US 20070231396A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0231396 A1 Ray (43) Pub. Date: Oct. 4, 2007

(54) SPRAY FORMULATION Publication Classification (51) Int. Cl. A 6LX 36/899 (2006.01) A6IR 36/47 (2006.01) (76) Inventor: Charles D. Ray, Santa Barbara, CA A6II 3/56 (2006.01) (US) A6II 3/545 (2006.01) A 6LX 9/50 (2006.01) (52) U.S. Cl...... 424/490; 424/731; 424/750; 514/200: 514/179 Correspondence Address: DICKE, BILLIG & CZAJA FIFTH STREET TOWERS (57) ABSTRACT 100 SOUTH FIFTH STREET, SUITE 2250 MINNEAPOLIS, MN 55402 (US) Formulations for delivery of a pharmaceutical agent include a thixotropic agent. The pharmaceutical agent may be slowly released from a hydrogel or microcapsule in the spray formulation. Various formulations of reasonable thixotropic (21) Appl. No.: 11/392.403 and hydrogel media are useful. Droplet size and thixotropy determine the distribution of the material along body sur faces and tissues such as the respiratory passages, and limit the displacement, running or dripping of the sprayed (22) Filed: Mar. 29, 2006 medium from its intended sites. US 2007/0231396 A1 Oct. 4, 2007

MEDCATION SPRAY FORMULATION would be welcomed by both manufacturers of health care products and consumers of Such products. FIELD OF THE INVENTION SUMMARY OF THE INVENTION 0001. The invention relates to thixotropic formulations for spray media delivery to body Surfaces and tissues such 0006 The present invention provides a thixotropic fluid as nasopharyngeal passages. The thixotropic effect allows media composition that is capable of being sprayed onto a for good fluidity during spraying but prevents running or patient's tissue (e.g., skin, wound, nasal cavity/mucous drippage loss of the medication from the body Surface so membrane), and generally consists of a primary carrier sprayed. Additionally, a suitable hydrogel or microencapsu component (or 'suspended medium') and a thixotropic lation is provided into which a medication is carried and agent. slowly released into absorptive tissues receiving the spray. 0007 Specifically, the invention provides an aqueous fluid Suspension for delivery of a pharmaceutical agent, said 0002. 2. Description of the Relevant Art Suspension having a sheared viscosity and an unsheared 0003 Atomization or jet spray of fluid media to deliver Viscosity, wherein said sheared viscosity is less than about various compounds, such as emollients, thin creams, oils, 200 centipoise, the Suspension being sprayable when aqueous or powdered Substances or medication to tissues, sheared, and wherein said unsheared viscosity is at least particularly within the nasopharyngeal mucosa or other body about 5 times greater than said sheared viscosity, and the Surfaces, have been known and practiced for centuries. Suspension returns to its unsheared viscosity within about 20 Various means to deliver a burst or steady flow of media by seconds after shearing, the Suspension comprising said phar a repelling agent, usually air, as by blowing through a maceutical agent and a carrier therefore, said carrier com hollow reed or using a compressible bulb or by a pressurized prising a thixotropic agent. compound or gas, are well described in existing art. The 0008. In one embodiment, the invention provides an expelled material may be atomized, fluidized or ejected in a aqueous fluid Suspension for delivery of a pharmaceutical stream. In order to obtain an optimized dispensing of the agent, said Suspension having a sheared viscosity and an medium to be sprayed, several interdependent functions unsheared Viscosity, wherein said sheared viscosity is less must be considered. These are related to the expulsion force, than about 200 centipoise, the Suspension being sprayable the nozzle or spray jet and the medium to be sprayed. For the when sheared, and wherein said unsheared Viscosity is spraying to continue with satisfaction, the following must be greater than about 400 centipoise said suspension compris optimized: applied ejection pressure, Velocity, fluidity (vis ing said pharmaceutical agent and a carrier therefore which cosity), turbulence and Surface tension of the Suspending includes a thixotropic agent, medium, as well as characteristics of the dissolved or Suspended particulates in the expellant medium. Also impor 0009. In another embodiment, the thixotropic agent com tant is the structure of the spray nozzle, or ventura. In the prises a hydrogel. case of plain or medicated Substances sprayed along the 0010. It will be recognized that the suspension in accor nasopharyngeal passages, additional parameters of conse dance with the present invention may have a variety of quence are the Substance particle or droplet size, the atom different carrier formulations, each specifically selected to izer nozzle and Suspension medium. They must all be generate a desired end effect in the patient. Thus, the