USOO5798093A United States Patent (19) 11 Patent Number: 5,798,093 Farrar et al. (45) Date of Patent: *Aug. 25, 1998

54 SPRAY FORMULATIONS OF 3,730.960 5/1973 Watchung et al...... 2S2/106 ANTHYPERALGESEC OPIATES AND 3,884,916 5/1975 Jannsen et al...... 260/247.

METHOD OF TREATING TOPCAL 5,035,883 7/1991 Witkin ...... 422/29 HYPERALGESC CONDITIONS AND 556.808 5/1996 Sawaya ww & 8 was was& saw a a as - a was 5,78 PRURTUS THEREWTH 5,667,773 9/1997 Farrar et al...... 424/28.05 75 Inventors: John J. Farrar. Chester Springs; OTHER PUBLICATIONS An-Chih Chang, Bensalem; Alan L. Maycock. Malvern; Imre Balogh, McMahon et al., TENS, vol. 15, No. 12 (1992). Perkasie, all of Pa. Bernstein et al., Journal of Investigative Dermatology, 78: 73 Assignee: Adolor Corporation. Malvern, Pa. 82-83 (1982). Ballantyne et al. Pain, 33: 149-160 (1988). * Notice: The term of this patent shall not extend beyond the expiration date of Pat. No. J. D. Bernhard, J. Am. Acad. Derm. 24; 309 (1991). 5,667,773. IASP Newsletter, Sep./Oct. 1996. (21) Appl. No.: 892,389 Thomas et al., Brain Research, 695: 267-270 (1995). 22 Filed: Jul. 14, 1997 Primary Examiner-Thurman K. Page Related U.S. Application Data Assistant Examiner-Kathryne E. Shelborne Attorney, Agent, or Firm-Imre Balogh 63 Continuation-in-part of Ser. No. 818.559, Mar. 14, 1997. 5 57 ABSTRACT 51) int. Cl...... A61L 9/04; A61K 31/74 52 U.S. C...... 424/45; 424/78.05; 424/47 Spray formulations of anti-pruritic opiates having a periph 58) Field of Search ...... 424/45, 78.05 eral selectivity of 251 to 1.280 in a solvent mixture of up to 15% ww alcohol selected from the group consisting of 56 References Cited ethyl, propyl and isopropyl alcohol and water greater than or equal to 85% w/w water. U.S. PATENT DOCUMENTS 3,714,59 1/1973 Jannsen et al...... 260/247. 2 Claims, No Drawings 5,798.093 1 2 SPRAY FORMULATIONS OF Spray formulations for topical application for cleansing ANTHYPERALGESCOPIATES AND the injured site are known and have been used by the prior METHOD OF TREATING TOPCAL art. Some of these formulations, known as first aid sprays HYPERALGESC CONDITIONS AND and antiseptics are applied to the site of the injury subse PRURITUS THEREWITH quent to flushing the site with water to remove foreign matter originating from the source of injury or the environ This application is a continuation-in-part of application ment. The substance contained in these sprays kills or Ser. No. 08/818,559, filed on Mar. 14, 1997. prevents the growth of microorganisms. A number of anti septic drugs are oxidizing agents which include: peroxides. BACKGROUND OF THE INVENTION O such as hydrogen peroxide; permanganates, such as potas 1. Field of the Invention sium permanganates, benzene derivatives and phenols. Spe This invention relates to spray formulations of anti cific examples of antiseptic agents include chlorhexidine, hyperalgesic opiates having substantially no effects on the calcium iodate, iodine, chloroxylenol, hexachlorophene. central nervous system and method of topically treating boric acid and cupric sulfate. hyperalgesic conditions. More particularly, the invention 15 Other pharmaceutical agents used to prevent or combat relates to anti-hyperalgesic opiates in non-sting spray for topical infection and to accelerate the healing process mulations for the treatment of topical hyperalgesic condi include: tions associated with injuries. Antibacterial agents, such as Streptomycin, Rifamycin, The present invention also relates to compositions and Ampicillin, Penicillin O. Penicillin V. Bacitracin. methods for the prevention and/or treatment of itch. also Doxycycline, Methacycline, Minocycline, Tetracycline. known as pruritus, which has many causes. The composi Acetyl Sulfisoxazole, Succinylsulfathiazole. Sulfaloxic tions which are formulated for topical spray administration Acid, Sulfapyrazine, and Acetosulfone; contain antihyperalgesic opiates that are substantially Antifungal agents, such as Dermostatin, Fungichromin, devoid of central nervous system effects and, thus, have very Clotrimazole. Econazole. Potassium Iodide, Propionic Acid, little, if any, potential for producing side effects associated 25 Ketoconazole. Cicloprox Olamine. Tolnaftate and Naftifine; with centrally acting antihyperalgesic opiates. Anti-inflammatory agents, such as Diclofenac, Tolimetin, 2. Reported Developments Ibuprofen. Protizinic Acid, Glycol Salicylate and Sulfasala A. Antihyperalgesic Opiates zine. Pain is the effect of noxious stimuli on nerve endings of 30 Antibiotics, such as Clindamycin, Erythromycin, a subject which results in the transmission of impulses to the Tetracycline, Mupirocin, Bacitracin and Neomycin; cerebrum. This sensation informs the subject of actual or Antiseptic agents such as Chlorhexidine, Calcium Iodate, impending tissue damage and elicits a defensive response. Iodine, Chloroxylenol, Hexachlorophene. Boric Acid, and The degree of response substantially correlates with the Cupric Sulfate; and degree of noxious stimuli in order to speedily avoid further 35 tissue damage and to re-establish normal pre-injury condi Antiviral agents, such as Acyclovir, Trifluridine and tions in the subject. The sensation of pain, however, does not Zidovudine. end with the stoppage of the noxious stimuli but continues These and other agents used on the site of injury tend to to persist during the inflammation stage of the injury. In turn, produce stinging, pricking, burning and pain so that their the continuation of pain perception causes discomfort to, utility to prevent or combat infection and to promote healing and deleteriously affects the well-being of, the subject. It is, is limited to those individuals who are willing to accept these therefore, important to reduce and/or eliminate pain percep undesirable sensations. This drawback of first aid products is tion of a subject subsequent to injuries. accentuated in the treatment of children having