A pyraquinone bis(hydroxynaphthyl)pyrazine tablet and its preparation method

Abstract

The method for preparing dihydroxynaphthylpyrazine-praziquantel tablets provided by this invention involves a pretreatment process in which dry starch is co-ground with dihydroxynaphthylpyrazine and praziquantel in the raw materials to a certain particle size. Compared with existing sieving and mixing methods, this method exhibits better dissolution effect and consistent dissolution behavior of the two drugs. It eliminates the need to increase the dosage, allowing both drugs in the tablets to safely and stably exert their exfoliative and toxic effects. While improving the dissolution effect, it also reduces the particle size requirements for dihydroxynaphthylpyrazine and praziquantel. The co-grinding method also avoids the electrostatic effect generated by praziquantel during sieving, improving the uniformity of praziquantel content and quality stability. The tablets provided by this invention have lower cost, uniform content, good dissolution effect, and stable quality.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing dihydroxynaphthylpyridinium pyrazinamide tablets. Background Technology

[0002] Paprikabine is a synthetic, broad-spectrum, and highly effective tetrahydropyrimidine nicotinic receptor agonist anthelmintic, with paprikabine as the active ingredient. Paprikabine is commonly used to treat gastrointestinal nematode infections and exhibits high activity against roundworms, hookworms, and pinworms. Praziquantel, an isoquinoline pyrazine derivative, is a highly effective anti-tapeworm and anti-trematode drug. Both antiparasitic drugs have significant anthelmintic effects and low toxicity. Their anthelmintic focus and mechanisms differ, and compounding them into tablets helps broaden their anthelmintic range. Both drugs are rapidly released into the gastrointestinal tract via oral administration to exert their anthelmintic effect. The concentration and dissolution level of their formulations affect the final efficacy. However, in the BCS classification of drugs, both paprikabine and praziquantel are classified as poorly soluble drugs; their disintegration and poor solubility are limiting factors for drug dissolution.

[0003] Under existing formulation procedures, the pretreatment method of sieving and mixing can cause praziquantel to generate static electricity. Due to its small proportion in the formulation, the drug cannot be evenly dispersed, resulting in uneven content. Simultaneously, the dissolution rates and levels of the two active pharmaceutical ingredients are not synchronized. Dihydropamoate is almost not absorbed in the gastrointestinal tract, and its dissolution rate and level are slower and lower than that of praziquantel. Its poor solubility is the main factor limiting the dissolution of dihydropamoate. The usual approach is to increase the recommended dosage to improve the amount of drug dissolved in the body to achieve therapeutic effects, which increases the risk of adverse reactions. Summary of the Invention

[0004] The main objective of this invention is to propose a pyraquinone tablet and its preparation method, aiming to solve the technical problems of asynchronous dissolution levels, poor dissolution, and uneven content when pyraquinone and pyraquinone are made into compound tablets in the prior art by improving the pretreatment method.

[0005] To achieve the above objectives, the present invention proposes a pyraquinone tablet and its preparation method, wherein the raw materials of the pyraquinone tablet include: pyraquinone, pyraquinone, dry starch and excipients;

[0006] The preparation steps include the following:

[0007] S1. Pretreatment for formulation: Dihydronaphthylpyridinium pyrantel, praziquantel, and dry starch are mixed and then ground together to obtain a particle size D. 90 At 1μm < D 90 Co-ground materials within the ≤5μm range enable the dry starch to form hydrogen bonds with bis(hydroxynaphthyl)pyrazine and praziquantel.

[0008] S2. The co-ground material obtained from the pretreatment is formulated, and an adjuvant is added during the formulation process to produce bis(hydroxynaphthyl)pyrazinidine tablets.

[0009] In the co-grinding process of this scheme, the pyrantel pamoate and praziquantel in the raw materials are thoroughly ground and collided together with the dry starch to a particle size D. 90 At 1μm < D 90 The ground material within the ≤5μm range undergoes hydrogen bonding. The infrared absorption spectrum of the co-ground material after KBr tableting shows absorption peaks at 3387.6, 3124.0, 2924.8, 1649.3, 1446.9, 1363.1, 1331.3, 1200.9, 1087.9, 996.3, 959.3, 904.8, 860.7, 713.15, 603.4, and 524.9 cm⁻¹. This hydrogen bonding helps improve the dissolution level of poorly soluble drugs. Regarding the formulation in step S2, those skilled in the art will know that conventional formulation methods such as wet tableting, dry tableting, and powder compression can all be used, and conventional excipients can be added during the formulation process.

