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Liposomal corticosteroids for treatment of inflammatory disorders in humans

A technology for inflammatory diseases and corticosteroids, used in liposome delivery, urinary system diseases, anti-inflammatory agents, etc., can solve the problems of increasing medical cost burden and high cost of treatment

Inactive Publication Date: 2014-11-12
ENCELADUS PHARMA BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

1mg / kg prednisolone has limited effect only for 4 days
2 mg / kg prednisolone, although slightly more potent, showed the same duration of potency
However, the cost of maintenance therapy with such biological products is many times higher than the cost of treatment with disease-modifying agents, and the trend of patients to switch to biological products will eventually cause a huge increase in the medical cost burden

Method used

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  • Liposomal corticosteroids for treatment of inflammatory disorders in humans
  • Liposomal corticosteroids for treatment of inflammatory disorders in humans
  • Liposomal corticosteroids for treatment of inflammatory disorders in humans

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1: Experimental Arthritis Study in Rats

[0070] preparation

[0071] PEG liposomes containing prednisolone phosphate are composed of 750 mg of dipalmitoylphosphatidylcholine (DPPC), 250.8 mg of cholesterol and 267.6 mg of PEG-distearoylphosphatidylethanolamine (PEG-DSPE) . The components were weighed and mixed in a 100ml round bottom flask. Lipids were dissolved in about 30 ml of ethanol and then evaporated to dryness under vacuum in a rotary evaporator at 40° C. within 1 hour. Weigh 1200 mg of prednisolone disodium phosphate and dissolve it in 12 ml of sterile water. This solution was added to the dried lipid film and shaken within one hour in the presence of glass beads to fully hydrate the lipid film. The liposome suspension was transferred to an extruder (Avestin, maximum volume 15 ml) and extruded under pressure using nitrogen gas using a polycarbonate filter with a pore size below 100 nm. Then, dialyze with sterile saline. The average particle size ...

Embodiment 2

[0077] Example 2: Human RA Study

[0078] preparation

[0079]Prednisolone containing polyethylene glycol (PEG) consists of a lipid bilayer surrounding an aqueous compartment in which a water-soluble disodium phosphate derivative of prednisolone is encapsulated. Each mL formulation contains 1.5 mg / mL prednisolone sodium phosphate, 30 mg palmitoylphosphatidylcholine (DPPC), 9 mg distearoylphosphatidylethanolamine-PEG2000 (PEG-DSPE) and 8 mg steroid. Liposomes were dispersed in 10% sucrose, pH 7.4, buffered with phosphate buffer.

[0080] The formulation is prepared by mixing the lipid component with an aqueous solution of the corticosteroid, followed by repeated high shear homogenization to reduce the size of the vesicles formed. Unencapsulated corticosteroids were removed by tangential flow filtration. Sterilize by dead-end filtration using a 0.2 micron filter.

[0081] The formulations were characterized and quality controlled by: particle size and polydispersity index (1...

Embodiment 3

[0095] Example 3: Human Inflammatory Bowel Disease Research

[0096] preparation

[0097] Prednisolone containing PEG liposomes was prepared as described in Example 2.

[0098] patient

[0099] Twenty patients with active ulcerative colitis (UC) between the ages of 18 and 75 years were selected during the 14-day screening phase according to the following main inclusion / exclusion criteria: age ≥18 years to 75 years, by Endoscopically evaluated and documented history of UC (at least 6 months), Mayo score ≥5 with a subscore of ≥2 for endoscopy and ≥1 for rectal bleeding, and stable medication (6 - MP / azathioprine, 5-ASA, MTX, biologics) and in good physical and mental health (except for the disease being studied) as determined by history and physical examination.

[0100] research proposal

[0101] When subjects were randomly assigned to the study product arm, 150 mg PEG liposomal prednisolone sodium phosphate (Nanocort) IV in 250 mL of normal saline was infused alone over a ...

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Abstract

The invention relates to a pharmaceutical composition comprising liposomes composed of non-charged vesicle-forming lipids, optionally including not more than 10 mole percent of negatively charged vesicle- forming lipids and / or not more than 10 mole percent of PEGylated lipids, the liposomes having a selected mean particle diameter in the size range of 40-200 nm and comprising a first corticosteroid in water soluble form, for the site-specific treatment of inflammatory disorders in humans, providing in human patients a fast, strong, and durable anti-inflammatory effect for at least 2 weeks at a dose of at most 5 mg / kg body weight of prednisolone or an equipotent dose corticosteroid other than prednisolone at a treatment frequency of at most once per two weeks. Furthermore the present invention relates to the application of the above-mentioned pharmaceutical composition given as intervention therapy in inflammatory disorders such as rheumatic disease or a related inflammatory connective tissue disorder, inflammatory diseases of the kidney or inflammatory bowel disorders, in combination with chronic therapy with a second free corticosteroid formulation or in combination with chronic treatment with a disease- modifying agent such as methotrexate.

Description

technical field [0001] The present invention relates to the field of medicine. More specifically, the invention relates to corticosteroid treatment of inflammatory diseases. Background technique [0002] Inflammatory diseases such as inflammatory connective tissue diseases, such as rheumatoid arthritis (RA), inflammatory diseases of the kidney, and inflammatory bowel disease (IBD), are chronic, progressive, and degenerative diseases that often result in disability. Prednisone Corticosteroids and other corticosteroids may be effective in inflammatory diseases, but due to conditions including osteoporosis, suppression of the hypothalamic-pituitary-adrenal axis (HPA), muscle atrophy, insulin resistance, prone to skin abrasions, severe bacterial infections The systemic use of the aforementioned corticosteroids is limited by the increased risk and high incidence of side effects (AEs) from cardiovascular conditions. In most cases, the severity of these AEs depends on the dose, du...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K31/573A61P29/00
CPCA61K45/06A61K31/573A61K9/1271A61K9/0019A61P1/04A61P13/12A61P29/00A61P43/00A61K2300/00
Inventor 若斯贝特·马尔滕·梅策拉尔
Owner ENCELADUS PHARMA BV
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