Compound paracetamol and amantadine hydrochloride capsule and preparation method thereof

Abstract

The invention discloses a compound paracetamol and amantadine hydrochloride capsule which is prepared from the following components in parts by weight: 250 parts of paracetamol, 100 parts of amantadine hydrochloride, 2 parts of chlorpheniramine maleate, 10 parts of calculus bovis factitius, 15 parts of caffeine, 20 parts of propyl gallate, a filler, a disintegrating agent, an adhesive and a lubricant. Propyl gallate is applied to prevent amantadine hydrochloride from being degraded into 2-aminoadamantane, the content of the impurity 2-aminoadamantane is reduced, and the filler, the disintegrating agent, the adhesive and the lubricant in a certain proportion are used for granulation, so that the problem that the dissolution rate is unqualified in the prior art is solved.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a compound acetaminophen capsule and a preparation method thereof. Background Art

[0002] Compound acetaminophen capsules are antipyretic and analgesic drugs used to relieve fever, headache, limb pain, sneezing, runny nose, nasal congestion, sore throat and other symptoms caused by common cold and influenza. They can also be used for the prevention and treatment of influenza. The components are acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, artificial bezoar and caffeine. Each capsule contains 250mg of acetaminophen, 100mg of amantadine hydrochloride, 2mg of chlorpheniramine maleate, 10mg of artificial bezoar and 15mg of caffeine. Among them, acetaminophen can inhibit the synthesis of prostaglandins and has antipyretic and analgesic effects; amantadine can resist "sub-A" influenza virus and inhibit virus reproduction; caffeine is a central nervous system stimulant, which can enhance the antipyretic and analgesic effects of acetaminophen, and can reduce the central nervous system inhibitory effects such as drowsiness and dizziness caused by other drugs; chlorpheniramine maleate is an antiallergic drug, which can relieve symptoms such as runny nose, nasal congestion and sneezing; artificial bezoar has antipyretic and sedative effects. The combination of various medicines to form a compound prescription can enhance the antipyretic and analgesic effects, and relieve or improve various symptoms caused by colds.

[0003] Chinese patent document CN1742751A discloses compound paracetamol and amantadine dripping pills and a preparation method thereof; the method comprises preparing and mixing paracetamol, amantadine hydrochloride, artificial bezoar, caffeine, chlorpheniramine maleate and a dripping pill base, heating to melt, stirring evenly, adding a coolant and dripping the mixture; since the method heats the mixture to a molten state at a high temperature, related substances may be produced in paracetamol, resulting in substandard product quality.

[0004] Chinese patent document CN106619593A discloses a method for improving the stability of drugs containing acetaminophen, wherein an aqueous solution containing catechin derivatives is added to the drugs containing acetaminophen. When acetaminophen and catechin derivatives exist at the same time, laccase preferentially catalyzes the oxidation of catechin derivatives to produce tea polyphenols, which hinders the laccase from catalyzing the oxidation of acetaminophen. However, the addition of catechin derivatives can easily lead to iron absorption disorders.

[0005] Chinese patent document CN1742751A discloses compound paracetamol and amantadine dripping pills and a preparation method thereof; the method comprises preparing and mixing paracetamol, amantadine hydrochloride, artificial bezoar, caffeine, chlorpheniramine maleate and a dripping pill base, heating to melt, stirring evenly, adding a coolant and dripping the mixture; since the method heats the mixture to a molten state at a high temperature, related substances may be produced in paracetamol, resulting in substandard product quality.

