has a good market prospect.
- FIG. 1 is a particle size distribution diagram of vilazodone solid particles in the suspension in Example 1.
- FIG. 1 is a particle size distribution diagram of vilazodone solid particles in the suspension in Example 1.
- FIG. 2 is a polarized light microscope particle size diagram of the vilazodone solid particles in the suspension in Example 1, and the scale is 15 microns.
- FIG. 3 is a particle size distribution diagram of vilazodone solid particles in the suspension in Example 2.
- FIG. 3 is a particle size distribution diagram of vilazodone solid particles in the suspension in Example 2.
- FIG. 4 is a particle size distribution diagram of vilazodone solid particles in the suspension of Formulation 3 in Example 3.
- FIG. 4 is a particle size distribution diagram of vilazodone solid particles in the suspension of Formulation 3 in Example 3.
- FIG. 5 is a particle size distribution diagram of vilazodone solid particles in the suspension of Formulation 4 in Example 3.
- FIG. 5 is a particle size distribution diagram of vilazodone solid particles in the suspension of Formulation 4 in Example 3.
- FIG. 6 is a particle size distribution diagram of vilazodone solid particles in the suspension of Formulation 5 in Example 3.
- FIG. 6 is a particle size distribution diagram of vilazodone solid particles in the suspension of Formulation 5 in Example 3.
- FIG. 7 is a particle size distribution diagram of vilazodone solid particles in the suspension of Formulation 6 in Example 3.
- FIG. 7 is a particle size distribution diagram of vilazodone solid particles in the suspension of Formulation 6 in Example 3.
- FIG. 8 is an electron microscope photograph of vilazodone solid particles in the suspension of Formulation 6 in Example 3.
- FIG. 8 is an electron microscope photograph of vilazodone solid particles in the suspension of Formulation 6 in Example 3.
- Figure 9 The drug-time curve of vilazodone administered to the animals in the G1 group in Example 4.
- Figure 10 The drug-time curve of vilazodone administered to the G2 group animals in Example 4.
- Fig. 11 The drug-time curve of vilazodone administered to G3 group animals in Example 4.
- Figure 13 The drug-time curve of vilazodone administered to the animals in the G5 group in Example 4.
- Fig. 14 The mean drug time curve of vilazodone administered to animals in G1-G5 groups in Example 4.
- the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.
- the experimental methods without specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
- the unit of mass volume ratio (W/V x 100%) in the context of the present invention is g/mL, and the disodium hydrogen phosphate and sodium dihydrogen phosphate used are anhydrous, with no The proportion of the water is calculated based on the molecular weight of the water.
- the vilazodone solid in the suspension is a lump of about 6-38 ⁇ m.
- the raw and auxiliary materials are weighed, and the initial suspension is prepared by stirring and mixing.
- the initial suspension was added with 1.5 times the volume of 0.3 mm zirconium beads, placed in a grinding jar for grinding, and ground for 10 hours to obtain a vilazodone pharmaceutical composition. Grinding is carried out with a ball mill.
- the parameters of the planetary ball mill are set: Fixed parameters: the diameter of the rotating disc is about 191mm, the diameter of the rotating cup is about 71mm, the height of the rotating cup is about 70mm, the capacity of the rotating cup is 100ml, and the rotating speed of the rotating disc is 10r/min. Rotation speed: 720r/ min.
- the particle size was measured by a nanoparticle particle size analyzer (NICOMP Particle Sizing Systems, parameter setting: dispersion medium: water; refractive index of dispersion medium: 1.333; viscosity: 0.933cp; temperature: 23 °C, light intensity setting value: 300 kHz).
- NICOMP Particle Sizing Systems parameter setting: dispersion medium: water; refractive index of dispersion medium: 1.333; viscosity: 0.933cp; temperature: 23 °C, light intensity setting value: 300 kHz).
- the raw and auxiliary materials are weighed according to the prescription amount in Table 4, and the initial suspension is prepared by stirring and mixing.
- the initial suspension was added with 1.5 times the volume of 0.6mm zirconium beads, placed in a grinding jar for grinding, and ground for 0min, 5min, 10min, and 10 hours to obtain the vilazodone drug combination of prescriptions 3, 4, 5, and 6, respectively. thing.
- the parameters of the planetary ball mill are set as fixed parameters: the diameter of the orbital disc is about 191mm, the diameter of the autorotation cup is about 71mm, the height of the autorotation cup is about 70mm, the capacity of the autorotation cup is 100ml, the rotation speed of the orbital disc is 10r/min, and the rotation speed is 720r/ min.
