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US-12622869-B2 - Lipid emulsion for parenteral administration

US12622869B2US 12622869 B2US12622869 B2US 12622869B2US-12622869-B2

Abstract

The present disclosure relates to lipid emulsions for parenteral administration, comprising 10 to 30% of a lipid phase comprising soybean oil, medium-chain triglycerides (MCT), olive oil and fish oil and less than 25 mg, preferably less than 20 mg, campesterol, less than 30 mg, preferably less than 25 mg, stigmasterol and less than 120 mg, preferably less than 100 mg, betasitosterol per 100 g of the lipid phase. The present disclosure also relates to the lipid emulsions according to the present disclosure for providing parenteral nutrition, in particular to neonates, as well as to methods for manufacturing the lipid emulsions according to the present disclosure.

Inventors

  • MELANIE DENKINGER
  • Ewald Schlotzer
  • Edmundo Brito De La Fuente
  • Lida A. Quinchia-Bustamante
  • Crispulo Gallegos-Montes

Assignees

  • FRESENIUS KABI DEUTSCHLAND GMBH

Dates

Publication Date
20260512
Application Date
20190701
Priority Date
20180703

Claims (19)

  1. 1 . A lipid emulsion for parenteral administration comprising an aqueous phase and 10 to 30% of a lipid phase based on the total volume of the emulsion (w/v), wherein the lipid phase comprises 20 wt. % to 40 wt. % soybean oil, 20 wt. % to 40 wt. % medium-chain triglycerides, 15 wt. % to 35 wt. % olive oil, and 1-15 wt. % fish oil extract, wherein the lipid phase comprises less than 25 mg campesterol, less than 30 mg stigmasterol and less than 120 mg beta-sitosterol per 100 g of the lipid phase, wherein the lipid phase further comprises 1 to 10 wt. % arachidonic acid based on the total weight of the lipid phase, wherein the arachidonic acid is provided by adding a fungal oil to the lipid phase, wherein the lipid phase comprises 2 to 20 wt. % fungal oil based on the total weight of the lipid phase, wherein the fish oil extract comprises both DHA and EPA, and wherein said DHA is present in an amount of at least 35 wt. % and said EPA is present in an amount of less than 10 wt. % based on the total weight of the fish oil extract.
  2. 2 . The lipid emulsion according to claim 1 , wherein the lipid phase comprises less than 0.2 wt. % total phytosterols based on the total weight of the lipid phase.
  3. 3 . The lipid emulsion according to claim 1 , wherein the emulsion comprises at least 1-10 wt. % DHA and less than 3 wt. % EPA based on the total weight of the lipid phase.
  4. 4 . The lipid emulsion according to claim 1 , wherein the lipid phase comprises 2 wt. % to 6 wt. % arachidonic acid based on the total weight of the lipid phase.
  5. 5 . The lipid emulsion according to claim 1 , wherein the lipid phase comprises 25 wt. % to 35 wt. %, soybean oil, 25 wt. % to 35 wt. % medium-chain triglycerides, 20 wt. % to 30 wt. % olive oil, 2 wt. % to 8 wt. % fish oil and 5 wt. % to 15 wt. % fungal oil based on the total weight of the lipid phase.
  6. 6 . The lipid emulsion according to claim 4 , wherein the fungal oil is derived from Mortierella alpina.
  7. 7 . The lipid emulsion according to claim 3 , said emulsion comprising 1-10 wt. % DHA and less than 5 wt. % EPA based on the total weight of the lipid phase.
  8. 8 . The lipid emulsion according to claim 1 , wherein the fungal oil comprises at least 20 wt. % arachidonic acid based on the total weight of the fungal oil.
  9. 9 . The lipid emulsion according to claim 4 , said emulsion further comprising alpha-tocopherol or a derivative thereof.
  10. 10 . A medicament, said medicament comprising a lipid emulsion according to claim 1 .
  11. 11 . A method for providing parenteral nutrition to a subject in need thereof, said method comprising administering a lipid emulsion of claim 1 to said subject.
  12. 12 . The method according to claim 11 , wherein the subject is a pediatric patient.
  13. 13 . The method according to claim 11 , wherein the subject is an adult patient.
  14. 14 . A method for supporting neurodevelopment and/or neurocognitive development and/or for improving growth and/or body composition, said method comprising administering a lipid emulsion of claim 1 to a pediatric patient in need thereof.
  15. 15 . A method supporting neurological functions, immune response, mitochondrial function, gut flora, liver function, bile flow and/or resolution of inflammation and/or for improving intestinal morphology and/or nutrient utilization, said method comprising administering a lipid emulsion of claim 1 to a subject in need thereof.
  16. 16 . A method for use in the treatment of sepsis, chronic lung disease, cachexia, liver fat accumulation, parenteral nutrition associated liver disease, inflammatory diseases, retinopathy or bronchopulmonary dysplasia, said method comprising administering a lipid emulsion of claim 1 to a subject in need thereof.
  17. 17 . A method for preparing a lipid emulsion, said method comprising a) providing an oil phase comprising soybean oil, medium-chain triglycerides, olive oil, and fish oil and optionally a pharmaceutically acceptable antioxidant, preferably alpha-tocopherol and/or a pharmaceutically acceptable co-surfactant, b) providing an aqueous phase comprising water for injection, a pharmaceutically acceptable emulsifier, and optionally a pharmaceutically acceptable tonicity agent and/or an agent for pH adjustment, c) forming a pre-emulsion by mixing the oil phase provided in step a) with the aqueous phase provided in step b); d) forming the emulsion by high-pressure homogenizing the pre-emulsion obtained in step c) and e) sterilising the emulsion obtained in step d), wherein optionally the emulsion is filled into a suitable container before or after sterilization.
