WO2007003020A1 - Oral formulations comprising ondansetron and a highly dosed sweeten - Google Patents
Oral formulations comprising ondansetron and a highly dosed sweeten Download PDFInfo
- Publication number
- WO2007003020A1 WO2007003020A1 PCT/BR2006/000015 BR2006000015W WO2007003020A1 WO 2007003020 A1 WO2007003020 A1 WO 2007003020A1 BR 2006000015 W BR2006000015 W BR 2006000015W WO 2007003020 A1 WO2007003020 A1 WO 2007003020A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ondansetron
- aspartame
- fact
- composition
- sweetening
- Prior art date
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
Definitions
- Oral formulations comprising ondansetron and a highly dosed sweetener
- pharmaceutically acceptable derivatives of ondansetron covers any pharmaceutically acceptable salts, complexes or solvates of ondansetron, as well as its optical isomers.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Hospice & Palliative Care (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Otolaryngology (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides pharmaceutical compositions for oral use, characterized by the fact of containing soluble salts of ondansetron and sweeteners with high sweetening power, in high proportions in relation to the active ingredient.
Description
Oral formulations comprising ondansetron and a highly dosed sweetener
Background of the Invention : The oral administration via, in the form of tablets, capsules, pills, and other traditional solid forms is the one generally preferred on account of the relative practicability for administration of drugs and its good acceptance on the part of the patients. Traditional solid compositions, designed to be integrally swallowed, however, are not appropriate for patients with difficulty in swallowing (as many times, is the case of elderly, children and patients with motor or neurological disabilities), so it becomes necessary to use the pharmaceutical forms more easily swallowed; as for example: solutions, suspensions, granules, chewable tablets and tablets of oral disintegration.
Despite the greater swallowing facility, the conveyance of active ingredients unpalatable in oral- dispersible compositions, in which spreading of the medicament in the oral cavity occurs (such as those mentioned above) have, however, as limitation, the necessity for disguising the flavor. Otherwise, the patients may not accept the treatment or may not conclude it, if the prescribed medicament has an unpalatable flavor.
Also known as 1, 2, 3, 9-tetrahydro-9-methyl-3- [ (2- methyl-lH-imidazol-1-yl) -methyl] -4H-carbazol-4-one, the ondansetron, is an antagonist drug highly selective and potent of 5HT3 receptors of 5-hydroxytriptamine (5HT) and may be used in the treatment of diseases such as: cognitive disorders, anxiety and emesis.
With reference to the organoleptic properties, the ondansetron, particularly its hydrochloride salt, has the
characteristic of having an unpalatable flavor and a strong bitter residual flavor. Considering that the main therapeutic indication of ondansetron is the inhibition of emesis, the disguising of the flavor of oral compositions based on this active ingredient becomes especially relevant .
In this way, it does not seem strange that several technical solutions have been proposed for disguising the flavor of ondansetron in oral-dispersible compositions: the use of ondansetron in the free-base form of lyophilized compositions (US 5.955.488, Glaxo Wellcome Inc.); the use of high concentrations of sweetening polyhidric alcohols in liquid compositions based on ondansetron (US 5.854.270, Glaxo Wellcome Inc.); coating of ondansetron crystals with polymeric material (WO 02/085336, Ethypharm S.A.).
However, such technical solutions have the following disadvantages: the relative fragility of the compositions and the necessity to use equipment that are apart from regular use for obtaining lyophils; the limited disguising of ondansetron flavor and the difficulty in incorporating high quantities of polyhidric alcohols in solid oral- dispersible formulations and the higher cost of processing and the potential delay in starting the action originating from the necessity of dissolution of the material used in coating the crystals.
As an alternative solution, the use of high potency sweetening agents (such as aspartame) , was described in several patent applications on oral-dispersible formulations based on ondansetron: WO 00/57857 (Yuan Corporation), WO 03/103629 (Laboratories Vita, S.A.) and WO 03/086361 (Dr. Reddy' s Laboratories Ltd.); it is worth to outline that such publications describe ondansetron tablets of oral disintegration with proportions of maximum 0.7
parts of aspartame on the part of the active ingredient and make no reference to the necessity of disguising the unpalatable bitter residual flavor of ondansetron.
