The invention provides a pharmaceutical composition for rectal or vaginal administration which comprises at least two parts wherein the composition comprises PA1 (i) two or more physiologically acceptable substances each in separate parts of the composition which are such that on admixture they react to produce a physiologically acceptable gas; PA1 (ii) in at least one part of the composition a polymer stabiliser which is adapted to facilitate the formation of a water-soluble collapsible foam structure; and PA1 (iii) in at least one part of the composition a pharmaceutically active substance; an its use in the treatment or prophylaxis of disorders of the intestines, rectum or vagina.

FIELD OF THE INVENTION
 The present invention provides a pharmaceutical composition for rectal or
 vaginal administration and its use in therapy.
 BACKGROUND OF THE INVENTION
 Various means of administering drugs to the intestine are known. For
 example oral controlled release compositions are used to reach the upper
 part whereas enemas are used to reach the lower part. Enemas are usually
 used in the form of a foam to overcome the problem of leakage from the
 rectum following administration which makes it necessary for patients to
 lie down during administration. Foams, as well as pessaries, tampons and
 creams are used to administer drugs to the vagina.
 Conventional foams for rectal or vaginal administration are filled in
 pressurised containers with a pharmaceutically active ingredient dissolved
 or suspended in a liquid vehicle, at least one propellant gas and a
 surfactant with foaming properties. Examples based on mesalazine,
 peppermint, sucralfate or budesonide as the active ingredient dispersed in
 a liquid vehicle containing a foaming surfactant and administered for
 topical action in the colon using a pressurised atomiser with a propellant
 gas are described in EP-A-468 555. Rectal foams formed by a propellant gas
 on expulsion from a pressurised container and containing other active
 ingredients such as flunisolide and its derivatives (see WO 94/12187),
 5-aminosalicylic acid (EP 395 329), and 4-aminosalicylic acid (DE 4316724)
 have also been described.
 Chlorofluorocarbons are generally used as the propellant gas but these are
 undesirable for environmental reasons. Also the use of pressurised
 containers to administer pharmaceutically active substances suffers from a
 number of problems. For example, it is difficult to administer an accurate
 dose of the pharmaceutical composition of the drug; the containers are
 difficult to store over long periods of time because of leakage of gas
 which results in reduced administration capacity. Furthermore the disposal
 of used containers can be dangerous because of the risk of explosions on
 incineration. Accordingly alternative formulations need to be found.
 DESCRIPTION OF THE INVENTION
 According to the invention there is provided a pharmaceutical composition
 for rectal or vaginal administration which comprises at least two parts
 wherein the composition comprises
 (i) two or more physiologically acceptable substances each in separate
 parts of the composition which are such that on admixture they react to
 produce a physiologically acceptable gas;
 (ii) in at least one part of the composition a polymer stabiliser which is
 adapted to facilitate the formation of a water-soluble collapsible foam
 structure; and
 (iii) in at least one part of the composition a pharmaceutically active
 substance.
 During administration the individual parts of the composition are mixed
 which causes the two or more substances defined in (i) to react to produce
 a gas which contacts the polymer stabiliser (ii) forming a water-soluble
 collapsible foam which may then be applied to the rectum or vagina. The
 polymer stabiliser is preferably used in a swelled form, e.g. in the form
 of a hydrogel. The composition of the invention is preferably administered
 from a multi-part syringe. The advantage of such a device is that the
 foaming action is smooth and the time for the administration is
 controllable using the piston of the syringe resulting in less discomfort
 for the patient.
 The two or more substances defined in (i) are preferably one or more acids,
 especially water-soluble acids and one or more effervescent compounds.
 Each is generally used as an aqueous solution in a concentration of from
 0.1 to 10% by weight of the compositions.
 The acid is preferably hydrochloric acid or a water-soluble mono- or
 polycarboxylic acid. Examples of suitable water-soluble mono- or
 polycarboxylic acids include citric, lactic, tartaric, succinic,
 glycollic, malonic, oxalic, malic, flumaric, maleic, or acetic acid. Most
 preferred is citric acid, preferably in a concentration of from 1 to 3% by
 weight of the composition.
