WO2017025930A1 - Oral solution of aripiprazole - Google Patents
Oral solution of aripiprazole Download PDFInfo
- Publication number
- WO2017025930A1 WO2017025930A1 PCT/IB2016/054859 IB2016054859W WO2017025930A1 WO 2017025930 A1 WO2017025930 A1 WO 2017025930A1 IB 2016054859 W IB2016054859 W IB 2016054859W WO 2017025930 A1 WO2017025930 A1 WO 2017025930A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solution
- aripiprazole
- oral solution
- pharmaceutical oral
- purified water
- Prior art date
Links
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 41
- 229940100688 oral solution Drugs 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 21
- 239000000796 flavoring agent Substances 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 13
- 238000009472 formulation Methods 0.000 claims description 13
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 12
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 12
- 239000001630 malic acid Substances 0.000 claims description 12
- 235000011090 malic acid Nutrition 0.000 claims description 12
- 235000013355 food flavoring agent Nutrition 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000006184 cosolvent Substances 0.000 claims description 8
- 239000003755 preservative agent Substances 0.000 claims description 8
- 239000002738 chelating agent Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 235000019634 flavors Nutrition 0.000 claims description 7
- 230000002335 preservative effect Effects 0.000 claims description 7
- 239000008213 purified water Substances 0.000 claims description 7
- 239000003981 vehicle Substances 0.000 claims description 7
- 235000003599 food sweetener Nutrition 0.000 claims description 6
- 235000011187 glycerol Nutrition 0.000 claims description 6
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003765 sweetening agent Substances 0.000 claims description 6
- 230000002708 enhancing effect Effects 0.000 claims description 5
- 229930091371 Fructose Natural products 0.000 claims description 4
- 239000005715 Fructose Substances 0.000 claims description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 3
- 229960003415 propylparaben Drugs 0.000 claims description 3
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical group [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000006172 buffering agent Substances 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 abstract description 8
- 239000000243 solution Substances 0.000 description 13
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- 239000003814 drug Substances 0.000 description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 239000003186 pharmaceutical solution Substances 0.000 description 6
- 208000020925 Bipolar disease Diseases 0.000 description 5
- 239000003693 atypical antipsychotic agent Substances 0.000 description 5
- 201000000980 schizophrenia Diseases 0.000 description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- 229940127236 atypical antipsychotics Drugs 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical group OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 208000020016 psychiatric disease Diseases 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
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- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000002253 acid Substances 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 239000000164 antipsychotic agent Substances 0.000 description 2
- 229940005529 antipsychotics Drugs 0.000 description 2
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- 208000029560 autism spectrum disease Diseases 0.000 description 2
- 208000028683 bipolar I disease Diseases 0.000 description 2
- 208000025307 bipolar depression Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
- 239000006194 liquid suspension Substances 0.000 description 2
- 239000007968 orange flavor Substances 0.000 description 2
- 239000004031 partial agonist Substances 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
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- 108020003175 receptors Proteins 0.000 description 2
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- 239000011975 tartaric acid Substances 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
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- 208000020706 Autistic disease Diseases 0.000 description 1
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- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- QZKRHPLGUJDVAR-UHFFFAOYSA-K EDTA trisodium salt Chemical compound [Na+].[Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O QZKRHPLGUJDVAR-UHFFFAOYSA-K 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010016759 Flat affect Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 235000019501 Lemon oil Nutrition 0.000 description 1
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 206010041243 Social avoidant behaviour Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
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- 125000005907 alkyl ester group Chemical group 0.000 description 1
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- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
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- 210000003169 central nervous system Anatomy 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
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- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
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- 208000024714 major depressive disease Diseases 0.000 description 1
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- 238000002483 medication Methods 0.000 description 1
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- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 1
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- 229960004838 phosphoric acid Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 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
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
Definitions
- the present invention pertains to pharmaceutical composition of aripiprazole.
- present invention relates to oral solution of aripiprazole improved solubility, stability and bioavailability of active ingredient, aripiprazole and process for preparation of the same.
- Atypical antipsychotics are the class of compounds used to treat psychiatric conditions including schizophrenia, bipolar disorder, autism and major depressive disorder and preferred over typical antipsychotics because of fewer chances to cause extrapyramidal and motor control disabilities.