[0006] The currently disclosed preparation method still has the problem of uneven mixing of the main drug and the auxiliary materials during the granulation process, resulting in uneven content of chlorpheniramine maleate in the finished product, large content fluctuations, and unstable product quality; in addition, the process temperature is high, causing acetaminophen to decompose to produce toxic para-aminophenol, and the content of related substances is high; the operation steps are many, cumbersome, and the production cost is high, which is not conducive to large-scale industrial production. It can be seen that the current research is focused on the stability of acetaminophen. The applicant believes in the long-term research that the content ratio of amantadine hydrochloride in the present invention is also very high, and the presence of related substances in amantadine hydrochloride may be related to the influence of other excipients in the synthesis process or preparation process of amantadine hydrochloride (Chen Pei, Zhai Yu. Determination of related substances in amantadine hydrochloride tablets by GC method [J]. China Pharmacy, 2011, 22(41): 3896-3898. Lou Yongjun, Chen Shuang, Tao Qiaofeng. Determination of related substances in amantadine hydrochloride by capillary gas chromatography [J]. Journal of Pharmaceutical Analysis, 2011, 31(03): 493-495.). Summary of the invention

[0007] In view of the deficiencies in the prior art, the present invention provides a compound acetaminophen capsule and a preparation method thereof, which successfully solves the problems of unsatisfactory drug disintegration, low drug solubility, poor drug stability, low human bioavailability, etc. through innovative excipient selection and optimized excipient ratio.

[0008] The technical solution of the present invention is as follows:

[0009] A compound acetaminophen capsule is prepared from the following components in parts by weight: 250 parts of acetaminophen, 100 parts of amantadine hydrochloride, 2 parts of chlorpheniramine maleate, 10 parts of artificial bezoars, 15 parts of caffeine, 20 parts of propyl gallate, a filler, a disintegrant, a binder and a lubricant.

[0010] The filler of the compound acetaminophen capsule is one or more of starch, lactose, anhydrous lactose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl methylcellulose, silicic anhydride, and calcium phosphate, preferably microcrystalline cellulose and calcium phosphate, which are 15 parts of microcrystalline cellulose and 10 parts of calcium phosphate respectively.

[0011] In the compound acetaminophen capsule, the disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, sodium glycolate starch, pregelatinized starch, and low-substituted hydroxypropyl cellulose, preferably 15 parts of pregelatinized starch.

[0012] The compound acetaminophen capsules, the binder is one or more of hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, guar gum, xanthan gum, xylitol, glucomannan, polyvinyl pyrrolidone, preferably 5 parts of polyvinyl pyrrolidone.

[0013] The lubricant of the compound acetaminophen capsule comprises magnesium stearate.

[0014] The compound acetaminophen capsule is prepared from the following components in parts by weight: 250 parts of acetaminophen, 100 parts of amantadine hydrochloride, 2 parts of chlorpheniramine maleate, 10 parts of artificial bezoar, 15 parts of caffeine, 20 parts of propyl gallate, 15 parts of microcrystalline cellulose, 10 parts of calcium phosphate, 15 parts of pregelatinized starch and 5 parts of polyvinyl pyrrolidone.

[0015] The preparation method of the compound paracetamol and amantadine capsules:

[0016] (1) acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, caffeine, microcrystalline cellulose, calcium phosphate, and pregelatinized starch are crushed and sieved for later use, and artificial bezoar is sieved for later use;

[0017] (2) Weigh propyl gallate and polyvinyl pyrrolidone according to the ratio, dissolve propyl gallate and polyvinyl pyrrolidone in a small amount of ethanol, and set aside;

[0018] (3) weighing acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, caffeine, microcrystalline cellulose, calcium phosphate, and pregelatinized starch according to the ratio, mixing them evenly, then adding the propyl gallate and polyvinyl pyrrolidone ethanol solution prepared in step (2), stirring and mixing evenly to form a soft material, and granulating to obtain wet granules;

[0019] (4) granulating the wet granules prepared in step (3) into wet micropellets by shot blasting, and sieving;

[0020] (5) drying the wet pellets obtained in step (4) to obtain compound acetaminophen and amantadine pellets, and filling the pellets into capsules to obtain compound acetaminophen and amantadine capsules.

