Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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QA 53 634
PHARM~CEUTICAL FORMULATION
This invention relates to improvements in
pessaries, and in particular to a pessary having
one or more active ingredients together with a
surfactant to improve the clinical effectiveness
of these ingredients.
It is desirable for a pessary to be able
to treat all the common forms of vaginitis, which
are most often caused by infection with candida
albicans, trichomonas vaginalis or qardnerella
sp, either singly or mixed. Commonly derivatives
of imidazole and nitroimidazole are used to treat
such conditions, examples of such drugs being miconazole,
clotrimazole and metronidazole, but despite the
good activity of these compounds none has so far
indivi~ually achieved the broad spectrum of activity
required to combat all the common types of infection.
Other types of drugs used in such infections include
nitrofurfuryl derivatives and various antibiotics.
While such drugs have been formulated as
pessaries and vaginal tablets, it has been found
for metronidazole that the relapse rate with trichomonal
infections (i.e. the rate of reappearance of infection
after cessation o~ the medicament) is higher when
administered in this way than when administration
is by the oral route. Consequently the oral route ~
is now the preferred route for administration of ~ ;
metronidazole, and pessaries containing this compound
have been virtually discontinued. This results
in mixed vaginal infections being treated by both
the oral and vaginal routes, with consequent inconven-
ience to the patient.
We have now developed an improved pessary
formulation which combats the problem of higher
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relapse rate when antitrichomonal drugs such as
metronidazole are administered as a pessary thus
enabling the use of the intravaginal route in
combating trichomonal infections and hence the
possibility of a single route of application of
therapy against all three of the principal infective
agents in vaginitis.
Thus one aspect of the invention provides
a pessary for human administration comprising an
effective amount of one or more drugs active against
trichomonas vaqinalis, a pessary base and a surfactant.
The preferred antitrichomonal drug is metronidazole.
The use of a surfactant according to the
invention allows the active antitrichomonal drug
fully to penetrate between the apposed layers of
vaginal epithelium which occur in the rugose surface
of the vagina so reaching the trichomonas sP. which
otherwise would be protected by such apposition
from contact with the active ingredients of conventional
pessary formulations. The relapse rate when treatment
ceases can therefore be expected to be lower than
when metronidazole is administered intravaginally
in a conventional pessary formulation.
In order to produce a broad spectrum of activity
against vaginal infections, it is desirable to
include one or more drugs active against candida
albicans and/or qardnerella sP. A fungicidally
active derivative of nitroimdazole such as butoconazole
or, more preferably, miconazole, is advantageously
used as the drug active against candida albicans,
Where metronidazole is used as the antitrichomonal
drug, it will also be effective against qardnerella
owever, a broad spectrum antibiotic such
as pivampicillin may advantageously also be included.
In order to counter the inflammation and itching
associated with vaginitis, it may be beneficial
to include an antiinflammatory drug such as hydrocortisone.
Lactic acid may also advantageously be included as
a further active ingredient.
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The pessaries of the present invention may
also advantageously include chlorophyll as a deodorant.
We have found that although some staining of clothes
by the green coloration of the chlorophyll may
take place, the surfactant in the composition ensures
that this such stains are readily removed.
The quantity of metronidazole is conveniently
from 250 to 750 mg per pessary, more preferably from
400 to 600 mg and suitably about 500 mg.
The pessary may conveniently contain from
50 to 150 mg of miconazole, more preferably from
80 to 120 mg. The miconazole may be in the form
of the free base or as a salt, for instance the
nitrate - a suitable quantity of miconazole nitrate
per pessary is then about 100 mg.
The active components are preferably incorporated
in the size range 5 to 200 microns but are preferably
at the low end of this range, for example 10 to
50 microns, e.g. about 20 microns.
The pessary base may be of any conventional
material for vaginal administration such as glycerol/
gelatin,glyco-gelatin, macrogols (polyethylene glycols),
natural, synthetic or semisynthetic hard fats, and
fractionated palm kernel oil. A particularly preferred
material is a hard fat such as cocoa butter (theobroma
oil), for instance the range of cocoa butter-based
products sold under the trade name Witepsol by Dynamit
Nobel, Slough, England.
The surfactant may be a cationic, non-ionic,
anionic or amphoteric surfactant although non-ionic
surfactants are preferred. Anionic surfactants
include salts of long chain alkyl sulphonate esters
such as sodium lauryl sulphate, sodium cetostearyl
sulphate and sodium tetradecyl sulphate; salts
of long chain carboxylic acids such as stearates.
Cationic surfactants include quaternary ammonium
or pyridinium compounds such as benzalkonium chloride
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(a mixture of benzyl alkyl dimetnyl chlorides,
the alkyl chain ranging from C8 to Cl~), tetradecyltri-
methyl ammonium bromide and cetylpyridinium chloride.
Amphoteric surfactants include lauryl l-carboxy
glycine and lecithins such as soya lecithin.
Non-ionic surfactants include glycol and
glycerol esters such as glyceryl monostearate;
macrogol esters and ethers such as cetomacrogol;
sorbitan and mannitan esters such as sorbitan tristearate;
and polyoxyethylene derivatives of such sorbitan
esters, for instance polyoxyethylene (20) sorbitan
mono-oleate.
The level of surfactant required in the pessary
formulation will be readily determined by those
skilled in the art and will depend on the specific
surfactant and the nature of the pessary base;
conveniently it is in the range 0.1 to 10 percent
by weight, preferably 1 to 5 percent.
It is especially preferred to use a cetomacrogol
surfactant in conjunction with a cocoa-butter base
such as Witepsol. In such a formulation the surfactant
is suita~ly present in the range 1 to 5 per cent
by weight, for instance about 40mg in an overall
pessary weight of 2540mg (including active ingredients).
The pessaries may be manufactured by conventional
methods, for instance by admixture of the active
ingredients and surfactant in the molten pessary
base and pouring the resulting mixture into chilled
moulds.
The invention is illustrated by the following
Examples MONATERIC and MONAQUAT surfactants are available
from Mona Industries Ltd, Paterson, New Jersey, U.S.A.
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Example 1
(1) Composition of pessary =
Metronidazole 500.Omg
Miconazole nitrate lOO.Omg
Witepsol w35 1940~4mg
Cetomacrogol 39.6mg
2000 mg -
per pessary
(2) Method of manufacture ~ ~-
The two active ingredients and the surfactant are
mixed into the molten pessary base and the resulting
mixture is poured into pre-cooled moulds. The
moulds are passed through a cooling tunnel at -
lo&, the pessaries are removed from the moulds
and packaged.
Example 2
(1) Composition of pessary =
' Polyethylene glycol 40001 448mg
Polyethylene glycol 1000 724mg
Polyethylene glycol 400 l91mg
MONATERIC 951A 51mg
metronidazole 500mg
miconazole nitrate lOOmg
3 014mg
per pessary
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. The pessary is prepared according to the method
of Example 1. The MONATERIC 951A may be replaced
by MONAQUAT PT-C, PT-L, PT-S or Phospholipid EFA.
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