U.S. patent application number 09/767656 was filed with the patent office on 2001-10-18 for pharmaceutical compositions.
Invention is credited to Jackman, Martin, Popp, Xue-Ping, Richter, Friedrich, Schmook, Fritz.
Application Number | 20010031769 09/767656 |
Document ID | / |
Family ID | 27267447 |
Filed Date | 2001-10-18 |
United States Patent
Application |
20010031769 |
Kind Code |
A1 |
Jackman, Martin ; et
al. |
October 18, 2001 |
Pharmaceutical compositions
Abstract
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. In
another aspect, this invention provides a topical pharmaceutical
composition that comprises a macrolide in suspension. In a further
aspect, this invention provides the use of an unsaturated fatty
alcohol to stabilize a macrolide in a pharmaceutical
composition.
Inventors: |
Jackman, Martin; (Allschwil,
CH) ; Popp, Xue-Ping; (Basel, CH) ; Richter,
Friedrich; (Grenzach-Wyhlen, DE) ; Schmook,
Fritz; (Vienna, AT) |
Correspondence
Address: |
Thomas Hoxie
Novartis Corporation
Patent and Trademark Dept.
564 Morris Avenue
Summit
NJ
07901-1027
US
|
Family ID: |
27267447 |
Appl. No.: |
09/767656 |
Filed: |
January 23, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09767656 |
Jan 23, 2001 |
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09488283 |
Jan 20, 2000 |
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09488283 |
Jan 20, 2000 |
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09302763 |
Apr 30, 1999 |
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09302763 |
Apr 30, 1999 |
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08836091 |
Apr 25, 1997 |
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Current U.S.
Class: |
514/340 ;
514/291 |
Current CPC
Class: |
A61P 31/00 20180101;
A61P 17/00 20180101; A61K 9/0014 20130101; A61K 47/14 20130101;
A61K 31/436 20130101; A61K 31/55 20130101; A61P 17/14 20180101;
A61K 47/10 20130101; A61K 47/06 20130101; A61P 37/02 20180101; A61P
29/00 20180101; A61K 9/107 20130101; A61P 17/06 20180101; A61P
37/00 20180101; A61P 37/06 20180101 |
Class at
Publication: |
514/340 ;
514/291 |
International
Class: |
A61K 031/4353 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 26, 1994 |
GB |
9421612.4 |
Nov 4, 1994 |
GB |
9422306.2 |
Feb 22, 1995 |
GB |
9503553.1 |
Oct 26, 1995 |
EP |
PCT/EP95/04208 |
Claims
1. 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.
2. A topical composition as claimed in claim 1 wherein the compound
of the FK506 class is ascomycin, 33-epi-chloro-33-desoxyascomycin
or FK506.
3. A topical composition according to claim 1 or claim 2 in which
the solvent is hexylene glycol.
4. A topical composition according to any preceding claim in which
the unsaturated fatty alcohol is oleyl alcohol.
5. A topical pharmaceutical composition that comprises a macrolide
in suspension.
6. A composition as claimed in claim 5 wherein the macrolide is an
ascomycin, a rapamycin or a compound of the FK506 class.
7. A composition as claimed in claim 6 wherein the macrolide is
ascomycin, 33-epi-chloro-33-desoxyascomycin or FK506.
8. A method of treating inflammatory or hyperproliferative skin
diseases or of cutaneous manifestations of immunologically-mediated
diseases comprising administering a topical composition according
to any one of claims 1 to 7 to the skin of a patient in need
thereof.
9. Use of an unsaturated fatty alcohol to stabilise a macrolide in
a pharmaceutical composition.
10. A method of stabilising a macrolide in a pharmaceutical
composition, which method comprises mixing an unsaturated fatty
alcohol with the macrolide.
Description
[0001] 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.
[0002] 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.
[0003] 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.
[0004] 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.
[0005] 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.
[0006] Compositions that contain water have been reported in the
literature and FK506 compounds have also been formulated as fine
suspensions (EP 484936).
[0007] 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.
[0008] 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.
[0009] This topical composition is effective, well tolerated on the
skin, and reasonably to extremely stable.
[0010] 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 1
[0011] in which:
[0012] each adjacent pair of R.sub.1 and R.sub.2, R.sub.3 and
R.sub.4, and R.sub.5 and R.sub.6 independently (a) is a pair of H
atoms but R.sub.2 may also be alkyl or (b) forms a second bond
between the carbon atoms to which they are attached;
[0013] R.sub.7 is H, OH, a protected OH group, a formyloxy group or
an alkoxy group, or R.sub.7 together with R.sub.1 forms an oxo
group;
[0014] R.sub.8 and R.sub.9 are independently H or OH;
[0015] R.sub.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;
[0016] X.sub.1 is H or OH;
[0017] X.sub.2 is H; or
[0018] X.sub.1 and X.sub.2 together are an oxo group or
--CH.sub.2O--;
[0019] Y.sub.1 is H or OH;
[0020] Y.sub.2 is H; or
[0021] Y.sub.1 and Y2 together are an oxo group,
N--NR.sub.11R.sub.12 or N--OR.sub.13;
[0022] R.sub.11 and R.sub.12 independently are H, an alkyl group,
an aryl group or a tosyl group;
[0023] R.sub.13, R.sub.14, R.sub.15, R.sub.16, R.sub.17, R.sub.18,
R.sub.19, R.sub.22, and R.sub.23 are independently H, or an alkyl
group;
[0024] R.sub.24 is an optionally substituted ring system which may
contain one or more heteroatoms;
[0025] n is 1, 2 or 3;
[0026] or Y.sub.1, Y.sub.2, R.sub.10 and R.sub.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.sub.2Se(C.sub.6H.sub.5) and alkyl substituted by one or more
OH groups; in free base or in acid addition form.
