ZA200400845B - Surfactant compounds and uses thereof. - Google Patents

Description

Surfactant Compounds and Uses Thereof

This invention relates to novel surfactants and aerosol formulations thereof for use in the ) administration of medicaments by inhalation. , The use of aerosols to administer medicaments has been known for several decades.

Such aerosols generally comprise the medicament, one or more chlorofluorocarbon propellants and either a surfactant or a co-solvent, such as ethanol. The most commonly used aerosol propellants for medicaments have been propellant 11 (CCI3F) and/or propellant 114 (CF2CICFoCl) with propellant 12 (CCIoF2). However, these propellants are now believed fo provoke the degradation of stratospheric ozone and there is thus a need to provide aerosol formulations for medicaments which employ so called "ozone-friendly" propellants.

A class of propellants which are believed to have minimal ozone-depleting effects in comparison to conventional chlorofluorocarbons comprise fluorocarbons and hydrogen- containing chloroflucrocarbons, and a number of medicinal aerosol formulations using such propellant systems are disclosed in, for example, EP0372777, W091/04011,

WO91/11173, WO91/11495 and WO91/14422. These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments and seek to overcome the problems associated with the use of the new class of propellants, in particular the problems of stability associated with the pharmaceutical formulations prepared. The applications all propose the addition of one or more of adjuvants such as alcohols, alkanes, dimethyl ether, surfactants (including fluorinated and non-fluorinated surfactants, carboxylic acids, polyethoxylates etc) and even conventional chlorofluorocarbon propellants in small amounts intended to minimise potential ozone damage.

It is essential that the prescribed dose of aerosol medication delivered from the MDI to the patient consistently meets the specifications claimed by the manufacturer and complies with the requirements of the FDA and other regulatory authorities. That is, every dose dispensed from the can must be the same within close tolerances.

Therefore, it is important that the formulation be substantially homogenous throughout * 30 the administered dose at the time of actuation of the metering valve. It is also important that the concentration of the suspension does not change significantly when stored for a ’ prolonged period.

It is particularly important that the FPM (fine particle mass) of the suspension does not significantly decrease on storage, as the FPM is a measure of the amount of drug from each dose that will reach the therapeutic target in the lung.

,

In the case of suspension formulations, to control aggregation of fine particles, and thereby influence the dispersability of the suspension it is well established in the art that fluorinated surfactants may be used to stabilise micronised drug suspensions in y fluorocarbon propellants such as 1,1,1,2-tetrafluoroethane (P134a) or 1,1,1,2,3,3,3- 5 heptafluoro-n-propane (P227), see for example US4352789, US5126123, US5376359, )

US application 09/580008, WO91/11173, WO091/14422, WO92/00062 and

WO096/09816.

W092/00061 discloses non-fluorinated surfactants for use with fluorocarbon propeliants.

Certain long chain alkanoic acids with perfluoroalkyl terminal segments including 12,12,13,13,13-pentafluorotridecanoic acid (CF3CF2(CH2);COOH) are disclosed in J.

Org. Chem. (1962) 27, 4491-4498 (Brace et al). The compounds are said to have surfactant properties in aqueous systems but no mention is made of suitability for use in pressurised aerosol formulations.

Processes for preparing trifluoromethylated organic molecules such as 12,12,12- trifluorododecanoic acid (CF3(CH,);COOH) are described in J. Org. Chem. (1984) 49, 2826-2827 (Muller), J. Fluorine Chem. (1998) 93, 107-115 (Graupe et al) and French patent application 2,613,357 (Atochem).

Certain long chain alkanoic acids with a trifluoromethyl terminus including 18,18,18- trifluorooctadecanoic acid and their use in preparing Langmuir-Blodgett fims are described in J. Am. Chem. Soc. (1999) 121, 10554-10562 (Gu et al).

Certain fluorinated alkyl and alkoxy acid compounds are disclosed in the following documents:

J. Mol. Struct. 485-486, 373-384, 1999 Publisher Elsevier Science;

Application WO 9821177,

Application EP 264080

J. Pharm. Sci., 75(10), 987-91, 1986;

Mitsui Petrochemical Industries Ltd, Japan: JP 58196247;

Application EP 021739;

Daikin Kogyo Co. Lid, Japan: JP 57018730;

J. Phys. Chem, 86(1l), 1982, 2047-9; .

J. Fluorine Chem. 12(6), 471-9, 1978;

ACS Symp. Ser., 688(Cellulose Derivatives) 315-331, 1998. Publisher American .

