Guaiol pentopromethazine controlled release tablet and preparation method thereof

Abstract

The invention relates to the technical field of medicines, and provides a guaiol pentopromethazine controlled release tablet and a preparation method thereof. The guaiol pentopromethazine controlled release tablet comprises a tablet core and a coating for coating the tablet core, the tablet core comprises the following raw material components: a first active pharmaceutical ingredient, a skeleton carrier, an osmotic pressure accelerant and a disintegrating agent; the coating comprises the following raw material components: a film-forming material and a second active pharmaceutical ingredient; the first medicine active component and the second medicine active component both comprise potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride. The invention has the beneficial effects that the controlled release tablet provided by the invention can realize relative stability of blood concentration, so as to solve the problems of'crest 'and'trough' phenomena of blood concentration caused by single administration in the clinical use process and short drug release action time, improve the clinical curative effect and reduce the cost. The adverse reaction caused by overhigh peak stage of the blood concentration is reduced, and the drug resistance phenomenon is reduced.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical technology, and in particular relates to a guaiac-pentol-promethazine controlled-release tablet and a preparation method thereof. Background Art

[0002] Guaifenpentol promethazine granules, also known as cold and cough granules, have antitussive and expectorant effects. The national drug standard [WS-1001-(HD-483)-2002] discloses the product's prescription, properties, identification, inspection, content determination and other standards. Years of clinical application have proved that the granules have good antitussive and expectorant functions, but the granules contain promethazine hydrochloride, which causes many adverse reactions and limits the clinical application of the granules.

[0003] Sustained-release preparations can delay drug release and release drugs at a constant or non-constant rate as required in a specified release medium. Compared with ordinary preparations, sustained-release preparations can greatly improve patient compliance, extend the half-life of drugs, and reduce the number of medications; fixed-release drugs can further control the drug release rate under the condition of fully evaluating the drug elimination rate and half-life to balance blood drug concentration and avoid peak and valley phenomena, which is conducive to reducing adverse drug reactions, reducing drug resistance, and even reducing the number of medications, improving compliance in clinical drug applications, etc.

[0004] Since the late 1950s, with the development of modern pharmaceutical preparation technology, the theory and technology of oral sustained-release preparations have become increasingly mature, and oral sustained-release preparations have also occupied a huge market share. Among sustained-release technologies, osmotic pump technology is considered to be the most ideal oral controlled-release preparation at present. It uses osmotic pressure as the release power of active drugs and controls drug release with zero-order kinetics, so that it is not affected by gastrointestinal pH and gastrointestinal motility, and has good in vitro and in vivo correlation. In addition, osmotic pump preparations can achieve sustained release of drugs and reduce fluctuations in blood drug concentrations, thereby reducing drug toxicity and drug resistance. Although sustained-release preparations can prolong the release and action time of drugs, they have an uneven drug release rate that changes with time. Although the fluctuation of blood drug concentration is significantly smaller than that of regular-release preparations, it is significantly higher than that of osmotic pump controlled-release preparations. Its clinical advantages are still significantly insufficient compared to osmotic pump controlled-release preparations. Summary of the invention

[0005] The purpose of the present application is to provide a guaiac-pentol-promethazine controlled-release tablet and a preparation method thereof, aiming to solve the problems of uneven drug release rate and unstable blood drug concentration in clinical use of existing controlled-release tablets.

[0006] In order to achieve the above application purpose, the technical solution adopted in this application is as follows:

[0007] In a first aspect of an embodiment of the present application, there is provided a guaiac-pentol promethazine controlled-release tablet, comprising a tablet core and a coating covering the tablet core; the tablet core comprises the following raw material components: a first active pharmaceutical ingredient, a skeleton carrier, an osmotic pressure enhancer and a disintegrant;

[0008] The coating comprises the following raw material components: a film-forming material and a second active pharmaceutical ingredient;

[0009] The first active pharmaceutical ingredient and the second active pharmaceutical ingredient both include raw materials potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride.

[0010] According to some embodiments of the guaiac pentol promethazine controlled-release tablets described in the present application, the tablet core comprises the following raw material components in parts by weight: 7-12 parts of the first active pharmaceutical ingredient, 13-23 parts of the skeleton carrier, 4-8 parts of the osmotic pressure enhancer and 2-4 parts of the disintegrant;

[0011] The coating comprises the following raw material components in parts by weight: 3-6 parts of film-forming material and 1-3 parts of the second active ingredient of the drug.

[0012] According to some embodiments of the guaiacol pentol promethazine controlled-release tablets described in the present application, the weight proportions of potassium guaiacol sulfonate, pentol citrate and promethazine hydrochloride contained in the first active pharmaceutical ingredient are as follows:

[0013] 6-12 parts of the potassium guaiacol sulfonate, 0.5-0.9 parts of the pentoxyverine citrate, and 0.2-0.5 parts of the promethazine hydrochloride;

[0014] According to some embodiments of the guaiacol pentoxyverine controlled-release tablets described in the present application, the weight portions of potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride contained in the second active pharmaceutical ingredient are as follows: 1 part to 2 parts of potassium guaiacol sulfonate, 0.1 part to 0.2 part of pentoxyverine citrate and 0.05 part to 0.08 part of promethazine hydrochloride.

[0015] According to some embodiments of the guaiac-pentol-promethazine controlled-release tablets described in the present application, the mass ratio of the tablet core to the coating is (84-86): (14-16).

[0016] According to some embodiments of the guaiac-pentol-promethazine controlled-release tablets described in the present application, the raw materials for preparing the tablet core further include the following ingredients in parts by weight: 7-13 parts of a diluent, 2-4 parts of a binder, 0.1-0.3 parts of a glidant, and 0.3-0.5 parts of a lubricant;

[0017] According to some embodiments of the guaiac-pentol-promethazine controlled-release tablets described in the present application, the raw materials for preparing the coating further include the following ingredients in parts by weight: 1 to 3 parts of a plasticizer and 40 to 65 parts of a solvent.

[0018] According to some embodiments of the guaiac pentol promethazine controlled-release tablets described in the present application, the skeleton carrier includes one or more of ethyl cellulose, methyl cellulose, chitosan, poly (meth) acrylic acid resin, β-sitosterol, palmitic acid glyceride and cholesterol glyceride.

[0019] According to some embodiments of the guaiac-pentol-promethazine controlled-release tablets described in the present application, the osmotic pressure enhancer includes one or more of dextran, glucose, xylitol and sorbitol.

[0020] According to some embodiments of the guaiacpentol promethazine controlled-release tablet described in the present application, the disintegrant includes one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose and microcrystalline cellulose.

[0021] According to some embodiments of the guaiac-pentol promethazine controlled-release tablets described in the present application, the film-forming material includes one or more of ethyl cellulose, cellulose acetate, and cellulose acetate.

[0022] According to some embodiments of the guaiac-pentol promethazine controlled-release tablets described in the present application, the diluent includes one or more of mannitol, micropowdered silica gel, microcrystalline cellulose, lactose, and starch.

[0023] According to some embodiments of the guaiac-pentol-promethazine controlled-release tablets described in the present application, the adhesive includes one or more of gum arabic, corn protein, maltodextrin, and methylcellulose.

[0024] According to some embodiments of the guaiac-pentol promethazine controlled-release tablets described in the present application, the glidant includes one or more of microcrystalline cellulose, micropowdered silica gel and silicon dioxide.

[0025] According to some embodiments of the guaiac-pentol promethazine controlled-release tablets described in the present application, the lubricant includes one or more of magnesium stearate, talc, micro-powdered silica gel and glyceryl behenate.

[0026] According to some embodiments of the guaiac-pentol-promethazine controlled-release tablets described in the present application, the plasticizer includes one or more of triethyl acetyl citrate, tributyl acetyl citrate and diethyl phthalate.

[0027] According to some embodiments of the guaiac pentol promethazine controlled-release tablets described in the present application, the solvent includes one or more of ethylene dichloride, ethanol, acetone-water, methanol, ethyl acetate, isopropanol, and acetone.

