A drug delivery system for local treatment of periodontitis and a method of preparing the same

Abstract

The application relates to the technical field of pharmaceutical preparations, in particular to a drug delivery system for local treatment of periodontitis and a preparation method thereof. Based on the total weight of the drug delivery system, the drug delivery system contains 1-10 wt% of an active ingredient, 10-40 wt% of a biodegradable material and 50-89 wt% of an amphiphilic solvent. The specific component proportioning of the biodegradable material and the amphiphilic solvent ensures that the drug delivery system can realize the effects of slow release of the active ingredient, avoidance of the peak-valley phenomenon of blood drug concentration, prolongation of the drug action time and reduction of the drug use frequency, greatly alleviates the pain of patients, improves the compliance of the patients and has no irritation to tissues. The preparation method of the composition preparation is simple, is beneficial to large-scale production, has high drug loading capacity and is low in cost.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a drug delivery system for local treatment of periodontitis and its preparation method. Background Technology

[0002] Periodontal disease is a common human ailment, and currently there is no fixed treatment model in clinical practice. Local drug administration is commonly used, primarily to maximally inhibit pathogenic anaerobic bacteria in the oral cavity of susceptible patients. Compared to systemic medication, local application is more suitable for treating periodontal disease. It not only increases local drug concentration and reduces dosage but also avoids various adverse reactions that may occur with systemic medication, such as liver and kidney damage, allergic reactions, and dysbiosis.

[0003] Existing oral topical drug delivery formulations, limited by the unique environment of the oral cavity, are difficult to maintain in a fixed position for long-term effective drug delivery, resulting in unsatisfactory therapeutic effects. Existing technologies utilize in-situ gels as drug delivery systems to achieve long-term, slow drug release. In-situ gel delivery systems, administered directly through the periodontal pocket, avoid the first-pass effect in the liver and gastrointestinal irritation associated with oral administration, reduce systemic blood drug concentrations, decrease side effects, reduce the frequency of administration, and offer advantages such as targeted enhancement of drug concentrations at the local periodontal lesions—advantages unmatched by oral medications. However, in-situ oral gels in related technologies suffer from problems such as unstable release and poor injectability.

[0004] Therefore, there is an urgent need to develop a drug delivery system with good fluidity and excellent sustained-release effect for the local treatment of periodontitis. Summary of the Invention

[0005] The purpose of this invention is to provide a drug delivery system for local treatment of periodontitis and its preparation method. The drug delivery system is a liquid at room temperature and is slowly injected into the periodontal pocket through a syringe. It generates a gel in the body and adheres to the periodontal pocket. The active ingredients are slowly released through dissolution, erosion and other means.

[0006] This application addresses at least one of the problems of the related technology in the following aspects.

[0007] To this end, a first aspect of this application provides a drug delivery system, wherein, based on the total weight of the drug delivery system, the drug delivery system comprises 1 wt% to 10 wt% of an active ingredient, 10 wt% to 40 wt% of a biodegradable material, and 50 wt% to 89 wt% of an amphiphilic solvent.

[0008] In some embodiments, the active ingredient is ornidazole.

[0009] In some embodiments, the biodegradable material is selected from the group consisting of: lactide-glycolic acid copolymer (PLGA), polylactic acid (PLA), polycaprolactone (PCL), polyethylene glycol-lactide-glycolic acid copolymer (PEG-PLGA or PEG-PLGA-PEG), and polyethylene glycol-polylactic acid block copolymer (PEG-PLA or PEG-PLA-PEG).

[0010] In some embodiments, the biodegradable material is selected from the group consisting of: lactide-glycolic acid copolymer (PLGA), polylactic acid (PLA), and polycaprolactone (PCL).

[0011] In some embodiments, the weight-average molecular weight of the lactide-glycolic acid copolymer is between 10,000 and 80,000.

[0012] In some embodiments, the weight-average molecular weight of the lactide-glycolic acid copolymer is between 10,000 and 30,000.

[0013] In some embodiments, the molar ratio of lactide to glycolide in the lactide-glycol copolymer is 60:40 to 40:60.

[0014] In some embodiments, the amphiphilic solvent is selected from the group consisting of: N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, triacetyl ester, ethanol, ethyl acetate, ethyl benzoate, benzyl benzoate, and benzyl alcohol.

[0015] In some embodiments, the amphiphilic solvent is N-methylpyrrolidone.

