WO2009000132A1

WO2009000132A1 - Immediate release effervescent-formulation and preparing process thereof

Info

Publication number: WO2009000132A1
Application number: PCT/CN2007/070436
Authority: WO
Inventors: Hongping Yie; Meg M. Sun; Zuolin Zhu
Original assignee: Pficker Pharmaceuticals Ltd.
Priority date: 2007-06-23
Filing date: 2007-08-08
Publication date: 2008-12-31
Also published as: CN101084881B; CN101084881A

Abstract

An immediate release effervescent-formulation in which unpleasant taste of drug is masked, comprising effervescent matrix, active compound coated with stomach-soluble polymers, and process for their preparation.

Description

Instant release effervescent preparation and preparation method thereof

The present invention relates to a novel preparation method, and more particularly to an effervescent preparation having targeted delivery, rapid onset of action, and good taste masking function, and a preparation method thereof. The product prepared by the preparation method disclosed by the invention also has certain functions of regulating the body pH, reducing oxidative stress and preventing diseases. Background technique

Effervescent tablets or effervescent granules have many advantages, such as rapid disintegration in water, rapid release of active ingredients, adequate maintenance of physiological activity of active ingredients, improvement of stability of biologically active substances, and promotion of rapid human active ingredients. Absorbed, easy to take, and more.

Acidification of the body is a ubiquitous phenomenon in patients with diseases and the elderly. The bodies of healthy people and adolescents are all slightly alkaline. In an acidic environment, the production of free radicals is easier, and the level of oxidative stress in the body is increased. Oxidative Stress (OS) is the main cause of various cell damage in the body and is thought to cause diabetes and diabetes. Chronic complications, pulmonary fibrosis, epilepsy, hypertension, atherosclerosis and corresponding cardiovascular diseases, cancer, nephropathy, and Parkinson's disease are important causes. Although it is found from the clinical evaluation results that the acidic body does not necessarily have lesions, many patients, such as cancer patients, are basically acidic, but maintaining the body in a slightly alkaline state is one of the important means to reduce the level of oxidative stress.

The acidity and alkalinity of foods are not determined by mouthfeel, but by the results of digestion and absorption of food in the body. If the phosphate, sulfate, and chloride ions produced by food metabolism are relatively high, the body will be acidified and acidic. If the food is metabolized, the sodium, potassium, magnesium, and calcium ions will be more. It is easy to cause alkalization of the body and is an alkaline food. Although citric acid and the like are acidic, the human body's metabolism converts it into water and carbon dioxide, which is a neutral food. It can be seen that the other one of the effervescent tablets or effervescent granules that has been neglected by humans has the advantage of providing the alkaline substances necessary for the body, helping to regulate the body to be slightly alkaline and reducing the oxidative stress.

The advantages of integrated effervescent tablets or effervescent granules can be found that this formulation method is very suitable for drugs that require rapid onset, such as lowering body temperature during fever, relieving pain, diarrhea, lowering blood pressure, sleeping, allergies, and treating motion sickness. and many more. But because many drugs have a strong stimulating taste, such as Ibuprofen, paracetamol

(Acetaminophen), loperamide hydrochloride, reserpine, Alprazolam, diphenhydramine, Dimenhydrinate, etc. Formulation method using effervescent tablets or effervescent granules. Although many studies have found ways to mask the aggressive taste of these drugs, prior to the present invention, these drugs have not been successfully prepared into effervescent tablets and effervescent granules. The key problem is that there are three major problems. First, the reported drug coatings for these irritating tastes may be broken in the presence of solid acid-base agents in the preparation of effervescent dosage forms, resulting in the preparation of effervescent agents. The taste function does not meet the requirements; secondly, the acid content in the traditional effervescent agent is very high, the pH value of the aqueous solution after water dissolution is less than 5, the dissolution of the drug is fast, and the prepared effervescent agent does not have the taste function. To the request; third, the reported wrapping methods are all caused The release of the active ingredient of the drug is slow and the effervescent design cannot be achieved quickly.

For example, U.S. Patent No. 5,587,179 discloses the use of low melting point fatty acid esters or beeswax as a wrapping material to encapsulate these stimulating tastes in high molecular fatty acid esters or beeswax because of these low melting fatty acid esters or The bee wax melts at a temperature above 30 ° C and releases the medicine wrapped therein. This method cannot completely avoid the dissolution of the drug at normal temperature, the taste-masking function is not required, and the drug release in the body is slow, and the preparation does not have a targeting function, and the drug effervescent agent prepared by the method has Both aqueous solutions exhibited a more aggressive taste, and the formulation method as an effervescent tablet or effervescent granule was not successful.

Therefore, there is an urgent need in the art for an effervescent formulation having targeted delivery, rapid onset of action, and good taste masking function, and a method for preparing the same. Summary of the invention

An object of the present invention is to obtain an effervescent agent which has targeted delivery, can quickly act, and has a good taste-masking function, and also has a certain function of regulating body pH, reducing oxidative stress, and preventing diseases.

Another object of the present invention is to provide a method of formulating a new invention of an effervescent.

A further object of the invention is to provide a use of the effervescent agent of the invention. A first aspect of the invention provides an effervescent agent comprising an effective amount of an effervescent matrix, further comprising:

A therapeutically effective amount of the active substance, and

An effective amount of a targeted release material, wherein the targeted release material is a high molecular polymer coating material covering the active material, and the high molecular polymer coating material comprises only soluble in human and/or animal stomachs a high molecular polymer in an internal pH environment;

5重量%。 The high molecular weight of the polymer coating material is not less than 0.5% by weight.

In a preferred embodiment, the active substance is selected from a fast acting drug or a stomach drug; preferably, the fast acting drug is selected from the group consisting of ibuprofen, acetaminophen, ropramine hydrochloride, reserpine, and apradazole. a benzoic acid, diphenhydramine, or tea diphenhydramine; the stomach drug is selected from the group consisting of bismuth subruthenate.

