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Solubilizing of metronidazole

a technology of metronidazole and cyclodextrin, which is applied in the field of bioactive ingredient formulations, can solve the problems of incompatibility with certain carriers or excipients, inability to meet the requirements of cyclodextrin, etc., and achieve the effect of reducing the cost of manufacturing the formulation, reducing the risk of side effects, and reducing the effect of cyclod

Inactive Publication Date: 2010-02-25
GALDERMA HLDG SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a new way to dissolve metronidazole in water without using traditional solvents like cyclodextrin or surfactant. Instead, a low amount of niacinamide is used to help dissolve the drug. The solution also contains glycolic cosolvents and water. This new process can be used to make pharmaceutical compositions for the treatment of skin conditions like rosacea, acne, and seborrhoeic dermatitis. The technical effect is a more effective and efficient way to dissolve metronidazole in water for use in dermatological treatments.

Problems solved by technology

However, cyclodextrins have drawbacks in terms of cost, of limited solubility, of incompatibility with certain carriers or excipients, or of potential local or systemic toxicity.
Furthermore, the formation of the inclusion complexes, complexation step, can be quite long, commonly several hours, and can affect the costs and processes for manufacturing the formulations.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Solutions

[0064]In this example, all the metronidazole solubility tests are carried out using a solution of niacinamide at 10% (m / m).

[0065]In the Case of Solutions Containing 1% (m / m) of Metronidazole without Cosolvent: (Solutions 1 to 3):

[0066]The metronidazole content is fixed at 1% (m / m).

[0067]According to the fixed niacinamide / metronidazole molar ratio, an amount of solution containing 10% of niacinamide is weighed out and is added to the amount of metronidazole previously weighed out, and then the mixture is made up to 100% through the addition of distilled water.

[0068]After magnetic stirring for 12 hours, the solution obtained is filtered through 1 μm and assayed by UV at the wavelength of 327 nm.

[0069]In the Case of Solutions Containing 1% (m / m) of Metronidazole with Cosolvent: (Solutions 4 to 6):

[0070]The metronidazole content is fixed at 1% (m / m) and the niacinamide / metronidazole molar ratio is fixed at 4.

[0071]Propylene glycol or PEG 400, alone or in combinat...

example 2

Stability Study

[0078]The solutions prepared according to Example 1 were monitored in terms of stability over a period of 8 weeks at ambient temperature and at +4° C. Since the latter condition is more drastic, it makes it possible to reveal more rapidly the potential metronidazole recrystallization phenomena.

[0079]The results obtained are the following:

TABLE IIStability at ambientStability at +4° C.temperature (visualSolutions(visual observation)observation)No. 1ClearClearNo. 2Precipitation at 13 daysClearNo. 3Precipitation at 5 daysClearNo. 4Precipitation at 8 daysPrecipitation at 18 daysNo. 5Precipitation at 8 daysPrecipitation at 18 daysNo. 6ClearClearNo. 7Precipitation at 8 daysPrecipitation at 8 daysNo. 8ClearClear

[0080]Conclusions:

[0081]The comparison of solutions 1 and 2 made it possible to confirm the results of Chien et al., showing that it is necessary to introduce niacinamide into the aqueous solutions of metronidazole in order to increase its solubility and its physical ...

example 3

Example of a Composition Containing Metronidazole at 1% (m / m)

[0087]a) Lotion at 1% (m / m):

IngredientsFormula (% m / m)Metronidazole1.00Niacinamide2.85Propylene glycol5.00Macrogol 400 (PEG 400)5.00Benzyl alcohol1.30Glycerol5.00Stearyl alcohol2.00Mineral oil6.00Carbomer 981 NF0.15Arlacel 165 FL3.00Potassium sorbate0.20Cyclomethicone4.00Steareth 213.0010% Sodium hydroxideqs pH 5.0 ± 0.5Purified waterqs 100.00

[0088]The lotion is prepared according to the following procedure:

[0089]Aqueous Phase:

[0090]1) The water is weighed out into a beaker and the niacinamide, the Macrogol 400, the propylene glycol and the metronidazole are introduced with stirring using a deflocculator (300 rpm).

[0091]2) After complete dissolution of the metronidazole, the glycerol, the Carbomer 981 and the Steareth 21 are added.

[0092]3) The aqueous phase is heated to 70° C.

[0093]Fatty Phase:

[0094]1) The stearyl alcohol, the mineral oil and the Arlacel 165 FL are weighed out into a beaker.

[0095]2) The mixture is heated t...

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Abstract

Metronidazole is solubilized in an aqueous phase, by mixing same with niacinamide and at least two glycolic cosolvents; the resulting solutions and pharmaceutical compositions comprised thereof are useful for the treatment of dermatological conditions / afflictions, notably rosacea.

Description

CROSS-REFERENCE TO PRIORITY / PCT APPLICATIONS[0001]This application claims priority under 35 U.S.C. §119 of FR 05 / 06182, filed Jun. 17, 2005, and is a continuation of PCT / FR 2006 / 001367, filed Jun. 16, 2006 and designating the United States (published in the French language on Dec. 21, 2006 as WO 2006 / 134279 A2; the title and abstract were also published in English), each hereby expressly incorporated by reference in its entirety and each assigned to the assignee hereof.BACKGROUND OF THE INVENTION[0002]1. Technical Field of the Invention[0003]The present invention relates to the formulation of bioactive ingredients for the purpose of pharmaceutical applications, in particular for topical application / administration.[0004]The present invention relates, in particular, to a novel process for solubilizing metronidazole in a pharmaceutical composition, by combining, in an aqueous phase, at least metronidazole, niacinamide, propylene glycol and polyethylene glycol. Such combinations make it...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/44
CPCA61K9/0014A61K9/06A61K9/08A61K9/12A61K31/44A61K31/4164A61K47/10A61K47/22A61K31/415A61K9/122A61P17/00
Inventor MALLARD, CLAIREBRZOKEWICZ, ALAIN
Owner GALDERMA HLDG SA
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