[0021] Compared with the prior art, the compound acetaminophen capsule and the preparation method thereof according to the present invention have the following advantages and significant progress:

[0022] (1) The compound acetaminophen capsule of the present invention uses propyl gallate to prevent the degradation of amantadine hydrochloride into 2-aminoadamantane, thereby reducing the content of the impurity 2-aminoadamantane.

[0023] (2) The present invention uses a certain proportion of filler, disintegrant, binder and lubricant for granulation, which solves the problem of unqualified dissolution in the prior art. DETAILED DESCRIPTION

[0024] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content of the present invention, those skilled in the art can make various changes or modifications to the present invention, but these equivalent forms fall within the scope limited by the appended claims of the application equally.

[0025] Embodiment 1:

[0026] Take 250 parts of acetaminophen, 100 parts of amantadine hydrochloride, 2 parts of chlorpheniramine maleate, 10 parts of artificial bezoar, 15 parts of caffeine, 20 parts of propyl gallate, 15 parts of microcrystalline cellulose, 10 parts of calcium phosphate, 15 parts of pregelatinized starch, and 5 parts of polyvinyl pyrrolidone, and prepare the mixture as follows:

[0027] (1) acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, caffeine, microcrystalline cellulose, calcium phosphate, and pregelatinized starch are crushed and sieved for later use, and artificial bezoar is sieved for later use;

[0028] (2) Weigh propyl gallate and polyvinyl pyrrolidone according to the ratio, dissolve propyl gallate and polyvinyl pyrrolidone in a small amount of ethanol, and set aside;

[0029] (3) weighing acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, caffeine, microcrystalline cellulose, calcium phosphate, and pregelatinized starch according to the ratio, mixing them evenly, then adding the propyl gallate and polyvinyl pyrrolidone ethanol solution prepared in step (2), stirring and mixing evenly to form a soft material, and granulating to obtain wet granules;

[0030] (4) granulating the wet granules prepared in step (3) into wet micropellets by shot blasting, and sieving;

[0031] (5) drying the wet pellets obtained in step (4) to obtain compound acetaminophen pellets, and filling the pellets into capsules to obtain compound acetaminophen capsules.

[0032] Embodiment 2:

[0033] Take 250 parts of acetaminophen, 100 parts of amantadine hydrochloride, 2 parts of chlorpheniramine maleate, 10 parts of artificial bezoar, 15 parts of caffeine, 20 parts of propyl gallate, 10 parts of microcrystalline cellulose, 15 parts of calcium phosphate, 5 parts of pregelatinized starch, and 5 parts of polyvinyl pyrrolidone, and prepare the mixture as follows:

[0034] (1) acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, caffeine, microcrystalline cellulose, calcium phosphate, and pregelatinized starch are crushed and sieved for later use, and artificial bezoar is sieved for later use;

[0035] (2) Weigh propyl gallate and polyvinyl pyrrolidone according to the ratio, dissolve propyl gallate and polyvinyl pyrrolidone in a small amount of ethanol, and set aside;

[0036] (3) weighing acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, caffeine, microcrystalline cellulose, calcium phosphate, and pregelatinized starch according to the ratio, mixing them evenly, then adding the propyl gallate and polyvinyl pyrrolidone ethanol solution prepared in step (2), stirring and mixing evenly to form a soft material, and granulating to obtain wet granules;

[0037] (4) granulating the wet granules prepared in step (3) into wet micropellets by shot blasting, and sieving;

[0038] (5) drying the wet pellets obtained in step (4) to obtain compound acetaminophen and amantadine pellets, and filling the pellets into capsules to obtain compound acetaminophen and amantadine capsules.

