WO2009127802A1 - Composition de rosiglitazone - Google Patents

Composition de rosiglitazone Download PDF

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Publication number
WO2009127802A1
WO2009127802A1 PCT/GB2009/000528 GB2009000528W WO2009127802A1 WO 2009127802 A1 WO2009127802 A1 WO 2009127802A1 GB 2009000528 W GB2009000528 W GB 2009000528W WO 2009127802 A1 WO2009127802 A1 WO 2009127802A1
Authority
WO
WIPO (PCT)
Prior art keywords
rosiglitazone
composition according
agent
composition
solution
Prior art date
Application number
PCT/GB2009/000528
Other languages
English (en)
Inventor
Geoffrey David Mould
Original Assignee
Rosemont Pharmaceuticals 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 Rosemont Pharmaceuticals Ltd filed Critical Rosemont Pharmaceuticals Ltd
Publication of WO2009127802A1 publication Critical patent/WO2009127802A1/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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Definitions

  • This invention relates to a Rosiglitazone containing composition, a method of use thereof and a method of manufacture.
  • Rosiglitazone is a member of the thiazolidinedione class of drugs and has the chemical formula 5- ((4-(2- (methyl-2- pyridinylamino)ethoxy) phenyl) methyl) -2, 4- thiazolidinedione or (C 18 H 19 N 3 O 3 S) . It is used in human patients to treat type 2 diabetes.
  • Rosiglitazone is only commercially available for use in a solid dosage form, such as in tablet form.
  • a liquid oral dosage form of Rosiglitazone to be provided.
  • a Rosiglitazone liquid solution with a long shelf life would be more cost effective to manufacture and the logistic chain from the manufacturer to the patient would be significantly improved.
  • a liquid solution is preferable to a solid dosage where a patient needs dose titration to obtain a correct maintenance treatment dose of Rosiglitazone.
  • Rosiglitazone has a bitter taste and is therefore too unpalatable for most patients if it were to be provided in a liquid form. It is undesirable to use a sweetener, such as sugar, with the Rosiglitazone since this would affect the control of the diabetic patient's sugar intake.
  • a rosiglitazone composition suitable for oral administration, said composition including a pharmaceutically acceptable salt of rosiglitazone in a carrier agent, and wherein said rosiglitazone salt is substantially or completely soluble in said carrier agent to form a solution.
  • composition includes one or more artificial sweetener agents.
  • artificial sweetener agent is typically a food additive that attempts to duplicate the effect of sugar in terms of taste but which has a lower energy or calorific value.
  • any or any combination of suitable artificial sweetener agents can be used with the solution of the present invention providing they are/it is totally substantially soluble in the carrier agent and is compatible with the pharmaceutically acceptable salt of Rosiglitazone used in the solution.
  • the artificial sweetening agent could be Acesulfame K.
  • Any or any suitable concentration of artificial sweetening agent(s) can be used to provide an acceptable palatable taste for the patient.
  • solution used herein is where the Rosiglitazone salt is substantially dissolved in the carrier agent. This is in contrast to a “suspension” wherein a particulate salt would be substantially homogenously suspended in a solution or carrier agent.
  • any suitable salt of Rosiglitazone can be used for the Rosiglitazone composition.
  • the pharmaceutically acceptable salt of Rosiglitazone is Rosiglitazone Maleate.
  • the salt is preferably in a powder form prior to dissolving the same in the carrier agent to form the solution.
  • the pH of the composition is typically required to be equal to or less than 3 in order to dissolve the Rosiglitazone salt therein.
  • the optimal pH range is 2-3.
  • the carrier agent is or includes one or more acidifying or buffering agents to reduce the pH to the equal to or less than pH 3.
  • the one or more acidifying agents can be include a mild acidifier suitable for human consumption, such as for example citric monohydrate.
  • the solution includes one or more preservative agents to reduce microbial spoilage of the product over the shelf life of said product.
  • the preservative is typically in a form to be compatible with the pharmaceutically acceptable salt of Rosiglitazone used in the solution and substantially or totally soluble therein.
  • the preservative is methyl hydroxybenzoate since this is effective with Rosiglitazone at the solution pH.
  • a preservative solubilising agent is used to help dissolve the preservative used in the solution.
  • the preservative solubilising agent used is propylene glycol.
  • One or more flavouring agents can be included in the solution to increase the palatability of the solution to the patient. Since the solution is acidic in nature, it is preferable to use a citrus flavouring agent, such as for example a lime flavouring agent.
  • the formulation of the Rosiglitazone solution includes Rosiglitazone Maleate, Acesulfame K, propylene glycol, citric acid monohydrate, lime flavouring and purified water.
  • a pharmaceutically acceptable dosage of the Rosiglitazone salt is used in the solution.
  • the dosage is 4mg of Rosiglitazone salt in a 5ml aqueous solution.
  • the carrier agent is distilled or purified water.
  • a method of manufacturing a rosiglitazone composition suitable for oral administration including the steps of mixing a pharmaceutically acceptable salt of rosiglitazone in a carrier agent until the salt has substantially dissolved in the same to form a solution.
  • the method includes the step of adjusting the pH of the solution to be equal to or less than 3.
  • the method further includes adding any or any combination of one or more preservative agents, flavouring agents, solubilising agents and/or the like to the solution.
  • the method of manufacture takes place at room temperature (i.e., approx 20-25 0 C) and pressure (approx. 1 bar) .
  • the composition constituents can be mixed together via any suitable mixing means.
  • a rosiglitazone composition for the manufacture of a medicament for the treatment of diabetes in a patient, said composition containing a pharmaceutically acceptable salt of rosiglitazone in a carrier agent, and wherein said rosiglitazone salt is substantially or completely soluble in said carrier agent to form a solution.
  • the solution is typically used to treat diabetes, and particularly type-2 diabetes, in patients.
  • the patient is a human being.
  • the present invention provide a pharmaceutically effective, safe and simple to administer dosage form that will benefit a patient group that have problems in swallowing and therefore limits the usage of a conventional solid dosage form.
  • the resulting solution has a low calorific value, thereby making it suitable for diabetic patients who need to tightly control their sugar intake.
  • a rosiglitazone composition suitable for oral administration, said composition including a pharmaceutically acceptable salt of rosiglitazone in a carrier agent, and wherein said rosiglitazone salt is substantially or completely soluble in said carrier agent to form a solution, the pH of the solution is equal to or less than 3 and one or more artificial sweetener agents are included.
  • Figure 1 is a graph illustrating the stability of Rosiglitazone in aqueous solution at different pH.
  • FIG 1 there is illustrated a graph showing the stability of Rosiglitazone in aqueous buffer solutions at a dose of 4mg/ 5ml at pH 2.2, 3 and 4 respectively over a four week time period.
  • the amount of Rosiglitazone remaining in solution in mg/ml was measured (% of stated amount API) at the start (0 weeks) and at 1 week, 2 weeks and 4 weeks.
  • the stability study was undertaken at an accelerated rate by storing the samples at 50 0 C, rather than the recommended storage conditions of 25°C.
  • Rosiglitazone was not soluble in buffer solutions at pH 5, 6, 7 and above so solutions with these pH values did not form part of the stability study.
  • the aqueous buffer solutions used for the stability study included disodium hydrogen phosphate and citric acid in amounts necessary to achieve the required pH.
  • the concentrations of the solutions are approximately 4 times greater than the concentration of solutions identified in the preferred formulation below.
  • Benzoic acid was initially chosen as the preservative system. When placed under stressed conditions (i.e. 50 0 C at room pressure) , the presence of Benzoic acid appeared to increase the amount of degradation of the product compared to a control batch with no Benzoic acid. In further studies, methyl hydroxybenzoate was used as the preservative. This was dissolved in propylene glycol prior to addition to the solution due to the low solubility of methyl hydroxybenzoate in water. No significant degradation of the Rosiglitazone solution was found with methyl hydroxybenzoate as the preservative.
  • an artificial sweetener Acesulfame K was used with the Rosiglitazone solution to make the solution more palatable whilst allowing a diabetic patient to control their sugar levels.
  • the Acesulfame K was used at a concentration in a range of between 0.1 % and 1.0% to achieve a desired taste for the product.
  • flavouring was introduced into the solution in the form of lime flavouring to compliment the sourness of the solution.