wounds, The reduction/elimination of pain perception can be abrasions and burns who are reluctant to suffer the stinging affected by the central nervous system (hereinafter some 45 effect of the products. times referred to as CNS)-mediated analgesia which leads to Peripheral antihyperalgesic compounds which inhibit sen an overall inhibition of the pain transmission. CNS sation of pain without CNS side effects would provide a mediated analgesia can be effected by systemically admin solution to the problem. It has now been discovered that istered opiates which, by interaction with specific receptors such peripheral antihyperalgesic compounds can render the in the brain and spinal cord, are able to block pain trans 50 spray formulations acceptable for delivering agents custom mission. Systemic opiates, such as morphine, which have arily used in the treatment of topical wound abrasions. burns been used for many years to control post injury pain, have and the like to prevent infection and accelerate wound side effects because their actions within the brain include healing. Sedation, depression of respiration, constipation, nausea and In the course of our investigation, however, we have development of addiction and dependence. When peripher 55 encountered another problem in delivering the spray formu ally applied, opiates have a short duration of action and still lation to the site of treatment. The peripheral antihyperal possess the undesirable side effects. gesic compounds are essentially insoluble?sparingly soluble Certain opiates, such as loperamide i.e., 4-(p- in water. Their solubility in water is about 0.002% whow to chlorophenyl)-4-hydroxy-N-N-dimethyl-O.0-diphenyl-1- 5% whv. To provide for the inhibition of pain, very large piperidinebutyramide hydrochloride and its analogs were amounts of the peripheral antihyperalgesic compounds were reported to be devoid of CNS effects, which is believed to required. The use of such large amounts, on the other hand, be due to the failure of the opiates to cross the blood brain caused clogging of the spray nozzle and deposition of the barrier. Loperamide HCl has been used for a long time in compounds on the wall of the container from which the antidiarrheal formulations and has been completely free of aqueous solution of the compounds were dispensed. the undesirable CNS effects. It is desirable to use such 65 While the peripheral antihyperalgesic compounds are opiates to inhibitfeliminate post-injury pain without con soluble in organic solvents, the use of such solvents is very comitant CNS effects. limited for treating topical injuries. The organic solvents 5.798.093 3 4 having oily consistency tend to hold the active compounds and do not allow quick and sufficient release to the site of TABLE a injury to be treated. Stimuli that can elecit or augment itch Other organic solvents without oily consistency, such as Physical methanol, have deleterious effects on open wounds through which they can enter the blood circulation system. Mechanical. Light touch, pressure, suction. Thermal. Warming. Accordingly, ethanol, propanol and isopropanol were Electrical. Focal transcutaneous repetitive stimulation, transcutaneous selected as carriers in which the active compounds are constant current stimulation intraneural microstiniulation. soluble and which can be used on open wounds without O Chemical deleterious side effects. However, these vehicles alone or in Non-specific irritants. Acids, alkalis. inflammatory mediators. Histamine, kallikrein, bradykinin, prostaglandins. an aqueous mixture in which they constituted a substantial Histamine-releasing substances. Compound 48780, protamine. C3a. amount resulted in stinging and burning sensations render Peptidases. Mucunain, papain, trypsin, mast cell chymase. ing the vehicle unsuitable for the delivery of the active 5 Neuropeptides. Substance P, vasoactive intestinal polypeptide, agent. Although, during the period of spraying a pleasant neurotensin, secretin. cooling effect was observed, the subsequent absorption of Opiods. Morphine, -endorphin, enkephalin analogues. the vehicle increased the pain already present at the site of injury. With extensive experimentation we have now discovered TABLE b that an effective antihyperalgesic non-sting spray formula Comparison of the established features of itch and pain tion can be provided by incorporating an antihyperalgesic opiate having a peripheral selectivity of from about 251 to ITCH PAN Psychophysiology about 1.280 in an aqueous alcohol mixture of up to about 25 15% whv ethyl-alcohol, propyl alcohol or isopropyl alcohol. Tissue Skin. Mucous membranes Most tissues B. Antihyperalgesic Opiates as Anti-Pruritic Agents Stimulus See Table a Many stimuli Intraneural microstimulation Occasionally es The prior art has investigated the physiology and treat Secondary sensations Allokinesis (itchy skin) Hyperalgesia Psychogenic modification Pronounced Present ment of pruritus as illustrated hereunder. 30 Counterstimuli Scratching, pain, cooling Tactile stim uli, cooling Itch is a well known sensory state associated with the Neurophysiology desire to scratch. As with pain, itch can be produced by a variety of chemical, mechanical, thermal or electrical Primary afferent neurons C- and A8-fibres C- and A8-fibres stimuli. In addition to the difference in the sensory quality of 35 Fare size Large Small itch and pain, they also differ in that (1) itch. unlike pain. can Spinal pathway Anterolateral funiculus Anterolateral only be evoked from the superficial layers of skin, mucosa, funiculus Protective reflexes Scratching, sneezing Flexion, and conjunctiva, and (2) itch and pain usually do not occur guarding simultaneously from the same skin region; in fact, mildly Autonomic reflexes es Yes painful stimuli, such as scratching, are effective in eliminat Pharmacology ing itch. In addition, the application of histamine to skin Capsaicin sensitivity