United States Patent Office
`
`2,880,138
`Patented Mar. 31, 195'9
`
`1
`making up solutions according to the invention. Accord(cid:173)
`2,880,138
`ing to one procedure, the nonionic surfactartt is dissolved
`ANTI-INFLAMMATORY STEROID SOLUTIONS
`in water, and the steroid hormofie is stirred in the result-
`ing solution at tooth temperature until the desired solu(cid:173)
`Richard H • .Johnson, Kalamazoo, Mich., assignor to The
`Upjohn Company, Kalamazoo, Mich., a corporation 5
`tion is obtained. Thereafter any adjuvants, such as salts,
`of Michigan
`where isotonic solutions are wanted, preservatives and
`.buffers are added. Also, other water soluble drugs may
`No Drawing. Application December 24, 1956
`then be added. It is not necessary, however, that the in(cid:173)
`Serial No. 630,014
`gredients be added in this sequence. They can be added
`6 ·Claims. (CI. 167-65)
`10 all at once for example. Advantageously, the nonionic
`This invention relates to novel compositions of matter
`surfactant is dissolved in a portion of the required water,
`say. from about fifty to ninety percent of that required,
`and to a novel process for the preparation of the same,
`and the steroid hormone and other soluble ingredients
`and is particularly directed to the preparation of chemi-
`are dissolved in the resulting .solution. The balance of
`cally and physically stable, clear aqueous solutions of
`anti-inflammatory steroid hormones of the l1,8,17a,21- 15 the water required in the formulation is then added. This
`trihydroxypregnane-3,20-dione class, such as, hydrocor-
`procedure provides for more facile control of the final
`tisone, 2-methylenehydrocortisone, ALhydrocortisone, 6-
`concentration and is made possible by the fact that when
`less than the full quantity of water is used, the concentra-
`methylhydrocortisone, 6-methyl-ALhydrocortisone, 16-hy-
`droxy-9a-fluorohydrocortisone, 16-hydroxy-9a-fluor~Al-
`tion of the nonionic surfactant is proportionally higher,
`hydrocortisone, and the 21-esters and the 16,21-diesters 20 and the dissolving power of the solution is proportionally
`thereof, which solutions are adapted for topical applica-
`greater.
`The second procedure, which· has been found advan-
`tion to sensitive tissues such as the tissues of the eye, ear,
`nose, and throat.
`tageous, is to heat the solution containing the steroid
`Compositions according to the invention having the
`hormone in order to facilitate the solution of the steroid
`desired clarity, stability, and adaptability for topical ap- 25 hormone and/or to stabilize the solution. It has been
`plication to sensitive tissues are obtained by dissolving
`found that by heating the solution between about forty
`the steroid hormone in a vehicle consisting essentially of
`degrees centigrade and the decomposition point, a .more
`water and as a solubilizing agent a nonionic surfactant
`stable solution is obtained. Advantageously the heating
`can be carrieP, out in an. autoclave at a temperature of
`obtained by condensing an alkylphenol, formaldehyde,
`and ethylene oxide as set forth in British Patent 594,475. 30 about 120 degrees centigrade in order to obtain simul-
`taneously both stabilization and sterilization. It has also
`The surfactant shall be referred to hereinafter as alkyl-
`phenol-formaldehyde-ethylene oxide, condensation prod-
`been found that approximately twice as much steroid
`uct. Using an alkylphenol-formaldehyde-ethylene ·oxide
`hormone can be dissolved if the solution is heated. Thus,
`condensation product such as Triton WR-1339, a con-
`two entirely different and distinct effects are obtained by
`densation product of diisobutylphenol, formaldehyde, and 35 the heating, namely ( 1) it is possible thereby to make
`ethylene oxides as the solubilizing agent in a concentra-.
`more concentrated solutions, and (2) it is possible to ob-
`tion of about two to about 25 percent of the vehicle, it ·
`tain more stable solutions.
`It appears, therefore, that
`is possible to obtain chemically and physically stable,
`some kind of complex is formed between the nonionic
`clear solutions of the steroid hormone in concentrations
`surfactant and the steroid hormone which is stabilized by
`substantially greater than the maximum solubility of the 40 heating. In any event, substantially more stable solutions
`hormone in water at normal temperatures. For example,
`are obtained on heating over a considerable period. Effec-
`with a vehicle consisting essentially of one cubic centime- .
