Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-09-11
2004-08-17
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C540S114000
Reexamination Certificate
active
06777400
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel composition containing an anti-inflammatory and anti-allergic compound of the androstane series and to processes for its preparation. The present invention also relates to pharmaceutical formulations containing the composition and to therapeutic uses thereof, particularly for the treatment of inflammatory and allergic conditions.
BACKGROUND OF THE INVENTION
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&bgr;-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 modern steroids are very much safer than those originally introduced, it remains an object of research to produce 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.
SUMMARY OF THE INVENTION
We have now identified a novel glucocorticoid compound and a crystalline composition thereof which substantially meets these objectives.
Thus, according to one aspect of the invention, there is provided a crystalline chemical composition comprising a compound of formula (I)
in which the crystal lattice is stabilised by the presence of a guest molecule, characterised in the crystalline composition is of space group P2
1
2
1
2
1
having unit cell dimensions of about 7.7±0.6 Å, 13.7±0.7 Å, and 37±3 Å when determined at 120K (hereinafter “a composition of the invention”).
In the composition of the invention the crystalline lattice is stabilised by a hydrogen bonding interaction between the hydrogen atom of the C11 hydroxy on the compound of formula (I) with the oxygen of the C3 carbonyl on a second molecule of the compound of formula (I).
The nature of the crystal lattice can be seen by reference to
FIG. 1
which shows the spacial arrangement of 4 molecules of steroid and 8 guests within a single unit cell for an example composition. Detail of the hydrogen bond interaction between the steroid molecules is shown in FIG.
3
.
FIG. 2
shows the conformation of the steroid molecule with 2 guest molecules present.
We have determined the XRPD profiles for a number of compositions according to the invention. These XRPD profiles are also apparently characteristic of the crystalline composition according to the invention. In particular they exhibit one or more of the following 3 features when determined at ambient temperature (eg around 295K):
(a) A peak in the range of around 4.3-5.0.
(b) A peak in the range of around 6.6-6.9.
(c) A peak in the range of around 11.5-11.8.
Typically they exhibit 2 or more of the above 3 features, especially 3 of the above features.
The XRPD profiles of compositions of the invention when crystallographically pure also preferably exhibit one or more of the following 6 features when determined at ambient temperature (eg around 295K):
(a) Absence of a peak at around 7.3 (eg around 7.1-7.5) which is associated with the profile of unsolvated Form 1, 2 and 3 polymorphs;
(b) Absence of a peak at around 7.5 (eg around 7.2-7.7) which is associated with the profile of another class of compositions of compound of formula (I);
(c) Absence of a peak at around 12.5 (eg around 12.3-12.7) which is associated with the profile of unsolvated Form 1, 2 and 3 polymorphs;
(d) Absence of a peak at around 8.8-9.6 which is associated with the profile of another class of compositions of compound of formula (I);
(e) Absence of a peak at around 10.5-11.1 which is associated with the profile of another class of compositions of compound of formula (I);
(f) Absence of a peak at around 12.2-12.6 which is associated with the profile of another class of compositions of compound of formula (I).
Preferably one or more preferably both of features (a) and (b) at least are exhibited. Preferably 3 or more preferably 4, especially 5, most especially all 6 of the above 6 features are exhibited.
The chemical name of the compound of formula (I) is 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.
The compound of formula (I) and compositions thereof have potentially beneficial anti-inflammatory or anti-allergic effects, particularly upon topical administration, demonstrated by, for example, its ability to bind to the glucocorticoid receptor and to illicit a response via that receptor, with long acting effect. Hence, the compound of formula (I) and compositions thereof is useful in the treatment of inflammatory and/or allergic disorders, especially in once-per-day therapy.
Space group P2
1
2
1
2
1
is characterised by angles of 90° being present in each of the 3 axes.
We have discovered that the compound of formula (I) can form a crystalline composition of characteristic space group, unit cell dimensions and crystalline structure as evidenced by X-ray diffraction with a number of guest molecules.
The guest molecule preferably has a relative molecular weight in the range 16 to 150, more preferably 60 to 130, especially 70 to 120. Preferably the guest molecule is a liquid at ambient temperature and pressure (eg 295K, 1.013×10
5
Pa). However guest molecules which are a liquid under pressure may also be capable of acting as a guest molecule (especially under pressurised conditions). Substances which are solids at ambient temperature and pressure are also included.
Examples of suitable guest molecules include solvents e.g.:
Aromatic compounds eg benzene and substituted derivatives, especially benzene substituted with one or more (eg 1 or 2) halogen or C
1-4
alkyl groups, for example toluene, o-xylene, m-xylene, fluorobenzene, chlorobenzene, ethylbenzene.
Preferred guest molecules are pharmaceutically acceptable substances and, as described below, compositions of the invention containing them may be used in therapy. However even if the guest molecule is not pharmaceutically acceptable then such compositions may be useful in the preparation of other compositions containing compound of formula (I), for example, other compositions of the invention containing guest molecules that are pharmaceutically acceptable or compound of formula (I) in unsolvated form.
The stoichiometry of the composition will usually be such that the ratio of compound to formula (I) to guest molecule, in molar terms, is 1:5-0.25, preferably 1:3.0-0.3, more preferably 1:2.2-0.6, especially 1: 2.2-0.8.
Unusually a composition of the invention has a crystal structure which is quite distinct from that of compound of formula (I) in the absence of a guest molecule, eg. the compound of formula (I) as unsolvated polymorph Form 1 which has a space group of P2
1
(i.e. two of the axis angles are 90°) and cell dimensions of 7.6, 14.1, 11.8 Å when determined at 150K. Thus if the guest molecule is removed below a threshold level (which will differ from guest to guest) for example by heating (optionally at reduced pressure eg under vacuum) then the crystal structure of the composition starts to break down and converts to that of the structure of an unsolvated compound of
Biggadike Keith
Coote Steven John
Craig Andrew
Jacewicz Victor
Millan Michael J.
Badio Barbara P.
Riek James P.
SmithKline Beecham Corporation
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