[0010] Existing pretreatment methods using sieving and mixing suffer from electrostatic adsorption due to friction between praziquantel and the sieve during individual sieving. When there is a significant difference in particle size between pyrazinyl pamoate and praziquantel, smaller particles are easily adsorbed onto the surface of larger particles, leading to uneven mixing and causing inconvenience to the production process. Therefore, it is often necessary to select micronized pyrazinyl pamoate and praziquantel to improve drug dissolution and content uniformity. Typically, a minimum particle size D at the factory is required. 90 Below 20μm, micronized pyrantel pamoate and praziquantel are relatively expensive. This solution, however, does not employ existing sieving and mixing methods in the pretreatment process. Instead, it co-mills the pyrantel pamoate and praziquantel in the raw materials with dry starch to a specific particle size. This pretreatment method improves content uniformity, enhances the consistency and dissolution effect of the two poorly soluble anthelmintic drugs, and allows even 80μm finished drug powder to achieve a dissolution effect similar to 10μm micronized powder. This reduces the required finished particle size for pyrantel pamoate and praziquantel, further lowering costs.

[0011] Preferably, the raw material composition, by weight percentage, is: 50%–80% pamoate, 4.35%–7% praziquantel, 12%–42% dry starch, and 1.5%–9% excipients. Pamoate tablets prepared within this preferred dry starch content range exhibit higher dissolution rate and dissolution degree.

[0012] Furthermore, the formulation described in step S2 is prepared by wet granulation, in which adjuvants are added to produce dihydroxynaphthyl pyrazinazole tablets; the adjuvants include binders and lubricants. The adjuvants in this formulation may also include excipients and surfactants. Excipients such as lactose monohydrate can further improve the gloss and smoothness of the tablet formulation; surfactants such as sodium dodecyl sulfate can accelerate the dissolution rate of the drug. More preferably, the raw material composition, by weight percentage, is: dihydroxynaphthyl pyrazinazole 62%–72%, praziquantel 5.4%–6.3%, dry starch 18%–26%, binder 1%–6%, and lubricant 0.5%–3%. Within this weight range, the hydrogen bonding effect is more pronounced after co-grinding of dihydroxynaphthyl pyrazinazole, praziquantel, and dry starch, resulting in better dissolution of dihydroxynaphthyl pyrazinazole and praziquantel.

[0013] In one specific implementation, the wet granulation process in step S2 involves adding the co-ground material obtained from the pretreatment of the formulation to a binder, mixing them evenly to form a soft material, granulating, drying, and sizing the material, then adding a lubricant for total mixing, and finally compressing it into tablets to produce bis(hydroxynaphthylpyridinium) pyrazinazole tablets.

[0014] Preferably, the dry starch is at least one of corn starch, potato starch, cassava starch, and wheat starch.

[0015] Preferably, the binder solute is at least one selected from starch paste, sodium carboxymethyl cellulose, and polyvinylpyrrolidone, and the binder concentration is 2-16%. The granulation process improves the flowability of the material; binders with suitable viscosity at this concentration exhibit good granulation properties and are less prone to dispersion. More preferably, the binder solute is sodium carboxymethyl cellulose, and the binder concentration is 2-5%, resulting in higher viscosity and a smaller proportion of raw materials.

[0016] Preferably, the lubricant is at least one selected from magnesium stearate, talc, and micronized silica gel. Adding a lubricant reduces friction between the material and the tablet and the die, resulting in a more uniform pressure distribution during tableting. More preferably, the lubricant is magnesium stearate and micronized silica gel in a 1:1 weight ratio. Using a 1:1 mixture of magnesium stearate and micronized silica gel as a lubricant combines the advantages of both, helping to maintain the overall quality of the tablets. Simultaneously, the micronized silica gel is a hydrophilic excipient, which facilitates tablet dissolution.

[0017] Preferably, in step S1, the grinding method is ball milling, and the ratio of the mass of the grinding balls to the mass of the material is 5-6:1. This ball-to-material ratio helps improve the ball milling efficiency during co-grinding.

[0018] In one specific embodiment, a wet granulation method for preparing dihydroxynaphthylpyrazine praziquantel tablets is provided. The preparation method includes: weighing 62%–72% dihydroxynaphthylpyrazine, 5.4%–6.3% praziquantel, and 18%–26% dry starch by weight percentage, adding them separately to a grinding jar, adding grinding balls with an appropriate ball-to-material ratio, and setting the ball mill speed; performing thorough grinding under constant temperature conditions, and removing the grinding balls after grinding to obtain co-ground material; the diameter of the grinding balls is 3–5 mm; the ratio of the mass of the grinding balls to the mass of the material in the mill (ball-to-material ratio) is 4–7:1, preferably 5–6:1; the ball mill speed is 200–400 rpm, and the grinding time is 1–8 h, preferably 2–4 h.