- An atypical antipsychotic, aripiprazole act as partial agonist at D 2 receptor and used for treatment of schizophrenia, bipolar disorder, depression and autism spectrum disorders.
- EP1381367 discloses oral pharmaceutical solution of aripiprazole with suitable solvent system, one or more taste-enhancing/masking agents and one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid, wherein said solution has a pH from 2.5 to 4.5.
- EP1933814 discloses stable nanoparticulate formulation of aripiprazole, or salts or derivatives of aripiprazole with improved bioavailability, faster rates of absorption and a faster onset of therapeutic effect, wherein an average effective particle size of aripiprazole is less than about 2000 nm and formulation contain at least one surface stabilizer which is useful for the treatment of diseases and disorders of the central nervous system, including mental diseases and disorders.
- EP2170279 discloses an aripiprazole suspension and method of preparation of aripiprazole suspension, wherein mean particle size of aripiprazole is 1 to 10 ⁇ .
- EP2299983 discloses a pharmaceutical composition of an atypical antipsychotic drug with succinic acid, fumaric acid or a mixture of succinic acid and fumaric acid.
- WO 2011107855 discloses sustained release oral liquid suspension dosage form of aripiprazole and method of its preparation.
- Oral liquid suspension comprises of sustained release pellets in which inert pellets are surrounded by seal coating.
- Drug layer comprises of active pharmaceutical ingredient with one or more pharmaceutically acceptable excipients surrounding seal coated inert pellets and this drug layer is surrounded by coating layer comprises of rate controlling polymer
- These prepared sustained release pellets are suspended with suitable suspending agen and other pharmaceutically acceptable excipients in a suspending media at a suitable pH.
- WO2014059363 discloses oral solution formulation of aripiprazole which comprises ofglycerin, propylene glycol, a buffer, a sweetener, and a flavoring agent, wherein said pharmaceutical formulation does not comprise a sugar and preservative
- the pH of formulation is 4.3 or greater.
- present invention provides a stable oral solution of aripiprazole with a malic acid and other pharmaceutically acceptable excipients having improved solubility and bioavailability which further influence patient compliance, wherein pH of solution is 2.0 to 4.0.
- the primary object of present invention is to provide oral pharmaceutical solution of aripiprazole with improved stability, solubility and bioavailability of active ingredient comprises of aripiprazole, malic acid and other pharmaceutically acceptable excipients, wherein pH of solution is 2.0 to 4.0.
- Another object of present invention is to provide oral solution having dose flexibility for patients who need special doses of the drug and have difficulties in swallowing oral dosage forms.
- Still another object of present invention is to provide oral solution with improved taste having high patient compliance.
- the present invention relates to the oral solution of aripiprazole having improved stability, solubility and bioavaillibity of active ingredient, aripiprazole.
- One aspect of present invention relates to oral solution of aripiprazole comprises of an active ingredient, aripiprazole and malic acid and other pharmaceutically acceptable ingredients selected from vehicle, co-solvent, preservative, sweetener, chelating agent, buffer, flavoring agent and sweetness/flavor enhancing agent wherein said formulation is with acidic pH, more particularly pH between 3 and 3.5.
- Schizophrenia is a mental disorder that generally appears in late adolescence or early adulthood, however it can emerge at any time in life. It is one of many brain diseases that may include delusions, loss of personality (flat affect), confusion, agitation, social withdrawal, psychosis, and playful behavior.
- the mainstay of treatment is antipsychotic medication, which primarily suppresses dopamine receptor activity.
- Atypical antipsychotics are preferred over typical antipsychotics because of fewer chances to cause severe side-effects such as extrapyramidal and motor control disabilities.
- aripiprazole is an atypical antipsychotic which act as partial agonist at D 2 receptor and used for treatment of schizophrenia, bipolar disorder, depression and autism spectrum disorders. Chemically, aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)piperazine-l-yl]butoxy]-3,4- dihydro-lH-quinolin-2-one. Aripiprazole has the following chemical structure:
- Carbostyril compounds are influenced by temperature, air and humidity conditions, so aripiprazole has stability problems related to environmental and physical conditions when formulated in oral solution form and undergo structural degradation and chemical behaviour changes when get exposed to air and humidity. Because of this reasons stability of aripiprazole is not maintained to desired level when formulated in solution form and shelf life is decreased and requires presence of preservative which further enhances stability of aripiprazole in solution form.