In a preferred embodiment, the high molecular polymer is selected from the group consisting of polymers having a functional group of an amino group;

Preferably, the high molecular polymer is selected from the group consisting of polyvinyl acetal diethylaminoacetate, IV gastric soluble resin (Jiangsu Jichuan Pharmaceutical Co., Ltd.), aminoalkyl methacrylate copolymer or a combination thereof. More preferably, the aminoalkyl methacrylate copolymer is preferably Eudragi t E polymer;

Preferably, the high molecular weight polymer is between 0.5% and 99.9%, more preferably between 5% and 95%, based on the total weight of the polymer coating material.

In a preferred embodiment, the weight ratio of the effervescent matrix, the active substance, and the targeted release material is: 25-90% of the effervescent matrix, 0.01%-70% of the active substance, and 0 of the targeted release substance. 5-%. The active substance is 0.10% to 90%, the active substance is 0.1%-50%, and the target release substance is 1-30%, Calculated based on the total weight of the effervescent agent. In a preferred embodiment, the high molecular polymer coating material further comprises a glycerin fatty acid ester, preferably a monoglyceride, and more preferably, the monoglyceride is selected from the group consisting of glyceryl monostearate, single palm. Acid glyceride, glycerol monooleate, glyceryl monocaprylate, glyceryl monocaprate, glycerol monolaurate or a combination thereof; most preferably selected from glyceryl monostearate;

And the weight ratio of the glycerin fatty acid ester to the high molecular polymer is between 95: 5 and 35: 65; preferably, between (1 and 8): 1.

In a preferred embodiment, the molar ratio of the acid agent to the alkaline agent in the effervescent matrix is 1: (0.95~1. 05); preferably, the alkali agent of the effervescent matrix is selected from the group consisting of sodium hydrogencarbonate , potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium glycinate carbonate or a combination thereof;

Preferably, the acidulant of the effervescent matrix is selected from the group consisting of citric acid, glycine citrate, monosodium citrate, malic acid, tartaric acid, fumaric acid or a combination thereof. Another aspect of the invention provides a method for preparing an effervescent agent, comprising the steps of:

(a) providing an effective amount of an effervescent matrix, a therapeutically effective amount of an active substance, an effective amount of a mixture of targeted release materials, and said mixture being free of volatile organic solvents;

Wherein the targeted release substance is a high molecular polymer coating material covering the active material, and the high molecular polymer coating material comprises a high molecular polymer which is only soluble in the pH environment of human and/or animal stomach. ;

(b) granulating the mixture to obtain the effervescent.

In a preferred embodiment, the mixture of step (a) is obtained by the following steps:

(i) providing particles of an active material, the active material externally covering the high molecular polymer coating material;

(i i) The particles of the step (i) are mixed with the effervescent matrix to obtain the mixture of the step (a).

In a preferred embodiment, the high molecular polymer coating material in the step (i) further contains a monoglyceride, and the weight ratio of the monoglyceride to the high molecular polymer is 95: 5 to 35. : 65 between.

In a preferred embodiment, the particles of the active material in step (i) are obtained by the following method:

(I) providing a monoglyceride solution of a high molecular polymer, and a mixture of active materials;

Preferably, the fineness of the active substance in the step (I) is not more than 100 mesh;

(I I) the mixture of the step (I) is granulated to obtain particles of the active material in the step (i);

Preferably, the step (Π) is granulated by a spray granulation method; more preferably, the granulation method of the step (Π) comprises the following steps: the mixture of the step (I) is passed at 40 ° C ± 5 ° C The granules were granulated at ° C for 30 minutes to 60 minutes; the granules of the active material in the step (i) were obtained. Another aspect of the invention provides the use of an effervescent agent of the invention for the targeted release of a drug, for the rapid onset of action of the drug, or for the irritating taste of the drug. detailed description Through intensive and intensive research and design, the inventors have utilized targeted release materials as coating materials, so that preparations requiring rapid onset can be prepared by using a formulation method of an effervescent agent such as an effervescent tablet or an effervescent granule. Lower body temperature, pain relief, diarrhea, blood pressure lowering, sleep, allergies, and treatment of motion sickness, etc. In a preferred embodiment of the present invention, the inventors have found that the addition of glycerin fatty acid ester to the coating can achieve particularly excellent effects. The present invention has been completed on this basis.

As used herein, "fast acting drug", unless otherwise indicated, refers to a drug that achieves a maximum blood concentration within two hours, preferably within thirty minutes. Specifically, for example, in an oral drug Advi l tablet, after drinking into the body, the blood concentration reaches the highest concentration at 101 minutes, and the drug is generally considered to be a fast-acting drug. The "quick-acting drug" of the present invention may be, but is not limited to, a medicine for lowering body temperature, relieving pain, diarrhea, lowering blood pressure, sleeping, allergic, or treating motion sickness, etc., or a strong stimulation. Sexual taste medications may be, but are not limited to, specific examples such as ibuprofen, paracetamol, ropramine hydrochloride, reserpine, alprazolam, diphenhydramine, or diphenhydramine.

As used herein, "stomach medicine", unless otherwise indicated, refers to a drug that lowers gastric acid or treats gastritis. It can be, but is not limited to, bi smuth subsal icylate.

As used herein, "a polymer that is only soluble in the pH environment of human and/or animal stomach" means that these polymers dissolve when they reach the low pH environmental liquid in the stomach, while in other in vivo environments. Insoluble polymer. Specifically, for example, a high-molecular polymer which can rapidly dissolve into a salt by a digestive solution having a pH of 0.5 or less such as gastric acid.

As used herein, "pharmaceutically acceptable carrier" refers to a carrier for therapeutic administration which is not a necessary active ingredient per se and which is not excessively toxic after administration. For example, excipients, fillers, disintegrators, emulsifiers, flavoring agents, lubricants, binders, fillers, colorants, flavoring agents, plasticizers, fat-soluble auxiliary substances, antioxidants, and the like.

As used herein, "effective amount of effervescent matrix" means carbon dioxide in an amount sufficient to produce a fully disintegrated effervescent tablet and a granule solid structure. Specifically, for example, the effervescent matrix accounts for 25 to 90% by weight of the effervescent agent.

As used herein, "effective amount of a targeted release substance" means that the amount of the targeted release substance can cover the active substance.

