United States Patent (19) 11 Patent Number: 5,789.399 Strube 45 Date of Patent: Aug

USOO5789.399A United States Patent (19) 11 Patent Number: 5,789.399 Strube 45 Date of Patent: Aug. 4, 1998

54 TREATMENT OF PRURTUS WITH 5,362,719 11/1994 Godtfredsen ...... 54767 WTAMN ID AND ANALOGS THEREOF 5,374,629 12/1994 Calverley et al...... 514,167 76 Inventor: Marilyn E. Strube, 1017 Olive St. OTHER PUBLICATIONS Belleville, i. 62220 Blachley et al., Uremic Pruritus: Skin Divalant Ion Content and Response to Ultraviolet Phototherapy, Am. J. Kidney 21 Appl. No.: 720,698 Dis. 5:237-241, 1985. Martindale. The Extra Pharmacopoeia 30th Ed., Martindale, 22 Filed: Oct. 2, 1996 1993, pp. 1058–1059. Related U.S. Application Data The Merck Index (11th Ed.) Budavari et al. Merck & Co., Inc., Rahway, N.J. (1989) p. 1206. 60 Provisional application No. 60/005,030 Oct. 10, 1995. Primary Examiner-Marianne M. Cintins (51 Int. Cl...... A61K3159 Assistant Examiner M. Moezie 52 U.S. Cl...... 514/167 Attorney, Agent, or Firn-Howell & Haferkamp, L.C. 58l58 Field of Search ...... 514/1614f1(57 57 ABSTRACT (56 References Cited A method for treating pruritus comprising topical adminis U.S. PATENT DOCUMENTS tration of formulation of vitamin D or an analog of vitamin D is disclosed. The formulation comprises a therapeutically 3,711,602 1/1973 Herschler ...... effective, water-based emulsion, water-based suspension or : t E". t oil-based formulation of vitamin D or analog of vitamin D. 5,190,935 3/1993 Binderup et al. ... 51467 5,342,833 8/1994 Doran et al...... 514/67 7 Claims, 1 Drawing Sheet U.S. Patent Aug. 4, 1998 5,789.399

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&: O 5,789.399 1 2 TREATMENT OF PRURTUS WITH wide variety of causes or that are able to alleviate pruritus WTAMIND AND ANALOGS THEREOF produced by different causes than those that can be treated by currently available agents. This application claims priority under 35 U.S.C. S 119(e) The ability of vitamin D to effectively treat pruritus when to provisional application No. 60/005.030 filed Oct. 10. 5 administered in a topical treatment formulation has not been 1995. heretofore known. The effectiveness of UVB light therapy in the treatment of pruritus has been noted to be incidentally BACKGROUND OF THE INVENTON related to the production of vitamin D in the skin (Blachley et al., Am J Kidney Dis 5:237-241, 1985). The same (1) Field of the Invention wavelengths of between 290 and 310 nm used in UVB This invention relates generally to the field of treating treatment is also able to photolyze provitamin D(7- pruritus and, more particularly, to the topical treatment of dehydrocholesterol) which then internally isomerizes to pruritus using vitamin D and analogs thereof. form vitamin D. Nevertheless no direct link between vita (2) Description of the Related Art min D production in the skin and the antipruritic effective Pruritus is a condition involving localized or general 15 ness of UVB light treatment has been reported and, in itching which can be mediated by stimulation of sensory addition, the mechanism of the therapeutic benefit of UVB nerve endings. Although usually occurring in the skin. light remains unknown. pruritus can also occur in non-cutaneous sites such as Vitamin D is also incidentally present in some formula mucous membranes or cornea. A variety of causes for the tions that are indicated to be useful in certain conditions condition of pruritus are known including external and 20 involving itching. One such nonspecific topical preparation exogenous causes, localized skin disorders and systemic was reported in U.S. Pat. No. 3,711.602 issued to Herschler. diseases. This patent discloses a formulation containing lanolin, The first line of treatment involves diagnosis of the DMSO, isopropyl myristate, vitamin A and vitamin D that underlying condition that causes the pruritus and intervening is applied topically for the treatment of burns, skin imitation, therapeutically to alleviate that underlying condition. Such 25 diaper rash and pruritus. This preparation is nonaqueous and therapeutic treatment is appropriate for example in the provides occlusion and physical soothing actions. It is treatment of psoriasis with UV light or with topical vitamin believed, however, that the vitamin D present in the formu D analogs. These treatments are not considered to be direct lation at a concentration of 7.5 g/ml does not directly treatments of the pruritus and only indirectly relieve the contribute any anti-pruritic effect. This is because the lowest itching. Indeed, some treatment modalities for psoriasis can 30 concentration found to have an anti-pruritic effect in a cause itching (for example, see product insert for the vitamin non-aqueous vehicle in the studies reported herein was 521 D analog Dovonex6, Westwood-Squibb). At the same time g/ml. the underlying disease is being treated, it might also be Other preparations that serve as nonspecific, physically desirable to directly treat the