United States Patent (19) [11] 3,886,268 Halpern (45) May 27, 1975

(54) IODOPHOR-STEROID COMPOUND "Antibacterial Agents Not Presently Employed As PHARMACEUTICAL COMPOSITIONS Preservatives in Ophthalmic Preparations Found Ef fective Against Pseudomonas Auruginosa'. (PVP-Io 75) Inventor: Alfred Halpern, Great Neck, N.Y. dine). 73 Assignee: Synergistic, New York, N.Y. Higuchi et al.; J. Am. Pharm. Assoc. Scl. Ed.43:3- 22 Filed: Mar. 29, 1974 98-401, July 1954, “Study of Possible Complex For mation Between Macromolecules and Certain Phar (21 Appl. No.: 456,333 maceuticals I'. (PVP-Cortisone). Related U.S. Application Data GAF (1967), PVP-An Annotated Bibliography E63) Continuation-in-part of Ser. No. 257,505, May 30, 1951-1966, Vol. I, 53, pp. esp. pp. 17-19, “Chemical 1972, abandoned. Complexes' Mfg. Brochure. 52 U.S. Cl...... 424/80; 260/88.3; 424/243 GAF (1967), PVP-An Annotated Bibliography 51 Int. Cl...... A61k 17700; A61k 27112 1951-1966, Vol. II, 51 pp. esp. pp. 15-20 “PVP-Io 58 Field of Search ...... 424/80, 243; 260/88.3 dine' Mfg. Brochure. (56) References Cited Primary Examiner-Shep K. Rose UNITED STATES PATENTS Attorney, Agent, or Firm-Wolder & Gross 2,861,920 l l (1958 Dale et al...... 424/80

2,897,120 7/1959 Cronin et al...... 424/80 X 3,062,712 11/1962 Dale et al...... 424/8O 57 ABSTRACT 3, 190,855 6/1965 Miki...... 260/63 3,671545 6/1972 Halpern...... 260/326.5 FL Iodophor-steroid complex compounds and composi 3,751,565 8/1973 Santorelli...... 424/80 tion employing the same, exhibiting synergistic anti 3,764,669 10/1973 Santorelli...... 424/80 inflammatory action, greater than the sum of the anti FOREIGN PATENTS OR APPLICATIONS inflammatory potency of the respective moieties. 1,319,413 6/1973 United Kingdom Methods for the preparation and use of the aforesaid 2,166,215 5/1973 United Kingdom iodophorsteroid complex compounds in the treatment of inflammatory, dermatologic disease are described, OTHER PUBLICATIONS Kohn et al.; J. Pharm. Scl. 52(12):I 126, Dec. 1963, 31 Claims, No Drawings 3,886,268 2 EODOPHOR-STEROD COMPOUND widely used for its germicidal properties because it re PHARMACEUTICAL COMPOSITIONS tains the broad microbiologic spectrum of elemental This application is a continuation-in-part application iodine but avoids its harmful tissue properties. The de of applicant's co-pending application, Ser. No. sirable germicidal properties of polyvinylpyrrolidone 257,505, filed May 30, 1972, now abandoned. iodine are due to its available iodine content, which This invention relates to synergistic, anti chemically is elemental iodine. Thus, it would be ex inflammatory iodophor-steroid complex compounds, pected that the well known chemical incompatibility pharmaceutical compositions employing the same and between a steroid anti-inflammatory compound and el methods for their use in the treatment of inflammatory emental iodine would remain when polyvinylpyrroli skin disease of humans and animals. In particular, it re 10 done-iodine is used in combination with a steroid com lates to a new molecular complex compound formed pound, although the harmful toxic effects of iodine between polyvinylpyrrolidone-iodine and an anti would be avoided. However, it was unexpectedly found inflammatory steroid compound, as for example, corti that when an iodophor compound, as for example, sone, cortisone acetate, hydrocortisone, hydrocorti polyvinylpyrrolidone-iodine, is combined with a steroid sone acetate, prednisone, prednisone acetate, prednis 15 anti-inflammatory compound, as for example, corti olone and prednisolone acetate, said new compound sone, cortisone acetate, hydrocortisone, hydrocorti complexes possessing an increased topical anti Sone acetate, prednisone, prednisone acetate, prednis inflammatory potency which is greater than the sum of olone and prednisolone acetate, that a new molecular topical anti-inflammatory activity determined for the complex compound is formed which possesses both an respective component moities when these are used ti-inflammatory and germicidal properties. The molec alone. ular complex formed between said steroid compound It is an object of this invention to describe a method and said iodophor compound does not exhibit the oxi for preparation of the synergistic iodophor-steroid dative degradation of the steroid moiety, such as is complexes and compositions employing the same, as known to occur for steroids in the presence of iodine well as to describe a method for treating inflammatory 25 and for the first time, stable pharmaceutical dosage skin diseases utilizing the aforesaid compositions. forms which are useful in the treatment of inflamma When a steroid anti-inflammatory compound is ap tory skin disease may be prepared to provide concur plied to the skin during therapy of inflammatory skin rent anti-inflammatory and germicidal activity. diseases, certain inherent defects limit the therapeutic When the new iodophor-steroid compound is sub utility of these compounds. It is known for example, jected to stability control testing, either in its pure form that increased anti-inflammatory activity renders the or when combined with a pharmaceutically acceptable skin more sensitive to infection and presents a serious non-toxic carrier, we find significant differences in the threat to the patient unless adequate antimicrobial pro stability of the new iodophor-steroid compound and cedures are employed. Thus, when a steroid anti compositions containing the same, when these are inflammatory compound is intended to be used in treat 35 compared to the behavior of a mixture of the separate ing