Description of the Invention:
Based on a wide research procedure, the present inventors found that the use of aspartame in high proportions (over 0.7:1 parts) in relation to the mass of ondansetron, allows to obtain compositions with a flavor acceptance superior to the one obtained with proportions regularly employed, not only in relation to the flavor of the compositions immediately felt, but specially, in relation to disguising the unpalatable bitter residual flavor of ondansetron. In a general aspect, the present invention consists of oral-dispersible pharmaceutical compositions, characterized by the fact of: (i) containing ondansetron or its pharmaceutically acceptable derivatives; (ii) containing one or more high potency sweetening agents or mixtures thereof, in equivalent quantity, in terms of sweetening power higher than 0.7 parts of aspartame per part of ondansetron free-base.
The expression "oral-dispersible pharmaceutical compositions" correspond to any composition, in which there exists the significant spreading of its components in the oral cavity after the administration; involving formulations in the form of liquids, gels, creams, pastes, mousses, as well as in solid form; such as: chewable or oral disintegrating tablets, pastilles, capsules, powder, granules, aggregated, etc.
The expression "pharmaceutically acceptable derivatives of ondansetron" covers any pharmaceutically
acceptable salts, complexes or solvates of ondansetron, as well as its optical isomers.
The proportions, in terms of parts or percentages, used in the present specification refer to the proportions based on mass, unless a specific reference is otherwise given.
The class of products formed by "sweetening agents with high sweetening power" comprises any substances or mixtures of substances able to promote the sensation of sweeten flavor; especially those with sweetening power, at least 10 times higher than saccarose. As an example, a sweetener which sweetening power of 10 mg corresponds to the saccarose sweetening power of 2000 mg, is considered to have a sweetening power 200 times higher than saccarose. Examples of sweetening agents of great sweetening power are: aspartame, acessulfame K, alitame, aspartame- acessulfame, cyclamate, neo-hesperidine, saccharine, stevioside, sucralose, taumatine and neotame.
Aspartame, also designated as 1-Methyl N-L-α-aspartyl- L-phenylalanine, is a sweetening agent of low caloric power, with a sweetening power of about 200 times higher than saccarose.
Acessulfame K, also designated as potassic salt of 6- methyl-, 2, 2-dioxide-l, 2, 3-oxatiazin-4 (3H) -one, is a non- caloric sweetening agent, with a sweetening power of approximately 130 to 200 times higher than saccarose.
Alitame, also designated as L-α-Aspartyl-N- (2, 2, 4 , 4- tetramethyl-3-tiethanyl) -D-alaninamide, is a sweetening agent formed by the amino acids of L-aspartic acid; D- alanine is a new amine. The sweetening power is about 2000 to 3000 times higher than saccarose, depending on the application, presenting synergic effect with the other sweeteners as saccharine, acessulfame K and cyclamate.
Acessulfame-aspartame is an aspartame and acessulfame salt, in which aspartame and acessulfame are ionically bound, with a sweetening power of about 350 times higher than saccarose. Cyclamate, also designated as cyclo-hexylamino sulfamic acid is a non caloric sweetening agent, with sweetening power of about 30 to 50 times higher than saccarose, presenting synergic effect with other hypo- caloric sweetening agents, such as acessulfame K, aspartame, neo-hesperidine DC, saccharine and sucralose.
Neo-hesperidine DC, also designated as 1- (4- ( (2-0- (6- deoxy-α-L-manopyranosyl) -beta-D-glucopyranosyl) oiy) -2, 6- dihydroxyphenyl) -3- (3-hydroxy-4-methoxyphenyl) propan-1-one, is a sweetening agent with sweetening power of about 1500- 1800 times higher than saccarose, presenting a synergic effect with other sweeteners, such as aspartame and acessulfame K.
Saccharine, also designated as 1, 1-Dioxyde-l, 2- benzisothiazolin-3-one is a non caloric sweetening agent, with sweetening power of about 300 to 500 times higher than saccarose.
Stevioside is a glycoside formed by three molecules of glucose and one of steviol, one diterpene-carboxylic alcohol, with sweetening power of about 100 to 150 times higher than saccarose.
Sucralose, also designated as 1, 6-Dichloro-l, 6- dideoxy-β-D-fructofuranosyl 4-chloro-4-deoxy-α-D-galacto- pyranoside, is a sugar derivate sweetening agent, with a sweetening power of about 600 times higher than saccarose. Taumatine consists of a mixture of two polypeptides, taumatine I and II, each one consisting of 207 residues of amino acids, obtained by extraction of the tropical fruit
Thaumatococcus daniellii, with sweetening power of about 2000 to 3000 times higher than saccarose.