- the particle size and distribution of prescriptions 3, 4 and 5 were measured by laser particle size analyzer.
- the parameters of the laser particle size analyzer were set as follows: dispersion medium: water; refractive index of dispersion medium: 1.333; absorption rate of sample material: 0.05; refractive index of sample material: 1.711.
- the particle size and distribution of prescription 6 were measured by a nanoparticle particle size analyzer.
- the instrument was NICOMP Particle Sizing Systems. Parameter settings: dispersion medium: water; dispersion medium refractive index: 1.333; viscosity: 0.933cp; temperature: 23 °C, light intensity setting Value: 300kHz.
- the particle size distribution data of the vilazodone solid particles in the suspensions of the formulations 3, 4 and 5 are shown in Table 5, Figures 4, 5 and 6.
- the particle size distribution data of the vilazodone solid particles in the formulation 6 suspension are shown in Table 6 and FIG. 7 .
- the morphology and size were observed by scanning electron microscope (FEI, model F50). Scanning electron microscope voltage 10kv, beam current 2.0 test. The electron microscope photo of the vilazodone solid particles in the suspension after the grinding of the prescription 6 is shown in FIG. 8 . Irregular massive particles of 0.1 to 0.5 ⁇ m were observed.
- control group (G1 group: prescription containing vilazodone 0.8%, cellulose HPMC 0.25% aqueous solution), test group 1 (G2 group: Example 3 prescription 3), test group 1 (G2 group: Example 3 prescription 3), test group 1 Test group 2 (G3 group: embodiment 3 prescription 4), test group 3 (G4 group: embodiment 3 prescription 5) and test group 4 (G5 group: embodiment 3 prescription 6) a total of 5 groups, each group 3 Only animals, the control group was given a dose of 4 mg/kg by intramuscular injection, and the test group was given an intramuscular dose of 120 mg/kg.
- Blood samples were collected from animals in G1 group before and 0.5h, 1h, 2h, 3h, 5h, 7h, and 24h after the first (D1) administration. , 7h, 24h, 96h, 168h, 264h, 360h, 480h, 600h, 720h, 840h, 960h, 1080h, blood samples were collected. Before blood collection, place the sampling tube containing EDTA-K 2 in an ice bath; add the collected blood to the sampling tube, invert manually at least 5 times, and store in an ice bath; Centrifugation was completed within 2 h. The centrifuged plasma was transferred to a new labeled Ep tube and stored below -60°C.
- the concentration of vilazodone in rat plasma was analyzed by LC-MS/MS method, and the lower limit of quantification of this method was 0.500 ng/mL.
- Concentration data were analyzed using the non-compartmental approach (NCA) of the metabolic kinetic data analysis software WinNonlin 8.0.0.3176.
- NCA non-compartmental approach
- the main pharmacokinetic parameters of vilazodone in animals are shown in Table 8, and the drug-time curves are shown in Figures 9-14.
- the results showed that the T1/2 and MRTlast of the test group were about 100-150 times and 50-70 times that of the control group, respectively, indicating that the sustained-release effect of the test preparation was significant; the Cmax of the test group was 40%-120 times that of the control group. %, indicating that the tested preparation has no risk of sudden release, the blood concentration is stable, and adverse reactions of poisoning are not easy to occur.
- the raw and auxiliary materials are weighed according to the prescription amount in Table 9, and the initial suspension is prepared by stirring and mixing.
- the initial suspension was added with 1.5 times the volume of 0.6 mm zirconium beads, placed in a grinding jar for grinding, and ground for 10 hours to obtain the vilazodone pharmaceutical composition of prescription 7.
- Grinding is carried out with a ball mill, and the parameters of the planetary ball mill are set as fixed parameters: the diameter of the rotating disk is about 191 mm, the diameter of the rotating cup is about 71 mm, the height of the rotating cup is about 70 mm, the capacity of the rotating cup is 100 ml, the rotating speed of the rotating disk is 10 r/min, and the rotating speed: 720 r /min.
- the particle size and distribution of prescription 7 were measured by a laser particle size analyzer.
- the laser particle size analyzer parameters were set: dispersion medium: water; dispersion medium refractive index: 1.333; sample material absorptivity: 0.05; sample material refractive index: 1.711.
- Table 10 shows the particle size distribution data of the vilazodone solid particles in the formulation 7 suspension.