dermatologic disease of humans and animals, which components. is complicated by infection, good germicidal activity In an experiment to determine the comparative sta must be present together with the anti-inflammatory bility of the new compound, polyvinylpyrrollidone action in order to avoid a septic state. iodine-hydrocortisone acetate molecular complex Of the antiseptic agents utilized to counteract surface 40 compound, its separate components, as for example, infections, iodine is considered to be one of the best polyvinylpyrrolidone-iodine and hydrocortisone ace germicidal agents because of its broad spectrum, rapid tate and a mixture of elemental iodine and hydrocorti microbicidal action against virtually every species of sone acetate were subjected to ambient room tempera micro-organism. However, elemental iodine is a strong ture storage for a period of two years, the samples were corrosive, oxidative halogen compound that interacts 45 stored as the dry powder in glass vials. The respective with many organic substances as well as to possess nox samples were analyzed for available iodine content and ious toxicologic and pharmacologic properties when hydrocortisone acetate content as specified intervals applied to the skin. When elemental iodine comes in and the respective analyses compared to the initial val contact with an anti-inflammatory steroid compound, ues. The results of this test is described in Table I, and oxidative degradation of the steroid compound results establishes that the new molecular complex, polyvinyl so that the anti-inflammatory potency of the composi pyrrolidone-iodine-hydrocortisone acetate compound tion is greatly reduced and, in many cases, even elimi is stable when stored for two years at room temperature nated. Elemental iodine stains the skin, causes burning whereas a mixture of iodine and hydrocortisone acetate and local tissue irritation and preparations containing showed marked decomposition within one month. elemental iodine cannot be bandaged. These and other 55 In a second experiment, a pharmaceutical solution well known chemical and toxicologic incompatibilities containing 10% of polyvinylpyrrolidone-iodine have prevented the formulation of a steroid compound hydrocortisone acetate molecular complex was com with elemental iodine into pharmaceutical preparations pared to a mixture of a solution of iodine and hydrocor for use in the treatment of infected inflammatory skin 60 tisone acetate. The concentration of the respective disease. moieties was adjusted to be equivalent to the molecular Recent years witnessed great advances in eliminating proportions of iodine and hydrocortisone acetate pres certain of the limitations of elemental iodine as a ger ent in the newly formed complex compound, polyvinyl micide. The introduction of polyvinylpyrrollidone pyrrollidone-iodine-hydrocortisone acetate. The re iodine marked a great step forward in avoiding the nox spective solutions were aged in a temperature ious toxicologic properties associated with iodine. 65 controlled oven set at 37°C. 2C. and assayed at de Polyvinylpyrrolidone-iodine is a well known compound termined intervals of 1 day, 3 days, 6 days, and 10 days. (see National Formulary XIII, page 581, (1970), and is The results of this test are reported in Table II and es 3,886,268 3 4 tablished that polyvinylpyrrolidone-iodine powders and ointments. The same inert pharmaceuti cally acceptable vehicles were used for preparing the hydrocortisone acetate is stable whereas a total degra respective test preparations. The respective samples dation of the hydrocortisone acetate and in iodine con were assayed at 1 month, 3 months, 6 months and 12 tent occurred with the mixture which made the mixture month intervals. The results reported in Table III dem unsatisfactory for pharmaceutical use. onstrate that the new polyvinylpyrrolidone-iodine In still another experiment, pharmaceutical composi hydrocortisone acetate compound complex when com tions containing the new steroid compound complex pounded into an ointment dosage form or a powder were compared to similar pharmaceutical compositions form, is stable for a period of one year whereas mix prepared with a mixture of iodine and the respective tures of the component moieties compounded in the steroid compound as to their storage stability. The re same molecular proportion in the same vehicle, showed spective pharmaceutical dosage forms tested were marked degradation of the steroid and iodine content. TABLE 1

THE STABILITY OF POLY WINYLPYRROLIDONE-ODINE-HYDROCORTISONE ACETATE COMPOUND AND ITS COMPONENTS WHEN STOREDAT ROOM TEMPERATURE ?t COMPOUND Initial l month 6 months 12 months 18 months 24 months I/mg/ HCA/ I/mg/ HCA/ /mg/ HCA/ I/mg/ HCA/ /mg. / HCA/ I/mg/ HCA/ gm. mg/gm. gm. mg/gm. gm. mg/gm. gm, mg/gm. gm, mg/gm. gm. mg/gm Polyvinylpyrrollidone-lodine 10 mg. 10 mg. 9.8 mg. 10 mg. 9.4 mg. 9.9 mg. 9.2 mg. 9.7 mg. 8.9 mg. 9.4 mg. 8.8 mg. 9.4 mg. hydrocortisone acetate, molecular complex compound Polyvinylpyrrolidone-Iodine 10 mg. - 9.7 mg. -- 9.6 mg. - 9.2 mg. - 9.1 mg. - 9.2 mg. - Hydrocortisone acetate -- 10 mg. --- 10.1 mg. - 9.8 mg. 9.4 mg. - 9.1 mg. 9.2mg. Elemental Iodine and 10 mg. 10 mg. 6.0 mg. 5.3 mg. 0.3 mg. 4.3 mg. ------m - hydrocortisone acetate, 1Xtute = available iodine contcnt determined by method described in National Formulary, Edition XII, page 58i, (1970). HCA = amount of hydrocortisone acetate determinca by method described in The United States Pharmacopeia, Revision XVIII, page 306, (1970), for hydrocortisone accitate. “'stored as the dry powder in a stoppered vial.