[0016] The second aspect of this application provides a method for preparing a drug delivery system as described in any of the embodiments of the first aspect above, comprising the steps S1 and S2, wherein...

[0017] Step S1 includes: mixing the biodegradable material with the amphiphilic solvent to obtain a first solution;

[0018] Step S2 includes: mixing the active ingredient with the first solution to obtain the drug delivery system.

[0019] The drug delivery system for local treatment of periodontitis prepared according to the embodiments of this application has the following beneficial effects:

[0020] (1) The drug delivery system involved in this invention is prepared using in-situ gel technology. In-situ gels are liquid at room temperature. When the drug-containing solution encounters tissues in the body, it will coagulate, solidify, and precipitate to form a gel skeleton. The drug is slowly released as the material degrades and dissolves, following the general rules of drug diffusion and dissolution from the material's gel skeleton.

[0021] (2) The preferred biodegradable material of the present invention is lactide-glycolic acid copolymer (PLGA), with a weight-average molecular weight range of 10,000-80,000 and a molar percentage of lactide and glycolide of 60:40-40:60. The preferred biodegradable material can ensure the stable release of active ingredients and avoid drug burst release.

[0022] (3) The preferred amphiphilic solvent of the present invention is N-methylpyrrolidone (NMP), which is a polar nonproton transfer solvent with the advantages of low toxicity, strong selectivity and good stability, thus improving the safety of patients taking the medication.

[0023] (4) The present invention uses a syringe to slowly inject the drug into the periodontal pocket, which generates gel in the body. The gel adheres to the periodontal position and releases the drug slowly through dissolution and erosion, thereby improving the patient's compliance with medication. Detailed Implementation

[0024] The present invention will now be described in further detail with reference to specific embodiments. The embodiments given are merely illustrative of the invention and are not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0025] This application is based on the inventor's following understanding:

[0026] The characteristics of the dynamic oral microenvironment (saliva secretion, chewing movements) and the specificity of periodontal infection pose significant challenges to the local drug delivery system in the oral cavity: the oral cavity is a moist environment, and factors such as saliva flushing, continuous flow of gingival crevicular fluid in the periodontal pocket, and chewing movements can all affect drug retention, affect the duration of drug action, and thus reduce efficacy and treatment effect.

[0027] In response, after extensive research, the inventors utilized in-situ gel technology and designed the component ratios of an oral local drug delivery system to achieve a long-lasting therapeutic effect after intraoral administration. The drug delivery system proposed in this application has the advantage of long-term, effective, and stable release within the body, without any burst release phenomenon.

[0028] A first aspect of this application provides a drug delivery system, wherein, based on the total weight of the drug delivery system, the drug delivery system comprises 1 wt% to 10 wt% (e.g., 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%) of an active ingredient, 10 wt% to 40 wt% (e.g., 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%) of a biodegradable material, and 50 wt% to 89 wt% (55 wt%, 57 wt%, 60 wt%, 65 wt%, 67 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, 87 wt%) of an amphiphilic solvent.

[0029] The drug delivery system provided in this application uses in-situ gel technology to keep the drug delivery system in the periodontal pocket for 5-7 days, unaffected by factors such as lip, cheek and tongue movements and saliva secretion.

[0030] In some embodiments, the drug delivery system contains 2 wt% to 4 wt% (e.g., 2.5 wt%, 3 wt%, 3.5 wt%) of an active ingredient.

[0031] In some embodiments, the active ingredient is ornidazole.

[0032] In some embodiments, the biodegradable material is selected from the group consisting of: lactide-glycolic acid copolymer (PLGA), polylactic acid (PLA), polycaprolactone (PCL), polyethylene glycol-lactide-glycolic acid copolymer (PEG-PLGA or PEG-PLGA-PEG), and polyethylene glycol-polylactic acid block copolymer (PEG-PLA or PEG-PLA-PEG).

[0033] In some embodiments, the biodegradable material is selected from the group consisting of: lactide-glycolic acid copolymer (PLGA), polylactic acid (PLA), and polycaprolactone (PCL).

[0034] In some embodiments, the weight-average molecular weight of the lactide-glycolic acid copolymer is from 10,000 to 80,000 (e.g., 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000).

[0035] In some embodiments, the weight-average molecular weight of the lactide-glycolic acid copolymer is between 10,000 and 30,000.

[0036] In some embodiments, the molar ratio of lactide to glycolide in the lactide-glycol copolymer is 60:40 to 40:60 (e.g., 60:40, 55:45, 50:50, 40:60).

