sign in sign up
<<
Home , Benzododecinium bromide, Betamethasone benzoate, Chlormidazole, Clostebol acetate, Croconazole, Fenticlor

US007 198800B1

(12) United States Patent (10) Patent No.: US 7,198,800 B1 K0 (45) Date of Patent: Apr. 3, 2007

(54) COMPOSITIONS AND METHODS (56) References Cited (75) Inventor: Thomas Sai Ying Ko. 4 Licence Road, U.S. PATENT DOCUMENTS Belgrave South, Victoria, 3160 (AU) 3,987,000 A * 10/1976 Gleichenhagen et al. ... 523/111 Y re. - - - 5,041.287 A * 8/1991 Driggers et al...... 424,81 (73) Assignee: Thomas Sai Ying Ko, Beijing (CN) 5,632,727 A * 5/1997 Tipton et al...... 602/47

5,708,023 A * 1/1998 Modak et al...... 514,494 (*) Notice: Subject to any disclaimer, the term of this 5,725.491 A * 3/1998 Tipton et al...... 602/43 patent is extended or adjusted under 35 6,183,770 B1* 2/2001 Muchin et al...... 424/448 U.S.C. 154(b) by 781 days. * cited by examiner (21) Appl. No.: 09/717,088 Primary Examiner Sreeni Padmanabhan Assistant Examiner Gina Yu (22) Filed: Nov. 22, 2000 (74) Attorney, Agent, or Firm—Sughrue Mion, PLLC (30) Foreign Application Priority Data (57) ABSTRACT Nov. 23, 1999 (AU) ...... PQ4190 Non-aerosol spray-on skin patch compositions as described (51) Int. Cl. comprising at least one Substantially water insoluble film A6DF 3/00 (2006.01) forming agent, at least one film plasticizer agent, at least one AOIN 55/00 (2006.01) water soluble compound, and at least one organic solvent, (52) U.S. Cl...... 424/443; 424/447; 424/448: the composition forming a flexible, porous and physiologi 424/449; 424/78.35: 525/363; 514/887: 514/494; cally compatible skin patch when sprayed on to skin and 602/43; 602/47 allowed to dry. Also described are methods of improving (58) Field of Classification Search ...... 424/443, wound healing by administering a physiologically active 424/447, 448, 449, 78.35, 61; 525/363; 514/887, ingredient to a patient in need of Such treatment. 514/494; 602/47, 43 See application file for complete search history. 17 Claims, No Drawings US 7,198,800 B1 1. 2 COMPOSITIONS AND METHODS Such substances for local delivery of active substances remained largely unchanged until as late as this century. The FIELD OF THE INVENTION concept of transdermal systemic drug delivery was first seriously advocated by Dr. Alejandro Zaffaroni, for The present invention relates to a non-aerosol spray-on 5 example, in U.S. Pat. Nos. 3,598,122 and 3,731,683 from the skin patch composition and methods of using it in improving early 1970s. Transdermal systemic drug delivery provides wound healing, and/or administering a physiologically an effective method of achieving improved bioavailability active ingredient to a patient. The invention also relates to a for physiologically active Substances where the drugs are spray on skin patch drug delivery system. Other aspects of poorly absorbed by traditional routes of delivery, and/or the invention will become apparent from the description that 10 follows. when oral dosing is poorly tolerated or not possible. Transdermal formulations are however limited. For BACKGROUND OF THE INVENTION example, polar drugs tend to penetrate the skin too slowly. Since most drugs are of a polar nature this limitation is Although there are several skin patch compositions avail 15 significant, as is the fact that many drugs cause irritation at able on the market, which can be used for forming a the site of topical application. protective film over a wound, they are associated with a One common method known for assisting the rate of number of problems. The spray-on skin patches presently penetration of drugs across the skin is to increase the known basically take the form of a water insoluble polymer thermodynamic activity of the drug. The thermodynamic dissolved in an organic solvent, with an appropriate propel activity of a drug is proportional to the concentration of the lant that will allow it to be applied in an aerosol form. A significant disadvantage with Such compositions is that after drug and the selection of the vehicle. According to the laws being applied to the skin and being left to dry a non-porous of thermodynamics, the maximum activity of a drug is film structure is formed that prevents the passage across it of related to that of the pure drug crystal. gasses or moisture. The failure to allow moisture to move 25 From the 1970s a principal focus of transdermal systemic away from the wound results in excess moisture being drug delivery has been, and remains, on transdermal patch trapped beneath the film Surface causing depredation of the devices. These patch devices are like bandages which are wound, and the possibility of . attached to the Surface of intact skin for prolonged periods It is also problematic that due to delivery via an aerosol of time to allow a desired systemic delivery of a drug or means with the aid of a propellant, the spray-on skin patch 30 other physiologically active agent. These transdermal patch is applied at a high pressure and can cause pain or discom devices occlude the skin and trap the drug, together with fort to the patient when applied to a wound area. It has volatiles and vehicle excipients, between the skin and an previously not been thought possible to eliminate the pro outer impermeable backing membrane. The membrane pre pellant from Such compositions in order that the composition vents the evaporation or diffusion of vehicle excipients, can be administered under lower pressure, the reason being 35 Volatiles and drag into an environment other than the spe that it was generally believed the presence of propellant was cific target skin site. The prolonged length of time required essential to prevent the clogging of the spraying nozzle for transfer of the drug and excipients from the patch into the through which the composition is applied. skin often results in local skin irritation. The irritation is Use of known spray-on skin patch composition has also caused by prolonged contact on the skin by the drug, been demonstrated in the past to allow the growth of 40 volatiles, vehicle excipients, or the adhesive used to attach microorganisms beneath the film covering that can lead to the patch device to the skin. The occlusive nature of the wound infection as indicated above. patch device also restricts the natural ability of the skin to The prevention or treatment of local or topical disease “breathe’, this being uncomfortable and increasing the risk states or conditions of the skin has traditionally used simple of irritation. With added problems of complex and costly non-occlusive delivery systems. These drug delivery sys 45 manufacturing processes for transdermal patch devices there tems usually include a volatile and/or non-volatile medium is a need for improved transdermal drug delivery systems where a composition of the drug and medium is topically which allow ease of administration, simple preparation and applied to the skin, in the vicinity of or directly on the area comparatively low cost preparation. of skin to be treated. These delivery systems usually take the The thermodynamic activity of a drug can be increased by form of emulsion, creams, ointments, foams, gels, liquids, 50 employing Supersaturated systems which give rise to unusu sprays and aerosols. Such delivery systems are generally ally high thermodynamic potentials (Coldman, et al., J. used to treat skin inflammations, fungal and bacterial topical Pharm Sci. 58(9): 119, 1969). However, topical vehicles infection, soft-tissue contusions, parasites and topical anal relying on Supersaturation have the major limitation of gesia. The limitation with this type of delivery system is that formulation instability, both prior to and during application systemic drugs are generally not suitable for this type of 55 to the skin. As such, they are of limited clinical value within administration, due to various factors possibly including the a non-occlusive volatile:non-volatile delivery vehicle, short interval of application. Some major problems with the because as soon as the formulation comes into contact with current state of the art relate to a lack of efficacy of systemic a person’s clothing or the like, the drug often precipitates; drugs because of the low drug flux across the skin, inability hence the formulation is no longer Supersaturated and any to adequately control the rate of drug delivery, or the 60 enhanced percutaneous absorption ceases. requirement for a very large application area. Problems with Other workers such as Kondo, et al (J. Pharmacobio the poor dermal penetration of drugs is that the drug can be Dyn., 10:743 1987) who