TABLE II

THE EFFECT OF MOLECULAR COMPLEXING ON HYDROCORTISONE ACETATESTABILITY ANDAVALABLE ODINE LEVELS UNDER ACCELERATED ELEVATED TEMPERATURE AGING AT 37°C. Polyvinylpyrrolidone-lodine Solution of iodine and hydro Aging Period hydrocortisone acetate" cortisone acetate' la HCA l HCA ASSAY mg/gm. mg/gm. mg/gm. mg/gm. Initial 0.0 10.0 10.0 10.0 Day 1 0.0 10.0 4.1 2.3 Day 3 9.2 10.0 (c) (c) Day 6 8.8 9.3 (c) (c) Day 10 8.8 9.4 (c) (c) l, = available iodine conticnt determined by method described in National Formulary, Edition XIII, page 581, (1970). HCA = amount of hydrocortisone acetatic determined by method described in The United States Pharmacopeia for hydrocortisonc acetatic, Revision XVIII, page 306. (1970). "Preparcd with the product of Example I. 'Adjusted to conform in concentration of respective moieies to that of the compound of Examplc i. (c) No available iodine content and no hydrocortisone acetate were found by the methods described above.

TABLE III

THE EFFECT OF MOLECULAR COMPLEXING ON HYDROCORTISONE ACETATE STABILITY AND IODINE LEVELS IN PHARMACEUTICAL COMPOSITIONS STORED AT ROOM TEMPERATURE COMPOSITION Initial 3 months 6 months 2 months Steroid Steroid Steroid Steroid

l Polyvinylpyrrolidone-lodine' hydrocortisone acetate ointment Iodine and hydrocortisone' 1.2 2.0 O O O O acetatePolyvinylpyrrollidone-lodine ointment 0.0 0.0 cortisone acetate ointment' 0.0 10.0 9.6 10.0 9.8 10.0 9.7 9.9 Iodine and cortisone acetate ointment 10.0 10.0 2.3 4.1 O 0 O O Polyvinylpyrrolidone-iodine' prednisolone acetate powder ().0 10.0 9.8 9.6 9.8 9.4 9.6 9.5 Iodine and prednisolone acetate powder 0.0 0.0 O O O O 0 O 3,886,268

TABLE III - Continued

THE EFFECT OF MOECULAR COMPLEXING ON HYDROCORTISONE ACETATESTABILITY AND ODINE LEWELS IN PHARMACETICAL COMPOSITIONS STOREDAT ROOM TEMPERATURE COMPOSITION initial 3 months 6 nonths 2 months Polyvinylpyrrolidone-lodine" hydrocortisone acetate powder ().() O).() 10.0 0.0 0.0 9.9 9.6 9.8 Iodine and hydrocortisone' acetate powder O.() ().() O O O O O O 1 = available iodine content determined by method described in National Formulary, Edition XIII, p. 58 (1970). Steroid = the respective steroid moiety was assayed by the respective United States Pharmacopeia or National Formulary Method. prepared in accord with Example 3: "prepared to conform in weights and vehicle to Example 3, but utilizing elemental iodine and hydrocortisone acetate in admixture prepared setin accord E. t withExample Example 9: “prepared 3 as to cquivalen as set forth weights in Example and yehicle. 9 but withElemental elemental iodine iodine and andcortison prednisolone acetate inacetate admixture or hydrocortisone were the active acetate agents: serving prepared as active as ingredients. On the basis of the above described studies, it is con- b. The resistance of elemental iodine against reduc cluded that polyvinylpyrrolidone-iodine forms a molec- tive degradation by the steroid moiety. ular complex with a steroid compound, as for example, c. The preservation of both germicidal and antiin hydrocortisone acetate, hydrocortisone, cortisone, cor- flammatory properties for the new complex com tisone acetate, prednisone, prednisone acetate, pred- 2O pounds. nisolone and prednisolone acetate which avoid the d. The increase in aqueous solubility of a steroid, i.e., known oxidative degradation occuring when iodine is hydrocortisone acetate in the presence of brought into contact with a steroid compound. Thus, polyvinylpyrrolidone-iodine. although it is well known that polyvinylpyrrolidone- e. The absence of the characteristic green fluores iodine releases available iodine which has all the chem- 25 cence of a steroid, i.e., hydrocortisoneacetate ical properties of elemental iodine, and that elemental when the new complex molecule, polyvinylpyrroli iodine will act as a potent oxidizing degradative Sub- done-iodine-hydrocortisone acetate is dissolved in stance to steroid compounds, the newly formed polyvi- concentrated sulfuric acid. nylpyrrollidone-iodine-steroid complex compound re Corresponding modification of the applicable prop sists such degradative oxidative changes to preserve the 30 erties of the respective steroid moiety described above anti-inflammatory and antiseptic properties of the com were obtained when the new complex compound was pound upon storage in both the isolated pure form, as prepared with polyvinylpyrrolidone-iodine and a ste well as in the form of a pharmaceutical composition roid selected from the group consisting of cortisone, when the new compound is combined with a carrier. cortisone acetate, hydrocortisone, prednisone, predni Further proof of the formation of a molecular com- 3.5 sone acetate, prednisolone and prednisolone acetate. plex between the moieties of the new compound is seen in the change in aqueous solubility of hydrocortisone It was further unexpectedly found that the new iodo acetate in