Yes Chemogenic produces itch but not pain. Itch and pain are further disso pain; yes ciated pharmacologically: itch appears to be insensitive to NSAID sensitivity Probably not Yes opiate and non-steroidal anti-inflammatory drug (NSAID) Morphine sensitivity No Yes treatment, both of which are effective in treating pain. 45 Abbreviation. NSAD, non-steroidal anti-inflammatory drugs. Although itch and pain are of a class in that both are Experimental focal itch stimuli are surrounded by a halo modalities of nociception transmitted by small unmyelinated of seemingly unaffected tissue where light tactile stimuli are C fibers, evidence that itch is not just a variety of low capable of eliciting itch-like sensations. The term itchy skin threshold pain is overwhelming. Itch leads to the reflex or 50 or allokinesis has been coined for these secondary, sensa urge to scratch; pain leads to withdrawal. Itch occurs only in tions that are reminiscent of the features of secondary hyperalgesia evolving around a painful focus. A crucial the skin; pain arises from deeper structures as well. Heat observation is that itch and pain usually do not coexist in the may stop pain but usually increases pain. Removal of the same skin region and a mild noxious stimulus such as epidermis eliminates itch but causes pain. Analgesics, par scratching is in fact the singly most effective way to abolish ticularly opiods, relieve pain but often cause itch (see, for 55 itch. This abolition of itch can be prolonged producing an example J. An. Acad. Derm. 24:309-310, 1991). There can 'antipruritic state'. Although mild scratch is often not be no doubt that itching is of eminent clinical importance; painful, microneurographic recordings from humans have many systemic and skin diseases are accompanied by per directly determined that such stimuli are among the most sistent or recurrent itch attacks. Current knowledge suggests effective ways to excite cutaneous unmyelinated nociceptive that itch has several features in common with pain but afferents. (See, for example: exhibits intriguing differences as well (see, for example. W. Shelly, W. B. and Arthur, R. P. (1957) Arch. Dermatol. 76. Magerl. IASP Newsletter, pp. 4-7. Sept/Oct. 1996). 296-323; Simone, D. A. et al. (1987) Somatosens. Res. 5, 81-92; McMahon et al (TINS. Vol. 15. No. 12, pp. 497-501. Graham, D. T. Goodell, H. and Wolff, H. G. (1951) J. 1992) provides a description of stimuli (Table a) and a 65 Clin. Invest. 30, 37-49; comparison of the established features of itch and pain Simone. D. A. Alreja, M. and LaMotte, R. H. (1991) (Table b): Sonatosers, Mot. Res. 8, 271-279; 5,798,093 5 6 Torebjork. E (1985) Philos. Trans. R. Soc. London Ser. B histaminergic mediation of opiate-induced itching 308, 227-234; and mechanism which could involve central opiate receptors. Vallbo. A. B., Hagbarth, K. E., Torebjork, H. E. and Although i.v. morphine only occasionally results in gener Wallin. B. G. (1979) Physiol. Rey. 59,919-957). alized itching (in about 1% of patients), pruritus is more Physiologically, there is evidence that substance P prevalent in opiate analgesia with epidural (8.5%) or released from nociceptor terminals can cause the release of intraspinal (45.8%) administration. (See, for example: Bern histamine from mast cells. Activation of mast cells, with stein et al. "Antipruritic Effect of an Opiate Antagonist. release of the pruritogen histamine. occurs in immediate Naloxone Hydrochloride". The Journal of Investigative type hypersensitivity diseases, such as anaphylactic reac Dermatology, 78:82-83, 1982; and Ballantyne et al., "Itch tions and urticaria. Urticarial eruptions are distinctly pruritic ing after epidural and spinal opiates", Pain, 33: 149-60, and can involve any portion of the body, and have a variety 1988.) of causes beyond hypersensitivity, including physical To date, treatment with opiates has not only proven stimuli such as cold, solar radiation, exercise and mechani useless in the treatment of itch, but appears to exacerbate cal irritation. Other causes of pruritus include: chiggers, the itch in man. The consistent findings from human studies larval form of which secretes substance that creates a red 5 indicate that whether by central or peripheral mechanisms, papule that itches intensely; secondary hyperparathyroidism opiates appear to promote rather than prevent itching, and associated with chronic renal failure; cutaneous larva that opiate antagonists have antipuritic activity. migrans, caused by burrowing larvae of animal hookworms; Human clinical studies have generally shown that opiates dermal myiasis, caused by maggots of the horse botfly, cause itching and there is evidence that these effects can be which can afflict horseback riders; onchocerciasis ("river reproduced in animal models, where itching sensations per blindness”) caused by filarial nematodes; pediculosis, se cannot be reported, but scratching behavior can be caused by lice infestations; enterobiasis (pinworm) observed. (See, for example:Thomas et al. "Microinjection infestations, which afflict about 40 million Americans, par of morphine into the rat medullary dorsal horn produces a ticularly school children; schistosome dermatitis dose-dependent increase in facial-scratching", Brain (swimmer's itch); poison ivy; excema, psoriasis; and astea 25 Research, 695: 267-270, 1996; Thomas et al., "Effects of totic eczema ("winter itch"). The role of histamine or other central administration of opioids on facial scratching in endogenous pruritogens in mediating itch associated with monkeys", Brain Res., 585: 315-317. 