CN115350144A

CN115350144A - Metronidazole hydrogel and preparation method thereof

Info

Publication number: CN115350144A
Application number: CN202210896691.2A
Authority: CN
Inventors: 陆红彬; 杨颖栋; 樊超
Original assignee: Suzhou Homesun Pharmaceutical Co ltd
Current assignee: Suzhou Homesun Pharmaceutical Co ltd
Priority date: 2022-07-28
Filing date: 2022-07-28
Publication date: 2022-11-18

Abstract

The invention belongs to the technical field of medicines, and particularly relates to metronidazole hydrogel and a preparation method thereof. Adding ethylene glycol diglycidyl ether into curdlan and metronidazole, and reacting to obtain a crosslinking reaction mixed solution; and then pouring the crosslinking reaction mixed solution, and removing impurities to obtain the metronidazole hydrogel. The hydrogel is formed by bonding macromolecules together through chemical bonds at two ends of a cross-linking agent so as to generate a cross-linked network structure, wherein metronidazole is inserted as a drug carrier. The prepared metronidazole hydrogel is uniform in color and luster, stable in performance, not easy to break, capable of absorbing a large amount of water, excellent in swelling performance, low in toxicity and has application prospects in the fields of biological medicines or preparation carriers and the like.

Description

Metronidazole hydrogel and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to metronidazole hydrogel and a preparation method thereof.

Background

Hydrogels are a class of aqueous materials that are known for their ability to absorb a large amount of water without dissolving. Hydrogels generally contain a large number of hydrophilic groups and their inter-entangled network structure helps the hydrogel to lock in its adsorbed water, helping it swell in water in a large proportion and to maintain its aqueous structure permanently in air. They can be classified into physically crosslinked hydrogels and chemically crosslinked hydrogels according to their formation methods, where physical hydrogels are generally hydrogels composed of crosslinked bonds formed by hydrogen bonds or electrostatic interactions, and chemical hydrogels are hydrogels formed by crosslinking chemical bonds. Chemical hydrogels are generally more stable in nature than physical hydrogels, and also are more prominent in mechanical strength.

The formation of hydrogels offers many application possibilities, especially because they are similar to soft tissues and extracellular matrix. Hydrogel networks have been widely used in many biomedical applications including tissue engineering, drug delivery and cell therapy (Mahinroosta, farsangi, alahvldi and Shakoori, 2018). The properties of hydrogels and their interaction with the biological environment are very important in biomedical applications. This may include such factors as biocompatibility, biodegradability, surface characteristics, mechanical strength and ionic charge. For administration, the charge and swelling ratio are very important, as they control the release rate of the drug. The mechanical strength, the biocompatibility and the cytotoxicity are three important index data and have important significance on tissue engineering, and the three have great influence on the viability of cells in the hydrogel.

Chemical hydrogels are one type of hydrogel that involves chemical crosslinking between polymer networks, which is irreversible. It involves the reaction of a polymer backbone with a crosslinking agent. Functional groups such as hydroxyl or amine groups can react with the crosslinking agent to form a gel structure. Crosslinking can occur by different mechanisms, such as condensation and vulcanization, among others. Where covalent bonds may bring the hydrogel to an equilibrium swollen state, depending on the polymer-solvent interaction and crosslink density.

Chemical crosslinking results in permanent or chemical hydrogels having covalent bonds. These hydrogels can reach an equilibrium swollen state depending on the crosslinking density and interaction strength of the polymer with water. Chemical crosslinking can be carried out by polymerization of functional groups on the backbone, polymerization in the presence of a crosslinking agent, and polymer-polymer crosslinking. Chemical crosslinking of polysaccharide hydrogels can be synthesized by different processes. In the presence of a cross-linking agent, chemically cross-linked polysaccharide hydrogels can be synthesized. The synthesis of polysaccharide hydrogel by using different crosslinking agents such as glyceraldehyde, formaldehyde, epichlorohydrin, N-methylene-bisacrylamide and the like is reported. Crosslinking involves reactive sites on the polysaccharide backbone, such as-OH groups. The divinyl sulfone is used as a cross-linking agent to prepare carboxymethyl cellulose sodium salt and hydroxyethyl cellulose hydrogel, and a novel water removal system for treating edema is developed. The cross-linked carboxymethyl konjac glucomannan is synthesized by taking monochloroacetic acid, konjac glucomannan and monochloroacetic acid as raw materials. Graft copolymerization in the synthesis of hydrogels is a promising technique for the synthesis of chemical hydrogels.

