WO1999051219A1

WO1999051219A1 - Pleuromutilin derivatives for treating nasopharynx infection

Info

Publication number: WO1999051219A1
Application number: PCT/GB1999/001055
Authority: WO
Inventors: Valerie Berry; Eric Hunt; Francis Dominic Sanderson; Gary Woodnutt
Original assignee: SmithKline Beecham Ltd; SmithKline Beecham Corp
Current assignee: SmithKline Beecham Ltd; SmithKline Beecham Corp
Priority date: 1998-04-07
Filing date: 1999-04-07
Publication date: 1999-10-14
Anticipated expiration: 2000-10-07
Also published as: GB9807503D0

Abstract

Pleuromutilin or a pharmaceutically acceptable derivative thereof may be used in the manufacture of a medicament for the prophylactic treatment of bacterial infection associated with the colonisation of the nasopharynx by pathogenic organisms, for instance recurrent sinusitis or otitis media.

Description

PLEUROMUTILIN DERIVATIVES FOR TREATING NASOPHARYNX INFECTION

The present invention relates to the use of pleuromutilin and derivatives therof in treating certain bacterial infections, in particular recurrent otitis media and recurrent sinusitis, and to formulations for use in such treatment.

Pleuromutilin, the compound of formula (1), is a naturally occurring antibiotic which has antimycoplasmal activity and modest antibacterial activity. It has been shown that the antimicrobial activity can be improved by replacing the glycolic ester moiety at position 14 by an R-X-CH2CO2- group, where R is an aliphatic or aromatic moiety and X is O, S, or NR' (H Egger and H Reinshagen, J Antibiotics, 1976, 29, 923). Tiamulin, the compound of formula (2), which is used as a veterinary antibiotic, is a derivative of this type (G Hogenauer in Antibiotics, Vol. V, part 1, ed. F E Hahn, Springer-Verlag, 1979, p.344).

O

(1) (2)

In this application, the non-conventional numbering system which is generally used in the literature (G Hogenauer, loc.cit.) is used.

More recently, further pleuromutilin derivatives have been described. For instance, International Patent Application Publication No. WO 97/25309 describes 14-O- carbamoyl derivatives of mutilin or 19, 20-dihydromutilin, in which the N-atom of the carbamoyl group is unsubstituted, mono- or di-substituted; including derivatives of formula (3):

in which:

R' is vinyl or ethyl; R2 and R^ are the same or different groups selected from: hydrogen; a straight or branch chained, saturated or unsaturated, optionally substituted, C \ to Cg hydrocarbon group; a saturated or unsaturated, optionally substituted, C3 to Cg cyclic hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted aryl group; or together form an optionally substituted cyclic group of 3 to 8 ring atoms, optionally containing one additional heteroatom selected from N, O and S, and optionally fused to a hydrocarbon ring, a heterocyclic group or an aromatic group; or

R2 is one of the above monovalent groups and R^ is a group selected from SO2R ,

COR⁵, OR⁵ and NR°R⁷ in which:

R4 is selected from a straight or branch chained, saturated or unsaturated, optionally substituted, C\ to Cg hydrocarbon group; a saturated or unsaturated, optionally substituted, C3 to Cg cyclic hydrocarbon group; an optionally substituted heterocyclic group; an optionally substituted aryl group; an optionally substituted C\ to Cg alkyl amino group; and an optionally substituted aryl amino group;

R⁵ is selected from hydrogen; a straight or branch chained, saturated or unsaturated, optionally substituted, C\ to Cg hydrocarbon group; a saturated or unsaturated, optionally substituted, C3 to Cg cyclic hydrocarbon group; an optionally substituted heterocyclic group; and an optionally substituted aryl group;

R6 and R are the same or different groups selected from hydrogen; a straight or branch chained, saturated or unsaturated, optionally substituted, C_j to Cg hydrocarbon group; a saturated or unsaturated, optionally substituted, C3 to Cg cyclic hydrocarbon group; an optionally substituted heterocyclic group, and an optionally substituted aryl group; or together form an optionally substituted cyclic group of 3 to 8 ring atoms, optionally containing one additional heteroatom selected from N, O and S, and optionally fused to a hydrocarbon ring, a heterocyclic group or an aromatic group.

