WO2013062497A1 - Formulations pharmaceutiques liquides - Google Patents

Formulations pharmaceutiques liquides Download PDF

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Publication number
WO2013062497A1
WO2013062497A1 PCT/TR2012/000169 TR2012000169W WO2013062497A1 WO 2013062497 A1 WO2013062497 A1 WO 2013062497A1 TR 2012000169 W TR2012000169 W TR 2012000169W WO 2013062497 A1 WO2013062497 A1 WO 2013062497A1
Authority
WO
WIPO (PCT)
Prior art keywords
liquid formulation
formulation according
pharmaceutically acceptable
range
formulation
Prior art date
Application number
PCT/TR2012/000169
Other languages
English (en)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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 Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2013062497A1 publication Critical patent/WO2013062497A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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

Definitions

  • the present invention relates to highly stable, ready-to-use, liquid pharmaceutical formulations comprising at least one active agent from antihistamine group; and to the production method and fields of use thereof.
  • the present invention discloses a drug composition to be used in the prophylaxis and/or treatment of symptoms related to allergic rhinitis such as sneeze, nasal flow and pruritus; congestion/nasal obstruction; pruritus, lacrimation and reddening of the eyes; pruritus of the palate and cough; and the symptoms related to chronic idiopathic urticaria such as pruritus and swelling and inflammation on the skin.
  • This drug composition comprises desloratadine (or a pharmaceutically acceptable salt, solvate, derivative, polymorph, hydrate or enantiomer thereof) as a non-sedative, long-acting Hl-antihistaminic agent.
  • Allergic reactions are the excessive responses that the immune system gives to a normally harmless substance.
  • the immune system comprising anticors, white blood cells, mast cells, supplementary proteins and other substances protects the body from impurities called antigen.
  • the immune system may give excessive responses to some antigens described as allergens in some people although they are harmless. This case is called allergic reaction.
  • the active agent group which is used most frequently in the treatment of allergic reactions is H-l receptor antagonists.
  • Desloratadine is a non-sedative, long-acting HI -receptor antagonist, chemical name of which is 8-chloro-6,l l-dihydro-l l-(4- piperidineylidene)-5H-benzo[5,6] cyclohepta[l,2-b]pyridine (Formula I):
  • the desloratadine formulations of the prior art are in the forms of syrup and film-coated tablet.
  • the dosage forms marketed for diseases which are commonly seen in community such as allergic diseases should address to a large majority.
  • solid dosage forms such as tablet cause swallowing problems for many patients, who are generally pediatric and geriatric patients.
  • An alternative solution for this problem is to present the active agent in a liquid formulation, for example, in solution, emulsion, suspension forms.
  • Liquid formulations which are mostly prepared via sweetening so as to give a nice taste are particularly preferred by pediatric patients. Liquid formulations are advantageous over solid forms in terms of both administration and their bioavailability value.
  • liquid formulations a problem regarding the liquid formulations is the difficulty to provide stabilization of the most active agents in liquid formulations. Generally, all active agents are less stable in liquid formulations as compared to solid formulations. For this reason, stabilizing the liquid formulations is a highly essential parameter.
  • liquid formulations comprising desloratadine or a pharmaceutically acceptable salt, solvate, derivative, polymorph, hydrate or enantiomer thereof as active agent have some difficulties resulting from the active agent in addition to those resulting from the liquidity of the formulations and described above in detail.
  • the present invention relates to highly stable, ready-to-use liquid formulations comprising desloratadine or a pharmaceutically acceptable salt, solvate, derivative, polymorph, hydrate or enantiomer thereof as active agent.
  • desloratadine or a pharmaceutically acceptable salt, solvate, derivative, polymorph, hydrate or enantiomer thereof as active agent.
  • the inventors have surprisingly achieved to prepare an easily disintegrating active agent like desloratadine in liquid form.
  • the formulations of the invention comprise desloratadine with a concentration in the range of 0.01 to 10 gr/L, preferably in the range of 0.01 to 5 gr L, more preferably in the range of 0.01 to 3 gr /L.
  • the amount of desloratadine in unit dose is at least 0.1 mg, preferably in the range of 0.1 mg to 5 mg, more preferably in the range of 0.1 mg to 1 mg.
  • the liquid formulations of the invention can comprise at least one pharmaceutically acceptable acidic agent, at least one viscosity regulating agent, at least one syrup base, at least one sweetener, at least one protecting agent, at least one flavoring agent, at least one coloring agent and solvent or solvent mixtures; and optionally at least another pharmaceutically acceptable excipient in addition to the active agent.
  • the pharmaceutically acceptable protecting agents that can be used in the formulations of the invention can comprise sodium benzoate or benzoic acid, sodium metabisulphite, isopropyl alcohol, ethyl paraben, potassium sorbate, bronopol, propyl gallate, lactic acid, dimethyl ether, phenyl alcohol, propylene glycol, sorbic acid and combinations thereof.
  • Amount of protecting agent required to protect a liquid formulation from contamination is generally based on the amount of water that the liquid formulation comprises.
  • the pharmaceutically acceptable viscosity regulating agents that can be used in the formulations of the invention can be selected from a group comprising guar gum, gelatin, xanthan gum, tamarind gum, water-soluble carboxy vinyl polymers, sodium alginate, pectin, carrageenan, polyethylene glycol, modified starch, carboxymethyl cellulose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, methyl cellulose, microcrystalline cellulose or combinations thereof.
  • the pharmaceutically acceptable sweeteners that can be used in the formulations of the invention can be aspartame, fructose, glucose, glycerin, maltitol, mannitol, saccharine, sorbitol, sodium cyclamate or aqueous solutions or combinations thereof.
  • the sweetener used in the formulations of the invention is preferably sorbitol, and it is used as a sorbitol solution 70% by weight.
  • the formulations of the invention comprise one or more sweeteners with a concentration in the range of 10 to 500 gr/L, preferably in the range of 10 to 400 gr/L.
  • the syrup base that can be used in the formulations of the invention can be a sugar or sugar derivative.
  • the concentration of the syrup base in a formulation is in the range of 10 to 500 gr/L, preferably in the range of 10 to 400 gr/L.
  • the pharmaceutically acceptable flavoring agents that can be used in the formulations of the invention can be peppermint, menthol, cinnamon, artificial vanilla, chocolate, artificial fruit nectar (strawberry, orange, tutti-frutti).
  • the concentration of flavoring agents in the formulations of the invention is in the range of 1 to 30 gr /L.
  • liquid formulations of the invention comprise at least one acidic component and/or a pharmaceutically acceptable salt thereof in order to provide stability in the formulations.
  • This component is selected from a group comprising tartaric, fumaric, maleic, phosphoric or acetic acids and/or pharmaceutically acceptable hydrates, anhydrates or salts thereof; the preferred acidic component is non-aqueous citric acid and or at least one pharmaceutically acceptable salt thereof
  • a characteristic of the formulations of the invention is that said formulations comprise nonaqueous citric acid and at least one pharmaceutically acceptable citric acid salt to provide stability in the formulations.
  • Another characteristic of the liquid formulations of the invention is that said formulations comprise non-aqueous citric acid and trisodium citrate dihydrate to provide stability.
  • a characteristic of the formulations of the invention is that said formulations comprise trisodium citrate dihydrate with a concentration in the range of 1 to 30 gr/L.
  • Another characteristic of the formulations of the invention is that said formulations comprise trisodium citrate dihydrate with a concentration in the range of 1 to 20 gr/L.
  • formulations of the invention comprise non-aqueous citric acid with a concentration in the range of 1 to 10 gr/L.
  • formulations of the invention comprise non-aqueous citric acid with a concentration in the range of 1 to 5 gr/L.
  • Another characteristic of the formulations of the invention is that the ratio of non-aqueous citric acid to trisodium citrate dihydrate is in the range of 0.01 to 5.
  • the ratio of non-aqueous citric acid to trisodium citrate dihydrate is in the range of 0.01 to 1. Using non-aqueous citric acid and trisodium citrate dihydrate produced within the scope of the invention and in the ratios given above has enabled the desloratadine formulations to remain stable for a longer time.
  • Liquid formulations of the invention were tested under accelerated stability conditions ( 40 ⁇ 2 °C / 75 ⁇ 5% relative moisture) and it was found that the desloratadine degradation products in the formulations were below 0.1% at the end of a period of 6 months. During the stability test, liquid formulations did not undergo degradation generally characterized in colour change.
  • the formulations of the invention can be combined with a second active agent.
  • Nasal decongestants, leukotriene receptor antagonists, antihistaminics, antidepressants can be used as the second active agent.
  • Leukotriene receptor antagonists that can be used in the formulations of the invention are selected from a group comprising montelukast, zafirlukast and zileuton or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof; preferably, montelukast sodium is used.
  • the decongestants that can be used in the formulations of the invention are selected from a group comprising ephedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, tetrahydrozoline or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof; preferably, pseudoephedrine is used.
  • Syrup formulation comprising desloratadine
  • Non-aqueous citric acid and trisodium citrate dihydrate are added into the final mixture; pH control is performed; and the mixture is sieved.

