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WO2009000132A1 - Formulation effervescente à libération immédiate et procédé de préparation de celle-ci - Google Patents

Formulation effervescente à libération immédiate et procédé de préparation de celle-ci Download PDF

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Publication number
WO2009000132A1
WO2009000132A1 PCT/CN2007/070436 CN2007070436W WO2009000132A1 WO 2009000132 A1 WO2009000132 A1 WO 2009000132A1 CN 2007070436 W CN2007070436 W CN 2007070436W WO 2009000132 A1 WO2009000132 A1 WO 2009000132A1
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WIPO (PCT)
Prior art keywords
effervescent
high molecular
drug
molecular polymer
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2007/070436
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English (en)
Chinese (zh)
Inventor
Hongping Yie
Meg M. Sun
Zuolin Zhu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
PFICKER PHARMACEUTICALS Ltd
Original Assignee
PFICKER PHARMACEUTICALS Ltd
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Publication of WO2009000132A1 publication Critical patent/WO2009000132A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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;
  • the high molecular weight of the polymer coating material is not less than 0.5% by weight.
  • 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.
  • the high molecular polymer is selected from the group consisting of polymers having a functional group of an amino group
  • 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;
  • 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.
  • 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.
  • 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;
  • 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.
  • 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;
  • 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:
  • 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. ;
  • step (a) is obtained by the following steps:
  • 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.
  • the particles of the active material in step (i) are obtained by the following method:
  • the fineness of the active substance in the step (I) is not more than 100 mesh;
  • the step ( ⁇ ) is granulated by a spray granulation method; more preferably, the granulation method of the step ( ⁇ ) 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.
  • 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.
  • an effervescent agent such as an effervescent tablet or an effervescent granule.
  • 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.
  • fast acting drug refers to a drug that achieves a maximum blood concentration within two hours, preferably within thirty minutes.
  • 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.
  • stomach medicine refers to a drug that lowers gastric acid or treats gastritis. It can be, but is not limited to, bi smuth subsal icylate.
  • 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.
  • 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.
  • excipients for example, excipients, fillers, disintegrators, emulsifiers, flavoring agents, lubricants, binders, fillers, colorants, flavoring agents, plasticizers, fat-soluble auxiliary substances, antioxidants, and the like.
  • 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.
  • terapéuticaally 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.
  • overlay 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.
  • 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 ⁇ 1 ⁇ 5 and is insoluble in other pH environments.
  • 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.
  • 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.
  • 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.
  • 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.
  • the additive can lower the melting point of the high molecular polymer to 42 to 100 °C.
  • glycerol fatty acid esters for example, 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.
  • the additive can lower the melting point of the high molecular polymer to 42 to 100 °C.
  • glycerol fatty acid esters for example glycerol fatty acid esters.
  • 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.
  • the prepared effervescent preparation has a function of being quick-dissolving in the stomach and having a particularly excellent taste-masking effect.
  • 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.
  • the prepared effervescent tablet 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.
  • 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.
  • 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.
  • the active substance is 0.01%-50%, based on the total weight of the effervescent agent.
  • the amount of each dose is 2 mg; bismuth subtussate, each dose containing the active ingredient 500 mg of bismuth subtussate and the like.
  • the effervescent matrix in the effervescent agent of the present invention 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.
  • 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.
  • preferred alkaline agents are anhydrous potassium hydrogencarbonate and sodium hydrogencarbonate.
  • 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.
  • 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.
  • 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.
  • 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).
  • the effervescent matrix accounts for 25 to 90% by weight based on the total weight of the 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% ⁇ ), based on the total weight of the effervescent.
  • the effervescent matrix is 25-90%
  • the active substance is 0.01%-50%
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • the mixture contains 60 parts by weight of glyceryl monostearate and 10 parts by weight.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. .
  • 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
  • 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.
  • 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.
  • antioxidants include vitamin C, vitamin E, lipoic acid, dibutylhydroxyl toluene (BHT), and hydroxyanisuccinate.
  • 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.
  • 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 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.;
  • 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;
  • 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.
  • a pharmaceutical granule powder for preparing a high molecular polymer and a glyceryl monostearate coating ie, a coating material:
  • 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.
  • 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 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 0 0 0 0 0 0 0
  • 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 .
  • step 1 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.
  • 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.
  • 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 .
  • 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:
  • 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.
  • 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.
  • 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.
  • 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 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
  • 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.
  • 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.
  • 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 ( ⁇ ⁇ / ⁇ 1 ); and the commercially available Advi l tablets, the highest blood drug The concentration is only 15 ( ⁇ ⁇ ).
  • 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.
  • 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.
  • 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).
  • ELISA enzyme-injected immunosorbent assay
  • 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 ⁇ 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 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.;
  • a strong stimulating taste medicine which may be, but not limited to, ibuprofen, acetaminophen, ropramin hydrochloride, and reserpine , alprazolam, diphenhydramine, and diphenhydramine, etc.
  • 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;
  • 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.