the presence of polyvinylpyrrolidone-iodine. phor-steroid compound complex possessed an im Thus, it is known that hydrocortisone acetate is Soluble proved anti-inflammatory potency that was greater in water to the extent of 1 mg. per 100 ml., but when 40 than the sum of the individual anti-inflammatory poten polyvinylpyrrolidone-iodine-hydrocortisone acetate is cies determined for the separate components. Thus, the dissolved in water, the hydrocortisone acetate moiety bio-assay of anti-inflammatory properties reveals a is now rendered significantly more soluble to form sta vastly increased potency for said new molecular com ble solutions up to about 20 mgs. per 100 ml. When the pound over the values determined for the individual concentration of polyvinylpyrrolidone-iodine in rela- 45 components to establish a synergism. tionship to that of hydrocortisone acetate is decreased, The alpha-2-glycoprotein immunoassay for anti there is a corresponding decrease in the Solubility of inflammatory activity of both steroid and non-steroid the hydrocortisone acetate, so that when the concen compounds, is a sensitive, accurate and rapid assay tration of polyvinylpyrrolidone-iodine per 100 ml. is procedure that lends itself to both qualitative and quan below 1 percent, we find that the change in aqueous 50 titative evluations. This test has been well documented solubility of hydrocortisone acetate is now appreciably in scientific literature and has been accepted as a reli altered and the solubility limis of hydrocortisone ace able method for ascertaining anti-inflammatory activity tate is 1.03 mg. per 100 ml. both qualitatively and quantitatively. (Endocrinology Still another change in physical properties of hydro 82: 1093-1097, 1968; Fed. Proc. 29 (2): 419, 1970: cortisone acetate occurs when it is combined with 55 Endocrinology 82: 1085-1092, 1968 and Proc. Amer. polyvinylpyrrolidone-iodine to form a new compound Assoc. Cancer Res. 3:305, 1962). which is indicative of complex formation. It is known In the case of steroids, and more specifically, the nat that hydrocortisone acetate when dissolved in concen- ural and synthetic 11-oxy-corticosteroids, anti trated sulfuric acid causes a green fluorescence. This inflammatory activity is measured by an increase in fluorescence is absent when a concentration of 60 S. alpha-2-glycoprotein levels. Non-steroids, on the polyvinylpyrrolidone-iodine equal in weight to the other hand, such as aspirin, phenylbutazone and indox weight of hydrocortisone acetate is added to the con- ole, influence alpha-2-glycoprotein synthesis in a dose centrated sulfuric acid in which the hydrocortisone ac- response relationship. The anti-inflammatory activity etate is dissolved. of these compounds is measured, therefore, by a de Thus, the proof of new compound formation between 65 crease in serum alpha-2-glycoprotein levels from that polyvinylpyrrolidone-iodine and hydrocortisone ace- determined for the untreated controls. This difference tate is readily established on the basis of of effect of the serum alpha-2-glycoprotein response a. The resistance of steroid moiety to oxidative deg- between steroids and non-steroids, has been utilized to radation by elemental iodine. obtain maximal assay of sensitivity and response. 3,886,268 7 8 As a result of injury to connective tissue, or during used to treat a broad range of inflammatory skin dis the initial phases of an acute inflammatory reaction, eases and topical infections wherein a germicidal anti there is release and/or synthesis of a humoral initiator inflammatory and/or anti-pruritic action is desired. substance, designated as “HIS'. The amount of “HIS' Such dermatologic entities as contact dermatitis, atopic released is dependent upon the amount of tissue in 5 dermatitis, eczema, infective dermatitis, stasis dermati volved. Upon reaching the liver, HIS initiates alpha-2- tis, lichen simplex chronicus, anogenital prurities, in glycoprotein synthesis in the presence of endogenous tertrigo and bacterial and mycotic infections of the skin glucocorticoid, the hepatic response being a quantita are readily controllable through the application of the tive expression of the amount of HIS perfusion. new compounds or pharmaceutical compositions con It has been postulated that alpha-2-glycoprotein is 10 taining the new molecular complex steroid-iodophor carried through the blood stream to the site of injury compounds, from one to six times daily, depending and is utilized in the initial phases of granuloma tissue upon the patient's needs. Such therapeutic use has formation. The administration of exogenous glucocor been found to be non-irritating to the skin and the af ticoids, topically or parenterally, superimposed on al fected area may be bandaged despite the presence of ready high endogenous levels, resulting from the stress 15 an iodine-containing germicidal compound. of