United States Patent Office
`
`2,880,130
`Pate11ted Mar,. 31, 1959
`
`1
`
`2,880,~~~
`AN,l'MNFLAM,M,ATORY ST£ROID SOL{:J'fiONS
`IUchard H. ,Jo)m$on, Kala~oo •. Mich., assignor to ~he
`Upiolm Company; .Kal~tmazoo1 Micl.L, a cprporatipn
`9.fMichi~n
`No .Prawing. Application December _24, 1956
`Serial No. 630,013
`~ c~. (CI. 167-65)
`
`';I'~~ invention ~elate$ ·to novel compositions of matter
`and to .. a novel p~;oce,ss. for tP.e preparation of the same,
`and is p~tij::u}arly d.irect.ed .to the preparation of chemi(cid:173)
`caUy a.nd physically stable; clear aqueous solutions of
`anti-inflammatory steroid hormones of the 11)3,17a:,21-tri(cid:173)
`hydroxypregnane-3,20-dione cl!lSS, such as hydrocortisone,
`2-meti:Jylenebydrocortisone, LV-hydrocortisone, 6-methyl(cid:173)
`hydrocortisone, 6-methyl-A 1-hydrocortisone, 16-hydroxy-
`9a:-fiuorohydrocortisone, 16-hydroxy-9a:-fiuoro-A 1-hydro(cid:173)
`cortisone, and the 21-esters l!lld tQ.e 16,21-diesters there(cid:173)
`of, which solutions are adapted for topical application to
`se11sitive tiss1,1es sucll as the tissues of the eye, ear, nose,
`~md :tll.roat.
`Compositions according to tbe invention having tbe
`desired clarity, stability, and adaptability for topical
`applicatio!l to sensitive tissues are obtained by dissolving
`the steroid hormone in a vehicle consisting essentially
`of water and as a solubilizing agent a nonionic surfacta11t
`obtained by condensing sorbitan monooleate and ethylene
`oxide. The surfactant shall be re.ferred to hereinafter as
`polyoxyethylene sorbitan monooleate. Using polyoxy(cid:173)
`ethylene sorbitan monooleate, i.e., Tween 80 as the solu(cid:173)
`bilizing agent in a concentration of about two to about
`25 percent of the vehicle, it is possible to obtain chemi(cid:173)
`cally and physical stable, clear solt1tions of the steroid
`hormone in concentrations substantially greater than the
`maximum solubilitY of ti:Je llo.rxnone in water at normal
`temperature. For example, witll a vehicle consisting
`essentially of one cubic centimeter of water and 100 milli(cid:173)
`grams of Tween 80, it i.s possible to obtain clear, stable
`sohJtions containing ~:~s llliJCh as two milligrams of hydro(cid:173)
`cortisone per cJJl>ic ce)ltimeter, whereas the maximum
`solubility of hydrocortiso11e witll.o\lt the surfactant is
`0.28 milligram per cubic centimeter.
`The novel solutions of this invention are pniquely
`characterized by the fact that they can be safely applied
`to sensitive tissues such as those of the eye, ear, nose,
`and throat without causing irritation, and by the fact
`that they contain sufficiently hig~ concentration of dis(cid:173)
`solved steroid hormone to bring about effective anti(cid:173)
`inflammatory action when applied to such tissl}es. Here(cid:173)
`tofore, it has not been possible to obtain clear, chemically,
`and physieally stable solutions of anti-inflammatory steroid
`hormones which are 110t irritating to sensitive tissues Sl!Ch
`as those of the eye, ear, nose, and throat and at the
`same time contain sufficient quantity of ·the hormone for
`effective anti-inflammatory action. The novel composi(cid:173)
`tions of the invention, t)lerefore, provide an entirely new
`type of medicament and make possible an entirely new
`type of treatment for jpffamed ti§~ues of the eye, ear,
`nose, and t)lroat. While claims )lave b.een !Dade of ~ucJ-1
`compositions and such a new type of treatment, It IS
`significant that heretofore no product making possible
`this new type of treatment has been offered to the medical
`profession. Thus, while it has been proposed to solubilize
`hydrocortisone with other types of solubilizing agents,
`tlie solutions so formed .have not b,een suitable for oph•
`thalmic purposes.
`
`5
`
`2
`Different procedures have been found effective f:9r
`making up solutions according to the invention. Accord(cid:173)
`ing to one procedure, the nonionic surfactant is dissolved
`in water, and the steroid hormone is stirred in the re(cid:173)
`sulting solution at room temperature until the desired
`solution is obtained. Tllereafter any adjuvants; such as
`salts, where isotonic solutions are wanted, preservatives,
`and buffers, are added. Also, o.tber water-soluble drugs
`may then be added.
