WO2012069149A1

WO2012069149A1 - Solution comprising cyclic oligopeptides

Info

Publication number: WO2012069149A1
Application number: PCT/EP2011/005718
Authority: WO
Inventors: Ian Harwigsson; Fredrick Lindstroem
Original assignee: Merck Patent Gmbh; Camurus Ab
Priority date: 2010-11-23
Filing date: 2011-11-14
Publication date: 2012-05-31

Abstract

The present invention relates to a solution comprising cyclic oligopeptides, preferably suitable for use as a pharmaceutical, said solution further comprising one or more selected lipids and water as the main ingredients, the use of the selected lipids for making said solution, methods of making said said solution, and said solution as a pharmaceutical.

Description

Solution comprising Cyclic Oligopeptides

The present invention relates to a solution comprising cyclic oligopeptides, preferably suitable for use as a pharmaceutical, said solution further comprising one or more selected lipids and water as the main ingredients, the use of the selected lipids for making said solution, methods of making said said solution, and said solution as a pharmaceutical. Introduction

Solubility of active pharmaceutical ingredients (API) represents one main issue for formulators as inadequate aqueous solubility may hinder development of parenterals for IV, IM or SC administration. Many new therapeutic compounds are of poor solubility; such compounds with insufficient solubility bring along a higher risk of failure during discovery and development since insufficient solubility may compromise both pharmacokinetic and pharmacodynamic properties of the compound. Commonly used excipients have a substantial potential for drug-excipient interactions, e. g. by altering protein binding and blood cell/plasma distribution. In consequence, the formulation vehicle can be an important determinant for the disposition of drug doses. Therefore, solubility may affect the overall commercial developability of the compound.

Solubility of peptides may range from low micrograms per ml to several hundreds of milligrams per ml, and is often very specific for the respective class of peptides. Even rather small structural differences can lead to significant changes in the characteristics of the respective class of peptides, including rather dramatic changes in the solubility. The required dose and route of administration may demand a higher concentration than possible in simple formulations, challenging the development of a clinically or commercially viable product. One important challenge is that peptides and proteins are typically administered via injections due to poor bioavailability by other delivery which restricts the types and concentration of excipients. On top, only small volumes of administration are appropriate for subcutaneous and intramuscular delivery routes in order to comply with patient compliance and ease of delivery, in contrast to volume and concentration constraints as known for intravenous administration settings. For subcutaneously delivery approximately 1.5 mL may be considered acceptable, preferably presented as clear solutions of low viscosity. This requires formulations which contain up to hundreds of mg/mL peptide or protein. Moreover, toxicological studies may assess approximately 10-fold higher doses than those planned for clinical studies in order to establish a safety window. This necessitates even higher concentrations for non- clinical formulations than for clinical formulations.

During formulation development, excipients are added to enhance the API's solubility (solubilizers) and/or stability (buffers, antioxidants, and chelating agents), as well as to assure safety (antimicrobial preservatives), to minimize pain and irritation upon injection (tonicity agents), and control or prolong drug delivery (polymers). On the down-side, incorporation of excipients, such as surfactants, can enhance solubility but may have negative impact on regulatory approval, toxicity and/or overall stability of the drug product.

Active pharmaceutical ingredients that belong to the class of peptidic compounds generally additionally face stability problems in many types of formulations. In formulations having about neutral pH-values, the peptides tend to show satisfying stability, but a rather low or even very low solubility in the presence of many solvents and/or excipients, even solvents and/or excipients having a rather high polarity, e.g. water. In formulations showing lower or higher than neutral pH-values, however, the solubility of said peptidic compounds often dramatically increases, but in most cases also the degradation of the peptidic structure increases dramatically. Detailed Description of the Invention

Subject of the instant invention is therefore to provide an advantageous formulation for cyclic oligopeptides as described herein, and compounds for use as formulation partners with advantageous effects on the desired formulation of said peptides.

Preferably, said formulation and/or said formulation partners should provide for more stable formulations of said peptides, higher concentration of said peptides in said formulations, improved routes or forms of administration of said formulation, an improved pharmacological profile of said formulation, an improved efficacy and/or an optimised efficacy at a comparable dose or even at a lower dose when applied to the respective patient.

Subject of the instant invention thus is a new formulation in form of a solution or preferably a pharmaceutical solution as described below. The new formulationin form of a solution or preferably a pharmaceutical solution as described below preferably shows one or more of the advantageous properties described herein. Thus, subjects of the instant invention are:

A solution, preferably a pharmaceutical solution, comprising

a) 1 to 60 %, more preferably 2 to 40 %, even more preferably 5 to 30 %, even more preferably 5 to 15 % and especially 5 to 10 % of at least one cyclic oligopeptide consisting of 2 to 12 amino acids as described herein, said cyclic oligopeptide preferably having a solubility in water at 20°C between 10 mg/ml and 100 mg/ml, preferably between 10 mg/ml and 70 mg/ml, more preferably between 12 mg/ml and 50 mg/ml, even more preferably between 14 mg/ml and 30 mg/ml, and especially between 15 mg/ml and 25 mg/ml,

b) 1 to 60 % , more preferably 2 to 40 %, even more preferably 5 to 30 % and especially 5 to 15 % of one or more amphiphilic compounds

comprising a polyol moiety and having a molar weight in the range of 200 g/mol to 2000 g/mol, preferably 300 g/mol to 1500 g/mol, more preferably 500 g/mol to 1000 g/mol, and especially 600 g/mol to 900 g/mol, and c) 39 to 98%, more preferably 59 to 97 %, even more preferably 70 to 95 % and especially 75 to 90 % of water or physiologic saline, preferably water;

with the proviso that the sum of a), b) and c) makes up to 40 or more %, preferably 50 or more percent, more preferably 70 or more percent, even more preferably 90 percent or more and especially 95 percent or more, of the total solution.

The solubilty of said cyclic oligopeptide(s) is preferably determined as described herein. ¹

If not explicitly stated otherwise, the percentages (%) given with respect to the instant invention and especially the percentages (%) given with respect to the solutions according to the invention are preferably selected from i) percent by weight (% by weight or % w/w),

ii) percent by volume (% by volume or % v/v), and

iii) percent weight by volume (% weight by volume or % w/v, e.g. % mg/mL)

For ease of use, percent by weight and percent weight by volume are prefered and percent weight by volume is especially preferred, especially with respect to the solutions according to the invention.

Amphiphilic compounds according to the invention in the broadest sense preferably are molecules which comprise both a polar (hydrophilic) moiety or group and an apolar (hydrophobic or lipophilic) moiety or group;

preferably, the amphiphilic compounds according to the invention show interfacial activity and/or surface activity. For example, they preferably are surface active agents and/or surfactants, or preferably are able to act as surface active agents and/or surfactants.

Preferably, the amphiphilic compounds according to b) comprise:

a) a glycerol moiety,

and at least one moiety selected from

β) one or more fatty acid moieties and

γ) one or more fatty alcohol moieties.

More preferably, the amphiphilic compounds according to b) comprise: a) a glycerol moiety, and

β) one or more fatty acid moieties.

A glycerol moiety according to the invention preferably is a moiety that is derived from glycerol or can be derived from glycerol. More specifically, the glycerol moiety is preferably selected from the following structures in the squares:

wherein R , R², R³, R⁴ and R⁵ are independently from each other are selected from H, methyl, ethyl and hydrophilic moieties, more preferably from H and hydrophilic moieties;

preferably with the proviso that only one or two of R¹, R², R³, R⁴ and R⁵ are hydrophilic moieties, and more preferably that only one of R¹, R², R³, R⁴ and R⁵ is a hydrophilic moiety;

and all salts and/or stereoisomers thereof. The glycerol moiety is preferably selected from the following structures in the squares:

wherein R is selected from methyl, ethyl and hydrophilic moieties, more preferably from methyl and hydrophilic moieties;

and all salts and/or stereoisomers thereof.

Hydrophilic moieties in this regard are preferably selected from the group consisting of:

a) -OH, -ONa, -OK, -O-, -NH₂, -NH₃ ⁺, -IS CH^*. -PO₃H, -PO₃Na, -PO₃K,

-PO₃ ^", -O-PO₃H, -O-PO₃Na, -O-PO₃K, -O-PO₃ ^";

β) -(CH₂)_n-OH, -(CH₂)n-ONa, -(CH₂)_n-OK, -(CH₂)„-0-, -(CH₂)_n-NH₂,

-(CH₂)_n-NH₃ ⁺, -(CHzJn-NiCHa , -(CH₂)_n-PO₃H, -(CH₂)_n-PO₃Na,

-(CH₂)_n-PO₃K, -(CH₂)_n-PO₃-, -(CH₂)n-O-PO₃H, ^'-(CH₂)n-O-PO₃Na₎

-(CH₂)_n-O-PO₃K, -(CH₂)_n-O-PO₃-,

wherein n is 1 , 2, 3 or 4, preferably 1 , 2 or 3 and especially 1 or 2; and/or γ) an ethanolamine moiety, a choline moiety, a phosphatidyl moiety, a phosphatidylcholine moiety, a sulfatidyl and a sulfatidylcholine moiety; and a salt or other salt thereof.

A fatty acid moiety in the context of the instant invention preferably is a moiety that is derived from a fatty acid or can be derived from a fatty acid. More preferably, a fatty acid moiety is the part of fatty acid, preferably a fatty acid as defined below, that is chemically bound to another moiety, e.g. esterified to another moiety, that is part of said amphiphilic compound.

The meaning of the term fatty acid is well known in the art and is preferably to be understood here in its broadest context. More preferably, a fatty acid in the context of the instant invention is an aliphatic saturated or (ethylenically) unsaturated, branched or unbranched carboxylic acid having 4 to 35 carbon atoms, more preferably 6 to 30 carbon atoms and especially 8 to 25 carbon atoms. Even more preferably, a fatty acid in the context of the instant invention is an aliphatic saturated or once, twice, three times or four times (ethylenically) unsaturated, branched or unbranched, preferably unbranched, carboxylic acid having 4 to 35 carbon atoms, more preferably 6 to 30 carbon atoms and especially 8 to 25 carbon atoms. Even more preferably, a fatty acid in the context of the instant invention is an aliphatic saturated or once or twice (ethylenically) unsaturated, branched or unbranched, preferably unbranched, carboxylic acid having 4 to 35 carbon atoms, more preferably 6 to 30 carbon atoms and especially 8 to 25 carbon atoms.

Thus, the fatty acid moiety according to the invention preferably is one of the structures given in the squares below, whereas the structures in the circles constitute the fatty acid as the whole:

Thus, especially preferably, a fatty acid moiety according to the invention the acyl moiety or acyl residue of the corrsponding fatty acid.

Even more preferred fatty acid moieties are selected from the following formulae:

wherein m is 2 to 33, more preferably 4 to 28 and even more preferably 6 to 23;

wherein

p is 1 to 20, more preferably 3 to 18, even more preferably 4 to 15 and especially 6 to 13,

q is 0 to 6, more preferably 1 to 5, more preferably 1 , 2, 3, or 4 and especially 1 , 2 or 3,

r is 1 to 20, more preferably 3 to 15, even more preferably 6 to 12 and especially 6, 7 or 8,

preferably with the proviso that the sum of p and r is 4 to 30, more preferably 5 to 25, even more preferably 8 to 22 and especially 10 to 20 and/or with the proviso that the sum of p, q and r is 5 to 30, more preferably 6 to 25, even more preferably 9 to 23 and especially 11 to 21 ;

wherein

r is 1 to 20, more preferably 3 to 15, even more preferably 6 to 12 and especially 6, 7 or 8, and

s is 1 to 20, more preferably 1 to 15, even more preferably 1 to 10 and especially 1 to 5,

preferably with the proviso that the sum of p, r and s is 4 to 30, more preferably 5 to 25, even more preferably 8 to 22 and especially 10 to 20 and/or with the proviso that the sum of p, q, r and s is 5 to 30, more preferably 6 to 25, even more preferably 9 to 23 and especially 11 to 21 and/or

wherein

p is 1 to 20, more preferably 3 to 15, even more preferably 6 to 12 and especially 6, 7 or 8,

r is 1 to 20, more preferably 3 to 18, even more preferably 4 to 15 and especially 6 to 12, and s is 0 to 6, more preferably 1 to 5, more preferably 1 , 2, 3, or 4 and especially 1 , 2 or 3,

t is 1 to 20, more preferably 1 to 15, even more preferably 1 to 10, even more preferably 3 to 8 and especially 4, 5, 6, 7 or 8,

preferably with the proviso that the sum of p, r and t is 4 to 30, more preferably 6 to 25, even more preferably 8 to 22 and especially 10 to 20 and/or with the proviso that the sum of p, q, r, s and t is 5 to 30, more preferably 7 to 25, even more preferably 9 to 23 and especially 11 to 21.