[0028] In a second aspect of the present application, there is provided a method for preparing the guaiac pentol promethazine controlled-release tablets described in the first aspect of the present application, comprising the following steps:

[0029] The first active pharmaceutical ingredient, the skeleton carrier, the osmotic pressure enhancer and the disintegrant are mixed to prepare a tablet core;

[0030] dissolving the film-forming material and the second active pharmaceutical ingredient in a solvent to obtain a coating solution;

[0031] The coating liquid is used to coat the tablet core to obtain the guaiac-pentol-promethazine controlled-release tablets.

[0032] According to some embodiments of the preparation method described in the present application, the solution containing the first active pharmaceutical ingredient and the solution containing the skeleton carrier are mixed, and the solvent is removed to obtain a solid dispersion; the solid dispersion, the osmotic pressure enhancer and the disintegrant are mixed and then prepared into a tablet core.

[0033] According to some embodiments of the preparation method described in the present application, the solution containing the first active pharmaceutical ingredient and the solution containing the skeleton carrier are both ethanol solutions.

[0034] According to some embodiments of the preparation method described in the present application, the method of removing the solvent includes concentration treatment and drying treatment; wherein, the concentration temperature is 70°C-75°C, the vacuum degree is -0.05MPa to -0.08MPa, and the relative density of the concentrated product is 1.30-1.35; the drying temperature is 70°C-75°C, the vacuum degree is -0.05MPa to -0.08MPa, and the water content of the solid dispersion is 3.1%-3.4%.

[0035] According to some embodiments of the preparation method described in the present application, the raw materials for preparing the tablet core further include a first auxiliary agent, and the first auxiliary agent includes a diluent, a binder, a glidant and a lubricant;

[0036] The solid dispersion, the osmotic pressure enhancer, the disintegrant, and the diluent are mixed to obtain a mixed powder, the mixed powder and a binder solution are mixed to form a soft material, and the soft material is dried, and the dried product is mixed with the flow aid and the lubricant, and pressed into tablets to obtain the tablet core.

[0037] According to some embodiments of the preparation method described in the present application, the raw material components for preparing the coating solution further include a second auxiliary agent, and the second auxiliary agent includes a plasticizer;

[0038] dissolving the second active pharmaceutical ingredient, the film-forming material and the plasticizer in the solvent to obtain a coating solution;

[0039] And / or, the equipment for implementing the coating includes a coating machine; the preheating speed of the coating machine is controlled to be 3 rpm-4 rpm, the preheating air inlet temperature is 70℃-80℃, the preheating air outlet temperature is 50℃-60℃, the preheating time is 30 minutes-40 minutes, the coating speed of the coating machine is adjusted to 6 rpm-8 rpm, the coating air inlet temperature is 80℃-90℃, the coating air outlet temperature is 60℃-70℃, and the coating liquid is sprayed to coat the tablet cores.

[0040] Compared with the prior art, the beneficial effects of the present invention are:

[0041] 1. The tablet core in the guaiac pentol promethazine controlled-release tablets described in the present application can delay the drug release time, and the coating coated on the outside of the tablet core serves as the drug rapid release part, which provides a sufficient initial drug concentration after the drug is taken, quickly exerts the drug efficacy, relieves cough and expectorates, quickly relieves and corrects the symptoms of cough and sputum caused by colds, and then the drug components in the coating are slowly and steadily released through the drug release holes into the digestive tract, absorbed into the blood, and form a stable blood drug concentration, which continuously and steadily exerts a therapeutic effect. The purpose is to solve the defect of the existing guaiac pentol promethazine particles with many adverse reactions to a certain extent. The controlled-release tablets described in the present application can achieve a relatively stable blood drug concentration, so as to solve the "peak" and "trough" phenomenon of blood drug concentration caused by a single administration during clinical use, as well as the problem of a short drug release action time, improve clinical efficacy, reduce adverse reactions caused by excessively high peaks in blood drug concentration, and reduce the occurrence of drug resistance.

[0042] 2. The preparation method of the guaiacol pentylene promethazine controlled-release tablets described in the present application disperses potassium guaiacol sulfonate, pentylene citrate, and promethazine hydrochloride in a molecular state in a controlled-release skeleton material to delay the drug release time. At the same time, 1 / 10 potassium guaiacol sulfonate, pentylene citrate, and promethazine hydrochloride are added to the coating solution as pore-forming agents and coated on the surface of the tablet core as the drug rapid-release part. The preparation method is simple, and the obtained controlled-release tablets can achieve a relatively stable blood drug concentration and a long therapeutic effect. DETAILED DESCRIPTION

[0043] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0044] In this application, the term "and / or" describes the association relationship of associated objects, indicating that there may be three relationships. For example, A and / or B can mean: A exists alone, A and B exist at the same time, and B exists alone. A and B can be singular or plural. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0045] In this application, "at least one" means one or more, and "plurality" means two or more. "At least one of the following" or similar expressions refers to any combination of these items, including any combination of single items or plural items. For example, "at least one of a, b, or c", or "at least one of a, b, and c" can all mean: a, b, c, ab (i.e., a and b), ac, bc, or abc, where a, b, c can be single or multiple, respectively.

[0046] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution, some or all of the steps can be executed in parallel or sequentially, and the execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0047] The terms used in the embodiments of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "said" and "the" used in the embodiments of the present application and the appended claims are also intended to include plural forms, unless the context clearly indicates other meanings.

[0048] The weight of the relevant components mentioned in the embodiment description of the present application can not only refer to the specific content of each component, but also represent the proportional relationship between the weights of the components. Therefore, as long as the content of the relevant components is proportionally enlarged or reduced according to the embodiment description of the present application, it is within the scope disclosed in the embodiment description of the present application. Specifically, the mass described in the embodiment description of the present application can be a mass unit known in the chemical industry such as μg, mg, g, kg, etc.

[0049] In a first aspect of the embodiments of the present application, there is provided a guaiac-pentol-promethazine controlled-release tablet, comprising a tablet core and a coating covering the tablet core;

[0050] The tablet core comprises the following raw material components: a first active pharmaceutical ingredient, a skeleton carrier, an osmotic pressure enhancer and a disintegrant;

[0051] The coating comprises the following raw material components: a film-forming material and a second active pharmaceutical ingredient;

[0052] The first active pharmaceutical ingredient and the second active pharmaceutical ingredient both include potassium guaiacol sulfonate, pentoxyverine citrate, and promethazine hydrochloride.

[0053] The controlled release tablet of the embodiment of the present application includes a tablet core and a coating coated on the surface of the tablet core. By adding a skeleton carrier material (the skeleton carrier material plays a role of controlled release), the drug and the skeleton carrier are mixed, and an osmotic pressure promoter is added to the tablet core to increase the osmotic pressure of potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride solution, promote potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride to release at a constant rate through the micropores of the coating film, eliminate the fluctuation amplitude of the curve when the above-mentioned components are released, and realize the zero-order release of guaiacol pentoxyverine in the body, improve the safety of the drug, reduce the incidence of adverse reactions, and reduce the probability of drug resistance. On the other hand, the embodiment of the present application uses potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride as pore-forming agents, which are dissolved by digestive juices at the first time after taking, enter the digestive tract, and are absorbed by the digestive tract mucosa at the first time to play a therapeutic role. In addition, the film-forming material in the coating is the main raw material and pore-forming agent (potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride are pore-forming agents) for establishing an osmotic pump controlled release system. The pore-forming agent has extremely high water solubility and will dissolve when in contact with the dissolution medium, so that the coating forms uniform, fine, sponge-like micropores. The release medium (human gastrointestinal digestive fluid) enters the tablet core through the micropores, so that the tablet core drug dissolves in the release medium, and under the action of the osmotic pressure enhancer dissolved in the release medium, a hypertonic saturated solution is continuously formed, and the tablet core drug penetrates out of these micropores at a constant rate to achieve near-zero-order release.

