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US 20080153885A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0153885 A1 Meadows et al. (43) Pub. Date: Jun. 26, 2008

(54) PHARMACEUTICAL COMPOSITIONS AND (22) Filed: Dec. 18, 2007 METHOD FOR TREATING INFLAMMATION O O IN CATTLE AND OTHER ANIMALS Related U.S. Application Data (60) Provisional application No. 60/870,907, filed on Dec. (76) Inventors: Cheyney Meadows, Peapack, NJ 20, 2006. (US); Keith A. Freehauf, Stockton, Publication Classification NJ (US); Robert D. Simmons, Martinsville, NJ (US); Allan J. (51) Int. Cl. Weingarten, Westfield, NJ (US) A6II 3/44 (2006.01) A6IP 29/00 (2006.01) Correspondence Address: (52) U.S. Cl...... S14/352 SCHERING-PLOUGH CORPORATION (57) ABSTRACT PATENT DEPARTMENT (K-6-1, 1990) 2000 GALLOPNGHILL ROAD Novel transdermal preparations combining a non-steroidal KENILWORTH NOTO33-0530 anti-inflammatory drug (NSAID) such as flunixin, are dis 9 closed. Methods for using and administering Such prepara tion in the treatment of inflammatory conditions in bovines, (21) Appl. No.: 11/959,185 including bovine respiratory disease, are also disclosed.

Mean Plasma Concentration for Transdermal Fiumixin 1 mL/20 kg (100 mg/mL (G. 5 mg/kg) and IV BANAMINE(E) 1 mL/22.7 kg (50 mg/mL G 2.2 mg/kg) 5000

4OOO | it -S-TRANSDERMAL------'-'."-"-" "-"-----"""v"''''''-----'------...... ------...... FLUNIXIN (100 mg/mL G5 mg/kg) 3000 | -- BANAMINEG (50 mg/mL a 2.2 mg/kg) room------...-----...-...------...--......

Patent Application Publication Jun. 26, 2008 Sheet 1 of 5 US 2008/O153885 A1

Mean Plasma Concentration for Transdermal Fiumixin 1 mL/20 kg (100 mg/mL (G. 5 mg/kg) and IV BANAMINE(E) 1 mL/22.7 kg (50 mg/mL (g 2.2 mg/kg) 5000

-S-TRANSDERMAL FLUNIXN (100 mg/mL (G. 5 mg/kg) -)- BANAMINEE (50 mg/mL a 2.2 mg/kg) ---...-...--...--...---...------. ---

O 6 2 18 24 3O 36 42 48 Patent Application Publication Jun. 26, 2008 Sheet 2 of 5 US 2008/O153885 A1

Mean (+ 1 SD) Plasma Profile Following Dosing of transdernal Fiunixin Batch 84675-10 (100 mg/mL (G. 5 mg/kg) - Formulation of Example 3 - Banamine M (2.2 mg/kg) - Banamine SC (2.2 mg/kg) 234OOO OOOO OO

O 6 12 18 24 Time Post-Dosing (hrs)

FG 2 Patent Application Publication Jun. 26, 2008 Sheet 3 of 5 US 2008/0153885 A1

Mean Fiumixin Plasma Concentration, Transdermai Fiumixin (50 mg/mL) dosed at 5 mg/kg

s "-Formulation With Menthol and Xylene 4000 -- Control 1 (Menthol only) -ö - Control 2 (D-imonene, no Menthol) E ------, -a-...------...... m. ------...... --...---- t : st 3000 : c C () E 2000 - CA c . 1000

Time Post-Dose (hrs)

F.G. 3 Patent Application Publication Jun. 26, 2008 Sheet 4 of 5 US 2008/0153885 A1

Comparison of Mean Change ( 1 SD) in Temperature Across Dose Groups O mg/kg 2.5 mg/kg 5 mg/kg

D Mean 6-hour temp : -3 5 C a r 9 4. O Dose Group (mg/kg transdermal flunixin)

FG. 4 Patent Application Publication Jun. 26, 2008 Sheet 5 of 5 US 2008/0153885 A1

Mean (+ 1 SD) Funixin Plasma Concentration Following Transdermat Dosing (G 2.5 mg/kg (1 mL/40 kg)

0 ------O 6 12 8 24 Time Post-Dosing (hr)