Even more preferably, the fatty acid moieties are selected from the group of:

and, in case of the unsaturated fatty acid moieties, all stereoisomers thereof.

Even more preferably, the fatty acid moieties are selected from the group consisting of myristoyi (corresponds to myristic acid), oleoyi (corresponds to oleic acid), palmitoyl (corresponds to palmitic acid), stearoyl

(corresponds to stearic acid), margaroyl (corresponds to margaric acid), arachidoyl (corresponds to arachic or arachidic acid), behenoyl

(corresponds to behenic acid), erucoyl (corresponds to erucic acid), linoleoyl (corresponds to linoleic acid) and linolenoyl (corresponds to linolenic acid).

Even more preferably, the fatty acid moieties are selected from the group consisting of myristoyi, oleoyi, palmitoyl and stearoyl. A fatty alcohol moiety in the context of the instant invention preferably is a moiety that is derived from a fatty alcohol or can be derived from a fatty alcohol. More preferably, a fatty alcohol moiety is a fatty alcohol, preferably a fatty alcohol as defined below, that is chemically bound to another moiety, e.g. esterified to another moiety, that is part of said amphiphilic compound. The meaning of the term fatty alcohol is well known in the art and is preferably to be understood here in its broadest context. More preferably, a fatty alcohol in the context of the instant invention is an aliphatic saturated or (ethylenically) unsaturated, branched or unbranched carboxylic acid having 4 to 35 carbon atoms, more preferably 6 to 30 carbon atoms and especially 8 to 25 carbon atoms. Even more preferably, a fatty alcohol in the context of the instant invention is an aliphatic saturated or once, twice, three times or four times (ethylenically) unsaturated, branched or unbranched, preferably unbranched, carboxylic acid having 4 to 35 carbon atoms, more preferably 6 to 30 carbon atoms and especially 8 to 25 carbon atoms. Even more preferably, a fatty alcohol in the context of the instant invention is an aliphatic saturated or once or twice (ethylenically) unsaturated, branched or unbranched, preferably unbranched, alcohol having 4 to 35 carbon atoms, more preferably 6 to 30 carbon atoms and especially 8 to 25 carbon atoms. Typically, such fatty alcohols are derived, can be derived or are obtainable from the

corresponding alcohol, e.g. by a reduction of the corresponding fatty acid.

Thus, the fatty alcohol moiety according to the invention preferably are the structures given in the squares below, whereas the structures in the circles constitute the fatty alcohol as the whole:

Thus, especially preferably, a fatty alcohol moiety according to the invention is the alkyl moiety or alkyl residue of the corrsponding fatty alcohol. Such fatty alcohols can be obtained, for example, by reducing the herein described fatty acids to the corresponding alcohol. Even more preferred fatty alcohol moieties are selected from the following formulae:

wherein m is 2 to 33, more preferably 4 to 28 and even more preferably 6 to 23;

wherein

wherein

preferably with the proviso that the sum of p, r and s is 4 to 30, more preferably 5 to 25, even more preferably 8 to 22 and especially 10 to 20 and/or with the proviso that the sum of p, q, r and s is 5 to 30, more preferably 6 to 25, even more preferably 9 to 23 and especially 11 to 21 ; and/or

wherein

r is 1 to 20, more preferably 3 to 18, even more preferably 4 to 15 and especially 6 to 12, and

s is 0 to 6, more preferably 1 to 5, more preferably 1 , 2, 3, or 4 and especially 1 , 2 or 3,

preferably with the proviso that the sum of p, r and t is 4 to 30, more preferably 6 to 25, even more preferably 8 to 22 and especially 10 to 20 and/or with the proviso that the sum of p, q, r, s and t is 5 to 30, more preferably 7 to 25, even more preferably 9 to 23 and especially 11 to 21. Even more preferably, the fatty alcohol moieties are selected from the group of:

Even more preferably, the fatty alcohol moieties are independently selected from the alkyl residues of the fatty alkohols of the group

consisting of oleic alcohol, myristic alcohol, palmitic alcohol, stearic alcohol, margaric alcohol, arachic alcohol, behenic alcohol, erucic alcohol, linolic alcohol and linolenic alcohol.

Preferred are solutions as described herein, wherein

at least one of the amphiphilic compounds according to b) comprises a hydrophilic moiety. Suitable hydrophilic moieties are known to the skilled artisan.

Preferred are solutions as described herein, wherein the hydrophilic moiety comprises a phosphatidyl moiety and/or a sulfatidyl moiety, and/or a salt thereof, or more preferably is a phosphatidyl moiety and/or a salt thereof.

Preferred are solutions as described herein, wherein the hydrophilic moiety comprises a phosphatidylglycerol moiety and/or a sulfatidylglycerol moiety, and/or a salt thereof, or more preferably is a phosphatidylglycerol moiety and/or a sulfatidylglycerol moiety, and/or a salt thereof.

Preferably, the solutions according to the invention are essentially free of amphiphilic compounds comprising a choline moiety, a

phosphatidylcholine moiety and/or a salt thereof.

As regards the salts thereof, a basic hydrophilic moiety can be present as a salt, such as an acid addition salt, or can be converted into a salt with an acid, such as into the associated acid addition salt, for example by reacting equivalent quantities of the compound comprising the basic hydrophilic moiety and the acid in an inert solvent such as ethanol and then

concentrating by evaporation. Suitable acids for such salts are, in particular, those which give rise to physiologically harmless salts. Thus, use can be made of inorganic acids, for example sulphuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, and sulphamic acid, and, in addition, organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulphonic or sulphuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulphonic acid, ethanesulphonic acid, ethanedisulphonic acid, 2-hydroxyethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid,

naphthalenemonosulphonic acid, naphthalenedisulphonic acid and lauryl sulphuric acid. Alternatively, an acidic hydrophilic moiety can be present as a salt, such as a base addition salt, or can be converted into a salt with a base, e.g. into the associated base addition salt. In this regard, the sodium, potassium, magnesium, calcium and ammonium salts of the acidic hydrophilic moieties are particularly preferred. Also preferred are

substituted ammonium salts, for example the dimethyl-, diethyl- or diisopropylammonium salts, monoethanol-, diethanol- or

diisopropylammonium salts, cyclohexyl- and dicyclohexylammonium salts, and dibenzylethylenediammonium salts, and also, for example, salts with arginine or lysine.

Especially preferred in this regard are the sodium salts, the potassium salts, ammonium salts and the hydrochloric acid salts.

Thus, even more preferred are amphiphilic lipids having a) phosphatidyl-glycerol or sulfatidyl-glycerol moieties, preferably as the hydrophilic part, and

β) one or two, preferably two fatty acid moieties, preferably as the lipophilic part,

and derivatives, salts and/or alcoholates thereof and more preferably the salts thereof.

A subject of the instant invention is a solution, preferably a pharmaceutical solution, comprising

a) 1 to 60 % of at least one cyclic peptide consisting of 3 to 6 naturally occurring amino acids and 0 to 4 amino acids, selected from non-naturally occurring amino acids or synthetically modified naturally occurring amino acids,

b) 1 to 60 % of one or more surface active compounds, selected from amphiphilic lipids having phosphatidyl- or sulfatidyl-polyol groups and derivatives, salts and/or alcoholates thereof, as the hydrophilic part, c) 20 to 98 % of water,

with the proviso that the sum of a), b) and c) makes up to 40 or more % of the total solution.

Preferably, the solution comprises

b) 1 to 60 % of one or more surface active compounds, selected from amphiphilic lipids having

i) phosphatidyl-glycerol groups and derivatives, salts and/or alcoholates thereof,

and/or

ii) sulfatidyl-glycerol groups and derivatives, salts and/or alcoholates thereof, as the hydrophilic part,

c) 20 to 98 % of water,

More preferably, the solution comprises

b) 1 to 60 % of one or more surface active compounds, selected from amphiphilic lipids having phosphatidyl-glycerol groups and derivatives, salts and/or alcoholates thereof, as the hydrophilic part,

c) 20 to 98 % of water,

Thus, one subject of the instant invention is a solution, preferably a pharmaceutical solution, comprising

a) 1 to 60 % of at least one cyclic peptide, preferably a pharmaceutically active cyclic peptide, consisting of 3 to 6 naturally occurring amino acids and 0 to 4 amino acids, selected from non-naturally occurring amino acids or synthetically modified naturally occurring amino acids,

b) 1 to 60 % of one or more compounds, preferably surface active compounds, selected from

b1) fatty acid mono-, di- or polyesters of phosphatidyl- or sulfatidyl-polyols, and derivatives, salts and/or alcoholates thereof, and

b2) fatty alcohol mono-, di- or polyethers of phosphatidyl- or sulfatidyl- polyols, and derivatives, salts and/or alcoholates thereof,

and

c) 20 to 98 % of water, with the proviso that the sum of a), b) and c) makes up to 40 or more % of the total solution.

More preferably, the sum of a), b) and c) makes up to 50 or more % of the total solution. Even more preferably, the sum of a), b) and c) makes up to 60 or more % of the total solution. Even more preferably, the sum of a), b) and c) makes up to 70 or more % of the total solution. Even more preferably, the sum of a), b) and c) makes up to 80 or more % of the total solution. Especially preferably, the sum of a), b) and c) makes up to 90 or more % of the total solution, such as about 93 % or more, about 95 % or more, about 97 % or more, or about 99 % or 100 %, of the total solution. The solution according to the invention can essentially consist of a), b) and c). However, it can comprise up to 40 %, preferably up to 30 %, more preferably up to 20 %, even more preferably up to 10 % and especially up to 5 %, of the total solution, compounds and/or exciepients other than a), b) and c).

More preferably, the sum of a), b) and c) makes up to 50 or more % by weight of the total weight of the solution. Even more preferably, the sum of a), b) and c) makes up to 60 or more % by weight of the total weight of the solution. Even more preferably, the sum of a), b) and c) makes up to 70 or more % by weight of the total weight of the solution. Even more preferably, the sum of a), b) and c) makes up to 80 or more % by weight of the total weight of the solution. Especially preferably, the sum of a), b) and c) makes up to 90 or more % by weight of the total weight of the solution, such as about 93 % or more, about 95 % or more, about 97 % or more, or about 99 % or 100 %, by weight of the total weight of the solution.

More preferably, the solution according to the invention can essentially consist of a), b) and c). However, it can comprise up to 40 %, preferably up to 30 %, more preferably up to 20 %, even more preferably up to 10 % and especially up to 5 %, by weight of the total weight of the solution, compounds and/or exciepients other than a), b) and c).

If the solution according to the invention comprises compounds and/or excipients other than a), b) and c), said compounds and/or excipients are preferably selected from further active ingredients, preferably further pharmaceutically active ingredients, and further excipients and/or auxilliaries, preferably pharmaceutically accetable excipients and/or auxilliaries. Excipients and/or auxilliaries and especially pharmaceutically accetable excipients and/or auxilliaries are known in the art, e.g. from Europaisches Arzneibuch, 6. Ausgabe, CD-ROM Official German Edition, US Pharmacopeia 29, European Pharmacopeia, and/or Deutsches Arzneimittelbuch, preferably in the respective current version or newer.

Preferably, the solutions according to the invention do not comprise active ingredients other than the oligppeptides as defined herein.