The drugs are rarely taken alone as chemical substances, and are almost always taken as prescription preparations or injected as injections. Pharmaceutical dosage forms contain many ingredients in addition to the active pharmaceutical ingredient, which aids in the manufacturing process and optimizes drug delivery. As drug release technology advances, excipients are now being incorporated into new dosage forms to achieve specific functions, in some cases, excipients directly or indirectly affect the degree or rate of drug release. Several drug delivery systems have been developed based on natural polysaccharides as excipients, which do not change their chemical structure, but these materials degrade in vivo due to natural biological processes, eliminating the need to remove the drug delivery system after release of the active agent.

Polymers have been successfully used in the preparation of solid, liquid and semi-solid dosage forms and are particularly useful in the design of modified release drug delivery systems. Both synthetic and natural polymers have been extensively studied for this purpose, but the use of natural polymers in medical applications is attractive because they are economical, readily available, non-toxic, and readily chemically modified, have potential biodegradability, and are furthermore biocompatible.

The means of drug release research is to improve the utilization rate of the drug through innovative formulation development. The intrinsic drug release of the drug can be influenced by the chemistry and/or excipient formulation, as follows:

1) The solubility of the medicine in biological fluids such as intestinal fluids is improved;

2) Improving drug stability in formulations and biological fluids;

3) Increase the permeability of drugs to biological membranes, such as small intestinal membranes;

4) Improving the drug targeting of the drug candidate;

5) Reducing drug candidate metabolism and/or reducing elimination thereof;

excipient complex formation can affect solubility in biological fluids. Stability can be optimized by using different cross-linking agents or by freeze-drying to preserve the formulation for a long period of time. The permeability of hydrogels can be increased by designing the drug candidate as a drug or prodrug that can absorb the membrane transporter matrix, or by developing lipid or particulate drug excipient systems (e.g., emulsions, liposomes, and permeability-affecting nanoparticles).

Metronidazole, an antibiotic and antiprotozoal agent. It is mainly used for treating or preventing systemic or topical infection caused by anaerobic bacteria, such as anaerobic bacteria infection of abdominal cavity, digestive tract, female reproductive system, lower respiratory tract, skin and soft tissue, bone and joint, etc., and is also effective in septicemia, endocarditis, meningeal infection and colitis caused by antibiotic. Tetanus is often treated in combination with Tetanus Antitoxin (TAT). Can also be used for oral cavity anaerobe infection.

The metronidazole is generally an amisole resistant drug, an anti-trichomonad drug and an anti-anaerobe drug, is a nitroimidazole derivative, has the functions of resisting anaerobic protozoa and anaerobes, and also has the radiosensitization function on anoxic tumor cells; metronidazole is generally administered in the form of a tablet, injection or effervescent tablet.

Glucans are polysaccharides composed of D-glucose monomers linked by glycosidic bonds. Members of the β - (1 → 3) glucan family, including linear glucans, branched side chain β - (1 → 3, 1 → 2) glucans, and β - (1 → 3, 1 → 6) glucans, are found in both prokaryotes and eukaryotes. The curdlan has simple property and structure, and is beneficial to synthesis operation. Curdlan is a linear glucan that is named because it "sets" when heated. Curdlan consists only of β - (1 → 3) glycosidic linkages, with no branching or substituents. Curdlan was also found in the study of the production of succinic acid by the Faecalis variant mucus gene 10C3 strain in professor Japan, earlier than 1966 at 2 months. In 1996, curdlan was approved by the FDA for use in food. A large number of hydroxyl groups exist in curdlan, so that strong hydrogen bonds can exist between macromolecular chains. Therefore, curdlan is difficult to dissolve in water and organic solvents. However, the intramolecular and intermolecular hydrogen bonds of curdlan are easily broken in an alkaline aqueous solution, and thus dissolved in water.

