WO2023173182A1 - Vilazodone docusate salt, production process, pharmaceutical composition and use - Google Patents
Vilazodone docusate salt, production process, pharmaceutical composition and use Download PDFInfo
- Publication number
- WO2023173182A1 WO2023173182A1 PCT/BR2022/050092 BR2022050092W WO2023173182A1 WO 2023173182 A1 WO2023173182 A1 WO 2023173182A1 BR 2022050092 W BR2022050092 W BR 2022050092W WO 2023173182 A1 WO2023173182 A1 WO 2023173182A1
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- WIPO (PCT)
- Prior art keywords
- vilazodone
- docusate
- salt
- add
- pharmaceutical composition
- Prior art date
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- 229960003740 vilazodone Drugs 0.000 title claims abstract description 100
- -1 Vilazodone docusate salt Chemical class 0.000 title claims abstract description 42
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 20
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- 238000000034 method Methods 0.000 claims abstract description 38
- 230000008569 process Effects 0.000 claims abstract description 32
- SGEGOXDYSFKCPT-UHFFFAOYSA-N vilazodone Chemical class 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 claims description 74
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 claims description 64
- 229940018602 docusate Drugs 0.000 claims description 54
- RPZBRGFNBNQSOP-UHFFFAOYSA-N vilazodone hydrochloride Chemical compound Cl.C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 RPZBRGFNBNQSOP-UHFFFAOYSA-N 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 30
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
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- 239000004480 active ingredient Substances 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
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- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
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- 238000005056 compaction Methods 0.000 description 1
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- 238000011109 contamination Methods 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 235000013980 iron oxide Nutrition 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 231100001223 noncarcinogenic Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 238000013379 physicochemical characterization Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229960005455 polacrilin Drugs 0.000 description 1
- 229940068917 polyethylene glycols Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229940057977 zinc stearate Drugs 0.000 description 1
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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the present invention relates to a vilazodone salt, specifically, vilazodone docusate, the process for obtaining said salt and a pharmaceutical composition comprising vilazodone docusate.
- the present invention also relates to the use of the vilazodone docusate salt and the use of the composition comprising the respective salt.
- Polymorphic forms or different salts of a given substance may have different chemical and physical properties, such as melting point, chemical reactivity, toxicity, solubility, dissolution rate, rheological properties and density. These characteristics can directly affect the processability and manufacturing of the active pharmaceutical ingredient (IFA) and the pharmaceutical form that contains it, as well as stability, dissolution, absorption in the gastrointestinal tract, bioavailability and organoleptic properties. Thus, the polymorphic form or type of salt of an active pharmaceutical ingredient (IFA) can impact the quality, safety and efficacy of a pharmaceutical product.
- hydrochloride salt of vilazodone are further described in patent applications US9145400, US20140303185, WO201 4049612, US9505744 and US1001 1590.
- Other salts of the active vilazodone with anions other than the hydrochloride are disclosed in documents WO201 4028473 and W O2014049609, the salts being claimed formed from the reaction of the base form of vilazodone with the following acids: phosphoric acid, sulfuric acid, methanesulfonic acid, lactic acid, maleic acid, benzoic acid, hydrobromic acid, oxalic acid, benzenesulfonic acid, para-toluenesulfonic acid, succinic acid, salicylic acid, tartaric acid, fumaric acid, malonic acid, pivalic acid, ascorbic acid and citric acid.
- Hydrochlorides are the most common salts for weak bases, but their widespread use is not only due to convenience, as they are derived from a very strong acid (hydrochloric acid - HCI), favoring the formation of salt, but also because the Chloride ions (Cl ) are part of the group of most abundant electrolytes in the human body and, therefore, are expected not to cause physiological changes in the body.
- hydrochlorides have low molecular weight and low toxicity, they present a decrease in solubility and dissolution rate in solutions with an excess of ions of the same type. This phenomenon is explained based on the law of mass action, for example, in a dissolution medium in HCI, and is known as the “common ion effect”.
- Another important point when choosing a new salt refers to the occurrence of polymorphism.
- an ideal drug must maintain its physical properties for long periods of storage so that repeated observations generate the same characteristics, such as melting point or solubility.
- many salts are polymorphic, that is, they are capable of existing in two or more crystalline forms with different arrangements and/or conformations of molecules and, in addition, they can transform from one form to another in the solid state.
- Polymorphism is a phenomenon that can be observed in more than half of APIs, and can be problematic, especially if one form transforms into another with different physical properties during the production of the drug. This can generate final substances with unpredictable characteristics.
- Vilazodone hydrochloride has low solubility, being a class II API (slightly soluble and very permeable) in the Biopharmaceutical Classification System. Furthermore, vilazodone hydrochloride salt presents many polymorphic crystalline forms (more than a dozen, including anhydrous, hydrate and solvate forms) and amorphous forms.
- Patent applications WO2014199313 and WO201 3175361 describe a process for obtaining vilazodone hydrochloride.
- Patent document WO2013164794 describes crystalline forms A, B and C of vilazodone hydrochloride.
- Patent document EP3360543 describes a pharmaceutical composition
- a pharmaceutical composition comprising vilazodone hydrochloride, crospovidone, lactose monohydrate, microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide and coating, wherein said composition can be incorporated in solid pharmaceutical form, as in a coated tablet, a multilayer tablet, an orally disintegrating tablet, an immediate release tablet, a pill, a capsule, among others.
- FIG. 1 shows the characteristic X-ray diffractogram of vilazodone docusate obtained by synthesis routes (A) and (B).
- Figure 2 shows the X-ray diffractograms of vilazodone docusate (A), vilazodone hydrochloride (B) and sodium docusate (C).
- Figure 3 shows the characteristic infrared absorption spectra of vilazodone docusate (A), sodium docusate (B) and vilazodone hydrochloride (C).
- FIG 4 shows the analysis curves thermogravimetric measurement (TGA) obtained with a heating rate of 10 °C/min for vilazodone docusate (A) and vilazodone hydrochloride (B).
- DSC differential scanning calorimetry
- FIG. 6 shows the infrared absorption spectra for vilazodone docusate after synthesis (A), after incubation at 50 °C and 75% RH for 10 days (B) and stored at ambient conditions for 3 months (C) .
- FIG. 7 shows the X-ray diffractograms for vilazodone docusate after synthesis (A), after incubation at 50 °C and 75% RH for 10 days (B) and stored at ambient conditions for 3 months (C) .
- the present invention relates to a new vilazodone salt, its obtaining process and a pharmaceutical composition comprising it.
- vilazodone salt commercially available in the form of vilazodone hydrochloride
- the present invention reveals the synthesis of a new salt of this active ingredient, vilazodone docusate with improved solubility in a simulated gastric environment, absence of polymorphism, and its potential use in pharmaceutical compositions.
- the compound has greater solubility in hydrochloric acid solutions, due to the absence of the effect of the common ion, and no polymorphs of the new salt were found under the conditions investigated. These characteristics can enable the use of a raw material without the risk of contamination with other polymorphic forms and, mainly, the development of new pharmaceutical forms with improved bioavailability of the active pharmaceutical ingredient.
- the present invention presents as its first object, the vilazodone docusate salt.
- the present invention presents a process for obtaining vilazodone docusate, as described in the first object and in any of its embodiments, comprising the steps of:
- the present invention presents a process for obtaining vilazodone docusate, as described in the first object and in any of its embodiments, comprising the steps of:
- the present invention presents a pharmaceutical composition
- a pharmaceutical composition comprising (a) vilazodone docusate, as described in the first object and in any of its embodiments; and (b) one or more pharmaceutically acceptable excipients.
- the present invention presents the use of vilazodone salt, as described in the first object and in any of its embodiments, for the preparation of a medicine for the treatment of major depressive disorder (MDD).
- MDD major depressive disorder
- the vilazodone docusate salt of the present invention may have fewer impurities, desirable pharmacokinetic properties for immediate and modified release formulations and ease of pharmaceutical processing.
- the expression “peaks expressed in 2-theta degrees” refers to the characteristic peaks of the diffractogram X-ray obtained using a wavelength of 1.54 ⁇ (Cu K-alpha) of vilazodone docusate salt.
- the present invention relates to obtaining and using the salt of vilazodone docusate or 1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate of 5-(4-[4-(5-cyano- 17 J-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxamide, with molecular formula C46H64N5O9S and molecular mass 862 g/mol, for use in pharmaceutical preparations and compositions.
- the present invention presents the vilazodone docusate salt.
- the vilazodone docusate salt presents peaks expressed in degrees 2-theta ( ⁇ 0.2°) to 3.8; 7.5; 1 1 .3; 12.9; 15.2; 18.0; 19.0; 21.6; 22.7; 23.9 and 28.0 on its X-ray diffractogram.
- the vilazodone docusate salt presents specific peaks expressed in degrees 2-theta ( ⁇ 0.2°) to 3.8; 7.5 and 15.2 on your X-ray diffractogram.
- the vilazodone docusate salt presents characteristic bands 3477; 2976; 2926; 2860; 2219; 1735; 1680; 1601; 1022; 961; 940; 888; 853; 810; 761 cm' 1 in its absorption spectrum in the infrared region.
- the salt has a melting point in the range of 172 to 178°C.
- the present invention presents a process for obtaining vilazodone docusate, as described in the first object and in any of its embodiments, comprising the steps of:
- the process comprises the steps of:
- the process comprises the steps of: (i) Add 60 mg of docusate sodium to 200 mL of water in a beaker and stir until complete solubilization;
- the present invention presents a process for obtaining vilazodone docusate, as described in the first object and in any of its embodiments, comprising the steps of:
- the process comprises the steps of:
- the process comprises the steps of:
- the present invention presents a pharmaceutical composition
- a pharmaceutical composition comprising (a) vilazodone docusate, as defined in the first object and in any of its embodiments; and (b) one or more pharmaceutically acceptable excipients.
- the excipients in (b) comprise one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, glidants, lubricants, coloring agents, opacifiers and, optionally, coatings.
- the excipients in (b) comprise one or more pharmaceutically acceptable excipients selected from the group consisting of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and vegetable magnesium stearate.
- the excipients of the composition can be used in other ranges of values (in % by mass) or replaced by excipients with the same function in the formulation.
- lactose is present in the composition of the present invention in the range of 0 to 80%; material with a diluent function, which can be combined or totally replaced by one or more excipients, combined or not, including but not limited to: microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, mannitol, starch, pregelatinized starch , sucrose, erythritol, xylitol, maltitol, glucose, dextrose, kaolin, calcium sulfate and talc in a proportion of 10 to 80% w/w of the composition.
- material with a diluent function which can be combined or totally replaced by one or more excipients, combined or not, including but not limited to: microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, mannitol, starch, pregelatinized starch , sucrose, erythritol, xylitol,
- microcrystalline cellulose is present in the composition of the present invention in the range of 0 to 80%; material with a diluent function, which can be combined or completely replaced by one or more excipients, combined or not, including but not limited to: lactose, dibasic calcium phosphate, tribasic calcium phosphate, mannitol, starch, pregelatinized starch, kaolin, sucrose, erythritol, xylitol, maltitol, glucose, dextrose, calcium sulfate and talc in a ratio of 10 to 80% w/w of the composition.
- material with a diluent function which can be combined or completely replaced by one or more excipients, combined or not, including but not limited to: lactose, dibasic calcium phosphate, tribasic calcium phosphate, mannitol, starch, pregelatinized starch, kaolin, sucrose, erythritol, xylito
- croscarmellose sodium is present in the composition of the present invention in the range of 0 to 5%; usual limit range of this specific excipient.
- This material acts as a disintegrant and can be exempt from the formulation, combined or completely replaced by one or more excipients, combined or not, in a proportion of 2 to 30% w/w of the formulation, including but not limited to: sodium starch glycolate, magnesium and aluminum silicate, magnesium and aluminum silicate, starch, pregelatinized starch, pectins, alginates, microcrystalline cellulose, alginic acid, alpha cellulose, potassium polacrilin, calcium carboxymethylcellulose, sodium carboxymethylcellulose.
- colloidal silicon dioxide is found in the composition of the present invention in the range of 0.05 to 2%; material with a sliding function, which may be exempt from the formulation, combined or replaced by one or more excipients, combined or not with each other, in a proportion of 0.05 to 10% w/w of the formulation, including, but not limited to, talc, magnesium oxide, magnesium trisilicate and cellulose.