were using supersaturation to easily washed off, or transferred to clothes, other surfaces. achieve enhanced transdermal drug delivery, have relied on The dermal delivery of drugs may represent one of the the use of anti-nucleating polymers to stabilize the formu oldest form of drug delivery in human history. Resins and 65 lation. However, the applied drug formulations stabilized animal fats were probably used by humans in early times to with polymers formed an appreciable Surface mass on the treat damage to the skin resulting from injuries and burns. skin which remained there over a prolonged duration of US 7,198,800 B1 3 4 many hours, not a few minutes. So, while Kondo advocated By the term “non-aerosol it is intended to mean that the the use of a metered spray to deliver these formulations, in composition does not comprise a propellant that will serve reality it would be impossible to obtain a non-occlusive to deliver it under pressure. By way of example, the com delivery system with a short application time and still position may conveniently be applied from a pump-pack maintain a clinically useful transdermal penetration 5 type of dispensing container that will utilise the pumped enhancement. influx of air to force the composition out through a spraying It is accordingly an object of the present invention to nozzle, under relatively low pressure. provide a spray-on skin patch composition that overcomes There are several aspects to the invention. In one main Some of the problems associated with prior art compositions aspect the skin patch composition is adapted to be sprayed and systems. Other objects of the present invention will 10 onto a wound. Such as for example a cut, sore, abrasion, burn become apparent from the following detailed description. or other affected part of the skin. In another aspect, a spray patch skin delivery composition is adapted to be applied to SUMMARY OF THE INVENTION normal skin as a means of delivering to or through the skin (transdermally) of the patient a physiologically active ingre According to one embodiment of the present invention 15 dient Such as Systemically active drug, or prodrug thereof. In there is provided a non-aerosol spray-on skin patch compo Such cases the spray-on skin patch composition will prefer sition comprising: ably be delivered/administered in a metered dose. (a) at least one substantially water insoluble film forming In a first aspect of the invention the composition com agent, prises at least one Substantially water insoluble film forming (b) at least one film plasticiser agent; agent, at least one film plasticiser agent, at least one water (c) at least one water soluble compound; and soluble compound and at least one organic solvent. The (d) at least one organic solvent; ingredients should of course be physiologically compatible and when combined, administered to the skin and allowed to the composition forming a flexible, porous and physiologi dry the composition forming a flexible, and physiologically cally compatible skin patch when sprayed onto skin and 25 compatible porous, skin patch or skin covering film which allowed to dry. degrades over time. The composition may also include a physiologically The film forming agents that may be used in the present active ingredient or pro-drug thereof for application to a invention include acrylic acid and its derivatives, poly wound site. acrylic and its derivatives such as polybutylmethacrylate and According to another embodiment of the invention there 30 polymethacrylic acid, polymethacrylate, ascorbyl palmitate, is provided a spray patch skin delivery composition com carbomer, carnauba wax, cellulose derivatives Such as cel prising: lulose phthalates, rosca mellose sodium, hydroxy (a) at least one substantially water insoluble film forming ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl agent, methylcellulose, ethyl cellulose and related compounds, (b) at least one film plasticiser agent; 35 hydroxypropyl methylcellulose phthalate, hypromellose (c) at least one water soluble compound; phthalate, crospovidone and derivatives/related compounds, (d) at least one organic solvent; and cetyl and derivatives, microcystalline wax, poloX (e) one or more physiologically active ingredient or a amer, , polyurethane, polyvinyl acetate, pro-drug thereof; polyvinyl acetate phthalate, polyvinyl alcohol, povidone, 40 silicone rubber and derivatives, shellac, triglycerides deriva the composition forming a flexible, porous and physiologi tives. These film forming agents are organic solvent soluble, cally compatible skin patch when sprayed onto skin and for example, in organic Solvents which are dermatological allowed to dry, and which provides transdermal drug deliv compatible solvents used in dermatological, pharmaceutical ery. and veterinary applications. According to another aspect of the invention there is 45 It is also possible for a number of substantially water provided a spray patch transdermal drug delivery system insoluble film forming agents to be included within the which comprises at least one physiologically active agent or composition, which when combined and applied to the skin pro-drug thereof in a water insoluble, porous, film structure will likewise form a flexible skin patch. containing drug depots. The composition should include at least one film plasti According to a still further embodiment of the present 50 ciser agent that will serve to soften the polymer film formed invention there is provided a method of improving wound by the film forming agent and to ensure that it is sufficiently healing or administering a physiologically active ingredient flexible that it can move with the skin on the area to which to a patient in need of Such treatment comprising applying it is applied without cracking and peeling (at least during the to a wound or to skin of the patient an effective amount of intended lifespan of the skin patch). Examples of suitable a composition as referred to above. 55 film plasticiser agents include polybutylphthalate, benzyl Other aspects of the invention are described hereinafter. benzoate, dibutyl sebacate, dimethyl phthalate, dibutyl phthalate, triacetin, glycol and derivatives thereof, benzyl DETAILED DESCRIPTION OF THE benzoate, glycerin, mineral oil, lanolin (such as INVENTION C, alcohols), petroleum and lanolin alcohols, polyethylene 60 glycol, glycerin, Sorbitol, triacetin, triethylene citrate, pro Throughout this specification and the claims which fol pylene glycol, chlorbutanol, castor oil and gelatin. low, unless the context requires otherwise, the word “com An important aspect of the present invention is that the prise', and variations such as “comprises' and "compris skin patch formed by use of the composition is porous. This ing, will be understood to imply the inclusion of a stated porosity is achieved by including within the composition at integer or step or group of integers or steps but not the 65 least one water soluble compound that will be integrated exclusion of any other integer or step or group of integers or within the polymer film when applied to the skin. Without steps. limiting the invention, it is believed that the presence of a US 7,198,800 B1 5 6 water soluble compound will, when the film comes into nated hydrocarbons such as methylene chloride, carbon contact with moisture, cause molecules of this compound to tetrachloride, trichloroethylene, chlorothene SM; esters such leach out of the film, resulting in the forming of windows or as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl pores within the film itself. These pores will allow the acetate, isobutyl acetate, amyl acetate, 2-thylhexyl acetate, passage of gases and water vapour through the skin patch duPont DBE, Exxate 500, 700, 900; glycol and /ester film. In a preferred embodiment of the invention the water derivatives, ethylene glycol, PM acetate, butyl celluosolve, soluble compound also has another role within the compo Carbritol acetate, butyl Carbritol acetate, Ektapro EEP; sition, Such as for example as a physiologically active hydrocarbons such as , eyxlene, VM&P naphtha, ingredient. Examples of physiologically active ingredients mineral spirits. Aromatic 100, Aromatic 150, ketones such that are also water soluble include quaternary 10 as acetone, methyl ethyl ketone, methylbutyl ketone; ammonium compounds such as for example cetrimide alky Such as dimethyl ether, benzyl benzoate; isoptopyl laryltrialkylammonium chloride, alkylaryltrimethylammo myristate; acetonitrile; ethyl oleate; glycerol, glycofurol nium chloride, amantanium bromide, benzalkonium chlo (tetraglycol); propylene glycol, polyethylene glycol (PEG); ride, , benzododecinium bromide, bexane; n-hexane, glycol ethers; methylene chloride; methyl cetalkonium chloride, cethexonium bromide, 15 chloride; octyl dodecanol; toluene; trichlorethane; diethyl bromine, and cetyldimethylethylammonium bromide. phthalate; and dibutyl phthalate. These solvents are volatile Compounds such as these will integrate evenly within the and, in general, in levels used in dermatological preparations film and act immediately on bacteria associated with the do not cause Substantial irritation to the skin, that is, are effected skin area covered by the film, leaving a multiplicity pharmaceutically acceptable. On application to the skin the of windows or pores within the film, allowing the skin Solvents rapidly Volatilize. A Small amount of a non-volatile beneath to breathe and perspire, and at the same time solvent (for example, less than 2% v/v of total solvent) may preventing the trapping of anaerobic bacteria beneath the be included. film. Quaternary ammonium compounds such as cetrimide The spray-on skin patch composition having wound treat are advantageous because they have action which ment application may optionally include one or more physi may assist in binding the film onto the skin to which it is 25 ologically active ingredients, or prodrugs thereof, that may applied. Quaternary ammonium compounds such as cetrim for example be one or more of, or a combination of the ide may also assist to soften and maintain the softness of following: rapidly-acting (such as cetrimide), blood clots with which it will come into contact. This action long-acting antimicrobials, such as , benzyl ben helps to prevent Scabbing of a wound, cut or abrasion, thus Zoate, dibutyl sebacate, dimethyl phthalate, dibutyl phtha facilitating the antimicrobial effects. 30 late, tiacetin, glycol and derivatives, cortico , pain Other examples of water soluble compounds that can be relieving agents, compounds having antiinflammatory activ incorporated within the composition to aid in formation of ity, , and biologically active peptides or pro pores within the skin patch are agents such as teins. This list of active agents is not intended to be limiting chlorbutanol, , phenol derivatives such as resorcinol, upon the nature of physiologically active ingredients that salicylic acids, acrisorcin, , amphotericin, 35 can be incorporated within Such compositions as any agents derivatives and related compounds (, butocona that are compatible with the other components of the com Zole nitrate, , , , position and which can be administered effectively via , enilconazole, , , flutri spraying onto the skin are considered to fall within this mazole, , , , lanocona aspect. Details of physiologically active ingredient which Zole, , , Saperconazole, Sertacona 40 may be used in this aspectare set out below in relation to the Zole, , , ), benzoyl spray patch skin delivery composition aspect of the inven disulphide, bromochlorosalicylanilide, buclosamide, buten tion. afine, candicidicaprylic acid, chlorphenesin, ola By the terms “rapidly-acting and “long-acting antimi mine, cilofingin, fenticlor, , criseofulvin, hachi crobials as used herein it is envisaged that short-acting mycin, , , hydroxyStilbamidine 45 antimicrobials will effect an anti-microbial activity at the isethionate, loflucarban, , , site of application for a period of between about one and nifuroxime, p-nitrophenol, , , propionic about four hours, whereas long-acting antimicrobials will acid , pyrrolnitrin, , , tolci demonstrate activity over a period of from about four hours clate, , tiacetin, undecenoic acid. Water soluble to about forty eight hours. Activity can be measured by agents are not limited to antimicrobial agents or antifungal 50 methods routine in the art, that involve taking a Swab from agents. Skin conditioners such as ethoxylated lanoline, alco a wound site and monitoring microorganism proliferation hols (such as C to Cs alcohols, for example, methanol, and viability following exposure to the anti-microbial con , propanol or isopropanol), and glycerin may be used. cerned. Any material that has good solubility in water and slight Where the water soluble component of the composition is solubility in Volatile organic solves Such as such as C to Cs 55 a physiologically active ingredient, the optional one or more alcohols (for example, methanol, ethanol, propanol or iso physiologically active ingredient may be the same or dif propanol), acetone, ethyl acetate, dimethyl ether and other ferent. polar solvents may also be used. In accordance with another aspect of the invention there In order to aid application of the skin patch composition is provided a spray patch skin delivery composition com by spraying, the composition will include at least one 60 prising: organic solvent, preferably a volatile organic solvent. By (a) at least one substantially water insoluble film forming way of example only, one or more solvents may be selected agent, from acetone, ethyl acetate and isopropanol. These solvents (b) at least one film plasticiser agent; are preferred as they may offer some bactericide activity. (c) at least one water Soluble compound; Other solvents that may be adopted include: alcohols, for 65 (d) at least one organic solvent; and example Co alcohols, such as benzyl alcohol, ethanol, (e) one or more physiologically active ingredient or a methanol, butanol, isobutanol, diacetone alcohol; chlori prodrug thereof. US 7,198,800 B1 7 8 the composition forming a flexible, porous and physiologi pate, diazepam, flunitrazepam, flurazepam, lorazepam, cally compatible skin patch when sprayed onto skin and nitrazepam, oxazepam, temazepam and triazolam. allowed to dry, and which provides transdermal drug deliv Neuroleptic and drugs such as the phenothi ery. azines, , fluiphenazine, pericyazine, per The physiologically active agent or prodrug thereof which phenazine, , , and trif may be used in this aspect includes any locally or systemi luoperazine and the butyrophenones, and cally active agents which are compatible with the porous and the other antipsychotic drugs such as film of the invention. These agents may be delivered trans , thiothixene and lithium. dermally through the skin without the need for dermal such as the antidepressants amit penetration enhancers (which may cause skin irritation or 10 ryptyline, , , dothiepin, , sensitivity). Examples of physiologically active agents or , nortriptytine, , and prodrugs thereof include, one or more conveniently classi and the tetracyclic antidepressants such as fied below by therapeutic class. and the monoamine oxidase inhibitors such as Alimentary System isocarboxazid, phenelizine, tranylcypromine and moclobe Antidiarrhoeals such as diphenoxylate, loperamide and 15 mide and selective serotonin re-uptake inhibitors such as . , , , and Sertra line. Cardiovascular System CNS stimulants such as caffeine. Antihypertensives such as hydralazine, minoxidil, capto pril, enalapril, clonidine, prazosin, debrisoquine, diaZoxide, Antialzheimer's agents such as tacrine. , methyldopa, , trimetaphan. Antiparkinson agents such as , benserazide, channel blockers such as diltiazem, felodopine, carbidopa, levodopa, benztropine, , benzhexol. , nitrendipine, and Verapamil. and dopamine-2 agonists such as S(-)-2-(N- Antiarrhyrthmics such as , flecainide, disopy propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0923). ramide, procainamide, mexiletene and . 