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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition de rosiglitazone pouvant être administrée par voie orale à un patient. Cette composition contient un sel pharmaceutiquement acceptable de rosiglitazone dans un excipient. Le sel de rosiglitazone est partiellement ou totalement soluble dans l'excipient.
PCT/GB2009/000528 2008-04-18 2009-02-25 Composition de rosiglitazone WO2009127802A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0807068.2 2008-04-18
GB0807068A GB0807068D0 (en) 2008-04-18 2008-04-18 Rosiglitazone solution

Publications (1)

Publication Number Publication Date
WO2009127802A1 true WO2009127802A1 (fr) 2009-10-22

Family

ID=39472319

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2009/000528 WO2009127802A1 (fr) 2008-04-18 2009-02-25 Composition de rosiglitazone

Country Status (2)

Country Link
GB (1) GB0807068D0 (fr)
WO (1) WO2009127802A1 (fr)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
COX PETER J ET AL: "Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans", DRUG METABOLISM AND DISPOSITION, vol. 28, no. 7, July 2000 (2000-07-01), pages 772 - 780, XP002533325, ISSN: 0090-9556 *
JAMALI ET AL: "Investigation of racemisation of the enantiomers of glitazone drug compounds at different pH using chiral HPLC and chiral CE", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, NEW YORK, NY, US, vol. 46, no. 1, 7 December 2007 (2007-12-07), pages 82 - 87, XP022382354, ISSN: 0731-7085 *

Also Published As

Publication number Publication date
GB0807068D0 (en) 2008-05-21

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