- magnesium stearate is present in the composition of the present invention in the range of 0.2 to 5%; material with a lubricant function, which may be exempt from the formulation, combined or replaced by one or more excipients, combined or not, in a proportion of 0.2 to 10% w/w of the formulation, including but not limited to talc, calcium stearate, sodium lauryl sulfate, castor oil, sodium benzoate, hydrogenated vegetable oil, sodium stearyl fumarate, magnesium lauryl sulfate, stearic acid, calcium stearate, glyceryl behenate, glyceryl monostearate, polyethylene glycols, polysorbates and zinc stearate.
- composition pharmaceutical has the following composition:
- Disintegrant from 2 to 30%;
- Lubricant from 0.2 to 10%.
- the pharmaceutical composition has the following composition:
- Lactose monohydrate from 0 to 80%
- Microcrystalline cellulose from 0 to 80%;
- Vegetable magnesium stearate from 0.2 to 5%.
- the pharmaceutical composition has the following composition:
- the composition additionally comprises coating in the range of 1 - 5% weight gain.
- the use of coating on tablets is optional in the recommended range of 1 - 5% weight gain, and ready-made coating systems can be used, such as Opadry®, or proceed with the formation of based films, but not limited to polymers polyvinyl alcohol (PVA) and hydroxypropylmethylcellulose (HMPC), plasticizing agents such as polyethylene glycol (PEG) and triethylcitrate, opacifiers such as titanium dioxide and colorants such as lacquers and iron oxides.
- PVA polyvinyl alcohol
- HMPC hydroxypropylmethylcellulose
- plasticizing agents such as polyethylene glycol (PEG) and triethylcitrate
- opacifiers such as titanium dioxide
- colorants such as lacquers and iron oxides.
- the present invention presents the use of vilazodone salt, as described in the first object and in any of its embodiments, for the preparation of a medicine for the treatment of major depressive disorder (MDD).
- MDD major depressive disorder
- vilazodone salt is also used for the preparation of a medicine for the treatment and prevention of anxiety disorders, bipolarity, mania, dementia, substance-related disorders, sexual dysfunctions, eating disorders, obesity, fibromyalgia, sleep disorders, psychiatric disorders, cerebral infarction, tension, for the therapy of side effects in the treatment of hypertension, cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome and unwanted puerperal lactation.
- the new vilazodone docusate salt may include advantages such as fewer impurities, desirable pharmacokinetic properties for immediate and modified release formulations and ease of pharmaceutical processing.
- the new vilazodone salt based on the counterion Docusate can be an alternative to vilazodone hydrochloride in the production of innovative, safe and effective pharmaceutical forms.
- Obtaining an active pharmaceutical ingredient with improved solubility characteristics, adequate stability and not susceptible to polymorphism opens up possibilities for developing innovative pharmaceutical forms for an already consolidated therapy, such as solutions, soft capsules and hard capsules.
- Example 1 Synthesis methodology - Reaction of vilazodone hydrochloride with sodium docusate in aqueous medium followed by extraction with apolar solvent (A).
- Example 2 Reaction of vilazodone hydrochloride with sodium docusate in DMSO solvent followed by the addition of water with precipitation of the vilazodone docusate salt (B).
- DMSO dimethyl sulfoxide
- B precipitation of the vilazodone docusate salt
- Figure 1 presents the characteristic X-ray diffractogram for the vilazodone docusate salt obtained by synthesis routes (A) and (B) and Table 1 contains the angles and relative intensity of the main peaks in the salt diffractogram.
- Figure 2 the X-ray diffractogram for the vilazodone docusate salt (A) is shown together with the diffractograms of the vilazodone hydrochloride (B) and sodium docusate (C) salts, used as starting reagents, illustrating the difference in position of diffraction peaks for different crystalline forms.
- Figure 4 shows the thermogravimetric analysis (TGA) that indicates a residual moisture of 0.2% by mass of vilazodone docusate (isotherm at 105 ° C for 60 minutes) (A) and a decomposition temperature of approximately 260 °C, a value similar to that found for vilazodone hydrochloride (B).
- TGA thermogravimetric analysis
- DSC Differential Scanning Calorimetry
- Table 2 shows the composition of vilazodone docusate tablets, containing excipients commonly used in the pharmaceutical industry.
- Table 2 Quali-quantitative composition of vilazodone docusate tablets.
- vilazodone docusate is equivalent to 0.498 mg of vilazodone in free base form.
- the dosage is relative to the hydrochloride salt, with 1.00 mg of vilazodone hydrochloride equivalent to 0.92 mg of vilazodone in free base form.
- vilazodone docusate the relationship was used that 1.846 mg of vilazodone docusate are equivalent to 0.92 mg of vilazodone (same concentration as the reference medicine).
- the tablets were obtained by the direct compression process, with good processability characteristics.
- the tablets presented physical characteristics of hardness, friability and disintegration suitable for a pharmaceutical form.
- the IFA (27.690g), a lactose fraction (30g) and microcrystalline cellulose (30g) were homogenized manually with rotational movements for 5 - 15 minutes (mixture 1).
- colloidal silicon dioxide (1.05g) and the remainder of lactose (30g) were added to mixture 1, being homogenized for another 5-15 minutes (mixture 2).
- colloidal magnesium stearate 1.5g was added to mixture 2 and homogenized for another 3 - 5 minutes (final mixture).
- the final mixture was added to the feeder of the compression simulator previously assembled with an EU-B circular die and a 6 mm biconcave circular punch without crease.
- the tablets were obtained with a Default Cycle - 1 compression cycle, machine speed of 25% and compression forces of 4KN to 12KN.
- the resulting ejection forces during the process were ⁇ 100N, indicating good processability of the bulk with low adhesion to the tooling.
- Disintegration was carried out in water at a temperature of 37 °C ⁇ 1 °C and the results showed disintegration times of less than 5 minutes for all tablets evaluated, regardless of hardness.
- the friability test which makes it possible to determine the resistance of the tablets to abrasion, was carried out with 20 tablets in a friability meter adjusted to operate at a speed of 25 rotations per minute for 4 minutes. The difference between the initial and final weight of the tablets was less than 0.5%, indicating low friability, in accordance with Brazilian pharmacopoeia guidelines.
- composition and process described in the embodiment exclude the presence of coating agent(s) in the tablets, which can be an optional additive process after the compression step.
- the coating as long as it does not alter the characteristics of the immediate release pharmaceutical form, can be used to mask flavor, facilitate swallowing, improve aesthetic characteristics, for better identification of the brand, among others.
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Abstract
The present invention relates to a vilazodone docusate salt, a process for producing same, a pharmaceutical composition containing the vilazodone docusate salt and the use thereof.
Description
SAL DE DOCUSATO DE VILAZODONA, PROCESSO DE OBTENÇÃO, COMPOSIÇÃO FARMACÊUTICA E USO Campo da Invenção VILAZODONE DOCUSATE SALT, PROCESS FOR OBTAINING, PHARMACEUTICAL COMPOSITION AND USE Field of the Invention
[0001] A presente invenção refere-se a um sal de vilazodona, especificamente, o docusato de vilazodona, ao processo de obtenção do referido sal e a uma composição farmacêutica compreendendo docusato de vilazodona. A presente invenção, também, refere-se ao uso do sal docusato vilazodona e ao uso da composição compreendendo o respectivo sal. [0001] The present invention relates to a vilazodone salt, specifically, vilazodone docusate, the process for obtaining said salt and a pharmaceutical composition comprising vilazodone docusate. The present invention also relates to the use of the vilazodone docusate salt and the use of the composition comprising the respective salt.
[0002]A presente invenção encontra-se nos campos da Química e da Farmácia. [0002] The present invention is found in the fields of Chemistry and Pharmacy.
Fundamentos da Invenção Fundamentals of Invention
[0003]A vilazodona, 5-(4-[4-(5-ciano-1 H-indol-3- il)butil]piperazin-1 -il)benzofurano-2-carboxamida, conforme Fórmula (I), é utilizada no tratamento do transtorno depressivo maior (TDM) em adultos, atuando como um inibidor seletivo da recaptação da serotonina e um antagonista parcial do receptor 5HTiA. O fármaco foi originalmente desenvolvido pela Merck KGaA, Alemanha, sendo comercializado na forma de sal de cloridrato, com nome comercial Viibryd®, nas dosagens de 10, 20 e 40 mg.
[0003] Vilazodone, 5-(4-[4-(5-cyano-1 H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxamide, according to Formula (I), is used in the treatment of major depressive disorder (MDD) in adults, acting as a selective serotonin reuptake inhibitor and a partial antagonist of the 5HTiA receptor. The drug was originally developed by Merck KGaA, Germany, and is sold in the form of hydrochloride salt, with the trade name Viibryd®, in dosages of 10, 20 and 40 mg.
Fórmula de Vilazodona Vilazodone Formula
[0004] Formas polimórficas ou diferentes sais de uma determinada substância podem apresentar propriedades químicas e físicas distintas, como ponto de fusão, reatividade química, toxicidade, solubilidade, taxa de dissolução, propriedades reológicas e densidade. Estas características
podem afetar diretamente a processabilidade e manufatura do insumo farmacêutico ativo (IFA) e a forma farmacêutica que o contém, bem como a estabilidade, dissolução, absorção no trato gastrointestinal, biodisponibilidade e propriedades organolépticas. Assim, a forma polimórfica ou o tipo de sal de um insumo farmacêutico ativo (IFA) pode impactar a qualidade, segurança e eficácia de um produto farmacêutico. [0004] Polymorphic forms or different salts of a given substance may have different chemical and physical properties, such as melting point, chemical reactivity, toxicity, solubility, dissolution rate, rheological properties and density. These characteristics can directly affect the processability and manufacturing of the active pharmaceutical ingredient (IFA) and the pharmaceutical form that contains it, as well as stability, dissolution, absorption in the gastrointestinal tract, bioavailability and organoleptic properties. Thus, the polymorphic form or type of salt of an active pharmaceutical ingredient (IFA) can impact the quality, safety and efficacy of a pharmaceutical product.
[0005JA síntese da molécula de vilazodona foi descrita na patente US5532241 , da empresa Merck KGaA (DE). A mesma empresa reportou diversas formas cristalinas anidras do sal cloridrato de vilazodona no pedido de patente W02002102794. Outros polimorfos do sal cloridrato de vilazodona nas formas de hidrato e solvato também são reportados no documento W020021 02794. A obtenção de formas amorfas do sal cloridrato de vilazodona são descritas nos documentos W02012131706, US20140378472 e US20150239871 . Outras formas polimórficas do sal cloridrato de vilazodona ainda são descritas nos pedidos de patentes US9145400, US20140303185, WO201 4049612, US9505744 e US1001 1590. Outros sais do ativo vilazodona com ânions distintos do cloridrato são revelados nos documentos WO201 4028473 e WO2014049609, sendo os sais reivindicados formados a partir da reação da forma base de vilazodona com os seguintes ácidos: ácido fosfórico, ácido sulfúrico, ácido metanossulfônico, ácido lático, ácido maleico, ácido benzoico, ácido bromídrico, ácido oxálico, ácido benzenossulfônico, ácido para-toluenossulfônico, ácido succínico, ácido salicílico, ácido tartárico, ácido fumárico, ácido malônico, ácido piválico, ácido ascórbico e ácido cítrico. [0005J The synthesis of the vilazodone molecule was described in patent US5532241, from the company Merck KGaA (DE). The same company reported several anhydrous crystalline forms of vilazodone hydrochloride salt in patent application W02002102794. Other polymorphs of vilazodone hydrochloride salt in hydrate and solvate forms are also reported in document W020021 02794. The obtaining of amorphous forms of vilazodone hydrochloride salt are described in documents W02012131706, US20140378472 and US20150239871. Other polymorphic forms of the hydrochloride salt of vilazodone are further described in patent applications US9145400, US20140303185, WO201 4049612, US9505744 and US1001 1590. Other salts of the active vilazodone with anions other than the hydrochloride are disclosed in documents WO201 4028473 and W O2014049609, the salts being claimed formed from the reaction of the base form of vilazodone with the following acids: phosphoric acid, sulfuric acid, methanesulfonic acid, lactic acid, maleic acid, benzoic acid, hydrobromic acid, oxalic acid, benzenesulfonic acid, para-toluenesulfonic acid, succinic acid, salicylic acid, tartaric acid, fumaric acid, malonic acid, pivalic acid, ascorbic acid and citric acid.
[0006] Na indústria farmacêutica, a exploração de diferentes sais é uma das estratégias mais utilizadas para contornar problemas no desenvolvimento de fármacos. Quando uma forma de sal adequada é identificada para uma entidade de pequena molécula, muitas vezes se torna a abordagem mais econômica no desenvolvimento de medicamentos. Por essas razões, grande parcela das aprovações e prescrições de medicamentos no Brasil e no mundo compreendem insumos farmacêuticos ativos (IFAs) em formas
de sal. [0006] In the pharmaceutical industry, the exploration of different salts is one of the most used strategies to overcome problems in drug development. When a suitable salt form is identified for a small molecule entity, it often becomes the most cost-effective approach in drug development. For these reasons, a large portion of drug approvals and prescriptions in Brazil and around the world comprise active pharmaceutical ingredients (APIs) in forms of salt.