F.G. 5 US 2008/O153885 A1 Jun. 26, 2008

PHARMACEUTICAL COMPOSITIONS AND inflammatory process, characterized by warmth, pain, red METHOD FOR TREATING INFLAMMATION ness, Swelling, and impaired function. The affected animal IN CATTLE AND OTHER ANIMALS often develops a fever and eats and drinks less. There is a transient decrease in milk production during the acute inflam matory stage, and Subsequent milk yield for the remainder of 0001. This application claims the benefit of U.S. Provi the lactation is reduced as a result of residual inflammatory sional Application No. 60/870,907, filed Dec. 20, 2006 damage. 0008. In addition to cattle, other species are similarly sus FIELD OF THE INVENTION ceptible to short-term and long-term effects of inflammatory episodes induced by a variety of causes. Regardless of species 0002 The present invention relates to compositions and or causative agent, the damage brought about by inflamma methods for the treatment of inflammation in animals. More tion evolves as neutrophils and other inflammatory cells particularly, the invention relates to transdermal administra destroy affected tissues. As cell membranes are damaged, tion of a non-steroidal anti-inflammatory drug (NSAID) in is released. Arachidonic acid is the Substrate animals. for the formation of various and other eicosanoids. The release of these biologically active sub BACKGROUND OF THE INVENTION stances is critical to driving the inflammatory response that 0003 All patents, applications, publications, test meth results in additional inflammatory damage and lesions. Non ods, and other materials cited herein are incorporated by steroidal anti-inflammatory drugs (NSAIDs) effectively reference. modulate inflammation by disrupting the arachidonic acid 0004 Inflammation is a process that occurs in response to cascade. injury or other abnormal stimulation by physical, chemical, 0009 Use of NSAIDs is a cornerstone of management of or biological agents, with the purpose of helping to overcome inflammatory processes in human and Veterinary medicine. the abnormal stimulus. Inflammation involves local tissue Regardless of the species or organ system affected or the reactions and morphologic changes, destruction or removal cause, pharmacologic modulation of inflammation offers of injurious material, and the initiation of repair and/or heal important quality of life benefits to painful or febrile animals, ing. Cardinal signs of active inflammation include redness, allowing the affected animal to eat and drink and thus increase heat, Swelling, pain, and reduction or loss of function; these the potential for recovery. Furthermore, use of NSAIDs helps signs can present locally and/or systemically. to reduce excessive damage that results in long-term reduc 0005 While the purpose of an inflammatory response is to tion of functionality, thus bringing economic benefits to live help the host overcome an abnormal stimulus, inflammatory stock producers. episodes can have deleterious effects. In the short-term, 0010 Flunixin megiumine is the active ingredient in febrile or painful animals may have reduced feed and water FINADYNER) and BANAMINER) (both available from intake, which can create the risk of developing problems Schering-Plough Animal Health Corporation). It has related to a negative energy balance or dehydration. Further emerged as one of the leading NSAIDs in large animal vet more, some inflammatory episodes can leave long-lasting erinary medicine and is a first choice NSAID for adjunctive residual damage, Scarring, and reduced functionality. therapy of BRD and mastitis in cattle. Flumixin 0006 For example, bovine respiratory disease (BRD) has been studied extensively in regard to its use in conjunction occurs in both dairy and beef cattle and is one of the leading with antibiotics for the treatment of BRD and mastitis. causes of economic loss to the cattle industry throughout the 0011. Both flunixin meglumine and flunixin base both world. Economic losses are attributable to excessive mortal have very poor lipid solubility. Traditionally, a compound ity, treatment and prevention costs, and decreased productiv needs to have a moderate degree of lipid solubility in order to ity—dairy cattle with clinical or sub-clinical BRD do not gain be delivered across the lipid layers of the skin. Because of the weight or produce milk as well as healthy animals, and beef undesirable solubility characteristics of flunixin meglumine, cattle with BRD gain less weight, have reduced feed effi it presents challenges regarding formulating it into an effec ciency and often produce a lower grade carcass at slaughter. A tive transdermal liquid preparation. direct correlation between pulmonary lesions observed at 0012 Flunixin meglumine is currently formulated for slaughter and reduced weight gains has been established in intravenous injection in cattle using a syringe and needle, cattle with sub-clinical BRD infections. The etiologic agents which introduces some challenges. Needles present chal of BRD are bacterial organisms such as Mannheimia lenges with respect to accumulation and disposal of sharp haemolytica, Pasteurella multocida and Histophilus somni. biowaste material, needle Stick hazards for human handlers, However, in BRD infections, the pulmonary damage that and an additional discomfort for animals being treated. Also, results in death or morbidity is often due to an excessive host the requirement for intravenous injection requires some tech inflammatory response to the invading pathogens. In the short nical expertise for proper administration. As a result of these term, febrile, painful animals eat and drinkless. Furthermore, requirements for proper administration of flunixin meglu long-term damage to host tissues occurs, resulting in long mine to cattle, Some animals in need may go untreated in the term declines in productivity even after BRD infection has interest of reducing needle waste, protecting human handlers, resolved. or because of technical limitations. 0007 Bovine mastitis is considered to be the most costly 0013 Thus, there is a need for an improved formulation production disease faced by the dairy industry, costing hun and method of administration, Such as a formulation for trans dreds of millions of dollars per year. Bovine mastitis is typi dermal drug delivery, which addresses these problems. One cally caused by infectious agents such as Staphylococcus difficulty faced, however, when attempting to arrive at a trans aureus, Streptococcus species, and Escherichia coli. In dermal formulation is the fact that the skin has been described response to infection, the mammary gland undergoes an as a “blackbox” with regard to drug delivery. This is due to the US 2008/O153885 A1 Jun. 26, 2008 lack of knowledge in the mechanisms of drug penetration done, ethyl lactate, and glycol ethers such as ethylene glycol through the epidermis and partitioning into the underlying monoethyl ether, diethylene glycol monoethyl ether, or dipro layers. Thus far, the boundaries for such properties have not pylene glycol monoethyl ether, while particular examples of been defined; making it very difficult to predict what com secondary solvents include ethanol, isopropyl alcohol, and pounds can be delivered transdermally. Transdermal systems effective for delivering one compound are almost always benzyl alcohol. ineffective with other compounds and systems and devices 0024. In another aspect of the invention, there are provided that work in one species are almost universally ineffective in methods of treating inflammatory conditions. Some of these other species. Furthermore, due to the presence of stratum methods include administering an effective amount of a trans corneum barrier, the mass transfer through the skin is usually dermal preparation as described above to an animal, like a too slow for rapid, massive systemic absorption. This mammal Such as a bovid (e.g. cow) in need thereof. explains why very few, if not any, of the commercially avail 0025. The present composition can also optionally include able transdermal products for human use are designed for immediate drug delivery. other NSAIDs besides flunixin, as well as other active phar 0014. Accordingly, there is a need for stable, transdermal maceutical ingredients such as anti-microbials, hormones for liquid preparation that offers away for handlers to safely and reproduction, growth enhancement, or other physiologic conveniently administer flunixinto animals in need thereof to intervention, anxiolytic compounds, antihistamines, immune ameliorate inflammation, while minimizing the pain and stimulants, vaccines and the like, for example. stress to the animal associated with treatment and the poten 0026. In another aspect of the invention, there are provided tial for injection site tissue damage. methods of administering the transdermal flunixin liquid preparation comprising incorporating the transdermal liquid SUMMARY OF THE INVENTION preparation into a press-in bottle application device, and 0015 The present invention fulfills this need by providing administering an effective amount of the transdermal liquid improved preparations and methods for the delivery of preparation to an animal in need thereof. flunixin and other NSAIDs in cattle and other animals. 0027. With the foregoing and other objects, advantages 0016. Accordingly, there are disclosed pharmaceutically acceptable preparations for transdermal administration to and features of the invention that will become apparent here animals and methods for the use thereof. Such preparations inafter, the nature of the invention may be more clearly under comprise flunixin or a pharmaceutically acceptable salt stood by reference to the following detailed description of the thereof, a pharmaceutically acceptable carrier system com invention and the appended claims. prising a solvent system and a combination of two penetration enhancing agents. In optional aspects of the invention, the BRIEF DESCRIPTION OF THE FIGURES transdermal liquid preparations can include a stabilizing or Viscosity lowering agent, such as water, ethanol, isopropanol, 0028 FIG. 1 is a graph showing the results of the tests propylene glycol, dimethylisosorbide, or triacetin. carried out in Example 2, in which the mean plasma concen 0017. One preferred aspect of the invention includes a tration (-1 SD) of flunixin (free acid) vs. time after a single transdermal liquid preparation containing: 2.2 mg/kg IV dose of BanamineR (flunixin megiumine) (dia 0018 a) flunixin or a pharmaceutically acceptable salt monds connected by dotted line) is compared to a single 5 thereof mg/kg transdermal dose of composition of the present inven 0019 b) a first and a second dermal penetration enhancer; tion (+1 SD, squares connected by solid line). and 0020 c) one or more aprotic primary solvents. 0029 FIG. 2 is a graph showing the results of the tests 0021. In a second preferred aspect of the invention, one or carried out in Example 4, in which the mean plasma concen more additional solvents or carriers (referred to herein as tration of flunixin (free acid) vs. time after a single 2.2 mg/kg “second’ or “secondary' solvents or vehicles) can also be intramuscular (IM, solid line) or subcutaneous (SC, dotted included in the transdermal liquid preparation. line) dose of BanamineR (flunixin meglumine) is compared 0022. Within the first and second aspect of the invention, to a single 5 mg/kg transdermal dose of composition of the the first dermal penetration enhancer can be present in an present invention (t1 SD, squares connected by Solid line). amount from about 2% to about 20% of the transdermal liquid 0030 FIG. 3 is a graph showing the results of tests carried preparation, while the second dermal penetration enhancer out in the experiment described in Example 6 wherein the can be present in an amount from about 2% to about 50% of mean flunixin (free acid) plasma concentration data is shown the transdermal liquid preparation. In particular, one first following dosing of 3 different flunixin meglumine transder dermal penetration enhancer is menthol, while xylene, D-li mal formulations at 5 mg/kg to show some differences with monene, isopropyl myristate, propylene glycol dicaprylate/ different dermal penetration enhancers. dicaprate, decanoic acid, decyl alcohol, oleic acid, or mix tures thereof are particular examples of second dermal 0031 FIG. 4 is a graph showing the results of tests carried penetration enhancers. out in the experiment described in Example 7 wherein the 0023 The amount of the drug included in the transdermal efficacy of transdermal flunixin meglumine (free liquid preparations described herein can be present in an acid) in naturally-occurring bovine respiratory disease is amount from about 1 to about 20% by wt. (calculated on the shown. The mean temperature change (+1 SD) following basis of the flunixin free acid), while the amount of the aprotic treatment with an antimicrobial plus transdermal flunixin at 0 primary solvent can broadly be from about 5 to about 90% by mg/kg (placebo), 2.5 mg/kg, or 5 mg/kg is shown. wt. In particular, aprotic primary solvents useful in the 0032 FIG. 5 is a graph showing the results of the tests present invention are 2-pyrrolidone, N-methyl-2-pyrroli carried out in Example 8, in which the mean plasma concen US 2008/O153885 A1 Jun. 26, 2008