`tive stabilization has been obtained on heating for sixty
`ter of water and 100 milligrams of Triton WR-1339, it is
`minutes at seventy to eighty degrees centigrade. Gen-
`possible to obtain clear, stable solutions containing as
`erally speaking satisfactory results can be obtained by
`much as two milligrams of hydrocortisone per cubic centi- 45 heating from fifteen minutes to ninety minutes or more
`meter; whereas the maximum solubility of hydrocortisone
`depending on the temperature. A shorter time, however,
`without the surfactant is 0.28 milligram per cubic cen-
`can sometimes be used and any greater practical time
`·
`timeter.
`can be used.
`The novel solutions of this invention are uniquely char-
`The above procedures can be utilized for preparing
`acterized by the fact that they can be safely applied to 50 chemically and physically clear, aqueous solutions of any
`sensitive tissues such as those of the eye, ear, nose, and
`anti-inflammatory steroid hormone of the ll,8,17a,21-
`throat without causing irritation, and by the fact that they..
`trihydroxypregnane-3,20-dione class. This comprises by-
`contain sufficiently high concentration of dissolved steroid
`drocortisone and the anti-inflammatory analogs . thereof.
`hormone to bring about effective anti-inflammatory action
`Since the solutions of the invention are intended for ap-
`when applied to such tissues. Heretofore, it has not been 55 plication to sensitive tissues such as those of the eye,
`ear, nose, and throat, it is desirable to avoid using an
`possible to obtain clear, chemically, and physically stable
`anti-inflammatory steroid hormone which has high min-
`solutions of anti-inflammatory steroid hormones which,
`are not irritating to sensitive tissues such as those of the.
`eral corticoid activity. Such anti-inflammatory steroid
`therefore, as hydrocortisone, 2-methylene-
`eye, ear, nose, and throat and at the same time contain
`hormones,
`sufficient quantity of the hormone for effective anti-inflam- 60 hydrocortisone, A1-hydrocortisone, 6-methylhydrocorti-
`matory action. The novel compositions of the invention,
`sone, 6-methyl-ALhydrocortisone, 16-hydroxy-9a-fluor~
`.therefore, provide an entirely new type of medicament and
`hydrocortisone, and 16-hydroxy-9a-fluoro-Al-hydrocorti-
`make possible an entirely new type of treatment for in-
`sone are preferred. 2-methylenehydrocortisone can be
`flamed tissues of the eye, ear, nose, and throat. While
`used advantageously where systemic activity is not de-
`claims have been made of such compositions and such a • 65 . sired. Unless otherwise specified, the free alcohols and
`new type of treatment, it is significant that heretofore no'
`the therapeutically active esters thereof are included.
`product making possible this new type of treatment has
`For example, the 21-esters and the 16,21-diesters of acetic
`been offered to the medical profession. Thus, while it
`acid, propionic acid, tertiary-butylacetic acid, diethylacetic
`has been proposed to solubilize hydrocortisone with other
`acid, acrylic acid, mono, di-, and trichloroacetic acid,
`types of solubilizing agents, the solutions so formed have 70 succinic acid, tricarballylic acid, glutaric acid, ,8,,8-di-
`not been suitable for ophthalmic purposes.
`methyl glutaric acid, aconitic acid, itaconic acid, and like
`Different procedures· have been found effective for
`aliphatic mon~ and poly carboxylic acids; benzoic acid~1
`
`Metrics EX1045, Page 1
`
`

`
`2,880,138
`
`4
`esses and products of this invention and are not to be
`construed as limiting.
`
`ExAMPLE 1
`Sterile aqueous solution of hydrocortisone (0.2%)
`Formulation:
`Triton WR-.1339 ------------------grams __ 100
`·Hydrocortisone ---------------------do ____ 2.1
`Sodium citrate ---------------------do____ 2.0
`Sodium chloride --------------------do____ 3.7
`Chlorobutanol ---------------------do____ 5.5
`Water for injection, q.s. ad !liter .