[0007JO processo de seleção do melhor contra-íon para obtenção de sais farmacologicamente ativos de uma molécula deve levar em consideração características de estabilidade, ocorrência de polimorfismo, toxicidade, viabilidade, aceitação clínica e regulatória. Não menos importante, a escolha de um contra-íon que ofereça maior solubilidade do sal em meio gástrico é preferível, pois é indicativo de uma melhor taxa de absorção in vivo, uma vez que a dissolução em meio gástrico simulado é rotineiramente empregada no processo de avaliação de candidatos a novos fármacos. [0007JThe process of selecting the best counterion to obtain pharmacologically active salts of a molecule must take into account characteristics of stability, occurrence of polymorphism, toxicity, viability, clinical and regulatory acceptance. No less important, the choice of a counter-ion that offers greater solubility of the salt in gastric media is preferable, as it is indicative of a better absorption rate in vivo, since dissolution in simulated gastric media is routinely used in the process of evaluation of new drug candidates.
[0008]0s cloridratos são os sais mais comuns para bases fracas, mas seu emprego disseminado não ocorre apenas pela conveniência, já que são derivados de um ácido muito forte (ácido clorídrico - HCI), favorecendo a formação de sal, mas também porque os íons cloreto (Cl ) fazem parte do grupo dos eletrólitos mais abundantes no corpo humano e, por isso, espera-se que não causem alterações fisiológicas no organismo. [0008] Hydrochlorides are the most common salts for weak bases, but their widespread use is not only due to convenience, as they are derived from a very strong acid (hydrochloric acid - HCI), favoring the formation of salt, but also because the Chloride ions (Cl ) are part of the group of most abundant electrolytes in the human body and, therefore, are expected not to cause physiological changes in the body.
[0009] Entretanto, embora os cloridratos possuam baixo peso molecular e baixa toxicidade, eles apresentam diminuição da solubilidade e da taxa de dissolução em soluções com excesso de íons de mesmo tipo. Este fenômeno é explicado a partir da lei da ação das massas, por exemplo, em um meio de dissolução em HCI, sendo conhecido como “efeito do íon comum”. [0009] However, although hydrochlorides have low molecular weight and low toxicity, they present a decrease in solubility and dissolution rate in solutions with an excess of ions of the same type. This phenomenon is explained based on the law of mass action, for example, in a dissolution medium in HCI, and is known as the “common ion effect”.
[0010] Um estudo na literatura investigou os efeitos da presença de íons cloreto na solubilidade dos sais cloridrato, fosfato e mesilato, utilizando o haloperidol como fármaco modelo. As taxas de dissolução dos sais em meio ácido de HCI 0,01 M e HCI 0,1 M, usando método de disco rotativo, seguiram a seguinte ordem: mesilato > fosfato > cloridrato. O estudo constatou que a menor solubilidade do sal cloridrato foi decorrente do efeito do íon comum, e sugeriu que sais não cloridratos são preferíveis para o desenvolvimento de formas farmacêuticas orais devido às vantagens cinéticas durante a dissolução. [0010] A study in the literature investigated the effects of the presence of chloride ions on the solubility of hydrochloride, phosphate and mesylate salts, using haloperidol as a model drug. The dissolution rates of the salts in an acidic medium of 0.01 M HCl and 0.1 M HCl, using the rotating disk method, followed the following order: mesylate > phosphate > hydrochloride. The study found that the lower solubility of the hydrochloride salt was due to the common ion effect, and suggested that non-hydrochloride salts are preferable for the development of oral dosage forms due to the kinetic advantages during dissolution.
[0011]0utro ponto importante na escolha de um novo sal, que será mais bem detalhado na presente invenção, refere-se à ocorrência de
polimorfismo. Como é de amplo conhecimento para um técnico no assunto, um fármaco ideal deve manter suas propriedades físicas por longos períodos de armazenamento de forma que observações repetidas gerem as mesmas características, como ponto de fusão ou solubilidade. Entretanto, muitos sais são polimórficos, ou seja, são capazes de existir em duas ou mais formas cristalinas com diferentes arranjos e/ou conformações de moléculas e, além disso, podem se transformar de uma forma para a outra no estado sólido. O polimorfismo é um fenômeno que pode ser observado em mais da metade dos IFAs, podendo ser problemático, principalmente, se uma forma se transforma em outra com propriedades físicas diferentes durante a produção do fármaco. Isso pode gerar substâncias finais com características imprevisíveis. Dessa forma, na seleção de sais para candidatos a novos fármacos, deve-se preferir aqueles que não apresentam ocorrência de polimorfismo. O cloridrato de vilazodona apresenta uma baixa solubilidade, sendo um IFA classe II (pouco solúvel e muito permeável) no Sistema de Classificação Biofarmacêutica. Além disso, o sal cloridrato de vilazodona apresenta muitas formas polimórficas cristalinas (mais de uma dezena, entre as formas anidra, hidrato e solvato) e formas amorfas. [0011] Another important point when choosing a new salt, which will be better detailed in the present invention, refers to the occurrence of polymorphism. As is widely known to those skilled in the art, an ideal drug must maintain its physical properties for long periods of storage so that repeated observations generate the same characteristics, such as melting point or solubility. However, many salts are polymorphic, that is, they are capable of existing in two or more crystalline forms with different arrangements and/or conformations of molecules and, in addition, they can transform from one form to another in the solid state. Polymorphism is a phenomenon that can be observed in more than half of APIs, and can be problematic, especially if one form transforms into another with different physical properties during the production of the drug. This can generate final substances with unpredictable characteristics. Therefore, when selecting salts for new drug candidates, those that do not present polymorphism should be preferred. Vilazodone hydrochloride has low solubility, being a class II API (slightly soluble and very permeable) in the Biopharmaceutical Classification System. Furthermore, vilazodone hydrochloride salt presents many polymorphic crystalline forms (more than a dozen, including anhydrous, hydrate and solvate forms) and amorphous forms.
[0012]A descoberta de novos sais de um insumo farmacêutico ativo pode fornecer materiais com melhores propriedades de processamento, como facilidade de manipulação, estabilidade no armazenamento e facilidade de purificação e conversão para obtenção de outros sais ou formas polimórficas. Estes novos sais também podem melhorar a performance de produtos farmacêuticos (por exemplo, perfil de dissolução, biodisponibilidade, dentre outras propriedades). Todas essas características aumentam o repertório de materiais que o cientista de formulação tem disponível para otimização da formulação. [0012] The discovery of new salts of an active pharmaceutical ingredient can provide materials with better processing properties, such as ease of handling, storage stability and ease of purification and conversion to obtain other salts or polymorphic forms. These new salts can also improve the performance of pharmaceutical products (for example, dissolution profile, bioavailability, among other properties). All of these features increase the repertoire of materials that the formulation scientist has available for formulation optimization.
[0013] No estado da técnica, não foram encontrados documentos que revelassem o sal de vilazodona da presente invenção, os seus processos de obtenção e uma composição farmacêutica compreendendo o referido sal, o que torna a presente invenção surpreendente.
[0014JO pedido de patente WO2016170542 descreve um processo de preparo da vilazodona. [0013] In the state of the art, no documents were found revealing the vilazodone salt of the present invention, its obtaining processes and a pharmaceutical composition comprising said salt, which makes the present invention surprising. [0014J Patent application WO2016170542 describes a process for preparing vilazodone.
[0015]Os pedidos de patentes WO2014199313 e WO201 3175361 descrevem um processo para a obtenção de cloridrato de vilazodona. [0015] Patent applications WO2014199313 and WO201 3175361 describe a process for obtaining vilazodone hydrochloride.
[0016]O documento patentário WO2013164794 descreve as formas cristalinas A, B e C do cloridrato de vilazodona. [0016] Patent document WO2013164794 describes crystalline forms A, B and C of vilazodone hydrochloride.
[0017]O documento patentário EP3360543 descreve uma composição farmacêutica compreendendo cloridrato de vilazodona, crospovidona, lactose monoidratada, celulose microcristalina, estearato de magnésio, dióxido de silício coloidal e revestimento, em que a referida composição pode ser incorporada em forma farmacêutica sólida, como em um comprimido revestido, um comprimido de multicamadas, um comprimido de desintegração oral, um comprimido de liberação imediata, uma pílula, uma cápsula, dentre outras. [0017] Patent document EP3360543 describes a pharmaceutical composition comprising vilazodone hydrochloride, crospovidone, lactose monohydrate, microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide and coating, wherein said composition can be incorporated in solid pharmaceutical form, as in a coated tablet, a multilayer tablet, an orally disintegrating tablet, an immediate release tablet, a pill, a capsule, among others.
[0018] Nenhum desses documentos patentários do estado da técnica revela o sal de vilazodona da presente invenção, o seu respectivo processo de obtenção e uma composição farmacêutica compreendendo o mesmo. [0018] None of these prior art patent documents discloses the vilazodone salt of the present invention, its respective obtaining process and a pharmaceutical composition comprising it.
[0019]Assim, não há indícios no estado da técnica que revelem ou levariam um técnico no assunto ao sal descrito na presente invenção. Breve Descrição das Figuras [0019] Thus, there is no evidence in the prior art that reveals or would lead a person skilled in the art to the salt described in the present invention. Brief Description of Figures
[0020JA Figura 1 mostra o difratograma de raios-X característico do docusato de vilazodona obtido pelas rotas de síntese (A) e (B). [0020JA Figure 1 shows the characteristic X-ray diffractogram of vilazodone docusate obtained by synthesis routes (A) and (B).
[0021] A Figura 2 mostra os difratogramas de raios-X do docusato de vilazodona (A), cloridrato de vilazodona (B) e docusato de sódio (C). [0021] Figure 2 shows the X-ray diffractograms of vilazodone docusate (A), vilazodone hydrochloride (B) and sodium docusate (C).
[0022]A Figura 3 mostra os espectros de absorção no infravermelho característicos do docusato de vilazodona (A), docusato de sódio (B) e cloridrato de vilazodona (C). [0022] Figure 3 shows the characteristic infrared absorption spectra of vilazodone docusate (A), sodium docusate (B) and vilazodone hydrochloride (C).
[0023]A Figura 4 mostra as curvas de análise
termogravimétrica (TGA) obtidas com taxa de aquecimento de 10 °C/min para docusato de vilazodona (A) e cloridrato de vilazodona (B). [0023] Figure 4 shows the analysis curves thermogravimetric measurement (TGA) obtained with a heating rate of 10 °C/min for vilazodone docusate (A) and vilazodone hydrochloride (B).
[0024JA Figura 5 mostra as curvas de calorimentria exploratória diferencial (DSC) obtidas com taxa de aquecimento de 10 °C/min para docusato de vilazodona (A) e cloridrato de vilazodona (B). [0024JA Figure 5 shows the differential scanning calorimetry (DSC) curves obtained with a heating rate of 10 °C/min for vilazodone docusate (A) and vilazodone hydrochloride (B).
[0025JA Figura 6 mostra os espectros de absorção no infravermelho para o docusato de vilazodona após a síntese (A), após incubação em 50 °C e 75 % UR por 10 dias (B) e armazenado em condições ambiente por 3 meses (C). [0025JA Figure 6 shows the infrared absorption spectra for vilazodone docusate after synthesis (A), after incubation at 50 °C and 75% RH for 10 days (B) and stored at ambient conditions for 3 months (C) .
[0026JA Figura 7 mostra os difratogramas de raios-X para o docusato de vilazodona após a síntese (A), após incubação em 50 °C e 75 % UR por 10 dias (B) e armazenado em condições ambiente por 3 meses (C). [0026JA Figure 7 shows the X-ray diffractograms for vilazodone docusate after synthesis (A), after incubation at 50 °C and 75% RH for 10 days (B) and stored at ambient conditions for 3 months (C) .
Sumário da invenção Summary of the invention
[0027JA presente invenção se refere a um novo sal de vilazodona, ao seu processo de obtenção e a uma composição farmacêutica compreendendo o mesmo. [0027J The present invention relates to a new vilazodone salt, its obtaining process and a pharmaceutical composition comprising it.