[0019] Weigh the co-ground material obtained above, add an appropriate amount of binder, mix and stir evenly to form a soft material; granulate by sieving, dry, granulate by sieving, add the sieved lubricant and mix, and compress into tablets to obtain bis(hydroxynaphthyl)pyrazinidine tablets. Specifically, the binder solution concentration is 2-16%; the state of the prepared soft material should be "clumpy when grasped, but crumbles when touched"; the drying conditions are: forced air drying at 40-65℃ for 1-6 hours; the moisture content of the dried material should be 2-5%; the sieve mesh size of the lubricant is 100 mesh; and the hardness is controlled at 6-10 kg during tablet compression.

[0020] This application also provides a bis(hydroxynaphthyl)pyrazinol tablet, prepared by the method described in any of the above-described schemes. Therefore, it possesses at least all the effects of the aforementioned technical solutions, which will not be elaborated upon here.

[0021] In the preparation method of bis(hydroxynaphthyl)pyraquinone tablets provided by the present invention, dry starch is co-ground with bis(hydroxynaphthyl)pyraquinone and the raw materials to a particle size D. 90 At 1μm < D 90 The pretreatment process within the ≤5μm range, compared to existing sieving and mixing methods, exhibits better dissolution effects and more consistent dissolution behavior of the two drugs, allowing both drugs to safely and stably exert their exfoliative effects in the tablets. While improving dissolution efficiency, it also reduces the particle size requirements for pyraquinone and pamoate. The co-grinding method also avoids the electrostatic effects generated by pamoate during sieving, improving the uniformity and quality stability of pamoate content. The tablets provided by this invention have lower costs, more uniform content, better dissolution, and more stable quality. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 The infrared spectrum of the co-ground material in Example 1 of infrared spectroscopy test is shown.

[0024] Figure 2 A comparison graph of the dissolution curves for dissolution curve test example 1;

[0025] Figure 3 A comparison graph of the dissolution curves for dissolution curve test example 2;

[0026] Figure 4 A comparison graph of the dissolution curves for dissolution curve test example 3;

[0027] Figure 5 A comparison chart of dissolution curves for dissolution curve test example 4;

[0028] Figure 6 A comparison graph of the dissolution curves for dissolution curve test example 5;

[0029] Figure 7 The infrared spectrum of bis(hydroxynaphthyl)thiamethoxam is shown in Example 1 of infrared spectroscopy test.

[0030] Figure 8 The infrared spectrum of corn starch is shown in Example 1 of infrared spectroscopy test.

[0031] The realization of the purpose, functional features and advantages of this application will be further explained in conjunction with the embodiments and with reference to the accompanying drawings. Detailed Implementation

[0032] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. In addition, the technical solutions of the various embodiments can be combined with each other, but this must be based on the ability of those skilled in the art to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be considered that such combination of technical solutions does not exist and is not within the scope of protection claimed by the present invention.

[0033] The following are the main instruments used in the embodiments:

[0034]

[0035] The raw materials, corn starch, and auxiliaries used in the comparative analysis of this plan can be purchased from legitimate commercial channels. Except for the raw materials that have been mentioned as having differences, the same batch and specifications of raw materials are generally used for the same component.

[0036] Example 1

[0037] The raw material composition is as follows: 67% bis(hydroxynaphthyl)thiamethoxam, 5.8% praziquantel, 24.2% corn starch, 1% sodium carboxymethyl cellulose, 1% magnesium stearate, and 1% micronized silica gel.

[0038] The preparation steps are as follows:

[0039] S1, Weigh bis(hydroxynaphthyl)pyrantilic acid thiamethoxam, factory particle size D 90 Praziquantel (80 μm) and corn starch were mixed and added to a grinding jar. Grinding balls with a diameter of 5 mm and a ball-to-material mass ratio of 6:1 were added. The ball mill speed was set to 400 rpm. Under constant temperature conditions, the material was ground until the particle size D was reached. 90 The particle size is 4μm. After grinding, the grinding balls are removed to obtain the co-ground material.

[0040] S2. The ground material obtained from the pretreatment of the formulation is added to a 3% sodium carboxymethyl cellulose solution, mixed and stirred evenly to form a soft material, sieved and granulated, dried at 60℃, with the moisture content controlled at about 2-3% by mass, sieved and granulated, and then the sieved magnesium stearate and micronized silica gel are added and mixed together. The tablets are compressed to control the hardness of each tablet to 6-10 kg, to obtain bis(hydroxynaphthyl)pyrazinidine tablets.

[0041] Example 2

[0042] The same preparation steps as in Example 1 were used to prepare bis(hydroxynaphthyl)pyraquinone tablets, except that the raw material composition was as follows: 50% bis(hydroxynaphthyl)pyraquinone, 4.35% praziquantel, 40% potato starch, 3.65% polyvinylpyrrolidone (PVPk25), 1% magnesium stearate, and 1% micronized silica gel. The concentration of PVPk30 as a binder solution was 12%.