[0037] In this application, an in-situ gel was created by combining a copolymer with a specific molecular weight and a specific ratio of lactide to glycolide with N-methylpyrrolidone as the matrix component of a periodontal drug delivery system. This gel exhibits excellent mechanical properties after periodontal curing and can withstand the vibrations of daily chewing without cracking or peeling. The inventors unexpectedly discovered that using PLGA with a higher molecular weight and lower content significantly improves the compliance of the solution during the preparation of the drug delivery system, resulting in significantly improved needle penetration and a more stable sustained-release effect, avoiding defects such as burst release or excessively slow release.

[0038] In some embodiments, the amphiphilic solvent is selected from the group consisting of: N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, triacetyl ester, ethanol, ethyl acetate, ethyl benzoate, benzyl benzoate, and benzyl alcohol.

[0039] In some embodiments, the amphiphilic solvent is N-methylpyrrolidone.

[0040] The second aspect of this application provides a method for preparing a drug delivery system as described in any of the embodiments of the first aspect above, comprising the steps S1 and S2, wherein...

[0041] Step S1 includes: mixing the biodegradable material with the amphiphilic solvent to obtain a first solution;

[0042] Step S2 includes: mixing the active ingredient with the first solution to obtain the drug delivery system.

[0043] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as understood by any person skilled in the art to which this invention pertains. The terminology used to describe this invention is intended only to describe a particular implementation and not to limit the scope of the teachings. Unless otherwise stated, all figures expressing quantities, percentages, and parts by weight, as well as other numerical values ​​used in the specification and claims, should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise stated, the numerical parameters shown in the specification and claims are approximate values ​​and may vary depending on the characteristics to be obtained.

[0044] Technical terms appearing in this application are used as they are common sense or as they would be understood by someone skilled in the art. Where certain terms have a specific meaning, their definitions will be given below in the context of their use.

[0045] The following embodiments are used to further illustrate the advantages and features of this method, and are not intended to limit the invention. Unless otherwise specified, the experimental methods in the following embodiments are conventional methods, performed according to the techniques or conditions described in the literature in the field or according to the product instructions.

[0046] Unless otherwise specified, all materials and reagents used in the following examples are commercially available. Unless otherwise specified, all quantitative analysis experiments in the following examples were performed in triplicate, and the results were averaged.

[0047] Example 1

[0048] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 20 wt% (molecular weight 30,000, lactide:glycol = 50:50), and NMP 77 wt%.

[0049] Preparation method:

[0050] S1: Mix the prescribed amounts of PLGA and NMP, and stir thoroughly at room temperature until completely dissolved to obtain solution 1;

[0051] S2: Mix ornidazole with solution 1 and stir thoroughly at room temperature to obtain the drug delivery system solution.

[0052] Example 2

[0053] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 20 wt% (molecular weight 30,000, lactide:glycol = 60:40), and NMP 77 wt%.

[0054] Prepare according to the preparation method in Example 1.

[0055] Example 3

[0056] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 20 wt% (molecular weight 30,000, lactide:glycol = 40:60), and NMP 77 wt%.

[0057] Prepare according to the preparation method in Example 1.

[0058] Example 4

[0059] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 20 wt% (molecular weight 30,000, lactide:glycol = 55:45), and NMP 77 wt%.

[0060] Prepare according to the preparation method in Example 1.

[0061] Example 5

[0062] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 20 wt% (molecular weight 10000, lactide:glycol = 50:50), and NMP 77 wt%.

[0063] Prepare according to the preparation method in Example 1.

[0064] Example 6

[0065] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 20 wt% (molecular weight 80,000, lactide:glycol = 50:50), and NMP 77 wt%.

[0066] Prepare according to the preparation method in Example 1.

[0067] Example 7

[0068] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 20 wt% (molecular weight 60,000, lactide:glycol = 50:50), and NMP 77 wt%.

[0069] Prepare according to the preparation method in Example 1.

[0070] Example 8

[0071] The drug delivery system was formulated with ornidazole 3 wt%, PLA 20 wt% (molecular weight 80,000), and dimethylformamide 77 wt%, according to the preparation method in Example 1.

[0072] Example 9

[0073] The drug delivery system was formulated with ornidazole 3wt%, PCL 20wt% (molecular weight 30,000), and dimethyl sulfoxide 77wt%, according to the preparation method in Example 1.

[0074] Example 10

[0075] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 10 wt% (molecular weight 30,000, lactide:glycol = 50:50), and NMP 87 wt%.