25 Anticonvulsants such as , valproic acid, primi Antiangina agents such as glyceryl trinitrate, erythritol done, phenobarbitone, methylphenobarbitone and carbam tetranitrate, pentaerythritol tetranitrate, mannitol hexani azepine, ethoSuximide, methSuximide, phensuXimXde, trate, perhexilene, isosorbide dinitrate and nicorandil. Sulthiame aid clonazepam Beta-adrenergic blocking agents such as alprenolol. Antiemetics, antinauseants such as the , atenolol, bupranolol, carteolol, labetalol, metoprolol, nad 30 prochloperazine, and 5HT3 receptor olol, nadoxolol, Oxprenolol, pindolol, , Sotalol. antagonists Such as ondansetron and granisetron and others timolol and timolol maleate. Such as , , , Cardiotonic glycosides such as digoxin and other cardiac , hyoscine, hyoscine hydrobromide, hyoscine glycosides and theophylline derivatives. hydrochloride, clebopride and brompride. Adrenergic stimulants such as adrenaline, ephedrine, 35 fenoterol, isoprenaline, orciprenaline, rimeterol, Salbutamol. Musculoskeletal System salmeterol, terbutaline, dobutambe, phenylephrine, phenyl Non-steroidal antiinflammatory agents including their propanolamine, pseudoephedrine and dopamine. Vasodila racemic mixtures or individual enantiomers where appli tors such as cyclandelate, isoxSuprine, papaverine, dipyri cable, such as ibuprofen, flurbiprofen, ketoprofen, madole, isosorbide dinitrate, phentolamine, nicotinyl 40 aclofenac, diclofenac, aloxiprin, aproxen, aspirin, diflunisal, alcohol, co-dergocrine, nicotinic acid, glyceryl trinitrate, fenoprofen, indomethacin, mefenarnic acid, naproxen, phe pentaerythritol tetranitrate and Xanthinol. Antimigraine nylbutaZone, piroxicam, salicylamide, , Sulin preparations such as ergotamine, dihydroergotamine, dac, desoxysulindac, tenoxicam, and ketoralac. methiysergide, and Sumatriptan. Additional non-steroidal antiinflammatory agents which 45 can be formulated in combination with the dermal penetra Drugs Affecting Blood and Haemopoietic Tissues. tion enhancers include Salicylamide, Salicylic acid, Anticoagulants and thrombolytic agents such as warfarin, flufenisal, Salsalate, triethanolamine salicylate, aminopy dicoumarol, low molecular weight heparins such as enox rine, antipyrine, oxyphenbutaZone, apaZone, cintaZone, aparin; plasminogen activators such as streptokinase and its flufenamie acid, clonixeril, clonixin, meclofenarnie acid, active derivatives, t-pA and its derivatives and the like. 50 flunixin, colchicine, , allopurinol, oxypurinol, Haemostatic agents such as aprotinin, tranexamic acid hydrochloride, dimefadane, indoxole, intra and protamine. Zole, mimbane hydrochloride, paranylene hydrochloride, Central Nervous System tetrydamine, benzindopyrine hydrochloride, fluprofen, ibufenac, naproXul, fenbufen, cinchophen, diflumidone Analgesics, antipyretics including the opiod analgesics 55 Such as buprenorphine, dextromoramide, dextropro Sodium, fenamole, flutiazin, metaZrnide, letimide hydro poxyphene, , alfentanil, Sufentarlil, hydromorphone, chloride, nexeridine bydrochloride, octaZamide, molinazole, , , oxycodone, papaveretum, pentazo neocinchophen, niazole, proxazole citrate, tesicam, tesim cine, , phenoperidine, codeine and dihydrocodeine. ide, tolmetin, and triflumidale. Others include acetylsalicylic acid (aspirin), paracetamol. 60 Antirhoumatoid agents such as penicillamine, aurothio and phenaZone. glucose, sodium aurothiomalate, methotrexate and aurano and sedatives such as the , amylo fin. barbitone, butobarbitone and pentobarbitone and other hyp Muscle relaxants such as baclofen, diazepam, cycloben notics and sedatives such as choral hydrate, chlormethiazole, Zaprine hydrocblotide, dantrolene, methocarbamol. hydroxy Zine and meprobamatc. 65 and quinine. Antianxiety agents such as the , alpra Agents used in gout and hyperuricaemia Such as allopu Zolam, bromazepam, chlordiazepoxide, clobazam, chloraZe rinol, colchicinc, probenecid and Sulphinpyrazone. US 7,198,800 B1 9 10 Hormones and Steroids Antidiuretics such as desmopressin, lypressin and vaso Oestrogens Such as oestradiol, oestriol, oestrone, ethiny pressin including their active derivatives or analogs. loestradiol, rnestranol, Stilboestrol, dienoestrol, epioestriol, Obstetric drugs including agents acting on the uterus Such estropipate and . as , oxytocin and gemeprost. and other progestagens Such as allyloestre Prostaglandins such as alprostadil (PGE1), prostacyclin nol, dydrgesterone, lynoestrenol, , norethyndrel, (PGI2), dinoprost (prostaglandin F2-) and misoprostol. , , , levonorg Antimicrobials estrel, medroxyprogesterone and megestrol. Antimicrobials including the cephalosporins such as such as acetate and . cephalexin, cefoxytin and cephalothin. Antioestrogens Such as tamoxien and and the 10 Penicillins such as amoxycillin, amoxycillin with clavu aromatase inhibitors, and 4-hydroxy-andros lanic acid, ampicillin, bacampicillin, benzathine penicillin, tenedione and its derivatives. benzylpenicillin, carbenicillin, cloxacillin, methicillin, and anabolic agents such as , phenetbicillin, phenoxymethylpenicillin, , , acetate, , meZlocillin, piperacillin, ticarcillin and azlocillin. , , , 15 Such as iminocycline, chlortetracycline, tet acetate, , 17-alpha-methyl-19-nortest racycline, demeclocycline, doxycycline, methaycline and osterone and 5-alpha reductase inhibitors and other -type . such as , , LY-191704 and MK-306. Aminoglycosides such as amikacin, gentamicin, kanamy such as , betamnethasone cin, , netilmicin and tobramycin. Valerate, , , dexamethasone such as amorolfine, isoconazole, clotrima 21-phosphate, , flunethasone, , Zole, econazole, miconazole, nystatin, terbinafine, bifona fluocinonide , , , Zole, amphotericin, , ketoconazole, fluconazole , , , , and flucytosine, salicylic acid, fezatione, , tolnaf hydrocortisone 17-valerate, hydrocortisone 17-butyrate, tate, tiacetin, , pyrithione and sodium pyrithione. Qui hydrocortisone 21-acetate , predniso 25 nolones such as nalidixie acid, cinoxacin, ciprofloxacin, lone, 21-phosphate, , tiamcinolone, enoxacin and norfloxacin. Sulphonamides such as phthalyl triameinolone acetonide. Sulphthiazole, Sulfadoxine, Sulphadiazine, Sulphamethizole Further examples of steroidal antiinflammatory agents for and Sulphametboxazole. use in the instant compositions include cortodoxone, fluo Sulphones Such as . racetonide, fludrocortisone, difluorSone diacetate, flurandre 30 Other miscellaneous antibiotics such as , nolone acetonide, , amcinafel, , , , erythromycin ethyl carbonate, betamethasone and its other esters, , clor erythromycin estolate, erythromycin glucepate, erythromy cortelone, , desonide, , diflupred cin ethylsuccinate, erythromycin lactobionate, roXithromy nate, flucloronide, flumethasone, flumnsolide, thucortolone, cin, lincomycin, natamycrin, nitrofurantoin, spectinomycin, fluoromehalone, fluparulone, , mepred 35 Vancomycin, aztreonam, colistin IV, , tinida nisone, methylmeprieisolone, paamethasone, cortisone Zole, and trimethopinm: 2-thiopyridine N-oxide: acctate, hydrocortisone cyclopentylpropionate, cortodox halogen compounds, particularly and iodine com one, flucetonide, fludrocottisone acetate, flurandrenolone pounds such as iodine-PVR complex and diiodohydrox acetonide, medrysone, , amcinafode, betametha youin; , ; chloroamine com Sone, , chloroprednisone acetate, 40 pounds; benylperoxide. acetate descinolone acctonide, desodnmeta Antituberculosis drugs such as ethambutol, isonizid, Sone, dichlorisonc acetate, , flucloronide, flu pyrazinamide, and clofazimine. pivalate, acetate, acetate, Antimalarials such as primaquine, pyrimethamine, chlo fluprednisolone Valerate, acetate, predniso roquine, hydroxychloroquine, quinine, mefloquine and halo lamate, prednival, hexacetonide, . 45 fantrine. and nivazol. Pituitary hormones and their active Antiviral agents such as acyclovir and acyclovir prodrugs, derivatives or analogs such as corticotrophin, thyrotropin, famciclovir, Zidovudine, didanosinc, stavudine, lamivudine, follicle stimulating hormone (FSH), luteinising hormone Zalcitabine, saquinavir, , , n-docosanol, (LH) and gonadotrophin releasing hormone (GnRH). tromantadine and idoxuridine. Hypoglycaemic agents such as insulin, chlorpropamide, 50 Anthelmintics Such as mebendazole, thiabendazole, glibenclamide, gliclazide, glipizide, tolazanide, tolbutamide niclosamide, praziquantel, pyrantel embonate and diethyl and metformin. carbamraZne. Thyroid hormones such as calcitonin, thyroxine and lio Cytotoxic agents such as , , thyronine and antithyroid agents such as carbimazole and dacarbazine, fluorouracit and its prodrugs (described, for propylthiouracil. 55 example, in International Journal of Pharmceutics 111: Other miscellaneous hormone agents such as Octreotide. 