Ophthalmic, intra-articular or intravesical preparations containing N-acyl-ethanolamines

Abstract

It is the object of the present invention a composition containing an N-acyl-ethanolamine in a solubilized form, particularly a solution for ophthalmic, intra-articular or intravesical use. Particularly, the present invention relates to a water-soluble composition comprising one or more N-acylethanolamines (NAE) in the form of an inclusion complex in methyl-beta-cyclodextrin (MCD).

Claims

1. A water-soluble composition comprising palmitoylethanolamine (PEA) in the form of an inclusion complex in methyl-beta-cyclodextrin (MCD) and a polymeric emulsifier, wherein a MCD/PEA weight ratio is of least 90:1 and wherein the polymeric emulsifier is contained in the composition in a weight ratio ranging between 2:1 and 20:1 polymer with respect to PEA.

2. The water-soluble composition according to claim 1, wherein the MCD/PEA weight ratio is at least 100:1.

3. The water-soluble composition according to claim 2, wherein the MCD/PEA weight ratio is at least 220:1.

4. The water-soluble composition according to claim 1, comprising PEA in the form of an inclusion complex in MCD, wherein MCD is present in a ratio of at least 120:1 with respect to PEA, wherein the polymeric emulsifier is selected from cellulose derivatives, polyvinyl alcohol (PVA), cross-linked acrylate/C10-C30 alkylacrylate copolymers, cross-linked polyacrylic acid/divinyl glycol copolymer (Polycarbophil) and Poloxamer 407.

5. The water-soluble composition according to claim 4, wherein the MCD/PEA weight ratio is at least 150:1.

6. The water-soluble composition according to claim 1, said composition comprising (w/w %): 0.001-0.6 PEA 0.1-55 MCD 0.002-12 polymeric emulsifier 0.1-0.3 other excipients water, balance to 100%.

7. The water-soluble composition according to claim 6, wherein said excipients are selected from a buffer, a wetting agent or glycerin, an eye and joint lubricating agent, or a restructuring agent for a bladder mucopolysaccharide layer.

8. The water-soluble composition according to claim 1, for use in the treatment of ocular, joint, bladder, and urethral diseases, in humans and animals.

9. The water-soluble composition for use according to claim 8, wherein said ocular diseases are selected from diseases characterized by a high inflammatory component, uveitis, iritis, iridociclitis, glaucoma, scleritis, conjunctivitis, keratoconjunctivitis, blepharitis, optic neuritis, retinitis pigmentosa, chorioretinitis, dry eye syndrome and Sjgren's syndrome.

10. The water-soluble composition according to claim 6, wherein said excipients are selected from: potassium citrate tribasic, glycerin, sodium hyaluronate, or combination thereof.

11. The water-soluble composition for use according to claim 8, for use in treatment of rheumatoid arthritis, traumatic and degenerative osteoarthrosis, bladder pain syndromes, interstitial cystitis and recurrent cystitis, post-coital cystitis, bladder distress following chemotherapy and radiotherapy treatments, and urethrites.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present invention relates to a water-soluble composition comprising one or more N-acylethanolamines (NAE) in the form of an inclusion complex in methyl-beta-cyclodextrin (MCD).

(2) By the term methyl-beta-cyclodextrin, or MCD, it is meant a randomly methylated cyclodextrin.

(3) By the term N-acylethanolamines, or NAEs, it is preferably meant a molecule of formula (I):

(4) ##STR00001##
wherein m is 0 or an integer between 1 and 6, and n is an integer between 1 and 13.

(5) In preferred embodiments, N-acylethanolamine is selected from N-palmitoylethanolamine (PEA), N-oleylethanolamine (OEA), N-stearoylethanolamine (SEA), N--linolenoylethanolamine (-LNEA), N--linolenoylethanolamine (-LNEA), N-linoleylethanolamine (LEA), N-eicosapentaenoylethanolamine (EPAEA), and N-docoesaenoylethanolamine (DHAEA).

(6) In a particularly preferred embodiment, NAE is N-palmitoylethanolamine (PEA).