[0076] Prepare according to the preparation method in Example 1.

[0077] Example 11

[0078] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 40 wt% (molecular weight 30,000, lactide:glycol = 50:50), and NMP 57 wt%.

[0079] Prepare according to the preparation method in Example 1.

[0080] Example 12

[0081] The drug delivery system is formulated with ornidazole 3wt%, PLGA 30wt% (molecular weight 30,000, lactide:glycolide = 50:50), and NMP 67wt%.

[0082] Prepare according to the preparation method in Example 1.

[0083] Example 13

[0084] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 20 wt% (molecular weight 30,000, lactide:glycolide = 50:50), and triacetin 77 wt%.

[0085] Prepare according to the preparation method in Example 1.

[0086] Compared to Example 1, replacing NMP with triacetyl ester resulted in decreased needle penetration (the test method is to fill the syringe with the drug solution, inject it using a 23-gauge needle, and evaluate the needle penetration by whether the drug solution can be smoothly injected). Furthermore, triacetyl ester as a solvent exhibited a poorer sustained-release effect than NMP, with a release rate that was too rapid compared to Example 1.

[0087] Example 14

[0088] The drug delivery system is formulated with ornidazole 1 wt%, PLGA 20 wt% (molecular weight 30,000, lactide:glycol = 50:50), and NMP 79 wt%.

[0089] Prepare according to the preparation method in Example 1.

[0090] Example 15

[0091] The drug delivery system is formulated with ornidazole 10wt%, PLGA 20wt% (molecular weight 30,000, lactide:glycol = 50:50), and NMP 70wt%.

[0092] Prepare according to the preparation method in Example 1.

[0093] Comparative Example 1

[0094] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 20 wt% (molecular weight 30,000, lactide:glycol = 65:35), and NMP 77 wt%.

[0095] Prepare according to the preparation method in Example 1.

[0096] In this comparative example, the biodegradable material PLGA contains a lactide to glycolide ratio of 65:35, resulting in a higher lactide content. Compared to Example 1, the release is slower and the release time is too long, thus the drug release amount cannot meet clinical requirements.

[0097] Comparative Example 2

[0098] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 20 wt% (molecular weight 100,000, lactide:glycol = 50:50), and NMP 77 wt%.

[0099] Prepare according to the preparation method in Example 1.

[0100] The biodegradable material PLGA in this comparative example has a molecular weight of 100,000, which is relatively large. This results in excessively high viscosity of the drug delivery system. Compared with Example 1, its injectability is reduced and its release is slower. The release time is too long, and the amount of drug released cannot meet the clinical requirements.

[0101] Comparative Example 3

[0102] The drug delivery system is formulated with ornidazole 3 wt%, PLGA 50 wt% (molecular weight 30,000, lactide:glycol = 50:50), and NMP 47 wt%.

[0103] Prepare according to the preparation method in Example 1.

[0104] The biodegradable material PLGA in this comparative example has a content of 50 wt%, which is relatively high (it may not be completely soluble and has a high viscosity, making it difficult to produce and inject). Compared with Example 1, the release rate is slower than that of Example 1, and the release rate is too slow, and the drug release amount cannot meet clinical requirements.

[0105] Comparative Example 4

[0106] The drug delivery system was formulated with ornidazole 3 wt%, PLGA 70 wt% (molecular weight 7000, lactide: glycolide = 50:50), and triacetin 27 wt%.

[0107] Prepare according to the preparation method in Example 1.

[0108] This invention uses PLGA with high molecular weight and low content, which results in better drug solution viscosity and compliance with the solution preparation process. If the PLGA content is high, the solvent ratio needs to be lower, which may not be able to completely dissolve the excipients, or the viscosity after dissolution may be high, making it difficult to inject and resulting in poor needle penetration (PLGA content has a greater impact on drug solution viscosity than molecular weight).

[0109] Detection Example 1

[0110] The in vitro release properties of the drug delivery systems prepared in Examples 1 to 15 and Comparative Examples 1 to 3 were tested according to the method in Table 1 below, and the test results are shown in Table 2 below.

[0111] Table 1

[0112]

[0113] Table 2

[0114]

[0115]

[0116]

[0117]

[0118] As shown in Table 1, the embodiments of this application utilize a copolymer (10wt%-40wt%) with a specific molecular weight (10000-80000, preferably 10000-30000) and a specific ratio of lactide to glycolide of 60:40-40:60, combined with N-methylpyrrolidone (50wt%-89wt%), as the matrix component of the periodontal drug delivery system, to achieve an in-situ gel that exhibits excellent mechanical properties after periodontal curing and can withstand the daily chewing vibrations in the oral cavity without breaking or peeling.