223-233 (1994)) methotrexate, procarbazine, 6-mercap Pituitary inhibitors such as . topurine and mucophenolic acid. Ovulation inducers such as clomiphene. Genitourinary System 60 Still other antimicrobial or agents which may be Diuretics such as the thiazides, related diuretics and loop used include alcohols such as ethanol, isopropanol and diuretics, bendrofluazide, chlorotwiazide, chlorthalidone, methylated spirit; cationic such as quaternary dopamine, cyclopenthiazide, hydrochlorothiazide, indapra ammonium compounds, , cetrimide, mide, mefuside, meiycholthiazide, metolaZone, quineth cetypyridinium chloride, bisdequalinium diacetate, and aZone, bumetanide, ethacrynic acid and frusemide and 65 chloride; bisbiguanides such as chlorhexidine potassium sparing diuretics, , amiloride and and its salts such as chlorhexidineacetate, and polymeric triamterene. such as PMMB; chlorine or chlorine containing US 7,198,800 B1 11 12 agents such as chloramine, sodium dichloroiseyanuate and Anti-itch agents such as capsaicin and its derivatives Such ; dyes such as acridinc derivatives, as nonivamide (Tsai, et al. Drug. Dev. Ind. Pharm., 2004): brilliant green, , magenta and malachite green; 719, (1994)). iodophores such as providone-iodine; mercurials such as agents, which are effective for the inhi chiomersal and mercurochrome; oxidising agents such as bition of axillary sweating and for the control of prickly , peracetic acid and potassium perman heat. The antiperspirant activity of agents such as methat ganate; phenoxyethanol; phenethyl alcohol; and ropine nitrate, propantheline bromide, , meth Such as chlorocresol, , cresol, chlorophenol Scopolamine bromide, and the new class of soft antiperspi (triclosane), hexachlorophane and phenol. rants, quaternary acyloxymethyl ammonium salts 10 (described, for example, by Bodor et al., J. Med. Chem., Metabolism 23:474 (1980) and also in United Kingdom Specification No Anorectic and weight reducing agents including dexfed 2010270, published 27 Jun. 1979). fluraminc, fenflurainine diethylpropion, maZndol and phen Other physiologically active peptides and proteins, Small termine. to medium-sized peptides, for example, vasopressin and Agents used in hypercalcaemia Such as calcitriol, dihy 15 human growth hormone. drotachysterol and their active derivatives or analogs. The physiologically active agent or a prodrug thereof is Respiratory System preferably present at a concentration which is soluble in the Antitussives such as ethylmorphine, delivery system, but after evaporation of solvent may pre and pholcodine. cipitate forming drug depots in the porous film. A concentration gradient is believed, without wished to be Expectorants such as acetylcysteine, bromhexine, emet bound by theory, to be the means through which biologically ine, guaiphenesin, ipecacuanha ans Saponins. agents or prodrugs thereof pass through the skin. It is Decongestants such as phenylephrine, phenylpropanola believed that the porous nature of the patch or film which mine ans pseudoephedrine. forms on the skin provides a depot like effect with foci of Bronchospasm relaxants such as ephedrine, fenoterol, 25 highly concentrated biologically active agents. The concen orciprenaline, rimiterol, salbutamol, Sodium cromoglyeate, tration gradient so formed is believed to force the agent cromoglycic acid and its prodrugs (described, for example, across the skin. A continuous delivery may result. It is also in International Journal of Pharmaceutics 7:63-75 (1980)), believed that the porous nature of the film, which allows the terbutaline, ipratropium bromide, salmeterol and theophyl passage of gases and water vapour, and avoids issues of skin line and theophylline derivatives. 30 irritation associated with films/patches applied to the skin Allergy and Immune System for transdermal application. Such as meclozine, , chiorcycliz An advantage of the compositions according to the ine, hydroxy Zine, , chlorpheniramine, present invention is that hey may disintegrate over a period , , , diphen of time so that peeling or scrubbing off of the film may be 35 unnecessary. The time frame of Such disintegration is gov hydramine, diphenyle, , , erned by the choice of the film forming agent and the degree mepyramine, , tripolidine, , diphe of interruption within the film that has been caused by nylpyraline, , terfexine, , loratidine addition to the composition of a water soluble compound. and . By selection of these components the lifespan of the skin Local anaesthetics such as bupivacaine, amethocaine, 40 patch can be varied as a design feature of the composition. lignocaine, , dibucaine, mepivacaine, prilocalne For example, the patch may disintegrate over say a twenty and etidocaine. four or forty eight hour time period. Stratum corneum lipids, such as ceramides, cholesterol In another aspect of the invention there is provided a spray and free fatty acids, for improved skin barrier repair (Man, patch transdermal drug delivery system which comprises at et al., J. Invest. Dermatol., 106(5):1096, 1996). 45 least one physiologically active agent or pro-drug thereof in Neuromuscular blocking agents such as Suxamcthonium, a water insoluble, porous, film structure containing drug alcuronium, pancuronium, atracurium, gallie, tubocurarinre depots. and vecuronium. The drug delivery system is adapted to transport the Smoking cessation agents such as , and physiologically active agent across a dermal Surface or . 50 mucosal membrane of an animal, including a human. The Insecticides and other pesticides which are suitable for device is of low toxicity to, and is exceptionally well local or systemic application. tolerated by the dermal surface or mucosal membrane of the Dermatological agents, such as vitamins A and E. Vitamin animal. Eacetate and vitamin E sorbate. The present invention also provides a method for admin Allergens for desensitization Such as house dust mite 55 istering at least one systemic or locally acting physiologi allergen. cally active agent or prodrug there of to an animal which Nutritional agents, such as vitamins, essential amino acids comprises applying an effective amount of the physiologi and essential fats. cally active agent in the form of a composition or a drug Keratolytics such as the alpha-hydroxy acids, glycolic delivery system according to the present invention. 60 Preferably the animal is a human but the invention also acid and salicylic acid. extends to the treatment of non-human animals, such as Psychicenergisers, such as 3-(2-aminopropyl)indole, companion animals (for example, dogs and cats), domestic 3-(2-aminobutyl)indole, and the like. animals, for example, cows/cattle, sheep, horses, goats, pigs Anti-acne agents such as containing isotretinoin, tretinoin and the like, and birds. and benzoyl peroxide. 65 Surprisingly, the compositions and device of the invention Anti-psoriasis agents such as containing etiretinate, enhances the absorption of active agents and prodrugs cyclosporin and calcipotriol. thereof through the skin and mucous membranes while US 7,198,800 B1 13 14 avoiding the significant pharmacological disadvantages and In one embodiment the skin delivery composition may toxicities of prior art approaches. comprise a non-aerosol spray-on skin patch composition In the compositions and drug delivery systems according compr1S1ng: to the various aspects of the invention a pharmaceutical 0.01% to 10% w/w of one or more water soluble com compounding agent, cosolvent, Surfactant, emulsifier, anti- 5 pounds oxidant, preservative, stabilizer, diluent or a mixture of two 0.01% to 10% w/w of one or more physiologically active or more of said components may be incorporated as is ingredient/s appropriate to the particular route of administration and 1% to 50% w/w of polymethacrylic acid dosage form. The amount and type of components used should be compatible with the polymer film structure. A 10 0.1% to 20% w/w of polybutylphthalate cosolvent, or other standard adjuvant such as a surfactant, 0% to 90% w/w of isopropanol may be used to maintain a physiologically active agent, or 0% to 90% w/w of acetone prodrug, thereof in a solution or Suspension at the desired ethylacetate up to 100% w/w, concentration. The pharmaceutical compounding agents can include 15 the composition forming a flexible, porous and physiologi paraffin oils, esters such as isopropyl, myristate, ethanol, cally compatible skin patch when sprayed onto skin and silicone oils and vegetable oils. These are preferably used in allowed to dry. the range of greater than 1%. Surfactants such as ethoxylated Other physiologically acceptable carriers, diluents, Sol fatty alcohols, glycerol monostearate, phosphate esters, and vents or excipients may also be included within the com other commonly used emulsifiers and Surfactants preferably 20 position, as is well known in the art of pharmaceutical in the range of 0.1% to 1% may be used, as may be formulation. preservatives such as hydroxybenzoate esters for preserva Details of such materials are provided within Max Rem tion of the compound preferably in amounts of 0.01% to ington's Pharmaceutical Sciences, 17th Edition, Mack Pub 0.5%. Typical cosolvents and adjuvants may be ethyl alco lishing Co., Easton Pa., USA, the disclosure of which is hol, , acetone, dimethyl ether and glycol 25 included herein in its entirety, by way of reference. ethers such as diethylene glycol monoethylether. These may The compositions according to the present invention may be used in amounts of 1% to 90%. be used in methods of treatment, Such as, for the treatment When a pharmaceutical compounding agent, cosolvent, of