CN-116617405-B - Liposome drug carrier with mucosa adhesiveness and preparation method and application thereof

Abstract

The invention discloses a liposome drug carrier with mucosa adhesiveness, a preparation method and application thereof, and particularly the drug carrier is DSPE-PEG-PBA, and can be used for encapsulating cyclosporin A and crocin I. The liposome coated with the two medicines has better stability and adhesiveness, can inhibit the side effect of cyclosporin A on the rise of ROS level, and has wide application prospect in the aspects of inflammation treatment and epithelial tissue injury treatment.

Inventors

• HE QIN
• HUANG KEXIN
• LI MAN
• LIU YINGKE
• GUO RONG

Assignees

• 四川大学

Dates

Publication Date

20260508

Application Date

20230421

Claims (6)

1. The application of CsA/Cro PBA Lip in preparing a medicament for treating xerophthalmia is characterized in that the preparation method comprises the following steps: Adding DSPE-PEG-PBA, soybean lecithin, cholesterol and cyclosporine A into a dichloromethane solvent, performing rotary evaporation in a mixed solvent of methanol and water to form a film, then adding crocin I, sequentially performing hydration and ultrasound to obtain a liposome solution, and removing the free cyclosporine A and crocin I from the liposome solution through a centrifugation method and a sephadex chromatography method to obtain the CsA/Cro PBA Lip coated with the cyclosporine A and the crocin I.
2. 2. The pharmaceutical use according to claim 1, wherein the molar ratio of DSPE-PEG-PBA, soybean lecithin, cholesterol, cyclosporin A and crocin I is 0.05-0.10:2:1:0.05-0.10:0.05.
3. 3. The pharmaceutical use according to claim 1, wherein the treatment of dry eye comprises promotion of epithelial tissue healing.
4. 4. The pharmaceutical use according to claim 1, wherein the DSPE-PEG-PBA has the structural formula: ; The DSPE-PEG-PBA is prepared from phenylboronic acid with carboxyl substitution on a benzene ring and DSPE-PEG-NH 2 through a crosslinking reaction, and has mucous membrane adhesion capability.
5. 5. The pharmaceutical use according to claim 4, wherein the preparation method of DSPE-PEG-PBA comprises the following steps: dissolving phenylboronic acid, N-hydroxy thiosuccinimide and 1-ethyl- (3-dimethylaminopropyl) carbodiimide with carboxyl substitution on a benzene ring in a mixed solvent of dichloromethane and methanol, then adding DSPE-PEG for acylation reaction, and sequentially dialyzing and freeze-drying reaction liquid obtained by the reaction to obtain the DSPE-PEG-PBA; Wherein the phenylboronic acid with carboxyl substitution on the benzene ring is 4-carboxyl-3-fluoro-phenylboronic acid; The DSPE-PEG is DSPE-PEG-NH 2 ; The molar ratio of the 4-carboxyl-3-fluoro-phenylboronic acid, the N-hydroxy thiosuccinimide, the 1-ethyl- (3-dimethylaminopropyl) carbodiimide and the DSPE-PEG-NH 2 is 1:3:2:0.6-0.8.
6. 6. The pharmaceutical use according to claim 5, wherein the acylation reaction is carried out at a reaction temperature of 35-40 ℃ for a reaction time of 36-72h.

Description

Liposome drug carrier with mucosa adhesiveness and preparation method and application thereof Technical Field The invention relates to the field of biological medicine, in particular to a liposome drug carrier with mucous membrane adhesiveness, and a preparation method and application thereof. Background Dry eye, i.e., keratoconjunctival dryness, is often accompanied by symptoms such as itching, foreign body sensation, burning sensation, photophobia, blurred vision, and vision fluctuation of the eyes, which are the main symptoms of dry eyes. Ocular inflammation is one of the key causes of dry eye, and cyclosporin a (CsA) is a drug commonly used for treating dry eye, and CsA can effectively treat dry eye by inhibiting infiltration of lymphocytes in the lacrimal gland, reducing inflammatory response, and inhibiting scarring of lacrimal gland tissue to increase tear secretion. However, csA causes hepatorenal toxicity when administered systemically, and studies have shown that it is caused by increasing the level of ROS (an upstream substance of the main inflammatory signaling pathway) in liver and kidney cells, and thus CsA is greatly limited in practical use. In the application of treating xerophthalmia, the large amount of ROS is a characteristic of xerophthalmia and a factor of xerophthalmia further worsening, and the research shows that CsA can cause irritation to eyes when topically applied to the eye surface, and the irritation is mainly manifested by discomfort symptoms such as ocular surface pain, conjunctival congestion and the like. On this basis, researchers have carried out experiments through human corneal epithelial cells, which prove that CsA can indeed raise the ROS level of normal corneal epithelial cells, and thus speculate that the reason for the irritation of CsA to the ocular surface is that the ROS level of normal cells of the ocular surface is raised. With the continued understanding of the structure and composition of ocular tissues, it has been found that the surface of the eye is covered with a complex structured surface tear film, which is formed from the outside to the inside of a lipid layer, an aqueous layer, and a mucus layer, respectively, which contains negatively charged mucins. The ocular surface mucus layer is composed of mucin and tear fluid, and has dual effects on the ocular bioavailability of the drug. The eye mucus layer can not only show a barrier effect on local administration (secreted protein in tear becomes a barrier for the drug entering the cornea, and can obviously influence the residence time of the drug before the cornea, thereby influencing the bioavailability of the drug in eyes, in particular to lipophilic compounds, large-sized biomolecules or drugs formulated in micro and nano particle forms), but also increase the residence of a cationic administration system on the eye surface, and the bioavailability of the drug in eyes depends on the barrier effect and the adhesion degree of the eye mucus layer. The CsA has poor water solubility, can be well dissolved in organic solvents such as ethanol acetone and the like, but has the solubility of 6.6-106 mug/mL in water and obvious temperature dependence, so that the medicine particles of the CsA have short residence time on the ocular surface and lower bioavailability when being locally used for the eye. In view of this, there is a need in the art for dry eye treatment for drugs with mucin adhesion and that can suppress ROS levels. Disclosure of Invention The invention aims to overcome the defects of the prior art and provide a liposome drug carrier with mucoadhesion, a preparation method and application thereof, so as to at least achieve a drug for treating xerophthalmia, which has strong mucoadhesion and no irritation to eyes. The aim of the invention is realized by the following technical scheme: a drug carrier is characterized in that the carrier is DSPE-PEG-PBA, and the structural formula is as follows: 。 further, the preparation method of the drug carrier comprises the following steps: Dissolving phenylboronic acid, N-hydroxy thiosuccinimide and 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) with carboxyl or amino substitution on benzene ring in a mixed solvent of dichloromethane and methanol (v/v=2:1), then adding DSPE-PEG for crosslinking reaction, and sequentially dialyzing and freeze-drying the reaction solution obtained by the reaction to obtain the drug carrier. Further, the phenylboronic acid having a carboxyl group substituent on the benzene ring is preferably 4-carboxyl-3-fluoro-phenylboronic acid (hereinafter abbreviated as PBA); When the substituted phenylboronic acid is phenylboronic acid with carboxyl on a benzene ring, the DSPE-PEG is selected as DSPE-PEG-NH 2; when the substituted phenylboronic acid is phenylboronic acid with amino substitution on a benzene ring, the DSPE-PEG is selected as DSPE-PEG-COOH; The molar ratio of the 4-carboxyl-3-fluoro-phenylboronic acid to the thio NHS to th