  18. 18 . The method according to claim 17 , wherein the aqueous phase provided in step b) is heated to a temperature of 55° C. to 75° C., before the surfactant is added and/or wherein step c) is conducted at a temperature of 55° C. to 75° C.
  19. 19 . The method according claim 17 , wherein step d) is conducted at a temperature of 40° C. to 60° C.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a U.S. national stage application of International Application No. PCT/EP2019/067511, filed Jul. 1, 2019, which claims the benefit of the filing date of European Application 18181432.8, filed Jul. 3, 2018, the contents of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION The present disclosure relates to lipid emulsions for parenteral administration, particularly for use in providing parenteral nutrition. BACKGROUND OF THE INVENTION Lipid emulsions for parenteral administration have been used clinically for nutritional and medical purposes for several years. Lipid emulsions comprising soybean or safflower oil were first introduced more than 50 years ago. Parenteral nutrition (PN) is prescribed as exclusive PN regimen or as PN complementary to enteral nutrition (EN) when oral or EN is impossible, contraindicated, or insufficient. Preterm infants, especially extremely low birth weight preterm infants and preterm infants of early gestational age, are usually on parenteral nutrition as part of their routine care during the first weeks of life as their gastrointestinal tract is not yet mature enough to tolerate, digest and assimilate breast milk or infant formula. Extremely low birth weight infants are at increased risk of poor growth and development and prone to develop morbidities and dysfunctions both short and long term. For many years the standard of care for preterm infants has been the parenteral administration of soybean and/or olive oil based lipid emulsions along with amino acid and glucose solutions. However, the fatty acid profile of these plant oil based lipid emulsions is very different from the provision in utero or that of human breast milk which may be considered to have the most appropriate composition. The administration of the above mentioned soybean and/or olive oil based commercial lipid emulsions has in many cases led to e.g. profound alterations in fatty acid status, fat accumulation in the liver, or parenteral nutrition associated liver disease (PNALD), particularly in neonates and preterm infants. Furthermore, it is assumed that neonatal morbidities such as e.g. late-onset sepsis and chronic lung disease may—at least in part—be related to the fatty acid profiles of these emulsions. Also, the plant oils comprised in commercial lipid emulsions are naturally rich in phytosteroles. Phytosteroles, however, have been controversially discussed as a contributing factor for the development of liver dysfunction and cholestasis, and it would thus be desirable to provide lipid emulsions with lower phytosterole content. Hence there is the need for lipid emulsions for parenteral nutrition at least partially overcoming the above mentioned drawbacks, particularly for lipid emulsions tailored to the needs of premature neonates. SUMMARY OF THE INVENTION The present disclosure relates to lipid emulsions for parenteral administration. The lipid emulsions according to the present disclosure comprise 10 to 30% of a lipid phase. The lipid phase comprises soybean oil, medium-chain triglycerides (MCT), olive oil and fish oil and less than 25 mg, preferably less than 20 mg, campesterol, less than 30 mg, preferably less than 25 mg, stigmasterol and less than 120 mg, preferably less than 100 mg, beta-sitosterol per 100 g of the lipid phase. Preferably, the lipid phase comprises less than 0.2 wt. %, preferably less than 0.15 wt. % total phytosteroles based on the total weight of this lipid phase. The present disclosure also relates to the lipid emulsions according to the present disclosure for providing parenteral nutrition, in particular to neonates, as well as to methods for manufacturing the lipid emulsions according to the present disclosure. DETAILED DESCRIPTION OF THE INVENTION The present disclosure relates to lipid emulsions for parenteral administration. The lipid emulsions according to the present disclosure are oil-in-water emulsions, i.e. the continuous phase is aqueous and comprises oil droplets. The emulsions according to the present disclosure comprise the continuous aqueous phase and preferably 10% to 30% of a lipid phase based on the total volume of the emulsion (w/v). For example, the emulsions comprise 10%, 20% or 30% of a lipid phase based on the total volume of the emulsion (w/v). More preferably, the emulsions comprise 20% of a lipid phase based on the total volume of the emulsion (w/v). The aqueous phase comprises water in purity suitable for parenteral administration, i.e. water for injection. Oil-in-water emulsions for parenteral administration have to be sterile, pyrogen-free, well tolerated, free of particulate impurities and storage stable. The Lipid Phase The lipid phase comprises soybean oil, olive oil, fish oil and medium chain triglycerides (MCT). Preferably, the lipid phase comprises 20 to 40 wt. %, preferably 25 to 35 wt. % soybean oil, 20 to 40 wt. %, preferably 25 to 35 wt. %, MCT, 15 t