skin wounds, fungal infection, healing after plastic Sur Surfactant, emulsifier, antioxidant, preservative, stabilizer, gery, eczema, bacterial infection in or on the skin and or diluent or a mixture of two or more of said components is 30 associated with skin wounds, athlete's foot, skin ulceration, used, these must be compatible with the ability of the system burns, Scalds, insect bites, local analgesia, itching, pain, and to become touch-dry after application. other method aspects as herein described. The non-aerosol spray-on skin patch compositions Pain treated herein may be rheumatic pain (such as joint according to the invention can conveniently be applied by and muscle pain), pain associated with skin ulcers, pain means of a positive displacement metered dose hand pump, 35 associated with anal fissure and the like. preferably having a lock down device that will seal the entry Administration may be to the site of injury or condition, of air into the can. The organic solvents included within the or remote thereto. composition will serve to clean the spraying nozzle and Further aspects of the present invention will be explained prevent build up of polymer film there within. By using the in the following non-limiting Examples. metered dose pump it is possible to deliver a precise amount 40 of film onto the skin, and this in association with knowledge of the concentration of physiologically active ingredients EXAMPLES within the composition can serve to ensure that the level of Example 1 active administered is tightly controlled. Other variables that will need to be considered in the control of active ingredient 45 administration (especially in the situation where the dose A composition is prepared as follows: application is not metered) include the area of skin contacted a non-aerosol spray-on skin patch composition compris with the composition, and the length of time of skin contact. 1ng: Naturally, it will be well within the capabilities of a skilled 0.05% w/w of centrimide physician to determine the effective amount of the physi- 50 0.07% w/w of triclosane ologically active ingredient that needs to be applied, as well 0.6% w/w of chlorbutanol as the number of applications required, and alter the vari ables mentioned above in order to ensure the correct level of 10% w/w of polymethacrylic acid administration. Factors that would be apparent to a skilled 1.2% w/w of polybutylphthalate clinician Such as the height, weight, age, sex and general 55 4% w/w of isopropanol state of health of the patient concerned may also need to be 24% w/w acetone considered, in determining the correct dose for a specific ethylacetate up to 100% w/w. patient. For example, dosage ranges may include an active ingredient in the range from about 0.01 ng to 500 mg, such Example 2 as 0.01 mg to 100 mg, for example 0.1 mg to 75 mg or 1 mg 60 to 300 mg per dose. Continuous release of antimicrobial actives from the Proportions of the components, according to various applied composition of Example 1 aspects of this invention, include, but are not limited to, 1% to 50% w/w film forming agent, 0.1% to 20% w/w film Sample plasticiser agent, 0.01% to 10% w/w water soluble com- 65 One liter of the compositions according to Example 1 pound or compounds, and 30% to 90% w/w organic solvent (Spray On Antimicrobial Bandage) in a Nalgene bottle was or solvents. received for validation. The bottle was labelled “Ref. BX258 US 7,198,800 B1 15 16 Method abrasions. Effectiveness in an artificial contusion in the The procedure was based on the Australian Standards rabbit was studied. The following results were obtained. AS1157.1 and 0.2, 1998 incorporating the microbes stipu 1. The date of testing lated in the BP Preservative Efficacy Test. 13 Jun. 1999 until 23 Jul 1999 One mL of the sample was used to Saturate a membrane 5 2. The testing materials and test method pad. Once dry, the pad was then placed onto the Surface of 1) Testing animal: Rabbit. agar plates containing a lawn culture of the following 2) Testing composition: Example 1 composition. microorganisms: 3) The two artificial wounds have been made on the centre of the back of the rabbits. 10 Observations were taken after contusion on treated and non-treated animals. Medium Micro-organism Challenge population plate a) The operative method to make the artificial contusion *TSA Escherichia coi 3 x 108 Hair has been shaved on the centre part of rabbits TSA Staphylococcusatiretts 3 x 108 back, and then the intrusion of *SDA Candida albicans 3 x 106 15 3 cm made by strong abrasion to the skin with sand SDA Aspergilius niger 1 x 107 paper. (spores) b) Observation (*TSA = Tryptone Soya Agar, SDA = Sabouraud Dextrose Agar) The visible observation to the naked eye has been made on the first day, the second day, the fifth day and the Positive and negative controls were performed in parallel. 20 tenth day respectively after the operation. On the The TSA plates were incubated at 37° C. for three days tenth day the rabbit has been killed so that the and the SDA plates were incubated at 25°C. for five days. inspection of pathological tissue can be made. 3. Result Results 1) Visible Observation Where 25 The visible change of the operated part is shown in the G-Growth evident on pad Table 1 below. NG=No growth evident on pad After incubation growth was noted on the plate, pad and TABLE 1. under the pad and any Zone of inhibition was measured. 30 Observation Items 1st day 2nd day 5th day 10th day Treatment Area of operated part 3 3 3 3 with (cm) Example 1 Redness Pad G or NG: Scabbing Micro-organism Zone of Inhibition 35 Hypertrophy -- Without Area of operated part 1.7 1.7 1.3 1.O E. coi: NGO.5 mm treatment (cm) S. airetts. NGO.5 mm Redness C. albicans. NGO.6 mm Scabbing ------A. niger. NGino Zone of inhibition Hypertrophy ------40 2) The inspection of the pathological tissue of the oper Findings ated part Pathological tissue analysis is shown in Table 1. All surfaces coated with Medico Spray-On Bandage 2 prevented microbial growth on the agar in contact with the product. This was irrespective of whether the field 45 TABLE 2 WaS (a) E. coli, a Gram-negative bacterial rod Treated with Example 1 Untreated object Epidermis normal Increase (b) S. aureus, a Gram-positive bacterial coccus Papilla normal Extend (c) C. albicans, a pathogenic yeast 50 Papilla layer normal Increase (d) A. niger, a spore-bearing mould Scabbing formation Ole Exist Cell infiltration Small Big 2. A Zone of inhibition was noted in challenges (a) to (c) above, although this effect is not deemed necessary for the product; i.e—the spray-on bandage need only prevent 4. Conclusion growth in the region sprayed which covers the open 55 1) As far as the visible observation is concerned, the wound. Efficacy beyond the Zone of broken skin is untreated wound has scabbing on the first day after independent of the functional application of the product. operation. Compression from the Surrounding tissue is 3. Controls were in line with expectation, that is, uninhibited visible on the operated part. Furthermore, hypertrophy bacterial growth took place. has been continuous. 60 On the other hand, as to the wound treated with Example 3 Example 1, we were unable to observe any atrophy on the operated part due to the performance of the composition Effect of Example 1 Composition on Contusion 2) Pathological tissue analysis of the untreated wound This example shows that the composition of Example 1 is 65 shows on the operated part, as to chronic dermatitis, a transparent, antiseptic, waterproof, washable "Spray-on increase of epidermis, increase of papilla layer, and cell Bandage' having application in cuts, minor wounds and infiltration. US 7,198,800 B1 17 18 On the contrary, as far as the specimen treated with Example 1 is concerned, no significant abnormality TABLE 4-continued has been observed except for the slight cell infiltra tion. The results of the bacteriological determination Full protection of wounds as well as the regeneration of 5 Cultivation results Number normal tissue is observed with the treatment com position. Yeast g-Staphylococci is 5 Plastic surgery tissue abrasions may be treated with the Sterile after forty eight hours 30 composition. Other examples of application include bandages for the wounds to cattle and other animals. 