[0028]Visando a melhora das características físico- químicas do sal de vilazodona, disponível comercialmente na forma de cloridrato de vilazodona, a presente invenção revela a síntese de um novo sal deste ativo, o docusato de vilazodona com solubilidade melhorada em meio gástrico simulado, ausência de polimorfismo, e seu potencial uso em composições farmacêuticas. [0028] Aiming at improving the physicochemical characteristics of vilazodone salt, commercially available in the form of vilazodone hydrochloride, the present invention reveals the synthesis of a new salt of this active ingredient, vilazodone docusate with improved solubility in a simulated gastric environment, absence of polymorphism, and its potential use in pharmaceutical compositions.
[0029JO novo sal de vilazodona, tendo como contra-íon o ânion docusato ou dioctil sulfoccinato ou 1 ,4-bis(2-etilhexoxi)-1 ,4-dioxobutano-2- sulfonato, conforme Fórmula (II), mostrou-se estável e reprodutível, com propriedades físico-químicas superiores à forma comercialmente disponível. Além disso, o docusato é um contra-íon não carcinogênico e não tóxico, sendo seu emprego já aprovado em medicamentos de uso humano, o que lhe confere potencial segurança na obtenção de novos sais farmacologicamente ativos.
[0029JThe new vilazodone salt, having as counter-ion the anion docusate or dioctyl sulfoccinate or 1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate, according to Formula (II), proved to be stable and reproducible, with physical-chemical properties superior to the commercially available form. Furthermore, docusate is a non-carcinogenic and non-toxic counterion, and its use is already approved in medicines for human use, which gives it potential safety in obtaining new pharmacologically active salts.
Fórmula de Vilazodona Vilazodone Formula
[0030] Por exemplo, o composto possui uma maior solubilidade em soluções de ácido clorídrico, devido à ausência do efeito do íon comum, e não foram verificados polimorfos do novo sal nas condições investigadas. Estas características podem propiciar a utilização de uma matéria- prima sem risco de contaminação com outras formas polimórficas e, principalmente, o desenvolvimento de novas formas farmacêuticas com melhoria na biodisponibilidade do insumo farmacêutico ativo. [0030] For example, the compound has greater solubility in hydrochloric acid solutions, due to the absence of the effect of the common ion, and no polymorphs of the new salt were found under the conditions investigated. These characteristics can enable the use of a raw material without the risk of contamination with other polymorphic forms and, mainly, the development of new pharmaceutical forms with improved bioavailability of the active pharmaceutical ingredient.
[0031] A presente invenção apresenta como conceitos inventivos os objetos a seguir. [0031] The present invention presents the following objects as inventive concepts.
[0032]A presente invenção apresenta como primeiro objeto, o sal de docusato de vilazodona. [0032] The present invention presents as its first object, the vilazodone docusate salt.
[0033] Em um segundo objeto, a presente invenção apresenta um processo de obtenção do docusato de vilazodona, conforme descrito no primeiro objeto e em qualquer uma de suas concretizações, compreendendo as etapas de: [0033] In a second object, the present invention presents a process for obtaining vilazodone docusate, as described in the first object and in any of its embodiments, comprising the steps of:
(i) Adicionar docusato de sódio em água e agitar até a completa solubilização; (i) Add docusate sodium to water and stir until complete solubilization;
(ii) Adicionar cloridrato de vilazodona (equivalente a 1 :1 em proporção molar de docusato e vilazodona) e manter sob agitação; (ii) Add vilazodone hydrochloride (equivalent to 1:1 molar ratio of docusate and vilazodone) and keep stirring;
(iii) Adicionar um solvente orgânico escolhido entre acetato de etila, éter etílico, diclorometano, clorofórmio ou hexano e agitar; (iii) Add an organic solvent chosen from ethyl acetate, ethyl ether, dichloromethane, chloroform or hexane and stir;
(iv) Após agitação, deixar a solução em repouso em um recipiente até a completa separação entre as fases aquosa e fase apoiar com acetato de etila;
(v) Separar as fases em recipientes diferentes; e (iv) After stirring, leave the solution to rest in a container until complete separation between the aqueous and nonpolar phases with ethyl acetate; (v) Separate the phases into different containers; It is
(vi) Obter o sal docusato de vilazodona por rotaevaporação do solvente ou estufa com temperatura controlada. (vi) Obtain the vilazodone docusate salt by rotary evaporation of the solvent or a temperature-controlled oven.
[0034] Em um terceiro objeto, a presente invenção apresenta um processo de obtenção do docusato de vilazodona, conforme descrito no primeiro objeto e em qualquer uma de suas concretizações, compreendendo as etapas de: [0034] In a third object, the present invention presents a process for obtaining vilazodone docusate, as described in the first object and in any of its embodiments, comprising the steps of:
(i) Adicionar cloridrato de vilazodona em dimetilsulfóxido (DMSO) e agitar até a completa solubilização; (i) Add vilazodone hydrochloride in dimethyl sulfoxide (DMSO) and stir until complete solubilization;
(ii) Adicionar docusato de sódio (equivalente a 1 :1 em proporção molar de docusato e vilazodona) e manter sob agitação; (ii) Add docusate sodium (equivalent to 1:1 molar ratio of docusate and vilazodone) and keep stirring;
(iii) Adicionar água; (iii) Add water;
(iv) Deixar em repouso; e (iv) Leave to rest; It is
(v) Filtrar o material precipitado e obter o sal docusato de vilazodona após a secagem em estufa até a completa remoção do solvente. (v) Filter the precipitated material and obtain the vilazodone docusate salt after drying in an oven until the solvent is completely removed.
[0035] Em um quarto objeto, a presente invenção apresenta uma composição farmacêutica compreendendo (a) docusato de vilazodona, conforme descrito no primeiro objeto e em qualquer uma de suas concretizações; e (b) um ou mais excipientes farmaceuticamente aceitáveis. [0035] In a fourth object, the present invention presents a pharmaceutical composition comprising (a) vilazodone docusate, as described in the first object and in any of its embodiments; and (b) one or more pharmaceutically acceptable excipients.
[0036] Em um quinto objeto, a presente invenção apresenta o uso do sal de vilazodona, conforme descrito no primeiro objeto e em qualquer uma de suas concretizações, para o preparo de um medicamento para o tratamento de transtorno depressivo maior (TDM). [0036] In a fifth object, the present invention presents the use of vilazodone salt, as described in the first object and in any of its embodiments, for the preparation of a medicine for the treatment of major depressive disorder (MDD).
[0037]0 sal de docusato de vilazodona da presente invenção pode apresentar menos impurezas, propriedades farmacocinéticas desejáveis para formulações de liberação imediata e modificada e facilidade no processamento farmacêutico. [0037] The vilazodone docusate salt of the present invention may have fewer impurities, desirable pharmacokinetic properties for immediate and modified release formulations and ease of pharmaceutical processing.
Definições Definitions
[0038] Na presente invenção, a expressão “picos expressos em graus 2-teta” refere-se aos picos característicos do difratograma
de raios-X obtido com utilização de comprimento de onda de 1 ,54 Â (Cu K-alfa) do sal de docusato de vilazodona. [0038] In the present invention, the expression “peaks expressed in 2-theta degrees” refers to the characteristic peaks of the diffractogram X-ray obtained using a wavelength of 1.54 Å (Cu K-alpha) of vilazodone docusate salt.
Descrição detalhada da invenção Detailed description of the invention
[0039JA presente invenção se refere à obtenção e utilização do sal docusato de vilazodona ou 1 ,4-bis(2-etilhexoxi)-1 ,4- dioxobutano-2-sulfonato de 5-(4-[4-(5-ciano-17 J-indol-3-il)butil]piperazin-l- il)benzofurano-2-carboxamida, com fórmula molecular C46H64N5O9S e massa molecular 862 g/mol, para utilização em preparações e composições farmacêuticas. [0039J The present invention relates to obtaining and using the salt of vilazodone docusate or 1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate of 5-(4-[4-(5-cyano- 17 J-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxamide, with molecular formula C46H64N5O9S and molecular mass 862 g/mol, for use in pharmaceutical preparations and compositions.
[0040]Em um primeiro objeto, a presente invenção apresenta 0 sal de docusato de vilazodona. [0040] In a first object, the present invention presents the vilazodone docusate salt.
[0041] Em uma concretização preferencial, 0 sal de docusato de vilazodona apresenta os picos expressos em graus 2-teta (±0,2°) a 3,8; 7,5; 1 1 ,3; 12,9; 15,2; 18,0; 19,0; 21 ,6; 22,7; 23,9 e 28,0 em seu difratograma de raios-X. [0041] In a preferred embodiment, the vilazodone docusate salt presents peaks expressed in degrees 2-theta (±0.2°) to 3.8; 7.5; 1 1 .3; 12.9; 15.2; 18.0; 19.0; 21.6; 22.7; 23.9 and 28.0 on its X-ray diffractogram.
[0042] Em uma concretização adicional, 0 sal de docusato de vilazodona apresenta picos específicos expressos em graus 2-teta (±0,2°) a 3,8; 7,5 e 15,2 em seu em seu difratograma de raios-X. [0042] In an additional embodiment, the vilazodone docusate salt presents specific peaks expressed in degrees 2-theta (±0.2°) to 3.8; 7.5 and 15.2 on your X-ray diffractogram.
[0043] Em uma concretização preferencial, 0 sal do docusato de vilazodona apresenta bandas características 3477; 2976; 2926; 2860; 2219; 1735; 1680; 1601 ; 1022; 961 ; 940; 888; 853; 810; 761 cm’1 em seu espectro de absorção na região do infravermelho. [0043] In a preferred embodiment, the vilazodone docusate salt presents characteristic bands 3477; 2976; 2926; 2860; 2219; 1735; 1680; 1601; 1022; 961; 940; 888; 853; 810; 761 cm' 1 in its absorption spectrum in the infrared region.
[0044] Em uma concretização adicional, 0 sal apresenta ponto de fusão na faixa de 172 a 178°C. [0044] In an additional embodiment, the salt has a melting point in the range of 172 to 178°C.
[0045] Em um segundo objeto preferencial, a presente invenção apresenta um processo de obtenção do docusato de vilazodona, conforme descrito no primeiro objeto e em qualquer uma de suas concretizações, compreendendo as etapas de: [0045] In a second preferred object, the present invention presents a process for obtaining vilazodone docusate, as described in the first object and in any of its embodiments, comprising the steps of:
(i) Adicionar docusato de sódio em água e agitar até a completa solubilização;
(ii) Adicionar cloridrato de vilazodona (equivalente a 1 :1 em proporção molar de docusato e vilazodona) e manter sob agitação mecânica; (i) Add docusate sodium to water and stir until complete solubilization; (ii) Add vilazodone hydrochloride (equivalent to 1:1 molar ratio of docusate and vilazodone) and keep under mechanical stirring;
(iii) Adicionar um solvente orgânico escolhido entre acetato de etila, éter etílico, diclorometano, clorofórmio ou hexano e agitar; (iii) Add an organic solvent chosen from ethyl acetate, ethyl ether, dichloromethane, chloroform or hexane and stir;
(iv) Após agitação, deixar a solução em repouso em um recipiente até a completa separação entre as fases aquosa e apoiar com acetato de etila; (iv) After stirring, leave the solution to rest in a container until complete separation between the aqueous phases and support with ethyl acetate;
(v) Separar as fases em recipientes diferentes; e (v) Separate the phases into different containers; It is
(vi) Obter o sal docusato de vilazodona por rotaevaporação do solvente ou estufa com temperatura controlada. (vi) Obtain the vilazodone docusate salt by rotary evaporation of the solvent or a temperature-controlled oven.
[0046] Em uma concretização adicional, o processo compreende as etapas de: [0046] In a further embodiment, the process comprises the steps of:
(i) Adicionar de 60 mg a 600 mg de docusato de sódio em um volume de 200 ml_ a 2 L de água em um béquer e agitar até a completa solubilização; (i) Add 60 mg to 600 mg of docusate sodium in a volume of 200 ml to 2 L of water in a beaker and shake until complete solubilization;
(ii) Adicionar de 64 mg a 640 mg de cloridrato de vilazodona (equivalente a 1 :1 em proporção molar de docusato e vilazodona) e manter sob agitação magnética por 30 a 35 minutos; (ii) Add 64 mg to 640 mg of vilazodone hydrochloride (equivalent to 1:1 molar ratio of docusate and vilazodone) and keep under magnetic stirring for 30 to 35 minutes;
(iii) Adicionar um volume de 100 mL a 1 L de um solvente orgânico escolhido entre acetato de etila, éter etílico, diclorometano, clorofórmio ou hexano e agitar por 10 a 15 minutos; (iii) Add a volume of 100 mL to 1 L of an organic solvent chosen from ethyl acetate, ethyl ether, dichloromethane, chloroform or hexane and stir for 10 to 15 minutes;
(iv) Após agitação, deixar a solução em repouso em um funil de separação até a completa separação entre as fases aquosa e apoiar com acetato de etila; (iv) After stirring, leave the solution to rest in a separation funnel until complete separation between the aqueous phases and support with ethyl acetate;
(v) Separar as fases em béqueres diferentes utilizando o funil de separação; e (v) Separate the phases into different beakers using the separation funnel; It is
(vi) Obter o sal docusato de vilazodona após a evaporação do solvente em temperatura ambiente ou estufa com temperatura controlada. (vi) Obtain vilazodone docusate salt after evaporation of the solvent at room temperature or a temperature-controlled oven.