present optimized relative to the delivery means, usually a hand invention is in no way limited to a particular carrier formu operated rubber bulb. Optimizing the media, medication lation (or desired end use), although in Some embodiments Suspension and dispensing device must be performed by a described below, a hydrogel material is included with the trial and error method. carrier component. Rather, the present invention is premised 0004 Further, for many applications the fluidity (viscos upon the provision of the thixotropic agent in combination ity) of the medium must be relatively low to permit easy with the primary carrier component to achieve the overall spray atomizing or dispersal as micro particles. After the reduced viscosity upon spraying to the targeted tissue, medium is in place, a preferred medium should not run down thereby minimizing undesired 'dripping of the sprayed from or drip out or off of the sprayed surface(s). These two compound from the targeted tissue. characteristics (spray fluidity and non-drip) are found in 0011. As used herein, these terms have the defined mean non-Newtonian thixotropic fluids. A Newtonian fluid shows ings. a viscosity that is directly related to the velocity of motion 0012 1. The term “thixotropic agent’ means an agent of the fluid. Water, air and most aqueous solutions typify which causes a Suspension to exhibit a consistency that such fluids. Thixotropic fluids show a viscosity that falls is viscous at rest, but fluid when agitated. Such a with increased velocity, becoming thicker when the fluid material has high Static shear strength and low dynamic medium is quiet or still. Unfortunately, much of the usual shear strength simultaneously. sprayed, watery material will coalesce and drain by gravity, especially when further diluted into the mucous, serous fluid 0013 2. The term “pharmaceutical agent’ means an or sweat present on body surfaces. The thixotropic effect agent which has a therapeutic or palliative effect. Such agent is not restricted to those agents requiring a reduces Such coalescence and drainage. prescription for availability. 0005. It would be very desirable to provide a means to dispense a pharmaceutical agent under low pressure using a DETAILED DESCRIPTION OF THE medium that has a low sheared viscosity, and which, after INVENTION spraying and deposition on the body Surface, returns to the 0014. The aqueous suspensions of the invention com unsheared viscosity and does not drip or run. Such a product prises a pharmaceutical agent in particle form, a carrier for US 2007/0231396 A1 Oct. 4, 2007 the pharmaceutical agent which includes a thixotropic agent 0020 Examples of useful vaccines include but are not and may also include bioacceptable additional ingredients limited to those for HIV, flue, avian flu, polio, rubella and and adjuvants. Such as preservatives, emollients and the like. rubeola. 0.015 Individual spray components may vary widely and 0021 Examples of useful diuretics include furosemide, particular pharmaceutical formulations are not the Subject of bumetanide, torsemide, ethacrynic acid, thiazides such as this invention. Any particulate pharmaceutical agent which clorothiazide, hydrochlorothiazide, hydrofluormethazide, is capable of being Suspended in an aqueous Suspension may bendroflumethazide, nethyclothiazide, metolazone, polythi be used in the Suspension. The pharmaceutical agents are azide, QuinethaZone and tichlormethiazide, potassium spar present in amounts effective to provide the desired treatment ing diuretics such as spironolactone, triamterene, and to the body Surfaces and/or tissues. Typical Suspensions will amiloride, and others, contain pharmaceutical agents in amounts of from about 0022. Examples of useful antihistamines include but are 0.001 weight percent up to about 20 weight percent, more not limited to ethylenediamines such as pyrilamine and typically from about 0.001 weight percent to about 10 antazoline, ethanolamines Such as diphenhydramine and weight percent or less. doxylamine, alkylamines such as pheniramine, chlorphe 0016 Numerous classes of useful pharmaceutical agents niramine, dexclorpheniramine, and brompehmiramine, pip exist. Useful agents include but are not limited to, erazines such as hydroxy Zine, , and , agents for pain relief Such as opiods and non-steroidal such as cyproheptidine, azatadine, and promethaZ anti-inflammatory agents, local anesthetics, antibiotics, hor ine, H1-receptor antagonists such as loratidine, fexofena mones, steroids such as soluble cortisones, antihistamines, dine, and other antihistamines known to the medical arts. diruretics, vaccines and bone loss prevention agents. While 0023 To prevent degradation of the pharmaceutical some examples are listed herein, one skilled in the art will agent, one or more bioacceptable antioxidants can also be be aware of many