 The effervescent compound is preferably a pharmaceutically acceptable
 alkali metal carbonate or bicarbonate e.g. sodium monohydrogen carbonate,
 potassium monohydrogen carbonate, sodium carbonate or potassium carbonate.
 Most preferred is sodium monohydrogen carbonate, preferably in a
 concentration of from 3.5 to 5.5% by weight of the composition. The exact
 concentration of each substance to be used depends on the volume of foam
 required and the desired pH and osmolarity of the foam to be formed.
 Generally where the two substances (i) are an acid and an effervescent
 compound, they should be used in a ratio of from 1:0.5 to 1:25, preferably
 from 1:1 to 1:4, by weight of the acid to the effervescent compound.
 The polymer stabiliser (ii) is preferably a hydrogel thickener. The polymer
 stabiliser used in the invention preferably displays pseudoplastic flow
 characteristics when in solution. More preferably the polymer stabiliser
 used in the invention is a water soluble hydrogel thickening polymer, e.g.
 a natural polysaccharide, semi-synthetic polymer or a synthetic polymer,
 or a mixture thereof Examples of natural polysaccharides are agar,
 alginates, carrageenan, guar, arabic, tragacanth, pectins, dextran, gellan
 and xanthan gums. Suitable semi-synthetic polymers are polysaccharide
 derivatives, e.g. cellulose esters and modified starches. Examples of
 synthetic polymers are polyvinyl alcohol, polyvinylpyrrolidone,
 polyacrylates, polyvinylacetate, and poloxamer. Preferably the viscosity
 of a solution thickened with the polymer stabiliser is remains
 substantially the same in a wide pH range and is relatively independent of
 ionic strength. More preferably the polymer stabiliser is xanthan gum or
 hydroxyethyl cellulose. Most preferably the polymer stabiliser is xanthan
 gum.
 The advantage of xanthan gum is that compositions containing it have a low
 viscosity at high shear rates, therefore they are easy to pump, spray and
 spread. They exhibit a high viscosity at low shear rates. This results in
 a good stabilisation of suspended drugs.
 The polymer stabiliser is preferably used in such concentrations that
 solutions or dispersions containing it in swelled form have a viscosity as
 measured by Bohlin.RTM. rotational viscosimeter CSR-10a within the ranges
 shown in Table 1 at the given shear rates. The concentration of a given
 polymer stabiliser required to meet the viscosity requirements may easily
 be determined empirically by a person of skill in the art.
 TABLE 1
 Viscosity Range Preferred Viscosity Range
 Shear Rate (s.sup.-1) (mPas) (mPas)
 0.1 10.sup.1 -10.sup.10 10.sup.3 -10.sup.7
 1 10.sup.1 -10.sup.9 10.sup.2 -10.sup.5
 10 10.sup.1 -10.sup.8 10.sup.2 -10.sup.4
 100 10.sup.1 -10.sup.5 10.sup.2 -10.sup.3
 In general the concentration of the polymer stabiliser should be from 0.1
 to 5% by weight of the composition where it is xanthan gum or hydroxyethyl
 cellulose. Preferably the concentration of xanthan gum used is from 0.5 to
 2% by weight of the composition and the concentration of hydroxyethyl
 cellulose where it is hydroxyethyl cellulose 4000 is from 2 to 3% by
 weight of the composition. When the polymer stabiliser is PVP 90, it is
 preferably used in a concentration of from 5 to 30% by weight of the
 composition, preferably 10 to 25% by weight.
 The pharmaceutically active substance to be used in the present invention
 depends on the disease to be treated by the composition or intended effect
 of the composition. It is preferably one or more of an anti-inflammatory
 drug, analgesic, local anaesthetic, anti-infection drugs, contraceptive
 and/or an anti-anginal agent. Suitable anti-inflammatoy drugs include
 steroids or non steroidal anti-inflammatory drugs (NSAIDs). Preferred
 analgesics and local anaesthetics are lidocaine, morphine or codeine.
 Preferred steroids are budesonide, suitable esters of beclomethasone,
 rofleponide or suitable derivatives (e.g. esters) thereof, hydrocortisone,
 betamethasone, prednisolone, dexamethasone, fluocinolone, amcinonide,
 bufexamac or flunisolide. Particularly preferred is budesonide. Preferred
 NSAIDs are 4-aminosalicylic acid, 5-aminosalicylic acid or sulphasalazine.