[0054] [Chip]

[0055] In some embodiments of the present application, the core comprises the following raw material components in parts by weight: 7-12 parts of the first active pharmaceutical ingredient, for example 7.062 parts, 7.18 parts, 7.60 parts, 8.32 parts, 9.69 parts, 10.01 parts, 10.51 parts, 11.30 parts, 11.76 parts, 11.85 parts, 12 parts, etc., and 13-23 parts of the skeleton carrier, for example 13.1 parts, 13.5 parts, 13.8 parts, 15 parts, 15.6 parts, 16.8 parts , 17.9 parts, 18.3 parts, 19.1 parts, 20.5 parts, 21.7 parts, 22.5 parts, 23 parts, etc., osmotic pressure enhancer 4-8 parts, such as 4.1 parts, 4.3 parts, 4.5 parts, 5.6 parts, 6.7 parts, 7.5 parts, 7.8 parts, 8 parts, disintegrant 2-4 parts, such as 2.21 parts, 2.25 parts, 2.50 parts, 2.67 parts, 2.89 parts, 3.01 parts, 3.23 parts, 3.68 parts, 3.75 parts, 4 parts. The amount of osmotic pressure enhancer added fully ensures the promotion effect on the osmotic release stability of the guaiac pentol promethazine drug in the tablet core, and the amount of disintegrant added is beneficial to promoting the disintegration and release of guaiac pentol promethazine in the tablet core, and is also beneficial to maintaining the drug release stability.

[0056] In some embodiments of the present application, the core tablet also includes the following components in parts by weight: 7-13 parts of diluent, for example 7.1 parts, 7.2 parts, 7.3 parts, 8.5 parts, 8.9 parts, 9.3 parts, 9.8 parts, 10.3 parts, 10.6 parts, 11.2 parts, 11.8 parts, 12.2 parts, and 13 parts; 2-4 parts of binder, for example 2.2 parts, 2.25 parts, 2.6 parts, 2.8 parts, 3.3 parts, 3.6 parts, 3.75 parts, and 4 parts; 0.1-0.3 parts of glidant, for example 0.12 parts, 0.16 parts, 0.18 parts, 0.23 parts, 0.25 parts, and 0.3 parts; and 0.3-0.5 parts of lubricant, for example 0.32 parts, 0.36 parts, 0.38 parts, 0.41 parts, 0.46 parts, and 0.5 parts. The amount of diluent, binder, glidant and lubricant ensures the molding effect of the tablet core. If the amount of diluent is too large, the tablet volume and weight will be too large, which is inconvenient for patients to take. Compressible lactose has always been used as a reference for diluents for direct powder tableting. It has better fluidity and compressibility, and the amount used is not limited. The weight of the binder can ensure that the particles are of appropriate hardness and that the particles will not break during the drying, granulation and mixing processes, resulting in poor particle fluidity. The dried particles can also be bonded together during the tableting process to form a tablet core with sufficient structural strength, which is beneficial to avoid various forms of flakes in the next coating process, ensure that the controlled-release coating is complete and has sufficient structural strength, but will not cause the particles to be too hard and unable to be pressed into tablets, or cause loose tablets, the hardness and brittleness of the tablet core not meeting the requirements, and ultimately resulting in the inability to coat, and even causing the integrity of the coating film after coating to be greatly adversely affected. Excessive use of binder can also cause the tablet core to be too hard and unable to disintegrate, the active components of the drug cannot be released, the total amount of drug absorbed by the body is too low, the basic therapeutic concentration cannot be reached, the efficacy is too low, and even delayed treatment leads to worsening of the condition. The weight of the disintegrant can ensure that the tablet core disintegrates into debris appropriately, fully increases the specific surface area of ​​the tablet core in contact with the release medium, and allows the active pharmaceutical ingredient highly dispersed in the skeleton carrier to fully dissolve in the release medium and enter the digestive tract through the drug release pores formed after the second active pharmaceutical ingredient is dissolved in the release medium as a pore-forming agent. Insufficient disintegrants may cause the tablet core to disintegrate for too long, or incompletely, resulting in the inability to fully release the active pharmaceutical ingredient, resulting in a too slow release rate. Excessive disintegrants may cause the tablet core to disintegrate too quickly, the tablet core volume expands too much, and the static pressure exceeds the mechanical strength of the controlled release film, resulting in film rupture and collapse of the controlled release system.The weight of the glidant can ensure the fluidity of the particles, ensure accurate filling during the tableting process, and accurate dosage of the active drug ingredients in the tablet core. Otherwise, too small a dosage may lead to poor granule fluidity, uneven filling during the tableting process, resulting in inaccurate dosage of the active drug ingredients in the tablet core, or failing to reach the therapeutic dose, or exceeding the upper limit of the therapeutic dose, or even a toxic dose, causing the patient to be poisoned or causing various unexpected side effects or adverse reactions. Excessive dosage will cause the tablet core to be loose, or even unable to be pressed into tablets, unable to be coated, or the integrity of the coating film is significantly adversely affected, and an effective osmotic pump controlled release system cannot be effectively established. The amount of lubricant can ensure that the prepared particles are smooth and complete during the tableting process, and the tablets are smoothly discharged to avoid sticking. Excessive dosage will lead to the consequences of excessive dosage of the above-mentioned glidant. Too small dosage will cause sticking during the tableting process, unsmooth tableting, and incomplete tablets due to sticking, thereby failing to provide good tablet core quality for coating, and even causing adverse effects on the integrity of the coating film, and thus failing to establish an effective osmotic pump controlled release system.

[0057] In some embodiments of the present application, the weight proportions of potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride contained in the first active pharmaceutical ingredient are as follows: potassium guaiacol sulfonate 6-12 parts, for example 6.1 parts, 6.3 parts, 7.6 parts, 8.5 parts, 9.3 parts, 10.3 parts, 10.5 parts, 11.2 parts, 12 parts, pentoxyverine citrate 0.5 parts-0.9 The weight portions of potassium guaiacolsulfonate, pentoxyverine citrate and promethazine hydrochloride can continuously replenish the active pharmaceutical ingredient to the required blood drug concentration at a constant release rate after the second active pharmaceutical ingredient is released and absorbed, so that the drug release and action are maintained for a sufficient time to reduce the number of times the patient takes the medicine, and avoid the cumbersomeness and inconvenience of intravenous injection by medical staff, especially avoid various infections that may be caused by intravenous injection.

[0058] In some embodiments of the present application, the skeleton carrier includes one or more of ethyl cellulose, methyl cellulose, chitosan, poly (meth) acrylic resin, beta sitosterol, palmitic acid glyceride and cholesterol glyceride. The skeleton carrier is mixed with the active ingredient of the medicine to play the role of sustained release of the active ingredient of the medicine.

[0059] In some embodiments of the present application, the osmotic pressure enhancer includes one or more of dextran, glucose, xylitol and sorbitol. After the osmotic pressure enhancer is dissolved in the digestive juice in the membrane, the osmotic pressure of the solution formed by the active drug ingredient dissolved in the digestive juice can be significantly increased. In this way, it can be ensured that the hypotonic state caused by the use of a controlled release skeleton dispersion to block the dissolution rate of a water-soluble drug and the resulting poor uniformity of the release rate can be avoided, and the digestive juice outside the membrane is prompted to quickly pass through the cellulose acetate semipermeable membrane and the uniform and fine drug release holes formed after contacting with the potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride inside the dissolving film, enter the inner side of the film, and under the action of the disintegrant, the tablet core is disintegrated into fragments, and fully contacted with it, dissolving the main drug, forming a solution, and maintaining a constant extreme high osmotic pressure relative to the outside of the membrane for a certain period of time, thereby promoting the potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride to be released through the holes of the coating at a constant rate.