1992; and Thomas et these and other pruritic conditions, such as atopic dermatitis, al., "The medullary dorsal horn: A site of action of opioids its not yet well established. For atopic dermatitis, in in producing facial scratching in monkeys". Anesthesiology. particular, it appears that itch is not inhibited by 30 79: 548-554, 1993). antihistamines, but by cyclosporin A, a drug which inhibits We have now surprisingly discovered that certain opiates, the production of cytokines which have been proposed as which are substantially devoid of central nervous system potential pruritogens. effects, in topical spray formulations possess anti-pruritic Current therapies for the treatment of itch include a activity in addition to anti-hyperalgesic activity. variety of topical and systemic agents, such as steroids, 35 antihistamines, and some psychotherapeutic tricyclic SUMMARY OF THE INVENTION compounds, such as doxepin hydrochloride. Many such The present invention provides topical spray formulations agents are listed in PDR Generics (see Second Edition, and methods of using the formulations as anti-hyperalgesics. 1996, p. cw for a listing of said agents). The limitations of The present invention further provides topical spray for these agents are well known to medical practitioners, and are mulations for the prevention and treatment of pruritus, summarized in the "Warnings" and "Precautions” sections The topical anti-hyperalgesic formulation comprises: for the individual agents listed in PDR Generics. In (A) a peripheral antihyperalgesic compound of the for particular, the lack of complete efficacy of antihistamines is mula (I) well known, but antihistamines are frequently used in der matology to treat pruritus due to urticaria, atopic dermatitis, 45 contact dermatitis, psoriasis, and a variety of other condi tions. Although sedation has been a frequent side effect of conventional systemically administered antihistamines, a new generation of antihistamines has been developed that are nonsedating. apparently due to their inability to cross the 50 blood-brain barrier. Intravenous administration of opiate analgesics, such as morphine and hydromorphone has been associated with pruritus, urticaria, other skin rashes, and wheat and flare over the vein being injected. These itch and itch-related 55 reactions are believed to be due to a histamine-releasing wherein property of these opiates, via mast cell degranulation. These R is N(CH), N(CHCH). N(CH)CH, N(CH), opiates are thought to act upon the mu subtype of opiate N(CH2) or N(CHCH)O; and receptor, but the possibility of interactions at the other X and X, are independently H. Cl, Br. For CF, and principal opiate receptor subtypes (delta and kappa) cannot wherein said antihyperalgesic compound has a periph be excluded since these and other pruritogenic analgesics are eral selectivity of from about 251 to about 1.280; not pure mu agonists. The cellular loci of the receptor type(s) (B) a solvent mixture for the compound of formula I mediating the itching effect is not known, although the mast comprising: a) up to about 15% w/w of an alcohol cell is a possible candidate since opiates cause histamine selected from the group consisting of ethyl alcohol, release from these cells. However, some investigators have 65 propyl alcohol and isopropyl alcohol or mixtures suggested that the frequent inability of antihistamines to thereof; and b) greater than or equal to 85% w/w water; block morphine-induced itching suggests a non and 5,798.093 7 8 C) one or more additional active ingredients selected from The peripheral selectivity of these compounds are shown the group consisting of antibacterials, antivirals, in Table I. antifungals, anti-inflammatories and anesthetics or mixtures thereof. TABLE The topical anti-pruritic formulation comprises the same Peripheral Selectivity compound and solvent mixture as the antihyperalgesic for Compound mulation: (ED/ED Castor Oil) (A) a peripheral anti-pruritic compound of the formula >128O 21.231 (II) 800 O 640 O R 593 533 500 467 OH ( ) N 437 15 >25 Peripheral selectivity is defined by the ratio of the EDs in the tail-withdrawal assay over the ED in the anti X diarrheal assay. The assay results for the above listed com pounds were obtained by the test methods described here wherein under. R is NCCH). N(CHCH), N(CH)C.H. N(CH), Measure of Centrally-Mediated Opiod Analgesia by the N(CH2) or N(CH2CH)O; and Tail-Withdrawal Assay (Janssen, P. A. J.; Niemegeers. C. J. X and X are independently H. Cl, Br. For CF and E.; Dony, J. G. H. The Inhibitory effect of Fentanyl and wherein said anti-pruritic compound has a peripheral 25 other morphine-like analgesics on the warm water induced selectivity of from about 251 to about 1,280; and tail withdrawal reflex in rats. Arzneimittel-Forschung 1963, (B) a solvent mixture for the compound of formula II 13. 502-507.) comprising: a) up to about 15% whv of an alcohol Young female Wistar rats (170-210 g body weight) are selected from the group consisting of ethyl alcohol, used only once. They are fed and watered ad ibitum in their propyl alcohol and isopropyl alcohol or mixtures 30 living quarters until 7:00 AM of the day of the experiment, thereof; and b) greater than or equal to 85% w/w water. when they are brought to the laboratory to be put into The spray formulations of formulae I and II may be individual restraining cages on hour later until the end of the contained in a propellant mixture or they may be dispensed experiment. The lower 5 cm portion of the tail is marked. from a pump-action container or the like. Around 8:30 AM the "normal' reaction time of each rat is Preferred antihyperalgesic compounds used in the present 35 determined by immersing the lower 5 cm portion of the tail invention are: in a cup freshly filled with water from a large constant (1) 1-4-(4-Hydroxy-4-phenyl-1-piperidino)-2.2- temperature (55° C) bath until the typical tail withdrawal diphenylbutyryllpiperidine R=N(CH2); X=H; response is observed. The cut off time is 15 seconds. The X=H reaction time is measured in 0.5 second units with a stop (2) 4-(p-Chlorophenyl)-4-hydroxy-N-ethyl-N-methyl-ol. watch. After each determination the tail is carefully dried. ot-diphenyl-1-piperidinebutyramide R=NMe Et; Around 9:00AM each rat is given saline (control rats) or an X=4-Cl; X=H) aqueous solution (or suspension) of the substance to be (3) 4-(p-Bronophenyl)-4-hydroxy-N,N-dimethyl-O.C.