pruritus. Furthermore in some soothing formulations also sometimes contain vitamin D conditions involving pruritus, either the underlying cause for 35 such as for example A and D6 Ointment for soothing relief the pruritic condition cannot be determined or it cannot be of diaper rash or Desitin(s) also used to sooth diaper rash eliminated. In such cases the direct treatment of the pruritic including preventing the burning, pain and itch produced by condition is required. irritants. These preparations, however, provide only a pro Currently available treatment modalities for pruritus tective physical barrier to water and irritants and the vitamin include nonspecific topical agents such as emollients and D present in these preparations is incapable of producing counterirritants, topical drugs such as steroids, local anes any direct antipruritic action as a result of not being bio thetics and antihistamines, and physical modalities such as available from such formulations. ultraviolet phototherapy and thermal stimulation. Some of Thus, although vitamin D has been incidentally related to these treatments are effective in pruritic conditions of par some treatment modalities for pruritus, it has not heretofore ticular etiology, while others may show general but nonspe 45 been known that vitamin D can be effectively used in the cific benefit. treatment of pruritic conditions. Nonspecific topical preparations can act as moisturizing lotions or creams or as oil-based ointments that are occlusive SUMMARY OF THE INVENTION and serve to soften dry skin as well as providing a protective 50 In accordance with the present invention, it has been covering. These can sometimes contain chemical substances discovered that vitamin D can be applied topically in certain in the preparation which do not contribute to the nonspecific formulations that make the vitamin D bioavailable. antipruritic action of the preparation and provide no anti Surprisingly, when administered in such formulations at pruritic action themselves. pruritic sites, the vitamin D becomes therapeutically effec Topical formulations containing pharmacologically active 55 tive and the pruritus is rapidly and completely relieved. agents are often useful in particular pruritic conditions but Because vitamin D is a fat soluble substance, a water may not be generally useful in all pruritic conditions. For based emulsion formulation that is bioavailable and suitable example, topical corticosteroids are not indicated for symp for topical treatment can be used. Thus, one formulation for tomatic treatment unless a steroid responsive disorder is vitamin D that is effective in treating pruritus comprises a diagnosed. Physical modalities such as UV light have been mixture of water, a water-insoluble organic liquid, a surface particularly effective in a variety of conditions although active agent, and a vitamin D or an analog thereof. This undesirable side effects can be produced by UV light such as formulation is effective when the vitamin D is present at a an increased risk of developing skin cancer as well as concentration as low as 2.5 g/ml. undesirable phototoxic reactions (see for example, Marks, J A second formulation that is also effective in treating Dernatol Treat 1:233-234, 1989) 65 pruritus is based upon a nonaqueous carrier vehicle for Thus it would be desirable to develop new anti-pruritic vitamin D. This formulation comprises a water-insoluble agents that are effective in treating pruritus resulting from a organic liquid such as petroleum or corn oil and vitamin D. 5,789.399 3 4 The vitamin D concentration in this formulation can be as D. The surface active agentis biocompatible and suitable for low as 521 ug/ml. application by topical formulation. The formulation also contains a biocompatible water-insoluble organic liquid Another vitamin D formulation effective in treating pru such as an oil or lipid suitable for forming an oil-in-water or ritus comprises a suspension of water and a dispersed phase water-in-oil emulsion so that the formulation is a cream, containing vitamin D or analog thereof. This formulation is ointment, paste or the like. By biocompatible it is meant that effective at concentration of 12.5 g/ml. the substance produces no untoward biological effects such Among the several advantages achieved by the present as local or generalized toxic effects or local irritation at the invention, therefore, may be noted the provision of new site of topical application, Suitable water-insoluble organic treatment for pruritus that is broadly effective in a variety of liquids are well known in the art field of topically applied pruritic conditions; the provision of a treatment modality cosmetics and therapeutics and include but are not limited to that is safe being neither irritating nor toxic; the provision of mineral oil, corn oil or other vegetable oil, petroleum, a treatment that is inexpensive; and the provision of a lanolin, fish oil and the like. treatment that has a low potential for sensitizing the treat The use of surface active agents in preparations that are ment site by virtue of its being an endogenous or closely topically applied is well known particularly in the field of related to an endogenous substance. 