[0027] Preferably R.sub.24 is selected from (a) a
3,4-di-oxo-cyclohexyl group, (b) a 3-R.sub.20-4-R.sub.21-cyclohexyl
group in which R.sub.20 is OH, an alkoxy group, or a
--OCH.sub.2OCH.sub.2CH.sub.2OCH.sub.3 group, and R.sub.21 is OH,
--OCN, an alkoxy group, a --OCH.sub.2OCH.sub.2CH.sub.- 2OCH.sub.3
group, a protected hydroxy group, chloro, bromo, iodo,
methylthiomethoxy, isobutanoyloxy, aminooxalyloxy, an azido group,
p-tolyloxythiocarbonyloxy or R.sub.25R.sub.26CHCOO-- in which
R.sub.25 is optionally protected hydroxy or optionally protected
amino and R.sub.26 is H or methyl, or R.sub.20 and R.sub.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.sub.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 quatemized, 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.
[0028] Suitable alkyl groups, alkenyl groups, aryl groups,
protecting groups and acyl groups are defined in EP 484936.
[0029] 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.sub.1 in which R.sub.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)-rap- amycin. 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.sub.3C(NH)O or CF.sub.3SO.sub.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.sub.3C(NH)O or in the
presence of a base like pyridine, a substituted pyridine,
diisopropylethylamine or pentamethylpiperidine when X is
CF.sub.3SO.sub.3.
[0030] A preferred compound is 40-0-(2-hydroxy)ethyl rapamycin
(hereinafter compound A) as disclosed in WO 94/09010.
[0031] 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.
[0032] 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.
[0033] The oil phase of the emulsion may comprise about 20 to about
80% w/w, more preferably 25 to 75% and even more preferably 35 to
65% by weight of the composition. The emulsion may be an oil in
water emulsion or a water in oil emulsion. The oil in water
emulsion may be in the form of an emulsion gel (in which case the
continuous aqueous phase may be thickened using a polymeric
thickener), or in the form of a cream.
[0034] The unsaturated fatty alcohol forms part of the oil phase of
the emulsion and is preferably a lanolin alcohol or a C.sub.16 to
C.sub.18 fatty alcohol; more preferably oleyl alcohol, or elaidic
alcohol, although oleyl alcohol is particularly preferred. The
composition preferably contains sufficient amounts of the
unsaturated fatty alcohol to promote absorption of the compound of
the FK506 class in the skin, more preferably about 2 to about 10%
w/w and even more preferably 5 to 10% w/w.
[0035] The oil phase also may contain other liquid oils, thickening
agents and fatty bases usually used in topical compositions.
[0036] Suitable liquid oils include medium chain triglycerides
obtained from fractionated vegetable oils, such as capryl/caprinic
acid triglycerides. One example of such a triglyceride is
commercially available under the trade name Miglyol 812 (which has
a molecular weight of about 520, a n.sub.D.sup.20 of about 1.448 to
1.450 and a viscosity of 0.28 to 0.32 Pas). The liquid oil may
comprise about 5 to about 60% w/w of the emulsion and preferably 5
to 15% w/w.
[0037] Suitable thickening agents include conventional stiffeners
such as cetyl alcohol, cetostearyl alcohol, stearyl alcohol,
hydrogenated castor oil (Cutina HR), Yellow wax, White wax, cetyl
ester wax, emulsifying wax, microcrystalline wax, and the like.
Preferably the thickening agent forms about 2 to about 30% w/w of
the emulsion and more preferably 2 to 10% w/w.
[0038] Suitable fatty bases include bases such as natural wax,
Vaseline (petroleum jelly, also available commercially as
Petrolatum), thick paraffin, wool wax alcohols (such as those sold
under the trade marks Eucerinum or Eucerin), wool wax derivatives,
triglyceride waxes (such as that available under the trade name
Softisan 378) and the like.