tration (+1 SD) of flunixin (free acid) vs. time after a single indirectly, from combination of the specified ingredients dis 2.5 mg/kg transdermal dose of composition of the present closed herein in the specified amounts disclosed herein; and invention. 0040 an “effective amount' is a dose required to alleviate a particular symptom of an infection or disease. DETAILED DESCRIPTION OF THE INVENTION 0041. In accordance with a first aspect of the invention, the transdermal liquid preparation contains a therapeutically 0033. It has been found that effective concentrations of effective amount offlunixin or a pharmaceutically acceptable flunixin or pharmaceutically acceptable salts thereof in the salt thereof, a first and a second dermal penetration enhancer, systemic circulation for the purpose of providing systemic and an aprotic primary solvent. anti-inflammatory activity can be achieved by the transder 0042. In the formulations of the invention, the concentra mal route of administration. This can encompass various tion of flunixin can be from about 1 to about 20% by weight types of delivery including pour-on, spot-on, spray, dip, wipe, of the transdermal liquid preparation (based on the free acid etc. content of flunixin), or particularly from about 5% to about 0034. The present invention relates to an NSAID product 15% by weight, or particularly with amounts being from for providing systemic anti-inflammatory (including anti about 7.5% to about 12.5%, or particularly with amounts pyrexia and analgesia) activity for animals, especially mam being from about 9 to about 11% by weight. The flunixin can mals such as cows. The present invention demonstrates that, be introduced into the formulation as a pharmaceutically through improved compositions and methods of delivery, acceptable salt, in which case the concentration of the salt flunixin can effectively diffuse through the skin and further would be adjusted in order to maintain the preferred flunixin partition into the underlying layers for rapid absorption. It concentration. was discovered that the pharmacokinetic parameters of the 0043. The pharmaceutically acceptable salt of flunixin is present invention are comparable to those obtained by the preferably flunixin meglumine. Flunixin meglumine is cur counterpart intramuscular injectable formulations. The high rently approved globally for use in the treatment of BRD and Cmax and the short Tmax values obtained Suggest Sufficient mastitis. It has become a mainstay of Veterinary practice for drug cargo was carried through the skin barrier with high flux. the treatment of inflammatory conditions. Flunixin meglu The high area under the time-plasma concentration curve mine is commercially available from, e.g., ISP (Wayne, N.J.), (AUC) indicates complete absorption of the active into the or may be made according to methods known in the art, e.g., systemic circulation. The pharmacokinetic data shows high the methods described in U.S. Pat. Nos. 3,337,570, 3,478,040 efficiency of skin barrier penetration, as well as tissue parti and 3,839,344. tioning from the current formulations. 0044) The transdermal liquid preparation of the invention 0035. It has also been discovered that when selected pen also includes a first dermal preparation enhancer. In particular etration enhancing agents are used together, they function embodiments of the invention, the first dermal penetration synergistically to provide increased systemic activity. In fact, enhancer is present in amounts from about 2 to about 20% w/v. the combination of two penetration enhancing agents is dem of the transdermal liquid preparation, particularly from about onstrated to be significantly Superior to the use of a single 5 to about 15% w/v or particularly from about 7.5 to about penetration enhancing agent alone. The compositions of the 12.5% w/v. present invention can be used to prevent or reduce inflamma 0045. Non-limiting examples of a suitable first dermal tion associated with an infectious disease, Surgery, injury, or preparation enhancer include, but are not limited to, terpe other cause. noids such as menthol, camphor, d-limonene, nerolidol, 1-8 0036. As used herein, the following terms, unless other Cineole and mixtures thereof. Particularly, the first dermal wise indicated, shall be understood to have the following penetration enhancer is menthol and is employed in an meanings: amount of 10% w/v. 0037 “transdermal application' and/or “transdermal liq 0046. A second dermal preparation enhancer is also uid preparation' is intended to encompass all such methods present in the transdermal liquid preparation of the invention. known for allowing a pharmaceutically active ingredient to be The second dermal penetration enhancer is particularly delivered at least partially through the skin, usually by apply present in an amount from about 2 to about 50% w/v of the ing the composition containing the active ingredient and for transdermal liquid preparation, particularly from about 5 to mulation excipients externally to the Surface, i.e. skin, fur, etc. about 30% w/V, or particularly from about 7.5 to about 12.5% of an animal and allowing Sufficient time for absorption w/v. through the dermal layers of the animal being treated. Meth 0047. Non-limiting examples of a suitable second dermal ods of administration include pour-on, spot-on, spray, dip, preparation enhancer include, but are not limited to, a second wipe, or other methods apparent to those skilled in the art; terpenoid, Saturated or unsaturated fatty acid esters or diesters 0038 pour-on' is intended to encompass routes of of propylene glycolor glycerol, Saturated or unsaturated fatty administration in which an effective amount of a suitable acids, Saturated or unsaturated fatty alcohols and mixtures pharmaceutically active ingredient is externally applied to a thereof. localized region, allowing for diffusion of an effective 0048 Particularly, the second dermal penetration amount of the pharmaceutically active ingredient to the enhancer is employed in an amount of 10% w/v and is Xylene, affected area(s) or systemic distribution or a region which D-limonene, isopropyl myristate, propylene glycol dicapry will facilitate delivery of the pharmaceutically active ingre late/dicaprate, decanoic acid, decyl alcohol, oleic acid or dient to the affected area(s) or systemic distribution; mixtures thereof. Particularly, the second dermal penetration 0039) “composition” “formulation” and/or “preparation” enhancer is propylene glycol dicaprylate/dicaprate and/or is intended to encompass a product comprising the specified Xylene and/or D-limonene and/or isopropyl myristate. ingredients disclosed herein in the specified amounts dis 0049. In one particular formulation of the invention, the closed herein, as well as any product which results, directly or first dermal penetration enhancer is menthol, and the second US 2008/O153885 A1 Jun. 26, 2008 dermal penetration enhancer is propylene glycol dicaprylate/ example. As will be appreciated by those of ordinary skill, a dicaprate and/or Xylene and/or D-limonene and/or isopropyl wide variety of pharmaceutically active compounds/agents myristate. can be included with the flunixin-based transdermal formu 0050 Particularly, the ratio of the first dermal penetration lations described herein. The only limitation on the type of enhancer to the second dermal penetration enhancer is from pharmaceutical agent which can be included is that the sec about 4:1 to about 1:4. ond agent must not significantly interact with or significantly 0051. It has been discovered that the combination of the diminish the activity of the flunixin or pharmaceutically first and second dermal penetration enhancers provides a acceptable salt being transdermally administered. synergistic increase in the systemic availability of flunixin or 0057. A non-limiting list of suitable pharmaceutically its pharmaceutically acceptable salt compared to the use of a active compounds include those falling in the categories of single penetration enhancer alone. As described, and, for anti-inflammatory agents. Such as NSAIDs and corticoster example, in Example 6 and illustrated in FIG. 3, the plasma oids, antibiotics, anti-pyretics, , etc. and the like. In uptake of flunixin is significantly enhanced when a first der one particular aspect, the transdermal formulations will mal penetration enhancer (menthol in Example 6) is include an antibiotic Such as a fluorine-containing analog of employed in combination with a second dermal penetration the antibiotics chloramphenicol and thiamphenicol, which enhancer (Xylene in Example 6). have been shown to have antibiotic activity both against 0052. The transdermal liquid preparation of the invention organisms sensitive to and resistant to chloramphenicol and also includes an aprotic primary solvent. In particular formu thiamphenicol. See Schafer, T. W. et al., “Novel Fluorine lations of the invention, the aprotic primary solvent is present Containing Analogs of Chloramphenicol and Thiampheni in an amount from about 5 to about 90% by weight of the col: Antibacterial and Biological Properties,” in CURRENT transdermal liquid preparation, particularly, from about 10 to CHEMOTHERAPY AND INFECTIOUS DISEASE PRO about 60% by weight, or particularly from about 20 to about CEEDINGS OF THE 11...sup.TH ICC AND THE 19.sup.TH 50% by weight. ICAAC AMERICAN SOCIETY OF MICROBIOLOGY 0053 Non-limiting examples of a suitable aprotic primary 1980, 444-446. Examples of such compounds, and methods Solvent include, but are not limited to, aprotic solvents such as for their manufacture, are described and claimed in U.S. Pat. a pyrrolidone solvent, such as 2-pyrrolidone, N-methyl-2- No. 4,235,892. pyrrolidone, and/or mixtures thereof, N,N-dimethylaceta 0058 Suitable NSAIDs, include, without limitation, mide, N,N-dimethylformamide, DMSO, acetone, glycerol , acetylsalicylic acid (), , formal, ethyllactate, and glycol ethers such as ethylene glycol , bucloxic acid, , , clidanac, monoethyl ether, diethylene glycol monoethyl ether, or dipro , , , dipyrone, , feno pylene glycol monoethyl ether, or mixtures thereof. Particu profen, , , flobufen, , larly, the aprotic primary solvent is 2-pyrrolidone, N-meth flufenisal, flunixin, fluprofen, , , ylpyrrolidone, mixtures thereof and the like. indomethacin, , , , , 0054) Other pharmaceutically acceptable secondary , , , miropro vehicles or solvents may be present in the formulations of the fen, , , , , oxepi present invention. Non-limiting examples of suitable second nac, , , , pramoprofen, ary vehicles or solvents include, but are not limited to, water, Sudoxicam, , , , , ethanol, isopropanol, 1,2-propanediol, glycerin, benzyl alco tiopinac, , , trioxaprofen, Zidometa hol, dimethylisosorbide, triacetin, propylene glycol, ethyl cin, or , pharmaceutically acceptable salts thereof lactate, glycol ethers such as ethylene glycol monoethyl ether, and mixtures thereof. However, particularly preferred is diethylene glycol monoethyl ether, or dipropylene glycol flunixin because a history of safe and effective use in BRD monoethyl ether, and polyethylene glycols (PEG) having an and mastitis has been established. Suitable animicrobials average molecular weight between about 200 and 400. In include, but are not limited to, compounds from classes Such particular, secondary vehicles or solvents include isopropyl as aminoglycosides, beta-lactams, cephalosporins, floroqui alcohol, benzyl alcohol, and PEG having an average molecu nolones, lincosamides, macrollides, Sulfonamides and poten lar weight between about 200 and about 400, triacetin, dim tiated Sulfonamides, tetracyclines, and fluorine-containing ethylisosorbide, ethanol, and water, and combinations analogs of chloramphenicol. Suitable growth enhancing thereof. These secondary vehicles or solvents may comprise agents include, without limitation, Somatotropin and Zeranol. up to about 80% by weight of the formulation. The secondary Suitable anxiolytic compounds include, without limitation, vehicles or solvents may comprise from about 10% to about NOP-1 receptor agonists, NK-1 receptor antagonists, benzo 75% by weight. Particularly, the secondary vehicles or sol diazepines, and phenothiazines. Suitable antihistamines vents comprise from about 20% to about 40% by weight of include, without limitation, diphenhydramine and tripelen the formulation. namine. 0055. The addition of one or more of such secondary 0059) Other ingredients can be added to the present com vehicles or solvents may be desirable to alter the viscosity of position, as desired. Such ingredients include preservatives, the formulation in order to provide a product with appropriate chelating agents, antioxidants, and Viscosity modifying characteristics for transdermal application. agents. Exemplary preservatives include without limitation 0056. The transdermal liquid preparation of the invention methyl p-hydroxybenzoate (methylparaben) and propyl can also optionally include a second pharmaceutically active p-hydroxybenzoate (propylparaben), added in an appropriate compound, or other therapeutic classes of drugs such as anti quantity known to one skilled in the art. Exemplary chelating microbials, anti-inflammatory agents, oxytocin, hormones agents include without limitation edetate disodium and for reproduction, growth enhancement compounds, physi EDTA. Exemplary antioxidants include without limitation ologic intervention compounds, anxiolytic compounds, anti butylated hydroxyanisole, ascorbic acid, and sodium mono histamines, immune stimulants, and vaccines and the like, for thioglycerol, added in an appropriate quantity known to one US 2008/O153885 A1 Jun. 26, 2008 skilled in the art. Suitable viscosity modifying agents include, 15% of flunixin or a pharmaceutically acceptable salt thereof without limitation, water, ethanol, isopropanol, propylene based on the free acid content of flunixin, from about 5% to glycol, dimethylisosorbide, triacetin, or glycerol, added in an about 90% of an aprotic primary solvent; and up to about 80% appropriate quantity known to one skilled in the art. of a second vehicle or solvent, wherein the transdermal com 0060. In order to prevent degradation of any of the active position exhibits with respect to flunixin a Cmax of from ingredients in the formulations of the present invention, the about 1600 to about 4800 ng/mL, and a Tmax of from about addition of at least one stabilizer has been found to be advan 30 minutes to about 2 hours when administered transdermally tageous. Citric acid and maleic acid are examples of stabiliz to bovids at a flunixin dose of about 5 mg/kg. The transdermal ers useful in the present invention. composition exhibits with respect to flunixin a Cmax of from 0061. In order to prevent degradation of any of the active about 1000 to about 2500 ng/mL, and a Tmax of from about ingredients in the formulations of the present invention, a pH 60 minutes to about 2 hours, and a bioavailability of greater adjusting agent has been found to be advantageous. than 50% when administered transdermally to bovids at a 0062. The amount of the active agent(s) or any other excipients may be varied to after the dose volume delivered or flunixin dose of about 2.5 mg/kg. the physical properties of the formulation. The amount of the 0067. In addition to greater convenience and ease of use, it second pharmaceutically or therapeutically active agent will is believed that a single daily administration of a transdermal depend on transdermal bioavailability and pharmacologic product in accordance with the present invention will pro synergy with other actives in the formulation and will be mote humane animal care by reducing the number of injec titrated to effect. tions needed to treat animals and providing rapid relief of 0063. In some particular embodiments, the transdermal disease symptoms. By reducing the number of injections, formulations in accordance with the invention have a similar manpower costs also may be significantly reduced. plasma profile to that observed with injectable Banamine(R) 0068. In a particular method of preparing the composition (flunixin meglumine) (a short onset of activity and clearance of the present invention, the vehicle(s) or a portion of the from plasma within 24 hours). Because the formulations of vehicle(s), are added to the compounding vessel, followed by the invention have a short onset of activity, animals will the remaining excipients and the actives. The mixture is benefit from rapid relief of clinical signs. Also, because the mixed until all solids are dissolved. An additional solvent to formulations of the invention clear from plasma within 24 bring the composition to final volume may be added if hours, shorter withhold times will be required prior to selling needed. Additives, such as those listed above, may also be milk or meat from treated animals. included in the vessel and mixed into the formulation. The 0064. It will also be appreciated that the present invention encompasses, in one aspect, methods of treating inflamma order of addition of the above vehicles, excipients, solvents tion by administering, for example, a pharmaceutically and additives is not critical. acceptable composition comprising, for example, flunixin or 0069. The compositions according to the present inven a pharmaceutically acceptable salt thereof, to an animal by tion will generally be administered to cattle at from about 1 transdermal administration. The composition can be applied mg to about 5 mg offlunixin per kilogram of body weight per in a variety of ways, such as a pouring, spraying, or wiping on day. Particularly, the compositions of the present invention to any area of the animal's skin, including the back, ears, or will be administered to cattle at about 2.5 mg of flunixin per udder, preferably the back. The amount of administered kilogram of body weight. flunixin or its pharmaceutically acceptable salt is from about 0070 The compositions may be administered once daily 1 to about 5 mg/kg flunixin active. or divided into multiple doses. In some circumstances, daily 0065 Formulation efforts on the product of the invention doses will be required to treat the animal. The precise dose were directed at creating a pharmacokinetic profile for will depend on the stage and severity of the condition being flunixin or its pharmaceutically acceptable salts following treated, and the individual characteristics of the animal spe transdermal applications to be as similar as possible to that cies being treated, as will be appreciated by one of ordinary observed for BanamineR injectable. A formulation contain ing 100 mg/mL of flunixin was developed and transdermally skill in the art. administered at a dose of 5 mg/kg of flunixin. The data pre 0071. The compositions of the present invention may be sented in FIG. 1 demonstrated that the flunixin plasma profile administered in a press in bottle insert application device is similar to that of a known effective profile. For example, (PIBA) to an animal in need thereof. Such a device allows a plasma concentrations of flunixin, following a single trans health care professional to easily dispense liquids from Stock dermal administration of about 5 mg/kg of flunixin achieved bottles into (oral) syringes. In administering the composition, a Cmax of greater than 3000 ng/ml at a Tmax of about 60 the professional opens the bottle and presses the plastic minutes. The data presented in FIG.5 show the plasma profile adapter into the opening of the bottle and then attaches the following transdermal administration at a dose of 2.5 mg/kg oral syringe to the port of the adapter. Next, the professional offlunixin. Following a single transdermal dose of 2.5 mg/kg, may withdraw the dose of medication from the bottle and a Cmax of about 1500 ng/mL was achieved at a Tmax of about administer the dose. Then the cap can be replaced on the 90 minutes. In this example (FIG. 5), the bioavailability of the bottle to be used later. Presently, animal pour-on products flunixin transdermal solution was greater than 50%. generally require administering larger Volumes of a compo 0066. The present invention also includes a transdermal sition, thus, the above-described method of administration is composition for the treatment of inflammatory conditions in not appropriate. Therefore, present pour-on products are an animal. Particularly, the transdermal composition com either administered in a dosing gun or a dosing cup. Such prises from about 5% to about 15% by wt of a first dermal methods of administration prove difficult to accurately penetration enhancer, from about 2% to about 50% by wt of a deliver small volumes of medication. Thus, the method of second dermal penetration enhancer, from about 5% to about administration of the present invention using the PIBA appli US 2008/O153885 A1 Jun. 26, 2008

