A metronidazole amorphous composition using polylysine or polyglutamic acid as a carrier

Abstract

The application belongs to the technical field of medicine, and discloses a kind of methylbenzimidazole amorphous composition with polylysine or polyglutamic acid as carrier and its preparation method and application.The methylbenzimidazole amorphous composition is obtained by mixing methylbenzimidazole and carrier material (polylysine or polyglutamic acid) according to three proportions (1:3-3:1) and fully ball milling.The preparation method has the advantages of simple operation, high yield, no solvent residue, etc.Compared with traditional solid dispersion and co-amorphous system, the drug loading of the composition is 25%-75%, and the composition has ideal physical stability.Compared with crystalline methylbenzimidazole, the amorphous composition significantly improves the dissolution rate and solubility of methylbenzimidazole, providing a good intermediate for oral preparation of methylbenzimidazole.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a method for preparing a toluene-based amorphous composition using polylysine or polyglutamic acid as a carrier and its application. Background Technology

[0002] Mebendazole, chemically known as methyl (5-phenylpropionyl-1H-benzimidazole-2-yl)carbamate, is one of the best drugs currently available for treating intestinal worms. It can be used to prevent and treat intestinal parasitic diseases such as hookworms, roundworms, pinworms, whipworms, and stercoralis. According to the biopharmaceutics classification system (BCS), mebendazole is characterized by low solubility and high osmotic pressure, belonging to BCS class II drugs. Its extremely poor water solubility (0.5 μg / mL) is one of the main reasons for the low oral bioavailability of mebendazole preparations.

[0003] Polyamino acids are a class of biopolymers based on natural amino acids linked by amide bonds. Studies have shown that polylysine possesses good bactericidal properties and thermal stability, making it suitable as a preservative in various foods. Furthermore, polylysine exists in a highly polymerized, multivalent cationic state, making it suitable for use as a non-viral vector for gene therapy, a coating for sustained drug release, and a biodegradable material. Polyglutamic acid is an edible, harmless, hydrophilic biopolymer with non-toxicity and good biocompatibility.

[0004] Converting poorly soluble crystalline drugs into their respective amorphous forms typically improves their water solubility and dissolution rate. However, amorphous forms are thermodynamically unstable and tend to recrystallize spontaneously. Therefore, to address the poor physical stability of amorphous drugs, various studies have been conducted, such as amorphous solid dispersions based on polymer carriers and co-amorphous systems using low molecular weight carriers such as amino acids. While traditional solid dispersion techniques can effectively improve the water solubility of poorly soluble drugs, achieving ideal solubility and physical stability of amorphous drugs usually requires dispersing (i.e., "dissolving") the drug in a molecular state within a carrier material. However, the solubility of poorly soluble drugs in carrier materials is generally limited, resulting in relatively large carrier volumes, low drug loading, and ultimately excessively large dosing volumes, making them inconvenient to use. Co-amorphous systems are a novel type of amorphous dispersion system that has emerged in recent years. They are single-phase amorphous systems with a single glass transition temperature formed by combining drugs with other small-molecule solid substances (drugs or excipients). As a novel solid state for drugs, it can improve the insufficient drug loading capacity of solid dispersions: drugs and small molecule carriers in co-amorphous systems are usually prepared by mixing them in a 1:1 molar ratio, resulting in a significantly higher drug loading capacity compared to traditional solid dispersions. Amino acids are the most important class of co-amorphous carriers, with advantages such as low cost and a wide range of choices. However, the physical stability of some co-amorphous systems using amino acids as carriers is not ideal, and the drug or carrier is prone to recrystallization. Therefore, how to combine the advantages of traditional solid dispersions and novel co-amorphous systems, and overcome their disadvantages, to construct an ideal tolmeazole amorphous dispersion system is a challenging problem worthy of research.

[0005] Based on polylysine or polyglutamic acid as a carrier, we have invented a novel tolmeadazole amorphous composition that combines the advantages of traditional solid dispersions and novel co-amorphous systems, overcoming the disadvantages of low drug loading in solid dispersions and less-than-ideal physical stability in some co-amorphous systems. This invention uses inexpensive, readily available, thermally stable polylysine or polyglutamic acid with a high glass transition temperature to form an amorphous composition with tolmeadazole, achieving a drug loading of up to 75%. Compared to the active pharmaceutical ingredient, this amorphous composition exhibits significantly improved water solubility, dissolution rate, and physical stability. Summary of the Invention