CN113476397 discloses a metronidazole gel and a preparation method thereof, wherein the metronidazole gel is obtained by compounding raw materials such as metronidazole, propylene glycol and carbomer. The gel is hydrogel, the carbomer is acrylic acid cross-linked resin obtained by cross-linking pentaerythritol and the like with acrylic acid, is a very important rheology regulator, has important applications of thickening, suspending and the like, has simple process and good stability, and is widely applied to the gel. Although the physical properties are good, the gel is prepared by blending, and the situations that the gel is combined by a physical mode, the interior is unstable and the metronidazole is easy to run off exist.

Disclosure of Invention

In order to solve the technical problems, the invention provides a preparation method of metronidazole hydrogel, which comprises the following steps:

s1: adding curdlan and metronidazole into alkaline water, and heating and mixing to obtain gel mixed solution;

s2: adding a cross-linking agent into the gel mixed solution, and reacting at room temperature (25 +/-5 ℃) for 10-20min to obtain a cross-linking reaction mixed solution; the cross-linking agent is ethylene glycol diglycidyl ether;

s3: pouring the crosslinking reaction mixed solution, and removing impurities to obtain the metronidazole hydrogel.

Preferably, the mass ratio of the curdlan to the metronidazole is 1-2:1-2.

Preferably, the alkaline water is an aqueous solution of NaOH or an aqueous solution of KOH.

Preferably, in the step S1, the temperature for heating and mixing is 35 to 60 ℃.

Preferably, in the step S1, the heating and mixing time is 8-20h.

Preferably, the concentration of metronidazole in the gel mixed liquor is 3-5wt%.

Preferably, the volume ratio of the crosslinking agent to the gel mixture is 1:30-50.

Preferably, in the step S3, the casting time is 1-2h.

Preferably, in the step S3, the impurity removing method is to dialyze the poured finished product for 3 to 5 days, and then freeze-dry the dialyzed finished product.

Specifically, in the step S3, the impurity removing method includes placing the poured finished product in deionized water, performing dialysis soaking by using a dialysis bag, changing water every 8-16 hours, and performing freeze drying treatment by using a freeze dryer after dialysis for one week.

The invention also provides the metronidazole hydrogel prepared by the preparation method.

Compared with the prior art, the technical scheme of the invention has the following advantages:

according to the invention, the ring opening of the epoxy groups of the two sections of the ethylene glycol diglycidyl ether is carried out under the alkaline condition, the epoxy groups react with the hydroxyl groups of curdlan and metronidazole, and the hydroxyl groups are bonded together at two ends of the cross-linking agents through ether bonds, so that a cross-linked network structure is generated, and the hydrogel is formed. The produced hydrogel is uniform in color and luster, stable in performance, not easy to break, capable of absorbing a large amount of water and excellent in swelling performance, and has low toxicity because the metronidazole drug and the curdlan are compounded to prepare the hydrogel, so that the hydrogel has wide application prospects in the fields of biological medicines or preparation carriers and the like.

Drawings

Fig. 1 is a schematic diagram of the metronidazole hydrogel prepared in example 1.

Detailed Description

The present invention is further described below in conjunction with specific examples to enable those skilled in the art to better understand the present invention and to practice it, but the examples are not intended to limit the present invention.

Example 1

Adding 1g of curdlan and 1g of metronidazole into 30ml of NaOH aqueous solution, heating to 35 ℃, and stirring for 8 hours by using a stirring device to obtain gel mixed solution;

adding 1ml of glycol and glycidyl ether into the gel mixed solution, and reacting for 15min at 25 ℃ to obtain a crosslinking reaction mixed solution;

pouring the cross-linking reaction mixed solution in a glass ware, after 1h, putting the finished product in deionized water for dialysis and soaking, changing water every 12h, dialyzing for 4 days, and then performing freeze drying treatment to obtain the metronidazole hydrogel.

