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WO2018002738A1 - Composition pharmaceutique liquide à goût masqué de (rs)-4-(éthyl [1- (4-méthoxyphényl) propan-2-yl] amino) butyl 3,4-diméthoxybenzoate ou de ses sels pharmaceutiquement acceptables - Google Patents

Composition pharmaceutique liquide à goût masqué de (rs)-4-(éthyl [1- (4-méthoxyphényl) propan-2-yl] amino) butyl 3,4-diméthoxybenzoate ou de ses sels pharmaceutiquement acceptables Download PDF

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Publication number
WO2018002738A1
WO2018002738A1 PCT/IB2017/052768 IB2017052768W WO2018002738A1 WO 2018002738 A1 WO2018002738 A1 WO 2018002738A1 IB 2017052768 W IB2017052768 W IB 2017052768W WO 2018002738 A1 WO2018002738 A1 WO 2018002738A1
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WO
WIPO (PCT)
Prior art keywords
liquid pharmaceutical
pharmaceutical formulation
taste masking
butyl
ethyl
Prior art date
Application number
PCT/IB2017/052768
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English (en)
Inventor
Kamlesh Patel
Original Assignee
Syri Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Syri Ltd filed Critical Syri Ltd
Publication of WO2018002738A1 publication Critical patent/WO2018002738A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia

Definitions

  • the present invention relates to taste masked liquid pharmaceutical composition of an active pharmaceutical ingredient (RS)-4-(ethyl[l-(4-methoxyphenyl)propan-2- yl] amino )butyl 3,4-dimethoxybenzoate or pharmaceutically acceptable salts thereof.
  • the present invention is suitable for oral administration with enhanced taste acceptability and stability.
  • a pharmaceutical active ingredient of structural formula (I) is chemically known as (RS)-4-(ethyl[l-(4-methoxyphenyl)propan-2-yl]amino)butyl 3,4-dimethoxybenzoate and generically Formula (I)
  • mebeverine herein referred as Formula (I). It is a white to almost white, crystalline powder having a very bitter taste.
  • Active ingredient of formula (I) is an antispasmodic that has been successfully used in the management of IBS for many years.
  • Mebeverine is a musculotropic agent that has antispasmodic activity and regulatory effects on the bowel function.
  • Active ingredient of formula (I) is available in the market as COLOFAC® immediate release tablets and COLOFAC MR modified release capsules.
  • COLOFAC ® is available as 135 mg strength and indicated for symptomatic treatment of irritable bowel syndrome and other conditions usually included in this grouping, such as: chronic irritable colon, spastic constipation, mucous colitis, spastic colitis and effectively used to treat the symptoms of these conditions, such as: colicky abdominal pain and cramps, persistent, non-specific diarrhoea (with or without alternating constipation) and flatulence.
  • COLOFAC ® MR is available as 200 mg strength and indicated for the symptomatic relief of irritable bowel syndrome.
  • COLOFAC® is a sugar coated tablet and COLOFAC® MR is capsule form; therefore in both the marketed formulation bitter taste is of active ingredient is gets masked by sugar coating in COLOFAC® and do not get exposure because of capsule shell in COLOFAC® MR.
  • liquid formulation is always preferred choice due to ease of administration without any swallowing difficulty for paediatric and geriatric patient.
  • liquid pharmaceutical composition or preparation is prepared or formulated by by grinding a tablet dosage form into a powder and mixing the powder with a vehicle or diluent in hospitals and pharmacies for use by paediatric or geriatric patients.
  • Such type of dispensing a liquid pharmaceutical formulation from solid formulation result in to non uniform formulation with many excipient and even active ingredient remain undissolved based on varying solubility in vehicle. Administration of such preparation may result in to under dosing or overdosing to a patient.
  • taste masking is further a challenging task. It is very difficult to mask taste of bitter active ingredient as compared to solid formulations like tablet and capsules. In case of liquid formulation, it gets exposure with larger surface area and for longer time comparatively to solid formulations.
  • the invention provides a taste masked liquid pharmaceutical composition of (RS)-4- (ethyl[ 1 -(4-methoxyphenyl)propan-2-yl] amino )butyl 3 ,4-dimethoxybenzoate or pharmaceutically acceptable salts thereof.
  • the main aspect of the present invention is a liquid pharmaceutical formulation with taste masking comprising; a) (RS)-4-(ethyl[l-(4-methoxyphenyl) propan-2-yl] amino)butyl 3,4-dimethoxy benzoate or pharmaceutically acceptable salts thereof, b) at least one sweetener, c) an auxiliary agent, d) at least one preservative and e) one or more pharmaceutically acceptable excipient.
  • the active ingredient (RS)-4-(ethyl[l-(4-methoxyphenyl)propan-2- yl] amino )butyl 3,4-dimethoxybenzoate is in the form of its hydrochloride salt.
  • Another aspect of the present invention is process for preparing liquid pharmaceutical formulation with taste masking comprising steps of; a) adding preservative in suitable solvent, b) adding sweetener, c) adding auxiliary agent, d) adding (RS)-4-(ethyl[l-(4-methoxyphenyl)propan-2-yl]amino)butyl 3,4- dimethoxybenzoate or pharmaceutically acceptable salts thereof, e) adding flavouring agent and f) adding purified water to make up to final volume and ensuring pH between 2.0 to 4.0.
  • the main purpose of this invention is to provide a taste masked liquid pharmaceutical composition of (RS)-4-(ethyl[l-(4-methoxyphenyl)propan-2-yl]amino)butyl 3,4- dimethoxybenzoate or pharmaceutically acceptable salts thereof.
  • pharmaceutically-acceptable salts includes salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • Suitable pharmaceutically-acceptable acid addition salts of mebeverine may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p- hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methane sulfonic, ethanesulfonic, 2-hydroxyethane sulfonic, pantothenic, benzenesulfonic, toluene sulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, alginic, ⁇ -hydroxybutyric, malonic, galactaric and galacturonic acid.
  • the pharmaceutically acceptable salt for present invention is hydrochloride.
  • the active pharmaceutical ingredient is (RS)-4-(ethyl[l-(4- methoxyphenyl)propan-2-yl] amino )butyl 3,4-dimethoxybenzoate or pharmaceutically acceptable salts thereof which can be identified as mebeverine or structural formula (I) and all this term represent the same active pharmaceutical ingredient and can be used interchangeably.
  • the active ingredient for present invention (RS)-4-(ethyl[l-(4- methoxyphenyl)propan-2-yl] amino )butyl 3,4-dimethoxybenzoate is preferably in the form of hydrochloride salt.
  • the (RS)-4-(ethyl[l-(4-methoxyphenyl)propan-2- yl] amino )butyl 3,4-dimethoxybenzoate or its pharmaceutically acceptable salt is present in the range from 0.1 to 10% w/v.
  • the liquid pharmaceutical formulation with taste masking property comprises (RS)-4-(ethyl[l-(4-methoxyphenyl)propan-2-yl]amino)butyl 3,4- dimethoxybenzoate or pharmaceutically acceptable salts thereof, at least one sweetener, an auxiliary agent, at least one preservative and one or more pharmaceutically acceptable excipient.
