WO2010112615A1

WO2010112615A1 - Lysine derivatives functionalised with lipids

Info

Publication number: WO2010112615A1
Application number: PCT/EP2010/054518
Authority: WO
Inventors: George Mihov
Original assignee: Dsm Ip Assets B.V.
Priority date: 2009-04-03
Filing date: 2010-04-06
Publication date: 2010-10-07

Abstract

The present invention relates to amino-acid derivatives functionalized with lipids. The amino-acid derivatives are functionalized with lipids via amide, urea or urethane bonds. The derivatives preferably have melting points in the range from 40 to 80 °C. The amino-acid derivative comprises protected lysinediisocyanate. The lipids are chosen from fatty alcohols, fatty amines, fatty acids, cholesterol or sterols. The invention also relates to a process for the preparation of amino-acid derivatives functionalized with lipids via amide, urea or urethane bonds by the reaction of a lipid with a protected lysinediisocyanate. The present invention further relates to the use of the amino acid derivatives in drug delivery.

Description

LYSINE DERIVATIVES FUNCTIONALISED WITH LIPIDS

The present invention relates to lysine derivatives functionalized with lipids via amide, urea or urethane bonds. The present invention further relates to a composition comprising the lysine derivatives and to the use of the lysine derivatives and the compositions comprising the lysine derivatives in the controlled delivery of drugs.

In drug delivery there is a continuous need for biocompatible materials with certain properties on molecular weight, morphology, melting point and viscosity which allow an easy tuning of polarity, phase transition rate and drug releasing properties.

Lysine derivatives functionalized with lipids via amide, urea or urethane bonds are known from John G. Hardy et al: "Exploring molecular recognition pathways within a family of gelators with different hydrogen bonding motifs" TETRAHEDRON, VoI 63, no 31 , 2007, pages 7397-7406, XP002542142. In this publication several lysine derivatives are disclosed functionalized with amide, urea or thio-urea bonds. The lysine derivatives are prepared via the reaction of lysine diisocyanate with dodecanol or amino-dodecane or via the reaction of lysine methylester with N-dodecylisothiocyanate. These lysine derivatives are used as gelators to immobilize a wide range of fuel oils, food oils or oils used in pharmaceutical formulations. The publication further discloses that the gelators are less effective but that this can generally be enhanced by converting the methyl ester group of the lysine derivative into a carboxylic group and subsequently mixing the lysine derivative with a second diaminododecane. The publication is silent about the delivery of drugs. In the present invention it is the object to provide new biocompatible and biodegradable compounds which can be used for the delivery of drugs in the human and animal body. More specific it is the object of the present invention to provide new biocompatible and biodegradable compounds which can be used for the delivery of drugs in the eye. Several diseases and conditions of the posterior segment of the eye threaten vision. Age-related macular degeneration (AMD), choroidal neovascularization (CNV), retinopathies (e.g., diabetic retinopathy, vitreoretinopathy), retinitis (e.g., cytomegalovirus (CMV) retinitis), uveitis, macular edema, glaucoma, and neuropathies are several examples. These, and other diseases, can be treated by injecting a drug into the eye. Such injections are typically manually performed using a conventional syringe and needle. In using such a syringe, the surgeon is required to pierce the eye tissue with the needle, hold the syringe steady, and actuate the syringe plunger to inject the drug into the eye. Tissue damage may occur due to an "unsteady" injection. Reflux of the drug may also occur when the needle is removed from the eye. When a drug is to be injected into the eye, it is desirable to minimize the number of injections. Therefore there is a need for biocompatible and biodegradable compounds which are injectable in the eye and which at the same time could control the delivery of drugs over a certain period of time.

It is therefore an object of the present invention to find compounds which have specific properties in view of molecular weight, crystallinity, melting point and viscosity.

It is a more specific object of the present invention to find biocompatible and biodegradable compounds which have a low molecular weight, which are crystalline, which have melting points in the range of 40-80 °C and which have a viscosity in the range from 10-500 cpoise at melt.