Landscapes

  • 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)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formulations pharmaceutiques liquides très stables, prêtes à l'emploi, qui comprennent au moins un agent actif appartenant au groupe des antihistaminiques, ainsi qu'un procédé de production et des domaines d'utilisation correspondants.
PCT/TR2012/000169 2011-10-13 2012-10-12 Formulations pharmaceutiques liquides WO2013062497A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2011/10158 2011-10-13
TR201110158 2011-10-13

Publications (1)

Publication Number Publication Date
WO2013062497A1 true WO2013062497A1 (fr) 2013-05-02

Family

ID=47553332

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2012/000169 WO2013062497A1 (fr) 2011-10-13 2012-10-12 Formulations pharmaceutiques liquides

Country Status (1)

Country Link
WO (1) WO2013062497A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104784110A (zh) * 2015-03-13 2015-07-22 浙江凯润制药有限公司 一种地氯雷他定糖浆制剂及其制备方法
CN114173761A (zh) * 2019-07-26 2022-03-11 核心医药化学有限公司 包含乌地那非的药物组合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080262017A1 (en) * 2006-06-29 2008-10-23 Ulloa Sergio R Sugar-Free Storage-Stable Antihistaminic Syrups

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080262017A1 (en) * 2006-06-29 2008-10-23 Ulloa Sergio R Sugar-Free Storage-Stable Antihistaminic Syrups

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "CLARINEX (desloratadine) TABLETS, SYRUP, REDITABS TABLETS", WWW.ACCESSDATA.FDA.GOV, 31 March 2009 (2009-03-31), pages 1 - 19, XP055055560, Retrieved from the Internet <URL:http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21563lbl.pdf> [retrieved on 20130306] *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104784110A (zh) * 2015-03-13 2015-07-22 浙江凯润制药有限公司 一种地氯雷他定糖浆制剂及其制备方法
CN114173761A (zh) * 2019-07-26 2022-03-11 核心医药化学有限公司 包含乌地那非的药物组合物
CN114173761B (zh) * 2019-07-26 2024-04-19 核心医药化学有限公司 包含乌地那非的药物组合物

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