Example 2

adding 1ml of ethylene glycol diglycidyl ether into the gel mixed solution, and reacting at 20 ℃ for 10min to obtain a crosslinking reaction mixed solution;

pouring the cross-linking reaction mixed solution in a glass ware, after 1h, putting the finished product in deionized water for dialysis and soaking, changing water every 12h, dialyzing for 3 days, and then performing freeze drying treatment to obtain the metronidazole hydrogel.

Example 3

Adding 2g of curdlan and 2g of metronidazole into 50ml of NaOH aqueous solution, heating to 60 ℃, and stirring for 20 hours by adopting a stirring device to obtain gel mixed solution;

adding 1ml of ethylene glycol diglycidyl ether into the gel mixed solution, and reacting at 30 ℃ for 20min to obtain a crosslinking reaction mixed solution;

pouring the crosslinking reaction mixed solution in a glassware, placing the finished product in deionized water for dialysis soaking after 2 hours, changing water every 12 hours, and performing freeze drying treatment after 5 days of dialysis to obtain the metronidazole hydrogel.

Example 4

Adding 1g of curdlan and 2g of metronidazole into 30ml of NaOH aqueous solution, heating to 35 ℃, and stirring for 20 hours by using a stirring device to obtain gel mixed solution;

adding 1ml of ethylene glycol diglycidyl ether into the gel mixed solution, and reacting at 25 ℃ for 10min to obtain a crosslinking reaction mixed solution;

Example 5

Adding 2g of curdlan and 1g of metronidazole into 50ml of NaOH/KOH aqueous solution, heating to 45 ℃, and stirring for 20 hours by adopting a stirring device to obtain gel mixed solution;

adding 1ml of ethylene glycol diglycidyl ether into the gel mixed solution, and reacting at 20 ℃ for 15min to obtain a crosslinking reaction mixed solution;

Example 6

Adding 1g of curdlan and 2g of metronidazole into 45ml of NaOH/KOH aqueous solution, heating to 50 ℃, and stirring for 10 hours by using a stirring device to obtain gel mixed solution;

adding 1ml of ethylene glycol diglycidyl ether into the gel mixed solution, and reacting at 30 ℃ for 10min to obtain a crosslinking reaction mixed solution;

pouring the crosslinking reaction mixed solution in a glassware, placing the finished product in deionized water for dialysis soaking after 1h, changing water every 12h, and performing freeze drying treatment after 3 days of dialysis to obtain the metronidazole hydrogel.

Example 7

Adding 1g of curdlan and 1g of metronidazole into 30ml of KOH aqueous solution, heating to 35 ℃, and stirring for 8 hours by using a stirring device to obtain gel mixed solution;

Example 8

Adding 2g of curdlan and 2g of metronidazole into 50ml of KOH aqueous solution, heating to 35 ℃, and stirring for 8 hours by using a stirring device to obtain gel mixed solution;

pouring the crosslinking reaction mixed solution in a glassware, placing the finished product in deionized water for dialysis soaking after 1h, changing water every 12h, and performing freeze drying treatment after 5 days of dialysis to obtain the metronidazole hydrogel.

Example 9

Adding 1g of curdlan and 2g of metronidazole into 30ml of KOH aqueous solution, heating to 50 ℃, and stirring for 10 hours by using a stirring device to obtain gel mixed solution;

pouring the crosslinking reaction mixed solution in a glassware, placing the finished product in deionized water for dialysis soaking after waiting for 2 hours, changing water every 12 hours, and carrying out freeze drying treatment after dialysis for 3 days to obtain the metronidazole hydrogel.

Example 10

Adding 2g of curdlan and 1g of metronidazole into 30ml of KOH aqueous solution, heating to 60 ℃, and stirring for 8 hours by adopting a stirring device to obtain gel mixed solution;

adding 1ml of ethylene glycol diglycidyl ether into the gel mixed solution, and reacting for 15min at 25 ℃ to obtain a crosslinking reaction mixed solution;

Example 11

Adding 1g of curdlan and 1g of metronidazole into 35ml of KOH aqueous solution, heating to 35 ℃, and stirring for 10 hours by using a stirring device to obtain gel mixed solution;

pouring the crosslinking reaction mixed solution in a glassware, placing the finished product in deionized water for dialysis soaking after 1h, changing water every 12h, dialyzing for 3-5 days, and performing freeze drying treatment to obtain the metronidazole hydrogel.

