Method for obtaining microcapsules with metronidazole

Abstract

FIELD: chemistry; pharmaceuticals.SUBSTANCE: method for producing microcapsules with metronidazole by ionic gelation in combination with electrospray. The proposed method includes: preparing a capsule-forming solution by compounding a metronidazole suspension in vaseline oil, then dissolving sodium alginate and sparsely cross-linked polymethacrylic acid in water, adding Tween-80 to the resulting solution, and then introducing the said metronidazole suspension with constant stirring using a dispersant; preparing a gelling solution by using an aqueous solution of a basic polymethacrylic acid derivative with additionally added metronidazole and calcium chloride; spraying the capsule-forming solution into the gelling solution using an encapsulator; after which the resulting microcapsules are filtered, washed, and dried.EFFECT: reliable encapsulation of water-soluble metronidazole from an oil suspension in an aqueous-salt medium without the use of organic solvents.1 cl, 6 dwg

Description

[0001] The invention relates to medicine, in particular pharmacy, and relates to systems for modified delivery of drugs (DS) and can be used in the pharmaceutical industry in the production of solid dosage forms based on microcapsules.

[0002] Increasing the efficacy and bioavailability of existing drugs is a pressing challenge in pharmaceutical science today. A possible solution to this problem is the development of micro-sized dosage forms capable of significantly enhancing the biopharmaceutical properties of existing and market-demand drugs. Furthermore, the search for a technology that would allow for the production of such systems on an industrial scale is becoming a pressing issue. One such drug is metronidazole, an antiprotozoal and antimicrobial agent widely used in pharmacotherapy. Recent studies have demonstrated its effectiveness in the eradication of Helicobacter pylori.

[0003] A known method for producing metronidazole nanocapsules in sodium alginate is characterized by the fact that metronidazole powder is added to a suspension of sodium alginate in hexane and 0.01 g of the drug E472c, then acetone is added, the resulting suspension of nanocapsules is filtered and dried, while the mass ratio of the core:shell in the nanocapsules is 1:3, 1:1, 1:5 or 5:1 (Patent RU No. 2611368 C1, IPC A61K 31 / 4164, A61K 47 / 36 - 02 / 21 / 2017, Bulletin No. 6).

[0004] The disadvantage of this method is the use of toxic organic solvents and other chemical compounds, which limits its use in pharmaceuticals in terms of safety and environmental friendliness.

[0005] In contrast to the said known method, the claimed invention is characterized by a set of features, including the use of a combination of specific polymers - sodium alginate and rarely cross-linked polymethacrylic acid, as well as the use of an oil suspension of metronidazole within the framework of an aqueous ionic gelation technology, which makes it possible to exclude toxic organic solvents.

[0006] A known method for producing metronidazole nanocapsules in carrageenan is characterized in that metronidazole powder is added to a suspension of carrageenan in petroleum ether in the presence of 0.01 g of the drug E472c as a surfactant, then 10 ml of chloroform is added, the resulting suspension of nanocapsules is filtered and dried, while the mass ratio of the core:shell when converted to dry matter is 1:1, 1:3, 5:1 or 1:5 (Patent RU No. 2646482 C2, IPC A61K 31 / 4164, A61K 47 / 36 - 05.03.2018, Bulletin No. 7).

[0007] A known method for producing metronidazole nanocapsules in kappa-carrageenan, characterized in that kappa-carrageenan is used as the shell of the nanocapsules, metronidazole is used as the core, while metronidazole powder is added to a suspension of kappa-carrageenan in hexane and 0.01 g of the drug E472c used as a surfactant, then 6 ml of freon-113 are added, the resulting suspension of nanocapsules is filtered and dried, while the mass ratio of the core: shell in the nanocapsules is 1: 3, 1: 1 or 1: 2 (Patent RU No. 2691391 C1, IPC A61K 9 / 51, B82Y 40 / 00, A61K 31 / 4164 - 13.06.2019, Bulletin No. 17).

[0008] A known method for producing metronidazole nanocapsules in guar gum is characterized in that guar gum is used as the shell of the nanocapsules, metronidazole is used as the core, while metronidazole powder is added to a suspension of guar gum in benzene and 0.01 g of the drug E472c used as a surfactant, then 6 ml of butyl chloride are added, the resulting suspension of nanocapsules is filtered and dried, while the mass ratio of the core: shell in the nanocapsules is 1:3, 1:1, or 1:2 (Patent RU No. 2669353 C1, IPC A61K 9 / 51, B82B 1 / 00, A61K 31 / 4164).

[0009] However, the encapsulation of metronidazole using these methods involves the use of toxic organic solvents, which necessitates proper production conditions: the provision of separate explosion-proof rooms with explosion-proof equipment, the cleanup and disposal of hazardous toxic waste, proper personnel safety measures, and the maintenance of inventory control. All of this increases costs and limits the application of these methods when scaling up in production environments.

[0010] Other methods of metronidazole encapsulation also appear in the literature [Formulation and Evaluation of Metronidazole Loaded Chitosan Nanoparticles. Human Journals Research Article October 2016 Vol.:4, Issue:4]. However, the encapsulation efficiency in this case is 69.3%.

[0011] The objective of the proposed invention is to develop a method for producing metronidazole microcapsules by ionic gelation in combination with electrospray in aqueous-salt media for using this product in the technology for producing dosage forms with prolonged action.

[0012] The technical result of the claimed invention is the encapsulation of water-soluble metronidazole in aqueous-salt solutions without the use of organic solvents.

