Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-02-04
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
06777399
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.
We have now identified a novel glucocorticoid compound and a crystalline composition thereof which substantially meets these objectives.
SUMMARY OF THE INVENTION
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 12.1±0.6 Å, 14.9±0.7 Å, and 16.2±0.8 Å when determined at either 120K or 150K (hereinafter “a composition of the invention”)
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 4 guests within a single unit cell for two example compositions and FIG.
2
A and
FIG. 2B
which shows detail of the spacial arrangment between steroid and guest molecule for the same two example compositions.
We have determined the XRPD profiles for a large 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 5 features when determined at ambient temperature (eg around 295K):
(a) A peak in the range of around 7.8-8.2; and
(b) A peak in the range of around 8.8-9.6; and
(c) A peak in the range of around 10.5-11.1
(d) A peak in the range of around 15.0-15.8
(e) A peak, often (but not always) associated with a pair of peaks, in the range of around 21.2-21.8
Typically they exhibit 2 or more typically 3 or more of the above 5 features, especially 4 and particularly all 5 of the above 5 features.
The XRPD profiles of compositions of the invention when crystallographically pure also preferably exhibit one or more of the following 2 features when determined at ambient temperature (eg around 295K):
(a) Absence of a peak at around 7 (eg around 6.8-7.4) which is associated with the profile of unsolvated Form 1, 2 and 3 polymorphs and present at particularly high intensity in Forms 2 and 3;
(b) Absence of a peak at around 11.5 (eg around 11.3-11.7) which is associated with the profile of unsolvated Form 1 polymorph (all figures are in degrees 2Theta).
Preferably both 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 very wide range of guest molecules.
The guest molecule preferably has a relative molecular weight in the range 16 to 150, more preferably 16 to 100, especially 40 to 100. 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.
The guest molecule preferably contains a moiety capable of acting as a hydrogen bond acceptor. Examples of moieties capable of acting as a hydrogen bond acceptor include carbonyl, sulphoxide, ether, —OH and amine groups (whether primary, secondary or tertiary amine groups) which moieties may form part of a carboxylic acid, ester or amide group. Moieties thioether and —SH may also be contemplated but are less preferred. Crystallographic studies have shown that a hydrogen bond acceptor on the guest is capable of interacting with the hydrogen atom of the C11 hydroxy on the compound of formula (I) thereby assisting the stabilisation of the crystal lattice (see in particular FIG.
2
A and FIG.
2
B). It is not ruled out that in some cases a hydrogen bond donor on the guest (eg the hydrogen atom of an —OH moiety) may be capable of interacting with the hydrogen bond acceptor on the compound of formula (I) thereby assisting the stabilisation of the crystal lattice.
Examples of suitable guest molecules include solvents e.g.:
amide moiety containing substances such as: dimethyl acetamide, dimethyl formamide, N-methyl-2-pyrrolidinone;
carbonyl moiety containing substances such as: acetone, methylethylketone, cyclopentanone;
sulphoxides such as dimethylsulphoxide;
alcohols such as: ethanol, butan-1-ol, propan-1-ol, propan-2-ol;
ethers such as: 1,4-dioxane, tetrahydrofuran;
esters such as: ethylformate, methylacetate;
carboxylic acids such as: acetic acid; water.
An example of a solid guest molecule is &egr;-caprolactam.
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.
In one sub-aspect of the invention, the composition is not an essentially stoichiometric composition containing as guest molecule one of the following:
acetone, dimethylformamide, dimethylacetamide, tetrahydrofuran, N-methyl-2-pyrrolidinone, propan-2-ol (isopropanol) or methylethylketone,
more particularly the composition is not a composition containing as guest molecule
Biggadike Keith
Coote Steven John
Craig Andrew S.
Crowe David M.
Jacewicz Victor W
Riek James P.
SmithKline Beecham Corporation
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