- It is an object of present invention is to provide oral pharmaceutical solution of aripiprazole with improved solubility, stability and bioavailability of active ingredient, aripiprazole and improved taste.
- malic acid is used in formulation of aripiprazole.
- the main reason of using malic acid is it has characteristic such as low hygroscopicity, easy dissolution, taste enhancement, free flowing, non dusty, even particle size and overall tartness is smoother than other acids.
- malice acid can be used to adjust pH.
- other excipients used can be selected from vehicle, co-solvent, preservative, sweetener, chelating agent, buffer, flavoring agent and sweetness/flavor enhancing agent.
- Vehicles used in pharmaceutical formulations are mainly liquid bases which carries drugs and other excipients in dissolved or dispersed state.
- Pharmaceutical vehicles are of two types:
- Oily vehicles Aqueous vehicles can be selected from but not limited to purified water, hydro- alcoholic, polyhydric alcohols and buffers, while oily vehicles can be selected from vegetable oils, mineral oils, organic oily bases or emulsified bases.
- Co-solvents are used to increase solubility of drugs that show low solubility in water. It is also used to improve viscosity, taste and flavor.
- Co-solvent system comprises of solvents selected from but not limited to propylene glycol, glycerin, alcohol, polyhydric alcohol and water for injection which is used alone or in combination.
- Preservatives are included in pharmaceutical solutions to control the microbial bioburden of the formulation having broad spectrum of antimicrobial activity, must be chemically and physically stable over the shelf-life of the product and have low toxicity.
- Preservative can be selected from group but not limited to alcohol, benzyl alcohol, chlorbutol, chlorocresol, alkyl esters of paraben, phenol, phenyl ethanol, sodium benzoate, antimicrobial solvents like propylene glycol, chloroform.
- Sweetener can be selected from but not limited to sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium and aspartame to impart sweetness to the formulation.
- Chelating agent is used for drug stabilization, to maintain potency of active ingredients and to stabilize colors and flavors.
- Chelating agent can be selected from but not limited to citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid and trisodium edetate.
- pH of the formulation can be controlled and optimize the physicochemical performance of the formulation by using base or buffer can be selected from but not limited to sodium acetate, sodium hydroxide, sodium citrate, sodium phosphate and disodium phosphate.
- Flavoring agents are mainly use to increase the palatability and enhance the aesthetic qualities of the formulation.
- Flavoring agent can be selected but not limited to oil based flavoring agent such as essential oils including peppermint oil, orange oil, lemon oil etc.
- Sweetness/flavor enhancing agent can be selected from but not limited to monoammonium glycyrrhizinate, fructose, and monosodium glutamate used to reduce the sharp bitter taste of medications.
- oral pharmaceutical solution of aripiprazole is formulated which comprises of an active ingredient, aripiprazole, malic acid and other excipients selected from vehicle, co-solvent, preservative, sweetener, chelating agent, buffer, flavoring agent and sweetness/flavor enhancing agent, wherein pH of formulation is maintained between 2.0 to 4.0, more particularly between 3 and 3.5.
- the oral pharmaceutical solution of above composition is prepared by following method: - a) Aripiprazole, methyl 4-hydroxybenzoate and propyl 4-hydroxybenzoate are dissolved in co-solvent propylene glycol.
- step b) Solution of step b) is added to solution of step c).
- step d) pH of solution of step d) is adjusted between 2.0 to 4.0 using 20 %w/w sodium hydroxide.
- Flavoring agent (orange flavor) is added to solution of step e).
- step f) Volume of solution of step f) is made up to batch size with purified water.
- step g) Solution of step g) is filled in amber colored PET bottles and capped using PP CR closure.
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Abstract
The present invention relates to oral solution of aripiprazole with improved solubility, stability and bioavailability of active ingredient and process for preparation of the same.
Description
Oral Solution Of Aripiprazole Field of invention
The present invention pertains to pharmaceutical composition of aripiprazole. In particular, present invention relates to oral solution of aripiprazole improved solubility, stability and bioavailability of active ingredient, aripiprazole and process for preparation of the same.