[0039] The composition may also include suitable emulsifiers as is
usual in emulsion compositions. Such emulsifiers are described in
standard texts such as Fiedler, H. P.; 1989; Lexikon der
Hilfsstoffe fur Pharmazie, Kosmetic und angrenzende Gebiete, Editio
Cantor, D-7960 Aulendorf, Germany and Handbook of Pharmaceutical
Excipients, A Joint Publication of the American Pharmaceutical
Association, Washington DC, USA and the Pharmaceutical Society of
Great Britain, London, UK; 1986. Examples of suitable emulsifiers
include:
[0040] (a) propylene glycol mono- and di-fatty acid esters such as
propylene glycol dicaprylate (which is commercially available under
the trade mark Miglyol 840), propylene glycol dilaurate, propylene
glycol hydroxystearate, propylene glycol isostearate, propylene
glycol laurate, propylene glycol ricinoleate, and propylene glycol
stearate;
[0041] (b) polyoxyethylene sorbitan fatty acid esters, such as
mono- and tri-lauryl, palmityl, stearyl and oleyl esters. Examples
of commercially available esters are those available under the
trade name Tween (see Fiedler, pages 1300 to 1304) and particularly
Tween 60 (polyoxyethylene(20) sorbitan mono stearate) and Tween 80
(polyoxyethylene(20) sorbitan mono oleate);
[0042] (c) polyoxyethylene fatty acid esters, for example
polyoxyethylene stearic acid esters of the type known and
commercially available under the trade name Myrj (See Fiedler,
pages 834 and 835) and in particular Myrj 52 (which has a D.sup.25
of about 1.1, a melting point of about 40 to 44.degree. C., and a
HLB value of about 16.9);
[0043] (d) Polyoxyethylene-polyoxypropylene co-polymers and block
co-polymers such as those known and commercially available under
the trade names Pluronic, Emkalyx and Poloxamer (see Fiedler, page
959) and in particular Pluronic F68 (which has a melting point of
about 52.degree. C. and a molecular weight of about 6800 to 8975)
and Poloxamer 188;
[0044] (e) dioctylsulfosuccinate or
di-[2-ethylhexyl]-succinate;
[0045] (f) phospholipids and in particular lecithins (see Fiedler,
pages 943 and 944);
[0046] (g) salts of fatty alcohol sulphates such as sodium lauryl
sulfate and sodium cetyl stearyl sulphate;
[0047] (h) sorbitan fatty acid esters such as sorbitan mono
stearate and sorbitan mono oleate which are commercially available
under the trade marks Arlacel 60 (which has an HLB of about 4.7 and
a melting point of about 53.degree. C.) and Span 80 (which has a
D.sup.25 of about 1, an HLB of about 4.3 and a viscosity of about
950 to 1100 cP); (i) glycerine mono stearate with is available
under the trade name lmwitor (see Fiedler, page 645) and
particularly Imwitor 960;
[0048] (j) esters of polyethylene-glycol glycerol ethers, that have
at least one free hydroxyl group, and aliphatic C.sub.6-C.sub.22
carboxylic acids. Examples include PEG-20 glycerine mono
stearate;
[0049] (k) reaction products of a natural or hydrogenated castor
oil and ethylene oxide and of which examples are available under
the trade name Cremophor such as Cremophor RH 40 (having a
saponification no. of about 50 to 60, an acid number of <1, an
n.sub.D.sup.25 of about 1.453 to 1.457 and an HLB value of about 14
to 16), Cremophor RH 60 (having a saponification no. of about 40 to
50, an acid number of <1, an n.sub.D.sup.25 of about 1.453 to
1.457 and an HLB value of about 15 to 17) and Cremophor EL (having
a saponification no. of about 65 to 70, an acid number of about 2,
an n.sub.D25 of about 1.471 and a molecular weight of about 1630).
Also suitable are various tensides available under the trade names
Nikkol, Emulgin, Mapeg and Incrocas (see Fiedler);
[0050] (l) stearic acid;
[0051] (m) oil and wax based emulsifiers such as cetyl alcohol and
emulsifying wax;
[0052] (n) polyoxyethylene glycerides such as those available under
the trade name Labrafil M2130 CS (See Fiedler, page 707);
[0053] (o) polyoxyethylene alkyl ethers such as polyoxyethylene
stearyl ether, polyoxyethylene oleyl ether and polyoxyethylene
cetyl ether which are available under the Brij and Cetomacrogol
series trade names (see Fiedler, pages 222 to 224 and 284);
[0054] (p) glycerine sorbitan fatty acid esters such as that
available under the trade name Arlacel 481 (which has a molecular
weight of about 630 and an HLB value of about 4.5) and
[0055] (q) mixtures thereof.
[0056] Preferably the emulsifier is selected from
polyethyleneglycol (20) glycerine monostearate, sorbitan mono
stearate (Arlacel 60), sorbitan mono oleate (Span 60), Tween 60,
Tween 80, glycerine mono stearate (Imwitor 960), stearic acid,
cetyl alcohol, wool wax derivatives and alcohols and Labrafil M2130
CS and mixtures thereof. If the emulsion is a water in oil
emulsion, the emulsifier selected preferably has a HLB value of 10
to 15. If the emulsion is an oil in water emulsion, the emulsifier
selected preferably has a HLB value of 4 to 8. Preferably the
emulsifiers are present in an amount of about I to about 30% w/w
and preferably 10 to 25% w/w.