Chemical Society;

UKR. Khim. 2h (Russian Ed). 44(10), 1057-9, 1978;

J. Chem, Soc., C(22), 2332-2, 1967;

United States Patent 6271422;

Ind. Eng. Chem., Prod. Res. Develop, li(l), 88-91, 1972; ) United States Patent 3997072.

Surprisingly, the inventors have now found that a particular group of novel low fluorine content compounds with good surfactant properties may be used to prepare novel pharmaceutical aerosol formulations, and may be advantageous in terms of improving the stability of the aerosol formulation by reducing drug deposition, increasing reproducibility of the dose delivered and the like. In addition the compounds of the invention are adequately soluble in the fluorocarbon or hydrogen-containing chlorofluorocarbon propellants or mixtures thereof, obviating the need to use a polar adjuvant, such as ethanol.

Thus, in one aspect the invention provides a pharmaceutical aerosol formulation comprising a particulate medicament, one or more fluorocarbon or hydrogen-containing chlorofluorocarbon propellants and a compound of the general formula (1) 0

PBN (1

A OH or a salt or solvate thereof, wherein:

A represents a straight chain Cy. alkylene substituted by n groups of formula B; n represents an integer 1 to 3; and

B independently represents C, fluoroalkylCos alkylene-, C14 fluoroalkylCoy.s alkylene-O-, or C,.4 alkylCqy alkylene-O-; wherein at least one substituent of formula B contains at least one fluorine atom and each C, fluoroalkyl moiety contains one or more fluorine atoms but not more than 3 consecutive perfluorinated carbon atoms.

In one embodiment, preferably A will represent Cy.42 alkylene, particularly Cs.12 alkylene, especially Cs. alkylene, most especially Ce or Cro alkylene substituted by n groups of formula B. * The n B groups may be located at any point along the straight chain Ci.6 alkylene section. It will be understood that where the B group is not located on the terminal CH.- ' then this carbon will bear three hydrogens. Preferably a B group will be located on the terminal carbon of the C,.is alkylene section. Preferably the B group that is located on the terminal carbon is selected from Ci fluoroalkylCq.s alkylene- and Cq4 fluoroalkylCo.s alkylene-O-. The Ci fluoroalkyl and C,, alkyl moieties within B may be branched or straight chain. The Cos alkylene moiety within B may be branched or straight chain, although preferably it will be a straight chain.

Preferably each C4 fluoroalkyl- moiety contains at least two fluorine atoms, especially 3 * to 5 fluorine atoms.

More preferably C4 fluoroalkylCq.¢ alkylene- of group B represents CF.HCq.q alkylene-, *

CF3Co. alkylene-, CF3CF,Co.s alkylene, (CF;),CHC,.; alkylene- or (CF3)sCCqys alkylene-, especially CF;- or CF3CF,-.

Also more preferably C4 fluoroalkylCo.s alkylene-O- of group B represents CF3Co.q alkylene-O-, CF3CF2Co.s alkylene-O-, (CF3);CCos alkylene-O-, CF,HCy.9 alkylene-O- or (CF3),CHC,.; alkylene-O-.

Preferably the Cos alkylene moiety of Cy, fluoroalkylCos alkylene-, Ci fluoroalkylCo.e alkylene-O- or Cy4 alkylCo. alkylene-O- in group B represents Co., alkylene, especially

Co.1 alkylene.

More preferably, B represents C,.4 fluoroalkylCo.; alkylene-, particularly Cy. fluoroalkylCo. » alkylene, more particularly C..4 fluoroalkylCo.; alkylene, especially C,_4 fluoroalkyl.

The invention includes branched compounds of formula (I) wherein n represents 2 or 3.

Preferably n represents 1 or 2, especially 1.

In particular there is provided a pharmaceutical aerosol formulation comprising a compound of the general formula (la) 0 pon m or a salt or solvate thereof, wherein: m represents an integer 1 to 16; and

R'@ represents Ci. fluoroalkylCq alkylene- or Cy fluoroalkylCo. alkylene-O- wherein each C,., fluoroalkyl moiety contains one or more fluorine atoms but not more than 3 consecutive perfluorinated carbon atoms.

In one aspect of the invention preferably R' represents C4 fluoroalkyiCo.s alkylene, especially C, fluoroalkyl, for example, containing at least 3 fluorine atoms e.g. 310 5 . fluorine atoms, particularly CFz- or CF3CF2-.

