CA1202901A - Corticoid-containing preparations for topical application - Google Patents
Corticoid-containing preparations for topical applicationInfo
- Publication number
- CA1202901A CA1202901A CA000431878A CA431878A CA1202901A CA 1202901 A CA1202901 A CA 1202901A CA 000431878 A CA000431878 A CA 000431878A CA 431878 A CA431878 A CA 431878A CA 1202901 A CA1202901 A CA 1202901A
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- Canada
- Prior art keywords
- oil
- preparation
- group
- water
- emulsion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Steroid Compounds (AREA)
Abstract
ABSTRACT
Corticoid-containing preparations for topical application.
Novel preparations suitable for topical application comprising jojoba oil and 0.005 to 2%
by weight of an anti-inflammatorily active corticoid.
The preparations are stable even when substan-tially diluted.
Corticoid-containing preparations for topical application.
Novel preparations suitable for topical application comprising jojoba oil and 0.005 to 2%
by weight of an anti-inflammatorily active corticoid.
The preparations are stable even when substan-tially diluted.
Description
:12~2~
The present invention is concerned with novel corticoid-containing preparations suitable for topical application.
The present invention provides a preparation suitable for topical application, which comprises jojoba oil and 0.005 to 2% by weight of an anti-inflammatorily active corticoid.
The novel preparations of the present invention are stable even when substantially dilutedO The novel preparations cause much less side-effects (such as irritation, sensibilisation,~ maceration, burning and itching) than known corticoid-containing preparations.
The present invention also provides a preparation of the present invention, for use as a medicament.
In principle, any anti-inflammatorily active corticoid is suitable for the manufacture of the corticoid~
containing preparations according to the presert invention.
However, preferred for this purpose are corticoids of the general formula I
IH2z C=O
3Q f ,~ Rl (I) ,/' ~ ~
/ ~ ~
$~
. ., ~21~
The present invention is concerned with novel corticoid-containing preparations suitable for topical application.
The present invention provides a preparation suitable for topical application, which comprises jojoba oil and 0.005 to 2% by weight of an anti-inflammatorily active corticoid.
The novel preparations of the present invention are stable even when substantially dilutedO The novel preparations cause much less side-effects (such as irritation, sensibilisation,~ maceration, burning and itching) than known corticoid-containing preparations.
The present invention also provides a preparation of the present invention, for use as a medicament.
In principle, any anti-inflammatorily active corticoid is suitable for the manufacture of the corticoid~
containing preparations according to the presert invention.
However, preferred for this purpose are corticoids of the general formula I
IH2z C=O
3Q f ,~ Rl (I) ,/' ~ ~
/ ~ ~
$~
. ., ~21~
- 2 in which _ represe~ts a single or double carbon-to-carbon bond~
~ represent~ a hydrogen or fluorine atom or a methyl group 9 represents a hydrogen, fluorine or chlorine atom, Z represents a hydro~yl group, an alkanoylo~y group conta;n;ne 2 to 6 carbon atoms~ an alksxymethoxy group, a benzoyloxy group or a chlorine atom7 and represents a hydrogen atom ~nd~ together with R2~ an isoprop~lidenedio~y group, or ~ represents two hydroge~ atoms, a hydroge~
atom and a hydroxyl group, a methyle~e group, or a hydrogen atom and a methyl group, and R2 represents a hydrogen atom, a hydroxyl group, an alkanoyloxy group cont~i ni n~ 2 to 6 carbon atoms, an alkoxymethox~ group or a benzo~lo~y group.
Compounds ~alling.within the scope of the general formula I are compounds of the general form~a Ia 1 2(:)R4 c - o HO ~ ~ -- OR3 ¦ ¦ (Ia) ~\/~/
O/~--J
~' in which _ represent8 a single or double carbon-to-carbo~ bond, ~' represents a hyàrogen atom or a methgl group, and R~ and R4 may have the same or different meaning~ and each represents a hydrogen atom, an alkanoyl group cont~; ni ng 2 to 6 carbon atoms, an aIkoxymethyl group or a ~enzoyl group;
compounds of the general formula Ib ~æo2~
1 20R~;
c=o ~\/~\~ ( lb ) o~f ~ "
in which has the meaning gi~en above, ~" represents a hydrogen or fluorine atom, a~d 5 R5 represent~ a hydrogen atom, an alkano~l group cont~inin~ 2 to 6 carbon atoms or a benzoyl group;
compound~ of the generaI formula Ic i ~2Z
~--0 :E~O ~ OR7 ( I c ) O
X
~Z~
in which and Z ha~e the mea~ngs given above, ~' represents a ~luori~e or chlorine atom, R6 represents two hydrogen atoms, a methylene group, or a hydrogen atom and a methyl group, and R7 represents a hydrogen atom, an al~anoyl group co~t~;nin~ 2 to 6 carbon atoms or a b~nzoyl group;
1~ and compounds o~ the gener~l ~ormula Id C=O
OR~
I
~ I (Id) û~ ~J
X'`
in which = represe~t~ a single or double carbo~-to-carbon bond~
Y~ Z and X" have the meanings given above, and R8 and ~ each represents a hydrogen atom or together represent an l~opropylidene group.
~ 8 c~rticoid~ of the general formula Ia suitable for the manufacture of the corticoid-cont~n~ n~ pre-parations according to the present i~vention, there may be mentioned hydrocortisone, prednisolone, 6a- -methylhydrocortisone and 6~-methylpredni~olo~e and e~ter~ or acetals thereof, for e~ample hydrocorti-sone 21-acetate9 hydrocortisone 17-butyrate, hydro-~O cortisone 17-valerate, prednisolone 21.-acetate~
prednisolone 17-valerate, 6a-methylhydrocorti~one~
21-acetate, ~a-methylprednisolo~e 21-acetate, 6o-methylhydrocQrti~o~e 17-butyrate-21-acetate, 6a-methylprednisolone 21-acetate-17-propionate~ 6~-methylhydrocorti~Gne 17,21-dipropionate or 21-ace-to~y-17a-ethoxymetho~y ll~-hydroxy-~l'4-pregnadie~e-
~ represent~ a hydrogen or fluorine atom or a methyl group 9 represents a hydrogen, fluorine or chlorine atom, Z represents a hydro~yl group, an alkanoylo~y group conta;n;ne 2 to 6 carbon atoms~ an alksxymethoxy group, a benzoyloxy group or a chlorine atom7 and represents a hydrogen atom ~nd~ together with R2~ an isoprop~lidenedio~y group, or ~ represents two hydroge~ atoms, a hydroge~
atom and a hydroxyl group, a methyle~e group, or a hydrogen atom and a methyl group, and R2 represents a hydrogen atom, a hydroxyl group, an alkanoyloxy group cont~i ni n~ 2 to 6 carbon atoms, an alkoxymethox~ group or a benzo~lo~y group.
Compounds ~alling.within the scope of the general formula I are compounds of the general form~a Ia 1 2(:)R4 c - o HO ~ ~ -- OR3 ¦ ¦ (Ia) ~\/~/
O/~--J
~' in which _ represent8 a single or double carbon-to-carbo~ bond, ~' represents a hyàrogen atom or a methgl group, and R~ and R4 may have the same or different meaning~ and each represents a hydrogen atom, an alkanoyl group cont~; ni ng 2 to 6 carbon atoms, an aIkoxymethyl group or a ~enzoyl group;
compounds of the general formula Ib ~æo2~
1 20R~;
c=o ~\/~\~ ( lb ) o~f ~ "
in which has the meaning gi~en above, ~" represents a hydrogen or fluorine atom, a~d 5 R5 represent~ a hydrogen atom, an alkano~l group cont~inin~ 2 to 6 carbon atoms or a benzoyl group;
compound~ of the generaI formula Ic i ~2Z
~--0 :E~O ~ OR7 ( I c ) O
X
~Z~
in which and Z ha~e the mea~ngs given above, ~' represents a ~luori~e or chlorine atom, R6 represents two hydrogen atoms, a methylene group, or a hydrogen atom and a methyl group, and R7 represents a hydrogen atom, an al~anoyl group co~t~;nin~ 2 to 6 carbon atoms or a b~nzoyl group;
1~ and compounds o~ the gener~l ~ormula Id C=O
OR~
I
~ I (Id) û~ ~J
X'`
in which = represe~t~ a single or double carbo~-to-carbon bond~
Y~ Z and X" have the meanings given above, and R8 and ~ each represents a hydrogen atom or together represent an l~opropylidene group.