- investigated by the oral route of administration. Periodically diphenyl-1-piperidinebutyramide R=NMe, X=4-Br; thereafter (i.e., A, 2, 1, 2, 3, 4, 5 and 6 hours after dosage) X=H} 45 the reaction time is again measured by trained technicians (4) 1-4-(3.4-Dichlorophenyl)-4-hydroxy-1-piperidino unaware of the nature of the compounds. Results of these 2,2-diphenylbutyrylpyrrolidine R=N(CH2); X=3- studies are expressed as ED concentration values (mg/kg), Cl; X=4-CI) calculated as the dose producing a tail withdrawal latency (5) 1-4-(4-Chlorophenyl)-4-hydroxy-1-piperidino-2,2- equal to half the difference between the maximum latency 5 (s.15 seconds) and the baseline latency (6 to 8 seconds). diphenylbutyrylpyrrolidine (R=N(CH2); X=4-Cl; Castor Oil Test in Rats see, e.g. Niemegeers et al (1972) X=H Arzneim Forsch, 22:516-518; U.S. Pat No. 4,867,979; U.S. (6) 4-(p-Chlorophenyl)-4-hydroxy-N,N-dimethyl-oo Pat. No. 4,990,521; U.S. Pat. No. 4,824.853 diphenyl-1-piperidinebutyramide R=NMe; X=4-Cl; Young female Wistar rats (230-250 g body weight) are X=H 55 fasted overnight and in the morning each animal is treated (7) 4-(p-Fluorophenyl)-4-hydroxy-N,N-dimethyl-O.o- orally with a dose level of the compound to be tested. One diphenyl-1-piperidinebutyramide R=NMe; X=4-F: hourthereafter, the animal received 1 ml of castor oil orally. X=H Each animal is kept in an individual cage. At different (8) 4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-N, selected time intervals (e.g. 1, 2, 3, 4, 6 and 8 hrs) after the N-dimethyl-O.O-diphenyl-1-piperidinebutyramide castor oil treatment, the presence or absence of diarrhea is R=NMe; X=4-Cl; X=3-CF, noted. In more than 95% of 500 control animals, severe (9) 1-4-(4-Hydroxy-4-phenyl-1-piperidino)-2.2- diarrhea is observed 1 hour after treatment with castor oil. diphenylbutyrylpyrrolidine and R=N(CH2): X=H; Using this all-or-none criterion, a significant positive effect X=H) occurs with the tested compound if no diarrhea is observed (10) 1-4-4-Hydroxy-4-(3-trifluoromethylphenyl)-1- 65 1 hour after the castor oil treatment. A minimum of 5 dose piperidino-2,2-diphenylbutyryl-morpholine R=N levels are use per drug, each dose level being given to 10 rats (CHCH)O; X=3-CF; X=4-H on ten different days. The EDs value is determined as that 5,798.093 9 10 dose in mg/kg body weight at which no diarrhea is present bromide and the whole is stirred and refluxed for about 15 in 50% of the tested animals. hours. The reaction mixture filtered hot and the filtrate is The solvent mixture for the compounds of formula I and evaporated. The oily residue is dissolved in 2-propanol and formula II is preferably of from about 1% whow to 15% w/w, to this solution is added an excess of 2-propanol previously more preferably of from 2 to 10% w/w, and most preferably saturated with gaseous hydrogen chloride. The whole is of from 5 to 8% w/w of an alcohol selected from the group evaporated and the oily residue is warmed in diluted hydro consisting of ethanol. propanol or isopropanol and of from chloric acid solution. Upon the addition of toluene, the salt about 99% w/w to about 85% w/w water. is precipitated. It is filtered off, boiled in acetone, and filtered off again after cooling, yielding 4-(p-Chlorophenyl)-4- DETALED DESCRIPTION OF THE O hydroxy-N,N-dimethyl-O.O.-diphenyl-piperidine-1 INVENTION -butyramide hydrochloride; m.p. 221.1° C. The Anti-Hyperalgesic/Anti-Pruritic Compounds The compounds for use in the compositions and methods EXAMPLE 3 herein possess peripheral anti-hyperalgesic and anti-pruritic activity and substantially no CNS activities because they do 15 1-4-(4-Hydroxy-4-phenylpiperidino)-2,2- not cross the blood brain barrier. The failure to cross the diphenylbutyrylpyrrollidine blood brain barrier precludes the occurrence of the CNS systemic side effects, so that there is no potential for abuse. A mixture of 13 parts of 1-(tetrahydro-3,3-diphenyl-2- The compounds for use in the methods and compositions furylidene) pyrrollidinium bromide, 5.3 parts of 4-phenyl-4- provided herein include compounds that by virtue of their piperidinol, 8 parts of sodium carbonate, 0.2 parts of potas interaction, either directly or indirectly, with peripheral sium iodide and 200 parts of 4-methyl-2-pentanone is stirred opioid receptors ameliorate the peripheral hyperalgesic and refluxed for 5 hours with water separator. The reaction state, but do not exhibit systemic CNS-mediated analgesic mixture is cooled and water is added. The organic layers activity or CNS side effects, including heaviness of the separated, washed with diluted sodium hydroxide solution, limbs, flush or pale complexion, clogged nasal and sinus dried, filtered, and while stirring the filtrate, the product is passages, dizziness, depression, respiratory depression. 25 crystallized. It is filtered off and dried, yielding 1-4-(4- sedation and constipation. These compounds include antidi hydroxy-4-phenylpiperidino)-2,2-diphenylbutyryl arrheals that act as antidiarrheals via interaction, with , 6. pyrrollidine; m.p. 187.5°C. or K receptors, and opiate agonists, such as metkephamide EXAMPLE 4 and related enkephalin analogs. The compounds of the 30 present invention have been reported in prior art patents U.S. Pat. Nos. 3,714.159 and 3,884,916 which are incorporated 4-(4-Chloro-3-trifluoromethylphenyl)-4-hydroxy-N. herein by reference. N-dimethyl-oo-diphenylpiperidine-1-butyramide Representative examples are included according to said hydrochloride patents to illustrate the preparation of some compounds used 35 A mixture of 12.1 parts of dimethyl (tetrahydro-3,3- in the present invention. diphenyl-2-furylidene) ammonium bromide, 8.4 parts of 4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol, 8 parts EXAMPLE 