WO2023130758A1

WO2023130758A1 - Sustained-release drug delivery system for oral administration, and preparation method therefor

Info

Publication number: WO2023130758A1
Application number: PCT/CN2022/118361
Authority: WO
Inventors: 于吉红; 唐康健; 衡璇
Original assignee: 苏州大学
Priority date: 2022-01-06
Filing date: 2022-09-13
Publication date: 2023-07-13
Also published as: CN114452246A

Abstract

The present invention provides a sustained-release drug delivery system for oral administration, and a preparation method therefor. According to the present invention, a drug for treating oral diseases is loaded on a porous material, and is combined with a medical oral material to prepare a special sustained-release drug delivery module, and the module is placed at the site of administration in the oral cavity to slowly and stably release the drug over a long period of time. The present invention effectively solves the problems in conventional treatments that administration is difficult, administration is not timely, and long treatment periods, poor treatment effects and oral discomfort of a patient due to difficulty in maintaining an effective drug concentration at an affected part. The method can be used in an efficient, long-term, stable and convenient oral disease treatment scheme.

Description

A sustained-release drug delivery system for oral administration and its preparation method

technical field

The invention belongs to the technical field of medical devices, in particular to an oral drug sustained-release drug delivery system and a preparation method thereof.

Background technique

Oral diseases are common diseases and frequently-occurring diseases that affect human health. According to the survey data, the caries rate of deciduous teeth of children in my country is as high as 67.0%, the rate of caries of permanent teeth in middle-aged people is 59.9%, and the rate of edentulous people in the elderly group is 6.9%. The detection rate of gingivitis and calculus is also high. , Oral health is generally poor. Oral diseases cause great economic burdens to patients, families, and society, and have an impact that cannot be ignored on social and economic development. It is the most prominent health problem in my country at this stage. At the same time, according to literature reports, there are a large number of microorganisms in the human oral cavity, among which there are about 1 million to 1 billion bacteria in each milliliter of secretions, and there are as many as 10 types, including bacteria (aerobic bacteria, anaerobic bacteria, etc.) ), viruses, spirochetes and other common microorganisms, these microorganisms can become pathogenic bacteria of infection under certain conditions, so it is necessary to pay great attention to antibacterial treatment in the treatment of oral diseases.

At present, there are drugs for the clinical treatment of oral diseases, such as hormones, antibiotics and vitamin drugs. Conventional drug therapy mainly has problems such as difficulty in administration, untimely administration, and difficulty in maintaining an effective concentration of the drug in the affected area, resulting in unsatisfactory therapeutic effects; if a single dose of the drug is increased or the drug is used frequently in order to enhance the overall curative effect, the drug in the body will be damaged. Accumulation can cause liver and kidney damage and other problems, endangering the health of patients. In addition, due to the inconvenience of the medical drug material itself during the medication process, the patient's normal diet is restricted, and the oral comfort of the patient is greatly reduced. In order to solve these problems, this method proposes to fix the slow-release module on the teeth, and use the drug slow-release system to release the drug only through the dissolution of saliva without any additional stimulus response signals. At the same time, it does not need to restrict the patient's normal diet and improves the comfort of the patient during treatment, achieving better therapeutic effect and user experience.

Existing common methods of administration for the treatment of oral diseases: (1) oral administration, the drug concentration at the required position of the oral cavity is relatively low through the circulatory system, and it is easy to produce side effects, and the curative effect is poor; (2) rice hydrochloride for the treatment of periodontitis Nocycline ointment (Paileo), because the drug needs to be injected into the periodontal pocket to coagulate in situ, which affects the comfort of the patient; (3) the dexamethasone acetate double-layer paste tablet for the treatment of oral ulcers, due to the stickiness of the patch, Affect the patient's normal diet (Liu Guoqin, Lv Yulin, Shi Jianming, Chen Tielou, Ma Xiaopeng, Liu Yun, Hou Huimin, He Fen. Development of dexamethasone acetate paste sheet [J]. Naval Medical Journal, 2000 (02): 138-139. 1464-1472.).

To sum up, the existing drug treatment methods for oral diseases either have a long treatment cycle and poor overall efficacy, or complex treatment methods and poor oral comfort. These factors have greatly limited the development and clinical application of using drug delivery methods to treat oral diseases.