[0006] To address the shortcomings of existing solid dispersions, such as low drug loading and less-than-ideal physical stability in some co-amorphous systems, this invention provides a novel amorphous composition of mebendazole using polylysine or polyglutamic acid as a carrier. This composition improves the solubility and dissolution rate of mebendazole, thereby enhancing its oral bioavailability. Compared to existing solid dispersion technologies, the mebendazole-polyglutamic acid and mebendazole-polylysine amorphous compositions provided by this invention have the advantage of high drug loading (up to 75%). Compared to co-amorphous systems, the mebendazole amorphous compositions provided by this invention retain the high stability advantage of solid dispersion technology, maintaining an amorphous state even after being stored at 40°C for 9 months. Furthermore, this invention also provides a method for preparing the mebendazole-polyglutamic acid and mebendazole-polylysine amorphous compositions. This method is simple to operate, has a high yield, requires no solvent, and is environmentally friendly.

[0007] The technical solution of the present invention is as follows:

[0008] A toluimidazole-polylysine amorphous composition, characterized in that the composition is a mixture prepared by mixing toluimidazole and polylysine (or polyglutamic acid) in a certain proportion, and its X-ray powder diffraction pattern has no sharp diffraction peaks.

[0009] Furthermore, in the aforementioned toluimidazole-polyglutamic acid amorphous composition, the mass ratio of toluimidazole to polylysine or polyglutamic acid ranges from 1:3 to 3:1.

[0010] The preparation method of the toluimidazole-polylysine or polyglutamic acid amorphous composition in this invention is ball milling. The preparation steps are as follows: after mixing toluimidazole and polyglutamic acid (or polylysine) in a certain mass ratio, the amorphous composition is prepared by mechanical ball milling.

[0011] Furthermore, in the ball milling method described above, the ball milling process is intermittent and includes the following steps:

[0012] A certain mass of tolimidazole and polyglutamic acid (or polylysine) were added to a ball mill jar containing a stainless steel ball at different mass ratios. The ball mill vibration frequency was set, and the jar containing the samples was first placed in a -80°C freezer for 20 minutes, followed by ball milling for 20 minutes, and then frozen for another 20 minutes, for a total ball milling time of 60 minutes. After ball milling, the samples were collected to obtain amorphous compositions of tolimidazole-polyglutamic acid or tolimidazole-polylysine at different mass ratios.

[0013] Furthermore, the total mass of the mebendazole and polyglutamic acid (or polylysine) is 200-1000 mg, more preferably 500-800 mg. The mass ratio of the mebendazole to polyglutamic acid (or polylysine) is 3:1 to 1:3.

[0014] The present invention also provides a medicament comprising a mebendazole-polyglutamic acid amorphous composition or a mebendazole-polylysine amorphous composition, characterized in that it comprises a mebendazole-polyglutamic acid amorphous composition or a mebendazole-polylysine amorphous composition, and one or more pharmaceutically acceptable excipients.

[0015] The present invention also provides a drug containing a mebendazole-polyglutamic acid amorphous composition or a mebendazole-polylysine amorphous composition for the treatment or prevention of intestinal parasitic diseases such as hookworm, roundworm, pinworm, whipworm, and stercoralis.

[0016] Compared with the prior art, the beneficial effects of the present invention are:

[0017] (1) The tolmepiride-polyglutamic acid amorphous composition or tolmepiride-polylysine amorphous composition prepared by the present invention not only effectively improves the water solubility of tolmepiride and accelerates the drug release rate, but also has the advantage of high drug loading. As needed, a composition with a drug loading of up to 75% can be prepared.

[0018] (2) The preparation method of the toluene-polyglutamic acid amorphous composition or the toluene-polylysine amorphous composition provided by the present invention has the advantages of being simple and easy to operate, having a high yield, low cost, no solvent residue, and being environmentally friendly.

[0019] (3) The amorphous composition of mebendazole prepared in this invention can significantly improve the solubility and dissolution rate of mebendazole. The dissolution curves of mebendazole-polylysine amorphous composition or mebendazole-polyglutamic acid amorphous composition with different mass ratios are different. Therefore, the release curve of mebendazole can be adjusted by changing the mass ratio of mebendazole and carrier to achieve the desired therapeutic effect. Attached Figure Description

[0020] Figure 1 X-ray powder diffraction patterns of crystalline toluene-imidazolium, polylysine, and polyglutamic acid.

[0021] Figure 2 X-ray powder diffraction patterns of amorphous toluimidazole and amorphous toluimidazole-polylysine compositions.