cation system allows for more accurate and convenient 0078 Some particular transdermal formulations in accor administration of the presently claimed pour-on liquid prepa dance with the present invention are set forth below. ration. 007.9 Formulation A 0072 The compositions according to the present inven tion are particularly useful for cattle, bovids, Swine, other mammals, and birds. In addition to the treatment of BRD, the compositions of this invention are also suitable for the treat Ingredient Percent wiv ment of other conditions associated with inflammation Such Flumixin meglumine 8.3 as footrot, acute mastitis, pinkeye (infectious keratoconjunc Menthol 1O.O tivitis), acute pneumonia, metritis and enteritis in cattle. Also, 2-pyrrollidone 3S.O other inflammatory conditions in other species could be Monothioglycerol 1.O treated with the compositions. The dosage regimen for treat Xylene qSAD ment of Such diseases should be appropriate for the species and condition being treated. 0080. Formulation B 0073 Mastitis is a complex disease that occurs in lactating females, and is of particular economic importance in dairy cows and goats. Several pathogenic agents may be involved, including Staphylococcus aureus, Escherichia coli and Strep Ingredient Percent wiv tococcus species. The acute form of mastitis has a Sudden Flumixin meglumine 8.3 onset, the udder is enlarged, hot to the touch and tender, and Menthol 1O.O 2-pyrrollidone 3S.O usually the affected animal will have a fever. If not treated Monothioglycerol 1.O promptly, the udder may be permanently damaged and milk D-limonene qSAD production may be decreased or lost. 0074 Currently, acute mastitis is treated with antibiotics, anti-inflammatories and oxytocin. The use of the formula 0081 Formulation C tions of the present invention would be an improvement by offering a way for animal handlers to safely and conveniently administer flunixin to animals in need thereof to ameliorate inflammation, while minimizing pain and stress to the animal Ingredient Percent wiv associated with the treatment and the potential for injection Flumixin meglumine 8.3 Menthol 1O.O site tissue damage. Additionally, the present invention pro Isopropyl myristate 2SO vides an improved method of administrating the formulation Monothioglycerol 1.O because it overcomes the challenges of needle Stick hazards 2-pyrrollidone qSAD and disposal of sharp biowaste material. Moreover, based on the pharmacokinetic data, transdermal flunixin allows for rapid onset of action. 0082 Formulation D 0075 Pinkeye is an acute infectious disease of cattle, sheep and other animals that is characterized by inflammation of the tissues of the eye, accompanied by nasal discharge, Ingredient Percent wiv lacrimation and copious ocular discharge. Affected animals Flumixin meglumine 8.3 may display extreme discomfort, resulting in decreased feed Menthol 1O.O intake and Subsequent reduction in body weight gain and/or a 2-pyrrollidone 2O.O drop in milk production. In extreme cases, permanent blind Isopropyl myristate 2O.O ness occurs. The disease, which is caused by Moraxella bovis Monothioglycerol 1.O in cattle, is widespread, especially among range and feedlot Isopropyl alcohol qSAD cattle, the cure of which is of great economic importance to the cattle industry. 0076 Footrot (interdigital phlegmon) is an acute infection EXAMPLES of the interdigital space that occurs throughout the world in Example 1 both beef and dairy cattle. Fusobacterium necrophorum is the major cause of footrot, although other organisms, including 0083 Bacteroides melaminogenicus, can be involved. The major symptoms include pain, severe lameness, fever, anorexia, and reduced milk production. Currently, footrot is treated by anti biotic therapy. Recommended therapy can involve treatment Ingredient Percent (w/v) for up to five days. The use of the formulations of the present flunixin meglumine 16.6% invention would be a useful adjunct therapy because the 2-pyrrollidone 35.0% Menthol 10.0% NSAID would reduce the inflammation caused by footrot and isopropyl myristate 10.0% make the animal feel better. isopropyl alcohol qSAD EXAMPLES Monothioglycerol 1.0% 0077. The materials and methods of the present invention are further illustrated by the examples which follow. These I0084. In order to prepare the composition of the present examples are offered to illustrate, but not to limit the claimed invention, the vehicle(s) or a portion of the vehicle(s), are invention. added to the compounding vessel, followed by the remaining US 2008/O153885 A1 Jun. 26, 2008

