Compound capable of improving liver targeting of nano preparation and preparation thereof

Abstract

The invention discloses an application of a glycyrrhetinic acid biguanide derivative, and a nano preparation prepared from the compound can achieve the purpose of improving liver targeting through intraperitoneal administration. In addition, the preparation for intraperitoneal administration also has the characteristic of tumor tissue targeting similar to intravenous administration. The compound and the preparation thereof provide a choice for liver tumor and a preparation for enhancing liver tissue targeting through intraperitoneal administration.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations and discloses use of a glycyrrhetinic acid biguanide conjugate in improving liver targeting of a nano preparation through intraperitoneal administration. Background Art

[0002] Targeting preparations to the liver is necessary for the treatment of liver diseases including liver tumors, inflammation, and fibrosis. In addition, there are some therapies that also require the preparation to be transported to the liver first, and then release the effective ingredients to work. Usually, after the nanoformulation is administered intravenously, the particles will be partially targeted to the liver, but the proportion distributed to the liver is limited. It is necessary to study methods to further improve the liver targeting of nanoformulations. Intraperitoneal administration usually has similar tissue distribution characteristics as intravenous administration, so intraperitoneal administration is often used instead of intravenous administration in animal experiments.

[0003] We have synthesized glycyrrhetinic acid biguanide conjugates and obtained patent authorization (CN202110802826.X). In subsequent studies, it was unexpectedly discovered that the nanoformulation prepared using this conjugate has significantly better liver targeting after intraperitoneal administration than intravenous administration. This feature helps to improve the liver targeting of the preparation and enrich the route of administration, so this patent was applied for. Summary of the invention

[0004] In view of the above situation, in order to overcome the defects of the prior art, the purpose of the present invention is to utilize glycyrrhetinic acid biguanide conjugate (GABG), make it into various nanoformulations, and administer it intraperitoneally to improve the liver targeting of the preparations.

[0005] The purpose of the present invention is achieved by the following technical solutions:

[0006] Glycyrrhetinic acid biguanide conjugate has the following basic structure:

[0007]

[0008] GABG itself or together with other carrier materials can be prepared into nanoparticles or drug-encapsulated nanoparticles, as described in patent CN202110802826.X. Specifically, GABG can be used with phospholipid materials to encapsulate drugs to prepare lipid nano drug delivery systems, or GABG can be used with other carrier excipients to encapsulate drugs to prepare other types of microparticle delivery systems. According to the properties of the drug, each dosage form can be prepared by a method that meets the purpose of the preparation. For example, liposomes can be prepared by thin film dispersion, freeze drying, reverse phase evaporation, ultrasound, etc.

[0009] For another example, the GABG self-assembled drug-loaded microparticles can be prepared by the emulsified solvent evaporation method. The basic preparation process is as follows: GABG and fat-soluble drugs are dissolved in an organic solvent to form an organic phase, and water-soluble excipients are dissolved in water to form an aqueous phase. The aqueous phase and the oil phase are mixed to obtain a suspension; the suspension is then dispersed by shearing, ultrasound, etc., and the organic solvent is removed by vacuum rotary evaporation, etc., to obtain a GABG self-assembled nanoparticle preparation.

[0010] When used in combination with other carrier excipients, the corresponding preparation method can be flexibly adopted according to the properties of the carrier and the drug. For example, when the drug to be encapsulated is a fat-soluble drug and the combined carrier excipient is a solid lipid, the lipid can be heated and melted, and then the drug and GABG can be added and mixed; when the combined excipient is a liquid lipid, such as when preparing an emulsion, the drug and GABG can be dissolved in the liquid lipid; when the combined excipient is PLGA, the drug, GABG, and PLAG can be dissolved together in an organic solution. Then mix it with the water phase, disperse it evenly, remove the organic solvent,

[0011] The phospholipid material includes a mixture of one or more of various types of natural phospholipids, semi-synthetic phospholipids and fully synthetic phospholipids.

[0012] The other carrier excipients are commonly used microparticle preparation carrier excipients, such as PLGA, mPEG-PLGA, fatty acid monoglycerides, fatty acid diglycerides, fatty acid triglycerides, fatty acids, etc., and also include one or a mixture of excipients modified with PEG and / or various targeting groups that play a long circulation role. In addition to the above-mentioned commonly used carrier materials, inorganic carriers or metal carriers can also be prepared using commonly used preparation methods.

[0013] The water-soluble excipients include PVA, PEG, poloxamer 188, poloxamer 407, Tween 80, Vc or SDS and other excipients that meet the requirements of the administration route or excipients that increase stability, adjust osmotic pressure and other requirements.

[0014] Preferably, the microparticle drug delivery system is one of nanoparticles, microparticles, liposomes, emulsions or polymer micelles.

[0015] Theoretically, the application described in this patent and the glycyrrhizic acid biguanide conjugate with a similar structure to GABG can all have such an effect.

