Composition comprising EPA and DHA ethylester for parenteral administration

Abstract

Described herein are compositions for parenteral administration that include an aqueous phase and 5 to 30%, by weight, of an oil phase, based on the total weight of the composition. The oil phase comprises the omega-3 fatty acid ethylesters eicosapentaenoic acid ethylester, docosahexaenoic acid ethylester, and mixtures thereof. The composition further comprises at least one anionic surfactant and at least one amphoteric surfactant, and less than 0.05% by weight of oleic acid, based on the total weight of the composition. Also described is a method for preparing such a composition as well as such compositions for use as a medicament, in particular for use in treating stroke, sepsis, Alzheimer's disease or cancer. Also featured are methods of treating these conditions by parenterally administering a composition to a patient in need thereof and methods of providing parenteral nutrition to such patients by administering to them a composition as described herein.

Claims

1. A composition comprising an aqueous phase and 5 to 30% by weight of an oil phase, based on the total weight of the composition, wherein the oil phase comprises eicosapentaenoic acid ethylester, docosahexaenoic acid ethylester or mixtures thereof and less than 1% by weight medium chain triglycerides, based on the total weight of the composition; an anionic surfactant; and an amphoteric surfactant, wherein the composition is formulated for parenteral administration and comprises less than 0.05% by weight of oleic acid, based on the total weight of the composition.

2. The composition of claim 1, wherein at least 60% by weight of the oil phase consists of eicosapentaenoic acid ethylester, docosahexaenoic acid ethylester or mixtures thereof.

3. The composition of claim 1, wherein the oil phase comprises a mixture of eicosapentaenoic acid ethylester and docosahexaenoic acid ethylester and wherein the weight ratio of the eicosapentaenoic acid ethylester to the docosahexaenoic acid ethylester is in the range of from 1 to 9 to 9 to 1.

4. The composition of claim 1, further comprising an agent with antioxidant activity.

5. The composition of claim 1, wherein the amphoteric surfactant is lecithin.

6. The composition of claim 1, wherein the anionic surfactant is sodium oleate.

7. The composition of claim 1, wherein the composition further comprises a tonicity agent.

8. The composition of claim 1, wherein the composition comprises in sum less than 1% by weigh of polyethylene glycol and propylene glycol, based on the total weight of the composition.

9. The composition of claim 1, wherein the composition comprises less than 0.01% by weight oleic acid.

10. A method for preparing a composition, wherein the method comprises: (a) providing an aqueous phase comprising an amphoteric surfactant and an anionic surfactant, (b) providing an oil phase comprising eicosapentaenoic acid ethylester, docosahexaenoic acid ethylester or mixtures thereof, and (c) mixing the oil phase according to (b) with the aqueous phase according to (a), wherein the oil phase constitutes 5 to 30% by weight of the total composition, and the composition comprises less than 1% by weight medium chain triglycerides and less than 0.05% by weight oleic acid.

11. The method of claim 10, further comprising (d) homogenizing the mixture obtained from step (c) at a temperature in the range of from 50 to 60° C. and at a pressure in the range of from 450 to 550 bar.

12. The method of claim 11, further comprising (e) autoclaving the mixture obtained from step (c) or step (d) at a temperature in the range of from 119° C. to 122° C. for a time in the range of from 10 min to 15 min.

13. A composition obtained by the method of claim 10.

14. A method of providing parenteral nutrition to a patient suffering from stroke, sepsis, Alzheimer's disease or cancer, the method comprising parenterally administering to the patient an effective amount of the composition of claim 1.

15. An infusion bag comprising the composition of claim 1.

16. The composition of claim 4, wherein the agent with antioxidant activity is alpha-tocopherol, beta-tocopherol, gamma-tocopherol, ascorbic acid, ascorbic acid palmitate, or an antioxidant obtained or obtainable from rosemary or rosemary extract.

17. The composition of claim 7, wherein the tonicity agent is glycerol.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the particle size distribution of composition 1 (as depicted in table 2, containing mixture 1) freshly prepared according to general procedure A containing 20% by weight of the oil phase measured with a LS 13 320 Laser Diffraction Particle Size Analyser (Beckman Coulter), according to USP <729>. The results comply with the requirements set forth in USP <729>.

(2) FIG. 2 shows the particle size distribution of the same composition as shown in FIG. 1, however after 1, 2, 3 and 4 weeks, measured with a LS 13 320 Laser Diffraction Particle Size Analyser (Beckman Coulter), according to USP <729>. The results comply with the requirements set forth in USP <729>.

(3) The following examples are intended to illustrate the present invention without limiting it.