`
`3
`phenyl acetic acid, phenoxyacetic acid, furoic acid and
`'like aromatic carboxylic acids; and cyclopentyl carboxylic
`acid, cyclohexyl carboxylic acid, cyclopentylpropionic
`acid and like cycloaliphatic carboxylic acids. As .the
`esters .ordinarily have a lower solubility than the free 5
`alcohols, the less active anti-inflammatory steroid hor-
`manes, such as hydrocortisone are advantageously used in
`the form of the free .alcohol. With the more active anti-
`inflammatory steroid hormones, such as A1-hydrocortisone
`and particularly with 6-methyl-A1-hydrocortisone, 16~hy- 10
`droxy-9a-fluorohydrocortisone,
`16-hydroxy-9a-fluoro~A1-
`hydrocortisone, the various 21-esters and 16,21-diesters
`. can be used advantageously because satisfactorily high
`PROCEDURE A
`concentrations of the anti-inflammatory steroid hormone
`.can be obtained within the permissible limits on the 15 Dissolve in about 860 cubic centimeters of water for
`amount .of the nonionic surface active agent that can be
`injection (room temperature) in the above order allow-
`.ing each to dissolve before the next ingredient is added.
`used satisfactorily.
`The amount of nonionic surfactant can be varied, but,
`. Add water for injection (room temperature) q.s.-ad one
`·in .;view of the purpose for which the compositions are
`liter. Sterilize ·by filtration.
`intended, namely, for topical application to sensitive tis- 20
`PROCEDURE B
`sues, .such as tissues of the eye, ear, nose, and throat, it
`Dissolve the Triton WR-1339 in 800 cc. of water for
`.is desirable that the concentration shall not exceed about
`injection by stirring and heating to sixty degrees centi-
`,25 percent. Entirely satisfactory solutions are obtained
`grade. Crush any large lumps in the hydrocortisone,
`with solutions containing ten percent of these surfactants,
`with and without the application of heat. Thus, stable 25 add 1o .the Triton solution and dissolve with stirring and
`heating at sixty to seventy degrees centigrade for one
`solutions containing as much as 0.2 percent (percentage
`.Cool . the solution to 25 degrees centigrade .and
`is by weight unless otherwise specified) hydrocortisone
`.hour.
`have been obtained with ten percent aqueous solutions
`add the sodium chloride and chlorobutanol. When the
`.of Triton WR-J339 .. Still, lower concentrations of the
`chlorobutanol is completely in solution (slow agitation),
`nonionic. surfactant give clear, ·stable solutions when the 30 . then .dissolve the sodium citrate and add water for .injec-
`tion to adjust to the final volume of one liter. Sterilize
`heating.procedure is followed, as more particularly shown
`i11 Example 1. Still lower concentrations of nonionic
`the solution by .filtration through a sterile filter pre-
`washed with five percent sodium bicarbonate .solution
`.surfactant can be used, especially where it is not neces-
`followed by distilled water.
`sary as in the case of the more active anti-inflammatory
`steroid .hormone, such as the 6-methyl-A1-hydrocortisone, 35
`Procedure B has an advantage over procedure A in
`In
`.that solutions which contain approximately two times the
`to .have such a high concentration in the .solution.
`.general, therefore, the concentration of nonionic sur-
`concentration of hydrocortisone can be obtained. The
`Jactant in th.e formulations according to this invention
`·effect cifheat on the solubility of hydrocortisone is shown
`can range from about two to about 25 percent.
`in the .following table:
`Compositions according to the invention, therefore, 40
`can .have the following general formulations:
`
`TABLE I
`
`·Concentration of Triton WR-1339
`
`Percent
`Anti-inflammatory steroid hormone -------------- 2nx
`Nonionic surfactant ------------------------- 2-25
`·Preservative ---------------------------- up to 1.5 45
`Soluble salts (including buffer salt if any) ___ up to 2.0
`Lactose -------------------------------- up to 25
`Other drugs ----------------------------- up to 30
`'5%----------------------------------- ---------
`10%.---- ----- ---------------------------------
`·Water, q.s. ·ad 100 percent.
`50 20%-------------------------------------------
`wherein x represents the solubility of the anti-inflamma(cid:173)
`tory steroid hormone .in water at room temperature in
`Procedure B also has the advantage that the stability of
`.the solutions is substantially greater. These data are
`percent and n is ;from one to ten. Lactose is added when
`.shown in the following table in which are compared dif-
`it is desired to lyophilize the preparations and functions
`55 .ferent lots of pharmaceutical grade hydrocortisone. Lot
`as a bulking agent. The other .drugs used are generally
`3 .required procedure B for satisfactory solution of the
`·antibacterial agents, water-soluble antibiotics and sulfa
`hydrocortisone whereas lots 1 and 2 did not. Procedure
`drugs for example.
`B also gave a more stable solution with lot 2.
