Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-23
2002-09-24
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S058000
Reexamination Certificate
active
06455533
ABSTRACT:
The present invention relates to pharmaceutical compositions for oral administration, comprising an active substance belonging to the substituted benzhydrylpiperazine family and a cyclodextrin.
Many substances belonging to the substituted benzhydrylpiperazine family are known as being substances which have advantageous pharmacological properties.
For example, GB patent 817,231 in the name of the Applicant describes substituted benzhydryl-piperazines corresponding to the general formula
in which R and R
1
represent, independently of each other, a hydrogen or halogen atom, or an alkyl or alkoxy group, where R and R
1
can be in an ortho, meta or para position, and n represents the number 1 or 2, as well as the pharmaceutically acceptable salts thereof.
Among these compounds is found, in particular, 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]ethanol, also known as hydroxyzine, and the dihydrochloride thereof, which are well known for their antihistaminic and tranquilizing properties.
Patent EP 58146 in the name of the Applicant describes substituted benzhydrylpiperazines corresponding to the general formula
in which L represents an —OH or —NH
2
group, X and X′, taken individually, represent a hydrogen atom, a halogen atom, a linear or branched C
1
or C
4
alkoxy radical or a trifluoromethyl radical, m is equal to 1 or 2 and n is equal to 1 or 2, as well as the pharmaceutically acceptable salts thereof.
Among these compounds, 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]acetic acid, also known as cetirizine and the dihydrochloride thereof are well known for their antihistaminic properties.
Hitherto, the only commercial pharmaceutical compositions for oral administration containing compounds of this type are of conventional type. In the case of film-coated tablets, administration takes place by swallowing by means of the simultaneous absorption of liquid. When the absorption needs to take place without simultaneous absorption of liquid (pre- or postoperative conditions, absence of drinking water, etc.), a conventional mode of administration is unsuitable on account of the extremely bitter taste of these substituted benzhydrylpiperazines.
Various techniques intended to mask the taste of pharmaceutical substances have been described.
For example, U.S. Pat. No. 3,558,600 describes a method for masking the bitter taste of antihistaminic agents belonging to the substituted 1-(p-chloro-benzhydryl)piperazine family, which consists in converting the active substance in free base form into the form of its salt with a long-chain alkyl sulfate, for example such as stearyl sulfate.
Another known method for masking the taste of active principles consists in forming an inclusion complex between the active principle and a cyclodextrin. In this case, the masking of the taste arises from the trapping of the active principle which cannot be released as it passes through the mouth. However, this solution to the problem of masking the taste entails another problem specific to the masking of the taste of orally administered pharmaceutically active substances, namely the problem of the bioavailability and speed of action of the active principle. Specifically, if the association constant of the inclusion complex is too large, there is a risk that the active principle will not be released easily enough to allow good absorption in the gastrointestinal tract. In this case, the expected therapeutic effect cannot be obtained.
Patent EP 399,902 mentions this twofold problem intrinsic to pharmaceutical compositions for oral administration, namely the masking of taste combined with good bioavailability. That patent describes freeze-dried and porous pharmaceutical forms comprising, besides the conventional excipients and additives for this type of formulation, the active principle and a cyclodextrin, as well as processes for preparing these pharmaceutical forms. Pharmaceutical compositions containing the following active principles are described in the embodiment examples of the invention: ketoprofen, trimipramine methanesulfonate, zopiclone, phenobarbital, vitamin A, lemon essence, pritinamycin or vitamin D3.
However, that document does not make it possible to conclude that the masking of taste and the bioavailability of these active principles are indeed obtained in all cases. In the case of pharmaceutical substances belonging to the substituted benzhydryl-piperazine family, this problem is of special importance since, although it is desirable to mask the extremely bitter, unpleasant taste of these active principles, it is also essential that they should be released immediately after administration in order to obtain a rapid and efficient effect.
The Applicant thus set itself the aim of searching for novel pharmaceutical compositions which allow easier oral administration of pharmaceutical substances belonging to the substituted benzhydryl-piperazine family than is possible with the current compositions, while still ensuring good bioavailability of the active substance.
We have just discovered novel pharmaceutical forms for oral administration which make it possible both to efficiently mask the taste of substances belonging to the substituted benzhydrylpiperazine family and to obtain good bioavailability of these compounds when they are administered orally, even without liquid being taken simultaneously. In particular, the Applicant set itself the aim of searching for such formulations which are in the form of chewable tablets, dry syrups, granules or sublingual tablets.
Accordingly, the present invention relates to orally administrative solid pharmaceutical compositions comprising an active substance belonging to the substituted benzhydrylpiperazine family and at least one cyclodextrin.
The cyclodextrins which can be used according to the present invention can be chosen from &agr;, &bgr; or &ggr; cyclodextrins, or from alkyl or hydroxyalkyl derivatives thereof, such as heptakis(2,6-di-o-methyl)-&bgr;-cyclodextrin (commonly abbreviated to DIMEB), randomly methylated &bgr;-cyclodextrin (commonly abbreviated to RAMEB) and hydroxypropyl &bgr;-cyclodextrin (commonly abbreviated to HP&bgr;CD).
Among the active substances belonging to the substituted benzhydrylpiperazine family which will be mentioned in particular are 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid (cetirizine), 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethanol (hydroxyzine), 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid (efletirizine), 1- (4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine (meclizine) or 1-[(4-tert-butylphenyl)methyl]-4-[(4-chlorophenyl)phenylmethyl]piperazine (buclizine), the optically active isomers thereof and the pharmaceutically acceptable salts thereof.
The pharmaceutical compositions according to the present invention can be in various orally-administrable forms. In particular, the pharmaceutical compositions according to the present invention can be in the form of dry syrups, chewable tablets, granules or sublingual tablets which are particularly suitable for oral administration without simultaneous absorption of liquid.
The excipients used are the conventional excipients used for compositions of this type.
In the case of dry syrups and granules, diluents such as polyols (mannitol, sorbitol, sucrose, etc.) and flavorings can be used, for example.
In the case of chewable tablets, any conventional excipient which gives good tabletting parameters can be used, such as diluents (mannitol, sorbitol, etc.), crumbling agents or swelling agents (polyvinylpolypyrrolidone, sodium croscarmellose, starches and derivatives, cellulose and derivatives, etc.), lubricants (magnesium stearate, etc.), flow agents (Aerosil 200, etc.) and flavorings.
In the case of sublingual tablets, the excipients cited above can be used, selecting those which are wat
Berwaer Monique
Deleers Michel
Fanara Domenico
Nolf Philippe
Vranckx Henri
Jones Dwayne C.
UCB S.A.
Wenderoth , Lind & Ponack, L.L.P.
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