excipients and the actives. The combination is mixed until all solids are dissolved. Although not included herein, additives, -continued Such as those mentioned in the detailed description, are also included in the vessel and mixed into the formulation. The Conc Conc order of addition was not critical. Excipient Purpose (% w/v) Conc (% w/v) (% w/v) Crodomal CAP Penetration 10.0% Example 2 Xylene Penetration Qs D-Limonene Penetration Qs Pharmacokinetics of Flunixin in Product Described Isopropyl Alcohol Vehicle 10.0% in Example 1 DEGMEE Solvent 15.0% qS 15.0% Methyl Paraben Preservative 3.0% 3.0% 3.0% 0085. The Formulation of Example 1 was assessed in a Monothioglycerol Anti-oxidant 1.0% 1.0% 1.0% pharmacokinetic study involving 6 cattle which received a single transdermal application of 1 mL/20 kg (5 mg/kg 0090 The procedures to prepare the compositions herein flunixin). Blood samples for determination of flunixin con centration were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 and were the same as that done in Example 1. 48 hours after dosing. The results are shown in FIG. 1, in comparison to IV dosing of Banamine(R) at 2.2 mg/kg. This Example 6 study provided evidence that the pharmacokinetic profile of Pharmacokinetics of Flumixin in Products Described the formulation from Example 1, when dosed at 5 mg/kg in Example 5 flunixin, is similar to that of the IV dosing of Banamine(R) at 2.2 mg/kg. 0091. The Formulations of Example 5 were assessed in a pharmacokinetic study involving 6 cattle, each of which Example 3 received a single transdermal application of 1 mL/20 kg (5 0086 mg/kg flunixin). Blood samples for determination of flunixin concentration were collected at 0, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dosing. The results are shown in FIG. 3. FIG. 3 demonstrates that the plasma uptake offlunixin was enhanced Excipient Conc (% w/v) when menthol is used in combination with another penetra tion enhancer. Flunixin Meglumine 16.60% 2-Pyrrollidone 35.00% 0092. Example 6 thus demonstrates the discovery that the Isopropyl Alcohol 8.00% combination of the first and second dermal penetration Benzyl Alcohol 20.0% enhancers of the invention provides a synergistic increase in Menthol 10.0% Propylene Glycol 10.0% the systemic availability of flunixin meglumine compared to Dicaprylate/Dicaprate the use of a single penetration enhancer alone.