The object of the present invention has been achieved in that new lysine derivatives have been found which are functionalized with lipids via amide, urea or urethane bonds whereby the acid functionality of the lysine is protected by a group selected from ethyl, propyl, butyl, oligo-ethylene oxide or polyethylene oxide. Unexpectedly it has been found that these lysine derivatives are fulfilling the requirements of biocompatibility, biodegradability, melting point and viscosity. The lysine derivatives are biocompatible, biodegradable, have melting points in the range of 40-80 °C and a viscosity in the range of 10-500 cpoise. The resulting lysine derivatives can be sterilized and remain stable after sterilization. In addition it is quite easy to tune the polarity, bio-erosion, melting point, phase transition rate and drug release properties of the new lysine derivatives just by introducing a variety of lipids of different molecular weight and structure. It is also possible to tune the properties via the protected carboxyl group of the lysine derivatives. Properties can be adjusted and will vary depending on the protecting group chosen from ethyl, propyl, butyl, oligo-ethylene oxide or polyethylene oxide.

The protected carboxylic group will contribute to the hydrophilicity, polarity, bio-erosion, melting point, phase transition rate and drug release properties of the lysine derivative but also have an additional essential function in the material performance. It is well known that ester bonds are susceptible to hydrolysis at physiological environment. When the lysine based molecule, which is described above, is exposed to physiological environment the ester bond is the first to by hydrolyzed triggering number of changes in the hydrophilicity, polarity and bio-erosion rate of the lysine derived material. In this way the choice of the protective group appears to be vital for the material performance. Furthermore, the protective group should be chosen in the way to ensure an easy hydrolysis and result in biocompatible byproduct upon ester bond cleavage. In order to fulfill these requirements the protective group is chosen from ethyl, propyl, butyl, oligo-ethylene oxide or polyethylene oxide.

The lysine derivatives of the present invention comprise protected lysinediisocyanate (LDI) which is functionalized with lipids via amide, urea or urethane bonds. The acid functionality of the lysinediisocyanate is protected by a group selected from ethyl, propyl, butyl, oligo-ethylene oxide or polyethylene oxide.

The lipids are chosen from saturated fatty alcohols, fatty amines, fatty acids, cholesterol or sterols. Examples of the saturated fatty alcohols are 1-dodecanol, 1-decanol and 1-tetradecanol. Examples of the fatty amines are 1-decanolamine, 1- dodecanamine, 1-tetradecanamine. Examples of the fatty acids are decanoic acid, 1- dodecanoic acid (lauric acid) and 1-tetradecanoic acid (myristic acid).

Preferably the lipid is chosen from a saturated fatty alcohol, fatty amine or fatty acid comprising at least 10 carbon atoms. More preferably the saturated fatty alcohol, fatty amine or fatty acid comprises from 12-14 C-atoms.

The lysine derivatives according to the present invention preferably have a melting point in the range from 40-80 °C. The viscosity of the lysine derivatives is preferably in the range of 50-300 cpoise, more preferably in the range of 90-200 cpoise. By adjusting the lysine derivative in the choice of lipid and the choice of protecting group chosen from ethyl, propyl, butyl, oligo-ethylene-oxide or polyethylene oxide on the carboxylic acid of the lysinediisocyanate, the resulting lysine derivatives can be transformed into a more liquid state which is more suitable for injection into the eye.

Examples of the lysine derivatives according to the present invention are given in below formulas:

ethyl 2,6-bis(dodecyloxycarbonylamino)hexanoate

ethyl 2,6-bis(tetradecyloxycarbonylamino)hexanoate

ethyl 2,6-didodecanamidohexanoate

The lysine derivatives are prepared by a process which includes the reaction of the ethyl, propyl, butyl, oligo-ethylene oxide or polyethylene oxide (PEG) protected lysinediisocyanate (LDI) with lipids via amide, urea or urethane bonds. An example is indicated in reaction scheme 1 :