[0057] Gelling agents may also be added to provide a gelled
emulsion. Suitable gelling agents are carbomers (polyacrylic acid
derivatives); such as those available under the trade name Carbopol
(see Fiedler, pages 254 to 256). Carbopol 974 and Carbopol 1342 are
preferred. The gelling agents are preferably present in an amount
of 0.2 to 2% w/w; more preferably less than about 1% w/w.
[0058] The emulsion may also include preserving agents and
anti-oxidants such as benzyl alcohol, butyl-hydroxytoluene,
ascorbyl palmitate, sodium pyrosulphite, butyl hydroxy anisole,
propyl p-hydroxybenzoate (available commercially, for example,
under the trade name Paraben), methyl p-hydroxybenzoate (available
commercially, e.g. as Paraben), sorbic acid and tocopherol. The
preserving agents and anti-oxidants serve to prevent bacterial
growth, and are preferably present in an amount of about 0.01 to
about 2.5% w/w. pH modifying agents may be included to bring the pH
of the emulsion to between 4 and 6 or by adding a pharmaceutically
acceptable buffer system. A pH of between 4 and 6 is desirable to
avoid skin irritation.
[0059] The aqueous phase of the emulsion may comprise about 20 to
about 80% w/w, more preferably 25 to 75% and even more preferably
35 to 65% of the emulsion. The aqueous phase is preferably in the
form of sterilized water.
[0060] The compound of the FK506 class is preferably present in the
emulsion in an amount of about 0.01 to about 10% w/w and more
preferably in an amount of 0.1 to 1% w/w.
[0061] Preferably the compound of the FK506 class and the
unsaturated fatty alcohol are present in a weight ratio of 1:1000
to 5:1; preferably 1:100 to 1:5.
[0062] It has now been surprisingly found that macrolides can be
formulated into stable pharmaceutical compositions, when the
compounds are in suspensions.
[0063] Accordingly, in another aspect, this invention provides a
topical pharmaceutical composition that comprises a macrolide in
suspension.
[0064] The term macrolide has the meaning as described above.
[0065] The pharmaceutical composition may be in solid form, but
preferably it is in semi solid form suitable for topical
administration.
[0066] This suspension compositions of this invention are
effective, well tolerated on skin, and reasonably to extremely
stable.
[0067] The suspension contains particles of macrolide of from about
5, e.g. from 10, to about 90 microns in diameter. The particles of
the macrolide may be produced in conventional manner, e.g. by
grinding or milling.
[0068] The suspension may be prepared as a cream, a water-free
ointment, a water-in-oil emulsion, an oil-in-water emulsion, an
emulsion gel or a gel.
[0069] In another aspect, this invention provides a topical
composition in the form of an oil-in-water emulsion gel
comprising
[0070] a) a macrolide in an amount of up to 5 weight %,
[0071] b) a thickener in an amount of up to 20 weight %,
[0072] c) a hydrophilic component in an amount of up to 40 weight
%,
[0073] d) one or more organic acids in a total amount of up to 5
weight %
[0074] e) one or more stabilisers in a total amount of up to 5
weight %
[0075] f) water in an amount of up to 90% by weight.
[0076] Suitable thickeners are as defined above and may include
paraffin, waxes, and petrolatum.
[0077] Appropriate hydrophilic components include propylene glycol,
alcohols such as cetyl alcohol, stearyl alcohol and oleyl
alcohol.
[0078] Examples of suitable organic acids contemplated for use in
this invention include sorbic acid. The acid functions as a
preservative and serves to substantially prevent bacterial
growth.
[0079] In another aspect the invention provides a topical
composition in the form of an emulsion or suspension as defined
above for use in the treatment of inflammatory and
hyperproliferative skin diseases and of cutaneous manifestations of
immunologically-mediated diseases.
[0080] In another aspect the invention provides a method of
treating inflammatory or hyperproliferative skin diseases or of
cutaneous manifestations of immunologically-mediated diseases
comprising administering a topical composition as defined above to
the skin of a patient in need thereof.
[0081] In yet another aspect, the invention provides the use of 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 in the preparation of a
medicament in the form of an emulsion for the treatment of
inflammatory and hyperproliferative skin diseases and of cutaneous
manifestations of immunologically-mediated diseases.
[0082] The emulsion compositions may be obtained by dissolving the
compound of the FK506 class in the solvent and the unsaturated
fatty alcohol to provide the oil phase. If desired liquid oils,
fatty bases and thickening agents may be mixed into the oil phase.
The oil phase is then emulsified with the aqueous phase and, if
necessary, suitable emulsifiers. Other excipients may be added at
the appropriate time to the appropriate phase as is
conventional.