[0039] Embodiment 3:

[0040] Take 250 parts of acetaminophen, 100 parts of amantadine hydrochloride, 2 parts of chlorpheniramine maleate, 10 parts of artificial bezoar, 15 parts of caffeine, 20 parts of propyl gallate, 25 parts of dextrin, 15 parts of pregelatinized starch, and 5 parts of polyvinyl pyrrolidone, and prepare the mixture as follows:

[0041] (1) acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, caffeine, microcrystalline cellulose, calcium phosphate, and pregelatinized starch are crushed and sieved for later use, and artificial bezoar is sieved for later use;

[0042] (2) Weigh propyl gallate and polyvinyl pyrrolidone according to the ratio, dissolve propyl gallate and polyvinyl pyrrolidone in a small amount of ethanol, and set aside;

[0043] (3) weighing acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, caffeine, dextrin, and pregelatinized starch according to the ratio, mixing them evenly, then adding the propyl gallate and polyvinylpyrrolidone ethanol solution prepared in step (2), stirring and mixing evenly to form a soft material, and granulating to obtain wet granules;

[0044] (4) granulating the wet granules prepared in step (3) into wet micropellets by shot blasting, and sieving;

[0045] (5) drying the wet pellets obtained in step (4) to obtain compound acetaminophen and amantadine pellets, and filling the pellets into capsules to obtain compound acetaminophen and amantadine capsules.

[0046] Comparative Example 1:

[0047] Take 250 parts of acetaminophen, 100 parts of amantadine hydrochloride, 2 parts of chlorpheniramine maleate, 10 parts of artificial bezoar, 15 parts of caffeine, 15 parts of microcrystalline cellulose, 10 parts of calcium phosphate, 15 parts of pregelatinized starch, and 5 parts of polyvinyl pyrrolidone, and prepare the mixture as follows:

[0048] (1) acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, caffeine, microcrystalline cellulose, calcium phosphate, and pregelatinized starch are crushed and sieved for later use, and artificial bezoar is sieved for later use;

[0049] (2) Weigh polyvinyl pyrrolidone according to the ratio, dissolve the polyvinyl pyrrolidone in a small amount of ethanol, and set aside;

[0050] (3) weighing acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, caffeine, microcrystalline cellulose, calcium phosphate, and pregelatinized starch according to the proportion, mixing them evenly, then adding the polyvinyl pyrrolidone ethanol solution prepared in step (2), stirring and mixing evenly to form a soft material, and granulating to obtain wet granules;

[0051] (4) granulating the wet granules prepared in step (3) into wet micropellets by shot blasting, and sieving;

[0052] (5) drying the wet pellets obtained in step (4) to obtain compound acetaminophen and amantadine pellets, and filling the pellets into capsules to obtain compound acetaminophen and amantadine capsules.

[0053] Embodiment 4:

[0054] Take the compound paracetamol and amantadine capsules prepared in Example 1 and Comparative Example 1, and establish a method for determining the related substances of amantadine hydrochloride by capillary column gas chromatography, wherein the chromatographic column is HP-5 (30m×0.32mm, 0.25μm); the carrier gas is nitrogen; the hydrogen flame ionization detector (FID), the injection port temperature is 200°C, and the detector temperature is 300°C; the column temperature is programmed, the initial temperature is 80°C, maintained for 4min, and then increased at 12°C·min -1 Heat to 280°C and maintain for 15 min; carrier gas flow rate is 1.0 mL min -1 ; Solution injection, the injection volume is 2μL.

[0055] Accurately weigh 0.2 g of 2-aminoadamantane standard, place it in a separatory funnel, and add 5 mol·L -1 20mL of sodium hydroxide solution was extracted with chloroform by shaking in batches (15 and 10mL), and the solution was allowed to stand for separation; the chloroform layer was taken, and an appropriate amount of anhydrous sodium sulfate was added to shake and dehydrate, and then filtered; the filtrate was placed in a 25mL volumetric flask, diluted to the mark with chloroform, and shaken well to prepare the standard stock solution. 1mL of the stock solution was accurately measured and placed in a 10mL volumetric flask, and diluted to the mark with chloroform, and shaken well to prepare the standard stock solution.