It has been found that the lysine derivatives according to the present invention remain stable even after sterilization, such as for example gamma-irradiation. The present invention further relates to microparticles, nanoparticles or micelles comprising the lysine derivatives according to the present invention. The microparticles, nanoparticles or micelles can be used as a delivery system for a bioactive agent, in particular a drug, a diagnostic aid or an imaging aid. Furthermore, the microparticles, nanoparticles or micelles can be incorporated in for example (rapid prototyped) scaffolds, coatings, patches, composite materials, gels or plasters. The microparticles, nanoparticles or micelles can be injected, sprayed, implanted or absorbed. Microparticles, nanoparticles or micelles are generally accepted as spherical particles with average diameters ranging from approximately 10 nm to 1000 micrometers. The preferred average diameter depends on the intended use. For instance, in case the microparticles are intended for use as an injectable drug delivery system, in particular as an intravascular drug delivery system, an average diameter of up to 10 μm, in particular of 1 to 10 μm may be desired. It is envisaged that microparticles with an average diameter of less than 800 nm, in particular of 500 nm or less, are useful for intracellular purposes. For such purposes, the average diameter preferably is at least 20 nm or at least 30 nm. In other applications, larger dimensions may be desirable, for instance a diameter in the range of 1-100 μm or 10-100 μm. In particular, the particle diameter as used herein is the diameter as determinable by a LST 230 Series Laser Diffraction Particle size analyzer (Beckman Coulter), making use of a UHMW-PE (0.02 - 0.04 μm) as a standard. Particle-size distributions are estimated from Fraunhofer diffraction data and given in volume (%).lf the particles are too small or non analyzable by light scattering because of their optical properties then scanning electron microscopy (SEM) or transmission electron microscopy (TEM) can be used.

The microparticles, nanoparticles or micelles are reservoir devices that come in a variety of different forms, including, but not limited to, porous, hollow, coated, or uncoated forms with a bioactive agent or drug incorporated into or encapsulated by the lysine derivatives according to the present invention. The amount of drug incorporated or encapsulated in the microsphere is generally between 0.001 % and about 50%. Several types of microparticle structures can be prepared according to the present invention. In case that more than one active agent has to be released or in case that one or more functionalities are needed it is preferred that the microparticles, nanoparticles or micelles are provided with a structure comprising an inner core and an outer shell. A core/shell structure enables more multiple mode of action for example in in drug delivery of incompatible compounds or in imaging.

The lysine derivatives can also be used as such in injectable or spray-able form or as a suspension in a free form or as an in-situ forming gel formulation. If for example injected in the eye, the surface area of the shape of the injected lysine derivative/drug mixture deposited in the eye influences the release rate of the drug. Since the erosion of the mixture in the eye is dependent on its surface area, the shape of that mixture (spherical, cylindrical, or some other shape) influences the rate of erosion and consequently the drug release rate. In most cases, it is desirable to maximize the duration between injections (and minimize the surface area) by depositing a near- spherical bolus in the eye. However, it may be desirable to increase drug delivery rates by depositing other shapes with greater surface area (such as cylindrical shapes. Drug delivery rates are also dependent on the type of lysine derivatives and concentration of drug - both of which can be selected to provide microparticles, nanoparticles or micelles suitable for varying dosages based on varying the shape of the injection. From the above, it may be appreciated that the present invention provides improved compounds for delivering drugs into the eye. Examples of bioactive or therapeutic agents are nutrients, pharmaceuticals, proteins and peptides, vaccines, genetic materials, (such as polynucleotides, oligonucleotides, plasmids, DNA and RNA), diagnostic agents, and imaging agents.

The active agent may also be chosen from growth factors (VEGF, FGF, MCP-1 , PIGF, antibiotics (for instance penicillin's such as B-lactams, chloramphenicol), anti-inflammatory compounds, antithrombogenic compounds, anti- claudication drugs, anti-arrhythmic drugs, anti-atherosclerotic drugs, anti-proliferatives, antihistamines, cancer drugs, vascular drugs, ophthalmic drugs, amino acids, vitamins, hormones, neurotransmitters, neurohormones, enzymes, signalling molecules and psychoactive medicaments. Examples of ophthalmic drugs used for treating glaucoma include beta-blockers (e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), alphal antagonists (e.g., nipradolol), alpha2 agonists (e.g. iopidine and brimonidine), miotics (e.g., pilocarpine and epinephrine), prostaglandin analogs (e.g., latanoprost, travoprost, unoprostone, and compounds set forth in U.S. Pat. Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151 ,444), "hypotensive lipids" (e.g., bimatoprost and compounds set forth in U.S. Pat. No. 5,352,708), and neuroprotectants (e.g., compounds from U.S. Pat. No. 4,690,931 , particularly eliprodil and R-eliprodil, as set forth in a pending application U.S. Ser. No. 60/203,350, and appropriate compounds from WO 94/13275, including memantine.