Contents of the invention

For this reason, the technical problem to be solved by the present invention is to overcome the difficulty in administration, untimely administration, difficulty in maintaining effective concentration of medicine in the affected area, thereby affecting the therapeutic effect, and Problems that affect the patient's oral comfort.

In order to solve the above technical problems, the present invention provides a sustained-release drug delivery method for treating oral diseases.

A preparation method of an oral drug sustained-release drug delivery system, comprising the following steps:

S1: dissolving the drug in a solvent to obtain a drug solution;

S2: immersing the porous material in the drug solution obtained in S1 to prepare a drug-loaded porous material;

S3: Combining the drug-loaded porous material obtained in S2 with a medical oral material to obtain the sustained-release drug delivery system for the oral cavity.

In one embodiment of the present invention, in S1, the drug includes hormone drugs, antibiotic drugs or vitamin drugs.

In one embodiment of the present invention, the drug is selected from silver nitric acid, sodium fluoride, metronidazole, tinidazole, ornidazole, tetracycline, minocycline, doxycycline, erythromycin, Salamycin, Mailelamycin, Roxithromycin, Azithromycin, Clarithromycin, Acetylhelicin, Amoxicillin, Flufloxacin, Ofloxacin, Ciprofloxacin, Lomefloxacin, Levofloxacin Ofloxacin, trofloxacin, chlorhexidine, chlorhexidine, tinlei powder, ice boron powder, trichloroacetic acid, zinc chloride, nystatin, clotrimazole cream, ketoconazole, miconazole and one or more of dexamethasone.

In one embodiment of the present invention, in S1, the solvent is selected from one or more of water, alcohols, amides, esters, vegetable oils and sulfoxides.

In one embodiment of the present invention, the solvent is selected from water, ethanol, propylene glycol, glycerol, butanol, benzyl alcohol, dimethylformamide, dimethylacetamide, triacetin, ethyl acetate, oil One or more of ethyl benzoate, benzyl benzoate, isopropyl myristate, peanut oil, corn oil, sesame oil and dimethyl sulfoxide.

In one embodiment of the present invention, in S1, the drug concentration is 0.001 mg/mL-100 mg/mL.

In one embodiment of the present invention, in S2, the porous material is selected from microporous materials, mesoporous materials or macroporous materials; wherein, the pore diameter of microporous materials<2nm, the pore diameter of mesoporous materials is 2-50nm, larger The pore size of the porous material is >50nm.

In one embodiment of the present invention, in S3, the specific surface of the porous material is 2-3000 m ² /g.

In one embodiment of the present invention, in S3, the medical oral material is selected from one or more of ceramics, glass ionomers, clove oil zinc oxide cement powder, zinc phosphate cement powder, silver amalgam and composite resin kind.

In one embodiment of the present invention, in S3, the combination method includes mechanical stirring, heating and melting, and solvent dissolution.

The present invention also provides an oral drug sustained-release drug delivery system obtained by the preparation method.

The above technical solution of the present invention has the following advantages compared with the prior art:

In the present invention, due to the impregnation method, the drug is loaded on the porous material, and then the drug-loaded porous material and the medical oral material are combined to form a sustained-release drug delivery module; due to the addition of the medical oral material, the drug molecules are dissolved from the pores of the porous material After that, further dissolution of medical oral materials is required to achieve the purpose of secondary controlled release. The sustained release rate of the obtained drug delivery module is more stable, the sustained release time of the drug is greatly improved, and the overall curative effect is much higher than that of conventional methods. In addition, because this method only needs to fix the slow-release module on the teeth, and release the drug through saliva, it does not need any additional stimulus response signal, which greatly reduces the complexity and cost of preparation, and at the same time does not need to restrict the patient's normal diet And improve the comfort of patients in the treatment process, and achieved better treatment effect and user experience.

Description of drawings

In order to make the content of the present invention more easily understood, the present invention will be described in further detail below according to specific embodiments of the present invention in conjunction with the accompanying drawings, wherein

Fig. 1 is a sample diagram of the sustained-release module C ₁ obtained in Example 1 of the present invention.