Suitable C\ to Cg hydrocarbon groups include straight and branched chain alkyl groups having from 1 to 6 carbon atoms, for instance methyl, ethyl, H-propyl and iso- propyl, preferably methyl.

Suitable C3 to Cg cyclic hydrocarbon groups include cyclopropyl, cyclopentyl and cyclohexyl.

Suitable optional substituents for the (Cι.g)alkyl groups and the (C3_g)cycloalkyl groups include, for example, halogen, hydroxy, (Cι-g)alkoxy, aryloxy, carboxy and salt thereof, (Cι-g)alkoxycarbonyl, carbamoyl, mono- or di(Cι-g)alkylcarbamoyl, sulphamoyl, mono- and di(Cι-g)alkylsulphamoyl, amino, mono- and di(C 1 -g)alkylamino, (Cι-g)acylamino, ureido, (Cι-g)alkoxycarbonylamino, aryl,

- 2 - heterocyclyl, oxo, hydroxyimino, acyl, (Cι-g)alkylthio, arylthio, (Cι-g)alkane-sulphinyl, arylsulphinyl, (Cι-g)alkanesulphonyl, arylsulphonyl.

When used herein, the term "heteroaryl" includes aromatic single and fused rings containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three substituents. Each heteroaryl ring suitably has 5 or 6 ring atoms. A fused heteroaryl ring may include carbocyclic rings and need include only one heteroaryl ring. Preferably a subs^'tituent for a heteroaryl or a heterocyclyl group is selected from halogen, (Cι_g)alkyl, aryl(C;ι_4)alkyl, (Cι_g)alkoxy, (Cι_g)alkoxy(Cι_g)alkyl, halo(C g)alkyl, hydroxy, amino, mono- and di-N-(Cι_g)alkyl-amino, acylamino, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(Cι_g)alkylcarbonyl, aryloxycarbonyl, (C\_ g)alkoxycarbonyl(Cι_g)alkyl, aryl, oxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl, (C \ _g)alkylthio, (C \ _g)alkylsulphinyl, (C \ _g)alkylsulphonyl, - heterocyclyl and heterocyclyl(Cj.4)alkyl. Particularly suitable values for R^ and R^ are hydrogen, hydroxy, methoxy, phenyl, methyl, wø-propyl, phenylsulphonyl, methoxyphenyl, nitrophenyl, trichloroacetyl, ben2yl, hydroxyiminoben2yl, benzylamino-sulfonyl, dichloropyridinyl, hydroxyethyl, 2-phenylethyl, l-(R)-phenyl-2-hydroxyethyl, 2-(methoxycarbonyl)ethyl, 2- carboxyethyl, dimethylamino, dimethylaminopropyl, methanesulphonylamino, methanesulphonyl, benzoylamino, benzoyl optionally substituted by trifluoromethyl, carboxy, methoxy, hydroxy, acetoxy, amino or nitro, furoyl, nicotinoyl, z^'sonicotinoyl, acetyl, phenylacetyl, and phenoxy. Particularly suitable values for cyclic groups R^R^N are indolino and morpholino.

In addition, further pleuromutilin derivatives are described in International Patent Application Publication No WO 98/05659. This discloses 14-O-carbamoyl derivatives of mutilin or 19, 20-dihydromutilin, in which the N-atom of the carbamoyl group is acylated by a group which includes an azabicyclic moiety; more specifically, compounds of general formula (4):

in which:

R! is vinyl or ethyl; and R² is a group R³, R⁴CH2^", or R⁵R⁶C=CH-; wherein each of R³ and R⁴ is an azabicyclic ring system or R⁵ and R" together with the carbon atom to which they are attached form an azabicyclic ring system.

The azabicyclic ring system is a bridged or fused non-aromatic ring system attached via a bridgehead or non-bridgehead ring carbon atom and containing one bridgehead nitrogen atom as the sole hetero ring atom. The ring system contains between 5 and 10 ring atoms in each ring and is optionally substituted on carbon by up to 3 substituents. Suitable substituents include alkyl, alkyloxy, alkenyl and alkenyloxy, each of which may be carried by either a bridgehead or a non-bridgehead carbon atom. In addition, the bridgehead nitrogen atom may be substituted by oxygen, to form an N- oxide, or by alkyl, to form a quaternary cation. The counterion may be a halide ion such as chloride or bromide, preferably chloride.