More preferably, the solutions according to the invention do not comprise further pharmaceutically active ingredients other than the oligppeptides as defined herein.

Preferred excipients include, but are not limited to tonicity agents and/or preservatives. Preservatives in this regard preferably are antimicrobial preservatives.

Examples of preservatives, preferably pharmaceutically accetable preservatives are known in the art, e.g. from Swarbrick, Pharmaceutical Technology.

In the context of the present invention, the water according to c) of the solution can preferably be substituted, partially or totally, by isotonic saline or physiologic saline, e.g. saline for infusion. In the context of the instant invention, the isotonic saline, physiologic saline or saline for infusion is preferably a solution of about 0.9 weight percent of NaCI in water.

Thus, a preferred subject of the instant invention is a solution, preferably a pharmaceutical solution, essentially consisting or preferably consisting of i) 1 to 60 % by weight, more preferably 2 to 40 % by weight, even more preferably 5 to 30 %, even more preferably 5 to 15 % and especially 5 to 10 % by weight of one or more compounds a) as defined herein;

ii) 1 to 60 % by weight, more preferably 2 to 40 % by weight, even more preferably 5 to 30 % and especially 5 to 15 % by weight of one or more compounds b) as defined herein;

iii) 39 to 98%, more preferably 59 to 97 % by weight, even more preferably 70 to 95 % and especially 75 to 90 % by weight of water or physiologic saline, preferably water;

and optionally

iv) 0 to 20%, preferably 0 to 15%, more preferably 0 to 10% and especially 0 to 5% of one or more compounds or ingredients other than compounds a) as defined herein, compounds b) as defined herein, and water or physiologic saline.

In the solutions according to the invention, the weight ratio between compounds a) as defined herein and compounds b) as defined herein is preferably in the range of 1:4 to 4:1 , more preferably in the range between 3:1 and 1 :3, even more preferably in the range between 2:1 and 1 :2, and especially in the range between 3:2 and 2:3. Especially preferably, the weight ratio between compounds a) as defined herein and compounds b) as defined herein is about 1 :1.

In the solutions according to the invention, the weight ratio between c) and the sum of compounds a) plus compounds b) as defined herein is preferably in the range between 20:1 and 3:1 , more preferably in the range between 15:1 and 4:1 , even more preferably in the range between 10:1 and 5:1.

In the solutions according to the invention, the weight ratio between water or physiologic saline and the sum of compounds a) plus compounds b) as defined herein is preferably in the range between 20:1 and 3:1, more preferably in the range between 15:1 and 4:1 , even more preferably in the range between 10:1 and 5:1.

Compounds according to b), b1) and/or b2) for use in the solutions according to the invention and preferably surface active compounds b), b1) and/or b2) for use in the the solutions according to the invention are preferably known in the art or can be readily determined in accordance with the teaching of the instant invention.

Preferably, the compounds according to b) and especially according to b1) are selected from the group consisting of:

fatty acid monoesters of phosphatidylpolyols, and derivatives, salts and alcoholates therof;

fatty acid diesters of phosphatidylpolyols, and derivatives, salts and alcoholates therof;

and the salts and alcoholates therof;

fatty acid triesters of phosphatidylpolyols, and derivatives, salts and alcoholates therof;

fatty acid polyesters of phosphatidylpolyols, and derivatives, salts and alcoholates therof;

fatty acid monoesters of sulfatidylpolyols, and derivatives, salts and alcoholates therof;

fatty acid diesters of sulfatidylpolyols, and derivatives, salts and

alcoholates therof;

and the salts and alcoholates therof; fatty acid triesters of sulfatidylpolyols, and derivatives, salts and

alcoholates therof;

fatty acid polyesters of sulfatidylpolyols, and derivatives, salts and alcoholates therof.

Preferably, the compounds according to b) and especially according to b2) are selected from the group consisting of:

fatty acid monoethers of phosphatidylpolyols, and derivatives, salts and alcoholates therof;

fatty alcohol diethers of phosphatidylpolyols, and derivatives, salts and alcoholates therof;

and the salts and alcoholates therof;

fatty alcohol triethers of phosphatidylpolyols, and derivatives, salts and alcoholates therof;

fatty alcohol poiyethers of phosphatidylpolyols, and derivatives, salts and alcoholates therof;

fatty alcohol monoethers of sulfatidylpolyols, and derivatives, salts and alcoholates therof;

fatty alcohol diethers of sulfatidylpolyols, and derivatives, salts and alcoholates therof;

and the salts and alcoholates therof;

fatty alcohol triethers of sulfatidylpolyols, and derivatives, salts and alcoholates therof;

fatty alcohol poiyethers of sulfatidylpolyols, and derivatives, salts and alcoholates therof.

Phosphatidylpolyols according to the invention preferably comprise mono- and pyrophosphatidylpolyols, including, but not limited to,

monophosphatidylpolyols, diphosphatidylpolyols, triphosphatidylpolyols, tetraphosphatidylpolyols and higher polyphosphatidylpolyols. Preferably, the phosphatidylpolyols according to the invention are selected from monophosphatidylpolyols, diphosphatidylpolyols and

triphosphatidylpolyols.

Sulfatidylpolyols according to the invention preferably comprise mono- and pyrosulfatidylpolyols, including, but not limited to, monosulfatidylpolyols, disulfatidylpolyols, trisulfatidylpolyols, tetrasulfatidylpolyols and higher polypsulfatidylpolyols. Preferably, the sulfatidylpolyols according to the invention are selected from monosulfatidylpolyols, disulfatidylpolyols and trisulfatidylpolyols.

The term "polyols" as used herein is known in the art. Preferably, the term "polyols" as used herein indicates a moiety derived from straight-chain or branched hydrocarbon group substituted with oxygen-containing functional groups and including at least two hydroxy groups. Even more preferably, the term "polyols" as used herein indicates a moiety derived from straight- chain or branched hydrocarbon group only substituted with oxygen- containing functional groups and including at least two hydroxy groups.

Polyols are preferably derived from structures substituted only with hydroxy groups. Preferred polyols are particularly derived from diols, triols, tetrols, pentols and hexols of (where appropriate) ethyl, propyl, butyl, pentyl, hexyl and heptyl groups including all isomeric forms thereof without other functional groups being present. Evidently, when included as part of a sulphatidyl or phosphatidy polyol component, at least one -OH group of the polyol moiety will be converted to the respective -O-S or -O-P group as appropriate.

Preferred for use according to the invention are phosphatidylpolyols and/or sufatidylpolyols, wherein the polyol-substructure therein is preferably derived or selected from diols, triols, tetrols, pentols and hexols, including, but not limited to glycol, propanediols, including, but not limited to propane-

1 ,3-diol and propane-1,2-diol, diethylene glycol, glycerol, butanediols, including, but not limited to butane-1 ,2-diol, butane-1 ,3-diol, butane-1 ,4- diol, butane-2,2-diol, butane-2,3-diol, butanetriols, including, but not limited to 2-Hydroxymethyl-propane-1 ,3-diol, 2-Methyl-propane-1 ₎2,3-triol, butane- 1 ,2,3-triol and butane-1 ,2,4-triol, and 1 ,2,3,4-butane1 ,2,3,4-tetrol, including, but not limited to erythritol and threitol.

More preferred for use according to the invention are phosphatidylpolyols and/or sufatidylpolyols, wherein the polyol-substructure therein is preferably derived or selected from diols, triols and tetrols, and espcially selected from triols, preferably triols as described above.

Compounds of part b) herein are lipids and as such will be understood by the skilled worker to comprise a polar "head" group and generally to comprise one or more non-polar "tail" groups. As indicated herein the polar head groups will comprise phosphatidyl- or sulfatidyl-polyol groups and more desirably the preferable groups referred to herein. As indicated above, these may be linked by ether and/or ester bonds to appropriate fatty alcohols or acids forming the non-polar "tail" groups.

Examples of non-polar groups forming the tail part of the lipid components include C6-C32 alkyl and alkenyl groups, which present as the esters or ethers of long chain carboxylic acids or alcohols respectively. These are often described in the art by reference to the number of carbon atoms and the number of unsaturations in the carbon chain. Thus, CX:Z indicates a hydrocarbon chain having X carbon atoms and Z unsaturations. Examples particularly include caproyl (C6:0), capryloyl (C8:0), capryl (C10:0), lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoyl (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2), linolenoyl (C18:3), arachidonoyl (C20:4), behenoyl (C22:0) and lignoceroyl (C24:9) groups. Thus, typical non-polar chains are based on the fatty acids of natural ester lipids, or fatty alcohols for correponding ethers. These include caproic, caprylic, capric, lauric, myristic, palmitic, phytanic, palmitolic, stearic, oleic, elaidic, linoleic, linolenic, arachidonic, behenic or lignoceric acids, or the corresponding alcohols. In all cases, where more than one non-polar chain is present, these may be the same or different. Preferable non-polar chains are myristic, palmitic, stearic, oleic and linoleic acids and alcohols (or mixtures thereof), particularly oleic acid and oleic alcohol. Fatty acids and thus their corresponding ester-linked lipids are preferred in the present invention, particularly oleic acid.

Especially preferably, the fatty acids are in each case independently selected from the group consisting of myristic acid, oleic acid, palmitic acid, stearic acid, margaric acid, arachic or arachidic acid, behenic acid, erucic acid, linoleic acid and linolenic acid. Even more preferably, the fatty acids are in each case independently selected from the group consisting of myristic acid, oleic acid, palmitic acid and stearic acid.

Thus, in the fatty acid esters comprising more than one fatty acid, the fatty acids can be all the same or different. For example, in a fatty acid diester, both fatty acid moieties can be the same, e.g. both oleoyi or both palmitoyi, or different, e.g. one oleoyi and one palmitoyi. Alternatively, fatty acid diesters or triesters can comprise two or more different fatty acid moieties in a mixture, e.g. a statistical mixture.

Thus, preferred amphiphilic compounds according to the invention are preferably selected from one or more of the following formulae:

wherein

α) R , R², R³, R⁴ and R⁵ are independently from each other are selected from H, methyl, ethyl and hydrophilic moieties, more preferably from H, methyl and ethyl;

preferably with the proviso that only one or two of R¹, R², R³, R⁴ and R⁵ are other than H, and more preferably that only one of R¹, R², R³, R⁴ and R⁵ is other than H;

β) R^a, R^b and R^c are independently from each other are selected from H and R⁶,

wherein each R⁶ is independently selected from the group consisting of

i) fatty acid moieties and fatty alcohol moieties, preferably fatty acid moieties and fatty alcohol moieties as described herein and especially fatty acid moieties as described herein, and

ii) hydrophilic moieties, preferably hydrophilic moieties as described herein;

with the proviso that one or more of R^a, R^b and R^c, preferably two or more of R^a, R^b and R^c and especially all of R^a, R^b and R^c are R⁶,

and with the further proviso that only one or two, preferably only one of R⁶ is a hydrophilic moiety;

and the salts and/or stereoisomers thereof, and preferably the salts thereof.

Thus, more preferred amphiphilic compounds according to the invention and/or amphiphilic lipids according to the invention are preferably selected from the following formula:

wherein

R^a, R^b and R^c are independently from each other are selected from

H and R⁶,

wherein each R⁶ is independently selected from the group consisting of i) fatty acid moieties and fatty alcohol moieties, preferably fatty acid moieties and fatty alcohol moieties as described herein and especially fatty acid moieties as described herein, and

ii) hydrophilic moieties, preferably hydrophilic moieties as described herein; with the proviso that one or more of R^a, R^b and R°, preferably two or more of R^a, R^b and R^c and especially all of R^a, R^b and R^c are R⁶,

and with the further proviso that only one or two, preferably only one of R⁶ is a hydrophilic moiety,

and the salts and/or stereoisomers thereof, and preferably the salts thereof.