[0083] The present applicants have found that macrolides may be
unstable in topical compositions. It is believed that this
instability is caused by degradation or rearrangement pathways
which are not completely understood. After extensive experimental
work, the applicants have found that an unsaturated fatty alcohol
may be used to stabilise macrolide compositions.
[0084] In a further aspect, this invention provides the use of an
unsaturated fatty alcohol in stabilising a macrolide in a
pharmaceutical composition.
[0085] In another aspect, this invention provides a method of
stabilising a macrolide in a pharmaceutical composition, which
method comprises mixing an unsaturated fatty alcohol with the
macrolide.
[0086] The unsaturated fatty alcohol may be a C.sub.8-C.sub.22
alcohol, or may comprise a mixture of alcohols. The unsaturated
fatty alcohol may have one, two or three double bonds. Preferably
the unsaturated fatty alcohol has one double bond, and a cis
configuration. Oleyl alcohol is preferred. A stabilising effect may
be observed at a weight ratio of unsaturated fatty alcohol to
active agent of at least about 1:5, for example 1:2 to 1:1 or
greater, e.g. about 5:1.
[0087] The present applicants have found that the unsaturated fatty
alcohol, e.g. oleyl alcohol, is suitable for stabilising a
macrolide in a topical pharmaceutical composition. Examples of
topical compositions are as described herein.
[0088] The unsaturated fatty alcohol, e.g. oleyl alcohol, may be
used to stabilise a macrolide having at least one moiety as
follows: 2
[0089] The present applicants have found that oleyl alcohol is
useful in stabilising ascomycins and compounds of the FK 506 class,
for example FK 506, ascomycin and
33-epi-chloro-33-desoxyascomycin.
[0090] The topical compositions defined above are useful in the
treatment of inflammatory and hyperproliferative skin diseases and
of cutaneous manifestations of immunologically-mediated diseases.
Examples of such diseases are psoriasis, atopic dermatitis, contact
dermatitis and further eczematous dermatitises, seborrhoeic
dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid,
Epidermolysis bullosa, urticaria, angioedemas, vasculitides,
erythemas, cutaneous eosinophilias, Lupus erythematous and Alopecia
areata.
[0091] The utility of the topical compositions can be observed in
standard clinical tests such as the test set out in Example 12
infra using a concentration of 0.01 to 10% w/w (preferably 0.1 to I
% w/w) of the compound of the FK506 class. The utility can also be
observed using standard animals models as described in EP
315978.
[0092] The exact amount of the compound of the FK506 class and of
the composition to be administered depends on several factors, for
example the desired duration of treatment and the rate of release
of the compound of the FK506 class. Satisfactory results are
obtained in larger mammals, for example humans, with the local
application over the area to be treated of a 0.01 to 10% w/w,
preferably 0.1 to 3%, concentration of the compound of the FK506
class once or several times a day (for example 2 to 5 times a day).
In general the composition may be applied to areas of skin as small
as 1 cm.sup.2 to as large as 1 m.sup.2. Suitable skin loadings of
the compound of the FK506 class fall within the range of 0.1
mg/cm.sup.2 to 1 mg/cm.sup.2.
[0093] The compositions of this invention are well tolerated on
skin. Good skin penetration and permeation rates may be achieved
using the compositions of this invention.
[0094] The compositions described in Examples 13, 14 and 19 infra
are preferred emulsion compositions for application to mammals,
e.g. humans.
[0095] For the compounds (i)
[3S-[3R*[E(1S*,3S*,4S*)],4S*,-5R*,8S*,9E,12R*-
,14R*,15S*,16R*,18S*,-19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,-
26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxy-cyclohexyl)--
]1-methylethenyl)]-14,16-dimethoxy-4,10,12,18,-tetramethyl-8-(2-propenyl)--
15,19-epoxy-3H-pyrido[2, 1-c][1,4]oxaazacyclotricosine-1,7, 20,21
(4H,23H)-tetrone,
[0096] (ii)
[3S-[3R*[E(1S*,3S*,4S*)],4S*,-5R*,8S*,9E,12R*,14R*,15S*,16R*,1-
8S*,-19S*,26aR*]]-5,6,8,1 1,12,13,14,15,16,17,18,1
9,24,25,26,26a-hexadeca-
hydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methylethenyl-
)]-14,16-dimethoxy-4,10,12,18,-tetramethyl-8-ethyl-5,19-epoxy-3H-pyrido[2,-
1-c][1,4]oxaazacyclotricosine-1,7,20,21 (4H,23H)-tetrone, and
[0097] (iii) [3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,-14R*,
15S*,16R*,18S*,19S*,
26aR*]]-5,6,8,11,12,13,14,15,16,-17,18,19,24,25,26,2-
6a-hexadecahydro-5,19-dihydroxy-3-(3-hydroxymethylcyclopentyl)-1-methyleth-
enyl)]-14,1 6-dimethoxy-4,10,12,1
8,-tetramethyl-8-ethyl-15,19-epoxy-3H-py-
rido[2,1-c][1,4]oxaazacyclotricosi topical application of
concentrations of 0.01 to 1% w/w once a day is effective in the
treatment of chronic plaque psoriasis in humans. In these
applications the compositions are as effective as the ultra-potent
Clobetasol composition (0.05%).