The azabicyclic ring system may for example be represented by formula (I):

/CH

(CH₂)_a ^X (CH₂)_C

^N (I) wherein R⁷ represents one or more optional substituents as set out above and each of a, b and c is between 0 and 4, such that any one ring has between 5 and 10 ring atoms. The azabicyclic ring system additionally may contain one or more double bonds.

Particular azabicyclic groups include azabicyclo[2.2.2]octyl, azabicyclo[2.2.1]heptyl, azabicyclo[3.2.1]octyl, azabicyclo[4.4.0]decyl, quinuclidinyl, azabicyclo[3.2.1]octenyl, and azabicyclo[3.3.1]non-5-yl.

Alkyl and alkenyl groups referred to herein include straight and branched groups containing up to six carbon atoms and are optionally substituted by one or more groups selected from the group consisting of aryl, heterocyclyl, (Cj_g)alkoxy, (Cι.g)alkylthio, aryl(Cι_g)alkoxy, aryl(Cι_g)alkylthio, amino, mono- or di-(C \ _g)alkylamino, cycloalkyl, cycloalkenyl, carboxy and esters thereof, hydroxy, and halogen.

Cycloalkyl and cycloalkenyl groups referred to herein include groups having between three and eight ring carbon atoms and are optionally substituted as described hereinabove for alkyl and alkenyl groups.

- 4 _ When used herein, the term "aryl" means single and fused rings suitably containing from 4 to 7, preferably 5 or 6, ring atoms in each ring, which rings, may each be unsubstituted or substituted by, for example, up to three substituents. A fused ring system may include aliphatic rings and need include only one aromatic ring. Suitable aryl groups include phenyl and naphthyl such as 1-naphthyl or 2- naphthyl.

Suitably any aryl group, including phenyl and naphthyl, may be optionally substituted by up to five, preferably up to three substituents. Suitable substituents include halogen, (Cι.g)alkyl, aryl, aryl(Cι_g)alkyl, (Cι .g)alkoxy, (Cι_g)alkoxy(Cι_g)alkyl, halo(Cι_g)alkyl, aryl(Cι_g)alkoxy, hydroxy, nitro, cyano, azido, amino, mono- and di-N- (Cι_g)alkylamino, acylamino, arylcarbonylamino, acyloxy, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-JV-(Cι _g)alkylcarbamoyl, (C i _g)alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, sulphonylamino, aminosulphonyl, (Cι_g)alkylthio, (Cι_g)alkyl sulphinyl, (Cι_g)alkylsulphonyl, heterocyclyl and heterocyclyl (Cι_g)alkyl. In addition, two adjacent ring carbon atoms may be linked by a (C3_5)alkylene chain, to form a carbocyclic ring.

When used herein the terms "heterocyclyl" and "heterocyclic" suitably include, unless otherwise defined, aromatic and non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings, may be unsubstituted or substituted by, for example, up to three substituents. Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.

Preferably a substituent for a heterocyclyl group is selected from halogen, (C i . g)alkyl, aryl(C _} _g)alkyl, (C i _g)alkoxy, (C i _g)alkoxy(C i _g)alkyl, halo(C i _g)alkyl, hydroxy, amino, mono- and di-N-(Cι_g)alkyl-amino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(Cι_g)alkylcarbonyl, aryloxycarbonyl, (Ci . g)alkoxycarbonyl(C|.g)alkyl, aryl, oxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl, (Cι.g)alkylthio, (C \ _g)alkylsulphinyl, (C \ _g)alkylsulphonyl, heterocyclyl and heterocycly 1(C j _g)alky 1.

- 5 - WO 98/14189 (SmithKline Beecham, published on 9 April 1998, after the priority date of the present application) describes the use of mupirocin in the manufacture of a medicament for the prophylactic treatment of bacterial infection associated with colonisation of the nasopharynx by pathogenic organisms, and in which the medicament is adapted for administration to, and residence within, the nasopharynx. Such infections include recurrent otitis media and recurrent sinusitis.

Otitis media is a disease state commonly seen in infants and young children. The acute condition is normally successfully treated with a systemic antibacterial agent such as amoxycillin, optionally in combination with potassium clavulanate. H. influenzae, S. pneumonia and M. catarrhalis are generally considered to be the most common bacterial pathogens. There however remains the problem of treating the recurrent painful episodes.

Accordingly, in a first aspect, the present invention provides for the use of pleuromutilin or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prophylactic treatment of bacterial infection associated with colonisation of the nasopharynx by pathogenic organisms, and in which the medicament is adapted for administration to, and residence within, the nasopharynx.

Typical bacterial infections include recurrent otitis media and recurrent sinusitis. Accordingly, in a further aspect, the present invention provides for the use of pleuromutilin or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prophylactic treatment of recurrent otitis media.

In addition, the present invention also provides for the use of pleuromutilin or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prophylactic treatment of recurrent sinusitis.

As used herein, the term 'prophylactic treatment' includes not only complete elimination of the bacterial infection, for instance recurrent otitis media or recurrent sinusitis, but also a partial elimination of thereof, that is a reduction in the number of acute episodes.

It is believed that the successful treatment of bacterial infections, such as recurrent otitis media and recurrent sinusitis, is associated with the elimination or reduction of nasal carriage of pathogenic bacteria such as S. aureus, H. influenzae, S. pneumonia and M. catarrhalis, in particular colonisation of the nasospharynx by such organisms.

Accordingly, in a further aspect, the present invention provides for the use of pleuromutilin or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for reducing or eliminating the nasal carriage of pathogenic organisms associated with recurrent otitis media, which medicament is adapted for nasal administration, in particular, focussed delivery to the nasopharynx.

To lessen the risk of encouraging the development of resistant organisms, it is preferred to administer the drug on an intermittent, rather than a continual, basis.

- 6 - Accordingly, in a further aspect, the present invention provides the use of pleuromutilin or a pharmaceutically acceptable derivative thereof (hereinafter referred to as drug substance) in the manufacture of a medicament adapted for administration to the nasopharynx and which is administered to a patient in need thereof on an intermittent basis.

In a suitable intermittent treatment regimen, drug substance is administered on a daily basis, for a small number of days, for instance from 2 to 10, suitably 3 to 8, more suitably about 5 days, the administration then being repeated after an interval, for instance, on a monthly basis over a period of months, for instance up to six months. Less preferably, the drug substance may be administered on a continuing, daily basis, over a prolonged period, for instance several months.

Suitably drug substance is administered once or twice a day. Suitably, drug substance is administered during the winter months when bacterial infections such as recurrent otitis media and recurrent sinusitis tend to be more prevelant. Suitably, drug substance is administered at a dosage of from 1 to lOmg, preferably from 3 to 8, typically about 5mg, in each nostril, twice a day.

The drug substance is administered to the nasopharynx, in particular the anterior nasopharynx.

Suitable pleuromutilin derivatives are well known in the art and include the compounds of formulae (2), (3), and (4) above.

Suitably, the drug substance is present in medicaments for use in the present invention in between 0.01 and 10%, preferably 0.1 and 5%, more preferably 1 and 5%. Suitable amounts include 2% and 4% by weight of the medicament. It is preferred to avoid low level dosages of drug substance as this might increase the risk of the development of resistant bacteria.

Accordingly, in a further aspect, the present invention provides for the use of drug substance in the manufacture of a medicament for the prophylactic treatment of bacterial infection, characterised in that the medicament is administered to the nasopharynx and comprises from 0.001 to 5%, for instance 0.01 to 5%, such as 0.5 to 5%, by weight of drug substance.

Preferred compositions for administration include those adapted for focussed delivery to, and residence within, the nasopharynx. The term "focussed delivery" is used to mean that the composition is delivered to the nasopharynx, rather than remaining within the nares. The term 'residence' within the nasopharynx is used to mean that the composition once delivered remains within the nasopharynx over a course of several hours, rather than being washed away more or less immediately. These two aspects may be conveniently studied by γ (gamma) ray scintigraphy. Suitable such compositions include sprays and creams. Representative spray compositions include aqueous

- 7 - compositions, as well as oily compositions which contain amphiphilic agents so that the composition increases in viscosity when in contact with moisture. Creams may also be used, especially creams having a rheology that allows the cream to spread readily in the nasopharynx. Preferred aqueous spray compositions include, in addition to water, further excipients including a tonicity modifier such as a salt, for instance sodium chloride; preservative, such as benzalkonium salt; a surfactant such as a non-ionic surfactant, for instance a polysorbate; and buffer, such as sodium dihydrogen phosphate; present in low levels, typically less than 1%. The pH of the composition may also be adjusted, for optimum stability of the drug substance during storage. For compounds of the present invention, a pH in the range 5 to 6, preferably about 5.3 to 5.8, typically about 5.5 is optimal.

Representative oily spray and cream compositions are described in WO 98/14189 (SmithKline Beecham). Spray compositions according to the present invention may be delivered to the nasal cavity by spray devices well known in the art for nasal sprays, for instance an air lift pump. Preferred devices include those which are metered to provide a unit volume of composition, prefereably about lOOμl, and optionally adpated for nasal administration by addition of a modified nozzle. Representative oily sprays comprise:

(a) an amphiphilic agent that increases in viscosity on contact with water;

(b) a non-aqueous diluent for the ampiphilic agent,

(c) powdered drug substance in suspension.

Amphiphilic agents are substances containing both hydrophilic and lipophilic groups. In liquid form, these agents are generally capable of spontaneous self-association in the presence of water, with a consequent increase in viscosity. This self-association results in a change in properties ranging from the formation of viscous liquids to semirigid gels. This behaviour has been characterised as due to the formation of long range order in the liquid system giving several distinct phases which have been called "liquid crystalline phases".

Materials known to exhibit such properties and which are suitable for use in a pharmaceutical formulation include mono-glycerides such as mono-olein and mono- linolein, phospholipids such as phosphatidyl cholines, and galactolipids such as galactoyl- diglycerides. Typically the monoglycerides are long-chain fatty acid monoglycerides, optionally comprising up to 10% (w/w) of a long-chain fatty acid diglyceride and/or a small amount by weight of a free long-chain fatty acid. The mono- and di-glycerides may each include blends of different long-chain fatty acid mono- and di-glycerides. Suitable

- 8 - long-chain fatty acid monoglycerides include glycerol monooleate, glycerol monopalmitate and glycerol monostearate. Suitable commercially available examples of such include the products available under the trade names MYVEROL, such as MYVEROL 18-99, MYVATEX, MYVAPLEX, and GMORPHIC 80 respectively, from Eastman Kodak Chemicals, Rochester, New York. A further useful long-chain fatty acid monoglyceride-containing product is ARLACEL 186 (available from ICI Americas Inc.) which includes, in addition to glycerol monooleate, propylene glycol (10%). The main fatty acids of MYVEROL 18-99 are oleic acid (61%), linoleic acid (21%), linolenic acid (9%) and palmitic acid (4%). Suitably in such long-chain monoglycerides, the major fatty acid component is a C \ g-saturated, monounsaturated or polyunsaturated fatty acid, preferably a C\ g-monounsaturated or polyunsaturated fatty acid. Suitably the monoglyceride will have an HLB value in the range of about 2.5 to 6. The HLB value of the product MYVEROL 18-99 is 3.7.

In the present invention the amphiphilic substance is preferably glyceryl mono- oleate (mono-olein). As indicated above, in its commercially available form, glyceryl mono-oleate is a material which is predominantly glyceryl mono-oleate but also contains minor amounts of related mono and di-glycerides. Accordingly, the amount that is effective in a particular spray formulation will vary dependent on the level of glyceryl mono-oleate in the commercial material used. To obtain a sprayable formulation, the amphiphilic substance is combined with a liquid diluent. The diluent is selected on the basis of compatibility e.g. producing a stable blend with the amphiphilic agent, and the ability to achieve a sprayable blend without excessive dilution that will reduce the self-association on contact with water and detract from the desired viscosity increase. Typically, a diluent is a pharmaceutically acceptable oil, most preferably a fatty acid triglyceride, typically vegetable (i.e. plant derived) oil, since mineral oils such as paraffin oil have been implicated in undesirable side effects when inhaled. Suitable vegetable oils include coconut oil, sesame oil and soya bean oil. In this invention, the preferred diluent is a vegetable oil, most preferably coconut oil, that has been fractionated so that it is predominantly medium chain length triglycerides. Typically the proportion of amphiphilic agent to oil is from 2:1 to 1 :4, preferably 1 : 1 to 1 :2. Ideally, the amount of diluent is adjusted so that the formulation is of a viscosity that is suitable for spray delivery at 20°C or above.

Suitable medium-chain fatty acid triglycerides for use in the present invention may be of natural, semi-synthetic or synthetic origin and may include blends of different medium chain fatty acid triglycerides. The term "medium-chain fatty acid" as used herein refers to a fatty acid having from 6 to 12, preferably 8 to 10 carbon atoms which may be branched or unbranched, preferably unbranched and which may be optionally substituted. Certain neutral plant oils, such as fractionated coconut oils, provide convenient sources of

- 9 - medium-chain fatty acid triglycerides. The triglyceride suitably comprises from 50 to 100% (w/w) of caprylic (Cg) acid and from 0 to 50% (w/w) of capric (CI Q) acid triglycerides. Suitable examples include those available under the trade names MYRITOL; CAPTEX (Karlshams Lipid Specialties, Columbus OH), for instance CAPTEX 355, CAPTEX 300, CAPTEX 350, CAPTEX 850 and CAPTEX 8000; MIGLYOL (BASF), for instance the grades MIGLYOL 810, MIGLYOL 812 AND MIGLYOL 818 (which also comprises a linoleic acid triglyceride) and MAZOL 1400 (Mazer Chemical, Guernee, II). The fatty acid content of representative products is: CAPTEX 355™ - CAPROIC ACID (2%), CAPRYLIC ACID (55%) and capric acid (42%); CAPTEX 8000 - at least 98% caprylic acid, MYGOL 810 - caproic acid (2%), caprylic acid (65-75%), capric acid (25-35%) and MIGLYOL 812 - caproic acid (3%), caprylic acid (50-65%), capric acid (30-45%) and lauric acid (5%) (manufacturer's data).

In the present formulations, the drug substance is used at between 2 and 8%, suitably between 3 and 5%, typically about 4%, by weight of the formulation. It is preferred to use a relatively high dosage level, to reduce the risk of the development of bacterial resistance. Also, to avoid excessive delivery volumes which will be uncomfortable in nasal administration, the drug substance is preferably present at a relatively high loading compared to other topical administration formulations.

The oily spray formulations are especially suitable for delivery to and residence within the nasopharynx, because in the humid environment of the nasal passages they increase in viscosity by contact with water, and so are better able to resist wash-out when in contact with nasal surfaces.

Other sprayable formulations for use in the present invention include solutions of drug substance in aqueous polyethylene glycol. Such sprays may be conveniently prepared on an extemporaneous basis by diluting a pharmaceutical composition comprising drug substance in polyethylene glycol, or a derivative thereof, with an aqueous solution, for instance water, or, preferably, a saline solution. Suitable such compositions are described in EP 0 095 897-A2 (Beecham Group). Suitably, the pharmaceutical composition comprises from 0.01 to 50% drug substance in polyethylene glycol, suitably a mixture of polyethylene glycol 400 and polyethylene glycol 4000. In a representative example, the pharmaceutical composition comprises 2% drug substance in mixture of polyethylene glycol 400 (59%) and polyethylene glycol 4000 (39%). Suitably, the composition is diluted with aqueous solution in a ratio of from 1 :1 to 1 :20, more suitably 1 :5 to 1 :15, preferably about 1 :9 to 1 :10. Suitably, in the nasal spray, drug substance is incorporated at between 0.01 and 1%, suitably 0.1 to 0.5% by weight of the composition. Suitably such aqueous compositions comprising drug substance are stored at about 5°C and are not stored for prolonged periods.

- 10 - The formulation and aqueous solution for the extemporaneous preparation of the nasal spray may be conveniently provided in a kit. Accordingly, in a further aspect, the present invention provides for a kit comprising, in a first part, a pharmaceutical formulation comprising drug substance in polyethylene glycol, or a derivative thereof, as hereinbefore described, and, in a second part, an aqueous solution. The first and second parts may be supplied in separate containers or in single container with the two parts separated by a barrier which is removed or broken prior to use. Suitably the kit includes a container adapted for use as a nasal spray device.

Further suitable formulations include creams adapted for focussed delivery to the nasopharynx. Such formulations with appropriate viscosity characteristics may be provided in containers adapted for nasal administration, for instance having an extended nozzle.

According, in a further aspect, the present invention provides a pharmaceutical formulation consisting essentially of 2 - 8 % by wt. of drug substance;

50 - 70 % by wt. of a fatty acid triglyceride; 2 - 6 % by wt. of a polyoxyethylene ether or ester surfactant; 2 - 4 % by wt. of a fatty alcohol or ester; 30 - 40 % by wt. of water; and up to 2 % by wt. of conventional additive such as preservatives and flavourings.