more Suitable pharmaceutical agents for included. Useful antioxidants include sodium disulfate, use in the suspensions which are currently available or will ascorbic acid, sodium ascorbate, Sodium thiosulfate and the become available when developed. like. When present, the antimicrobial agent typical com 0017 Examples of suitable include but are not prises from about 0.001 weight percent to about 1 weight limited to , acetaminophen, acetaminosalol, percent of the formulation. , acetylsalicylsalicylic acid, , almino 0024 For bio-stability of the suspension, an antimicro profen, , aluminum bis(acetylsalicylate), aminoclo bial agent may be included in the formulation so long as it rthenoxazin, aminopyrine, ammonium salicylate, antipyrine, is bioacceptable. Examples of Such agents include quater antipyrine salicylate, antrafenine, apaZone, , benox nary ammonium compounds such as bezalkonium chloride, aprofen, , bernoprofen, calcium acetylsali mercurial agents such as thimerosal, alcohols such as benzyl cyate, , , , fluprodu , esters of parabenzoic acids, and other antimicrobial Zone, , imidazole Salicylate, , agents. When present, the antimicrobial agent typical com , , , talniflumate, , prises from about 0.001 weight percent to about 1 weight , , and other analgesics known in the percent of the formulation. medical arts. 0025 Dispersing agents such as fatty alcohols and esters 00.18 Examples of useful antibiotics include but are not may also be present in the formulation Such as polyoxyeth limited to, third generation cephalosporins such as cefotax ylene oleates, commercially available under Such names as ine, moxolactam, cefoperazon, ceftizoxime, ceftazidime, PolysorbateTM 80. ceftriaxone, cefitofur, and cefixime, penicillins such as amdinocillin, amoxicillin, bacampicillin, benzylpenicillinic 0026. Typical formulations for contact with body tissues acid, benzyl penicillin sodium, penicillin 0, penicillin Vand and mucous membranes also may include some or all of the derivatives thereof, macrollides Such as eriythromycin, and following: propylene glycol, polyethylene glycol, Sodium derivates, dirithromycin, clarithromysine, and azithromycin, phosphate monobasic, water, hydroxyethyl cellulose, polypeptides Such as amphomycin, bacitracin, and capreo Sodium chloride and a buffering agent or Sodium hydroxide mycin, tetracyclines Such as apicycline, clomocycline, clo or hydrochloric acid to adjust the pH. rtetrocycline and the like, 2,4-diaminopyrimidines Such as 0027. The compositions may further include flavoring brodimoprim, quinolones and analogs thereof Such as cino agents and Sweetening agents including but not limited to, Xacin, , clinafloxacin, and flumequine, Sulfones oil of peppermint, spearmint, wintergreen, clove, eucalyp Such as glucosulfone sodium, and other antibiotics known in tus, cinnamon, lemon, lime and orange, cherry, Sucrose, the medical arts. lactose, maltose, Sorbitol. Xylitol, Sodium cyclamate, sac 0019. Examples of useful non-steroidal anti-inflamma charine, and the like. tory agents include, but are not limited to, aminoarylcar 0028. Formulations of the final thixotropic fluid media boxylic acid derivatives such as enfemamic acid, flufenamic may also contain additional mixtures of Such adjuvants as a acid, isosnixin, , ferofenamate, , clopi food-grade vegetable oil, canola or safflower, dispersed in a rac, , and the like, arylbutryic acid derivatives, mixture of a Suitable fumed silica compounded to moisturize arylbutryic acid derivatives, arylpropionic acid derivatives, the nasopharynx. Subject to drying. In this situation, the Such as fenoprofen, ibuprofen, indoprofen, ketoprofen, fumed silica also acts as an emulsifying agent for the oxaporzin, and the like, derivatives oil-water mixture. The addition of a medication may be Such as aspirin, phenyl salicylate, acetylsalicylate, and the combined together with a suitable hydrogel for slow release like. of the medication into the sprayed body Surface. Impor US 2007/0231396 A1 Oct. 4, 2007

tantly, as the resultant compound is sprayed through a molecular barbs fail to hinder the motion and the viscosity calibration system as disclosed here or a standard manually declines. The characteristic thixotropy achieved is related to operated spray bottle for nasal applications, droplets in the concentration of the fumed silica, the inherent viscosity of 50-200LL range should be produced such that they will the fluid medium, the velocity of fluidic displacement, remain on the mucosa of the nasopharynx and not pass into external forces such as gravity, Surface tension and capil the bronchi. larity and pH of the medium, as well as the surface to which the medium is applied. Thixotropy increases with increasing 0029 Water is also present in the suspension, preferably acidity (falling pH). Most body surfaces, however, including purified water, such as distilled water, deoinized water, and mucous membranes, are at nearly neutral pH. A typical the like. The amount of water present in the final suspension formulation for use in the nasopharyngeal passages might may be from 10 weight percent to about 98 weight percent contain 0.25-1% fumed silica, by weight. When applied to of the formulation. the skin, the formulation may contain 1-2% fumed silica. 