Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-11-06
2004-09-21
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S570000, C424S439000
Reexamination Certificate
active
06794411
ABSTRACT:
The present invention relates to an oral pharmaceutical ibuprofen composition intended for facilitated oral administration.
The oral administration of solid forms such as tablets can prove difficult or even dangerous for children and the elderly, who prefer chewable tablets, tablets which dissolve in the mouth or in a spoon of water, granules, powders, solutions or suspensions.
The active ingredients incorporated into these types of formulations sometimes have a bitter taste which persists for a long time and which cannot be effectively masked by the addition of a sweetener or a flavoring. However, the taste and the aftertaste are important criteria for the acceptance of the medicament by the patient.
In the oral suspensions of bitter active ingredient already described in the prior art, the active ingredient is generally coated with a lipid substance, either directly or after incorporation into a core. The lipid substances used are for example a partially hydrogenated vegetable oil (EP 670 722), stearic acid and/or palmitic acid (FR 2 615 101), glyceryl tripalmitate (EP 664 701), or a mixture of glyceryl monostearate and beeswax in the proportions 9/1 (EP 769 948).
Ibuprofen is an active ingredient with a bitter taste which has been the subject of numerous studies in order to formulate it in stable compositions in which its taste is masked.
A prior art solution consists in coating the ibuprofen- containing granules with a polymer intended to mask its bitter taste. This polymer is for example a phthalate (WO 91/16043), a vinyl acetal (JP 91/83922), a cellulose acetate phthalate (WO 95/05166) or a methacrylic acid copolymer (EP 524 180).
Another prior art solution consists in preparing an aqueous suspension of ibuprofen. This suspension contains either a lipid substance and a surfactant (WO 94/25006, U.S. Pat. No. 5,110,606, WO 96/22762, WO 94/05260), or a suspending agent, such as a polysaccharide (JP 98/182 449), a mixture of cellulose and of xanthan gum (EP 556 057), a mixture of polyethylene glycol and of sodium carboxymethyl cellulose (U.S. Pat. No. 5,602,182), a mixture of xanthan gum and of pregelatinized starch (EP 405 930), a mixture of xanthan gum, of microcrystalline cellulose and of carboxymethyl cellulose (EP 298 740).
The subject of the present invention is an oral pharmaceutical ibuprofen suspension which is provided in a dry form, reconstitutable in liquid form, or which is ready for use in liquid form comprising a liquid phase in which ibuprofen in a solid state is dispersed, characterized in that the solubilized fraction of ibuprofen in the liquid phase is less than 10% by weight relative to the total quantity of ibuprofen, preferably less than 5% by weight, preferably less than 1% by weight.
The active ingredient is in the form of crystals, preferably crystals of less than 500 microns in size, or formulated in granules. The crystals may or may not be coated with a film-forming substance.
The active ingredient is dispersed in the liquid phase so as to obtain a stable and homogeneous suspension.
The granules are optionally coated with a material intended either to allow the modified release of the active ingredient embedded on a neutral support, or to mask the taste of said active ingredient, or to avoid solubilizing the active ingredient in the liquid phase of the suspension.
The granules have a final size of between 50 and 1 000 microns, preferably between 200 and 600 microns. They consist of an inert core having a size substantially between 100 and 350 microns and a spherical shape onto which the active ingredient is applied by means of a binder or by mere absorption if the active ingredient is in solution.
The granules are for example obtained by coating the active ingredient(s) onto a neutral support consisting of sugar and starch.
The coating of the neutral support with the active ingredient may be carried out according to several techniques, such as dusting, spraying of a solution or suspension of the active ingredient, or any other conventional technology known to persons skilled in the art.
The neutral support coated with active ingredient is then optionally coated with a polymer film consisting of a single polymer or of a combination of several polymers or coated with a succession of different layers of polymer, depending on the expected effect. This step may be carried out using the various excipients and technologies well known to persons skilled in the art. Aqueous solvents will preferably be used.
The oral pharmaceutical suspension according to the invention advantageously consists of a liquid phase which is aqueous or consists of a mixture of water with a cosolvent, for example an oil, propylene glycol, glycerin or a solution of sorbitol.
The suspension according to the invention may also be provided in the form of a dry mixture of excipients and of active ingredient, which may be freshly prepared by simply adding water. The active ingredient is then dispersed by stirring manually, so as to obtain a homogeneous and stable formulation.
The dry suspension is prepared by mixing the active ingredient, in the form of crystals or granules, and the suspension adjuvants. It may be granulated according to various conventional granulation techniques well known to persons skilled in the art, or may result from simple physical mixing of the various components.
The powder is then distributed into bottles. The bottles are sufficiently large for the quantity of water needed for the reconstitution to be added.
The oral pharmaceutical suspension according to the invention contains at least one viscosity agent, at least one filler and at least one preservative.
The viscosity agent is chosen from pharmaceutically acceptable viscosity agents, for example xanthan gum, hydroxypropylmethyl cellulose, methyl cellulose, carageenan, carboxymethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone and carbomers.
The viscosity agent is advantageously a carbomer. Carbomers are acrylic acid polymers containing interchain allylsucrose and allypentaerythritol groups. A grade is preferably chosen whose synthesis does not require the use of benzene as solvent, such as carbomer 971P. In addition, carbomers have the advantage of being used in small quantities.
The viscosity agent represents 0.1 to 10%, preferably 0.1 to 2.5%, by weight relative to the weight of the suspension.
Throughout the application, in the expression “% by weight relative to the weight of the suspension”, there is understood to mean a suspension in liquid form which has been optionally reconstituted.
The filler represents 10 to 70%, preferably 30 to 55%, by weight relative to the weight of the suspension. It is chosen from sucrose or noncariogenic agents such as sorbitol, xylitol, mannitol, lactitol or maltodextrins.
The preservative represents 0.05 to 3%, preferably 0.1 to 1%, by weight relative to the weight of the suspension.
The preservative or the mixture of preservatives makes it possible to maintain the microbiological integrity of the suspension and to satisfy the regulatory requirements relating to the enumeration of total and specific microorganisms and to the study of efficacy of the preservatives.
A mixture of preservatives is preferably chosen so as to obtain a synergy of antibacterial effects.
At least one of the preservatives is chosen from the esters of parabens or the corresponding salts.
The oral suspension according to the invention may contain, in addition, at least one agent chosen from an alkalinizing or acidifying agent, a flavoring, an antioxidant, a coloring, a lubricant and a sweetener.
The sweetener is chosen based on its higher sweetening power than sucrose, such as aspartame, saccharin, sodium cyclamate and mixtures thereof.
The flavoring may be of natural or synthetic origin. It represents 0.1 to 3% by weight relative to the weight of the suspension.
The coloring is a natural or synthetic pigment, chosen based on the suspension flavor. In the case of a strawberry flavor, cochineal red or Ponceau red 4R will be preferably chosen.
The lubricant is, for example, talc, alumi
Guerin Emmanuel
Lebon Christophe
Suplie Pascal
Delacroix-Muirheid C.
Foley & Lardner
Laboratoire des Produits Ethiques Ethypharm
Spivack Phyllis G.
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