 Preferred anti-infection drugs are anti-microbial agents (e.g. bacitracin
 or iodine), antiseptics (e.g. cetrimide), fungicides (e.g. clotrimazole,
 metronidazole or cyclospoline) and anti-viral agents (e.g. acyclovir or
 idoxuridin). Preferred anti-anginal agents are isosorbide-5-mononitrate or
 isosorbide dinitrate. The pharmaceutically active substances can be
 administered alone or in combination.
 The concentration of the pharmaceutically active substance to be used
 depends upon the intended volume of the foam to be produced by the
 composition on administration, the potency of the substance, the nature of
 the condition to be treated etc. and can easily be determined by a person
 of skill in the art.
 The pH of the part of the composition comprising the pharmaceutically
 active substance and the pH of the foam resulting from mixing the two
 components depends upon the requirements for the stability of the
 pharmaceutically active substance incorporated therein. For example, when
 the pharmaceutically active substance is budesonide, the pH of the part
 containing it should be from 2 to 5. At the time of administration of the
 composition of the invention, the pH of the foam should be from 5 to 8,
 which is a physiologically well tolerated pH range.
 If the pharmaceutically active substance used in the present invention is
 suspended within one of the parts of the composition, it is preferably in
 micronised form. Preferably it has a particle size of below 20 .mu.m in
 order to minimise the risk of sedimentation during storage of the
 composition and to facilitate the dispersion of the substance in the
 composition without decreasing the foam rigidity during administration.
 The composition according to the invention may optionally comprise
 pharmaceutically acceptable excipients such as surfactants, preservatives,
 and other types of stabilisers, for example antioxidants, chelating
 agents, tonicity modifiers (e.g. sodium chloride, mannitol, sorbitol or
 glucose), spreading agents and water soluble lubricants, e.g. propylene
 glycol, glycerol or polyethylene glycol. The concentration of each
 excipient required may easily be determined empirically by a person
 skilled in the art.
 Suitable surfactants include ionic surfactants, e.g. lauryl sulphate, or
 non-ionic surfactants e.g. phospholipids, poloxamer, and polysorbate.
 Non-ionic surfactants are preferably used.
 Suitable preservatives include benzalkonium chloride, parabens,
 chlorhexidine acetate, chlorhexidine gluconate, sorbic acid, potassium
 sorbitol, chlorbutanol and phenoxyethanol.
 In order to improve the stability of the pharmaceutically active substance
 chelating agents such as EDTA or phosphates can be added.
 Suitable spreading agents are those used for topical applications e.g.
 di-n-octyl ether (for example Cetiol.RTM. OE), fatty alcohol polyalkylene
 glycol ether (for example Aethoxal.RTM. B), 2-ethylhexyl palmitate (for
 example Cegesoft.RTM. C 24), and isopropyl fatty acid esters. The
 spreading agent should preferably be dispersed in the same part as the
 polymer stabiliser.
 One advantage of using the composition of the invention is that since the
 gas used to form the foam is produced by reaction, the composition is
 under less pressure on administration which minimises the risk of inducing
 a defecation reaction reflex.
 The composition according to the invention is such that it forms a foam
 which is collapsible. The volume of the foam formed by the composition
 preferably is reduced by 50% in from 2 to 120 minutes after administration
 and completely collapses to its original volume after 5 to 240 minutes.
 The time before the foam collapses is preferably sufficiently long so that
 the foam spreads as far up the colon as possible but it is preferably not
 so long that it is removed from the area to be treated by the natural
 movement of the intestines before it has collapsed.
 The collapse time depends on a number of factors. For example the greater
 the amount of gas produced by the two or more substances (i) or the higher
 the viscosity of the component comprising the polymer stabiliser, the
 longer the collapse time. The collapse time also depends on the nature of
 the other additives to the composition which have surface active
 properties e.g. surfactants or preservatives.
 The advantage of the collapsibility of the foam formed by the composition
 of the present invention is that removal of foam from the patient is more
 comfortable for the patient and there is less chance of the active
 substance being trapped in the centre of the foam ancL being unable to
 contact the area of the body to be treated.