Fig. 2 is a 7-day sustained-release curve in vitro of the sustained-release module C ₁ obtained in Example 1 of the present invention. Sustained-release module C ₁ was subjected to an in vitro sustained-release test in phosphate buffer at pH 7.2 at room temperature, and the drug dissolved on the 7th day was only 12.92% of the drug load.

Fig. 3 is an in vitro 7-day antibacterial experiment diagram of the slow-release module C ₁ obtained in Example 1 of the present invention. The slow-release module C ₁ was fully contacted with the medium of Actinomyces viscosus and cultured in a constant temperature incubator at 37°C. On the 7th day, the slow-release module C ₁ had obvious antibacterial activity against Actinomyces viscosus.

Fig. 4 is a 3-hour sustained-release curve in vitro of comparative modules X1 and X2 obtained in comparative examples 1 and 2 of the present invention. Sustained-release module C ₁ was tested in vitro in phosphate buffer at pH 7.2 at room temperature, and the dissolved drug reached 12.75% and 45.24% of the drug load in the third hour.

Detailed ways

The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, so that those skilled in the art can better understand the present invention and implement it, but the examples given are not intended to limit the present invention.

Example 1

Dissolve 0.2g of minocycline hydrochloride in 20mL of deionized water at 25°C to obtain a solution A ₁ with a drug concentration of 10 mg/mL; soak 2g of SBA-15 in solution A ₁ to form a porous drug carrier B ₁ ; Under normal temperature and pressure, 0.2 g of porous drug carrier B ₁ was combined with 1.6 g of medical oral material Dentec fluid photocurable resin to obtain sustained-release drug delivery module C ₁ .

Example 2

Dissolve 0.2g of minocycline hydrochloride in 20mL of ethanol at 25°C to obtain a solution A ₁ with a drug concentration of 10mg/mL; soak 2g of SBA-15 in solution A ₁ to form a porous drug carrier B ₁ ; Combine 0.2g of porous drug carrier B ₁ with 1.6g of medical oral material Dentec fluid photocurable resin under pressure to obtain a sustained-release drug delivery module.

Example 3

Dissolve 0.2g of minocycline hydrochloride in 20mL of methanol at 25°C to obtain a solution A ₁ with a drug concentration of 10mg/mL; soak 2g of SBA-15 in solution A ₁ to form a porous drug carrier B ₁ ; Combine 0.2g of porous drug carrier B ₁ with 1.6g of medical oral material Dentec fluid photocurable resin under pressure to obtain a sustained-release drug delivery module.

Example 4-10

According to the method of Example 1, only the dissolution temperature (0°C, 15°C, 30°C, 45°C, 60°C, 75°C, 90°C) was changed to obtain different sustained-release modules.

Examples 11-15

According to the method of Example 1, only the drug concentration of solution A1 (0.001mg/mL, 1mg/mL, 5mg/mL, 15mg/mL, saturated solution concentration) was changed to obtain different sustained-release modules.

Examples 16-21

According to the method of Example 1, only the porous materials (MCM-41, TDU-1, FSM, FDU-15, ZSM-5, activated carbon) were changed to obtain different slow-release modules.

Examples 22-27

According to the method of Example 1, just change the specific surface area of the porous material (500m ² /g, 600m ² /g, 700m ² /g, 800m ² /g, 900m ² /g, 1000m ² /g), to obtain different sustained release module.

Examples 28-32

According to the method of embodiment 1, just change medical oral cavity material (ceramic, glass ionomer, clove oil zinc oxide cement powder, zinc phosphate cement powder, silver amalgam), obtain different slow-release modules.

Examples 33-52

According to the method of embodiment 1, just change medicine (metronidazole, tinidazole, ornidazole, tetracycline, minocycline, doxycycline, erythromycin, josamycin, melelamycin, Luo Hong azithromycin, clarithromycin, acetylspiral, amoxicillin, floxacin, ofloxacin, ciprofloxacin, lomefloxacin, levofloxacin, trofloxacin), Get different slow release modules.

Comparative example 1

0.2 g of minocycline hydrochloride was mixed with 1.6 g of medical oral material Dentec fluid photocurable resin at 25° C. by mechanical stirring to prepare a comparative module X ₁ .

