CN115252608B - Compound medicament for treating cold and preparation method thereof - Google Patents
Compound medicament for treating cold and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a compound medicament for treating cold and a preparation method thereof. The preparation method comprises the following steps: mixing ibuprofen, phenylephrine hydrochloride, chlorphenamine maleate, microcrystalline cellulose, pregelatinized starch and a disintegrating agent, adding the boiled corn starch slurry water solution, the propyl gallate and the lactic acid water solution, performing wet granulation, and drying and granulating; adding a lubricant and a glidant into the granules after finishing to obtain total mixed granules, and sequentially tabletting and coating the total mixed granules to obtain the finished product; the using amount of the lactic acid is 0.01 to 1 percent of the total mass of all the components; the dosage of the propyl gallate is 0.23 to 0.28 percent of the total mass of all the components. According to the invention, by optimizing the using amount of lactic acid, the stability of the prepared ibuprofen hydrochloride tablet is more stable than that of a commercially available product; the invention adds the corn starch as the adhesive into the granules in the form of boiling slurry, so that the product disintegration and dissolution curve results are closer to those of products sold on the market, and the preparation method has low cost and simple process, and has obvious advantages compared with the prior art.
Description
Technical Field
The invention relates to a compound medicament for treating cold and a preparation method thereof, belonging to the technical field of medicinal preparations.
Background
The Bulorennin tablet is an oral compound preparation developed by a pflug pharmaceutical for treating cold, and consists of ibuprofen (200 mg/tablet), phenylephrine hydrochloride (10 mg/tablet) and chlorphenamine maleate (4 mg/tablet).
Ibuprofen is a nonsteroidal anti-inflammatory drug, can inhibit the synthesis of prostaglandin, and has analgesic, antipyretic and anti-inflammatory effects. Phenylephrine hydrochloride is an alpha-adrenoceptor agonist, and although a compound medicine which contracts blood vessels and eliminates nasal obstruction accompanying cold and rhinitis is used for a long time, the phenylephrine hydrochloride is not widely applied to anti-cold medicines in recent years. Chlorpheniramine maleate serving as a histamine H1 receptor antagonist can resist telangiectasia caused by anaphylaxis, reduce capillary permeability and relieve asthma caused by bronchial smooth muscle contraction, has a relatively long histamine resisting effect, also has an obvious central inhibition effect, and can increase the effects of narcotics, analgesics, hypnotics and local anesthetics.
The brelopanabasine tablet contains phenylephrine hydrochloride and chlorphenamine maleate, the phenylephrine hydrochloride structure contains phenolic hydroxyl and branched hydroxyl, the chemical stability is poor, the tablet is easy to degrade under the conditions of oxygen, high humidity, high temperature and alkalinity, and the degradation reaction can be accelerated by illumination; meanwhile, the ibuprofen and chlorphenamine maleate tablet contains chlorphenamine maleate, and maleic acid can interact with phenylephrine to generate phenylephrine-maleic acid adduct, so that the product quality is influenced. Therefore, it is very important to develop a stable prescription process of the ibuprofen and renin resistant tablet.
The currently known solution for solving the stability of phenylephrine hydrochloride and chlorpheniramine maleate refers to patent application CN101820862A, which is to dissolve phenylephrine hydrochloride, chlorpheniramine maleate and citric acid, and then spray-dry them onto the silicified surface of microcrystalline cellulose to solve the stability problem. However, the process is complicated in procedure, complex in control and high in production cost, and the applicability of commercial production needs to be improved. Therefore, on the premise of meeting the stability, the development of a process which is simple in process, low in production cost and easy for commercial production is very significant.
Disclosure of Invention
The invention aims to provide a compound medicament for treating cold and a preparation method thereof, solves the stability problems of phenylephrine hydrochloride and chlorphenamine maleate, and has the advantages of simple process, low production cost and easy commercial production.
The preparation method of the compound medicament for treating the cold provided by the invention comprises the following steps:
s1, mixing ibuprofen, phenylephrine hydrochloride, chlorphenamine maleate, microcrystalline cellulose, pregelatinized starch and a disintegrating agent, adding a boiled corn starch slurry aqueous solution, a propyl gallate and a lactic acid aqueous solution, performing wet granulation, and drying and granulating;
s2, adding a lubricant and a glidant into the granules after finishing to obtain total mixed granules, and sequentially tabletting and coating the total mixed granules to obtain the ibuprofen and chlorphenamine tablets;
the dosage of the lactic acid is 0.01-1 percent of the total mass of all the components, preferably 0.01-0.5 percent, 0.5-1 percent, 0.01 percent, 0.5 percent or 1 percent;
the dosage of the propyl gallate is 0.23-0.28% of the total mass of each component, the total mass of each component refers to the total mass of the ibuprofen, the phenylephrine hydrochloride, the chlorpheniramine maleate, the microcrystalline cellulose, the pregelatinized starch, the corn starch, the propyl gallate, the lactic acid, the lubricant and the glidant, and the dosage is preferably 0.23-0.25%, 0.25-0.28%, 0.23%, 0.25% or 0.28%.