0030 Approximate particle sizes useful in suspensions of For application to exposed body parts, the formulation may the invention (references: Stanford Research Inst. Journal contain 0.5-1.5% fumed silica. Fumed silica is commercially Vol. 5, 3 Quarter, 1961 and Ray, CD: Medical Engineer available under such trademarks as Cab-o-Sil.R from Cabot ing, Year Book Medical Publishers, 1974 p1213) include: Corporation, and Aerosil R) from DeGussa. Smoke dusts and fumes=0.01u to 100LL (microns or 0033. A number of water-soluble hydrogels may be used micrometers) in diameter. Sprays, from 10LL upwards to in certain preferred formulations of a novel medium. Gela 1000LL (1 mm). Nebulizer droplets, between 1L and 20L tins, agars and other cellulosics, e.g., organic polysaccha (about the size of a small human hair). The preferred droplet rides; inorganic polymers (polyvinyl chloride, polyacryloni size should range around 1L for medication to be carried by trile, ethylene oxide, and certain water-soluble waxes) may inhalation into the bronchi and lung bed, about 10L to halt be used. A typical formulation for use on or in body surfaces in the pharynx and bronchi and 10L to 100LL that will lodge may consist of a water-soluble hydrogel, e.g., polyacryloni in nasal passages and nasopharynx. For an open tissue trile in an aqueous Suspension of 1-5%, by weight. In that the wound applications or for most lubricant or paint sprays, mutual presence of various components as above indicated droplets ranging upwards to 500LL would be preferable. as well as both fumed silica and a hydrogel will exert Highly viscous media or most organic gels are insufficiently combined influences on the real and apparent viscosity, the fluid to be easily sprayed and then achieve the preferred combinations must be optimized, which can be performed higher viscosity on tissue contact. The more Newtonian or only by trial and error or a spray calibration device as watery the medium, the easier it is to be sprayed. (Bulletin disclosed in a parallel application. Cab-O-Sil.R Properties and Functions, Cabot Corp. 9-2005, 8 pp.). While thixotropy can be found in certain gels it is 0034. In that an optimization process for mixture control more particularly characteristic of other synthetic sub is required, precise singular or plural thixotropic formula stances, such as fumed silica which can be added to New tions need not be recited in this application. One skilled in tonian fluids to achieve thixotropy. the art will be able to perform controlled calibration tests on individual formulations in order to optimize a specific 0.031) Another desirable attribute for optimal delivery of compounded thixotropic medium. In addition, trial and error the pharmaceutical agent and adjuvants by means of an experimentation can be employed for medium optimization. atomizer or pump sprayer would be the use of a suspension In keeping with the above, typical formulations are moder medium composed in part by a hydrogel. Hydrogels and ately but not precisely detailed herein. microencapsulated compounds are successfully used to con trollably release contained or dissolved medication. The EXAMPLE OF USE medication is dissolved and in part bonded within the complex of the hydrogel, and the medication may be in the 0035. When applied to the nasopharyngeal tracts, the form of a microencapsulation, then slowly dissolved or preferred, optimized formulation containing the prescribed leached out at a rate determined by characteristics of the or non-prescription materials (such as a simple medication, the hydrogel or coating of the microcapsules. moistening agent or an anti-drying oil) is loaded into an These characteristics are selectable, depending on the nature optimized atomizer and the bulb of the atomizer is firmly and formulation of the hydrogel and microcapsules, as part Squeezed in the upright direction into the nares, dispensing of the pharmaceutical manufacturing art. Appropriate ones the medium. The user may be instructed to inhale (or not, of these agents may release hormones, various vascular with or without the mouth open) during this maneuver. For active medication, vaccines and other drugs that are readily application on Surgically exposed body Surfaces (such as absorbed through the nasal membranes or other body sur where an anti-inflammatory drug, e.g., cortisone or local faces. Fumed silica is FDA approved for use in foods and anesthetic may be applied prior