CA2006978A1 - Pharmaceutical formulation - Google Patents

Abstract

ABSTRACT

Pharmaceutical Formulation Disclosed are pessaries for human administration comprising an effective amount of one or more drugs active agains trichomonas vaqinalis, a pessary base and a surfactant.
The active ingredients are advantageously metromidazole and miconazole in combination.

Description

200fi~7~

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 .~

200697~

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 .

20065~78 (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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-- s 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 200697~

. 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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Claims (12)

1. A pessary for human administration comprising an effective amount of one or more drugs active agains trichomonas vaginalis, a pessary base and a surfactant.

2. A pessary as claimed in claim 1 in which metronidazole is used as the drug active against trichomonas vaqinalis.

3. A pessary as claimed in claim 1 or claim 2 which further comprises one or more drugs active against candida albicans and/or gardnerella sp,

4. A pessary as claimed in claim 1 comprising effective amounts of metronidazole and miconazole.

5. A pessary as claimed in any of the preceding claims also comprising one or more antiinflammatory drugs.

6. A pessary as claimed in any of the previous claims containing 250 to 750 mg of metronidazole.

7. A pessary as claimed in any of the preceding claims containing 50 to 150 mg of miconazole.

8. A pessary as claimed in any of the preceding claims in which the pessary base is cocoa butter.

9. A pessary as claimed in any of the preceding claims in which the surfactant is an anionic, cationic, amphoteric or non-ionic surfactant.

10. A pessary as claimed in claim 9 in which the surfactant is a macrogol ester or ether.

11. A pessary as claimed in claim 10 in which the surfactant is cetomacrogol.

12. A pessary as claimed in any of the previous claims in which the concentration of the surfactant in the pessary composition is 0.1 to 10 percent.