~ 8 c~rticoid~ of the general formula Ia suitable for the manufacture of the corticoid-cont~n~ n~ pre-parations according to the present i~vention, there may be mentioned hydrocortisone, prednisolone, 6a- -methylhydrocortisone and 6~-methylpredni~olo~e and e~ter~ or acetals thereof, for e~ample hydrocorti-sone 21-acetate9 hydrocortisone 17-butyrate, hydro-~O cortisone 17-valerate, prednisolone 21.-acetate~
prednisolone 17-valerate, 6a-methylhydrocorti~one~
21-acetate, ~a-methylprednisolo~e 21-acetate, 6o-methylhydrocQrti~o~e 17-butyrate-21-acetate, 6a-methylprednisolone 21-acetate-17-propionate~ 6~-methylhydrocorti~Gne 17,21-dipropionate or 21-ace-to~y-17a-ethoxymetho~y ll~-hydroxy-~l'4-pregnadie~e-
3~20-dione~
~ corticoids of the general formula Ib suitable for the manufacture of the corticoid-containing pre-parations according to the present inventio , theremay be mentioned, ~or e~ample, fluocortolone, clo-cortolone, di~lucortolone and desoximetasone and esters thereof, for example fluocortolone 21-acetate~
fluocortolone 21-caproate, fluocortolone 21-tri-methylacetate, clocortolone 2~-caproate, clocortolone 21-trimethylacetate and diflucortolone 21-valerate~
As corticolds of the ~eneral ~ormula Ic ~uit~ble for the manufacture of the corticoid-cont~in;n~ pre-parations according to the present in~ention, there may be mentioned, ~or e~ample, betametha~one, beclo-5 methasone, fluprednylidene, clobetasol, dexamethasone1flumetasone and 9-chloropredni6010ne and ester~ there-o~, for example betamethasone 17-valerate, beta-methasone 17-benzoate, betamethasone 17,21-dipropio-nate, beclometha~one 17,21-dipropionate, flupredn~
dene 21-acetate, clobetasol 17-propionate, ~lumetasone 21-trimethylacetate, 9-chloropredni~olone 21-acetate-17 propionate and 9-chloropredni~olone 17-butyrate 21-propionate.
As corticoids of the general formula Id ~uitable ~or the manu~actuxe of the corticoid-cont~; n; n~ pr~-paration~ according to the present invention, there may be mentioned9 for example, triamcinolone9 tri-amcinolone acetamide, halcinonide, ~luocinolone, fluocinolone acetonide~ desonide and fludroxicortide and e~ters thereof, ~or e~ample fluocinonideJ
~owever, anti-infla~matorily acti~e corticoids that do not come within the scope of the general formula I are also suitable ~or the manuPacture of the corticoid-cont~in;n~ preparations accordlng ~o the ~5 present in~ention. ~s such compounds, there may be mentioned by way of e~ample corticoidq that differ tll ~4 from those of the general formula I in that, instead o~ the grouping IH2Z, they carry a group COORlo (~ 0 representing an ~lkyl group cont~ n; n~ up to 6 carbon atoms) - disclosed in United States Patent Speci~ica-tion I~os~ ~,824,260~ ~,919,421 and 3,9447577. Theremay be mentioned as an example of a corticoid ha~ing this class of structure fluocortin butyl ester.
~owever, other suitable corticoids are, for example, tho~e that differ from the corticoids of the formula I in that they carry a keto group i~stead o~ a hydro~yl group in the ll-position. Clobeta~one 17-butyrate may be mentioned as an example.
The preparations of the present invention con-tain from 0.005 to 2% by weight, but preferably irom 0.05 to 0.5~ by weight, o~ the cor~icoid~ the co~-centration of the corticoid is, o~ course, dependent on the relati~e activity of the corticoid.
The preparations of the present invention may contain the jojoba oil in an a~ount within the range of from 1 to 50~ by weight, for example 1 to 25% by weight~ preferably 3 to 15% by weight, more pre-ferably 3 to 10~ by weight.
As in the case of the previously known corticoid-cont~i n; n~ preparations suitable for topical applica-tion, the preparations of the present invention mayalso be in the form of an oil/water emulsion (for e~ample in the form of a miIk or cream) t in the form of a water/oil emulsion (~or e~ample in the form o~ a fatty ointment) or ln the ~orm of an oily suspension (for example i~ the ~orm o~ a ~atty spray). Accord-. 5 ing to the present invention, from 1 to 15% by ~eight,and preferably from ~ to 10~ by weight, of jojoba oil i9 used in the case o~ the oil~water emulsions or water/oil emulsions and at least 50~ by weight o~
jojoba oil is used in the case of the oily suspensions.
The jojoba oil i~ preferably used in a purified form (for example puroba oil). The jojoba oil ma~ for example, have been decolorise~ and purified by mea~s of activa carbon7 The oil/water emulsions and the water~oil emul sions may be prepared in a co~Yentional manner usLng conventional emulsifiers (Eirk Othmer: ~ncyclopaedia of Chem~cal Technology, ~rd edition, lQ79; John Wiley & Sons; New York etc. vol. 8, pages 900 to 930 and Dr. Otto-Albrecht ~eum~ller: R~mpps Chemie ~exikon, 7th edition, 1973; Franck'sche Verlags-handlung Stuttgart, pages 1009 to 1013). ~he waxes, emulsifiers and other additives used ~or these emulsions may be the same as are conventionally used in emulsi~ied skin-care agents (Dr. Otto-~lbrecht Neum~ller: R~mpps Chemie ~exikon, 7th edition 197~;
~ranck'sche Verlag~h~n~lung Stuttgart, pages 1427 and 1428~.
~ preparation according to the present invention in the form of an oil/water emulsion may comprise one or more hydrophilic and/or lipophilic active sub-stance~ (one of which such substances is the jojobaoil), a fatty phase, an oil/water emulsi~ier, an aqueous phase and a preservative.
There may be used as the hydrophilic and/or lipo-philic active substancea humectant ~actors (hydro-comple~es), ~or example glycerine, polyethyleneglycols or ~m;no acid mixtures, puroba oil (=jojoba oil~, ~itamins (preferably vitamins h and E), vital comple~es(for example placenta egtracts)9 enzymesy herb extracts(for example Eamamelis extract or c~mo~;le extract~ or proteins(for e~ample collagen).
Suitable as the oily phase or the fatty phase in the oil/water emulsions are hydrocarbons, for example vaseline, paraffins or stearin, or waxes, for e~ample beesw~. Suitable oil~water emulsifiers are, ~or e~ample, stearyl alcohol, polyoxyethylene stearates (for example ~nRJ(R)), complex emulsifiers ~or example Qmphoterin(R)) and sorbitan ~atty acid esters (for e~ample Span(R)) or carbo~yvinyl polymers (for example Carbopol(R)). The aqueous phase may also contain a bu~fer substance, for example the disodium salt of ethylene~i~mine-N,N,~',N'-tetraacetic acid, and a preservati~e, ~or e~ample chlorquinaldol9 parabens or benzalkonium chloride.
In the oil/water emNlsions, the proportion of the inner em~ ;o~ is preferably from ~0 to 49% by weight . 5 and the particle si~e of the inner emulsion is pre-ferably between 1 ~ and 50 ~
preparation accordin~ to the present invention, ~or example a cosmeti~ ~reparation, in the form of a water/oil emulsion may likewise comprise one or more hydrophilic and/or lipophilic active substances, of the type also used in the oil/water emulsions, a ~atty phase, a water~oîl emulsifier and an aqueous phase~ There may be used as the oily phase or the fatty phase of the water/oil emulsio~s hydrocarbonsf for example paraffins ~nd vaseline, and synthetic, vegetable and ~n;m~l oils or wa~es(for example olive oil, ground-nut oil, fine bone oil, almond oil, lanolin, beeswa~ or sunflower oil), as the aqueous ph2se puri~ied ~emineralised water and, as the water/
oil emulsifier, wool ~at (=lanolin), fatty alcohols, for example cetyl alcohol, myristyl alcohol, stearyl alcohol or ceryl alcohol, fatty acid esters, for example beeswax (cera alba) or wax alcohol ester~ or mixed esters(for e~ample Dehymuls(R)).
~he proportion of the inner emulsion in the water/oil emulsions is pre~erably from 30 to 4g~ by weight and the particle si~e of the inner emulsion iB preferably between 1 ~ and 100 ~ ~urir~ the dispersion of the two phases, the particle ~ize is reduced further and in the ~inlshed product it is less than 50 ~.
The preparations oi the present invention pre-ferably contain the corticoid in a micronised form (particle size predom;n~tly from 1 to 20 ~) and ma~
also contain a perfume, for example one o~ the 10 Crematest( ) series. These components are uni~ormly dispersed in the preparations hav~ng been incorporated, for e~ample, into the finely dispersed system~ as described above by stirring.