- Prescription 7 was subjected to accelerated stability experiments at 40° C. and RH 75%, and the test results of related substances are shown in Table 11. The related substances did not change significantly, indicating that the formulation was stable.
- the raw materials and auxiliary materials of different particle diameters were weighed, stirred and mixed to prepare a suspension to obtain prescriptions 8 to 13.
- the particle size and its distribution were measured by a laser particle size analyzer.
- the parameters of the laser particle size analyzer were set as follows: dispersion medium: water; refractive index of dispersion medium: 1.333; absorptivity of sample material: 0.05; refractive index of sample material: 1.711.
- a 22g (outer diameter 0.7mm) needle was used to test the needle penetration of the suspension; the sedimentation volume ratio (H/H 0 ) of the suspension was tested according to the Chinese Pharmacopoeia 2020 edition general rule 0123 method.
- the needle penetration of the test suspension was extracted by 22g (outer diameter 0.7mm) and 23g (outer diameter 0.6mm) needles; the sedimentation volume ratio (H/H 0 ) of the suspension was tested according to the Chinese Pharmacopoeia 2020 edition general rule 0123 method.
- Table 15 shows the osmotic pressure, acupuncture properties, and sedimentation volume ratios of the suspensions in the formulations 14 to 23.
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Abstract
Description
处方1 | 组成(W/V%) |
盐酸维拉佐酮 | 30 |
吐温20 | 1 |
甘露醇 | 2.15 |
无水磷酸二氢钠 | 0.08 |
无水磷酸氢二钠 | 0.4 |
灭菌注射用水 | q.s.100 |
D10(μm) | D25(μm) | D50(μm) | D75(μm) | D90(μm) |
7.187 | 11.160 | 17.245 | 25.717 | 34.657 |
处方No. | D10(μm) | D50(μm) | D90(μm) |
3 | 4.813 | 25.913 | 70.580 |
4 | 5.522 | 13.825 | 24.728 |
5 | 0.808 | 1.210 | 1.744 |
D10(μm) | D25(μm) | D50(μm) | D75(μm) | D90(μm) |
0.873 | 1.125 | 1.550 | 2.074 | 2.597 |
组成 | 百分比(W/V%) |
盐酸维拉佐酮 | 30 |
吐温20 | 1.00 |
磷酸氢二钠 | 0.38 |
磷酸二氢钠 | 0.08 |
甘露醇 | 2.20 |
羧甲纤维素钠 | 0.23 |
灭菌注射用水 | Qs.100 |
Claims (10)
- 一种维拉佐酮药物组合物,其特征在于其包括:维拉佐酮固体粒子,所述的维拉佐酮固体粒子的粒径为:Dv(10)不大于20微米、Dv(50)不大于50微米且Dv(90)不大于100微米;优选地,所述的维拉佐酮固体粒子的粒径Dv(10)不大于10微米,例如不大于8微米;所述的维拉佐酮固体粒子的粒径Dv(50)不大于40微米,例如不大于30微米;所述的维拉佐酮固体粒子的粒径Dv(90)不大于80微米,例如不大于50微米。
- 如权利要求1所述的维拉佐酮药物组合物,其特征在于:所述维拉佐酮固体粒子选自维拉佐酮、维拉佐酮药学上可接受的盐(如盐酸盐)或其溶剂合物的固体粒子。