trauma, causes an inhibition of anabolic processes, The following examples describe the present inven and alpha-2-glycoprotein therefore is not incorporated tion but it is not intended to be limited thereby. into granuloma tissue but accumulates in the plasma in a dose-related phenomenon. EXAMPLE I The anti-inflammatory non-steroid compounds as ex In a suitable glass reaction vessel, fitted with an inlet emplified by aspirin, on the other hand, apparently act tube and a stirrer is placed a solution of 12 gm. of at the site of trauma inhibiting HIS release with a resul polyvinylpyrrollidone-iodine dissolved in 50 ml. of etha tant depression of serum alpha-2-glycoprotein levels as nol. The stirring is started and the mixture warmed to compared to untreated controls. This is further sup 50°C., whereupon l gm. of hydrocortisone acetate is ported by the effectiveness of alpha-2-glycoprotein re 25 added. The stirring continues until a clear, homoge sponse as a sensitive and quantitative indicator of the nous solution is obtained and the pH of the solution is anti-inflammatory activity of topically applied salicy adjusted to be between pH 4 and pH 6. After four hours lates. of stirring, while warming, the solution is cooled to When this test for anti-inflammatory activity was ap room temperature, allowed to stand overnight and the plied to the subject new iodophor-steroid compound 30 solvent distilled to one-third of the original volume complex and the results compared with a side-by-side whereupon a solid, amber colored powder separates. study of respective components, it was found that the The whole is then set aside in an ice-chest and the sepa subject new compound, polyvinylpyrrolidone-iodine rated solid material filtered, washed with small portions hydrocortisone acetate caused an increase in the level of cold, dried acetone and cold, absolute alcohol, and of serum alpha-2-glycoprotein of 132 percent over the 35 the powder dried in a vacuum. placebo control, while 1 percent hydrocortisone ace The isolated formed new compound, polyvinylpyrrol tate in the same vehicle induced only a 39 percent in idone-iodine-hydrocortisone acetate, is an amber col crease over the placebo control level. The results of ored amorphous powder, soluble in water and alcohol this test establish that the new compound, polyvinylpy but insoluble in chloroform, acetone and petroleum rrolidone-iodine-hydrocortisone acetate compound 40 ether. The aqueous solubility of polyvinylpyrrolidone complex, causes an increased alpha-2-glycoprotein iodine-hydrocortisone acetate complex compound, at level greater than the sum of values determined for the 25°C., is 44.3 mg. per 100 ml. When the new com separated components, to result in a synergistic action pound is treated with chloroform, iodine is not ex for the new compound. tracted and when suspended in acetone, there is no ex To achieve the aforesaid synergistic increase in anti 45 traction of the hydrocortisone acetate moiety. The io inflammatory properties for the combination of an io dine content of the new molecule is 32.8 percent, dophor with the steroid, from 1 to 10 parts by weight which is in good agreement with the calculated theoret of iodophor compound is combined with each 1/10 ical value of 31.4 percent. The percentage concentra part to 5 parts by weight of the steroid compound, and tion of hydrocortisone acetate in the new molecule is a preferred composition contains 10 parts by weight of 50 53.4 percent by weight, which is in good agreement iodophor compound for each part by weight of steroid with its theoretical value of 52.6 percent. When the po compound. lyvinylpyrrolidone-iodine-hydrocortisone acetate is Although undiluted combination of active com dissolved in concentrated sulfuric acid, the green fluo pounds may be utilized in therapy by direct application rescence, as is well known to occur with hydrocorti to the skin of humans and animals, it is preferred that 55 Sone acetate, no longer is present. the combination of iodophor and anti-inflammatory agent be compounded with a suitable pharmaceutically EXAMPLE 2 acceptable carrier. Such carriers as a polyethylene gly In place of the hydrocortisone acetate described in col having a molecular weight of from 200 to 6000; hy Example above, there may be substituted in stoichio drophilic and lipophilic ointment bases, propylene gly 60 metric equivalent amounts, such steroid compounds as col, glycerin and mixtures of the same and talc, starch cortisone, cortisone acetate, hydrocortisone, predni and magnesium Stearate are examples of suitable phar Sone, prednisone acetate, prednisolone, prednisolone maceutically acceptable carriers. When preparing solid acetate, the remainder of the steps being the same and pharmaceutical compositions containing the new iodo the properties of Some of the respective formed new phor-steroid compounds, either simple levigagation