[0047] Em uma outra concretização, o processo compreende as etapas de:
(i) Adicionar 60 mg de docusato de sódio em 200 mL de água em um béquer e agitar até a completa solubilização; [0047] In another embodiment, the process comprises the steps of: (i) Add 60 mg of docusate sodium to 200 mL of water in a beaker and stir until complete solubilization;
(ii) Adicionar 64 mg de cloridrato de vilazodona (equivalente a 1 :1 em proporção molar de docusato e vilazodona) e manter sob agitação magnética por 30 minutos; (ii) Add 64 mg of vilazodone hydrochloride (equivalent to 1:1 molar ratio of docusate and vilazodone) and keep under magnetic stirring for 30 minutes;
(iii) Adicionar 100 mL de acetato de etila e agitar por 30 minutos; (iii) Add 100 mL of ethyl acetate and shake for 30 minutes;
(iv) Após agitação, deixar a solução em repouso em um funil de separação até a completa separação entre as fases aquosa e apoiar com acetato de etila; (iv) After stirring, leave the solution to rest in a separation funnel until complete separation between the aqueous phases and support with ethyl acetate;
(v) Separar as fases em béqueres diferentes utilizando o funil de separação; e (v) Separate the phases into different beakers using the separation funnel; It is
(vi) Obter o sal docusato de vilazodona após a evaporação do solvente em temperatura ambiente ou estufa com temperatura controlada. (vi) Obtain vilazodone docusate salt after evaporation of the solvent at room temperature or a temperature-controlled oven.
[0048] Em um terceiro objeto, a presente invenção apresenta um processo de obtenção do docusato de vilazodona, conforme descrito no primeiro objeto e em qualquer uma de suas concretizações, compreendendo as etapas de: [0048] In a third object, the present invention presents a process for obtaining vilazodone docusate, as described in the first object and in any of its embodiments, comprising the steps of:
(i) Adicionar cloridrato de vilazodona em dimetilsulfóxido (DMSO) e agitar até a completa solubilização; (i) Add vilazodone hydrochloride in dimethyl sulfoxide (DMSO) and stir until complete solubilization;
(ii) Adicionar docusato de sódio (equivalente a 1 :1 em proporção molar de docusato e vilazodona) e manter sob agitação mecânica; (ii) Add docusate sodium (equivalent to 1:1 molar ratio of docusate and vilazodone) and keep under mechanical stirring;
(iii) Adicionar água; (iii) Add water;
(iv) Deixar em repouso; e (iv) Leave to rest; It is
(v) Filtrar o material precipitado e obter o sal docusato de vilazodona após secagem em estufa até a completa remoção do solvente. (v) Filter the precipitated material and obtain the vilazodone docusate salt after drying in an oven until the solvent is completely removed.
[0049]Verificou-se que, no item (iii), a adição de água faz com que o sal docusato de vilazodona precipite de maneira imediata, ao passo que o repouso do item (iv) é aplicado por tempo suficiente para que o processo atinja maiores rendimentos.
[0050] Em uma concretização preferida, o processo compreende as etapas de: [0049] It was found that, in item (iii), the addition of water causes the vilazodone docusate salt to precipitate immediately, while resting in item (iv) is applied for sufficient time for the process to occur. achieve higher yields. [0050] In a preferred embodiment, the process comprises the steps of:
(i) Adicionar de 256 mg a 2560 mg de cloridrato de vilazodona em um volume de 4 ml_ a 40 ml_ de dimetilsulfóxido (DMSO) em um béquer e agitar até a completa solubilização; (i) Add 256 mg to 2560 mg of vilazodone hydrochloride in a volume of 4 ml_ to 40 ml_ of dimethyl sulfoxide (DMSO) in a beaker and stir until complete solubilization;
(ii) Adicionar de 240 a 2400 mg de docusato de sódio (equivalente a 1 :1 em proporção molar de docusato e vilazodona) e manter sob agitação magnética por 15 a 20 minutos; (ii) Add 240 to 2400 mg of docusate sodium (equivalent to 1:1 molar ratio of docusate and vilazodone) and keep under magnetic stirring for 15 to 20 minutes;
(iii) Adicionar de 4 m L a 40 m L de água; (iii) Add 4 m L to 40 m L of water;
(iv) Deixar em repouso por 60 a 90 minutos; e (iv) Leave to rest for 60 to 90 minutes; It is
(v) Filtrar o material precipitado e secar em estufa até a completa remoção do solvente. (v) Filter the precipitated material and dry in an oven until the solvent is completely removed.
[0051]Após a adição dos 4 m L a 40 m L de água, é possível observar a precipitação instantânea do sal docusato de vilazodona, enquanto que o repouso ocorre por um período entre 60 e 90 minutos para que o processa tenha maior rendimento. [0051] After adding 4 m L to 40 m L of water, it is possible to observe the instantaneous precipitation of the vilazodone docusate salt, while resting occurs for a period between 60 and 90 minutes so that the process has greater yield.
[0052] Em uma concretização adicional, o processo compreende as etapas de: [0052] In a further embodiment, the process comprises the steps of:
(i) Adicionar 256 mg de cloridrato de vilazodona em 4 ml_ de dimetilsulfóxido (DMSO) em um béquer e agitar até a completa solubilização; (i) Add 256 mg of vilazodone hydrochloride in 4 ml of dimethyl sulfoxide (DMSO) in a beaker and stir until complete solubilization;
(ii) Adicionar 240 mg de docusato de sódio (equivalente a 1 :1 em proporção molar de docusato e vilazodona) e manter sob agitação magnética por 15 minutos; (ii) Add 240 mg of docusate sodium (equivalent to 1:1 molar ratio of docusate and vilazodone) and keep under magnetic stirring for 15 minutes;
(iii) Adicionar 4 ml_ de água; (iii) Add 4 ml of water;
(iv) Deixar em repouso por 90 minutos; e (iv) Leave to rest for 90 minutes; It is
(v) Filtrar o material precipitado em filtro de nylon 45 pm e secar por 24 h em estufa à 40 °C. (v) Filter the precipitated material through a 45 pm nylon filter and dry for 24 h in an oven at 40 °C.
[0053]Após a adição dos 4 ml_ de água, é possível observar a precipitação instantânea do sal docusato de vilazodona, ao passo que o repouso ocorre por um período de 90 minutos para que o processo tenha
maior rendimento. [0053] After adding the 4 ml of water, it is possible to observe the instantaneous precipitation of the vilazodone docusate salt, while the rest occurs for a period of 90 minutes for the process to complete. higher yield.
[0054] Em um quarto objeto, a presente invenção apresenta uma composição farmacêutica compreendendo (a) docusato de vilazodona, conforme definido no primeiro objeto e em qualquer uma de suas concretizações; e (b) um ou mais excipientes farmaceuticamente aceitáveis. [0054] In a fourth object, the present invention presents a pharmaceutical composition comprising (a) vilazodone docusate, as defined in the first object and in any of its embodiments; and (b) one or more pharmaceutically acceptable excipients.
[0055] Em uma concretização preferencial, os excipientes em (b) compreendem um ou mais excipientes farmaceuticamente aceitáveis selecionados dentre diluentes, desintegrantes, deslizantes, lubrificantes, agentes colorantes, opacificantes e, opcionalmente, revestimentos. [0055] In a preferred embodiment, the excipients in (b) comprise one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, glidants, lubricants, coloring agents, opacifiers and, optionally, coatings.
[0056]Em uma concretização adicional, os excipientes em (b) compreendem um ou mais excipientes farmaceuticamente aceitáveis selecionados do grupo consistindo em lactose monoidratada, celulose microcristalina, croscarmelose sódica, dióxido de silício coloidal e estearato de magnésio vegetal. [0056] In a further embodiment, the excipients in (b) comprise one or more pharmaceutically acceptable excipients selected from the group consisting of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and vegetable magnesium stearate.
[0057] Em uma concretização complementar, os excipientes da composição podem ser utilizados em outras faixas de valores (em % de massa) ou substituídos por excipientes com a mesma função na formulação. [0057] In a complementary embodiment, the excipients of the composition can be used in other ranges of values (in % by mass) or replaced by excipients with the same function in the formulation.
[0058] Em uma outra concretização, a lactose se encontra presente na composição da presente invenção na faixa de 0 a 80%; material com função de diluente, podendo ser combinado ou substituído totalmente por um ou mais excipientes, combinados entre si ou não, incluindo mas não se limitando a: celulose microcristalina, fosfato de cálcio dibásico, fosfato de cálcio tribásico, manitol, amido, amido pregelatinizado, sacarose, eritritol, xilitol, maltitol, glicose, dextrose, caulim, sulfato de cálcio e talco na proporção de 10 a 80% p/p da composição. [0058] In another embodiment, lactose is present in the composition of the present invention in the range of 0 to 80%; material with a diluent function, which can be combined or totally replaced by one or more excipients, combined or not, including but not limited to: microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, mannitol, starch, pregelatinized starch , sucrose, erythritol, xylitol, maltitol, glucose, dextrose, kaolin, calcium sulfate and talc in a proportion of 10 to 80% w/w of the composition.
[0059] Em uma concretização adicional, a celulose microcristalina se encontra presente na composição da presente invenção na faixa de 0 a 80%; material com função de diluente, podendo ser combinado ou substituído totalmente por um ou mais excipientes, combinados entre si ou não,
incluindo mas não se limitando a: lactose, fosfato de cálcio dibásico, fosfato de cálcio tribásico, manitol, amido, amido pregelatinizado, caulim, sacarose, eritritol, xilitol, maltitol, glicose, dextrose, sulfato de cálcio e talco na proporção de 10 a 80% p/p da composição. [0059] In an additional embodiment, microcrystalline cellulose is present in the composition of the present invention in the range of 0 to 80%; material with a diluent function, which can be combined or completely replaced by one or more excipients, combined or not, including but not limited to: lactose, dibasic calcium phosphate, tribasic calcium phosphate, mannitol, starch, pregelatinized starch, kaolin, sucrose, erythritol, xylitol, maltitol, glucose, dextrose, calcium sulfate and talc in a ratio of 10 to 80% w/w of the composition.
[0060] Em uma concretização preferencial, a croscarmelose sódica se encontra presente na composição da presente invenção na faixa de 0 a 5%; faixa limite usual deste excipiente em específico. Este material atua com função de desintegrante, podendo ser isento na formulação, combinado ou substituído totalmente por um ou mais excipientes, combinados entre si ou não, na proporção de 2 a 30% p/p da formulação, incluindo mas não se limitando a: amidoglicolato de sódio, silicato de magnésio e alumínio, silicato de magnésio e alumínio, amido, amido pregelatinizado, pectinas, alginatos, celulose microcristalina, ácido algínico, alfa celulose, polacrilina potássica, carboximetilcelulose cálcica, carboximetilcelulose sódica. [0060] In a preferred embodiment, croscarmellose sodium is present in the composition of the present invention in the range of 0 to 5%; usual limit range of this specific excipient. This material acts as a disintegrant and can be exempt from the formulation, combined or completely replaced by one or more excipients, combined or not, in a proportion of 2 to 30% w/w of the formulation, including but not limited to: sodium starch glycolate, magnesium and aluminum silicate, magnesium and aluminum silicate, starch, pregelatinized starch, pectins, alginates, microcrystalline cellulose, alginic acid, alpha cellulose, potassium polacrilin, calcium carboxymethylcellulose, sodium carboxymethylcellulose.
[0061]Em uma concretização adicional, o dióxido de silício coloidal se encontra na composição da presente invenção na faixa de 0,05 a 2%; material com função de deslizante, podendo ser isento na formulação, combinado ou substituído por um ou mais excipientes, combinados ou não entre si, na proporção de 0,05 a 10% p/p da formulação, incluindo, mas não se limitando, a talco, óxido de magnésio, trissilicato de magnésio e celulose. [0061] In an additional embodiment, colloidal silicon dioxide is found in the composition of the present invention in the range of 0.05 to 2%; material with a sliding function, which may be exempt from the formulation, combined or replaced by one or more excipients, combined or not with each other, in a proportion of 0.05 to 10% w/w of the formulation, including, but not limited to, talc, magnesium oxide, magnesium trisilicate and cellulose.