0087. The procedure to prepare the composition herein Example 7 was the same as that done in Example 1. Efficacy of Transdermal Flunixin in Naturally-Oc Example 4 curring Bovine Respiratory Disease 0093. The Formulation of Example 3 was evaluated in a Pharmacokinetics of Flunixin in Product Described study to determine the antipyretic efficacy of different doses in Example 3 in naturally-occurring bovine respiratory disease (BRD). 0088. The Formulation of Example 3 was assessed in a One-hundred twenty (120) beef calves exhibiting signs of pharmacokinetic study involving 4 cattle which received a acute BRD and with rectal temperature: 104.5° F were single transdermal application of 1 mL/20 kg (5 mg/kg selected. All 120 calves were treated with an approved anti flunixin). Blood samples for determination of flunixin con microbial for BRD (subcutaneous injection of NuflorR at 2 centration were collected at 0, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 mL/15 kg body weight) and randomly assigned to transder hours after dosing. The results are shown in FIG. 2, in com mal treatment with one of two doses of the Formulation parison to intramuscular (IM) or Subcutaneous (SC) dosing of described in Example 3 or with a placebo Formulation that Banamine(R) at 2.2 mg/kg. This study demonstrated that the contained no flunixin, but had all of the excipients used in the pharmacokinetic profile of the formulation from Example 3, Formulation of Example 3: when dosed at 5 mg/kg flunixin, is similar to that of the IMor SC dosing of Banamine(R) at 2.2 mg/kg. Example 5 Number of Flumixin Active Flumixin Dose Dose Rate 0089 Group Calves Concentration Rate Volume A. 40 100 mg/mL 5 mg/kg 1 mL/20 kg Conc Conc B 40 100 mg/mL 2.5 mg/kg 1 mL/40 kg Excipient Purpose (% w/v) Conc (% w/v) (% w/v) C 40 O mg/mL (placebo) NA 1 mL/20 kg Flunixin Meglumine Active 8.3% 8.3% 8.3% 2-Pyrrollidone Solvent 35.0% 35.0% 35.0% 0094. At six hours following treatment, the rectal tempera Menthol Penetration 10.0% 10.0% ture of calves was assessed again. The changes in rectal temperature for each group of calves are summarized in FIG. US 2008/O153885 A1 Jun. 26, 2008