Preferably in this aspect m represents an integer in the range 3 to 12, especially 6 to 10 ‘ or 8 to 12, particularly 9 or 10.

More particularly the invention extends to a pharmaceutical aerosol formulation comprising a compound of the formula (Ib) . O ) EEE (1b)

Eo on or a salt or solvate thereof, wherein: n' represents an integer 1 to 9; n? represents an integer 1 to 8; and

R? represents Cy; fluoroalkyl wherein said moiety contains one or more fluorine atoms.

Preferably R? contains 3 to 5 fluorine atoms, and especially represents CF; or CF3CFo.

Preferably n' represents an integer in the range 1 to 6, especially 1 to 5 particularly 1.

Preferably n° represents an integer in the range 1 to 6, especially 3 to 6, particularly 3 or 6.

There is also provided use of compounds of formula (I) as a suspending agent in a pharmaceutical aerosol suspension formulation adapted for use in a metered dose inhaler.

Certain compounds of formula (I) are new. Therefore we provide as a further aspect of the invention a compound of formula (1) or a salt or solvate thereof with the proviso that it is not 12,12,13,13,13-pentafluorotridecanoic acid (CF3CF5(CH,)1cCOOH) or 12,12,12- trifluorododecanoic acid (CF3(CH2)10COOH).

Preferably in the compounds of formula (I) the Cs. fluoroalkyl moiety contains 3 to 5 fluorine atoms, especially wherein the fluorine atoms are located on adjacent carbon atoms, particularly CFa- or CFsCFo-.

Preferably for these compounds n represents 1.

Preferably B is located on the terminal carbon of the C1.16 alkylene section of the moiety

A.

A preferable series of novel compounds according to the invention are provided of the general formula (la’)

Oo . wg ph (1a")

R ~~ “OH or a salt or solvate thereof, wherein: m represents an integer 1 to 16; and

R'® represents Ci fluoroalkylCo.s alkylene- or Ci fluoroalkylCo.s alkylene-O-

, wherein each C4 fluoroalkyl moiety contains at least 3 fluorine atoms but not more than 3 consecutive perfluorinated carbon atoms with the proviso that: (i) when R'™ represents C. fluoroalkylCq. alkylene the compound of formula (la’) . represents something other than: 5 CF3CF3(CH»)10COOH,; v

CF3(CH.);COOH;

F.CHCF,CF,CH,COOH,;

CF3CHFCF,(CH.),COOH,;

CF3;CH(CH;)CH,COOH

CF3CH(CH3)(CH2)sCOOH,;

CF3CH(CH,CH,)CH,COOH; or

CF3;CH,CH(CH3)CH,COOH wherein q represents an integer 10 or 16; and r represents 3 fo 5 or 11 (i) when R' represents C,4 fluoroalkyCos alkylene-O- the compound of formula (1a’) represents something other than:

CF3CH,0O(CH,),COOH,;

CF3(CH,),0O(CH,),COOH

F,CH(CF,)3CH,O(CH;),COOH;

F,CH(CF,);CH,OCH,COOH;

CF3CH(CH3)O(CH_.),COOH (CF3),CHOCH,COOH;

CF3;CH,; CH,OCH,COOH,;

CF3OCH,COOH,

F,CHCF,CH,OCH,COOH; or

CF3C(F)HCF.CH,OCH,CH,COOH wherein y represents an integer 1, 10 or 15.

Preferably m represents an integer 3 to 12, especially 6 to 10, particularly 9 or 10.

Equally preferable is wherein m represents C;o alkylene or Cyiis alkylene, more preferably Cs, Co, C11 OF Cy, alkylene, especially Cy or C44 alkylene.

Preferably R'® represents Cy fluoroalkyl- or C4 fluoroalkyl-O-. .

More preferably R'™ represents CF,H-Co., alkylene- CF;Co. alkylene-, CF3;CF2Co, alkylene-, (CF3),CHCq.s alkylene-, (CF3)sC-, CFzHCo. alkylene-O-, (CF3);C-O-, } (CF3),CHC,.1 alkylene-O-, CF3Co.; alkylene-O- or CF3CF2Co-2 alkylene-O-.

Especially preferred groups for R' are selected from CF,H, CF3, CFsCF,, CF3CF.CH,, (CF3):CH and (CF;)3C, particularly CF; and CFsCF.