Examples of other active agents or drugs are neurological drugs (amphetamine, methylphenidate), alphal adrenoceptor antagonist (prazosin, terazosin, doxazosin, ketenserin, urapidil), alpha2 blockers (arginine, nitroglycerin), hypotensive (clonidine, methyldopa, moxonidine, hydralazine minoxidil), bradykinin, angiotensin receptor blockers (benazepril, captopril, cilazepril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril, zofenopril), angiotensin-1 blockers (candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan), endopeptidase (omapatrilate), beta2 agonists (acebutolol, atenolol, bisoprolol, celiprolol, esmodol, metoprolol, nebivolol, betaxolol), beta2 blockers (carvedilol, labetalol, oxprenolol, pindolol, propanolol) diuretic actives (chlortalidon, chlorothiazide, epitizide, hydrochlorthiazide, indapamide, amiloride, triamterene), calcium channel blockers (amlodipin, barnidipin, diltiazem, felodipin, isradipin, lacidipin, lercanidipin, nicardipin, nifedipin, nimodipin, nitrendipin, verapamil), anti arthymic active (amiodarone, solatol, diclofenac, enalapril, flecainide) or ciprofloxacin, latanoprost, flucloxacillin, rapamycin and analogues and limus derivatives, paclitaxel, taxol, cyclosporine, heparin, corticosteroids (triamcinolone acetonide, dexamethasone, fluocinolone acetonide), anti- angiogenic (iRNA, VEGF antagonists: bevacizumab, ranibizumab, pegaptanib), growth factor, zinc finger transcription factor, triclosan, insulin, salbutamol, oestrogen, norcantharidin, microlidil analogues, prostaglandins, statins, chondroitinase, diketopiperazines, macrocycli compounds, neuregulins, osteopontin, alkaloids, immuno suppressants, antibodies, avidin, biotin, clonazepam.

The present invention further relates to compositions comprising the lysine derivatives according to the present invention and a further biodegradable polymer. Unexpected it has been found that by blending the lysine derivatives according to the present invention with a further biodegradable polymer the biodegradability of the composition is improved compared to the biodegradability of the individual compounds. This means that the biodegradability of the lysine derivatives can be influenced or tuned by blending them with a further biodegradable polymer. In drug delivery it is important that the biodegradability of the lysine derivatives can be tuned easily. For some drug delivery applications one might need lysine derivative compositions with a different rate of biodegradation or bioerosion.