or 65 molecular complex compounds isolated are: milling may be utilized to uniformly disperse the active a. Polyvinylpyrrolidone-iodine-cortisone, an amber ingredients in the carrier. colored amorphous powder, soluble in water to the ex The new pharmaceutical compositions comprising tent of 38 mg. per 100 ml, but insoluble in acetone and the anti-inflammatory iodophor compound may be petroleum ether. The compound does not reduce am 3,886,268 9 10 moniacal silver nitrate solution at room temperature in ratio of iodophor compound to steroid will be deter contrast to cortisone, per se. The melting point of poly mined by the patient's needs and the compounds pre vinylpyrrolidone-iodine-cortisone is over 280°C., with ferred. The remainder of the steps are the same. decomposition. b. Polyvinylpyrrollidone-iodine-cortisone acetate is EXAMPLE 6 soluble in water to the extent of 30 mg. per 100 ml. and In place of the polyethylene glycols described in Ex melts with decomposition above 210°C. amples 1 through 5 above, there may be substituted in c. Polyvinylpyrrollidone-iodine-hydrocortisone is sol equal parts by weight, the following compounds: uble in Water to the extent of 16 mg. per 100 ml, and a. For polyethylene glycol-400: a liquid polyethylene does not cause a green fluorescence when dissolved in O glycol compound having a molecular weight of from concentrated Sulfuric acid. The new compound does 200 to 800, glycerine, propylene glycol and mixtures of not reduce alkaline silver nitrate solution as does hy the same. drocortisone, b. For polyethylene glycol-4000 and polyethylene d. Polyvinylpyrrolidone-iodine-prednisone is soluble glycol-6000: a solid polyethylene glycol, having a mo in water to the extent of 12 mg. per. 100 ml. and melts 15 lecular weight of from between 1000 and 6000 molecu at 24.6°C., with decomposition. lar weight, and mixtures of the same. e. Polyvinylpyrrolidone-iodine-prednisone acetate The remainder of the steps remain the same. melts at 210°C., with decomposition. f. Polyvinylpyrrollidone-iodine-prednisolone melts at EXAMPLE 7 265°C., with decomposition. To 100 gms. of propylene glycol is added 5 gms. of g. Polyvinylpyrrollidone-iodine-prednisolone acetate prednisolone acetate and the mixture is warmed until is soluble in water to the extent of 8 mg per 100 ml. solution is achieved. Twenty ml. of a 10 percent aque and melts at 221°C., with decomposition. ous Sclution of polyvinylpyrrolidone-iodine is then added and the mixture stirred until a homogenous EXAMPLE 3 25 preparation results. The resultant product is suitable to In a tared, suitable container is placed 70gm. of poly treat humans and animals presenting dermatologic dis ethylene glycol-1000 which is carefully melted and ease complicated by infection wherein an anti while maintaining the warming temperature to be just inflammatory effect is desired. above the solidification point of the polyethylene gly It may be desired to substitute in equivalent weight, col-1000 compound, l l gms. of polyvinylpyrrolidone glycerin or a polyethylene glycol having a molecular iodine-hydrocortisone acetate and 8 ml. of distilled weight of between 200 and 800 or mixtures of the same water are added and the whole stirred until a uniform for all or part of the propylene glycol used above. distribution is achieved. The weight of the composition is now determined and brought up to final weight of EXAMPLE 8 100 gm. with distilled water. The composition is now 35 To 50gms. of glycerin is added 2 gms. of hydrocorti cooled to room temperature and packaged in unit dos sone and 10 gms. of polyvinylpyrrolidone-iodine. The age form, if desired. The resulting composition may be mixture is stirred until solution is achieved and the re used with great advantage in dermatologic therapy to sultant product is suitable for use in the treatment of treat infected inflammatory skin disease. dermatologic disease complicated by infection wherein 40 an anti-inflammatory effect is desired. It may be de EXAMPLE 4 sired to substitute an equivalent weight of propylene In a suitable vessel is placed 52.7 gms. of polyethyl glycol or a polyethylene glycol having a molecular ene glycol-400; 8.3 gms. of polyethylene glycol-4000 weight of between 200 and 800 for all or part of the and 16.9 gms. of polyethylene glycol-6000. The poly glycerin used above. ethylene glycols are melted and to this is added 10 ml. 45 of deionized water. The mixture is stirred and set aside EXAMPLE 9 to cool. When it is desired to utilize the pharmaceutical dos With rapid stirring, 10 gms. of polyvinylpyrrolidone age form, powders, in the treatment of dermatologic iodine is added and the pH adjusted to between pH 4.5 disease requiring antiseptic-anti-inflammatory therapy, and pH 6. One gram of hydrocortisone acetate is then 50 then an iodophor-steroid molecular complex com added and the whole milled until a uniform dispersion