Neotame, also designated as (N- [N- (3, 3-diitιethylbutyl) - L-α-aspartyl] -L-phenylalanine 1-methylester) is a sweetening agent with a sweetening power of about 7000 to 13000 times higher than saccarose.
Considering the fact that different sweetening agents have distinct sweetening potencies and, based on the knowledge, evidenced herein, that high doses of sweeteners allow a better correction of the flavor of oral-dispersible compositions of ondansetron, it is expected that those skilled in the art may prepare several combinations between the sweeteners in order to obtain an effect equivalent to that obtained by the present inventors. Considering the potential synergism of the action between the different sweetening agents, a possible basis for calculation of equivalent quantities of sweetening agents in relation to aspartame is the use of a correction factor FSWeetenerc in which Fsweetener = sweetening power of the sweetener or the mixture of sweeteners / sweetening power of aspartame.
In a particular aspect, the pharmaceutical compositions comprised by the present invention are characterized by the fact of: (i) containing 1 to 30 mg of base ondansetron; especially in the form of hydrochloride dihydrate salt; (ii) containing 1 to 8 parts of aspartame per part ondansetron free-base; more specifically, from 2 to β parts.
It is understood as "dose", the quantity of pharmaceutical composition to be administered to the patient at each take. In the case of monolithic compositions, such as tablets, the "dose" corresponds to the amount of tablets to be administered each time, in
order to achieve the desired therapeutic quantity. In the case of liquids, the term "dose" may be interpreted as the total volume to be administered at each take. For practicability purposes, the doses of monolithic compositions are preferably made through the administration of a single unit dosage and, in the case of liquid formulations or semi-solid, the total volume to be administered is preferably lower than or equal to 10 ml.
The pharmaceutical compositions according to the present invention may also contain several other excipients used by the pharmaceutical industry, such as flavoring, thickeners, agents for compression, disintegrating agents, lubricants, buffering agents, etc.
The use of flavoring is recommended as an additional resource for disguising ondansetron flavor. The appropriate flavoring includes flavors of caramel, vanilla and fruits; being that strawberry flavor is especially appropriate for use in compositions based on ondansetron.
The present invention is additionally illustrated by the following experimental examples:
Example 1 :
Ten healthy volunteers, of both sexes, after the signature of the informed consent, have tasted ondansetron solutions containing different proportions of aspartame, according to the quantities indicated in Table 1, hereunder :
Table 1: Composition of ondansetron and aspartame test solutions
For tasting purposes, were administered doses of 2,5 mL of each test solution, in random order; the volunteers were instructed to keep the solutions in the mouth during a period of 5 to 10 seconds, trying to pass it on several regions of the oral cavity, preferably inhaling a little air during the process, and at the end they should expel the total content of the solutions, without swallowing it.
At the end of each test the volunteers (whom were not aware of which solution they have tasted) were questioned on the parameters shown in Tables 2 and 3 hereunder, respectively relating to the "immediate flavor" and to the "residual flavor"; and were also instructed to give a general grade, from zero to ten, for each solution, where: zero = bad and ten = good.
Table 2: Flavor of the composition, 5 to 10 seconds after the administration (solution flavor)
Table 3: Composition flavor, 1 minute after elimination of the solutions (residual flavor)
A minimum period of one hour between different tests were applied, with a minimum period of 48 hours established, so that the volunteer could take part in additional tests, in event of incidental ingestion of a significant volume of the test solution. Upon conclusion of the first series of tests, a second series was carried out in duplicate. The statistical assessment of the data obtained evidenced (i) that the use of a larger quantity of sweetening agents in the ratios of tested concentrations,
provided a discrete increase in the acceptability of the compositions in general terms; (ii) that, surprisingly, when aspartame is used in weight proportions equal or higher than 2:1 in relation to the mass of ondansetron free-base, there exists a significant change in the residual flavor in relation to the formulations in which such proportion is equal to 0.7:1 (Table 4) .
