EP2571484A2 - Formulations effervescentes - Google Patents
Formulations effervescentesInfo
- Publication number
- EP2571484A2 EP2571484A2 EP11740739A EP11740739A EP2571484A2 EP 2571484 A2 EP2571484 A2 EP 2571484A2 EP 11740739 A EP11740739 A EP 11740739A EP 11740739 A EP11740739 A EP 11740739A EP 2571484 A2 EP2571484 A2 EP 2571484A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- effervescent
- pharmaceutically acceptable
- formulation
- sorbitol
- maltodextrin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 238000009472 formulation Methods 0.000 title claims abstract description 59
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 claims abstract description 23
- 229960001508 levocetirizine Drugs 0.000 claims abstract description 23
- 239000000796 flavoring agent Substances 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 7
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- 239000000600 sorbitol Substances 0.000 claims description 16
- 235000010356 sorbitol Nutrition 0.000 claims description 16
- 238000005469 granulation Methods 0.000 claims description 15
- 230000003179 granulation Effects 0.000 claims description 15
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- 239000005913 Maltodextrin Substances 0.000 claims description 14
- 235000003599 food sweetener Nutrition 0.000 claims description 14
- 229940035034 maltodextrin Drugs 0.000 claims description 14
- 239000003765 sweetening agent Substances 0.000 claims description 14
- 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 claims description 11
- 239000013543 active substance Substances 0.000 claims description 10
- 229920000858 Cyclodextrin Polymers 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 6
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- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000009285 allergic inflammation Effects 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000021029 blackberry Nutrition 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 229940096516 dextrates Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- RRPFCKLVOUENJB-UHFFFAOYSA-L disodium;2-aminoacetic acid;carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O.NCC(O)=O RRPFCKLVOUENJB-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 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
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000005722 itchiness Effects 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 230000000873 masking effect Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 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
- 229940100692 oral suspension Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 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
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
-
- 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
- A61K31/4965—Non-condensed pyrazines
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
Definitions
- the present invention relates to stable levocetirizine effervescent formulations flavor and taste of which has been improved in order to be used in the treatment of seasonal allergic rhinitis, perennial allergic rhinitis, chronic idiopathic urticaria, and the methods for preparation of said formulations.
- Levocetirizine is a non-sedating, long-acting HI anti-histaminic displayed in formula (I) below which has the chemical name 2-[4-[(i?)-(4-chlorophenyl)-phenyl-methyl]piperazin- l-yl]ethoxy] acetic acid (Formula I).
- Cetirizine was first disclosed in the patent numbered EP0058146 Al.
- Levocetirizine which is an R-enantiomer of cetirizine is a piperazine derivative, potent and selective HI receptor antagonist.
- Levocetirizine is a new anti-histaminic that binds to HI receptors with high affinity, even twelve times higher than cetirizine.
- Levocetirizine competes with histamine and prevents histamine to bind to HI receptors. This antagonism blocks the effects of histamine on gastrointestinal channel, uterus, large blood vessels and bronchial smooth muscle. Blockage of HI receptors impedes histaminic activities such as edema, warmness and itchiness.
- the facts that levocetirizine does not enter the central nervous system in significant amounts and its affinity to HI receptors there is low can explain its non-sedating characteristics to some extent.
- Levocetirizine has antiallergic and anti-inflammatory activity.
- the studies conducted have presented that levocetirizine inhibits the wide range of chain of events starting and spreading out the allergic inflammation.
- Levocetinzine formulations existing in the prior art are in oral solution, oral drop and film tablet form.
- solid dosage forms such as tablets have lower bioavailability than solution forms and they generally pose difficulty of use for geriatric, pediatric and physically handicapped patients who have swallowing difficulties.
- Oral solution and suspension forms produced as an alternative to these forms, on the other hand are not preferable much as the stability of active agents cannot be maintained for long in these forms and they have short shelf life.
- Another disadvantage of these forms is that they have a risk of high and/or uncontrolled dose intake in pediatric and geriatric patients.
- dosage forms Another alternative in terms of dosage forms is effervescent forms which satisfy the expectations of bioavailability, shelf life, ease of use and carrying and accurate dosing.
- Effervescent forms are more advantageous than conventional forms owing to fast dispersion.
- Effervescent formulations disperse fast; emit the component/components simultaneously and rapidly into aqueous liquid.
- the time which passes between adding the formulation into water and swallowing the solution is relatively short. Consumption of the formulations in a short time prevents the degradation of the active agent with water and thus, this type of formulations that are consumed in a short time do not require high amounts of stabilizing agent.
- levocetirizine formulations Another significant problem about levocetirizine formulations is that it is hard to formulate them due to the bitter taste of the active agent and its difficulty of use by patients.
- various pharmaceutical excipients such as sweeteners, flavoring agents or aroma in formulations of levocetirizine. Most often, use of sweeteners only is not enough to mask the bitter taste in the formulations.
- some other excipients are used in addition to sweeteners.
- the most frequently used excipients for this purpose are sugar alcohols such as mannitol, sorbitol; sugars such as sucrose, fructose; polyols such as cyclodextrins.
- the present invention relates to user-friendly levocetirizine formulations having high bioavailability bitter taste of which are masked and which can be produced without conducing to undesirable by-products, and the production method of said formulations.
- the inventors have surprisingly masked the bitter taste by using at least one polyol and/or derivative thereof in the formulations and managed to produce stable formulations of levocetirizine.
- the formulations of the present invention are characterized in being in effervescent form.
- a characteristic feature of formulations of the present invention is that polyol derivative excipients can be included in the formulations of the present invention without conducing to any stability problem resulting from their interaction with cetirizine derivatives.
- polyol derivative excipients utilized in the formulations of the present invention for different purposes such as bulking agent is also known in the prior art in addition to their sweetening and/or taste masking functions.
