SPECIFICATION
`
`NO DRAWINGS
`
`955989 1
`Date of Application and filing Complete Specification jan. 22, I962.
`No. 2264/62.
`Application made in Netherlands (No. 260,648) on Jan. 3!, I 96] .
`Complete Specification Published April 22, I964.
`© Crown Copyright I964.
`
`Index at acceptance: ——'A5 B(1N, 1R2, IS, IZ, 2N, 2R2, ZS, 2Z)
`International Classification: ——A 61 k
`
`COMPLETE SPECIFICATION
`
`Stable Preparations of Prednisone Derivatives and Process for
`the Manufacture thereof
`
`We, ORGANON LABORATORIES LIMITED, a
`British Company, of Brettenham House, Lan-
`caster Place, London, W.C.2, do hereby de-
`clare the invention, for which we pray that a
`patent may be granted to us, and the method
`by which it is to be performed, to be particu-
`larly described in and by the following state-
`ment:—
`
`The invention relates to the preparation of
`stable, water-containing emulsions of 6-halo-
`prednisone and carboxylic acid esters there-
`of.
`
`It is known that said derivatives of prednis-
`one and particularly _6—fluoro- and 6-chloro-
`prednisone and esters thereof possess consider-
`able biological activity. The 6a-chloro-pred-
`nisone-acetate is, for example, extremely suit-
`able for local treatment of infectious and/or
`allergic cutaneous affections, acute, subchronic
`and chronic eczema and other conditions at-
`tended with itching. See for example R.
`Ledig, Dermatol, Wschr. 141, 121 (1960) and
`W. Schneider, Dtsch. med. Wschr. :84, 2219
`(1959).
`Up to now these medicines have been ap-
`plied in the form of an anhydraulic ointment
`There was, however, a need to have a form
`of administration in which water might be
`used as a vehicle for other uses such as nose-,
`ear— and eye-drops.
`It had been found, how-
`ever,
`that
`the aqueous suspensions of these
`compounds decompose very quickly and that
`independently of the total concentration. Ap-
`parently the part dissolved in water decom-
`poses quickly, after which additional quanti-
`ties of the substances are dissolved each time,
`so that in a short time all its activity has dis-
`appeared.
`Now a process has been found for the manu-
`facture of stable preparations of the predni-
`sone derivatives, characterized in that a 6-
`halo-prednisone or
`a carboxylic acid ester
`thereof is dissolved in an oil suitable for
`
`[Price 45. 6d.]
`
`therapeutic purposes, which solution is emul-
`sified with an aqueous medium. Preferably an
`oil is chosen which chiefly consists of an ester
`of a lower aliphatic alcohol having 1——8 car-
`bon atoms and a higher fatty acid having 12-
`20 carbon atoms, and/or a vegetable oil. It
`was found that thus prepared emulsions of, for
`example, 1 mg of 6s-chloro-prednisone ace-
`tate per ml of a mixture of equal parts of
`ethyl oleate and castor oil show no measur-
`able decomposition when stored for 6 weeks
`at 45° C. In suspensions of the same strength
`the decomposition of
`the active constituent
`amounted on the contrary to 40-50 % in the
`same period of time.
`In the systems according to the invention the
`partition coefiicient for the steroid (water:
`oil) is very small and consequently favourable
`to the stability of the preparation. In the above
`example this coeflicient
`is about 1:400,
`so
`that in a concentration of say 1 mg. per ml
`only 2.5 y at most of the active constituent
`can pass into the water phase and is exposed
`to decomposition. For preference a water-oil
`system is applied with a partition coefficient
`for the steroid (water: oil) of below 1:200.
`As esters of 6~ha1o-prednisones to which
`the invention is applicable, are mentioned the
`esters of aliphatic carboxylic acids with 1-12
`C-atoms, such as acetic acid, propionic acid,
`butyric acid, oenanthylic acid, capric acid and
`lauric acid, further aromatic acids, such as
`benzoic acid and salicylic acid, aryl-aliphatic
`acids, such as ,8—phenylpropionic acid and ali-
`cyclic carboxylic acids,
`such as cyclohexyl
`butyric acid,
`hexahydro-benzoic
`acid and
`cyclopentyl propionic acid.
`The invention relates to the preparation of
`oil-in-water-emulsions, 0/W type,
`as well
`as water-in-oil-emulsions, W/O type. Further
`it was found that very good results are ob-
`tained when using an oil consisting of a
`mixture of castor oil and one or more of
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`AKN 1002
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`955,891 ._—::g
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`the esters: ethyl oleate, ethyl ricinoleate and
`isopropyl myristate as a solvent for the steroid.