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Abstract

L'invention se réfère à une formulation effervescente à libération immédiate dans laquelle le goût désagréable du médicament est masqué, cette formulation comprenant une matrice effervescente, un composé actif enrobé de polymères solubles dans l'estomac; et à un procédé de préparation de celle-ci.
PCT/CN2007/070436 2007-06-23 2007-08-08 Formulation effervescente à libération immédiate et procédé de préparation de celle-ci Ceased WO2009000132A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010149755A1 (fr) 2009-06-26 2010-12-29 Novartis Ag Dérivés d'imidazolidin-2-one 1,3-disubstitués en tant qu'inhibiteurs de cyp 17
WO2011066823A2 (fr) 2009-12-05 2011-06-09 Jens Mehnert Procédé et dispositif permettant l'analyse de l'utilisation d'énergie lors du fonctionnement d'un système de production
WO2012035078A1 (fr) 2010-09-16 2012-03-22 Novartis Ag Inhibiteurs de la 17α-hydroxylase/c17,20-lyase
WO2012149413A1 (fr) 2011-04-28 2012-11-01 Novartis Ag Inhibiteurs de 17α-hydroxylase/c17,20-lyase
WO2014058785A1 (fr) 2012-10-10 2014-04-17 Novartis Ag Polythérapie

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CN102296947A (zh) * 2011-05-30 2011-12-28 中国海洋石油总公司 一种油田用速溶型微量元素示踪剂及制备方法
CN103977427A (zh) * 2014-05-08 2014-08-13 王�琦 一种糖衣产气粉配方及其制备方法
CN104940961B (zh) * 2015-07-07 2017-10-17 上海交通大学医学院附属瑞金医院 一种胃内pH检测微丸及其用途
CN108685864A (zh) * 2018-07-25 2018-10-23 江苏黄河药业股份有限公司 一种茶苯海明含片及其制备方法

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US5587179A (en) * 1992-01-13 1996-12-24 Gerhard Gergeky Pharmaceutical formulation in the form of an effervescent and/or disintegrating tablet or of instant granulate, and process for their preparation
CN1921836A (zh) * 2003-12-31 2007-02-28 维克特拉有限公司 口服递送用多粒子制剂
CN1953734A (zh) * 2004-12-10 2007-04-25 科学与工业研究委员会 改善药物适口性的药用组合物及其制备方法

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CN1269478C (zh) * 2004-06-14 2006-08-16 湖北丽益医药科技有限公司 盐酸小檗碱微囊及其制备方法

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Publication number Priority date Publication date Assignee Title
US5587179A (en) * 1992-01-13 1996-12-24 Gerhard Gergeky Pharmaceutical formulation in the form of an effervescent and/or disintegrating tablet or of instant granulate, and process for their preparation
CN1921836A (zh) * 2003-12-31 2007-02-28 维克特拉有限公司 口服递送用多粒子制剂
CN1953734A (zh) * 2004-12-10 2007-04-25 科学与工业研究委员会 改善药物适口性的药用组合物及其制备方法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010149755A1 (fr) 2009-06-26 2010-12-29 Novartis Ag Dérivés d'imidazolidin-2-one 1,3-disubstitués en tant qu'inhibiteurs de cyp 17
WO2011066823A2 (fr) 2009-12-05 2011-06-09 Jens Mehnert Procédé et dispositif permettant l'analyse de l'utilisation d'énergie lors du fonctionnement d'un système de production
WO2012035078A1 (fr) 2010-09-16 2012-03-22 Novartis Ag Inhibiteurs de la 17α-hydroxylase/c17,20-lyase
WO2012149413A1 (fr) 2011-04-28 2012-11-01 Novartis Ag Inhibiteurs de 17α-hydroxylase/c17,20-lyase
WO2014058785A1 (fr) 2012-10-10 2014-04-17 Novartis Ag Polythérapie

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