[0056] Take 20 capsules of compound paracetamol and amantadine capsules prepared in Example 1 and Comparative Example 1, take the contents, accurately weigh, grind, accurately weigh an appropriate amount (equivalent to 0.1 g of 2-aminoadamantane), place in a separatory funnel, add 5 mol·L -1 20mL of sodium hydroxide solution was extracted with chloroform by shaking in batches (15 and 10mL). The chloroform layer was taken and an appropriate amount of anhydrous sodium sulfate was added to shake and dehydrate. After filtering, the filtrate was placed in a 25mL volumetric flask, diluted to the scale with chloroform, and shaken well as the test solution.

[0057] Take 2 μL of the test solution and 2-aminoadamantane standard respectively, inject them into the gas chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 20% of the full scale, and the separation degree between the amantadine hydrochloride peak and the 2-aminoadamantane peak should be not less than 20. Record the chromatogram and calculate the 2-aminoadamantane content by the normalization method. The results are shown in Table 1.

[0058] Table 1 2-aminoadamantane content in Example 1 and Comparative Example 1

[0059] sample 2-Aminoadamantane(%) Example 1 0.038** Comparative Example 1 0.152

[0060] Compared with the control group 1 *P<0.05, **P<0.01

[0061] As shown in Table 1, the addition of propyl gallate can reduce the content of related substances in amantadine hydrochloride, which is beneficial to improving the quality of the drug, which may be related to the antioxidant properties of propyl gallate.

[0062] Experimental Example 5: Dissolution Test of Compound Paracetamol and Amantadine Capsules of the Present Invention

[0063] 1. Dissolution test of acetaminophen;

[0064] According to the sampling method specified in the National Pharmacopoeia, the compound paracetamol and amantadine capsules prepared in the above-mentioned embodiment 1, embodiment 2, embodiment 3, and comparative example 1 were respectively subjected to the dissolution and release determination method (General Rule 0931 Method 1), with 24 ml of dilute hydrochloric acid added with water to 1000 ml as the dissolution medium, the rotation speed was 100 revolutions per minute, and the operation was carried out in accordance with the law. After 5, 10, 20, 30, and 45 minutes, the solution was filtered, and an appropriate amount of the subsequent filtrate was accurately measured and diluted with 0.04% sodium hydroxide solution to form a solution containing 5-10 μg of paracetamol per 1 ml. According to the ultraviolet-visible spectrophotometry (General Rule 0401), the absorbance was measured at a wavelength of 257 nm, and the absorption coefficient (E of C8H9NO2) was 0. 1cm 1％ ) is 715 to calculate the dissolution amount of each tablet. The limit is 80% of the labeled amount, which should meet the regulations. The results are shown in Table 2.

[0065] 2. Dissolution test of amantadine hydrochloride;

[0066] According to the sampling method specified in the National Pharmacopoeia, the above-mentioned Example 1, Example 2, Example 3, and Comparative Example 1 capsules were respectively subjected to the dissolution and release determination method (General Rule 0931 Method 1), using 24 ml of dilute hydrochloric acid and water to 1000 ml as the medium, the speed was 100 revolutions per minute, and the operation was carried out in accordance with the law. After 5, 10, 20, 30, and 45 minutes, the solution was filtered, and an appropriate amount of the subsequent filtrate was accurately measured and placed in a 100 ml volumetric bottle, water was added to dissolve and diluted to the scale, shaken, filtered with dry filter paper, and 50 ml of the subsequent filtrate was accurately measured, 2 drops of bromophenol blue indicator solution were added, 36% acetic acid solution was added to change the solution from blue-purple to yellow-green, 6 drops of bromophenol blue indicator solution were added, and the solution was titrated with silver nitrate titration solution (0.1 mol / L) until the precipitate was gray-purple. Each 1 ml of silver nitrate titration solution (0.1 mol / L) is equivalent to 18.77 mg of C 10 H 17 The results are shown in Table 2.