`It is generally desirable to use an emulsi-
`fying agent in the preparation of the present
`emulsions. Very suitable are, the polyoxyethy-
`lene-sorbitan-esters of higher fatty acids and
`the sorbitan-esters of these fatty acids, such
`as the monolaurate, monopalmitate, mono-
`stearate and mono-oleate. Preferably a mix-
`ture thereof is applied. The choice and the
`quantity of the emulsifying agent to be added
`is in the first place determined by their solu-
`bilizing power
`as compared with that of
`the active component. If too high a concen-
`tration is taken the solubility of
`the active
`substance in the water phase is unnecessarily
`increased and the stability decreased. Hence
`the smallest possible quantity of emulsifying
`agent
`is preferably applied.
`When choosing the most suitable emulsify-
`ing agents the HLB-value must be taken into
`account (see Pharmacy International 11, Nr.
`11, 29 (1957). It has been found that for a
`mixture of equal parts of ethyl oleate and cas-
`tor oil an HLB-value is desirable of about
`10 to 10.5. This is the case, for example, with
`a mixture of 1 per cent. by weight of poly-
`and 1
`per
`eoxyethylenesorbitan-monooleate
`centby weight of sorbitan mono-oleate or
`with a mixture of 80 per cent. by weight of
`sorbitan-mono-laurate and 20 per cent. by
`weight
`of
`polyoxyethylene-sorbitan-mono-
`laurate. In this way excellent emulsions may
`be prepared which are physically stable and
`in which the solubility of the active constitu-
`ent in the water phase has not been materially
`increased.
`The ratio of the volumes of the oil- and
`water-phases may vary widely in the present
`emulsions. It is possible, for example, to pre-
`pare emulsions suitable for nose-drops with
`an oil-phase of 5—40% by weight of
`the
`total emulsion and emulsions
`to be used
`as ointments with an oil-phase of 5-—6()’,?.'.
`by weight of the total emulsion. Emulsions of
`the W/O type can be prepared, for example,
`by taking up water in a fat phase consisting
`of one or more of the solvents mentioned and
`lanolin and/or
`cholesterol as
`emulsifying
`agents.
`It stands to reason that, if desired, flavours,
`such as ethereal oils, may be added to the
`emulsions. In view of the solvent getting ran-
`cid and to avoid deterioration of the ethereal
`oil it is advisable to use the lauric acid esters
`of the said emulsifying agents.
`Although it has appeared that emulsions do
`not get rancid after proper preparation, an
`antioxidant soluble in fat is added by way of
`precaution,
`such as butylhydroxy-anisole, a
`gallate, for example, propyl, octyl or dodecyl-
`gallate and nordihydro-guaiaretinic acid, and
`to the water-phase a compound which can
`form a complex with metals, such as salts of
`ethylene-diamine-tetra-acetic
`acid, salts
`of
`
`hydroxy acids, for example, citric acid, as-
`corbic acid and sulphhydryl compounds, such
`as
`thioureum and_thiolactic acid.
`To preparations for external use various
`other
`therapeutically active substances may
`also be added, which is also possible with the
`present emulsions, either to the oil-phase or
`to the water-phase, provided that these sub-
`stances do not affect the physical and chemical
`stability of the emulsions detrimentally, It is
`possible, for example,
`to prepare nose-drops
`which,
`in the water-phase, contains one or
`more of an antibiotic, an antihistaminic, a
`vasoconstrictor, an
`antiseptic
`or a
`local
`anesthetic. To the oil-phase aromatic oils may
`be added, such as cinnamon oil and pepper-
`mint oil. In the case of ointmcnts, too, it is
`often desirable to add to the water-phase one
`or more of the other active substances men-
`tioned.
`
`EXAMPLE I
`A mixture of 0.5 g of finely pulverized 61-
`chloro-prednisone-acetate, 250 mg of dodecyl-
`gallate and 5 g of cinnamon oil are dis-
`solved, while heating gently,
`in a mixture of
`30 g of ethyl oleate and 30 g of ethyl recin-
`oleate. Next a mixture is prepared of a solu-
`tion of 10 g of
`the hydrochloride of pro-
`caine, 5 g of sorbitan-monostearate, 5 g of
`polyoxyethylene sorbitan monostearate and 100
`mg of sodium salt of eth_vlmercurithiosalicy-
`lic acid in 450 g of boiled, distilled water. The
`two phases are mixed and the emulsion of
`O/\‘’./' type formed is homogenised. This pre-
`paration can be used in the form of nose-
`drops.
`
`EXAMPLE II
`1 g of finely pulverized 6u-chloro-predni-
`sone-acetate, 500 mg of octylgallate and 6 ,2:
`of peppermint oil are dissolved in a mixture
`of 100 g of ethyl oleate and 100 g of Castor
`oil with gentle heating. A solution is pre-
`pared of 5 g of _neomycin sulphate, 5 g
`of the hydrochloride of tripelennamine, 2.5 g
`of the hydrochloride of phenylephrine, 16 g
`of sorbitan rnonolaurate, 4 g of polyoxyethy-
`lene sorbitan monolaurate, 100 mg of ethy-
`lenediaminetetra-acetate, 400 mg of benz-
`alkoniurn chloride and 100 mg of sodium salt
`of ethylmercurithiosalicylic
`acid in 780
`g
`of boiled, distilled water.
