Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-23
2002-03-05
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06352998
ABSTRACT:
The present invention relates to topical pharmaceutical compositions comprising a macrolide, and in particular to formulations which comprise a macrolide such as an ascomycin, a rapamycin or a compound of the FK506 class.
FK506 is a known macrolide antibiotic that is produced by
Streptomyces tsukubaensis
No 9993. It is also a potent immunosuppressant. The structure of FK506 is given in the appendix to the Merck Index, 11th Edition as item A5. Methods of preparing FK506 are described in EP 184162.
A large number of derivatives, antagonists, agonists and analogues of FK506, which retain the basic structure and at least one of the biological properties (for example immunological properties) of FK506, are now known. These compounds are described in a large number of publications, for example EP 184162, EP 315978, EP 323042, EP 423714, EP 427680, EP 465426, EP 474126, WO 91/13889, WO 91/19495, EP 484936, EP 532088, EP 532089, EP 569337, EP 626385, WO 93/5059 and the like. These compounds are termed collectively compounds of the FK506 class.
It is also known (for example from EP 315978 and EP 474126) that compounds of the FK506 class are extremely useful in the topical treatment of inflammatory and hyperproliferative skin diseases and of cutaneous manifestations of immunologically-mediated illnesses.
Ointments containing a compound of the FK506 class and solubilizing and adsorption promoting agents to dissolve the compound are disclosed in EP 474126. Various organic solvents are proposed as solubilizing and adsorption promoting agents. However the compositions disclosed in EP 474126 are oil based compositions and do not contain water.
Compositions that contain water have been reported in the literature and FK506 compounds have also been formulated as fine suspensions (EP 484936).
It has now been surprisingly found that compounds of the FK506 class can be formulated into stable emulsions. Emulsions, since they contain an aqueous phase, are much less occlusive than oil-based compositions and hence are better tolerated in many situations.
Accordingly, in one aspect, this invention provides a topical composition, in the form of an emulsion, that comprises a compound of the FK506 class; a physiologically acceptable alkanediol, ether diol or diether alcohol containing up to 8 carbon atoms as solvent for the compound of the FK506 class; an unsaturated fatty alcohol and water.
This topical composition is effective, well tolerated on the skin, and reasonably to extremely stable.
In this specification, “a compound of the FK506 class” is a compound which has the same basic structure as FK506 and which has at least one of the biological properties of FK506 (for example immunosuppressant properties). The compound may be in free base form or pharmaceutically acceptable, acid addition, salt form. Examples of compounds of the FK506 class are compounds of the formula I
in which:
each adjacent pair of R
1
and R
2
, R
3
and R
4
, and R
5
and R
6
independently (a) is a pair of H atoms but R
2
may also be alkyl or (b) forms a second bond between the carbon atoms to which they are attached;
R
7
is H, OH, a protected OH group, a formyloxy group or an alkoxy group, or R
7
together with R
1
forms an oxo group;
R
8
and R
9
are independently H or OH;
R
10
is H, an alkyl group, an alkyl group substituted by one or more OH groups, an alkenyl group, an alkenyl group substituted by one or more OH groups, or an alkyl group substituted by an oxo group;
X
1
is H or OH;
X
2
is H; or
X
1
and X
2
together are an oxo group or —CH
2
O—;
Y
1
is H or OH;
Y
2
is H; or
Y
1
and Y
2
together are an oxo group, N—NR
11
R
12
or N—OR
13
;
R
11
and R
12
independently are H, an alkyl group, an aryl group or a tosyl group;
R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
22
, and R
23
are independently H, or an alkyl group;
R
24
is an optionally substituted ring system which may contain one or more heteroatoms;
n is 1, 2 or 3;
or Y
1
, Y
2
, R
10
and R
23
, together with the carbon atoms to which they are attached, are a saturated or unsaturated 5- or 6-membered nitrogen, sulphur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from alkyl, OH, alkoxy, benzyl, —CH
2
Se(C
6
H
5
) and alkyl substituted by one or more OH groups; in free base or in acid addition form.