10 The trial results indicate the composition promotes rapid TABLE 5 healing of Surface abrasions and Surgical wounds. The result of the clinical examination three The applied compositions of Example 1 effectively acts as days after treatment with Example 1 bandage. a true pseudoskin and as Such allows rapid Sub-membrane proliferation of an epithelial cellular layer. In this manner the 15 Yes No % contused surface is rapidly reepithelialised with associated Colour 6 87 7 minimisation of epithelial cellular hypertrophy and contrac Sensibility O 93 O ture. Smell 1 92 1 Humidity 22 71 24 Pus 5 88 5 Example 4 Water-repellent 90 3 97 Viscosity O 93 O A Semipermeable Wound Spray, Example 1 Bandage for Scate production 3 90 3 Dogs and Cats The example 1 spray has been used in the treatment of 25 wounds, dermatitis (eczema madidans), abscesses, furuncu CONCLUSION losis, otitis external and postoperative wounds. Before treat ment with Example 1 composition, samples from the various The use of Example 1 bandage for minor cuts and wounds conditions were taken for laboratory determination of bac has shown that it relieves the erythema in 93% of the cases teria. 30 and that it has a water-repellent effect in 97% Three days after treatment with Example 1 composition From the results obtained Example 1 bandage obviously which formed a skin patch or bandage the treated area was has a good antiseptic quality for treatment of minor cuts, evaluated for colour, sensibility, humidity and pus as well as post-operative wounds, dermatitis and abscesses. water repellent quality, adhesiveness and scale production. Ninety three animals, eighty dogs and thirteen cats, were 35 Example 5 treated with the Example 1 bandage. The objective of the study was to ascertain: Spray On Antifungal Bandage for athlete foot caused by 1. Will it be possible for the Example 1 bandage to protect Tinea spp the wound and avoid water penetration. Most common non-fatal skin are cause by 2. Will the Example 1 bandage be able to stop the irritation 40 various bacterial and fungi tinea pedis, , tinea and red erythema, characteristic of acute wounds and corporis and cutancous candida albacan. Miconazole is one eczema madidans. of the common antifungal agents against Such infections. Miconazole appears to act on cell wall and membranes, TABLE 3 inducing permeability changes that alter the ionic micromo 45 lecular composition of the affected cells. The recommended Number of animals and age distribution in the test product strength containing miconazole (for example, Dak Diagnose Number tarin by Janssen-Cillag) is 2% as powder, tincture or cream applied twice daily to the infected area. Dermatitis 13 Flegmone, adsces 7 50 The difficulty of using an antibacterial/antifungal cream, Furunculose 4 tincture or powder for tinea infection is that the Operating 55 cannot adhere to the infected area. This is particularly true Otitis externa 8 if the infection is on the foot (for example, athlete foot). This Vulnus inc., morsum 6 giving rises to unsatisfactory results and repeated infections. 55 The following example product formulation demonstrated the usefulness of the spray on patch delivery system, which TABLE 4 greatly improves the efficacy of miconazole and the likes of The results of the bacteriological determination antifungal agents. The formulation also contains Chlorbu tanol, which is a traditional anti bacterial, and anti fungal Cultivation results Number 60 agent the use of which is well documented in various g+ and g- Staphylococcits 21 pharmacopoeiae. g-Clostridium Staphylococcits 18 The spray on medicated patch adheres to surface of Haemolytic Staphylococcus 18 infected skin over a long period of time (about twenty four Proietis 2 Anahaemolytic g-Staphylococcus 3 hours) delivering active ingredients continuously to the Staphylococci is faecais 1 65 infected Surface. In addition, the spray can be used to fungal Kiebsiella 1 proof footwear to prevent further re-infections. Product strength compared to other commercial product (for US 7,198,800 B1 19 20 example, Daktarin) is halved (from 2% to 1%) and dosage Example 6 rate is also halved to daily application only (from twice daily to once daily). Spray on Betamethasone bandage for allergic skin con Spray On Antifungal Bandage for athlete foot caused by ditions, eczema and psoriasis Betamethasone is a corticos Tinea spp. teroid indicated for treatment of allergic skin disorders. The product is marketed under the trade name of BetnovateTM as cream, ointment or gel containing betamethasone 0.05% to 0.1% strength. Dosage application is up to four times daily. Formulae 10 It is a well known practice in Australian hospitals that Miconazole USP 1.0% ww. Active, antifungal after applying the BetnovateTM cream, gel or ointment, Chlorbutanol BEur. P 0.6% wiv Active, antibacterial antifungal efficacy can be improved by wrapping the area in "Glad Pheno BP.Eur. P 0.2% wiv Preservative Wrap'TM (a thin polymer film) to enhance absorption and Poly methacrylate USNF 10.0% Wiv Film fonner prolong drug contact. Polybutyl Phthalate BP/Eur. P 1.0% ww. Film softener 15 Isopropanol USP 24% Wiv Solvent The following formulation is capable of replacing the Acetone BP.Eur. P 24% Wiv Solvent “Glad Wrap' practice efficiently. Application is also reduced Ethyl Acetate USP 40.7% Wiw Solvent from up to four ties daily to once daily. Formulation also contains an effective antimicrobial agent that treat and Total 100% Wiv prevents bacterial or fungal infections in case of weeping wound or ulcers. Method of Manufacturing: Spray on Betamethasone bandage for allergic skin con Dissolve miconazole and chlorbutanol in isopropanol, ditions, eczema and psoriasis phenol, acetone and ethyl acetate. Add in Polybutyl phtha late. Add in Poly methacrylate with gentle stirring. Pack in 25 Spray apparatus. BP.Eur. P 0.12% w/v Active anti inflammatory Chlorbutano BP.Eur. P 0.6% w/v Active antimicrobial Direction for Use: agent The spray on medication adheres to skin effectively over Triolosan (Ciba Geigy 0.1% wiw Preservative 30 Irgasan DP300) twenty four hours. Spray on affected area to ensure adequate Poly methacrylate USNF 10.0% Wiv Film former cover. Used as continues release antifungal spray once daily. Polybutyl Phthalate BP/Eur. P 1.0% w/v Film softener To prevent reinfection, spray into foot ware daily during Isopropanol USP 24% Wiv Solvent Acetone BP.Eur. P 24% Wiv Solvent treatment and thereafter at least once weekly for six months. Ethyl Acetate USP 40.7% Wiv Solvent A twenty five year old female used the above spray after 35 repeatedly failed to eradicate the fugal problem on her right Total 100% ww. foot for over five years. Before application, the area was ulcerated, weeping and itchy Recommended Dosage: The miconazole?chlorbutanol spray on bandage was used 40 Apply once daily to the affected area for treatment of daily for five days. Her foot wear was fungal proofed by eczema, psoriasis and allergic skin to conditions. spraying the same product into the inside of the shoes once daily for five days. After five days, the infected area was Method of Manufacture: visibly reduced. The use of the miconazole spray was 1. Dissolve betamethasone in the mixture of solvents. Add in stopped. After two weeks the area was clear of infections (no 45 Triclosan and Chlorbutanol. longer weeping, nor cracked, nor itchy and skin healed quite 2. Add Poly butyl phthalate then Poly methacrylate with well). After the initial treatment, no incidence of reinfection gentle stirring. was reported during the next six months. 3. Pack in airtight aluminum cans and attach actuator and A fifty five year old male also used the above spray for 50 spray nozzle. five days after failure to control severe fungal problem on the right foot for over ten years. Previous Example of Use: including iodine tincture, Daktarin cream, salicylic acid A twenty three year old female who suffers both eczema ointment and NiZoral cream. and psoriasis badly since birth has used Betnovate Cream on 55 and off to relieve the skin irritation due to her condition. Her The miconazole?chlorbutanol spray on patch was used skin affliction was particularly bad during period of stress. daily for five days. The foot wear was fungal proofed by She tried the formulated Betamethasone spray on bandage spraying the same product into the inside of the shoes once for two weeks prior to her university examination and found daily for five days. After five days, the infected area was her condition is much improved. Symptomatic relieve was visibly reduced. Skin lesions starts to heal there after. The 60 achieve within forty eight hours. Relieve of itch and weep use of the miconazole?chlorbutanol spray was continued for ing due to constant Scratching was fast and effective. She another five days and then stopped. After two weeks the area only requires to use the spray once daily at night instead of was clear of infections (no longer weeping, bleeding, morning and night She can wear the betamethsone spray cracked, or itchy). After the initial treatment, no incidence of bandage to shower without having to repeat application. The reinfection was reported during the next six months. All 65 affected area heals well particularly where it is not practical footwear was fungal proof by spraying into footwear once to put a bandage on top to prevent clothes scratching on the weekly for about six months. affected area. US 7,198,800 B1 21 22 Example 7 (C) Phenethyl alcohol 2% 0.07% w/w of triclosane Spray on Mepyramine Antihistamine Adhesive Patch—a 0.6% w/w of chlorbutanol first aid treatment for burns, scalds, insect bites, 10% W/W of polymethacrylic acid and local analgesic application in all conditions character- 5 1.2% w/w of polybutylphthalate ized by intense itching or pain. 4% w/w of isopropanol Mepyramine is a well known, well tried and well used 24% w/w acetone antihistamine. Over a hundred medications contain ethylactate up to 100% w/w mepyramine as one of its major ingredients. 