For nasal administration the issue of patient comfort is important in compliance with the intended treatment regime. The formulation of this invention provides a low viscosity cream that is easy to administer and which readily changes in consistency and softens in the temperature conditions of the nose. Accordingly when inserted into the upper regions of the nose it can be transported deeper into the nasal passages by natural processes. The composition is intended to be in the form of an oil-in-water cream emulsion. In view of the large triglyceride content which provides the desired consistency for nasal administration, and the relatively low content of surfactant, the amounts of the components within the above ranges must be selected for individual components by routine trials to ensure that an oil-in-water emulsion is obtained.

The fatty acid triglycerides are typically vegetable ( i.e. plant-derived) oils, such as coconut oil, sesame oil or soya bean oil. An especially suitable vegetable oil is one that has to been fractionated so that it is predominantly medium chain length triglycerides. Suitable medium-chain fatty acid triglycerides for use in the present invention may be of natural, semi-synthetic or synthetic origin and may include blends of different medium chain fatty acid triglycerides. The term "medium-chain fatty acid" as used herein refers to a fatty acid having from 6 to 12, preferably 8 to 10 carbon atoms which may be

- 11 - branched or unbranched, preferably unbranched and which may be optionally substituted. Certain neutral plant oils, such as fractionated coconut oils, provide convenient sources of medium-chain fatty acid triglycerides. The triglyceride suitably comprises from 50 to 100% (w/w) of caprylic (Cg) acid and from 0 to 50% (w/w) of capric (C\ Q) acid triglycerides. Suitable examples include those available under the trade names MYRITOL; CAPTEX (Karlshams Lipid Specialties, Columbus OH), for instance CAPTEX 355, CAPTEX 300, CAPTEX 350, CAPTEX 850 and CAPTEX 8000; MIGLYOL (BASF), for instance the grades MIGLYOL 810, MIGLYOL 812 AND MIGLYOL 818 (which also comprises a linoleic acid triglyceride) and MAZOL 1400 (Mazer Chemical, Guernee, II). The fatty acid content of representative products is: CAPTEX 355™ - CAPROIC ACID (2%), CAPRYLIC ACID (55%) and capric acid (42%); CAPTEX 8000 - at least 98% caprylic acid, MYGOL 810 - caproic acid (2%), caprylic acid (65-75%), capric acid (25-35%) and MIGLYOL 812 - caproic acid (3%), caprylic acid (50-65%), capric acid (30-45%) and lauric acid (5%) (manufacturer's data). The polyoxyethylene ether or ester used in this invention is one which will function as a non-ionic surfactant. Especially suitable materials include polyoxyethylene glycol monocetyl ethers, such as Cetomacrogol 1000. Other suitable non-ionic surfactants include:

(a) polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid esters of the type available under the trade name MYRJ (ICI Americas, Inc.), for instance the product MYRJ 52 (a polyoxyethylene 40 stearate);

(b) polyoxyetheylene-sorbitan fatty acid esters (polysorbates), for example the mono- and tri-lauryl, palmityl, stearyl and oleyl esters, for instance the polyoxyethylene sorbitan monooleates available under the trade name of TWEEN (ICI Americas Inc.), such as TWEEN 20, 21, 40, 60, 61, 65, 80, 81 and 85, of which class TWEEN 80 is especially preferred;

(c) polyoxyethylene glycol long-chain alkyl ethers, such as polyoxyethylated glycol lauryl ether; and

(d) polyoxyethylene glycol long-chain alkyl esters, such as PEG-monostearate. For use herein, the surfactant preferably has an HLB value in the range of 13 to

20.

As fatty alcohol or ester there may be used any of such materials conventionally used in pharmaceutical or veterinary formulations such as stearyl alcohol, cetyl alcohol, cetyl stearyl alcohol, myristyl alcohol and glycerin monostearate. Preferably, cetostearyl alcohol is used, or a mixture of stearyl alcohol and cetyl alcohol.