In the above preparation method, the mass concentration of the corn starch slurry aqueous solution is 8 to 12%, preferably 8% or 12%.
In the preparation method, the temperature for boiling the soybean milk is 95-100 ℃, and the soybean milk is cooled to 45-50 ℃ after being boiled.
In the above preparation method, the disintegrant is at least one of croscarmellose sodium, crospovidone, hydroxypropyl cellulose and sodium carboxymethyl starch, preferably croscarmellose sodium.
In the preparation method, the lubricant is at least one of glyceryl behenate, magnesium stearate, sodium stearyl fumarate and hydrogenated castor oil, and preferably glyceryl behenate;
the glidant is at least one of talc, silicon dioxide and colloidal silicon dioxide, preferably colloidal silicon dioxide.
In the above preparation method, the mass composition of each component in the brelescence nersoon tablet is any one of 1) to 7) as follows:
1) 42 parts of ibuprofen; 2 parts of phenylephrine hydrochloride; 0.8 part of chlorpheniramine maleate; 5 parts of corn starch; 0.23-0.28 part of propyl gallate; 0.01-1 part of lactic acid; 25 parts of microcrystalline cellulose and 17 parts of pregelatinized starch; 5 parts of a disintegrating agent; 2 parts of a lubricant; 1 part of a flow aid;
2) 42 parts of ibuprofen; 2 parts of phenylephrine hydrochloride; 0.8 part of chlorpheniramine maleate; 5 parts of corn starch; 0.23 part of propyl gallate; 0.5 part of lactic acid; 25 parts of microcrystalline cellulose and 17 parts of pregelatinized starch; 5 parts of a disintegrating agent; 2 parts of a lubricant; 1 part of a flow aid;
3) 42 parts of ibuprofen; 2 parts of phenylephrine hydrochloride; 0.8 part of chlorpheniramine maleate; 5 parts of corn starch; 0.25 part of propyl gallate; 0.5 part of lactic acid; 25 parts of microcrystalline cellulose and 17 parts of pregelatinized starch; 5 parts of a disintegrating agent; 2 parts of a lubricant; 1 part of a flow aid;
4) 42 parts of ibuprofen; 2 parts of phenylephrine hydrochloride; 0.8 part of chlorpheniramine maleate; 5 parts of corn starch; 0.28 part of propyl gallate; 0.5 part of lactic acid; 25 parts of microcrystalline cellulose and 17 parts of pregelatinized starch; 5 parts of a disintegrating agent; 2 parts of a lubricant; 1 part of a flow aid;
5) 42 parts of ibuprofen; 2 parts of phenylephrine hydrochloride; 0.8 part of chlorpheniramine maleate; 5 parts of corn starch; 0.25 part of propyl gallate; 0.5 part of lactic acid; 25 parts of microcrystalline cellulose and 17 parts of pregelatinized starch; 5 parts of a disintegrating agent; 2 parts of a lubricant; 1 part of a flow aid;
6) 42 parts of ibuprofen; 2 parts of phenylephrine hydrochloride; 0.8 part of chlorpheniramine maleate; 5 parts of corn starch; 0.25 part of propyl gallate; 1 part of lactic acid; 25 parts of microcrystalline cellulose and 17 parts of pregelatinized starch; 5 parts of a disintegrating agent; 2 parts of a lubricant; 1 part of a flow aid;
7) 42 parts of ibuprofen; 2 parts of phenylephrine hydrochloride; 0.8 part of chlorpheniramine maleate; 5 parts of corn starch; 0.25 part of propyl gallate; 0.01 part of lactic acid; 25 parts of microcrystalline cellulose and 17 parts of pregelatinized starch; 5 parts of a disintegrating agent; 2 parts of a lubricant; 1 part of glidant.
The ibuprofen and renin resistant tablets prepared by the method also belong to the protection scope of the invention.