[0043] Example 3

[0044] The same preparation steps as in Example 1 were used to prepare bis(hydroxynaphthyl)pyraquinone tablets, except that the raw material composition was: 79% bis(hydroxynaphthyl)pyraquinone, 7% praziquantel, 12% tapioca starch, 1% sodium carboxymethyl cellulose, 0.5% magnesium stearate, and 0.5% micronized silica gel.

[0045] Example 4

[0046] The same raw material composition and preparation steps as in Example 1 were used to prepare pyraquinone tablets with a particle size of D at the factory. 90 The praziquantel is 10 μm in size.

[0047] Example 5

[0048] The same preparation steps as in Example 1 were used to prepare bis(hydroxynaphthyl)pyraquinone tablets, except that the raw material composition was: 71% bis(hydroxynaphthyl)pyraquinone, 6% praziquantel, 20% corn starch, 1% sodium carboxymethyl cellulose, 1% magnesium stearate, and 1% micronized silica gel.

[0049] Example 6

[0050] The same preparation steps as in Example 1 were used to prepare bis(hydroxynaphthyl)pyraquinone tablets, except that the raw material composition was as follows: 65% bis(hydroxynaphthyl)pyraquinone, 5.6% praziquantel, 23.4% corn starch, 1% sodium carboxymethyl cellulose, 1% magnesium stearate, 1% micronized silica gel, and 3% lactose monohydrate, wherein the lactose monohydrate was added together with the lubricant as an excipient.

[0051] Example 7

[0052] The same preparation steps as in Example 1 were used to prepare bis(hydroxynaphthyl)pyraquinone tablets, except that the raw material composition was: 67% bis(hydroxynaphthyl)pyraquinone, 5.8% praziquantel, 24.2% corn starch, 1% sodium carboxymethyl cellulose, and 2% magnesium stearate.

[0053] Comparative Example 1

[0054] The same raw material composition and preparation steps as in Example 1 were used to prepare bis(hydroxynaphthyl)pyrazinone tablets, except that: in step S1, bis(hydroxynaphthyl)pyrazinone was weighed and the particle size D was measured. 90 After 80 μm praziquantel and corn starch were separated, they were passed through a 60-mesh sieve and mixed to obtain a mixture.

[0055] Comparative Example 2

[0056] Bis(hydroxynaphthyl)pyrazinidine tablets were prepared using the same raw material composition and preparation steps as Comparative Example 1, the difference being that: the particle size D at the factory was selected. 90 The praziquantel is 10 μm in size.

[0057] Comparative Example 3

[0058] The same raw material composition and preparation steps as in Example 1 were used to prepare bis(hydroxynaphthyl)pyrazinone tablets, except that: in step S1, co-grinding was not used; instead, bis(hydroxynaphthyl)pyrazinone and particle size D were weighed. 90After adding 80μm praziquantel and corn starch separately to a grinding jar, grind them to a particle size of 4μm. Then mix the three materials obtained from the final grinding to obtain a total mixture.

[0059] Comparative Example 4

[0060] The same raw material composition and preparation steps as in Example 1 were used to prepare pyraquinone tablets with thiamethoxam acetaminophen, except that the material was ground to a particle size D. 90 It is 10μm.

[0061] Comparative Examples 5-1 and 5-2 were prepared using the same preparation steps as in Example 1, with the difference being the different content of corn starch in the raw material formulation, as detailed in the table below:

[0062] Comparative Example 5-1 Comparative Example 5-2 Corn starch content (%) 7 50

[0063] Other components were adaptively adjusted as follows:

[0064] Comparative Example 5-1: The raw material composition is as follows: 83% bis(hydroxynaphthyl)thiamethoxam, 7% praziquantel, 7% corn starch, 1% sodium carboxymethyl cellulose, 1% magnesium stearate, and 1% micronized silica gel.

[0065] Comparative Example 5-2: The raw material composition is as follows: 43% bis(hydroxynaphthyl)thiamethoxam, 4% praziquantel, 50% corn starch, 1% sodium carboxymethyl cellulose, 1% magnesium stearate, and 1% micronized silica gel.

[0066] The relevant materials or bis(hydroxynaphthyl)pyrazinone tablets obtained in the above comparative examples were subjected to relevant tests, as follows:

[0067] 1. Infrared spectroscopy testing method:

[0068] Fourier transform infrared (FTIR) spectroscopy analysis: Sample preparation was performed using the KBr pellet method. A small amount of sample was taken, mixed with KBr, and pelleted. The KBr pellet was used as a blank control. The sample was analyzed at 4000-4000 cm⁻¹. -1 Infrared absorption spectra were measured within the specified range.

[0069] 2. Content determination method:

[0070] Chromatographic conditions and system suitability test: Octadecylsilane-bonded silica gel was used as the stationary phase; mobile phase A was 0.005 mol / L sodium heptanesulfonate-0.02 mol / L potassium dihydrogen phosphate solution, and mobile phase B was 0.005 mol / L sodium heptanesulfonate-0.02 mol / L potassium dihydrogen phosphate solution-acetonitrile. Linear gradient elution was performed according to the table below, with detection wavelengths of 300 nm (pyrantel thiamethoxam) and 210 nm (praziquantel). The retention times for each component were approximately 4 minutes for pyrantel thiamethoxam and approximately 12 minutes for praziquantel.