  • Sweetener as per present invention is selected from group consisting of saccharin, saccharin sodium, aspartame, cyclamate, invert syrup, sucralose, acesulfame, acesulfame potassium, neotame, thaumatin, neohesperidine, neohesperidine dihydrochalcone, sucrose, trehalose, lactose, fructose, xylitol, mannitol, sorbitol or combinations thereof.
  • invert syrup is to be used as sweetener.
  • sucralose is another preferred embodiment, combination of invert syrup and sucralose to be used.
  • the sweetener is to be used in the range from 50 to 85 %w/v, preferably in the range from about 70 to 80 %w/v.
  • auxiliary agent as used herein is the substance used to enhance the effective taste masking in the formulation.
  • auxiliary agent is selected from group consisting of Levomenthol, monoammonium glycyrrhizinate, L-arginine, L- lysine, citric acid, lactic acid, cineol and myrtol.
  • Levomenthol is to be used as an auxiliary agent.
  • the auxiliary agent as per present invention is to be used in the range from 0.01 to 0.04 % w/v, preferably in the range from 0.02 to 0.03 %w/v.
  • combination of sweetener and auxiliary agent is to be used for enhanced taste masking effect.
  • combination of invert syrup and Levomenthol is to be used.
  • combination of invert syrup, sucralose and Levomenthol is to be used for more effective taste masking effect.
  • invert syrup and Levomenthol is to be used in ratio from 0.8 to 0.000444 to 1.2 to 0.000296, preferably in the ratio of 1:0.00037 for effective taste masking result of liquid formulation.
  • the liquid formulation also contains one or more pharmaceutically acceptable excipient selected from preservative, flavouring agent, pH modifier and solvent.
  • Preservative for present invention is selected from group consisting of benzoic acid, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, sodium benzoate and benzalkonium chloride.
  • Benzoic acid is preferred one.
  • Flavouring agent for present invention is selected from group consisting of rape, banana, vanilla, cherry, citrus, peach, strawberry, bubble gum, peppermint, wintergreen or combination thereof.
  • combination of one or more flavouring agent is to be used.
  • combination of banana and vanilla flavour is to be used.
  • pH modifier is to be used to adjust the pH of final formulation in the range from about 2.0 to 4.0 preferably about 3.0 to 4.0 and more preferably at about 3.5.
  • sodium hydroxide or hydrochloric acid can be used as a pH modifier.
  • sodium hydroxide in the form of solution can be used.
  • glycerine As a solvent for the liquid formulation of present invention, glycerine, alcohols, propylene glycol, polyethylene glycol, purified water, ethanol, isopropyl alcohol or combinations thereof can be used. According to solubility and requirement of active ingredient and excipient any suitable solvent from above list can be used. For making final volume of the formulation purified water is to be used.
  • liquid pharmaceutical formulation of (RS)-4-(ethyl[l-(4-methoxyphenyl)propan-2-yl]amino)butyl 3,4- dimethoxybenzoate or pharmaceutically acceptable salts thereof is to be advised to administer in dosage of 135 mg to 405 mg per day.
  • the liquid pharmaceutical formulation of present invention is advised to administer as 13.5 ml of composition three times a day.
  • liquid pharmaceutical formulation is to be used for treatment of irritable bowel syndrome and other conditions including chronic irritable colon, spastic constipation, mucous colitis, spastic colitis, colicky abdominal pain and cramps, persistent, non-specific diarrhoea with or without alternating constipation and flatulence.
  • the present invention is a liquid pharmaceutical formulation with taste masking comprising a) 0.1 to 10 % w/v of (RS)-4-(ethyl[l-(4-methoxyphenyl)propan-2-yl]amino)butyl 3 ,4-dimethoxybenzoate hydrochloride, b) 50 to 80% w/v of invert syrup, c) 0.01 to 0.04 % w/v of levomenthol, d) Benzoic acid e) one or more pharmaceutically acceptable excipient.
  • the present invention is a liquid pharmaceutical formulation with taste masking comprising a) 1.0 % w/v of (RS)-4-(ethyl[l-(4-methoxyphenyl)propan-2-yl]amino)butyl 3,4- dimethoxybenzoate hydrochloride, b) 75 % w/v of invert syrup, c) 0.028 % w/v of levomenthol, d) Benzoic acid e) one or more pharmaceutically acceptable excipient.
  • the present invention is a liquid pharmaceutical formulation with taste masking comprising a) 1.0 % w/v of (RS)-4-(ethyl[l-(4-methoxyphenyl)propan-2-yl]amino)butyl 3,4- dimethoxybenzoate hydrochloride, b) 75 % w/v of invert syrup and 0.6 % w/v of sucralose, c) 0.028 % w/v of levomenthol, d) Benzoic acid e) one or more pharmaceutically acceptable excipient.
  • the liquid pharmaceutical formulation of the present invention is chemically and physically stable without any precipitation or crystallization during stability study and further overcame problem of bitter taste.
  • liquid pharmaceutical formulation of present invention being in the form of solution also offers an advantage of clear formulation, uniform dosing, no physical stability problem and also offers very less chances of medication error.
  • Benzoic acid was dissolved in glycerol with heating at 80-90°C to get a clear colourless solution and later kept aside to cool at room temperature.
  • step 3 Solution of step 3) was mixed with solution of step 2) to get clear colourless to pale yellow solution.
  • pH of solution of step 5 was checked and found 3.5. If not to be adjusted to pH 3.5 using NaOH solution.
  • Example 4 Based on taste parameter result it was found that formulation of example 4 found satisfactory and acceptable compared to rest. Therefore stability study of formulation of Example 4 was conducted at different temperature and relative humidity conditions for 6 months in Type III 100ml Amber glass bottle and results are as described below;
  • *Drug (RS)-4-(ethyl[l-(4-methoxy phenyl) propan-2-yl] amino) butyl 3,4- dimethoxy benzoate hydrochloride
  • *Drug (RS)-4-(ethyl[l-(4-methoxy phenyl) propan-2-yl] amino) butyl 3,4- dimethoxy benzoate hydrochloride Storage Condition : 30 ⁇ 2°C/65 ⁇ 5 % RH
  • *Drug (RS)-4-(ethyl[l-(4-methoxy phenyl) propan-2-yl] amino) butyl 3,4 dimethoxy benzoate hydrochloride

