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Pharmaceutical Nasal Compositions and Methods for Peptid Treatment

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Pharmaceutical Nasal Compositions and Methods for Peptid Treatment (19) TZZ ¥Z_T (11) EP 2 283 850 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/485 (2006.01) A61K 9/107 (2006.01) 25.04.2018 Bulletin 2018/17 A61K 9/08 (2006.01) A61K 38/02 (2006.01) A61K 38/25 (2006.01) A61K 31/12 (2006.01) (2006.01) (2006.01) (21) Application number: 10186116.9 A61K 31/365 A61K 9/00 A61K 47/32 (2006.01) A61K 47/22 (2006.01) A61K 47/06 (2006.01) A61K 47/08 (2006.01) (22) Date of filing: 07.03.2005 A61K 47/10 (2017.01) A61K 47/18 (2017.01) A61K 47/44 (2017.01) (54) Pharmaceutical nasal compositions and methods for peptid treatment Pharmazeutische nasale Zubereitungen und Peptidbehandlungen Compositions pharmaceutiques nasales et traitements aux peptides (84) Designated Contracting States: • Reppucci, Carl AT BE BG CH CY CZ DE DK EE ES FI FR GB GR North Andover, MA 01845 (US) HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR (74) Representative: Chajmowicz, Marion et al (30) Priority: 05.03.2004 US 895465 Becker & Associés 25, rue Louis Le Grand (43) Date of publication of application: 75002 Paris (FR) 16.02.2011 Bulletin 2011/07 (56) References cited: (62) Document number(s) of the earlier application(s) in WO-A-03/000158 accordance with Art. 76 EPC: 05724894.0 / 1 773 369 Remarks: Thefile contains technical information submitted after (73) Proprietor: CPEX Pharmaceuticals, Inc. the application was filed and not included in this Exeter, NH 03833 (US) specification (72) Inventors: • Gyurik, Robert Exeter, NH 03833 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 283 850 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 283 850 B1 2 Description effect when administered intra-nasally. The intra-nasal administration of peptides would thus lead to fewer im- [0001] The present invention relates to a composition munological problems for the patient. The present inven- useful for drug delivery. More particularly the invention tion includes within its scope the intra-nasal method of relates to compositions and methods for the delivery of 5 delivering peptides, peptide drugs, through the nasal mucosa. The pharma- [0006] The treatment of patients with compositions in ceutical compositions of the present invention include a the form of intra-nasal sprays containing pharmaceuti- permeation enhancer, that is, a material which is capable cally-active compounds has been disclosed in the art. of increasing the rate of passage of the peptide through For example, U.S. Patent No. 5,989,535 discloses an the nasal mucosa. 10 intra-nasal spray which contains insulin. Such intra-nasal [0002] A peptide is a protein fragment comprising a sprays, however, have had limited success because var- short chain of amino acids, no less than two amino acids. ious pharmaceutically-active compounds, including, for A protein is generally a longer chain of amino acids, example, insulin, are not particularly effective in pene- though there is no exact rule as to where a peptide ends trating the mucous membrane of the nasal passage. His- and a protein begins. The general peptide / protein no- 15 torically, effective intra-nasal delivery of peptides has menclature also considers whether the structure is a been unachievable because of the peptide’s inability to wholemolecule, suchas insulin-like growth factor-1(IGF- permeate the nasal mucosa and the tendency of some 1) that is a 73 amino acids long peptide, or if the structure permeation agents to irritate those membranes. The in- is a fragment of a protein molecule, such as a trypsin stant invention overcomes both of those prior art prob- cleaved fragment of a protein that would normally be20 lems. called a trypsin peptide. [0007] The use of an enhancer to improve the delivery [0003] In one embodiment the peptides used in the of a pharmaceutically-active compound to a targeted ar- present invention have molecular weights on the order ea has been proposed. U.S. Patent 5,023,252 describes of about 100 to about 30,000 daltons, though other pep- a composition for delivery of drugs by a route other than tides, which, due to their coiling may be larger than25 by injection. More particularly, such patent describes the 30,000 daltons, are also within the scope of the invention. use of compositions that include permeation enhancers In a preferred embodiment the peptides used in the for delivery of drugs through skin and membranes of body present invention have molecular weights on the order cavities without requiring an injection. of about 100 to about 10,000 daltons. In a more preferred [0008] The present invention is directed to an improve- embodiment the peptides used in the present invention 30 ment in such compositions and the use thereof. have molecular weights on the order of about 100 to [0009] In accordance with the invention, there is pro- about 7,000 daltons. In one embodiment the peptide is vided a pharmaceutical composition for treating a patient within the more preferred range and it is a peptide other comprising: a pharmaceutically active peptide; a perme- than insulin. ation enhancer; an emulsifying agent and a liquid carrier [0004] Peptides are used to treat patients suffering 35 wherein the composition is in a form suitable for intrana- from myriad conditions such as osteoporosis, cystic fi- sal delivery thereof and wherein the peptide is present brosis, endometriosis, encephalomyelitis, pancreatic in an amount effective for treating a patient. disorders, obesity, pain, growth problems, appetite dis- [0010] The disclosure further relates to treating a pa- orders, and sequelae of diabetes. The foregoing are non- tient in need of a peptide medication with a combination limiting examples of just some disorders that the instant 40 of a pharmaceutically active peptide, a permeation en- inventionmay be usedto treat. While the instant invention hancer, an emulsifying agent and a liquid carrier. may be used to treat acute conditions, it is preferably [0011] In general, the permeation enhancer that is em- used to treat chronic conditions. In general, peptides like ployed is one that enhances the permeation of the phar- many proteins are delivered to a patient by injection, ow- maceutically active peptide composition through the na- ing to the tendency that these macromolecules have to 45 sal mucosa. be destroyed by the digestive tract when ingested orally. [0012] In a composition containing an effective amount Injection therapies however have numerous drawbacks of a pharmaceutically active peptide the permeation en- such as the discomfort to the patient, poor patient com- hancer is a compound of the structure: pliance, and the need for administration by trained tech- nicians. There is therefore a need in the art for alternative 50 methods of delivering peptide medications to patients other than by injection. [0005] A desired alternative method of peptide treat- ment would be the intra-nasal administration of a com- position containing pharmaceutically active peptides.55 This form of administration is more convenient. In addi- tion, certain agents that produce an antigenic effect when administered by injection do not produce an antigenic 2 3 EP 2 283 850 B1 4 wherein X and Y are oxygen, sulfur or an imino group of vention are macrocyclic enhancers. The term "macrocy- the structure clic" is used herein to refer to cyclic compounds having at least 12 carbons in the ring. Examples of preferred macrocyclic enhancers for use in the present invention 5 include: (A) macrocyclic ketones, for example, 3 methyl- cyclopentadecanone (muscone), 9-cycloheptadecen-1 -one (civetone), cyclohexadecanone, and cyclopentade- canone (normuscone); and (B) macrocyclic esters, for or =N-R with the proviso that when Y is the imino group, example, pentadecalactones such as oxacyclohexade- X is an imino group, and when Y is sulfur, X is sulfur or 10 can-2-one (cyclopentadecanolide, ω-pentadecalac- an imino group, A is a group having the structure tone). [0016] Oxacyclohexadecan-2-one and cyclopentade- canone are especially preferred. [0017] The enhancer is present in the composition in 15 a concentration effective to enhance penetration of the pharmaceutically active peptide that is to be delivered through the nasal mucosa. Various considerations wherein X and Y are defined above, m and n are integers should be taken into account in determining the amount having a value from 1 to 20 and the sum of m+n is not of enhancer to use. Such considerations include, for ex- greater than 25, p is an integer having a value of 0 or 1, 20 ample, the amount of flux (rate of passage through the q is an integer having a value of 0 or 1, r is an integer membrane) achieved and the stability and compatibility having a value of 0 or 1, and each of R, R1, R2, R3, R4, of the components in the formulations. The enhancer is R5 and R6 is independently hydrogen or an alkyl group generally used in an amount of about 0.1 to about 10 having from 1 to 6 carbon atoms which may be straight wt.% of the composition, and more generally in an 25 chained or branched provided that only one of R1 to R6 amount of about 1.0 to about 3 wt.% of the composition.
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