A preparation according ~o the present invention cont~; ni n~ a fatty phase and an aqueous phase may be in the form of a finely dispersed mixture o~ an oil/water emulsion cont~;n;ng an oil/water emulsifier and a pre~ervative and (ii~ a water/oil emulsion con-t~inin~ a water/oil emulsifier. In such a preparation which may~ for egample, be in the ~orm of an ointment, paste or cream, the jojoba oil is advantageously present in the oil/water emulsion. This type of preparation ma~ also contain a hydrophilic and~or lipophilic active substance other than jojoba oil~
The oil/water emulsion and the water/oil emulsion ma~
haYe been produced in the manner already described above.
When ueing a cream of this type of constitution cont~;n;n~ an extremely ~inely dispersed mixture o~
the two types o~ emul~ion, a corresponding oil/water . 5 or water/oil hydrolipid film can be produced on the s~in depending on the moistne3s in the various skin areas, or depending on the skin type~
In such a preparation according to the present inve~tion, the particle size of the emulsion is pre-ferably ~rom 2 to 50 ~.
?here is also included within the scope of thepresent invention a process for the manufacture of the corticoid-cont~inin~ preparation in the for~ of a finely dispersed mi~ture of an oil~water emulsio~
and a water/oil emulsion, for e~ample an ointment, paste or cream, wherein an oil~water emulsion that has been produced from a fatty phase, ~n aqueous phase, an oil/water emulsi~ier and a preservative is intimately mixed, preferably in acuo, at a tem-perature within the range of from 20 to 40C with a water/oil emulsion that has been produced from afatt~ phase, an aqueous phase and a water/oil emul-sifier, the oil/water emulsion and/or the water/oil emulsion cont~l;n~n~ jojoba oil, and then an anti-inflammatorily acti~e corticoid in a micronised form~particle size preferably predominantly 1 to 20 ~) and also, i~ desired, a perfume is/are added to the resulting mixture, stirring then being carried out - until these ingredients are uniformly dispersed.
Ii the two types of emulsion are combined in this way in a stirrer vessel at temperatures of between 20 and 40~C, pre-ferably particularly gentl~ -at 30C in vacuo, but, whether or not under these preferred specific conditions, then ~ery intensively, so that a very fine dispersion of the two emulsions 0 i9 finally obtained, the particle size o~ which is bet~een 2 and 50 ~, preferably between 5 and 15 ~, then the two types of emulsion are maintained together in an unaltered state in, for exampleJ a cream ~o produced. This emulsion system remains stable when substantiPlly diluted, for example with a liquid phase~
It is assumed that the particle size as well as the interaction of the emulsifiers is important ~or the stability of this emul~ion system~ It is essential that, ~hen manufacturing such a corticoid-cont~ n~
preparation according to the present invention, the emul~ions used are dlspersed and not homogenised.
The two emulsions are combined preferably under a vacuum of from 0.5 torr to 50 torr. ~s is well known to the person skilled in the art, the ~tirring speed depends on the stirring apparatus used and must be ascertained in a manner Xnown per se.
The mi~ture ratio of the oil/water emulsion and the water/oil emulsion is preferably irom 20 to 30%
by weight, and especially from 35 to 65% ~y weight, of the oil/~later emulsion.
. 5 As indicated above, perfumes, for example those of the Crematest(R) series, may also be added to the ~inely dispersed systemO
A corticoid-contai n; n~ preparation according to the present invention in the form of a cream may, ~or e~ample, consist o~ the following components:
Table I
~olerance~
hydrocortisone 21-acetate, micronised 0~5~ 0~1 - 1%
15 (particle si~e pre-dominantly from 1 to 20 ~
puroba oil 5~D 5 ~ lO~o cer~ alba (beeswax) 1~D 1 ~ 5~o Dehymul8(R) 1/~D 1 ~ 3%
20 stearyl alcohol, 4~ 4 - 8~
hYdrOCarbOn9 30~'D ~50 ~ 50~;
Carbopol(~
(R) ~% 2 - 5~o disodium edetate 1~
25 chlorquinaldol 1%
puri~ied demineralised water 52~D 30 - 55%
Table I continued:
perfume oil 0.5~o 3Q _ 55 The percen~ages given are percentage~ by weight~
~he ~ollowing ~ample~ illustrate the invent~on.
The procedures described therein for the manufacture of the preparations may be carried out usin~ any of the apparatus conventionally used for the manufacture of, for example, ointments and creams.
~xample 1 Manufacture of an oil/water emulsion 10.00 g of disodium edetate and 10~00 g o~
chlorquinaldol were dissolved in 300.00 g of puri fied demineralised water and 10.00 g of Carbopol(R) were added thereto.
While stirring vigorously, this mixture was incorporated into a melt of 80.00 g of vaseline (DA~ 8), DAB being the abbre~iation ~or the Deutsche Arzneibuch tGerman Pharmacopoeia), official publica-tion, 8th edition 1978, 40.00 g of stearyl alcohol, 30.00 g of ~nRJ~R) and 50.00 g of puroba oil. ~he mi~ture was further stirred until an emulsion ha~
ing a particle size of from 20 to 70 ~ wa~ formed.
Manufacture of a water/oil emulsion . While stirrlng vigorously~ 228.00 g of purified demineralised water were incorporated into a melt of 220.00 g of vaseline (DAB 8), 10.00 g of Dehymuls(R) and 10.00 g of cera alba. The mixture was further stirred until an emulsion having a particle size o~ from 20 to 70 ~ was formed, Manufacture of a cream While stirring vigorously, the water/oil emulsion prepared as described above was incorpor-ated at room temperature under a vacuum of 10 torr into the oil/water emulsion prepared as desoribed above. Stirring was continued until a disper~ion having a particle size of from 10 to 50 ~ was formed; the vacuum was then removed and, while stirring, 5.000 g of hydrocortisone 21-acetate -in a micronised form having a particle size of pre-dominantly from 1 to 20 ~ - and 2.00 g o~ a Crematest(R) perfume were added and stirring ~as continued until the two components had been uniform~
ly dispersed in the ointment base.
~xam~le 2 Manufacture of an oil/~ater emulsion 10.00 g of disodium edet~te and 10.00 g of chlorquinaldol were dissolved in 300.00 g o~ puri-fied demineralised water and 10~00 g of ~arbopol(R) were added thereto.
~ hile stirring vigorously, this mixture was incorporated into a melt of 80.00 g of vaseline (D~B 8), DA3 being the abbreviation for the Deutsche Arzneibuch (German Pharmacopoela), official publica-tion, 8th edition 1978, 40.00 g of stearyl alcohol, 30~00 g of ~rYRJ(R) and 50.00 g o~ puroba oil. The mi~ture was ~urther stirred until an emulsion having a particle size of ~rom 20 to 70 ~ was formed.
Manufacture of a wa~er/oil em~lsion While stirring vigorously, 227.00 g of puri-fied demineralised water were incorporated into a melt of 220.00 g of vaseline (DAB 8), 10.00 g of Dehymuls(R) and 10.00 g of cera alba. ~he mixture was further stirred until an emulsion having a particle size of from 20 to 70 ~ was formed.
Manufacture of a cream While stirring ~igorously, the water/oil emulsion prepared as described above was incorpor-ated at room temperature under a vacuum,of 10 torr into the oil/water emulsio~ prepared as described above. Stirring was continued until a disper~ion having a particle size of ~rom 10 to 50 ~ was formed; the vacuum was then removed9 and, while stirring, 1.000 g of 21-aceto~y~ hydroxy-6a-methyl-17o-propion~loxy-~1'4-pregnadiene-3,20-dione - in a micronised form having a particle size of predominantly from 1 to 20 ll - and 2~00 g of a Crematest(R) perfume were added and stirring was continued until the two components had been uniformly dispersed in the ointment base.
Exam~le 3 Manufacture of an oil/water emulsion 10.00 g o~ di~odium edetate and 10.00 g oi chl~rql~in~l~ol were d~ssolved in 300~00 g o~ puri-~ied demineral~sed water and 10.00 g of Carbopol(~) were added theretoO
While ~tirring vlgorously, this mi~ture was incorporated into a melt of 80.00 g of vaseli~e (DAB 8), DAB being the abbreviation for the Deutsche Arzneibuch (German Pharmacopoeia), official publica-tion, 8th edition 1978, 40.00 g of stearyl alcohol, ~0.00 g of MYRJ(R) and 50.00 g of puroba oil. The mixture wa~ further ~tirred until a~ emulsion having a particle size of ~rom 20 to 70 ~ was formed~
Manu~acture o~ a water~oil emulsion While stirring vigorously, 227.00 g of puri-fied demineralised water were incorporated into amelt of 220.00 g of ~aseline (DAB 8), 10.00 g of Dehymuls(R) and 10.00 g of cera alba. The mixture was further stirre~ until an emulsion having a particle size of from 20 to 70 u was formed~
Manuiacture of a cream While stirring vigorously, the water/oil emulsion prepared as described above was incorpor-ated at room temperature under a vacuum o~ 10 torr into the oil/water emulsion prepared as described above. Stirring ~a~ continued until a disper~ion having a partlcle size of from 10 to 50 ~ was formed; the vacuum wa~ then removed and 9 while stirring, 1.000 g of 21-aceto~y-17a-butyrylo~y~
hydroxy-6-methyl-~4-pregnene-3,20-dione - in a micronised form having a particle size of pre-dominantly from 1 to 20 ~ - and 2.00 g of a ~rematest(R) perfume were added and stirring was continued until the two components had been uni-formly dispersed in the ointment baseO
Exam~le 4 Nanufacture of an oil/water emulsion 10.00 g o~ disodium edetate and 10.00 g ofchlorquinaldol were dissolved in 300.00 g of puri-~ied demineralised water and 10.00 g of ~arbopol(were added thereto.