As used herein, "therapeutically effective amount" refers to an amount that produces a function or activity to a human and/or animal and that is acceptable to humans and/or animals. The specific amount to be used depends on the specific drug to be used, as long as it does not limit the object of the present invention.

As used herein, "overlay", unless otherwise indicated, includes various means of reducing the surface area of contact of the active substance with the living being, including humans and animals, such as partially or fully encapsulating the active. Preferably, all of the wrapping is carried out to form a coating material. Various aspects of the invention are detailed below:

Targeted release substance

The targeted release material of the present invention is a high molecular polymer coating material covering the active material, wherein The high molecular polymer includes a high molecular polymer which is only soluble in the pH environment of the stomach of humans and/or animals.

These high molecular polymers are characterized by being soluble only in the acidic phase of the aqueous phase and not in any other aqueous solution of pH. This feature ensures that the product dissolves only in the relatively low pH environment of the human stomach, and the product has a targeted delivery effervescent tablet or effervescent granule in the stomach. For example, it is only soluble in the stomach ρΗ1~5 and is insoluble in other pH environments.

Preferably, the release rate of the targeted release material is measured as the effective maximum blood drug concentration achievement time, generally less than two hours, preferably less than one hour, and ideally between 30 minutes and one hour.

More preferably, the high molecular polymer selected in the present invention is a polymer having a functional group of an amino group and having no significant toxic effect on humans and animals, since the amino group rapidly forms a salt under acidic conditions and dissolves rapidly. Such polymers include, but are not limited to, polyethylidene; polyvinylacetal di ethylaminoacetate, a gastric-soluble resin IV produced by Jiangsu Jichuan Pharmaceutical Co., Ltd., aminoalkyl methacrylate Ester copolymer. Nowadays, the most popular one is the product of the commercial famous special E (Eudragit E polymer, the Uchit E functional group is a tertiary amino group, the material can be quickly dissolved into salt after the PH 5. 0 or lower of the stomach acid, effectively avoiding the mouth, The esophagus and other parts are released, but do not affect the dissolution time of the drug, and a mixture of these high molecular polymers and the like.

Other additives may be included in the high molecular polymer coating material of the present invention, and the additives are not particularly limited as long as the object of the present invention is not limited. For example, glycerol fatty acid esters, various cellulose organic acid esters, amylose organic acid esters, derivatized cellulose organic acid esters (e.g., hydroxypropyl cellulose, etc.), gelatin, shellac, keratin, or combinations thereof. Preferably, the additive can lower the melting point of the high molecular polymer to 42 to 100 °C. For example glycerol fatty acid esters.

In a preferred embodiment, we have found that a mixture of a polymer having a functional group and an amino group added to a high molecular weight polymer in a high molecular polymer coating material is used for a pharmaceutical ingredient. In the case of the coating material, the prepared effervescent preparation has a function of being quick-dissolving in the stomach and having a particularly excellent taste-masking effect. And after mixing a certain amount of glycerin fatty acid ester, the obtained mixture has a melting point lower than 100 ° C, for example, the mixture contains 60 parts by weight of glyceryl monostearate and 10 parts of Eudragit E polymerization. In the case of a mixture, the melting point of the mixture is lower than 90 ° C.

After the addition of the glycerol fatty acid ester, the prepared effervescent tablet has a more accelerated effect on the dissolution rate in the stomach; the second is to better achieve the taste-masking function in the preparation of the effervescent agent, and at the same time, the macromolecular polymerization is used alone. Volatile organic solvents are required for dissolution, and the use of volatile solvents causes a series of problems such as complicated production processes, production safety problems, and solvent residues in the products. The addition of glycerin fatty acid esters solves the above problems.

The "fatty acid" in the glycerin fatty acid ester means "organic substance having one long hydrocarbon chain and one terminal carboxyl group", and the long hydrocarbon chain is preferably a C6 to C30 hydrocarbon chain, preferably stearic acid or palmitic acid. , oleic acid octanoic acid, citric acid, lauric acid or a combination thereof.

The glycerin fatty acid ester used in the present invention may be a monoglyceride, a diglyceride, a triglyceride or a combination thereof, preferably a monoglyceride. Monoglycerides are generally glyceryl monostearate, glyceryl monopalmitate, glyceryl monooleate, glyceryl monocapry ate J, monodecanoic acid Glyceryl monocaprate, glyceryl monolaurate Monolaurate ) , or a combination thereof. Commonly used glyceryl monostearate.

The ratio of the high molecular polymer to the glycerin fatty acid ester is selected according to the following guidelines: The melting point of the mixture is lower than 100 ° C, the mixture is easily melted, and the active ingredient of the main drug is prevented from deteriorating at a high temperature; The melting point of the mixture is again higher than 45 ° C to prevent the prepared product from being dissolved in other parts of the body. Because if the patient has a fever, the temperature in the body may reach 42 ° C. At this temperature, the drug-encapsulated polymer will be thermally melted to release the drug, which will affect the product's targeting ability. Preferably, the weight ratio of the glycerin fatty acid ester to the polymer is generally selected to be between 95:5 and 35:65, and the range of usual is between (1 and 8):1.

The amount of the targeted release substance to be used is not particularly limited as long as the targeted release substance can cover the active substance. Specifically, for example, 0.5% by weight to 74.9% by weight, preferably 1% to 30% by weight based on the total weight of the effervescent agent.

5%。 Preferably, the polymer polymer is 0. 5%, preferably the polymer comprises 0% of the total weight of the polymer coating material. Between 5% and 99.9%, more preferably between 5% and 95%. Active substance

The active substance of the present invention may be a drug having a strong stimulating taste, and may be, but not limited to, ibuprofen, acetaminophen, ropramine hydrochloride, reserpine, alprazolam, diphenhydramine, and Tea diphenhydramine, etc.; may also be a stomach drug, which may be, but is not limited to, bi smuth subsal icylate.

The amount of the active material to be used depends on the specific drug to be used, as long as it does not limit the object of the present invention. For example, the active substance is 0.01%-50%, based on the total weight of the effervescent agent. Specifically, for example, ropramin hydrochloride, the amount of each dose is 2 mg; bismuth subtussate, each dose containing the active ingredient 500 mg of bismuth subtussate and the like. Effervescent matrix

The effervescent matrix in the effervescent agent of the present invention (e.g., effervescent granules or effervescent tablets) consists of an edible acid agent and an edible alkaline agent which produces carbon dioxide.