[0016] In summary, in order to overcome the limitations of liver-targeted administration routes, the present invention provides a GABG and a nanoformulation thereof, which can be administered intraperitoneally to achieve a higher liver-targeted application. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1These are tissue imaging photos of the intravenous administration and intraperitoneal administration described in the present invention. DETAILED DESCRIPTION

[0018] The present invention is further described in detail below in conjunction with embodiments and drawings, but the embodiments of the present invention are not limited thereto.

[0019] Example 1 Preparation of IR780 GABG lipid nanoparticles

[0020] 15 mg of egg yolk phosphatidylcholine (EPC), 1 mg of IR780 and 5 mg of GABG were dissolved in 2 mL of a mixed solution of ethanol and chloroform (ethanol: chloroform = 1:1, v / v). The organic solvent was evaporated under reduced pressure using a rotary evaporator in a 40°C water bath to form a uniform lipid film. 2 mL of 2% PVA was added and hydrated by ultrasound at 40°C to form a uniform milky white liquid. The cells were ultrasonicated using a cell crusher (5 min, 5 s on, 4 s off, power 360 W) to obtain lipid nanoparticles 780@GABG LNPs encapsulating IR780.

[0021] Example 2 Preparation of IR780 lipid nanoparticles

[0022] 15 mg EPC and 1 mg IR780 were dissolved in 2 mL of a mixed solution of ethanol and chloroform (ethanol: chloroform = 1:1, v / v). The organic solvent was evaporated under reduced pressure using a rotary evaporator in a 40°C water bath to form a uniform lipid film. 2 mL of 2% PVA was added and hydrated by ultrasound at 40°C to form a uniform milky white liquid. The lipid nanoparticles 780@LNPs loaded with IR780 were obtained by ultrasound (5 min, 5 s on, 4 s off, power 360 W).

[0023] The representative examples above will be selected to conduct relevant experiments to illustrate the characteristics and advantages of GABG preparations. Grouping, preparation and conclusion are all set and analyzed according to the relevant basic rules of scientific experiments. Therefore, if there are any omissions in the specific details of the experiment, please refer to the basic principles.

[0024] Experimental Example 1 Tissue Distribution Experiment

[0025] The conventional method was used to establish the H22 tumor model in the axilla of female Kunming mice. The basic operation was to extract the ascites of the mice with ascites tumor containing H22 tumor cells, dilute it appropriately, and inoculate it into the subcutaneous part of the right upper axilla of the mice. Each mouse was inoculated with 200 μl of ascites. After the average tumor volume reached 100 mm3, the mice were randomly divided into intravenous administration group and intraperitoneal administration group. The specific experimental groups of each large group were as follows: A) 780 solution group, B) 780@LNPs group, C) 780GABG@LNPs group, 3 mice for each preparation, and the dosage concentration of the model drug IR780 was 2 mg / kg. After 24h and 48h of administration, the mice were killed, the heart, liver, spleen, lung, kidney and tumor tissues were dissected out, and the fluorescence intensity of IR780 was detected under a small animal imaging device, and photos were taken. The higher the fluorescence intensity value, the stronger the targeting of the preparation to the tissue. Photos of intravenous administration (iv) and intraperitoneal administration (ip) are attached. Figure 1 Comparing the results of the two, it can be seen that the addition of GABG significantly promoted the accumulation and retention of IR780 nanoformulations in the liver after intraperitoneal administration compared with intravenous administration. Under intravenous administration conditions, GABG also showed a longer retention in the tumor. IR780 is used as a model drug to illustrate the role of the carrier.

[0026] Therefore, this experiment significantly supports our claim that glycyrrhetinic acid biguanide conjugate has the advantage of improving the liver targeting of nanoformulations through intraperitoneal administration. In addition to GABG, other structurally similar biological glycyrrhetinic acid biguanide conjugates can be expected to have similar effects. This patent further supplements the application field of glycyrrhetinic acid biguanide conjugates, which can improve the liver tissue targeting of nanoformulations through intraperitoneal administration, which is an unexpected use.

[0027] It should be pointed out that the above examples are preparations prepared only to demonstrate the targeting of glycyrrhetinic acid biguanide conjugates. The present invention is not limited in any form. Any technician familiar with the profession can make changes or modify the equivalent embodiments with equivalent changes by using the above disclosed technical contents without departing from the scope of the technical solution of the present invention, which fall within the protection scope of the present invention.

Claims

1. A use of a glycyrrhetinic acid biguanide derivative, characterized in that a nanoformulation prepared by using the compound can be intraperitoneally administered to achieve the purpose of improving the liver targeting of the preparation. The structure of the compound is as follows:

2. The use of the compound according to claim 1, characterized in that The nano preparations include nanoparticles, liposomes, micelles, emulsions, nanocrystals and other nano preparations in the pharmaceutical field.

3. The use of the compound according to claim 1, characterized in that The compound and its nanoformulation can be used for liver diseases such as liver tumors after intraperitoneal administration.

4. The use of the compound according to claim 1, characterized in that The compound and the nano preparation thereof can be used in the preparation of preparations which are beneficial to the efficacy or safety of the preparations by enhancing the targeting of liver tissues.

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