[0067] Table 2 Dissolution of compound paracetamol and amantadine capsules of the present invention

[0068]

[0069] The above experimental results show that the compound acetaminophen and amantadine hydrochloride capsules prepared by the process of Example 1 are tested for the solubility of acetaminophen and amantadine hydrochloride in the compound acetaminophen and amantadine hydrochloride capsules and the data are analyzed, indicating that Example 1 is completely dissolved at 45 minutes, while Examples 2 and 3 have slightly decreased dissolution at 45 minutes due to different proportions of filler, disintegrant and binder. Comparative Example 1 cannot be completely dissolved within 45 minutes due to the absence of propyl gallate. This indicates that a specific proportion of 15 parts of microcrystalline cellulose, 10 parts of calcium phosphate, 15 parts of pregelatinized starch, 5 parts of polyvinyl pyrrolidone, and 20 parts of propyl gallate can completely dissolve acetaminophen and amantadine hydrochloride at 45 minutes, indicating that the specific combination and specific proportion of filler, disintegrant and binder, as well as the selection of propyl gallate, have a very significant effect on the solubility of acetaminophen and amantadine hydrochloride, and the setting of the auxiliary materials and process parameters used in the present invention is reasonable.

[0070] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound acetaminophen capsule, characterized in that: The invention is prepared from the following components in parts by weight: 250 parts of acetaminophen, 100 parts of amantadine hydrochloride, 2 parts of chlorpheniramine maleate, 10 parts of artificial bezoar, 15 parts of caffeine, 20 parts of propyl gallate, a filler, a disintegrant, a binder and a lubricant.

2. The compound acetaminophen capsule according to claim 1, characterized in that: The filler is one or more of starch, lactose, anhydrous lactose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl methylcellulose, silicic anhydride, and calcium phosphate, preferably microcrystalline cellulose and calcium phosphate, which are 15 parts of microcrystalline cellulose and 10 parts of calcium phosphate respectively.

3. The compound acetaminophen capsule according to claim 1, characterized in that: The disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, sodium glycolate starch, pregelatinized starch, and low-substituted hydroxypropyl cellulose, preferably 15 parts of pregelatinized starch.

4. The compound acetaminophen capsule according to claim 1, characterized in that: The binder is one or more of hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, guar gum, xanthan gum, xylitol, glucomannan, and polyvinyl pyrrolidone, preferably 5 parts of polyvinyl pyrrolidone.

5. The compound acetaminophen capsule according to claim 1, characterized in that: The lubricant is magnesium stearate.

6. The compound acetaminophen capsule according to claim 1, characterized in that: The invention is prepared from the following components in parts by weight: 250 parts of acetaminophen, 100 parts of amantadine hydrochloride, 2 parts of chlorpheniramine maleate, 10 parts of artificial bezoar, 15 parts of caffeine, 20 parts of propyl gallate, 15 parts of microcrystalline cellulose, 10 parts of calcium phosphate, 15 parts of pregelatinized starch and 5 parts of polyvinyl pyrrolidone.

7. The compound acetaminophen capsule according to claim 6, characterized in that: The preparation method comprises the following steps: (1) acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, caffeine, microcrystalline cellulose, calcium phosphate, and pregelatinized starch are crushed and sieved for later use, and artificial bezoar is sieved for later use; (2) Weigh propyl gallate and polyvinyl pyrrolidone according to the ratio, dissolve propyl gallate and polyvinyl pyrrolidone in a small amount of ethanol, and set aside; (3) weighing acetaminophen, amantadine hydrochloride, chlorpheniramine maleate, caffeine, microcrystalline cellulose, calcium phosphate, and pregelatinized starch according to the ratio, mixing them evenly, then adding the propyl gallate and polyvinyl pyrrolidone ethanol solution prepared in step (2), stirring and mixing evenly to form a soft material, and granulating to obtain wet granules; (4) granulating the wet granules prepared in step (3) into wet micropellets by shot blasting, and sieving; (5) drying the wet pellets obtained in step (4) to obtain compound acetaminophen pellets, and filling the pellets into capsules to obtain compound acetaminophen capsules.

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