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United States Patent 19 11 Patent Number: 5,449,515 Hamilton Et Al

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United States Patent 19 11 Patent Number: 5,449,515 Hamilton Et Al USOO5449515A United States Patent 19 11 Patent Number: 5,449,515 Hamilton et al. 45 Date of Patent: Sep. 12, 1995 (54). ANTI-INFLAMMATORY COMPOSITIONS WO9005183 5/1990 WIPO : AND METHODS OTHER PUBLICATIONS 75 Inventors: John A. Hamilton, Kew; Prudence H. Schleimer, R. P. et al., "Regulation of Human Basophil Hart, Millswood, both of Australia mediator ... ', J. Immuno., vol. 143, (4), Aug. 15, 1989, 73 Assignee: University of Melbourne, Victoria, pp. 1310-1317. Australia Hart et al., “Augmentation of Glucocorhicoid Action 21 Appl. No.: 858,967 on Human...” Lymphokine Research, vol. 9 (2), 1990, pp. 147-153. 22, PCT Filed: Nov. 21, 1990 Hart, P. H. et al., "Potential antiinflammatory effects of 86 PCT No.: PCT/AU90/00558 IL-4, Proc. Natl. Acad. Sci., vol. 86, pp. 3803-3807, May 1989. S 371 Date: Jul. 14, 1992 Hart, et al., Proc. Natl. AcadSci, vol. 86 pp. 3803-3807, S 102(e) Date: Jul. 14, 1992 May (1989). 87 PCT Pub. No.: WO91/07186 Primary Examiner-Michael G. Wityshyn Assistant Examiner-C. Sayala PCT Pub. Date: May 30, 1991 Attorney, Agent, or Firm-Jan P. Brunelle; Walter H. 30 Foreign Application Priority Data Dreger Nov. 21, 1989 IAU Australia ............................... PJTSO3 57 ABSTRACT 51 Int. CI.'.............................................. A61K 45/05 Therapeutic compositions and methods for the treat 52 U.S.C. .................................... 424/85.2; 530/351 ment of inflammation are disclosed. The compositions 58) Field of Search ........................ 424/85.2; 530/351 comprise at least one anti-inflammatory drug in combi nation with the lymphokine interleukin-4 (IL-4), which 56) References Cited components interact synergistically in the treatmement U.S. PATENT DOCUMENTS of inflammation. Methods for the treatment of inflam 4,985,241 1/1991 Zimmerman et al. ............. 424/85.2 mation comprise administering to a subject in need of such treatment an effective amount of at least one anti FOREIGN PATENT DOCUMENTS inflammatory drug and IL-4. 4156389 3/1990 Australia . WO8702990 5/1987 WIPO . 13 Claims, 7 Drawing Sheets U.S. Patent Sep. 12, 1995 Sheet 1 of 7 5,449,515 QS t O) () 30 g O 9 35 20 5SZ O) s C E O 2x10-8M 5x10-9M Dex E 10-7M Dex O O IL-4 (Ulm) 10 FIG. 1 U.S. Patent Sep. 12, 1995 Sheet 2 of 7 5,449,515 800 s 9 s 600 S. 400 s as No Dex 1. 200 O-9M Dex Z H 2x10-8M Dex 5x 0-9M Dex 1 O-7M Dex O . 1 O IL-4 (U/ml) FIG. 2 U.S. Patent Sep. 12, 1995 Sheet 3 of 7 5.449,515 4. 3 2 2x1O-8M 0-7M Dex 10-9M Dex O O . 10 IL-4 (U/ml) FIG. 3 U.S. Patent Sep. 12, 1995 Sheet 4 of 7 5,449,515 0. 1 4. 0. 2 0.0 0.08 0.06 0.04 . O OO Dex (nM) FIG. 4A U.S. Patent Sep. 12, 1995 Sheet 5 of 7 5,449,515 2 10-9M Dex 5X10-9M. Dex O ... 1 1 10 IL-4 (U/ml) FIG. 4B U.S. Patent Sep. 12, 1995 Sheet 6 of 7 5,449,515 30 10-5M indo 10-6M indo O . 10 IL-4 (U/ml) FIG. 5A U.S. Patent Sep. 12, 1995 Sheet 7 of 7 5,449,515 1 2 es l 10 10-5M indo Z H (f C) A i 6 10-6M indo 9 O S. C C 4 E E 2 O O 1 1 O IL-4 (Ulm) FIG. 5B 5,449,515 1. 2 dexamethasone, fluprednisolone, hydrocortisone, meth ANTI-NFLAMMATORY COMPOSITIONS AND ylprednisolone, paramethasone, prednisolone, predni METHODS sone and triamcinolone. Any non-steroidal anti-inflam matory drug may also be utilized in the invention. For This invention relates to therapeutic compositions example, non-steroidal anti-inflammatory drugs may be and methods for the treatment of inflammation. selected from aspirin, inodomethacin, ibuprophen, phe Inflammation is associated with many disease states, nylbutasone and diflusinal. Compositions may contain a such as rheumatoid arthritis, psoriasis, asthma and aller combination of steroidal anti-inflammatory agents, non gies, and it is generally thought to be caused by inflam steroidal anti-inflammatory agents, or both-steroidal matory mediators such as interleukin-1 (IL-1), tumour O and non-steroidal anti-inflammatory agents. necrosis factor-a. (TNF-a), histamine and prostaglandin Reference to IL-4 is to be taken as reference to princi E2 (PGE2). pally the human lymphokine IL-4, as described, for Therapeutics used for the treatment of inflammation example, in International Patent Application No. WO fall into two principle classes, namely glucocorticoids 87/02990 which is incorporated herein in its entirety by and non-steroidal anti-inflammatory agents. Glucocorti 15 reference. Notwithstanding the above definition, IL-4 coids (also known as corticosteroids) are among the also refers to animal IL-4, as produced for example by most potent and widely used anti-inflammatory agents mice, rats, horses, cats, dogs and sheep. The definition and include naturally occurring corticosteroids such as IL-4 includes all proteins, polypeptides and peptides cortisone and hydrocortisone, and synthetic analogues which are natural or recombinant IL-4's or derivatives such as betamethasone, dexamethasone, flupredniso 20 thereof having IL-4 activity which are characterised in lone, prednisone and paramethasone. Non-steroidal