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Disease-site-specific liposomal formulation

a disease-site and liposomal technology, applied in the digestive system, medical preparations, drug compositions, etc., can solve the problems of difficult production of clinically applicable ns formulations containing pgi2 receptor agonists, extremely difficult to produce ns formulations capable of containing compound (a), and short drug-release time of nanoparticle formulations having a large surface area, so as to improve drug efficacy and reduce side effects.

Pending Publication Date: 2021-04-22
OSAKA UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a pharmaceutical composition that can be used to treat various medical conditions, including cardiovascular, respiratory, gastrointestinal, and inflammatory diseases. The composition can be administered at a lower dose than traditional PGI2 receptor agonists and can provide sustained effects over time. The invention also provides a stealth liposomal formulation that can be administered through various routes, including intravenous and inhalation. The formulation can help promote endogenous repair mechanisms and is effective in treating heart, lung, and neurological diseases. Overall, the invention provides a safer and more effective way to treat a variety of medical conditions.

Problems solved by technology

However, this method has a risk such that mass administration may cause the development of a pulmonary embolism, and thus has a safety problem.
However, the production of a clinically applicable NS formulation comprising a PGI2 receptor agonist, such as compound (A), has been difficult due to the stability, content, yield, safety, sustained release rate, efficacy, etc., of the formulation.
In addition, it was extremely difficult to produce an NS formulation containing compound (A) capable of accumulation at a disease site and exhibiting the effect.
Since an encapsulated drug is released from such a PLGA or PLA nanoparticle formulation by hydrolysis of a lactic acid-glycolic acid bond with water, a nanoparticle formulation having a large surface area has a very short drug-release time.

Method used

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  • Disease-site-specific liposomal formulation
  • Disease-site-specific liposomal formulation
  • Disease-site-specific liposomal formulation

Examples

Experimental program
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Effect test

examples

[0194]The present invention is described in detail below with reference to Examples; however, the present invention is not limited to these Examples.

[0195]The following are the reagents used. In the Examples, these reagents are referred to by the following abbreviations.

[0196](1) HSPC (hydrogenated soybean phospholipid, hydrogenated lecithin), product name: COATSOME NC-21 (NOF corporation), CAS: 921228-87-5, 92128-87-5

[0197](2) DSPE (1,2-Distearoyl-sn-glycero-3-phosphoethanolamine), CAS: 1069-79-0 (Nippon Fine Chemical Co., Ltd.)

[0198](3) DEPC: 1,2-Dierucoyl-sn-glycerol-3-phosphorylcholine, CAS: 51779-95-4 (Nippon Fine Chemical Co., Ltd.)

[0199](4) MPEG2000-DSPE: N-(carbonyl-methoxypolyethyleneglycol-5000)-1,2 distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt, CAS: 147867-65-0 (Nippon Fine Chemical Co., Ltd.)

[0200](5) DOPC: 1,2-Dioleoyl-sn-glycero-3-phosphocholine, CAS: 4235-95-4 (Nippon Fine Chemical Co., Ltd.)

[0201](6) Cholesterol: Cholesterol HP (NOF Corporation)

[0202](7) P...

formulation example 2 (

2. Formulation Example 2 (Bangham Method) Preparation of Liposome

[0219]1) HSPC (102.0 mg), DSPE (8.5 mg), and cholesterol (33.5 mg) were weighed and placed in an eggplant flask, and a chloroform / methanol solution (1 / 1, v / v) was added and dissolved so that the lipid concentration was 20 mg / mL.

[0220]2) The chloroform / methanol was evaporated with a rotary evaporator, followed by vacuum-drying. Four eggplant flasks each containing 30 mg of the lipids in total were thus obtained.

[0221]3) Compound (A) (170.6 mg) was weighed, and 4.5 mL of a 0.1N sodium hydroxide solution was added thereto. The mixture was dissolved by vortexing, and 2.6 ml of 10 mM phosphate buffer (pH: 8.0) was added thereto to thus prepare a solution of 24 mg / mL (compound (A) solution).

[0222]4) The compound (A) solution was added to the vacuum-dried lipid film (three concentration conditions), followed by stirring at 37° C. for 1 hour. Since each eggplant flask contained 30 mg of the lipids, the amount of each solution ...

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Abstract

The present invention provides a clinically applicable, safe and convenient, pharmaceutical composition for disease site-specific treatment. The pharmaceutical composition for disease site-specific treatment comprises a stealth liposome having a prostaglandin I2 receptor agonist encapsulated therein.

Description

TECHNICAL FIELD[0001]The present invention relates to a disease-site-specific liposomal formulation.BACKGROUND ART[0002]Compound (A) (ONO-1301) is a low-molecular-weight compound having both PGI2 receptor (IP) agonism and thromboxane (TX) A2 synthase inhibitory activity. Compound (A), which has PGI2 agonistic activity, is known to be useful for prevention and / or treatment of thrombosis, arteriosclerosis, ischemic heart disease, gastric ulcer, hypertension, etc. (Patent Literature (PTL) 1).[0003]On the other hand, prostaglandin (PG) I2 receptor (IP) agonists, prostaglandin EP2 agonists, and prostaglandin EP4 agonists, such as ONO-1301, can be used as endogenous repair factor production promoters for many diseases at low doses by inducing many body regeneration factors, such as a hepatocyte growth factor (HGF), a vascular endothelial cell growth factor (VEGF), a stromal cell-derived factor (SDF-1), and a high-mobility group box protein 1 (HMGB1); and these agonists are known to be use...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K31/4406
CPCA61K9/127A61K9/1277A61K31/4406A61K9/1271A61K31/5585A61K31/5575A61K31/4965A61P1/00
Inventor SAWA, YOSHIKIMIYAGAWA, SHIGERUSAKAI, YOSHIKIYANAGI, YASUHIRO
Owner OSAKA UNIV