WO2016050734A1 - Combinaisons d'inhibiteurs de la recapture de la norépinéphrine et de la sérotonine et sources de folate - Google Patents
Combinaisons d'inhibiteurs de la recapture de la norépinéphrine et de la sérotonine et sources de folate Download PDFInfo
- Publication number
- WO2016050734A1 WO2016050734A1 PCT/EP2015/072362 EP2015072362W WO2016050734A1 WO 2016050734 A1 WO2016050734 A1 WO 2016050734A1 EP 2015072362 W EP2015072362 W EP 2015072362W WO 2016050734 A1 WO2016050734 A1 WO 2016050734A1
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- WIPO (PCT)
- Prior art keywords
- pharmaceutical combination
- folate
- combination according
- methylfolate
- weight
- Prior art date
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
Definitions
- the present invention relates to a pharmaceutical combination comprising a serotonin norepinephrine reuptake inhibitor and a folate source. More specifically, this invention relates to a pharmaceutical combination comprising duloxetine or a pharmaceutically acceptable salt thereof in combination with a folate source.
- Antidepressants work by increasing the amount of neurotransmitters active in the synapse, thereby enhancing neuronal activity and increasing the responsiveness of mood. Modern antidepressants usually achieve this effect by blocking the transporter proteins that reabsorb certain neurotranmitters, hence the name “reuptake inhibitors”.
- the serotonin norepinephrine reuptake inhibitors are a group of compounds typically used as antidepressants in the treatment of major depressive disorder (depression), anxiety disorders, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS) for the relief of menopausal symptoms and some personality disorders.
- Serotonin and norepinephrine are neurotransmitters which carry massages to the brain. Serotonin can elevate mood and cause a calming effect. Norepinephrine can increase alertness, concentration and motivation. After carrying messages, serotonin and norepinephrine are usually reuptake by the nerve cells. Serotonin-norepinephrine reuptake inhibitors (SNRIs) block or delay the reuptake of these neurotransmitters. This increases the levels of these two neurotransmitters in the synapse and tends to relieve depression and other mood disorders.
- SNRIs Serotonin-norepinephrine reuptake inhibitors
- Serotonin-norepinephrine reuptake inhibitors include desvenlafaxine (Pristiq), venlafaxine (Effexor), milnacipran (Dalcipran), levomilnacipran (Fetzima), sibutramine (Meridia) and duloxetine (Cymbalta) and they are all authorized for the depression treatment.
- Duloxetine inhibits serotonin and norepinephrine reuptake at all doses. It is extensively metabolized in the liver to numerous metabolites. The half-life is approximately 12 hours.
- Folic acid also called folate or folacin
- folate is necessary for the proper biosynthesis of the monoamine neurotransmitters serotonin, norepinephrine, epinephrine, and dopamine.Researches show that people with depression and low folate levels are less likely to respond to treatments such as antidepressants and less likely to achieve remission. While SNRIs block the reuptake of neuratransmitters, folate helps to further increase these neurotransmitters. For these reasons, during the treatment of depression, folate sources are recommended as an additional supplement to improve the efficacy of treatment on patients.
- L-methylfolate (Deplin)
- MTHF Methyl folate, Methyltetrahydrofolate, methyltetrahydrofolic acid
- SAMe S-adenosylmethionine
- L-methylfolate medical source of folate that can cross the blood brain barrier and help with the synthesis of the neurotransmitters associated with mood and, consequently, mood disorders such as depression.
- a pharmaceutical combination comprising duloxetine or a pharmaceutically acceptable salt thereof in combination with a folate source has been developed to achieve a stable pharmaceutical combination with a safe and effective release.
- the main embodiment of this present invention is to provide a pharmaceutical combination comprising duloxetine or a pharmaceutically acceptable salt thereof in combination with a folate source.
- One embodiment of this present invention is to provide a pharmaceutical combination comprising duloxetine or a pharmaceutically acceptable salt thereof in combination with a folate source has been developed to achieve a stable pharmaceutical combination with a safe and effective dissolution profile.
- folate source used in the pharmaceutical combination of this present invention is selected from the group comprising L-methylfolate, L-methylfolate calcium, folic acid (pteroylglutamic acid), vitamin B or other pharmaceutically acceptable folate source, preferably L-methyl folate.