~ ile stirring vigorously, this mixture was incorporated into a me}t of 80.00 g of vaseline (DAB 8~ 7 DAB being the abbreviation ~or the Deutsche Arzneibuch (German Pharmacopoeia), official publ~ca-tion, 8th edition 1978, 40.00 g of stearyl alcohol, 30.00 g of ~ J(R) and 50.00 g of puroba oil.
The mixture was further s~irred until an emulsion having a particle size of from 20 to 70 ~ wa~
formed.
Manufscture o~ a water/oil emulsion While stirring vigorously, 227.00 g o~ puri~ied demineralised water were ~ncorporated into a melt o~
220.00 g of vaseli.ne (DAB 8), 10.00 g o~ Dehymuls(R) and 10.00 g of cera albaO The mixture was ~urther stirred until an emulsion having a particle size of ~rom 20 to 70 ~ was formed.
~anu~acture of a cream While stirring vigorously, the water~oil emul9ion prepared as described above was incorpora-ted at room temperature under a vacuum of 10 torr into the oil/water emulsion prepared a~ described above~ Stirring was continued until a disper~ion having a particle size of ~rom 10 to 50 ~ was formed; the vacuum was the~ removed and, while stirring, 1~000 g of 21-acetoxy-9a-chloro-11~-hydro~y-17a-propionyloxy-~1~4-pregnadiene-3 t 20-dione - in a micronised ~orm having a particle size of predom;n~ntly ~rom 1 to 20 ~ - and 2.00 g of a Crematest( ) per~ume were added and stirring was continued until the ~wo components had been uni~ormly dispersed in the ointment baseO
Example ~
Manu~acture o~ an oil~water emulsion 10~00 g of disodium edetate and 10.00 g o~
chlorquinaldol were dissolved in 300~00 g of puri-fied demineralised water ~nd 10.00 g of Carbopol~) were added thereto~
While stirring vigorously, this mixture was incorporated into a melt of 80.00 g of vaseline (DAB 8), DAB being the abbreviation for the Deutsche Ar~.neibuch (German Pharmacopoeia), official publi-cation, 8th edition 1978, 40.00 g of stearyl alco-hol, ~0.~0 g of MYRJ(R) and 50.00 g of puroba oil.
The mixture was further stirred until an emulsion having a particle size of from 20 to 70 ~ was formed.
Manufacture of a ~ater~oil emulsion While stirring vigorously1 227050 g of purified demi~eralised water were incorporated into a melt of 220.00 g of vaseline (DA3 8) t 10.00 g of Dehymul~(R) and 10.00 g of cera albaa The mixture wa~ further stirred until a~ emulsion having a . 20 particle size o~ from 20 to 70 ~ was formedO
Manufacture of a cream While stirring vigorously, the water~oil emulsion prepared as described a~ove was incorpor-ated at room temperature under a vacuum of 10 torr ~o~
i~to the oil/water emulsion prepared a~ described above. Stirring was continued until a disperæion having a particle size of from 10 to 50 ~ wa9 formed; the vacuum was then removed and, while stirring, 0.500 g of clobetasol 17-propionate -in a micronised form having a particle ~ize of predom;nPntly ~rom 1 to 20 ~ - and 2.00 g of a Cremates~(R) perfume were added and ~tirr~ng was continued until the two components had been uni-formly dispersed in the ointment base.
E2am~>1e 6 ~anufacture of an oil/water emulsion 10.00 g of disodium edetate and 10.00 g of chlorquinaldol were dissolved in 300 00 g of puri~ied demineralised wat~r and 10.00 g of Carbopol(R) were added thereto.
While stirring vigorously, this mixture was incorporated into a melt of 80000 g of vaseline (DAB 8), DAB being the abbreviation for the Deutsche Arzneibuch (German Pharmacopoeia), official publica-tion, 8th edition 1978, 40.00 g of stearyl alcohol, ~0.00 g of MYRJ(R) and 50.00 g of puroba oil. ~he mixtur~ was further stirred until an emulsion having a particle ~ize of from 20 - 70 ~ was formed.
Manufacture of a water/oil emulsion While ~tirring vigorously, 227.00 g of puri-fied demineralised water were incorporated into a melt of 220.00 g of vaseline tD~B 8), 10.00 g of Dehymuls(R) and 10.00 g o~ cera albaO The mixture was further stirred until an emulsion having a particle size of from 20 to 70 ~ was formedO
Manufacture of a cream While stirring vigorously, the wster/oil emulsion prepared as described above was incorpora-ted at room temperature under a vacuum of 10 torr into the oil/~ater emulsion prepared as described.
above~ Stirring was continued until a dispersion having a particle size of from 10 to 50 ~ was formed; the vacuum was then removed and, while stirring, 1.000 g of diflucortolone 21-valerate -in a micronised form having a particle size of predom;n~ntly from 1 to 20 ~ - and 2.00 g of a Crematest(R) perfume were added and stirring was continued until the two components had been uni-formly dispersed in the ointment base.
ExamPle 7 Manufacture of an oil/water emulsi.on 10-00 e of disodium edetate and 10.00 ~ of chlorquinaldol were dis~olved in ~00.00 g o~ puri fied demineraliced water and 10.00 g o~ Carbopol(~) were added thereto.
While stirring vigorously; this mixture was incorporated into a melt of 80.00 g of vaseline (D~B 8), DAB being the abbreviation for the Deut~che Arzneibuch (German Pharmacopoeia), official publi-cation, 8th edition 1978, 40.00 g of stearyl ~lco-hol, 30.00 g of MYRJ(R~ and 50.00 g of puroba oil~
The mixture was further ~tirred until a~ emulsion having a particle size o~ from 20 to 70 ~ was formed~
Manufacture of a water~oil emulsion While stirring v}gorously, 227.00 g of puri-fied demineralised water were incorporated into a melt of 220~00 g of vaseline (D~B 8), 10.00 g of Dehymuls(R~ a~d 10.00 g of cera alba. The mixture was further stirred until a~ emulsion ha~i~g a par-ticle ~ize of from 20 to 70 ~ was formed.
Manufacture of a cream While stirring vigorously, the waterJoil emulsion prepared as described above was incorpor-ated at room temperature under a ~acuum of 10 torr into the oil/water emul~ion prepared as describe~
above. Stir.ring wa8 continued until a dispersion having a particle size of from 10 to 50 ~ wa~
formed; the vacuum was then removed and, while stirring, 1.000 g of 21-acetoxy-17~ethoxymethoxy-~ hydroxy-~l'4-pregnadiene-3,20-dione - in a microni~ed form having a particle s~ze of pre-dom~n~ntly from 1 to 20 ~ - and 2.00 g of a Cremate6t(R) perfume were added and stirring was continued until the two components had been uni-formly dispersed in the ointment base.
~ corticoids of the general formula Ib suitable for the manufacture of the corticoid-containing pre-parations according to the present inventio , theremay be mentioned, ~or e~ample, fluocortolone, clo-cortolone, di~lucortolone and desoximetasone and esters thereof, for example fluocortolone 21-acetate~
fluocortolone 21-caproate, fluocortolone 21-tri-methylacetate, clocortolone 2~-caproate, clocortolone 21-trimethylacetate and diflucortolone 21-valerate~
As corticolds of the ~eneral ~ormula Ic ~uit~ble for the manufacture of the corticoid-cont~in;n~ pre-parations according to the present in~ention, there may be mentioned, ~or e~ample, betametha~one, beclo-5 methasone, fluprednylidene, clobetasol, dexamethasone1flumetasone and 9-chloropredni6010ne and ester~ there-o~, for example betamethasone 17-valerate, beta-methasone 17-benzoate, betamethasone 17,21-dipropio-nate, beclometha~one 17,21-dipropionate, flupredn~
dene 21-acetate, clobetasol 17-propionate, ~lumetasone 21-trimethylacetate, 9-chloropredni~olone 21-acetate-17 propionate and 9-chloropredni~olone 17-butyrate 21-propionate.
