CN-121971383-A - Rotigotine lyotropic liquid crystal precursor solution and preparation method and application thereof

CN121971383ACN 121971383 ACN121971383 ACN 121971383ACN-121971383-A

Abstract

The invention discloses a rotigotine lyotropic liquid crystal precursor solution, a preparation method and application thereof, belonging to the field of pharmaceutical preparations, and comprising the following components of phospholipid, grease, a release regulator, an organic solvent and rotigotine or pharmaceutically acceptable salts thereof, wherein the organic solvent accounts for 10% -40% of the mass of the precursor and the rotigotine or pharmaceutically acceptable salts thereof accounts for 1% -30%. The rotigotine lyotropic liquid crystal precursor solution has low viscosity, is easy to inject, can form lyotropic liquid crystal gel when meeting body fluid after injection, has good slow release effect when the gel wraps medicines, can reduce the medicine use times, increases the compliance of patients, has good auxiliary material biocompatibility, is not easy to cause organism inflammatory reaction, and has low production cost, simple preparation method and easy industrialization. The invention can be used for the adjuvant therapy of early stage primary parkinsonism and late stage parkinsonism.

Inventors

WANG SILING
HE YE
Zou Peizhi
ZHOU MENGYUE
ZHAO QINFU
QIAN YU
LIU YAQI

Assignees

沈阳药科大学

Dates

Publication Date: 20260505
Application Date: 20260204

Claims (10)

1. The rotigotine lyotropic liquid crystal precursor solution is characterized by comprising, by weight, 10% -50% of phospholipids, 10% -50% of grease, 10% -40% of organic solvents, 2% -20% of release regulators and 1% -30% of rotigotine or pharmaceutically acceptable salts thereof.
2. The rotigotine lyotropic liquid crystal precursor solution according to claim 1, wherein the phospholipid is one or more of soy phosphatidylcholine, dioleoyl phosphatidylcholine, dithianoyl phosphatidylcholine, dioleoyl phosphatidylethanolamine, dilauroyl phosphatidylcholine, dioleoyl phosphatidylglycerol sodium salt, pegylated phospholipids.
3. The rotigotine lyotropic liquid crystal precursor solution of claim 1, wherein the lipid is one or more of glycerol monooleate, glycerol dioleate, glycerol trioleate, propylene glycol monolaurate, caprylic capric acid mono-di-glyceride, propylene glycol laurate, glycerol monolinoleate, span 80, span 83, propylene glycol oleate, tween 20, tween 40, tween 60, tween 80.
4. The rotigotine lyotropic liquid crystal precursor solution according to claim 1, wherein the organic solvent is one or more of absolute ethanol, propylene glycol, PEG-400, N-methylpyrrolidone, dimethyl sulfoxide, glycerol formal, PEG-400, N-dimethylacetamide, N-dimethylformamide; The release regulator is one or more of medium chain triglyceride, palmitic acid, stearic acid, nonadecanoic acid, polyethylene glycol distearate, triglycerol monostearate, polyethylene glycol-15-hydroxystearate, cholesterol, chitosan, octadecylamine and TEG-polyorthoester.
5. Rotigotine lyotropic liquid crystal precursor solution according to claim 2, wherein said phospholipid is soy phosphatidylcholine.
6. A rotigotine lyotropic liquid crystal precursor solution according to claim 3, wherein the oil is one or more of glycerol dioleate, glycerol monolinoleate.
7. The rotigotine lyotropic liquid crystal precursor solution according to claim 4, wherein the organic solvent is one or more of N-methylpyrrolidone and glycerol formal, and the release regulator is one or more of stearic acid, cholesterol, polyethylene glycol-15-hydroxystearate and TEG-polyorthoester.
8. A method for preparing rotigotine lyotropic liquid crystal precursor solution according to any one of claims 1 to 7, comprising the steps of mixing grease, phospholipid, release regulator and organic solvent, stirring at room temperature until a clear transparent precursor solution is formed, adding rotigotine or pharmaceutically acceptable salt thereof, continuously stirring until a clear transparent solution is formed again, filtering and sterilizing by a 0.22 mu m filter membrane, thus obtaining rotigotine lyotropic liquid crystal precursor solution, and finally filling nitrogen for sealing and preserving.
9. Use of a rotigotine lyotropic liquid crystal precursor solution as defined in any of claims 1 to 7 for the preparation of a medicament for the treatment of parkinson's disease.
10. The use according to claim 9, wherein said medicament is for the treatment of early stage primary parkinson's disease and for the adjuvant treatment of late stage parkinson's disease.