[0060] In some embodiments of the present application, the disintegrant includes one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose and microcrystalline cellulose. Cross-linked polyvinylpyrrolidone is a pharmaceutical excipient, a water-insoluble synthetic cross-linked N-vinyl-2-pyrrolidone homopolymer, which can be used in both dry and wet granulation, can quickly show high capillary activity and excellent hydration ability, and has almost no tendency to gel. Studies have shown that the size of cross-linked polyvinylpyrrolidone particles strongly affects the disintegration of antipyretic analgesic tablets; cross-linked sodium carboxymethylcellulose is an odorless, white or off-white powder, which is used as a disintegrant for capsules, tablets and granules in oral solid preparations. In tablets, cross-linked sodium carboxymethylcellulose is suitable for direct tableting and release granulation tableting processes. During wet granulation, cross-linked sodium carboxymethylcellulose can be added in the wetting stage or the drying stage, respectively, so that the capillary and swelling effects of the disintegrant can be best exerted. In the present application, it is only added in the wetting stage to control the degree of disintegration of the tablet core.

[0061] Microcrystalline cellulose is a purified, partially depolymerized cellulose, white, odorless, tasteless, crystalline powder composed of porous particles, the main component of which is a linear polysaccharide bonded by β-1,4-glucosidic bonds. The degree of polymerization is about 3000-10000 glucose molecules. As a disintegrant, it can disintegrate the core of the film into debris, so that the active ingredients of the drug slowly dissolve in the digestive fluid entering the inner side of the film under the action of the controlled release skeleton material.

[0062] In some embodiments of the present application, the diluent includes one or more of mannitol, micropowder silica gel, microcrystalline cellulose, lactose, and starch. Micropowder silica gel is a white powdery inorganic chemical product with strong surface activity, stable active properties, and no reaction with acid and alkali. The main component of microcrystalline cellulose is a linear polysaccharide substance bonded by β-1,4-glucosidic bonds. It is a white, odorless, tasteless crystalline powder composed of extremely fine short rods or powdered porous particles that can flow freely after natural cellulose is hydrolyzed with dilute acid to the limit degree of polymerization. The diluent not only plays the role of diluting the main drug and filling, but also plays a molding role. The selected diluent has good fluidity, and can improve the fluidity and compressibility of the material, and can make the surface smooth.

[0063] In some embodiments of the present application, the binder includes one or more of gum arabic, corn protein, maltodextrin, and methylcellulose. The choice of the binder can be used not only for wet granulation, but also for direct powder tableting, which is flexible and convenient to use.

[0064] In some embodiments of the present application, the glidant includes one or more of microcrystalline cellulose, micropowdered silica and silicon dioxide.

[0065] In some embodiments of the present application, the lubricant includes one or more of magnesium stearate, talc, micro-powdered silica gel and glyceryl behenate; the lubricant can prevent the material from sticking during tableting, which damages the quality of the tablet core and makes it impossible to coat. In some preferred embodiments, the lubricant is magnesium stearate.

[0066] [Coating]

[0067] The coating includes the following raw material components in parts by weight: 3-6 parts of film-forming material, such as 3.1 parts, 3.3 parts, 3.6 parts, 4.1 parts, 4.8 parts, 5.2 parts, 5.6 parts, 6.0 parts, and 1-3 parts of the second active ingredient, such as 1.12 parts, 1.23 parts, 1.35 parts, 1.86 parts, 2.01 parts, 2.21 parts, 2.25 parts, 3.0 parts. The second active ingredient has good water solubility and dissolves when in contact with the dissolution medium, so that the coating forms loose sponge-like micropores, and the core drug is released from these micropores, providing a controlled release channel for the drug controlled release system, and more importantly, it is quickly released into the digestive tract at the first time, absorbed into the blood through the digestive tract mucosa, and exerts a therapeutic effect at the first time, thereby improving the controlled release effect of the drug.

[0068] The weight portions of potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride contained in the second active ingredient of the drug are as follows: 1 part to 2 parts of the potassium guaiacol sulfonate, for example, 1.1 parts, 1.2 parts, 1.7 parts, 1.9 parts, and 2 parts, 0.1 part to 0.2 parts of the pentoxyverine citrate, for example, 0.1 parts, 0.13 parts, 0.15 parts, 0.16 parts, 0.18 parts, and 0.20 parts, and 0.05 part to 0.08 parts of the promethazine hydrochloride, for example, 0.05 parts, 0.06 parts, 0.07 parts, and 0.08 parts. The potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride in this weight portion can be dissolved into the release medium immediately, absorbed into the blood through the digestive mucosa, and quickly provide sufficient blood drug concentration to relieve clinical symptoms, which can significantly relieve the symptoms of clinical cough and avoid the blood drug concentration being too low before the active drug ingredients in the controlled release part are absorbed into the blood, thereby failing to achieve a therapeutic effect.

[0069] The coating also includes the following components in parts by weight: 1-3 parts of plasticizer, for example 1.21 parts, 1.26 parts, 1.32 parts, 1.35 parts, 1.43 parts, 1.48 parts, 1.76 parts, 1.89 parts, 2.01 parts, 2.21 parts, 2.25 parts, 2.64 parts, 2.79 parts, 3 parts; 40-65 parts of solvent, for example 40 parts, 43 parts, 49 parts, 51 parts, 53 parts, 56 parts, 59 parts, 60 parts, 62 parts, 65 parts.

[0070] The weight of plasticizer can ensure that the coating film has good plasticity and toughness, and increase the mechanical strength of the coating film. If the amount is too small, the coating film will not have enough plasticity and toughness, and the coating film will not be able to withstand the release medium entering the coating film, resulting in the disintegration of the tablet core, and dissolving the active pharmaceutical ingredients and auxiliary materials such as osmotic pressure enhancers in the coating film, causing the static pressure brought by the violent volume expansion to cause rupture; if the amount is too large, the coating film may be too plastic and cause rupture, or the coating film may not be able to maintain the ultimate osmotic pressure, resulting in serious insufficient release of the active pharmaceutical ingredients and a significant reduction in the release rate. Solvents dissolve coating materials, plasticizers and pore-forming agents. The amount used can ensure that a sufficient amount of coating materials, pore-forming agents and plasticizers are fully dissolved in them, but it will not cause these materials to be unable to be completely dissolved due to too small an amount, or cause the coating process to take too long due to too large an amount, wasting energy. The amount of coating material can ensure that the coating film has sufficient mechanical strength, and it will not cause insufficient coating strength or too fast drug release due to too small a quantity, nor will it cause excessive coating thickness and too slow drug release due to too large a quantity. In particular, when the coating film is too thick and expands significantly after the tablet core disintegrates, the tension cannot be evenly diffused, resulting in rupture, which in turn causes the controlled release system to collapse.

[0071] In some embodiments, the film-forming material includes one or more of ethyl cellulose, cellulose acetate, and cellulose acetate. The film-forming materials are non-toxic, stable in nature, and insoluble in acid, alkali, and aqueous solution, and can coat the tablet core to form a stable coating with sufficient toughness. In some specific embodiments, cellulose acetate is selected as a semipermeable membrane-forming material, and the tablet core is coated to obtain a tablet. The coating made of the film-forming material is used as the main raw material for establishing an osmotic pump controlled release system. Its main function is to construct a barrier for the controlled release system, control the release of the active ingredient of the drug, avoid its free release, and ensure that it can only be released through the micropores formed in the coating after the cellulose acetate semipermeable membrane and the porogen are dissolved. The reason is that cellulose acetate has better film-forming properties and can be used as a semipermeable membrane coating for film-forming tablets, especially osmotic pump controlled-release preparations and implantable preparations to control and delay the release of drugs. When used in combination with other substances, it can achieve the purpose of controlled release without having to make a hole in the coating like a general osmotic pump controlled-release system. More importantly, cellulose acetate is insoluble in artificial gastric juice and intestinal juice, and can maintain good stability in digestive juice, thereby achieving better controlled-release effects.