In a first preferred subset of the series of compounds of formula (la’) are provided the compounds of the general formula (laa) , @]

SEIT (laa) m or a salt or solvate thereof, wherein: m represents an integer 1 to 16; and

R'® represents CF3 or CFsCF..

In this first series preferably m represents an integer in the range 7 to 9 or 11 to 15, especially 8, 9, 11 or 12, particularly 9 or 11.

In a second preferred subset of the series of compounds of the formula (la’) are provided compounds of the formula (Ib’) 0 otro

On Ton or a salt or solvate thereof, wherein: n' represents an integer 1 to 9; n? represents an integer 1 to 8; and

R? represents Ci. fluoroalkyl wherein said moiety contains one or more fluorine atoms.

Preferably n' represents 1 to 6, especially 1 to 5, particularly 1.

Preferably n° represents 1 to 6, particularly 3 to 6, especially 3, more especially 6.

Preferably R? represents —CF5 or ~CF,CF3, more preferably ~CF.CF.

Generally when R? represents CFs, in compounds of formula (Ib), compounds of particular interest are those wherein n' represents an integer in the range 3 to 9 and n? represents an integer in the range 3 to 8.

Generally when R? represents CF3;CF», in compounds of formula (Ib’), compounds of particular interest are those wherein n' represents an integer in the range 1 to 9 and n’ ) represents an integer in the range 1 to 8.

Suitable salts include alkali metal salts such as sodium and potassium and tertiary alkyl ammonium salts such as tert-butyl ammonium.

Preferably compounds of formula (1), (I'), (1a), (1a’), (laa) (Ib) and (Ib’) will be present as the free acid.

Compounds of formula (I) may contain one or more chiral centres. it will be understood that compounds of formula (1) include all optical isomers of the compounds of formula (1) and mixtures thereof, including racemic mixtures thereof. .

The compounds of formula (I) employed for the preparation of formulations according to the present invention are effective stabilisers of aerosol suspension formulations at low ’ concentrations relative to the amount of medicament. Thus, the amount of compound of formula (I) employed is desirably in the range of 0.05% to 20% w/w, particularly 0.5% to 10% w/w, more particularly 0.5% to 5% w/w, relative to the medicament.

The particle size of the particulate (e.g. micronised) medicament should be such as to permit inhalation of substantially all of the medicament into the lungs or nasal cavity upon administration of the aerosol formulation and will thus be less than 100 microns, desirably less than 20 microns, and preferably will have a mass median aerodynamic diameter (MMAD) in the range 1-10 microns, e.g. 1-5 microns.

The final aerosol formulation desirably contains 0.005-10% w/w, preferably 0.005 - 5% w/w, especially 0.01-1.0% w/w, of medicament relative to the total weight of the formulation.

Medicaments which may be administered in aerosol formulations according to the invention include any drug useful in inhalation therapy and which may be presented ina form which is substantially completely insoluble in the selected propellant. Appropriate medicaments may thus be selected from, for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate (e.g. as sodium salt), ketotifen or nedocromil (e.g. as sodium salt); anti-infectives e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; anti-histamines, e.g., methapyrilene; anti-inflammatories, e.g. beclomethasone (e.g. as dipropionate), fluticasone (e.g. as propionate), flunisolide, budesonide, rofleponide, mometasone furoate, ciclesonide, triamcinolone acetonide or 6a, 9a-difluoro-11p3-hydroxy-16a-methyi-3-oxo-17a- propionyloxy-androsta-1,4-diene-17p-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester: anti-tussives, e.g., noscapine; bronchodilators, e.g., albuterol (e.g. as free base or sulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline, fenoterol (e.g. as . hydrobromide), formoterol (e.g. as fumarate), isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (e.g. as acetate), reproterol (e.g. as . hydrochloride), rimiterol, terbutaline (e.g. as sulphate), isoetharine, tulobuterol, 4- hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyllsulfonyl]ethyllamino]ethyl-2(3H)-benzothia- zolone; diuretics, e.g., amiloride; anticholinergics, e.g. ipratropium (e.g. as bromide),

tiotropium, atropine or oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthines, e.g. aminophylline, choline theophyllinate, lysine theophyllinate ’ or theophylline; therapeutic proteins and peptides, e.g. insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be ’ 5 used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise the activity and/or stability of the medicament and/or to minimise the solubility of the medicament in the propellant. It will be further clear to a person skilled in the art that where appropriate the medicaments may be used in the form of a pure isomer, for example, R-albuterol, R- salmeterol or RR-formoterol.