`The following examples are illustrative of the proc-
`Stability of solutions prepared from different lots of
`hydrocortisone
`
`Approximate Maximum
`solubility, mg./cc.
`
`Procedure
`A(witb(cid:173)
`out heat)
`
`Procedure
`B (with
`heat)
`
`0.8
`1. 7
`3.0
`
`1.7
`3.8
`6.0
`
`Temperature
`
`.w• c ____________
`
`4o• c ____________
`25° c ____________
`4• c _____________
`
`Lot 1 (10,297-21)
`
`Lot 2 (FZ.501)
`
`Lot 2 (FZ.501)
`
`Lot 3 (FZ-504)
`
`Lot 3 (FZ.504)
`
`Example 1A
`
`Example1A
`
`Example lEI
`
`Example1A
`
`Example'lB •
`
`Not tested __________ Unsatisfactory at
`Trace of precip\ta·
`Clear for at least
`3months.
`tion at 3 months
`3months.
`(47° C.).
`_____ do. _________ -----
`Trace of precipita-
`Clear for at least
`·Clear for at least
`3 months,
`12 months.
`tion at 6 montns.
`_- •.• do _______________ -- ___ do ________ ------- ---_.do __________ -- ___
`Clear for at least
`18months.
`--· •• do ______ --------- _ ____ do __________ ----_
`---------------------- Clear for at least
`6·months.
`
`Clear for at least
`2months.
`
`Clear for at least
`3 months.
`Do.
`
`Do.
`
`:1 'Heated at 56-68° C. for 45 minutes.
`J Five percent of Triton WR-13391nstead·o! ten percent;heated·to:71Hl5° C. for ninety minutes.
`
`Metrics EX1045, Page 2
`
`

`
`6
`room temperature. Then dissolve the sodium chloricte
`and chlorobutanol making sure the solution is complete.
`Then dissolve the sodium citrate and adjust volume with
`water for injection to one liter. Pass the solution
`through a sterile filter, pre-washed with five percent so(cid:173)
`dium bicarbonate solution and water for injection.
`EXAMPLE 6
`Sterile aqueous solution of .6.1-hydrocortisone (0.1%)
`Formulation:
`Triton WR-1339 __________________ grams__ 100
`Delta hydrocortisone ---------------do____ 1.05
`Sodium chloride -------------------do____ 3.7
`Chlorobutanol ---------------------do____ 5.5
`Sodium citrate ---------------------do____ 2.0
`Water for injection, q.s. ad 1liter.
`PROCEDURE
`Dissolve the Triton in 400 cubic centimeters of water
`for injection. Then add and dissolve the .6.1-hydrocorti(cid:173)
`sone. Add 458 cubic centimeters of water for injection
`and dissolve the sodium chloride and chlorobutanol. Fi(cid:173)
`nally dissolve the sodium citrate and adjust to one liter
`with water for injection. Pass the solution through a
`sterile filter, pre-washed with five percent sodium bicar(cid:173)
`bonate solution and water.
`With the lower concentration of .6.1-hydrocortisone it
`is not necessary to use heat to obtain a clear, stable solu(cid:173)
`tion.
`
`50
`1.05
`6.5
`0.6
`12
`250
`3.0
`
`fa,880,138
`
`5
`
`10
`
`5
`EXAMPLE 2
`Siertie aqueous solution, hydrocortisone 0.2 percent,
`neomycin sulfate 0.6 percent
`Using the formulation and procedures of Example 1
`with the following formulation:
`1Jiton ~-1339 ______________________ grams __ 100
`Flydrocortisone ------------------------dO----
`2
`3
`Sodium citrate -------------------------do____
`3
`Sodium chloride -----------------------do____
`Neomycin sulfate ----------------------do____ 6.4
`Chlorobutanol -------------------------do____ 5.5
`Water for injection, q.s. ad 1 liter.
`clear, stable solutions containing 0.2 percent hydrocorti- 15
`sone and 0.6 percent neomycin sulfate in a neutral iso(cid:173)
`tonic vehicle were obtained. Procedure A was satisfact(cid:173)
`ory for hydrocortisone lot 1; procedure B for other lots
`of hydrocortisone.
`In place of or in addition to the neomycin sulfate there 20
`can be substituted other water-soluble antibiotics such
`as tetracycline and oxy- and chlor-tetracycline hydro(cid:173)
`chlorides, sodium penicillin (G, 0, V and like forms~,
`polymyxin (B and other forms) sulfate, streptomycin
`sulfate, erythromycin, hydrochloride, bacitracin, grami- 25
`cidin, and novobiocin, or a combination of two or more
`of the same. The following examples are illustrative.