The alkaline agent of the present invention is not particularly limited as long as it does not limit the object of the present invention. For example, a mixed carbonate of potassium and sodium, or a mixed hydrogencarbonate, or a mixed salt of a carbonate and a hydrogencarbonate, the carbonate and hydrogencarbonate used may be, but not limited to, sodium hydrogencarbonate, carbonic acid Potassium hydrogen, sodium carbonate, potassium carbonate, sodium glycinate carbonate, etc., and preferred alkaline agents are anhydrous potassium hydrogencarbonate and sodium hydrogencarbonate. In the present invention, the fineness of the alkali agent is not particularly limited, and may specifically be, for example, 60 to 200 mesh, as long as the object of the present invention is not limited. The drying time of the alkaline agent is also not particularly limited as long as it does not limit the object of the present invention, specifically, for example, before use, the hydrogencarbonate is dried at 60-80 ° C for 2-4 hours; the carbonate is at 105 - Dry at 1200 °C for 2-4 hours.

The acid agent of the present invention is not particularly limited as long as it does not limit the object of the present invention. For example, the acid agent is an edible organic acid, and may be, but not limited to, one or more of citric acid, glycine citrate, monosodium citrate, malic acid, tartaric acid, fumaric acid, and the like (for example, two kinds). The fineness is, for example, 60-200 mesh, and should be dried at 105-110 °C for 2-4 hours before use. The ratio of the acid-base agent in the commonly used effervescent agent is different. In the effervescent matrix of the present invention, the ratio of the alkali agent to the acid agent is a nearly equal molar ratio, or the alkali agent is slightly higher than the molar amount of the acid agent. , generally higher than 0.1%, not more than 5%, otherwise the alkalinity of the effervescent prepared is too large to be taken orally.

The amount of the effervescent base of the present invention is not particularly limited as long as an effervescent effective amount is reached. By "effective amount" is meant carbon dioxide in an amount sufficient to produce a solid structure of a fully disintegrating effervescent (e.g., effervescent tablet and granule). Specifically, for example, the effervescent matrix accounts for 25 to 90% by weight based on the total weight of the effervescent agent. Effervescent agent

The effervescent agents of the present invention can be prepared into a variety of suitable traits, such as tablets, granules.

The effervescent agent of the present invention comprises an effective amount of an effervescent matrix, a therapeutically effective amount of an active substance, and an effective amount of a targeted release substance. 5%之间之间之间之间之间的重量之间之间的重量之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间之间), based on the total weight of the effervescent. Preferably, the effervescent matrix is 25-90%, the active substance is 0.01%-50%, and the targeted release material is 1-30%, calculated as the total weight of the effervescent agent.

The effervescent agent of the present invention may also contain a pharmaceutically acceptable carrier. For example, Corn starch acts as a filler and disintegrant; Cellulite gel and pregelatinized starch as a plasticizer and binder; Gelatin as an emulsifier , binders and disintegrants; Glycerin as a flavoring agent; Hydroxypropyl cel lulose as a water-dispersible material; Magnesium/Zinc stearate, Talc (talc) ) , silicon powder ( si l ica ), and mineral oil (Mineral oi l ) as a lubricant; microcrystalline cellulose (microcel lulose) or sodium carboxymethyl starch as a binder and disintegrant; cross-linked carboxy Corscarmel lose sodium as a binder and disintegrant; Lactose as a filler and binder; Acacia as an emulsifier and binder; Stearic acid As an emulsifier and binder; Hydroxypropyl methyl cel lulose as a binder and disintegrant; Sorbitol, Sucralose, Acesulfame Potassium), and sucrose (Sugar) as a flavoring agent; Polyethyl ene glycol as a filler, emulsifier, and disintegrant; Modified food starch as a filler and disintegrant ; as a fat-soluble auxiliary substance such as soybean oil (Oysan) and lecithin (Lecithin); sorbitol as a binder, and titanium dioxide (Titanium dioxide) as a coloring agent. In addition, effervescent tablets or effervescent granules can also be added to flavors such as orange, strawberry, lemon, etc. to adjust to the desired taste.

The amount of the pharmaceutically acceptable carrier to be used is not particularly limited as long as it does not limit the object of the present invention. Specifically, for example, sodium carboxymethyl starch is used in an amount of 4% to 8%, based on the total weight of the effervescent agent. Formulation method

The preparation method of the effervescent agent of the present invention comprises the following steps: (a) providing an effective amount of an effervescent matrix, and having treatment a mixture of an active substance, an effective amount of a targeted release substance, wherein the targeted release substance is a high molecular polymer coating material covering the active material, and the high molecular polymer coating material includes only a high molecular polymer soluble in the PH environment of the human and/or animal stomach; (b) granulating the mixture to obtain the effervescent agent. In a preferred embodiment of the present invention, the preparation method used in the present invention is to first prepare a high molecular polymer for encapsulating a drug. The above polymers have a higher melting point, and when they are used to coat the drug microparticles, it is necessary to use an organic solvent to dissolve them first to prepare a coating liquid, and conventionally, an organic solvent such as chloroform, carbon tetrachloride, toluene, or the like is used. And ethanol, etc., but using the above volatile organic solvent to dissolve, the use of volatile solvents causes a series of problems such as complicated production processes, production safety problems, and solvent residues in the products.