[0022] Figure 3 X-ray powder diffraction pattern of toluimidazole-polyglutamic acid amorphous composition

[0023] Figure 4 The DSC diagrams are for amorphous tolmepiride, polylysine, and polyglutamic acid.

[0024] Figure 5 The images show the DSC diagrams of the tolimidazole-polylysine amorphous composition and the tolimidazole-polyglutamic acid amorphous composition.

[0025] Figure 6 This is a powder dissolution curve of crystalline toluimidazole and amorphous toluimidazole, representing an amorphous composition of toluimidazole-polylysine.

[0026] Figure 7 This is a powder dissolution curve of crystalline toluimidazole and amorphous toluimidazole, representing an amorphous composition of toluimidazole and polyglutamic acid.

[0027] Figure 8 X-ray powder diffraction patterns of toluimidazole-polyamino acid amorphous composition and amorphous toluimidazole after being placed at 25°C for 2 weeks, 2 months, 3 months and 9 months.

[0028] Figure 9 X-ray powder diffraction patterns of toluimidazole-polyamino acid amorphous composition and amorphous toluimidazole after being placed at 40°C for 2 weeks, 2 months, 3 months and 9 months. Detailed Implementation

[0029] The following examples illustrate specific embodiments of the present invention and are intended to explain the invention, but not to limit it in any way.

[0030] Example 1: Preparation of amorphous tolmeazole

[0031] A total of 750 mg of mebendazole was added to a 50 mL ball mill jar equipped with 25 mm stainless steel grinding balls. The jar was sealed, and the mixture was then milled in a ball mill at a frequency of 25 Hz for 60 min. During this period, the ball mill jar was placed in a -80°C freezer for 20 min every 20 min to prevent heat generation, which is detrimental to the crystal-amorphous transformation. After milling, the sample powder was collected and stored in a -20°C freezer.

[0032] Example 2: Preparation of atomized toluidine-polylysine composition

[0033] Table 1. Formulation information for toluidine-polylysine amorphous compositions

[0034]

[0035] A total of 750 mg of mebendazole and polylysine were added to 50 mL ball mill jars equipped with 25 mm stainless steel grinding balls at mass ratios of 3:1, 1:1, and 1:3, respectively. The jars were sealed, and the mixtures were then ground in a ball mill at a frequency of 25 Hz for 60 min. During this process, the ball mill jars were placed in a -80°C freezer for 20 min every 20 min to prevent heat generation, which is detrimental to the crystal-amorphous transformation. After grinding, the sample powder was collected and stored in a -20°C freezer.

[0036] Example 3: Preparation of atomized toluidine-polyglutamic acid composition

[0037] Table 2 Formulation information for toluidine-polyglutamic acid amorphous compositions

[0038]

[0039] A total of 750 mg of mebendazole and polyglutamic acid were added to 50 mL ball mill jars equipped with 25 mm stainless steel grinding balls at mass ratios of 3:1, 1:1, and 1:3, respectively. The jars were sealed, and the mixtures were then ground in a ball mill at a frequency of 25 Hz for 60 min. During this process, the ball mill jars were placed in a -80°C freezer for 20 min every 20 min to prevent heat generation, which is detrimental to the crystal-amorphous transformation. After grinding, the sample powder was collected and stored in a -20°C freezer.

[0040] Example 4: X-ray powder diffraction test of the sample

[0041] Measuring instrument: Bruker D8 Advance X-ray diffractometer, Bruker GmbH, Germany.

[0042] Measurement conditions:

[0043] Scanning method: Continuous scan; Drive mode: 0-2θ linkage

[0044] Starting angle: 5° Ending angle: 30°

[0045] Scanning speed: 0.02° / second; Sampling time: 1 second

[0046] Target material: Cu; Tube voltage: 40kV

[0047] Tube current: 40mA

[0048] A small amount of each of the samples prepared in Examples 1-3 was spread evenly onto a sample dish with a zero background and gently compacted to ensure a smooth and uniform surface. The sample dish was then placed in the eight-position autosampler of an X-ray powder diffractometer for testing. The diffraction patterns were recorded and saved after the test. The results are attached. Figures 1-3 As shown.

[0049] The results showed that the starting drug mebendazole had obvious crystal peaks, while the X-ray powder diffraction patterns of all ball-milled samples did not have sharp diffraction peaks, and all were transformed into an amorphous state.

[0050] Example 5: Differential Scanning Calorimetry (DSC) of the Sample

[0051] Measurement instrument: DSC 250 (Version 5.1.1), TA Instruments, USA.