[0071]

[0072]

[0073] Assay: Accurately weigh 10 tablets of this product, grind them into a fine powder, accurately weigh approximately one tablet, place it in a 100ml volumetric flask, dissolve and dilute to the mark with acetonitrile-acetic acid-water-diethylamine solution (94:2.5:2.5:1), sonicate, centrifuge, accurately measure 10ml of the supernatant, place it in a 20ml volumetric flask, dilute to the mark with 0.2mol / L disodium phosphate solution, and shake well to obtain the test solution; Separately, accurately weigh appropriate amounts of praziquantel reference standard and pyrantel pamoate reference standard, prepare a solution with praziquantel concentration of 0.2mg / ml and pyrantel pamoate concentration of 2.3mg / ml, dissolve and dilute to the mark with acetonitrile-acetic acid-water-diethylamine solution (94:2.5:2.5:1), accurately measure 10ml of the filtrate, add 10ml of 0.2mol / L disodium hydrogen phosphate buffer, and shake well to obtain the reference solution. Accurately measure 2 μL each of the test solution and the reference solution, and inject them separately into the liquid chromatograph, recording the chromatograms. Calculate the contents of praziquantel and pyrantel pamoate using the external standard method based on the peak areas of praziquantel and pyrantel pamoate, respectively.

[0074] 3. Content uniformity test method:

[0075] According to the content uniformity test method (Chinese Veterinary Pharmacopoeia 2020 Appendix 0941), take 10 tablets of the test sample, and determine the relative content of each tablet with the labeled amount as 100 according to the content determination method. Calculate the average content x and standard deviation S of the 10 tablets, as well as the absolute value A of the difference between the labeled amount and the mean. The calculated value A+2.2S indicates the quality of the tablet content uniformity.

[0076] 4. Dissolution curve determination method:

[0077] Take this product and perform the dissolution test according to the method (Chinese Veterinary Pharmacopoeia 2020 Appendix 0931 Method II). Use 900 ml of 0.1 mol / L hydrochloric acid solution (9→1000) containing 0.2% sodium dodecyl sulfate as the dissolution medium, and rotate at 50 rpm. When passing the sampling point, accurately take 2 ml of the filtrate, add 2 ml of acetonitrile, and shake well to obtain the test sample. Separately, take appropriate amounts of praziquantel reference standard and pyrantel pamoate reference standard, accurately weigh them, and prepare solutions with a praziquantel concentration of 2 μg / ml and a pyrantel pamoate concentration of 23 μg / ml. Dissolve them in 30% acetonitrile-acetic acid-water-diethylamine solution (94:2.5:2.5:1), dilute to the mark with 70% dissolution medium, accurately measure 2 ml of the filtrate, add 2 ml of acetonitrile, and shake well to obtain the reference solution. Under the chromatographic conditions specified in the Assay section, accurately measure 2 μL each of the test solution and the reference solution, inject them into the liquid chromatograph, and record the chromatograms. Calculate the dissolution amounts of praziquantel and pyrantel pamoate in each tablet using the peak areas of praziquantel and pyrantel pamoate, respectively, according to the external standard method. The limits are: praziquantel not less than 75% of the labeled amount, and pyrantel pamoate not less than 70% of the labeled amount.

[0078] Infrared spectroscopy test example 1:

[0079] Infrared spectroscopy was performed on the materials before and after co-grinding in step S1 of Example 1, and the spectra were obtained as follows: Figure 1 In Example 1, the infrared absorption spectra obtained by grinding the samples and pressing them with KBr were at 3387.6, 3124.0, 2924.8, 1649.3, 1446.9, 1363.1, 1331.3, 1200.9, 1087.9, 996.3, 959.3, 904.8, 860.7, 713.15, 603.4, and 524.9 cm⁻¹. -1 An absorption peak is observed at [location missing]. The characteristic wavenumber of the infrared spectrum of bis(hydroxynaphthyl)thiamethoxam is 1205 cm⁻¹. -1 1322cm -1 ,like Figure 7 The characteristic wavenumber of starch is 3378 cm⁻¹. -1 1387cm -1 ,like Figure 8 In the co-ground material, starch 3378 cm³ -1 The -OH peak shifts to lower wavenumbers, reaching 1387 cm⁻¹. -1 The intensity of the -OH stretching vibration peak at the position decreased, and the peak intensity of bis(hydroxynaphthyl)pyrantilic acid was 1205 cm⁻¹. -1 The CO stretching vibration peak at 1649 cm⁻¹ weakened, while the peak at 1649 cm⁻¹ decreased. -1 The C=O peak at the location remained unchanged, which is speculated to be because hydrogen bonds are formed between the -OH group in starch and the CO group in bis(hydroxynaphthyl)thiamethoxam, while the C=O group in bis(hydroxynaphthyl)thiamethoxam participates in intramolecular hydrogen bonding, thus the peak shape remained unchanged.