As corticoids of the general formula Id ~uitable ~or the manu~actuxe of the corticoid-cont~; n; n~ pr~-paration~ according to the present invention, there may be mentioned9 for example, triamcinolone9 tri-amcinolone acetamide, halcinonide, ~luocinolone, fluocinolone acetonide~ desonide and fludroxicortide and e~ters thereof, ~or e~ample fluocinonideJ
~owever, anti-infla~matorily acti~e corticoids that do not come within the scope of the general formula I are also suitable ~or the manuPacture of the corticoid-cont~in;n~ preparations accordlng ~o the ~5 present in~ention. ~s such compounds, there may be mentioned by way of e~ample corticoidq that differ tll ~4 from those of the general formula I in that, instead o~ the grouping IH2Z, they carry a group COORlo (~ 0 representing an ~lkyl group cont~ n; n~ up to 6 carbon atoms) - disclosed in United States Patent Speci~ica-tion I~os~ ~,824,260~ ~,919,421 and 3,9447577. Theremay be mentioned as an example of a corticoid ha~ing this class of structure fluocortin butyl ester.
~owever, other suitable corticoids are, for example, tho~e that differ from the corticoids of the formula I in that they carry a keto group i~stead o~ a hydro~yl group in the ll-position. Clobeta~one 17-butyrate may be mentioned as an example.
The preparations of the present invention con-tain from 0.005 to 2% by weight, but preferably irom 0.05 to 0.5~ by weight, o~ the cor~icoid~ the co~-centration of the corticoid is, o~ course, dependent on the relati~e activity of the corticoid.
The preparations of the present invention may contain the jojoba oil in an a~ount within the range of from 1 to 50~ by weight, for example 1 to 25% by weight~ preferably 3 to 15% by weight, more pre-ferably 3 to 10~ by weight.
As in the case of the previously known corticoid-cont~i n; n~ preparations suitable for topical applica-tion, the preparations of the present invention mayalso be in the form of an oil/water emulsion (for e~ample in the form of a miIk or cream) t in the form of a water/oil emulsion (~or e~ample in the form o~ a fatty ointment) or ln the ~orm of an oily suspension (for example i~ the ~orm o~ a ~atty spray). Accord-. 5 ing to the present invention, from 1 to 15% by ~eight,and preferably from ~ to 10~ by weight, of jojoba oil i9 used in the case o~ the oil~water emulsions or water/oil emulsions and at least 50~ by weight o~
jojoba oil is used in the case of the oily suspensions.
The jojoba oil i~ preferably used in a purified form (for example puroba oil). The jojoba oil ma~ for example, have been decolorise~ and purified by mea~s of activa carbon7 The oil/water emulsions and the water~oil emul sions may be prepared in a co~Yentional manner usLng conventional emulsifiers (Eirk Othmer: ~ncyclopaedia of Chem~cal Technology, ~rd edition, lQ79; John Wiley & Sons; New York etc. vol. 8, pages 900 to 930 and Dr. Otto-Albrecht ~eum~ller: R~mpps Chemie ~exikon, 7th edition, 1973; Franck'sche Verlags-handlung Stuttgart, pages 1009 to 1013). ~he waxes, emulsifiers and other additives used ~or these emulsions may be the same as are conventionally used in emulsi~ied skin-care agents (Dr. Otto-~lbrecht Neum~ller: R~mpps Chemie ~exikon, 7th edition 197~;
~ranck'sche Verlag~h~n~lung Stuttgart, pages 1427 and 1428~.
~ preparation according to the present invention in the form of an oil/water emulsion may comprise one or more hydrophilic and/or lipophilic active sub-stance~ (one of which such substances is the jojobaoil), a fatty phase, an oil/water emulsi~ier, an aqueous phase and a preservative.
There may be used as the hydrophilic and/or lipo-philic active substancea humectant ~actors (hydro-comple~es), ~or example glycerine, polyethyleneglycols or ~m;no acid mixtures, puroba oil (=jojoba oil~, ~itamins (preferably vitamins h and E), vital comple~es(for example placenta egtracts)9 enzymesy herb extracts(for example Eamamelis extract or c~mo~;le extract~ or proteins(for e~ample collagen).
Suitable as the oily phase or the fatty phase in the oil/water emulsions are hydrocarbons, for example vaseline, paraffins or stearin, or waxes, for e~ample beesw~. Suitable oil~water emulsifiers are, ~or e~ample, stearyl alcohol, polyoxyethylene stearates (for example ~nRJ(R)), complex emulsifiers ~or example Qmphoterin(R)) and sorbitan ~atty acid esters (for e~ample Span(R)) or carbo~yvinyl polymers (for example Carbopol(R)). The aqueous phase may also contain a bu~fer substance, for example the disodium salt of ethylene~i~mine-N,N,~',N'-tetraacetic acid, and a preservati~e, ~or e~ample chlorquinaldol9 parabens or benzalkonium chloride.
In the oil/water emNlsions, the proportion of the inner em~ ;o~ is preferably from ~0 to 49% by weight . 5 and the particle si~e of the inner emulsion is pre-ferably between 1 ~ and 50 ~
preparation accordin~ to the present invention, ~or example a cosmeti~ ~reparation, in the form of a water/oil emulsion may likewise comprise one or more hydrophilic and/or lipophilic active substances, of the type also used in the oil/water emulsions, a ~atty phase, a water~oîl emulsifier and an aqueous phase~ There may be used as the oily phase or the fatty phase of the water/oil emulsio~s hydrocarbonsf for example paraffins ~nd vaseline, and synthetic, vegetable and ~n;m~l oils or wa~es(for example olive oil, ground-nut oil, fine bone oil, almond oil, lanolin, beeswa~ or sunflower oil), as the aqueous ph2se puri~ied ~emineralised water and, as the water/
oil emulsifier, wool ~at (=lanolin), fatty alcohols, for example cetyl alcohol, myristyl alcohol, stearyl alcohol or ceryl alcohol, fatty acid esters, for example beeswax (cera alba) or wax alcohol ester~ or mixed esters(for e~ample Dehymuls(R)).
~he proportion of the inner emulsion in the water/oil emulsions is pre~erably from 30 to 4g~ by weight and the particle si~e of the inner emulsion iB preferably between 1 ~ and 100 ~ ~urir~ the dispersion of the two phases, the particle ~ize is reduced further and in the ~inlshed product it is less than 50 ~.
The preparations oi the present invention pre-ferably contain the corticoid in a micronised form (particle size predom;n~tly from 1 to 20 ~) and ma~
also contain a perfume, for example one o~ the 10 Crematest( ) series. These components are uni~ormly dispersed in the preparations hav~ng been incorporated, for e~ample, into the finely dispersed system~ as described above by stirring.
A preparation according ~o the present invention cont~; ni n~ a fatty phase and an aqueous phase may be in the form of a finely dispersed mixture o~ an oil/water emulsion cont~;n;ng an oil/water emulsifier and a pre~ervative and (ii~ a water/oil emulsion con-t~inin~ a water/oil emulsifier. In such a preparation which may~ for egample, be in the ~orm of an ointment, paste or cream, the jojoba oil is advantageously present in the oil/water emulsion. This type of preparation ma~ also contain a hydrophilic and~or lipophilic active substance other than jojoba oil~
The oil/water emulsion and the water/oil emulsion ma~
haYe been produced in the manner already described above.
When ueing a cream of this type of constitution cont~;n;n~ an extremely ~inely dispersed mixture o~
the two types o~ emul~ion, a corresponding oil/water . 5 or water/oil hydrolipid film can be produced on the s~in depending on the moistne3s in the various skin areas, or depending on the skin type~
In such a preparation according to the present inve~tion, the particle size of the emulsion is pre-ferably ~rom 2 to 50 ~.
?here is also included within the scope of thepresent invention a process for the manufacture of the corticoid-cont~inin~ preparation in the for~ of a finely dispersed mi~ture of an oil~water emulsio~
and a water/oil emulsion, for e~ample an ointment, paste or cream, wherein an oil~water emulsion that has been produced from a fatty phase, ~n aqueous phase, an oil/water emulsi~ier and a preservative is intimately mixed, preferably in acuo, at a tem-perature within the range of from 20 to 40C with a water/oil emulsion that has been produced from afatt~ phase, an aqueous phase and a water/oil emul-sifier, the oil/water emulsion and/or the water/oil emulsion cont~l;n~n~ jojoba oil, and then an anti-inflammatorily acti~e corticoid in a micronised form~particle size preferably predominantly 1 to 20 ~) and also, i~ desired, a perfume is/are added to the resulting mixture, stirring then being carried out - until these ingredients are uniformly dispersed.