The stability of the brelesinimine tablets prepared by the method is superior to that of the products sold on the market. According to the invention, the stability of the prepared ibuprofen and renin resistant tablets is more stable than that of a commercially available product by optimizing the dosage of lactic acid. The invention adds the corn starch as the adhesive into the granules in a pulp boiling manner, so that the product disintegration and dissolution curve results are closer to those of products sold on the market, and the preparation method has low cost and simple process and has obvious advantages compared with the prior art.
Drawings
Figure 1 is a graph of the dissolution profile of a commercial tablet (Advil) versus self-product in water at 0.5% tween 80-ibuprofen.
FIG. 2 is a graph showing the dissolution profile of a commercially available tablet (Advil) versus its own formulation in 0.5% Tween 80 in water-phenylephrine hydrochloride.
FIG. 3 is a graph of the dissolution profile of a commercially available tablet (Advil) versus its own formulation in 0.5% Tween 80 in water-chlorpheniramine maleate.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1 preparation of Bulorennin tablets
Treating raw materials and auxiliary materials: sieving the raw materials and the auxiliary materials by a 40-mesh sieve; weighing 42 parts of ibuprofen, 2 parts of phenylephrine hydrochloride, 0.8 part of chlorpheniramine maleate, 25 parts of microcrystalline cellulose, 17 parts of pregelatinized starch, 5 parts of corn starch, 0.5 part of lactic acid, 0.25 part of propyl gallate, 5 parts of croscarmellose sodium, 2 parts of glyceryl behenate and 1 part of colloidal silicon dioxide; adding corn starch into boiled purified water of 100 deg.C, boiling to obtain 12% starch slurry water solution, and cooling to 50 deg.C. The propyl gallate and the lactic acid are dissolved in a proper amount of water for standby.
The preparation process comprises the following steps:
1) The ibuprofen, the phenylephrine hydrochloride, the chlorpheniramine maleate, the microcrystalline cellulose, the pregelatinized starch and the croscarmellose sodium are uniformly mixed in a wet granulator, then the starch slurry aqueous solution and the propyl gallate and lactic acid aqueous solution are added, stirring, shearing and granulating are started (the stirring speed is 120rpm, the shearing speed is 1000rpm, and the granulation is carried out for 5 minutes), and drying is carried out by using a fluidized bed at the temperature of 60 ℃. The resulting granules were sized using a 1.5mm sieve.
2) Adding glyceryl behenate and colloidal silicon dioxide into the whole granules, and mixing in a mixer. Tabletting the uniformly mixed total mixed particles by using a rotary tabletting machine, finally preparing a film coating premix (gastric soluble type) into a film coating premix aqueous solution with the concentration of 12%, and coating in a high-efficiency coating machine.
Example 2 preparation of Bulorennin tablets
The preparation was carried out in the same manner as in example 1, except that the amount of lactic acid used was 0.01 part.
Example 3 preparation of Broreninamine tablets
The preparation was carried out in the same manner as in example 1, except that the amount of lactic acid used was 1 part.
Example 4 preparation of Bulorennin tablets
The preparation was carried out in the same manner as in example 1 except that the amount of propyl gallate was 0.23 part.
Example 5 preparation of Bulorennin tablets
The preparation was carried out in the same manner as in example 1 except that the amount of propyl gallate was 0.28 part.
Example 6 preparation of Bulorennin tablets
The preparation method was the same as example 1 except that the concentration of the starch slurry was 8%.
Comparative example 1 preparation of Brorennin tablets
The preparation was as in example 1, except that the amount of lactic acid used was 2 parts.
Comparative example 2 preparation of Bulorenmin tablet
The preparation method is the same as that of example 1 except that the dosage of the propyl gallate is 0.1 part.
Comparative example 3 preparation of Brorennin tablet
Treating raw materials and auxiliary materials: sieving the raw materials and the auxiliary materials by a 40-mesh sieve; weighing 42 parts of ibuprofen, 2 parts of phenylephrine hydrochloride, 0.8 part of chlorpheniramine maleate, 25 parts of microcrystalline cellulose, 17 parts of pregelatinized starch, 5 parts of corn starch, 0.5 part of lactic acid, 0.25 part of propyl gallate, 5 parts of cross-linked sodium carboxymethyl cellulose, 2 parts of glyceryl behenate and 1 part of colloidal silicon dioxide; the propyl gallate and the lactic acid are dissolved in a proper amount of water for standby.