[0080] The dissolution rates of the piracetam pyraquinone tablets obtained in Examples 1-7 and Comparative Examples 1-5 were tested, and the dissolution data from 0 to 60 minutes are shown in the table below:

[0081]

[0082] Dissolution curve test example 1:

[0083] The dissolution profiles of the bis(hydroxynaphthyl)pyrazinazole tablets obtained in Example 1, Comparative Examples 1 and 3 were measured to compare the changes in dissolution behavior of bis(hydroxynaphthyl)pyrazinazole tablets obtained with different pretreatment methods. The dissolution profiles are shown below. Figure 2 .

[0084] Depend on Figure 2 It can be clearly seen that the dissolution curve slopes of Example 1 for both praziquantel and pamoate are greater than those of Comparative Example 1 and Comparative Example 3, indicating a faster dissolution rate. At 10 min, the drugs are in the rapid dissolution phase. Example 1 achieves a dissolution rate of 72% for both praziquantel and pamoate, while Comparative Example 3 and Comparative Example 1 show dissolution rates below 60% for both. Specifically, Comparative Example 1 shows 50% and 38% dissolution rates for praziquantel and pamoate, respectively, while Comparative Example 3 shows 58% and 50%, respectively. The dissolution rates of Comparative Example 3 and Comparative Example 1 are significantly lower than those of Example 1. At 60 min, the drugs are in the equilibrium dissolution phase, and the dissolution rates achieved by Comparative Example 1 and Comparative Example 3 are also significantly higher. Compared to Example 1, the dissolution rates of praziquantel and pyrantel pamoate in Example 1 both reached over 94%, while the dissolution rates of praziquantel and pyrantel pamoate in Comparative Example 1 were 86% and 83%, respectively, and the dissolution rates of praziquantel and pyrantel pamoate in Comparative Example 3 were 87% and 86%, respectively. It can be seen that the pretreatment method of this scheme can significantly improve the dissolution rate. At the same time, the dissolution behavior, i.e., the slope of the dissolution curve and the dissolution effect, of praziquantel and pyrantel pamoate in Example 1 are consistent, which accelerates the dissolution rate and improves the dissolution rate. However, in Comparative Examples 1 and 3, the dissolution curve of pyrantel pamoate is flatter than that of praziquantel, i.e., the dissolution rate is inconsistent, which disrupts the consistency of the dissolution behavior.

[0085] Dissolution curve test example 2:

[0086] Dissolution curves of the piracetam pyraquinone tablets obtained in Examples 1 and 4, and Comparative Examples 1-2 were measured. The changes in the dissolution behavior of piracetam pyraquinone tablets with different particle sizes from different manufacturers were compared, and the dissolution curves are shown below. Figure 3 .

[0087] Depend on Figure 3 It can be visually observed that the dissolution curves formed in Examples 1 and 4 almost overlap. This means that the pretreatment method of this scheme, used to treat praziquantel particles with factory particle sizes of 10 μm and 80 μm, achieves a high degree of consistency in dissolution behavior. The dissolution rates of Examples 1 and 4 in the 60-minute equilibrium dissolution stage are both 94.34%, significantly higher than the 86% and 90.5% of Comparative Examples 1 and 2, respectively. The slope of the praziquantel dissolution rate curve in Comparative Example 2 is larger than that in Comparative Example 1, and the dissolution rate in the 60-minute equilibrium dissolution stage is also higher. This demonstrates that the existing pretreatment method of sieving and mixing significantly affects the dissolution rate when using praziquantel with different factory particle sizes. Furthermore, the factory particle size D... 90 The dissolution effect of praziquantel at 10 μm is better than that of D. 90 80μm is better.

[0088] The praziquantel and pyrantel pamoate in Examples 1 and 4 showed highly similar dissolution rates and dissolution rates, indicating a high degree of consistency in their dissolution behavior. In contrast, the dissolution behaviors of Comparative Examples 1 and 2 were significantly inconsistent. This demonstrates that co-grinding, compared to existing sieving and mixing methods, can reduce the requirements for the particle size of the raw material at the factory, even for particle sizes D. 90 Even 80-micron praziquantel powder can achieve the same level as D. 90 The dissolution behavior of 10-micron praziquantel powder is highly consistent, and the dissolution effect is significantly better than existing sieving and mixing methods.