Particularly preferred medicaments for administration using aerosol formulations in accordance with the invention include anti-allergics, bronchodilators and anti- inflammatory steroids of use in the treatment of respiratory disorders such as asthma,

COPD or rhinitis by inhalation therapy, for example cromoglycate (e.g. as sodium salt), albuterol (e.g. as free base or the sulphate), salmeterol (e.g. as xinafoate), formoterol (e.g. as fumarate), terbutaline (e.g. as sulphate), reproterol (e.g. as hydrochloride), a beclomethasone ester (e.g. as diproprionate), a fluticasone ester (e.g. as propionate).

Salmeterol, especially salmeterol xinafoate, albuterol sulphate, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof are especially preferred.

It will be appreciated by those skilled in the art that the aerosol formulations according to the invention may, if desired, contain a combination of two or more active ingredients.

Thus suitable combinations include bronchodilators (e.g. albuterol or isoprenaline) in combination with an anti-inflammatory steroid (e.g. beclomethasone ester); a bronchodilator in combination with -an anti-allergic (e.g. cromoglycate). Exemplary combinations also include: ephedrine and theophylline; fenoterol and ipratropium (e.g. as bromide); isoetharine and phenylephrine; ipratropium (e.g. as bromide) and salmeterol (particularly as xinafoate); albuterol (e.g. as free base or as sulphate) and beclomethasone ester (e.g. as dipropionate); budesonide and formoterol (e.g. as : 30 fumarate) which is of particular interest; and salmeterol (particularly as xinafoate) and fluticasone ester (e.g. as propionate) also of particular interest. . The propellants for use in the invention may be any fluorocarbon or hydrogen- containing chlorofluorocarbon or mixtures thereof having a sufficient vapour pressure to render them effective as propellants. Preferably the propellant will be a non-solvent for the medicament. Suitable propellants include, for example, C1.4hydrogen-containing

Claims (15)

PCT/GB02/03586 Claims:

1. A pharmaceutical aerosol formulation comprising a particulate medicament, one or more fluorocarbon or hydrogen-containing chlorofluorocarbon propellants and [(7,7,8,8,8- pentafluorooctyl)oxy] acetic acid or a salt or solvate thereof.

2. A pharmaceutical aerosol formulation according to claim 1 where [(7,7,8,8,8- pentafluorooctyl)oxy] acetic acid is present as the free acid.

3. A pharmaceutical aerosol formulation according to claim 1 or 2 wherein the fluorocarbon propellant is selected from 1,1,1,2- tetrafluoroethane, or 1,1,1,2,3,3,3- heptafluoro-n-propane or mixtures thereof.

4. A pharmaceutical aerosol formulation according to claim 3 wherein the propellant is 1,1,1,2- tetrafluoroethane.

5. A pharmaceutical aerosol formulation according to any one of claims 1 to 4 wherein the particulate medicament is selected from albuterol or a physiologically acceptable salt thereof, fluticasone propionate or a physiologically acceptable solvate thereof, salmeterol or a physiologically acceptable salt thereof.

6. A pharmaceutical aerosol formulation according to any one of claims 1 to 5 wherein the formulation comprises a further medicament.

7. A pharmaceutical aerosol formulation according to claim 6 which comprises salmeterol or a physiologically acceptable salt thereof in combination with fluticasone propionate or a physiologically acceptable solvate thereof.

8. [(7,7,8,8,8-pentafluorooctyl)oxylacetic acid or a salt or solvate thereof. .

9. Use of [(7,7,8,8,8-pentafluorooctyl)oxy]acetic acid or a salt or solvate thereof as a suspending agent in a pharmaceutical aerosol suspension adapted for use in a metered dose inhaler. AMENDED SHEET

PCT/GB02/03586

10. A process for the preparation of [(7,7,8,8,8-pentafluorooctyl)oxy]acetic acid which comprises reacting 6-(pentafluoroethyl)hexan-1-ol with ethyl bromoacetate.

11. A formulation according to any one of claims 1 to 7, substantially as herein described and illustrated.

12. A compound according to claim 8, substantially as herein described and illustrated.

13. Use according to claim 9, substantially as herein described and illustrated.

14. A process according to claim 10, substantially as herein described and illustrated.

15. A new formulation, a new compound, a new use of a compound as defined in claim 9 or a salt or solvate thereof, or a new process for the preparation of a compound, oo substantially as herein described. AMENDED SHEET