[0062] Em uma concretização preferida, o estearato de magnésio se encontra presente na composição da presente invenção na faixa de 0,2 a 5%; material com função de lubrificante, podendo ser isento na formulação, combinado ou substituído por um ou mais excipientes, combinados entre si ou não, na proporção de 0,2 até 10% p/p da formulação, incluindo mas não se limitando a talco, estearato de cálcio, lauril sulfato de sódio, óleo de rícino, benzoato de sódio, óleo vegetal hidrogenado, estearil fumarato de sódio, lauril sulfato de magnésio, ácido esteárico, estearato de cálcio, behenato de glicerila, monoestearato de glicerila, polietilenoglicois, polissorbatos e estearato de zinco. [0062] In a preferred embodiment, magnesium stearate is present in the composition of the present invention in the range of 0.2 to 5%; material with a lubricant function, which may be exempt from the formulation, combined or replaced by one or more excipients, combined or not, in a proportion of 0.2 to 10% w/w of the formulation, including but not limited to talc, calcium stearate, sodium lauryl sulfate, castor oil, sodium benzoate, hydrogenated vegetable oil, sodium stearyl fumarate, magnesium lauryl sulfate, stearic acid, calcium stearate, glyceryl behenate, glyceryl monostearate, polyethylene glycols, polysorbates and zinc stearate.
[0063] Em uma concretização preferencial, a composição
farmacêutica apresenta a seguinte composição: [0063] In a preferred embodiment, the composition pharmaceutical has the following composition:
Docusato de Vilazodona de 5 a 40%; Vilazodone docusate from 5 to 40%;
Diluente de 10 a 80%; Diluent from 10 to 80%;
Desintegrante de 2 a 30%; Disintegrant from 2 to 30%;
Deslizante de 0,05% a 10%; e Sliding from 0.05% to 10%; It is
Lubrificante de 0,2 a 10%. Lubricant from 0.2 to 10%.
[0064] Em uma concretização adicional, a composição farmacêutica apresenta a seguinte composição: [0064] In a further embodiment, the pharmaceutical composition has the following composition:
Docusato de Vilazodona de 5 a 40%; Vilazodone docusate from 5 to 40%;
Lactose monoidratada de 0 a 80%; Lactose monohydrate from 0 to 80%;
Celulose microcristalina de 0 a 80%; Microcrystalline cellulose from 0 to 80%;
Croscarmelose sódica de 0 a 5%; Croscarmellose sodium 0 to 5%;
Dióxido de silício coloidal de 0,05 a 2%; e Colloidal silicon dioxide from 0.05 to 2%; It is
Estearato de magnésio vegetal de 0,2 a 5%. Vegetable magnesium stearate from 0.2 to 5%.
[0065] Em uma outra concretização, a composição farmacêutica apresenta a seguinte composição:
[0065] In another embodiment, the pharmaceutical composition has the following composition:
[0066] Em uma concretização, a composição compreende adicionalmente revestimento na faixa de 1 - 5% de ganho de peso. [0066] In one embodiment, the composition additionally comprises coating in the range of 1 - 5% weight gain.
[0067] Em uma concretização, o emprego de revestimento nos comprimidos é opcional na faixa recomendada de 1 - 5% de ganho de peso, podendo ser utilizados sistemas prontos de revestimento, como Opadry®, ou proceder com a formação de filmes baseados, mas não limitados, aos polímeros álcool polivinílico (PVA) e hidroxipropilmetilcelulose (HMPC), agentes plastificantes como polietilenoglicol (PEG) e trietilcitrato, opacificantes como
dióxido de titânio e colorantes como lacas e óxidos de ferro. [0067] In one embodiment, the use of coating on tablets is optional in the recommended range of 1 - 5% weight gain, and ready-made coating systems can be used, such as Opadry®, or proceed with the formation of based films, but not limited to polymers polyvinyl alcohol (PVA) and hydroxypropylmethylcellulose (HMPC), plasticizing agents such as polyethylene glycol (PEG) and triethylcitrate, opacifiers such as titanium dioxide and colorants such as lacquers and iron oxides.
[0068] Em um quinto objeto, a presente invenção apresenta o uso do sal de vilazodona, conforme descrito no primeiro objeto e em qualquer uma de suas concretizações, para o preparo de um medicamento para o tratamento de transtorno depressivo maior (TDM). [0068] In a fifth object, the present invention presents the use of vilazodone salt, as described in the first object and in any of its embodiments, for the preparation of a medicine for the treatment of major depressive disorder (MDD).
[0069] Em uma concretização adicional, o uso do sal de vilazodona é também usado para o preparo de um medicamento para o tratamento e prevenção de desordens de ansiedade, bipolaridade, mania, demência, transtornos relacionados a substâncias, disfunções sexuais, desordens alimentares, obesidade, fibromialgia, desordens do sono, desordens psiquiátricas, infarto cerebral, tensão, para a terapia de efeitos colaterais no tratamento da hipertensão, desordens cerebrais, dor crônica, acromegalia, hipogonadismo, amenorreia secundária, síndrome pré-menstrual e lactação puerperal indesejada. [0069] In a further embodiment, the use of vilazodone salt is also used for the preparation of a medicine for the treatment and prevention of anxiety disorders, bipolarity, mania, dementia, substance-related disorders, sexual dysfunctions, eating disorders, obesity, fibromyalgia, sleep disorders, psychiatric disorders, cerebral infarction, tension, for the therapy of side effects in the treatment of hypertension, cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome and unwanted puerperal lactation.
[0070] Para obtenção do novo sal foram utilizadas duas rotas, não restritivas, de síntese: a) Reação de cloridrato de vilazodona com docusato de sódio em meio aquoso seguido de extração com solvente apoiar (Exemplo 1 ). b) Reação de cloridrato de vilazodona com docusato de sódio em solvente dimetilsulfóxido seguido da adição de água com precipitação do sal docusato de vilazodona (Exemplo 2). [0070] To obtain the new salt, two non-restrictive synthesis routes were used: a) Reaction of vilazodone hydrochloride with sodium docusate in aqueous medium followed by extraction with apolar solvent (Example 1). b) Reaction of vilazodone hydrochloride with sodium docusate in dimethylsulfoxide solvent followed by the addition of water with precipitation of the vilazodone docusate salt (Example 2).
[0071 ]O escopo desta invenção não se restringe à obtenção do sal docusato de vilazodona utilizando o sal cloridrato de vilazodona como reagente de partida, sendo possível a utilização de outras formas salinas, tal como os sais descritos nos documentos WO2014028473 e WO2014049609. [0071] The scope of this invention is not restricted to obtaining the vilazodone docusate salt using the vilazodone hydrochloride salt as a starting reagent, making it possible to use other salt forms, such as the salts described in documents WO2014028473 and WO2014049609.
[0072] De forma ampla, o novo sal docusato de vilazodona pode incluir vantagens como menos impurezas, propriedades farmacocinéticas desejáveis para formulações de liberação imediata e modificada e facilidade no processamento farmacêutico. [0072] Broadly speaking, the new vilazodone docusate salt may include advantages such as fewer impurities, desirable pharmacokinetic properties for immediate and modified release formulations and ease of pharmaceutical processing.
[0073]0 novo sal de vilazodona baseado no contra-íon
docusato pode ser uma alternativa ao cloridrato de vilazodona na produção de formas farmacêuticas inovadoras, seguras e eficazes. A obtenção de um insumo farmacêutico ativo com características melhoradas de solubilidade, adequada estabilidade e não suscetível ao polimorfismo abre possibilidades de desenvolvimento de formas farmacêuticas inovadoras para uma terapia já consolidada, como soluções, cápsulas moles e cápsulas duras. [0073] The new vilazodone salt based on the counterion Docusate can be an alternative to vilazodone hydrochloride in the production of innovative, safe and effective pharmaceutical forms. Obtaining an active pharmaceutical ingredient with improved solubility characteristics, adequate stability and not susceptible to polymorphism opens up possibilities for developing innovative pharmaceutical forms for an already consolidated therapy, such as solutions, soft capsules and hard capsules.
Exemplos Examples
[0074]0s exemplos a seguir servem para ilustrar aspectos da presente invenção sem possuir, porém, qualquer caráter limitativo. [0074] The following examples serve to illustrate aspects of the present invention without, however, having any limiting character.
Exemplo 1 - Metodologia de síntese - Reação de cloridrato de vilazodona com docusato de sódio em meio aquoso seguido de extração com solvente apoiar (A). Example 1 - Synthesis methodology - Reaction of vilazodone hydrochloride with sodium docusate in aqueous medium followed by extraction with apolar solvent (A).
[0075]Adicionar 60 mg de docusato de sódio em 200 ml_ de água em um béquer e agitar até a completa solubilização. Então, adicionar 64 mg de cloridrato de vilazodona (equivalente a 1 :1 em proporção molar de docusato e vilazodona) e manter em agitação magnética por 30 minutos. Na sequência adicionar 100 ml_ de acetato de etila e agitar por mais 30 minutos. Após agitação, deixar a solução em repouso por 10 minutos em um funil de separação até a completa separação entre as fases aquosa e fase apoiar com acetato de etila. Separar as fases em béqueres diferentes utilizando o funil de separação. O sal docusato de vilazodona é obtido após a evaporação do solvente em temperatura ambiente ou estufa com temperatura controlada. A quantidade total de docusato de vilazodona obtido foi de 20 mg. [0075] Add 60 mg of sodium docusate to 200 ml of water in a beaker and shake until complete solubilization. Then, add 64 mg of vilazodone hydrochloride (equivalent to a 1:1 molar ratio of docusate and vilazodone) and keep under magnetic stirring for 30 minutes. Then add 100 ml of ethyl acetate and stir for another 30 minutes. After stirring, leave the solution to rest for 10 minutes in a separation funnel until complete separation between the aqueous phase and the non-polar phase with ethyl acetate. Separate the phases into different beakers using the separation funnel. Vilazodone docusate salt is obtained after evaporation of the solvent at room temperature or a temperature-controlled oven. The total amount of vilazodone docusate obtained was 20 mg.
[0076]Uma melhora no rendimento e tempo de processo por esta metodologia pode ser obtido por extrações sucessivas da fase aquosa com o solvente apoiar e utilização de rotaevaporação para remoção da fase apoiar e obtenção do sal. [0076] An improvement in yield and process time using this methodology can be obtained by successive extractions of the aqueous phase with the apolar solvent and the use of rotary evaporation to remove the apolar phase and obtain the salt.
Exemplo 2 - Reação de cloridrato de vilazodona com docusato de sódio em solvente DMSO seguido da adição de água com precipitação do sal docusato de vilazodona (B).
[0077] Adi ci on ar 256 mg de cloridrato de vilazodona em 4 mL de dimetilsulfóxido (DMSO) em um béquer e agitar até a completa solubilização. Então, adicionar 240 mg de docusato de sódio (equivalente a 1 :1 em proporção molar de docusato e vilazodona) e manter em agitação magnética por cerca de 15 minutos. Na sequência adicionar 4 mL de água e verificar a ocorrência de precipitação instantânea do sal docusato de vilazodona. Para um maior rendimento, deixar em repouso por aproximadamente 6 horas. Filtrar o material precipitado em filtro de nylon 45 pm e secar por 24 h em estufa à 40 °C. A quantidade total de docusato de vilazodona obtido foi de 250 mg. Example 2 - Reaction of vilazodone hydrochloride with sodium docusate in DMSO solvent followed by the addition of water with precipitation of the vilazodone docusate salt (B). [0077] Add 256 mg of vilazodone hydrochloride to 4 mL of dimethyl sulfoxide (DMSO) in a beaker and stir until complete solubilization. Then, add 240 mg of docusate sodium (equivalent to a 1:1 molar ratio of docusate and vilazodone) and keep under magnetic stirring for about 15 minutes. Then add 4 mL of water and check for instantaneous precipitation of the vilazodone docusate salt. For greater performance, leave to rest for approximately 6 hours. Filter the precipitated material through a 45 pm nylon filter and dry for 24 hours in an oven at 40 °C. The total amount of vilazodone docusate obtained was 250 mg.
[0078] Uma melhora no tempo de processo por esta metodologia pode ser obtida pela utilização de rotaevaporação para remoção do solvente DMSO e obtenção do sal. [0078] An improvement in process time using this methodology can be obtained by using rotary evaporation to remove the DMSO solvent and obtain the salt.