[0052] Measurement conditions: Weigh 2.0–6.0 mg of each of the samples prepared in Examples 1–3 and place them in an aluminum Tzero sample pan. Gently compact the sample with a small steel rod to ensure uniform dispersion. Then, seal the sample with an aluminum Tzero cap. All samples were measured in a modulated temperature mode: the sample was isothermated at -10°C for 5 min, then heated to 240°C at a rate of 3°C / min. During the test, the amplitude of the modulated DSC was 0.21°, the period was 40 s, and the nitrogen flow rate was 50 mL / min.

[0053] The measurement results of Examples 1, 2, and 3 are shown in Table 3 and Appendix. Figures 4-5 As shown.

[0054] Table 3 Thermal analysis results of Examples 1, 2, and 3

[0055]

[0056]

[0057] Table 3 and Appendix Figures 4-5 The results showed that the tolmepiride-polyamino acid amorphous composition system contained two glass transition temperatures, indicating that a single-phase homogeneous amorphous system was not formed, and the individual glass transition temperatures were close to those of the excess component. The higher glass transition temperatures (around 175℃ and 190℃) in the amorphous composition system both originated from the polyamino acid carrier. This may be beneficial to improving the physical stability of the system, but further stability experiments are needed to confirm this.

[0058] Example 6: Powder solubility test of crystalline toluidine, amorphous toluidine, toluidine-polylysine amorphous composition, and toluidine-polyglutamic acid amorphous composition.

[0059] In this experiment, the powder dissolution behavior of crystalline mebendazole, amorphous mebendazole, and mebendazole-polyamino acid amorphous composition was studied according to the dissolution test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II (Paddle Method)). 6 mg of crystalline mebendazole, 6 mg of amorphous mebendazole prepared in Example 1, and amorphous compositions containing 6 mg of mebendazole prepared in Examples 2-3 (mebendazole concentration at least 5 times the saturation concentration in phosphate buffer) were placed in 200 mL of 0.05 M pH 6.8 phosphate buffer (37°C) with a stirring speed of 100 rpm. At pre-set time points (2, 5, 10, 20, 30, 60, 120, 180, 240, 360, 1440 min), 3 mL of solution was taken, filtered through a 0.45 μm aqueous filter, 2 mL was discarded, and the filtrate was collected as the final product. Preheated 3 mL of the same medium was added promptly. Then, 300 μL of the filtrate was added to 300 μL of acetonitrile and mixed thoroughly to prevent supersaturation and precipitation of the sample. All dissolution experiments were performed in triplicate. The concentration of tolueneimidazole in the obtained samples was determined by high-performance liquid chromatography (HPLC), and dissolution curves of tolueneimidazole in each sample were plotted.

[0060] Determination of mebendazole concentration in dissolved experimental samples

[0061] Determination method: High performance liquid chromatography

[0062] Instrument used for measurement: Agilent 1260 high performance liquid chromatograph, Agilent Technologies, USA

[0063] Chromatographic column: Agilent C18 reversed-phase column (150×4.6mm, 5μm)

[0064] Mobile phase: 0.02M phosphate buffer: acetonitrile = 45:55 (v / v)

[0065] Flow rate: 1 mL / min

[0066] Detection wavelength: 312nm

[0067] Retention time: 3.2 min

[0068] The test results are attached. Figures 6-7 The solubility and dissolution rate of the toluimidazole-polyamino acid amorphous composition in the dissolution medium were improved to varying degrees compared with crystalline toluimidazole and amorphous toluimidazole. For example, compared with crystalline toluimidazole, the saturated solubility of the toluimidazole amorphous composition with polylysine as the carrier was increased by approximately 8.5 times. Overall, the prepared amorphous composition significantly improved the solubility of toluimidazole.

[0069] Example 7: Determination of the physical stability of amorphous toluidine, toluidine-polylysine amorphous composition, and toluidine-polyglutamic acid amorphous composition.

[0070] The amorphous tolmepiride and tolmepiride amorphous composition prepared in Examples 1-3 were placed under two conditions: (1) drying at 25°C and (2) drying at 40°C. Samples were taken at 2 weeks, 2 months, 3 months and 9 months, respectively, and X-ray powder diffraction was used to detect whether the samples maintained an amorphous state.