Thus, even more preferred amphiphilic compounds according to the invention and/or amphiphilic lipids according to the invention are preferably selected from the following formula:

wherein a) both R^a and R^b independently of each other are selected from acid moieties and fatty alcohol moieties, preferably fatty acid moieties and fatty alcohol moieties as described herein and especially fatty acid moieties as described herein.and R° is a hydrophilic moiety, preferably a hydrophilic moiety as described herein,

b) both R^a and R^c independently of each other are selected from acid moieties and fatty alcohol moieties, preferably fatty acid moieties and fatty alcohol moieties as described herein and especially fatty acid moieties as described herein.and R^b is a hydrophilic moiety, preferably a hydrophilic moiety as described herein, or

c) both R^b and R^c independently of each other are selected from acid moieties and fatty alcohol moieties, preferably fatty acid moieties and fatty alcohol moieties as described herein and especially fatty acid moieties as described herein.and R^a is a hydrophilic moiety, preferably a hydrophilic moiety as described herein

and the salts and/or stereoisomers thereof, and preferably the salts thereof.

With regard to R^a, R^b and/or R^c the hydrophilic moieties are preferably selected from the group consisting of:

i) -PO3H, -P0₃Na, -PO3K, -PO3^";

ii) -(P0₂-0)_v-P0₃H, -(P0₂-0)_v-P0₃Na, -(P0₂-0)v-P0₃K, -(P0₂-0)_v-P0₃ ^" iii) -S0₃H, -S0₃Na, -SO₃K, -S0₃ ^";

iv) -(S0₂-0)_w-S0₃H, -(S0₂-0)_w-S0₃Na, -(SO₂-0)_w-S0₃K, -(S0₂-O)_w-S0₃ ^" v) -(CH₂)n-OH, -(CH₂)_n-ONa, -(CH₂)_n-OK, -(CH₂)_n-0-, -(CH₂)_n-NH₂,

-(CH₂)n-NH₃ ⁺, -(CH^n-NiCH^, -(CH₂)_n-PO₃H, -(CH₂)_n-P0₃Na, -(CH₂)_n-P0₃K, -(CH₂)_n-PO₃-, -(CH₂)_n-0-PO₃H, -(CH₂)_n-0-P0₃Na, -(CH₂)_n-O-P0₃K, -(CH₂)_n-0-P0₃- vi) -(CH₂)n-(P0₂-0)_x-P0₃H, -(CH₂)_n-(P0₂-0)_x-P0₃Na, -(CH₂)_n-(P0₂-0)_x- P0₃K, -(CH₂)n-(PO₂-0)_x-P0₃-, vii) -(CH₂)n-(S02-0)_y-S0₃H, -(CH₂)_n-(S0₂-0)_y-S0₃Na, -(CH₂)_n-(S0₂-0)_y S0₃K, -(CH₂)_n-(S0₂-0)_y-SO₃-,

wherein

n is 1 , 2, 3 or 4, preferably 1 , 2 or 3 and especially 1 or 2, v is 1 , 2, 3 or 4, preferably 1 , 2 or 3 and especially 1 or 2, w is 1 , 2, 3 or 4, preferably 1 , 2 or 3 and especially 1 or 2, x is 1 , 2, 3 or 4, preferably 1 , 2 or 3 and especially 1 or 2, and y is 1 , 2, 3 or 4, preferably 1 , 2 or 3 and especially 1 or 2;

and/or

γ) a phosphatidyl moiety and a sulfatidyl moiety;

and a salt or other salt thereof.

With regard to R^a, R^b and/or R^c the hydrophilic moieties are even more preferably selected from the group consisting of:

i) -PO₃H, -P0₃Na, -PO₃K, -P0₃ ^";

ii) -(PO₂-O)_v-P0₃H, -(P0₂-O)_v-P0₃Na, -(P0₂-0)_v-P0₃K, -(PO₂-0)_v-P0₃ iii) -(CH₂)_n-OH, -(CH₂)_n-ONa, -(CH₂)_n-OK, -(CH₂)„-0-, -(CH₂)_n-NH₂₎ -(CH₂)_n-NH₃ ⁺, -(CHzJn-N CHs , -(CH₂)_n-P0₃H, -(CH₂)_n-P0₃Na, -(CH₂)_n-P0₃K, -(CH₂)_n-PO₃-, -(CH₂)_n-0-P0₃H, -(CH₂)_n-O-P0₃Na, -(CH₂)n-0-P0₃K, -(CH₂)_n-0-P0₃-,

wherein

n is 1 , 2, 3 or 4, preferably 1 , 2 or 3 and especially 1 or 2, and v is 1 , 2, 3 or 4, preferably 1 , 2 or 3 and especially 1 or 2, and/or

iv) a phosphatidyl moiety and a sulfatidyl moiety;

and a salt or other salt thereof.

With regard to R^a, R^b and/or R^c, the fatty acid moieties are preferably selected from the group of:

wherein m is 2 to 33, more preferably 4 to 28 and even more preferably 6 to 23;

wherein

wherein

r is 1 to 20, more preferably 3 to 15, even more preferably 6 to 12 and especially 6, 7 or 8, and s is 1 to 20, more preferably 1 to 15, even more preferably 1 to 10 and especially 1 to 5,

wherein

With regard to R^a, R^b and/or R^c, the fatty acid moieties are even more preferably selected from the group of:

and, in case of the unsaturated fatty acid moieties, all stereoisomers thereof. With regard to R^a, R^b and/or R°, the fatty acid moieties are even more preferably selected from the group of:

the fatty acid moieties are selected from the group consisting of myristoyl, oleoyl, palmitoyl (corresponds to palmitic acid), stearoyl, margaroyl, arachidoyl, behenoyl, erucoyl, linoleoyl and linolenoyl.

With regard to R^a, R^b and/or R^c, the fatty acid moieties are selected from the group consisting of myristoyl, oleoyl, palmitoyl and stearoyl.

Especially preferred amphiphilic compounds according to the invention and/or amphiphilic lipids according to the invention are preferably selected from dioleoylphosphatidylglycerol (DOPG), distearoylphosphatidylglycerol (DSPG), dipalmitoylglycerophosphoglycerol (DPPG), more preferably dioleoylphosphatidylglycerol (DOPG), dimyristoylphosphatidylglycerol (DMPG), distearoylphosphatidylglycerol (DSPG),

dipalmitoylglycerophosphoglycerol (DPPG), even more preferably dioleoylphosphatidylglycerol (DOPG), dimyristoylphosphatidylglycerol (DMPG), distearoylphosphatidylglycerol (DSPG),

dipalmitoylglycerophosphoglycerol (DPPG), and especially

dioleoylphosphatidylglycerol (DOPG);

and/or the salts thereof, preferably the salts described herein, and especially the alkaline and/or amonium salts thereof. Also preferred are mixtures of said amphiphilic compounds and/or the salts thereof, preferably including mixtures of different salts of the same compound and mixtures of different salts of different compounds.

Particularly preferred compounds b) of the present invention include phosphatidyl glycerols (PGs), particularly diacyl phosphatidyl glycerols (DAPGs). PGs, such as DAPGs, used in the present invention may have the same or different fatty-acyl groups, where more than one fatty acyl group is present. Fatty acyl groups suitable in component b) of the invention, such as in PGs, including DAPGs, are preferably selected from lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoyl (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2) and linolenoyl (C18:3) fatty acyl groups, and mixtures thereof. In one preferred embodiment, the non-polar groups of component b) consist of at least 50%, preferably at least 60% more preferably at least 75% of these indicated fatty acyl groups or their mixtures. Especially preferred amphiphilic compounds and/or the salts thereof according to the invention can preferably also defined by their Chemical

Abstracts Numbers (CAS-Numbers):

DOPG (sodium salt): 67254-28-8

DMPG (sodium salt): 67232-80-8

DSPG (sodium salt): 108347-80-4

DPPG (sodium salt): 42367232-81-9

Even more preferred amphiphilic compounds and/or the salts thereof according to the invention can preferably also defined by their Chemical Abstracts Numbers (CAS-Numbers):

DOPG (sodium salt): 67254-28-8

DMPG (sodium salt): 67232-80-8

DSPG (sodium salt): 108347-80-4

DPPG (sodium salt): 42367232-81-9

Preferably, the ratio a) to b) by weight is in the range of 1 :4 to 4:1 , more preferably 1 :3 to 3:1 and even more preferably 1 :2 to 2:1.

More preferably, the ratio a) to b) by weight is in the range of 1 :3 to 2:1 , more preferably 1 :2 to 2:1 and even more preferably 1 :2 to 3:2, for example about 2:1, about 3:2, about 4:3, about 1 :1 , about 3:4, about 2:3, about 1 :2 or about 1 :3. Preferably, the overall content of surface active compounds other than b), b1) and/or b2) in the solutions according to the invention is 30 % or less, more preferably 20 % or less and especially 10 % or less, by weight based on the total weight of the solution. However, an overall content of surface active compounds other than b), b1 ) and/or b2) of 0-20 %, 0-15 %, 0-10 %, 0-5 % or 0-2 %, based on the total weight of the solution, in the solutions according to the invention may be tolerable. In this regard, the surface active compounds other than b), b1) and/or b2) are preferably selected from soaps, tensides, surfactants and emulsifiers being structurally different from b), b1) and/or b2). More preferably, surface active compounds other than b), b1) and/or b2) are one or more of the following:

Polyalkylene glycols, fatty acid mono -, di- and triesters of polyols, fatty acid mono-, di- and triethers of polyols, fatty acid mono-, di- and triesters of glycerol, fatty acid mono-, di- and triethers of glycerol, free fatty acids, salts of free fatty acids.

The solution, preferably the pharmaceutical solution, according to the invention comprises (a) at least one cyclic peptide consisting of 2 to 6 naturally occuring amino acids and 0 to 4 amino acids, selected from synthetic amino acids or synthetically modified naturally occuring amino acids. More preferably, said at least one cyclic peptide consists of 3 to 6 naturally occuring amino acids and 1 to 4 amino acids, selected from synthetic amino acids or synthetically modified naturally occuring amino acids. Even more preferably, said at least one cyclic peptide consists of 3 to 5 naturally occuring amino acids and 2 to 3 amino acids, selected from synthetic amino acids or synthetically modified naturally occuring amino acids. Especially preferably, said cyclic peptide consists of 2 to 4 naturally occurring amino acids, 1 or 2 synthetic amino acids and 1 or 2 synthetically modified naturally occuring amino acids. Said cyclic pepetide and/or said at least one cyclic peptide, preferably as defined herein, is preferably also referred to as "one or more compounds a)", "compound a)" and or "a)", if not defined otherwise.

The meaning of the term "peptide" or "peptides" is known in the art.

According to the invention, peptides are preferably defined as amides derived from two or more (the same or different) amino carboxylic acid molecules (i.e. amino acids) by formation of a covalent bond from the carbonyl carbon of one to the nitrogen atom of another with formal loss of water. The term is usually applied to structures formed from a-amino acids, but it preferably also includes those derived from any amino carboxylic acid or amino acid.

The meaning of the term "oligopeptide" or "oligopeptides" is known in the art. According to the invention, oligopeptides are preferably defined to be comprised of 3 to 20 amino acids, more preferably 4 to 15 amino acids and especially 4 to 10 amino acids, preferably amino acids as described herein.

Cyclic peptides and methods for obtaining cyclic peptides are known in the art. According to the invention, cyclic peptides are preferably peptides in which a bridge or a link is formed between two amino acids that are part of the peptide or constitute the peptide. The bridge can be formed between amino acids having a reactive group (other than the amino and the carboxyl group that are essential for the respective amino acid), preferably, such as a sulphide group. Generally, peptides comprising two or more, preferably two amino acids having such a reactive group can be cyclised. For example, a peptide comprising two amino acids that have a sulphide group can be cyclised under conditions wherein a disulphite bridge between the sulphide groups of the two amino acids containing a sulphide group is formed. Examples of amino acids having a sulphide group and thus being capable of forming a bridge, i.e. a disulphite bridge include, but are not limited to penicillamine and cysteine. Peptides in which the bonds forming the ring are not solely peptide linkages (or eupeptide linkages according to the lUPAC) are preferably referred to as heterodetic cyclic peptides. In this case, the bonds between the reactive groups (other than the amino and the carboxyl group that are essential for the respective amino acid) forming the ring are preferably referred to as "bridge".