(7) NAEs are known compounds that are commercially available, or they can be prepared according to conventional methods of condensation between a carboxylic acid in an activated form, for example, by the formation of acyl chloride, and the corresponding amine.

(8) It has been noticed that, in order to obtain the solubilization of a NAE by MCD, it is necessary to use a minimum amount of cyclodextrin that is different depending on the NAE to be solubilized, but which generally ranges between a MCD/NAE weight ratio of at least 90:1 and at least 220:1, according to the used NAE.

(9) Particularly, the MCD/NAE weight ratio will be at least: 100:1 for PEA 90:1 for OEA 140:1 for SEA 180:1 for alpha- or gamma-LNEA 100:1 for LEA and EPAEA 220:1 for DHAEA.

(10) However, it has been noticed that, bringing the solutions of said NAEs, containing the minimum amount of cyclodextrin in the above-indicated ratios, to temperatures ranging between 8 C. and 25 C., the NAE solutions undergo a formation of a precipitate within a few weeks, while such precipitate forms already after a few hours at temperatures below 8 C.

(11) Therefore, it has been found that stable solutions of NAEs in MCD can be obtained by working with an excess of cyclodextrin ranging between 25% and 125% with respect to the minimum concentration required to solubilize the NAE.

(12) Therefore, it is a preferred embodiment of the invention a water-soluble pharmaceutical composition comprising an N-acylethanolamine in the form of a complex with MCD, wherein MCD is present in a ratio ranging between at least 160:1 and at least 300:1 with respect to NAE.

(13) Particularly, the MCD/NAE weight ratio will be at least: 220:1 for PEA 200:1 for OEA 300:1 for SEA, alpha- and gamma-LNEA 160:1 for LEA and EPAEA 260:1 for DHAEA.

(14) Furthermore, it has been noticed that by adding a polymeric emulsifier, preferably selected from cellulose derivatives, polyvinyl alcohol (PVA), cross-linked acrylate/C10-C30 alkylacrylate copolymers, cross-linked polyacrylic acid/divinyl glycol copolymer (Polycarbophil) and Poloxamer 407, to the composition of the invention, a stable solution of NAE is obtained at any temperatures, in some cases even by using the minimum amount of MCD indicated above, or anyhow by considerably reducing the excess of cyclodextrin otherwise required.

(15) Among the polymers that are used, PVA is preferred.

(16) Therefore, it is a further object of the invention a water-soluble pharmaceutical composition comprising a NAE as an inclusion complex in MCD, wherein the MCD is present in a ratio ranging between at least 120:1 and at least 210:1 with respect to NAE, said composition further comprising a polymeric emulsifier selected from cellulose derivatives, polyvinyl alcohol (PVA), cross-linked acrylate/C10-C30 alkylacrylate copolymers, cross-linked polyacrylic acid/divinyl glycol copolymer (Polycarbophil) and Poloxamer 407, preferably PVA.

(17) Particularly, the MCD/NAE weight ratio will be at least: 150:1 for PEA 130:1 for OEA 190:1 for SEA 180:1 for alpha- and gamma-LNEA 120:1 for LEA and EPAEA 210:1 for DHAEA.

(18) The polymeric emulsifier is preferably contained in the composition of the invention in a weight ratio ranging between 2:1 and 20:1 polymer with respect to NAE.

(19) A typical formulation of the invention comprises (w/w %): 0.001-2 NAE 0.1-55 MCD 0-25, preferably, 0.001-25 polymeric emulsifier 0.1-0.3 other excipients water, balance to 100%.

(20) The excipients that can be used are, for example, a buffer, such as potassium citrate tribasic, a wetting agent, such as glycerin, and an eye and joint lubricating agent or a restructuring agent for the bladder mucopolysaccharide layer, such as sodium hyaluronate.

(21) The solution is prepared by adding to a solution of MCD in water the NAE in the above-indicated ranges and stirring the combined solutions to complete dissolution. Optionally, other pharmaceutically acceptable excipients and additives are added to such solution.