Background of invention
Atypical antipsychotics are the class of compounds used to treat psychiatric conditions including schizophrenia, bipolar disorder, autism and major depressive disorder and preferred over typical antipsychotics because of fewer chances to cause extrapyramidal and motor control disabilities.
An atypical antipsychotic, aripiprazole act as partial agonist at D2 receptor and used for treatment of schizophrenia, bipolar disorder, depression and autism spectrum disorders.
EP1381367 discloses oral pharmaceutical solution of aripiprazole with suitable solvent system, one or more taste-enhancing/masking agents and one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid, wherein said solution has a pH from 2.5 to 4.5.
EP1933814 discloses stable nanoparticulate formulation of aripiprazole, or salts or derivatives of aripiprazole with improved bioavailability, faster rates of absorption and a faster onset of therapeutic effect, wherein an average effective particle size of aripiprazole is less than about 2000 nm and formulation contain at least one surface stabilizer which is useful for the treatment of diseases and disorders of the central nervous system, including mental diseases and disorders.
EP2170279 discloses an aripiprazole suspension and method of preparation of aripiprazole suspension, wherein mean particle size of aripiprazole is 1 to 10 μπι. EP2299983 discloses a pharmaceutical composition of an atypical antipsychotic drug with succinic acid, fumaric acid or a mixture of succinic acid and fumaric acid.
WO 2011107855 discloses sustained release oral liquid suspension dosage form of aripiprazole and method of its preparation. Oral liquid suspension comprises of sustained release pellets in which inert pellets are surrounded by seal coating. Drug layer comprises of active pharmaceutical ingredient with one or more pharmaceutically acceptable excipients surrounding seal coated inert pellets and this drug layer is surrounded by coating layer comprises of rate controlling polymer These prepared sustained release pellets are suspended with suitable suspending agen and other pharmaceutically acceptable excipients in a suspending media at a suitable pH. WO2014059363 discloses oral solution formulation of aripiprazole which comprises ofglycerin, propylene glycol, a buffer, a sweetener, and a flavoring agent, wherein said pharmaceutical formulation does not comprise a sugar and preservative The pH of formulation is 4.3 or greater.
Although many dosage form of aripiprazole have been described in prior, present invention provides a stable oral solution of aripiprazole with a malic acid and other pharmaceutically acceptable excipients having improved solubility and bioavailability which further influence patient compliance, wherein pH of solution is 2.0 to 4.0.
Object of invention
The primary object of present invention is to provide oral pharmaceutical solution of aripiprazole with improved stability, solubility and bioavailability of active ingredient comprises of aripiprazole, malic acid and other pharmaceutically acceptable excipients, wherein pH of solution is 2.0 to 4.0. Another object of present invention is to provide oral solution having dose flexibility for patients who need special doses of the drug and have difficulties in swallowing oral dosage forms.
Still another object of present invention is to provide oral solution with improved taste having high patient compliance.
It is yet another object of present invention to provide process of preparation of oral solution of aripiprazole.
Summary of invention
The present invention relates to the oral solution of aripiprazole having improved stability, solubility and bioavaillibity of active ingredient, aripiprazole.
One aspect of present invention relates to oral solution of aripiprazole comprises of an active ingredient, aripiprazole and malic acid and other pharmaceutically acceptable ingredients selected from vehicle, co-solvent, preservative, sweetener, chelating agent, buffer, flavoring agent and sweetness/flavor enhancing agent wherein said formulation is with acidic pH, more particularly pH between 3 and 3.5.
Detail description of invention
Schizophrenia is a mental disorder that generally appears in late adolescence or early adulthood, however it can emerge at any time in life. It is one of many brain diseases that may include delusions, loss of personality (flat affect), confusion, agitation, social withdrawal, psychosis, and bizarre behavior.
An imbalance of dopamine, a neurotransmitter is involved in the onset of schizophrenia.
The mainstay of treatment is antipsychotic medication, which primarily suppresses dopamine receptor activity.
Atypical antipsychotics are preferred over typical antipsychotics because of fewer chances to cause severe side-effects such as extrapyramidal and motor control disabilities.