`It is not necessary, however, that
`10 the ingredients be added in this sequence. They can
`be added all at once for example. Advantageously, the
`nonionic surfactant is dissolved in a portion· of the re(cid:173)
`quired water, say from about fifty to n,inety percent 9f
`that required, and the steroid hormone and other soluble
`15 ingredients are dissolved in the resulting solution. The
`b1;1lance of the water required in the formulation is the.n
`added. This procedure provides for more facile control
`of the final concentration and is made possible by the
`fact that when less than the full .quantity of water is
`20 used, the concentration of the nonionic su.rfactant is
`proportionally higher, and the dissolving power of the
`solution is proportionally greater.
`The second procedure, which has been found advan(cid:173)
`tageous, is to heat the solution containing the steroid
`25 hormone in order to facilitate the solution of the steroid
`hormone and/or to stabiliZe the solution.
`It has been
`found that by heating the solution between about forty
`degrees centigrade and the decomposition point, a more
`stable solution is obtained. Advantageously the heatmg
`30 can be carried out in an autoclave at a temperature of
`abo~t 120 degrees centigrade in order to obtain simul(cid:173)
`taneously both stabilization and sterilization.
`It has also
`been found that appx:oximately twice as much steroid
`hormone can be dissolved if the solution is heated.
`35 Thus, two entirely different and distinct effects are ob(cid:173)
`tained by the heating, namely, (1) it is possible thereby
`to make more concentrated solutions, and (2) it is
`possible to obtain more stable solutions.
`It appears,
`therefore that some kind of complex is formed between
`40 the noni~nic surfactant and the steroid hormone which is
`stabilized by heating.
`In any event, substantially more
`stable solutions are obtained on heating over a consider(cid:173)
`able period. Effective stabilization has been obtained on
`heating for sixty minutes at seventy to eighty degrees
`45 centigrade. Generally speaking satisfactory results can
`be obtained by heating from fifteen minutes to ninety
`minutes or more depending on the temperature. A shorter
`time, however, can sometimes be used and· any greater
`practical time can be used;
`The above procedures can be utilized for preparing
`chemically and physically clear, aqueous solutions of any
`anti-inflammatory steriod hormone of the ll,B,17a:,21-tri(cid:173)
`hydroxypregnane-3,20-dione class. This comprises hy(cid:173)
`drocortisone and the anti-inflammatory analogs thereof.
`55 Since the solutions of the invention are intended for ap(cid:173)
`plication to sensitive tissues such as those of the eye, ear,
`nose, and throat, it is desirable to avoid using an anti(cid:173)
`infiammatory steroid honnone which has high mineral
`corticoid activity. Such anti-inflammatory steroid hor-
`60 mones
`therefore, as hydrocortisone, 2-methylenehydro(cid:173)
`cortisdne, Al-byclroco:rtisone, 6-methylhydrocortisone, 6-
`methyl-ALhydrocortisone, 16-hydroxy - 9a: - fluorohydro(cid:173)
`corstisone, and 16-hydroxy-9a-fluoro-A1-hydrocortisone
`are preferred. 2-methylene:hydrocortisone can be used ad-
`65 val).tageously where systemic activity is I).Ot desired. Un(cid:173)
`less otherwise specified, the free alcohols and the thera(cid:173)
`peutically active esters thereof are included. For example,
`the 21-esters and the 16,21-diesters of acetic acid, pro(cid:173)
`pionic acid, tertiarybutylacetic acid, diethylacetic acid,
`acrylic acid, mono, di-, and trichloracetic acid, succinic
`acid, tricarballylic acid, glutaric acid, j3,,B-dimethy1 glutaric
`acid, aconitic acid, itaconic acid, and like aliphatic mono-
`
`50
`
`70
`
`Innopharma EX1044, Page 1
`
`

`

`3
`and poly-carboxylic acids; benzoic acids, phenyl acetic
`acid, phenoxyacetic acid, furoic acid and like aromatic
`carboxylic acids; and cyclopentyl carboxylic acid, cyclo(cid:173)
`hexY,lcarboxylic acid,. cyclopentylpropionic acid and like
`cycloaliphatic carboxylic acids. As the esters ordinarily 6
`have a lower solubility than the free alcohols, the less
`active anti-inflammatory steroid hormones, such as hy(cid:173)
`.drocortisone are advantageously used in the form of the
`free alcohol. With the more active anti-inflammatory
`steroid hormones, such as .!lLhydrocortisone and par- 10
`ticularly with 6-methyl-Lll-hydrocortisone, 16-hydroxy-9a(cid:173)
`fluorohydrocortisone, 16-hydroxy-9o:-fluoro-LlLhydrocorti(cid:173)
`sone, the various 21-esters and 16,21-diesters can be used
`advantageously .because satisfactorily high concentrations
`of the anti-inflammatory steroid hormone can be obtained 15
`within the permissible limits on the amount of the non(cid:173)
`ionic surface active agent that can be used satisfactorily.