In the compositions of the present invention, the blending of further biodegradable polymers is not limited to the lysine derivatives only; also other amino- acid derivatives can be applied. By amino-acid derivatives is meant a derivative of an amino-acid functionalized with lipids via amide, urea or urethane bonds. The amino acids include for example natural alpha-amino-acids such as alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, lysine or isoleucine in their protected or unprotected form. The lipids include for example fatty alcohols, cholesterol, fatty acids, fatty amines or sterols. Preferably the lipid is chosen from a saturated fatty alcohol, fatty amine or fatty acid comprising at least 10 carbon atoms. More preferably the saturated fatty alcohol, fatty amine or fatty acid comprises from 12- 14 C-atoms. The biodegradable polymer may be selected from a polymer and/or a copolymer and/or a block co-polymer selected from the group consisting of poly-lactic acid (PLA), poly-glycolic acid (PGA), poly-lactide-co-glycolide (PLGA), polyesters, polyesteramides, poly (ortho ester), poly(phosphazine), poly (phosphate ester), oligo- or poly-ε-caprolactones, polyethylene glycol (PEG), block copolymers of ε- caprolactones and oligo-ethyleneglycols, gelatin, collagen, poly(D,L-lysine), derivatives thereof, and combinations thereof. Preferably the biodegradable polymer is selected from the group consisting of block copolymers of ε-caprolactones and oligo- ethyleneglycols. More preferably the biodegradable polymer is selected from the group consisting of block copolymers of ε-caprolactones and oligo-ethyleneglycols selected form the group consisting of alkyl ethyleneglycols such as mono alkyl triethylene glycol, mono alkyl tetra-ethylene glycol or mono alkyl penta-ethyleneglycol. The alkyl residue is selected from the group consisting of linear or branched alkyl comprising between 1- 1OC atoms. Examples of such linear or branched alkyls are methyl, ethyl, propyl, isopropyl butyl or isobutyl. Most preferred the biodegradable polymer is selected from the group consisting of block copolymers of ε-caprolactones and triethyleneglycol monomethylether. The physical properties of the oligo- or poly-ε-caprolactone derivatives such as melting point, viscosity at melt temperature, biocompatibility and the hydrophilic properties can easily be tuned by the degree of polymerization. The molecular weight of the oligo- or poly-ε-caprolactone derivatives is preferably in the range of 500-10.000 g/mol.

The compositions of the present invention preferably maintain the properties of low viscosity in the melt, sharp phase transition and a melting point from 40-80C. Moreover it is preferred that the amino-acid derivatives, especially the lysine derivatives and the biodegradable polymer show no phase separation if mixed together.

The amount of amino-acid derivatives, in particular the lysine derivatives may vary from 10-90 weight %, the amount of biodegradable polymer may vary from 90-10 weight % based on the total weight of the composition. Preferably the amount of amino-acid derivatives, in particular the lysine derivatives varies from 30-70 weight % and the amount of biodegradable polymer varies from 70-30 weight % based on the total weight of the composition. It is clear that the amount of amino-acid derivatives, in particular lysine derivatives and the amount of biodegradable polymer can be chosen such that the composition fulfils the above requirements of low viscosity in the melt, sharp phase transition and a melting point from 40-80C.

The compositions of the present invention can advantageously be used in drug delivery devices such as injection devices for ophthalmology. It is moreover possible to load the drug delivery devices with microspheres, microcapsules, nanospheres or micelles. The form of the microspheres, microcapsules, nanospheres or micelles may vary from porous, hollow, coated, or uncoated forms with a bioactive agent either incorporated into or encapsulated by the compositions of the present invention. The amount of bioactive agent or drug incorporated or encapsulated in the microsphere is generally between 0.001 % and about 50%. The microsphere content incorporated into the drug delivery device is generally between 1 % and 50%.

The present invention further relates to coatings comprising the lysine derivatives or the compositions according to the present invention.

The invention will now be illustrated by the following examples without being limited thereto.

Method to determine melting point:

Materials were accurately weighted and placed in aluminum pans. Thermal behavior was assessed using a Mettler 822e heat-flux differential scanning calorimeter using the following method: -20⁰C to 85°C at 10°C/min, isotherm for 3 min (heat 1 ) 85°C to -20°C at 10°C/min, isotherm for 3 min (cool) -20⁰C to 85°C at 10°C/min, isotherm for 3 min (heat 2)

Method to determine viscosity:

The measurements on molten samples were performed on the Physica MCR501-1 rheometer using the DoubleGAP geometry (DG26,7 with 26.66 diameter and 7 μm concentricity).

Example 1 : Synthesis of (1-dodecanolkLDKEtV GM 5127-105

30.75 g (0.164 mol) of 1-dodecanol were added to a dry one neck- 100 ml-round bottom flask. Then the flask was evacuated twice with N₂ and heated to 40 ⁰C. A solution, of 18 g (0.08 mol) lysine-diisocyano-ethyl ester (LDI) in 20 ml. THF was placed in a dropping funnel under nitrogen atmosphere and added drop wise to the melted 1-dodecanol while stirring. Next a solution was prepared of 65 mg tin(ll)octanoate in 10 ml. of hexane and 1 ml. of this solution was added to the reaction mixture. The temperature was fixed on 60 ⁰C and allowed to run under stirring and inert atmosphere overnight. Next day the reaction mixture was poured in an aluminum box and let to crystallize. The crystals were dried in the fume hood for overnight and then in the vacuum oven.