Alternatively, peptides in which the bonds forming the ring are solely peptide linkages (or eupeptide linkages according to the lUPAC) are preferably referred to as homodetic cyclic peptides. According to the invention, both heterodetic cyclic peptides and homodetic cyclic peptides can be used. Generally, peptides comprised of two or more, preferably three or more, even more preferably four or more amino acids can be cyclised. In principle, the number of amino acids in a cyclic peptide is not limited. According to the invention, the cyclic peptides generally do not comprise more than 10 amino acids.

The terms "naturally occurring amino acids", "non-naturally occurring amino acids" and "synthetically modified naturally occuring amino acids" are well understood in the art. However, a non-exhaustive list of non- naturally amino acids, "synthetically modified naturally occuring amino acids" as well as naturally occurring amino acids can preferably be found in "The Peptides", Volume 5 (1983), Academic Press, Chapter VI, by D. C. Roberts and F. Vellacio.

Generally, the term "non-naturally occurring amino acids" is preferably intended to include any small molecule having at least one carboxyl group and at least one primary or secondary amino group capable of forming a peptide bond. The term "peptide" is preferably intended to include any molecule having at least one peptide bond. The term "peptide" preferably also embraces structures as defined above having one or more linkers, spacers, terminal groups or side chain groups which are not amino acids.According to the invention, the naturally occurring amino acids comprise all amino acids ocurring naturally in any cellular reactions, and are preferably selected from the group consisting of Gly, Ala, β-Ala, Asn, Asp, Arg, Cys, Gin, Glu, His, lie, Leu, Lys, Met, Nle, Orn, Phe, Pro, Ser, Thr, Trp, Tyr and Val, and more preferably exclusively selected from the L forms thereof.

According to the invention, the non-naturally occurring amino acids or synthetically modified naturally occuring amino acids are preferably selected from the group consisting of:

i) the D forms of naturally occurring amino acids, i.e. the D forms of Gly, Ala, β-Ala, Asn, Asp, Arg, Cys, Gin, Glu, His, lie, Leu, Lys, Met, Nle, Orn, Phe, Pro, Ser, Thr, Trp, Tyr and Val,

ii) the N-alkyl derivatives of Gly, Ala, β-Ala, Asn, Asp, Arg, Cys, Gin, Glu, His, lie, Leu, Lys, Met, Nle, Orn, Phe, Pro, Ser, Thr, Trp, Tyr and Val, preferably including both the D and L forms thereof, and iii) Lys(Ac), Lys(AcNH₂), Lys(AcSH), Tic, Asp(OR), Cha, Nal, 4-Hal- Phe, homo-Phe, Phg, Pya, Abu, Acha, Acpa, Aha, Ahds, Aib, Aos,

N-Ac-Arg, Dab, Dap, Deg, hPro, Nhdg, homoPhe, 4-Hal-Phe, Phg, Sar, Tia, Tic and Tie, preferably including both the D and L forms thereof;

wherein

R is alkyl having 1-18 carbon atoms, preferably alkyl having 1-6 carbon atoms and especially alkyl having 1-4 carbon atoms,

Hal is F, CI, Br, I

Ac is alkanoyl having 1-10 and more preferably 1-6 carbon atoms, aroyl having 7-11 carbon atoms or aralkanoyl having 8-12 carbon atoms.

With respect to the N-alkyl dervatives of said amino acids, alkyl is preferably selected from methyl, ethyl, isopropyl, n-butyl, sec-butyl and tert-butyl. However, alkyl is furthermore also preferably selected from n- pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and n-hexadecyl. According to the invention, the non-naturally occurring amino acids are preferably selected from the group consisting of the D forms of naturally occurring amino acids, i.e. the D forms of Gly, Ala, β-Ala, Asn, Asp, Arg,

Cys, Gin, Glu, His, lie, Leu, Lys, Met, NIe, Orn, Phe, Pro, Ser, Thr, Trp, Tyr and Val.

According to the invention, the synthetically modified naturally occuring amino acids are preferably selected from the group consisting of the N- alkyl derivatives of the L forms of Gly, Ala, β-Ala, Asn, Asp, Arg, Cys, Gin, Glu, His, He, Leu, Lys, Met, NIe, Orn, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the N-alkyl residues preferably consist of 1-18 carbon atoms, more preferably 1-6 carbon atoms and even more preferably 1-4 carbon atoms.

According to the invention, the synthetically modified naturally occuring amino acids are preferably selected from the group consisting of the N- methyl derivatives and/or N-ethyl dervatives of the L forms of Gly, Ala, β- Ala, Asn, Asp, Arg, Cys, Gin, Glu, His, lie, Leu, Lys, Met, NIe, Orn, Phe, Pro, Ser, Thr, Trp, Tyr and Val. Especially preferably, the synthetically modified naturally occuring amino acids are selected from the group consisting of the L forms of N-Methyl-Gly, N-Methyl-Ala, N-Methyl-p-Ala, N- Methyl-Asn, N-Methyl-Asp, N-Methyl-Arg, N-Methyl-Cys, N-Methyl-Gln, N- Methyl-Glu, N-Methyl-His, N-Methyl-lle, N-Methyl-Leu, N-Methyl-Lys, N- Methyl-Met, N-Methyl-Nle, N-Methyl-Orn, N-Methyl-Phe, N-Methyl-Pro, N- Methyl-Ser, N-Methyl-Thr, N-Methyl-Trp, N-Methyl-Tyr and N-Methyl-Val, which are preferably also referred to as NMeGly, NMeAla, ΝΜββ-Ala, NMeAsn, NMeAsp, NMeArg, NMeCys, NMeGIn, NMeGlu, NMeHis, NMelle, NMeLeu, NMeLys, NMeMet, NMeNle, NMeOrn, NMePhe,

NMePro, NMeSer, NMeThr, NMeTrp, NMeTyr and NMeVal. It is well within the skill in the art to prepare cyclic peptides, including cyclic peptides consisting of naturally occurring amino acids exclusively and also cyclic peptides comprising both naturally occurring non- natural amino acids. For example, conventional protection and activation chemistry can be used. Typically, the amino functionality of a first amino acid is protected with a removable amino protecting group and the carboxyl functionality of a second amino acid is protected with a removable carboxyl protecting group. Suitable amine protecting groups include, without limitation, benzoyloxycarbonyl (Cbz), tert- butoxycarbonyl (t-Boc), and 9- flourenylmethloxycarbonyl (FMOC). The carboxyl group may be protected protecting by forming an acid or base labile ester such as a methyl, ethyl, benzyl, or trimethylsilyl esters. After protection, the first and second amino acids are reacted in a suitable solvent such as water or DMF in the presence of an in situ activating agent such as N.N'- dicyclohexylcarbodiimide (DCCI), diisopropylcarbodiimide (DIPCDI), or 1- ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDCI) to effect peptide bond formation. Reactive moieties on the side chains of either amino acid are protected with protecting groups such as teff-butyl or benzyl for OH and SH; methyl, ethyl, tert-butyl or benzyl for carboxyl groups, 2,2,5,7,8- pentamethylchroman-6-sulphonyl for the -NHC(NH₂)=NH functionality of Arg, and trityl for the imidazole group of His. Following the coupling reaction, selective deprotection of the amino group of the first amino acid is accomplished by acid hydrolysis under conditions that do not remove the carboxyl protecting group of the second amino acid. The procedure is repeated with a additional amino protected amino acids. Solid phase synthesis, such as the well-known Merrifield method, is especially useful for synthesizing the peptides of the invention. Generally, the synthesis of the cyclic peptides is done by first synthesising a linear peptide of the desired sequence, for example as described above, followed by a cyclization step. Suitable methods and conditions for cyclizing a linear peptide into a cyclic peptide are known in the art. The incorporation of non-natural amino acids into peptides is described in Hohsaka T, Sisido M "Incorporation of non-natural amino acids into proteins" Curr. Opin. Chem. Biol. 6: 809-815 (2002); Noren CJ et al. "A general method for site-specific incorporation of unnatural amino acids into proteins" Science 244: 182-188 (1989); and Hodgson, David R.W., Sanderson, John M., "The Synthesis of Peptides and Proteins Containing Non-Natural Amino Acids", Chem. Soc. Rev., 2004, 33, 422-430, the disclosures of which are hereby incorporated by reference.

According to the invention, said cyclic peptide is preferably a homodetic cyclic peptide. The meaning of the terms "homodetic" and "homodetic cyclic peptide" is known in the art. According to the invention, a homodetic cyclic peptide preferably is a cyclic peptide in which the ring (or backbone of the cyclic peptide) consists solely of amino-acid residues in peptide linkage (or in eupeptide linkage according to the nomenclature of the lUPAC).

Especially preferably, said cyclic peptide comprises the Arg-Gly-Asp sequence (or RGD sequence in the one letter code for amino acids).

According to the invention, the Arg-Gly-Asp sequence is preferably comprised exclusively of the respective L-amino acids, i.e comprised of L- Arg, L-Gly and L-Asp.

Preferred cyclic peptides according to the invention are the cyclic peptides according to formula I,

Cyclo-(Arg-Gly-Asp-Q) I, wherein

Ω is an amino acid subsequence comprised of 1 to 4 and especially 2 or 3 amino acids selected from the group consisting of the L- and D- forms of: hPro, Ahds, Aos, Nhdg, Acha, Aib, Acpa, Tie, Gly, Ala, β-Ala, Asn, Asp, Asp(OR), Arg, Cha, Cys, Gin, Glu, His, lie, Leu, Lys, Lys(Ac), Lys(AcNH₂), Lys(AcSH), Met, Nal, NIe, Orn, Phe, 4-Hal-Phe, homo-Phe, Phg, Pro, Pya, Ser, Thr, Tia, Tic, Trp, Tyr or Val,

and the N-alkyl derivatives thereof,

wherein

R is alkyl having 1-18 carbon atoms, preferably alkyl having 1-6 carbon atoms and especially alkyl having 1-4 carbon atoms,,

Hal is F, CI, Br, I,

Ac is alkanoyl having 1-10 and more preferably 1-6 carbon atoms, aroyl having 7-11 carbon atoms or aralkanoyl having 8-12 carbon atoms, and especially is is alkanoyl having 1-6 and more preferably 1-3 carbon atoms,

with the proviso that Ω comprises at least one non-naturally occurring amino acid or synthetically modified naturally occuring amino acid, preferably at least one non-naturally occurring amino acid and at least one synthetically modified naturally occuring amino acid, and especially preferably one non-naturally occurring amino acid and one synthetically modified naturally occuring amino acid,

and the derivatives, salts and solvates thereof, more preferably the pharmaceutically acceptable derivatives, salts and/or solvates thereof.

In the cyclic peptide according to formula I,

Ω is especially preferably comprised of one non-naturally occurring amino acid and one synthetically modified naturally occuring amino acid, preferably as defined above/below.

Where the abovementioned amino acids can occur in a number of enantiomeric forms, then all of these forms and also their mixtures (e.g. the DL forms) are included above and below, for example as constituents of the compounds of the formula I. The amino acids, for example as a constituent of compounds to the formula I, can also be provided with appropriate protecting groups which are known per se.