Exemplo 3 - Caracterização físico-química do sal docusato de vilazodona. Example 3 - Physicochemical characterization of vilazodone docusate salt.
[0079]A Figura 1 apresenta o difratograma de raios-X característico para o sal docusato de vilazodona obtido pelas rotas de síntese (A) e (B) e a Tabela 1 contém os ângulos e intensidade relativa dos principais picos no difratograma do sal. Na Figura 2, o difratograma de raios-X para o sal docusato de vilazodona (A) é mostrado conjuntamente aos difratogramas dos sais cloridrato de vilazodona (B) e docusato de sódio (C), utilizados como reagentes de partida, ilustrando a diferença na posição dos picos de difração para as diferentes formas cristalinas. [0079] Figure 1 presents the characteristic X-ray diffractogram for the vilazodone docusate salt obtained by synthesis routes (A) and (B) and Table 1 contains the angles and relative intensity of the main peaks in the salt diffractogram. In Figure 2, the X-ray diffractogram for the vilazodone docusate salt (A) is shown together with the diffractograms of the vilazodone hydrochloride (B) and sodium docusate (C) salts, used as starting reagents, illustrating the difference in position of diffraction peaks for different crystalline forms.
Tabela 1. Principais picos de difração de Bragg característicos do docusato de vilazodona. Table 1. Main Bragg diffraction peaks characteristic of vilazodone docusate.
2 - theta (2 = 1 ,54 À) Distância Intensidade relativa2 - theta (2 = 1.54 À) Distance Relative intensity
(graus) (Angstrôns) (unidades arbitrárias)(degrees) (Angstrôns) (arbitrary units)
3,8 23,2 15539 3.8 23.2 15539
7,5 1 1 ,7 609 7.5 1 1 .7 609
1 1 ,3 7,8 720 1 1 .3 7.8 720
15,2 5,8 821 15.2 5.8 821
19,0 4,7 1043 19.0 4.7 1043
21 .6 4,2 1576 21.6 4.2 1576
22.7 4,0 468
[0080JO espectro de absorção no infravermelho do sal docusato de vilazodona (A) é mostrado na Figura 3, juntamente ao espectro para cloridrato de vilazodona (B) e docusato de sódio (C). Algumas das bandas no espectro que caracterizam o sal na forma docusato de vilazodona são: 3477; 2976; 2926; 2860; 2219; 1735; 1680; 1601 ; 1022; 961 ; 940; 888; 853; 810; 761 cm-1. 22.7 4.0 468 [0080JThe infrared absorption spectrum of vilazodone docusate salt (A) is shown in Figure 3, along with the spectrum for vilazodone hydrochloride (B) and sodium docusate (C). Some of the bands in the spectrum that characterize the salt in the form of vilazodone docusate are: 3477; 2976; 2926; 2860; 2219; 1735; 1680; 1601; 1022; 961; 940; 888; 853; 810; 761 cm -1 .
[0081] A Figura 4 mostra a análise termogravimétrica (TGA) que indica uma umidade residual de 0,2% em massa do docusato de vilazodona (isoterma a 105 °C por 60 minutos) (A) e a temperatura de decomposição de aproximadamente 260 °C, valor similar ao verificado para o cloridrato de vilazodona (B). O experimento de calorimetria exploratória diferencial (Differential Scanning Calorimetry, DSC) (Figura 5) indicou um ponto de fusão mais baixo para o docusato de vilazodona (A) em relação ao cloridrato de vilazodona (B), respectivamente a 175 °C e 281 °C. [0081] Figure 4 shows the thermogravimetric analysis (TGA) that indicates a residual moisture of 0.2% by mass of vilazodone docusate (isotherm at 105 ° C for 60 minutes) (A) and a decomposition temperature of approximately 260 °C, a value similar to that found for vilazodone hydrochloride (B). The Differential Scanning Calorimetry (DSC) experiment (Figure 5) indicated a lower melting point for vilazodone docusate (A) compared to vilazodone hydrochloride (B), respectively at 175 °C and 281 ° W.
[0082]A estabilidade da forma sal docusato de vilazodona foi testada mantendo-se a amostra em estufa nas condições de 50 °C e 75 % de umidade relativa (UR) por 10 dias (B) e armazenada em condições ambiente por 3 meses (C). Os espectros de absorção no infravermelho apresentados na Figura 6 indicam que não houve mudança no perfil espectral do composto em ambas condições. [0082] The stability of the salt form of vilazodone docusate was tested by keeping the sample in an oven under conditions of 50 °C and 75% relative humidity (RH) for 10 days (B) and stored at ambient conditions for 3 months ( W). The infrared absorption spectra presented in Figure 6 indicate that there was no change in the spectral profile of the compound under both conditions.
[0083]0s difratogramas de raios-X apresentados na Figura 7 das amostras utilizadas no estudo de estabilidade indicam que não ocorre transição polimórfica nas condições em que o docusato de vilazodona foi submetido. A análise térmica realizada por DSC (Figura 5) também não indica nenhum evento térmico relacionado à transição de fase para outra forma polimórfica, apenas o pico de fusão bem definido de 172 a 178 °C. [0083] The X-ray diffractograms presented in Figure 7 of the samples used in the stability study indicate that no polymorphic transition occurs under the conditions in which vilazodone docusate was subjected. The thermal analysis performed by DSC (Figure 5) also does not indicate any thermal event related to the phase transition to another polymorphic form, only the well-defined melting peak of 172 to 178 °C.
[0084] Para avaliar a estabilidade da fase cristalina de docusato de vilazodona, foi realizado um teste para a análise do sal na fase cristalina em excesso em equilíbrio com diferentes soluções tampões nos pHs 1 ,2, 4,5 e 6,8. Os resultados indicaram que não houve mudanças para outras
formas polimórficas, corroborando com a estabilidade da fase cristalina obtida do sal docusato de vilazodona. [0084] To evaluate the stability of the crystalline phase of vilazodone docusate, a test was carried out to analyze the salt in the crystalline phase in excess in equilibrium with different buffer solutions at pHs 1.2, 4.5 and 6.8. The results indicated that there were no changes for other polymorphic forms, corroborating the stability of the crystalline phase obtained from vilazodone docusate salt.
[0085]Estudos de solubilidade em equilíbrio utilizando o método de agitação orbital em frasco (shake flask) (24 h) do sal docusato de vilazodona em solução de ácido clorídrico 0,1 M (pH 1 ,2) mostram um valor de solubilidade ~ 1 ,8 vezes maior em relação ao cloridrato de vilazodona, respectivamente a 0,025 mg/mL e 0,014 mg/mL. [0085] Equilibrium solubility studies using the shake flask orbital shaking method (24 h) of vilazodone docusate salt in 0.1 M hydrochloric acid solution (pH 1.2) show a solubility value ~ 1.8 times higher in relation to vilazodone hydrochloride, respectively at 0.025 mg/mL and 0.014 mg/mL.
Exemplo 4 - Protótipos de comprimidos de docusato de vilazodona. Example 4 - Vilazodone docusate tablet prototypes.
[0086JA seguir é descrita uma composição farmacêutica obtida a partir do sal de docusato de vilazodona preparado conforme metodologia descrita no Exemplo 2. The following describes a pharmaceutical composition obtained from vilazodone docusate salt prepared according to the methodology described in Example 2.
[0087] A Tabela 2 apresenta a composição dos comprimidos de docusato de vilazodona, contendo excipientes comumente utilizados na indústria farmacêutica. [0087] Table 2 shows the composition of vilazodone docusate tablets, containing excipients commonly used in the pharmaceutical industry.
Tabela 2: Composição quali-quantitativa dos comprimidos de docusato de vilazodona.
Table 2: Quali-quantitative composition of vilazodone docusate tablets.
(1 ) 1 mg de docusato de vilazodona equivale a 0,498 mg de vilazodona na forma de base livre. No medicamento de referência Viibryd a dosagem é relativa ao sal de cloridrato, sendo que 1 ,00 mg de cloridrato de vilazodona equivalem a 0,92 mg de vilazodona na forma base livre. Para utilização do docusato de vilazodona, empregou-se a relação que 1 ,846mg de docusato de vilazodona equivalem a 0,92 mg de vilazodona (mesma concentração do medicamento referência). (1) 1 mg of vilazodone docusate is equivalent to 0.498 mg of vilazodone in free base form. In the reference medicine Viibryd, the dosage is relative to the hydrochloride salt, with 1.00 mg of vilazodone hydrochloride equivalent to 0.92 mg of vilazodone in free base form. To use vilazodone docusate, the relationship was used that 1.846 mg of vilazodone docusate are equivalent to 0.92 mg of vilazodone (same concentration as the reference medicine).
[0088]0s comprimidos foram obtidos pelo processo de compressão direta, com boas características de processabilidade. Os comprimidos apresentaram características físicas de dureza, friabilidade e desintegração adequadas para uma forma farmacêutica.
[0089] Primeiramente, o IFA (27,690g), uma fração lactose (30g) e a celulose microcristalina (30g) foram homogeneizados manualmente com movimentos rotacionais por 5 - 15 minutos (mistura 1 ). Em seguida, a croscarmelose sódica (2,25g), o dióxido de silício coloidal (1 ,05g) e o restante da lactose (30g) foram adicionados à mistura 1 , sendo homogeneizados por mais 5-15 minutos (mistura 2). Posteriormente, o estearato de magnésio coloidal (1 ,5g) foi adicionado a mistura 2 e homogeneizado por mais 3 - 5 minutos (mistura final). [0088] The tablets were obtained by the direct compression process, with good processability characteristics. The tablets presented physical characteristics of hardness, friability and disintegration suitable for a pharmaceutical form. [0089] Firstly, the IFA (27.690g), a lactose fraction (30g) and microcrystalline cellulose (30g) were homogenized manually with rotational movements for 5 - 15 minutes (mixture 1). Then, croscarmellose sodium (2.25g), colloidal silicon dioxide (1.05g) and the remainder of lactose (30g) were added to mixture 1, being homogenized for another 5-15 minutes (mixture 2). Subsequently, colloidal magnesium stearate (1.5g) was added to mixture 2 and homogenized for another 3 - 5 minutes (final mixture).
[0090]A mistura final foi adicionada ao alimentador do simulador de compressão previamente montado com matriz circular EU-B e punção circular bicôncavo de 6 mm sem vinco. Os comprimidos foram obtidos com ciclo de compressão Default Cycle - 1 compression, velocidade da máquina de 25% e forças de compressão de 4KN a 12KN. As forças de ejeção resultantes durante o processo foram < 100N, indicando boa processabilidade do bulk com baixa aderência ao ferramental. [0090] The final mixture was added to the feeder of the compression simulator previously assembled with an EU-B circular die and a 6 mm biconcave circular punch without crease. The tablets were obtained with a Default Cycle - 1 compression cycle, machine speed of 25% and compression forces of 4KN to 12KN. The resulting ejection forces during the process were < 100N, indicating good processability of the bulk with low adhesion to the tooling.
[0091 ]O teste de dureza, que possibilita determinar a resistência do comprimido ao esmagamento ou à ruptura sob pressão radial, apresentou resultados na faixa de 6 a 12Kp, dependendo da força de compressão empregada durante a compressão. [0091] The hardness test, which makes it possible to determine the tablet's resistance to crushing or rupture under radial pressure, presented results in the range of 6 to 12Kp, depending on the compression force used during compression.
[0092]A desintegração foi realizada em água na temperatura de 37 °C ± 1 °C e os resultados mostraram tempos de desintegração menores que 5 minutos para todos os comprimidos avaliados, independente da dureza. [0092] Disintegration was carried out in water at a temperature of 37 °C ± 1 °C and the results showed disintegration times of less than 5 minutes for all tablets evaluated, regardless of hardness.
[0093]0 teste de friabilidade, que possibilita determinar a resistência dos comprimidos à abrasão, foi realizado com 20 comprimidos em friabilômetro ajustado para operar em velocidade de 25 rotações por minuto durante 4 minutos. A diferença entre o peso inicial e final dos comprimidos foi inferior a 0,5%, indicando baixa friabilidade, estando de acordo com as diretrizes da farmacopeia brasileira. [0093] The friability test, which makes it possible to determine the resistance of the tablets to abrasion, was carried out with 20 tablets in a friability meter adjusted to operate at a speed of 25 rotations per minute for 4 minutes. The difference between the initial and final weight of the tablets was less than 0.5%, indicating low friability, in accordance with Brazilian pharmacopoeia guidelines.