Another feature of the new production process is the elimination of volatile organic solvents. We have found that a certain amount of fatty acid glyceride is added to the above polymer, and the obtained mixture has a melting point of less than 100 ° C. For example, the mixture contains 60 parts by weight of glyceryl monostearate and 10 parts by weight. For the Eudragit E polymer, the melting point of the mixture is below 90 °C. The guiding principle of the ratio is that the melting point of the mixture is lower than 100 ° C, the mixture is easy to melt, and the active ingredient of the main drug is prevented from deteriorating at high temperature; at the same time, the melting point of the mixture is higher than 45 ° C. To prevent the prepared product from being dissolved in other parts of the body. Because if the patient has a fever, the temperature in the body may reach 42 ° C. At this temperature, the drug-encapsulated polymer will melt and release the drug, affecting the product's targeting ability. The weight ratio of the monoglyceride to the polymer is generally selected to be between 95:5 and 35:65, and the range of usual selection is (1 to 8):1. In a preferred embodiment of the present invention, the polymer mixture is generally prepared by using a monoglyceride as a solvent. At a certain temperature, the high molecular polymer is dissolved in the monoglyceride, but the pulverization of the desired preparation is added. The drug (API), the fineness of the drug is generally less than 100 mesh or finer. After mixing well in the mixture, the resulting mixture was used directly for granulation. The conventional granulation method can be used for granulation of a polymer polymer-coated drug in the present invention with little variation, and a spray-granulat ion is commonly used in the present invention. The obtained granules are generally granulated at a temperature of about 40 ° C to obtain desired granules of the drug powder. As a result, it was found that the prepared coated drug granules were granulated at a temperature of about 40 ° C for more than 30 minutes, and when the coated drug granules were used for preparing the effervescent agent, the masking effect on the stimulating effect of the drug was better than when the granules were not granulated. .

Other excipients may also be included in the present invention, and may be used as excipients including: corn starch as a filler and a disintegrant; cellulose gum and pregelatinized starch (Cel lulose gel and

Pregelatinized starch) as a plasticizer and binder; Gelat in as an emulsifier, binder and disintegrant; Glycerin as a flavoring agent; Hydroxypropyl cel lulose as a water dispersion Material; magnesium stearate or zinc (Magnesium/Zinc stearate), talc (tal c), silicon powder (si l ica), and mineral oil (Mineral oi l) as a lubricant; microcrystalline cellulose (microcel Lulose) as a binder and disintegrant; Croscarmel lose sodium as a binder and disintegrant; lactose

(Lactose) as a filler and binder; Acacia as an emulsifier and binder; Stearic acid (Stearic acid) as emulsifier and binder; Hydroxypropyl methyl cel lulose as binder and disintegrant; Sorbitol (Sorbito l), Sucralose, Acesulfonamide Potassium acid (Acesulfame potassium), and sucrose (Sugar) as flavoring agents; polyethylene glycol

(Polyethyl ene glycol) as a filler, emulsifier, and disintegrant; Modified food starch as a filler and disintegrant; and Soybean oi and Lecithin as fat Soluble auxiliary substance; sorbitol as a binder, and titanium dioxide (Titanium dioxide) as a coloring agent. In addition, effervescent tablets or effervescent granules can also be added to flavors such as orange, strawberry, lemon, etc. to adjust to the desired taste.

The production process employed in the effervescent agent (effervescent granule or effervescent tablet) of the present invention may further include other steps. If the product formulation contains other desired matching ingredients, lipid or fat-soluble auxiliary substances, and excipients, these ingredients are separately mixed and granulated.

The preparation method of the effervescent agent of the present invention is not particularly limited as long as it does not limit the object of the present invention.

For example, the drug powder particles and other material particles prepared above are mixed with an acid-base effervescent agent at a temperature of 15 to 25 ° C and a relative humidity of about 10%, and uniformly mixed to prepare an effervescent granule.

The above effervescent granules are press-molded on a tableting machine at a temperature of 15 to 25 ° C and a relative humidity of about 10% using a die having a diameter of 2 to 3 cm to obtain an effervescent tablet. Each tablet weighs 2. 5 to 8 grams, preferably 3 to 6 grams. package.

The preparation method in the present invention generally uses a lubricant, the lubricant includes an internal lubricant and an external lubricant, and the internal lubricant is a lubricant added to the material before the granulation; the external lubricant is added before or after tableting. Add to the mold during the process. The lubricant is one or two of polyethylene glycol 6000, fumaric acid, adipic acid, leucine, vegetable oil, or medicinal mineral oil, wherein leucine, vegetable oil, or medicinal mineral oil can be Add lubricant.

The preparations of the present invention are generally also added with an antioxidant. Commonly used antioxidants include vitamin C, vitamin E, lipoic acid, dibutylhydroxyl toluene (BHT), and hydroxyanisuccinate.

(butylhydroxyani so l, BHA) and the like.

The preparation product of the present invention can be used in the following method: Take a piece of effervescent tablet into a small amount of purified water, and dissolve it after all three minutes of dissolution. The amount and frequency of each day can be adjusted according to the specific drug situation and patient needs. When the prepared preparation product is used for rapidly lowering body temperature, such as when the active ingredient is paracetamol, the amount and frequency of use of paracetamol; when the preparation product is used for rapid diarrhea, if the active ingredient is ropramine hydrochloride , the analogy of the amount and frequency of use of ropramine hydrochloride; when the preparation of the preparation is used to quickly adjust the stomach discomfort, such as the active ingredient is bismuth subtussal, the amount and frequency of use of analog bismuth subtussal; By analogy, each dose used to treat a particular condition depends on a number of factors, including weight, age, sex, inevitable medical condition, severity of the disease, route of administration, and the like. The advantages of the invention are:

(1) The present invention can be used for preparing an effervescent tablet or effervescent granule having a strong stimulating taste, and can be, but not limited to, ibuprofen, acetaminophen, ropramine hydrochloride, reserpine, Alprazolam, diphenhydramine, and Tea diphenhydramine, etc.;

(2) The preparation method disclosed in the present invention avoids the use of a volatile organic solvent, reduces the probability of contamination of the drug by the organic solvent, and reduces the production steps;

(3) The products prepared by the preparation method have good targeting ability, and they are only dissolved in the stomach and do not dissolve in other parts. This feature makes the preparation method particularly suitable for the preparation of gastric medicine, but It is not limited to the sputum tincture of bi smuth subsal icylate. The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in which the specific conditions are not specified in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. All percentages and parts are by weight unless otherwise stated.

Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention. The preferred embodiments and materials described herein are for illustrative purposes only. Example 1

1. A pharmaceutical granule powder for preparing a high molecular polymer and a glyceryl monostearate coating (ie, a coating material):

156 g of glyceryl monostearate was melted at around 100 ° C under the protection of nitrogen, then 26 g of Eudragi t E polymer was added, and the polymer was completely dissolved under stirring, and then mixed into the mixture. Add 19 grams of ropramine hydrochloride (also known as loperamide), mix well and then granulate by cooling spray granulation. The internal temperature of the spray dryer gun is controlled at 80 ° C, and the obtained crude product is nitrogen. Under the protection of 40 ° C, the whole granules were obtained, and 190 g of a drug granule powder wrapped in a polymer and a glyceryl monostearate coating was obtained.

2. Dry the acid and alkali agents in the effervescent.

The citric acid is dried at 105-110 °C for 2-4 hours, sodium bicarbonate and potassium hydrogencarbonate are dried at 60-80 °C for 2-4 hours, then pulverized and sieved.

3, the preparation of flavoring agents and other excipients pre-formed particles

Flavoring agents and other excipients required in effervescent, 860 g of sorbitol, 21 g of maltodextrin, 2 g of titanium dioxide, 162 g of orange flavoring powder, 2 g of sucralose, 10 g of antioxidant vitamins E (acetate), and 2 g of AK sugar, after mixing the components uniformly, the granules were mixed and granulated in a high-efficiency mixing granulation apparatus, and dried to obtain 1036 g of pre-formed granules of the flavoring agent and other excipients.

4. Preparation of effervescent granules

The granules of the polymer powder and the glyceryl monostearate-coated drug granules (4.2%) obtained in the first step. ), 1042 g of dry citric acid obtained in step 2 (41.6%), 756 g of dry sodium hydrogencarbonate obtained in step 2 (30.2%), 172 g of dry potassium hydrogencarbonate obtained in step 2 (6) 9%), 500 g of the dried flavor and other excipient pre-formed granules (20%) obtained in step 3, and 26 g (1%) of mineral oil were added while stirring, and the mixture was uniformly mixed to obtain a total mixture. The particles can be directly packaged into effervescent granules Agent, each dose contains 2 mg of ropramine hydrochloride as the active ingredient.

5, effervescent tablet preparation

The total weight of the mixture is 5. 0g, a total weight of 5. 0g, a total of 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Approximately 500 tablets were obtained, and then sealed in a moisture-proof package under dry conditions, each tablet containing 2 mg of ropramine hydrochloride as an active ingredient. Example 2

1. Preparation of high molecular weight polymer and glyceryl monostearate coated pharmaceutical granule powder:

780 g of glyceryl monostearate was melted at around 100 ° C under the protection of nitrogen, and then 130 g of Eudragi t E polymer was added. After stirring, the polymer was completely dissolved and then mixed into the mixture. Add 105 grams of ibuprofen, mix well and then use granulation by cooling spray granulation. The internal temperature of the spray dryer gun is controlled at 80 ° C. The obtained crude product is under the protection of nitrogen at 40 ° C. The whole granule obtained 965 g of a drug granule powder which was wrapped in a high molecular weight polymer and a glyceryl monostearate coating.

2. Dry the acid and alkali agents in the effervescent.

The citric acid is dried at 105 - 10 ° C for 2-4 hours, and sodium bicarbonate and potassium hydrogencarbonate are dried at 60-80 ° C for 2-4 hours, then pulverized and sieved.

Flavoring agents and other excipients required in effervescent, 860 g of sorbitol, 21 g of maltodextrin, 12 g of zinc sulfate, 2 g of titanium dioxide, 162 g of orange flavoring powder, 2 g of sucralose, 10 grams of antioxidant vitamin E (acetate), and 2 grams of AK sugar, the components are mixed evenly, mixed granulation in high-efficiency mixing granulation equipment, dried to obtain flavoring agent and other excipients good pre-formed particles 1040 grams .

4. Preparation of effervescent granules

In a temperature of 15-25 ° C, a relative humidity of about 10%, weigh 965 grams of the polymer obtained in step 1 and the glyceryl monostearate coated drug granule powder, 533 grams of step 2 obtained Dry citric acid, 388 g of the dried sodium hydrogencarbonate obtained in the second step, 88 g of the dried potassium hydrogencarbonate obtained in the step 2, 500 g of the dried flavouring agent obtained in the step 3 and other excipients are preliminarily granulated while stirring 26 grams of mineral oil was added and mixed to obtain a total mixture. The granules can be packaged directly into effervescent granules.

5, effervescent tablet preparation

The total mixture obtained in the step 4 of preparing the granules is pressed and formed on a tableting machine at a temperature of 15-25 ° C and a relative humidity of about 10% using a die having a diameter of 20-30 mm, each piece weighing 5. 0 g, a total of about 500 tablets, and then sealed in a moisture-proof package under dry conditions, each tablet containing 200 mg of effective distribution. Example 3

234 grams of glyceryl monostearate was melted at around 100 ° C under the protection of nitrogen, then added 39 grams Eudragi t E polymer, after the polymer is completely dissolved under stirring, add 57 g of bismuth subruthenium to the mixture, stir well, and then granulate by cooling spray granulation, the internal temperature of the spray dryer spray gun Controlled at 80 ° C, the obtained crude granules were granulated under the protection of nitrogen at 40 ° C to obtain 320 g of the coating in the high molecular polymer and glyceryl monostearate coating material. Drug granule powder.

2. Dry the acid and alkali agents in the effervescent.

The citric acid is dried at 105-110 ° C for 2-4 hours, and sodium bicarbonate and potassium hydrogencarbonate are dried at 60-80 ° C for 2-4 hours, then pulverized and sieved.

Flavoring agents and other excipients required in effervescent, 860g of sorbitol, 21g of maltodextrin, 12g of zinc sulfate, 2g of white powder, 162g of orange flavoring powder, 2g of sucralose, 10 grams of antioxidant vitamin E (acetate), and 2 grams of AK sugar, the components are mixed evenly, mixed granulation in high-efficiency mixing granulation equipment, dried to obtain good pre-formed particles of flavoring agent and other excipients 1039 grams .