`EXAMPLE 3
`Sterile aqueous solution, hydrocortisone 0.2 percent,
`polymyxin B sulfate 12,000 units!cc.
`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 35
`milligrams of hydrocortisone and 12,000 units of poly-
`. myxin B sulfate per cubic centimeter.
`EXAMPLE 4
`Sterile aqueous solution, hydrocortisone 0.2 percent, neo(cid:173)
`mycin sulfate 0.6 percent, polymyxin B sulfate 12,000
`units/cc.
`Using the formulation and procedures of Example 2
`except that two grams of polymyxin B sulfate (6,000
`units/mg.) was added along with the neomycin sulfate,
`there were obtained clear, stable solutions containing two
`milligrams of hydrocortisone, six milligrams of neomycin
`sulfate, and 12,000 units of polymyxin B sulfate per cc.
`In place of hydrocortisone in th~. above formulatioD;s,
`there can be substituted other antr-mfiammatory sterord 50
`hormones of the 11,8,17a,21-trihydroxypregnane-3,20-di(cid:173)
`one class. Preferably those having low mineral corti(cid:173)
`coid activity such as hydrocortisones, 2-methyle~ehydro­
`cortisone, .6.l.hydrocortisone, 6-methylhydrocortrsone, 6-
`methyl-.6.l.hydrocortisone, 16-hydroxy-9a-fiuorohydrocor- 55
`tisone, 16-hydroxy-9a-fiuoro-.6.1-hydrocortisone, a.nd the
`esters thereof as set forth above. The following ex(cid:173)
`amples are ill~strative.
`EXAMPLE 5
`Sterile aqueous solution of .6.1-hydrocortisone (0.2%)
`Formulation:
`Triton WR-1339 ________________ grams __
`.6.l.hydrocortisone _________________ do ___ _
`Sodium chloride ------------------do ___ _
`Chlorobutanol ____________________ do ___ _
`Sodium citrate --------------------do ___ _
`Water for injection q.s. ad 1 liter.
`
`100.0
`2.1
`4.7 65
`5.5
`2.0
`
`30
`
`60
`
`PROCEDURE
`Dissolve the Triton WR-1339 in 833 cubic centimeters
`of water for injection by stirring while heating to approxi(cid:173)
`mately 65 degrees centigrade. Add the .6.1-hydrocortisone
`and dissolve by stirring and heating at seventy to eighty
`·"degrees centigrade for one hour. Cool the solution to .75
`
`EXAMPLE 7
`.6.1-hydrocortisone
`Sterile aqueous solution containing
`(0.1%) and neomycin sulfate (0.6%) and bacitracin
`(500 u!cc.) and polymyxin (5,000 u!cc.) and a soluble
`powder for preparing the same
`Using the procedure of Example 6 with the following
`formulations:
`Triton WR-1339 _____________________ grams __
`.6_1-hydrocortisone ----------------------do ___ _
`40 Neomycin sulfate ----------------------do ___ _
`Polymyxin B sulfate (10,000 units/mg.) ___ do ___ _
`Bacitracin (50 units/mg.) _______________ do ___ _
`Lactose -------------------------------do ___ _
`Sodium citrate ------------------------do ___ _
`45 Water for injection, q.s. ad 1liter.
`there are obtained (a) a clear, stable solution containing
`one milligram of .6.1-hydrocortisone, 6.5 milligrams of
`neomycin, 600 units of bacitracin and 6,000 units of poly(cid:173)
`myxin B sulfate per cubic centimeter and (b) a water(cid:173)
`soluble product from which said solution can be recon-
`stituted. This water-soluble product is obtained by ap·
`portioning the solution in five cubic centimeter portions
`into vials and lyophilizing the solution in the vials. Each
`vial then contains 250 milligrams Triton WR-1339, 5.25
`milligrams .6.l.hydrocortisone, 32.5 milligrams neomycin
`sulfate fifteen milligrams sodium citrate, 1250 milli(cid:173)
`grams 'of lactose, 30,000 units of polymyxin B sulfate
`and 3,000 units of bacitracin.
`:
`In the lyophilized preparations the amount of nonionic
`surfactant should not exceed about five percent, since too
`much surfactant results in a nonredispersible cake.