1. of sodium carbonate, 0.4 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 3 1-4-(4-Hydroxy-4-phenylpiperidino)-2,2- hours with water separator. The reaction mixture is cooled diphenylbutyrylpiperidine hydrochloride and water is added. The organic layer is separated, washed A mixture of 13.5 parts of 1-(tetrahydro-3-3-diphenyl-2- with diluted sodium hydroxide solution. dried and concen furylidene) piperidinium bromide, 5.3 parts of 4-phenyl-4- trated to a volume of about 200 parts. The concentrate is piperidinol, 8 parts of sodium carbonate, 0.2 parts of potas acidified with an excess of 2-propanol previously saturated sium iodide and 200 parts of 4-methyl-2-pentanone is stirred 45 with gaseous hydrogen chloride. Upon stirring, the salt is and refluxed for 3 hours with water-separator. The reaction crystallized. It is filtered off and dried, yielding 4-(4-chloro mixture is cooled and 200 parts of water is added. The 3-trifluoromethylphenyl)-4-hydroxy-N,N-dimethyl-O.O- organic layer is separted, dried and evaporated. The solid diphenylpiperidine-1 -butyramide hydrochloride; m.p. residue is crystallized from 120 parts of 4-methyl-2- 215.3° C. pentanone (activated charcoal), yielding 7.8 parts of the 50 crude free base of 1-4-(4-hydroxy-4-phenyl-piperidino)-2. EXAMPLE 5 2diphenylbutyryllpiperidine hydrochloride. It is dissolved in 4-methyl-2-pentanone and this solution is acidified with an 4-(p-Bromophenyl)-4-hydroxy-N,N-dimethyl-O,0- excess of 2-propanol previously saturated with gaseous diphenylpiperidine-1-butyramide hydrate hydrogen chloride. The precipitated salt is filtered off and 55 A mixture of 12.1 parts of dimethyl (tetrahydro-3,3- dried, yielding 1-4-(4-hydoxy-4-phenylpiperidino)-2,2- diphenyl-2-furylidene) ammonium bromide, 8.8 parts of diphenylbutyryllpiperidine hydrochloride; m.p. 240.3° C. 4-(p-bromophenyl)-4-piperidinol hydrochloride, 10.6 parts of sodium carbonate, 0.5 parts of potassium iodide and 200 EXAMPLE 2 parts of 4-methyl-2-pentanone is stirred and refluxed for 14 4-(p-Chlorophenyl)-4-hydroxy-N,N-dimethyl-oo hours with water separator. The reaction mixture is cooled diphenylpiperidine-1-butyramide hydrochloride and water (200 parts) is added. The organic layer is separated, washed with diluted sodium hydroxide solution, A mixture of 6.33 parts of 4-(p-chlorophenyl)- dried, filtered, and while stirring the filtrate, the product is 4piperidinol. 8 parts sodium carbonate, 0.2 parts of potas crystallized. It is filtered off and recrystallized from 80 parts sium iodide and 240 parts of 4-methyl-2-pentanone is dis 65 of 4-methyl-2-pentanone (activated charcoal), yielding 4-(p- tilled azeotropically, Then there are added 12.12 parts of bromophenyl)-4-hydroxy-N,N-dimethyl-O.C.- dimethyl (tetrahydro-3-3-diphenyl-2-furylidene)ammonium diphenylpiperidine-1-butyramide hydrate; m.p. 123.7°C. 5,798,093 11 12 The anti-hyperalgesiclanti-pruritic compounds are dis Alkylisooxazoles. Amantadine, Amidinomycin, Cuminalde solved in the alcohol-water mixture and can be dispensed as hyde Thiosemicarbzone. Foscarnet Sodium, Kethoxal, anti-hyperalgesic/anti-pruritic spray from containers having Lysozyme, Methisazone. Moroxydine, Podophyllotoxin. a pump action or from aerosol containers which are charged Ribavirin, Rimantadine, Stallimycin. Statolon, Thymosins, with propellants. The spray on the site of injury will inhibit Tromantadine and Xenazoic Acid. pain or itching without causing a stinging or burning sen Dispensing the Compositions sation to the patient. However, it is preferable to include The compositions of the present invention may be dis other pharmaceutical agents into the anti-hyperalgesic for pensed as a liquid from a conventional spray bottle by mulations such as antibacterials. antivirals, antifungals, anti pumping action by which the bottle is air-pressurized, and inflammatories and antiseptics which will prevent or elimi O the liquid is expelled in a relatively fine spray form. nate infection and help the healing process. The preferred way of dispensing the compositions of the Antibacterial Agents/Antibiotics present invention is in the form of aerosols. Compositions Suitable antibacterial agents include: Aminoglycosides, for administration as aerosols are prepared by dissolving an Amphenicols. Ansamycins, B-Lactams, Carbapenems, anti-hyperalgesic compound of formula I in the aqueous Cephalosporins, Cephamycins, Monobactams. 15 solution of up to 15% w/w ethanol, propanol or isopropanol, Oxacephems, Penicillins, Lincosamides, Macrollides, mixing with a volatile propellant, and placing the mixture in Amphomycin, Bacitracin, Capreomycin, Colistin, a pressurized container having a metering valve to release Enduracidin, Enviomycin, Fusafungine, Gramicidin(s), the mixture in extra fine droplet size. Mikamycin, Polymyxin, Polymyxin B-Methanesulfonic The liquefied propellant employed typically is one which Acid. Pristinamycin, Ristocetin. Teicoplanin. Thiostrepton, 20 has a boiling point below ambient temperature at atmo Tuberactinomycin, Tyrocidine. Tyrothricin, Vancomycin, spheric pressure. For use in compositions intended to pro Viomycin(s), Virginiamycin Zinc Bacitracin, Tetracyclines, duce aerosols for medicinal use, the liquefied propellant Cycloserine, Mupirocin, Tuberin, 2,4-Diaminopyrimidines, should be non-toxic. Among the suitable liquefied propel Nitrofurans. Quinolones. Sulfonamides. Sulfones, lants which can be employed are the lower alkanes contain Clofoctol. Hexedine, Magainins, Methenamine. Meth 25 ing up to five carbon atoms, such as butane and pentane, or enamine Anhydromethylene-citrate. Methe namine an alkyl chloride, such as methyl ethyl or propyl chlorides. Hippurate. Methenamine Mandelate. Methenamine Further suitable liquefied propellants are the fluorinated and Sulfosalicylate, Nitroxoline, Squalamine, and Zibornol, fluorochlorinated alkanes such as are sold under the trade Preferred antibacterial agents/antibiotics include: marks "Freon" and "Genetron". Mixtures of the above Clindamycin. Erythromycin, Tetracycline, Mupirocin, Baci mentioned propellants can suitably be employed. tracin and Neomycin. Preferred liquefied propellants are chlorine free Antifungal Agents propellants, for example 134a (tetrafluoroethane) and 227c Suitable antifungal agents include: Polyenes. (heptafluoropropane) which can be used as described above. Allylamines. Imidazoles, Triazoles. Acrisorcin, Amorolfine, The aerosol sprays are made by nebulizing the solution Biphenamine, Bromosalicylchloranilide. Buclosamide. 