The preparation process comprises the following steps:
1) The ibuprofen, the phenylephrine hydrochloride, the chlorpheniramine maleate, the microcrystalline cellulose, the corn starch, the pregelatinized starch and the croscarmellose sodium are uniformly mixed in a wet granulator, the propyl gallate and the lactic acid aqueous solution are added, stirring, shearing and granulating are started (the stirring speed is 120rpm, the shearing speed is 1000rpm, and the granulating lasts for 5 minutes), and the drying is carried out by using a fluidized bed at the temperature of 60 ℃. The resulting granules were sized using a 1.5mm screen.
2) Adding glyceryl behenate and colloidal silica to the granules, and mixing in a mixer. Tabletting the uniformly mixed total mixed particles by using a rotary tabletting machine, finally preparing a film coating premix (gastric soluble type) into a film coating premix aqueous solution with the concentration of 12%, and coating in a high-efficiency coating machine.
Comparative example 4 preparation of Brorennin tablet
The preparation was identical to example 1, except that the starch slurry concentration was 5%.
The example 1 tablet, the example 2 tablet, the example 3 tablet, the example 4 tablet, the example 5 tablet, the example 6 tablet, the comparative example 1 tablet, the comparative example 2 tablet, the comparative example 3 tablet, the comparative example 4 tablet and a commercially available tablet (Advil) were left at a high temperature of 60 ℃ for 10 days, and the related substances 1 and 2 of the stability samples were examined using high performance liquid chromatography.
Method for detecting substance 1: measuring by high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general regulation 0512). Chromatographic conditions are as follows: using octadecylsilane chemically bonded silica as a filler, using water (the pH value is adjusted to 2.5 by using phosphoric acid) as a mobile phase A, and using acetonitrile as a mobile phase B, and performing gradient elution; the flow rate was 1.0ml per minute; the column temperature is 30 ℃; the detection wavelength is 214nm; the injection volume was 20. Mu.l.
The results of the test for substance 1 (ibuprofen system) are shown in table 1.
TABLE 1 summary of the original formulation and data on the factors affecting the product-related substance 1 (ibuprofen System)
Detection method of substance 2: measured according to high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general rules 0512). Chromatographic conditions are as follows: gradient elution was performed using octadecylsilane chemically bonded silica as a filler, acetonitrile-0.1% sodium octane sulfonate solution (pH adjusted to 3.0 with phosphoric acid) (20); flow rate was 1.5ml per minute; the column temperature is 30 ℃; the detection wavelength is 215nm; the injection volume was 20. Mu.l.
The results of the measurement of substance 2 (phenylephrine hydrochloride and chlorpheniramine maleate system) are shown in Table 2.
TABLE 2 summary of data on the original formulation and the influence factors of the self-preparation-related substances 2 (phenylephrine hydrochloride and chlorpheniramine maleate system)
From the results of tables 1 to 2, it can be seen that:
as can be seen from the comparison of the data of the related substances 1 of the tablets in examples 1 to 6 and the tablets in comparative examples 1 to 4 with the commercially available tablet (Advil), the related substance change of the ibuprofen system under high temperature conditions has no significant difference between different prescriptions.
As can be seen from the comparison of the data of the substance 2 in the tablets of example 1, example 2, example 3 and comparative example 1, when the dosage of lactic acid is 0.01-1%, the variation of each impurity of the tablets of different formulas under high temperature conditions meets the limit requirement, but when the dosage of lactic acid is 2%, the impurity related to lactic acid is obviously increased, and the maximum single impurity under high temperature conditions is beyond the limit requirement.
From the comparison of the data of substance 2 in the tablets of example 1, example 4, example 5 and comparative example 2, it can be seen that when the dosage of propyl gallate is 0.23-0.28%, the variation of each impurity of different prescription tablets under high temperature condition meets the limit requirement, but when the dosage of propyl gallate is 0.1%, the oxidation impurities PE-G and PE-F increase obviously under high temperature condition, and the oxidation impurity PE-F exceeds the limit requirement.
From the data of substance 2 after 0 day and 10 days at high temperature of the tablets of examples 1 to 6 and the commercially available tablets, it can be seen that when the amount of lactic acid is 0.01 to 1% and the amount of propyl gallate is 0.23 to 0.28%, the content of each impurity in the product is lower than that in the commercially available product, and the stability of the prepared sample is significantly higher than that in the commercially available tablets, which is a significant advantage.
The tablets of example 1, example 6, comparative example 3, comparative example 4 and a commercially available tablet (Advil) were examined for their dissolution profiles, and the content of the dissolution samples was checked by high performance liquid chromatography.