pound such as is described in Examples and 2 above, is achieved. The resultant composition may be used in may be combined with a pharmaceutically acceptable dermatologic therapy or may be packaged into individ powder vehicle, as for example, talc, starch or magne ual single dose units. sium stearate. The iodophor-steroid complex com 55 pound may also be formed, in situ, in the course of pre EXAMPLES paring the powder unit dosage form in which case the In place of the hydrocortisone acetate utilized in Ex following procedure may be used: amples through 4 above, there may be substituted in Fifty grams of talc, pharmaceutical grade, are moist equal parts by weight a steroid compound as for exam ened with 50 percent ethanol and a solution of 1 gm. ple, cortisone, cortisone acetate, hydrocortisone, pred 60 of hydrocortisone acetate in 20 ml. of 70 percent etha nisone, prednisone acetate, prednisolone and predniso nol is added. The whole is stirred until a uniform distri lone acetate. While a preferred ratio between iodophor bution results. A solution of 10 gms. of polyvinylpyr compound and steroid compound is 10 parts by weight rolidone-iodine dissolved in 20 ml. of 70 percent alco of iodophor compound for each part by weight of ste hol is then added, and the stirring continues for 1 hour, roid compound, the range in concentration useful to 65 and additional quantity of 39 gms. of talc is added in achieve the synergistic effect is from 1 part to 10 parts small increments and the whole set aside overnight. by weight of iodophor for each 1/10 part to 5 parts by The solvents are removed to dryness under 2 mm/Hg weight of the selected steroid compound. The exact pressure. The resultant amber colored powder com 3,886,268 2 prises polyvinylpyrrolidone-iodine-hydrocortisone ace 9. The compound of claim 1, said compound being tate molecular complex absorbed on talc and the active polyvinylpyrrollidone-iodine prednisolone acetate. compound corresponds to polyvinylpyrrolidone 10. A pharmaceutical germicidal composition com iodine-hydrocortisone acetate as a result of Example 1. prising the compound of claim 1 and a pharmaceuti Other iodophor-steroid complex compounds may be cally acceptable carrier therefrom. prepared by utilizing the above described procedure 11. The pharmaceutical composition of claim 10, and substituting stoichiometric equivalent weights of said compound being polyvinylpyrrolidone-iodine prednisone, prednisone acetate, prednisolone, prednis hydrocortisone acetate. olone acetate, cortisone, cortisone acetate, and hydro 12. The pharmaceutical composition of claim 10, cortisone for the hydrocortisone acetate described 10 said compound being polyvinylpyrrolidone-iodine cor above. The respective iodophor-steroid compound pre tisone. pared which is absorbed on the surface of the talc pow 13. The pharmaceutical composition of claim 10, der carrier corresponds to the product described in Ex said compound being polyvinylpyrrollidone-iodine cor ample 2 above. tisone acetate. 15 14. The pharmaceutical composition of claim 10, EXAMPLE 10 said compound being polyvinylpyrrolidone-iodine hy When it is desired to treat a dermatologic disease as drocortisone. for example, a contact dermatitis, atopic dermatitis, ec 15. The pharmaceutical composition of claim 10, zema, endogenous infective dermatitis, stasis dermati said compound being polyvinylpyrrolidone-iodine tis, lichen simplex chronicus, anogenital pruritis, inter 20 prednisone. trigo, bacterial and mycotic infections or other entities 16. The pharmaceutical composition of claim 10, wherein an anti-inflammatory action is desired, then said compound being polyvinylpyrrolidone-iodine any of the products obtained as a result of Examples 1 prednisone acetate. through 9 above, may be applied to the skin of a human 17. The pharmaceutical composition of claim 10, or animal presenting the symptoms of said dermato said compound being polyvinylpyrrolidone-iodine logic disease from one to six times daily, depending prednisolone. upon the patient's needs. 18. The pharmaceutical composition of claim 10, A prompt anti-inflammatory action occurs together said compound being polyvinylpyrrollidone-iodine with a germicidal action, which provide a rapid relief 30 prednisolone acetate. in painful symptomatology. Bacteriological tests of the 19. A pharmaceutical germicidal anti-inflammatory affected skin surface reveals a significant degerming composition comprising from one to ten parts by action to occur at the same time maximal anti weight of polyvinylpyrrolidone-iodine and from one inflammatory activity is observed. The new prepara tenth part to five parts by weight of a steroid compound tions are free of local tissue irritation and are without 35 selected from the group consisting of cortisone, corti stinging or burning actions such as would be expected sone acetate, hydrocortisone, hydrocortisone