[0098] The following Examples describe compositions of this
invention.
[0099] In the Examples,
[0100] "compound 1" is the compound
[3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9- E,12R*,14R*,1
5S*,16R*,18S*,19S*, 26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19-
,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxy-cyclo-
hexyl)-1-methylethenyl)]-14,16-dimethoxy-4,10,12,18,-tetramethyl-8-(2-prop-
enyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,2-
3H)-tetrone. This compound is better known as FK506.
[0101] "Compound 2" is the compound
[3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9-
E,12R*,-14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,-
24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-(3-hydroxymethylcyclopentyl)-1-
-methylethenyl)]-14,16-dimethoxy-4,10,12,18,-tetramethyl-8-ethyl-15,19-epo-
xy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone.
This compound and a method of producing it are described in EP
465426.
[0102] "Compound 3" is
[3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,1-
5S*,16R*,18S*,-19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a--
hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methy-
lethenyl)]-14,16-dimethoxy-4,10,12,18,-tetramethyl-8-ethyl-15,1
9-epoxy-3H-pyrido[2,
1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetr- one. This
compound is known as ascomycin.
[0103] Compound A, compound B, compound C and compound D have the
respective meanings as described above.
[0104] The term stable, as used in the following Examples, will be
understood to mean that no separation of components is observed of
the respective composition when stored at room temperature for a
period of four months or longer.
[0105] Chemical analysis of the active agent is undertaken using
reverse phase HPLC with UV detection; .lambda.=210 nm.
Quantification limit is 0.1% by weight.
[0106] Tolerability of the compositions is carried out, in vivo, on
pig skin and on human skin. A visual assessment is made at 0.5, 1,
2 and 4 hours after application.
EXAMPLE 1
[0107] An oil in water emulsion is prepared containing the
following ingredients (in parts by weight):
1 Compound 2 0.10 Oleyl alcohol 10.00 Miglyol 812 10.00 Hexylene
glycol 10.00 Cetyl alcohol 5.00 Stearyl alcohol 5.00 Benzyl alcohol
1.00 Sorbitan mono stearate 2.00 Tween 80 4.00 Glycerine mono
stearate 3.00 Water 49.90
[0108] The composition is prepared by mixing together the compound
2, the oleyl alcohol, the Miglyol 812, the hexylene glycol, the
cetyl alcohol and the stearyl alcohol and heating to 65.degree. C.
until all components are dissolved. The Arlacel 60, Tween 80
(polyoxyethylene(20)sorbitanmonoo- leate) and glycerine mono
stearate are then added to the oil phase and stirred until all
components are dissolved. The water is then heated in a vessel
containing a stirrer and homogenizer. The benzyl alcohol is then
added. The oil phase is then slowly added while stirring and
homogenizing until a homogenous emulsion with a droplet size of
less than 20 .mu.m is obtained. The emulsion is then cooled to room
temperature. The emulsion is stable.
EXAMPLE 2
[0109] An oil in water emulsion is prepared in a manner analogous
to that in Example 1, and containing the following ingredients (in
parts by weight):
2 Compound 1 0.10 Oleyl alcohol 10.00 Miglyol 812 10.00 Hexylene
glycol 10.00 Cetyl alcohol 5.00 Stearyl alcohol 5.00 Benzyl alcohol
1.00 Sorbitan mono stearate 2.00 Tween 80 4.00 Glycerine mono
stearate 3.00 Water 49.90
[0110] The emulsion is stable. No component separatiion is
observed.
EXAMPLE 3
[0111] A water in oil emulsion is prepared in a manner analogous to
that in Example 1 except that the water is added slowly to the oil
phase. The composition contains the following ingredients (in parts
by weight):
3 Compound 2 0.10 Oleyl alcohol 5.00 Hexylene glycol 5.00 Yellow
wax 3.00 Benzyl alcohol 1.00 Arlacel 481 7.00 White Petroleum 15.00
Thick Paraffin 5.00 Water 58.4 MgSO.sub.4.7H.sub.2O 0.5
[0112] The emulsion is stable.
EXAMPLE 4
[0113] An oil in water emulsion is prepared in a manner analogous
to that in Example 1, and containing the following ingredients (in
parts by weight):
4 Compound 2 0.10 Oleyl alcohol 7.50 PEG-glycerine monostearate
7.00 propylene glycol 10.00 Cetyl alcohol 6.00 Glycerine mono
stearate 4.00 Paraffin (thick) 10.00 White Petroleum 15.50 Sorbic
acid 0.01 Water 39.89
EXAMPLES 5, 6 and 7
[0114] Oil in water emulsions are prepared in a manner analogous to
that in Example 1, and containing the following ingredients (in
parts by weight):
5 Example 5 6 7 Compound 2 1.00 Compound 1 0.10 1.00 Oleyl alcohol
7.50 7.50 7.50 PEG-glycerine monostearate 7.00 7.00 7.00 propylene
glycol 10.00 10.00 10.00 Cetyl alcohol 6.00 6.00 6.00 Glycerine
mono stearate 4.00 4.00 4.00 Paraffin (thick) 10.00 10.00 10.00
White Petroleum 15.50 15.50 15.50 Sorbic acid 0.01 0.01 0.01 Water
38.99 39.89 38.99
EXAMPLES 8 to 11
[0115] The following emulsions are prepared in an analogous manner
to that in Example 1.