[0071] The test results are shown in Table 4 and Figures 8-9 As shown, the results indicate that amorphous toluene-methylbenzazole underwent crystallization after 2 months (25℃) and 2 weeks (40℃), respectively, while the toluene-methylbenzazole amorphous composition with polylysine as the carrier significantly delayed the recrystallization time of toluene-methylbenzazole. Except for the toluene-methylbenzazole-polylysine amorphous composition (mass ratio 1:3, 40℃), which underwent crystallization after three months, the other samples remained stable for 9 months during the test. For polyglutamic acid, the toluene-methylbenzazole-polyglutamic acid amorphous composition (mass ratio 3:1, 25℃) also remained stable for at least 9 months. In conclusion, toluene-methylbenzazole amorphous compositions based on polylysine or polyglutamic acid significantly improved the physical stability of amorphous toluene-methylbenzazole.

[0072] Table 4. Stability test results (×: crystal transformation, √: stable)

[0073]

[0074] Example 8: Preparation of capsules of atomized toluidine-polylysine composition

[0075] Capsules were prepared using the mebendazole-polylysine (1:1) amorphous composition obtained in Example 2 as an intermediate, and lactose monohydrate, microcrystalline cellulose (SH102), and magnesium stearate as excipients. Lactose monohydrate and microcrystalline cellulose were passed through a 100-mesh sieve, as was the mebendazole-polylysine (1:1) amorphous composition. 60.0 g of lactose monohydrate, 40.0 g of microcrystalline cellulose, 1.0 g of magnesium stearate, and 200.0 g of the mebendazole-polylysine (1:1) amorphous composition were weighed sequentially and placed in a three-dimensional mixer, where they were mixed uniformly for 5 minutes. The material was then removed and added to the hopper of a fully automatic capsule filling machine for capsule filling, with a theoretical fill weight of 301 mg / capsule. The filling process was smooth, with capsule weight variation within 3%, and the content of the active ingredient mebendazole within ±3% of the predetermined dosage (100 mg). The filling accuracy met the quality requirements.

[0076] Example 9: Preparation of a tablet of tolimidazole-polyglutamic acid amorphous composition

[0077] Using the mebendazole-polyglutamic acid (3:1) amorphous composition obtained in Example 3 as an intermediate, mebendazole amorphous composition tablets were prepared using lactose monohydrate, microcrystalline cellulose (SH102), sodium carboxymethyl cellulose, and magnesium stearate as excipients. First, the mebendazole-polyglutamic acid (3:1) amorphous composition, lactose monohydrate, and microcrystalline cellulose (SH102) were passed through a 100-mesh sieve and set aside. Then, 80.0 g of lactose monohydrate, 40.0 g of microcrystalline cellulose, 12.0 g of sodium carboxymethyl cellulose, 0.8 g of magnesium stearate, and 133.4 g of the mebendazole-polyglutamic acid (3:1) amorphous composition were weighed sequentially and placed in a three-dimensional mixer, where they were mixed uniformly for 5 minutes. The material was then removed and added to the hopper of an 8-punch fully automatic tablet press, which used a shallow concave arc punch with a diameter of 12 mm for tableting. The theoretical tablet weight was 266.2 mg. The tableting process was smooth, and the production pressure was stable. The tablet hardness is controlled at 6-10 kg, the tablet press speed is 30 RPM, the production pressure is stable, and the weight difference can be controlled within ±3%. The powder flowability and compressibility of the toluene-polyglutamic acid amorphous composition meet the requirements of direct powder compression process, enabling rapid large-scale production.

Claims

1. A toluene-imidazolium-polyamino acid amorphous composition, characterized in that, The composition is a mixture prepared by mixing mebendazole and polyamino acids in a certain proportion, and its X-ray powder diffraction pattern has no sharp diffraction peaks; the polyamino acid is selected from polyglutamic acid and polylysine, and the mass ratio of mebendazole to polyamino acid is in the range of 1:3 to 3:

1. The composition is used to prepare drugs for treating or preventing hookworm, roundworm, pinworm, whipworm, and stercoralis infections.

2. The tolmepiride-polyamino acid amorphous composition according to claim 1, characterized in that, The preparation method is ball milling, and the preparation steps are to mix the toluene-imidazolium and the polyamino acid and then prepare an amorphous composition by mechanical ball milling.

3. The tolmepiride-polyamino acid amorphous composition according to claim 2, characterized in that, In the ball milling method, the ball milling process is intermittent. Before ball milling, the sample is first placed in a -80℃ freezer for 20 minutes, and then frozen for another 20 minutes after ball milling. The total ball milling time is 60 minutes.

4. A pharmaceutical preparation, characterized in that, The composition comprises the tolimidazole-polyamino acid amorphous composition according to any one of claims 1-3, and one or more pharmaceutically acceptable excipients.

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