35 containing the anti-hyperalgesic compound, using a variety Chlophenesin, Ciclopirox. Cloxyquin, Coparaffinate. of known nebulizing techniques. The aerosol system con Diamthazole. Dihydrochloride. Exalamide, Flucytosine. sists of a solution of the anti-hyperalgesic compound, and Halethazole, Hexetidine. Loflucarban, Nifuratel, Potassium other therapeutic agents, if desired, in a liquid propellant. Iodide, Propionates, Propionic Acid, Pyrithione, Both liquid and vapor phases are present in a pressurized Salidylanilide, Sulbentine, Tenonitrozole, Tolciclate. 40 container and when a valve on the container is opened, Tolindate, Tolnaftate. Tricetin, Ujothion, and Undecylenic liquid propellant containing the dissolved anti-hyperalgesic Acid. compound, and other therapeutic agents, is released in the Preferred antifungal agents include: Ketoconazole. Clotrimazole, Ciclopirox olamine, Tolnaftate and Naftifine. form of a fine aerosol mist or aerosol wet spray. Anti-inflammatory Agents 45 There are a variety of commercially available nebulizers Suitable Anti-inflammatory agents include: to produce the aerosols of the present invention including Corticosteroids, Aminoarylcarboxylic Acid Derivatives. small volume nebulizers which can be carried ready for use Arylacetic Acid Derivatives. Arylbutyric Acid Derivatives. in first aid requiring circumstances. Arylcarboxylic Acids, Arylpropionic Acid Derivatives. Compressor driven nebulizers are also available which Pyrazoles, Pyrazolones. Salicylic Acid and derivatives 50 incorporate jet technology and use compressed air to gen thereof. Thiazinecarboxamides, E-Acetamidocaproic Acid, erate the aerosol. These devices are commercially available, S-Adenosylmethionine, 3-Amino-4-hydroxy-butyric Acid, for example, from: Healthdyne Technologies, Inc.; Omron Amixe trine, Bendazac. Bucolome. Carbazones, Healthcare Inc.; Mountain Medical Equipment Inc.; and Difenpiramide. Ditazol Guaiazulene, Heterocyclid Ami Hospitak Inc. noalkyl Esters of Mycophenolic Acid and derivatives 55 Dissolution Studies thereof, Nabumetone, Nimesulide. Orgotein, Oxaceprol, Dissolution studies were conducted to ascertain the Oxazole derivatives. Paranyline, Pifoxime. 2-substituted-4, degree of solubility of the anti-hyperalgesiclanti-pruritic 6-di-tertiary-butyl-s-hydroxy-1,3-pyrimidines, ProquaZone compounds used in the formulation of the present invention. and Tenidap. Various concentrations of the alcohol/water mixtures Antiseptics were prepared. At low concentrations of alcohol. e.g. 1 to Suitable antiseptics include: Guanidines, Halogens/ 2% whow, extensive stirring was required to dissolve suffi Halogen Compounds, Nitrofurans, Phenols, Quinolines, cient amounts of the anti-hyperalgesic compounds. The Boric Acid, Chloroazodin, m-Cresyl Acetate. Cupric Sulfate higher the alcohol content of the alcohol/water mixture, the and Ichthammol. easier the dissolution of the anti-hyperalgesic compounds. Antiviral Agents 65 However, the ratio of alcohol/water mixture is limited by the Suitable antiviral agents include: Purines/Pyrimidinones, stinging, burning sensation caused by the presence of alco Acetylleucine, Monoethanolamine. Acridinamide. hol in the alcohol/water mixture. 5,798.093 13 14 Sensitization Studies of the Alcohol/Water Mixtures injuries by spraying the formulations from pump-action Human volunteers rubbed the inside of both their fore containers and from pressurized aerosol containers contain arms approximately midway between the wrist and the ing a propellant or other gaseous substance. The formula elbow with 100 grit sandpaper to cause dermal abrasion tions were found to relievelinhibit hyperalgesic pain without thereon. The treatment produced a reddened abraded area. causing stinging, burning sensation upon application to a The abrading process continued until a mild stinging pain was experienced. topical injured site. The abraded areas were then treated with various ratios of Formulation of the present invention were tested for alcohol/water mixtures by spraying the solutions onto the anti-pruritic activity as described by the following test method. abraded areas. The sprayings were performed in a "double O blind" manner so that the volunteers were unaware of the relative concentrations of the alcohol/water mixture. TESTING FOR ANTI-PRURTIC ACTVITY Responses were tabulated based on the "lowering" or "increasing” of the stinging, burning sensation caused by the Testing was performed in a mouse scratch model under sprays as compared with the stinging, burning sensation blind conditions. caused by the abrading process prior to the application of the 15 sprayS. Groups of 8-10 male Swiss albino mice (Hilltop Lab When the responses were tabulated and the code was Animals. Inc.. Scottsdale, Pa.), weighing 2.5-2.6 g. were broken the alcohol/water mixture which had a ratio of 15% used in the testing. They were housed under controlled wiw or less alcohol, the remaining percentage being water, temperature of 23-25° C. Food and water were freely was found to be the least stinging and burning. Above the available. Before the experiments, the mice were weighed, 15/85 percent alcohol/water ratio the mixtures caused put into individual boxes and allowed to acclimate for 30 increased stinging and burning. Formulations of the Present Invention Materials