[0089] Dissolution curve test example 3:

[0090] The dissolution curves of the bis(hydroxynaphthyl)pyrazinamide tablets obtained in Examples 1-3 and Examples 5-7 were measured to compare the changes in dissolution effect and dissolution behavior of the bis(hydroxynaphthyl)pyrazinamide tablets under different raw material compositions. The dissolution curves are shown below. Figure 4 .

[0091] Depend on Figure 4 It can be seen that Examples 1-3 and Examples 5-6 are quite similar in terms of dissolution behavior. The dissolution curves all reach a dissolution rate of over 90% in the 60-minute equilibrium dissolution stage. Example 7 changed the lubricant compared to Example 1, and its dissolution curve slope was worse than that of Example 1. However, the dissolution rate reached at 60 minutes was very similar to that of Example 1. The dissolution rates of praziquantel and pyrantel dihydroxynaphthyl sulfadiazine in Example 1 were 94.34% and 96.8%, respectively. The dissolution rates of praziquantel and pyrantel dihydroxynaphthyl sulfadiazine in Example 7 were 94% and 96.5%, respectively. It can be seen that the lubricant, which is a compound of 1% magnesium stearate and 1% micronized silica gel, can accelerate the dissolution rate, but has little effect on the dissolution rate in the equilibrium dissolution stage.

[0092] Dissolution curve test example 4:

[0093] The dissolution curves of the bis(hydroxynaphthyl)pyrazinol tablets obtained in Example 1 and Comparative Example 4 were measured. The changes in the dissolution behavior of the bis(hydroxynaphthyl)pyrazinol tablets obtained from co-ground materials with different particle sizes were compared, and the dissolution curves are shown below. Figure 5 .

[0094] Depend on Figure 5 As can be seen, Example 1 (grinding particle size D) 90 The dissolution curves of praziquantel and dihydroxynaphthyl thiamethoxam (with a particle size of 4 μm) showed similar slopes and dissolution rates, indicating consistent dissolution behavior. At the 60-minute equilibrium dissolution stage, the dissolution rates of praziquantel and dihydroxynaphthyl thiamethoxam were 94.34% and 96.8%, respectively, which were also quite close. In contrast, Comparative Example 4 (with a particle size of D...)... 90 The dissolution curves of praziquantel tablets (with a particle size of 10 μm) and praziquantel showed inconsistent slopes. The dissolution curve of praziquantel was relatively flat at 20 min, which disrupted the consistency of dissolution behavior. At the equilibrium dissolution stage at 60 min, the dissolution rates of praziquantel and praziquantel were relatively close, at 89.5% and 90.34%, respectively. This indicates that the particle size of the co-ground material can only achieve consistent dissolution behavior for praziquantel and praziquantel within a certain range, while particle sizes outside the range cannot achieve good consistency in dissolution behavior.

[0095] Dissolution curve test example 5

[0096] The dissolution curves of the bis(hydroxynaphthyl)pyrazinamide tablets obtained in Example 1, Comparative Examples 5-1, and 5-2 were measured. The changes in the dissolution behavior of the bis(hydroxynaphthyl)pyrazinamide tablets with different corn starch contents were compared, and the dissolution curves are shown below. Figure 6 .

[0097] Depend on Figure 6It is evident that the dry starch content significantly affects the dissolution rate of both dihydroxynaphthylpyridinium pyrazinamide and praziquantel. Compared to Example 1 (corn starch content of 24.2%), the dissolution rate of praziquantel in Comparative Example 5-1 (corn starch content of 7%) decreased from 94.34% to 82% in the 60-minute equilibrium dissolution phase, while the dissolution rate of praziquantel in Comparative Example 5-2 (corn starch content of 50%) decreased from 94.34% to 89% in the 60-minute equilibrium dissolution phase. Meanwhile, the dissolution rate of dihydroxynaphthylpyridinium pyrazinamide in this phase decreased from 96% in Comparative Examples 5-1 and 5-2, respectively. The content of corn starch was reduced from 0.8% to 76% and 86%. Meanwhile, from the dissolution curves, when comparing the individual comparative examples, their dissolution behavior on dihydroxynaphthylpyridinium pyrazinol and praziquantel was relatively consistent. Among them, the curve slope of Comparative Example 5-1 was closer to that of Example 1, while the curve slope of Comparative Example 5-2 was significantly lower than that of Example 1 and Comparative Example 5-1. It can be seen that different corn starch contents affect the dissolution concentration and curve slope, but do not affect the consistency of the dissolution behavior of dihydroxynaphthylpyridinium pyrazinol and praziquantel. Within a certain range, corn starch content helps to improve the dissolution rate and the dissolution degree in the equilibrium dissolution stage in this scheme.

[0098] The content uniformity of Examples 1-3, 5, and Comparative Examples 1, 3, and 4 was tested, and the overall content uniformity table is as follows:

[0099]

[0100]

[0101] *: The value of A+2.2S indicates the uniformity of tablet content. S is the standard deviation of the relative content of 10 tablets; A is the absolute value of the difference between the labeled amount and the mean.