5 cosmetics (for example see Surfactants in Cosmetics, Rieger. M., Ed., Marcel Dekker. Inc., N.Y. 1985 which is BRIEF DESCRIPTION OF THE DRAWING incorporated by reference). Thus, a number of biocompat The FIGURE illustrates the concentration-response rela ible surface active agents can be used in the present inven tionship of the antipruritic effect of vitamin D (0.25-5.0 tion including but not limited to (1) anionic surfactants such g/ml) in alleviating the itching produced by poison ivy. as monovalent or polyvalent carboxylate salts, acyl lactylates, alkyl ether carboxylates. N-Acyl Sarcosinates, DESCRIPTION OF THE PREFERRED N-Acyl Glutamates, fatty acid-polypeptide condensates, sul EMBODEMENTS furic acid esters including alkyl sulfates and ethoxylated alkyl sulfates, ester-linked sulfonates, alpha olefin The present invention is thus based upon the discovery 25 sulfonates, phosphated ethoxylated alcohols; (2) cationic that vitamin D can effectively treat pruritic conditions when surfactants such as monoalkyl quaternary ammonium salts, administered topically in a therapeutically effective formu dialkyl quaternary ammonium compounds, amidoamines lation. By a therapeutically effective formulation it is meant and aminimides; (3) amphoteric surfactants such as that the active substance is bioavailable, that is able to exert N-substituted alkyl amides, N-alkyl betaines, sulfobetaines, a biological activity when administered in that formulation. 30 and N-alkyl beta-aminopropionates; and (4) nonionic sur Such formulations effectively exhibit the biological activity factants such as (a) polyoxyethylene compounds including of vitamin D in diminishing or completely alleviating the ethoxylated alcohols, ethoxylated esters and ethoxylated itching involved in pruritic conditions. The formulation is amines; (b) polyoxypropylene compounds such as propoxy also pharmaceutically acceptable for topical application. 35 lated alcohols, ethoxylated/propoxylated block polymers Vitamin D within the scope of this invention is intended and propoxylated esters; (c) alkanolamines; (d) amine to include vitamin D or cholecalciferol as well as the oxides; and (e) fatty acid esters of polyhydric alcohols such several related steroids and their metabolites that are refer as ethylene glycol esters, diethylene glycol esters, propylene enced in the art by the term vitamin D provided such glycol esters, glyceryl esters, polyglyceryl fatty acid esters. compound show the biological activity of vitamin D. Thus sorbitan esters, sucrose esters and glucose esters. vitamin D compounds include alfacalcidol, calcifediol. The selection of a particular surface active agent would calcitriol, cholecalciferol, dihydrotachysterol, and ergocal depend upon a number of factors including but not limited ciferol (Martindale, The Extra Pharmacopoeia 30th Ed. to the particular causation agent for the pruritic condition Martindale. 1993, pp. 1058-1059). and whether topical lesions accompany the pruritic condi Also included within the scope of this invention and 45 tion. The formulations of the present invention are useful in within the meaning of the term vitamin D are analogs of treating pruritic conditions on the skin, mucous membranes vitamin D. Analogs of vitamin D are well known in the art or cornea. Selection of a suitable surface active agent can and such compounds can have modifications in the side thus be based in part on the site being treated. For example, chain and/or changes in the nuclear part of the secosteroid amphoteric or nonionic surface active agents known in the molecule. Vitamin D analogs can contain side chain modi 50 art are selected for uses in and around the eyes to avoid fications involving introduction of unsaturation; corneal irritation. One skilled in the art can readily select a transposing, adding. removing or substituting hydroxyl surface active agent and formulation suitable for a particular groups; substituting hydrogens; forming carbocyclic struc site and pruritic condition as well as for other factors. ture; introducing a heteroatom link; inverting stereochemi In another embodiment of the present invention a water cally; removing or adding alkyl groups and changing the 55 insoluble formulation is provided comprising a number of links in the side chain. (see Calverly and Jones, biocompatible, water-insoluble organic liquid such as a in Antitumor Steroids blickenstagg. Ed., Academic Press, biocompatible oil or lipid suitable as a carrier for the vitamin Inc., San Diego, 1992, 193-270 which is incorporated by D. The carrier must be suitable in the sense of being reference). All of these compound are thus included in the compatible with the vitamin D and any other ingredients and term vitamin D so long as they