[0072] In some embodiments of the present application, the plasticizer includes one or more of triethyl acetyl citrate, tributyl acetyl citrate and diethyl phthalate. When film-forming materials such as cellulose acetate are applied alone to the coating film, most of the formed coating films will have poor toughness, brittleness, and easy to break. In order to improve the performance of the coating film, plasticizers are often added to the coating solution to improve the film-forming properties of the coating material, strengthen its flexibility and mechanical strength, and obtain a coating film with excellent controlled release performance. The present application embodiment adds these plasticizers to the semipermeable membrane coating material, which can improve the plastic deformation performance of the coated semipermeable membrane, avoid cracking after the semipermeable membrane is formed, and cause the coating film to rupture, and it is impossible to make potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride achieve uniform constant speed zero-order release. In certain embodiments, the plasticizer includes triethyl acetyl citrate, which has good compatibility with film-forming materials such as cellulose acetate, and can make the drug release curve present zero-order release kinetics.

[0073] In some embodiments of the present application, the mass ratio of the tablet core to the coating is (84-86): (14-16), such as 84:14, 84:15, 84:16, 85:14, 85:15, 85:16, 86:14, 86:15, 86:16. This ratio not only ensures the isolation effect of the coating on the tablet core and maintains the stability of the coating film structure, but also facilitates the stable constant-rate release of potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride through the micropores in the coating film, and realizes the constant-rate zero-order release of potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride in vivo, and the amount of guaiacol pentoxyverine released per unit time tends to be constant. In some specific embodiments, the mass percentage of the coating in the guaiacol pentoxyverine controlled-release tablets includes but is not limited to 14%, 14.5%, 15%, 15.5% and 16%, etc.

[0074] In some embodiments of the present application, the solvent includes one or more of ethylene dichloride, ethanol, acetone-water, methanol, ethyl acetate, isopropanol, and acetone. These solvents have good solubility for film-forming materials, porogens, and plasticizers.

[0075] The second aspect of the present invention provides a method for preparing the guaiac-pentol-promethazine controlled-release tablets according to the first aspect of the present invention:

[0076] The following steps are involved:

[0077] S10: mixing the first active ingredient, the skeleton carrier, the osmotic pressure enhancer and the disintegrant to prepare a tablet core;

[0078] S20: combining the film-forming material and the second active ingredient of the drug to obtain a coating solution;

[0079] S30: coating the tablet core with a coating solution to obtain guaiac-pentol-promethazine controlled-release tablets.

[0080] The prepared guaiacol pentol promethazine controlled-release tablets, through the synergistic effect of each raw material component, make the tablet core fully disintegrate, the active ingredient of the drug slowly dissolves into the release medium under the retardation of the controlled-release skeleton material, and at the same time, the dissolution of the osmotic pressure enhancer greatly increases the osmotic pressure of the aqueous solution, so that the film is in a swollen state, and under the impetus of the high osmotic pressure, the drug potassium guaiacol sulfonate, pentolamine citrate and promethazine hydrochloride are dissolved in the digestive medium through the pore-forming agent to form uniform and fine drug release pores and passively diffuse into the release medium at a constant speed, reducing or even eliminating the fluctuation amplitude of the guaiacol pentol promethazine drug-time curve, achieving zero-order release of guaiacol pentol promethazine in the body, improving the safety of the drug, reducing the incidence of adverse reactions and drug resistance, and prolonging the release and action time of the drug. The preparation process of the embodiment of the present application is simple, the conditions are mild, and it is suitable for industrial large-scale production and application.

[0081] Step S10:

[0082] In some embodiments, a solution containing the first active pharmaceutical ingredient and a solution containing a skeleton carrier are mixed, and the solvent is removed to obtain a solid dispersion; the solid dispersion, an osmotic pressure enhancer, and a disintegrant are mixed to prepare a tablet core.

[0083] In some embodiments, the solution containing the first pharmaceutically active ingredient and the solution containing the skeleton carrier are both ethanol solutions;

[0084] In some embodiments, the method of removing the solvent includes concentration treatment and drying treatment; wherein, the concentration temperature is 70°C-75°C, for example, 70°C, 72°C, 73°C, 75°C, the vacuum degree is -0.05MPa to -0.08MPa, for example, -0.05MPa, -0.06MPa, -0.07MPa, -0.08MPa, and the relative density of the concentrated product is 1.30-1.35, for example, 1.30, 1.32, 1.33, 1.35.

[0085] In some embodiments, the drying temperature is 70°C-75°C, for example 70°C, 72°C, 73°C, 75°C, the vacuum degree is -0.05MPa to -0.08MPa, for example -0.05MPa, -0.06MPa, -0.07MPa, -0.08MPa, and the water content of the solid dispersion is 3.1%-3.4%, for example 3.1%, 3.2%, 3.3%, 3.4%.

[0086] In some embodiments, the raw materials for preparing the core further include a first auxiliary agent, and the first auxiliary agent includes a diluent, a binder, a glidant and a lubricant;

[0087] The solid dispersion, osmotic pressure enhancer, disintegrant and diluent are uniformly mixed to obtain a mixed powder, the mixed powder and a binder solution are mixed to form a soft material, and the soft material is dried. The dried product is mixed with a flow aid and a lubricant, and pressed into tablets to obtain a tablet core.

[0088] In some embodiments, the raw material components for preparing the coating solution further include a second auxiliary agent, and the second auxiliary agent includes a plasticizer;

[0089] The second active pharmaceutical ingredient, film-forming material and plasticizer are dissolved in a solvent to obtain a coating solution.

[0090] In some embodiments, the coating equipment includes a coating machine; the speed of the coating machine is controlled to be 3 rpm-4 rpm, for example, 3 rpm, 3.5 rpm, 4 rpm, the preheating air inlet temperature is 70°C-80°C, for example, 70°C, 72°C, 75°C, 78°C, 80°C, the preheating air outlet temperature is 50°C-60°C, for example, 50°C, 52°C, 55°C, 58°C, 60°C, and the preheating time is 30 minutes-40 minutes, for example, 30 minutes. , 32 minutes, 35 minutes, 38 minutes, 40 minutes, adjust the coating speed of the coating machine to 6 rpm-8 rpm, for example, 6 rpm, 7 rpm, 8 rpm, the coating inlet air temperature is 80℃-90℃, for example, 80℃, 82℃, 85℃, 88℃, 89℃, 90℃, the coating outlet air temperature is 60℃-70℃, for example, 60℃, 62℃, 65℃, 68℃, 69℃, 70℃, spray the coating liquid to coat the tablet cores.

[0091] In some embodiments, the method for preparing the guaiac pentol promethazine controlled release tablets comprises the following steps:

[0092] 6.3-10.5 parts of potassium guaiacol sulfonate, 0.51-0.84 parts of pentoxyverine citrate and 0.252-0.42 parts of promethazine hydrochloride are dissolved in 95% ethanol to prepare a 20% solution, and 13.5-22.5 parts of a skeleton carrier are dissolved in 95% ethanol to prepare a 20% solution. The two ethanol solutions are mixed and homogenized at 8000rpm-10000rpm for 90 seconds, and concentrated under reduced pressure at -0.05MPa to -0.08MPa and 70℃-75℃ to a relative density of 1.30-1.35 (70℃), and dried under reduced pressure at -0.05MPa to -0.08MPa and 70℃-75℃ to a moisture content of 3.1%-3.4%, and crushed into fine powder to prepare a guaiacol pentoxyverine skeleton controlled-release solid dispersion.

[0093] S20. Add the prescribed amount of adhesive to 65% ethanol to prepare a 2% adhesive solution.

[0094] S30. Grind the prescribed amount of disintegrant, diluent and osmotic pressure enhancer into fine powder passing through 80-mesh sieve, add the guaiac pentol promethazine skeleton controlled-release solid dispersion and mix for 30 minutes, add the binder solution, mix for 10 minutes, make into a soft material, sieve through 18 mesh to make wet granules, dry at 70℃-75℃ to 3.4%-3.9% moisture, sieve through 14 mesh to size granules, add the prescribed amount of glidant and lubricant, mix for 36 minutes, and press into tablets to obtain the guaiac pentol promethazine skeleton osmotic pump controlled-release tablet cores.

[0095] S40. Grind 1.2 to 2 parts of potassium guaiacol sulfonate, 0.1 to 0.16 parts of pentoxyverine citrate and 0.05 to 0.08 parts of promethazine hydrochloride into 120 mesh fine powder, mix well, and prepare a rapid-release pore-forming agent.