`The two phases are mixed and the emul-
`sion of O/W type formed is homogenized.
`This preparation can be used as a nose spray
`in the case of allergic conditions.
`
`EXAMPLE III
`
`1 g of 6a-chloro-prednisone-acetate is dis-
`solved in 100 g of castor oil and 500 g of
`acleps lanae with 250 mg of propylgallate with
`heating. After cooling a solution is added,
`while stirring continuously, of 5 g of neu-
`mycin sulphate, 0.5 mg of ethylenediamine-
`tetra-acetate in 394 g of distilled water. This
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`955,891
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`preparation, which is an emulsion of W/O
`type is suitable for use as skin-ointment.
`
`EXAMPLE IV
`30 mg of octylgallate are dissolved in a
`mixture of 30 g of castor oil and 30 g of
`ethyl oleate with heating. In this solution is
`dissolved 0.5 g of 6a-chloro-p1'ednisone-ace-
`tate while heating on a water-bath to a maxi-
`mum temperature of 80° C. Next 50 g of a
`mixture of fatty alcohols are added with 18
`C—atoms on an average and 25 g of isopro-
`pyhnyristate. The mixture is‘ melted while
`heating to a maximum temperature of 70° C.
`A solution is prepared of 20 g of sorbitol
`in 341 g of distilled water,
`to which 0.5
`g of ethylene diaminetetra-acetate and 3.45 g
`of neomycin sulphate are added. This aqueous
`solution is subsequently added to the fat phase
`at about 75° C, after which the mixture is
`stirred till
`it is cooled down.
`
`The cream formed is finally homogenized in
`an colloid mill. This preparation, which is
`an emulsion of W/O type is suitable for use
`as skin—ointment.
`
`In the same way ear-, nose- and eye—drops,
`creams and ointments are prepared with other
`esters of 6a—chloro—prednisone and with 6a-
`fluoro-prednisone and esters thereof as active
`substances.
`WHAT WE CLAIM IS:—
`1. Process for the manufacture of stable
`preparations comprising 6-halo-prednisone or
`carboxylic acid esters thereof wherein a 6-
`halo-prednisone or a carboxylic acid ester
`thereof
`is dissolved in an oil suitable for
`therapeutic purposes, which solution is emul-
`sified with an aqueous medium.
`2. A process according to claim 1, wherein
`the oil chiefly consists of an ester of a lower
`aliphatic alcohol and a higher fatty acid and/
`or a vegetable oil.
`3. Process according to claim 2, wherein
`
`castor oil
`the oil consists of a mixture of
`and one or more of the esters: ethyl oleate,
`ethyl recinoleate and isopropyl myristate.
`the
`4. Process according to any one of
`preceding claims, wherein the emulsion con-
`tains
`6<z—chloro—prednisone, 6o:-fluoro-predni-
`sone or carboxylic acid esters thereof as active
`substances.
`
`the
`5. Process according to any one of
`preceding claims, wherein the emulsion con-
`tains 6a—chloro-prednisone-acetate as an ac-
`tive substance.
`'
`
`the
`6. Stable, water containing emulsions,
`oil-phase of which is a solution a a 6-halo-
`prednisone, or an ester thereof derived from
`an aliphatic carboxylic acid with 1-12 C
`atoms, or from an aromatic carboxylic acid
`or from an aryl—aliphatic carboxylic acid in
`an oil suitable for therapeutic purposes.
`7. Emulsions according to claim 6, in which
`the oil contains an ester of a lower aliphatic
`alcohol and a higher fatty acid.
`8. Emulsions according to claim 6, in which
`the oil is a vegetable oil.
`9. Emulsions according to claim 6, in which
`the oil consists of a mixture of castor oil and
`an ester of the group ethyl oleate, ethyl ricin-
`oleate and isopropyl myristate.
`10. Emulsions according to claim 6 con-’
`taining 6a—ch1oroprednisone acetate as active
`substance.
`
`11. Process for the manufacture of stable
`preparations comprising prednisone derivatives
`according to claim 1 and substantially as here-
`in described with reference to the foregoing
`examples.
`12. Stable preparations comprising predni-
`sone derivatives whenever produced by the
`methods particularly described herein.
`BROMHEAD & C0.,
`Chartered Patent Agents,
`St. Paul’s Chambers, 19—23 Ludgate Hill,
`London, E.C.4.
`
`Leamington Spa: Printed for Her Maiesty’s Stationery Office by the Courier Press.7—1964._
`Published at The Patent Office, 25, Southampton Buildings, London, W.C.2, from which copies may be obtained,
`
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