Above and below, the radicals X and Y have the meanings given in the case of the formulae la and lb unless expressly stated otherwise. The letters used for said radicals X and Y preferably have nothing to do with the corresponding single-letter codes for amino acids. A preferred group of cyclic peptides according the invention are the cyclic peptides of formula subformula la,

wherein

X and Y in each case independently of one another are:

Gly, Ala, β-Ala, Asn, Asp, Asp(OR), Arg, Cha, Cys, Gin, Glu, His, lie, Leu, Lys, Lys(Ac), Lys(AcNH₂), Lys(AcSH), Met, Nal, NIe, Orn, Phe, 4-Hal- Phe, homo-Phe, Phg, Pro, Pya, Ser, Thr, Tia, Tic, Trp, Tyr or Val, which amino acid residues can also be derivatized,

Hal is F, CI, Br, I,

Ac is alkanoyl having 1-10 carbon atoms and especially 2-4 carbon atoms, aroyl having 7-11 carbon atoms or aralkanoyl having 8-12 carbon atoms,

n denotes no substituent or is a substituent on the a-amino function of the respective amino acid residue, selected from the group consisting of alkyl radicals R, benzyl and aralkyi radicals having 7-18 carbon atoms, and especially denotes no substituent or is a substituent on the a-amino function of the respective amino acid residue, selected from the group consisting of alkyl radicals having 1-4 carbon atoms,

with the proviso that at least one amino acid residue has a substituent n and with the further proviso that, where residues of optically active amino acids and amino acid derivatives are involved, both the D and the L forms are included,

and derivatives, salts and solvates thereof, more preferably the

pharmaceutically acceptable derivatives, salts and/or solvates thereof.

A more preferred group of cyclic peptides according to formula Id are the cyclic peptides of formula lb,

wherein

nX is selected from D-Gly, D-Ala, ϋ-β-Ala, D-Asn, D-Asp, D-Asp(OR), D-Arg, D-Cha, D-Cys, D-GIn, D-Glu, D-His, D-lle, D-Leu, D-Lys, D-Lys(Ac), D-Lys(AcNH₂), D-Lys(AcSH), D-Met, D-Nal, D-Nle, D-Orn, D-Phe, D-4-Hal- Phe, D-homo-Phe, D-Phg, D-Pro, D-Pya, D-Ser, D-Thr, D-Tia, D-Tic, D- Trp, D-Tyr or D-Val, more preferably D-Gly, D-Ala, D-Asn, D-Asp, D-Arg, D-Cys, D-GIn, D-Glu, D-Lys, D-Lys(Ac), D-Nal, D-Nle, D-Phe, D-4-Hal-Phe, D-homo-Phe, D-Ser, D-Thr, D-Trp, D-Tyr or D-Val,

nY is selected from NMeGIy, NMeAla, NMep-Ala, NMeAsn, NMeAsp, NMeArg, NMeCha, NMeCys, NMeGIn, NMeGlu, NMeHis, NMelle,

NMeLeu, NMeLys, NMe NMeMet, NMeNal, NMeNle, NMeOrn, NMePhe, NMePhg, NMePro, NMePya, NMeSer, NMeThr, NMeTia, NMeTic,

NMeTrp, NMeTyr or NMeVal, more preferably NMeGIy, NMeAla, NMeAsn, NMeAsp, NMeArg, NMeCys, NMeGIn, NMeGlu, NMeLys, NMeNal,

NMeNle, NMePhe, NMeSer, NMeThr, NMeTrp, NMeTyr or NMeVal, R is alkyl having 1-18 carbon atoms, preferably alkyl having 1-6 carbon atoms and especially alkyl having 1-4 carbon atoms,

Hal is F, CI, Br, I,

Ac is alkanoyl having 1-10 and preferably 2-4 carbon atoms, aroyl having 7-11 carbon atoms or aralkanoyl having 8-12 carbon atoms, preferably alkanoyl having 1-6 and preferably 2-4 carbon atoms,

and the derivatives, salts and solvates thereof, more preferably the pharmaceutically acceptable derivatives, salts and/or solvates thereof. Preferably, the cyclic peptide of the formula I, la and lb is not cyclo-(Arg- Gly-Asp-NMe-Phe-Gly).

According to the invention, the cyclic peptides that comprise the Arg-Gly-

Asp sequence preferably comprise Arg, Gly and Asp in the natural L configuration.

A further preferred group of compounds can be expressed by the formulae la, in which only one of the amino acid residues X or Y is present in the D form, whereas all the others are in the L configuration.

Furthermore, particular preference is given to all physiologically acceptable salts of the compounds which come under one or more of formulae I, la and lb.

A further preferred group of compounds can be expressed by the subformula lb, in which only the amino acid residue X is present in the D form, whereas all the others are in the L configuration.

Especially preferred with respect to the invention is the cyclic peptide according to formual lc,

and/or the derivatives, salts and solvates thereof, preferably the

pharmaceutically acceptable derivatives, salts and/or solvates thereof, and especially the pharmaceutically acceptable salts and/or solvates therof.

Even more preferred with respect to the invention is the cyclic peptide according to formual Id,

and/or the derivatives, salts and solvates thereof, preferably the

pharmaceutically acceptable derivatives, salts and/or solvates thereof, and especially the pharmaceutically acceptable salts and/or solvates therof. The cyclic peptides according the invention and especially the cyclic peptides according to I, la and/or lb, and also the starting materials for their preparation are preferably prepared by known methods, preferably as described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), in particular under reaction conditions which are known and appropriate for the said reactions. In this context, use can also be made of known variants which are not mentioned in any greater detail here.

If desired, the starting substances can also be formed in situ, so that they are not isolated from the reaction mixture but are immediately reacted further to give the cyclic peptides according to the invention and especially the cyclic peptides according to formula I, la, lb, lc and/or Id.

The cyclic peptides according to the invention and especially the cyclic peptides according to formula I, la, lb, lc and/or Id can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis are those which contain appropriate protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino protecting group instead of a hydrogen atom which is attached to a nitrogen atom, examples being those which correspond to the formula I but which, instead of an NH₂ group, contain an NHR' group (where R' is an amino protecting group, e.g. BOC or CBZ).

Other preferred starting materials are those which carry a hydroxyl protecting group instead of the hydrogen atom of a hydroxyl group, for example those which correspond to the formula I but contain, instead of a hydroxyphenyl group, a R"0-phenyl group (where R" is a hydroxyl protecting group).

It is also possible for two or more - identical or different - protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present are different from one another, then in many cases they can be eliminated selectively. The expression "amino protecting group" is generally known and relates to groups which are suitable for protecting (for blocking) an amino group from chemical reactions but which are readily removable after the desired chemical reaction has been carried out at other positions of the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or arakyl groups. Since the amino protecting groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be interpreted in its widest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular,

alkoxycarbonyl, aryloxycarbonyl and, above all, aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluoyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichlorethoxy-carbonyl, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxy- carbonyl, FMOC; and arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, and also CBZ, Fmoc, benzyl and acetyl.

The expression "hydroxyl protecting group" is also generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions but which are readily removable after the desired chemical reaction has been carried out at other positions of the molecule. Typical of such groups are the abovementioned unsubstituted or

substituted aryl, aralkyl or acyl groups, and also alkyl groups. The nature and size of the hydroxyl protecting groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1-20, especially 1-10, carbon atoms. Examples of hydroxyl protecting groups include benzyl, p-nitrobenzoyl, p- toluenesulf-onyl, tert-butyl and acetyl, with particular preference being given to benzyl and tert-butyl. The COOH groups in aspartic acid and glutamic acid are preferably protected in the form of their tert-butyl esters (e.g. Asp(OBut)).

The functional derivatives of the cyclic peptides according to the invention and especially of the cyclic peptides according to formula I, la, lb, lc and/or Id which are to be used as starting materials can be prepared by

customary methods of amino acid and peptide synthesis, as are described, for example, in the patent applications and standard works mentioned, including for example by the solid-phase method according to Merrifield (B.F. Gysin and R.B. Merrifield, J. Am. Chem. Soc. 94, 3102 ff. (1972)).

The liberation of the compounds of the cyclic peptides according to the invention and especially of the cyclic peptides according to formula I, la, lb, lc and/or Id from their functional derivatives is preferably carried out - depending on the protecting group used - with, for example, strong acids, expediently with TFA or perchloric acid, but also with other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids such as benzene- or p- toluenesulfonic acid. The presence of an additional inert solvent is possible but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic, acids such as acetic acid, ether such as

tetrahydrofuran or dioxane, amides such as DMF, halogenated

hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Also suitable are mixtures of the abovementioned solvents. TFA is preferably used in excess without the addition of a further solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9:1. The reaction temperatures for the cleavage are expediently between about 0 and about 50°; it is preferably carried out between 15 and 30° (room temperature).

The groups BOC, OBut and Mtr can be removed, for example, preferably using TFA in dichloromethane or with about 3 to 5 N HCI in dioxane at 15- 30°, while the FMOC group can be eliminated with an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15- 30°.

Protecting groups which can be removed by hydrogenolysis (e.g. CBZ or benzyl) can be eliminated, for example, by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst such as palladium, preferably on a support such as charcoal). Suitable solvents in this context are those mentioned above, especially, for example, alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is carried out, as a rule, at temperatures between about 0 and 100° and at pressures of between about 1 and 200 bar, preferably at 20-30° and 1-10 bar. Hydrogenolysis of the CBZ group, for example, takes place readily on 5 to 10% Pd-C in methanol or using ammonium formate (instead of H₂) on Pd-C in methanol/DMF at 20-30°.

The cyclic peptides according to the invention and especially the cyclic peptides according to formula I, la, lb, lc and/or Id can also be obtained by cyclization of linear peptides having the same amino acid sequence as the desired cyclic peptide, preferably under the conditions of a peptide synthesis. In this case, the reaction is expediently carried out in

accordance with customary methods of peptide synthesis as described, for example, in Houben-Weyl, I .e., Volume 15/11, Pages 1 to 806 (1974). The reaction is preferably carried out in the presence of a dehydrating agent, for example a carbodiimide such as DCCI or EDCI, and additionally propanephosphonic anhydride (cf. Angew. Chem. 92, 129 (1980)), diphenyl phosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1 ,2- dihydroquinoline, in an inert solvent, for example a halogenated

hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile, or in mixtures of these solvents, at temperatures between about -10 and 40°, preferably between 0 and 30°. In order to promote intramolecular cyclization over intermolecular peptide bonding, it is expedient to work in dilute solutions (dilution principle).

Instead of linear peptides having the same amino acid sequence as the desired cyclic peptide, suitable reactive derivatives of said linear peptides can also be employed in the reaction, for example those in which reactive groups are intermediately blocked by protecting groups. Said linear peptides can be used, for example, in the form of their activated esters which are expediently formed in situ, for example by addition of HOBt or N- hydroxysuccinimide. The starting materials for the manufacture of the cyclic peptides are either novel, commercially available or they are readily available by methods known in the art. In any case, they can preferably be prepared by known methods, for example the abovementioned methods of peptide synthesis and of elimination of protecting groups.

The derivatization of a cyclopeptide which corresponds per se to a compound of the formula I, la, lb, lc and/or Id is preferably likewise effected by methods known per se, as are known for the alkylation of amines, the esterification of carboxylic acids or nucleophilic substitution at aliphatic carbon atoms and are described in any textbook of organic chemistry, for example J. March, Adv. Org. Chem., John Wiley & Sons N.Y. (1985).

A base of a cyclic peptide according to the invention and especially the days of a cyclic peptide according to formula I, la, lb, lc and/or Id can be converted into the associated acid addition salt using an acid. Suitable acids for this reaction are, in particular, those which yield physiologically acceptable salts. Thus inorganic acids can be used, examples being sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acid such as orthophosphoric acid, sulfamic acid, and also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethyl-acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and -disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for isolating and/or purifying the

compounds of the formula I.

Alternatively, an acid of a cyclic peptide according to the invention and especially an acid of a cyclic peptide according to formula I, la, lb, lc and/or Id can be converted into one of its physiologically acceptable metal or ammonium salts by reaction with a base. Particularly suitable salts in this context are the sodium, potassium, magnesium, calcium and

ammonium salts, and also substituted ammonium salts, for example the dimethyl-, diethyl- or diisopropylammonium salts, monoethanol-, diethanol- or triethanolammonium salts, cyclohexylammonium salts,

dicyclohexylammonium salts, dibenzylethylenediammonium salts, and also, for example, salts with N-methyl-D-glucamine or with arginine or lysine.