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
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  • Molecular Biology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique liquide à goût masqué d'un sel d'un principe actif pharmaceutique, (RS)-4-(éthyl [1- (4-méthoxyphényl)propan-2-yl] amino)butyl 3,4-diméthoxybenzoate ou des sels pharmaceutiquement acceptables de celui-ci.
PCT/IB2017/052768 2016-06-29 2017-05-11 Composition pharmaceutique liquide à goût masqué de (rs)-4-(éthyl [1- (4-méthoxyphényl) propan-2-yl] amino) butyl 3,4-diméthoxybenzoate ou de ses sels pharmaceutiquement acceptables WO2018002738A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1611276.5A GB2551971B (en) 2016-06-29 2016-06-29 Taste masked liquid pharmaceutical composition of mebeverine or pharmaceutically acceptable salts thereof
GB1611276.5 2016-06-29

Publications (1)

Publication Number Publication Date
WO2018002738A1 true WO2018002738A1 (fr) 2018-01-04

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Application Number Title Priority Date Filing Date
PCT/IB2017/052768 WO2018002738A1 (fr) 2016-06-29 2017-05-11 Composition pharmaceutique liquide à goût masqué de (rs)-4-(éthyl [1- (4-méthoxyphényl) propan-2-yl] amino) butyl 3,4-diméthoxybenzoate ou de ses sels pharmaceutiquement acceptables

Country Status (2)

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GB (1) GB2551971B (fr)
WO (1) WO2018002738A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2827328C2 (ru) * 2021-11-24 2024-09-24 Надежда Анатольевна Капай Спазмолитическое, нормализующее перистальтику кишечника лекарственное средство для ветеринарии

Citations (1)

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Publication number Priority date Publication date Assignee Title
US20030032600A1 (en) * 2001-03-05 2003-02-13 Ulrich Stephen A. Taste masked liquid pharmaceutical compositions

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US5563177A (en) * 1995-01-30 1996-10-08 American Home Products Corporation Taste masking guaifenesin containing liquids
US5763449A (en) * 1996-08-07 1998-06-09 Ascent Pediatrics, Inc. Pleasant-tasting aqueous liquid composition of a bitter-tasting drug
US6391886B1 (en) * 2000-12-04 2002-05-21 The Procter & Gamble Company Oral compositions having improved consumer aesthetics
MXPA04001026A (es) * 2001-07-31 2005-06-20 Wyeth Corp Formulacion de sucralosa para disimular sabores desagradables.
PL2048948T3 (pl) * 2006-07-21 2012-07-31 Lyne Laboratories Inc Płynne kompozycje octanu wapnia
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US20030032600A1 (en) * 2001-03-05 2003-02-13 Ulrich Stephen A. Taste masked liquid pharmaceutical compositions

Non-Patent Citations (1)

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Title
ANONYMOUS: "SUMMARY OF PRODUCT CHARACTERISTICS: Mebeverine 50mg/5ml Sugar Free Oral Suspension", 11 November 2015 (2015-11-11), pages 1 - 5, XP055390947, Retrieved from the Internet <URL:http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1449209160749.pdf> [retrieved on 20170714] *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2827328C2 (ru) * 2021-11-24 2024-09-24 Надежда Анатольевна Капай Спазмолитическое, нормализующее перистальтику кишечника лекарственное средство для ветеринарии

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GB201611276D0 (en) 2016-08-10
GB2551971A (en) 2018-01-10

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