IR: shows no traces of residual isocyanates. Melting point about 56 ⁰C.

NMR shows the presence of 1-dodecanol.

Purification:

Di-dodecanol-LDI ( 13,5 g) was dissolved in 40 ml. THF. Dissolution takes 20-30 min under stirring conditions until a clear solution is obtained. Next the solution was filtered to remove dust impurities and added by a glass pipette to ethanol ( 96%, 400 ml.) in a 500 ml_- Erlenmeyer- flask under stirring. Then the solution was placed at -20 ⁰C for two hours which resulted in a precipitation. The precipitate was filtered by Buchner filter, washed with cold ethanol and dried under reduced pressure. NMR of the so obtained didodecanol-LDI shows only traces of unreacted dodecanol.

Example 2: Synthesis of (1-decanolkLDKEtV GM 5127-107.

30.3 g (0.19 mol) of 1-decanol were added to a dry one neck-100 ml- round bottom flask. Then the flask was evacuated twice with N₂. A solution, of 21.25 g (0.08 mol) LDI ethyl ester in 20 ml. THF was placed in a dropping funnel under nitrogen atmosphere and added drop wise to the 1-decanol while stirring. Next a solution was prepared of 76 mg tin(ll)octanoate in 10 ml. of hexane was prepared and 1 ml. of this solution was added to the reaction mixture.The temperature was fixed on 65 ⁰C and allowed to run under stirring and inert atmosphere overnight. Next day the reaction mixture was poured in an aluminum box and let to crystallize. The crystals were dried in the fume hood for overnight and then in the vacuum oven.

IR: shows no traces of residual isocyanates.

Melting point about 62 ⁰C.

Purification: Di-decanol-LDI ( 40 g) was dissolved in 40 ml. THF. Dissolution takes

1-2 hours under stirring conditions until a clear solution is obtained. Next the solution was filtered to remove dust impurities and added by a glass pipette to ethanol ( 96%, 500 ml.) in an one liter Erlenmeyer- flask under stirring. Then the solution was placed at -20 ⁰C for over night which resulted in a precipitation. The precipitate was filtered by Buchner filter, washed with cold ethanol and dried under reduced pressure.

NMR of the so obtained dodecanol-LDI shows only traces of unreacted decanol.

Example 3: Synthesis of PCL- triethyleneqlvcolmonomethylether (PCL-TEG) 13.29g triethyleneglycolmonomethylether was weight in a 250ml round bottomed flask along with 87.59g ε-caprolactone. 329mg. The flask was brought under an inert atmosphere and heated to 150⁰C and stirred till a homogene mixture was formed. At this point 1 mL of a freshly prepared Sn(ll)octoate catalyst solution in hexane was added (C_(cataiyst)= 33 g/L). Continued stirring and heated for an additional 16 hours to allow the reaction to proceed. The reaction mixture was cooled to room temperature after completion. The material was used as such without the need for additional purification.

1 H-NMR samples were prepared in CDCI3, no significant impurities were detected, Mw (NMR) = 1297 g/mol,. melting point: 45.8⁰C (1297g/mol), melting point: 51.2°C (1590g/mol)

Example 4: Blend of PCL-TEG and C12-LDI (30/70)

1.5 g PCL-TEG was weighed into a 10 ml glass vial and 3.5 g C12- LDI was added. The vial is closed and placed into an oven at ca. 85 ⁰C. When the material was completely molten, the vial is taken out of the oven and the material was homogenized on a vortex for 1 min at 2500 rpm. The melt was pured into a mold where it solidified quickly.

Example 5: Blend of PCL-TEG and C12-LDI (70/30)

3.5 g PCL-TEG was weighed into a 10 ml glass vial and 1.5 g C12- LDI was added. The vial is closed and placed into an oven at ca. 85 ⁰C. When the material was completely molten, the vial is taken out of the oven and the material is homogenized on a vortex for 1 min at 2500 rpm. The melt was pured into a mold where it solidifies quickly.