to tissue closure, or another cosmetics. Some formulations for use on internal body parts agent, such as a protecting film, oil or polymer, may be may require additional study of bioacceptance. applied), a sterile atomizer and contained medium would be used. The atomizer may require further optimization for use 0032. As indicated above, the compounded material with in the horizontal plane or when inverted over the exposed the thixotropic agent increases the mutual molecular holding tissues. strength (viscosity) when the fluid to which it is added is essentially non-moving or slowly moving. Fumed silica 0036) Although specific and general embodiments have exhibits this effect due to its peculiar molecular configura been described herein, it will be appreciated by those of tion having a great plurality of side projections that act in ordinary skill in the art that a variety of alternate and/or molecular dimensions as barbs or catching Surfaces. As the equivalent implementations may be substituted for the spe fluid is more rapidly moved through the atomizer nozzle, the cific embodiments described without departing from the US 2007/0231396 A1 Oct. 4, 2007

Scope of the present invention. This application is intended 10. An aqueous fluid suspension for delivery of a phar to cover any adaptations or variations of the specific maceutical agent, said Suspension having a sheared viscosity embodiments discussed herein. Therefore, it is intended that and an unsheared viscosity, wherein said sheared viscosity is this invention be limited only by the claims and the equiva less than about 200 centipoise, the Suspension being spray lents thereof. able when sheared, and wherein said unsheared viscosity is What is claimed is: at least about 5 times greater than said sheared viscosity, and 1. An aqueous fluid Suspension for delivery of a pharma the Suspension returns to its unsheared viscosity within ceutical agent, said Suspension having a sheared viscosity about 20 seconds after shearing, the Suspension comprising and an unsheared viscosity, wherein said sheared viscosity is said pharmaceutical agent and a carrier therefore, said less than about 200 centipoise, the Suspension being spray carrier comprising a thixotropic agent. able when sheared, and wherein said unsheared viscosity is 11. The composition of claim 10 wherein said aqueous greater than about 400 centipoise, said Suspension compris Suspension is delivered in droplets having an average droplet ing said pharmaceutical agent and a carrier therefor, said size of from about 10 microns to about 100 microns. carrier comprising a thixotropic agent. 12. The composition of claim 10, wherein the thixotropic 2. The composition of claim 1 wherein said aqueous agent includes fumed silica. Suspension is delivered in droplets having an average droplet 13. The composition of claim 1 wherein said carrier is a size of from about 10 microns to about 100 microns. hydrogel. 3. The composition of claim 1, wherein the thixotropic 14. The composition of claim 13 wherein said hydrogel agent includes fumed silica. encapsulates said pharmaceutical agent. 4. The composition of claim 1 wherein said carrier is a 15. The suspension of claim 13 wherein said hydrogel hydrogel. comprises water and at least one hydrophilic polymer. 5. The composition of claim 4 wherein said hydrogel 16. The composition of claim 10 wherein said pharma encapsulates said pharmaceutical agent. ceutical agent is selected from the group consisting of 6. The suspension of claim 3 wherein said hydrogel antibiotics, hormones, Soluble cortisones, antihistamines, comprises water and at least one hydrophilic polymer. diruretics, vaccines and bone loss prevention agents. 7. The composition of claim 1 wherein said pharmaceu 17. The suspension of claim 16 wherein the pharmaceu tical agent is selected from the group consisting of pain relief tical agent is selected from the group consisting of third agents, antibiotics, hormones, soluble cortisones, antihista generation cephalosporins, soluble cortisones, and antihis mines, diruretics, vaccines and bone loss prevention agents. tamines. 8. The suspension of claim 5 wherein the pharmaceutical 18. The suspension of claim 10 wherein said suspension agent is selected from the group consisting of third genera further comprises an emollient and Surface evaporation tion cephalosporins, soluble cortisones, and antihistamines. retardant comprising an inert bioacceptable oil. 9. The suspension of claim 1 wherein said suspension 19. The suspension of claim 18 wherein said inert bioac further comprises an emollient and Surface evaporation ceptable oil is selected from the group consisting of veg retardant comprising an inert bioacceptable oil selected from etable oil, canola oil, sesame oil and corn oil. the group consisting of vegetable oil, canola oil, sesame oil and corn oil.