`EXAMPLE 8
`Sterile aqueous solution containing .6.1-hydrocortisone
`( 0.1%) and neomycin sulfate ( 0.6% )
`Using the procedure of Example 6, with the following
`formulation:
`Triton WR-1339 _____________________ grams__ 100
`70 .6.Lhydrocortisone ----------------------dO---- 1.05
`Neomycin sulfate ----------------------do____ 6.5
`Sodium chloride -----------------------do____ 2.0
`Sodium citrate -----------------:-------dO--,-- 4.5
`Chlorobutanol -------------------------do_.,.__ 5.5
`Water for injection, q.s. ad 1 liter.
`·
`
`Metrics EX1045, Page 3
`
`

`
`1
`>there :is obtained a clear, .stable, neutral .solution con-
`1aining one milligram of Al-hydrocortisone .and 6.5 milli(cid:173)
`;grams :of 'neomy.cin .sulfate per cubic centimeter.
`
`2;880;138
`
`8
`percent and n is from one to ten, said anti-inflammatory
`steroid hormone being selected from the class consisting
`of hydrocortisone, 2-methylenehydrocortisone, At-hydro(cid:173)
`cortisone, 6-methylhydrocortisone, 6-methyl-A1-hydrocor-
`5 tisone, 16-hydroxy-9a-fluorohydrocortisone, 16-hydroxy-
`9«-fluoro-A1-hydrocortisone, and the substantially water(cid:173)
`insoluble 21-esters and the substantially water-insoluble
`16,21-diesters thereof.
`2. A composition of matter comprising an aqueous
`10 solution containing two to 25 percent alkylphenolform(cid:173)
`aldehyde-ethyleneoxide condensation product and 0.056 to
`to 0.56 percent hydrocortisone.
`3. The process which comprises dissolving an alkyl(cid:173)
`phenol-formadlehyde-ethylene oxide condensation prod-
`15 uct in water and then dissolving in the solution obtained
`a member selected from the group of steroid hormones
`consisting of hydrocortisone, 2-methylene-hydrocortisone,
`A 1-hydrocortisone, 6-methylhydrocortisone, 6-methyl-Al(cid:173)
`hydrocortisone, 16-hydroxy-9«-fiuorohydrocortisone, 16-
`20 hydroxy-9a-fluoro-ALhydrocortisone, and the substantially
`water-insoluble 21-esters and the substantially water-in(cid:173)
`soluble 16,21-diesters thereof, the amount of alkylphenol(cid:173)
`formaldehyde-ethylene oxide condensation product being
`in the range of from about 2 to about 25% and being
`25 sufficient to increase the solubility of the steroid hormone
`substantially above that which can be dissolved in water
`alone, the amount of steroid hormone thus dissolved being
`greater than the amount which can be dissolved 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
`35 group consisting of hydrocortisone, 2-methylene-hydro(cid:173)
`cortisone, A1-hydrocortisone, 6-methyl-hydrocortisone, 6-
`methyl-A1-hydrocortisone, 16-hydroxy-9«-fluorohydrocor(cid:173)
`tisone, 16-hydroxy-9«-fluoro-Al-hydrocortisone, and the
`substantially water-insoluble 21-esters and the substan-
`40 tially water-insoluble 16,21 diesters thereof which com(cid:173)
`prises dissolving an alkylphenol-formaldehyde-ethylene
`oxide condensation product in about 50 to 90% of the
`required water, dissolving the anti-inflammatory steroid
`hormone in the solution thus prepared and diluting the
`45 obtained solution with the remainder of the required
`water, the amount of alkylphenol-formaldehyde-ethylene
`oxide condensation product 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
`50 which can be dissolved in water alone and its total amount
`of water being insufficient in the absence of said alkyl(cid:173)
`phenol-f?rmaldehyde-ethylene oxide condensation prod(cid:173)
`uct to dissolve all of said anti-inflammatory steroid hor(cid:173)
`mone.
`6. The process of .claim 5 in which .the solution of the
`anti-inflammatory steroid hormone is .heated to at least
`40o C. for at least about 15 minutes.
`
`EXAMPLE 9
`Sterile aqueous solution .containing At-hydrocortisone
`(0.1%) and bacitracin and a soluble powder for pre(cid:173)
`paring the same
`Using the formulation and procedures of Example 7 ex(cid:173)
`~ept th~t twenty grams of bacitracin (fifty units per mg.)