6 Example 8 9 10 11 Compound 3 0.10 0.10 0.10 0.10 Hexylene glycol
5.00 10.00 10.00 5.00 Cetyl palmitate 2.00 -- -- -- Oleyl alcohol
-- 10.00 10.00 -- Lanolin alcohols -- -- -- 1.50 MC* triglycerides
-- 10.00 10.00 5.00 Isopropyl myristate 8.00 -- -- -- Cetyl alcohol
4.00 5.00 5.00 2.00 Stearyl alcohol 4.00 5.00 -- 2.00 Benzyl
alcohol 1.00 1.00 1.00 1.00 Sorbitan monostearate 1.90 2.00 -- 3.00
Sorbitan monooleate -- 4.00 -- -- Glycerin monostearate -- 3.00
10.00 -- Tween 80 6.10 -- -- -- Petroleum, white -- -- -- 23.50
Water 67.90 49.90 53.90 56.40 Magnesium sulfate, heptahydrate -- --
-- 0.50 *MC = medium chain, e.g. Miglyol 812.
[0116] The compositions of Examples 4 to 11 are stable.
EXAMPLE 12
[0117] A single centre, double-blind, placebo-controlled trial is
conducted to determine the efficacy of the compositions of Examples
4 to 7 in chronic plaque psoriasis. 10 patients who are over 18
years of age, have chronic plaque psoriasis and who have not had
systemic or topical therapy for chronic plaque psoriasis, within 1
month and 1 week respectively, are chosen. On day -1, scales are
removed with a topical composition containing 10% salicylic acid in
Vaseline. On day 0, the compositions of examples 4 to 7, a 0.05%
Clobetasol composition available under the trade mark Dermovate and
a placebo are applied to the desquamated plaques under
semi-occlusive conditions and left for 24 hours.
[0118] The patient is allowed to bath and the lesions are dried
gently. The lesions are evaluated visually (erythema) and by
palpation (infiltration) with scores ranging from of 0 (absent) to
3 (severe). The procedure is repeated daily until the 10/11
day.
[0119] The cumulative scores are presented in tables 1 and 2.
7TABLE 1 Erythema Scores day 0 2 4 6 8 10 11 Example 3 30 20.5 15
11.5 9 6 7.5 Example 4 30 21.5 17.0 12 9.5 6 6.5 Example 5 30 22 17
11 8 5.5 5 Example 6 30 20 15.5 10 8.5 4.5 4.5 Placebo 30 28 25.5
25 23 23 22.5 Dermovate 30 20 13.5 10.5 8.5 8.0 8.0
[0120]
8TABLE 2 Infiltration Scores day 0 2 4 6 8 10 11 Example 3 30 21
15.5 12 5.5 2 3 Example 4 30 24 16.5 12 6.5 3 2.5 Example 5 30 21.5
17 12 5 2 2 Example 6 30 21.5 14.5 10 5.5 2.5 1.5 Placebo 30 28.5
24.5 23 21 19 18.5 Dermovate 30 19 14 8 3.5 2 2.5
[0121] No adverse events are observed with the compositions of
examples 4 to 7 but skin atrophy is observed in 2 patients
receiving Dermovate. However the compositions of examples 4 to 7
are at least as effective as Dermovate.
[0122] The active agent used in the compositions described in
Examples 1 to 11 may be replaced by Compound A, B, C or D.
EXAMPLES 13 to 16
[0123] Oil in water emulsions are prepared in analogous manner to
Example 1 and having the following compositions.
[0124] The compositions of Examples 13 to 16 are well-tolerated on
pig skin and on human skin. Assay of main degradation product is
0.1% (quantification limit) for compositions 15 and 16 after 72
hours at 70.degree. C.; the oleyl alcohol is replaced by Miglyol
812 and assay of main degradation product increases to 0.5%. No
separation of components is observed when stored at room
temperature for four months.
EXAMPLES 17 to 19
[0125] Oil in water emulsion compositions are prepared having 1
wt-% active agent.