(22) In those embodiments in which the polymeric emulsifier is present, it is added directly, or after it has first been dissolved in water, optionally by heating at 70-75 C. to obtain a rapid dissolution of the polymer.

(23) The composition of the invention is preferably a composition for ocular use, for example, eye drops, a gel, a cream, an ointment, or a composition for intra-articular use, for example a solution that can be injected into the joint cavity; or a composition for intravesical use, for example, a solution for instillation by means of a bladder catheter.

(24) Examples of compositions for ocular use, for intra-articular injection or for intravesical infusion are described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA.

(25) The ocular composition of the invention can be used for the treatment of ocular diseases in humans and animals. The intra-articular composition can be used for the treatment of articular diseases in humans and animals; the intravesical composition can be used for the treatment of bladder and ureter diseases in humans and animals.

(26) Such diseases are preferably diseases characterized by a high inflammatory component, particularly: uveitis, iritis, iridociclitis, glaucoma, scleritis, conjunctivitis, keratoconjunctivitis, blepharitis, optic neuritis, retinitis pigmentosa, chorioretinitis, dry eye syndrome and Sjgren's syndrome, rheumatoid arthritis, traumatic and degenerative osteoarthrosis, bladder pain syndromes, such as interstitial cystitis and recurrent cystitis, post-coital cystitis, bladder distress following chemotherapy and radiotherapy treatments, urethrites.

(27) The most appropriate dosage and pharmaceutical form will be selected by the physician depending on the disease, the severity thereof, and the patient's characteristics.

(28) The following examples of composition further describe the invention, without however limiting the protection scope thereof as defined by the appended claims.

SPECIFIC EXAMPLES

PEAExample 1.0

(29) PEA Formulation giving a temporary precipitation when stored at 8-25 C.

(30) TABLE-US-00001 COMPONENT % w/w PEA 0.05 M--CD* 5 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *the amount of M--CD is the one required and sufficient for the solubilization.

PEAExample 1.1

(31) Non-precipitating PEA formulation: high concentrations of cyclodextrin.

(32) TABLE-US-00002 COMPONENT % w/w PEA 0.05 M--CD 11 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g

PEAExample 1.2

(33) Non-precipitating PEA formulation: presence of a polymer

(34) TABLE-US-00003 COMPONENT % w/w PEA 0.05 M--CD 7.5 PVA* 0.5 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *or 0.1% Polycarbophil or 0.15% CMC or 0.1% HPMC

OEAExample 2.0

(35) OEA Formulation giving temporary precipitation when stored at 8-25 C.

(36) TABLE-US-00004 COMPONENT % w/w OEA 0.05 M--CD 4.5 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *the amount of M--CD is the one required and sufficient for the solubilization.

OEAExample 2.1

(37) Non-precipitating OEA Formulation: high concentrations of cyclodextrin

(38) TABLE-US-00005 COMPONENT % w/w OEA 0.05 M--CD 10 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g

OEAExample 2.2

(39) Non-precipitating OEA Formulation: presence of a polymer

(40) TABLE-US-00006 COMPONENT % w/w OEA 0.05 M--CD 6.5 POLICARBOPHIL* 0.1 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *or 0.5% PVA or 0.15% CMC or 0.1% HPMC

SEAExample 3.0

(41) SEA Formulation giving temporary precipitation when stored at 8-25 C.

(42) TABLE-US-00007 COMPONENT % w/w SEA 0.05 M--CD 7.0 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *the amount of M--CD is the one required and sufficient for the solubilization.

SEAExample 3.1

(43) Non-precipitating SEA Formulation: high concentrations of cyclodextrin

(44) TABLE-US-00008 COMPONENT % w/w SEA 0.05 M--CD 15 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g

SEAExample 3.2

(45) Non-precipitating SEA Formulation: presence of a polymer

(46) TABLE-US-00009 COMPONENT % w/w SEA 0.05 M--CD 9.5 PVA* 1.0 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *or 0.5% Polycarbophil or 0.25% CMC or 0.3% HPMC

( or ) LNEAExample 4.0

(47) ( or ) LNEA Formulation giving temporary precipitation when stored at 8-25 C.