Measurement of the biodeqradability:

In a continuous-flow system with a flow rate of 7.5 ml/min of PBS at 37°C, weight loss of inserts of the different blends based on C12-LDI/PCL-TEG and candidate materials were observed. Hereto, 10 inserts were placed in a glass filter (diameter 10mm, porosity 1 ) and gentle flow was applied from the bottom. A volume of 1 liter PBS was re-circulated for one week upon which the samples were removed from the glass filter, rinsed in Dl water three times and dried under vacuum at 30⁰C for 40 hrs. Weight was recorded and samples were again transferred to the flow system for erosion testing.

Results are given in Figure 1.

Claims

1. Lysine derivatives functionalized with lipids via amide, urea or urethane bonds characterized in that the acid functionality of the lysine is protected by a group selected from ethyl, propyl, butyl, oligo-ethylene oxide or polyethylene oxide.

2. Lysine derivatives according to claim 1 whereby the lipids are chosen from fatty alcohols, fatty amines, fatty acids, cholesterol or sterols.

3. Lysine derivatives according to any one of the claims 1-2 whereby the lipid is chosen from a fatty alcohol, fatty amine or fatty acid comprising at least 10 carbon atoms.

4. Lysine derivatives according to any one of the claims 1-3 having a melting point in the range of 40-80 °C.

5. Compositions comprising the lysine derivatives according to any one of the claims 1-4 with a biodegradable polymer.

6. Compositions according to claim 5 wherein the biodegradable polymer is selected from the group consisting of poly-lactic acid (PLA), poly-glycolic acid (PGA), poly-lactide-co-glycolide (PLGA), polyesters, polyesteramides, poly (ortho ester), poly(phosphazine), poly (phosphate ester), polyethylene glycol (PEG), block copolymers of caprolactones and oligo-ethyleneglycol, gelatin, collagen, poly(D,L-lysine), derivatives thereof, and combinations thereof.

7. Composition according to claim 6 wherein the biodegradable polymer is a block copolymer comprising tri-ethyleneglycol monomethylether and ε- caprolactone.

8. Composition comprising amino-acid derivatives functionalized with lipids via amide, urea or urethane bonds and at least a biodegradable polymer.

9. Composition according to claim 8 wherein the aminoacid derivatives have a melting point in the range of 40-80 °C

10. Composition according to any one of the claims 8-9 whereby the aminoacid derivatives comprise lysine functionalized with lipids which are selected from the group of fatty alcohols, fatty amines, fatty acids, cholesterol or sterols.

1 1. Composition according to any one of the claims 8-10 whereby the biodegradable polymer is selected from the group consisting of poly-lactic acid (PLA), poly-glycolic acid (PGA), poly-lactide-co-glycolide (PLGA), polyesters, polyesteramides, poly (ortho ester), poly(phosphazine), poly (phosphate ester), polyethylene glycol (PEG), block copolymers of caprolactones and ethyleneglycol, gelatin, collagen, poly(D,L-lysine), derivatives thereof, and combinations thereof

12. Composition according to any one of the claims 8-1 1 whereby the biodegradable polymer is a block copolymer comprising tri-ethyleneglycol monomethylether and ε-caprolactone.

13. Use of the lysine derivatives according to any one of the claims 1 -4 or the compositions according to any one of the claims 5-12 for the controlled release of drugs.

14. Use according to claim 13 for the controlled release of drugs in ophthalmology.

15. Use according to any one of claims 13 or 14 for the controlled release of drugs via drug delivery depots, rods, spheres, films or strips.

16. Use of the lysine derivatives according to any one of the claims 1 -4 or the compositions according to any one of the claims 5-12 in a drug delivery device.

17. Microparticles, nanoparticles or micelles comprising the lysine derivatives according to any one of the claims 1-4 or the compositions according to any one of the claims 5-12.

18. Coatings comprising the lysine derivatives according to any one of the claims 1-4 or the compositions according to any one of the claims 5-12.