Ii the two types of emulsion are combined in this way in a stirrer vessel at temperatures of between 20 and 40~C, pre-ferably particularly gentl~ -at 30C in vacuo, but, whether or not under these preferred specific conditions, then ~ery intensively, so that a very fine dispersion of the two emulsions 0 i9 finally obtained, the particle size o~ which is bet~een 2 and 50 ~, preferably between 5 and 15 ~, then the two types of emulsion are maintained together in an unaltered state in, for exampleJ a cream ~o produced. This emulsion system remains stable when substantiPlly diluted, for example with a liquid phase~
It is assumed that the particle size as well as the interaction of the emulsifiers is important ~or the stability of this emul~ion system~ It is essential that, ~hen manufacturing such a corticoid-cont~ n~
preparation according to the present invention, the emul~ions used are dlspersed and not homogenised.
The two emulsions are combined preferably under a vacuum of from 0.5 torr to 50 torr. ~s is well known to the person skilled in the art, the ~tirring speed depends on the stirring apparatus used and must be ascertained in a manner Xnown per se.
The mi~ture ratio of the oil/water emulsion and the water/oil emulsion is preferably irom 20 to 30%
by weight, and especially from 35 to 65% ~y weight, of the oil/~later emulsion.
. 5 As indicated above, perfumes, for example those of the Crematest(R) series, may also be added to the ~inely dispersed systemO
A corticoid-contai n; n~ preparation according to the present invention in the form of a cream may, ~or e~ample, consist o~ the following components:
Table I
~olerance~
hydrocortisone 21-acetate, micronised 0~5~ 0~1 - 1%
15 (particle si~e pre-dominantly from 1 to 20 ~
puroba oil 5~D 5 ~ lO~o cer~ alba (beeswax) 1~D 1 ~ 5~o Dehymul8(R) 1/~D 1 ~ 3%
20 stearyl alcohol, 4~ 4 - 8~
hYdrOCarbOn9 30~'D ~50 ~ 50~;
Carbopol(~
(R) ~% 2 - 5~o disodium edetate 1~
25 chlorquinaldol 1%
puri~ied demineralised water 52~D 30 - 55%
Table I continued:
perfume oil 0.5~o 3Q _ 55 The percen~ages given are percentage~ by weight~
~he ~ollowing ~ample~ illustrate the invent~on.
The procedures described therein for the manufacture of the preparations may be carried out usin~ any of the apparatus conventionally used for the manufacture of, for example, ointments and creams.
~xample 1 Manufacture of an oil/water emulsion 10.00 g of disodium edetate and 10~00 g o~
chlorquinaldol were dissolved in 300.00 g of puri fied demineralised water and 10.00 g of Carbopol(R) were added thereto.
While stirring vigorously, this mixture was incorporated into a melt of 80.00 g of vaseline (DA~ 8), DAB being the abbre~iation ~or the Deutsche Arzneibuch tGerman Pharmacopoeia), official publica-tion, 8th edition 1978, 40.00 g of stearyl alcohol, 30.00 g of ~nRJ~R) and 50.00 g of puroba oil. ~he mi~ture was further stirred until an emulsion ha~
ing a particle size of from 20 to 70 ~ wa~ formed.
Manufacture of a water/oil emulsion . While stirrlng vigorously~ 228.00 g of purified demineralised water were incorporated into a melt of 220.00 g of vaseline (DAB 8), 10.00 g of Dehymuls(R) and 10.00 g of cera alba. The mixture was further stirred until an emulsion having a particle size o~ from 20 to 70 ~ was formed, Manufacture of a cream While stirring vigorously, the water/oil emulsion prepared as described above was incorpor-ated at room temperature under a vacuum of 10 torr into the oil/water emulsion prepared as desoribed above. Stirring was continued until a disper~ion having a particle size of from 10 to 50 ~ was formed; the vacuum was then removed and, while stirring, 5.000 g of hydrocortisone 21-acetate -in a micronised form having a particle size of pre-dominantly from 1 to 20 ~ - and 2.00 g o~ a Crematest(R) perfume were added and stirring ~as continued until the two components had been uniform~
ly dispersed in the ointment base.
~xam~le 2 Manufacture of an oil/~ater emulsion 10.00 g of disodium edet~te and 10.00 g of chlorquinaldol were dissolved in 300.00 g o~ puri-fied demineralised water and 10~00 g of ~arbopol(R) were added thereto.
~ hile stirring vigorously, this mixture was incorporated into a melt of 80.00 g of vaseline (D~B 8), DA3 being the abbreviation for the Deutsche Arzneibuch (German Pharmacopoela), official publica-tion, 8th edition 1978, 40.00 g of stearyl alcohol, 30~00 g of ~rYRJ(R) and 50.00 g o~ puroba oil. The mi~ture was ~urther stirred until an emulsion having a particle size of ~rom 20 to 70 ~ was formed.
Manufacture of a wa~er/oil em~lsion While stirring vigorously, 227.00 g of puri-fied demineralised water were incorporated into a melt of 220.00 g of vaseline (DAB 8), 10.00 g of Dehymuls(R) and 10.00 g of cera alba. ~he mixture was further stirred until an emulsion having a particle size of from 20 to 70 ~ was formed.
Manufacture of a cream While stirring ~igorously, the water/oil emulsion prepared as described above was incorpor-ated at room temperature under a vacuum,of 10 torr into the oil/water emulsio~ prepared as described above. Stirring was continued until a disper~ion having a particle size of ~rom 10 to 50 ~ was formed; the vacuum was then removed9 and, while stirring, 1.000 g of 21-aceto~y~ hydroxy-6a-methyl-17o-propion~loxy-~1'4-pregnadiene-3,20-dione - in a micronised form having a particle size of predominantly from 1 to 20 ll - and 2~00 g of a Crematest(R) perfume were added and stirring was continued until the two components had been uniformly dispersed in the ointment base.
Exam~le 3 Manufacture of an oil/water emulsion 10.00 g o~ di~odium edetate and 10.00 g oi chl~rql~in~l~ol were d~ssolved in 300~00 g o~ puri-~ied demineral~sed water and 10.00 g of Carbopol(~) were added theretoO
While ~tirring vlgorously, this mi~ture was incorporated into a melt of 80.00 g of vaseli~e (DAB 8), DAB being the abbreviation for the Deutsche Arzneibuch (German Pharmacopoeia), official publica-tion, 8th edition 1978, 40.00 g of stearyl alcohol, ~0.00 g of MYRJ(R) and 50.00 g of puroba oil. The mixture wa~ further ~tirred until a~ emulsion having a particle size of ~rom 20 to 70 ~ was formed~
Manu~acture o~ a water~oil emulsion While stirring vigorously, 227.00 g of puri-fied demineralised water were incorporated into amelt of 220.00 g of ~aseline (DAB 8), 10.00 g of Dehymuls(R) and 10.00 g of cera alba. The mixture was further stirre~ until an emulsion having a particle size of from 20 to 70 u was formed~
Manuiacture of a cream While stirring vigorously, the water/oil emulsion prepared as described above was incorpor-ated at room temperature under a vacuum o~ 10 torr into the oil/water emulsion prepared as described above. Stirring ~a~ continued until a disper~ion having a partlcle size of from 10 to 50 ~ was formed; the vacuum wa~ then removed and 9 while stirring, 1.000 g of 21-aceto~y-17a-butyrylo~y~
hydroxy-6-methyl-~4-pregnene-3,20-dione - in a micronised form having a particle size of pre-dominantly from 1 to 20 ~ - and 2.00 g of a ~rematest(R) perfume were added and stirring was continued until the two components had been uni-formly dispersed in the ointment baseO
Exam~le 4 Nanufacture of an oil/water emulsion 10.00 g o~ disodium edetate and 10.00 g ofchlorquinaldol were dissolved in 300.00 g of puri-~ied demineralised water and 10.00 g of ~arbopol(were added thereto.
~ ile stirring vigorously, this mixture was incorporated into a me}t of 80.00 g of vaseline (DAB 8~ 7 DAB being the abbreviation ~or the Deutsche Arzneibuch (German Pharmacopoeia), official publ~ca-tion, 8th edition 1978, 40.00 g of stearyl alcohol, 30.00 g of ~ J(R) and 50.00 g of puroba oil.
The mixture was further s~irred until an emulsion having a particle size of from 20 to 70 ~ wa~
formed.
Manufscture o~ a water/oil emulsion While stirring vigorously, 227.00 g o~ puri~ied demineralised water were ~ncorporated into a melt o~
220.00 g of vaseli.ne (DAB 8), 10.00 g o~ Dehymuls(R) and 10.00 g of cera albaO The mixture was ~urther stirred until an emulsion having a particle size of ~rom 20 to 70 ~ was formed.