4. Example 7thus demonstrates the discovery that a transder group of terpenoids consisting of menthol, camphor, d-li mal flunixin dose using the Formulation described in monene, nerolidol, or 1-8 Cineole and mixtures thereof. Example 3 at a transdermal dose of 2.5 mg/kg or 5 mg/kg 8. The transdermal liquid preparation of claim 1, wherein leads to a greater decrease in rectal temperature at 6 hours the second dermal penetration enhancer is selected from the following dosing than that observed with placebo treatment. group consisting of terpenoids, Saturated or unsaturated fatty acid esters or diesters of propylene glycol and glycerol, Satu Example 8 rated or unsaturated fatty acids, Saturated or unsaturated fatty alcohols, and mixtures thereof. 0095 9. The transdermal liquid preparation of claim 8, wherein the second dermal penetration enhancer is Xylene, D-li monene, isopropyl myristate, propylene glycol dicaprylate/ Excipient Conc (% w/v) dicaprate, decanoic acid, decyl alcohol, oleic acid, or mix tures thereof. Flunixin Meglumine 16.6% 2-Pyrrollidone 35.0% 10. The transdermal liquid preparation of claim 1, wherein Isopropyl Alcohol 12.8% the transdermal liquid preparation comprises from about 1 to Benzyl Alcohol 20.4% about 20% by wt of flunixin active. L-Menthol 10.0% 11. The transdermal liquid preparation of claim 1, wherein Propylene Glycol Dicaprylate/Dicaprate 10.0% the aprotic primary solvent is selected from the group con sisting of a pyrrolidone solvent, N,N-dimethylacetamide, 0096. The procedure to prepare the composition herein N,N-dimethylformamide, DMSO, acetone, glycerol formal was the same as that done in Example 1. ethyl lactate, glycol ethers, and/or mixtures thereof. 12. The transdermal liquid preparation of claim 11, Example 9 wherein the glycol ether is selected from the group consisting Pharmacokinetics of Flunixin in Product Described of ethylene glycol monoethyl ether, diethylene glycol mono in Example 8 ethyl ether, and/or dipropylene glycol monoethyl ether. 13. The transdermal liquid preparation of claim 11, 0097. The Formulation of Example 8 was assessed in a wherein the aprotic primary Solvent is a 2-pyrrolidone, N-me pharmacokinetic study involving 6 cattle which received a thyl-2-pyrrolidone, and/or mixtures thereof. single transdermal application of 1 mL/40 kg (2.5 mg/kg 14. The transdermal liquid preparation of claim 1, wherein flunixin). Following dosing, animals were maintained in the aprotic primary solvent comprises from about 5 to about headgates to prevent any licking of their own or their pen 90% by wt of the transdermal liquid preparation. mates application sites. Blood samples for determination of flunixin concentration were collected at 0, 0.25, 0.5,0.75, 1, 15. The transdermal liquid preparation of claim 1, further 1.5.2, 4, 6, 8, and 24 hours after dosing. The results are shown comprising a second vehicle or solvent comprising up to in FIG. 5. These plasma data were used to estimate bioavail about 80% by wt of the transdermal liquid preparation. ability based on data generated for IV dosing (2.2 mg/kg) of 16. The transdermal liquid preparation of claim 15, Banamine(R) (SPRI SN 06482). This study demonstrates that wherein the second vehicle or solvent is water, ethanol, iso the flunixin detected in the plasma of study subjects is attrib propanol. 1,2-propanediol, glycerin, benzyl alcohol, dimeth utable to transdermal absorption. It also generates a bioavail ylisosorbide, triacetin, propylene glycol, glycol ethers, ethyl ability estimate of greater than 50% for the transdermal for lactate and/or mixtures thereof. mulation presented in Example 8. 17. The transdermal liquid preparation of claim 16, wherein the glycol ether is selected from the group consisting We claim: of ethylene glycol monoethyl ether, diethylene glycol mono 1. A transdermal liquid preparation comprising: ethyl ether, and/or dipropylene glycol monoethyl ether. a) a first and a second dermal penetration enhancer, b) an aprotic primary solvent; and 18. The transdermal liquid preparation of claim 1, further c) a therapeutically effective amount of flunixin or a phar comprising a second pharmaceutically active compound. maceutically acceptable salt thereof. 19. The transdermal liquid preparation of claim 18, 2. The transdermal liquid preparation of claim 1, wherein wherein the second pharmaceutically active compound is the pharmaceutically acceptable salt is flunixin meglumine. selected from the group consisting of antimicrobials, anti 3. The transdermal liquid preparation of claim 1, wherein inflammatory agents, oxytocin, hormones for reproduction, the first dermal penetration enhancer comprises from about 2 growth enhancement compounds, physiologic intervention to about 20% w/v of the transdermal liquid preparation. compounds, anxiolytic compounds, antihistamines, immune 4. The transdermal liquid preparation of claim 3, wherein stimulants, and vaccines. the first dermal penetration enhancer comprises from about 5 20. A transdermal liquid preparation of claim 1, compris to about 15% w/v of the transdermal liquid preparation. 1ng: 5. The transdermal liquid preparation of claim 1, wherein a) from about 5% to about 15% by wt of said first dermal the second dermal penetration enhancer comprises from penetration enhancer, about 2 to about 50% w/v of the transdermal liquid prepara b) from about 2% to about 50% by wt of said second dermal tion. penetration enhancer, 6. The transdermal liquid preparation of claim 1, wherein c) from about 5% to about 15% of said flunixin based on the ratio of the first dermal penetration enhancer to the second free acid content: dermal penetration enhancer is from about 4:1 to about 1:4. d) from about 5% to about 90% of said aprotic primary 7. The transdermal liquid preparation of claim 1, wherein Solvent; and the first dermal penetration enhancer is selected from the e) up to about 80% of a second vehicle or solvent. US 2008/O153885 A1 Jun. 26, 2008