having a potentiating activity on anti-inflammatory anti-inflammatory agents include aspirin, indomethacin, drugs in the treatment of inflammation. IL-4 derivatives ibuprofen, phenylbutazone and diflusinal. are generally substitution, insertion or deletion variants These prior therapeutic agents are often character of IL-4, wherein one or more amino acids are substi ised by adverse side effects such as oedema, hyperten 25 tuted, inserted or deleted into or from the “native' IL-4 sion, osteoporosis, delayed wound healing, increased amino acid sequence. The IL-4's used in the processes susceptibility to infection, menorrhea, liver disfunction, and compositions of this invention may be produced by nausea and vomiting. purification from natural sources using conventional Interleukin-4 (IL-4), a product of activated T lym techniques or may be produced by recombinant DNA phocytes has a variety of stimulatory effects on B cells, 30 methodology. Generally IL-4 used in this invention is T cells and mast cells and may be regarded as a proim homogenous or substantially homogeneous, that is, is at mune, proinflammatory molecule. As described in In least 95% and more preferably 99% pure as ascertained ternational Patent Application No. WO 87/02990, IL-4 by analytical techniques such as polyacrylamide gel may stimulate mast cells to produce molecules such as electrophoresis (PAGE) and high performance liquid histamines and prostaglandins. These agents have been 35 chromatography (HPLC). For example, IL-4 may be implicated as inflammatory mediators. produced according to the teachings of WO 87/02990 To date, conventional compositions and methods for which, as mentioned previously, is incorporated herein the treatment of inflammation have been associated by reference. with significant disadvantageous side effects as detailed IL-4 and anti-inflammatory drugs, particularly steroi above. Accordingly, a need exists for compositions and dal anti-inflammatory drugs, interact synergistically methods which avoid these disadvantages while provid over a wide range of concentrations of both compo ing effective treatment of inflammation. nents, ranging from equimolar amounts of IL-4 to ste The present invention solves the problems referred to roid, to excess of steroid or excess of IL-4. Without above by providing therapeutic compositions and meth limiting the invention in any way, the molar excess of ods for treating inflammation. This invention is based 45 anti-inflammatory agent over IL-4 in a therapeutic com on the surprising and unexpected finding that IL-4 and position may for example be between 100.5 to 104. anti-inflammatory agents interact synergistically in the In accordance with a further aspect of the present treatment of inflammation, that is, IL-4 potentiates the invention there is provided a method for the treatment activity of steroidal and non-steroidal anti-inflamma of inflammation which comprises administering to a tory drugs. As a consequence, significantly less anti-in 50 subject in need of such treatment a composition com flammatory drug may be required in the treatment of prising a therapeutically effective amount of: inflammation, with a reduction An attendant side effects (i) one or more anti-inflammatory agents; and which typically characterise anti-inflammatory treat (ii) a synergistic amount of IL-4; mentS. optionally in the presence of one or more pharmaceuti According to one aspect of the present invention 55 cally acceptable carriers or excipients. there is provided a composition for the treatment of The pharmaceutical composition may be adminis inflammation which comprises: tered in a convenient manner such as by the oral, intra (a) one or more anti-inflammatory drugs; and venous, intranuscular, subcutaneous, intraperitoneal, (b) IL-4; intranasal, intradermal or suppository routes. optionally Anthe presence of one or more pharmaceuti 60 The composition also may be administered to a cally acceptable carriers or excipients. human or animal subject by continuous infusion over a As has been previously stated in this specification, predetermined time period, for example, for 30 minutes anti-inflammatory drugs fall into the categories of glu to 24 hours. Administration may be by way of an intra cocorticoids or steroidal anti-inflammatory agents, and venous catheter connected to an appropriate pump, or non-steroidal anti-inflammatory agents. Any steroidal 65 by gravity feed. anti-inflammatory agent may be utilized in the present The amounts of and dosage regimes of IL-4 and anti invention. For example, steroidal anti-inflammatory inflammatory agents which are administered to a sub drugs may be selected from cortisone, betamethasone, ject will depend on a number of factors such as the 5,449,515 3 4 mode of administration, the nature of the condition therapeutic administration, the active material finay ite being treated, the body weight of the subject being incorporated with excipients and used in the for in cf treated, and the judgement of the prescribing physician ingestible tablets, buccal tablets, troches, capsules, eli:- or veterinarian.
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