10 The invention claimed is: 1. A non-aerosol sprayable skin patch composition con sisting essentially of Spray on Mepyramine Antihistamine Adhesive Patch (a) 0.01% to 10% w/w of at least one water-soluble Mepyramine Maleate BP/Eur. P 2.0% wiv Active physiologically active ingredient; antihistamine 15 (b) 1% to 50% w/w of at least one substantially water Chlorbutano BP.Eur. P 0.6% w/v Active antimi crobial agent insoluble film forming agent selected from the group Triclosan (Ciba Geigy Irgasan DP300) 0.1% wiv Preservative consisting of acrylic acid, polyacrylic acid, polybutyl Poly methacrylate USNF 10.0% wiv Film former methacrylate, polymethacrylic acid, ascorbyl palmitate, Polybutyl Phthalate BP/Eur. P 1.0% w/v Film softener carbomer, cellulose acetate phthalate, hydroxyethyl Isopropanol USP 24% Wiv Solvent 2O cellulose, hydroxypropyl cellulose, hydroxypropyl Acetone BP.Eur. P 24% Wiv Solvent methylcellulose, ethyl cellulose, hydroxypropyl meth Ethyl Acetate USP 40.7% Wiv Solvent lycellulose phthalate, hypomellose phthalate, crospovi Total 100% Wiv done, cetyl alcohol, poloaxmer, polyethylene glycol, polyvinyl acetate, polyvinyl acetate phthalate, polyvi 25 nyl alcohol, and povidone; Method of Manufacture; (c) 0.1% to 20% w/w of at least one film plasticiser agent; 1. Dissolve Mepyramine maleate in the mixture of solvents. and Add in Triclosan and Chlorbutanol. (d) 30% to 90% w/w of at least one volatile organic 2. Add Poly butyl phthalate then Poly methacrylate with 30 Solvent, gentle stirring. wherein said composition forms a flexible, porous and 3. Pack in airtight aluminum cans and attach actuator and physiologically compatible skin patch when sprayed onto spray nozzle. skin and is allowed to dry, wherein said patch disintegrates A group of boy Scouts and parent used the Spray on progressively over a 24–48 hour time period. Mepyramine Antihistamine Adhesive Patch during recent 2. The composition according to claim 1, wherein said at camping. General observation from adults indicated that the 35 least one physiologically active ingredient is an antimicro formulation relieved symptoms of insect bites fast and bial agent and/or an antifungal agent. efficiently. In one occasion, a twelve year old boy Scout was 3. The composition according to claim 2, wherein said mildly burned by camp fire on the back of the hand while antimicrobial agent is a quaternary ammonium compound. roasting marshmallow. After one application, pain was 40 4. The composition according to claim 3, wherein said quickly relieved and no blister formed. It was indicated that quaternary ammonium compound is selected from the group the Mepyramine antihistmine spray on bandage also formed consisting of cetrimide, alkylaryltrialkylammonium chlo a protective cover for the would and was waterproof. The ride, alkylaryltrimethylammonium chloride, amantanium bandage remained on skin even after Swimming and self bromide, benzalkonium chloride, benzethonium chloride, disintegrated in about twenty-four hours. 45 benzododecinium bromide, cetalkonium chloride, cethexo nium bromide, centrimonium bromine, and cetyldimethyl Example 8 ethylammonium bromide. 5. The composition according to claim 4, wherein said Further compositions are prepared as follows: quaternary ammonium compound is cetrimide. (A) Chlorhexidine acetate 0.5% w/w 50 6. The composition according to claim 2, wherein said 0.07% w/w of triclosane water-soluble compound is a mixture of a water-soluble antimicrobial agent and a water-soluble antifungal agent. 0.6% w/w of chlorbutanol 7. The compound according to claim 6, wherein said 10% w/w of polymethacrylic acid antimicrobial agent is a quaternary ammonium compound 1.2% w/w of polybutylphthalate 55 and said antifungal agent is selected from the group con 4% w/w of isopropanol sisting of chlorbutanol, phenol, Salicylic acids, arisoran, 24% w/w acetone amoralfine, amphotericin, bifonazole, nitrate, ethylacetate up to 100% W/W chlormidazole, clotrimazole, croconazole, econazole, enil (B) Phenoxyethanol 2% w/w conazole, fenticonazole, fluconazole, , isocona 0.07% w/w of triclosane 60 Zole, itraconazole, ketoconazole, lanoconazole, miconazole, 0.6% w/w of chlorbutanol omoconazole, Saperconazole, , Sulconazole, terconazole, tioconazole, benzoyl disulphide, bromochloro 10% w/w of polymethacrylic acid salicylanilide, buclosamide, , candicidicaprylic 1.2% w/w of polybutylphthalate acid, chlorphenesin, ciclopiroX olamine, cillofungin, fenti 4% w/w of isopropanol 65 clor, flucytosine, criseofulvin, , haloprogin, 24% w/w acetone hamycin, hydroxyStilbamidine, isethionate, loflucarban, ethylacetate up to 100% w/w mepartricin, natamycin, nifuroxime, p-nitrophenol, nystatin, US 7,198,800 B1 23 24 pentamycin, propionic acid, protiofate, pyrrolnitrin, Sulben (d) 0% to 90% w/w of isopropanol: tine, terbinafine, , tolnaftate, triacetin, and unde (e) 0% to 90% w/w of acetone; and cenoic acid. (f) ethylacetate up to 100% w/w, 8. The compound according to claim 7, wherein said wherein said composition forms a flexible, porous and antifungal agent is chlorbutanol. physiologically compatible skin patch when sprayed onto 9. The composition according to claim 1, wherein said at skin and is allowed to dry, and wherein said patch disinte least one physiologically active ingredient is selected from grates progressively over a 24–48 hour time period. the group consisting of an antiseptic, an antiparasitic, a 15. The composition according to claim 14, consisting nicotine, a cortico , a pain relieving agent, a cardiac essentially of: dilater, a cardiac stimulant, an antihistamine, an anti-inflam 10 (a) 0.05% w/w of cetrimide, matory, an anti blood clotting agent, a growth hormone, a (b) 0.07% w/w of triclosan, , a drug commonly used for diseases in the (c) 0.6% w/w of chlorbutanol, alimentary system, central nervous system, musculoskeletal (d) 10% w/w of polymethacrylic acid, system, genitourinary system allergy or immune system, and (e) 1.2% w/w of polybutylphthalate, a biologically active peptide or protein. 15 10. The composition according to claim 9, wherein said at (f) 4% w/w of isopropanol, least one physiologically active ingredient is triclosan. (g) 24% w/w of acetone, and 11. The composition according to claim 1, wherein the (h) ethylacetate up to 100% w/w. film forming agent is selected from the group consisting of 16. A method of improving wound healing or adminis polymethacrylic acid, polybutyl methacrylate and poly tering a physiologically active ingredient to a patient com acrylic acid. prising spraying on to a wound or on to skin of a patient in 12. The composition according to claim 1, wherein said need thereof, an effective amount of a composition accord film plasticiser agent is polybutylphthalate. ing to claim 1. 13. The composition according to claim 1, wherein said 17. A method for the treatment of skin wounds, fungal organic solvent is selected from the group consisting of 25 infections, eczema, bacterial infections in or on the skin isopropanol, acetone and ethylacetate. and/or associated with skin wounds, athlete's foot, skin 14. A non-aerosol sprayable skin patch composition con ulceration, burns, Scalds, insect bites, allergic skin diseases, sisting essentially of psoriasis, itching and pain, which comprises spraying on to (a) 0.01% to 10% w/w of at least one water-soluble skin in need of Such treatment a composition according to physiologically active ingredient; 30 claim 1. (b) 1% to 50% w/w of polymethacrylic acid; (c) 0.1% to 20% w/w of polybutylphthalate: