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 treatment would be the intra-nasal administration of a composition containing pharmaceutically active peptides.55 This form of administration is more convenient. In addition, 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 cyclopentadecanone (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 cyclopentadecanone 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. can be an alkyl group, with the proviso that when p, q [0018] The liquid carrier is present in the composition and r have a value of 0 and Y is oxygen, m+n is at least in a concentration effective to serve as a suitable vehicle 11, and with the further proviso that when X is an imino for the compositions of the present invention. In general, group, q is equal to 1, Y is oxygen, and p and r are 0, the carrier is used in an amount of about 40 to about 98 then m+n is at least 11, and said compound will enhance 30 wt.% of the composition and in preferred embodiments the rate of the passage of the pharmaceutically active in an amount of about 50 to about 98 wt.% of the com- peptideacross body membranes.Hereinafter these composition. pounds are referred to as enhancers. When R, R1, R2, [0019] The pharmaceutically active peptide composi- R3, R4, R5 or R6 is alkyl it may be methyl, ethyl, propyl, tions of the present invention are delivered as nasal isopropyl, butyl, isobutyl, sec-butyl, amyl, hexyl, and the 35 sprays. In such embodiments, the preferred liquid carrier like. Such permeation enhancers are described in U.S. is water with the pharmaceutically active peptide being Patent 5,023,252 and U.S. Patent 5,731,303. dispersed or dissolved in the water in a therapeutically [0013] Preferably, the permeation enhancer com- effective amount. The water may contain suitable buff- pounds used in this invention are the cyclics lactones ering agents to result in a pH wherein the particular pep- (the compounds wherein both X and Y are oxygen, (q is 40 tide is delivered optimally, or it may contain other co- 1 and r is 0), the cyclic diesters (the compounds wherein carriers, such as glycerin, propylene glycol, polyethylene both X and Y are oxygen, and both q and r are 1), and glycols of various sizes, amino acid modifiers, such as the cyclic ketones (the compounds wherein both q and r arginine and the like, and other suitable soluble excipi- are 0 and Y is oxygen). In the cyclic diesters m+n is pref- ents, as is known to those who are proficient in the art of erably at least 3. In the cyclic ketones m+n is preferably 45 compounding or pharmaceutics. from 11 to 15 and p is preferably 0. [0020] As non-limiting examples of peptides useful in [0014] Enhancers of the above structural formula are the present invention there may be mentioned: Anti-In- referred to herein as "Hsieh enhancers" and are de- flammatory Peptides such Anti-Inflammatory Peptide 1; scribed, for example, in aforementioned U.S. Patent Nos. Anti-Aging Peptides; Apelin Peptides such as Apelin-12; 5,023,252 and 5,731,303 (hereinafter the "Hsieh Pat- 50 Atrial Natriurectic Peptides such as Urodilatin; Bombesin ents"). Such enhancers are lipophilic and are "mem- and Analogs thereof; Brain Injury Derived Peptide; Cal- brane-compatible," meaning that they do not cause dam- citonin; Defensins; Deltorphins, Dermorphins and Ana- age to the membrane on which the composition of the logs thereof including other opiod peptides such as Ace- present invention is to be applied (hereinafter the "target talins, BAM Peptides, α-Casein Exorphins, β-Casomor- membrane"). Such enhancers also produce a low level 55 phins, Dynorphins, Endomorphins, Endorphins, of irritability or no irritability to the target membrane, and Enkephalins, Gluten Exorphins, Kyotorphins, Methor- in fact serve as emollients. phamide, Neoendorphins, Syndyphalins, H-Tyr-D/L-Tic- [0015] Preferred enhancers for use in the present in- OH, and Valorphin; Dynorphin and Analogs and Se-

3 5 EP 2 283 850 B1 6 quences thereof; Enterostatins; GHrelins; Glucagons those between 7 and 14 more preferred, and those be- and Glucagon-Like Peptides such as GLP-1 and GLP-2; tween 9 and 13 most preferred. Examples of such non- Gonadotropin Releasing Hormones; Growth Hormones; ionic surfactants are PEG-60 corn glycerides, PEG-20 Growth Hormone Releasing Hormones; Insulino-Tropic sorbitan monostearate, phenoxy-poly(ethyleneoxy)eth- Compounds; Kyotorphins; Leptin and Fragments there- 5 anol, sorbitan monooleate, and the like. Especially pre- of; Lutein; Myelin Basic Protein Fragments; Physalaemin ferred are compendial surfactants such as those de- and Fragments thereof; Secretins; Thymosins and Frag- scribed in compendia such as the Food Chemicals Co- ments thereof such as Thymosinβ4; Transforming dex, National Formulary, U.S. Pharmacopeia, and the Growth Factors (TGF) and Fragments thereof; Tuftsin; Code of Federal Regulations. It is preferred that the av- Tumor Necrosis Factors (TNF) and Related Peptides; 10 erage diameter of the droplets of the emulsion be from and VIP, Prepro VIP, and Analogs and Fragments there- about 50 nanometers (nm) to about 20 micrometers ( mm) of. and more preferably from about 200 nm to about 5 mm. [0021] The composition of the present invention may In general each surfactant is present in an amount no exist in various forms, for example, an oil-in-water emul- greater than about 2 wt.% of the composition and more sion, a water-in-oil emulsion, and a water-in-oil-in-water 15 generally no greater than about 1 wt.% of the composi- emulsion. The active compounds of the compositions of tion. Also, it is important to prefer the nature of the side- the present invention may exist in either the continuous chains of the surfactants to those with no double bonds, or the dispersed phase or in both phases depending upon and this invention is most preferred to include those with- whether the compounds are hydrophilic, lipophilic, or am- out unsaturated carbon-carbon bonds. The reason for phiphilic. In an example of a preferred embodiment of 20 this is that unsaturated fatty acid side chains (called also the present invention, the emulsion comprises oil drop- "olefinic" fatty acids) tend to oxidize over time, rendering lets dispersed in a continuous aqueous phase with a li- them unsuitable. They tend to become colored, or dark, pophilic enhancer being contained in the oil droplets and and give rise to intermediates that may react with the a water-soluble pharmaceutically-active compound dis- important peptide in the same formulation, rendering it solved in the continuous aqueous phase. 25 less useful or unsuitable from a regulatory vantage point [0022] The composition of the present invention also (in the US, for example, the key regulatory body being comprises an emulsifying agent for use in aiding the for- the FDA, and in other countries its counterpart). Olefins mation of an emulsion. are suspected to have the additional liability of contrib- [0023] In forming an emulsion in which the water-in- uting to irritation which must be avoided for intranasal solubleenhancer isa normally solid material, theenhanc- 30 applications. However, unsaturated side-chain sur- er is dissolved in a suitable solvent. If the enhancer is a factants are not excluded from use in this invention. For normally liquid material which is water-immiscible, a suit- example, polysorbate 80, containing a monounsaturated able solvent for the enhancer may or may not be used, side chain of oleic acid ester, may be mitigated in its as appropriate. irritation liability by using a limited concentration of same, [0024] The emulsifying agent is present in the compo- 35 generally under1% in theformulation, or by adding sooth- sition in a concentration that is effective to form the de- ing components, such as glycerin, to the formulation to sired liquid emulsion. In general the emulsifying agent is negate such undesired effect. used in an amount of about 0.001 to about 5 wt.% of the [0027] In one preferred embodiment, the emulsified or composition, and more generally in an amount of about discontinuous phase that contains the permeation en- 0.01 to about 5 wt.% of the composition, and most gen- 40 hancer is in the form of droplets. In general, smaller drop- erally in an amount of about 0.1 to about 2 wt.% of the lets confer greater stability. Larger droplets may cause composition. instability and may decrease shelf-life. In preferred em- [0025] The composition of the present invention may bodiments the lipid droplet size ranges from 0.025 mi- include, as an optional ingredient, particulate solids dis- crons (25 nm) to 20 microns and preferably from 0.1 mi- persed in the composition. For example, the composition 45 crons to 5 microns. may include an additional pharmaceutically-active com- [0028] In one embodiment of the present invention, the pound dispersed in the liquid continuous phase of the composition comprises a pharmaceutically-effective emulsion in the form of microcrystalline solids or nano- amount of a reproductive hormone peptide capable of particulates. treating prostate cancer or relieving the symptoms of fi- [0026] In one preferred embodiment, the permeation 50 brosis or endometriosis. Essentially any suitable repro- enhancer is emulsified in the aqueous phase that con- ductive hormone peptide can be used, including, for ex- tains the pharmaceutically active peptide The emulsifi- ample, luteinizing hormone (LH) and its analogs, follicle- cation may be effected through the use of one or more stimulating hormone (FSH) and its analogs, and gona- suitable surfactants, which are anionic, cationic, or non- dotropin-releasing hormone (GnRH-also known as lutei- ionic surfactants. Preferred surfactants are non-ionic sur- 55 nizing hormone releasing hormone (LHRH)) and its ana- factants. Alone or in combination with one or more other logs, for example, goserelin, nafarelin, buserelin, and le- surfactants, those having a hydrophilic-lipophilic balance uprolide. Examples of suitable reproductive hormone number (HLB) of from about 4 to about 18 are preferred, peptides are described also in K. Saeb-Parsy, et al., In-

4 7 EP 2 283 850 B1 8 stant Pharmacology, 57-62 (1999). LHRH-Lamprey III employed and that may be incorporated into the present and closely related analogs thereof are particularly pre- invention include, but are not limited to leupeptin, apro- ferred because of their relatively high activity. Yu et al., tinin, and the like. PNAS, 94: 9499 (1997). [0033] The composition of the present invention may [0029] In still another embodiment of the present in- 5 exist in various forms, for example, an oil-in-water emul- vention, the composition comprises a pharmaceutically- sion, a water-in-oil emulsion, and a water-in-oil-in-water effective amount of an opioid peptide or peptidomimetic emulsion. The active compounds of the compositions of (synthetic peptide) capable of reducing pain. Essentially the present invention may exist in either the continuous any suitable opioid peptide or peptidomimetic may be or the dispersed phase or in both phases depending upon employed. Examples of suitable opioid peptides include 10 whether the compounds are hydrophilic, lipophilic, or am- enkephalins, endorphins, exorphins, dynorphins, endo- phiphilic. In an example of a preferred embodiment of morphins, syndyphalins, BAM peptides, metorphamide, the present invention, the emulsion comprises oil drop- and valorphin. Shorter peptides are preferred, with es- lets dispersed in a continuous aqueous phase with a li- pecially potent shorter peptides such as, for example, pophilic enhancer being contained in the oil droplets and the endomorphins being particularly preferred. For use 15 a water-soluble pharmaceutically-active compound dis- in an emulsion of the present invention, opiate alkaloids solved in the continuous aqueous phase. In a preferred of the morphine class are preferred because the free bas- embodiment wherein an oil phase is utilized, the concen- es of such alkaloids are capable of stabilizing emulsions tration of the oil in the oil phase is such that it does not formed using acidic emulsifying agents. This functions promote crystallization. to stabilize the resulting emulsion without the need for 20 [0034] In some instances the permeation enhancers further pH modifiers. Examples of such opiate alkaloids used in the instant invention may crystallize at room tem- are morphine, codeine, oxycodone, hydrocodone, hydro- perature or at higher temperatures. In order to inhibit or morphone, fentanyl, sufentanil, levorphanol, meperidine, prevent such crystallization, in a preferred embodiment methadone, and the like. the composition includes one or more crystallization in- [0030] Yet another embodiment of the present inven- 25 hibitors to inhibit the crystallization of the permeation en- tion is a composition which comprises a pharmaceutical- hancer. Crystallization, if allowed to proceed, renders the ly-effective amount of an anti-obesity agent which is ca- emulsion unstable and has an adverse effect on shelf pable of alleviating a disorder which causes obesity in life. Preferred crystallization inhibitors function by lower- mammals, particularly humans. Essentially any suitable ing the temperature at which the involved compound anti-obesity agent may be employed. Examples of such 30 crystallizes. Examples of such crystallization inhibitors agents include galanins, bombesin, incretins such as glu- include natural oils, oily substances, waxes, esters, and cagon and glucagon-like peptides, insulin-like growth hydrocarbons. Examples of natural oils or oily substanc- factors, leptins, melanotropin, peptides which interact es include Vitamin E acetate, octyl palmitate, sesame oil, with the melanocortin receptor, and analogs thereof. Glu- soybean oil, safflower oil, avocado oil, palm oil, and cot- cagon and glucagon-like peptides are preferred, with35 tonseed oil. The selection of a suitable crystallization in- GLP-1 being particularly preferred. Leptins are also pre- hibitor is deemed to be within the scope of those skilled ferred, with leptin fragments, such as leptin 22-56 (obese in the art from the teachings herein. Preferred crystalli- gene peptide), being particularly preferred. Peptides zation inhibitors function by lowering the temperature at which interact with the melanocortin receptor such as, which the permeation enhancer crystallizes. for example, alpha-MSH and their analogs, are preferred 40 [0035] Inhibitors which are capable of lowering the (such peptides have been reported to decrease appetite. temperature of crystallization of the involved compound Science, 291: 1691 (2001)). to below about 25°C are particularly preferred, with those [0031] A further embodiment of the present invention capable of lowering the crystallization of the involved is a composition which comprises a pharmaceutically- compound tobelow about 5°C being especially preferred. effective amount of an appetite-enhancing peptide which 45 Examples of especially preferred crystallization inhibitors is capable of increasing appetite in mammals, preferably for use in inhibiting the crystallization of oxacyclohexa- humans. Essentially any suitable appetite-enhancing decan-2-one include hexadecane, isopropyl myristate, compound may be employed. Examples of such appe- octyl palmitate, cottonseed oil, safflower oil, and Vitamin tite-enhancing compounds include compounds which E acetate, each of which may be used in pharmaceutical serve as antagonists of the aforementioned anti-obesity 50 preparations. agents. Science, 291: 1691 (2001). [0036] The crystallization inhibitor is present in the [0032] A further embodiment of the present invention composition in a concentration effective to inhibit the is the addition to the formulation of an enzyme inhibitor. crystallization of the permeation enhancer. In general the As is well known to practitioners in peptide and protein crystallization inhibitor is present in an amount of about biochemistry, peptides tend to be very sensitive to the 55 0.001 to about 5 wt.% of the composition, and more gen- presence of enzymes, such as proteolytic enzymes, that erally in an amount of from about 0.01 to about 2 wt% of rapidly degrade the peptide when present in even minute the composition. In one embodiment the crystallization amounts. Typical enzyme inhibitors that are commonly inhibitor is present in an amount of from about 0.1 to

5 9 EP 2 283 850 B1 10 about 1 wt.% of the composition. The crystallization in- Claims hibitor is one preferrably used when the enhancer has a crystallization temperature above about 0 degrees Cen- 1. A pharmaceutical composition in the form of a nasal tigrade. In particular, for example, a crystallization inhib- spray comprising: a macrocyclic permeation en- itor is preferrably used when the enhancer is, pentade- 5 hancer, a liquid carrier, an emulsifying agent, and a calactone and / or cyclohexadecanone, since these crys- therapeutically effective amount of a pharmaceuti- tallize above room temperature. cally active peptide; wherein the emulsifying agent [0037] The composition of the present invention is de- consists of one or more anionic, cationic, or nonionic livered through a nasal spray applicator. If intra-nasal surfactants as the sole emulsifying agent in the com- application is desired, the composition may be placed in 10 position, and wherein said macrocyclic permeation an intra-nasal spray-dosing device or atomizer and may enhancer is a Hsieh enhancer, said Hsieh enhancer be applied by spraying it into the nostrils of a patient for having the following structure: delivery to the mucous membrane of the nostrils. A suf- ficient amount is applied to achieve the desired systemic or localized drug levels. For an intra-nasal spray, up to 15 about 200 microliters is typically applied, with an application of about 50 to about 150 microliters being preferred, and 75 to 120 microliters most preferred. One or more nostrils may be dosed and application may occur as often as desired or as often as is necessary. In pre- 20 ferred embodiments, the nasal spray applicator is selected to provide droplets of the composition of a mean size of from about 10 microns to about 200 microns. More wherein X and Y are oxygen, sulfur or an imino group generally the droplet size is from about 30 microns to of the structure about 100 microns. 25 [0038] The pharmaceutically active peptide spray composition of the invention is generally employed in a dosing regimen that is dependent on the patient being treated. Thus the frequency of the use and the amount of the dose may vary from patient to patient. In general, 30 or =N-R with the proviso that when Y is the imino dosing is in an amount (the amount internalized after ab- group of the structure =N-R, X is an imino group of sorption from the mucosa) of from about 0.05 mg to about the structure 10 mg and the frequency of dose is 3 to 4 times per day. This will vary with the potency of each peptide in question. As known in the art, the treatment of a disease varies 35 from patient to patient, and based on known pharmaceutically active peptide therapies and the teachings herein one skilled in the art can select the dosing regimen and and when Y is sulfur, X is sulfur or an imino group dosage for a particular patient or patients. of the structure [0039] The composition of the present invention com- 40 prises a pharmaceutically active peptide. The pharmaceutically active peptide is present in the composition in a therapeutically-effective amount. In general the pharmaceutically active peptide is present in an amount of about 0.005 to about 10 wt.% of the composition, and 45 A is a group having the structure more generally an amount of about 0.01 to about 5 wt.% of the composition. In one embodiment the pharmaceutically active peptide is present in an amount of about 0.1 to about 2 wt.% of the composition. [0040] Although a preferred embodiment is a prefor- 50 mulated composition, it is also within the scope of the present invention that a patient may be treated with the wherein X and Y are defined above, m and n are hereinabove-described and hereinbelow-described integers having a value from 1 to 20 and the sum of combination that is not preformulated; i.e., the pharma- m+n is not greater than 25, p is an integer having a ceutically active peptide in liquid carrier and the enhancer 55 value of 0 or 1, q is an integer having a value of 0 or may be mixed at the time of application, such as where 1, r is an integer having a value of 0 or 1, and each the mixing occurs in an atomizer at the time the compo- of R, R1, R2, R3, R4, R5 and R6 is independently sition is sprayed. hydrogen or an alkyl group having from 1 to 6 carbon

6 11 EP 2 283 850 B1 12

atoms which may be straight chained or branched provided that only one of R1 to R6 can be an alkyl group, with the proviso that when p, q and r have a value of 0 and Y is oxygen, m+n is at least 11, and with the further proviso that when X is an imino group, 5 q is equal to 1, Y is oxygen, and p and r are 0, then m+n is at least 11.

2. The composition of claim 1, wherein said surfactant has an HLB between 4 and 18, preferably between 10 wobei X und Y Sauerstoff, Schwefel oder eine Imi- 7 and 14. nogruppe der Struktur

3. The composition of claim 1, wherein said surfactant has carbon-carbon bond fully saturated elements. 15 4. The pharmaceutical composition of claim 1, further comprising an enzyme inhibitor, preferably selected oder =N-R sind unter der Voraussetzung, dass wenn from the group consisting of leupeptin and aprotinin. Y die Iminogruppe nach der Struktur =N-R ist, X eine Iminogruppe nach der Struktur 5. The pharmaceutical composition of claim 1, further 20 comprising a saturated hydrocarbon or mixture of saturated hydrocarbons, which is preferably petro- latum.

6. The pharmaceutical composition according to claim 25 ist und wenn Y Schwefel ist, X Schwefel oder eine 1, further comprising a pH buffer, preferably provid- Iminogroppe nach der Struktur ing optimal pH for the desired peptide.

7. The pharmaceutical composition according to claim 1, wherethe peptide hasa molecularweight between 30 100 and 7,000 Daltons. ist, A ist eine Gruppe, die die Struktur 8. The composition of claim 1, wherein said Hsieh enhancer is cyclopentadecalactone or cylcohexade- canone. 35

Patentansprüche aufweist, wobei X und Y oben definiert sind, m und 1. Eine pharmazeutische Zusammensetzung in der 40 n Zahlen sind, die einen Wert von 1 bis 20 aufweisen Form eines Nasensprays umfassend: einen makro- und die Summe von m+n nicht größer als 25 ist, p zyklischen Permeationsförderer, einen flüssigen eine Zahl ist, die einen Wert von 0 oder 1 aufweist, Träger, einen Emulgator und eine therapeutisch q eine Zahl ist, die einen Wert von 0 oder 1 aufweist, wirksame Menge eines pharmazeutisch aktiven r eine Zahl ist, die einen Wert von 0 oder 1 aufweist Peptids; wobei der Emulgator aus ein oder mehreren 45 und jeder von R, R1, R2, R3, R4, R5 und R6 unab- anionischen, kationischen oder nichtionischen Ten- hängig Wasserstoff oder eine Alkylgruppe ist, die 1 siden als der alleinige Emulgator in der Zusammen- bis 6 Kohlenstoffatome aufweist, die eine gerade setzung besteht und wobei der makrozyklische Per- Kette oder verzweigt sein kann, vorausgesetzt, dass meationsförderer ein Hsieh Förderer ist, der Hsieh nur einer von R1 bis R6 eine Alkylgruppe sein kann, Förderer weist die folgende Struktur auf: 50 unter der Voraussetzung, dass wenn p, q und r einen Wert von 0 aufweisen und Y ein Sauerstoff ist, m+n mindestens 11 ist und mit der weiteren Vorausset- zung, dass wenn X eine Iminogruppe ist, q gleich 1 ist, Y ein Sauerstoff ist und p und r 0 sind, dann ist 55 m+n mindestens 11.

2. Die Zusammensetzung nach Anspruch 1, wobei das Tensid einen HLB zwischen 4 und 18 aufweist, vor-

7 13 EP 2 283 850 B1 14

zugsweise zwischen 7 und 14.

3. Die Zusammensetzung nach Anspruch 1, wobei das Tensid vollständig gesättigte Kohlenstoff-Kohlen- stoff-Bindungselemente aufweist. 5 ou =N-R à condition que lorsqu’Y est le groupe imino de structure =N-R, X soit un groupe imino de struc- 4. Die pharmazeutische Zusammensetzung nach An- ture spruch 1, ferner umfassend einen enzymatischen In- hibitor, vorzugsweise ausgewählt aus der Gruppe bestehend aus Leupeptin und Aprotinin. 10

5. Die pharmazeutische Zusammensetzung nach An- spruch 1, ferner umfassend einen gesättigten Koh- et lorsqu’Y est un atome de soufre, X soit un atome lenwasserstoff oder eine Mischung aus gesättigten de soufre ou un groupe imino de structure Kohlenwasserstoffen, die vorzugsweise Vaseline 15 ist.

6. Die pharmazeutische Zusammensetzung nach An- spruch 1, ferner umfassend einen pH Puffer, der vorzugsweise einen optimalen pH für das gewünschte 20 A est un groupe ayant la structure Peptid zur Verfügung stellt.

7. Die pharmazeutische Zusammensetzung nach An- spruch 1, wobei das Peptide ein Molekulargewicht zwischen 100 und 7.000 Dalton aufweist. 25

8. Die Zusammensetzung nach Anspruch 1, wobei der dans laquelle X et Y sont définis ci-dessus, m et n Hsieh Förderer ein Cyclopentadecalacton oder Cyl- sont des nombres entiers ayant une valeur de 1 à cohexadecanon ist. 20 et la somme de m+n n’est pas supérieure à 25, 30 p est un nombre entier ayant une valeur de 0 ou 1, q est un nombre entier ayant une valeur de 0 ou 1, Revendications r est un nombre entier ayant une valeur de 0 ou 1, et chacun des R, R1, R2, R3, R4, R5 et R6 est indé- 1. Composition pharmaceutique sous forme de spray pendamment un atome d’hydrogène ou un groupe nasal comprenant : un agent d’amélioration de per- 35 alkyle ayant de 1 à 6 atomes de carbone qui peut méation macrocyclique, un véhicule liquide, un être à chaîne droite ou ramifié à condition qu’un seul agent émulsifiant, et une quantité thérapeutique- des R1 à R 6 puisse être un groupe alkyle, à condition mentefficace de peptidepharmaceutiquement actif ; que lorsque p, q et r ont la valeur 0 et qu’Y est un dans laquelle l’agent émulsifiant est constitué par un atome d’oxygène, m+n soit d’au moins 11, et à con- ou plusieurs tensioactifs anioniques, cationiques, ou 40 dition en outre que lorsque X est un groupe imino, q non ioniques en tant que seul agent émulsifiant dans soit égal à 1, Y soit un atome d’oxygène, et p et r la composition, et dans laquelle ledit agent d’amé- soient 0, auquel cas m+n est d’au moins 11. lioration de perméation macrocyclique est un agent d’amélioration Hsieh, ledit agent d’amélioration 2. Composition selon la revendication 1, dans laquelle Hsieh ayant la structure suivante : 45 ledit tensioactif a une valeur HLB entre 4 et 18, de préférence entre 7 et 14.

3. Composition selon la revendication 1, dans laquelle ledit tensioactif comporte des éléments entièrement 50 saturés à liaison carbone-carbone.

4. Composition pharmaceutique selon la revendication 1, comprenant en outre un inhibiteur d’enzyme, de préférence choisi dans le groupe constitué par la leu- 55 peptine et l’aprotinine. dans laquelle X et Y sont des atomes d’oxygène, de soufre ou un groupe imino de structure 5. Composition pharmaceutique selon la revendication 1, comprenant en outre un hydrocarbure saturé ou

8 15 EP 2 283 850 B1 16

un mélange d’hydrocarbures saturés, qui est de pré- férence la vaseline.

6. Composition pharmaceutique selon la revendication 1, comprenant en outre un tampon de pH, fournis- 5 sant de préférence un pH optimal pour le peptide souhaité.

7. Composition pharmaceutique selon la revendication 1, où le peptide a un poids moléculaire entre 100 et 10 7 000 Daltons.

8. Composition selon la revendication 1, dans laquelle ledit agent d’amélioration Hsieh est la cyclopenta- décalactone ou la cyclohexadécanone. 15

9 EP 2 283 850 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 5989535 A [0006] • US 5731303 A [0012] [0014] • US 5023252 A [0007] [0012] [0014]

Non-patent literature cited in the description

• K. SAEB-PARSY et al. Instant Pharmacology, 1999, • YU et al. PNAS, 1997, vol. 94, 9499 [0028] 57-62 [0028] • Science, 2001, vol. 291, 1691 [0030] [0031]