(48) TABLE-US-00010 COMPONENT % w/w ( or ) LNEA 0.05 M--CD 9.0 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *the amount of M--CD is the one required and sufficient for the solubilization.

( or ) LNEAExample 4.1

(49) Non-precipitating ( or ) LNEA Formulation: high concentrations of cyclodextrin

(50) TABLE-US-00011 COMPONENT % w/w ( or ) LNEA 0.05 M--CD 15 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g

( or ) LNEAExample 4.2

(51) Non-precipitating ( or ) LNEA Formulation: presence of a polymer

(52) TABLE-US-00012 COMPONENT % w/w ( or ) LEA 0.05 M--CD 9.0 CMC* 1.0 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *or Polycarbophil 1.0% or 0.25% PVA or 0.3% HPMC

LEAExample 5.0

(53) LEA Formulation giving temporary precipitation when stored at 8-25 C.

(54) TABLE-US-00013 COMPONENT % w/w LEA 0.1 M--CD 10 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *the amount of M--CD is the one required and sufficient for the solubilization.

LEAExample 5.1

(55) Non-precipitating LEA Formulation: high concentrations of cyclodextrin

(56) TABLE-US-00014 COMPONENT % w/w LEA 0.1 M--CD 16 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g

LEAExample 5.2

(57) Non-precipitating LEA Formulation: presence of a polymer

(58) TABLE-US-00015 COMPONENT % w/w LEA 0.1 M--CD 12 PVA* 1.0 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *or 0.5% Polycarbophil or 0.25% CMC or 0.3% HPMC

EPAEAExample 6.0

(59) EPAEA Formulation giving temporary precipitation when stored at 8-25 C.

(60) TABLE-US-00016 COMPONENT % w/w EPAEA 0.1 M--CD 10 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *the amount of M--CD is the one required and sufficient for the solubilization.

EPAEAExample 6.1

(61) Non-precipitating EPAEA Formulation: high concentrations of cyclodextrin

(62) TABLE-US-00017 COMPONENT % w/w EPAEA 0.1 M--CD 16 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g

EPAEAExample 6.2

(63) Non-precipitating EPAEA Formulation: presence of a polymer

(64) TABLE-US-00018 COMPONENT % w/w EPAEA 0.1 M--CD 12 PVA* 1.0 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *or 0.5% Polycarbophil or 0.25% CMC or 0.3% HPMC

DHAEAExample 7.0

(65) DHAEA Formulation giving temporary precipitation when stored at 8-25 C.

(66) TABLE-US-00019 COMPONENT % w/w DHAEA 0.09 M--CD 20 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *the amount of M--CD is the one required and sufficient for the solubilization.

DHAEAExample 7.1

(67) Non-precipitating DHAEA Formulation: high concentrations of cyclodextrin

(68) TABLE-US-00020 COMPONENT % w/w DHAEA 0.095 M--CD 25 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g

DHAEAExample 7.2

(69) Non-precipitating DHAEA Formulation: presence of a polymer

(70) TABLE-US-00021 COMPONENT % w/w DHAEA 0.095 M--CD 20 PVA* 1.0 SODIUM HYALURONATE 0.1 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g *or 0.5% Polycarbophil or 0.25% CMC or 0.3% HPMC Pemulen, Poloxamers (Pluronic 127).

PEAExample 8

(71) Sterile formulation injectable into a joint.

(72) TABLE-US-00022 COMPONENT % w/w PEA 0.05 M--CD 11 SODIUM HYALURONATE 0.5 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g

PEAExample 9

(73) Sterile formulation for intravesical instillation by means of a catheter

(74) TABLE-US-00023 COMPONENT % w/w PEA 0.05 M--CD 11 SODIUM HYALURONATE 0.3 POTASSIUM CITRATE TRIBASIC 0.10 NaCl 0.42 WATER for Injectables Q.S. 100 g