Detection conditions of the high performance liquid chromatography: measuring by high performance liquid chromatography (Chinese pharmacopoeia 2020 edition general rule 0512). Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler; gradient elution is carried out by taking phosphate buffer solution (1.0 g to 1000ml of water of monopotassium phosphate is taken, the pH value is adjusted to 2.3 by phosphoric acid) with pH2.3 as a mobile phase A and acetonitrile as a mobile phase B; flow rate 0.8ml per minute; the column temperature is 30 ℃; the detection wavelength is 215nm; the injection volume was 5. Mu.l.
The dissolution method comprises the following steps: the paddle method comprises sampling 10ml of water with a medium of 0.5% Tween 80 at a rotation speed of 50rpm for 5min, 10min, 15min, 20min, 30min, 45min and 60min, and filtering with high performance liquid chromatograph.
The disintegration in the dissolution cup is reported in table 3:
TABLE 3 summary of disintegration of commercially available tablets (Advil) with self-formulation in dissolution cups in aqueous medium of 0.5% Tween 80
The results of the dissolution profile test are shown in Table 4, and the dissolution profiles are shown in FIGS. 1 to 3, respectively.
TABLE 4 summary of dissolution curves of commercially available tablets (Advil) and self-formulations in 0.5% Tween 80 in water
From the results of tables 3 to 4, it can be seen that:
as can be seen from the comparison of the disintegration phenomena of the tablets of example 1, example 6, comparative examples 3 and 4 and the commercially available tablets, when the corn starch slurry concentration is 8 to 12%, the disintegration phenomena of the self-prepared product and the commercially available tablets are consistent; when the corn starch is not boiled, the self-prepared product has larger difference with the commercially available tablet in the phenomenon of disintegration. The addition mode of the corn starch has great influence on the disintegration phenomenon of the product.
As can be seen from the comparison of the dissolution curves of the tablets in example 1, example 6, comparative example 3 and comparative example 4 and the commercially available tablets, when the corn starch slurry concentration is 8-12%, the dissolution curves of the tablets in the product and the commercially available tablets are all larger than 50, and the dissolution is similar; when the concentration of the corn starch slurry is 5%, the self-prepared product is compared with a commercially available tablet in a dissolution curve, the f2 factor is less than 50, and the dissolution is dissimilar.
Claims (5)
1. A preparation method of high-stability bromelinamine tablets comprises the following steps:
s1, mixing ibuprofen, phenylephrine hydrochloride, chlorphenamine maleate, microcrystalline cellulose, pregelatinized starch and a disintegrating agent, adding a boiled corn starch slurry aqueous solution, a propyl gallate and a lactic acid aqueous solution, performing wet granulation, and drying and granulating;
the mass concentration of the corn starch slurry aqueous solution is 8 to 12 percent;
s2, adding a lubricant and a glidant into the whole granules to obtain total mixed granules, and sequentially tabletting and coating the total mixed granules to obtain the ibuprofen and chlorphenamine maleate tablets;
the mass composition of each component in the brompheniramine tablet is as follows:
42 parts of ibuprofen; 2 parts of phenylephrine hydrochloride; 0.8 part of chlorpheniramine maleate; 5 parts of corn starch; 0.23 to 0.28 portion of propyl gallate; 0.01 to 1 part of lactic acid; 25 parts of microcrystalline cellulose and 17 parts of pregelatinized starch; 5 parts of a disintegrating agent; 2 parts of a lubricant; 1 part of glidant.
2. The method of claim 1, wherein: the temperature of the boiling slurry is 95 to 100 ℃, and the boiling slurry is cooled to 45 to 50 ℃.
3. The production method according to claim 1 or 2, characterized in that: the disintegrant is at least one of croscarmellose sodium, crospovidone, hydroxypropyl cellulose and carboxymethyl starch sodium.
4. The production method according to claim 3, characterized in that: the lubricant is at least one of glyceryl behenate, magnesium stearate, sodium stearyl fumarate and hydrogenated castor oil;
the glidant is at least one of talcum powder, silicon dioxide and colloidal silicon dioxide.
5. A buchnerinine tablet prepared by the process of any of claims 1-4.
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Effective date of registration: 20230728 Address after: No. 7 Shanghai Street, Limin Economic and Technological Development Zone, Harbin City, Heilongjiang Province, 150500 Patentee after: HARBIN HUARUI BIOCHEMICAL PHARMACEUTICAL CO.,LTD. Address before: Building 7&29&30, Zhongke Yunguyuan, No. 79 Shuangying West Road, Changping District, Beijing, 102200 Patentee before: Beijing Sunshine Nuohe Pharmaceutical Research Co.,Ltd. |