- duloxetine or a pharmaceutically acceptable salt thereof is present in an amount of between 5 - 90%, preferably 15 - 50% and more preferably 10 - 20% by weight of total formulation.
- L-methylfolate is present in an amount of between 1 - 30%, preferably 2 - 20%, more preferably 2 - 10% by weight of total formulation.
- the ratio of duloxetine to L-methylfolate is in the range of 1 to 20 (w/w), preferably 1 to 10 (w/w), more preferably 1 to 5 (w/w).
- the pharmaceutical combination is in the form of a capsule, gelatin capsule, tablet, bilayer tablet, multilayer tablet, mini tablet, oral granule, powder or sachet.
- Duloxetine is water soluble, while L-methyl folate is water non-soluble. Due to solubility difference of two active agents, they pressed into different forms with different excipients. Moreover, with these two forms in one capsule, while stability is achieved, safe and efficient dissolution profile of both active agent is also achieved.
- the pharmaceutical combination is in the form of a capsule comprising pellets and mini tablets.
- Pellets comprise duloxetine and mini tablets comprise L-methyl folate.
- duloxetin or a pharmaceutically acceptable salt thereof is present in an amount of between 14 - 25% by weight of pellet.
- L-methylfolate is present in an amount of between 40 - 50% by weight of mini tablet.
- the SNRI used in the formulation may also be desvenlafaxine (Pristiq), venlafaxine (Effexor), milnacipran (Dalcipran), levomilnacipran (Fetzima) and sibutramine (Meridia).
- pharmaceutical combination of this present invention comprise at least one pharmaceutical excipient selected from the group comprising disintegrants, binders, diluents, glidants, lubricants or mixtures thereof.
- Suitable disintegrants are selected from the group comprising sodium starch glycolate, HPMC (hydroxylpropyl methyl cellulose), cross-linked polyvinylpyrrolidone (crospovidon or copovidon), croscarmellose sodium, low-substitue HPC (hydroxylpropyl cellulose), microcristalline cellulose, starch, alginic acid and alginates, ion-exchange resins, magnesium aluminum silica, sodium dodecyl sulphate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, docusate sodium, guar gam, polyacrylin potasium, poloxomer, sodium alginate, sodium glysin carbonate, sodium lauryl sulphate or mixtures thereof.
- Suitable binders are selected from the group comprising starch, cellulose, polyvinylpyrrolidone (povidone), polymethacrylate, poloxamer, glyceryl behenate, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), methyl cellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose calcium, ethyl cellulose and other cellulose derivatives, polymetacrylates, polyethylene oxide, polyvinyl alcohol, polyvinyl acetate and their copolymers, gelatin, xanthan gum, guar gum, alginate, pullulan, carrageen, kollagen, agar, pectin, hyaluronic acid, carbomer, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose, polyethylene glycol (PEG), sugars,
- Suitable diluents are selected from the group comprising mannitol, sucrose, lactose anhydrate, microcrystalline cellulose, sorbitol, trehalose, isomalt, starch, calcium phosphate anhydrate, calcium phosphate dihydrate, calcium phosphate trihydrate, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, calcium sulfate, carboxymethyl cellulose calcium, powdered cellulose, cellulose acetate, pregelatinized starch, lactose monohydrate, sodium carbonate, sodium bicarbonate, maltodextrine, dextrose, izomalt, calcium carbonate, xylitol, corn starch or mixtures thereof.
- Suitable glidants are selected from the group comprising colloidal silicon dioxide (aerosil), talk, aluminum silicate, powdered cellulose, calcium phosphate tribasic, hydrophobic colloidal silica, magnesium oxide, magnesium trisilicate, magnesium silicate or mixtures thereof.
- Suitable lubricants are selected from the group comprising poloxamer, sodium lauryl sulphate, magnesium stearate, calcium stearate, mineral oil, sodium stearyl fumarate, talk, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulphate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin or mixtures thereof. Coating may also preferably be used for the combination.