A carbostyril derivative, aripiprazole is an atypical antipsychotic which act as partial agonist at D2 receptor and used for treatment of schizophrenia, bipolar disorder, depression and autism spectrum disorders.
Chemically, aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)piperazine-l-yl]butoxy]-3,4- dihydro-lH-quinolin-2-one. Aripiprazole has the following chemical structure:
Carbostyril compounds are influenced by temperature, air and humidity conditions, so aripiprazole has stability problems related to environmental and physical conditions when formulated in oral solution form and undergo structural degradation and chemical behaviour changes when get exposed to air and humidity. Because of this reasons stability of aripiprazole is not maintained to desired level when formulated in solution form and shelf life is decreased and requires presence of preservative which further enhances stability of aripiprazole in solution form.
It is an object of present invention is to provide oral pharmaceutical solution of aripiprazole with improved solubility, stability and bioavailability of active ingredient, aripiprazole and improved taste.
In the present invention a preferred embodiment, malic acid is used in formulation of aripiprazole. The main reason of using malic acid is it has characteristic such as low hygroscopicity, easy dissolution, taste enhancement, free flowing, non dusty, even particle size and overall tartness is smoother than other acids. Also malice acid can be used to adjust pH. In a preferred form of present invention with malic acid other excipients used can be selected from vehicle, co-solvent, preservative, sweetener, chelating agent, buffer, flavoring agent and sweetness/flavor enhancing agent.
Vehicles used in pharmaceutical formulations are mainly liquid bases which carries drugs and other excipients in dissolved or dispersed state. Pharmaceutical vehicles are of two types:
1 ) Aqueous vehicles
2) Oily vehicles
Aqueous vehicles can be selected from but not limited to purified water, hydro- alcoholic, polyhydric alcohols and buffers, while oily vehicles can be selected from vegetable oils, mineral oils, organic oily bases or emulsified bases.
Co-solvents are used to increase solubility of drugs that show low solubility in water. It is also used to improve viscosity, taste and flavor. Co-solvent system comprises of solvents selected from but not limited to propylene glycol, glycerin, alcohol, polyhydric alcohol and water for injection which is used alone or in combination. Preservatives are included in pharmaceutical solutions to control the microbial bioburden of the formulation having broad spectrum of antimicrobial activity, must be chemically and physically stable over the shelf-life of the product and have low toxicity. Preservative can be selected from group but not limited to alcohol, benzyl alcohol, chlorbutol, chlorocresol, alkyl esters of paraben, phenol, phenyl ethanol, sodium benzoate, antimicrobial solvents like propylene glycol, chloroform.
Sweetener can be selected from but not limited to sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium and aspartame to impart sweetness to the formulation. Chelating agent is used for drug stabilization, to maintain potency of active ingredients and to stabilize colors and flavors. Chelating agent can be selected from but not limited to citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid and trisodium edetate.
pH of the formulation can be controlled and optimize the physicochemical performance of the formulation by using base or buffer can be selected from but not limited to sodium acetate, sodium hydroxide, sodium citrate, sodium phosphate and disodium phosphate.
Flavoring agents are mainly use to increase the palatability and enhance the aesthetic qualities of the formulation. Flavoring agent can be selected but not limited to oil based flavoring agent such as essential oils including peppermint oil, orange oil, lemon oil etc.
Sweetness/flavor enhancing agent can be selected from but not limited to monoammonium glycyrrhizinate, fructose, and monosodium glutamate used to reduce the sharp bitter taste of medications.
In aspect of present invention, oral pharmaceutical solution of aripiprazole is formulated which comprises of an active ingredient, aripiprazole, malic acid and other excipients selected from vehicle, co-solvent, preservative, sweetener, chelating agent, buffer, flavoring agent and sweetness/flavor enhancing agent, wherein pH of formulation is maintained between 2.0 to 4.0, more particularly between 3 and 3.5.
Examples
The present invention can be described by way of example only. It is to be recognized that modifications falling within the scope and spirit of the description or claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this disclosure.