Table 4 : Response of the volunteers in relation to the characteristic of the residual flavor and average of the general grades ascribed to the liquid compositions
Example 2 :
Chewable tablets containing ondansetron hydrochloride and aspartame, in the proportions of 1:0.7 and 1:2, in accordance with Table 4 hereunder, were manufactured by direct compression, with the use of the following as excipients: mannitol, microcrystalline cellulose, polyvinyl pyrrolidone, colloidal silicon dioxide, talc and strawberry flavor.
Table 5: Composition of chewable tablets of ondansetron hydrochloride
The tablets were then submitted to a tasting test, by 10 volunteers, according to the protocol described in Example 1, with the remark that a single series of tests were carried out for each formulation. The results relating to the responses obtained for the tablets are shown in Table 6.
Table 6: Responses of volunteers in relation to the characteristic of residual flavor and average of the general grades ascribed to the chewable compositions:
Claims
1. Oral dispersible pharmaceutical composition, characterized by the fact of: (i) containing ondansetron or its pharmaceutically acceptable derivatives; (ii) containing one or more high potency sweetening agents or mixtures thereof, in equivalent quantity, in terms of sweetening power, higher than 0.7 parts of aspartame per part of ondansetron ' free-base.
2. Composition in accordance with Claim 1, characterized by the fact of containing one or more high potency sweetening agents or mixtures thereof, in quantity, in terms of sweetening power, between 1 and 10 parts of aspartame per part of ondansetron free-base.
3. Composition in accordance with Claim 1, characterized by the fact of containing one or more high potency sweetening agents or mixtures thereof, in quantity, in terms of sweetening power, between 2 and 6 parts of aspartame per part of ondansetron free-base.
4. Composition in accordance with Claim 1, characterized by the fact of containing ondansetron hydrochloride dihydrate.
5. Composition in accordance with Claim 1, characterized by the fact of containing one or more high potency sweetening agents selected from the group composed by: acessulfame K, alitame, aspartame, aspartame-acessulfame, cyclamate, neo- hesperidine, saccharine, stevioside, sucralose, taumatine, neotame or mixtures thereof.
6. Composition in accordance with Claim 1, characterized by the fact of containing aspartame as sweetening agent.
7. Composition in accordance with Claim 1, characterized by the fact of being presented in solid form.
8. Composition in accordance with Claim 1, characterized by the fact of being presented in liquid form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BRPI0502736-5A BRPI0502736A (en) | 2005-07-05 | 2005-07-05 | oral formulations of masked residual flavor ondansetron |
| BRPI0502736-5 | 2005-07-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007003020A1 true WO2007003020A1 (en) | 2007-01-11 |
Family
ID=37604052
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/BR2006/000015 WO2007003020A1 (en) | 2005-07-05 | 2006-02-06 | Oral formulations comprising ondansetron and a highly dosed sweeten |
Country Status (3)
| Country | Link |
|---|---|
| BR (1) | BRPI0502736A (en) |
| EC (1) | ECSP088079A (en) |
| WO (1) | WO2007003020A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMC20100077A1 (en) * | 2010-07-19 | 2012-01-20 | Farmalip S R L | SWEETENER. |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10109763A1 (en) * | 2001-02-28 | 2002-09-05 | Gruenenthal Gmbh | Pharmaceutical salts |
| WO2003086361A1 (en) * | 2002-04-18 | 2003-10-23 | Dr. Reddy's Laboratories Ltd. | Rapidly dispersing solid oral compositions |
-
2005
- 2005-07-05 BR BRPI0502736-5A patent/BRPI0502736A/en not_active Application Discontinuation
-
2006
- 2006-02-06 WO PCT/BR2006/000015 patent/WO2007003020A1/en active Application Filing
-
2008
- 2008-01-04 EC EC2008008079A patent/ECSP088079A/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10109763A1 (en) * | 2001-02-28 | 2002-09-05 | Gruenenthal Gmbh | Pharmaceutical salts |
| WO2003086361A1 (en) * | 2002-04-18 | 2003-10-23 | Dr. Reddy's Laboratories Ltd. | Rapidly dispersing solid oral compositions |
Non-Patent Citations (1)
| Title |
|---|
| DATABASE WPI Week 200548, Derwent World Patents Index; AN 2005-470510, XP003004351 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMC20100077A1 (en) * | 2010-07-19 | 2012-01-20 | Farmalip S R L | SWEETENER. |
Also Published As
| Publication number | Publication date |
|---|---|
| ECSP088079A (en) | 2008-02-20 |
| BRPI0502736A (en) | 2007-02-27 |
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