EXAMPLES

(4) Different mixtures comprising highly concentrated omega-3 fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) as ethyl esters as obtained from Solutex S.L. were used.

(5) Mixture 1:

(6) EPA ethylester (g/g) 0.6842

(7) DHA ethylester (g/g) 0.0838

(8) Mixture 2:

(9) EPA ethylester (g/g) 0.1256

(10) DHA ethylester (gig) 0.6722

(11) Mixture 3:

(12) EPA ethylester (g/g) 0.4501

(13) DHA ethylester (g/g) 0.2813

Example 1: General Procedure A for the Preparation of an Emulsion According to the Invention

(14) Using a shear mixer, first glycerol and sodium oleate, and then lecithin (PL90, obtainable from egg yolk (=egg lecithin with a phosphatidylcholine content of 64-79% and a phosphatidylethanolamine content of 10-18% by weight) were dispersed in water for injection, at a temperature between 55-60° C. The dispersion was continuously mixed until lecithin was homogeneously dispersed in water. Afterwards, the aqueous dispersion was submitted to ultrasonic treatment for 15 minutes. The PL90/sodium oleate/glycerol dispersion was then transferred to a separate container and an oily phase, containing highly-enriched omega-3 fatty acids with different EPA:DHA ratios (Mixtures 1 to 3), previously heated at 55° C., was added while continuously dispersing, using a Rayneri TURBOTEST high shear mixer, to obtain an oil-in-water emulsions with an oil phase concentration between 10 and 30% by weight. The coarse emulsion was then passed, six times through a homogenizer (Niro Soavi Panda Plus 2000), at 500 bar and temperature between 50-60° C. Finally, the emulsion was autoclaved at 122° C. for 15 min. A final lipid emulsion was obtained (see Table 1). The mean particle size of the lipid emulsions was measured using a Malvern Mastersizer 2000. The mixture was sterilized by autoclaving at a temperature of 120 to 122° C.

(15) TABLE-US-00001 TABLE 1 General composition of the formulation prepared according to general example A weight-% Ingredients: Ethyl ester EPA/DHA 20 Egg lecithin 1.2 Sodium Oleate 0.3 Glycerol 2.5 Water for injection adds up to 100 Properties: pH after manufacture 9-10 Droplet size distribution [3, 2] ≦0.3 Volume weighted mean D [4, 3] ≦0.3 % Droplets >5 micrometer ≦0.05

(16) Further compositions prepared are given in Table 2. For some of these compositions, no stable emulsion could be obtained. Surprisingly, in particular emulsions comprising a combination of sodium oleate and lecithin turned out to be particularly stable.

(17) TABLE-US-00002 Composition 1 2 3 4 5 6 7 8 9 10 a, b, c a, b, c a, b, c a, b, c a, b, c a, b, c a, b, c a, b, c a, b, c a, b, c DHA/EPA 20 20 20 20 20 20 20 20 20 20 [weight.-%] Mixtures Mixtures Mixtures Mixtures Mixtures Mixtures Mixtures Mixtures Mixtures Mixtures 1, 2, 3 1, 2, 3 1, 2, 3 1, 2, 3 1, 2, 3 1, 2, 3 1, 2, 3 1, 2, 3 1, 2, 3 1, 2, 3 Egg lecithin 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 [weight.-%] Glycerol 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 [weight.-%] Tocopherols 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 [weight.-%] Oleic Acid — — — — 0.12 0.12 0.05 0.15 0.25 0.15 [weight.-%] Sodium Oleate 0.3 0.2 0.15 0.1 0.18 0.03 0.2 — — — [weight.-%] PEG 400 — — — — — — — 2 1 — [weight.-%] Propylene — — — — — — — — — 1 glycol [weight.-%] Water for Adds up Adds up Adds up Adds up Adds up Adds up Adds up Adds up Adds up Adds up injection to 100 to 100 to 100 to 100 to 100 to 100 to 100 to 100 to 100 to 100 Stable Y Y Y Y N N N N N N Emulsion spontaneously spontaneously spontaneously After After After Y = yes; some some some N = no weeks weeks weeks pH release 8-9 8-9 8-9 8-9 8-9 8-9 8-9 8-9 8-9 8-9 Surface mean ≦0.3 ≦0.3 ≦0.3 ≦0.3 >0.3 >0.3 >0.3 ≦0.3 ≦0.3 ≦0.3 droplet diameter D [3,2] Volume ≦0.3 ≦0.3 ≦0.3 ≦0.3 >0.3 >0.3 >0.3 ≦0.3 ≦0.3 ≦0.3 weighted mean diameter D [4,3] % Droplets >5 ≦0.05 ≦0.05 ≦0.05 ≦0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 micrometer