`The amount of nonionic surfactant can be varied, but,
`in view of the purpose for which the compositions are
`intended, namely, for topical application to sensitive tis- 20
`.sues, such as tissues of the eye, ear, nose, and throat,
`it is desirable that the concentration shall not exceed
`about' 25 percent. Entirely satisfactory solutions are ob(cid:173)
`tained with solutions containing ten percent of these sur(cid:173)
`factants, with and without the application of heat. Thus, 25
`stable solutions containing as much as 0.2 percent (per(cid:173)
`centage is· by weight unless otherwise specified) hydro(cid:173)
`cortisol1e .have been obtained with ten percent aqueous
`solutions of Tween 80. Still, lower concentrations of
`the nonionic surfactant give . tlear, ·stable solutions when 30
`the heating procedure is followed, as more particularly
`shown in Example 1. Still lower concentrations of non(cid:173)
`ionic surfactant can be used, especially where it is not
`necessary as in the. case of the more active anti-inflam(cid:173)
`matory steroid hormone, such as the 6-methyl-LlLhydro(cid:173)
`cortiscine, to have such a high concentration in the solu(cid:173)
`tion. In general, therefore, the concentration of nonionic
`surfactant in the formulations according to this invention
`can range from about two to about 25 percent.
`Compositions according to the invention, therefore, can 40
`have the following general formulations:
`
`:3,880,180
`
`4
`water for injection (room temperature) q.s.-ad one liter.
`Sterilize by filtration.
`PROCEDURE B
`Dissolve the Tween 80 in 800 cc. of water for injec(cid:173)
`tion by stirring and he'ating to sixty degrees centigrade.
`Crush any large lumps in the hydrocortisone, add to the
`Tween 80 solution and dissolve with stirring and heating
`at sixty to seventy degrees centigrade for one hour. Cool
`the solution to 25 degrees centigrade and add the sodium
`chloride and chlorobutanol. When the chlorobutanol is
`completely in solution (slow agitation), .then dissolve the
`the sodium citrate a!ld.add water for injection to adjust
`to the final volume of one liter. Sterilize the solution by
`filtration through a sterile filter pre-washed with five
`percent sodium bicarbonate solution followed by distilled
`water.
`Procedure B has an·advantage over procedure Ain that
`solutions which contain approximately two times the
`concentration of hydrocortisone can be obtained; The
`effect of heat on the solubility of. hydrocortisone is shown
`in the following table:
`
`TABLE I
`
`Concentration of Tween 80
`
`Approximate Maxi(cid:173)
`mum solubility, mg.{cc.
`
`Procedure
`A(without
`heat)
`
`Procedure
`B (with
`heat)
`
`5%--------- -----------------'-----------------
`10%-------------------------------------- -----
`20%-------------------------'-----------------
`
`0.8
`1.7
`3.0
`
`1. 7
`3.8
`6.0
`
`35 Procedure B also has the advantage that the stability of
`the solutions is substantially greater.
`ExAMPLE 2
`Sterile aqueous solution, hydrocortisone 0.2 percent
`neomycin sulfate 0.6 percent
`
`Using the formulation and procedures of Example
`with the following formulation:
`
`Percent
`Anti-inflammatory steroid hormone ------- 2nx
`Nonionic surfactant ---------------------· 2-25
`Preservative ---------------------------- Up to 1.5 45
`Solution salts (including buffer salt if any)_ Up to 2.0
`Lactose ----.,.--------------------------· Up to 25
`Other drugs ----------------------------· Up to 30
`Water --------------------------------- 100
`wherein x represents the solubility of the anti-inflam(cid:173)
`li\atory steroid hormone in water at room temperature in
`percent and n is from one to ten. Lactose is added when
`it is de.sired to lyophilize the preparations and functions
`as a bulking agent. The other drugs used are generally
`antibacterial agents, water-soluble antibiotics and sulfa 55
`drugs for example.
`l)le following examples are illustrative of the processes
`and products of this invention and are not to be con(cid:173)
`strued as limiting.
`
`EXAMPLE 1
`Sterile aqueous solution of hydrocortisone (0.2%)
`
`Tween 80 ---~------------------------grams __
`Hydrocortisone ·------------------------do ___ _
`Sodium citrate -------------------------do ___ _
`Sodium chloride --------'---------------do ___ _
`Neomycin sulfate ______________________ do ___ _
`Chlorobutanol ------------------~------do ___ _
`50 Water for injection, q.s. ad. !liter.
`
`100
`2
`3
`3
`6.4
`5.5
`
`clear, stable solutions. containing 0.2 percent byl;lrocorti(cid:173)
`sone and 0.6 percent neomycin sulfate in a neutral Isotonic
`vehicle were obtained. Procedure A was satisfactory.for
`hydrocortisone lot 1; procedure B for other lots of hydro(cid:173)
`cortisone.
`In place of or in addition to the neomycin sulfate there
`can be substituted other water-soluble antibiotics such
`as tetracycline and oxy- and chlor-tetracycline hydro-
`60 chlorides, sodium penicillin (G, 0, V and like forms),
`polymyxin (B and other forms) sulfate, streptomycin
`sulfate, erythromycin hydrochloride, bacitracin, grami(cid:173)
`cidin, and novobiocin, or a combination of two. or more
`of the same. The following examples are illustrative.
`
`Formulation:
`Tween 80 ------------------------grams __
`100 65
`2.1
`·Hydrocortisone ---------------------do ___ _
`Sodium citrate _____________________ do ___ _ 2.0
`Sodium chloride -------------------do ___ _ 3.7
`Chlorobutanol ---------------------do ___ _ 5.5
`• Water for injection, q.s. ad. 1 liter.
`
`PROCEDURE A
`
`Dissolve in about 860 cubic centimeters of water for
`injection (room temperature) in the above order allowing
`each to. dissolve before the next ingredient is added. Add
`
`ExAMPLE 3
`Sterile aqueous solution, hydrocof'tisone 0.2 percent,
`polymyxin B sulfate 12,000 units/cc.
`
`70
`
`Using the formulation and procedures of Example 2
`except that two grams of polymyxin B sulfate (6,000
`units/mg.) was used in place of the neomycin sulfate,
`there were obtained clear, stable solutions containing two
`milligrams of hydrocortisone and 12,000 units of poly-
`'lts myxin B sulfate per cubic centimeter.
`·
`
`Innopharma EX1044, Page 2
`
`

`

`

`

`2,880,130
`
`15
`
`·s
`hydrocortisone, 6-methyl-.1 t.hydrocortisone, 16-hydroxy-
`9 a:-fluorohydrocortisone, 16-hydroxy -9 a:-fluoro-.1 Lhydro(cid:173)
`cortisone, and the. substantially water-insoluble 21-esters
`and the substantially water-insoluble 16,21-diesters there(cid:173)
`of, the amount of polyoxyethylene sorbitan monooleate
`being in the range of from about 2 to about 25% and
`being sufficient to increase the solubility of the steroid
`hormone substantially above that which can be dissolved
`in water alone, tlle amount of steroid hormone thus dis(cid:173)
`solved being greater than the amount which can ·be dis(cid:173)
`solved in water alone.
`4. The process of claim 3 in which the solution of the
`steroid hormone is heated to at least about 40° C. for at
`least about 15 minutes.
`5. The process for preparing an aqueous solution of an
`anti-inflammatory steroid hormone selected from the
`group consisting of hydrocortisone, 2-methylene-hydro(cid:173)
`cortisone, .11-hydrocortisone, 6-methyl-hydrocortisone, 6-
`methyi-.1Lhydrocortisone, 16-hydroxy-9a:-fluorohydrocor(cid:173)
`tisone, 16-hydroxy-9a:-fluoro-A1hydrocortisone, and
`the
`substantially water-insoluble 21-esters and the substan-
`tially water-insoluble 16,21-diesters thereof which com(cid:173)
`prises dissolving polyoxyethylene sorbitan monooleate in
`about 50 to 90% of the required water, dissolving tlle
`anti-inflammatory steroid hormone in tlle solution tllus
`prepared and diluting the obtained solution with the re-
`mainder of the required water, the amount of polyoxy(cid:173)
`ethylene sorbitan monooleate being in the range of from
`about 2 to about 25% and being sufficient to increase the
`30 solubility of the steroid hormone substantially above that
`which can be dissolved in water alone and its total amount
`of water being insufficient in tlle absence of said poly(cid:173)
`oxyethylene sorbitan monooleate to dissolve all of the
`said anti-inflammatory steroid hormone.