Preferred cyclic peptides for all aspects of the instant invention are preferably selected from the group consisting of the cyclic peptides according to formula 1, 1a, 1b, 1c and/or Id, more preferably selected from consisting of the cyclic peptides according to formula la, lb, Ic and/or Id, even more preferably selected from the group consisting of the cyclic peptides according to formula lb, Ic and/or Id, and especially preferred selected from the group consisting of the cyclic peptides according to formula Ic and/or Id. According to the invention, the at least one cyclopeptide preferably comprises cyclo-(Arg-Gly-Asp-DPhe-NMeVal) and/or (Arg-Gly-Asp-DPhe- Val),

and/or a salt or solvate thereof.

According to the invention, the at least one cyclopeptide is especially preferably selected from cyclo-(Arg-Gly-Asp-DPhe-NMeVal) and cyclo- (Arg-Gly-Asp-DPhe-Val), and/or a salt or solvate thereof. Especially preferably, the at least one cyclopeptide preferably is cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and/or a salt or solvate thereof.

The peptide of the formula Cyclo-(Arg-Gly-Asp-DPhe-NMeVal) is preferably employed as a pharmaceutically acceptable salt, more preferably the pharmacologically acceptable hydrochloride salt, and especially preferably applied as the inner (or internal) salt, which is the compound cyclo-(Arg-Gly-Asp-DPhe-NMeVal) as such.

With regard to the peptide of the formula cyclo-(Arg-Gly-Asp-DPhe- NMeVal), the following kinds of writing the name are preferably to be regarded as equivalent:

Cyclo-(Arg-Gly-Asp-DPhe-NMeVal) = cyclo-(Arg-Gly-Asp-DPhe-NMeVal) = cyclo-(Arg-Gly-Asp-DPhe-[NMe]Val) = cyclo-(Arg-Gly-Asp-DPhe-[NMe]- Val) = cyclo-(Arg-Gly-Asp-DPhe-NMeVal) = cyclo-(Arg-Gly-Asp-DPhe- NMe-Val) =

cyclo(Arg-Gly-Asp-DPhe-NMeVal) = cyclo(Arg-Gly-Asp-DPhe-NMe-Val) = cRGDfNMeV = c(RGDfNMeV). The peptide of the formula cyclo-(Arg-Gly-Asp-DPhe-NMeVal) is preferably also referred to as Cilengitide, which is the INN (International Non- propriety Name) of said compound. The peptide of the formula cyclo-(Arg-Gly-Asp-DPhe-NMeVal) is also described in EP 0 770 622 A, US 6,001 ,961 , WO 00/15244 and

PCT/US07/01446 of the same applicant, the disclosure of which is explicitly incorporated into the instant application by reference.

The cyclic peptides according to the invention and especially the cyclic peptides according to formula I, la, lb, lc and/or Id possess very valuable properties. In particular, they act as integrin inhibitors, in which context they preferably modulate and especially preferably inhibit the interactions of β3- or ₅-integrin receptors with ligands. The compounds are preferably particularly active in the case of the integrins a_vP3, a_v s and/or an ₃, and more preferably particularly active in the case of the integrins avP3 and/or a_vP5, but preferably also relative to a_vPi-, a_vP6- and/or a_v s receptors. These actions can be demonstrated, for example, according to the method described by J.W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990). In addition, there are anti-inflammatory effects.

Preferred are solutions as described herein, wherein the cyclic

oligopeptide has a solubility in water at 20 °C or at 25 °C, preferably at at 20 °C, between 10 mg/mL and 100 mg/mL, more preferably between 10 mg/mL and 70 mg/mL, even more preferably between 12 mg/mL and 50 mg/mL, even more preferably between 14 mg/mL and 30 mg/mL, and especially between 15 mg/mL and 25 mg/mL.

Preferred are solutions as described herein, wherein the cyclic

oligopeptide is selected from the group consisting of cyclo-(Arg-Gly-Asp- DPhe-NMeVal) and the pharmaceutically acceptable dervatives, solvates and/or salts thereof having a solubility in water at 20 °C or at 25 °C, preferably at at 20 °C, between 10 mg/mL and 100 mg/mL, more

preferably between 10 mg/mL and 70 mg/mL, even more preferably between 12 mg/mL and 50 mg/mL, even more preferably between 14 mg/mL and 30 mg/mL, and especially between 15 mg/mL and 25 mg/mL.

Methods for determining the solubility of said cyclic oligopeptide(s) in water are known in the art. Preferably, the solubility in water at 20 °C or at 25 °C, preferably at 20 °C, is determined at an about neutral pH of the solution of said cyclic oligopeptide(s) in water. Even more preferably, the solubility in water at 20 °C or at 25 °C, preferably at 20 °C, is determined at a pH = 7 +/- 0.5 of the solution of said cyclic oligopeptide(s) in water. Accordingly, the solubility is preferably determined in water at 20 °C or at 25 °C, preferably at 20 °C, at a pH in the range of 6.5 to 7.5, more preferably in the range of 6.5 to 7.0, such as at a pH value of about 6.8, about 7.0 or about 7.4. The solubility of the inner (or internal) salt of the peptide of the formula cyclo-(Arg-Gly-Asp-DPhe-NMeVal) in water at 20 °C or at 25 °C, preferably at 20 °C, is preferably determined at the isoelectric point, which preferably corresponds to a pH value of about 6.8 and especially preferably

corresponds to a pH value in the range of 6.7 to 6.9. The term "solution" is known and understood in the art. More specifically, the term "solution" preferably means a liquid mixture of two or more components, more preferably an amorphous liquid mixture of two or more components, in which the components are present in molecular dispersed form and/or form a fluid, macroscopically homogeneous phase and even more preferably a fluid, macroscopically homogeneous limpid phase.

More specifically, the term "solution" preferably also means a liquid mixture of two or more components, in which two or more components may form aggregates of micellar type and/or aggregates without long-range order, which is thus a true liquid phase in the thermodynamic sense and thus preferably also forms a fluid, macroscopically homogeneous phase and even more preferably a fluid, macroscopically homogeneous limpid phase.

Even more specifically, the term "solution" as used according to the instant invention preferably means a liquid mixture wherein at least the

components

a) the one or more cyclic oligopeptides consisting of 2 to 12 amino acids, b) the one or more amphiphilic compounds comprising a polyol moiety and having a molar weight in the range of 200 g/mol to 2000 g/mol, and c) the water,

contained therein form a fluid, macroscopically homogeneous phase and even more preferably a fluid, macroscopically homogeneous limpid phase.

Preferably, in the solutions according the invention, the components preferably do not have a long-range order and/or do not form liquid crystalline phases.

Thus, a solution according to the invention preferably does not show any structured features under an optical microscope and is not turbid, e.g. preferably shows less than 100 NTU (nephelometric turbidity units, as described in European Pharmacopoeia 6th Edition, 6.8). The term "macroscopically homogeneous" is known and understood in the art. Preferably, "macroscopically homogeneous" means a low content or more preferably the absence of non-homogeneous ingredients or components, such as solids, aggregates or micelles, having a spatial extent of more than 200 nm, more preferably a spatial extent of more than 100 nm, even more preferably a spatial extent of more than 50 nm, even more preferably a spatial extent of more than 20 nm and especially preferably a spatial extent of more than 10 nm. A low content in this regard preferably means a content of 5% or less , 1% or less, more preferably 0.5% or less, even more preferably 0.1% or less or especially preferably 0.01% or less. In this context, the percentages given for the content are preferably percentages by weight or percentages by volume, more preferably percentages by volume.

Thus, the solutions according to the invention are preferably essentially free of solid particles of the contained cyclic oligopeptide(s). More preferably, the solutions according to the invention are also essentially free of colloidal solid particles of the contained cyclic oligopeptide(s). Even more preferably, the solutions according to the invention are essentially free of crystalline solid particles of the contained cyclic oligopeptide(s).

Even more preferably, the solutions according to the invention are characterised or preferably additionally characterised as liquid mixtures of the components and the amounts as described herein that are

a) limpid,

b) non-turbid, and/or

c) essentially free of crystalline solid particles of the contained one or more cyclic oligopeptides.

Especially preferably, the solutions according to the invention are characterised or preferably additionally characterised as liquid mixtures of the components in the amounts as described herein, that are essentially free of crystalline solid particles of the contained one or more cyclic oligopeptides.

Alternatively preferably, the solutions according to the invention are characterised or preferably additionally characterised as liquid mixtures of the components in the amounts as described herein, that are essentially free of colloidal and/or crystalline solid particles of the contained one or more cyclic oligopeptides.

Essentially free of solid particles and/or of colloidal solid particles of the contained cyclic oligopeptides in this regard preferably means that 2% or less, more preferably 1% or less, even more preferably 0.5 % or less, even more preferably 0.1 % or less and especially 0.01 % or less of the contained cyclic oligopeptide(s) is present in said solution as solid particles and/or solid colloidal particles. Typically, the solutions according to the invention contain no solid particles and/or no colloidal particles of said cyclic oligopeptide(s), or they contain between 1 ppt and 1 %, more preferably between 1 ppm and 1 % and especially between 0.0001 % and 0.1% of said cyclic oligopeptide(s) as solid particles and/or colloidal particles.

Essentially free of crystalline solid particles of the contained cyclic oligopeptides in this regard preferably means that 1% or less, more preferably 0.5% or less, even more preferably 0.1 % or less, even more preferably 0.05 % or less, even more preferably 0.01 % or less and especially 0.001 % or less of the contained cyclic oligopeptide(s) is present in said solution as crystalline solid particles. Typically, the solutions according to the invention contain no crystalline solid particles of said cyclic oligopeptide(s), or they contain between 1 ppt and 1 %, more preferably between 1 ppt and 0.1 %, even more preferably between 1 ppm and 0.1 % and especially between 0.0001 % and 0.1% of said cyclic oligopeptide(s) as crystalline solid particles.

However, in a preferred aspect, the instant invention relates to solutions as defined herein that are free or essentially free of liquid crystalline phases.

However, in a preferred aspect, the instant invention relates to solutions as defined herein, wherein at least a part of the contained cyclic oligopeptide and/or at least a part of the contained one or more amphiphilic compounds are present in the form of micelles. More preferably, the instant invention relates to solutions as defined herein, wherein at least a part of the contained cyclic oligopeptide and at least a part of the contained one or more amphiphilic compounds are present in the form of micelles that are formed by said cyclic oligopeptide and the one or more amphiphilic compounds.

In a preferred aspect, the two above described characteristics are combined in the solutions as defined herein.

Preferably, the solutions of the present invention are surprisingly stable to storage, preferably including both the chemical stability of the components and especially the chemical stability of the cyclic oligopeptide and/or the physical stability of the solutions. In particular, the solutions of the invention are generally stable to storage at ambient temperature (e.g. 25°C/60 % rel. hum.) for a period of no less than 4 weeks (e.g. 4 weeks to 3 years), preferably no less than three months, more preferably no less than 6 months.

Chemical stability in this regard preferably refers to the absence of significant degradation of one or more of the contained components and especially refers to the absence of significant degradation of the contained cyclic oligopeptide(s). Physical stability in this regard preferably refers to the absence of significant precipitation, segregation and/or exsolution and especially refers to the absence of significant precipitation of the contained cyclic oligopeptide(s).

Physical stability in this regard preferably refers to the absence of significant amounts of solid particles of the contained cyclic

oligopeptide(s), more preferably the absence of significant amounts of colloidal solid particles of the contained cyclic oligopeptide(s) and especially the absence of significant amounts of crystalline solid particles of the contained cyclic oligopeptide(s), preferably at all times, preferably even on prolonged storage at typical storage conditions for pharmaceutical products.

Typical storage conditions for pharmaceutical products are preferably selected from storage at 2-8°C and storage at 25°C/60% relative humidity.

For liquid pharmaceutical products, storage at 2-8°C is especially preferred.

The absence of significant amounts of solid particles of the contained cyclic oligopeptide(s) in this regard preferably means that the solutions contain 1% or less, more preferably 0.5% or less, even more preferably 0.1 % or less, even more preferably 0.05 % or less, even more preferably 0.01 % or less and especially 0.001 % or less of the contained cyclic oligopeptide(s) as solid particles, colloidal solid particles and/or crystalline solid particles.