acetate, when a conventional iodine germicidal preparation is prednisone, prednisone acetate, prednisolone, prednis applied to irritated skin. The subject preparations will olone acetate and a pharmaceutically acceptable car not stain the skin and are readily removed by simple rier therefor. washing. A further advantage to the use of the above 40 20. The pharmaceutical composition of claim 19, described preparation is that the treated area may be said pharmaceutically acceptable vehicle being se bandaged. lected from the group consisting of polyethylene gly What is claimed is: cols having a molecular weight of from 200 to 6000, 1. A germicidal anti-inflammatory pharmaceutical glycerin and propylene glycol. compound selected from the group consisting of polyv 45 21. The method for preparing a compound of claim inylpyrrollidone-iodine-cortisone, polyvinyl 1, comprising the steps of: pyrrolidone-iodine-cortisone acetate, polyvinylpyrroli a. dissolving 12 parts of polyvinylpyrrolidone-iodine done-iodine-hydrocortisone, polyvinylpyrrolidone in 50 parts of ethanol, iodine-hydrocortisone acetate, polyvinylpyrrolidone b. warming and stirring to achieve complete solution, iodine-prednisone, polyvinylpyrrolidone-iodine 50 c. adding one part of a steroid compound selected prednisone acetate, polyvinyl-pyrrolidone-iodine from the group consisting of cortisone, cortisone prednisolone, polyvinylpyrrollidone-iodine acetate, hydrocortisone, hydrocortisone acetate, prednisolone acetate. prednisone, prednisone acetate, prednisolone, 2. The compound of claim 1, said compound being prednisolone acetate, polyvinylpyrrolidone-iodine cortisone. 55 d. adjusting the pH of the mixture to be not less than 3. The compound of claim 1, said compound being pH 4 and not greater than pH 6, polyvinylpyrrolidone-iodine cortisone acetate. e. stirring, while warming, for a period of at least one 4. The compound of claim 1, said compound being hour, polyvinylpyrrolidone-iodine hydrocortisone. f. concentrating the solvent and isolating the formed 5. The compound of claim 1, said compound being 60 polyvinylpyrrolidone-iodine-steroid molecular polyvinylpyrrolidone-iodine hydrocortisone acetate. complex compound. 6. The compound of claim 1, said compound being 22. The method of claim 21, said steroid being corti polyvinylpyrrolidone-iodine prednisone. sone and said polyvinylpyrrolidone-iodine steroid mo 7. The compound of claim 1, said compound being lecular complex compound isolated, being polyvinyl polyvinylpyrrolidone-iodine prednisone acetate. 65 pyrrolidone-iodine cortisone. 8. The compound of claim 1, said compound being 23. The method of claim 21, said steroid being corti polyvinylpyrrolidone-iodine prednisolone. sone acetate and said polyvinylpyrrolidone-iodine ste 3,886,268 13 14 roid molecular complex compound isolated, being 29. The method for synergistically augmenting the polyvinylpyrrolidone-iodine cortisone acetate. anti-inflammatory potency of a steroid compound 24. The method of claim 21, said steroid being hydro which comprises combining from one to 10 parts by cortisone and said polyvinylpyrrolidone-iodine steroid weight of polyvinylpyrrollidone-iodine with from one molecular complex compound isolated, being tenth part to five parts by weight of a steroid compound polyvinylpyrrolidone-iodine hydrocortisone. selected from the group consisting of hydrocortisone, 25. The method of claim 21, said steroid being pred hydrocortisone acetate, cortisone, cortisone acetate, nisone and said polyvinylpyrrolidone-iodine steroid prednisone, prednisone acetate, prednisolone, prednis molecular complex compound isolated, being olone acetate and isolating the formed compound polyvinylpyrrolidone-iodine prednisone. 10 therefrom. 26. The method of claim 21, said steroid being pred 30. A method for treating inflammatory skin disease nisone acetate and said polyvinylpyrrolidone-iodine on the skin of a human or animal comprising applying steroid molecular complex compound isolated, being from one to six times daily, a therapeutically sufficient polyvinylpyrrolidone-iodine prednisone acetate. quantity of a compound of claim 1 to said inflamed skin 27. The method of claim 21, said steroid being pred 15 of said human or animal. nisolone and said polyvinylpyrrolidone-iodine steroid 31. A method for treating inflammatory skin disease molecular complex compound isolated, being on the skin of a human or animal having said inflamma polyvinylpyrrolidone-iodine prednisolone. tory skin disease complicated by infection comprising 28. The method of claim 21, said steroid being pred applying from one to six times daily, a therapeutically nisolone acetate and said polyvinylpyrrolidone-iodine 20 sufficient quantity of a composition of claim 19 to said steroid molecular complex compound isolated, being inflamed skin of a human or animal. polyvinylpyrrolidone-iodine prednisolone acetate. k k :k k :