Comparative example 2

Dissolve 0.2g of minocycline hydrochloride in 20mL of deionized water at 25°C to obtain a solution A ₁ with a drug concentration of 10mg/mL; soak 2g of SBA-15 in solution A ₁ , porous drug carrier B ₁ , and Tablet processing was performed on B ₁ to obtain a comparative module X ₂ .

test case

The slow-release modules obtained in Example 1, Comparative Example 1, and Comparative Example 2 were subjected to an in vitro sustained-release test. The specific experimental operation was as follows: the slow-release module was subjected to an in vitro sustained-release test in a phosphate buffer solution of pH 7.2 at room temperature. The experimental results are shown in Figures 2 and 4. It can be seen from Figure 2 that the slow-release module _C1 was tested in vitro in phosphate buffer at pH 7.2 at room temperature, and the drug dissolved on the 7th day was only 12.92% of the drug load. %. It can be seen from Fig. 4 that the drug dissolved in Comparative Example 1 and Comparative Example 2 reached 12.75% and 45.24% of the drug load in 3 hours.

Experimental conclusion: Loading the drug on the carrier alone or mixing it into the medical oral material cannot make the drug release efficiently, long-term and stably. By combining the carrier with the medical oral material, the purpose of secondary controlled release of drug dissolution is achieved, so that the sustained release rate of the drug delivery module is more stable, and the sustained release time of the drug is greatly improved.

Apparently, the above-mentioned embodiments are only examples for clear description, and are not intended to limit the implementation. For those of ordinary skill in the art, on the basis of the above description, other changes or changes in various forms can also be made. It is not necessary and impossible to exhaustively list all the implementation manners here. However, the obvious changes or changes derived therefrom are still within the scope of protection of the present invention.

Claims

A preparation method for an oral drug sustained-release drug delivery system, characterized in that it comprises the following steps:

S1: dissolving the drug in a solvent to obtain a drug solution;

S2: immersing the porous material in the drug solution obtained in S1 to prepare a drug-loaded porous material;

S3: Combining the drug-loaded porous material obtained in S2 with a medical oral material to obtain the sustained-release drug delivery system for the oral cavity.
The preparation method according to claim 1, characterized in that, in S1, the drugs include hormone drugs, antibiotic drugs or vitamin drugs.
The preparation method according to claim 2, wherein the drug is selected from the group consisting of silver penate, sodium fluoride, metronidazole, tinidazole, ornidazole, tetracycline, minocycline, doxycycline, Erythromycin, josamycin, mabemycin, roxithromycin, azithromycin, clarithromycin, acetylspirane, amoxicillin, flufloxacin, ofloxacin, ciprofloxacin, Lomefloxacin, levofloxacin, trofloxacin, chlorhexidine, chlorhexidine, tin powder, ice boron powder, trichloroacetic acid, zinc chloride, nystatin, clotrimazole cream, ketocon One or more of azole, miconazole and dexamethasone.
The preparation method according to claim 1, characterized in that, in S1, the solvent is selected from one or more of water, alcohols, amides, esters, vegetable oils and sulfoxides.
The preparation method according to claim 4, wherein the solvent is selected from water, ethanol, propylene glycol, glycerol, butanol, benzyl alcohol, dimethylformamide, dimethylacetamide, glyceryl triacetate, One or more of ethyl acetate, ethyl oleate, benzyl benzoate, isopropyl myristate, peanut oil, corn oil, sesame oil, and dimethyl sulfoxide.
The preparation method according to claim 1, characterized in that, in S1, the drug concentration is 0.001 mg/mL-100 mg/mL.
The preparation method according to claim 1, wherein, in S2, the porous material is selected from microporous materials, mesoporous materials or macroporous materials; wherein, the pore diameter of microporous materials<2nm, and the pore diameter of mesoporous materials 2-50nm, the pore size of the macroporous material is >50nm.
The preparation method according to claim 1, characterized in that, in S3, the specific surface of the porous material is 2-3000m 2 /g.
The preparation method according to claim 1, wherein, in S3, the medical oral material is selected from ceramics, glass ionomers, clove oil zinc oxide cement, zinc phosphate cement, silver amalgam and composite resin one or more of .
The sustained-release drug delivery system for oral administration obtained by the preparation method described in any one of claims 1-9.