A particularly preferred low viscosity cream vehicle formulation comprises fractionated coconut oil (typically about 55 to 60, especially about 57, parts by weight); polyoxyethylene glycol monocetyl ether (typically about 2 to 4, especially about 3, parts

- 12 - by weight); cetostearyl alcohol (typically about 2 to 4, especially about 3, parts by weight); with water for emulsification, and also preservatives, and flavourings if desired. Typical preservatives include benzyl alcohol and phenoxyethanol. In the formulation of this invention the drug substance is used at between 2 and 8%o, suitably between 3 and 5%, typically about 4%, by weight of the formulation. It is preferred to use a relatively high dosage level, to reduce the risk of the development of bacterial resistance. Also, to avoid excessive delivery volumes which will be uncomfortable in nasal administration, the drug substance is preferably present at a relatively high loading compared to other topical administration formulations. The formulation may typically be administered into the nasal passages by a pump, such as an air lift pump. This may be adapted for nasal administration by addition of a modified nozzle.

Formulations of this invention may be produced by conventional pharmaceutical techniques. Thus, for example, the components of the carrier may be blended by mixing together at an elevated temperature until an emulsion has formed. The mixture may then be cooled to room temperature, and, after the addition of any further optional ingredients, stirred to ensure adequate dispersion. The antibiotic may be added during hot preparation of the base, or may be added with additional ingredients after cooling of the base. If necessary the composition may be provided in sterile condition. Optional ingredients that may be added if desired include colourings and flavourings.

The invention is illustrated by the following Examples.

13 Example 1 - Spray Formulation

A carrier for a nasal spray formulation was prepared by forming a blend of 67% w/w fractionated coconut oil (medium chain length)* and 33% w/w of glyceryl monooleate **. To this blend was added 0.2% w/w of powdered lemon juice flavour, followed by 4% w/w of micronized drug substance***.

The resultant formulation has a viscosity which is sprayable at 20°C or above. When sprayed into the nose of a patient, the liquid coats the nasal passages and contact with moisture inside the nose (from the mucous membranes, and the humid environment generally) causes the carrier to thicken. This prolongs the residence time of the sprayed formulation on the nasal surfaces. A spray volume of about 125 μl contains approximately 5 mg drug substance. * Commercial product Miglyol, obtainable from Hϋls ** Commercial product Myverol 18-99, obtainable from Eastman

Example 2 - cream

An oil-in-water emulsion cream was prepared from the following:

Drug substance * * * 4% Fractionated Coconut Oil* 57.3%

Polyoxyethylene glycol monocetyl ether 3%

Cetostearyl alcohol 3%

Benzyl Alcohol 1%

Phenoxy ethanol 0.5% Water 35%

Lemon j uice flavour (powdered) 0.2%

* Commercial product Miglyol, obtainable from BASF

Example 3 - Aqueous Spray formulation

Component % Purpose

Drug 0.001-1.00 Active Sodium Chloride 0.5-0.9 Tonicity modifier

Benzalkonium chloride 0.02 Preservative Disodium edetate 0.1 Preservative/ chelatingagent

Polysorbate 80 0.2 Surfactant solubiliser

- 14 - Sodium dihydrogen orthophosphate 0.2 Buffer

Water qs Carrier

Hydrochloric acid and sodium hydroxide were used to adjust the pH of the composition to about pH 5.5. The drug molecule shows optimum stability at this pH.

***Drug substance was as described in any one of the Examples of WO 97/25309 or WO 98/05659

- 15

Claims

1. The use of pleuromutilin or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prophylactic treatment of bacterial infection associated with colonisation of the nasopharynx by pathogenic organisms, and in which the medicament is adapted for administration to, and residence within, the nasopharynx.

2. A use as claimed in claim 1 in which the bacterial infection is recurrent otitis media or recurrent sinusitis.

3. The use of pleuromutilin or a pharmaceutically acceptable derviative thereof in the manufacture of a medicament adapted for administration to the nasopharynx for the prophylactic treatment of recurrent otitis media or recurrent sinusitis.

4. The use of pleuromutilin or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for reducing or eliminating the nasal carriage of pathogenic organisms associated with recurrent otitis media or recurrent sinusitis, which medicament is adapted for nasal administration.

5. The use of pleuromutilin or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament which is administered to the nasopharynx of a patient in need thereof on an intermittent basis.

6. A use as claimed in claim 5 in which the medicament is administered on a daily basis, for 2 to 10 days, and then repeated on a monthly basis.

7. A use as claimed in any one of the preceding claims in which drug substance is administered at a dosage of from 1 to lOmg in each nostril, once or twice a day.

- 16 -