[0094]0 processo exemplificado na concretização foi o de
compressão direta, que é um processo menos complexo e, geralmente, o de primeira escolha em relação aos demais processos para obtenção de comprimidos. Entretanto, embora não demonstrado em concretizações, é claramente possível para um técnico no assunto, também obter comprimidos de docusato de vilazodona pelos processos de granulação úmida e granulação seca (compactação). [0094] The process exemplified in the implementation was that of direct compression, which is a less complex process and, generally, the first choice in relation to other processes for obtaining tablets. However, although not demonstrated in embodiments, it is clearly possible for one skilled in the art to also obtain vilazodone docusate tablets by the wet granulation and dry granulation (compaction) processes.
[0095]Além disso, a composição e processo descritos na concretização isentam a presença de agente(s) de revestimento nos comprimidos, que pode ser um processo aditivo opcional após a etapa de compressão. O revestimento, desde que não altere a característica de forma farmacêutica de liberação imediata, pode ser empregado com objetivo de mascaramento de sabor, facilitador da deglutição, melhoramento de características estéticas, para melhor identificação da marca, dentre outras. [0095] Furthermore, the composition and process described in the embodiment exclude the presence of coating agent(s) in the tablets, which can be an optional additive process after the compression step. The coating, as long as it does not alter the characteristics of the immediate release pharmaceutical form, can be used to mask flavor, facilitate swallowing, improve aesthetic characteristics, for better identification of the brand, among others.
[0096] Deve-se compreender que as realizações descritas acima são meramente ilustrativas e que qualquer modificação ao longo delas pode ocorrer para um técnico no assunto. Consequentemente, a presente invenção não deve ser considerada limitada às realizações descritas no presente pedido de patente.
[0096] It should be understood that the achievements described above are merely illustrative and that any modifications to them may occur to a person skilled in the art. Consequently, the present invention should not be considered limited to the embodiments described in the present patent application.
Claims
1. SAL DE VILAZODONA, caracterizado por ser o docusato de vilazodona. 1. VILAZODONE SALT, characterized by being vilazodone docusate.
2. SAL, de acordo com a reivindicação 1 , caracterizado por compreender picos expressos em graus 2-teta (± 0,2°) a 3,8; 7,5; 1 1 ,3; 12,9; 15,2; 18,0; 19,0; 21 ,6; 22,7; 23,9 e 28,0 em seu difratograma de raios-X. 2. SAL, according to claim 1, characterized by comprising peaks expressed in degrees 2-theta (± 0.2°) to 3.8; 7.5; 1 1 .3; 12.9; 15.2; 18.0; 19.0; 21.6; 22.7; 23.9 and 28.0 on its X-ray diffractogram.
3. SAL, de acordo com a reivindicação 1 ou 2, caracterizado por apresentar bandas características a 3477; 2976; 2926; 2860; 2219; 1735; 1680; 1601 ; 1022; 961 ; 940; 888; 853; 810; 761 cm’1 em seu espectro de absorção na região do infravermelho. 3. SAL, according to claim 1 or 2, characterized by presenting characteristic bands at 3477; 2976; 2926; 2860; 2219; 1735; 1680; 1601; 1022; 961; 940; 888; 853; 810; 761 cm' 1 in its absorption spectrum in the infrared region.
4. SAL, de acordo com qualquer uma das reivindicações 1 a 3, caracterizado por apresentar ponto de fusão na faixa de 172 a 178 °C. 4. SALT, according to any one of claims 1 to 3, characterized by having a melting point in the range of 172 to 178 °C.
5. PROCESSO DE OBTENÇÃO DO SAL DE DOCUSATO DE VILAZODONA, conforme definido em qualquer uma das reivindicações 1 a 4, caracterizado por compreender as etapas de: 5. PROCESS FOR OBTAINING VILAZODONE DOCUSATE SALT, as defined in any one of claims 1 to 4, characterized by comprising the steps of:
(i) Adicionar docusato de sódio em água e agitar até a completa solubilização; (i) Add docusate sodium to water and stir until complete solubilization;
(ii) Adicionar cloridrato de vilazodona (equivalente a 1 :1 em proporção molar de docusato e vilazodona) e manter sob agitação; (ii) Add vilazodone hydrochloride (equivalent to 1:1 molar ratio of docusate and vilazodone) and keep stirring;
(iii) Adicionar um solvente orgânico escolhido entre acetato de etila, eter etílico, diclorometano, clorofórmio ou hexano e agitar; (iii) Add an organic solvent chosen from ethyl acetate, ethyl ether, dichloromethane, chloroform or hexane and stir;
(iv) Após agitação, deixar a solução em repouso em um recipiente até a completa separação entre as fases aquosa e fase apoiar com acetato de etila; (iv) After stirring, leave the solution to rest in a container until complete separation between the aqueous and nonpolar phases with ethyl acetate;
(v) Separar as fases em recipientes diferentes; e (v) Separate the phases into different containers; It is
(vi) Obter o sal docusato de vilazodona por rotaevaporação do solvente ou estufa com temperatura controlada. (vi) Obtain the vilazodone docusate salt by rotary evaporation of the solvent or a temperature-controlled oven.
6. PROCESSO DE OBTENÇÃO DO SAL DE DOCUSATO DE VILAZODONA, conforme definido em qualquer uma das reivindicações 1 a 4, caracterizado por compreender as etapas de:
(i) Adicionar de cloridrato de vilazodona em di metilsulfóxido (DMSO) e agitar até a completa solubilização; 6. PROCESS FOR OBTAINING VILAZODONE DOCUSATE SALT, as defined in any one of claims 1 to 4, characterized by comprising the steps of: (i) Add vilazodone hydrochloride in dimethyl sulfoxide (DMSO) and stir until complete solubilization;
(ii) Adicionar docusato de sódio (equivalente a 1 :1 em proporção molar de docusato e vilazodona) e manter em agitação; (ii) Add docusate sodium (equivalent to 1:1 molar ratio of docusate and vilazodone) and keep stirring;
(iii) Adicionar água; (iii) Add water;
(iv) Deixar em repouso; e (iv) Leave to rest; It is
(v) Filtrar o material precipitado e obter o sal docusato de vilazodona após secagem em estufa até a completa remoção do solvente. (v) Filter the precipitated material and obtain the vilazodone docusate salt after drying in an oven until the solvent is completely removed.
7. COMPOSIÇÃO FARMACÊUTICA, caracterizada por compreender (a) docusato de vilazodona, conforme definido em qualquer uma das reivindicações 1 a 4; e (b) um ou mais excipientes farmaceuticamente aceitáveis. 7. PHARMACEUTICAL COMPOSITION, characterized by comprising (a) vilazodone docusate, as defined in any one of claims 1 to 4; and (b) one or more pharmaceutically acceptable excipients.
8. COMPOSIÇÃO FARMACÊUTICA, de acordo com a reivindicação 7, caracterizada por compreender em (b) um ou mais excipientes farmaceuticamente aceitáveis selecionados dentre diluentes, desintegrantes, deslizantes, lubrificantes, agentes colorantes, opacificantes e, opcionalmente, revestimentos. 8. PHARMACEUTICAL COMPOSITION, according to claim 7, characterized by comprising in (b) one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, glidants, lubricants, coloring agents, opacifiers and, optionally, coatings.
9. COMPOSIÇÃO FARMACÊUTICA, de acordo com a reivindicação 7 ou 8, caracterizada por apresentar a seguinte composição: 9. PHARMACEUTICAL COMPOSITION, according to claim 7 or 8, characterized by having the following composition:
Docusato de Vilazodona de 5 a 40%; Vilazodone docusate from 5 to 40%;
Diluente de 10 a 80%; Diluent from 10 to 80%;
Desintegrante de 2 a 30%; Disintegrant from 2 to 30%;
Deslizante de 0,05 a 10%; e Sliding from 0.05 to 10%; It is
Lubrificante de 0,2 a 10%. Lubricant from 0.2 to 10%.
10. COMPOSIÇÃO FARMACÊUTICA, de acordo com a reivindicação 9, caracterizada por apresentar a seguinte composição: 10. PHARMACEUTICAL COMPOSITION, according to claim 9, characterized by having the following composition:
Docusato de Vilazodona de 5 a 40%; Vilazodone docusate from 5 to 40%;
Lactose monoidratada de 0 a 80%; Lactose monohydrate from 0 to 80%;
Celulose microcristalina de 0 a 80%; Microcrystalline cellulose from 0 to 80%;
Croscarmelose sódica de 0 a 5%;
Dióxido de silício coloidal de 0,05 a 2%; e Estearato de magnésio vegetal de 0,2 a 5%. Croscarmellose sodium 0 to 5%; Colloidal silicon dioxide from 0.05 to 2%; and Vegetable magnesium stearate from 0.2 to 5%.
11. COMPOSIÇÃO FARMACÊUTICA, de acordo com qualquer uma das reivindicações 7 a 10, caracterizada por compreender adicionalmente revestimento na faixa de 1 - 5% de ganho de peso. 11. PHARMACEUTICAL COMPOSITION, according to any one of claims 7 to 10, characterized in that it additionally comprises a coating in the range of 1 - 5% weight gain.
12. USO DO SAL DE VILAZODONA, conforme definido em qualquer uma das reivindicações 1 a 4, caracterizado por ser para o preparo de um medicamento para o tratamento de transtorno depressivo maior (TDM). 12. USE OF VILAZODONE SALT, as defined in any one of claims 1 to 4, characterized in that it is for the preparation of a medication for the treatment of major depressive disorder (MDD).
13. USO, de acordo com a reivindicação 12, caracterizado por ser para o preparo de um medicamento para o tratamento e prevenção de disordens de ansiedade, bipolaridade, mania, demência, transtornos relacionados a substâncias, disfunções sexuais, desordens alimentares, obesidade, fibromialgia, disordens do sono, disordens psiquiátricas, infarto cerebral, tensão, para a terapia de efeitos colaterais no tratamento da hipertensão, disordens cerebrais, dor crônica, acromegalia, hipogonadismo, amenorreia secundária, síndrome pré-menstrual e lactação puerperal indesejada.
13. USE, according to claim 12, characterized in that it is for the preparation of a medicine for the treatment and prevention of anxiety disorders, bipolarity, mania, dementia, substance-related disorders, sexual dysfunctions, eating disorders, obesity, fibromyalgia , sleep disorders, psychiatric disorders, cerebral infarction, tension, for the therapy of side effects in the treatment of hypertension, cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome and unwanted puerperal lactation.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014028473A1 (en) * | 2012-08-13 | 2014-02-20 | Assia Chemical Industries Ltd. | New salts of vilazodone and solid state forms thereof |
WO2014049609A2 (en) * | 2012-09-26 | 2014-04-03 | Cadila Healthcare Limited | Novel salts of vilazodone |
WO2014049612A2 (en) * | 2012-09-27 | 2014-04-03 | Msn Laboratories Limited | Processes and polymorphs of 5-[4-[4-(5-cyano-1h-indol-3-yl) butyl]-1-piperazinyl]-2-benzofuran carboxamide and its salts |
-
2022
- 2022-03-16 WO PCT/BR2022/050092 patent/WO2023173182A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014028473A1 (en) * | 2012-08-13 | 2014-02-20 | Assia Chemical Industries Ltd. | New salts of vilazodone and solid state forms thereof |
WO2014049609A2 (en) * | 2012-09-26 | 2014-04-03 | Cadila Healthcare Limited | Novel salts of vilazodone |
WO2014049612A2 (en) * | 2012-09-27 | 2014-04-03 | Msn Laboratories Limited | Processes and polymorphs of 5-[4-[4-(5-cyano-1h-indol-3-yl) butyl]-1-piperazinyl]-2-benzofuran carboxamide and its salts |
Non-Patent Citations (2)
Title |
---|
PEDRO SÓNIA N., R. FREIRE CARMEN S., SILVESTRE ARMANDO J. D., FREIRE MARA G.: "The Role of Ionic Liquids in the Pharmaceutical Field: An Overview of Relevant Applications", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 21, no. 21, pages 8298, XP093092548, DOI: 10.3390/ijms21218298 * |
SUTAR YOGESH, FULTON SOPHIE R., PAUL SAGARKUMAR, ALTAMIRANO SOPHIE, MHATRE SUSMIT, SAEED HIWA, PATEL PRATIKKUMAR, MALLICK SUDIPTA,: "Docusate-Based Ionic Liquids of Anthelmintic Benzimidazoles Show Improved Pharmaceutical Processability, Lipid Solubility, and in Vitro Activity against Cryptococcus neoformans", ACS INFECTIOUS DISEASES, AMERICAN CHEMICAL SOCIETY, US, vol. 7, no. 9, 10 September 2021 (2021-09-10), US , pages 2637 - 2649, XP093092547, ISSN: 2373-8227, DOI: 10.1021/acsinfecdis.1c00063 * |
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