exhibit the biological activity not deleterious to the patient being treated. Suitable organic of antipruritic effectiveness in a bioavailable formulation. liquids include petroleum jelly, corn oil or other vegetable Such biologically active vitamin D compounds may not oil, mineral oil, lanolin, fish oil and the like. show the same degree of activity as vitamin D, but need The Vitamin D compounds of the present invention can only show at least some discernable antipruritic effect. also be formulated into bioavailable suspensions or disper One embodiment of the present invention is an aqueous 65 sions such as, for example, hydrosols and hydrogels in based emulsion formulation comprising water, a water which a true emulsion is not formed. The formulation is a insoluble organic liquid, a surface active agent and vitamin mixture of two or more substances forming a dispersed 5,789.399 5 6 phase which is finely divided and uniformly distributed pletely and immediately alleviated. The effect of the cream through a dispersion medium which is usually water. The lasted for several hours and when the itching returned, I dispersed phase can be a solid or an oil phase with stabilizers reapplied the cream with the result that the pruritus was to form a stabilized colloidal system. Suspending or dis again completely and immediately alleviated. persing agents may also be added to the formulation and can Vita Moist Cream is sold as a skin moisturizer and carries include surface active agents capable of stabilizing the no indication for use in treating pruritus. Upon reviewing the suspension or dispersion. The preparation of suspensions medical literature. I learned that UVB light was effective in and ingredients used in the formation of suspensions are treating pruritic conditions and that, incidentally, UVB light also produces vitamin D, I concluded that vitamin D was well known in the art and one skilled in the art can readily likely to be the active ingredient in Vita Moist Cream. As prepare such suspension. 10 commercially available, Vita Moist Cream contains 10 In addition to the above ingredients, the formulations of g/ml vitamin D among other ingredients. Ingredients this invention may also include one or more additional present in Vita Moist Cream are as follows: auxiliary ingredients such as diluents, buffers, or preserva tives such as methyl hydroxybenzoate and/or anti-oxidants and the like. Such additional ingredients can also be 15 WTAMOIST CREAM pharmaceutically-acceptable excipients for modifying or Purified Water maintaining the pH, osmolarity, viscosity, clarity, color, Glycol Stearate sterility, stability, rate of dissolution, or odor of the formu Glycerin lation. Similarly, the formulation may contain still other Isopropyl Palmitate Dimethicone pharmaceutically-acceptable excipients for modifying or Myristyl Myristate maintaining release or absorption or penetration of the site Peg-40 Stearate by the vitamin D compound. Moreover, other therapeutic Stearyl Alcohol substances can be incorporated into the formulation such as. Steareth-2 for example, other antipruritic agents, vitamins, antifungals, Mineral Oil 25 Methylparaben antiinflammatory agents, antibiotics, sunscreens and the Imidazolidinyl Urea like. Triethanola nine Fragrance The topical formulations described herein can be used in Carbomer-934 treating virtually any pruritic site such as for example on the Retinyl Palmitate skin, mucous membranes or cornea. Such treatments include TocopherylAcetate scalp treatment as in shampoos, conditioners and the like, 30 Corn Oil Hydrolyzed Animal Keratin rectal treatment, eye treatment, treatment of nasal Propylene Glycol membranes, treatment of the ear canal, etc. SD Alcohol 40-8 The formulations in the present invention are intended for Cholecalciferol Disodium EDTA use in treating a wide variety of pruritic conditions in 35 FD&C Yellow No. 5 humans as well as in non-human mammals, birds, reptiles, FD&C Red No. 4 amphibians and fish. Conditions that are intended for treat EXT D & C Violet No. 2 ment by the present invention include but are not limited to A - MORE THAN 50% chickenpox, shingles, plant toxins such as poison ivy, insect E = MORE THAN 5% bites, chronic kidney failure, liver diseases such as primary F = .1%TO 19% biliary cirrhosis and alcoholic cirrhosis, malabsorption syn G = LESS THAN.1% dromes such as steatorhea, HIV infection, AIDS related eosinophilic pustular folliculitus, psoriasis, atopic EXAMPLE 2 dermatitis, photosensitivity disorders, lichen planus, poly This example illustrates the antipruritic effect of vitamin cythemia vera, Grover's disease, glanuloma annulare, lichen 45 D formulated in corn oil for alleviating the pruritus of nitidus, prurigo nodularis, macular amyloidosis, urticaria sunburn. pigmentosa, aquagenic pruritus, pemphigus vulgarus, lupis Acorn oil solution of vitamin D was prepared by adding vulgaris, healing cuts and burns, senile pruritus, hypereosi 1 gram of vitamin D to 20 ml corn oil with mixing for nophilic syndrome, chronic uticaria, pruritic eye conditions, approximately 1 hour followed by brief heating to approxi and stress. 