Description

Rotigotine lyotropic liquid crystal precursor solution and preparation method and application thereof Technical Field The invention belongs to the field of pharmaceutical preparations, and particularly relates to a rotigotine lyotropic liquid crystal precursor solution, a preparation method and application thereof. Background Parkinson's Disease (PD) is a common degenerative Disease of the central nervous system, and its pathological features are mainly progressive death of the substantia nigra dopaminergic neurons of the midbrain, resulting in insufficient secretion of dopamine neurotransmitters in the brain, and further causing a series of motor symptoms such as resting tremors, muscle stiffness, bradykinesia and dysposture balance, and also often accompanied by non-motor symptoms such as sleep disorder, depression, cognitive decline and the like. Along with the acceleration of the global population aging process, the incidence rate of the parkinsonism is in an annual rising trend, and a heavy burden is brought to families of patients and social medical systems. Currently, the treatment of parkinson's disease is still mainly drug symptomatic treatment, and the core treatment aims at relieving symptoms, improving the life quality of patients and delaying disease progression by supplementing dopamine or enhancing dopaminergic nerve functions. Rotigotine (Rotigotine, RTG) is used as a novel non-ergot dopamine receptor agonist, can highly selectively excite D1 and D2 subtype dopamine receptors, and regulates central dopaminergic nerve pathways by simulating the action mechanism of endogenous dopamine, thereby effectively improving the motor symptoms of patients suffering from Parkinson's disease. Compared with the traditional levodopa drugs, rotigotine has the advantages of long action duration, difficult initiation of movement fluctuation and catabolism and the like, and is increasingly widely applied to the clinical treatment of the parkinsonism. However, the physical and chemical properties of rotigotine and the limitations of the existing preparation technology severely restrict the full play of the clinical application efficacy. Firstly, rotigotine has extremely strong lipophilicity and extremely poor water solubility, which makes it difficult to prepare an oral preparation with higher bioavailability, and meanwhile, the rotigotine has unstable chemical structure and is easy to generate oxidative degradation, so that the stability of the preparation is poor, and a plurality of challenges are brought to the production, storage and transportation processes. Secondly, the rotigotine preparation in the existing clinical application mainly comprises a transdermal patch, and the preparation can be administrated through skin to avoid the first pass effect of the liver, but has obvious defects that on one hand, the transdermal absorption efficiency is greatly influenced by the physiological state of the skin (such as the thickness of a horny layer, the water content and the skin temperature), the application part and the individual difference, so that the fluctuation of the blood concentration is large, and the stable drug effect release is difficult to realize, and on the other hand, the patch needs to be applied once daily for 24h, and the drug compliance of a patient is easy to be reduced after long-term use. In order to solve the problems, researchers try to develop other administration routes and preparation forms of rotigotine, such as common injections and slow release microspheres, but all face respective technical bottlenecks. For example, common injections need frequent administration and cannot realize long-acting treatment, and the slow release microspheres have complex preparation process, high production cost, need uniform mixing before administration and have burst release risks. Therefore, the novel preparation which can give consideration to physical and chemical properties of rotigotine, has simple preparation process, is convenient to administer, can realize stable and long-acting administration, improves the stability of the preparation and has good patient compliance is developed, and becomes an urgent need in the field of research and development of current parkinsonism treatment medicines. The lyotropic liquid crystal is a novel lipid-based carrier, is a colloid dispersion system with an ordered structure, which is formed by self-assembly of amphiphilic molecules in water or other polar solvents, and the three-dimensional network structure of the lyotropic liquid crystal can provide a stable carrier environment for medicines, and can realize slow release of the medicines by adjusting the composition and the structure of the system, so that the lyotropic liquid crystal long-acting injection has great application potential in the long-acting delivery field, and has good safety and feasibility verified in the clinical application scene of the present marketed lyotropic liquid crystal long-act