 The foam formed by the composition according to the invention is
 water-soluble because the composition is substantially free from
 water-insoluble di- or trivalent metal salts which could complex with the
 polymer stabiliser to make the foam insoluble.
 The invention further provides the use of the composition according to the
 invention in the manufacture of a medicament for the treatment of
 disorders of the intestines, rectum or vagina. The invention also provides
 a method of treatment or prophylaxis of disorders of the intestines,
 rectum or vagina which comprises administering a therapeutically effective
 amount of the composition according to the invention to a patient
 suffering from or liable to suffer from a said disorder.

The present invention is further illustrated by the following examples
 which should not be interpreted as limiting the scope of the invention.
 EXAMPLE 1
 A composition according to the invention comprising the components set out
 in Table 2 was prepared. It was then mixed to form a foam whose
 collapsibility was determined.
 Component 1 was prepared by dissolving the citric acid, sodium edetate and
 poloxamer in purified water and dispersing xanthan and budesonide in the
 resulting solution. To hydrate the xanthan the dispersion was agitated at
 room temperature under vacuum for 30 minutes. The resulting hydrogel was
 filled into one chamber of a two chamber mixing syringe s (MIX System
 50 manufactured by Mixpac Systems AG, Switzerland).
 Component 2 was prepared by dissolving the sodium bicarbonate and sodium
 edetate in purified water and dispersing xanthan in the solution obtained
 by agitation at room temperature under vacuum for 30 minutes. The
 resulting alkaline hydrogel was filled in the other chamber of the two
 chamber syringe.
 Both chambers of the syringe were connected with a mixing tip, in which
 thorough mixing of the two components took place upon discharging the
 chambers by a plunger.
 The foam produced was filled into a measuring cylinder. The volume of the
 expanded foam was measured and its collapse with time was monitored.
 10 g of each component was used and it took 10 seconds to discharge the
 syringe. A volume of 95 ml was obtained 5 seconds after discharge. After 5
 minutes the volume had decreased to 90 ml, and after 10 minutes the volume
 had decreased to 85 ml. It took two and half hours before the foam
 collapsed completely. The pH of the foam was 6.28.
 TABLE 2
 Ingredient Component 1/g Component 2/g
 Purified water 10 10
 Citric acid 0.28
 Sodium monohydrogencarbonate 0.42
 Xanthan* 0.1 0.1
 Sodium edetate 0.001 0.001
 Poloxamer** 0.02 0.02
 Budesonide 0.002
 *Keltrol .RTM. RD, Kelco, Hamburg
 **Lutrol .RTM. F68
 EXAMPLE 2
 A composition according to the invention comprising the components set out
 in Table 3 was prepared. It was then mixed to form a foam whose
 collapsibility was determined.
 Component 1 was prepared by dissolving the citric acid, sodium edetate,
 polysorbate 80 and lidocain in purified water and dispersing hydroxyethyl
 cellulose in the solution obtained. The dispersion was agitated under
 vacuum at room temperature for 3 hours. The resulting hydrogel was filled
 into one chamber of a two chamber mixing syringe as used in Example 1.
 Component 2 was prepared by dissolving sodium bicarbonate in purified water
 and dispersing hydroxyethyl cellulose in the solution obtained by
 agitation at room temperature and vacuum for 3 hours. A foam was generated
 as described in Example 1.
 The foam produced was filled into a measuring cylinder. The volume of the
 expanded foam was measured and its collapse with time was monitored.
 10 g of each component was used and it took 5 seconds to discharge the
 syringe. A volume of 86 ml was obtained 60 seconds after discharge. After
 15 minutes the volume had decreased to 83 ml and after 30 minutes the
 volume had decreased to 69 ml. It took two hours before the foam collapsed
 completely. The pH of the foam was 6.82.
 TABLE 3
 Ingredient Component 1/g Component 2/g
 Purified water 10 10
 Citric acid 0.28
 Sodium monohydrogencarbonate 0.42
 Hydroxyethyl cellulose* 0.28 0.28
 Surfactant** 0.02 0.02
 Lidocain HCl 0.2
 *Tylose H 4000 PHA
 **Polysorbate 80