For the composition of aripiprazole lmg/ml, drug and excipients with its range are shown below in table:
Quantity
No. Drug/ Excipients
(% w/w)
1 Aripiprazole 0.080
2 Propylene glycol 8.019
3 Glycerin 3.256
4 Malic acid 1.123
5 Methyl 4-hydroxybenzoate 0.144
6 Propyl 4-hydroxybenzoate 0.016
7 Fructose 16.038
8 Sucrose 32.077
9 Disodium edetate 0.080
10 Orange flavor 0.080
11 Sodium hydroxide 0.401
12 Purified water QS
The oral pharmaceutical solution of above composition is prepared by following method: - a) Aripiprazole, methyl 4-hydroxybenzoate and propyl 4-hydroxybenzoate are dissolved in co-solvent propylene glycol.
b) Glycerine solution is added to solution of step a).
c) Fructose, sucrose and malic acid are dissolved in Purified water.
d) Solution of step b) is added to solution of step c).
e) pH of solution of step d) is adjusted between 2.0 to 4.0 using 20 %w/w sodium hydroxide.
f) Flavoring agent (orange flavor) is added to solution of step e).
g) Volume of solution of step f) is made up to batch size with purified water. h) Solution of step g) is filled in amber colored PET bottles and capped using PP CR closure.
Claims
We claim,
1) A pharmaceutical oral solution comprises of aripiprazole and malic acid with improved stability, solubility and bioavailability with acidic pH.
2) A pharmaceutical oral solution as claimed in claim 1, wherein pH of formulation is between 3 and 3.5.
3) A pharmaceutical oral solution as claimed in claim 1, wherein other pharmaceutically accepted excipients are selected from vehicle, co-solvent, preservative, sweetener, chelating agent, buffer and flavoring agent and sweetness/flavor enhancing agent.
4) A pharmaceutical oral solution as claimed in claim 3, wherein vehicle is purified water.
5) A pharmaceutical oral solution as claimed in claim 3, wherein co-solvent system comprises of combination of glycerin and propylene glycol.
6) A pharmaceutical oral solution as claimed in claim 3, wherein chelating agent is disodium edetate.
7) A process for preparation of a pharmaceutical oral solution of aripiprazole comprises of following steps:
a) Dissolution of aripiprazole, methyl 4-hydroxybenzoate and propyl 4- hydroxybenzoate in co-solvent propylene glycol.
b) Addition of glycerine solution is to solution of step a).
c) Dissolution of fructose, sucrose and malic acid in Purified water.
d) Addition of solution of step b) to solution of step c).
e) Adjusted of pH of solution of step d) between 2.0-4.0
f) Addition of flavoring agent to solution of step e).
g) Adjustment of volume of solution of step f) to up to batch size with purified water.
Filling of solution of step g) is in amber colored PET bottles and capped using PP CR closure.
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Cited By (1)
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CN112666267A (en) * | 2019-10-15 | 2021-04-16 | 上海上药中西制药有限公司 | Method for detecting related substances of aripiprazole medicine |
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EP2170279A1 (en) | 2007-07-31 | 2010-04-07 | Otsuka Pharmaceutical Co., Ltd. | Methods for producing aripiprazole suspension and freeze-dried formulation |
EP2299983A1 (en) | 2008-07-24 | 2011-03-30 | Handa Pharmaceuticals, Llc | Stabilized atypical antipsychotic formulation |
WO2011107855A2 (en) | 2010-03-04 | 2011-09-09 | Torrent Pharmaceuticals Limited | Sustained release oral liquid suspension dosage form |
WO2014059363A1 (en) | 2012-10-11 | 2014-04-17 | Antrim Pharmaceuticals Llc | Oral solution formulations of aripiprazole |
JP2015164907A (en) * | 2013-07-10 | 2015-09-17 | 共和薬品工業株式会社 | Aripiprazole-comprising aqueous liquid agent |
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WO2002085366A1 (en) * | 2001-04-25 | 2002-10-31 | Bristol-Myers Squibb Company | Aripiprazole oral solution |
EP1381367A1 (en) | 2001-04-25 | 2004-01-21 | Bristol-Myers Squibb Company | Aripiprazole oral solution |
EP1933814A2 (en) | 2005-09-15 | 2008-06-25 | Elan Pharma International Limited | Nanoparticulate aripiprazole formulations |
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