- Polyol derivatives used in the formulations of the present invention can fulfill one or more functions at the same time.
- the formulations of the present invention comprise levocetirizine or pharmaceutically acceptable salt, ester, solvate, derivative, polymorph or hydrate thereof as the active agent.
- the formulations of the present invention are used in the treatment of allergic rhinitis (including seasonal allergic rhinitis comprising ocular symptoms), persistent allergic rhinitis, perennial allergic rhinitis and chronic idiopathic urticaria.
- the purpose of the present invention is to produce an effervescent tablet which provides ease of administration by the oral route in aqueous solution form.
- the formulation rapidly disperses in the aqueous liquid and it can be administered by the oral route, by spoon or dropper where necessary. This type of formulations are more advantageous for use especially in physically handicapped and elderly patients.
- the formulations of the present invention comprise the following constituents:
- Active agent in an amount in the range of 0.1 % to 80% by weight
- At least one effervescent couple in an amount in the range of 60% to 90% by weight
- At least one pharmaceutically acceptable polyol and/or derivative thereof in an amount in the range of 1 % to 30% by weight
- At least one pharmaceutically acceptable sweetener in an amount in the range of 5% to 30% by weight
- At least one pharmaceutically acceptable flavoring agent in an amount in the range of l% to 10% by weight
- At least one pharmaceutically acceptable solvent in an amount in the range of 5% to 20% by weight
- the pharmaceutical formulations of the present invention comprise other pharmaceutically acceptable additives and excipients selected from a group comprising disintegrants, viscosity enhancers, filling materials, drying agents, lubricants, diluents, binders, glidants, anti-foam agents, wetting agents, effervescent mixtures, sweeteners and flavoring agents.
- the effervescent bases which can be used in the formulations of the present invention comprise sodium, potassium and calcium carbonates, bicarbonates and/or sodium glycine carbonate or a combination thereof.
- the effervescent couple used in the formulations of the present invention is preferably composed of hydrogen carbonate and citric acid.
- the disintegrant which can be used in the present invention can be selected from polymers having high disintegrating characteristics such as cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high molecular weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, the products known as Crospovidone®, Polyplasdone® or Kollidon® XL, alginic acid, sodium alginate.
- polymers having high disintegrating characteristics such as cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high molecular weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, the products known as Crospovidone®, Polyplasdone® or Kollidon® XL, alginic acid, sodium alginate.
- the filling materials which can be used in the formulations of the present invention can be selected from a group comprising talc, calcium carbonate, microcrystalline cellulose, powderized cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, maltodextrin or a combination thereof.
- Polyol derivative excipients used in the granulation solution are preferably sorbitol and maltodextrin.
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention porte sur des formulations effervescentes stables de lévocétirizine, dont l'arôme et le goût sont améliorés, et sur un procédé pour la préparation desdites formulations.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR201003940 | 2010-05-18 | ||
| PCT/TR2011/000112 WO2011146032A2 (fr) | 2010-05-18 | 2011-05-16 | Formulations effervescentes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2571484A2 true EP2571484A2 (fr) | 2013-03-27 |
Family
ID=44484008
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP11740739A Withdrawn EP2571484A2 (fr) | 2010-05-18 | 2011-05-16 | Formulations effervescentes |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP2571484A2 (fr) |
| WO (1) | WO2011146032A2 (fr) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013058721A1 (fr) * | 2011-10-13 | 2013-04-25 | Mahmut Bilgic | Granulés pharmaceutiques et leur procédé de production |
| WO2016140630A1 (fr) | 2015-03-05 | 2016-09-09 | PHARMACTIVE ILAÇ SANAYI VE TlCARET A. Ş. | Composition effervescente comprenant de la lévocétirizine et de la pseudoéphédrine |
| WO2022106923A1 (fr) | 2020-11-18 | 2022-05-27 | BioPharma Synergies, S. L. | Composition de poudre orodispersible comprenant un composé antihistaminique |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK154078C (da) | 1981-02-06 | 1989-05-22 | Ucb Sa | Analogifremgangsmaade til fremstilling af 2-(2-(4-(diphenyl-methyl)-1-piperazinyl)ethoxy)-acetamider eller syreadditionssalte heraf |
| CA2212829A1 (fr) | 1995-02-21 | 1996-08-29 | Jiro Takeo | Agoniste de recepteur d'acide glutamique |
| DE19814256A1 (de) * | 1998-03-31 | 1999-10-07 | Asta Medica Ag | Feste, schnellzerfallende Cetirizin-Formulierungen |
| NZ534039A (en) * | 2002-01-15 | 2006-08-31 | Ucb Farchim S | Formulations of pharmaceutical compositions for oral administration |
| US20060083786A1 (en) * | 2004-07-29 | 2006-04-20 | Glenmark Pharmaceuticals Limited | Taste masking pharmaceutical composition containing levocetirizine |
| US20060127479A1 (en) * | 2004-10-08 | 2006-06-15 | Natrajan Kumaraperumal | Solvent free taste masked pharmaceutical compositions |
| US20090269393A1 (en) * | 2006-06-12 | 2009-10-29 | Jubliant Organosys Limited | Chewable Bilayer Tablet Formulation |
| ES2564056T3 (es) * | 2008-09-05 | 2016-03-17 | Johnson & Johnson Consumer Inc. | Método para hacer pastillas de cetirizina |
-
2011
- 2011-05-16 EP EP11740739A patent/EP2571484A2/fr not_active Withdrawn
- 2011-05-16 WO PCT/TR2011/000112 patent/WO2011146032A2/fr not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2011146032A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011146032A2 (fr) | 2011-11-24 |
| WO2011146032A3 (fr) | 2012-03-08 |
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