[0096] S50. Dissolve 3.6 parts to 6.0 parts of film-forming material, 1.35 parts to 2.25 parts of quick-release pore-forming agent, and 1.35 parts to 2.25 parts of plasticizer in 40 parts to 65 parts of coating agent solvent to prepare a coating solution.

[0097] S60. Place the tablet core prepared in S30 into the coating machine, control the preheating speed to 3 rpm-4 rpm, preheat the air inlet temperature to 70℃-80℃, preheat the air outlet temperature to 50℃-60℃, preheat for 35 minutes, adjust the coating speed of the coating machine to 6 rpm-8 rpm, the coating air inlet temperature to 80℃-90℃, and the coating air outlet temperature to 60℃-70℃, spray the coating liquid, control the flow rate until the coating liquid dries layer by layer on the tablet surface, and ensure that all the coating liquid covers the surface of the tablet core, so as to obtain the guaiac-pentol promethazine controlled-release tablets.

[0098] The preparation method of the present application has a simple preparation process and mild conditions, and is suitable for industrial large-scale production and application. The prepared guaiacol pentol promethazine skeleton osmotic pump controlled-release tablets, through the synergistic effect of various raw material components, the rapid-release pore-forming agent in the coating is dissolved by the release medium to form uniformly distributed micropores with uniform pore size, providing a channel for the release medium to enter the coating. At the same time, the rapid-release pore-forming agents potassium guaiacol sulfonate, pentol citrate and promethazine hydrochloride are dissolved in the release medium at the first time, absorbed into the blood through the digestive tract mucosa, providing a certain initial concentration of the drug, and exerting a therapeutic effect at the first time; at the same time, the drug release pores formed after dissolving in the digestive medium allow the release medium to enter the inner side of the coating. Under the action of the disintegrant, the tablet core quickly disintegrates in the release medium entering the coating. The osmotic pressure enhancer in the tablet core slowly dissolves into the release medium together with potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride under the retardation of the controlled release skeleton carrier, and continuously forms a hypertonic saturated solution. Potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride are driven by the osmotic pressure of the hypertonic saturated solution to penetrate and transfer from the inner side of the hypertonic coating to the outer side of the hypotonic coating. At the same time, the release medium continuously promotes the release medium to penetrate and transfer from the outer side of the hypotonic coating to the inner side of the hypertonic coating through the micropores, enters the coating, continuously dissolves the active ingredients and osmotic pressure enhancer in the tablet core, and continues to maintain the saturation of the hypertonic solution, thereby forming a constant osmotic pressure. At the same time, due to its constant osmotic pressure and fixed number of coating micropores, the near-zero-order release of guaiacol pentoxyverine in the body is achieved, while the drug release and action time are prolonged, the safety of the drug is improved, the incidence of adverse reactions is reduced, and the drug release and action time are prolonged.

[0099] Example 1

[0100] The raw material formula of the guaiac pentol promethazine controlled-release tablets prepared in Example 1 is shown in Table 1:

[0101] Table 1

[0102]

[0103] 10,000 pieces were made.

[0104] Note: Potassium guaiacol sulfonate Ⅰ, pentoxyverine citrate Ⅰ, and promethazine hydrochloride Ⅰ are the raw material ingredients in the tablet core;

[0105] Potassium guaiacol sulfonate II, pentoxyverine citrate II, and promethazine hydrochloride II are the raw material ingredients in the coating.

[0106] The preparation steps include:

[0107] 1. Preparation of guaiac-pentol-promethazine skeleton controlled-release solid dispersion:

[0108] 1.1 Dissolve 420 g of potassium guaiacol sulfonate I, 33.3 g of pentoxyverine citrate I and 16.7 g of promethazine hydrochloride I in 95% ethanol to prepare a solution with a mass concentration of 20%, and dissolve 900 g of ethyl cellulose in 95% ethanol to prepare a solution with a mass concentration of 20%;

[0109] 1.2 The two ethanol solutions were mixed and homogenized at 10000 rpm for 90 seconds to prepare a guaiac-pentol-promethazine skeleton controlled-release solid dispersion solution;

[0110] 1.3 The guaiac pentol promethazine skeleton controlled-release solid dispersion solution was concentrated under reduced pressure at a vacuum degree of -0.06 MPa and 70°C to a relative density of 1.30 (70°C), and then dried under reduced pressure at a vacuum degree of -0.05 MPa and 70°C to a moisture content of 3.4%, and crushed into fine powder to obtain a solid dispersion;

[0111] 2. Preparation of Tablet Cores

[0112] 2.1 Preparation of adhesive: Add the prescribed amount of corn protein to 65% ethanol to prepare an adhesive solution with a mass concentration of 2% to obtain an adhesive;

[0113] 2.2 Granulation: 150g of cross-linked sodium carboxymethyl cellulose, 577g of compressible starch and 300g of xylitol were crushed into fine powder through an 80-mesh sieve, added to the solid dispersion and mixed for 30 minutes, 65% ethanol solution of 2% corn protein was added and mixed for 10 minutes to make a soft material, sieved through an 18-mesh sieve to make wet granules, dried at 75°C to 3.4% moisture, sieved through a 14-mesh sieve, added with the prescribed amount of micro-powdered silica gel and magnesium stearate, mixed for 36 minutes, and the total mixed granules of the guaiac-pentol-promethazine controlled-release tablets were obtained;

[0114] 1.3 Tableting: The above-mentioned total mixed granules are pressed into 10 mm shallow arc-shaped tablets, each weighing 0.258 g, to obtain the core of the guaiac-pentol-promethazine controlled-release tablets.

[0115] 3. Coating

[0116] 3.1 Preparation of rapid-release pore-forming agent: 80 g of potassium guaiacol sulfonate II, 6.7 g of pentoxyverine citrate II, 3.3 g of promethazine hydrochloride II were crushed into 120 mesh fine powder, mixed evenly, and prepared into rapid-release pore-forming agent.

[0117] 3.2 Preparation of coating solution: Dissolve 240 g cellulose acetate, 90 g quick-release pore-forming agent, and 90 g triethyl acetyl citrate in 2700 ml acetone-water to prepare a coating solution.

[0118] 3.3 Coating: Place the tablet cores prepared in 1.3 into a high-efficiency coating machine, control the preheating speed to 4 rpm, preheat the air inlet temperature to 80°C, and preheat the air outlet temperature to 60°C. Preheat for 35 minutes, adjust the coating speed of the coating machine to 8 rpm, the coating air inlet temperature to 90°C, and the coating air outlet temperature to 70°C, spray the coating liquid, control the flow rate until the coating liquid dries layer by layer on the tablet surface, and ensure that all the coating liquid covers the surface of the tablet core, thereby obtaining the guaiac-pentol promethazine controlled-release tablets.

[0119] Example 2

[0120] The difference between the guaiac pentol promethazine controlled release tablets prepared in Example 2 and Example 1 is that the amount of the osmotic pressure enhancer xylitol is reduced to 180 g, and the amount of the diluent compressible starch is increased to 697 g. The other components and preparation steps are the same as those in Example 1. The specific formula is shown in Table 2 below:

[0121] Table 2

[0122]

[0123]

[0124] 10,000 pieces were made.

[0125] Example 3

[0126] The difference between the guaiac pentol promethazine controlled-release tablets prepared in Example 3 and Example 1 is that the amount of the skeleton carrier is reduced to 540 g, and the amount of the diluent compressible starch is increased to 937 g. The other components and preparation steps are the same as those in Example 1. The specific formula is shown in Table 3 below:

[0127] Table 3

[0128]

[0129] 10,000 pieces were made.

[0130] Example 4

[0131] The difference between the guaiac pentol promethazine controlled-release tablets prepared in Example 4 and Example 1 is that the amount of disintegrant croscarmellose sodium is reduced to 90 g, and the amount of diluent compressible starch is increased to 637 g. The other components and preparation steps are the same as those in Example 1. The specific formula is shown in Table 4 below:

[0132] Table 4

[0133]

[0134]

[0135] 10,000 pieces were made.