~anu~acture of a cream While stirring vigorously, the water~oil emul9ion prepared as described above was incorpora-ted at room temperature under a vacuum of 10 torr into the oil/water emulsion prepared a~ described above~ Stirring was continued until a disper~ion having a particle size of ~rom 10 to 50 ~ was formed; the vacuum was the~ removed and, while stirring, 1~000 g of 21-acetoxy-9a-chloro-11~-hydro~y-17a-propionyloxy-~1~4-pregnadiene-3 t 20-dione - in a micronised ~orm having a particle size of predom;n~ntly ~rom 1 to 20 ~ - and 2.00 g of a Crematest( ) per~ume were added and stirring was continued until the ~wo components had been uni~ormly dispersed in the ointment baseO
Example ~
Manu~acture o~ an oil~water emulsion 10~00 g of disodium edetate and 10.00 g o~
chlorquinaldol were dissolved in 300~00 g of puri-fied demineralised water ~nd 10.00 g of Carbopol~) were added thereto~
While stirring vigorously, this mixture was incorporated into a melt of 80.00 g of vaseline (DAB 8), DAB being the abbreviation for the Deutsche Ar~.neibuch (German Pharmacopoeia), official publi-cation, 8th edition 1978, 40.00 g of stearyl alco-hol, ~0.~0 g of MYRJ(R) and 50.00 g of puroba oil.
The mixture was further stirred until an emulsion having a particle size of from 20 to 70 ~ was formed.
Manufacture of a ~ater~oil emulsion While stirring vigorously1 227050 g of purified demi~eralised water were incorporated into a melt of 220.00 g of vaseline (DA3 8) t 10.00 g of Dehymul~(R) and 10.00 g of cera albaa The mixture wa~ further stirred until a~ emulsion having a . 20 particle size o~ from 20 to 70 ~ was formedO
Manufacture of a cream While stirring vigorously, the water~oil emulsion prepared as described a~ove was incorpor-ated at room temperature under a vacuum of 10 torr ~o~
i~to the oil/water emulsion prepared a~ described above. Stirring was continued until a disperæion having a particle size of from 10 to 50 ~ wa9 formed; the vacuum was then removed and, while stirring, 0.500 g of clobetasol 17-propionate -in a micronised form having a particle ~ize of predom;nPntly ~rom 1 to 20 ~ - and 2.00 g of a Cremates~(R) perfume were added and ~tirr~ng was continued until the two components had been uni-formly dispersed in the ointment base.
E2am~>1e 6 ~anufacture of an oil/water emulsion 10.00 g of disodium edetate and 10.00 g of chlorquinaldol were dissolved in 300 00 g of puri~ied demineralised wat~r and 10.00 g of Carbopol(R) were added thereto.
While stirring vigorously, this mixture was incorporated into a melt of 80000 g of vaseline (DAB 8), DAB being the abbreviation for the Deutsche Arzneibuch (German Pharmacopoeia), official publica-tion, 8th edition 1978, 40.00 g of stearyl alcohol, ~0.00 g of MYRJ(R) and 50.00 g of puroba oil. ~he mixtur~ was further stirred until an emulsion having a particle ~ize of from 20 - 70 ~ was formed.
Manufacture of a water/oil emulsion While ~tirring vigorously, 227.00 g of puri-fied demineralised water were incorporated into a melt of 220.00 g of vaseline tD~B 8), 10.00 g of Dehymuls(R) and 10.00 g o~ cera albaO The mixture was further stirred until an emulsion having a particle size of from 20 to 70 ~ was formedO
Manufacture of a cream While stirring vigorously, the wster/oil emulsion prepared as described above was incorpora-ted at room temperature under a vacuum of 10 torr into the oil/~ater emulsion prepared as described.
above~ Stirring was continued until a dispersion having a particle size of from 10 to 50 ~ was formed; the vacuum was then removed and, while stirring, 1.000 g of diflucortolone 21-valerate -in a micronised form having a particle size of predom;n~ntly from 1 to 20 ~ - and 2.00 g of a Crematest(R) perfume were added and stirring was continued until the two components had been uni-formly dispersed in the ointment base.
ExamPle 7 Manufacture of an oil/water emulsi.on 10-00 e of disodium edetate and 10.00 ~ of chlorquinaldol were dis~olved in ~00.00 g o~ puri fied demineraliced water and 10.00 g o~ Carbopol(~) were added thereto.
While stirring vigorously; this mixture was incorporated into a melt of 80.00 g of vaseline (D~B 8), DAB being the abbreviation for the Deut~che Arzneibuch (German Pharmacopoeia), official publi-cation, 8th edition 1978, 40.00 g of stearyl ~lco-hol, 30.00 g of MYRJ(R~ and 50.00 g of puroba oil~
The mixture was further ~tirred until a~ emulsion having a particle size o~ from 20 to 70 ~ was formed~
Manufacture of a water~oil emulsion While stirring v}gorously, 227.00 g of puri-fied demineralised water were incorporated into a melt of 220~00 g of vaseline (D~B 8), 10.00 g of Dehymuls(R~ a~d 10.00 g of cera alba. The mixture was further stirred until a~ emulsion ha~i~g a par-ticle ~ize of from 20 to 70 ~ was formed.
Manufacture of a cream While stirring vigorously, the waterJoil emulsion prepared as described above was incorpor-ated at room temperature under a ~acuum of 10 torr into the oil/water emul~ion prepared as describe~
above. Stir.ring wa8 continued until a dispersion having a particle size of from 10 to 50 ~ wa~
formed; the vacuum was then removed and, while stirring, 1.000 g of 21-acetoxy-17~ethoxymethoxy-~ hydroxy-~l'4-pregnadiene-3,20-dione - in a microni~ed form having a particle s~ze of pre-dom~n~ntly from 1 to 20 ~ - and 2.00 g of a Cremate6t(R) perfume were added and stirring was continued until the two components had been uni-formly dispersed in the ointment base.
Claims (32)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A preparation suitable for topical applica-tion, which comprises jojoba oil and 0.005 to 2% by weight of an anti-inflammatorily active corticoid.
2. A preparation as claimed in claim 1, wherein the corticoid is present in an amount within the range of from 0.05 to 0.5% by weight.
3. A preparation as claimed in claim 1 or 2, wherein the corticoid is a compound of the genaral formula I
(I) in which = represents a single or double carbon-to-carbon bond, X represents a hydrogen or fluorine atom or a methyl group, Y represents a hydrogen, fluorine or chlorine atom, Z represents a hydroxyl group, an alkanoyloxy group containing 2 to 6 carbon atoms, an alkoxymethoxy group, a benzoyloxy group or a chlorine atom, and R1 represents a hydrogen atom and, together with R2, an isopropylidenedioxy group, or R1 represents two hydrogen atoms, a hydrogen atom and a hydroxyl group, a methylene group, or a hydrogen atom and a methyl group, and R2 represents a hydrogen atom, a hydroxyl group, an alkanoyloxy group containing 2 to 6 carbon atoms, an alkoxymethoxy group or a benzoyloxy group.
(I) in which = represents a single or double carbon-to-carbon bond, X represents a hydrogen or fluorine atom or a methyl group, Y represents a hydrogen, fluorine or chlorine atom, Z represents a hydroxyl group, an alkanoyloxy group containing 2 to 6 carbon atoms, an alkoxymethoxy group, a benzoyloxy group or a chlorine atom, and R1 represents a hydrogen atom and, together with R2, an isopropylidenedioxy group, or R1 represents two hydrogen atoms, a hydrogen atom and a hydroxyl group, a methylene group, or a hydrogen atom and a methyl group, and R2 represents a hydrogen atom, a hydroxyl group, an alkanoyloxy group containing 2 to 6 carbon atoms, an alkoxymethoxy group or a benzoyloxy group.
4. A preparation as claimed in claim 1 or 2 wherein the corticoid is a compound of the general formula Ia (Ia) in which = represents a single or double carbon-to carbon bond, X' represents a hydrogen atom or a methyl group, and R3 and R4 each represents a hydrogen atom, an alkanoyl group containing 2 to 6 carbon atoms, an alkoxymethyl group or a benzoyl group.
5. A preparation as claimed in claim 1 or 2 wherein the corticoid is a compound of the general formula Ib (Ib) in which Y is hydrogen or a chlorine or fluorine atom, X" represents a hydrogen or fluorine atom, and R5 represents a hydrogen atom, an alkanoyl group containing 2 to 6 carbon atoms or a benzoyl group.