Furthermore, the solutions of the present invention preferably are able to stably incorporate the cyclic peptide agent (cyclic oligopetide or component a)) at a level far greater than has previously been demonstrated or proposed. This offers considerable advantages in terms of the volume of solution administered, which in turn impacts upon patient compliance and the viability of subcutaneous and intramuscular delivery routes. Levels of cyclic peptide which may be incorporated include all of those indicated as suitable and preferable above for component a), such as at least 1%, (e.g.

1 to 60 % by weight), more preferably at least 2% by weight, even more preferably at least 5% (e.g. 5 to 15%).

The solutions of the present invention are preferably suitable for administration by subcutaneous or intramuscular injection.

In a further aspect, the present invention additionally provides a solution as described herein for use in the control or treatment of diseases, preferably of angiogenesis related diseases. In particular the invention provides for such solutions (preferably in any of the preferred embodiments of the solutions in any combination) for use in the treatment of hyperplastic and/or neoplastic diseases and especially in the treatment of cancer... The invention correspondingly provides a method for the treatment of a hyperplastic and/or neoplastic disease, such as those described herein, comprising administration of a solution as described herein.

In a yet further aspect, the present invention further provides for the use of a solution as described herein (preferably in any of the preferred

embodiments of the solutions in any combination) in the manufacture of a medicament for the treatment of disorders. Thus, in a yet further aspect, the present invention further concerns the use of a solution as described herein (preferably in any of the preferred embodiments of the solutions in any combination) as a pharmaceutical.

In a yet still further aspect, the present invention further provides a method for the manufacture of a solution as described herein comprising mixing the appropriate components, such as components a), b) and c) as described herein and heating the resulting mixture to a temperature in the range 30°C to 70°C for a period of 5 minutes to 24 hours. The heating step is advantageous in that it allows for the stable and permanent

incorporation of an enhanced concentration of cyclic peptide component a) in the solution. Preferred heating temperatures are in the range 35°C to 60°C, preferably 38°C to 55°C. The preferred period for heating is sufficient to stably incorporate the desired cyclic peptide at the desired concentration and will typically be from 10 minutes to 12 hours, preferably from 30 minutes to 2 hours. The solutions formed and formable by the described method evidently form further embodiments of the invention, and this method may be used in combination with any of the solutions and preferred solutions described herein.

Moreover, the following examples are given in order to assist the skilled artisan to better understand the present invention by way of

exemplification. The examples are not intended to limit the scope of protection conferred by the claims. The features, properties and

advantages exemplified for the processes, compounds, solutions and/or uses defined in the examples may be assigned to other processes, compounds, solutions and/or uses not specifically described and/or defined in the examples, but falling under the scope of what is defined in the claims.

Experimental Section

A formulation was prepared by mixing the following components:

i) DOPG

ii) Cilengitide

iii) water for injection

In the following ratios: i/ii/iii/ 10/10/80. A low viscosity clear and

homogenous formulation was achieved. This formulation was both chemically and physically stable at 40 °C/75%RH for at least 4 weeks.

A formulation was prepared by mixing the following components followed by heating at more than 40°C:

i) DPPG

ii) Cilengitide

iii) water for injection

In the following ratios: i/ii/iii/ 5/5/90. A low viscosity clear and homogenous formulation was achieved.

A formulation was prepared by mixing the following components followed by heating at more than 30°C:

i) DMPG

ii) Cilengitide

iii) water for injection

In the following ratios: i/ii/iii/ 16/13/71. A low viscosity homogenous formulation was achieved.

A formulation was prepared by mixing the following components:

i) DOPG

ii) Cilengitide

iii) water for injection

iv) Electrolyte (such as sodium chloride)

In the following ratios: i/ii/iii/iv 10/10/79/1. A low viscosity clear and homogenous formulation was achieved. A formulation was prepared by mixing the following components followed by heating at more than 30°C:

i) DMPG

ii) Cilengitide

iii) water for injection

iv) Electrolyte (such as sodium chloride)

In the following ratios: i/ii/iii/iv 10/10/79/1. A low viscosity clear and homogenous formulation was achieved.

Claims

Patent Claims 1. Solution comprising

a) 1 to 60 % of at least one cyclic oligopeptide consisting of 2 to 12 amino acids,

b) 1 to 60 % of one or more amphiphilic compounds comprising a polyol moiety and having a molar weight in the range of 200 g/mol to 2000 g/mol, and

c) 20 to 98 % of water,

2. Solution according to claim 1 , wherein at least one of the amphiphilic

compounds according to b) comprises

a) a glycerol moiety, and

β) one or more fatty acid moieties, and/or

γ) one or more fatty alcohol moieties.

3. Solution according to claim 1 and/or claim 2, wherein at least one of the amphiphilic compounds according to b) comprises a hydrophilic moiety.

4. Solution according to claim 3, wherein the hydrophilic moiety comprises a phosphatidyl moiety and/or a sulfatidyl moiety, and/or a salt thereof.

5. Solution according to claim 3 to 4, wherein the hydrophilic moiety

comprises a phosphatidylglycerol moiety and/or a sulfatidylglycerol moiety, and/or a salt thereof

6. Solution according to one or more of claims 1 to 5, wherein the at least one amphiphilic compounds according to b) comprise one or more compounds selected from amphiphilic lipids having phosphatidyl-polyol or sulfatidyl- polyol groups as the hydrophilic part, and derivatives, salts and/or alcoholates thereof.

7. Solution comprising

a) 1 to 60 % by weight of at least one cyclic oligopeptide consisting of 2 to 6 naturally occuring amino acids and 0 to 4 amino acids, selected from non- naturally occurring amino acids or synthetically modified naturally occuring amino acids,

b) 1 to 60 % by weight of one or more amphiphilic compounds, selected from amphiphilic lipids having phosphatidyl- or sulfatidyl-polyol groups as the hydrophilic part, and derivatives, salts and/or alcoholates therof, c) 20 to 98 % by weight of water,

with the proviso that the sum of a), b) and c) makes up to 40 or more % by weight of the total weight of the solution.

8. Solution according to one or more of the preceeding claims, comprising a) 1 to 60 % by weight of at least one cyclic oligopeptide consisting of 2 to 6 naturally occuring amino acids and 0 to 4 amino acids, selected from non- naturally occurring amino acids or synthetically modified naturally occuring amino acids,

b) 1 to 60 % by weight of one or more amphiphilic compounds, selected from

b1) fatty acid mono-, di- or polyesters of phosphatidyl- or sulfatidyl-polyols, and derivatives, salts and/or alcoholates therof, and

b2) fatty alcohol mono-, di- or polyethers of phosphatidyl- or sulfatidyl- polyols, and derivatives, salts and/or alcoholates therof,

c) 20 to 98 % by weight of water,

9. Solution according to one or more of the preceeding claims,, comprising a) 1 to 60 % by weight of at least one cyclic oligopeptide consisting of 2 to 6 naturally occuring amino acids and 0 to 4 amino acids, selected from non- naturally occurring amino acids or synthetically modified naturally occuring amino acids,

b) 1 to 60 % by weight of one or more amphiphilic compounds, selected from

b1) fatty acid di- or polyesters of phosphatidyl- or sulfatidyl-polyols and b2) fatty acid di- or polyethers of phosphatidyl- or sulfatidyl-polyols, and derivatives, salts and/or alcoholates therof,

c) 20 to 98 % by weight of water, and optionally

d) 0 to 50 % by weight of one or more compounds other than a), b) and c), selected from

d1) pharmaceutically active ingridients,

d2) pharmaceutically accetable excipients.

10. Solution according to one or more of claims 7 to 9, wherein the polyol comprises glycerol.

11. Solution according to one or more of claims 7 to 10, wherein the

phosphatidyl- or sulfatidyl-polyols are selcted from

a) polyphosphatidylglycerol, triphosphatidylglycerol,

diphosphatidylglycerol, monophosphatidylglycerol, and/or

b) polysulfatidylglycerol, trisulfatidylglycerol, disulfatidylglycerol, and monosulfatidylglycerol.

12. Solution according to one or more of claims 2 to 11 , wherein

the fatty acids or fatty acid moieties are independently selected from the group consisting of oleic acid, myristic acid, palmitic acid, stearic acid, margaric acid, arachic acid, behenic acid, erucic acid, phytanic acid, elaidic acid, linolic acid and linolenic acid, and mixtures thereof;

and

the fatty alcohols or fatty alcohol moieties are independently selected from the group consisting of oleic alcohol, myristic alcohol, palmitic alcohol, stearic alcohol, margaric alcohol, arachic alcohol, behenic alcohol, erucic alcohol, phytanic alcohol, elaidic alcohol, linolic alcohol and linolenic alcohol, and mixtures thereof.

13. Solution according to one or more of claims 1 to 12, wherein the

amphiphilic compounds and/or the the fatty acid di- or polyesters of polyphosphatidyl-polyols are selected from the group consisting of Dioleoylphosphatidyglycerol (DOPG), Dimyristoylphosphatidyglycerol (DMPG), Palmitoylmyristoylphosphatidylglycerol (PMPG),

Palmitoyloleoylphosphatidylglycerol (POPG),

Distearoylphosphatidylglycerol (DSPG) and

Dipalmitoylphosphatidylglycerol (DPPG), and the pharmaceutically acceptable dervatives, salts and/or alcoholates thereof.

14. Solution according to one or more of claims 1 to 13, wherein the

amphiphilic compounds and/or the fatty acid di- or polyesters of polyphosphatidyl-polyols are selected from the group consisting of Dioleoylphosphatidyglycerol (DOPG),

Dimyristyloylphosphatidyglycerol (DMPG),

Palmitoylmyristoylphosphatidylglycerol (PMPG) and

Palmitoyloleoylphosphatidylglycerol (POPG),

Distearoylphosphatidylglycerol (DSPG) and

Dipalmitoylphosphatidylglycerol (DPPG), and the alkali salts or ammonium salts thereof.

15. Solution according to one or more of claims 1 to 14, wherein the

cyclic oligopeptide comprises the Arg-Gly-Asp-subsequence.

16. Solution according to one or more of claims 1 to 15, wherein the

cyclic oligopeptide is selected from the group consisting of cyclo-(Arg- Gly-Asp-DPhe-NMeVal), cyclo-(Arg-Gly-Asp-DPhe-Val),

and the pharmaceutically acceptable dervatives, solvates and/or salts thereof.

17. Solution comprising

a) 1 to 60 % by weight of cyclo-(Arg-Gly-Asp-DPhe-Val),

and the pharmaceutically acceptable dervatives, solvates and/or salts thereof,

b) 1 to 60 % by weight of one or more amphiphilic compounds, selected from Dioleoylphosphatidyglycerol (DOPG),

Dimyristyloylphosphatidyglycerol (DMPG), PMPG, POPG, DSPG and

DPPG,

and the pharmaceutically acceptable dervatives, salts and/or alcoholates thereof,

c) 20 to 98 % by weight of water,

with the proviso that the sum of a), b) and c) makes up to 90 or more % by weight of the total weight of the solution.

18. Solution according to one or more of the preceeding claims, wherein the cyclic oligopeptide is selected from the group consisting of cyclo- (Arg-Gly-Asp-DPhe-NMeVal) and the pharmaceutically acceptable dervatives, solvates and/or salts thereof having a solubility in water at 20 °C between 10 mg/ml and 100 mg/ml.

19. Process for the manufacture of a solution according to one or more of the preceeding claims, comprising mixing the components a), b) and c) as described herein and heating the resulting mixture to a temperature in the range 30°C to 70°C for a period of 5 minutes to 24 hours.

20. Solution obtainable by the process according to claim 19.

21. Use of the solution according to one or more of claims 1 to 21 as a pharmaceutical.

22. Use of cyclo-(Arg-Gly-Asp-DPhe-Val), the pharmaceutically

acceptable dervatives, solvates and/or salts thereof for the manufacture of a solution according one or more of claims 1 to 18 and 20.