`Is ·used m place of the three antibiotics, there are obtained
`'(a) a clear, neutral-solution (limited stability due to the
`bacitracin) containing 1 mg. of ALhydrocortisone and
`-1;000 ·units ·of ·bacitracin per cubic ·centimeter in an
`'isotonic ·vehicle and (b) a soluble powder from which
`said solution can be reconstituted.
`Using the same formulations, except for the antibiotic,
`and the same procedure, soluble reconstitutable powders
`can be prepared with other antibiotics such as sodium
`peniCillin and polymyxin B sulfate, whlch have limited
`:stability in aqueous solutions.
`In place of .the chlorobutanol, other preservatives can
`be used to prevent bacterial and fungal contamination of
`·the solutions. Other such suitable preservatives include
`benzyl alcohol, myristyl gamma picolinium chloride,
`.phenyl mercuric nitrate, benzalkonium chloride, phenyl(cid:173)
`ethyl alcohol, p-chlorophenyl-«-glycerol ether, methyl
`and propyl parabens, thimerosal. Also the buffer salt
`(sodium citrate) can be omitted provided it is replaced
`with sufficient other salt to maintain isotonicity. The 30
`solutions can contain also other water soluble drugs
`·such as phenylephrine hydrochloride, sodium sulfa(cid:173)
`cetamide, chlorprophenyridamine gluconate,
`thonzyl(cid:173)
`amine hydrochloride, sodium propionate, and the like.
`The hydrocortisone and At-hydrocortisone in the above
`examples can be replaced by 6-methyl-hydrocortisone (6-
`n;ethyl - 11,13,17«,21 - trihydroxy - 4- pregnene - 3,20 -
`dwne), 6-methyl-ALhydrocortisone ( 6-methyl-11,13,17 «,21-
`trihydroxy~1,4-pregnadiene-3 ,20-dione),
`16-hydroxy-9«(cid:173)
`fiuorohydrocortisone
`(11,13, 16«, 17 «,21 - tetrahydroxy -
`and 16-hydroxy-9«(cid:173)
`9«-fiuoro-4-pregnene-3,20-dione),
`fiuoro-A1-hydrocortisone
`( 11,13, 16«, 17 «,21-tetrahydroxy-
`9 .. -fiuoro-1,4-pregnadiene-3,20-dione ), and the 21 esters
`thereof to give more potent formulations because of the
`higher anti-inflammatory activity of these steroids. Al(cid:173)
`ternatively the amount of these steroids can be reduced
`to give formulations of equivalent potency. 2-methylene(cid:173)
`hydrocortisone (2- methylene- 11,13,17«,21- trihydroxy-
`4~pregnene-3,20-dione) can be used where an anti-inflam(cid:173)
`matory 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 55
`the art, and the invention is therefore to be limited only
`by the:scope of the appended claims.
`I claim:
`J. A composition of matter comprising an aqueous
`.solution of an anti-inflammatory steroid hormone of the 60
`ll,B,17a,21-trihydroxypregnane•3,20-dione class and as a
`nonionic surfactant solubilizing agent, alkylphenol-form(cid:173)
`aldehyde-ethyleneoxide condensation product, said com(cid:173)
`position having the following formula:
`
`Percent
`Anti-inflammatory steroid hormone ------------
`2nx
`Nonionic surfactant -------------------------
`2-25
`p
`.
`reservattve ----------------------------- Up to 1.5
`'Soluble salts (including buffer salt if any) ____ Up to 2.0
`Lactose -------------------------------- Up to 25 70
`Other drugs ----------------------------- Up to 30
`Water, q;s. ad. 100 percent.
`
`2,497,509
`2,653,955
`2,779,707
`65 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
`FOREIGN PATENTS
`Gr
`t B 't ·
`ea
`n am -----------
`OTHER REFE E c
`R N ES
`Ekwall: Chemical Abstracts, 49, 7754F, 1955.
`.in POSL.)
`Ekwall: Acta Chemica Scandinavica, 5:2, pp. 1383-
`1387, 1951.
`Ekwall: Acta Endocrinol., 4, pages 179-191, 1950.
`Dulin: P.S.E.B.M., 19: ~.pages 115-117, October .1955.
`
`12 1947
`,
`
`594,475
`
`N
`ov.
`
`(Copy
`
`wherein x represents the solubility of the anti-inflamma(cid:173)
`tory steroid hormone in 'Water at room temperature in 75
`
`Metrics EX1045, Page 4