50 mately 45° C. until dissolved. One ml of this solution was Preferred embodiments of the invention are illustrated in mixed with 47 ml corn oil and 2 ml isopropyl myristate to the following examples. Other embodiments within the obtain a final concentration of vitamin D of 1000 g/ml. scope of the claims herein will be apparent to one skilled in Subject CS developed a sunburn on the back and expe the art from consideration of the specification or practice of rienced severe pruritus. Application of Vita Moist Cream the invention as disclosed herein. It is intended that the 55 provided some but incomplete relief. An intense pruritus specification, together with the examples, be considered returned and was then dealt by applying 1000 ug/ml in corn exemplary only, with the scope and spirit of the invention oil with the result that the prutitus was immediately and being indicated by the claims which follow the examples. completely alleviated. Approximately an one and one-half hours later, the pruritus returned and was alleviated by EXAMPLE 1. multiple applications of Vita Moist Cream, vitamin D at This example illustrates antipruritic effect of vitamin D 1000 g/ml in corn oil, and constant massaging. The pruritus in Vita Moist Hand and Nail Cream in the alleviating the abated completely about one-half hour after these applica pruritus of chickenpox. tions. Having becoming ill with chickenpox, I developed severe EXAMPLE 3 pruritus. I applied the commercially available skin cream, 65 This example illustrates the antipruritic effect of vitamin Vita Moist Hand and Nail Cream (Avon, N.Y.) hereinafter D formulated in water-based emulsions in alleviating the referenced as Vita Moist Cream and the pruritus was com pruritus caused by poison ivy. 5,789.399 7 8 Water-based Emulsion Formulations As placebo control Care Deeply Hand and Nail Cream (Avon, N.Y.) hereinafter referenced as Care Deeply, has the Water-based emulsions were prepared using Kerics) lotion following composition: (Bristol-Meyers Squibb Co., NY) and Eucering lotion (Beiersdorf, Inc., Norwalk. Conn.). Keris lotion has the following composition as indicated CARE DEEPLY HAND AND NAL CREAM on the container label. Purified Water Glycerin Cocoa Butter KERI ( LOTION Cetearyl Alcohol 10 Isopropyl Myristate Water Emulsifying Wax Petroleum Ceteareth-20 Glycerin Isopropyl Lanolate Dimethicone Cholieth-24 Steareth-2 Glycol Stearate Cetyl Alcohol 15 Methylparaben Benzyl Alcohol Lanolin Oil Laureth-23 Imidazolidinyl Urea Magnesium Alimunim Silicate Carboner-94 Tbcopheryl Linoleate Dimethicone Carboner Magnesium. Aluminum Silicate BHT Triethanolamine Sodium Hydroxide Fragrance Disodium EDTA Tetrasodium EDTA Quaternium-16 FD&C Yellow No. 5 FD&C Red No. 4 FD&C Blue No. 1 Eucering lotion has the following composition as indi 25 cated on the container label. Testing Procedure

EUCERN LOTTON Subject MS contracted poison ivy rash and tested the 30 various preparations above. Preparations were evaluated by Water the subject after application to an area of rash approximately Mineral Oil Isopropyl Myristate 1-10 square centimeters. Comparisons were made of anti PEG-40 Sorbitan pruritic effect by marking on a 100 mm visual analog scale Peroleate consisting of a plain line with the left end labeled "None" Glyceryl Lanolate and the right end labeled "Maximal". The subject was Sorbitol 35 Propylene Glycol instructed to mark the scale at a point which she felt Cetyl Palmitate corresponded to the level of itchiness that she was feeling at Magnesium Sulfate the treatment site at the appropriate time. The samples were Aluminum Sterate coded so that the subject was not aware of what a given Lanolin sample was and she was not told if they were expected to Alcohol have an effect. She carried out the evaluation unaided, BHT Methylchloroisothiazolinone applying the samples in any order she chose except where Methylisothiazolinone side-by-side comparisons were made as indicated in the tables. From the marked scale the pruritic score was deter mined as the number of mm from the left side of the scale Keris lotion preparations were made containing various 45 to the subject's mark. Thus a higher value indicates a high concentrations of vitamin D by mixing stock solutions as level or pruritus and a low value indicates a low level to no indicated below and heating the mixture at 46-50° C. with pruritus. Tables 1a through 1c show the antipruritic effect of occasional stirring. 869 g/ml: One ml of the 5% solution of water-based emulsion preparations. vitamin D. from example 2 was mixed with 2 ml corn oil to Table 1a shows an antipruritic effect of Vita Moist Cream obtain 16.666 g/ml solution. 0.55 ml of this solution was 50 containing vitamin D at 10 pg/ml compared to the control then mixed with ten ml of Keris) lotion. 