21. A method of treating inflammatory conditions, com c) from about 5% to about 15% of flunixin or a pharma prising administering an effective amount of a transdermal ceutically acceptable salt thereof based on the free acid liquid preparation of claim 1 to an animal in need thereof. content of flunixin; 22. The method of claim 21, wherein the amount offlunixin d) from about 5% to about 90% of an aprotic primary administered is from about 1 to about 5 mg/kg active content. Solvent; and 23. The method of claim 21, further comprising adminis e) up to about 80% of a second vehicle or solvent, tering a second pharmaceutical agent to said animal in need wherein said transdermal liquid preparation exhibits with thereof. respect to flunixin a Cmax of from about 1000 to about 24. The method of claim 23, wherein the second pharma 2500 ng/mL, a Tmax of from about 60 minutes to about ceutical agent is selected from the group consisting of anti 2 hours, and a bioavailability of greater than 50% when microbials, anti-inflammatory agents, oxytocinhormones for administered transdermally to bovids at a flunixin dose reproduction, growth enhancement compounds, physiologic of about 2.5 mg/kg. intervention compounds, anxiolytic compounds, antihista 26. A method of administering the transdermal liquid mines, immune stimulants, and vaccines. preparation of claim 1 comprising 25. A transdermal liquid preparation for the treatment of a) incorporating said transdermal liquid preparation into a inflammatory conditions in an animal comprising: press-in bottle application device, and a) from about 5% to about 15% by wt of a first dermal b) administering an effective amount of said transdermal penetration enhancer, liquid preparation to an animal in need thereof. b) from about 2% to about 50% by wt of a second dermal penetration enhancer, c c c c c