6. A preparation as claimed in claim 1 or 2, wherein the corticoid is a compound of the general formula Ic (IC) in which X represents a hydrogen or fluorine atom or methyl, Z represents a hydroxyl group, an alkanoyloxy group con-taining 2 to 6 carbon atoms, an alkoxymethoxy group, a benzoyloxy group or a chlorine atom, Y' represents a fluorine or chlorine atom, R6 represents two hydrogen atoms, a methylene group, or a hydrogen atom and a methyl group, and R7 represents a hydrogen atom, an alkanoyl group contain-ing 2 to 6 carbon atoms or a benzoyl group.
7. A preparation as claimed in claim 1 or 2, wherein the corticoid is a compound of the general formula Id (Id) in which ==== represents a single or double carbon-to-carbon bond, Y represents hydrogen or a chlorine or fluorine atom, Z represents a hydroxyl group, an alkanoyloxy group containing 2 to 6 carbon atoms, an alkoxymethoxy group, a benzoyloxy group or a chlorine atom, X" represents hydrogen or a fluorine atom, R8 and each represents a hydrogen atom or together repre-R9 sent an isopropylidene group.
8. A preparation as claimed in claim 1 or 2, wherein the jojoba oil has been decolorised and purified by means of active carbon.
9. A preparation as claimed in claim 1, wherein the jojoba oil is present in an amount within the range of from 1 to 50% by weight.
10. A preparation as claimed in claim 9, wherein the jojoba oil is present in an amount within the range of from 1 to 25% by weight.
11. A preparation as claimed in claim 10, wherein the jojoba oil is present in an amount within the range of from 3 to 15% by weight.
12. A preparation as claimed in claim 11, wherein the jojoba oil is present in an amount within the range of from 3 to 10% by weight.
13. A preparation as claimed in claim 1, which also contains a fatty phase, an aqueous phase and an emulsi-fier.
14. A preparation as claimed in claim 1, which also contains a preservative.
15. A preparation as claimed in claim 13, which is in the form of an oil/water emulsion.
16. A preparation as claimed in claim 15, wherein the particle size is within the range of from 1 to 50 µ .
17. A preparation as claimed in claim 13, which is in the form of water/oil emulsion.
18. A preparation as claimed in claim 17, wherein the particle size is within the range of from 1 to 50 µ .
19. A preparation as claimed in claim 1, which is in the form of a finely dispersed mixture of (i) an oil/water emulsion containing an oil/water emulsifier and a preserva-tive and (ii) a water/oil emulsion containing a water/oil emulsifier.
20. A preparation as claimed in claim 19, wherein the jojoba oil is present in the oil/water emulsion.
21. A preparation as claimed in claim 19 or 20, wherein the mixture contains 20 to 80% by weight of the oil/
water emulsion.
water emulsion.
22. A preparation as claimed in claim 19 or 20, wherein the mixture contains 35 to 65% by weight of the oil/
water emulsion.
water emulsion.
23. A preparation as claimed in claim 19 or 20, wherein the particle size of the emulsions is within the range of from 2 to 50 µ.
24. A preparation as claimed in claim 13, 14 or 15, which also contains a hydrophilic and/or lipophilic active substance other than jojoba oil.
25. A preparation as claimed in claim 1, which is in the form of an oily suspension.
26. A preparation as claimed in claim 25, wherein the jojoba oil is present in an amount of at least 50% by weight.
27. A preparation as claimed in claim 1 or 2, which also contains a perfume.
28. A preparation as claimed in claim 1, which is in the form of a cream.
29. A preparation as claimed in claim 1 for use as a medicament.
30. A process for the manufacture of a prepara-tion as claimed in claim 19, wherein an oil/water emulsion that has been produced from a fatty phase, an aqueous phase, an oil/water emulsifier and a preservative is intimately mixed at a temperature within the range of from 20 to 40°C
with a water/oil emulsion that has been produced from a fatty phase, an aqueous phase and an water/oil emulsifier, the oil/water emulsion and/or the water/oil emulsion contain-ing jojoba oil, and then an anti-inflammatorily active cor-ticoid in a micronised form is added to the resulting mixture.
with a water/oil emulsion that has been produced from a fatty phase, an aqueous phase and an water/oil emulsifier, the oil/water emulsion and/or the water/oil emulsion contain-ing jojoba oil, and then an anti-inflammatorily active cor-ticoid in a micronised form is added to the resulting mixture.
31. A process as claimed in claim 30, wherein the mixing is carried out in vacuo.
32. A process as claimed in claim 30 or 31, where-in a perfume is added to the mixture of the oil/water and water/oil emulsions.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823225849 DE3225849A1 (en) | 1982-07-07 | 1982-07-07 | PREPARATION OF CORTICOIDS FOR TOPICAL APPLICATION |
| DEP3225849.6 | 1982-07-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1202901A true CA1202901A (en) | 1986-04-08 |
Family
ID=6168122
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000431878A Expired CA1202901A (en) | 1982-07-07 | 1983-07-06 | Corticoid-containing preparations for topical application |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0098568B1 (en) |
| JP (1) | JPS5976014A (en) |
| AT (1) | ATE66596T1 (en) |
| AU (1) | AU570638B2 (en) |
| CA (1) | CA1202901A (en) |
| DE (2) | DE3225849A1 (en) |
| DK (1) | DK312483A (en) |
| GB (1) | GB2122899A (en) |
| NZ (1) | NZ204774A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3225848A1 (en) * | 1982-07-07 | 1984-01-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | PREPARATION OF CORTICOIDS FOR TOPICAL APPLICATION |
| JPS59137408A (en) * | 1983-01-27 | 1984-08-07 | Taisho Pharmaceut Co Ltd | Ointment |
| JPS59139315A (en) * | 1983-01-31 | 1984-08-10 | Taisho Pharmaceut Co Ltd | Cream agent |
| DE3836971C1 (en) | 1988-10-31 | 1990-05-17 | Weck, Wolfgang, Dr.Med., 6990 Bad Mergentheim, De |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI44459B (en) * | 1968-10-25 | 1971-08-02 | K Rehtijaervi | |
| US4070462A (en) * | 1976-10-26 | 1978-01-24 | Schering Corporation | Steroid ointment |
| FR2471775A1 (en) * | 1979-12-18 | 1981-06-26 | Oreal | Cosmetic oils based on jojoba and sunflower oils - contg. added unsaponifiable fraction, used as sun tan preparations, shaving creams etc. |
| FR2474310A1 (en) * | 1980-01-25 | 1981-07-31 | Oreal | STABLE SOLUTION WITH OXIDATION OF VITAMIN F AND JOJOBA OIL AND COSMETIC COMPOSITIONS CONTAINING THE SAME |
| JPS56135416A (en) * | 1980-03-27 | 1981-10-22 | Mitsubishi Chem Ind Ltd | Pharmaceutical preparation for skin |
| SE8004580L (en) * | 1980-06-19 | 1981-12-20 | Draco Ab | PHARMACEUTICAL PREPARATION |
| DE3225848A1 (en) * | 1982-07-07 | 1984-01-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | PREPARATION OF CORTICOIDS FOR TOPICAL APPLICATION |
-
1982
- 1982-07-07 DE DE19823225849 patent/DE3225849A1/en not_active Withdrawn
-
1983
- 1983-07-01 NZ NZ204774A patent/NZ204774A/en unknown
- 1983-07-01 AU AU16469/83A patent/AU570638B2/en not_active Ceased
- 1983-07-04 AT AT83106512T patent/ATE66596T1/en active
- 1983-07-04 EP EP83106512A patent/EP0098568B1/en not_active Expired - Lifetime
- 1983-07-04 DE DE8383106512T patent/DE3382386D1/en not_active Expired - Lifetime
- 1983-07-06 DK DK312483A patent/DK312483A/en not_active Application Discontinuation
- 1983-07-06 JP JP58121699A patent/JPS5976014A/en active Pending
- 1983-07-06 CA CA000431878A patent/CA1202901A/en not_active Expired
- 1983-07-07 GB GB08318397A patent/GB2122899A/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| DE3382386D1 (en) | 1991-10-02 |
| AU1646983A (en) | 1984-01-12 |
| EP0098568A3 (en) | 1985-05-15 |
| ATE66596T1 (en) | 1991-09-15 |
| EP0098568B1 (en) | 1991-08-28 |
| DK312483D0 (en) | 1983-07-06 |
| DK312483A (en) | 1984-01-08 |
| DE3225849A1 (en) | 1984-01-19 |
| EP0098568A2 (en) | 1984-01-18 |
| NZ204774A (en) | 1986-03-14 |
| JPS5976014A (en) | 1984-04-28 |
| AU570638B2 (en) | 1988-03-24 |
| GB8318397D0 (en) | 1983-08-10 |
| GB2122899A (en) | 1984-01-25 |
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Legal Events
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| MKEX | Expiry |