9 Example 17 18 19 Oleyl alcohol 2.5 5 10 Miglyol 812 22.5 20 15
Cetyl alcohol 4 4 4 Stearyl alcohol 4 4 4 Glycerol monostearate 2 2
2 Sorbitan monostearate 3 3 3 Polysorbate 60 5 5 5 Methyl Paraben
0.07 0.07 0.07 Propyl Paraben 0.03 0.03 0.03 Citric acid 0.05 0.05
0.05 NaOH 1M abs. wt./100 g 0.02 0.02 0.02 Propylene glycol 5 5 5
Compound B 1 1 1 Demin. water to 100 to 100 to 100
[0126] The emulsions of Examples 17, 18 and 19 are stable and no
separation of components is observed. The compositions are found to
be well-tolerated on human skin. The compositions are stored at
40.degree. C. for eight weeks and chemical analysis undertaken
using HPLC. Assay of main degradation product for compositions 17,
18 and 19 is 1.1%, 0.8% and 0.4% respectively.
[0127] In the compositions of Examples 13 to 19, the active agent
compound B may be replaced by compound A compound C, compound D,
compound 1, compound 2 or compound 3.
EXAMPLE 20
[0128] An oil in water emulsion composition is prepared as a cream
using compound C as active agent:
10 Amount Component weight-% Compound C 0.3 hexylene glycol 10
oleyl alcohol 10 Miglyol 812 10 methyl Paraben 0.07 propyl Paraben
0.03 cetylalcohol 5 glycerol monostearate 10 water to 100
[0129] The cream is stable and no separation of components is
observed.
EXAMPLES 21 to 30
[0130] Suspension compositions are prepared in Examples 21 to
30.
EXAMPLE 21
[0131] A topical suspension composition is prepared containing the
following ingredients (in parts by weight):
11 Compound 1, 2, 3, A, B, C or D 0.10 Petroleum jelly 99.9
[0132] The composition is prepared by mixing together the compound
and other excipients.
EXAMPLE 22
[0133] A single centre, double-blind, placebo-controlled trial is
conducted to determine the efficacy of the compositions of Example
21 in chronic plaque psoriasis. 10 patients who are over 18 years
of age, have chronic plaque psoriasis and who have not had systemic
or topical therapy for chronic plaque psoriasis, within 1 month and
1 week respectively, are chosen. On day 1, scales are removed with
a topical composition containing 10% salicylic acid in Vaseline. On
day 0, the compositions of Example 21, a 0.05% Clobetasol
composition available under the trade mark Dermovate and a placebo
are applied to the desquamated plaques under semi-occlusive
conditions and left for 24 hours.
[0134] The patient is allowed to bath and the lesions are dried
gently. The lesions are evaluated visually (erythema) and by
palpation (infiltration) with scores ranging from of 0 (absent) to
3 (severe). The procedure is repeated daily until the 10/11 day;
clearing of psoriasis is observed.
EXAMPLE 23
[0135] A topical suspension composition is prepared containing the
following ingredients (in parts by weight) as an oil-in-water
emulsion gel:
12 Compound B 0.3 Paraffin, thick 15 glycerol monostearate 0.3
propylene glycol 10 Carbopol 974p 0.5 Carbopol 1342 0.5 NaOH 5% 2.5
sorbic acid 0.1 water 70.8
[0136] The composition is prepared by mixing together the compound
and other ingredients. The composition is subjected to stress
conditions in a centrifuge for 24 hours at a temperature of up to
95.degree. C. No degradation of the active agent is observed using
HPLC.
[0137] Suspension compositions are prepared in Examples 24 to
30.
13 Amount (g/100 g) Example 24 Compound B 0.1 Paraffin, thick 48
Glycerol monostearate 8 Petrolatum, white 43.9 Example 25 Compound
B 0.1 Paraffin, thin 20 Petrolatum, white 71.9 Wax,
microcrystalline 8 Example 26 Paraffin, thick 30 Cetyl alcohol 5
Stearyl alcohol 5 Sorbitan monostearate 2 Polysorbate 80
polyhydroxyethylen- 4 sorbitanmonooleate) Glycerol monostearate 3
Ascorbyl palmitate 0.05 Compound B 0.1 Sorbic acid 0.1 Propylene
glycol 5 Water 45.75 Example 27 Propylene glycol 10 Paraffin, thick
15 Compound B 0.1 Carbopol 1342 (Polyacrylic acid, 1 partly long
chain alkylester) Methyl Parabens 0.07 Propyl Parabens 0.03 NaOH
aqueous solution 5% 2.5 Water 71.30 Example 28 Compound B 0.1
Carbopol 947 1 NaOH aqueous solution 1N 2.5 Water 96.4 Example 29
Compound B 0.1 Cetylstearyl alcohol 0.5 Wool wax alcohols 6
Petrolatum, white 93.4 Example 30 Compound B 0.1 Cetylstearyl
alcohol 0.25 Wool wax alcohols 3 Petrolatum, white 46.65 Water
50
[0138] Good to very good stability is observed for the suspension
compositions of Examples 24 to 30. The suspensions are applied to
healthy volunteers and are found to be well tolerated. Compound B
may be replaced by compound 1, 2, 3, A, C or D in any of the
compositions as described in Examples 23 to 30.
* * * * *