- 如权利要求2所述的维拉佐酮药物组合物,其特征在于:所述的维拉佐酮药物组合物还包括载体;优选地,所述的载体可以为非油载体或油类载体。
- 如权利要求3所述的维拉佐酮药物组合物,其特征在于:所述的非油载体包括但不限于水;和/或,所述的油性载体包括但不限于蓖麻油、甘油三酸酯、棉籽油和芝麻油等中的一种或多种。
- 如权利要求1-4任一项所述的维拉佐酮药物组合物,其特征在于:所述的维拉佐酮药物组合物还包含选自以下的一种或多种:助悬剂、润湿剂、渗透压调节剂、溶剂、稳定剂、缓冲剂、PH调节剂、表面活性剂、聚合物、电解质和非电解质。
- 如权利要求5所述的维拉佐酮药物组合物,其特征在于:所述的助悬剂包括但不限于羧甲基纤维素钠、聚乙二醇和聚维酮中的一种或多种;和/或,所述的润湿剂包括但不限于泊洛沙姆、聚维酮、多库酯钠、脱氧胆酸钠和吐温中的一种或多种;和/或,所述的渗透压调节剂包括但不限于氯化钠、甘露醇和蔗糖中的一种或多种;和/或,所述的溶剂包括但不限于注射用水;和/或,所述的稳定剂包括但不限于抗氧化剂、金属离子螯合剂、聚环氧乙烷、聚环氧乙烷衍生物、聚山梨醇酯、脱氧胆酸钠、多库酯钠、泊洛沙姆、聚乙氧基化植物油、聚乙氧基化蓖麻油、脱水山梨糖醇棕榈酸酯、卵磷脂、聚乙烯醇、人血清白蛋白、聚乙烯吡咯烷酮、聚维酮、聚乙二醇、氯化钠、氯化钙、右旋糖、丙三醇、甘露糖醇和交联聚合物中的一种或多种;和/或,所述的缓冲剂包括但不限于磷酸、磷酸盐、枸橼酸、枸橼酸钠、盐酸、氢氧化钠、三羟甲基氨基甲烷、氢氧化钠、盐酸或其混合物的缓冲剂;和/或,所述的PH调节剂包括但不限于磷酸、磷酸盐、枸橼酸、枸橼酸钠、盐酸和氢氧化钠。
- 如权利要求6所述的维拉佐酮药物组合物,其特征在于:所述的抗氧化剂包括但不限于枸橼酸、维生素C和维生素E中的一种或多种;和/或,所述的金属离子螯合剂包括但不限于乙二胺四乙酸;和/或,所述的泊洛沙姆包括但不限于泊洛沙姆188、泊洛沙姆124和泊洛沙姆407中的一种或多种;和/或,所述的聚山梨醇酯包括但不限于聚山梨醇酯80和聚山梨醇酯20中的一种或多种;和/或,所述的聚维酮包括但不限于:聚维酮K12、聚维酮K17、PLASDONETM C-12聚维酮、PLASDONETM C-17聚维酮和PLASDONETM C-30聚维酮中的一种或多种;和/或,所述的聚乙二醇包括但不限于聚乙二醇3350;和/或,所述的交联聚合物包括但不限于羧甲基纤维素钠;和/或,所述的磷酸盐包括但不限于磷酸二氢钠、磷酸氢二钠、磷酸二氢钠的无水物或水合物、磷酸氢二钠的无水物或水合物中的一种或多种,例如一水磷酸二氢钠、二水磷酸二氢钠、无水磷酸二氢钠、一水磷酸二氢钠、二水磷酸二氢钠和无水磷酸二氢钠中的一种或多种。
- 如权利要求1-7任一项所述的维拉佐酮药物组合物的制备方法,其包括以下步骤:步骤1:将维拉佐酮固体粒子与配方中的其他组分混合,得到预混物;步骤2:将步骤1得到的预混物与锆珠共同研磨,得到所述的维拉佐酮药物组合物。
- 一种药物制剂,包含如权利要求1-7任一项所述的维拉佐酮药物组合物。
- 如权利要求1-7任一项所述的维拉佐酮药物组合物在制备药物中的应用;优选地,所述的维拉佐酮药物包括但不限于片剂、颗粒剂、胶囊、微丸、口服液和注射剂中的一种或多种;优选地,所述的注射剂为液体注射剂、注射用粉剂或注射用片剂;优选地,所述的注射剂是混悬剂;或者所述的注射剂为长效注射剂;更优选地,所述的混悬剂为水混悬剂或混悬用粉末;所述的长效注射剂为水混悬剂或混悬用粉末。优选地,所述药物作为5-羟色胺1A(5-HT lA)部分激动剂和/或选择性5-羟色胺(5-HT)再摄取抑制剂(SSRI);更优选地,所述药物用于预防和/或治疗抑郁症,例如成人重度抑郁症。
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JP2023538986A JP2024501527A (ja) | 2020-12-23 | 2021-12-20 | ビラゾドン医薬組成物、その製造方法及び応用 |
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EP3360543A1 (en) * | 2017-02-13 | 2018-08-15 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical compositions of vilazodone hydrochloride |
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2021
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- 2021-12-20 EP EP21909339.0A patent/EP4268802A1/en active Pending
- 2021-12-20 WO PCT/CN2021/139678 patent/WO2022135343A1/zh active Application Filing
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EP4268802A1 (en) | 2023-11-01 |
CN114652671A (zh) | 2022-06-24 |
US20240050363A1 (en) | 2024-02-15 |
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