Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-02-04
2004-09-07
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S826000
Reexamination Certificate
active
06787532
ABSTRACT:
The present invention relates to a pharmaceutical formulations containing anti-inflammatory and anti-allergic compound of the androstanes series and to processes for their preparation. The present invention also relates to therapeutic uses thereof, particularly for the treatment of inflammatory and allergic conditions.
Glucocorticoids which have anti-inflammatory properties are known and are widely used for the treatment of inflammatory disorders or diseases such as asthma and rhinitis. For example, U.S. Pat. No. 4,335,121 discloses 6&agr;, 9&agr;-Difluoro-17&agr;-(1-oxopropoxy)-11&bgr;-hydroxy-16&agr;-methyl-3-oxo-androsta-1,4-diene-
17-0
-carbothioic acid S-fluoromethyl ester (known by the generic name of fluticasone propionate) and derivatives thereof. The use of glucocorticoids generally, and especially in children, has been limited in some quarters by concerns over potential side effects. The side effects that are feared with glucocorticoids include suppression of the Hypothalamic-Pituitary-Adrenal (HPA) axis, effects on bone growth in children and on bone density in the elderly, ocular complications (cataract formation and glaucoma) and skin atrophy. Certain glucocorticoid compounds also have complex paths of metabolism wherein the production of active metabolites may make the pharmacodynamics and pharmacokinetics of such compounds difficult to understand. Whilst the modem glucocorticoids are very much safer than those originally introduced, it remains an object of research to produce new molecules and formulations of old and new molecules which have excellent anti-inflammatory properties, with predictable pharmacokinetic and pharmacodynamic properties, with an attractive side effect profile, and with a convenient treatment regime.
We have now identified a novel glucocorticoid compound and formulation thereof which substantially meets these objectives. In particular we have invented a novel glucocorticoid compound and other esters of fluticasone including fluticasone propionate.
Many millions of individuals suffer from seasonal and perennial allergic rhinitis worldwide. Symptoms of seasonal and perennial allergic rhinitis include nasal itch, congestion, runny nose, sneezing and watery eyes. Seasonal allergic rhinitis is commonly known as ‘hay fever’. It is caused by allergens which are present in the air at specific times of the year, for example tree pollen during Spring and Summer. Perennial allergic rhinitis is caused by allergens which are present in the environment during the entire year, for example dust mites, mold, mildew and pet dander.
To formulate an effective pharmaceutical nasal composition, the medicament must be delivered readily to all portions of the nasal cavities (the target tissues) where it performs its pharmacological function. Additionally, the medicament should remain in contact with the target tissues for relatively long periods of time. The longer the medicament remains in contact with the target tissues, the medicament must be capable of resisting those forces in the nasal passages that function to remove particles from the nose. Such forces, referred to as ‘mucociliary clearance’, are recognised as being extremely effective in removing particles from the nose in a rapid manner, for example, within 10-30 minutes from the time the particles enter the nose.
Other desired characteristics of a nasal composition are that it must not contain ingredients which cause the user discomfort, that it has satisfactory stability and shelf-life properties, and that it does not include constituents that are considered to be detrimental to the environment, for example ozone depletors. In the case of administration of glucocorticoids, the potential for any undesirable side effects should preferably be minimised.
Thus, according to one aspect of the invention, there is provided a pharmaceutical formulation comprising an aqueous carrier liquid having dissolved therein (a) an ester of fluticasone or a solvate thereof as medicament and (b) a solubilising agent for assisting the solubilisation of the medicament in the aqueous carrier liquid.
Preferably the ester of fluticasone is a compound of formula (I)
wherein R represents ethyl or a 5 membered heterocyclic aromatic ring containing 1 to 3 heteroatoms selected from O, N and S, optionally substituted by one or more methyl or halogen atoms or a solvate thereof.
Solvates of esters of fluticasone includes solvates with pharmaceutically acceptable solvents eg hydrates.
In a first embodiment of the invention, preferably R represents ethyl and the compound of formula (I) is fluticasone propionate.
In a second embodiment of the process, preferably R represents furan-2-yl and the compound of formula (I) has the chemical name: 6&agr;, 9&agr;-difluoro-17&agr;-[(2-furanylcarbonyl)oxy]-11&bgr;-hydroxy-16&agr;-methyl-3-oxo-androsta-1,4-diene-17&bgr;-carbothioic acid S-fluoromethyl ester.
Hitherto, nasal formulations of glucocorticoid compounds, particularly aqueous formulations of glucocorticoid compounds, have been in the form of suspensions. In such suspension products the active ingredient is suspended in the aqueous carrier in the form of finely divided particles, typically of mass median diameter (MMD) 1-5 microns. Particles of this size are typically produced by micronisation, which is a wasteful and hazardous process.
Solution formulations have advantages in that the use of micronisation processes may be avoided and also in that onset of action may be increased since it is not necessary for any dissolution process to take place before the drug enters the cells in which it acts and exerts its anti-inflammatory effect. However fluticasone esters are quite insoluble in water (typically less than 1 &mgr;g/ml) and so it might be thought that the large volumes of dilute liquid which would need to be administered to have therapeutic effect would be impractical. We have now surprisingly discovered that the presence of a solubilising agent which is preferably a surfactant, especially a surfactant selected from the group consisting of a &agr;-[4-(1,1,3,3-tetramethylbutyl)phenyl]-&ohgr;-hydroxypoly(oxy-1,2-ethanediyl) polymer (also known as a octylphenoxypolyethoxyethanol) and a 4-(1,1,3,3-tetramethylbutyl)phenol polymer with formaldehyde and oxirane significantly increases the solubility of fluticasone esters in water thus permitting acceptably concentrated solutions to be developed. The solubility of fluticasone esters in water in the presence of such a surfactant is maximised when the formulation is prepared in a particular manner as described later which forms a particular aspect of the invention.
We have also surprisingly discovered that the solubility of fluticasone esters can be increased yet further by dissolution in the aqueous carrier liquid of a hydroxyl containing organic co-solvating agent or of phosphatidiyl choline. Thus formulations including this additional component have further advantages and are preferred.
Examples of &agr;-[4-(1,1,3,3-tetramethylbutyl)phenyl]-&ohgr;-hydroxypoly(oxy-1,2-ethanediyl) polymer surfactants include those of the Triton series eg Triton X-100, Triton X-114 and Triton X-305 in which the X number is broadly indicative of the average number of ethoxy repeating units in the polymer. For example the average number of ethoxy repeating units in a series of Triton X surfactants is as follows:
Triton
Average number of ethoxy units
X-45
5
X-114
7-8
X-100
9-10
X-102
12-13
X-165
16
X-305
30
X-405
40
X-705
70
Preferably the number of repeating units in the &agr;-[4-(1,1, 3,3-tetramethylbutyl)phenyl]-&ohgr;-hydroxypoly(oxy-1,2-ethaned-iyl) polymer is around 7-70, particularly around 7-30 especially around 7-10.
4-(1,1,3,3-Tetramethylbutyl)phenol polymers with formaldehyde and oxirane typically have a relative molecular weight of 3500-5000 especially 4000-4700. An example structure is given below:
Thus as just noted, m may represent 6-8 eg 7 and n may represent 1-5, especially 3-5 eg 5. The preferred example is Tyloxapol.
Preferably the surfactant i
Biggadike Keith
Buxton Ian
Reed Kenton
Sayani Amyn P.
Badio Barbara P.
Riek James P.
SmithKline Beecham Corporation
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