[0119] Detection Example 2

[0120] Detection method: Take 100 mg of gel (i.e. the drug delivery system prepared in the examples and comparative examples) and place it in a 1 mL centrifuge tube. Slowly add pH 6.8 phosphate buffer (potassium dihydrogen phosphate + sodium hydroxide solution) along the tube wall and continuously rinse to completely solidify the sample. Take out the solidified sample and perform shear performance (simulating buccal and tongue movement) and dynamic mechanical analysis (simulating long-term creep) tests.

[0121] standard:

[0122] (1) Shear properties:

[0123] The shear strength of the sample after 24 hours of curing is ≥10 N / cm. 2 It is considered to have good gel toughness, which can prevent it from being peeled off by cheek and tongue movements;

[0124] After 7 days of curing, the shear fracture strain of the sample was ≤10%, which is considered to be a relatively stable rigid gel structure that can withstand moderate deformation caused by oral movement and has a low risk of fracture.

[0125] (2) Dynamic mechanical analysis:

[0126] The storage modulus (G') of the cured sample at 37℃ and 1Hz scanning frequency should be ≥4kPa and the loss factor (tanδ) should be <0.1, indicating that the gel has high strength and can withstand the daily chewing vibrations in the oral cavity without easily breaking.

[0127] The storage modulus (G') at 37℃ and 10Hz scanning frequency should be ≥2kPa and the loss factor (tanδ) should be <0.05, indicating that the gel has good flexibility, can adapt to daily oral movements, and has little foreign body sensation.

[0128] Table 3

[0129]

[0130]

[0131] Comparative Examples 1-3 all used high-dosage / high-molecular-weight PLGA. The higher dosage / molecular weight of PLGA enhanced their mechanical properties, making them similar to those of the examples. However, the drug delivery systems prepared in Comparative Examples 1-3 had excessively high viscosity and slow release, which reduced needle penetration and process compliance.

[0132] The embodiments of this application simultaneously consider needle penetration, process compliance, mechanical properties, and sustained-release properties, providing a drug delivery system for local treatment of periodontitis with good fluidity and excellent sustained-release effect.

[0133] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0134] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A drug delivery system, characterized in that, Based on the total weight of the drug delivery system, the drug delivery system comprises 1 wt% to 10 wt% of active ingredient, 10 wt% to 40 wt% of biodegradable material and 50 wt% to 89 wt% of amphiphilic solvent.

2. The drug delivery system according to claim 1, characterized in that, The active ingredient is ornidazole.

3. The drug delivery system according to claim 1 or 2, characterized in that, The biodegradable material is selected from the group consisting of: lactide-glycolic acid copolymer, polylactic acid, polycaprolactone, polyethylene glycol-lactide-glycolic acid copolymer, and polyethylene glycol-polylactic acid block copolymer.

4. The drug delivery system according to claim 3, characterized in that, The biodegradable material is selected from the group consisting of: lactide-glycolic acid copolymer, polylactic acid, and polycaprolactone.

5. The drug delivery system according to claim 3 or 4, characterized in that, The weight-average molecular weight of the lactide-glycolic acid copolymer is between 10,000 and 80,000.

6. The drug delivery system according to claim 5, characterized in that, The weight-average molecular weight of the lactide-glycol copolymer is between 10,000 and 30,000.

7. The drug delivery system according to claim 6, characterized in that, The molar ratio of lactide to glycolide in the lactide-glycol copolymer is 60:40 to 40:

60.

8. The drug delivery system according to any one of claims 1 to 7, characterized in that, The amphiphilic solvent is selected from the group consisting of: N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, triacetyl ester, ethanol, ethyl acetate, ethyl benzoate, benzyl benzoate, and benzyl alcohol.

9. The drug delivery system according to claim 8, characterized in that, The amphiphilic solvent is N-methylpyrrolidone.

10. A method for preparing a drug delivery system as described in any one of claims 1 to 9, characterized in that, Includes the following steps S1 and S2, Step S1 includes: mixing the biodegradable material with the amphiphilic solvent to obtain a first solution; Step S2 includes: mixing the active ingredient with the first solution to obtain the drug delivery system.

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