521 g/ml: 0.55 ml cream, Care Deeply. The pruritus was completely alleviated of vitamin D in corn oil at 10,000 g/ml as described above one minute after application. was added to 10 ml Keris Lotion. 502 ug/ml: 0.55 ml of the 10,000 solution of was mixed with 10 ml KeriC) Lotion and 0.4 ml isopropyl myristate. 52 pg/ml: 0.55 ml of 1,000 g/ml 55 TABLE 1a stock solution, prepared by mixing 1 ml of 5% vitamin D WTAMOST Vitamin D3 - 10 ugm) stock with 2 ml isopropyl myristate and 47 ml corn oil, was added to 10 ml Keri(S) Lotion. 10 g/ml: 0.55 ml of 200 Time Care Deeply Vita Moist g/ml stock solution, prepared by mixing 1 ml of 5% (min) Control (D-10 ugml) vitamin D stock with 49 ml corn oil and subsequently O 81 81 1. 75 O diluted 1:5 in corn oil, was added to 0.4 ml isopropyl 5 74 O myristate and 10 ml Keris Lotion. 10 76 O Eucering lotion preparation at 869 g/ml was made as *Side-by-side comparison was made. described above for Kerig lotion. 65 Vita Moist Cream had the composition as shown in In Table 1b, it is seen that Keri(g) lotion as a vehicle for example 1. vitamin D also produces a rapid and complete antipruritic 5,789.399 9 10 effect as was seen in Table la for Vita Moist Cream. Also, In Table 2a it is seen that corn oil as a vehicle for vitamin it is seen that the addition of isopropyl myristate to the D at 1000 pg/ml produced no detectable antipruritic effect formulation did not effect the antipruritic effect of vitamin when the mean of two tests were compared to vehicle D. control. In contrast, Table 2b showed an antipruritic effect for vitamin Data concentration of 521 pg/ml in the vehicle, TABLE 1b. petroleum jelly. The commercial product, A and Dointment shown in Table 2c showed no antipruritic effect. KERILOTION (containing Vitamin Da) Time TABLE 2a (min) O 1O 10 O Mean 10 CORN OL O 80 77 78 80 79 1 1. O O O O Witamin D 5 O O O O Time Control (1000 gin) 10 O O O O O 15 (min) 1 2 Mean 1. 2 Mean Preparation conatined no Isopropyl Myristate. O 82 82 82 80 81 8 8 48 65 80 8 8 Table 1c shows that concentrations of vitamin D. from 10 5 8 12 47 8. 58 O through 869 lug/ml are effective in rapidly and effectively 10 83 2 43 60 58 59 relieving pruritus. 20 TABLE C TABLE 2 KERILOTION (with added sopropyl Myristate) PETROLEUMELLY Time Vitamin Da Concentrations 25 Time Witamin D (min) O 101st 52 SO2 521 it 869 (min) Control (52 pg/ml) O 82 7g 77 8O 80 82 O 80 72 1. 66 O 35 81 O 1. 79 1. 5 4. O O O O O 5 78 O O 25 O O O O 30 O 58 9 *Mean values from Table 1b. *Preparation contained no sopropyl Myristate. TABLE 2c The formulation of 869 ug/ml vitamin D in Eucering was compared with a Eucerints control vehicle prepared 35 AAND DONTMENT from Eucerin() with an added amount of corn oil identical A and D to that in the active formulation but containing no vitamin Petroleum Ointment D. No scores were recorded, however, the subject indicated time Jelly (D-6.75 ugm that the Eucering-vitamin D. preparation stopped the pru ritus instantly and completely whereas the control had no (min) 2 Mean 1. 2 Mean antiprutitic effect. O 8 68 75 81 58 70 1. 8 2 42 61 31 EXAMPLE 4 5 O O O 80 61 71 O O 43 22 82 52 67 This example illustrates the antipruritic effect of vitamin D formulated in oil-based preparations in alleviating the 45 A side-by-side comparison was made. pruritus caused by poison ivy. A petroleum jelly formulation was prepared as follows. EXAMPLE 5 One gram of vitamin D was dissolved in 20 ml corn oil as described in example 2. One ml of the resultant 5% solution 50 This example illustrates the antipruritic effect of vitamin was mixed with 4 ml corn oil to obtain a 10,000 g/ml D formulated in a water-based suspension in alleviating the solution. Ten ml of petroleum jelly was then mixed with 0.55 pruritus caused by poison ivy. ml of the 10,000 pg/ml solution upon heating to 50°-55° C. Vita Moist Cream was used as control reference formu to give a resultant concentration of 521 g/ml. Placebo lation and this had the composition as shown in example 1. control was made by adding 0.55 ml corn oil to 10 ml Vita Moist Body Lotion (Avon, N.Y.), is a commercially petroleum jelly. 55 available aqueous suspension formulation containing vita The corn oil formulation was prepared by adding 1 ml of min D. This composition contains the following ingredi the 5% stock solution of vitamin D in 2 ml isopropyl Its. myristate and 47 ml corn oil to give a final concentration of 1000 g/ml. Vitamin A and D Ointment (Schering-Plough, Memphis, WTAMOST BODY LOON Tenn.) contained the label-indicated ingredients of vitamin A Purified Water Stearic Acid at 1856 IU/g and vitamin D at 270 LU/g or 6.75 g/ml in Hydrogenated Soybean white petrolatum and zinc oxide. Oil The patient and test procedures were as described in 65 Glycerin example 3. The results of tests using oil-based formulations Squalane are in tables 2a through 2c. 5,789.399 11 12 -continued 6.5 ml diluent After coding with numbers 1-6 as above, the preparations WTAMOST BODY LOTTON were randomly sorted and again coded A-E and tested two Cetyl Acetate at a time