Formulations of the present invention contain from about Vehicle used to dissolve the test compounds: 20% w/w 0.01% whv to about 40% w/w, and preferably about 1.0% to 25 cremophor EL. about 10% Whw of an anti-hyperalgesic compound of for To induce scratching Compound 48/80 (Sigma. St. Louis, mula I or formula I; of from about 0.0% w/w to about 40% U.S.A.) was used which has been shown to produce an itch wfw, and preferably of from about 1% w/w to about 10% sensation in humans (Armstrong et al., J. of Physiol., 120: wfw of an additional active ingredient selected from the 30 326, 1953). group consisting of antibacterials, antivirals, antifungals, The compounds to be tested for anti-pruritic activity were anti-inflammatory and anesthetics or mixtures thereof, and of from about 20% w/w to 99.09% whv of a solvent dissolved in the vehicle of 20% w/w cremophor EL. consisting of from about 1% w/w to about 15% w/w, and Method preferably of from about 2% whvf to about 10% w/w of an 100 ml of the vehicle (3-5 doses, n-8-10) was injected alcohol selected from the group consisting of ethanol, pro 35 s.c. into the back of the neck of mice 20 min. before panol and isopropanol or mixtures thereof and of from about challenging them with 100 pil of Compound 48/80 (2 mg/ml; 99% w/w to about 85% w/w water. 50 g) injected s.c. into the back of the neck. One minute Illustrative examples follow. later the mice were observed for 30 min. and the number of hindleg scratching movements directed to the neck was EXAMPLE 6 counted. 100 grams of 4-(p-chlorophenyl)-4-hydroxy-N,N- The vehicle-injected mice scratched 7916 times in the 30 dimethyl-O.O-diphenyl-1-piperidine-butyramide was dis min after the standard challenge with Compound 48780. solved in 2 liter of a 5% whv ethanol/95% whv water To each mouse of a group of 8-10 mice previously mixture with agitation. The solution was transferred to a 45 subjected to the standard challenge various doses of the pump action spray bottle. compounds, to be tested for anti-pruritic activity, were Similarly, using analogous procedures, the following for administered s.c. into the back of the neck. One minute later mulations were prepared in which "other active agents" the mice were observed for 30 min and the number of denote one or more of an antibacterial, antifungal, antiviral, antiseptic or anti-inflammatory agent. hindleg scratching movements directed to the neck was 50 counted. EXAMPLES 7 For each group of 8-10 mice, the mean values for scratching were normalized to relative 9% antagonism of scratching and then plotted vs. dose of test compounds. % ww Anti-hyperalgesic %. Alcohol/Water Compound % Other Active Agent Solution Interval estimates of mean A50 were determined by nonlin 55 ear regression analysis (Kalcida Graph) and mean % inhi 0.2 1. bition of scratching was calculated. O.O 1. 2 0.5 3 The following compounds were tested: 2 O.O 3 (1) 1-4-(4-Hydroxy-4-phenyl-1-piperidino)-2.2- O 70 8 O OO 8 diphenylbutryl)piperidine; 5 30 15 (3) 4-(p-Bromophenyl)-4-hydroxy-N-N-dimethyl-o.o- 15 O.O 15 diphenyl-1-piperidinebutyramide; and 40 0.0 O (6) 4-(p-Chloropehnyl-4-hydroxy-N-N-dimethyl-o.o- 40 OO O diphenylpiperidine-1-butyramideloperamidel. 65 Each compound (1.3, 6) antagonized Compound 48/80 Formulations of the present invention were tested for the induced scratching in a dose-related manner. Results are inhibition of hyperalgesic activity associated with topical shown in Table C. 5,798.093 1S 16 wherein TABLE C R is N(CH), N(CHCH), N(CH)C.H. N(CH), N(CH2)6 or N(CH2CH2)2O; and Mean % inhibition of Scratching X and X are independently H. Cl, Br. For CF and Compound Dose (mg/kg, s.c.) Mean? inhibition 5 wherein said antihyperalgesic compound has a periph (1) 2.5 32 eral selectivity of from about 251 to about 1,280; and 5.0 65 (B) a solvent mixture for the compound of formula II 100 83 (2) 1. 35 comprising: a) up to about 15% wiv of an alcohol 2.5 68 O selected from the group consisting of ethyl alcohol. 50 94 propyl alcohol and isopropyl alcohol or mixtures (3) 0.5 18 thereof; and b) greater than or equal to 85% w/w water. 47 2. The method for the prevention or treatment of pruritus 2.5 65 in a patient comprising administering to said patient an 15 effective anti-pruritic amount of a formulation according to Other compounds tested have shown similar anti-puritic, claim 1 wherein said peripheral anti-hyperalgesic compound dose-responsive activity in the range of from about 15 to is selected from the group consisting of: about 95% based on doses of form about 0.5 to 10.0 mg/kg, 1-4-(4-Hydroxy-4-phenyl-1-piperidino-2,2- S.C. diphenylbutyrylpiperidine It should be understood by those skilled in the art that, 20 while the invention has been described and illustrated above 4-(p-Chlorophenyl)-4-hydroxy-N-ethyl-N-methyl-O.0- in connection with certain specific embodiments, many diphenyl-1-piperidinebutyramide variations and modifications may be employed without 4-(p-Bromophenyl)-4-hydroxy-N,N-dimethyl-o,0- departing from the scope of the invention. diphenyl-1-piperidinebutyramide What is claimed is: 1-4-(3,4-Dichlorophenyl)-4-hydroxy-1-piperidino-2, 1. A method for the prevention or treatment of pruritus in 25 2-diphenylbutyrylpyrrollidine a patient comprising administering to said patient an effec 1-4-(4-Chlorophenyl)-4-hydroxy-1-piperidino-2,2- tive anti-pruritic amount of a formulation comprising: diphenylbutyrylpyrrolidine (A) a peripheral anti-hyperalgesic compound of the for 4-(p-Chlorophenyl)-4-hydroxy-N,N-dimethyl-O.O- mula (II) 30 diphenyl-1-piperidinebutyramide 4-(p-Fluorophenyl)-4-hydroxy-N,N-dimethyl-O.o- O R diphenyl-1-piperidinebutyramide 4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-N,N- dimethyl-O,0-diphenyl-1-piperidinebutyramide () N---- 35 1-4-(4-Hydroxy-4-phenyl-1-piperidino)-2.2- diphenylbutyrylpyrrolidine and 1-4-4-Hydroxy-4-(3-trifluoromethylphenyl)-1- O X piperidino-2,2-diphenylbutyryl-morpholine. X sk :: * : :