[0136] Example 5

[0137] The difference between the guaiac pentol promethazine controlled-release tablets prepared in Example 5 and Example 1 is that the amount of the plasticizer triethyl acetyl citrate is reduced to 54 g, and the amount of the film-forming material cellulose acetate is increased to 276 g. The other components and preparation steps are the same as those in Example 1. The specific formula is shown in Table 5 below:

[0138] Table 5

[0139]

[0140] 10,000 pieces were made.

[0141] Example 6

[0142] The difference between the guaiacol pentol promethazine controlled-release tablets prepared in Example 6 and Example 1 is that the amounts of the quick-release pore-forming agents potassium guaiacol sulfonate II, pentol citrate II, and promethazine hydrochloride II are reduced to 48g, 3.84g, and 2.52g, respectively, the amounts of the controlled-release drug components potassium guaiacol sulfonate I, pentol citrate I, and promethazine hydrochloride I are increased to 452g, 36.16g, and 17.48g, the amount of the diluent compressible starch is reduced to 541.36g, and the amount of the film-forming material cellulose acetate is increased to 275.64g. The other components and preparation steps are the same as in Example 1. The specific formula is shown in Table 6 below:

[0143] Table 6

[0144]

[0145]

[0146] 10,000 pieces were made.

[0147] Comparative Example 1

[0148] The difference between the guaiac pentol promethazine controlled-release tablets prepared in Comparative Example 1 and Example 1 is that the osmotic pressure enhancer xylitol is removed from the raw material components, and the diluent compressible starch is increased to 877g. The other components and preparation steps are the same as those in Example 1. The specific formula is shown in Table 7 below:

[0149] Table 7

[0150]

[0151] 10,000 pieces were made.

[0152] Comparative Example 2

[0153] The difference between the guaiac pentol promethazine controlled-release tablets prepared in Comparative Example 2 and Example 1 is that the skeleton carrier ethyl cellulose is removed from the raw material components, and the diluent compressible starch is increased to 1477g. The other components and preparation steps are the same as those in Example 1. The specific formula is shown in Table 8 below:

[0154] Table 8

[0155]

[0156]

[0157] 10,000 pieces were made.

[0158] Comparative Example 3

[0159] The difference between the guaiacol pentol promethazine controlled release tablets prepared in Comparative Example 3 and Example 1 is that 90 g of sodium chloride, a pore-forming agent, is used to replace the second active ingredient of the drug, the amounts of potassium guaiacol sulfonate I, pentol citrate I, and promethazine hydrochloride I are increased to 500 g, 40 g, and 20 g, respectively, and the amount of diluent compressible starch is reduced to 487 g. The other components and preparation steps are the same as those in Example 1. The specific formula is shown in Table 9 below:

[0160] Table 9

[0161]

[0162] 10,000 pieces were made.

[0163] Comparative Example 4

[0164] The difference between the guaiac pentol promethazine controlled-release tablets prepared in Comparative Example 4 and Example 1 is that the disintegrant croscarmellose sodium is removed from the raw material components, and the amount of the diluent compressible starch is increased to 727 g. The other components and preparation steps are the same as those in Example 1. The specific formula is shown in Table 10 below:

[0165] Table 10

[0166]

[0167]

[0168] 10,000 pieces were made.

[0169] Comparative Example 5

[0170] The difference between the guaiacol pentol promethazine controlled-release tablets prepared in Comparative Example 5 and Example 1 is that the second active ingredient of the raw material components is removed, the amount of the film-forming material is increased to 330g, the amount of the controlled-release drug components guaiacol sulfonate potassium I, pentol citrate I, and promethazine hydrochloride I is increased to 500g, 40g, and 20g, and the amount of the diluent compressible starch is reduced to 487g. The other components and preparation steps are the same as those in Example 1. The specific formula is shown in Table 11 below:

[0171] Table 11

[0172]

[0173] 10,000 pieces were made.

[0174] Performance study of the guaiac pentol promethazine controlled-release tablets prepared in Examples 1-6 and Comparative Examples 1-5 of the present application:

[0175] 1. Assay method for guaiac pentol promethazine matrix osmotic pump controlled release tablets

[0176] 1.1 Pentoxetine Citrate

[0177] 1.1.1 Test Solution Take 6 tablets of each example and comparative example sample respectively, and adopt the second method (slurry method) of "Dissolution and Release Determination" of the 2020 edition of the "Chinese Pharmacopoeia" (Part IV), with water as the dissolution medium, a volume of 1000 mL, a rotation speed of 75 r / min, and a temperature of (37±5°C). Operate according to the law, and take 10 mL of the dissolution solution at 0, 2 min, 10 min, 0.5 h, 1.0 h, 1.5 h, 2.0 h, 3.0 h, 4.0 h, 8.0 h, 16.0 h, and 24.0 h, respectively. Filter through a 0.45 μm microporous filter membrane, and take the filtrate to obtain.

[0178] 1.1.2 Reference solution Accurately weigh 0.01278 g of pentoxyverine citrate reference substance, place it in a 50 mL volumetric flask, add mobile phase to dissolve and make up to volume, shake well, and use it as the pentoxyverine citrate reference substance stock solution. Take 10 mL of the pentoxyverine citrate reference substance stock solution, place it in a 50 mL volumetric flask, shake well, and obtain.

[0179] 1.1.3 Chromatographic conditions Chromatographic column: CAPCELL PAK C18 MGⅡS-5 (250 mm×4.6 mm, 5 μm); mobile phase: acetonitrile-triethylamine phosphate buffer solution (pH 2.6±0.05) (33:67, V / V); detection wavelength: 215 nm (pentylene citrate); flow rate: 1.0 ml / min; column temperature: 35°C, injection volume 20 μl.

[0180] 1.1.4 System suitability requirements: The theoretical plate number calculated based on the pentoxyverine citrate peak shall not be less than 2000, and the separation between adjacent chromatographic peaks shall not be less than 1.8.

[0181] 1.1.5 Determination method: Accurately measure 20 μl of the test solution and the reference solution and inject them into the liquid chromatograph, record the chromatogram, and calculate the peak area according to the external standard method.

[0182] The cumulative release rates and curves of pentoxyverine citrate in each embodiment and comparative example are shown in Table 12.

[0183] The test results are shown in Table 12 below:

[0184] Table 12 Cumulative release of pentoxyverine citrate

[0185]

[0186]

[0187] The cumulative release of pentoxyverine citrate was used as the evaluation index in the examples and comparative examples of the present application. The slope of the release curve indicated its release rate, and the linear correlation coefficient indicated the uniformity of its release rate and the zero-order release level.

[0188] The overall correlation coefficient of the cumulative release curve of Example 1 is 0.9952, and the slope is 0.0641. Its release rate is greater than that of Examples 2, 4, 6 and Comparative Examples 1, 4, and 5. This is because the osmotic pressure enhancer, disintegrant, and rapid-release pore-forming agent (rapid-release pore-forming agent is the second active ingredient of the drug) are reduced, resulting in a decrease in osmotic pressure and a prolongation of disintegration time, which slows down the release rate and even significantly reduces the zero-order release level of Examples 2 and 4.

[0189] Examples 3 and 5 respectively reduce the amount of skeleton controlled release carrier material and plasticizer, resulting in a significant reduction in the zero-order release degree of Examples 3 and 5. However, the release rate is reduced due to the reduction in skeleton material and plasticizer, resulting in a reduced retardation degree, accelerated dissolution rate, and increased release rate in Example 3. The reduction in plasticizer in Example 5 leads to reduced plasticity and toughness of the film, accelerated release rate of the film, and significantly reduced zero-order release level.

[0190] The zero-order release level of Example 6 is higher than that of Example 1 because the amount of its rapid-release pore-forming agent is reduced, resulting in a decrease in its osmotic release rate and a significant increase in the osmotic pressure in the membrane, which leads to a significant increase in its zero-order release level.