[0013] The technical result of the claimed invention is achieved due to the fact that the developed technological process for obtaining microcapsules prevents the dissolution of metronidazole in an aqueous medium, and the shell of the microcapsules, formed by the interpolyelectrolyte complex between the components of the capsule-forming and gelling solutions, ensures its encapsulation with an efficiency of 85-95%.

[0014] The details, features, and advantages of the present invention follow from the following description of the implementation of the claimed technical solution using drawings, which show:

[0015] Fig. 1 - flow chart for producing microcapsules with metronidazole.

[0016] Fig.2 - finished product.

[0017] Fig. 3 - IR spectrum of metronidazole and microcapsules with metronidazole.

[0018] Figure 4 - DSC thermograms of metronidazole, “empty” microcapsules and microcapsules with metronidazole.

[0019] Fig. 5 - Release profile of metronidazole from microcapsules in a medium simulating gastric pH over 6 hours.

[0020] Fig. 6 - Release profile of metronidazole from tablet microcapsules in a medium simulating gastric pH over 6 hours.

[0021] Implementation of the invention (Fig. 1).

[0022] Preparatory work: prepare the premises and necessary equipment, and train personnel. Personnel should wear laboratory clothing: long-sleeved lab coats, gloves, and protective goggles.

[0023] Equipment: Buchi B-390 encapsulator, UltraTurex T-25 disperser, 250 ml beaker, separatory funnel, magnetic stirrer, Buchner funnel, freeze dryer.

[0024] Materials: metronidazole, polymethacrylic acid derivatives, sodium alginate, vaseline oil, tween-80, deionized water.

[0025] Preparation of metronidazole suspension in vaseline oil

[0026] 2.5 g of metronidazole was added to 7.5 g of vaseline oil and dispersed on an UltraTurex T-25 for 5 min at 8000 rpm.

[0027] Preparation of capsule-forming solution

[0028] Sodium alginate and lightly cross-linked polymethacrylic acid were dissolved in water, and Tween-80 was added to the resulting solution. A suspension of metronidazole in vaseline oil was added to the resulting solution using a separatory funnel while constantly stirring with a dispersant.

[0029] Preparation of gelling solution

[0030] A solution of a basic polymethacrylic acid derivative with metronidazole and calcium chloride was prepared using a magnetic stirrer. The gelling solution was prepared using deionized water.

[0031] Obtaining microcapsules

[0032] The capsule-forming and gelling solutions were cooled to a temperature of 10 to 18°C. The capsule-forming solution was sprayed into the gelling solution using a Buchi B-390 encapsulator through a 600-μm nozzle with constant stirring, at an ultrasonic frequency of 180-280 Hz, a pressure of 120-180 mbar, and a potential of 2000-2500 V. The resulting capsules were washed and filtered on a Buchner funnel.

[0033] Drying microcapsules

[0034] The resulting capsules were dried in a drying oven at a temperature of 80°C for 4 hours.

[0035] Microcapsule tabletting

[0036] Microcapsule tablets were produced by direct compression without the use of excipients on a manual hydraulic press (PerkinElmer, USA). The pressing pressure was 2.45 MPa. The tablet diameter was 8 mm, the tablet shape was biconvex, and the radius of curvature was 1.1 D. The average tablet weight of the microcapsules was 100 mg.

[0037] The invention is illustrated by the following examples.

[0038] During the encapsulation of metronidazole, microcapsules with a quantitative metronidazole content of 28-36% were obtained (Fig. 2). The quantitative content was determined by UV spectrophotometry at a wavelength of 318 nm.

[0039] To confirm the inclusion of metronidazole in the microcapsules, IR spectroscopy was performed using a Nicolet iS5 IR spectrometer (Thermo Scientific, USA) with an ATR attachment. The IR spectra of the resulting microcapsules showed characteristic metronidazole bands, namely, vibrations of the OH group at 3212 cm -1 , vibrations of aromatic CH groups at 3100 cm -1 , NO2 group oscillations at 1534 cm -1 and vibrations of the aromatic ring at 825 cm -1 The presence of these bands in the IR spectrum of microcapsules confirms the encapsulation of metronidazole (Fig. 3).

[0040] A thermal analysis of the obtained microcapsules was also conducted using the DSC-MT method (TA Instruments, USA). The resulting thermograms of the microcapsules revealed a melting peak for metronidazole, further confirming its inclusion in the microcapsules (Fig. 4).

[0041] Using optical microscopy (Olympus, Japan), the spherical shape of the microcapsules was established, the average size was 900 µm.

[0042] The resulting microcapsules and tablets were subjected to a dissolution test in a stomach-simulating environment for 6 hours using the rotating paddle method 2 at 37°C and 50 rpm. Metronidazole release from the microcapsules and tablets after 6 hours of testing in an environment with a pH of 1.2 reached 94% and 73%, respectively (Figs. 5 and 6). Furthermore, the microcapsules and tablets were stable in an acidic environment, as well as their buoyancy, ensured by the addition of vaseline oil to the microcapsules.

Claims

A method for producing metronidazole microcapsules by ionic gelation combined with electrospray, comprising preparing capsule-forming and gelling solutions, spraying the capsule-forming solution into the gelling solution, followed by filtration, washing and drying the resulting microcapsules, characterized in that for preparing the capsule-forming solution, a metronidazole suspension is first prepared in vaseline oil, after which sodium alginate and rare cross-linked polymethacrylic acid are dissolved in water, tween-80 is added to the resulting solution and then the said metronidazole suspension is introduced with constant stirring using a dispersant, and an aqueous solution of a basic polymethacrylic acid derivative with additionally added metronidazole and calcium chloride is used as the gelling solution, while spraying the capsule-forming solution into the gelling solution is carried out using an encapsulator,after which the resulting microcapsules are filtered, washed and dried.

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