4. Preparation of effervescent granules

At a temperature of 15-25 ° C and a relative humidity of about 10%, weigh 320 grams of high molecular weight polymer and glyceryl monostearate coated drug granules, 105 grams of dry citric acid, 76 grams of dry The sodium bicarbonate, 17 g of dry potassium bicarbonate, 80 g of dried flavor and other excipients were pre-formed, and 10 g of mineral oil was added with stirring, and the mixture was uniformly mixed to obtain a total mixture. The granules can be packaged directly into effervescent granules.

5, effervescent tablet preparation

The total mixture obtained in the step 4 of preparing the granules is pressed and formed on a tableting machine at a temperature of 15-25 ° C and a relative humidity of about 10% using a die having a diameter of 20-30 mm, each piece weighing 5. 5 grams, a total of about 110 products, and then sealed in a moisture-proof package under dry conditions, each containing 500 mg of the active ingredient barium sulphate. Example 4 Preparation of a drug powder granule and effervescent tablet of a single high molecular polymer coating material:

Under the protection of nitrogen, 26 g of Eudragit E polymer was added to 200 ml of chloroform at room temperature. After the polymer was completely dissolved under stirring, 19 g of ropramine hydrochloride was added to the mixture. (i.e., loperamide), granulated by spray drying granulation after stirring uniformly, and 43 g of a drug granule powder wrapped in a high molecular polymer coating material was obtained.

The rest of the production steps were the same as those given in Example 1, to obtain an effervescent tablet Al. Comparative example 1

Control sample

1. Dry the acid and alkali agents in the effervescent.

2, prefabricated drug particles 2, 1 g of dry ropramin hydrochloride, and 860 g of sorbitol, 21 g of maltodextrin, 2 g of white powder, 162 g of orange flavoring powder, 2 g of sucralose, 10 g of antioxidant vitamin E (acetic acid Ester), and 2 g of AK sugar, after mixing the components uniformly, the granules were mixed and granulated in a high-efficiency mixing granulation apparatus, and dried to obtain 1036 g of good pre-formed granules of flavoring agent and other excipients.

3. Preparation of effervescent granules

At a temperature of 15-25 ° C and a relative humidity of about 10%, weigh 1042 g of the dried citric acid obtained in the step 1, 756 g of the dried sodium hydrogencarbonate obtained in the step 1, and 172 g of the dried step obtained in the step 1. Potassium hydrogencarbonate, 500 g of the dried pre-formed drug granules obtained in the step 2, 26 g of mineral oil was added while stirring, and the mixture was uniformly mixed to obtain a total mixture. The granules can be packaged directly into effervescent granules.

4. Preparation of effervescent tablets:

The total mixture obtained in the step 3 of preparing the granules is pressed and formed on a tableting machine at a temperature of 15-25 ° C and a relative humidity of about 10% using a die having a diameter of 20-30 mm, each piece weighing 5. 0 g, a total of about 500 tablets, and then sealed in a moisture-proof package under dry conditions, each tablet containing 2 mg of the active ingredient ropramine hydrochloride. Example 5 Performance Test

Taste test:

The effervescent tablets of Examples 1 to 4 and Comparative Example 1 were dissolved in drinking water, and about 20 ml of water was used for each tablet. A total of 20 healthy persons participated, and one mouth was taken in the mouth, and then spit off to test the aqueous solution. Inspiring and tolerable.

The test results are as follows:

After the preparation of the aqueous solution of the effervescent tablet of Comparative Example 1, all 20 people immediately tested a severe irritating taste, 6 people thought it could be tolerated, and 14 people thought it could not be tolerated.

After the preparation of the aqueous solution of the effervescent tablet A 1 of Example 4, 14 people did not test the pungent taste, 6 people felt the irritating taste, 6 people thought it could be tolerated; after 24 hours, 11 people did not test To the stimulating taste, 9 people felt an irritating taste, but 9 people thought it could be tolerated.

On the other hand, the aqueous solutions of the effervescent tablets of Examples 1 to 3 did not feel an irritating taste after preparation; after 24 hours, no irritating taste was still tested.

As a result, in the new preparation method disclosed in the present invention, the examples 1 to 4 of the present invention all achieved the effect of covering the taste, and in particular, the effervescent tablets of Examples 1 to 3 were capable of covering the taste of the coated drug. Very strong, no dissolution-release drugs were detected after 24 hours. Performance Test Example 6

Differences in pharmacokinetics:

The ibuprofen effervescent tablet of Example 2 was dissolved in drinking water, using about 150 ml of water per tablet, compared to 200 mg of commercially available Adv il tablets. A total of 18 healthy people participated in the test. Each group of 9 people measured the change of blood ibuprofen drug concentration with time after taking the patient into the body. The measurement result was the average value of 9 people. Using the effervescent tablet aqueous solution of Example 2 of the present invention, the blood drug concentration reached the highest concentration in 41 minutes after the tester drank into the body; and the Advi l tablets purchased on the market, the blood drug concentration was absorbed into the body by the tester. After that, the highest concentration was reached at 101 minutes; and using the effervescent tablet aqueous solution of Example 2 of the present invention, the highest blood concentration was 22 (μ _δ /πι1 ); and the commercially available Advi l tablets, the highest blood drug The concentration is only 15 (μ _δ ).

Further, the results of the taste masking test showed that the drug-coated drug exhibited a strong taste-masking ability in the new formulation method disclosed in the present invention, and no dissolution-release drug was detected after 24 hours. Example 7

Preparation of drug-free effervescent:

1. Dry the acid and alkali agents in the effervescent.

2, the preparation of flavoring agents and other excipients pre-formed particles

Flavoring agents and other excipients required in effervescent, 860 g of sorbitol, 21 g of maltodextrin, 2 g of white powder, 162 g of orange flavoring powder, 2 g of sucralose, 10 g of antioxidant vitamins E (acetate), and 2 g of AK sugar, after mixing the components uniformly, the granules were mixed and granulated in a high-efficiency mixing granulation apparatus, and dried to obtain 1036 g of pre-formed granules of the flavoring agent and other excipients.

3. Preparation of effervescent granules

Weigh 1042 g of dry citric acid, 756 g of dry sodium bicarbonate, 172 g of dry potassium bicarbonate, 500 g of dry flavoring agent and other at a temperature of 15-25 ° C and a relative humidity of about 10%. The pre-formed granules of the excipient were added with 26 g of mineral oil while stirring, and the mixture was uniformly mixed to obtain a total mixture. The granules can be packaged directly into effervescent granules.