[0191] In Comparative Example 1, due to the lack of an osmotic pressure enhancer, the osmotic pressure of the sample dropped significantly, the release dynamics decreased significantly, and the release rate decreased significantly. At the same time, the zero-order release level of the release curve decreased significantly.

[0192] Comparative Example 2 lacks the skeleton control carrier ethyl cellulose, which causes its dissolution retardation for the active ingredient to disappear, resulting in a significant increase in its release rate, and the slope of the cumulative release curve reaches 0.0707, causing it to reach the maximum cumulative release prematurely, and its zero-order release level is also further reduced.

[0193] Comparative Example 3 uses sodium chloride to replace the rapid-release pore-forming agent (the second active pharmaceutical ingredient). Although its release rate and zero-order release level are significantly improved, its initial drug concentration at 2 minutes is lower than all the embodiments and comparative examples except Comparative Example 5 in which no pore-forming agent is added.

[0194] The lack of disintegrant in Comparative Example 4 results in only a natural disintegration state, which inevitably leads to a serious reduction in the dissolution rate of the active pharmaceutical ingredient, thereby significantly reducing its release rate. At the same time, even under the promotion of high osmotic pressure, it cannot maintain its constant zero-order release level.

[0195] The absence of the porogen (second active pharmaceutical ingredient) in Comparative Example 5 causes the film coating to lose its drug release pores, and its release behavior relies solely on the osmotic release of the cellulose acetate semipermeable membrane, causing its release rate to be reduced to the minimum. However, under the control of the semipermeable membrane, its zero-order release level is greatly improved.

[0196] Therefore, as a preferred technical solution, Example 1 shows unparalleled advantages over other examples and comparative examples. Even the linear correlation coefficient from 2min to 24h is higher than that of all other examples and comparative examples, revealing that its zero-order release level is at the highest level among all examples and comparative examples.

[0197] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A guaiac-pentol promethazine controlled-release tablet, characterized in that: comprising a tablet core and a coating covering the tablet core; The core comprises the following raw material components: A first active pharmaceutical ingredient, a skeleton carrier, an osmotic pressure enhancer and a disintegrant; The coating comprises the following raw material components: a film-forming material and a second active pharmaceutical ingredient; The first active pharmaceutical ingredient and the second active pharmaceutical ingredient both include potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride.

2. The guaiac-pentol promethazine controlled-release tablets according to claim 1, characterized in that: The tablet core comprises the following raw material components in parts by weight: 7-12 parts of the first active ingredient, 13-23 parts of the skeleton carrier, 4-8 parts of the osmotic pressure enhancer and 2-4 parts of the disintegrant; And / or, the coating comprises the following raw material components in parts by weight: 3-6 parts of film-forming material and 1-3 parts of the second active ingredient.

3. The guaiac-pentol promethazine controlled-release tablet according to claim 1, characterized in that: The weight proportions of potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride contained in the first active ingredient are as follows: 6-12 parts of the potassium guaiacol sulfonate, 0.5-0.9 parts of the pentoxyverine citrate, and 0.2-0.5 parts of the promethazine hydrochloride; And / or, the weight proportions of potassium guaiacol sulfonate, pentoxyverine citrate and promethazine hydrochloride contained in the second active pharmaceutical ingredient are as follows: The potassium guaiacol sulfonate is 1 part to 2 parts, the pentoxyverine citrate is 0.1 part to 0.2 parts, and the promethazine hydrochloride is 0.05 part to 0.08 parts.

4. The guaiac-pentol promethazine controlled-release tablet according to claim 1, characterized in that: The mass ratio of the tablet core to the coating is (84-86):(14-16).

5. The guaiacpentol promethazine controlled-release tablet according to any one of claims 1 to 4, characterized in that: The tablet core further comprises the following components in parts by weight: 7-13 parts of diluent, 2-4 parts of binder, 0.1-0.3 parts of glidant and 0.3-0.5 parts of lubricant; And / or, the coating further comprises the following ingredients in parts by weight: 1 to 3 parts of a plasticizer and 40 to 65 parts of a solvent.

6. The guaiac-pentol promethazine controlled-release tablets according to claim 4, characterized in that: The skeleton carrier comprises one or more of ethyl cellulose, methyl cellulose, chitosan, poly (meth) acrylic acid resin, beta sitosterol, palmitic acid glyceride and cholesterol glyceride; and / or, the osmotic pressure enhancer comprises one or more of dextran, glucose, xylitol and sorbitol; and / or, the disintegrant comprises one or more of crospovidone, croscarmellose sodium, croscarmellose calcium and microcrystalline cellulose; and / or, the film-forming material comprises one or more of ethyl cellulose, cellulose acetate, and cellulose acetate; and / or, the diluent comprises one or more of mannitol, micropowdered silica gel, microcrystalline cellulose, lactose, and starch; and / or, the adhesive comprises one or more of gum arabic, zein, maltodextrin, and methylcellulose; and / or, the glidant comprises one or more of microcrystalline cellulose, micropowdered silica gel and silicon dioxide; and / or, the lubricant comprises one or more of magnesium stearate, talc, micro powder silica gel and glyceryl behenate; And / or, the plasticizer includes one or more of triethyl acetyl citrate, tributyl acetyl citrate and diethyl phthalate; And / or, the solvent includes one or more of ethylene dichloride, ethanol, acetone-water, methanol, ethyl acetate, isopropanol, and acetone.

7. The method for preparing the guaiacpentol promethazine controlled-release tablets according to any one of claims 1 to 4, characterized in that: The following steps are involved: The first active pharmaceutical ingredient, the skeleton carrier, the osmotic pressure enhancer and the disintegrant are mixed to prepare a tablet core; dissolving a film-forming material and the second active pharmaceutical ingredient in a solvent to obtain a coating solution; The coating liquid is used to coat the tablet core to obtain the guaiac-pentol-promethazine controlled-release tablets.

8. The method for preparing the guaiacpentol promethazine controlled-release tablets according to claim 7, characterized in that: The solution containing the first active pharmaceutical ingredient and the solution containing the skeleton carrier are mixed, and the solvent is removed to obtain a solid dispersion; the solid dispersion, the osmotic pressure enhancer and the disintegrant are mixed to prepare a tablet core.

9. The method for preparing the guaiacpentol promethazine controlled-release tablets according to claim 8, characterized in that: The solution containing the first active pharmaceutical ingredient and the solution containing the skeleton carrier are both ethanol solutions; And / or, the method of removing the solvent includes concentration treatment and drying treatment; wherein the concentration temperature is 70°C-75°C, the vacuum degree is -0.05MPa to -0.08MPa, and the relative density of the concentrated product is 1.30-1.35; the drying temperature is 70°C-75°C, the vacuum degree is -0.05MPa to -0.08MPa, and the water content of the solid dispersion is 3.1%-3.4%; And / or, the raw materials for preparing the tablet core further include a first auxiliary agent, wherein the first auxiliary agent includes a diluent, a binder, a glidant and a lubricant; The solid dispersion, the osmotic pressure enhancer, the disintegrant, and the diluent are mixed to obtain a mixed powder, the mixed powder and a binder solution are mixed to form a soft material, and the soft material is dried, and the dried product is mixed with the flow aid and the lubricant, and pressed into tablets to obtain the tablet core.

10. The method for preparing the guaiacpentol promethazine controlled-release tablets according to claim 7, characterized in that: The raw material components for preparing the coating solution also include a second auxiliary agent, and the second auxiliary agent includes a plasticizer; dissolving the second active pharmaceutical ingredient, the film-forming material and the plasticizer in the solvent to obtain a coating solution; And / or, the equipment for implementing the coating includes a coating machine; the preheating speed of the coating machine is controlled to be 3 rpm-4 rpm, the preheating air inlet temperature is 70℃-80℃, the preheating air outlet temperature is 50℃-60℃, the preheating time is 30 minutes-40 minutes, the coating speed of the coating machine is adjusted to 6 rpm-8 rpm, the coating air inlet temperature is 80℃-90℃, the coating air outlet temperature is 60℃-70℃, and the coating liquid is sprayed to coat the tablet cores.

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