[0102] Example 1 of content uniformity test:

[0103] Now, taking the content uniformity of praziquantel as an example, the content uniformity of the praziquantel tablets obtained in Examples 1-3, Example 5, Comparative Example 1, and Comparative Example 3 was determined.

[0104] As can be seen from the content uniformity table, by comparing RSD and A+2.20S, the content uniformity of the tablets in Example 1 is significantly better than that in Comparative Example 1 and Comparative Example 3, and the quality is more stable. The RSD and A+2.20S values ​​of Examples 1-3 and Example 5 are all low, which indicates that the method of co-grinding with dry starch can obtain better content uniformity and stability than the existing sieving method.

[0105] Example 2 of content uniformity test:

[0106] The content uniformity of the bis(hydroxynaphthylpyridinium) tablets obtained in Example 1 and Comparative Example 4 was determined, and the changes in content uniformity of the bis(hydroxynaphthylpyridinium) tablets with different particle sizes after grinding were compared.

[0107] As can be seen from the data in the content uniformity table, by comparing RSD and A+2.20S, it is evident that Example 1 (the particle size D of the co-mixture) is... 90 The tablet content uniformity (with a particle size of 4 μm) was better than that of Comparative Example 4 (the mixture had a particle size of D). 90 The particle size of the co-mixture is 10 μm, and the quality is more stable, indicating that the grinding particle size D of the co-mixture is... 90 It affects both the uniformity of content and the stability of quality.

[0108] The above description is merely a preferred embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structural transformations made using the contents of the present invention under the inventive concept of the present invention, or direct / indirect applications in other related technical fields, are included within the patent protection scope of the present invention.

Claims

1. A method for preparing pyraquinone pamoate tablets, characterized in that, The dihydroxynaphthylpyrazine praziquantel tablets contain the following raw materials: dihydroxynaphthylpyrazine, praziquantel, dry starch, and excipients. By weight percentage, the raw material composition is: dihydroxynaphthylpyrazine 50%~80%, praziquantel 4.35%~7%, dry starch 12%~42%, and excipients 1.5%~9%. The preparation steps include the following: S1. Pretreatment for formulation: Dihydronaphthylpyridinium pyrantel, praziquantel, and dry starch are mixed and then ground together to obtain a particle size D. 90 At 1μm < D 90 Co-ground materials within the ≤5μm range enable the dry starch to form hydrogen bonds with bis(hydroxynaphthyl)pyrazine and praziquantel. S2. The co-ground material obtained from the pretreatment is formulated, and an adjuvant is added during the formulation process to produce bis(hydroxynaphthyl)pyrazinidine tablets.

2. The method for preparing bis(hydroxynaphthyl)pyraquinone tablets as described in claim 1, characterized in that, The formulation method described in step S2 is wet granulation, in which an adjuvant is added to prepare dihydroxynaphthylpyridinium pyrazinazole tablets; The additives include adhesives and lubricants.

3. The method for preparing bis(hydroxynaphthyl)pyraquinone tablets as described in claim 2, characterized in that: The raw materials, by weight percentage, consist of: 62%~72% pamoate, 5.4%~6.3% praziquantel, 18%~26% dry starch, 1%~6% binder, and 0.5%~3% lubricant.

4. The method for preparing bis(hydroxynaphthyl)pyraquinone tablets according to any one of claims 1 to 3, characterized in that, The dry starch is at least one of corn starch, potato starch, cassava starch, and wheat starch.

5. The method for preparing bis(hydroxynaphthyl)pyraquinone tablets as described in any one of claims 2 or 3, characterized in that: The wet granulation process in step S2 involves adding the co-ground material obtained from the pretreatment of the formulation to a binder, mixing them evenly to form a soft material, granulating, drying, and sizing, then adding a lubricant for total mixing, and finally compressing it into tablets to produce bis(hydroxynaphthylpyridinium) pyrazinazole tablets.

6. The method for preparing bis(hydroxynaphthyl)pyraquinone tablets as described in any one of claims 2 or 3, characterized in that, The adhesive solute is sodium carboxymethyl cellulose, and the adhesive concentration is 2-5%.

7. The method for preparing bis(hydroxynaphthyl)pyrazinidine tablets as described in any one of claims 2 or 3, characterized in that, The lubricant is at least one of magnesium stearate, talc, and micronized silica gel.

8. The method for preparing bis(hydroxynaphthyl)pyraquinone tablets as described in claim 7, characterized in that, The lubricant is magnesium stearate and micronized silica gel, and the weight ratio of magnesium stearate to micronized silica gel is 1:

1.

9. A pyraquinone dihydroxynaphthyl thiamethoxam tablet, characterized in that, It is prepared by the method of any one of claims 1 to 8 for preparing bis(hydroxynaphthyl)pyrazinidine tablets.

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