in alphabetical order. The results are shown in the Triethanolamine FIGURE. As can be seen concentrations of 2.5 and 5 g/ml Glyceryl Stearate produced rapid and complete alleviation of pruritus. The Sesame Oil Methylparaben concentrations of 1.25 g/ml and 0.5 g/ml produced some Magnesium Aluminum Silicate antipruritic effect but the effect was not complete nor was it Fragrance rapid and sustained. The minimal effective concentration in Propylparaben 10 this formulation appears to be between 1.25 and 2.5 g/ml. Acetylated Lanolin Alcohol Tocopheryl Acetate EXAMPLE 7 Retinyl Palmitate Corn Oil The following example illustrates the clinical testing of BHT vitamin D formulations in patients having uremic pruritus. Propylene Glycol 15 SD Alcohol 40-B In this study, vitamin D formulations will be tested against OO Cholecalciferol placebo. The vitamin D preparations will be based upon the BHA disodium EDTA formulations discussed above. The placebo will contain only FD&C Yellow No. 5 the formulation without vitamin D. FD&C Red No. 4 The study would be double blind, meaning that both the EXT D & C Violet No. 2 nurse and the patient will be unaware of which cream A = MORE THAN 50% contains the test material and which contains only placebo. E = FROM19 TO 5% The containers will be coded so that only the attending F = 1% TO 19 physician will know which is which. The code may be G - LESS THAN.1% 25 different from one formulation set to the next. The patient and test procedures were as described in The nurse protecol is as follows: example 3. The results of tests using oil-based formulations The patient must be suffering from chronic kidney failure are in Table 3. and be experiencing bothersome itchiness at the time of the office visit. The patient will be asked if they would like to TABLE 3 30 volunteer to try this new treatment. It will be explained that this is a trial of a cream that relieves itchiness in chickenpox VITAMINDSUSPENSION (VITAMOIST LOTION) and poison ivy and that it may or may not help them. Vita Moist Crean Vita Moist Lotion The patient will be assisted in understanding and com Time (D-10 ugml) (Da-125 ugml) pleting the questionnaire. If needed, the nurse can assist by 35 writing the answers given by the patient. The questionnaire (min) l 2 Mean 2 Mean is as follows: O 70 79 74 71 78 74 1. O 78 39 49 78 64 5 O O O 1. 56 34 Cream Number 10 O O O 3 5 4. Patient's name and phone number. Date and time. Age/Sex. As reported in example 3, Vita Moist Cream again com Date when dialysis was started. pletely alleviated the pruritus, although in this test, complete What kind of renal disease do you have? effectiveness was seen at the 5 minute observation rather Do you have a history of persistent itchiness? than at the 1 minute observation in example 3. In compari 45 If so, for how long? 7 . Is your itchiness constant or does it come and son to this, Vita Moist Lotion only partially alleviation of the go? If it's not constant, when is it usually pruritis at 5 minutes and nearly complete relief was obtained the worst? by 10 minutes. Thus the suspension preparation appeared to 8. Are you itching right now? be less rapid in producing the antipruritic effect than was the 9. Do you have itchiness all over your body or 50 only on part of your body? If only on part of emulsion preparation. Vita Moist Cream. your body, please indicate where. EXAMPLE 6 0. What treatments have you tried to reduce the itchiness and which have been the most This example illustrates the dose-response relationship of effective? Vitamin D in a water-based emulsion vehicle prepared by Nurses' comments (to be filled out after evaluation): 55 Follow up comments: mixing Vita Moist Cream containing Vitamin D with Care Nurses' signature Deeply Cream which contains no Vitamin D. Doctors' signature Serial dilutions of Vita Moist Cream were made from an initial 5 ml quantity of Vita Moist Cream by adding suc Chose the sites to apply the creams based on where the cessive 5 ml quantities of the diluent, Care Deeply Cream. itching is most severe. Apply creams "X" and "O" to areas to the starting formulation and subsequent 5 ml aliquots of of roughly equal size and itchiness. Indicate under "Nurses' successive dilutions as follows: comments" where the creams were applied. If the itching is 1.5 ml Vita Moist+5 ml diluent-5.0 g/ml general, use one forearm for the test cream and the other 2.5 ml of 5 ugml+5ml diluent-2.5 g/ml forearm for the placebo cream. The cream should soak in 3.5 ml of 2.5 g/ml+5 ml diluent-1.25 g/ml 65 completely. If it doesn't, you put too much on. If the patient 4.5 ml of 1.2 pug/ml+5 ml diluent-0.5 g/ml has an adverse reaction to the cream, stop the trial and 5.5 ml of 0.5 g/ml+5ml diluent-0.25 g/ml remove the cream immediately. 