- It can be selected from the group comprising poly(methacrylic acid - ethyl acrylate) (1 :1 ), talc, polyvinyl alcohol- polyethylene glycol copolymers (Kollicoat IR), polyvinyl alcohol or copolymers or mixtures thereof (Opadry AMB), Ethylcellulose Dispersions (Surelease), Kerry-HPC, polyethylene glycol, polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer(PVP-VA) and all kinds of OpadryTM, as well as pigments, dyes, titanium dioxide, iron oxide and polymethylmetacrylate copolymers (Eudragit).
- Plasticizers may include, but not limited to tributyl citrate, triethyl citrate (TEC) ,diethyl phthalate (DEP), dibutyl sebacate (DBS), acetylated monoglycerides, triacetin or acetyltriethyl citrate.
- TEC triethyl citrate
- DEP diethyl phthalate
- DBS dibutyl sebacate
- acetylated monoglycerides triacetin or acetyltriethyl citrate.
- duloxetine and folate source combinations comprising of the following: Pellets;
- duloxetin or pharmaceutically acceptable salt thereof
- Mini tablets
- magnesium stearate - 0.01 - 5.0 % by weight of magnesium stearate
- Pellet preparation duloxetine, mannitol, starch and talk are mixed. A solution is prepared with ethyl alcohol, povidone, poloxamer, purified water and sucrose. Mixture containing duloxetin is applicated on cellulose pellets by this syrup. Observed wet pellets are dried. Subcoating of pellets is done by HPMC (E5), Tributhyl citrate, ethyl alcohol and talk. Then, enteric coating is done by poly(methacrylic acid - ethyl acrylate) 1 : 1 mixture, Tributhyl citrate and water. Enteric coated pellets are sieved and dried.
- HPMC E5
- Tributhyl citrate Tributhyl citrate
- enteric coated pellets are sieved and dried.
- Mini tablet preparation L-methyl folate, lactose anhydrate and sodium starch glycolate are mixed. Aerosil and magnesium sterate are added to mixture and mixed again. Total homogenous mixture compressed into mini tablets.
- pellets comprising duloxetine and mini tablets comprising L-methylfolate are filled into capsules.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Engineering & Computer Science (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne une combinaison pharmaceutique comprenant un inhibiteur du recaptage de la sérotonine-norépinéphrine et un folate source.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TR2014/11491 | 2014-09-30 | ||
TR201411491 | 2014-09-30 |
Publications (1)
Publication Number | Publication Date |
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WO2016050734A1 true WO2016050734A1 (fr) | 2016-04-07 |
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ID=54324941
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/EP2015/072362 WO2016050734A1 (fr) | 2014-09-30 | 2015-09-29 | Combinaisons d'inhibiteurs de la recapture de la norépinéphrine et de la sérotonine et sources de folate |
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WO (1) | WO2016050734A1 (fr) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005011642A1 (fr) * | 2003-08-05 | 2005-02-10 | Galephar M/F | Composition pharmaceutique a unite simple comprenant un melange de fibranne et un agent reducteur d'homocysteine |
WO2008129501A2 (fr) * | 2007-04-20 | 2008-10-30 | Wockhardt Research Centre | Compositions pharmaceutiques de duloxetine |
-
2015
- 2015-09-29 WO PCT/EP2015/072362 patent/WO2016050734A1/fr active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005011642A1 (fr) * | 2003-08-05 | 2005-02-10 | Galephar M/F | Composition pharmaceutique a unite simple comprenant un melange de fibranne et un agent reducteur d'homocysteine |
WO2008129501A2 (fr) * | 2007-04-20 | 2008-10-30 | Wockhardt Research Centre | Compositions pharmaceutiques de duloxetine |
Non-Patent Citations (2)
Title |
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SIRISHA K V R ET AL: "A review of pellets and pelletization process - a multiparticulate drug delivery system", INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH 2013 SOCIETY OF PHARMACEUTICAL SCIENCES AND RESEARCH IND, vol. 4, no. 6, 2013, pages 2145 - 2158, XP002752069, ISSN: 2320-5148 * |
WADE ROLIN L ET AL: "Comparative assessment of adherence measures and resource use in SSRI/SNRI-treated patients with depression using second-generation antipsychotics or L-methylfolate as adjunctive therapy.", JOURNAL OF MANAGED CARE PHARMACY : JMCP JAN 2014, vol. 20, no. 1, January 2014 (2014-01-01), pages 76 - 85, XP009187654, ISSN: 1944-706X * |
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