Preferably R
24
is selected from (a) a 3,4-di-oxo-cyclohexyl group, (b) a 3-R
20
-4-R
21
-cyclohexyl group in which R
20
is OH, an alkoxy group, or a —OCH
2
OCH
2
CH
2
OCH
3
group, and R
21
is OH, —OCN, an alkoxy group, a —OCH
2
OCH
2
CH
2
OCH
3
group, a protected hydroxy group, chloro, bromo, iodo, methylthiomethoxy, isobutanoyloxy, aminooxalyloxy, an azido group, p-tolyloxythiocarbonyloxy or R
25
R
26
CHCOO— in which R
25
is optionally protected hydroxy or optionally protected amino and R
26
is H or methyl, or R
20
and R
21
together form an oxygen atom in an epoxide ring, or (c) a 5- or 6-membered cycloalkyl group which may be optionally substituted. For example R
24
may be a cyclopentyl group substituted by methoxymethyl, optionally protected hydroxymethyl, acyloxymethyl (in which the acyl moiety optionally contains either a dimethylamino group which may be quaternized, or a carboxy group which may be esterified), or one or more amino and/or hydroxy groups which may be protected, or aminooxalyloxymethyl. A preferred example is a 2-formyl-cyclopentyl group.
Suitable alkyl groups, alkenyl groups, aryl groups, protecting groups and acyl groups are defined in EP 484936.
The macrolide used in the compositions of the present invention preferably has immunosuppressant properties. The macrolide may be rapamycin or an O-substituted derivative in which the hydroxy in position 40 of formula A illustrated at page 1 of WO 95/16691, incorporated herein by reference, is replaced by —OR
1
in which R
1
is hydroxyalkyl hydroalkoxyalkyl, acylaminoalkyl and aminoalkyl; for example 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin and 40-O-(2-acetaminoethyl)-rapamycin. These O-substituted derivatives may be produced by reacting Rapamycin (or dihydro or deoxorapamycin) with an organic radical attached to a leaving group (for example RX where R is the organic radical which is desired as the O-substituent, such as an alkyl, allyl, or benzyl moiety, and X is a leaving group such as CCl
3
C(NH)O or CF
3
SO
3
) under suitable reaction conditions. The conditions may be acidic or neutral conditions, for example in the presence of an acid like trifluoromethanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid or their respective pyridinium or substituted pyridinium salts when X is CCl
3
C(NH)O or in the presence of a base like pyridine, a substituted pyridine, diisopropylethylamine or pentamethylpiperidine when X is CF
3
SO
3
.
A preferred compound is 40-0-(2-hydroxy)ethyl rapamycin (hereinafter compound A) as disclosed in WO 94/09010.
A preferred compound of the FK 506 class is disclosed in EP 427 680, e.g. Example 66a (also called 33-epi-chloro-33-desoxyascomycin) hereinafter compound B. Other preferred compounds of the FK 506 class are disclosed in EP 465 426, EP 569 337, and in EP 626 385, for example the compound of Example 6d in EP 569 337 hereinafter compound C, or the compound of Example 8 of EP 626385 hereinafter compound D.
Examples of alkanediol solvents which are capable of dissolving compounds of the FK506 class are propylene glycol (1,2-propanediol), butylene glycol, 2-ethyl-1,3-hexanediol, hexylene glycol (2-methyl-2,4-pentanediol) and the like. Examples of ether diol solvents are dipropyleneglycol, diethyleneglycol and the like. Examples of diether alcohol solvents are diethyleneglycol mono ethyl ether and the like. Preferably the solvent is hexylene glycol. The solvent is preferably present in an amount of about 5 to about 50% w/w, more preferably 5 to 20% w/w and even more preferably 5 to 10% w/w of the emulsion.
The oil phase of the emulsion may comprise about 20 to about 80% w/w, more preferably 25 to 75% and even m
Jackman Martin
Popp Xue-Ping
Richter Friedrich
Schmook Fritz
Jarvis William R. A.
Kim Vickie
Loeschorn Carol A.
Novartis AG
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