5,789.399 13 14 If one of the creams relieves the itching, let them apply the invention, it is intended that all matter contained in the cream to all of the affected areas of skin after the trial is above description and shown in the accompanying drawings completed before leaving the office. Ask the patient to make shall be interpreted as illustrative and not in a limiting sense. a note of when the itchiness returns and explain that you will make a follow up call ask how long the treatment lasted. Do What is claimed is: not give any extra to take home. Explain that the attending 1. A method for treating pruritus comprising topically physician is barred by law to prescribe or dispense it. administering an antipruritic effective amount of a vitamin D Please indicate under "Nurses' comments” if there is compound or an analog thereof in a therapeutically effective anything about the patient that you think we should know formulation which lacks dimethyl sulfoxide and is pharmac when reviewing the questionnaire. This could include prob 10 cutically acceptable for topical application, wherein the lems other than uremia that could cause pruritus. Treatment is evaluated by the patient as discussed in therapeutically effective formulation is an emulsion com Example 3 above. The patient is instructed as to how to mark prising water, a water-insoluble organic liquid, a surface the 100 mm visual scale from "None" to "Maximal" pruri active agent, and the vitamin D compound or analog thereof. tus. The scale is explained with no suggestion as to where 2. The method according to claim 1 wherein the vitamin the mark should be placed. Only the patient will decide 15 D compound is selected from the group consisting of where to place the mark. alacalcidol, calcifediol, calcitriol, cholecalciferol, dihydro The evaluation sheet is as follows: tachysterol and ergocalciferol. 3. The method according to claim 1 wherein the analog of Patient's name and date: vitamin D comprises a vitamin D compound having side TREATMENTEWALUATION chain modifications, said modifications being made by intro Please indicate how serious the itchiness is using the following scales. duction of unsaturation; transposing, adding, removing or make a mark on the line at the point that you feel corresponds to the substituting hydroxyl groups; substituting hydrogens; form severity of the itchiness that you are experiencing at the treatment sites for each appropriate time. Slight itchiness would be indicated by making a ing carbocyclic structure; introducing a heteroatom link; mark near the left side of the scale while severe itchiness would be 25 inverting stereochemically; removing or adding alkyl indicated by making a mark near the right side of the scale. Maximal groups; or changing the number of links in the side chain. itchiness means the most severe itchiness that you can imagine. 4. The method according to claim 1 wherein the surface BEFOREAPPLICATION active agent is selected from the group consisting of PEG-40 Site XNONE MAXIMAL stearate, steareth-2, PEG-40 sorbitan peroleate. laureth-23 Site O NONE MAXIMAL and combinations thereof. ONE MINUTEAFTERAPPLICATION 5. The method according to claim 4 wherein the thera Site XNONE MAXIMAL peutically effective formulation comprises at least about Site O NONE MAXIMAL 50% water, from about 1 to about 5% PEG-40 stearate, from FIVE MINUTES AFTERAPPLICATION 1 to about 5% steareth-2 and cholecalciferol at a concen Site XNONE MAXIMAL 35 tration of about 10 g/ml. Site O NONE MAXIMAL 6. The method according to claim 5 wherein the thera TEN MINUIES AFTERAPPLECATION peutically effective formulation comprises cholecalciferol at Site XNONE MAXIMAL a concentration of at least about about 2.5 g/ml. Site O NONE MAXIMAL Please describe in your own words the effect of the cream on the itchi 7. The method according to claim 6 wherein the pruritus CSS. results from a condition selected from the group consisting If this treatment is effective, we will call you for a follow up assessment of chickenpox. shingles, plant toxins, insect bites, chronic to find out how kong the treatment is effective. Please try to note when the kidney failure, liver diseases, malabsorption syndromes, itchiness returns. Thank you very much HIV infection, AIDS related cosinophilic pustular 45 folliculitis, psoriasis, atopic dermatitis, photosensitivity Approximately 10 patients will be used in the study and disorders, lichen planus, polycythemia vera, Grover's each patient will receive both vitamin D treatment formu disease, glanuloma annular, lichen nitidus, prurigo lation and placebo. Data will be collected and statistical comparison will be made between effects of the formulation nodularis, macular amyloidosis, urticaria pigmentosa, and effects of placebo. aquagenic pruritus, pemphigus vulgarus, lupis vulgaris. In view of the above, it will be seen that the several 50 healing cuts and burns, senile pruritus, hypereosinophilic advantages of the invention are achieved and other advan syndrome, chronic uticaria, pruritic eye conditions, stress. tageous results attained. and combinations thereof. As various changes could be made in the above methods and compositions without departing from the scope of the