`6. The process of claim 5 in which the solution of tlle
`anti-inflammatory steroid hormone is heated to at least
`40° C. for at least about 15 minutes.
`
`7
`methyl-1 fp, 17 a:,21-tribydroxy-4-pregnene-3,20-dione), 6-
`methyl-.1Lhydrocortisone (6- methyl- llp,l7a:,21- trihy(cid:173)
`droxy-1 ,4~pregnadiene-3,20-dione), 16-hydroxy-9a:-fluoro(cid:173)
`hydrocortisone ( 11 p, 16a:, 17 a:,21-tetrahydroxy-9a:-fluoro-4-
`pregnene-3,20-dione), and 16-hydroxy-9a:-fluoro-.1Lhydro- 5
`'cortisone (11p,16a:,17a:,21- tetrahydroxy- 9a:- fluoro-1,4-
`pregnadiene-3,20-dione), and the 21 esters thereof to
`give more potent formulations because of the higher anti(cid:173)
`inflammatory activity of these steroids. . Alternatively the
`amount of these steroids can be reduced to give formu- 10
`lations of equivalent potency. 2-methylene-hydrocor(cid:173)
`tisone (2- methylene-11p,17a:,21-trihydroxy-4-pregene-3,
`20-dione) can be used where an anti-inflammatory steroid
`hormone having topical but little systemic activity is
`desired.
`It is to be understood that the invention is not to be
`limited to the exact details of operation or exact com(cid:173)
`pounds shown and described herein, as obvious modifica(cid:173)
`tions and equivalents will be apparent to one skilled in
`the art, and the invention is therefore to be limited only 20
`by the scope of the appended claims.
`We claim:
`1. A composition of matter comprising an aqueous
`solution of an anti-inflammatory steroid hormone of the
`ll,B,17a:,21-trihydroxypregnane-3,20-dione class and as a 25
`nonionic surfactant solubilizing agent, polyoxyethylene
`sorbitan monooleate, said composition having the follow-
`ing formula:
`
`35
`
`Percent
`Anti-inflammatory steroid hormone -------------
`2nx
`Nonionic surfactant --------------------~----- 2-25
`Preservative --------------------------- Up to 1.5
`Soluble salts (including buffer salt if an:y) __ Up to 2.0
`Lactose ------------------------------- Up to 25
`Other drugs --------------------------- Up to 30
`Water, q.s. ad. 100 percent.
`wherein x represents the solubility of the anti-inflamma(cid:173)
`tory steroid hormone iri water at room temperature in
`percent and n is from one to ten, said anti-inflammatory 40
`steroid hormone being selected from the class consisting
`of hydrocortisone, 2-methylene-hydrocortisone, LlLhydro(cid:173)
`cortisone, 6-methylhydrocortisone, 6-methyl-.11-hydrocor(cid:173)
`tisone, 16-hydroxy-9a:-fluorohydrocortisone, 16-hydroxy-
`9a:-fluoro-A1-hydrocortisone, and the substantially water(cid:173)
`insoluble 21-esters and the substantially water-insoluble 45
`16,21-diesters thereof.
`2. A composition of matter comprising an aqueous
`solution containing two to 25 percent polyoxyethylene
`sorbitan monooleate and 0.056 to 0.56 percent hydrocor- 50
`tisone.
`·
`3. The process which comprises dissolving a polyoxy(cid:173)
`ethylene sorbitan monooleate in water and then dissolv-
`ing in the solution obtained a member selected from the
`group of steroid hormones consisting of hydrocortisone, 55
`2-methylene-hydrocortisone, 41-hydro~;ortisone! 6-methrl-
`
`2,497,509
`2,653,955
`2,779,707
`2,779,775
`
`References Cited in the file of this patent
`UNITED STATES PATENTS
`Miescher -------------- Feb. 14, 1950
`Rogers ---------------- Sept. 29, 1953
`Jacobson -------------- Jan. 29, 1957
`Sarett ---------------- Jan. 29, 1957
`OTHER REFERENCES
`Ekwall: ·Chemical Abstracts, 49:7754F.
`POSL.)
`Ekwall: Acta Chemica Scandinavica 5:2, pp. 1383-
`1387, 1951.
`Ekwall: Acta Endocrinol, 4, pp. 179-i91, 1950.
`Dulin: P.S.E.B.M., 90:1, pp. 115-117, October 1955.
`"Spans and Tweens," Atlas powder Co., 1942, 17 page
`pamphlet,
`
`(Copy in
`
`Innopharma EX1044, Page 4
`
`