Example 12

Adding 2g of curdlan and 2g of metronidazole into 40ml of KOH aqueous solution, heating to 35 ℃, and stirring for 12 hours by using a stirring device to obtain gel mixed solution;

Comparative example 1

adding 1ml of epoxy chloropropane into the gel mixed solution, and reacting for 15min at 25 ℃ to obtain a crosslinking reaction mixed solution;

pouring the crosslinking reaction mixed solution in a glassware, placing the finished product in deionized water for dialysis soaking after 1h, changing water every 12h, and performing freeze drying treatment after dialysis for 4 days to obtain the metronidazole hydrogel.

Comparative example 2

Adding 1g of starch and 1g of metronidazole into 30ml of NaOH aqueous solution, heating to 35 ℃, and stirring for 8 hours by using a stirring device to obtain a gel mixed solution;

Comparative example 3

Adding 1g of hydroxypropyl methyl cellulose and 1g of metronidazole into 30ml of NaOH aqueous solution, heating to 35 ℃, and stirring for 8 hours by using a stirring device to obtain gel mixed solution;

Effect evaluation 1

Swelling property test:

8gNaCl,3.6gNa were taken ₂ HPO ₄ And 0.2NaH ₂ PO ₄ Dissolving the mixture in 500mL of deionized water, and then fixing the volume to 1L of deionized water solution to obtain 0.01mol/L PBS water solution.

A mass of hydrogel was soaked in about 100mL of the above aqueous PBS until it was ready to soak to swelling equilibrium. The hydrogel was then removed, dried, and placed in a weigh platform for weighing.

TABLE 1 hydrogel Performance testing

Number of	Structural stability	Deformation pressure test	Degree of swelling
				Example 1	Stabilization of	48kPa	740％
Comparative example 1	Stabilization	25kPa	1050％
				Comparative example 2	Is easy to break	10kPa	1300％
Comparative example 3	Stabilization of	45kPa	700％

As can be seen from Table 1, the metronidazole hydrogel prepared by the method has stable structure and mechanical property far superior to that of the metronidazole hydrogel prepared by epichlorohydrin and starch. The swelling degree of the metronidazole hydrogel is higher than that of the metronidazole hydrogel prepared from hydroxypropyl methylcellulose. And the epichlorohydrin contains chlorine element, has toxicity and is not suitable to be used as a cross-linking agent to be added into the preparation process of the metronidazole hydrogel.

It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the spirit or scope of the invention.

Claims

1. The preparation method of the metronidazole hydrogel is characterized by comprising the following steps:

s1: adding curdlan and metronidazole into alkaline water, and heating and mixing to obtain a gel mixed solution;

s2: adding a cross-linking agent into the gel mixed solution, and reacting at room temperature for 10-20min to obtain a cross-linking reaction mixed solution; the cross-linking agent is ethylene glycol diglycidyl ether;

2. The preparation method of claim 1, wherein the mass ratio of curdlan to metronidazole is 1-2:1-2.

3. The method of claim 1, wherein the alkaline water is an aqueous NaOH solution or an aqueous KOH solution.

4. The method according to claim 1, wherein the temperature for heating and mixing in step S1 is 35 to 60 ℃.

5. The method of claim 1, wherein the heating and mixing time in step S1 is 8 to 20 hours.

6. The method according to claim 1, wherein the concentration of metronidazole is 3-5wt% in the gel mixture.

7. The method according to claim 1, wherein the volume ratio of the crosslinking agent to the gel mixture is 1:30-50.

8. The method of claim 1, wherein in step S3, the casting time is 1-2h.

9. The method of claim 1, wherein in step S3, the step of removing impurities is a step of freeze-drying the poured finished product after dialysis for 3-5 days.

10. A metronidazole hydrogel prepared by the method of preparation of any one of claims 1 to 9.