4, effervescent tablet preparation

The total mixture obtained in the step 3 of preparing the granules is pressed and formed on a tableting machine at a temperature of 15-25 ° C and a relative humidity of about 10% using a die having a diameter of 20-30 mm, each piece weighing 5. 0 grams, a total of about 500 products, and then sealed moisture-proof packaging under dry conditions.

Example 8

Antitumor effect test

The effervescent tablet prepared in Example 7 was subjected to an antitumor effect test to test the inhibition of the growth of malignant mesothelioma without any pharmaceutical ingredient. Each effervescent tablet was dissolved in 100 ml of distilled water, and the cells were treated with the filtered supernatant.

The test was compared with normal benign mesothelial cells. The growth of the cells was determined by measuring the synthesis of DNA, and the colorimetric assay was performed using an enzyme-injected immunosorbent assay (ELISA). Two kinds of cells were simultaneously implanted into the 24-well culture plate, and 10 ⁵ cells were seeded into each well. Each well was filled with an equal volume of effervescent supernatant and incubated in a 37 ° C incubator. 48, and 72 hours, then at 2 μΜ of 5-bromo-2- The deoxyuridine was incubated in a 37 ° C incubator for 2 hours, and then the cells were fixed by incubation with a FixDenat solution in a 37 ° C incubator for 30 minutes.

The above cells were further incubated for 90 minutes under the action of anti-5-bromo-2-deoxyuridine antibody, and then incubated for another 30 minutes (after adding tetramethylbenzidine Tetramethylbenz i dine), and then 1 M sulfuric acid was added to stop the reaction. The absorbance at 450 nm was measured.

The blank control of the experiment did not use effervescent tablets, using distilled water, cell growth using a blank control as a base to calculate relative values.

The results show that, in the new formulation method disclosed in the present invention, the drug-free effervescent formulation has a certain ability to inhibit the growth of tumor cells without affecting the growth of normal cells. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entirety as if they are individually incorporated by reference. In addition, it should be understood that various modifications and changes may be made to the present invention, and the equivalents of the scope of the present invention. Industrial applicability

The main advantages of the effervescent agent of the present invention and its formulation method are:

First, the method of the present invention can be used to prepare an effervescent tablet or effervescent granule having a strong stimulating taste medicine, which may be, but not limited to, ibuprofen, acetaminophen, ropramin hydrochloride, and reserpine , alprazolam, diphenhydramine, and diphenhydramine, etc.;

Second, the formulation method disclosed in the present invention avoids the use of volatile organic solvents, reduces the probability of contamination of the drug by the organic solvent, and reduces the production steps;

Third, the effervescent products of the present invention have a good targeting ability, and they dissolve only in the stomach and do not dissolve in other parts.

Claims

Rights request

An effervescent agent comprising an effective amount of an effervescent matrix, characterized in that it further comprises

A therapeutically effective amount of the active substance, and

2. The effervescent composition of claim 1 wherein

The active substance is selected from the group consisting of a fast acting drug or a stomach drug; preferably, the fast acting drug is selected from the group consisting of ibuprofen, acetaminophen, ropramin hydrochloride, reserpine, alprazolam, diphenhydramine Or tea diphenhydramine; the stomach drug is selected from the group consisting of bismuth subruthenate;

and / or

The high molecular polymer is selected from a polymer having a functional group of an amino group;

Preferably, the high molecular polymer is selected from the group consisting of polyvinyl acetal diethylaminoacetate, IV gastric acid resin, aminoalkyl methacrylate copolymer or a combination thereof, and more preferably, the ammonia The alkyl methacrylate copolymer is preferably Eudragit E polymer;

The effervescent composition according to claim 1, wherein the weight ratio of the effervescent base, the active substance, and the targeted release substance is:

The effervescent matrix is 25-90%, the active substance is 0.01%-70%, and the targeted release material is 0.5-74.9%, calculated by the total weight of the effervescent agent;

Preferably, the weight ratio is: 25-90% of the effervescent matrix, 0.01%-50% of the active substance, and 1-30% of the targeted release substance, calculated as the total weight of the effervescent agent.

4. The effervescent composition of claim 1 wherein

The high molecular polymer coating material further includes a glycerin fatty acid ester, preferably a monoglyceride, and more preferably, the monoglyceride is selected from the group consisting of glyceryl monostearate, glyceryl monopalmitate, and mono olive. a glyceride, a monocaprylin, a glyceryl monocaprate, a glycerol monolaurate or a combination thereof; most preferably selected from the group consisting of glyceryl monostearate; And the weight ratio of the glycerin fatty acid ester to the high molecular polymer is between 95: 5 and 35: 65; preferably, between (1 and 8): 1.

5. The effervescent composition of claim 1 wherein

The molar ratio of the acid agent to the alkali agent is 1: (0. 95~1. 05);

Preferably, the alkali agent of the effervescent matrix is selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium glycinate carbonate or a combination thereof;

Preferably, the acidulant of the effervescent matrix is selected from the group consisting of citric acid, glycine citrate, monosodium citrate, malic acid, tartaric acid, fumaric acid or a combination thereof.

6. A method for preparing an effervescent agent, comprising the steps of:

(b) granulating the mixture to obtain the effervescent.

7. The method according to claim 6, wherein the mixture of the step (a) is obtained by the following steps:

The method according to claim 7, wherein the high molecular polymer coating material in the step (i) further contains a monoglyceride, and the monoglyceride and the high molecular polymer The weight ratio is between 95: 5 and 35: 65.

9. The method according to claim 7, wherein the particles of the active material in the step (i) are obtained by the following method:

Preferably, the step (Π) is granulated by a spray granulation method; more preferably, the granulation method of the step (II) The method comprises the following steps: the mixture of the step (I) is granulated for 30 minutes to 60 minutes at 40 ° C ± 5 ° C; the granules of the active material in the step (i) are obtained.

10. Use of an effervescent agent according to claim 1 wherein the effervescent agent is used to target release of the drug, to effect rapid onset of the drug, or to evade the pungent taste of the drug.